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Feingold KR, Ahmed SF, Anawalt B, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-.

ABSTRACT

Testosterone, together with its bioactive metabolites dihydrotestosterone and estradiol, determines the development and maintenance of male sexual differentiation and the characteristic mature masculine features. Defects in androgen action at various epochs of life produce characteristic clinical features. From an outline of the biochemistry and physiology of androgen action, the pathophysiology of defects in androgen action are derived and defined. The pharmacology of testosterone and its applications to replacement therapy for pathological hypogonadism as well as for pharmacological androgen therapy based on using either testosterone or synthetic androgens is described. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text,WWW.ENDOTEXT.ORG.

INTRODUCTION

An androgen, or male sex hormone, is defined as a substance capable of developing and maintaining masculine characteristics in reproductive tissues (notably the genital tract, secondary sexual characteristics, and fertility) and contributing to the anabolic status of somatic tissues. Testosterone together with its potent metabolite, dihydrotestosterone (DHT), are the principal androgens in the circulation of mature male mammals. Testosterone has a characteristic four ring C18 steroid structure and is synthesized mainly by Leydig cells, located in the interstitium of the testis between the seminiferous tubules. Leydig cell secretion creates a very high local concentration of testosterone in the testis as well as a steep downhill concentration gradient into the bloodstream maintaining circulating testosterone levels which exert characteristic androgenic effects on distant androgen sensitive target tissues. The classical biological effects of androgens are primarily mediated by binding to the androgen receptor, a member of the steroid nuclear receptor superfamily encoded by a single gene located on the X chromosome, which then leads to a characteristic patterns of gene expression by regulating the transcription of an array of androgen responsive target genes. This physiological definition of an androgen in the whole animal is now complemented by a biochemical and pharmacological definition of an androgen as a chemical that effectively competes with testosterone binding to the androgen receptor (1) to stimulate post-receptor functions in isolated cells or cell-free systems. In addition, non-genomic mechanisms of androgen action involving rapid, membrane-mediated nontranscriptional processes in the cytoplasm have been described but not yet fully characterized (2-4).

Testosterone is used clinically at physiologic doses for androgen replacement therapy and, at typically higher doses, testosterone or synthetic androgens based on its structure are also used for pharmacologic androgen therapy. The principal goal of androgen replacement therapy is to restore a physiologic pattern of androgen exposure to all tissues. Such treatment is usually restricted to the major natural androgen, testosterone, and aims to replicate physiological circulating testosterone levels and the full spectrum (including pre-receptor androgen activation) of endogenous androgen effects on tissues and recapitulating the natural history of efficacy and safety. Pharmacologic androgen therapy exploits the anabolic or other effects of androgens on muscle, bone, and other tissues as hormonal drugs that aim to modify the natural history of the underlying disorder and are judged on their efficacy, safety, and relative cost effectiveness like other therapeutic agents. Insight into the physiology of testosterone is a prequisite for understanding and making most effective use of androgen pharmacology (5,6).

TESTOSTERONE PHYSIOLOGY

Biosynthesis

Testosterone is synthesized by an enzymatic sequence of steps from cholesterol (7,8) (Figure 1) within the 500 million Leydig cells located in the interstitial compartment of the testis between the seminiferous tubules, which constitutes approximately 5% of mature testis volume (seeEndotext, Endocrinology of Male Reproduction, Chapter entitled Endocrinology of the Male Reproductive System and Spermatogenesis, for details) (9). The cholesterol is predominantly formed by de novo synthesis from acetate, although preformed cholesterol either from intracellular cholesterol ester stores or extracellular supply from circulating low-density lipoproteins also contributes (8). Testosterone biosynthesis involves two multifunctional cytochrome P-450 complexes involving hydroxylations and side-chain scissions (cholesterol side-chain cleavage [CYP11A1 or P450scc which produces C20 and C22 hydroxylation and C20,22 lyase activity] and 17-hydroxylase/17,20 lyase [CYP17A1 or P450c17 which hydroxylates the C17 and then excises two carbons (20 & 21) coverting a 21 to a 19 carbon structure]) together with 3 and 17β-hydroxysteroid dehydrogenases and ∆^4,5 isomerase (8). The highly tissue-selective regulation of the 17,20 lyase activity (active in gonads but inactive in adrenals) independently of 17-hydroxylase activity (active in all steroidogenic tissues) is a key branch-point in steroidogenic pathways. Both activities reside in a single, multifunctional protein with the directionality of pathway flux determined by enzyme co-factors, notably electron supply from NADPH via the P450 oxidoreductase (POR), a membrane-bound flavoprotein serving diverse roles as a reductase, and cytochromeb₅ (10,11). In addition, some extragonadal biosynthesis of testosterone and dihydrotestosterone from circulating weak adrenal androgen precursor DHEA within specific tissues has been described (12); however, the net contribution of adrenal androgens to circulating testosterone in men is minor (13,14) though it makes a much larger proportional contribution to circulating testosterone in women (15,16).

FIGURE 1.

Pathways of testosterone biosynthesis and action. In men, testosterone biosynthesis occurs almost exclusively in mature Leydig cells by the enzymatic sequences illustrated. Cholesterol originates predominantly by the de novo synthesis pathway from acetyl‑CoA with luteinizing hormone regulating the rate‑limiting step, the conversion of cholesterol to pregnenolone within mitochondria, while remaining enzymatic steps occur in smooth endoplasmic reticulum. The Δ⁵ and Δ⁴ steroidal pathways are on the left and right, respectively. Testosterone and its androgenic metabolite, dihydrotestosterone, exert biological effects directly through binding to the androgen receptor and indirectly through aromatization of testosterone to estradiol, which allows action via binding to the estrogen receptor (ER). The androgen and ERs are members of the steroid nuclear receptor superfamily with highly homologous structure differing mostly in the C-terminal ligand binding domain. The LH receptor has the structure of a G-protein linked receptor with its characteristic seven transmembrane spanning helical regions and a large extracellular domain which binds the LH molecule. LH is a dimeric glycoprotein hormone consisting of an α subunit common to other pituitary glycoprotein hormones and a β subunit specific to LH. Most sex steroids bind to sex hormone binding globulin (SHBG) which binds tightly and carries the majority of testosterone in the bloodstream.

Testicular testosterone secretion is principally governed by luteinizing hormone (LH) through its regulation of the rate-limiting conversion of cholesterol to pregnenolone within Leydig cell mitochondria by the cytochrome P-450 cholesterol side-chain cleavage enzyme complex located on the inner mitochondrial membrane. Cholesterol supply to mitochondrial steroidogenic enzymes is governed by proteins including sterol carrier protein 2 (17). This facilitates cytoplasmic transfer of cholesterol to mitochondria together with steroidogenic acute regulatory protein (18) and translocator protein (19), which govern cholesterol transport across the mitochondrial membrane. All subsequent enzymatic steps are located in the Leydig cell endoplasmic reticulum. The high testicular production rate of testosterone creates both high local concentrations (up to 1 μg/g tissue, ~100 times higher than blood concentrations) and rapid turnover (200 times per day) of intratesticular testosterone (20); however, the precise physical state in which such high concentrations of intratesticular testosterone and related steroids exist in the testis remains to be clarified.

Metabolism

After testicular secretion, a small proportion of testosterone undergoes activation to two bioactive metabolites, estradiol and DHT, whereas the bulk of secreted testosterone undergoes inactivation by hepatic phase I and II metabolism to inactive oxidized and conjugated metabolites for urinary and/or biliary excretion (figure 2) (120).

FIGURE 2.

Pathways of Testosterone Action. In men, most (>95%) testosterone is produced under LH stimulation through its specific receptor, a heptahelical G-protein coupled receptor located on the surface membrane of the steroidogenic Leydig cells. The daily production of testosterone (5-7 mg) is disposed along one of four major pathways. The direct pathway of testosterone action is characteristic of skeletal muscle in which testosterone itself binds to and activates the androgen receptor. In such tissues there is little metabolism of testosterone to biologically active metabolites. The amplification pathway is characteristic of the prostate and hair follicle in which testosterone is converted by the type 2 5α reductase enzyme into the more potent androgen, dihydrotestosterone. This pathway produces local tissue-based enhancement of androgen action in specific tissues according to where this pathway is operative. The local amplification mechanism was the basis for the development of prostate-selective inhibitors of androgen action via 5α reductase inhibition, the forerunner being finasteride. The diversification pathway of testosterone action allows testosterone to modulate its biological effects via estrogenic effects that often differ from androgen receptor mediated effects. The diversification pathway, characteristic of bone and brain, involves the conversion of testosterone to estradiol by the enzyme aromatase which then interacts with the ERs α and/or β. Finally, the inactivation pathway occurs mainly in the liver with oxidation and conjugation to biologically inactive metabolites that are excreted by the liver into the bile and by the kidney into the urine.

The amplification pathway converts ~4% of circulating testosterone to the more potent, pure androgen, DHT (50,52). DHT has higher binding affinity to (121) and 3-10 time greater molar potency in transactivation (122-124) of the androgen receptor relative to testosterone. Testosterone is converted to the most potent natural androgen DHT by the 5α-reductase enzyme that originates from two distinct genes (I and II) (125). Type 1 5α-reductase is expressed in the liver, kidney, skin, and brain, whereas type 2 5α-reductase is characteristically expressed strongly in the prostate but also at lower levels in the skin (hair follicles) and liver (125). Congenital 5α-reductase deficiency due to mutation of the type 2 enzyme protein (126) leads to a distinctive form of genital ambiguity causing undermasculinization of genetic males, who may be raised as females, but in whom puberty leads to marked virilization including phallic growth, normal testis development and spermatogenesis (127) and bone density (128) as well as, occasionally, masculine gender reorientation (129). Prostate development remains rudimentary (130) and sparse body hair without balding is characteristic (131). This remarkable natural history reflects the dependence of urogenital sinus derivative tissues on strong expression of 5α-reductase as a local androgen amplification mechanism for their full development. This amplification mechanism for androgen action was exploited in developing azasteroid 5α-reductase inhibitors (132). As the type 2 5α-reductase enzyme results in over 95% of testosterone entering the prostate being converted to the more potent androgen DHT (133), blockade of that isoenzyme (the expression of which is largely restricted to the prostate) confines the inhibition of testosterone action to the prostate (and other urogenital sinus tissue derivatives) without blocking extra-prostatic androgen action. DHT circulates at ~10% of blood testosterone concentrations, due to spillover from the prostate (134,135) and nonprostatic sources (136). Whereas genetic mutations disrupting type 2 5α-reductase produce disorders of urogenital sinus derived tissues in men and mice (137), genetic inactivation of type 1 5α-reductase has no male phenotype in mice and no mutations of the human type 1 enzyme have been reported. Whether this reflects the type I enzyme having an unexpected phenotype or an evolutionarily conserved vital function, remains unclear. A third 5α-reductase enzyme (type 3, SRD5A3) has been described (138) but is widely expressed in human tissues, lacks steroidal 5α-reductase activity and has other roles in fatty acid metabolism (139).

An important issue is whether eliminating intraprostatic androgen amplification by inhibition of 5α-reductase can prevent prostate disease. Two major randomized, placebo-controlled studies of men at high risk of (but without diagnosed) prostate cancer have both shown that oral 5α reductase inhibitors (finasteride, dutasteride) reduced the incidence of low-grade prostate cancer as well as prevalence of lower urinary tract symptoms from benign prostate hyperplasia(140,141). The Prostate Cancer Prevention Trial (PCPT) was a major 10-year chemoprevention study randomizing 18,882 men over 55 years of age without known prostate disease to daily treatment with 5 mg finasteride (inhibitor of type 2 5α reductase) or placebo observed a cumulative 25% reduction after 7 years of treatment in early stage, organ-confined, low-grade prostate cancer. Another study randomized over 8231 men aged 50-75 years with serum PSA <10 ng/mL and negative prostate biopsy to either daily treatment with 0.5 mg dutasteride (inhibitor of both type 1 and 2 5α reductases) or placebo for 4 years observed a 23% reduction in incidence of biopsy-proven prostate cancer. Although neither study was designed to determine mortality benefit, both showed no reduction in higher grade, but still organ-confined, cancers. Although this stage selectivity may be explained by diagnostic biases due to drug effects on prostate size and histology (142,143), registration for chemoprevention of prostate cancer was refused by FDA (144). Overall, the evidence indicates that 5α-reductase inhibition reduces the incidence of early stage, screen-detected and organ-confined prostate cancers but there is insufficient evidence that such treatment reduces mortality from advanced (metastatic) prostate cancer. Whether or not preventive use of prostatic 5α-reductase inhibition in men with high prostate cancer risk proves warranted, novel synthetic androgens refractory to 5α-reductive amplification may have advantages for clinical development.

The diversification pathway of androgen action involves testosterone being converted by the enzyme aromatase to estradiol (145) to activate estrogen receptors (ERs) (also seeEndotext, Endocrinology of Male Reproduction, Chapter entitled Estrogens and Male Reproduction). Although this involves only a small proportion (~0.2%) of testosterone output, the higher molar potency of estradiol (~100-fold higher vs testosterone) makes aromatization a potentially important mechanism to diversify androgen action via ER-mediated effects in tissues where aromatase is expressed. The diversification pathway is governed by the cytochrome P-450 enzyme (CYP19) aromatase (145,146). In eugonadal men, most (~80%) circulating estradiol is derived from extratesticular aromatization (53). The biological importance of aromatization in male physiology was first recognized in the early 1970’s (147) when the local conversion of testosterone to estradiol within the neural tissues was identified and subseqeuntly shown to have an important role in mediating testosterone action, including negative feedback as well as activational and organisational effects, on the brain (148). More recently the importance of local aromatization in testosterone action has been reinforced by the striking developmental defects in bone and other tissues of men and mice with genetic inactivation of aromatase, leading to complete estrogen deficiency due to genetic inactivation of the aromatase (149). This phenotype is also strikingly similar to that of a man (150) and mice (150) with genetic mutations inactivating ERα. Furthermore, men with aromatase deficiency treated with exogenous estradioll or other estrogens also demonstrated significant bone maturation. By contrast, genetic inactivation of ERβ has no effect on male mice (151) and no human mutations have been reported. Aromatase expression in tissue such as bone (152) and brain (148) may influence development and function by variation in aromatization that modulates local tissue-specific androgen action. By contrast other tissues, like mature liver and muscle, express little or no aromatase. Nevertheless, despite the importance of aromatization for male bone physiology, other observations indicate that androgens acting via androgen receptors have important additional direct effects on bone. These include the greater mass of bone in men despite very low circulating estradiol concentrations compared with young women (153), the failure of androgen insensitive rats lacking functional androgen receptors but normal estradiol and ERs to maintain bone mass of normal males (154) and the ability of nonaromatizable androgens to increase bone mass in estrogen-deficient women (155,156). Testosterone action on bone and in the brain cannot be accounted for solely as a prohormone for local estradiol production (and action via estrogen receptors α and/or β) and androgen receptor mediated effects are required to manifest the full spectrum of testosterone effects on bone (157,158) and in the brain (159). Conflicting evidence is available about the need for aromatization to mediate the effects of testosterone on male sexual function. One study using aromatase inhibitor-induced estrogen deficiency showed partial dependence (160) whereas another using DHT-induced estrogen deficiency showing no requirement of male sexual function for aromatization (161). Further studies are needed to fully understand the significance of aromatization in maintaining androgen action in mature male animals (162).

Testosterone is metabolized to inactive metabolites in the liver, kidney, gut, muscle, and adipose tissue. Inactivation is predominantly by hepatic oxidases (phase I metabolism), notably cytochrome P-450 3A family (163) leading ultimately to oxidation of most oxygen moieties followed by hepatic conjugation to glucuronides (phase II metabolism), which are rendered sufficiently hydrophilic for renal excretion. Uridine diphospho (UDP) glucuronosyl transferase (UGT) enzymes UGT2B7, UGT2B15 and UGT2B17 catalyze most phase II metabolism (glucuronidation) of testosterone with 2B17 being quantitatively the most important (164). A functional polymorphism of UGT 2B17, a deletion mutation several times more frequent in Asian than European populations (165), explains the concordant population difference in testosterone to epitestosterone (T/E) ratio (165), a World AntiDoping Agency-approved urine screening test for testosterone doping in sport, which constitutes an ethnic differential, false negative in surveillance for exogenous testosterone doping (166).

The metabolic clearance rate of testosterone is reduced by increases in circulating SHBG levels (57) or decreases in hepatic blood flow (e.g. posture) (49) or liver function. Theoretically, drugs that influence hepatic oxidase activity could alter metabolic inactivation of testosterone, but empirical examples of sufficient magnitude to influence clinical practice are rare. Rapid hepatic metabolic inactivation of testosterone leads to both low oral bioavailability (167,168) and short duration of action when injected parenterally (169). To achieve sustained androgen replacement, these limitations dictate the need to deliver testosterone via parenteral depot products (e.g., injectable testosterone esters, testosterone implants, transdermal testosterone) or oral delivery systems that either bypass hepatic portal absorption (buccal (170,171), sublingual (170,172), gut lymphatic (173)) or use synthetic androgens with substituents rendering them resistant to first pass hepatic inactivation (174).

ANDROGEN RECEPTOR

The androgen receptor is required for masculine sexual differentiation and sexual maturation that ultimately leads to development of a mature testis capable of supporting spermatogenesis and testosterone production that form the basis for male fertility. The human androgen receptor is specified by a single X chromosome encoded gene located at Xq11-12 that specifies a protein of 919 amino acids (1), a classical member of the large nuclear receptor superfamily (228) which includes receptors for the 5 mammalian steroid classes (androgen, estrogen, progesterone, glucocorticoid, mineralocorticoid) as well as for thyroid hormones, retinoic acid and vitamin D and numerous orphan receptors where the ligand was originally not identified (229). Androgen receptor expression is not confined to reproductive tissues and it is ubiquitously expressed, athough levels of expression and androgen sensitivity of non-reproductive tissues vary.

The androgen receptor gene has 8 exons specifying a protein of 919 amino acids with the characteristic structure of mammalian steroid receptors. It has an N-terminal domain (NTD) that specifies a long transactivating functional domain (exon 1), a middle region specifying a DNA-binding domain (DBD) consisting of two zinc fingers (exons 2 and 3) separated by a hinge region from the C-terminal ligand binding domain (LBD) which specifies the steroid binding pocket (exons 4 to 8).

The NTD (exon 1) is relatively long comprising over half (535/919) the overall length of the AR. It has the least conserved sequence compared with other steroid receptors with a flexible and mobile tertiary structure harbouring a transactivation domain (AF-1) that interacts with AR co-regulator proteins and target genes (230). Its loose, naturally disordered structure (231) also contains three homopolymeric repeat sequences (glutamine, glycine, proline) with the most important being the CAG triplet (glutamine) repeat polymorphism (232). The less variable glycine (usually 24 residues) and proline (9 residues) repeat polymorphisms have little apparent independent pathophysiological significance although linkage dysequilibrium between the glutamine and glycine repeat polymorphisms requires haplotype analysis for interpretation (232). Among healthy people, where the glutamine repeat polymorphism has alleles of lengths between 5 and 35 (population mean ~21), the length of the glutamine repeat is inversely proportional to AR transcriptional efficiency so that this polymorphism dictates genetic differences between individuals in the androgen sensitivity of their target tissues (233). This genetic variation in in vivo tissue androgen sensitivity is proven experimentally (234) but, although modest in magnitude, influences physiological responses to endogenous testosterone in prostate size (235) and erythropoeisis (236) in carefully controlled studies. Wider epidemiological implications of population variation in the genetic androgen sensitivity as specified by the polyglutamine repeat have been studied in a variety of potentially androgen sensitive disorders (reviewed in (232)) including reproductive health disorders and hormone dependent cancers in men and women as well as non-gonadal disorders where there are significant gender disparities in prevalence. In men these include prostate (237) and other male preponderant cancers (liver, gastrointestinal, head & neck), prostate hypertrophy, cryptorchidism and hypospadias, male infertility (238) whereas in women they include reproductive health disorders (polycystic ovary syndrome, premature ovarian failure, endometriosis, uterine leiomyoma, preeclampsia) and hormone dependent cancers (breast, ovary, uterus). In addition, studies have also examined risks of obesity and cardiovascular disease, mental and behavioural disorders including dementia, psychosis, migraine, and personality disorders (232). However, as in many large-scale genetic association studies (239), the findings remain mostly inconsistent reflecting methdological limitations notably in recruitment, participation and publication bias as well as multiple hypothesis testing all of which tend to inflate spurious associations.

Remarkably, the pathological elongation of the polygutamine (CAG triplet) repeat to lengths of over 37 cause a neurodegenerative disease, Spinal Bulbar Muscular Atrophy (SBMA, also known as Kennedy’s syndrome). This is a form of late-onset, slow progressing but ultimately fatal motor neuron disease (240), one of several late-onset neurodegenerative polyglutamine repeat disorders (241). Although the extreme length of the polyglutamine repeat does determine mild androgen resistance, these men usually have normal reproductive function including fertility and virilization prior to diagnosis in mid-life (242). Furthermore, since complete androgen receptor inactivation in humans and other mammals does not cause motor neuron disease and female carriers are protected from symptomatic neurodegeneration, SBMA represents a toxic gain-of-function involving pathological protein aggregates of the mutant AR (243) like other genetic polyglutamine repeat neurodegenerative diseases do with other proteins (244). Surprisingly, transgenic mouse models of SBMA suggest that testosterone deprivation by medical castration using a GnRH agonist may slow progression of neuropathy (243) and that genetic (245) or pharmacological (246) administration of IGF-I may slow disease progression. However the first major clinical trial of leuprolide, a GnRH analog, failed to demonstrate neuromuscular benefit in swallowing (247) and further studies of selected subgroups and therapeutic targets are warranted (248,249).

The DBD (exons 2 and 3) consists of ~70 amino acids with a high proportion of basic amino acids including eight cysteines distributed as two sets of 4 cysteines, each forming a zinc cooordination center for a single zinc atom, thereby creating two zinc fingers. The DBD is highly conserved between steroid receptors reflecting its tightly defined function of forming the two zinc fingers that bind to DNA by intercalating between its grooves. The first zinc finger (exon 2) is directly involved with the major DNA groove of the androgen response element through a proximal (P-box) region whereas the second zinc finger (exon 3) is also responsible for enhancing receptor dimerization through its distal (D-box) region.

The hinge region (first half of exon 4) of ~40 amino acids between the DBD and LBD is considered a flexible linker region but may have additional functions involving interactions with DNA (nuclear localization, androgen response element) and protein (AR dimerization, co-regulators) which influence AR transcriptional activity.

The LBD (mid-exon 4 to 8) of AR comprises ~250 amino acids which specify a steroid binding pocket which creates the characteristic high affinity, stable and selective binding of testosterone, DHT and synthetic androgens. While the LBD’s overall architecture is broadly conserved among nuclear receptors, the AR sequence diverges significantly to ensure the specificity of binding from other steroid classes and their different cognate ligands. Structural studies of the AR’s LBD shows it has similar tertiary conformation as other steroid receptors (most closely resembling PR) with 12 stretches of α helix interspersed with short β pleated sheets. The most C terminal helix 12 seals the binding pocket and influences whether a bound ligand acts as an agonist or antagonist as well as forming a hydrophobic surface for binding of co-regulator proteins that modify transcriptional activity of the androgen target genes. The LBD also participates in receptor dimerization, nuclear localization and transactivation via its activation function (AF-2) domain.

The AR has a predominantly nuclear location in androgen target cells regardless of whether bound to its ligand or not, unlike other steroid receptors which are more often evenly distributed between cytoplasm and nucleus when not bound to their cognate ligands. Androgen binding to the C-terminal LBD causes a conformational change in the androgen receptor protein and dimerization to facilitate binding of the ligand-loaded receptor to segments of DNA featuring a characteristic palindromic motif known as an androgen-response element, located in the promoter regions of androgen target genes. Ligand binding leads to shedding of heat shock proteins 70 and 90 that act as a molecular chaperone for the unliganded androgen receptor (250). Specific binding of the dimerized, ligand-bound androgen receptor complex to tandem androgen-response elements initiates gene transcription so that the androgen receptor acts as a ligand-activated transcription factor. Androgen receptor transcriptional activation is governed by a large number of coregulators (251,252) whose tissue distribution and modulation of androgen action remain incompletely understood.

PHARMACOLOGY OF ANDROGENS

Androgen Replacement Therapy

The sole unequivocal clinical indication for testosterone treatment is in replacement therapy for androgen deficient men suffering from pathological disorders of their reproductive system (hypothalamus, pituitary, testis) that prevent the testes from producing sufficient testosterone supply to meet the body’s usual needs. Establishing a pathological basis for androgen replacement therapy requires identifying well-defined disorders of the hypothalamus, pituitary or testis which have a known and clearly defined pathological basis. These disorders can, and often do, lead to persistent testosterone deficiency either due to disorders of the testis, where damaged Leydig cells cannot produce sufficient testosterone, or disorders of the hypothalamus and/or pituitary, where impaired pituitary luteinizing hormone (LH) secretion reduces the sole driving force to testosterone production by Leydig cells.

The principal goal of androgen (testosterone) replacement therapy is to restore a physiologic pattern of net tissue androgen exposure in androgen deficient men whose damaged reproductive systems are unable to secrete adequate testosterone to levels comparable with those of eugonadal men. This treatment uses only the natural androgen, testosterone, aimed at restoring a physiologic pattern of androgen exposure using a dose limited to that which maintains blood testosterone levels within the eugonadal range. Such treatment aims to restore the full spectrum of androgen effects when endogenous testosterone production fails due to pathological disorders of the reproductive system (testicular-hypothalamic-pituitary axis). This requires restricting replacement therapy to the major natural androgen, testosterone, which aims to not only replicate physiological circulating testosterone levels but also to provide testosterone’s two bioactive metabolites, DHT and estradiol, so that all 3 bioactive sex steroids are available to androgen target tissues. Synthetic androgens are unsuitable because they are incapable of metabolism to the more potent 5α reduced metabolites or being aromatized to estrogens. The overall goal of such replacement therapy is to replicate the efficacy and safety experience of eugonadal men of similar age by recreating the full spectrum of endogenous natural androgen effects on tissues so as to recapitulate the natural history of efficacy and safety of endogenous testosterone.

The prevalence of male hypogonadism requiring androgen repacement therapy in the general community can be estimated from the known prevalence of Klinefelter’s syndrome (15.6 per 1000 male births in 33 prospective birth survey studies (313)) because Klinefelter syndrome accounts for 25-35% of men requiring androgen replacement therapy. The estimated prevalence of ~5 per 1000 men in the general community makes androgen deficiency the most common hormonal deficiency disorder among men. Although life expectancy is not reduced by castration as an adult (303-307) or only minimally (~2 years) shortened (308) by life-long androgen deficiency, the hormonal deficit causes preventable morbidity and a suboptimal quality of life (313). Due to its variable and often subtle clinical features, androgen deficiency remains significantly underdiagnosed, thus denying sufferers simple and effective medical treatment with often striking benefits. Only ~20% of men with Klinefelter syndrome characterized by the highly distinctive tiny (<4 mL) testes, are diagnosed during their lifetime (314) indicating that most men go through life without a single pelvic examination by any medical professional in stark contrast to the usual expectation of reproductive health care for women.

The testis has two physiological functions, spermatogenesis and steroidogenesis, either of which can be impaired independently, resulting in infertility or androgen deficiency, respectively, so the term hypogonadism is inherently ambiguous. However, hypogonadism of any cause may require androgen replacement therapy if the deficit in endogenous testosterone production is sufficient to cause clinical and biochemical manifestations of androgen deficiency. Androgen deficiency is a clinical diagnosis with a characteristic presentation and underlying pathological basis in hypothalamus, pituitary or testis disorder, and confirmed by blood hormone assays (see other Endotext chapters for details). The clinical features of androgen deficiency vary according to the severity, chronicity, and epoch of life at presentation. These include ambiguous genitalia, microphallus, delayed puberty, sexual dysfunction, infertility, osteoporosis, anemia, flushing, muscular ache, lethargy, lack of stamina or endurance, easy fatigue, or incidental biochemical diagnosis. For each androgen deficient man, his leading clinical symptoms of androgen deficiency are distinctive, reproducible and corresponds to a specific blood testosterone threshold for any individual but both the symptom(s) and threshold vary between men (315). Because the underlying disorders are mostly irreversible, lifelong treatment is usually required. Androgen replacement therapy can rectify most clinical features of androgen deficiency apart from defective spermatogenesis (316). When fertility is required in gonadotropin-deficient men, spermatogenesis can be initiated by treatment with pulsatile GnRH (317) (if pituitary gonadotroph function is intact (318)) or gonadotropins (319) to substitute for pituitary gonadotropin secretion (320) (see alsoEndotext, Endocrinology of Male Reproduction, Hypogonadotropic Hypogonadism (HH) and Gonadotropin Therapy). The short half-life of LH would require multi-daily injections rendering it unsuitable for gonadotrophin therapy (321). Instead practical gonadotropin therapy uses hCG, a placental heterodimeric glycoprotein which has a much longer duration of action allowing it to be administered every two or three days. The chorionic gonadotropin hCG consists of an identical α subunit as LH (also the same as in FSH and TSH) combined with a distinct β subunit that is highly homologous to the LH β subunit except for a C terminal extension of 22 amino acids which includes four O-linked sialic acid-capped, carbohydrate side chains. This C terminal extension markedly prolongs the circulating half-life of hCG relative to LH thereby making it a naturally occuring long-acting LH analog. Both endogenous LH and hCG act on the Leydig cell LH/hCG receptor to stimulate endogenous testosterone production. Pharmaceutical hCG, originally purified from pregnancy urine and more recently its recombinant form, can be administered 2-3 times weekly for several months. Where spermatogenesis remains persistently suboptimal, recombinant FSH may subsequently be added (319). Once fertility is no longer required and any pregnancy has passed the 1^st trimester, androgen replacement therapy usually reverts to the simpler and cheaper use of testosterone while preserving the ability subsequently to reinitiate spermatogenesis by gonadotropin replacement (319). The potential value of hCG therapy in gonadotropin-deficient adolescents to produce timely testis growth replicating physiologic puberty (322), rather than reliance on exogenous testosterone which leaves a dormant testis but remains standard management, has yet to be fully evaluated (323,324).

The extension of testosterone replacement therapy to men with partial, subclinical or compensated androgen deficiency states remain of unproven value (figure 3). Biochemical features of Leydig cell dysfunction, notably persistently elevated LH with low to normal levels of testosterone constituting a high LH/testosterone ratio are observed in aging men (325-327), in men with testicular dysfunction associated with male infertility (328), or after chemotherapy-induced testicular damage (329-332). Although such features may signify mild androgen deficiency, substantial clinical benefits from testosterone replacement therapy remain to be demonstrated (333,334). Furthermore, testosterone administration may have deleterious effects on spermatogenesis so that its potential adverse effect on men’s fertility must be considered with regard to their marital and fertility status.

Hormonal male contraception can be considered a form of androgen replacement therapy because all currently envisaged regimens aiming to suppress spermatogenesis (and thereby endogenous testosterone production) by inhibiting gonadotropin secretion, use testosterone either alone or with a progestin or a GnRH antagonist (335) (see alsoEndotext, Endocrinology of Male Reproduction, Male Contraception). As a consequence, exogenous testosterone is required to replace endogenous testosterone secretion.

FIGURE 3.

The Hypothalamo-Pituitary Testicular Axis in Health and Intrinsic and Extrinsic Diseases. Schematic representation of the hypothalamo-pituitary-testicular (HPT) system in health (left panel) and in disease (right panel). Note in the right panel the distinction between organic disorders of the reproductive system causing pathologcal hypogonadism leading to male infertility and/or androgen deficiency and, alternatively, non-reproductive disorders which lead to an adaptive hypothalamic response to systemic non-reproductive disorders. While these non-reproductive disorders may lead to a reduced serum testosterone, that is neither a testosterone deficiency state nor warrants testosterone treatment without convincing evidence of safety and efficacy.

Pharmacologic Androgen Therapy

Pharmacologic androgen therapy uses androgens to maximal therapeutic efficacy within adequate safety limits but without regard to androgen type, dose, duration of treatment, or gender. In this, the goal is to improve mortality and/or morbidity of an underlying non-gonadal disease through eliciting androgen effects on muscle, bone, brain, or other target tissues. To obtain morbidity benefits requires that androgens must modify the natural history of an underlying disease, a goal not yet achieved in any nongonadal disorder. Morbidity benefits are more achievable in aiming to improve quality of life by enhancing muscle, bone, brain, or other androgen-sensitive function (including mood elevation) as an adjuvant therapy in non-reproductive diseases. Such treatment is judged by the efficacy, safety, and cost-effectiveness standards of other drugs but very few studies fulfill the requirements of adequate study design (prospective design, randomization, placebo control, objective and validated end points, adequate power, and appropriate duration) (310,336). Accordingly, the role of pharmacological androgen therapy is mostly relegated to an affordable but second line, supportive or adjunctive therapy (336).

The range of pharmacologic uses of androgens include: treatment of anemia due to marrow or renal failure; osteoporosis especially where estrogen therapy is contraindicated; advanced ER-positive breast cancer; hereditary angioedema (C1 esterase inhibitor deficiency); and for immunologic, pulmonary, and muscular diseases (reviewed in detail (336)). In anemia due to renal or marrow failure, androgens have proven beneficial effects on morbidity by improving hemoglobin levels, reducing transfusion requirements and improving quality of life. However, characteristically androgens do not improve mortality as they do not change the natural history of the underlying disease. In renal anemia, androgens are equally effective with erythropoeitin in maintaining hemoglobin levels and reducing transfusion requirement (337-339). However, their virilizing effects in women are limiting so that the affordability and augmentation of erythropoeitin effects by androgens provides an ongoing adjuvant role in older men or where erythropoeitin is unavailable (337-339). Similarly, in anemia due to marrow failure androgens reduce transfusion dependence but do not improve survival from the underlying marrow disorders. They remain secondary line, supportive therapy for men in whom marrow transplantation is not feasible or fails.

Although these traditional indications for androgen therapy are often superseded by more specific, effective but costly treatments, androgens usually persist as second-line, empirical therapies for which the lower cost and/or equivalent or synergistic efficacy may still favor androgen therapy in some settings. For historical reasons, pharmacologic androgen therapy has often involved synthetic, orally active 17α-alkylated androgens despite their hepatotoxicity including cholestasis, hepatitis, adenoma and peliosis (340,341). Other than in treating angioedema, in which direct hepatic effects of 17α-alkyl androgens (rather than androgen action per se) may be crucial to increasing circulating C1 esterase inhibitor levels to prevent attacks (342-344), safer (nonhepatotoxic) testosterone preparations should generally be favored for long-term clinical use, although the risk-benefit balance may vary according to prognosis. For hereditary angioedema, newer mechanism-based, more specific and costly therapies such as purified or recombinant C1 inhibitor and bradykinin or kallekrein antagonists may overtake the traditional role of 17α-alkylated androgens such as danazol for long-term prophylaxis of hereditary angioedema (311,312,345) or endometriosis. In most clinical applications, pharmacological androgen therapy remains a cost-effective option relative to newer, more costly therapies.

An important watershed was the proof via a well-designed, placebo-controlled randomized clinical trial that pharmacologic testosterone doses increase muscular size and strength even in eugonadal men (346), overturning prior belief to the contrary (347). Testosterone has clear dose-dependent effects, extending from below to well above the physiological concentrations without evidence of a plateau, on muscle size and strength (but not performance function or fatigue) in young (348) and older (349) men with similar magnitude of ultimate effect (350). Nevertheless, ageing reduced the responsiveness of older muscle to testosterone as the same doses produced higher blood testosterone concentrations in older men. The higher blood testosterone concentrations are the result of decreased testosterone metabolic clearance rate due to age-related higher blood SHBG concentrations (351). Similarly, erythropoeitic effects of testosterone are greater in older men who developed a higher rate of polycythemia (352). Diverse androgen-sensitive effects including changes in metabolic function, cognition, mood and sexual function were minimal at physiological testosterone doses (353,354). The wide dose-response to testosterone through and beyond the physiologic range suggests that androgens may have beneficial effects in reversing the frailty observed in many medical settings. Whether such effects can be applied effectively and safely (355) to improve frailty and quality of life in chronic disease or in male ageing remains an important challenge to be determined.

Pharmacological androgen therapy for human immunodeficiency virus (HIV) infection in the absence of classical hypogonadism has been investigated for its effects on disease-associated morbidity, notably AIDS wasting. However pharmacologic androgen therapy does not alter the natural history of underlying disease and the objective functional benefits remain modest being confined to reversing some aspects of AIDS wasting. The rationale for pharmacologic androgen therapy in AIDS wasting is that body weight loss is an important determinant of survival in AIDS and other terminal diseases with death estimated to occur when lean body mass reaches 66% of ideal (356). This leads to the hypothesis that androgens may delay death by increasing appetite and/or body weight. Meta-analysis of randomized, placebo-controlled studies of pharmacologic androgen therapy in HIV-positive men with AIDS wasting indicate modest increase in lean and decreased fat mass with additive effects from resistance training but inconsistent improvement in quality of life (357,358). Among HIV-positive men without wasting there is less improvement in body composition and none in quality of life although, in affluent countries, there is a popular subculture of androgen abuse (359). The oral progestin, megestrol acetate, used alone as an appetite stimulant induces profound gonadotropin and testosterone suppression to castrate levels and predominanty increases fat mass rather than reversing the loss of muscle (360,361).

It is now well recognized that chronic use of opiates has multiple effects on the human endocrine system (362), including prominent mu-opioid receptor mediated effects on the hypothalamus resulting in suppression of pituitary LH secretion and thereby testicular testosterone production (363,364). However, despite an open-label study suggesting quality of life benefits for testosterone replacement therapy (365), placebo-controlled studies show no clinically significant benefit (366,367) possibly due to failure to rectify non-androgenic effects of opiates.

A special application of pharmacologic androgen treatment is its use in women with estrogen-resistant menopausal symptoms such as loss of energy or libido. The similarity of blood testosterone in women, children, and orchidectomized men indicates that the term female androgen deficiency is not meaningful in women (368) with normal adrenal function (369). In women with adrenal failure due to hypothalamo-pituitary or adrenal disease, DHEA replacement therapy (14) has significant but modest clinical benefits in some (369,370) but not all (371,372) studies with relatively frequent, mild virilizing side-effects. Similar effects are observed using testosterone instead of DHEA (373). Well controlled studies of testosterone administration for menopausal symptoms or sexual hypofunction in women with normal adrenal function show strong placebo effects (374,375) but minimal or no consistent symptomatic benefits (376) despite supraphysiological blood testosterone levels (374). High-dose testosterone used at male androgen replacement therapy doses (377,378) produce markedly supraphysiologic blood testosterone levels and virilization including voice changes and androgenic alopecia (379-381). Lower but still supraphysiologic testosterone doses and blood levels increase bone density in menopausal women (382) but produce virilizing adverse effects (hirsutism, acne) in short-term studies. Overall the long-term efficacy and safety risks for cardiovascular disease and hormone dependent cancers (breast, uterus, ovary) for testosterone therapy in women remain unclear (383-385). Studies of testosterone administration as a form of adjuvant pharmacologic androgen therapy in women with chronic medical disorders such as anorexia nervosa (386), HIV (387) and systemic lupus erythematosus (388) have little consistent effect on disease activity or quality of life including sexual function.

Many important questions and opportunities remain for pharmacologic androgen therapy in nongonadal disease, but careful clinical trials are essential for proper evaluation (336). Recent well designed placebo-controlled clinical studies of pharmacologic androgen therapy in chronic disease have been reported. In men with severe chronic obstructive pulmonary disease it produces modest increases in muscle mass and strength with improved quality of life but no effect on underlying lung function (389-391) whereas oral megestrol administration had similar effects despite marked suppression of blood testosterone levels (392). Similarly, although in an observational study chronic heart failure is associated with lower blood testosterone that is proportional to the decrease in cardiac function and which predicts survival (393), a placebo-controlled prospective study of testosterone administration showed improvement in effort-dependent exercise capacity but not in left ventricular function or survival (394). This discrepancy suggests that the lowered blood testosterone is the consequence of a non-specific adaptive reaction of the reproductive hormonal axis to chronic disease (ontogenic regression (395)) rather than a detrimental effect susceptible to being overcome by androgen supplementation. Both testosterone and its non-aromatizable derivative nandrolone, produce increased bone density in men with glucocorticoid-induced osteoporosis with minimal short-term side-effects (396,397). The best opportunities for future evaluation of adjuvant use of androgen therapy in men with nongonadal disease include steroid-induced osteoporosis; wasting due to AIDS or cancer cachexia; and chronic respiratory, rheumatologic, and some neuromuscular diseases. In addition, the role of pharmacologic androgen therapy in recovery and/or rehabilitation after severe catabolic illness such as burns, critical illness, or major surgery are promising (398) but requires thorough evaluation because detrimental effects may occur (399). Future studies of adjuvant androgen therapy require high-quality clinical data involving randomization and placebo controls as well as finding the optimal dose and authentic clinical, rather than surrogate, end points.

FIGURE 4.

Serum Testosterone Across the Lifespan in Men and Women. Serum testosterone, SHBG & calculated "free" testosterone in males and females over the lifetime as determined in >100,000 consecutive blood samples from a single laboratory. After Handelsman et al. Ann Clin Biochem 2016.

Formulation, Route, and Dose

UNMODIFIED TESTOSTERONE

Testosterone Implants

Implants of fused crystalline testosterone provide stable, physiologic testosterone levels for as long as 6 months after a single implantation procedure (590). Typically, four 200-mg pellets are inserted under the skin of the lateral abdominal wall or hip using in-office minor surgery and a local anesthetic. No suture or antibiotic is required, and the pellets are fully biodegradable and thus do not require removal. This old testosterone formulation (591) has excellent depot properties, with testosterone being absorbed by simple dissolution from a solid reservoir into extracellular fluid at a rate governed by the solubility of testosterone in the extracellular fluid resulting in a standard 800 mg testosterone dose releasing ~5 mg per day (592) replicating the testosterone production rate in healthy eugonadal men (49-51,593). The long duration of action makes it popular among younger androgen-deficient men as reflected by a high continuation rate (594). The major limitations of this form of testosterone administration are the cumbersome implantation procedure and extrusion of a single pellet after ~5% of procedures. Extrusions are more frequent among thin men undertaking vigorous physical activities (594) but surface washing (595), antibiotic impregnation (596) or varying the site of implantation or track geometry (597) do not reduce extrusion rate. Other side effects such as bleeding or infection are rare (<1%) (594). Recent studies using a smaller (75 mg) implant reproduce these features although requiring administration of a larger number of pellets (598-600). Despite its clinical advantages and popularity, this simple, non-patented technology has limited commercial marketing appeal and, consequently, is not widely available apart from compounding chemists and niche manufacturers (598).

Transdermal Testosterone

Delivery of testosterone across the skin has long been of interest (174). More recently products delivering testosterone via adhesive dermal patches and gels have been developed to maintain physiologic testosterone levels by daily application. The first transdermal patch was developed for scrotal application where the thin, highly vascular skin facilitates steroid absorption (601,602) and scrotal patches showed long-term efficacy (603) including minimal skin irritation (604,605). However, their large size, need for shaving and disproportionately high increase blood DHT levels due to 5α-reduction of testosterone during transdermal passage led to the development of a smaller non-scrotal patch (606) effective for long-term use (607). For non-scrotal patches, the smaller size and application to less permeable non-scrotal (trunk, proximal limb) skin limit testosterone absorption. Although this can be enhanced by heating (608), in practice this required inclusion of absorption enhancers that cause skin irritation (604,605) of varying severity (609). Although skin irritation may be reduced by topical corticosteroid cream (610), the majority of users experience some skin reaction with ~25% having to discontinue due to dermal intolerance (394).

Dermal testosterone (611) or DHT (612,613) gels developed in Europe are now more widely available as topical gels (571,614-619), solution (620) or a cream (72). They must be applied daily on the trunk or axilla, and the volatile hydroalcoholic gel base evaporates rapidly with a short-lived stinging sensation but is relatively nonirritating to the skin so there are few discontinuations for adverse skin reactions (571,621). Transdermal testosterone delivery depends on a small fraction (typically <5%) of testosterone applied to the skin in the dermal gel or solution transfering into the skin where it forms a secondary reservoir in the stratum corneum. From this depot, testosterone is gradually released into the circulation by diffusion down a concentration gradient into the blood stream. A novel and well accepted form of transdermal testosterone delivery is application of a testosterone cream to the sccrotum taking advantage of the thin, highly vascular scrotal skin which demonstrates an 8-fold greater permeability to testosterone than truncal skin (622). As a large amount of testosterone remains on the skin after topical application, transfer of testosterone by direct skin contact is a risk for an intimate partner (623-625) or children (626-631). Serum testosterone concentrations are increased in non-dosed female partners making direct skin contact with men using transdermal testosterone products (632). Creating a physical barrier such as using a testosterone transdermal patch (633) or covering the application site with clothing (632,634) reduces this risk. Washing off excess gel from the application site after a short time (<30 min) may reduce the risk of transfer (632,634,635) but also reduces effective testosterone absorption in some (636) but not all (637) studies. Unlike transdermal patches, topical gel or solutions have considerable misuse and abuse potential.

Testosterone Microspheres

Suspensions of biodegradable microspheres, consisting of polyglycolide-lactide matrix similar to absorbable suture material and laden with testosterone, can deliver stable, physiologic levels of testosterone for 2 to 3 months after intramuscular injection (638,639). Subsequent findings (640) suggest that the practical limitations of microsphere technology such as loading capacity, large injection volumes, and batch variability may be overcome.

Oral Testosterone

Finely milled testosterone (167,641) or testosterone suspended in an oil vehicle (642,643) have low oral bioavailability requiring high daily doses (200–400 mg) to maintain physiologic testosterone levels. Such a heavy androgen load causes prominent hepatic enzyme induction (644) without hepatotoxicity (645). Although effective in small studies (646), oral testosterone is not commercially available and little used. Sufficiently high oral testosterone doses (400-900 mg daily) also reduce serum SHBG (647) which may explain the concomitant acceleration of testosterone metabolism (167,646,648).

Buccal and Sublingual Testosterone

Buccal or sublingual delivery of testosterone is an old technology (170) designed to bypass the avid first-pass hepatic metabolism of testosterone that is inevitable with the portal route of absorption. Once absorbed into the general circulation, however, testosterone is rapidly inactivated in accord with its short circulating half-time. Revivals of this technology include testosterone in a sublingual cyclodextrin formulation (649) and in a buccal lozenge (171,650). The multiple daily dosing required to maintain physiologic testosterone levels are drawbacks for long-term androgen replacement using such products, and their effectiveness and acceptability remain to be established. Like all transepithelial (nonparenteral) testosterone delivery systems, disproportionate amounts of testosterone undergo 5α-reduction during local absorption, resulting in higher blood DHT levels than those in eugonadal men (651). Because intraprostatic DHT is produced locally within the prostate and unlikely to be affected by changes in circulating DHT levels as well as the fact that prostate diseases remain rare among androgen deficient men receiving androgen replacement therapy, the higher blood DHT levels appear to pose no real risk of accelerating prostate disease (652).

TESTOSTERONE ESTERS

FIGURE 5.

Schematic overview of the pharmacology of testosterone esters. Testosterone is esterified through the 17 β hydroxyl group with fatty acid esters of different aliphatic or other chain length which is a biologically inactive pro-drug. The esterified testosterone in an oil vehicle is injected deeply into a muscle forming a local drug depot from which the testosterone ester is released at a slow rate determined by its physico-chemical partitioning according to the testosterone ester’s hydrophobicity. Once the testosterone ester exits the depot and enters the extracellular fluids, it is rapidly hydrolyzed by ubiquitous non-specific esterases thereby releasing the testosterone into the general circulation.

Injectable Testosterone

The most widely used testosterone formulation for many decades has been intramuscular injection of testosterone esters (figure 5), formed by 17β-esterification of testosterone with fatty acids of various aliphatic and/or aromatic chain lengths, injected in a vegetable oil vehicle (653). This depot product relies on retarded release of the testosterone ester from the oil vehicle injection depot because esters undergo rapid hydrolysis by ubiquitous esterases to liberate free testosterone into the circulation. The pharmacokinetics and pharmacodynamics of androgen esters is therefore primarily determined by ester side-chain length, volume of oil vehicle, and site of injection via hydrophobic physicochemical partitioning of the androgen ester between the hydrophobic oil vehicle and the aqueous extracellular fluid (654).

The short 3-carbon aliphatic ester side-chain of testosterone propionate gives the product a brief duration of action requiring injections of 25 to 50 mg at 1-2 day intervals for effective testosterone replacement therapy. In contrast, the 7-carbon side-chain of testosterone enanthate has a longer duration of action so that it is used at doses of 200 to 250 mg per 10 to 14 days for androgen replacement therapy in hypogonadal men (655-657) and has been for decades the most widely used form of testosterone used in replacement therapy. Other testosterone esters (cypionate, cyclohexane carboxylate) have simillar pharmacokinetics making them pharmacologically equivalent to testosterone enanthate (658). Similarly, mixtures of short- and longer acting testosterone esters also have essentially the same pharmacokinetics of the longest ester.

Longer acting testosterone esters, testosterone buciclate and undecanoate, intended to provide depot release over months rather than weeks, have been developed. Testosterone buciclate (trans-4-n-butyl cyclohexane carboxylate) is an insoluble testosterone ester in an aqueous suspension that produces prolonged testosterone release due to steric hindrance of ester side-chain hydrolysis slowing the liberation of unesterified testosterone. Although the buciclate ester produces blood testosterone levels in the low-normal physiologic range for up to 4 months after injection in nonhuman primates (659) as well as hypogonadal (660) and eugonadal (661) men, product development has not progressed. Injectable testosterone undecanoate, an ester of an 11 carbon aliphatic fatty acid, in an oil vehicle provides a longer (~12 weeks) duration of action (662-664) now widely marketed as a long-acting injectable depot testosterone product. Due to its limited solubility in the castor oil vehicle, testosterone undecanoate is administered as a 1000 mg dose in a large (4 mL) injection volume at 12 week intervals after the first and one 6 week loading dose or multiple loading doses (665) or in the USA, 750 mg in 3ml volume administered at the start of treatment and then 4 and subsequently at 10 weekly intervals. Once available, the rapid uptake of long-acting injectables show that they are very popular among younger hypogonadal men whereas transdermal products are more suited for older men in case of need to rapidly discontinue testosterone treatment such as after diagnosis of prostate cancer. The relatively long duration of action is also well suited to male hormonal contraception either alone in Chinese men (666) or as part of an androgen-progestin combination (667-669). For treatment of androgen deficiency, although its longer duration of action entails fewer injections with advantages for convenience and compliance, the efficacy and safety does not differ from that of the shorter acting testosterone enanthae (670).

Although testosterone esters in oil vehicle are approved for im injection, they can be effectively used by subcutaneous injection (671) in their marketed formulation or via a pre-filled autoinjector (672). There is increasing use of subcutaneous injections (1 ml) of medium acting testosterone esters (cypionate or enanthate) in oil vehicle especially for masculinizing female to male transgender (673-675). However, the sc use of larger volume (4 ml) for injecting testosterone undecanoate is feasible but less popular than im injection (676).

Oral Testosterone Undecanoate

Oral testosterone undecanoate, a suspension of the ester in 40-mg oil-filled capsules, is administered as 160 to 240 mg in two or more doses per day (677). The hydrophobic, long aliphatic chain ester in a castor oil/propylene glycol laurate vehicle favors preferential absorption into chylomicrons entering the gastrointestinal lymphatics and largely bypassing hepatic first-pass metabolism (173). Oral testosterone undecanoate is not absorbed under fasting conditions but is taken up when ingested with food (678) containing a moderate amount (at least 19 gm) of fat (679). Although oral testosterone undecanoate produces a disproportionate increase in serum DHT which is unaffected by concomitant administration of an oral 5 α reductase inhibitor (680); such modest increases in circulating DHT would have no impact on prostate size (681) or apparent risk of prostate cancer (454,682) presumably because DHT of extra-prostatic origin fails to increase intra-prostatic DHT concentrations (683). Its low oral bioavailability (684) and short duration of action requiring high and multiple daily doses of testosterone lead to only modest clinical efficacy compared with injectable testosterone esters (657,685). Widely marketed, it may cause gastrointestinal intolerance but has otherwise well established safety (682). A new formulation of oral testosterone undecanoate was approved for US marketing in 2019 (686) over four decades after its introduction in Europe (687) to close the gap in the market for a safe non-hepatotoxic oral androgen. Its limitations in efficacy, notably its capricious bioavailability, make it a second choice (657), unless parenteral therapy is best avoided (e.g., bleeding disorders, anticoagulation) or a low dose, as for induction of male puberty, must be provided (688,689) as a better option than the hepatotoxic alkylated androgen, oxandrolone (690).

SYNTHETIC ANDROGENS

Synthetic androgens include both steroidal and non-steroidal androgens. Synthetic steroidal androgens, most developed by 1970, comprise categories of 17α-alkylated androgens, 1-methyl androgens and nandrolone and its derivatives (figure 6).

FIGURE 6.

Testosterone and its pharmacological derivatives. Listed are the most common synthetic androgens displaying their structural relationship with testosterone.

Steriodal Androgens

Most oral androgens are hepatotoxic 17α-alkylated androgens (methyltestosterone, fluoxymesterone, oxymetholone, oxandrolone, ethylestrenol, stanozolol, danazol, methandrostenolone, norethandrolone) making them unacceptable for long-term androgen replacement therapy. The 1-methyl androgen mesterolone is an orally active DHT analog that undergoes neither amplification by 5α reduction nor aromatization but it is free of hepatotoxicity. Mesterolone is not used for long-term androgen replacement due to the need for multiple daily dosing, its poorly defined pharmacology (691) and suboptimal efficacy at standard dose (570,577). For historical reasons, the other marketed 1-methyl androgen methenolone is used almost exclusively in anemia due to marrow failure (692,693) although it has no specific pharmacological advantage over testosterone or other androgens.

Nandrolone (19-nor testosterone) is a widely used injectable androgen in the form of aliphatic fatty acid esters in an oil vehicle mainly for treatment of postmenopusal osteoporosis where it is effective at increasing bone density and reducing fracture rate (694,695). It is also the most popular androgen abused in sports doping and in body building. Nandrolone is a naturally occuring steroid but is not normally secreted in the human bloodstream although it occurs as an intermediate in the aromatization of testosterone to estradiol by the aromatase enzyme (696). This enzyme complex undertakes two successive hydroxylations on the angular C19 methyl group of testosterone followed by a cleavage of the C10-C19 bond to releases formic acid and aromatize the A ring (697). Nandrolone represents a penultimate step of the molecule undergoing aromatization bound to the enzyme complex with the C19 methyl group excised but a still non-aromatized A ring. Paradoxically, despite being an intermediate in the aromatization reaction, nandrolone is virtually not aromatized after parenteral administration in men (698,699), presumably because it is a very poor substrate for the human aromatase enzyme (700). It is susceptible to amplification by 5α reductase with its 5α reduced metabolites being moderately activated in androgenic potency (701). The minimal aromatizability of nandrolone makes it suitable for treatment of osteoporosis in women in whom estrogen therapy is contraindicated due to hormone sensitive cancers (breast, uterus) or for older women, although virilization limits its acceptability (702).

Synthetic nandrolone derivatives 7α-methyl 19-nortestosterone (MENT) (703) and 7α, 11β-dimethyl 19-nortestosterone (dimethandrolone) (704) are potent, non-hepatotoxic androgens. MENT is being developed as a depot androgen (705) for androgen replacement (706) and male contraception in an androgen-progestin combination regimen (707) while dimethandrolone has potential for male contraception as a single steroid with dual androgen and progestin activity (708). As nandrolone derivatives, these synthetic androgens are less susceptible to amplification by 5α-reduction (700,709) whereby their 5α-reduced metabolites have reduced AR binding affinity (710). Disparities in reported susceptibility to aromatization vary from minimal using a recombinant human aromatase assay (700) whereas greater aromatization is reported using purified human or equine placental aromatase (709,711,712). The inability of MENT to maintain bone density in androgen deficient men (575) may be due to underdosing rather than an intrinsic feature of this synthetic androgen but illustrates the need for thorough dose titration in different tissues for synthetic androgens that may not possess the full characteristic spectrum of testosterone effects.

Nonsteroidal Androgens

The first nonsteroidal androgen was reported in 1998 (582) and the first placebo-controlled randomized clinical trial in 2013 (713). None are yet approved for clinical use but registration studies are underway for enobosarm (714). Based on structural modifications of the nonsteroidal class of the aryl-propionamide antiandrogens (bicalutamide, flutamide), these compounds offer the possibility of orally active, potent androgens. Subsequently, additional classes of non-steroidal androgen based on structures including quinolines, hydantoins, tetracyclic indoles and oxachrysensones have been reported. Lacking the classical steroid ring structure such androgens are likely to be not subject to androgen activation either by 5α reductase or aromatization but, if taken orally, subject to first-pass hepatic metabolism. Such hepatic metabolism can eliminate in vivo bioactivity of analogs with potent in vitro androgenic effects (715) whereas metabolically resistant analogs can produce potent and disproportionate androgenic effects on the liver in transit. Many of the novel non-steroidal androgens demonstrate potent androgenic effects experimentally on muscle, bone and sexual function while minimizing prostate effects in experimental animals but none have yet undergone full clinical evaluation. These selective effects may be attributable to the tissue-selective distribution of 5α-reductase as a local tissue, pre-receptor androgen amplification mechanism (716) or more complex mechanisms involving ligand-induced receptor conformation changes and/or post-receptor co-regulator interaction mechanisms such as define the tissue selectivity and agonist/antagonist specificity of non-steroidal estrogen partial agonists (717). These features suggest that non-steroidal androgens have potential for development into pharmacologic androgen therapy regimens as tissue-selective mixed or partial androgen agonists (“selective androgen receptor modulators”, SARM) (419,718). Conversely, they are not ideal for androgen replacement therapy where the full spectrum of testosterone effects including aromatization is idealy required, especially for tissues such as the brain (148,159) and bone (153) where aromatization is a prominent feature of testosterone action. The clinical efficacy and safety of non-steroidal androgens have yet to be reported and none are yet marketed. Whether the hepatotoxicity of antiandrogens (719,720) will also be a feature of non-steroidal androgens remains to be determined.

REFERENCES

1.

Quigley CA, DeBellis A, Marschke KB, El-Awady MK, Wilson EM, French FF. Androgen receptor defects: historical, clinical and molecular perspectives.Endocrine Reviews.1995;16:271–321. [PubMed: 7671849]

2.

Foradori CD, Weiser MJ, Handa RJ. Non-genomic actions of androgens.Frontiers in Neuroendocrinology.2008;29:169–181. [PMC free article: PMC2386261] [PubMed: 18093638]

3.

Michels G, Hoppe UC. Rapid actions of androgens.Frontiers in Neuroendocrinology.2008;29:182–198. [PubMed: 17983646]

4.

Gonzalez-Montelongo MC, Marin R, Gomez T, Diaz M. Androgens are powerful non-genomic inducers of calcium sensitization in visceral smooth muscle.Steroids.2010;75:533–538. [PubMed: 19800357]

5.

Kochakian CD ed. 1976 Anabolic-Androgenic Steroids. Berlin: Springer-Verlag.

6.

Nieschlag E, Behre HM eds. 2012 Testosterone: Action.Deficiency.Substitution. 4th ed. Cambridge: Cambridge University Press.

7.

Hall PF 1988 Testicular steroid synthesis: organization and regulation. In: Knobil E, Neill J eds. The Physiology of Reproduction. New York: Raven Press; 975-998.

8.

Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders.Endocrine Reviews.2011;32:81–151. [PMC free article: PMC3365799] [PubMed: 21051590]

9.

Neaves WB, Johnson L, Porter JC, Parker CR, Petty CS. Leydig cell numbers, daily sperm production, and serum gonadotropin levels in aging men.Journal of Clinical Endocrinology and Metabolism.1984;55:756–763.

10.

Miller WL, Tee MK. The post-translational regulation of 17,20 lyase activity.Molecular and Cellular Endocrinology.2015;408:99–106. [PubMed: 25224484]

11.

Peng HM, Im SC, Pearl NM, Turcu AF, Rege J, Waskell L, Auchus RJ. Cytochrome b5 Activates the 17,20-Lyase Activity of Human Cytochrome P450 17A1 by Increasing the Coupling of NADPH Consumption to Androgen Production.Biochemistry.2016;55:4356–4365. [PMC free article: PMC5287367] [PubMed: 27426448]

12.

Labrie F. Adrenal androgens and intracrinology.Seminars in Reproductive Medicine.2004;22:299–309. [PubMed: 15635498]

13.

Oesterling JE, Epstein JI, Walsh PC. The inability of adrenal androgens to stimulate the adult human prostate: an autopsy evaluation of men with hypogonadotropic hypogonadism and panhypopituitarism.Journal of Urology.1986;136:1030–1034. [PubMed: 2945933]

14.

Young J, Couzinet B, Nahoul K, Brailly S, Chanson P, Baulieu EE, Schaison G. Panhypopituitarism as a model to study the metabolism of dehydroepiandrosterone (DHEA) in humans.Journal of Clinical Endocrinology and Metabolism.1997;82:2578–2585. [PubMed: 9253337]

15.

Arlt W, Justl HG, Callies F, Reincke M, Hubler D, Oettel M, Ernst M, Schulte HM, Allolio B. Oral dehydroepiandrosterone for adrenal androgen replacement: pharmacokinetics and peripheral conversion to androgens and estrogens in young healthy females after dexamethasone suppression.Journal of Clinical Endocrinology and Metabolism.1998;83:1928–1934. [PubMed: 9626121]

16.

Davison SL, Bell R, Donath S, Montalto JG, Davis SR. Androgen levels in adult females: changes with age, menopause, and oophorectomy.Journal of Clinical Endocrinology and Metabolism.2005;90:3847–3853. [PubMed: 15827095]

17.

Gallegos AM, Atshaves BP, Storey SM, Starodub O, Petrescu AD, Huang H, McIntosh AL, Martin GG, Chao H, Kier AB, Schroeder F. Gene structure, intracellular localization, and functional roles of sterol carrier protein-2.Progress in Lipid Research.2001;40:498–563. [PubMed: 11591437]

18.

Miller WL. Disorders in the initial steps of steroid hormone synthesis.Journal of Steroid Biochemistry and Molecular Biology.2016

19.

Midzak A, Zirkin B, Papadopoulos V. Translocator protein: pharmacology and steroidogenesis.Biochemical Society Transactions.2015;43:572–578. [PubMed: 26551695]

20.

Jarow JP, Zirkin BR. The androgen microenvironment of the human testis and hormonal control of spermatogenesis.Annals of the New York Academy of Sciences.2005;1061:208–220. [PubMed: 16467270]

21.

Gray A, Berlin JA, McKinlay JB, Longcope C. An examination of research design effects on the association of testosterone and male aging: results of a meta-analysis.Journal of Clinical Epidemiology.1991;44:671–684. [PubMed: 1829756]

22.

Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications.Endocrine Reviews.2005;26:833–876. [PubMed: 15901667]

23.

Wu FC, Tajar A, Pye SR, Silman AJ, Finn JD, O'Neill TW, Bartfai G, Casanueva F, Forti G, Giwercman A, Huhtaniemi IT, Kula K, Punab M, Boonen S, Vanderschueren D. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study.Journal of Clinical Endocrinology and Metabolism.2008;93:2737–2745. [PubMed: 18270261]

24.

Sartorius G, Spasevska S, Idan A, Turner L, Forbes E, Zamojska A, Allan C, Ly L, Conway A, McLachlan R, Handelsman D. Serum Testosterone, Dihydrotestosterone and Estradiol Concentrations in Older Men Self-Reporting Very Good Health:The Healthy Man Study.Clinical Endocrinology.2012;77:755–763. [PubMed: 22563890]

25.

Handelsman DJ, Staraj S. Testicular size: the effects of aging, malnutrition, and illness.Journal of Andrology.1985;6:144–151. [PubMed: 3997660]

26.

Gray A, Feldman HA, McKinlay JB, Longcope C. Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachussetts Male Aging Study.Journal of Clinical Endocrinology and Metabolism.1991;73:1016–1025. [PubMed: 1719016]

27.

Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, Bremner WJ, McKinlay JB. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study.Journal of Clinical Endocrinology and Metabolism.2002;87:589–598. [PubMed: 11836290]

28.

Andersson AM, Jensen TK, Juul A, Petersen JH, Jorgensen T, Skakkebaek NE. Secular decline in male testosterone and sex hormone binding globulin serum levels in Danish population surveys.Journal of Clinical Endocrinology and Metabolism.2007;92:4696–4705. [PubMed: 17895324]

29.

Travison TG, Araujo AB, Hall SA, McKinlay JB. Temporal trends in testosterone levels and treatment in older men.Curr Opin Endocrinol Diabetes Obes.2009;16:211–217. [PubMed: 19396984]

30.

Perheentupa A, Makinen J, Laatikainen T, Vierula M, Skakkebaek NE, Andersson AM, Toppari J. A cohort effect on serum testosterone levels in Finnish men.European Journal of Endocrinology.2013;168:227–233. [PubMed: 23161753]

31.

Taieb J, Mathian B, Millot F, Patricot MC, Mathieu E, Queyrel N, Lacroix I, Somma-Delpero C, Boudou P. Testosterone measured by 10 immunoassays and by isotope-dilution gas chromatography-mass spectrometry in sera from 116 men, women, and children.Clinical Chemistry.2003;49:1381–1395. [PubMed: 12881456]

32.

Sikaris K, McLachlan RI, Kazlauskas R, de Kretser D, Holden CA, Handelsman DJ. Reproductive hormone reference intervals for healthy fertile young men: evaluation of automated platform assays.Journal of Clinical Endocrinology and Metabolism.2005;90:5928–5936. [PubMed: 16118337]

33.

Vermeulen A, Desylpere JP, Kaufman JM. Influence of antiopioids on luteinizing hormone pulsatility in aging men.Journal of Clinical Endocrinology and Metabolism.1989;68:68–72. [PubMed: 2909555]

34.

Deslypere JP, Kaufman JM, Vermeulen T, Vogelaers D, Vandalem JL, Vermeulen A. Influence of age on pulsatile luteinizing hormone release and responsiveness of the gonadotrophs to sex hormone feedback in men.Journal of Clinical Endocrinology and Metabolism.1987;64:68–73. [PubMed: 3536984]

35.

Veldhuis JD, Urban RJ, Lizarralde G, Johnson ML, Iranmanesh A. Attenuation of luteinizing hormone secretory burst amplitude as a proximate basis for the hypoandrogenism of healthy aging men.Journal of Clinical Endocrinology and Metabolism.1992;75:707–713. [PubMed: 1517359]

36.

Liu PY, Pincus SM, Takahashi PY, Roebuck PD, Iranmanesh A, Keenan DM, Veldhuis JD. Aging attenuates both the regularity and joint synchrony of LH and testosterone secretion in normal men: analyses via a model of graded GnRH receptor blockade.Am J Physiol Endocrinol Metab.2006;290:E34–E41. [PubMed: 16339924]

37.

Mulligan T, Iranmanesh A, Gheorghiu S, Godschalk M, Veldhuis JD. Amplified nocturnal luteinizing hormone (LH) secretory burst frequency with selective attenuation of pulsatile (but not basal) testosterone secretion in healthy aged men: possible Leydig cell desensitization to endogenous LH signaling--a clinical research center study.Journal of Clinical Endocrinology and Metabolism.1995;80:3025–3031. [PubMed: 7559891]

38.

Mulligan T, Iranmanesh A, Kerzner R, Demers LW, Veldhuis JD. Two-week pulsatile gonadotropin releasing hormone infusion unmasks dual (hypothalamic and Leydig cell) defects in the healthy aging male gonadotropic axis.European Journal of Endocrinology.1999;141:257–266. [PubMed: 10474123]

39.

Liu PY, Takahashi PY, Roebuck PD, Iranmanesh A, Veldhuis JD. Aging in healthy men impairs recombinant human luteinizing hormone (LH)-stimulated testosterone secretion monitored under a two-day intravenous pulsatile LH clamp.Journal of Clinical Endocrinology and Metabolism.2005;90:5544–5550. [PubMed: 16030163]

40.

Regadera J, Nistal M, Paniagua R. Testis, epididymis, and spermatic cord in elderly men: correlation of angiographic and histologic studies with systemic arteriosclerosis.Archives of Pathology and Laboratory Medicine.1985;109:663–667. [PubMed: 3839365]

41.

Veldhuis JD, Keenan DM, Iranmanesh A. Mechanisms of ensemble failure of the male gonadal axis in aging.Journal of Endocrinological Investigation.2005;28:8–13.

42.

Veldhuis JD, Keenan DM, Liu PY, Iranmanesh A, Takahashi PY, Nehra AX. The aging male hypothalamic-pituitary-gonadal axis: pulsatility and feedback.Molecular and Cellular Endocrinology.2009;299:14–22. [PMC free article: PMC2662347] [PubMed: 18838102]

43.

Prostate Cancer Trialists' Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials.Lancet.2000;355:1491–1498. [PubMed: 10801170]

44.

Arlt W, Callies F, Koehler I, van Vlijmen JC, Fassnacht M, Strasburger CJ, Seibel MJ, Huebler D, Ernst M, Oettel M, Reincke M, Schulte HM, Allolio B. Dehydroepiandrosterone supplementation in healthy men with an age-related decline of dehydroepiandrosterone secretion.Journal of Clinical Endocrinology and Metabolism.2001;86:4686–4692. [PubMed: 11600526]

45.

Nair KS, Rizza RA, O'Brien P, Dhatariya K, Short KR, Nehra A, Vittone JL, Klee GG, Basu A, Basu R, Cobelli C, Toffolo G, Dalla Man C, Tindall DJ, Melton LJ 3rd, Smith GE, Khosla S, Jensen MD. DHEA in elderly women and DHEA or testosterone in elderly men.New England Journal of Medicine.2006;355:1647–1659. [PubMed: 17050889]

46.

Baird DT, Horton R, Longcope C, Tait JF. Steroid dynamics under steady-state conditions.Recent Progress in Hormone Research.1969;25:611–664. [PubMed: 4900738]

47.

Gurpide E 1975 Tracer Methods in Hormone Research. New York: Springer.

48.

Setchell BP 1978 The Mammalian Testis. London: Paul Elek.

49.

Southren AL, Gordon GG, Tochimoto S. Further studies of factors affecting metabolic clearance rate of testosterone in man.Journal of Clinical Endocrinology and Metabolism.1968;28:1105–1112. [PubMed: 5676174]

50.

Santner S, Albertson B, Zhang GY, Zhang GH, Santulli M, Wang C, Demers LM, Shackleton C, Santen RJ. Comparative rates of androgen production and metabolism in Caucasian and Chinese subjects.Journal of Clinical Endocrinology and Metabolism.1998;83:2104–2109. [PubMed: 9626146]

51.

Wang C, Catlin DH, Starcevic B, Leung A, DiStefano E, Lucas G, Hull L, Swerdloff RS. Testosterone metabolic clearance and production rates determined by stable isotope dilution/tandem mass spectrometry in normal men: influence of ethnicity and age.Journal of Clinical Endocrinology and Metabolism.2004;89:2936–2941. [PubMed: 15181080]

52.

Ishimaru T, Edmiston WA, Pages L, Horton R. Splanchnic extraction and conversion of testosterone and dihydrotestosterone in man.Journal of Clinical Endocrinology and Metabolism.1978;46:528–533. [PubMed: 755039]

53.

Longcope C, Sato K, McKay C, Horton R. Aromatization by splanchnic tissue in men.Journal of Clinical Endocrinology and Metabolism.1984;58:1089–1093. [PubMed: 6725508]

54.

Diver MJ, Imtiaz KE, Ahmad AM, Vora JP, Fraser WD. Diurnal rhythms of serum total, free and bioavailable testosterone and of SHBG in middle-aged men compared with those in young men.Clinical Endocrinology.2003;58:710–717. [PubMed: 12780747]

55.

Bremner WJ, Vitiello MV, Prinz PN. Loss of circadian rhythmicity in blood testosterone levels with aging in normal men.Journal of Clinical Endocrinology and Metabolism.1983;56:1278–1281. [PubMed: 6841562]

56.

Keenan DM, Takahashi PY, Liu PY, Roebuck PD, Nehra AX, Iranmanesh A, Veldhuis JD. An ensemble model of the male gonadal axis: illustrative application in aging men.Endocrinology.2006;147:2817–2828. [PubMed: 16513832]

57.

Petra P, Stanczyk FZ, Namkung PC, Fritz MA, Novy ML. Direct effect of sex-steroid binding protein (SBP) of plasma on the metabolic clearance rate of testosterone in the rhesus macaque.Journal of Steroid Biochemistry and Molecular Biology.1985;22:739–746.

58.

Vanbillemont G, Bogaert V, De Bacquer D, Lapauw B, Goemaere S, Toye K, Van Steen K, Taes Y, Kaufman JM. Polymorphisms of the SHBG gene contribute to the interindividual variation of sex steroid hormone blood levels in young, middle-aged and elderly men.Clinical Endocrinology.2009;70:303–310. [PubMed: 18681858]

59.

Ohlsson C, Wallaschofski H, Lunetta KL, Stolk L, Perry JR, Koster A, Petersen AK, Eriksson J, Lehtimaki T, Huhtaniemi IT, Hammond GL, Maggio M, Coviello AD, Ferrucci L, Heier M, Hofman A, Holliday KL, Jansson JO, Kahonen M, Karasik D, Karlsson MK, Kiel DP, Liu Y, Ljunggren O, Lorentzon M, Lyytikainen LP, Meitinger T, Mellstrom D, Melzer D, Miljkovic I, Nauck M, Nilsson M, Penninx B, Pye SR, Vasan RS, Reincke M, Rivadeneira F, Tajar A, Teumer A, Uitterlinden AG, Ulloor J, Viikari J, Volker U, Volzke H, Wichmann HE, Wu TS, Zhuang WV, Ziv E, Wu FC, Raitakari O, Eriksson A, Bidlingmaier M, Harris TB, Murray A, de Jong FH, Murabito JM, Bhasin S, Vandenput L, Haring R. Genetic determinants of serum testosterone concentrations in men.PLoS Genet.2011;7:e1002313. [PMC free article: PMC3188559] [PubMed: 21998597]

60.

Jin G, Sun J, Kim ST, Feng J, Wang Z, Tao S, Chen Z, Purcell L, Smith S, Isaacs WB, Rittmaster RS, Zheng SL, Condreay LD, Xu J. Genome-wide association study identifies a new locus JMJD1C at 10q21 that may influence serum androgen levels in men.Human Molecular Genetics.2012;21:5222–5228. [PMC free article: PMC3607470] [PubMed: 22936694]

61.

Xita N, Tsatsoulis A. Genetic variants of sex hormone-binding globulin and their biological consequences.Molecular and Cellular Endocrinology.2010;316:60–65. [PubMed: 19733622]

62.

Goldman AL, Bhasin S, Wu FCW, Krishna M, Matsumoto AM, Jasuja R. A Reappraisal of Testosterone's Binding in Circulation: Physiological and Clinical Implications.Endocr Rev.2017;38:302–324. [PMC free article: PMC6287254] [PubMed: 28673039]

63.

Dunn JF, Nisula BC, Rodbard D. Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma.Journal of Clinical Endocrinology and Metabolism.1981;53:58–68. [PubMed: 7195404]

64.

Fournier T, Medjoubi NN, Porquet D. Alpha-1-acid glycoprotein.Biochimica et Biophysica Acta.2000;1482:157–171. [PubMed: 11058758]

65.

Hammond GL, Wu TS, Simard M. Evolving utility of sex hormone-binding globulin measurements in clinical medicine.Curr Opin Endocrinol Diabetes Obes.2012;19:183–189. [PubMed: 22531107]

66.

Wu TS, Hammond GL. Naturally occurring mutants inform SHBG structure and function.Molecular Endocrinology.2014;28:1026–1038. [PMC free article: PMC5414826] [PubMed: 24892637]

67.

Luppa PB, Thaler M, Schulte-Frohlinde E, Schreiegg A, Huber U, Metzger J, Fahrner CL, Hackney AC. Unchanged androgen-binding properties of sex hormone-binding globulin in male patients with liver cirrhosis.Clinical Chemistry and Laboratory Medicine.2006;44:967–973. [PubMed: 16879062]

68.

Selva DM, Hammond GL. Human sex hormone-binding globulin is expressed in testicular germ cells and not in sertoli cells.Hormone and Metabolic Research.2006;38:230–235. [PubMed: 16700003]

69.

Diaz L, Queipo G, Carino C, Nisembaum A, Larrea F. Biologically active steroid and thyroid hormones stimulate secretion of sex hormone-binding globulin by human term placenta in culture.Archives of Medical Research.1997;28:29–36. [PubMed: 9078584]

70.

Handelsman DJ, Conway AJ, Boylan LM. Pharmacokinetics and pharmacodynamics of testosterone pellets in man.Journal of Clinical Endocrinology and Metabolism.1990;71:216–222. [PubMed: 2115044]

71.

Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, Weber T, Berman N, Hull L, Swerdloff RS. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men.Journal of Clinical Endocrinology and Metabolism.2004;89:2085–2098. [PubMed: 15126525]

72.

Wittert GA, Harrison RW, Buckley MJ, Wlodarczyk J. An open-label, phase 2, single centre, randomized, crossover design bioequivalence study of AndroForte 5 testosterone cream and Testogel 1% testosterone gel in hypogonadal men: study LP101.Andrology.2016;4:41–45. [PubMed: 26754331]

73.

Jaruvongvanich V, Sanguankeo A, Riangwiwat T, Upala S. Testosterone, Sex Hormone-Binding Globulin and Nonalcoholic Fatty Liver Disease: a Systematic Review and Meta-Analysis.Ann Hepatol.2017;16:382–394. [PubMed: 28425408]

74.

Sarkar M, VanWagner LB, Terry JG, Carr JJ, Rinella M, Schreiner PJ, Lewis CE, Terrault N. Sex Hormone-Binding Globulin Levels in Young Men Are Associated With Nonalcoholic Fatty Liver Disease in Midlife.Am J Gastroenterol.2019;114:758–763. [PMC free article: PMC6599461] [PubMed: 30730350]

75.

Ahrentsen OD, Jensen HK, Johnsen SG. Sex-hormone-binding globulin deficiency.Lancet.1982;2:377.

76.

Hogeveen KN, Cousin P, Pugeat M, Dewailly D, Soudan B, Hammond GL. Human sex hormone-binding globulin variants associated with hyperandrogenism and ovarian dysfunction.Journal of Clinical Investigation.2002;109:973–981. [PMC free article: PMC150924] [PubMed: 11927624]

77.

Vos MJ, Mijnhout GS, Rondeel JM, Baron W, Groeneveld PH. Sex hormone binding globulin deficiency due to a homozygous missense mutation.Journal of Clinical Endocrinology and Metabolism.2014;99:E1798–1802. [PubMed: 24937543]

78.

Pardridge WM. Plasma protein-mediated transport of steroid and thyroid hormones.American Journal of Physiology.1987;252:E157–164. [PubMed: 3548415]

79.

Mendel CM. The free hormone hypothesis: a physiologically based mathematical model.Endocrine Reviews.1989;10:232–274. [PubMed: 2673754]

80.

Ekins R. Measurement of free hormones in blood.Endocrine Reviews.1990;11:5–46. [PubMed: 2180687]

81.

Rowland M, Tozer TN 2011 Chapter 17: Drug Interactions. In: Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications. 4th ed. Baltimore: Wolters Kluwer/Lippincott Willaims & Wilkins; 483-525.

82.

Queipo G, Deas M, Arranz C, Carino C, Gonzalez R, Larrea F. Sex hormone-binding globulin stimulates chorionic gonadotrophin secretion from human cytotrophoblasts in culture.Human Reproduction.1998;13:1368–1373. [PubMed: 9647574]

83.

Rosner W, Hryb DJ, Khan MS, Nakhla AM, Romas NA. Sex hormone-binding globulin mediates steroid hormone signal transduction at the plasma membrane.Journal of Steroid Biochemistry and Molecular Biology.1999;69:481–485. [PubMed: 10419028]

84.

Rosner W, Hryb DJ, Khan MS, Nakhla AM, Romas NA. Androgen and estrogen signaling at the cell membrane via G-proteins and cyclic adenosine monophosphate.Steroids.1999;64:100–106. [PubMed: 10323678]

85.

Kahn SM, Li YH, Hryb DJ, Nakhla AM, Romas NA, Cheong J, Rosner W. Sex hormone-binding globulin influences gene expression of LNCaP and MCF-7 cells in response to androgen and estrogen treatment.Advances in Experimental Medicine and Biology.2008;617:557–564. [PubMed: 18497082]

86.

Hamada A, Sissung T, Price DK, Danesi R, Chau CH, Sharifi N, Venzon D, Maeda K, Nagao K, Sparreboom A, Mitsuya H, Dahut WL, Figg WD. Effect of SLCO1B3 haplotype on testosterone transport and clinical outcome in caucasian patients with androgen-independent prostatic cancer.Clinical Cancer Research.2008;14:3312–3318. [PMC free article: PMC2701141] [PubMed: 18519758]

87.

Hammes A, Andreassen TK, Spoelgen R, Raila J, Hubner N, Schulz H, Metzger J, Schweigert FJ, Luppa PB, Nykjaer A, Willnow TE. Role of endocytosis in cellular uptake of sex steroids.Cell.2005;122:751–762. [PubMed: 16143106]

88.

Adams JS. "Bound" to work: the free hormone hypothesis revisited.Cell.2005;122:647–649. [PubMed: 16143095]

89.

Poole CN, Roberts MD, Dalbo VJ, Sunderland KL, Kerksick CM. Megalin and androgen receptor gene expression in young and old human skeletal muscle before and after three sequential exercise bouts.J Strength Cond Res.2011;25:309–317. [PubMed: 21322835]

90.

Holt SK, Karyadi DM, Kwon EM, Stanford JL, Nelson PS, Ostrander EA. Association of megalin genetic polymorphisms with prostate cancer risk and prognosis.Clinical Cancer Research.2008;14:3823–3831. [PMC free article: PMC2675883] [PubMed: 18559602]

91.

Handelsman DJ. Free Testosterone: Pumping up the Tires or Ending the Free Ride?Endocr Rev.2017;38:297–301. [PubMed: 28898980]

92.

Hsu B, Cumming RG, Blyth FM, Naganathan V, Waite LM, Le Couteur DG, Seibel MJ, Handelsman DJ. Evaluating Calculated Free Testosterone as a Predictor of Morbidity and Mortality Independent of Testosterone for Cross-sectional and 5-Year Longitudinal Health Outcomes in Older Men: The Concord Health and Ageing in Men Project.J Gerontol A Biol Sci Med Sci.2018;73:729–736. [PubMed: 28958048]

93.

Sodergard R, Backstrom T, Shanbhag V, Carstensen H. Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature.Journal of Steroid Biochemistry.1982;16:801–810. [PubMed: 7202083]

94.

Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum.J Clin Endocrinol Metab.1999;84:3666–3672. [PubMed: 10523012]

95.

Zakharov MN, Bhasin S, Travison TG, Xue R, Ulloor J, Vasan RS, Carter E, Wu F, Jasuja R. A multi-step, dynamic allosteric model of testosterone's binding to sex hormone binding globulin.Mol Cell Endocrinol.2015;399:190–200. [PubMed: 25240469]

96.

Ly LP, Sartorius G, Hull L, Leung A, Swerdloff RS, Wang C, Handelsman DJ. Accuracy of calculated free testosterone formulae in men.Clin Endocrinol (Oxf).2010;73:382–388. [PubMed: 20346001]

97.

Sartorius G, Ly LP, Sikaris K, McLachlan R, Handelsman DJ. Predictive accuracy and sources of variability in calculated free testosterone estimates.Ann Clin Biochem.2009;46:137–143. [PubMed: 19225026]

98.

Nanjee MN, Wheeler MJ. Plasma free testosterone--is an index sufficient?Ann Clin Biochem.1985;22(Pt 4):387–390. [PubMed: 4041156]

99.

Hackbarth JS, Hoyne JB, Grebe SK, Singh RJ. Accuracy of calculated free testosterone differs between equations and depends on gender and SHBG concentration.Steroids.2011;76:48–55. [PubMed: 20816687]

100.

Salameh WA, Redor-Goldman MM, Clarke NJ, Reitz RE, Caulfield MP. Validation of a total testosterone assay using high-turbulence liquid chromatography tandem mass spectrometry: total and free testosterone reference ranges.Steroids.2010;75:169–175. [PubMed: 19925815]

101.

Ellis GB, Desjardins C. Male rats secrete luteinizing hormone and testosterone episodically.Endocrinology.1982;110:1618–1627. [PubMed: 7200422]

102.

Coquelin A, Desjardins C. Luteinizing hormone and testosterone secretion in young and old male mice.American Journal of Physiology.1982;243:E257–263. [PubMed: 7114252]

103.

Shackleton C. Clinical steroid mass spectrometry: a 45-year history culminating in HPLC-MS/MS becoming an essential tool for patient diagnosis.Journal of Steroid Biochemistry and Molecular Biology.2010;121:481–490. [PubMed: 20188832]

104.

Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H. Position statement: Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement.Journal of Clinical Endocrinology and Metabolism.2007;92:405–413. [PubMed: 17090633]

105.

Herold DA, Fitzgerald RL. Immunoassays for testosterone in women: better than a guess?Clinical Chemistry.2003;49:1250–1251. [PubMed: 12881438]

106.

Umstot ES, Baxter JE, Andersen RN. A theoretically sound and practicable equilibrium dialysis method for measuring percentage of free testosterone.Journal of Steroid Biochemistry.1985;22:639–648. [PubMed: 4040191]

107.

Swinkels LM, Ross HA, Benraad TJ. A symmetric dialysis method for the determination of free testosterone in human plasma.Clinica Chimica Acta.1987;165:341–349.

108.

Hammond GL, Nisker JA, Jones LA, Siiteri PK. Estimation of the percentage of free steroid in undiluted serum by centrifugal ultrafiltration-dialysis.Journal of Biological Chemistry.1980;255:5023–5026. [PubMed: 7372622]

109.

Vlahos I, MacMahon W, Sgoutas D, Bowers W, Thompson J, Trawick W. An improved ultrafiltration method for determining free testosterone in serum.Clinical Chemistry.1982;28:2286–2291. [PubMed: 7127776]

110.

Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum.Journal of Clinical Endocrinology and Metabolism.1999;84:3666–3672. [PubMed: 10523012]

111.

Rosner W. An extraordinarily inaccurate assay for free testosterone is still with us.Journal of Clinical Endocrinology and Metabolism.2001;86:2903. [PubMed: 11397908]

112.

Fritz KS, McKean AJ, Nelson JC, Wilcox RB. Analog-based free testosterone test results linked to total testosterone concentrations, not free testosterone concentrations.Clinical Chemistry.2008;54:512–516. [PubMed: 18171714]

113.

Kapoor P, Luttrell BM, Williams D. The free androgen index is not valid for adult males.Journal of Steroid Biochemistry and Molecular Biology.1993;45:325–326. [PubMed: 8499341]

114.

Mazer NA. A novel spreadsheet method for calculating the free serum concentrations of testosterone, dihydrotestosterone, estradiol, estrone and cortisol: with illustrative examples from male and female populations.Steroids.2009;74:512–519. [PubMed: 19321131]

115.

Ly LP, Handelsman DJ. Empirical estimation of free testosterone from testosterone and sex hormone-binding globulin immunoassays.European Journal of Endocrinology.2005;152:471–478. [PubMed: 15757865]

116.

Ly LP, Sartorius G, Hull L, Leung A, Swerdloff RS, Wang C, Handelsman DJ. Accuracy of calculated free testosterone formulae in men.Clinical Endocrinology.2010;73:382–388. [PubMed: 20346001]

117.

Sartorius G, Ly LP, Sikaris K, McLachlan R, Handelsman DJ. Predictive accuracy and sources of variability in calculated free testosterone estimates.Annals of Clinical Biochemistry.2009;46:137–143. [PubMed: 19225026]

118.

Egleston BL, Chandler DW, Dorgan JF. Validity of estimating non-sex hormone-binding globulin bound testosterone and oestradiol from total hormone measurements in boys and girls.Annals of Clinical Biochemistry.2010;47:233–241. [PMC free article: PMC2863123] [PubMed: 20406780]

119.

Giton F, Fiet J, Guechot J, Ibrahim F, Bronsard F, Chopin D, Raynaud JP. Serum bioavailable testosterone: assayed or calculated?Clinical Chemistry.2006;52:474–481. [PubMed: 16384884]

120.

Van Eenoo P, Delbeke FT. Metabolism and excretion of anabolic steroids in doping control--new steroids and new insights.Journal of Steroid Biochemistry and Molecular Biology.2006;101:161–178. [PubMed: 17000101]

121.

Kumar N, Crozat A, Li F, Catterall JF, Bardin CW, Sundaram K. 7alpha-methyl-19-nortestosterone, a synthetic androgen with high potency: structure-activity comparisons with other androgens.Journal of Steroid Biochemistry and Molecular Biology.1999;71:213–222. [PubMed: 10704910]

122.

Deslypere JP, Young M, Wilson JD, McPhaul MJ. Testosterone and 5 alpha-dihydrotestosterone interact differently with the androgen receptor to enhance transcription of the MMTV-CAT reporter gene.Molecular and Cellular Endocrinology.1992;88:15–22. [PubMed: 1334007]

123.

Zhou ZX, Lane MV, Kemppainen JA, French FS, Wilson EM. Specificity of ligand-dependent androgen receptor stabilization: receptor domain interactions influence ligand dissociation and receptor stability.Molecular Endocrinology.1995;9:208–218. [PubMed: 7776971]

124.

McRobb L, Handelsman DJ, Kazlauskas R, Wilkinson S, McLeod MD, Heather AK. Structure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay.Journal of Steroid Biochemistry and Molecular Biology.2008;110:39–47. [PubMed: 18395441]

125.

Russell DW, Wilson JD. Steroid 5 alpha-reductase: two genes/two enzymes.Annual Review of Biochemistry.1994;63:25–61.

126.

Thigpen AE, Davis DL, Milatovich A, Mendonca B, Imperato-McGinley J, Griffin JE, Francke U, Wilson JD, Russell DW. Molecular genetics of steroid 5a-reductase 2 deficiency.Journal of Clinical Investigations.1992;90:799–809.

127.

Cai LQ, Fratiani CM, Gautier T, Imperato-McGinley J. Dihydrotestosterone regulation of semen in males pseudohermaphrodites with 5-a reductase deficiency.Journal of Clinical Endocrinology and Metabolism.1994;79:409–414. [PubMed: 8045956]

128.

Sobel V, Schwartz B, Zhu YS, Cordero JJ, Imperato-McGinley J. Bone mineral density in the complete androgen insensitivity and 5alpha-reductase-2 deficiency syndromes.Journal of Clinical Endocrinology and Metabolism.2006;91:3017–3023. [PubMed: 16735493]

129.

Imperato-McGinley J, Peterson RE, Gautier T, Sturla E. Androgens and the evolution of male gender identity among male pseudohemaphrodites with 5-a reductase deficiency.New England Journal of Medicine.1979;300:1233–1237. [PubMed: 431680]

130.

Imperato-McGinley J, Gautier T, Zirinsky K, Hom T, Palomo O, Stein E, Vaughan ED, Markisz JA, deArellano ER, Kazam E. Prostate visualization studies in males homozygous and heterozygous for 5-a reductase deficiency.Journal of Clinical Endocrinology and Metabolism.1992;75:1022–1026. [PubMed: 1400866]

131.

Imperato-McGinley J, Zhu YS. Androgens and male physiology the syndrome of 5alpha-reductase-2 deficiency.Molecular and Cellular Endocrinology.2002;198:51–59. [PubMed: 12573814]

132.

Steers WD. 5alpha-reductase activity in the prostate.Urology.2001;58:17–24. [PubMed: 11750244]

133.

Frick J, Aulitzky W. Physiology of the prostate.Infection.1991;19 Suppl 3:S115–118. [PubMed: 2055645]

134.

Gisleskog PO, Hermann D, Hammarlund-Udenaes M, Karlsson MO. A model for the turnover of dihydrotestosterone in the presence of the irreversible 5 alpha-reductase inhibitors GI198745 and finasteride.Clinical Pharmacology and Therapeutics.1998;64:636–647. [PubMed: 9871428]

135.

Miller LR, Partin AW, Chan DW, Bruzek DJ, Dobs AS, Epstein JI, Walsh PC. Influence of radical prostatectomy on serum hormone levels.Journal of Urology.1998;160:449–453. [PubMed: 9679896]

136.

Toorians AW, Kelleher S, Gooren LJ, Jimenez M, Handelsman DJ. Estimating the contribution of the prostate to blood dihydrotestosterone.Journal of Clinical Endocrinology and Metabolism.2003;88:5207–5211. [PubMed: 14602751]

137.

Zhu YS, Katz MD, Imperato-McGinley J. Natural potent androgens: lessons from human genetic models.Baillieres Clinical Endocrinology and Metabolism.1998;12:83–113. [PubMed: 9890063]

138.

Uemura M, Tamura K, Chung S, Honma S, Okuyama A, Nakamura Y, Nakagawa H. Novel 5 alpha-steroid reductase (SRD5A3, type-3) is overexpressed in hormone-refractory prostate cancer.Cancer Sci.2008;99:81–86. [PMC free article: PMC11158902] [PubMed: 17986282]

139.

Cantagrel V, Lefeber DJ, Ng BG, Guan Z, Silhavy JL, Bielas SL, Lehle L, Hombauer H, Adamowicz M, Swiezewska E, De Brouwer AP, Blumel P, Sykut-Cegielska J, Houliston S, Swistun D, Ali BR, Dobyns WB, Babovic-Vuksanovic D, van Bokhoven H, Wevers RA, Raetz CR, Freeze HH, Morava E, Al-Gazali L, Gleeson JG. SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder.Cell.2010;142:203–217. [PMC free article: PMC2940322] [PubMed: 20637498]

140.

Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA Jr. The influence of finasteride on the development of prostate cancer.New England Journal of Medicine.2003;349:215–224. [PubMed: 12824459]

141.

Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger M, Montorsi F, Pettaway CA, Tammela TL, Teloken C, Tindall DJ, Somerville MC, Wilson TH, Fowler IL, Rittmaster RS. Effect of dutasteride on the risk of prostate cancer.New England Journal of Medicine.2010;362:1192–1202. [PubMed: 20357281]

142.

Lucia MS, Epstein JI, Goodman PJ, Darke AK, Reuter VE, Civantos F, Tangen CM, Parnes HL, Lippman SM, La Rosa FG, Kattan MW, Crawford ED, Ford LG, Coltman CA Jr, Thompson IM. Finasteride and high-grade prostate cancer in the Prostate Cancer Prevention Trial.Journal of the National Cancer Institute.2007;99:1375–1383. [PubMed: 17848673]

143.

Redman MW, Tangen CM, Goodman PJ, Lucia MS, Coltman CA Jr, Thompson IM. Finasteride does not increase the risk of high-grade prostate cancer: a bias-adjusted modeling approach.Cancer Prev Res (Phila).2008;1:174–181. [PMC free article: PMC2844801] [PubMed: 19138953]

144.

Kim J, Amos CI, Logothetis C. 5alpha-Reductase inhibitors for prostate-cancer prevention.New England Journal of Medicine.2011;365:2340.

145.

Simpson ER, Zhao Y, Agarwal VR, Michael MD, Bulun SE, Hinshelwood MM, Graham-Lorence S, Sun T, Fisher CR, Qin K, Mendelson CR. Aromatase expression in health and disease.Recent Progress in Hormone Research.1997;52:185–213. [PubMed: 9238853]

146.

Bulun SE, Takayama K, Suzuki T, Sasano H, Yilmaz B, Sebastian S. Organization of the human aromatase p450 (CYP19) gene.Seminars in Reproductive Medicine.2004;22:5–9. [PubMed: 15083376]

147.

Naftolin F. Brain aromatization of androgens.Journal of Reproductive Medicine.1994;39:257–261. [PubMed: 8040841]

148.

Roselli CF. Brain aromatase: roles in reproduction and neuroprotection.Journal of Steroid Biochemistry and Molecular Biology.2007;106:143–150. [PMC free article: PMC2002474] [PubMed: 17643294]

149.

Jones ME, Boon WC, Proietto J, Simpson ER. Of mice and men: the evolving phenotype of aromatase deficiency.Trends Endocrinol Metab.2006;17:55–64. [PubMed: 16480891]

150.

Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS, Smithies O. Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene.Proceedings of the National Academy of Sciences USA.1993;90:11162–11166.

151.

Couse JE, Mahato D, Eddy EM, Korach KS. Molecular mechanism of estrogen action in the male: insights from the estrogen receptor null mice.Reproduction, Fertility, and Development.2001;13:211–219. [PubMed: 11800160]

152.

Gennari L, Nuti R, Bilezikian JP. Aromatase activity and bone homeostasis in men.Journal of Clinical Endocrinology and Metabolism.2004;89:5898–5907. [PubMed: 15579733]

153.

Vanderschueren D, Vandenput L, Boonen S, Lindberg MK, Bouillon R, Ohlsson C. Androgens and bone.Endocrine Reviews.2004;25:389–425. [PubMed: 15180950]

154.

Vandenput L, Swinnen JV, Boonen S, Van Herck E, Erben RG, Bouillon R, Vanderschueren D. Role of the androgen receptor in skeletal homeostasis: the androgen-resistant testicular feminized male mouse model.Journal of Bone and Mineral Research.2004;19:1462–1470. [PubMed: 15312246]

155.

Chesnut CH 3rd, Ivey JL, Gruber HE, Matthews M, Nelp WB, Sisom K, Baylink DJ. Stanozolol in postmenopausal osteoporosis: therapeutic efficacy and possible mechanisms of action.Metabolism: Clinical and Experimental.1983;32:571–580. [PubMed: 6341772]

156.

Need AG, Nordin BEC, Chatterton BE. Double-blind placebo-controlled trial of treatment of osteoporosis with the anabolic steroid nandrolone decanoate.Osteoporosis International.1993;3 Suppl 1:S218–222.

157.

Venken K, De Gendt K, Boonen S, Ophoff J, Bouillon R, Swinnen JV, Verhoeven G, Vanderschueren D. Relative impact of androgen and estrogen receptor activation in the effects of androgens on trabecular and cortical bone in growing male mice: a study in the androgen receptor knockout mouse model.Journal of Bone and Mineral Research.2006;21:576–585. [PubMed: 16598378]

158.

Callewaert F, Venken K, Ophoff J, De Gendt K, Torcasio A, van Lenthe GH, Van Oosterwyck H, Boonen S, Bouillon R, Verhoeven G, Vanderschueren D. Differential regulation of bone and body composition in male mice with combined inactivation of androgen and estrogen receptor-alpha.FASEB Journal.2009;23:232–240. [PubMed: 18809737]

159.

Zuloaga DG, Puts DA, Jordan CL, Breedlove SM. The role of androgen receptors in the masculinization of brain and behavior: what we've learned from the testicular feminization mutation.Hormones and Behavior.2008;53:613–626. [PMC free article: PMC2706155] [PubMed: 18374335]

160.

Finkelstein JS, Lee H, Burnett-Bowie SA, Pallais JC, Yu EW, Borges LF, Jones BF, Barry CV, Wulczyn KE, Thomas BJ, Leder BZ. Gonadal steroids and body composition, strength, and sexual function in men.New England Journal of Medicine.2013;369:1011–1022. [PMC free article: PMC4142768] [PubMed: 24024838]

161.

Sartorius GA, Ly LP, Handelsman DJ. Male sexual function can be maintained without aromatization: randomized placebo-controlled trial of dihydrotestosterone (DHT) in healthy, older men for 24 months.J Sex Med.2014;11:2562–2570. [PubMed: 24751323]

162.

Vanderschueren D, Gaytant J, Boonen S, Venken K. Androgens and bone.Curr Opin Endocrinol Diabetes Obes.2008;15:250–254. [PubMed: 18438173]

163.

Zhou SF. Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4.Current Drug Metabolism.2008;9:310–322. [PubMed: 18473749]

164.

Chouinard S, Yueh MF, Tukey RH, Giton F, Fiet J, Pelletier G, Barbier O, Belanger A. Inactivation by UDP-glucuronosyltransferase enzymes: the end of androgen signaling.Journal of Steroid Biochemistry and Molecular Biology.2008;109:247–253. [PubMed: 18467088]

165.

Jakobsson J, Ekstrom L, Inotsume N, Garle M, Lorentzon M, Ohlsson C, Roh HK, Carlstrom K, Rane A. Large differences in testosterone excretion in Korean and Swedish men are strongly associated with a UDP-glucuronosyl transferase 2B17 polymorphism.Journal of Clinical Endocrinology and Metabolism.2006;91:687–693. [PubMed: 16332934]

166.

Schulze JJ, Lundmark J, Garle M, Skilving I, Ekstrom L, Rane A. Doping test results dependent on genotype of uridine diphospho-glucuronosyl transferase 2B17, the major enzyme for testosterone glucuronidation.Journal of Clinical Endocrinology and Metabolism.2008;93:2500–2506. [PubMed: 18334593]

167.

Johnsen SG, Bennet EP, Jensen VG. Therapeutic effectiveness of oral testosterone.Lancet.1974;ii:1473–1475.

168.

Frey H, Aakvag A, Saanum D, Falch J. Bioavailability of testosterone in males.European Journal of Clinical Pharmacology.1979;16:345–349. [PubMed: 520403]

169.

Parkes AS. Effective absorption of hormones.British Medical Journal.1938:371–373.

170.

Lisser H, Escamilla RF, Curtis LE. Testosterone therapy of male eunuchoids. III Sublingual administration of testosterone compounds.Journal of Clinical Endocrinology.1942;2:351–360.

171.

Korbonits M, Slawik M, Cullen D, Ross RJ, Stalla G, Schneider H, Reincke M, Bouloux PM, Grossman AB. A comparison of a novel testosterone bioadhesive buccal system, striant, with a testosterone adhesive patch in hypogonadal males.Journal of Clinical Endocrinology and Metabolism.2004;89:2039–2043. [PubMed: 15126518]

172.

Wang C, Eyre DR, Clark R, Kleinberg D, Newman C, Iranmanesh A, Veldhuis J, Dudley RE, Berman N, Davidson T, Barstow TJ, Sinow R, Alexander G, Swerdloff RS. Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone formation markers in hypogonadal men--a clinical research center study.Journal of Clinical Endocrinology and Metabolism.1996;81:3654–3662. [PubMed: 8855818]

173.

Shackleford DM, Faassen WA, Houwing N, Lass H, Edwards GA, Porter CJ, Charman WN. Contribution of lymphatically transported testosterone undecanoate to the systemic exposure of testosterone after oral administration of two andriol formulations in conscious lymph duct-cannulated dogs.Journal of Pharmacology and Experimental Therapeutics.2003;306:925–933. [PubMed: 12807999]

174.

Foss GL. Clinical administration of androgens.Lancet i.1939:502–504.

175.

Bousfield GR, Butnev VY, Gotschall RR, Baker VL, Moore WT. Structural features of mammalian gonadotropins.Molecular and Cellular Endocrinology.1996;125:3–19. [PubMed: 9027339]

176.

Gromoll J, Eiholzer U, Nieschlag E, Simoni M. Male hypogonadism caused by homozygous deletion of exon 10 of the luteinizing hormone (LH) receptor: differential action of human chorionic gonadotropin and LH.Journal of Clinical Endocrinology and Metabolism.2000;85:2281–2286. [PubMed: 10852464]

177.

O'Shaughnessy PJ, Baker P, Sohnius U, Haavisto AM, Charlton HM, Huhtaniemi I. Fetal development of Leydig cell activity in the mouse is independent of pituitary gonadotroph function.Endocrinology.1998;139:1141–1146. [PubMed: 9492048]

178.

Abreu AP, Dauber A, Macedo DB, Noel SD, Brito VN, Gill JC, Cukier P, Thompson IR, Navarro VM, Gagliardi PC, Rodrigues T, Kochi C, Longui CA, Beckers D, de Zegher F, Montenegro LR, Mendonca BB, Carroll RS, Hirschhorn JN, Latronico AC, Kaiser UB. Central precocious puberty caused by mutations in the imprinted gene MKRN3.N Engl J Med.2013;368:2467–2475. [PMC free article: PMC3808195] [PubMed: 23738509]

179.

Dauber A, Cunha-Silva M, Macedo DB, Brito VN, Abreu AP, Roberts SA, Montenegro LR, Andrew M, Kirby A, Weirauch MT, Labilloy G, Bessa DS, Carroll RS, Jacobs DC, Chappell PE, Mendonca BB, Haig D, Kaiser UB, Latronico AC. Paternally Inherited DLK1 Deletion Associated With Familial Central Precocious Puberty.J Clin Endocrinol Metab.2017;102:1557–1567. [PMC free article: PMC5443333] [PubMed: 28324015]

180.

Roberts S, Kaiser UB. GENETICS IN ENDOCRINOLOGY: Genetic etiologies of central precocious puberty and the role of imprinted genes.Eur J Endocrinol.2020

181.

Howard SR. The Genetic Basis of Delayed Puberty.Front Endocrinol (Lausanne).2019;10:423. [PMC free article: PMC6606719] [PubMed: 31293522]

182.

Meikle AW, Bishop DT, Stringham JD, West DW. Quantitating genetic and nongenetic factors that determine plasma sex steroid variation in normal male twins.Metabolism.1986;35:1090–1095. [PubMed: 3097456]

183.

Eaves L, Silberg J, Foley D, Bulik C, Maes H, Erkanli A, Angold A, Costello EJ, Worthman C. Genetic and environmental influences on the relative timing of pubertal change.Twin Res.2004;7:471–481. [PubMed: 15527663]

184.

Grotzinger AD, Mann FD, Patterson MW, Herzhoff K, Tackett JL, Tucker-Drob EM, Paige Harden K. Twin models of environmental and genetic influences on pubertal development, salivary testosterone, and estradiol in adolescence.Clin Endocrinol (Oxf).2018;88:243–250. [PMC free article: PMC5771835] [PubMed: 29161770]

185.

Silventoinen K, Haukka J, Dunkel L, Tynelius P, Rasmussen F. Genetics of pubertal timing and its associations with relative weight in childhood and adult height: the Swedish Young Male Twins Study.Pediatrics.2008;121:e885–891. [PubMed: 18381517]

186.

Day FR, Perry JR, Ong KK. Genetic Regulation of Puberty Timing in Humans.Neuroendocrinology.2015;102:247–255. [PMC free article: PMC6309186] [PubMed: 25968239]

187.

Busch AS, Hollis B, Day FR, Sørensen K, Aksglaede L, Perry JRB, Ong KK, Juul A, Hagen CP. Voice break in boys-temporal relations with other pubertal milestones and likely causal effects of BMI.Hum Reprod.2019;34:1514–1522. [PMC free article: PMC6688887] [PubMed: 31348498]

188.

Sultan C, Gaspari L, Maimoun L, Kalfa N, Paris F. Disorders of puberty.Best Pract Res Clin Obstet Gynaecol.2018;48:62–89. [PubMed: 29422239]

189.

Sisk CL, Foster DL. The neural basis of puberty and adolescence.Nature Neuroscience.2004;7:1040–1047. [PubMed: 15452575]

190.

Abreu AP, Kaiser UB. Pubertal development and regulation.Lancet Diabetes Endocrinol.2016;4:254–264. [PMC free article: PMC5192018] [PubMed: 26852256]

191.

Veldhuis JD. Neuroendocrine facets of human puberty.Neurobiology of Aging.2003;24 Suppl 1:S93–S119. [PubMed: 12829118]

192.

Terasawa E, Fernandez DL. Neurobiological mechanisms of the onset of puberty in primates.Endocrine Reviews.2001;22:111–151. [PubMed: 11159818]

193.

de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54.Proceedings of the National Academy of Sciences of the United States of America.2003;100:10972–10976. [PMC free article: PMC196911] [PubMed: 12944565]

194.

Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O'Rahilly S, Carlton MB, Crowley WF Jr, Aparicio SA, Colledge WH. The GPR54 gene as a regulator of puberty.New England Journal of Medicine.2003;349:1614–1627. [PubMed: 14573733]

195.

Lomniczi A, Ojeda SR. The Emerging Role of Epigenetics in the Regulation of Female Puberty.Endocrine Development.2016;29:1–16. [PMC free article: PMC4955615] [PubMed: 26680569]

196.

Wu FC, Borrow SM, Nicol K, Elton R, Hunter WM. Ontogeny of pulsatile gonadotrophin secretion and pituitary responsiveness in male puberty in man: a mixed longitudinal and cross-sectional study.Journal of Endocrinology.1989;123:347–359. [PubMed: 2514245]

197.

Pedersen-White JR, Chorich LP, Bick DP, Sherins RJ, Layman LC. The prevalence of intragenic deletions in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.Molecular Human Reproduction.2008;14:367–370. [PMC free article: PMC2434956] [PubMed: 18463157]

198.

Delemarre-van de Waal HA. Secular trend of timing of puberty.Endocrine Development.2005;8:1–14. [PubMed: 15722614]

199.

Ong KK, Ahmed ML, Dunger DB. Lessons from large population studies on timing and tempo of puberty (secular trends and relation to body size): the European trend.Molecular and Cellular Endocrinology.2006;254-255:8–12. [PubMed: 16757103]

200.

Parent AS, Teilmann G, Juul A, Skakkebaek NE, Toppari J, Bourguignon JP. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration.Endocrine Reviews.2003;24:668–693. [PubMed: 14570750]

201.

Gluckman PD, Hanson MA. Changing times: the evolution of puberty.Molecular and Cellular Endocrinology.2006;254-255:26–31. [PubMed: 16713071]

202.

Slyper AH. The pubertal timing controversy in the USA, and a review of possible causative factors for the advance in timing of onset of puberty.Clinical Endocrinology.2006;65:1–8. [PubMed: 16817811]

203.

Juul A, Teilmann G, Scheike T, Hertel NT, Holm K, Laursen EM, Main KM, Skakkebaek NE. Pubertal development in Danish children: comparison of recent European and US data.International Journal of Andrology.2006;29:247–255. [PubMed: 16466546]

204.

Day FR, Elks CE, Murray A, Ong KK, Perry JR. Puberty timing associated with diabetes, cardiovascular disease and also diverse health outcomes in men and women: the UK Biobank study.Sci Rep.2015;5:11208. [PMC free article: PMC4471670] [PubMed: 26084728]

205.

Day FR, Bulik-Sullivan B, Hinds DA, Finucane HK, Murabito JM, Tung JY, Ong KK, Perry JR. Shared genetic aetiology of puberty timing between sexes and with health-related outcomes.Nat Commun.2015;6:8842. [PMC free article: PMC4667609] [PubMed: 26548314]

206.

Veldhuis JD, Keenan DM, Pincus SM. Regulation of complex pulsatile and rhythmic neuroendocrine systems: the male gonadal axis as a prototype.Progress in Brain Research.2010;181:79–110. [PubMed: 20478434]

207.

Chin WW, Boime I eds. 1990 Glycoprotein Hormones: Structure, Synthesis and Biologic Function. Norwell: Serono Symposia, USA.

208.

Boime I, Ben-Menahem D. Glycoprotein hormone structure-function and analog design.Recent Progress in Hormone Research.1999;54:271–288. [PubMed: 10548880]

209.

Ascoli M, Fanelli F, Segaloff DL. The lutropin/choriogonadotropin receptor, a 2002 perspective.Endocrine Reviews.2002;23:141–174. [PubMed: 11943741]

210.

Rosa C, Amr S, Birken S, Wehmann R, Nisula B. Effect of desialylation of human chorionic gonadotropin on its metabolic clearance rate in humans.Journal of Clinical Endocrinology and Metabolism.1984;59:1215–1219. [PubMed: 6490798]

211.

Muyan M, Furuhashi M, Sugahara T, Boime I. The carboxy-terminal region of the beta-subunits of luteinizing hormone and chorionic gonadotropin differentially influence secretion and assembly of the heterodimers.Molecular Endocrinology.1996;10:1678–1687. [PubMed: 8961276]

212.

Bouloux PM, Handelsman DJ, Jockenhovel F, Nieschlag E, Rabinovici J, Frasa WL, de Bie JJ, Voortman G, Itskovitz-Eldor J. First human exposure to FSH-CTP in hypogonadotrophic hypogonadal males.Human Reproduction.2001;16:1592–1597. [PubMed: 11473948]

213.

Joshi L, Murata Y, Wondisford FE, Szkudlinski MW, Desai R, Weintraub BD. Recombinant thyrotropin containing a beta-subunit chimera with the human chorionic gonadotropin-beta carboxy-terminus is biologically active, with a prolonged plasma half-life: role of carbohydrate in bioactivity and metabolic clearance.Endocrinology.1995;136:3839–3848. [PubMed: 7544273]

214.

Fares F, Ganem S, Hajouj T, Agai E. Development of a long-acting erythropoietin by fusing the carboxyl-terminal peptide of human chorionic gonadotropin beta-subunit to the coding sequence of human erythropoietin.Endocrinology.2007;148:5081–5087. [PubMed: 17641000]

215.

Saunders PT. Germ cell-somatic cell interactions during spermatogenesis.Reproduction Supplement.2003;61:91–101. [PubMed: 14635929]

216.

Rudolfsson SH, Wikstrom P, Jonsson A, Collin O, Bergh A. Hormonal regulation and functional role of vascular endothelial growth factor a in the rat testis.Biology of Reproduction.2004;70:340–347. [PubMed: 14561656]

217.

Schnorr JA, Bray MJ, Veldhuis JD. Aromatization mediates testosterone's short-term feedback restraint of 24-hour endogenously driven and acute exogenous gonadotropin-releasing hormone-stimulated luteinizing hormone and follicle-stimulating hormone secretion in young men.Journal of Clinical Endocrinology and Metabolism.2001;86:2600–2606. [PubMed: 11397860]

218.

Pitteloud N, Dwyer AA, DeCruz S, Lee H, Boepple PA, Crowley WF Jr, Hayes FJ. Inhibition of luteinizing hormone secretion by testosterone in men requires aromatization for its pituitary but not its hypothalamic effects: evidence from the tandem study of normal and gonadotropin-releasing hormone-deficient men.Journal of Clinical Endocrinology and Metabolism.2008;93:784–791. [PMC free article: PMC2266963] [PubMed: 18073301]

219.

Wilson JD. The role of 5alpha-reduction in steroid hormone physiology.Reproduction, Fertility, and Development.2001;13:673–678. [PubMed: 11999320]

220.

Simpson ER. Aromatase: biologic relevance of tissue-specific expression.Seminars in Reproductive Medicine.2004;22:11–23. [PubMed: 15083377]

221.

Cooke PS, Nanjappa MK, Ko C, Prins GS, Hess RA. Estrogens in Male Physiology.Physiol Rev.2017;97:995–1043. [PMC free article: PMC6151497] [PubMed: 28539434]

222.

Naftolin F, Ryan KJ, Petro Z. Aromatization of androstenedione by the diencephalon.J Clin Endocrinol Metab.1971;33:368–370. [PubMed: 4935642]

223.

Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man.N Engl J Med.1994;331:1056–1061. [PubMed: 8090165]

224.

Krege JH, Hodgin JB, Couse JF, Enmark E, Warner M, Mahler JF, Sar M, Korach KS, Gustafsson JA, Smithies O. Generation and reproductive phenotypes of mice lacking estrogen receptor beta.Proc Natl Acad Sci U S A.1998;95:15677–15682. [PMC free article: PMC28103] [PubMed: 9861029]

225.

Finkelstein JS, Lee H, Burnett-Bowie SA, Pallais JC, Yu EW, Borges LF, Jones BF, Barry CV, Wulczyn KE, Thomas BJ, Leder BZ. Gonadal steroids and body composition, strength, and sexual function in men.N Engl J Med.2013;369:1011–1022. [PMC free article: PMC4142768] [PubMed: 24024838]

226.

Vanderschueren D, Laurent MR, Claessens F, Gielen E, Lagerquist MK, Vandenput L, Borjesson AE, Ohlsson C. Sex steroid actions in male bone.Endocr Rev.2014;35:906–960. [PMC free article: PMC4234776] [PubMed: 25202834]

227.

Russell N, Grossmann M. MECHANISMS IN ENDOCRINOLOGY: Estradiol as a male hormone.Eur J Endocrinol.2019;181:R23–R43. [PubMed: 31096185]

228.

Gronemeyer H, Gustafsson JA, Laudet V. Principles for modulation of the nuclear receptor superfamily.Nature Reviews Drug Discovery.2004;3:950–964. [PubMed: 15520817]

229.

Shi Y. Orphan nuclear receptors in drug discovery.Drug Discov Today.2007;12:440–445. [PMC free article: PMC2748783] [PubMed: 17532527]

230.

Adachi M, Takayanagi R, Tomura A, Imasaki K, Kato S, Goto K, Yanase T, Ikuyama S, Nawata H. Androgen-insensitivity syndrome as a possible coactivator disease.New England Journal of Medicine.2000;343:856–862. [PubMed: 10995865]

231.

McEwan IJ, Lavery D, Fischer K, Watt K. Natural disordered sequences in the amino terminal domain of nuclear receptors: lessons from the androgen and glucocorticoid receptors.Nucl Recept Signal.2007;5:e001. [PMC free article: PMC1853069] [PubMed: 17464357]

232.

Rajender S, Singh L, Thangaraj K. Phenotypic heterogeneity of mutations in androgen receptor gene.Asian Journal of Andrology.2007;9:147–179. [PubMed: 17334586]

233.

Zitzmann M, Nieschlag E. The CAG repeat polymorphism within the androgen receptor gene and maleness.International Journal of Andrology.2003;26:76–83. [PubMed: 12641825]

234.

Simanainen U, Brogley M, Gao YR, Jimenez M, Harwood DT, Handelsman DJ, Robins DM. Length of the human androgen receptor glutamine tract determines androgen sensitivity in vivo.Molecular and Cellular Endocrinology.2011;342:81–86. [PMC free article: PMC3148310] [PubMed: 21664242]

235.

Zitzmann M, Depenbusch M, Gromoll J, Nieschlag E. Prostate volume and growth in testosterone-substituted hypogonadal men are dependent on the CAG repeat polymorphism of the androgen receptor gene: a longitudinal pharmacogenetic study.Journal of Clinical Endocrinology and Metabolism.2003;88:2049–2054. [PubMed: 12727953]

236.

Zitzmann M, Nieschlag E. Androgen receptor gene CAG repeat length and body mass index modulate the safety of long-term intramuscular testosterone undecanoate therapy in hypogonadal men.Journal of Clinical Endocrinology and Metabolism.2007;92:3844–3853. [PubMed: 17635942]

237.

Zeegers MP, Kiemeney LA, Nieder AM, Ostrer H. How strong is the association between CAG and GGN repeat length polymorphisms in the androgen receptor gene and prostate cancer risk?Cancer Epidemiology, Biomarkers and Prevention.2004;13:1765–1771.

238.

Davis-Dao CA, Tuazon ED, Sokol RZ, Cortessis VK. Male infertility and variation in CAG repeat length in the androgen receptor gene: a meta-analysis.Journal of Clinical Endocrinology and Metabolism.2007;92:4319–4326. [PubMed: 17684052]

239.

Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG. Replication validity of genetic association studies.Nature Genetics.2001;29:306–309. [PubMed: 11600885]

240.

Palazzolo I, Gliozzi A, Rusmini P, Sau D, Crippa V, Simonini F, Onesto E, Bolzoni E, Poletti A. The role of the polyglutamine tract in androgen receptor.Journal of Steroid Biochemistry and Molecular Biology.2008;108:245–253. [PubMed: 17945479]

241.

Thomas PS Jr, Fraley GS, Damian V, Woodke LB, Zapata F, Sopher BL, Plymate SR, La Spada AR. Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy.Human Molecular Genetics.2006;15:2225–2238. [PubMed: 16772330]

242.

Atsuta N, Watanabe H, Ito M, Banno H, Suzuki K, Katsuno M, Tanaka F, Tamakoshi A, Sobue G. Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients.Brain.2006;129:1446–1455. [PubMed: 16621916]

243.

Adachi H, Waza M, Katsuno M, Tanaka F, Doyu M, Sobue G. Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy.Neuropathology and Applied Neurobiology.2007;33:135–151. [PubMed: 17359355]

244.

Ross CA, Poirier MA. Opinion: What is the role of protein aggregation in neurodegeneration?Nature Reviews Molecular Cell Biology.2005;6:891–898. [PubMed: 16167052]

245.

Palazzolo I, Stack C, Kong L, Musaro A, Adachi H, Katsuno M, Sobue G, Taylor JP, Sumner CJ, Fischbeck KH, Pennuto M. Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy.Neuron.2009;63:316–328. [PMC free article: PMC2735765] [PubMed: 19679072]

246.

Rinaldi C, Bott LC, Chen KL, Harmison GG, Katsuno M, Sobue G, Pennuto M, Fischbeck KH. IGF-1 administration ameliorates disease manifestations in a mouse model of spinal and bulbar muscular atrophy.Molecular Medicine.2012

247.

Katsuno M, Banno H, Suzuki K, Takeuchi Y, Kawashima M, Yabe I, Sasaki H, Aoki M, Morita M, Nakano I, Kanai K, Ito S, Ishikawa K, Mizusawa H, Yamamoto T, Tsuji S, Hasegawa K, Shimohata T, Nishizawa M, Miyajima H, Kanda F, Watanabe Y, Nakashima K, Tsujino A, Yamashita T, Uchino M, Fujimoto Y, Tanaka F, Sobue G. Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial.Lancet Neurol.2010;9:875–884. [PubMed: 20691641]

248.

Banno H, Katsuno M, Suzuki K, Tanaka F, Sobue G. Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy (SBMA).Cell and Tissue Research.2012;349:313–320. [PubMed: 22476656]

249.

Grunseich C, Fischbeck KH. Spinal and Bulbar Muscular Atrophy.Neurologic Clinics.2015;33:847–854. [PMC free article: PMC4628725] [PubMed: 26515625]

250.

Prescott J, Coetzee GA. Molecular chaperones throughout the life cycle of the androgen receptor.Cancer Letters.2006;231:12–19. [PubMed: 16356826]

251.

Heinlein CA, Chang C. Androgen receptor (AR) coregulators: an overview.Endocrine Reviews.2002;23:175–200. [PubMed: 11943742]

252.

Smith CL, O'Malley BW. Coregulator function: a key to understanding tissue specificity of selective receptor modulators.Endocrine Reviews.2004;25:45–71. [PubMed: 14769827]

253.

Gottlieb B, Beitel LK, Nadarajah A, Paliouras M, Trifiro M. The androgen receptor gene mutations database: 2012 update.Human Mutation.2012;33:887–894. [PubMed: 22334387]

254.

Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, Lotan TL, Zheng Q, De Marzo AM, Isaacs JT, Isaacs WB, Nadal R, Paller CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer.New England Journal of Medicine.2014;371:1028–1038. [PMC free article: PMC4201502] [PubMed: 25184630]

255.

McCrea E, Sissung TM, Price DK, Chau CH, Figg WD. Androgen receptor variation affects prostate cancer progression and drug resistance.Pharmacological Research.2016;114:152–162. [PMC free article: PMC5154811] [PubMed: 27725309]

256.

Sarpel U, Palmer SK, Dolgin SE. The incidence of complete androgen insensitivity in girls with inguinal hernias and assessment of screening by vaginal length measurement.Journal of Pediatric Surgery.2005;40:133–136. [PubMed: 15868573]

257.

Hiort O, Holterhus PM, Horter T, Schulze W, Kremke B, Bals-Pratsch M, Sinnecker GH, Kruse K. Significance of mutations in the androgen receptor gene in males with idiopathic infertility.Journal of Clinical Endocrinology and Metabolism.2000;85:2810–2815. [PubMed: 10946887]

258.

Belgorosky A, Rivarola MA. Sex hormone binding globulin response to testosterone. An androgen sensitivity test.Acta Endocrinologica.1985;109:130–138. [PubMed: 2860769]

259.

Sinnecker GH, Hiort O, Nitsche EM, Holterhus PM, Kruse K. Functional assessment and clinical classification of androgen sensitivity in patients with mutations of the androgen receptor gene. German Collaborative Intersex Study Group.European Journal of Pediatrics.1997;156:7–14. [PubMed: 9007482]

260.

Cheikhelard A, Morel Y, Thibaud E, Lortat-Jacob S, Jaubert F, Polak M, Nihoul-Fekete C. Long-term followup and comparison between genotype and phenotype in 29 cases of complete androgen insensitivity syndrome.Journal of Urology.2008;180:1496–1501. [PubMed: 18710728]

261.

Marcus R, Leary D, Schneider DL, Shane E, Favus M, Quigley CA. The contribution of testosterone to skeletal development and maintenance: lessons from the androgen insensitivity syndrome.Journal of Clinical Endocrinology and Metabolism.2000;85:1032–1037. [PubMed: 10720035]

262.

Danilovic DL, Correa PH, Costa EM, Melo KF, Mendonca BB, Arnhold IJ. Height and bone mineral density in androgen insensitivity syndrome with mutations in the androgen receptor gene.Osteoporosis International.2007;18:369–374. [PubMed: 17077943]

263.

Han TS, Goswami D, Trikudanathan S, Creighton SM, Conway GS. Comparison of bone mineral density and body proportions between women with complete androgen insensitivity syndrome and women with gonadal dysgenesis.European Journal of Endocrinology.2008;159:179–185. [PubMed: 18463105]

264.

Wisniewski AB, Migeon CJ, Meyer-Bahlburg HF, Gearhart JP, Berkovitz GD, Brown TR, Money J. Complete androgen insensitivity syndrome: long-term medical, surgical, and psychosexual outcome.Journal of Clinical Endocrinology and Metabolism.2000;85:2664–2669. [PubMed: 10946863]

265.

Hines M, Ahmed SF, Hughes IA. Psychological outcomes and gender-related development in complete androgen insensitivity syndrome.Archives of Sexual Behavior.2003;32:93–101. [PubMed: 12710824]

266.

Minto CL, Liao KL, Conway GS, Creighton SM. Sexual function in women with complete androgen insensitivity syndrome.Fertility and Sterility.2003;80:157–164. [PubMed: 12849818]

267.

Brinkmann L, Schuetzmann K, Richter-Appelt H. Gender assignment and medical history of individuals with different forms of intersexuality: evaluation of medical records and the patients' perspective.J Sex Med.2007;4:964–980. [PubMed: 17627743]

268.

Hughes IA, Werner R, Bunch T, Hiort O. Androgen insensitivity syndrome.Seminars in Reproductive Medicine.2012;30:432–442. [PubMed: 23044881]

269.

Ahmed SF, Cheng A, Dovey L, Hawkins JR, Martin H, Rowland J, Shimura N, Tait AD, Hughes IA. Phenotypic features, androgen receptor binding, and mutational analysis in 278 clinical cases reported as androgen insensitivity syndrome.Journal of Clinical Endocrinology and Metabolism.2000;85:658–665. [PubMed: 10690872]

270.

Deeb A, Mason C, Lee YS, Hughes IA. Correlation between genotype, phenotype and sex of rearing in 111 patients with partial androgen insensitivity syndrome.Clinical Endocrinology.2005;63:56–62. [PubMed: 15963062]

271.

Migeon CJ, Wisniewski AB, Gearhart JP, Meyer-Bahlburg HF, Rock JA, Brown TR, Casella SJ, Maret A, Ngai KM, Money J, Berkovitz GD. Ambiguous genitalia with perineoscrotal hypospadias in 46,XY individuals: long-term medical, surgical, and psychosexual outcome.Pediatrics.2002;110:e31. [PubMed: 12205281]

272.

Gottlieb B, Beitel LK, Wu JH, Trifiro M. The androgen receptor gene mutations database (ARDB): 2004 update.Human Mutation.2004;23:527–533. [PubMed: 15146455]

273.

Rodien P, Mebarki F, Mowszowicz I, Chaussain JL, Young J, Morel Y, Schaison G. Different phenotypes in a family with androgen insensitivity caused by the same M780I point mutation in the androgen receptor gene.Journal of Clinical Endocrinology and Metabolism.1996;81:2994–2998. [PubMed: 8768864]

274.

Boehmer AL, Brinkmann O, Bruggenwirth H, van Assendelft C, Otten BJ, Verleun-Mooijman MC, Niermeijer MF, Brunner HG, Rouwe CW, Waelkens JJ, Oostdijk W, Kleijer WJ, van der Kwast TH, de Vroede MA, Drop SL. Genotype versus phenotype in families with androgen insensitivity syndrome.Journal of Clinical Endocrinology and Metabolism.2001;86:4151–4160. [PubMed: 11549642]

275.

Kohler B, Lumbroso S, Leger J, Audran F, Grau ES, Kurtz F, Pinto G, Salerno M, Semitcheva T, Czernichow P, Sultan C. Androgen insensitivity syndrome: somatic mosaicism of the androgen receptor in seven families and consequences for sex assignment and genetic counseling.Journal of Clinical Endocrinology and Metabolism.2005;90:106–111. [PubMed: 15522944]

276.

Boehmer AL, Brinkmann AO, Nijman RM, Verleun-Mooijman MC, de Ruiter P, Niermeijer MF, Drop SL. Phenotypic variation in a family with partial androgen insensitivity syndrome explained by differences in 5alpha dihydrotestosterone availability.Journal of Clinical Endocrinology and Metabolism.2001;86:1240–1246. [PubMed: 11238515]

277.

MacLean HE, Favaloro JM, Warne GL, Zajac JD. Double-strand DNA break repair with replication slippage on two strands: a novel mechanism of deletion formation.Human Mutation.2006;27:483–489. [PubMed: 16619235]

278.

Rogowski W. Genetic screening by DNA technology: a systematic review of health economic evidence.International Journal of Technology Assessment in Health Care.2006;22:327–337. [PubMed: 16984061]

279.

Hiort O, Sinnecker GH, Holterhus PM, Nitsche EM, Kruse K. Inherited and de novo androgen receptor gene mutations: investigation of single-case families.Journal of Pediatrics.1998;132:939–943. [PubMed: 9627582]

280.

Yeh SH, Chiu CM, Chen CL, Lu SF, Hsu HC, Chen DS, Chen PJ. Somatic mutations at the trinucleotide repeats of androgen receptor gene in male hepatocellular carcinoma.International Journal of Cancer.2007;120:1610–1617. [PubMed: 17230529]

281.

Hiort O, Naber SP, Lehners A, Muletta-Feurer S, Sinnecker GH, Zollner A, Komminoth P. The role of androgen receptor gene mutations in male breast carcinoma.Journal of Clinical Endocrinology and Metabolism.1996;81:3404–3407. [PubMed: 8784104]

282.

Paul R, Breul J. Antiandrogen withdrawal syndrome associated with prostate cancer therapies: incidence and clinical significance.Drug Safety.2000;23:381–390. [PubMed: 11085345]

283.

Suzuki H, Okihara K, Miyake H, Fujisawa M, Miyoshi S, Matsumoto T, Fujii M, Takihana Y, Usui T, Matsuda T, Ozono S, Kumon H, Ichikawa T, Miki T. Alternative nonsteroidal antiandrogen therapy for advanced prostate cancer that relapsed after initial maximum androgen blockade.Journal of Urology.2008;180:921–927. [PubMed: 18635218]

284.

Hara T, Miyazaki J, Araki H, Yamaoka M, Kanzaki N, Kusaka M, Miyamoto M. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome.Cancer Research.2003;63:149–153. [PubMed: 12517791]

285.

Miyamoto H, Rahman MM, Chang C. Molecular basis for the antiandrogen withdrawal syndrome.Journal of Cellular Biochemistry.2004;91:3–12. [PubMed: 14689576]

286.

Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate.Cancer Research.1941;1:293–297.

287.

Labrie F, Cusan L, Gomez JL, Martel C, Berube R, Belanger P, Belanger A, Vandenput L, Mellstrom D, Ohlsson C. Comparable amounts of sex steroids are made outside the gonads in men and women: Strong lesson for hormone therapy of prostate and breast cancer.Journal of Steroid Biochemistry and Molecular Biology.2008

288.

Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, Barrett M, Parker C, Martins V, Folkerd E, Clark J, Cooper CS, Kaye SB, Dearnaley D, Lee G, de Bono JS. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven.Journal of Clinical Oncology.2008;26:4563–4571. [PubMed: 18645193]

289.

Anonymous Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate Cancer Trialists' Collaborative Group.Lancet.2000;355:1491–1498. [PubMed: 10801170]

290.

Pezaro CJ, Mukherji D, De Bono JS. Abiraterone acetate: redefining hormone treatment for advanced prostate cancer.Drug Discov Today.2012;17:221–226. [PubMed: 22198164]

291.

Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Flechon A, Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Selby B, Seely L, de Bono JS, Investigators A. Increased survival with enzalutamide in prostate cancer after chemotherapy.New England Journal of Medicine.2012;367:1187–1197. [PubMed: 22894553]

292.

Meikle AW. The interrelationships between thyroid dysfunction and hypogonadism in men and boys.Thyroid.2004;14 Suppl 1:S17–25. [PubMed: 15142373]

293.

Payne KL, Loidl NM, Lim CF, Topliss DJ, Stockigt JR, Barlow JW. Modulation of T3-induced sex hormone-binding globulin secretion by human hepatoblastoma cells.European Journal of Endocrinology.1997;137:415–420. [PubMed: 9368511]

294.

Isojarvi J. Disorders of reproduction in patients with epilepsy: antiepileptic drug related mechanisms.Seizure.2008;17:111–119. [PubMed: 18164216]

295.

Wheeler MJ, Toone BK, Dannatt A, Fenwick PB, Brown S. Metabolic clearance rate of testosterone in male epileptic patients on anti-convulsant therapy.Journal of Endocrinology.1991;129:465–468. [PubMed: 2066701]

296.

Death AK, McGrath KC, Handelsman DJ. Valproate is an anti-androgen and anti-progestin.Steroids.2005;70:946–953. [PubMed: 16165177]

297.

Green JRB, Goble HL, Edwards CRW, Dawson AM. Reversible insensitivity to androgens in men with untreated gluten enteropathy.Lancet i.1977:280–282.

298.

Farthing MJR, Rees LH, Edwards CRW, Dawson AM. Male gonadal dysfunction in coeliac disease: 2. Sex hormones.Gut.1983;24:127–135. [PMC free article: PMC1420172] [PubMed: 6682819]

299.

Frydman M, Kauschansky A, Bonne-Tamir B, Nassar F, Homburg R. Assessment of the hypothalamic-pituitary-testicular function in male patients with Wilson's disease.Journal of Andrology.1991;12:180–184. [PubMed: 1917681]

300.

Herrick AL, McColl KE, Wallace AM, Moore MR, Goldberg A. Elevation of hormone-binding globulins in acute intermittent porphyria.Clinica Chimica Acta.1990;187:141–148.

301.

Iturriaga H, Lioi X, Valladares L. Sex hormone-binding globulin in non-cirrhotic alcoholic patients during early withdrawal and after longer abstinence.Alcohol and Alcoholism.1999;34:903–909. [PubMed: 10659727]

302.

Handelsman DJ, Strasser S, McDonald JA, Conway AJ, McCaughan GW. Hypothalamic-pituitary testicular function in end-stage non-alcoholic liver disease before and after liver transplantation.Clinical Endocrinology.1995;43:331–337. [PubMed: 7586603]

303.

Hamilton JB, Mestler GE. Mortality and survival: comparison of eunuchs with intact men and women in a mentally retarded population.Journal of Gerontology.1969;24:395–411. [PubMed: 5362349]

304.

Nieschlag E, Nieschlag S, Behre HM. Lifespan and testosterone.Nature.1993;366:215. [PubMed: 8232579]

305.

Jenkins JS. The voice of the castrato.Lancet.1998;351:1877–1880. [PubMed: 9652686]

306.

Eyben FE, Graugaard C, Vaeth M. All-cause mortality and mortality of myocardial infarction for 989 legally castrated men.European Journal of Epidemiology.2005;20:863–869. [PubMed: 16283477]

307.

Min KJ, Lee CK, Park HN. The lifespan of Korean eunuchs.Current Biology.2012;22:R792–793. [PubMed: 23017989]

308.

Bojesen A, Juul S, Birkebaek N, Gravholt CH. Increased mortality in Klinefelter syndrome.Journal of Clinical Endocrinology and Metabolism.2004;89:3830–3834. [PubMed: 15292313]

309.

Liu PY, Death AK, Handelsman DJ. Androgens and cardiovascular disease.Endocrine Reviews.2003;24:313–340. [PubMed: 12788802]

310.

Liu PY, Handelsman DJ 2004 Androgen therapy in non-gonadal disease. In: Nieschlag E, Behre HM eds. Testosterone: Action, Deficiency and Substitution. 3rd ed. Berlin: Springer-Verlag; 445-495.

311.

Zuraw BL. Clinical practice. Hereditary angioedema.New England Journal of Medicine.2008;359:1027–1036. [PubMed: 18768946]

312.

Longhurst H, Cicardi M. Hereditary angio-oedema.Lancet.2012;379:474–481. [PubMed: 22305226]

313.

Handelsman DJ. Update in andrology.Journal of Clinical Endocrinology and Metabolism.2007;92:4505–4511. [PubMed: 18056776]

314.

Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study.Journal of Clinical Endocrinology and Metabolism.2003;88:622–626. [PubMed: 12574191]

315.

Kelleher S, Conway AJ, Handelsman DJ. Blood testosterone threshold for androgen deficiency symptoms.Journal of Clinical Endocrinology and Metabolism.2004;89:3813–3817. [PubMed: 15292310]

316.

Schaison G, Young J, Pholsena M, Nahoul K, Couzinet B. Failure of combined follicle-stimulating hormone-testosterone administration to initiate and/or maintain spermatogenesis in men with hypogonadotropic hypogonadism.Journal of Clinical Endocrinology and Metabolism.1993;77:1545–1549. [PubMed: 8263139]

317.

Pitteloud N, Hayes FJ, Dwyer A, Boepple PA, Lee H, Crowley WF Jr. Predictors of outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic hypogonadism.Journal of Clinical Endocrinology and Metabolism.2002;87:4128–4136. [PubMed: 12213860]

318.

Wang C, Tso SC, Todd D. Hypogonadotropic hypogonadism in severe beta-thalassemia: effect of chelation and pulsatile gonadotropin-releasing hormone therapy.Journal of Clinical Endocrinology and Metabolism.1989;68:511–516. [PubMed: 2493034]

319.

Liu PY, Baker HW, Jayadev V, Zacharin M, Conway AJ, Handelsman DJ. Induction of spermatogenesis and fertility during gonadotropin treatment of gonadotropin-deficient infertile men: predictors of fertility outcome.Journal of Clinical Endocrinology and Metabolism.2009;94:801–808. [PubMed: 19066302]

320.

Dwyer AA, Raivio T, Pitteloud N. Gonadotrophin replacement for induction of fertility in hypogonadal men.Best Practice and Research Clinical Endocrinology and Metabolism.2015;29:91–103. [PubMed: 25617175]

321.

Handelsman DJ, Goebel C, Idan A, Jimenez M, Trout G, Kazlauskas R. Effects of recombinant human LH and hCG on serum and urine LH and androgens in men.Clinical Endocrinology.2009;71:417–428. [PubMed: 19170708]

322.

Barrio R, de Luis D, Alonso M, Lamas A, Moreno JC. Induction of puberty with human chorionic gonadotropin and follicle-stimulating hormone in adolescent males with hypogonadotropic hypogonadism.Fertility and Sterility.1999;71:244–248. [PubMed: 9988392]

323.

Bouvattier C, Maione L, Bouligand J, Dode C, Guiochon-Mantel A, Young J. Neonatal gonadotropin therapy in male congenital hypogonadotropic hypogonadism.Nat Rev Endocrinol.2011;8:172–182. [PubMed: 22009162]

324.

Howard S, Dunkel L. Sex Steroid and Gonadotropin Treatment in Male Delayed Puberty.Endocrine Development.2016;29:185–197. [PubMed: 26680579]

325.

Belanger A, Candas B, Dupont A, Cusan L, Diamond P, Gomez JL, Labrie F. Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men.Journal of Clinical Endocrinology and Metabolism.1994;79:1086–1090. [PubMed: 7962278]

326.

Orwoll E, Lambert LC, Marshall LM, Phipps K, Blank J, Barrett-Connor E, Cauley J, Ensrud K, Cummings S. Testosterone and estradiol among older men.Journal of Clinical Endocrinology and Metabolism.2006;91:1336–1344. [PubMed: 16368750]

327.

Travison TG, Araujo AB, Kupelian V, O'Donnell AB, McKinlay JB. The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men.Journal of Clinical Endocrinology and Metabolism.2007;92:549–555. [PubMed: 17148559]

328.

Andersson AM, Jorgensen N, Frydelund-Larsen L, Rajpert-De Meyts E, Skakkebaek NE. Impaired Leydig cell function in infertile men: a study of 357 idiopathic infertile men and 318 proven fertile controls.Journal of Clinical Endocrinology and Metabolism.2004;89:3161–3167. [PubMed: 15240588]

329.

Howell SJ, Radford JA, Adams JE, Shalet SM. The impact of mild Leydig cell dysfunction following cytotoxic chemotherapy on bone mineral density (BMD) and body composition.Clinical Endocrinology.2000;52:609–616. [PubMed: 10792341]

330.

Howell SJ, Radford JA, Smets EM, Shalet SM. Fatigue, sexual function and mood following treatment for haematological malignancy: the impact of mild Leydig cell dysfunction.British Journal of Cancer.2000;82:789–793. [PMC free article: PMC2374403] [PubMed: 10732747]

331.

Gerl A, Muhlbayer D, Hansmann G, Mraz W, Hiddemann W. The impact of chemotherapy on Leydig cell function in long term survivors of germ cell tumors.Cancer.2001;91:1297–1303. [PubMed: 11283930]

332.

Somali M, Mpatakoias V, Avramides A, Sakellari I, Kaloyannidis P, Smias C, Anagnostopoulos A, Kourtis A, Rousso D, Panidis D, Vagenakis A. Function of the hypothalamic-pituitary-gonadal axis in long-term survivors of hematopoietic stem cell transplantation for hematological diseases.Gynecological Endocrinology.2005;21:18–26. [PubMed: 16048797]

333.

Howell SJ, Radford JA, Adams JE, Smets EM, Warburton R, Shalet SM. Randomized placebo-controlled trial of testosterone replacement in men with mild Leydig cell insufficiency following cytotoxic chemotherapy.Clinical Endocrinology.2001;55:315–324. [PubMed: 11589674]

334.

Merza Z, Blumsohn A, Mah PM, Meads DM, McKenna SP, Wylie K, Eastell R, Wu F, Ross RJ. Double-blind placebo-controlled study of testosterone patch therapy on bone turnover in men with borderline hypogonadism.International Journal of Andrology.2006;29:381–391. [PubMed: 16390499]

335.

Nieschlag E. Male hormonal contraception.Handb Exp Pharmacol.2010:197–223. [PubMed: 20839093]

336.

Handelsman DJ 2011 Androgen therapy in non-gonadal disease. In: Nieschlag E, Behre HM eds. Testosterone: Action, Deficiency and Substitution. 4th ed. Cambridge: Cambridge University Press; 372-407.

337.

Teruel JL, Aguilera A, Marcen R, Antolin JN, Otero GG, Ortuno J. Androgen therapy for anaemia of chronic renal failure.Scandanavian Journal of Urology and Nephrology.1996;30:403–408.

338.

Gascon A, Belvis JJ, Berisa F, Iglesias E, Estopinan V, Teruel JL. Nandrolone decanoate is a good alternative for the treatment of anemia in elderly male patients on hemodialysis.Geriatric Nephrology and Urology.1999;9:67–72. [PubMed: 10518249]

339.

Navarro JF, Mora C, Macia M, Garcia J. Randomized prospective comparison between erythropoietin and androgens in CAPD patients.Kidney International.2002;61:1537–1544. [PubMed: 11918762]

340.

Ishak KG, Zimmerman HJ. Hepatotoxic effects of the anabolic-androgenic steroids.Seminars in Liver Disease.1987;7:230–236. [PubMed: 3317860]

341.

Velazquez I, Alter BP. Androgens and liver tumors: Fanconi's anemia and non-Fanconi's conditions.American Journal of Hematology.2004;77:257–267. [PubMed: 15495253]

342.

Sloane DE, Lee CW, Sheffer AL. Hereditary angioedema: Safety of long-term stanozolol therapy.Journal of Allergy and Clinical Immunology.2007;120:654–658. [PubMed: 17765757]

343.

Banerji A, Sloane DE, Sheffer AL. Hereditary angioedema: a current state-of-the-art review, V: attenuated androgens for the treatment of hereditary angioedema.Annals of Allergy, Asthma, and Immunology.2008;100:S19–22.

344.

Bork K, Bygum A, Hardt J. Benefits and risks of danazol in hereditary angioedema: a long-term survey of 118 patients.Annals of Allergy, Asthma, and Immunology.2008;100:153–161.

345.

Sabharwal G, Craig T. Recombinant human C1 esterase inhibitor for the treatment of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE).Expert Rev Clin Immunol.2015;11:319–327. [PubMed: 25669442]

346.

Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, Bunnell TJ, Tricker R, Shirazi A, Casaburi R. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men.New England Journal of Medicine.1996;335:1–7. [PubMed: 8637535]

347.

Elashoff JD, Jacknow AD, Shain SG, Braunstein GD. Effects of anabolic-androgenic steroids on muscular strength.Annals of Internal Medicine.1991;115:387–393. [PubMed: 1830732]

348.

Storer TW, Magliano L, Woodhouse L, Lee ML, Dzekov C, Dzekov J, Casaburi R, Bhasin S. Testosterone dose-dependently increases maximal voluntary strength and leg power, but does not affect fatigability or specific tension.Journal of Clinical Endocrinology and Metabolism.2003;88:1478–1485. [PubMed: 12679426]

349.

Storer TW, Woodhouse L, Magliano L, Singh AB, Dzekov C, Dzekov J, Bhasin S. Changes in muscle mass, muscle strength, and power but not physical function are related to testosterone dose in healthy older men.Journal of the American Geriatrics Society.2008

350.

Bhasin S, Woodhouse L, Casaburi R, Singh AB, Mac RP, Lee M, Yarasheski KE, Sinha-Hikim I, Dzekov C, Dzekov J, Magliano L, Storer TW. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle.Journal of Clinical Endocrinology and Metabolism.2005;90:678–688. [PubMed: 15562020]

351.

Coviello AD, Lakshman K, Mazer NA, Bhasin S. Differences in the apparent metabolic clearance rate of testosterone in young and older men with gonadotropin suppression receiving graded doses of testosterone.Journal of Clinical Endocrinology and Metabolism.2006;91:4669–4675. [PubMed: 16912120]

352.

Coviello AD, Kaplan B, Lakshman KM, Chen T, Singh AB, Bhasin S. Effects of graded doses of testosterone on erythropoiesis in healthy young and older men.Journal of Clinical Endocrinology and Metabolism.2008;93:914–919. [PMC free article: PMC2266950] [PubMed: 18160461]

353.

Singh AB, Hsia S, Alaupovic P, Sinha-Hikim I, Woodhouse L, Buchanan TA, Shen R, Bross R, Berman N, Bhasin S. The effects of varying doses of T on insulin sensitivity, plasma lipids, apolipoproteins, and C-reactive protein in healthy young men.Journal of Clinical Endocrinology and Metabolism.2002;87:136–143. [PubMed: 11788637]

354.

Gray PB, Singh AB, Woodhouse LJ, Storer TW, Casaburi R, Dzekov J, Dzekov C, Sinha-Hikim I, Bhasin S. Dose-dependent effects of testosterone on sexual function, mood and visuospatial cognition in older men.Journal of Clinical Endocrinology and Metabolism.2005;90:3838–3846. [PubMed: 15827094]

355.

Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, Eder R, Tennstedt S, Ulloor J, Zhang A, Choong K, Lakshman KM, Mazer NA, Miciek R, Krasnoff J, Elmi A, Knapp PE, Brooks B, Appleman E, Aggarwal S, Bhasin G, Hede-Brierley L, Bhatia A, Collins L, LeBrasseur N, Fiore LD, Bhasin S. Adverse events associated with testosterone administration.The New England Journal of Medicine.2010;363:109–122. [PMC free article: PMC3440621] [PubMed: 20592293]

356.

Kotler DP, Tierney AR, Wang J, Pierson RN. Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS.American Journal of Clinical Nutrition.1989;50:444–447. [PubMed: 2773823]

357.

Moyle GJ, Schoelles K, Fahrbach K, Frame D, James K, Scheye R, Cure-Bolt N. Efficacy of selected treatments of HIV wasting: a systematic review and meta-analysis.Journal of Acquired Immune Deficiency Syndromes.2004;37 Suppl 5:S262–276. [PubMed: 15722869]

358.

Johns K, Beddall MJ, Corrin RC. Anabolic steroids for the treatment of weight loss in HIV-infected individuals.Cochrane Database Syst Rev.2005:CD005483. [PMC free article: PMC12174972] [PubMed: 16235407]

359.

Bolding G, Sherr L, Maguire M, Elford J. HIV risk behaviours among gay men who use anabolic steroids.Addiction.1999;94:1829–1835. [PubMed: 10717961]

360.

Lambert CP, Sullivan DH, Freeling SA, Lindquist DM, Evans WJ. Effects of testosterone replacement and/or resistance exercise on the composition of megestrol acetate stimulated weight gain in elderly men: a randomized controlled trial.Journal of Clinical Endocrinology and Metabolism.2002;87:2100–2106. [PubMed: 11994348]

361.

Mulligan K, Zackin R, Von Roenn JH, Chesney MA, Egorin MJ, Sattler FR, Benson CA, Liu T, Umbleja T, Shriver S, Auchus RJ, Schambelan M. Testosterone supplementation of megestrol therapy does not enhance lean tissue accrual in men with human immunodeficiency virus-associated weight loss: a randomized, double-blind, placebo-controlled, multicenter trial.Journal of Clinical Endocrinology and Metabolism.2007;92:563–570. [PubMed: 17090640]

362.

Vuong C, Van Uum SH, O'Dell LE, Lutfy K, Friedman TC. The effects of opioids and opioid analogs on animal and human endocrine systems.Endocrine Reviews.2010;31:98–132. [PMC free article: PMC2852206] [PubMed: 19903933]

363.

Bawor M, Bami H, Dennis BB, Plater C, Worster A, Varenbut M, Daiter J, Marsh DC, Steiner M, Anglin R, Coote M, Pare G, Thabane L, Samaan Z. Testosterone suppression in opioid users: a systematic review and meta-analysis.Drug and Alcohol Dependence.2015;149:1–9. [PubMed: 25702934]

364.

O'Rourke TK Jr, Wosnitzer MS. Opioid-Induced Androgen Deficiency (OPIAD): Diagnosis, Management, and Literature Review.Current Urology Reports.2016;17:76. [PubMed: 27586511]

365.

Daniell HW, Lentz R, Mazer NA. Open-label pilot study of testosterone patch therapy in men with opioid-induced androgen deficiency.J Pain.2006;7:200–210. [PubMed: 16516826]

366.

Basaria S, Travison TG, Alford D, Knapp PE, Teeter K, Cahalan C, Eder R, Lakshman K, Bachman E, Mensing G, Martel MO, Le D, Stroh H, Bhasin S, Wasan AD, Edwards RR. Effects of testosterone replacement in men with opioid-induced androgen deficiency: a randomized controlled trial.Pain.2015;156:280–288. [PMC free article: PMC6036339] [PubMed: 25599449]

367.

Huang G, Travison TG, Edwards RR, Basaria S. Effects of Testosterone Replacement on Pain Catastrophizing and Sleep Quality in Men with Opioid-Induced Androgen Deficiency.Pain Med.2016

368.

Wierman ME, Basson R, Davis SR, Khosla S, Miller KK, Rosner W, Santoro N. Androgen therapy in women: an Endocrine Society Clinical Practice guideline.Journal of Clinical Endocrinology and Metabolism.2006;91:3697–3710. [PubMed: 17018650]

369.

Arlt W, Callies F, van Vlijmen JC, Koehler I, Reincke M, Bidlingmaier M, Huebler D, Oettel M, Ernst M, Schulte HM, Allolio B. Dehydroepiandrosterone replacement in women with adrenal insufficiency.New England Journal of Medicine.1999;341:1013–1020. [PubMed: 10502590]

370.

Gurnell EM, Hunt PJ, Curran SE, Conway CL, Pullenayegum EM, Huppert FA, Compston JE, Herbert J, Chatterjee VK. Long-term DHEA replacement in primary adrenal insufficiency: a randomized, controlled trial.Journal of Clinical Endocrinology and Metabolism.2008;93:400–409. [PMC free article: PMC2729149] [PubMed: 18000094]

371.

Johannsson G, Burman P, Wiren L, Engstrom BE, Nilsson AG, Ottosson M, Jonsson B, Bengtsson BA, Karlsson FA. Low dose dehydroepiandrosterone affects behavior in hypopituitary androgen-deficient women: a placebo-controlled trial.Journal of Clinical Endocrinology and Metabolism.2002;87:2046–2052. [PubMed: 11994339]

372.

Lovas K, Gebre-Medhin G, Trovik TS, Fougner KJ, Uhlving S, Nedrebo BG, Myking OL, Kampe O, Husebye ES. Replacement of dehydroepiandrosterone in adrenal failure: no benefit for subjective health status and sexuality in a 9-month, randomized, parallel group clinical trial.Journal of Clinical Endocrinology and Metabolism.2003;88:1112–1118. [PubMed: 12629093]

373.

Miller KK, Biller BM, Beauregard C, Lipman JG, Jones J, Schoenfeld D, Sherman JC, Swearingen B, Loeffler J, Klibanski A. Effects of testosterone replacement in androgen-deficient women with hypopituitarism: a randomized, double-blind, placebo-controlled study.Journal of Clinical Endocrinology and Metabolism.2006;91:1683–1690. [PubMed: 16478814]

374.

Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP, Burki RE, Ginsburg ES, Rosen RC, Leiblum SR, Caramelli KE, Mazer NA. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy.New England Journal of Medicine.2000;343:682–688. [PubMed: 10974131]

375.

Davis S, Papalia MA, Norman RJ, O'Neill S, Redelman M, Williamson M, Stuckey BG, Wlodarczyk J, Gard'ner K, Humberstone A. Safety and efficacy of a testosterone metered-dose transdermal spray for treating decreased sexual satisfaction in premenopausal women: a randomized trial.Annals of Internal Medicine.2008;148:569–577. [PubMed: 18413618]

376.

Somboonporn W, Davis S, Seif MW, Bell R. Testosterone for peri- and postmenopausal women.Cochrane Database Syst Rev.2005:CD004509. [PubMed: 16235365]

377.

Greenblatt RB, Barfield WE, Garner JF, Calk GL, Harrod JP. Evaluation of an estrogen, androgen, estrogen-androgen combination, and a placebo in the treatment of the menopause.Journal of Clinical Endocrinology and Metabolism.1950;10:1547–1558. [PubMed: 14803543]

378.

Sherwin BB, Gelfand MM. The role of androgens in the maintenance of sexual functioning in oophorectomized women.Psychosomatic Medicine.1987;49:397–409. [PubMed: 3615768]

379.

Urman B, Pride SM, Yuen BH. Elevated serum testosterone, hirsutism, and virilism associated with combined androgen-estrogen hormone replacement therapy.Obstetrics and Gynecology.1991;77:1124–1131.

380.

Gerritsma EJ, Brocaar MP, Hakkesteegt MM, Birkenhager JC. Virilization of the voice in post-menopausal women due to the anabolic steroid nandrolone decanoate (Decadurabolin). The effects of medication for one year.Clin Otolaryngol Allied Sci.1994;19:79–84. [PubMed: 8174308]

381.

Baker J. A report on alterations to the speaking and singing voices of four women following hormonal therapy with virilizing agents.Journal of Voice.1999;13:496–507. [PubMed: 10622516]

382.

Davis SR, McCloud P, Strauss BJG, Burger H. Testosterone enhances estradiol's effects on postmenopausal bone density and sexuality.Maturitas.1995;21:227–236. [PubMed: 7616872]

383.

Elraiyah T, Sonbol MB, Wang Z, Khairalseed T, Asi N, Undavalli C, Nabhan M, Firwana B, Altayar O, Prokop L, Montori VM, Murad MH. Clinical review: The benefits and harms of systemic testosterone therapy in postmenopausal women with normal adrenal function: a systematic review and meta-analysis.Journal of Clinical Endocrinology and Metabolism.2014;99:3543–3550. [PMC free article: PMC5393495] [PubMed: 25279572]

384.

Davis SR, Wahlin-Jacobsen S. Testosterone in women--the clinical significance.Lancet Diabetes Endocrinol.2015;3:980–992. [PubMed: 26358173]

385.

Reed BG, Bou Nemer L, Carr BR. Has testosterone passed the test in premenopausal women with low libido? A systematic review.Int J Womens Health.2016;8:599–607. [PMC free article: PMC5066846] [PubMed: 27785108]

386.

Miller KK, Grieco KA, Klibanski A. Testosterone administration in women with anorexia nervosa.Journal of Clinical Endocrinology and Metabolism.2005;90:1428–1433. [PubMed: 15613421]

387.

Choi HH, Gray PB, Storer TW, Calof OM, Woodhouse L, Singh AB, Padero C, Mac RP, Sinha-Hikim I, Shen R, Dzekov J, Dzekov C, Kushnir MM, Rockwood AL, Meikle AW, Lee ML, Hays RD, Bhasin S. Effects of testosterone replacement in human immunodeficiency virus-infected women with weight loss.Journal of Clinical Endocrinology and Metabolism.2005;90:1531–1541. [PubMed: 15613414]

388.

Gordon C, Wallace DJ, Shinada S, Kalunian KC, Forbess L, Braunstein GD, Weisman MH. Testosterone patches in the management of patients with mild/moderate systemic lupus erythematosus.Rheumatology.2008;47:334–338. [PubMed: 18238794]

389.

Ferreira IM, Verreschi IT, Nery LE, Goldstein RS, Zamel N, Brooks D, Jardim JR. The influence of 6 months of oral anabolic steroids on body mass and respiratory muscles in undernourished COPD patients.Chest.1998;114:19–28. [PubMed: 9674442]

390.

Casaburi R, Bhasin S, Cosentino L, Porszasz J, Somfay A, Lewis MI, Fournier M, Storer TW. Effects of testosterone and resistance training in men with chronic obstructive pulmonary disease.American Journal of Respiratory and Critical Care Medicine.2004;170:870–878. [PubMed: 15271690]

391.

Svartberg J, Aasebo U, Hjalmarsen A, Sundsfjord J, Jorde R. Testosterone treatment improves body composition and sexual function in men with COPD, in a 6-month randomized controlled trial.Respiratory Medicine.2004;98:906–913. [PubMed: 15338805]

392.

Weisberg J, Wanger J, Olson J, Streit B, Fogarty C, Martin T, Casaburi R. Megestrol acetate stimulates weight gain and ventilation in underweight COPD patients.Chest.2002;121:1070–1078. [PubMed: 11948034]

393.

Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M, Anker SD, Banasiak W, Poole-Wilson PA, Ponikowski P. Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival.Circulation.2006;114:1829–1837. [PubMed: 17030678]

394.

Malkin CJ, Pugh PJ, West JN, van Beek EJ, Jones TH, Channer KS. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial.European Heart Journal.2006;27:57–64. [PubMed: 16093267]

395.

Handelsman DJ, Dong Q 1992 Ontogenic regression: a model of stress and reproduction. In: Sheppard K, Boublik JH, Funder JW eds. Stress and Reproduction. New York: Raven Press; 333-345.

396.

Reid IR, Wattie DJ, Evans MC, Stapleton JP. Testosterone therapy in glucocorticoid-treated men.Archives of Internal Medicine.1996;156:1173–1177. [PubMed: 8639011]

397.

Crawford BA, Liu PY, Kean M, Bleasel J, Handelsman DJ. Randomised, placebo-controlled trial of androgen effects on bone and muscle in men requiring long-term systemic glucocorticoid therapy.Journal of Clinical Endocrinology and Metabolism.2003;88:3167–3176. [PubMed: 12843161]

398.

Jeschke MG, Finnerty CC, Suman OE, Kulp G, Mlcak RP, Herndon DN. The effect of oxandrolone on the endocrinologic, inflammatory, and hypermetabolic responses during the acute phase postburn.Annals of Surgery.2007;246:351–360. [PMC free article: PMC1959346] [PubMed: 17717439]

399.

Bulger EM, Jurkovich GJ, Farver CL, Klotz P, Maier RV. Oxandrolone does not improve outcome of ventilator dependent surgical patients.Annals of Surgery.2004;240:472–478. [PMC free article: PMC1356437] [PubMed: 15319718]

400.

Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging.Journal of Clinical Endocrinology and Metabolism.2001;86:724–731. [PubMed: 11158037]

401.

Travison TG, Shackelton R, Araujo AB, Hall SA, Williams RE, Clark RV, O'Donnell AB, McKinlay JB. The natural history of symptomatic androgen deficiency in men: onset, progression, and spontaneous remission.Journal of the American Geriatrics Society.2008;56:831–839. [PMC free article: PMC5556701] [PubMed: 18454749]

402.

Deslypere JP, Vermeulen A. Aging and tissue androgens.Journal of Clinical Endocrinology and Metabolism.1981;53:430–434. [PubMed: 7251820]

403.

Deslypere JP, Vermeulen A. Influence of age on steroid concentration in skin and striated muscle in women and in cardiac muscle and lung tissue in men.Journal of Clinical Endocrinology and Metabolism.1985;60:648–653.

404.

Mohr BA, Guay AT, O'Donnell AB, McKinlay JB. Normal, bound and nonbound testosterone levels in normally ageing men: results from the Massachusetts Male Ageing Study.Clinical Endocrinology.2005;62:64–73. [PubMed: 15638872]

405.

Corona G, Monami M, Rastrelli G, Aversa A, Tishova Y, Saad F, Lenzi A, Forti G, Mannucci E, Maggi M. Testosterone and metabolic syndrome: a meta-analysis study.J Sex Med.2011;8:272–283. [PubMed: 20807333]

406.

Brand JS, van der Tweel I, Grobbee DE, Emmelot-Vonk MH, van der Schouw YT. Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies.International Journal of Epidemiology.2011;40:189–207. [PubMed: 20870782]

407.

Ruige JB, Mahmoud AM, De Bacquer D, Kaufman JM. Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis.Heart.2011;97:870–875. [PubMed: 21177660]

408.

Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA. Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis.Journal of Clinical Endocrinology and Metabolism.2011;96:3007–3019. [PMC free article: PMC3200249] [PubMed: 21816776]

409.

Toma M, McAlister FA, Coglianese EE, Vidi V, Vasaiwala S, Bakal JA, Armstrong PW, Ezekowitz JA. Testosterone supplementation in heart failure: a meta-analysis.Circ Heart Fail.2012;5:315–321. [PubMed: 22511747]

410.

Borst SE, Shuster JJ, Zou B, Ye F, Jia H, Wokhlu A, Yarrow JF. Cardiovascular risks and elevation of serum DHT vary by route of testosterone administration: a systematic review and meta-analysis.BMC Med.2014;12:211. [PMC free article: PMC4245724] [PubMed: 25428524]

411.

Onasanya O, Iyer G, Lucas E, Lin D, Singh S, Alexander GC. Association between exogenous testosterone and cardiovascular events: an overview of systematic reviews.Lancet Diabetes Endocrinol.2016

412.

Alexander GC, Iyer G, Lucas E, Lin D, Singh S. Cardiovascular Risks of Exogenous Testosterone Use Among Men: A Systematic Review and Meta-Analysis.American Journal of Medicine.2016

413.

Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels.Journal of Clinical Endocrinology and Metabolism.2012;97:2050–2058. [PubMed: 22496507]

414.

Wu FC. Caveat emptor: does testosterone treatment reduce mortality in men?Journal of Clinical Endocrinology and Metabolism.2012;97:1884–1886. [PubMed: 22675063]

415.

Gruenewald DA, Matsumoto AM. Testosterone supplementation therapy for older men: potential benefits and risks.Journal of the American Geriatrics Society.2003;51:101–115. [PubMed: 12534854]

416.

Ly LP, Jimenez M, Zhuang TN, Celermajer DS, Conway AJ, Handelsman DJ. A double-blind, placebo-controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility, and quality of life in older men with partial androgen deficiency.Journal of Clinical Endocrinology and Metabolism.2001;86:4078–4088. [PubMed: 11549629]

417.

Kunelius P, Lukkarinen O, Hannuksela ML, Itkonen O, Tapanainen JS. The effects of transdermal dihydrotestosterone in the aging male: a prospective, randomized, double blind study.Journal of Clinical Endocrinology and Metabolism.2002;87:1467–1472. [PubMed: 11932266]

418.

Liu PY, Wishart SM, Handelsman DJ. A double-blind, placebo-controlled, randomized clinical trial of recombinant human chorionic gonadotropin on muscle strength and physical function and activity in older men with partial age-related androgen deficiency.Journal of Clinical Endocrinology and Metabolism.2002;87:3125–3135. [PubMed: 12107212]

419.

Bhasin S, Calof OM, Storer TW, Lee ML, Mazer NA, Jasuja R, Montori VM, Gao W, Dalton JT. Drug insight: Testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging.Nat Clin Pract Endocrinol Metab.2006;2:146–159. [PMC free article: PMC2072878] [PubMed: 16932274]

420.

Isidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, Lenzi A, Fabbri A. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis.Clinical Endocrinology.2005;63:280–293. [PubMed: 16117815]

421.

Tracz MJ, Sideras K, Bolona ER, Haddad RM, Kennedy CC, Uraga MV, Caples SM, Erwin PJ, Montori VM. Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials.Journal of Clinical Endocrinology and Metabolism.2006;91:2011–2016. [PubMed: 16720668]

422.

Ottenbacher KJ, Ottenbacher ME, Ottenbacher AJ, Acha AA, Ostir GV. Androgen treatment and muscle strength in elderly men: A meta-analysis.Journal of the American Geriatrics Society.2006;54:1666–1673. [PMC free article: PMC1752197] [PubMed: 17087692]

423.

Isidori AM, Giannetta E, Gianfrilli D, Greco EA, Bonifacio V, Aversa A, Isidori A, Fabbri A, Lenzi A. Effects of testosterone on sexual function in men: results of a meta-analysis.Clinical Endocrinology.2005;63:381–394. [PubMed: 16181230]

424.

Bolona ER, Uraga MV, Haddad RM, Tracz MJ, Sideras K, Kennedy CC, Caples SM, Erwin PJ, Montori VM. Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials.Mayo Clinic Proceedings.2007;82:20–28. [PubMed: 17285782]

425.

Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, Tenover JL, Bhasin S. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials.Journals of Gerontology Series A, Biological Sciences and Medical Sciences.2005;60:1451–1457. [PubMed: 16339333]

426.

Liverman CT, Blazer DG eds. 2004 Testosterone and Aging: Clinical Research Directions. Washington, DC: Institute of Medicine: The National Academies Press.

427.

Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, Gill TM, Barrett-Connor E, Swerdloff RS, Wang C, Ensrud KE, Lewis CE, Farrar JT, Cella D, Rosen RC, Pahor M, Crandall JP, Molitch ME, Cifelli D, Dougar D, Fluharty L, Resnick SM, Storer TW, Anton S, Basaria S, Diem SJ, Hou X, Mohler ER 3rd, Parsons JK, Wenger NK, Zeldow B, Landis JR, Ellenberg SS, Testosterone Trials I. Effects of Testosterone Treatment in Older Men.New England Journal of Medicine.2016;374:611–624. [PMC free article: PMC5209754] [PubMed: 26886521]

428.

Orwoll ES. Establishing a Framework--Does Testosterone Supplementation Help Older Men?New England Journal of Medicine.2016;374:682–683. [PubMed: 26886526]

429.

Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.Jama.2002;288:321–333. [PubMed: 12117397]

430.

Kalin MF, Zumoff B. Sex hormones and coronary disease: a review of the clinical studies.Steroids.1990;55:330–352. [PubMed: 2237942]

431.

Zhang Y, Ouyang P, Post WS, Dalal D, Vaidya D, Blasco-Colmenares E, Soliman EZ, Tomaselli GF, Guallar E. Sex-steroid hormones and electrocardiographic QT-interval duration: findings from the third National Health and Nutrition Examination Survey and the Multi-Ethnic Study of Atherosclerosis.American Journal of Epidemiology.2011;174:403–411. [PMC free article: PMC3202165] [PubMed: 21768401]

432.

Carnes CA, Dech SJ. Effects of dihydrotestosterone on cardiac inward rectifier K(+) current.International Journal of Andrology.2002;25:210–214. [PubMed: 12121570]

433.

Liu XK, Katchman A, Whitfield BH, Wan G, Janowski EM, Woosley RL, Ebert SN. In vivo androgen treatment shortens the QT interval and increases the densities of inward and delayed rectifier potassium currents in orchiectomized male rabbits.Cardiovascular Research.2003;57:28–36. [PubMed: 12504811]

434.

Fulop L, Banyasz T, Szabo G, Toth IB, Biro T, Lorincz I, Balogh A, Peto K, Miko I, Nanasi PP. Effects of sex hormones on ECG parameters and expression of cardiac ion channels in dogs.Acta Physiol (Oxf).2006;188:163–171. [PubMed: 17054656]

435.

Ridley JM, Shuba YM, James AF, Hancox JC. Modulation by testosterone of an endogenous hERG potassium channel current.Journal of Physiology and Pharmacology.2008;59:395–407. [PubMed: 18953086]

436.

Wu ZY, Chen K, Haendler B, McDonald TV, Bian JS. Stimulation of N-terminal truncated isoform of androgen receptor stabilizes human ether-a-go-go-related gene-encoded potassium channel protein via activation of extracellular signal regulated kinase 1/2.Endocrinology.2008;149:5061–5069. [PMC free article: PMC5398425] [PubMed: 18599551]

437.

Charbit B, Christin-Maitre S, Demolis JL, Soustre E, Young J, Funck-Brentano C. Effects of testosterone on ventricular repolarization in hypogonadic men.American Journal of Cardiology.2009;103:887–890. [PubMed: 19268751]

438.

Pecori Giraldi F, Toja PM, Filippini B, Michailidis J, Scacchi M, Stramba Badiale M, Cavagnini F. Increased prevalence of prolonged QT interval in males with primary or secondary hypogonadism: a pilot study.International Journal of Andrology.2010;33:e132–138. [PubMed: 19747201]

439.

van Noord C, Rodenburg EM, Stricker BH. Invited commentary: sex-steroid hormones and QT-interval duration.American Journal of Epidemiology.2011;174:412–415. [PubMed: 21768402]

440.

Sieveking DP, Lim P, Chow RW, Dunn LL, Bao S, McGrath KC, Heather AK, Handelsman DJ, Celermajer DS, Ng MK. A sex-specific role for androgens in angiogenesis.Journal of Experimental Medicine.2010;207:345–352. [PMC free article: PMC2822613] [PubMed: 20071503]

441.

Lecce L, Lam YT, Lindsay LA, Yuen SC, Simpson PJ, Handelsman DJ, Ng MK. Aging impairs VEGF-mediated, androgen-dependent regulation of angiogenesis.Molecular Endocrinology.2014;28:1487–1501. [PMC free article: PMC4154238] [PubMed: 25058601]

442.

Wu FC, von Eckardstein A. Androgens and coronary artery disease.Endocrine Reviews.2003;24:183–217. [PubMed: 12700179]

443.

Khaw KT, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, Welch A, Day N. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study.Circulation.2007;116:2694–2701. [PubMed: 18040028]

444.

Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men.Journal of Clinical Endocrinology and Metabolism.2008;93:68–75. [PMC free article: PMC2190742] [PubMed: 17911176]

445.

Smith GD, Ben-Shlomo Y, Beswick A, Yarnell J, Lightman S, Elwood P. Cortisol, testosterone, and coronary heart disease: prospective evidence from the Caerphilly study.Circulation.2005;112:332–340. [PubMed: 16009799]

446.

Araujo AB, Kupelian V, Page ST, Handelsman DJ, Bremner WJ, McKinlay JB. Sex steroids and all-cause and cause-specific mortality in men.Archives of Internal Medicine.2007;167:1252–1260. [PubMed: 17592098]

447.

Maggio M, Lauretani F, Ceda GP, Bandinelli S, Ling SM, Metter EJ, Artoni A, Carassale L, Cazzato A, Ceresini G, Guralnik JM, Basaria S, Valenti G, Ferrucci L. Relationship between low levels of anabolic hormones and 6-year mortality in older men: the aging in the Chianti Area (InCHIANTI) study.Archives of Internal Medicine.2007;167:2249–2254. [PMC free article: PMC2646096] [PubMed: 17998499]

448.

Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials.BMC Med.2013;11:108. [PMC free article: PMC3648456] [PubMed: 23597181]

449.

Handelsman DJ. An old emperor finds new clothing: rejuvenation in our time.Asian Journal of Andrology.2011;13:125–129. [PMC free article: PMC3739386] [PubMed: 21102475]

450.

Haring R, Teumer A, Volker U, Dorr M, Nauck M, Biffar R, Volzke H, Baumeister SE, Wallaschofski H. Mendelian randomization suggests non-causal associations of testosterone with cardiometabolic risk factors and mortality.Andrology.2013;1:17–23.

451.

Zhao J, Jiang C, Lam TH, Liu B, Cheng KK, Xu L, Au Yeung SL, Zhang W, Leung GM, Schooling CM. Genetically predicted testosterone and cardiovascular risk factors in men: a Mendelian randomization analysis in the Guangzhou Biobank Cohort Study.International Journal of Epidemiology.2014;43:140–148. [PubMed: 24302542]

452.

Gong J, Zubair N. Commentary: Mendelian randomization, testosterone, and cardiovascular disease.International Journal of Epidemiology.2015;44:621–622. [PubMed: 25652575]

453.

Swerdlow AJ, Higgins CD, Schoemaker MJ, Wright AF, Jacobs PA. Mortality in patients with Klinefelter syndrome in Britain: a cohort study.Journal of Clinical Endocrinology and Metabolism.2005;90:6516–6522. [PubMed: 16204366]

454.

Roddam AW, Allen NE, Appleby P, Key TJ. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies.Journal of the National Cancer Institute.2008;100:170–183. [PMC free article: PMC6126902] [PubMed: 18230794]

455.

Boyle P, Koechlin A, Bota M, d'Onofrio A, Zaridze DG, Perrin P, Fitzpatrick J, Burnett AL, Boniol M. Endogenous and exogenous testosterone and the risk of prostate cancer and increased prostate specific antigen (PSA): a meta-analysis.BJU International.2016

456.

Millar AC, Lau AN, Tomlinson G, Kraguljac A, Simel DL, Detsky AS, Lipscombe LL. Predicting low testosterone in aging men: a systematic review.Cmaj.2016;188:E321–330. [PMC free article: PMC5026531] [PubMed: 27325129]

457.

Huo S, Scialli AR, McGarvey S, Hill E, Tugertimur B, Hogenmiller A, Hirsch AI, Fugh-Berman A. Treatment of Men for "Low Testosterone": A Systematic Review.PLoS One.2016;11:e0162480. [PMC free article: PMC5031462] [PubMed: 27655114]

458.

Conway AJ, Handelsman DJ, Lording DW, Stuckey B, Zajac JD. Use, misuse and abuse of androgens: The Endocrine Society of Australia consensus guidelines for androgen prescribing.Medical Journal of Australia.2000;172:220–224. [PubMed: 10776394]

459.

Petak SM, Nankin HR, Spark RF, Swerdloff RS, Rodriguez-Rigau LJ. American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients--2002 update.Endocr Pract.2002;8:440–456. American Association of Clinical E. [PubMed: 15260010]

460.

Nieschlag E, Swerdloff R, Behre HM, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morley JE, Schulman C, Wang C, Weidner W, Wu FC. Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAU recommendations.International Journal of Andrology.2005;28:125–127. [PubMed: 15910536]

461.

Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline.Journal of Clinical Endocrinology and Metabolism.2006;91:1995–2010. [PubMed: 16720669]

462.

Handelsman DJ. Pharmacoepidemiology of testosterone prescribing in Australia, 1992-2010.Medical Journal of Australia.2012;196:642–645. [PubMed: 22676880]

463.

Gan EH, Pattman S. A UK epidemic of testosterone prescribing, 2001-2010.Clinical Endocrinology.2013;79:564–570. S HSP, Quinton R. [PubMed: 23480258]

464.

Nigro N, Christ-Crain M. Testosterone treatment in the aging male: myth or reality?Swiss Medical Weekly.2012;142:w13539. [PubMed: 22430839]

465.

Bhasin S, Singh AB, Mac RP, Carter B, Lee MI, Cunningham GR. Managing the risks of prostate disease during testosterone replacement therapy in older men: recommendations for a standardized monitoring plan.Journal of Andrology.2003;24:299–311. [PubMed: 12721204]

466.

Tan RS, Salazar JA. Risks of testosterone replacement therapy in ageing men.Expert Opin Drug Saf.2004;3:599–606. [PubMed: 15500418]

467.

Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011.JAMA Intern Med.2013;173:1465–1466. [PMC free article: PMC4100547] [PubMed: 23939517]

468.

Handelsman DJ. Global trends in testosterone prescribing, 2000-2011: expanding the spectrum of prescription drug misuse.Medical Journal of Australia.2013;199:548–551. [PubMed: 24138381]

469.

Yeap BB, Grossmann M, McLachlan RI, Handelsman DJ, Wittert GA, Conway AJ, Stuckey BG, Lording DW, Allan CA, Zajac JD, Burger HG. Endocrine Society of Australia position statement on male hypogonadism (part 1): assessment and indications for testosterone therapy.Medical Journal of Australia.2016;205:173–178. [PubMed: 27510348]

470.

Yeap BB, Grossmann M, McLachlan RI, Handelsman DJ, Wittert GA, Conway AJ, Stuckey BG, Lording DW, Allan CA, Zajac JD, Burger HG. Endocrine Society of Australia position statement on male hypogonadism (part 2): treatment and therapeutic considerations.Medical Journal of Australia.2016;205:228–231. [PubMed: 27581270]

471.

Vandekerckhove P, Lilford R, Vail A, Hughes E. Androgens versus placebo or no treatment for idiopathic oligo/asthenospermia.Cochrane Database Syst Rev.2000:CD000150. [PMC free article: PMC10865963] [PubMed: 10796496]

472.

Gabrielsen JS, Najari BB, Alukal JP, Eisenberg ML. Trends in Testosterone Prescription and Public Health Concerns.Urologic Clinics of North America.2016;43:261–271. [PubMed: 27132584]

473.

Handelsman DJ. Trends and regional differences in testosterone prescribing in Australia, 1991-2001.Medical Journal of Australia.2004;181:419–422. [PubMed: 15487956]

474.

Layton JB, Li D, Meier CR, Sharpless J, Sturmer T, Jick SS, Brookhart MA. Testosterone Lab Testing and Initiation in the United Kingdom and the United States, 2000-2011.Journal of Clinical Endocrinology and Metabolism.2014:jc20133570.

475.

Rao PK, Boulet SL, Mehta A, Hotaling J, Eisenberg ML, Honig SC, Warner L, Kissin DM, Nangia AK, Ross LS (2016) Trends in Testosterone Replacement Therapy Use Among Reproductive-Age US Men, 2003-2013. Journal of Urology.

476.

Jasuja GK, Bhasin S, Reisman JI, Berlowitz DR, Rose AJ. Ascertainment of Testosterone Prescribing Practices in the VA.Medical Care.2015;53:746–752. [PubMed: 26196850]

477.

Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.Journal of Clinical Endocrinology and Metabolism.2010;95:2536–2559. [PubMed: 20525905]

478.

Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morales A, Morley JE, Schulman C, Thompson IM, Weidner W, Wu FC. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations.Journal of Andrology.2009;30:1–9. [PubMed: 18772485]

479.

Handelsman DJ 2010 Androgen Physiology, Pharmacology and Abuse. In: DeGroot LJ, Jameson JL eds. Endocrinology. 6th ed. Philadelphia: Elsevier Saunders; 2469-2498.

480.

Herlihy AS, Halliday JL, Cock ML, McLachlan RI. The prevalence and diagnosis rates of Klinefelter syndrome: an Australian comparison.Medical Journal of Australia.2011;194:24–28. [PubMed: 21449864]

481.

Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study.International Journal of Clinical Practice.2006;60:762–769. [PMC free article: PMC1569444] [PubMed: 16846397]

482.

Araujo AB, O'Donnell AB, Brambilla DJ, Simpson WB, Longcope C, Matsumoto AM, McKinlay JB. Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study.Journal of Clinical Endocrinology and Metabolism.2004;89:5920–5926. [PubMed: 15579737]

483.

Haring R, Ittermann T, Volzke H, Krebs A, Zygmunt M, Felix SB, Grabe HJ, Nauck M, Wallaschofski H. Prevalence, incidence and risk factors of testosterone deficiency in a population-based cohort of men: results from the study of health in Pomerania.Aging Male.2010;13:247–257. [PubMed: 20504090]

484.

Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, O'Neill TW, Bartfai G, Casanueva FF, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Boonen S, Vanderschueren D, Labrie F, Huhtaniemi IT. Identification of late-onset hypogonadism in middle-aged and elderly men.New England Journal of Medicine.2010;363:123–135. [PubMed: 20554979]

485.

Hoberman JM, Yesalis CE. The history of synthetic testosterone.Scientific American.1995;272:76–81.

486.

Franke WW, Berendonk B. Hormonal doping and androgenization of athletes: a secret program of the German Democratic Republic government.Clinical Chemistry.1997;43:1262–1279. [PubMed: 9216474]

487.

Bhasin S, Woodhouse L, Casaburi R, Singh AB, Bhasin D, Berman N, Chen X, Yarasheski KE, Magliano L, Dzekov C, Dzekov J, Bross R, Phillips J, Sinha-Hikim I, Shen R, Storer TW. Testosterone dose-response relationships in healthy young men.Am J Physiol Endocrinol Metab.2001;281:E1172–1181. [PubMed: 11701431]

488.

Pope HG Jr, Kouri EM, Hudson JI. Effects of supraphysiologic doses of testosterone on mood and aggression in normal men: a randomized controlled trial.Archives of General Psychiatry.2000;57:133–140. [PubMed: 10665615]

489.

Kanayama G, Hudson JI, Pope HG Jr. Long-term psychiatric and medical consequences of anabolic-androgenic steroid abuse: A looming public health concern?Drug and Alcohol Dependence.2008;98:1–12. [PMC free article: PMC2646607] [PubMed: 18599224]

490.

Sagoe D, Molde H, Andreassen CS, Torsheim T, Pallesen S. The global epidemiology of anabolic-androgenic steroid use: a meta-analysis and meta-regression analysis.Annals of Epidemiology.2014;24:383–398. [PubMed: 24582699]

491.

Buckley WE, Yesalis CE, Freidl KE, Anderson WA, Streit AL, Wright JE. Estimated prevalence of anabolic steroid use among male high school students.Journal of the American Medical Association.1988;260:3441–3445. [PubMed: 3210283]

492.

Nilsson S. Androgenic anabolic steroid use among male adolescents in Falkenberg.Europen Journal of Clinical Pharmacology.1995;48:9–11.

493.

Handelsman DJ, Gupta L. Prevalence and risk factors for anabolic-androgenic steroid abuse in Australian secondary school students.International Journal of Andrology.1997;20:159–164. [PubMed: 9354185]

494.

Lambert MI, Titlestad SD, Schwellnus MP. Prevalence of androgenic-anabolic steroid use in adolescents in two regions of South Africa.South African Medical Journal.1998;88:876–880. [PubMed: 9698716]

495.

Ferenchick GS. Validity of self-report in identifying anabolic steroid use among weightlifters.Journal of General Internal Medicine.1996;11:554–556. [PubMed: 8905508]

496.

Pope HG, Kouri EM, Powell KF, Campbell C, Katz DL. Anabolic-androgenic steroid use among 133 prisoners.Comprehensive Psychiatry.1996;37:322–327. [PubMed: 8879906]

497.

Isacsson G, Garle M, Ljung EB, Asgard U, Bergmen U. Anabolic steroids and violent crime - an epidemiological study at a jail in Stockholm, Sweden.Comprehensive Psychiatry.1998;39:203–205. [PubMed: 9675504]

498.

Catlin DH, Ahrens BD, Kucherova Y. Detection of norbolethone, an anabolic steroid never marketed, in athletes' urine.Rapid Communication in Mass Spectrometry.2002;16:1273–1275.

499.

Death AK, McGrath KC, Kazlauskas R, Handelsman DJ. Tetrahydrogestrinone is a potent androgen and progestin.Journal of Clinical Endocrinology and Metabolism.2004;89:2498–2500. [PubMed: 15126583]

500.

Catlin DH, Sekera MH, Ahrens BD, Starcevic B, Chang YC, Hatton CK. Tetrahydrogestrinone: discovery, synthesis, and detection.Rapid Communication in Mass Spectrometry.2004;18:1245–1249.

501.

Sekera MH, Ahrens BD, Chang YC, Starcevic B, Georgakopoulos C, Catlin DH. Another designer steroid: discovery, synthesis, and detection of 'madol' in urine.Rapid Communication in Mass Spectrometry.2005;19:781–784.

502.

Handelsman DJ, Heather A. Androgen abuse in sports.Asian Journal of Andrology.2008;10:403–415. [PubMed: 18385902]

503.

vandenBerg P, Neumark-Sztainer D, Cafri G, Wall M (2007) Steroid use among adolescents: longitudinal findings from Project EAT. Pediatrics 119:476-486.

504.

McCabe SE, Brower KJ, West BT, Nelson TF, Wechsler H. Trends in non-medical use of anabolic steroids by U.S. college students: results from four national surveys.Drug and Alcohol Dependence.2007;90:243–251. [PMC free article: PMC2383927] [PubMed: 17512138]

505.

Holma PK. Effects of an anabolic steroid (metandienone) on spermatogenesis.Contraception.1977;15:151–162. [PubMed: 837689]

506.

Knuth UA, Maniera H, Nieschlag E. Anabolic steroids and semen parameters in bodybuilders.Fertility and Sterility.1989;52:1041–1047. [PubMed: 2512180]

507.

Turek PJ, Williams RH, Gilbaugh JH, Lipshultz LI. The reversibility of anabolic steroid-induced azoospermia.Journal of Urology.1995;153:1628–1630. [PubMed: 7714991]

508.

Sorensen M, Ingerslev HJ. Azoospermia in two bodybuilders taking anabolic steroids.Ugeskrift for Laeger.1995;157:1044–1045. [PubMed: 7879307]

509.

Gazvani MR, Buckett W, Luckas MJ, Aird IA, Hipkin LJ, Lewis-Jones DI. Conservative management of azoospermia following steroid abuse.Human Reproduction.1997;12:1706–1708. [PubMed: 9308797]

510.

Reyes RJ, Zicchi S, Hamed H, Chaudary MA, Fentiman IS. Surgical correction of gynaecomastia in bodybuilders.British Journal of Clinical Practice.1995;49:177–179. [PubMed: 7547155]

511.

Friedl KE. Reappraisal of health risks associated with use of high doses of oral and injectable androgenic steroids.NIDA Research Monograph.1990;102:142–177. [PubMed: 1964199]

512.

Sklarek HM, Mantovani RP, Erens E, Heisler D, Niederman MS, Fein AM. AIDS in a bodybuilder using anabolic steroids.New England Journal of Medicine.1984;311:1701. [letter]

513.

Nemechek PM. Anabolic steroid users--another potential risk group for HIV infection.New England Journal of Medicine.1991;325:357. [letter]

514.

Henrion R, Mandelbrot L, Delfieu D. HIV contamination after injections of anabolic steroids.Presse Medicale.1992;21:218. (letter)

515.

Rich JD, Dickinson BP, Merriman NA, Flanigan TP. Hepatitis C virus infection related to anabolic-androgenic steroid injection in a recreational weight lifter.American Journal of Gastroenterology.1998;93:1598. [letter]

516.

Aitken C, Delalande C, Stanton K. Pumping iron, risking infection? Exposure to hepatitis C, hepatitis B and HIV among anabolic-androgenic steroid injectors in Victoria, Australia.Drug and Alcohol Dependence.2002;65:303–308. [PubMed: 11841901]

517.

Rich JD, Dickinson BP, Feller A, Pugatch D, Mylonakis E. The infectious complications of anabolic-androgenic steroid injection.International Journal of Sports Medicine.1999;20:563–566. [PubMed: 10606223]

518.

Khankhanian NK, Hammers YA. Exuberant local tissue reaction to intramuscular injection of nandrolone decanoate (Deca-Durabolin) - a steroid compound in sesame seed oil base - mimicking soft tissue malignant tumors: a case report and review of the literature.Military Medicine.1992;157:670–674. [PubMed: 1470383]

519.

Evans NA. Local complications of self administered anabolic steroid injections.British Journal of Sports Medicine.1997;31:349–350. [PMC free article: PMC1332578] [PubMed: 9429018]

520.

Freeman BJ, Rooker GD. Spontaneous rupture of the anterior cruciate ligament after anabolic steroids.British Journal of Sports Medicine.1995;29:274–275. [PMC free article: PMC1332242] [PubMed: 8808545]

521.

Daniels JM, van Westerloo DJ, de Hon OM, Frissen PH.Nederlands Tijdschrift Voor Geneeskunde.2006;150:1077–1080. [Rhabdomyolysis in a bodybuilder using steroids] [PubMed: 16733985]

522.

Lepori M, Perren A, Gallino A. The popliteal-artery entrapment syndrome in a patient using anabolic steroids.New England Journal of Medicine.2002;346:1254–1255. [PubMed: 11961162]

523.

Sahraian MA, Mottamedi M, Azimi AR, Moghimi B. Androgen-induced cerebral venous sinus thrombosis in a young body builder: case report.BMC Neurol.2004;4:22. [PMC free article: PMC539263] [PubMed: 15579201]

524.

Liljeqvist S, Hellden A, Bergman U, Soderberg M. Pulmonary embolism associated with the use of anabolic steroids.Eur J Intern Med.2008;19:214–215. [PubMed: 18395167]

525.

Alaraj AM, Chamoun RB, Dahdaleh NS, Haddad GF, Comair YG. Spontaneous subdural haematoma in anabolic steroids dependent weight lifters: reports of two cases and review of literature.Acta Neurochirurgica.2005;147:85–87. [PubMed: 15565482]

526.

Petersson A, Garle M, Granath F, Thiblin I. Convulsions in users of anabolic androgenic steroids: possible explanations.Journal of Clinical Psychopharmacology.2007;27:723–725. [PubMed: 18004151]

527.

Pope HG, Katz DL. Affective and psychotic symptoms associated with anabolic steroid use.American Journal of Psychiatry.1988;145:487–490. [PubMed: 3279830]

528.

Bahrke MS, Yesalis CE, Wright JE. Psychological and behavioural effects of endogenous testosterone levels and anabolic-androgenic steroids among male. An update.Sports Medicine.1996;22:367–390. [PubMed: 8969015]

529.

Rockhold RW. Cardiovascular toxicity of anabolic steroids.Annual Review of Pharmacology and Toxicology.1993;33:497–520.

530.

Melchert RB, Welder AA. Cardiovascular effects of androgenic-anabolic steroids.Medicine and Science in Sports and Exercise.1995;27:1252–1262. [PubMed: 8531623]

531.

Sullivan ML, Martinez CM, Gennis P, Gallagher EJ. The cardiac toxicity of anabolic steroids.Progress in Cardiovascular Diseases.1998;41:1–15.

532.

Dhar R, Stout CW, Link MS, Homoud MK, Weinstock J, Estes NA 3rd. Cardiovascular toxicities of performance-enhancing substances in sports.Mayo Clinic Proceedings.2005;80:1307–1315. [PubMed: 16212144]

533.

Furlanello F, Serdoz LV, Cappato R, De Ambroggi L. Illicit drugs and cardiac arrhythmias in athletes.Eur J Cardiovasc Prev Rehabil.2007;14:487–494. [PubMed: 17667636]

534.

Larkin GL. Carcinoma of the prostate.New England Journal of Medicine.1991;324:1892. [PubMed: 2041554]

535.

Roberts JT, Essenhigh DM. Adenocarcinoma of prostate in 40 year old body-builder.Lancet.1986;2:742.

536.

Nakata S, Hasumi M, Sato J, Ogawa A, Yamanaka H. Prostate cancer associated with long-term intake of patent medicine containing methyltestosterone: a case report.Hinyokika Kiyo - Acta Urologica Japonica.1997;43:791–793. [PubMed: 9436023]

537.

Hartgens F, Cheriex EC, Kuipers H. Prospective echocardiographic assessment of androgenic-anabolic steroids effects on cardiac structure and function in strength athletes.International Journal of Sports Medicine.2003;24:344–351. [PubMed: 12868045]

538.

Chung T, Kelleher S, Liu PY, Conway AJ, Kritharides L, Handelsman DJ. Effects of testosterone and nandrolone on cardiac function: a randomized, placebo-controlled study.Clinical Endocrinology.2007;66:235–245. [PubMed: 17223994]

539.

Jin B, Turner L, Walters WAW, Handelsman DJ. Androgen or estrogen effects on the human prostate.Journal of Clinical Endocrinology and Metabolism.1996;81:4290–4295. [PubMed: 8954029]

540.

Palatini P, Giada F, Garavelli G, Sinisi F, Mario L, Michieletto M, Baldo-Enzi G. Cardiovascular effects of anabolic steroids in weight-trained subjects.Journal of Clinical Pharmacology and New Drugs.1996;36:1132–1140.

541.

Krieg A, Scharhag J, Albers T, Kindermann W, Urhausen A. Cardiac tissue Doppler in steroid users.International Journal of Sports Medicine.2007;28:638–643. [PubMed: 17549658]

542.

D'Andrea A, Caso P, Salerno G, Scarafile R, De Corato G, Mita C, Di Salvo G, Severino S, Cuomo S, Liccardo B, Esposito N, Calabro R. Left ventricular early myocardial dysfunction after chronic misuse of anabolic androgenic steroids: a Doppler myocardial and strain imaging analysis.British Journal of Sports Medicine.2007;41:149–155. [PMC free article: PMC2465218] [PubMed: 17178777]

543.

Lane HA, Grace F, Smith JC, Morris K, Cockcroft J, Scanlon MF, Davies JS. Impaired vasoreactivity in bodybuilders using androgenic anabolic steroids.European Journal of Clinical Investigation.2006;36:483–488. [PubMed: 16796605]

544.

Nottin S, Nguyen LD, Terbah M, Obert P. Cardiovascular effects of androgenic anabolic steroids in male bodybuilders determined by tissue Doppler imaging.American Journal of Cardiology.2006;97:912–915. [PubMed: 16516601]

545.

Urhausen A, Albers T, Kindermann W. Are the cardiac effects of anabolic steroid abuse in strength athletes reversible?Heart.2004;90:496–501. [PMC free article: PMC1768225] [PubMed: 15084541]

546.

Climstein M, O'Shea P, Adams KJ, DeBeliso M. The effects of anabolic-androgenic steroids upon resting and peak exercise left ventricular heart wall motion kinetics in male strength and power athletes.Journal of Science and Medicine in Sport.2003;6:387–397. [PubMed: 14723389]

547.

Grace F, Sculthorpe N, Baker J, Davies B. Blood pressure and rate pressure product response in males using high-dose anabolic androgenic steroids (AAS).Journal of Science and Medicine in Sport.2003;6:307–312. [PubMed: 14609147]

548.

Karila TA, Karjalainen JE, Mantysaari MJ, Viitasalo MT, Seppala TA. Anabolic androgenic steroids produce dose-dependant increase in left ventricular mass in power atheletes, and this effect is potentiated by concomitant use of growth hormone.International Journal of Sports Medicine.2003;24:337–343. [PubMed: 12868044]

549.

Sader MA, Griffiths KA, McCredie RJ, Handelsman DJ, Celermajer DS. Androgenic anabolic steroids and arterial structure and function in male bodybuilders.Journal of the American College of Cardiology.2001;37:224–230. [PubMed: 11153743]

550.

Di Bello V, Giorgi D, Bianchi M, Bertini A, Caputo MT, Valenti G, Furioso O, Alessandri L, Paterni M, Giusti C. Effects of anabolic-androgenic steroids on weight-lifters' myocardium: an ultrasonic videodensitometric study.Medicine and Science in Sports and Exercise.1999;31:514–521. [PubMed: 10211845]

551.

Dickerman RD, Schaller F, Zachariah NY, McConathy WJ. Left ventricular size and function in elite bodybuilders using anabolic steroids.Clinical Journal of Sports Medicine.1997;7:90–93.

552.

Di Bello V, Pedrinelli R, Giorgi D, Bertini A, Talarico L, Caputo MT, Massimiliano B, Dell'Omo G, Paterni M, Giusti C. Ultrasonic videodensitometric analysis of two different models of left ventricular hypertrophy. Athlete's heart and hypertension.Hypertension.1997;29:937–944. [PubMed: 9095080]

553.

Thiblin I, Petersson A. Pharmacoepidemiology of anabolic androgenic steroids: a review.Fundamental and Clinical Pharmacology.2005;19:27–44. [PubMed: 15660958]

554.

Sarna S, Sahi T, Koskenvuo M, Kaprio J. Increased life expectancy of world class male athletes.Medicine and Science in Sports and Exercise.1993;25:237–244. [PubMed: 8450727]

555.

Sarna S, Kaprio J, Kujala UM, Koskenvuo M. Health status of former elite athletes. The Finnish experience.Aging.1997;9:35–41. [PubMed: 9177584]

556.

Parssinen M, Kujala U, Vartiainen E, Sarna S, Seppala T. Increased premature mortality of competitive powerlifters suspected to have used anabolic agents.International Journal of Sports Medicine.2000;21:225–227. [PubMed: 10834358]

557.

Kashkin KB, Kleber HD. Hooked on hormones? An anabolic steroid addiction hypothesis.Journal of the American Medical Association.1989;262:3166–3170. [PubMed: 2681859]

558.

Fingerhood MI, Sullivan JT, Testa M, Jasinski DR. Abuse liability of testosterone.Journal of Psychopharmacology.1997;11:59–63. [PubMed: 9097895]

559.

Gazvani MR, Buckett W, Luckas MJ, Aird IA, Hipkin LJ, Lewis-Jones DI. Conservative management of azoospermia following steroid abuse.Hum Reprod.1997;12:1706–1708. [PubMed: 9308797]

560.

Gill GV. Anabolic steroid induced hypogonadism treated with human chorionic gonadotropin.Postgrad Med J.1998;74:45–46. [PMC free article: PMC2360778] [PubMed: 9538490]

561.

Boyadjiev NP, Georgieva KN, Massaldjieva RI, Gueorguiev SI. Reversible hypogonadism and azoospermia as a result of anabolic-androgenic steroid use in a bodybuilder with personality disorder. A case report.J Sports Med Phys Fitness.2000;40:271–274. [PubMed: 11125771]

562.

Torres-Calleja J, Gonzalez-Unzaga M, DeCelis-Carrillo R, Calzada-Sanchez L, Pedron N. Effect of androgenic anabolic steroids on sperm quality and serum hormone levels in adult male bodybuilders.Life Sci.2001;68:1769–1774. [PubMed: 11270623]

563.

Shankara-Narayana N, Yu C, Savkovic S, Desai R, Fennell C, Turner L, Jayadev V, Conway AJ, Kockx M, Ridley L, Kritharides L, Handelsman DJ. Rate and Extent of Recovery from Reproductive and Cardiac Dysfunction Due to Androgen Abuse in Men.J Clin Endocrinol Metab.2020:105.

564.

Menon DK. Successful treatment of anabolic steroid-induced azoospermia with human chorionic gonadotropin and human menopausal gonadotropin.Fertility and Sterility.2003;79 Suppl 3:1659–1661. [PubMed: 12801577]

565.

Drakeley A, Gazvani R, Lewis-Jones I. Duration of azoospermia following anabolic steroids.Fertility and Sterility.2004;81:226. [PubMed: 14711580]

566.

Nejat RJ, Rashid HH, Bagiella E, Katz AE, Benson MC. A prospective analysis of time to normalization of serum testosterone after withdrawal of androgen deprivation therapy.Journal of Urology.2000;164:1891–1894. [PubMed: 11061874]

567.

Kaku H, Saika T, Tsushima T, Ebara S, Senoh T, Yamato T, Nasu Y, Kumon H. Time course of serum testosterone and luteinizing hormone levels after cessation of long-term luteinizing hormone-releasing hormone agonist treatment in patients with prostate cancer.Prostate.2006;66:439–444. [PubMed: 16329145]

568.

Goldberg L, MacKinnon DP, Elliot DL, Moe EL, Clarke G, Cheong J. The adolescents training and learning to avoid steroids program: preventing drug use and promoting health behaviors.Archives of Pediatrics and Adolescent Medicine.2000;154:332–338. [PubMed: 10768668]

569.

Behre HM, Kliesch S, Leifke E, Link TM, Nieschlag E. Long-term effect of testosterone therapy on bone mineral density in hypogonadal men.Journal of Clinical Endocrinology and Metabolism.1997;82:2386–2390. [PubMed: 9253305]

570.

Jockenhovel F, Vogel E, Reinhardt W, Reinwein D. Effects of various modes of androgen substitution therapy on erythropoiesis.European Journal of Medical Research.1997;2:293–298. [PubMed: 9233903]

571.

Wang C, Swedloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G, Matsumoto AM, Weber T, Berman N. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. Testosterone Gel Study Group.Journal of Clinical Endocrinology and Metabolism.2000;85:2839–2853. [PubMed: 10946892]

572.

Aminorroaya A, Kelleher S, Conway AJ, Ly LP, Handelsman DJ. Adequacy of androgen replacement influences bone density response to testosterone in androgen-deficient men.European Journal of Endocrinology.2005;152:881–886. [PubMed: 15941928]

573.

Wong FH, Pun KK, Wang C. Loss of bone mass in patients with Klinefelter's syndrome despite sufficient testosterone replacement.Osteoporosis International.1993;3:3–7. [PubMed: 8422513]

574.

Ishizaka K, Suzuki M, Kageyama Y, Kihara K, Yoshida K. Bone mineral density in hypogonadal men remains low after long-term testosterone replacement.Asian Journal of Andrology.2002;4:117–121. [PubMed: 12085102]

575.

Anderson RA, Wallace AM, Sattar N, Kumar N, Sundaram K. Evidence for tissue selectivity of the synthetic androgen 7 alpha-methyl-19-nortestosterone in hypogonadal men.Journal of Clinical Endocrinology and Metabolism.2003;88:2784–2793. [PubMed: 12788888]

576.

Zacharin MR, Pua J, Kanumakala S. Bone mineral density outcomes following long-term treatment with subcutaneous testosterone pellet implants in male hypogonadism.Clinical Endocrinology.2003;58:691–695. [PubMed: 12780744]

577.

Schubert M, Bullmann C, Minnemann T, Reiners C, Krone W, Jockenhovel F. Osteoporosis in male hypogonadism: responses to androgen substitution differ among men with primary and secondary hypogonadism.Hormone Research.2003;60:21–28.

578.

Finkelstein JS, Klibanski A, Neer RM. A longitudinal evaluation of bone mineral density in adult men with histories of delayed puberty.Journal of Clinical Endocrinology and Metabolism.1996;81:1152–1155. [PubMed: 8772591]

579.

Finkelstein JS, Neer RM, Biller BM, Crawford JD, Klibanski A. Osteopenia in men with a history of delayed puberty.New England Journal of Medicine.1992;326:600–604. [PubMed: 1734250]

580.

Huhtaniemi IT, Pye SR, Limer KL, Thomson W, O'Neill TW, Platt H, Payne D, John SL, Jiang M, Boonen S, Borghs H, Vanderschueren D, Adams JE, Ward KA, Bartfai G, Casanueva F, Finn JD, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Silman AJ, Wu FC. Increased estrogen rather than decreased androgen action is associated with longer androgen receptor CAG repeats.Journal of Clinical Endocrinology and Metabolism.2009;94:277–284. [PubMed: 18840639]

581.

Kicman AT. Pharmacology of anabolic steroids.British Journal of Pharmacology.2008;154:502–521. [PMC free article: PMC2439524] [PubMed: 18500378]

582.

Dalton JT, Mukherjee A, Zhu Z, Kirkovsky L, Miller DD. Discovery of nonsteroidal androgens.Biochemical and Biophysical Research Communications.1998;244:1–4. [PubMed: 9514878]

583.

Thevis M, Schanzer W. Mass spectrometry of selective androgen receptor modulators.Journal of Mass Spectrometry.2008;43:865–876. [PubMed: 18521833]

584.

Lubahn D, Joseph DR, Sullivan PM, Williard HF, French FS, Wilson EM. Cloning of the human androgen receptor complementary DNA and localisation to the X-chromosome.Science.1988;240:327–330. [PubMed: 3353727]

585.

Chang CS, Kokontis J, Liao ST. Molecular cloning of human and rat complementary DNA encoding androgen receptors.Science.1988;240:324–326. [PubMed: 3353726]

586.

Trapman J, Klaassen P, Kuiper GG, van der Korput JA, Faber PW, van Rooij HC, Geurts van Kessel A, Voorhorst MM, Mulder E, Brinkmann AO. Cloning, structure and expression of a cDNA encoding the human androgen receptor.Biochemical and Biophysical Research Communications.1988;153:241–248. [PubMed: 3377788]

587.

Wilson JD. The use and misuse of androgens.Metabolism: Clinical and Experimental.1980;29:1278–1295. [PubMed: 7005620]

588.

Negro-Vilar A. Selective androgen receptor modulators (SARMs): a novel approach to androgen therapy for the new millennium.Journal of Clinical Endocrinology and Metabolism.1999;84:3459–3462. [PubMed: 10522980]

589.

Bhasin S, Jasuja R. Selective androgen receptor modulators as function promoting therapies.Current Opinion in Clinical Nutrition and Metabolic Care.2009;12:232–240. [PMC free article: PMC2907129] [PubMed: 19357508]

590.

Handelsman DJ, Conway AJ, Boylan LM. Pharmacokinetics and pharmacodynamics of testosterone pellets in man.Journal of Clinical Endocrinology and Metabolism.1990;71:216–222. [PubMed: 2115044]

591.

Deansley R, Parkes AS. Further experiments on the administration of hormones by the subcutaneous implantation of tablets.Lancet.1938;ii:606–608.

592.

Kelleher S, Howe C, Conway AJ, Handelsman DJ. Testosterone release rate and duration of action of testosterone pellet implants.Clinical Endocrinology.2004;60:420–428. [PubMed: 15049955]

593.

Vierhapper H, Nowotny P, Waldhausl W. Reduced production rates of testosterone and dihydrotestosterone in healthy men treated with rosiglitazone.Metabolism: Clinical and Experimental.2003;52:230–232. [PubMed: 12601638]

594.

Handelsman DJ, Mackey MA, Howe C, Turner L, Conway AJ. Analysis of testosterone implants for androgen replacement therapy.Clinical Endocrinology.1997;47:311–316. [PubMed: 9373452]

595.

Kelleher S, Turner L, Howe C, Conway AJ, Handelsman DJ. Extrusion of testosterone pellets: a randomized controlled clinical study.Clinical Endocrinology.1999;51:469–471. [PubMed: 10583314]

596.

Kelleher S, Conway AJ, Handelsman DJ. A randomised controlled clinical trial of antibiotic impregnation of testosterone pellet implants to reduce extrusion rate.European Journal of Endocrinology.2002;146:513–518. [PubMed: 11916619]

597.

Kelleher S, Conway AJ, Handelsman DJ. Influence of implantation site and track geometry on the extrusion rate and pharmacology of testosterone implants.Clinical Endocrinology.2001;55:531–536. [PubMed: 11678837]

598.

Cavender RK, Fairall M. Subcutaneous testosterone pellet implant (Testopel) therapy for men with testosterone deficiency syndrome: a single-site retrospective safety analysis.J Sex Med.2009;6:3177–3192. [PubMed: 19796052]

599.

Pastuszak AW, Mittakanti H, Liu JS, Gomez L, Lipshultz LI, Khera M. Pharmacokinetic evaluation and dosing of subcutaneous testosterone pellets.Journal of Andrology.2012;33:927–937. [PubMed: 22403285]

600.

McCullough AR, Khera M, Goldstein I, Hellstrom WJ, Morgentaler A, Levine LA. A multi-institutional observational study of testosterone levels after testosterone pellet (Testopel((R))) insertion.J Sex Med.2012;9:594–601. [PubMed: 22240203]

601.

Bals-Pratsch M, Knuth UA, Yoon YD, Nieschlag E. Transdermal testosterone substitution therapy for male hypogonadism.Lancet.1986;2:943–946. [PubMed: 2877131]

602.

Findlay JC, Place VA, Snyder PJ. Transdermal delivery of testosterone.Journal of Clinical Endocrinology and Metabolism.1987;64:266–268. [PubMed: 3793849]

603.

Bals-Pratsch M, Langer K, Place VA, Nieschlag E. Substitution therapy of hypogonadal men with transdermal testosterone over one year.Acta Endocrinologica.1988;118:7–13. [PubMed: 3133918]

604.

Jordan WP Jr, Atkinson LE, Lai C. Comparison of the skin irritation potential of two testosterone transdermal systems: an investigational system and a marketed product.Clinical Therapeutics.1998;20:80–87. [PubMed: 9522106]

605.

Jordan WP Jr. Allergy and topical irritation associated with transdermal testosterone administration: a comparison of scrotal and nonscrotal transdermal systems.American Journal of Contact Dermatitis.1997;8:108–113. [PubMed: 9153333]

606.

Meikle AW, Mazer NA, Moellmer JF, Stringham JD, Tolman KG, Sanders SW, Odell WD. Enhanced transdermal delivery of testosterone across nonscrotal skin produces physiological concentrations of testosterone and its metabolites in hypogonadal men.Journal of Clinical Endocrinology and Metabolism.1992;74:623–628. [PubMed: 1740497]

607.

Arver S, Dobs AS, Meikle AW, Caramelli KE, Rajaram L, Sanders SW, Mazer NA. Long-term efficacy and safety of a permeation-enhanced testosterone transdermal system in hypogonadal men.Clinical Endocrinology.1997;47:727–737. [PubMed: 9497881]

608.

Shomaker TS, Zhang J, Ashburn MA. A pilot study assessing the impact of heat on the transdermal delivery of testosterone.Journal of Clinical Pharmacology.2001;41:677–682. [PubMed: 11402637]

609.

Bennett NJ. A burn-like lesion caused by a testosterone transdermal system.Burns.1998;24:478–480. [PubMed: 9725692]

610.

Wilson DE, Kaidbey K, Boike SC, Jorkasky DK. Use of topical corticosteroid pretreatment to reduce the incidence and severity of skin reactions associated with testosterone transdermal therapy.Clinical Therapeutics.1998;20:299–306. [PubMed: 9589821]

611.

Guerin JF, Rollet J. Inhibition of spermatogenesis in men using various combinations of oral progestagens and percutaneous or oral androgens.International Journal of Andrology.1988;11:187–199. [PubMed: 2970439]

612.

Fiet J, Morville R, Chemana D, Villette JM, Gourmel B, Brerault JL, Dreux C. Percutaneous absorption of 5a-dihydrotestosterone in man. I Plasma androgen and gonadotrophin levels in normal adult men after percutaneous administration of 5a-dihydrotestosterone.International Journal of Andrology.1982;5:586–594. [PubMed: 6819234]

613.

Chemana D, Morville R, Fiet J, Villette JM, Tabuteau F, Brerault JL, Passa P. Percutaneous absorption of 5a-dihydrotestosterone in man. II Percutaneous administration of 5a-dihydrotestosterone in hypogonadal men with idiopathic haemochromatosis; clinical, metabolic and hormonal effectiveness.International Journal of Andrology.1982;5:595–606. [PubMed: 7160922]

614.

Wang C, Iranmanesh A, Berman N, McDonald V, Steiner B, Ziel F, Faulkner SM, Dudley RE, Veldhuis JD, Swerdloff RS. Comparative pharmacokinetics of three doses of percutaneous dihydrotestosterone gel in healthy elderly men--a clinical research center study.Journal of Clinical Endocrinology and Metabolism.1998;83:2749–2757. [PubMed: 9709942]

615.

Swerdloff RS, Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, Weber T, Longstreth J, Berman N. Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men.Journal of Clinical Endocrinology and Metabolism.2000;85:4500–4510. [PubMed: 11134099]

616.

Rolf C, Kemper S, Lemmnitz G, Eickenberg U, Nieschlag E. Pharmacokinetics of a new transdermal testosterone gel in gonadotrophin-suppressed normal men.European Journal of Endocrinology.2002;146:673–679. [PubMed: 11980623]

617.

Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, Bachand R. AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function.Journal of Clinical Endocrinology and Metabolism.2003;88:2673–2681. [PubMed: 12788872]

618.

McNicholas TA, Dean JD, Mulder H, Carnegie C, Jones NA. A novel testosterone gel formulation normalizes androgen levels in hypogonadal men, with improvements in body composition and sexual function.BJU International.2003;91:69–74. [PubMed: 12614254]

619.

Kuhnert B, Byrne M, Simoni M, Kopcke W, Gerss J, Lemmnitz G, Nieschlag E. Testosterone substitution with a new transdermal, hydroalcoholic gel applied to scrotal or non-scrotal skin: a multicentre trial.European Journal of Endocrinology.2005;153:317–326. [PubMed: 16061839]

620.

Wang C, Ilani N, Arver S, McLachlan RI, Soulis T, Watkinson A. Efficacy and safety of the 2% formulation of testosterone topical solution applied to the axillae in androgen-deficient men.Clinical Endocrinology.2011;75:836–843. [PubMed: 21689131]

621.

Muram D, Melby T, Alles Kingshill E. Skin reactions in a phase 3 study of a testosterone topical solution applied to the axilla in hypogonadal men.Current Medical Research and Opinion.2012;28:761–766. [PubMed: 22458919]

622.

Iyer R, Mok SF, Savkovic S, Turner L, Fraser G, Desai R, Jayadev V, Conway AJ, Handelsman DJ. Pharmacokinetics of testosterone cream applied to scrotal skin.Andrology.2017;5:725–731. [PubMed: 28334510]

623.

Delanoe D, Fougeyrollas B, Meyer L, Thonneau P. Androgenisation of female partners of men on medroxyprogesterone acetate/percutaneous testosterone contraception.Lancet i.1984:276.

624.

Moore N, Paux G, Noblet C, Andrejak M. Spouse-related drug side-effects.Lancet.1988;1:468.

625.

de Ronde W (2009) Hyperandrogenism after transfer of topical testosterone gel: case report and review of published and unpublished studies. Human Reproduction 24:425-428.

626.

Yu YM, Punyasavatsu N, Elder D, D'Ercole AJ. Sexual development in a two-year-old boy induced by topical exposure to testosterone.Pediatrics.1999;104:e23. [PubMed: 10429141]

627.

Bhowmick SK, Ricke T, Rettig KR. Sexual precocity in a 16-month-old boy induced by indirect topical exposure to testosterone.Clinical Pediatrics.2007;46:540–543. [PubMed: 17579107]

628.

Brachet C, Vermeulen J, Heinrichs C. Children's virilization and the use of a testosterone gel by their fathers.European Journal of Pediatrics.2005;164:646–647. [PubMed: 16025298]

629.

Svoren BM, Wolfsdorf JI. Sexual development in a 21 month-old boy caused by testosterone contamination of a topical hydrocortisone cream.Journal of Pediatric Endocrinology and Metabolism.2005;18:507–510. [PubMed: 15921181]

630.

Kunz GJ, Klein KO, Clemons RD, Gottschalk ME, Jones KL. Virilization of young children after topical androgen use by their parents.Pediatrics.2004;114:282–284. [PubMed: 15231947]

631.

Franklin SL, Geffner ME. Precocious puberty secondary to topical testosterone exposure.Journal of Pediatric Endocrinology and Metabolism.2003;16:107–110. [PubMed: 12585348]

632.

Stahlman J, Britto M, Fitzpatrick S, McWhirter C, Testino SA, Brennan JJ, Zumbrunnen TL. Serum testosterone levels in non-dosed females after secondary exposure to 1.62% testosterone gel: effects of clothing barrier on testosterone absorption.Current Medical Research and Opinion.2012;28:291–301. [PubMed: 22188558]

633.

Mazer N, Fisher D, Fischer J, Cosgrove M, Bell D, Eilers B. Transfer of transdermally applied testosterone to clothing: a comparison of a testosterone patch versus a testosterone gel.J Sex Med.2005;2:227–234. [PubMed: 16422890]

634.

Stahlman J, Britto M, Fitzpatrick S, McWhirter C, Testino SA, Brennan JJ, Zumbrunnen TL. Effect of application site, clothing barrier, and application site washing on testosterone transfer with a 1.62% testosterone gel.Current Medical Research and Opinion.2012;28:281–290. [PubMed: 22188557]

635.

Rolf C, Kemper S, Lemmnitz G, Eickenberg U, Nieschlag E. Pharmacokinetics of a new transdermal testosterone gel in gonadotrophin-suppressed normal men.Eur J Endocrinol.2002;146:673–679. [PubMed: 11980623]

636.

de Ronde W, Vogel S, Bui HN, Heijboer AC. Reduction in 24-hour plasma testosterone levels in subjects who showered 15 or 30 minutes after application of testosterone gel.Pharmacotherapy.2011;31:248–252. [PubMed: 21361734]

637.

Rolf C, Knie U, Lemmnitz G, Nieschlag E. Interpersonal testosterone transfer after topical application of a newly developed testosterone gel preparation.Clin Endocrinol (Oxf).2002;56:637–641. [PubMed: 12030915]

638.

Burris AS, Ewing LL, Sherins RJ. Initial trial of slow-release testosterone microspheres in hypogonadal men.Fertility and Sterility.1988;50:493–497. [PubMed: 3410101]

639.

Bhasin S, Swerdloff RS, Steiner B, Peterson MA, Meridores T, Galmirini M, Pandian MR, Goldberg R, Berman N. A biodegradable testosterone microcapsule formulation provides uniform eugonadal levels of testosterone for 10-11 weeks in hypogonadal men.Journal of Clinical Endocrinology and Metabolism.1992;74:75–83. [PubMed: 1727832]

640.

Amory JK, Anawalt BD, Blaskovich PD, Gilchriest J, Nuwayser ES, Matsumoto AM. Testosterone release from a subcutaneous, biodegradable microcapsule formulation (Viatrel) in hypogonadal men.Journal of Andrology.2002;23:84–91. [PubMed: 11780927]

641.

Page ST, Bremner WJ, Clark RV, Bush MA, Zhi H, Caricofe RB, Smith PM, Amory JK. Nanomilled oral testosterone plus dutasteride effectively normalizes serum testosterone in normal men with induced hypogonadism.Journal of Andrology.2008;29:222–227. [PubMed: 18077826]

642.

Amory JK, Bremner WJ. Oral testosterone in oil plus dutasteride in men: a pharmacokinetic study.Journal of Clinical Endocrinology and Metabolism.2005;90:2610–2617. [PubMed: 15713724]

643.

Amory JK, Page ST, Bremner WJ. Oral testosterone in oil: pharmacokinetic effects of 5alpha reduction by finasteride or dutasteride and food intake in men.Journal of Andrology.2006;27:72–78. [PubMed: 16400081]

644.

Johnsen SG, Kampmann JP, Bennet EP, Jorgensen F. Enzyme induction by oral testosterone.Clinical Pharmacology and Therapeutics.1976;20:233–237. [PubMed: 947655]

645.

Johnsen S. Long-term oral testosterone and liver function.Lancet.1978;1:50.

646.

Daggett PR, Wheeler MJ, Nabarro JD. Oral testosterone, a reappraisal.Hormone Research.1978;9:121–129. [PubMed: 640576]

647.

Lee A, Rubinow K, Clark RV, Caricofe RB, Bush MA, Zhi H, Roth MY, Page ST, Bremner WJ, Amory JK. Pharmacokinetics of modified slow-release oral testosterone over 9 days in normal men with experimental hypogonadism.Journal of Andrology.2012;33:420–426. [PMC free article: PMC4034539] [PubMed: 21868746]

648.

Amory JK, Bush MA, Zhi H, Caricofe RB, Matsumoto AM, Swerdloff RS, Wang C, Clark RV. Oral testosterone with and without concomitant inhibition of 5alpha-reductase by dutasteride in hypogonadal men for 28 days.Journal of Urology.2011;185:626–632. [PMC free article: PMC4267472] [PubMed: 21168874]

649.

Salehian B, Wang C, Alexander G, Davidson T, McDonald V, Berman N, Dudley RE, Ziel F, Swerdloff RS. Pharmacokinetics, bioefficacy, and safety of sublingual testosterone cyclodextrin in hypogonadal men: comparison to testosterone enanthate--a clinical research center study.Journal of Clinical Endocrinology and Metabolism.1995;80:3567–3575. [PubMed: 8530600]

650.

Dobs AS, Hoover DR, Chen MC, Allen R. Pharmacokinetic characteristics, efficacy, and safety of buccal testosterone in hypogonadal males: a pilot study.Journal of Clinical Endocrinology and Metabolism.1998;83:33–39. [PubMed: 9435413]

651.

Mazer N, Bell D, Wu J, Fischer J, Cosgrove M, Eilers B. Comparison of the steady-state pharmacokinetics, metabolism, and variability of a transdermal testosterone patch versus a transdermal testosterone gel in hypogonadal men.J Sex Med.2005;2:213–226. [PubMed: 16422889]

652.

Swerdloff RS, Wang C. Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent.Baillieres Clinical Endocrinology and Metabolism.1998;12:501–506. [PubMed: 10332569]

653.

Junkman K. Long-acting steroids in reproduction.Recent Progress in Hormone Research.1957;13:380–419.

654.

Minto C, Howe C, Wishart S, Conway AJ, Handelsman DJ. Pharmacokinetics and pharmacodynamics of nandrolone esters in oil vehicle: effects of ester, injection site and volume.Journal of Pharmacology and Experimental Therapeutics.1997;281:93–102. [PubMed: 9103484]

655.

Snyder PJ, Lawrence DA. Treatment of male hypogonadism with testosterone enanthate.Journal of Clinical Endocrinology and Metabolism.1980;51:1335–1339. [PubMed: 6777395]

656.

Cantrill JA, Dewis P, Large DM, Newman M, Anderson DC. Which testosterone replacement therapy?Clinical Endocrinology.1984;24:97–107.

657.

Conway AJ, Boylan LM, Howe C, Ross G, Handelsman DJ. A randomised clinical trial of testosterone replacement therapy in hypogonadal men.International Journal of Andrology.1988;11:247–264. [PubMed: 3139571]

658.

Behre HM, Wang C, Handelsman DJ, Nieschlag E 2004 Pharmacology of testosterone preparations. In: Nieschlag E, Behre HM eds. Testosterone: Action Deficiency Substitution. 3rd ed. Cambridge: Cambridge University Press; 405-444.

659.

Weinbauer GF, Marshall GR, Nieschlag E. New injectable testosterone ester maintains serum testosterone of castrated monkeys in the normal range for four months.Acta Endocrinol.1986;113:128–132.

660.

Behre HM, Nieschlag E. Testosterone buciclate (20 Aet-1) in hypogonadal men: pharmacokinetics and pharmacodynamics of the new long-acting androgen ester.Journal of Clinical Endocrinology and Metabolism.1992;75:1204–1210. [PubMed: 1430080]

661.

Behre HM, Baus S, Kliesch S, Keck C, Simoni M, Nieschlag E. Potential of testosterone buciclate for male contraception: endocrine differences between responders and nonresponders.Journal of Clinical Endocrinology and Metabolism.1995;80:2394–2403. [PubMed: 7543113]

662.

Zhang GY, Gu YQ, Wang XH, Cui YG, Bremner WJ. A pharmacokinetic study of injectable testosterone undecanoate in hypogonadal men.Journal of Andrology.1998;19:761–768. [PubMed: 9876028]

663.

Nieschlag E, Buchter D, Von Eckardstein S, Abshagen K, Simoni M, Behre HM. Repeated intramuscular injections of testosterone undecanoate for substitution therapy in hypogonadal men.Clinical Endocrinology.1999;51:757–763. [PubMed: 10619981]

664.

von Eckardstein S, Nieschlag E. Treatment of male hypogonadism with testosterone undecanoate injected at extended intervals of 12 weeks: a phase II study.Journal of Andrology.2002;23:419–425. [PubMed: 12002444]

665.

Schubert M, Minnemann T, Hubler D, Rouskova D, Christoph A, Oettel M, Ernst M, Mellinger U, Krone W, Jockenhovel F. Intramuscular testosterone undecanoate: pharmacokinetic aspects of a novel testosterone formulation during long-term treatment of men with hypogonadism.Journal of Clinical Endocrinology and Metabolism.2004;89:5429–5434. [PubMed: 15531493]

666.

Gu YQ, Wang XH, Xu D, Peng L, Cheng LF, Huang MK, Huang ZJ, Zhang GY. A multicenter contraceptive efficacy study of injectable testosterone undecanoate in healthy Chinese men.Journal of Clinical Endocrinology and Metabolism.2003;88:562–568. [PubMed: 12574181]

667.

Gu YQ, Tong JS, Ma DZ, Wang XH, Yuan D, Tang WH, Bremner WJ. Male hormonal contraception: effects of injections of testosterone undecanoate and depot medroxyprogesterone acetate at eight-week intervals in chinese men.Journal of Clinical Endocrinology and Metabolism.2004;89:2254–2262. [PubMed: 15126550]

668.

Qoubaitary A, Meriggiola C, Ng CM, Lumbreras L, Cerpolini S, Pelusi G, Christensen PD, Hull L, Swerdloff RS, Wang C. Pharmacokinetics of testosterone undecanoate injected alone or in combination with norethisterone enanthate in healthy men.Journal of Andrology.2006;27:853–867. [PubMed: 16837736]

669.

Mommers E, Kersemaekers WM, Elliesen J, Kepers M, Apter D, Behre HM, Beynon J, Bouloux PM, Costantino A, Gerbershagen HP, Gronlund L, Heger-Mahn D, Huhtaniemi I, Koldewijn EL, Lange C, Lindenberg S, Meriggiola MC, Meuleman E, Mulders PF, Nieschlag E, Perheentupa A, Solomon A, Vaisala L, Wu FC, Zitzmann M. Male hormonal contraception: a double-blind, placebo-controlled study.Journal of Clinical Endocrinology and Metabolism.2008;93:2572–2580. [PubMed: 18413423]

670.

Jockenhovel F, Minnemann T, Schubert M, Freude S, Hubler D, Schumann C, Christoph A, Ernst M. Comparison of long-acting testosterone undecanoate formulation versus testosterone enanthate on sexual function and mood in hypogonadal men.European Journal of Endocrinology.2009;160:815–819. [PubMed: 19225035]

671.

Singh GK, Turner L, Desai R, Jimenez M, Handelsman DJ. Pharmacokinetic-pharmacodynamic study of subcutaneous injection of depot nandrolone decanoate using dried blood spots sampling coupled with ultrapressure liquid chromatography tandem mass spectrometry assays.J Clin Endocrinol Metab.2014;99:2592–2598. [PubMed: 24684468]

672.

Kaminetsky JC, McCullough A, Hwang K, Jaffe JS, Wang C, Swerdloff RS. A 52-Week Study of Dose Adjusted Subcutaneous Testosterone Enanthate in Oil Self-Administered via Disposable Auto-Injector.J Urol.2019;201:587–594. [PubMed: 30296416]

673.

Olson J, Schrager SM, Clark LF, Dunlap SL, Belzer M. Subcutaneous Testosterone: An Effective Delivery Mechanism for Masculinizing Young Transgender Men.LGBT Health.2014;1:165–167. [PubMed: 26789709]

674.

Spratt DI, Stewart II, Savage C, Craig W, Spack NP, Chandler DW, Spratt LV, Eimicke T, Olshan JS. Subcutaneous Injection of Testosterone Is an Effective and Preferred Alternative to Intramuscular Injection: Demonstration in Female-to-Male Transgender Patients.J Clin Endocrinol Metab.2017;102:2349–2355. [PubMed: 28379417]

675.

Wilson DM, Kiang TKL, Ensom MHH. Pharmacokinetics, safety, and patient acceptability of subcutaneous versus intramuscular testosterone injection for gender-affirming therapy: A pilot study.Am J Health Syst Pharm.2018;75:351–358. [PubMed: 29367424]

676.

Turner L, Ly LP, Desai R, Singh GKS, Handelsman TD, Savkovic S, Fennell C, Jayadev V, Conway A, Handelsman DJ. Pharmacokinetics and Acceptability of Subcutaneous Injection of Testosterone Undecanoate.J Endocr Soc.2019;3:1531–1540. [PMC free article: PMC6676071] [PubMed: 31384715]

677.

Kohn FM, Schill WB. A new oral testosterone undecanoate formulation.World Journal of Urology.2003;21:311–315. [PubMed: 14579074]

678.

Bagchus WM, Hust R, Maris F, Schnabel PG, Houwing NS. Important effect of food on the bioavailability of oral testosterone undecanoate.Pharmacotherapy.2003;23:319–325. [PubMed: 12627930]

679.

Schnabel PG, Bagchus W, Lass H, Thomsen T, Geurts TB. The effect of food composition on serum testosterone levels after oral administration of Andriol Testocaps.Clinical Endocrinology.2007;66:579–585. [PMC free article: PMC1859980] [PubMed: 17371478]

680.

Roth MY, Dudley RE, Hull L, Leung A, Christenson P, Wang C, Swerdloff R, Amory JK. Steady-state pharmacokinetics of oral testosterone undecanoate with concomitant inhibition of 5alpha-reductase by finasteride.International Journal of Andrology.2011;34:541–547. [PMC free article: PMC4269219] [PubMed: 20969601]

681.

Idan A, Griffiths KA, Harwood DT, Seibel MJ, Turner L, Conway AJ, Handelsman DJ. Long-term effects of dihydrotestosterone treatment on prostate growth in healthy, middle-aged men without prostate disease: a randomized, placebo-controlled trial.Annals of Internal Medicine.2010;153:621–632. [PubMed: 21079217]

682.

Gooren LJ. A ten-year safety study of the oral androgen testosterone undecanoate.Journal of Andrology.1994;15:212–215. [PubMed: 7928661]

683.

Page ST, Lin DW, Mostaghel EA, Marck BT, Wright JL, Wu J, Amory JK, Nelson PS, Matsumoto AM. Dihydrotestosterone administration does not increase intraprostatic androgen concentrations or alter prostate androgen action in healthy men: a randomized-controlled trial.Journal of Clinical Endocrinology and Metabolism.2011;96:430–437. [PMC free article: PMC3048323] [PubMed: 21177791]

684.

Tauber U, Schroder K, Dusterberg B, Matthes H. Absolute bioavailability of testosterone after oral administration of testosterone-undecanoate and testosterone.European Journal of Drug Metabolism and Pharmacokinetics.1986;11:145–149. [PubMed: 3770015]

685.

Ahmed SF, Tucker P, Mayo A, Wallace AM, Hughes IA. Randomized, crossover comparison study of the short-term effect of oral testosterone undecanoate and intramuscular testosterone depot on linear growth and serum bone alkaline phosphatase.Journal of Pediatric Endocrinology and Metabolism.2004;17:941–950. [PubMed: 15301041]

686.

Swerdloff RS, Wang C, White WB, Kaminetsky J, Gittelman MC, Longstreth JA, Dudley RE, Danoff TM. A New Oral Testosterone Undecanoate Formulation Restores Testosterone to Normal Concentrations in Hypogonadal Men.J Clin Endocrinol Metab.2020:105.

687.

Nieschlag E, Mauss J, Coert A, Kicovic P. Plasma androgen levels in men after oral administration of testosterone or testosterone undecanoate.Acta Endocrinol (Copenh).1975;79:366–374. [PubMed: 1173495]

688.

Butler GE, Sellar RE, Walker RF, Hendry M, Kelnar CJH, Wu FCW. Oral testosterone undecanoate in the management of delayed puberty in boys: pharmacokinetics and effects on sexual maturation and growth.Journal of Clinical Endocrinology and Metabolism.1992;75:37–44. [PubMed: 1619029]

689.

Brown DC, Butler GE, Kelnar CJ, Wu FC. A double blind, placebo controlled study of the effects of low dose testosterone undecanoate on the growth of small for age, prepubertal boys.Archives of Disease in Childhood.1995;73:131–135. [PMC free article: PMC1511206] [PubMed: 7574856]

690.

Albanese A, Kewley GD, Long A, Pearl KN, Robins DG, Stanhope R. Oral treatment for constitutional delay of growth and puberty in boys: a randomised trial of an anabolic steroid or testosterone undecanoate.Archives of Disease in Childhood.1994;71:315–317. [PMC free article: PMC1030008] [PubMed: 7979523]

691.

Luisi M, Franchi E. Double-blind group comparative study of testosterone undecanoate and mesterolone in hypogonadal male patients.Journal of Endocrinological Investigations.1980;3:305–308.

692.

Androgen therapy of aplastic anaemia--a prospective study of 352 cases.Scandinavian Journal of Haematology.1979;22:343–356. [PubMed: 472658]

693.

Shimoda K, Shide K, Kamezaki K, Okamura T, Harada N, Kinukawa N, Ohyashiki K, Niho Y, Mizoguchi H, Omine M, Ozawa K, Haradaa M. The effect of anabolic steroids on anemia in myelofibrosis with myeloid metaplasia: retrospective analysis of 39 patients in Japan.International Journal of Hematology.2007;85:338–343. [PubMed: 17483079]

694.

Gennari C. Effects of nandrolone decanoate therapy on bone mass and calcium metabolism in women with established post-menopausal osteoporosis: a double-blind placebo-controlled study.Maturitas.1989;11:187–197. AgnusDei D, Gonnelli S, Nardi P. [PubMed: 2687645]

695.

Frisoli A Jr, Chaves PH, Pinheiro MM, Szejnfeld VL. The effect of nandrolone decanoate on bone mineral density, muscle mass, and hemoglobin levels in elderly women with osteoporosis: a double-blind, randomized, placebo-controlled clinical trial.Journals of Gerontology Series A, Biological Sciences and Medical Sciences.2005;60:648–653. [PubMed: 15972619]

696.

Simpson ER, Mahendroo MS, Means GD, Kilgore MW, Hinshelwood MM, Graham-Lorence S, Amarneh B, Ito Y, Fisher CR, Michael MD, et al. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis.Endocrine Reviews.1994;15:342–355. [PubMed: 8076586]

697.

Hong Y, Yu B, Sherman M, Yuan YC, Zhou D, Chen S. Molecular basis for the aromatization reaction and exemestane-mediated irreversible inhibition of human aromatase.Molecular Endocrinology.2007;21:401–414. [PubMed: 17095574]

698.

Hobbs CJ, Jones RE, Plymate SR. Nandrolone, a 19-nortestosterone, enhances insulin-independent glucose uptake in normal men.Journal of Clinical Endocrinology and Metabolism.1996;81:1582–1585. [PubMed: 8636371]

699.

Behre HM, Kliesch S, Lemcke B, von Eckardstein S, Nieschlag E. Suppression of spermatogenesis to azoospermia by combined administration of GnRH antagonist and 19-nortestosterone cannot be maintained by this non-aromatizable androgen alone.Human Reproduction.2001;16:2570–2577. [PubMed: 11726576]

700.

Attardi BJ, Pham TC, Radler LC, Burgenson J, Hild SA, Reel JR. Dimethandrolone (7alpha,11beta-dimethyl-19-nortestosterone) and 11beta-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase.Journal of Steroid Biochemistry and Molecular Biology.2008;110:214–222. [PMC free article: PMC2575079] [PubMed: 18555683]

701.

Lemus AE, Enriquez J, Garcia GA, Grillasca I, Perez-Palacios G. 5alpha-reduction of norethisterone enhances its binding affinity for androgen receptors but diminishes its androgenic potency.Journal of Steroid Biochemistry and Molecular Biology.1997;60:121–129. [PubMed: 9182866]

702.

Geusens P. Nandrolone decanoate: pharmacological properties and therapeutic use in osteoporosis.Clinical Rheumatology.1995;14:32–39. [PubMed: 8846659]

703.

Sundaram K, Kumar N. 7alpha-methyl-19-nortestosterone (MENT): the optimal androgen for male contraception and replacement therapy.International Journal of Andrology.2000;23 Suppl 2:13–15.

704.

Cook CE, Kepler JA. 7alpha,11beta-Dimethyl-19-nortestosterone: a potent and selective androgen response modulator with prostate-sparing properties.Bioorganic and Medicinal Chemistry Letters.2005;15:1213–1216. [PubMed: 15686944]

705.

Suvisaari J, Sundaram K, Noe G, Kumar N, Aguillaume C, Tsong YY, Lahteenmaki P, Bardin CW. Pharmacokinetics and pharmacodynamics of 7a-methyl-19-nortestosterone after intramuscular administration in healthy men.Human Reproduction.1997;12:967–973. [PubMed: 9194649]

706.

Sundaram K, Kumar N, Bardin CW. 7 alpha-Methyl-19-nortestosterone: an ideal androgen for replacement therapy.Recent Progress in Hormone Research.1994;49:373–376. [PubMed: 8146434]

707.

Sundaram K, Kumar N, Bardin CW. 7a-Methyl-nortestosterone (MENT): the optimal androgen for male contraception.Annals of Medicine.1993;25:199–205. [PubMed: 8489761]

708.

Attardi BJ, Hild SA, Reel JR. Dimethandrolone undecanoate: a new potent orally active androgen with progestational activity.Endocrinology.2006;147:3016–3026. [PubMed: 16497801]

709.

Sundaram K, Kumar N, Monder C, Bardin CW. Different patterns of metabolism determine the relative anabolic activity of 19-norandrogens.Journal of Steroid Biochemistry and Molecular Biology.1995;53:253–257. [PubMed: 7626464]

710.

Toth M, Zakar T. Relative binding affinities of testosterone, 19-nortestosterone and their 5 alpha-reduced derivatives to the androgen receptor and to other androgen-binding proteins: a suggested role of 5 alpha-reductive steroid metabolism in the dissociation of "myotropic" and "androgenic" activities of 19-nortestosterone.Journal of Steroid Biochemistry.1982;17:653–660. [PubMed: 6891012]

711.

LaMorte A, Kumar N, Bardin CW, Sundaram K. Aromatization of 7 alpha-methyl-19-nortestosterone by human placental microsomes in vitro.Journal of Steroid Biochemistry and Molecular Biology.1994;48:297–304. [PubMed: 8142308]

712.

Moslemi S, Dintinger T, Dehennin L, Silberzahn P, Gaillard JL. Different in vitro metabolism of 7 alpha-methyl-19-nortestosterone by human and equine aromatases.European Journal of Biochemistry.1993;214:569–576. [PubMed: 8513806]

713.

Dobs AS, Boccia RV, Croot CC, Gabrail NY, Dalton JT, Hancock ML, Johnston MA, Steiner MS. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial.Lancet Oncology.2013;14:335–345. [PMC free article: PMC4898053] [PubMed: 23499390]

714.

Crawford J, Prado CM, Johnston MA, Gralla RJ, Taylor RP, Hancock ML, Dalton JT. Study Design and Rationale for the Phase 3 Clinical Development Program of Enobosarm, a Selective Androgen Receptor Modulator, for the Prevention and Treatment of Muscle Wasting in Cancer Patients (POWER Trials).Current Oncology Reports.2016;18:37. [PMC free article: PMC4853438] [PubMed: 27138015]

715.

Yin D, Xu H, He Y, Kirkovsky LI, Miller DD, Dalton JT. Pharmacology, pharmacokinetics, and metabolism of acetothiolutamide, a novel nonsteroidal agonist for the androgen receptor.Journal of Pharmacology and Experimental Therapeutics.2002;304:1323–1333.

716.

Gao W, Dalton JT. Ockham's razor and selective androgen receptor modulators (SARMs): are we overlooking the role of 5alpha-reductase?Mol Interv.2007;7:10–13. [PMC free article: PMC2040232] [PubMed: 17339601]

717.

Sengupta S, Jordan VC. Selective estrogen modulators as an anticancer tool: mechanisms of efficiency and resistance.Advances in Experimental Medicine and Biology.2008;630:206–219. [PubMed: 18637493]

718.

Gao W, Dalton JT. Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs).Drug Discov Today.2007;12:241–248. [PMC free article: PMC2072879] [PubMed: 17331889]

719.

Thole Z, Manso G, Salgueiro E, Revuelta P, Hidalgo A. Hepatotoxicity induced by antiandrogens: a review of the literature.Urologia Internationalis.2004;73:289–295. [PubMed: 15604569]

720.

Manso G, Thole Z, Salgueiro E, Revuelta P, Hidalgo A. Spontaneous reporting of hepatotoxicity associated with antiandrogens: data from the Spanish pharmacovigilance system.Pharmacoepidemiol Drug Saf.2006;15:253–259. [PubMed: 16294367]

721.

Minnemann T, Schubert M, Hubler D, Gouni-Berthold I, Freude S, Schumann C, Oettel M, Ernst M, Mellinger U, Sommer F, Krone W, Jockenhovel F. A four-year efficacy and safety study of the long-acting parenteral testosterone undecanoate.Aging Male.2007;10:155–158. [PubMed: 17701659]

722.

Saad F, Kamischke A, Yassin A, Zitzmann M, Schubert M, Jockenhel F, Behre HM, Gooren L, Nieschlag E. More than eight years' hands-on experience with the novel long-acting parenteral testosterone undecanoate.Asian Journal of Andrology.2007;9:291–297. [PubMed: 17486268]

723.

Stege R, Frohlander N, Carlstrom K, Pousette A, von Schoultz B. Steroid-sensitive proteins, growth hormone and somatomedin C in prostatic cancer: effects of parenteral and oral estrogen therapy.Prostate.1987;10:333–338. [PubMed: 2440014]

724.

Serin IS, Ozcelik B, Basbug M, Aygen E, Kula M, Erez R. Long-term effects of continuous oral and transdermal estrogen replacement therapy on sex hormone binding globulin and free testosterone levels.European Journal of Obstetrics, Gynecology, and Reproductive Biology.2001;99:222–225. [PubMed: 11788176]

725.

von Schoultz B, Carlstrom K. On the regulation of sex-hormone-binding globulin. A challenge of an old dogma and outlines of an alternative mechanism.Journal of Steroid Biochemistry and Molecular Biology.1989;32:327–334.

726.

Small M, Beastall GH, Semple CG, Cowan RA, Forbes CD. Alterations of hormone levels in normal males given the anabolic steroid stanozolol.Clinical Endocrinology.1984;21:49–55. [PubMed: 6430603]

727.

Christiansen K 2004 Behavioural correlates of testosterone. In: Nieschlag E, Behre HM eds. Testosterone: Action Deficiency Substitution. 3rd ed. Cambridge: Cambridge University Press; 125-172.

728.

Anderson RA, Bancroft J, Wu FCW. The effects of exogenous testosterone on sexuality and mood of normal men.Journal of Clinical Endocrinology and Metabolism.1992;75:1503–1507. [PubMed: 1464655]

729.

Buena F, Peterson MA, Swerdloff RS, Pandian MR, Steiner BS, Galmarini M, Lutchmansingh P, Bhasin S. Sexual function does not change when serum testosterone levels are pharmacologically varied within the normal male range.Fertility and Sterility.1993;59:1118–1123. [PubMed: 8486184]

730.

Bagatell CJ, Heiman JR, Matsumoto AM, Rivier JE, Bremner WJ. Metabolic and behavioral effects of high-dose, exogenous testosterone in healthy men.Journal of Clinical Endocrinology and Metabolism.1994;79:561–567. [PubMed: 8045977]

731.

Tricker R, Casaburi R, Storer TW, Clevenger B, Berman N, Shirazi A, Bhasin S. The effects of supraphysiological doses of testosterone on angry behavior in healthy eugonadal men--a clinical research center study.Journal of Clinical Endocrinology and Metabolism.1996;81:3754–3758. [PubMed: 8855834]

732.

O'Connor DB, Archer J, Hair WM, Wu FC. Exogenous testosterone, aggression, and mood in eugonadal and hypogonadal men.Physiology and Behavior.2002;75:557–566. [PubMed: 12062320]

733.

O'Connor DB, Archer J, Wu FC. Effects of testosterone on mood, aggression, and sexual behavior in young men: a double-blind, placebo-controlled, cross-over study.Journal of Clinical Endocrinology and Metabolism.2004;89:2837–2845. [PubMed: 15181066]

734.

Meriggiola MC, Cerpolini S, Bremner WJ, Mbizvo MT, Vogelsong KM, Martorana G, Pelusi G. Acceptability of an injectable male contraceptive regimen of norethisterone enanthate and testosterone undecanoate for men.Human Reproduction.2006;21:2033–2040. [PubMed: 16731547]

735.

Su TP, Pagliaro M, Schmidt PJ, Pickar D, Wolkowitz O, Rubinow DR. Neuropsychiatric effects of anabolic steroids in male normal volunteers.Journal of the American Medical Association.1993;269:2760–2764. [PubMed: 8492402]

736.

Yates WR, Perry PJ, MacIndoe J, Holman T, Ellingrod V. Psychosexual effects of three doses of testosterone cycling in normal men.Biological Psychiatry.1999;45:254–260. [PubMed: 10023498]

737.

Daly RC, Su TP, Schmidt PJ, Pagliaro M, Pickar D, Rubinow DR. Neuroendocrine and behavioral effects of high-dose anabolic steroid administration in male normal volunteers.Psychoneuroendocrinology.2003;28:317–331. [PubMed: 12573299]

738.

Schmidt PJ, Berlin KL, Danaceau MA, Neeren A, Haq NA, Roca CA, Rubinow DR. The effects of pharmacologically induced hypogonadism on mood in healthy men.Archives of General Psychiatry.2004;61:997–1004. [PubMed: 15466673]

739.

WHO Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men.Fertility and Sterility.1996;65:821–829. [PubMed: 8654646]

740.

WHO Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia in normal men.Lancet.1990;336:955–959. [PubMed: 1977002]

741.

Bjorkvist K, Nygren T, Bjorklund AC, Bjorkvist SE. Testosterone intake and aggressiveness: real effect or anticipation?Aggressive Behavior.1994;20:17–26.

742.

Archer J. The influence of testosterone on human aggression.British Journal of Psychiatry.1991;82:1–28.

743.

Melnik B, Jansen T, Grabbe S. Abuse of anabolic-androgenic steroids and bodybuilding acne: an underestimated health problem.J Dtsch Dermatol Ges.2007;5:110–117. [PubMed: 17274777]

744.

Grunstein RR, Handelsman DJ, Lawrence SJ, Blackwell C, Caterson ID, Sullivan CE. Hypothalamic dysfunction in sleep apnea: reversal by nasal continuous positive airways pressure.Journal of Clinical Endocrinology and Metabolism.1989;68:352–358. [PubMed: 2493027]

745.

Sandblom RE, Matsumoto AM, Scoene RB, Lee KA, Giblin EC, Bremner WJ, Pierson DJ. Obstructive sleep apnea induced by testosterone administration.New England Journal of Medicine.1983;308:508–510. [PubMed: 6823267]

746.

Liu PY, Yee BJ, Wishart SM, Jimenez M, Jung DG, Grunstein RR, Handelsman DJ. The short-term effects of high dose testosterone on sleep, breathing and function in older men.Journal of Clinical Endocrinology and Metabolism.2003;88:3605–3613. [PubMed: 12915643]

747.

Martinez C, Suissa S, Rietbrock S, Katholing A, Freedman B, Cohen AT, Handelsman DJ. Testosterone treatment and risk of venous thromboembolism: population based case-control study.BMJ.2016;355:i5968. [PMC free article: PMC5130924] [PubMed: 27903495]

748.

Glueck CJ, Goldenberg N, Wang P. Thromboembolism peaking 3 months after starting testosterone therapy: testosterone-thrombophilia interactions.J Investig Med.2018;66:733–738.

749.

Glueck CJ, Goldenberg N, Budhani S, Lotner D, Abuchaibe C, Gowda M, Nayar T, Khan N, Wang P. Thrombotic events after starting exogenous testosterone in men with previously undiagnosed familial thrombophilia.Transl Res.2011;158:225–234. [PubMed: 21925119]

750.

Walker RF, Zakai NA, MacLehose RF, Cowan LT, Adam TJ, Alonso A, Lutsey PL. Association of Testosterone Therapy With Risk of Venous Thromboembolism Among Men With and Without Hypogonadism.JAMA Intern Med.2019;180:190–197.

751.

Baillargeon J, Urban RJ, Morgentaler A, Glueck CJ, Baillargeon G, Sharma G, Kuo YF. Risk of Venous Thromboembolism in Men Receiving Testosterone Therapy.Mayo Clin Proc.2015;90:1038–1045. [PubMed: 26205547]

752.

Li H, Benoit K, Wang W, Motsko S. Association between Use of Exogenous Testosterone Therapy and Risk of Venous Thrombotic Events among Exogenous Testosterone Treated and Untreated Men with Hypogonadism.J Urol.2016;195:1065–1072. [PubMed: 26523880]

753.

Cole AP, Hanske J, Jiang W, Kwon NK, Lipsitz SR, Kathrins M, Learn PA, Sun M, Haider AH, Basaria S, Trinh QD. Impact of testosterone replacement therapy on thromboembolism, heart disease and obstructive sleep apnoea in men.BJU Int.2018;121:811–818. [PubMed: 29383868]

754.

Houghton DE, Alsawas M, Barrioneuvo P, Tello M, Farah W, Beuschel B, Prokop LJ, Layton JB, Murad MH, Moll S. Testosterone therapy and venous thromboembolism: A systematic review and meta-analysis.Thromb Res.2018;172:94–103. [PMC free article: PMC10601700] [PubMed: 30396049]

755.

Glueck CJ, Goldenberg N, Wang P. Testosterone Therapy, Thrombophilia, Venous Thromboembolism, and Thrombotic Events.J Clin Med.2018:8. [PMC free article: PMC6352282] [PubMed: 30577544]

756.

Luo S, Au Yeung SL, Zhao JV, Burgess S, Schooling CM. Association of genetically predicted testosterone with thromboembolism, heart failure, and myocardial infarction: mendelian randomisation study in UK Biobank.Bmj.2019;364:l476. [PMC free article: PMC6402044] [PubMed: 30842065]

757.

Svartberg J, Braekkan SK, Laughlin GA, Hansen JB. Endogenous sex hormone levels in men are not associated with risk of venous thromboembolism: the Tromso study.Eur J Endocrinol.2009;160:833–838. [PubMed: 19208774]

758.

Welder AA, Robertson JW, Melchert RB. Toxic effects of anabolic-androgenic steroids in primary rat hepatic cell cultures.Journal of Pharmacological and Toxicological Methods.1995;33:187–195. [PubMed: 8527826]

759.

Gitlin N, Korner P, Yang HM. Liver function in postmenopausal women on estrogen-androgen hormone replacement therapy: a meta-analysis of eight clinical trials.Menopause.1999;6:216–224. [PubMed: 10486791]

760.

Gelfand MM, Wiita B. Androgen and estrogen-androgen hormone replacement therapy: a review of the safety literature, 1941 to 1996.Clinical Therapeutics.1997;19:383–404. [PubMed: 9220205]

761.

Pertusi R, Dickerman RD, McConathy WJ. Evaluation of aminotransferase elevations in a bodybuilder using anabolic steroids: hepatitis or rhabdomyolysis?Journal of the American Osteopathic Association.2001;101:391–394. [PubMed: 11476029]

762.

Tsokos M, Erbersdobler A. Pathology of peliosis.Forensic Science International.2005;149:25–33. [PubMed: 15734106]

763.

Falk H, Thomas LB, Popper H, Ishak KG. Hepatic angiosarcoma associated with androgenic-anabolic steroids.Lancet.1979;2:1120–1123. [PubMed: 91848]

764.

Daneshmend TK, Bradfield JW. Hepatic angiosarcoma associated with androgenic-anabolic steroids.Lancet.1979;2:1249.

765.

Mackey MA, Conway AJ, Handelsman DJ. Tolerability of intramuscular injections of testosterone ester in an oil vehicle.Human Reproduction.1995;10:862–865. [PubMed: 7650133]

766.

Bhagat R, Holmes IH, Kulaga A, Murphy F, Cockcroft DW. Self-injection with olive oil. A cause of lipoid pneumonia.Chest.1995;107:875–876. [PubMed: 7874970]

767.

Hjort M, Hoegberg LC, Almind M, Jansen T. Subacute fat-embolism-like syndrome following high-volume intramuscular and accidental intravascular injection of mineral oil.Clin Toxicol (Phila).2015;53:230–232. [PubMed: 25684399]

768.

Middleton T, Turner L, Fennell C, Savkovic S, Jayadev V, Conway AJ, Handelsman DJ. Complications of injectable testosterone undecanoate in routine clinical practice.European Journal of Endocrinology.2015;172:511–517. [PubMed: 25637074]

769.

Meyer RJ, Mann M. Pulmonary oil micro-embolism (POME) syndrome: a review and summary of a large case series.Current Medical Research and Opinion.2015;31:837–841. [PubMed: 25686650]

770.

Darsow U, Bruckbauer H, Worret WI, Hofmann H, Ring J. Subcutaneous oleomas induced by self-injection of sesame seed oil for muscle augmentation.Journal of the American Academy of Dermatology.2000;42:292–294. [PubMed: 10642691]

771.

Lawrentschuk N, Fleshner N. Severe irritant contact dermatitis causing skin ulceration secondary to a testosterone patch.TheScientificWorldJournal.2009;9:333–338.

772.

Rolf C, Knie U, Lemmnitz G, Nieschlag E. Interpersonal testosterone transfer after topical application of a newly developed testosterone gel preparation.Clinical Endocrinology.2002;56:637–641. [PubMed: 12030915]

773.

Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men.Journal of Clinical Endocrinology and Metabolism.2006;91:4335–4343. [PubMed: 16926258]

774.

Jockenhovel F, Minnemann T, Schubert M, Freude S, Hubler D, Schumann C, Christoph A, Gooren L, Ernst M. Timetable of effects of testosterone administration to hypogonadal men on variables of sex and mood.Aging Male.2009;12:113–118. [PubMed: 19909203]

775.

Mooradian AD, Morley JE, Korenman SG. Biological actions of androgens.Endocrine Reviews.1987;8:1–28. [PubMed: 3549275]

776.

Palacios A, Campfield LA, McClure RD, Steiner B, Swerdloff RS. Effect of testosterone enanthate on hematopoesis in normal men.Fertility and Sterility.1983;40:100–104. [PubMed: 6862037]

777.

Drinka PJ, Jochen AL, Cuisinier M, Bloom R, Rudman I, Rudman D. Polycythemia as a complication of testosterone replacement therapy in nursing home men with low testosterone levels.Journal of the American Geriatric Society.1995;43:899–901.

778.

Ip FF, di Pierro I, Brown R, Cunningham I, Handelsman DJ, Liu PY. Trough serum testosterone predicts the development of polycythemia in hypogonadal men treated for up to 21 years with subcutaneous testosterone pellets.European Journal of Endocrinology.2010;162:385–390. [PubMed: 19903801]

779.

Viallard JF, Marit G, Mercie P, Leng B, Reiffers J, Pellegrin JL. Polycythaemia as a complication of transdermal testosterone therapy.British Journal of Haematology.2000;110:237–238. [PubMed: 10931008]

780.

Tefferi A. Polycythemia vera and essential thrombocythemia: 2012 update on diagnosis, risk stratification, and management.American Journal of Hematology.2012;87:285–293. [PubMed: 22331582]

781.

Siddique H, Smith JC, Corrall RJ. Reversal of polycythaemia induced by intramuscular androgen replacement using transdermal testosterone therapy.Clinical Endocrinology.2004;60:143–145. [PubMed: 14678301]

782.

Wu JP, Gu FL. The prostate 41-65 years post castration.Chinese Medical Journal.1987;100:271–272. [PubMed: 3115690]

783.

Swerdlow AJ, Schoemaker MJ, Higgins CD, Wright AF, Jacobs PA. Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study.Journal of the National Cancer Institute.2005;97:1204–1210. [PubMed: 16106025]

784.

Behre HM, Bohmeyer J, Nieschlag E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls.Clinical Endocrinology.1994;40:341–349. [PubMed: 7514512]

785.

Jin B, Conway AJ, Handelsman DJ. Effects of androgen deficiency and replacement on prostate zonal volumes.Clinical Endocrinology.2001;54:437–445. [PubMed: 11318778]

786.

Handelsman DJ 1998 The safety of androgens: prostate and cardiovascular disease. In: Wang C ed. Male Reproductive Function. Boston: Kluwer Academic Publishers; 173-190.

787.

Fowler JE Jr, Whitmore WF Jr. The response of metastatic adenocarcinoma of the prostate to exogenous testosterone.Journal of Urology.1981;126:372–375. [PubMed: 7277602]

788.

Fowler JE Jr, Whitmore WF Jr. Considerations for the use of testosterone with systemic chemotherapy in prostatic cancer.Cancer.1982;49:1373–1377. [PubMed: 7059952]

789.

Wright JL, Higano CS, Lin DW. Intermittent androgen deprivation: clinical experience and practical applications.Urologic Clinics of North America.2006;33:167–179. vi. [PubMed: 16631455]

790.

Feltquate D, Nordquist L, Eicher C, Morris M, Smaletz O, Slovin S, Curley T, Wilton A, Fleisher M, Heller G, Scher HI. Rapid androgen cycling as treatment for patients with prostate cancer.Clinical Cancer Research.2006;12:7414–7421. [PubMed: 17189414]

791.

Manni A, Bartholomew M, Caplan R, Boucher A, Santen R, Lipton A, Harvey H, Simmonds M, White-Hershey D, Gordon R, et al. Androgen priming and chemotherapy in advanced prostate cancer: evaluation of determinants of clinical outcome.Journal of Clinical Oncology.1988;6:1456–1466. [PubMed: 3047336]

792.

Santen RJ, Manni A, English HF, Heitjan D. Androgen-primed chemotherapy-experimental confirmation of efficacy.Journal of Steroid Biochemistry and Molecular Biology.1990;37:1115–1120. [PubMed: 2285585]

793.

Szmulewitz R, Mohile S, Posadas E, Kunnavakkam R, Karrison T, Manchen E, Stadler WM. A randomized phase 1 study of testosterone replacement for patients with low-risk castration-resistant prostate cancer.European Urology.2009;56:97–103. [PMC free article: PMC2885777] [PubMed: 19282098]

794.

Morris MJ, Huang D, Kelly WK, Slovin SF, Stephenson RD, Eicher C, Delacruz A, Curley T, Schwartz LH, Scher HI. Phase 1 trial of high-dose exogenous testosterone in patients with castration-resistant metastatic prostate cancer.European Urology.2009;56:237–244. [PMC free article: PMC2738932] [PubMed: 19375217]

795.

Cui Y, Zong H, Yan H, Zhang Y. The effect of testosterone replacement therapy on prostate cancer: a systematic review and meta-analysis.Prostate Cancer Prostatic Dis.2014;17:132–143. [PubMed: 24445948]

796.

Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men.Journal of Urology.2004;172:920–922. [PubMed: 15310998]

797.

Rhoden EL, Averbeck MA, Teloken PE. Androgen replacement in men undergoing treatment for prostate cancer.J Sex Med.2008;5:2202–2208. [PubMed: 18638000]

798.

Morgentaler A. Testosterone therapy in men with prostate cancer: scientific and ethical considerations.Journal of Urology.2009;181:972–979. [PubMed: 19150547]

799.

Hormones in advanced cancer.British Medical Journal.1971;2:760–763. [PMC free article: PMC1796325] [PubMed: 4253671]

800.

Muggia FM. Overview of cancer-related hypercalcemia: epidemiology and etiology.Seminars in Oncology.1990;17:3–9.

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