Androgens increase in both males and females during puberty.[3] The major androgen in males istestosterone.[4]Dihydrotestosterone (DHT) andandrostenedione are of equal importance in male development.[4] DHTin utero causes differentiation of the penis, scrotum and prostate. In adulthood, DHT contributes to balding, prostate growth, andsebaceous gland activity.
Although androgens are commonly thought of only as malesex hormones, females also have them, but at lower levels: they function inlibido andsexual arousal. Androgens are the precursors toestrogens in both men and women.
Dehydroepiandrosterone (DHEA) is a steroid hormone produced in the adrenal cortex fromcholesterol.[5] It is the primary precursor of both the androgen andestrogen sex hormones. DHEA is also called dehydroisoandrosterone or dehydroandrosterone.
Androstenedione (A4) is an androgenic steroid produced by thetestes, adrenal cortex, andovaries. While androstenedione is converted metabolically totestosterone and other androgens, it is also the parent structure ofestrone. Use of androstenedione as an athletic orbodybuilding supplement has been banned by theInternational Olympic Committee, as well as other sporting organizations.
Androsterone is a chemical byproduct created during the breakdown of androgens, or derived fromprogesterone, that also exerts minor masculinising effects, but with one-seventh the intensity of testosterone. It is found in approximately equal amounts in theplasma andurine of both males and females.
Dihydrotestosterone (DHT) is a metabolite of testosterone, and a more potent androgen than testosterone in that it binds more strongly to androgen receptors. It is produced in the skin and reproductive tissue.
A4 and testosterone can also have an extra hydroxyl (-OH) or ketone (=O) group bound on position 11. In this case you can have11-hydroxyandrostenedione,11-ketoandrostenedione,11-hydroxytestosterone, and11-ketotestosterone. The latter has the same biological activity as testosterone[6] and, therefore, these are also very important in healthy individuals and patients with diseases like, congenital adrenal hyperplasia, polycystic ovarian syndrome, or premature adrenarche.[6]
Determined by consideration of all biological assay methods (c. 1970):[7]
The ovaries and adrenal glands also produce androgens, but at much lower levels than the testes. Regarding the relative contributions of ovaries and adrenal glands to female androgen levels, in a study with six menstruating women the following observations have been made:[8]
Adrenal contribution to peripheral T, DHT, A, DHEA and DHEA-S is relatively constant throughout themenstrual cycle.
Ovarian contribution of peripheral T, A and DHEA-S reaches maximum levels at mid-cycle, whereas ovarian contribution to peripheral DHT and DHEA does not seem to be influenced by the menstrual cycle.
Ovary and adrenal cortex contribute equally to peripheral T, DHT and A, with the exception that at mid-cycle ovarian contribution of peripheral A is twice that of the adrenal.
Peripheral DHEA and DHEA-S are produced mainly in the adrenal cortex which provides 80% of DHEA and over 90% of DHEA-S.
Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle[8]
Androgen
Ovarian (%) (F, M, L)
Adrenal (%)
DHEA
20
80
DHEA-S
4, 10, 4
90–96
Androstenedione
45, 70, 60
30–55
Testosterone
33, 60, 33
40–66
DHT
50
50
F = early follicular, M = midcycle, L = late luteal phase.
During mammalian development, the gonads are at first capable of becoming eitherovaries or testes.[9] In humans, starting at about week 4, the gonadal rudiments are present within theintermediate mesoderm adjacent to the developing kidneys. At about week 6, epithelialsex cords develop within the forming testes and incorporate thegerm cells as they migrate into the gonads. In males, certainY chromosome genes, particularlySRY, control development of the male phenotype, including conversion of the early bipotential gonad into testes. In males, the sex cords fully invade the developing gonads.
The mesoderm-derivedepithelial cells of the sex cords in developing testes become theSertoli cells, which will function to support sperm cell formation. A minor population of nonepithelial cells appear between the tubules by week 8 of human fetal development. These areLeydig cells. Soon after they differentiate, Leydig cells begin to produce androgens.
The androgens function asparacrinehormones required by the Sertoli cells to support sperm production. They are also required for the masculinization of the developing male fetus (including penis and scrotum formation). Under the influence of androgens, remnants of themesonephron, theWolffian ducts, develop into theepididymis,vas deferens andseminal vesicles. This action of androgens is supported by a hormone from Sertoli cells, Müllerian inhibitory hormone (MIH), which prevents the embryonic Müllerian ducts from developing into fallopian tubes and other female reproductive tract tissues in male embryos. MIH and androgens cooperate to allow for movement of testes into the scrotum.
Before the production of the pituitary hormoneluteinizing hormone (LH) by the embryo starting at about weeks 11–12,human chorionic gonadotrophin (hCG) promotes the differentiation of Leydig cells and their production of androgens at week 8. Androgen action in target tissues often involves conversion of testosterone to 5α-dihydrotestosterone (DHT).
During puberty, androgen, LH andfollicle stimulating hormone (FSH) production increase and the sex cords hollow out, forming the seminiferous tubules, and the germ cells start to differentiate into sperm. Throughout adulthood, androgens and FSH cooperatively act on Sertoli cells in the testes to support sperm production.[10] Exogenous androgen supplements can be used as amale contraceptive. Elevated androgen levels caused by use of androgen supplements can inhibit production of LH and block production of endogenous androgens by Leydig cells. Without the locally high levels of androgens in testes due to androgen production by Leydig cells, the seminiferous tubules can degenerate, resulting in infertility. For this reason, many transdermal androgen patches are applied to the scrotum.
Males typically have less body fat than females. Recent results indicate androgens inhibit the ability of some fat cells to store lipids by blocking a signal transduction pathway that normally supports adipocyte function.[11] Also, androgens, but not estrogens, increase betaadrenergic receptors while decreasing alpha adrenergic receptors—which results in increased levels of epinephrine/norepinephrine due to lack of alpha-2 receptor negative feedback and decreased fat accumulation due to epinephrine/norepinephrine then acting on lipolysis-inducing beta receptors.
Males typically have moreskeletal muscle mass than females. Androgens promote the enlargement of skeletal muscle cells in a coordinated manner by acting on several cell types in skeletal muscle tissue.[12] One cell type, called themyoblast, conveys androgen receptors for generating muscle. Fusion of myoblasts generatesmyotubes, in a process linked to androgen receptor levels.[13] Higher androgen levels lead to increased expression ofandrogen receptor.
Circulating levels of androgens can influence human behavior because someneurons are sensitive to steroid hormones. Androgen levels have been implicated in the regulation of humanaggression and libido. Indeed, androgens are capable of altering the structure of the brain in several species, including mice, rats, and primates, producingsex differences.[14] More recent studies showing the generalmood oftransgender men, who have undergonetransgender hormone replacement therapy replacingestrogens with androgens, do not show any substantial long-termbehavioral changes.[15][16][17]
Numerous reports have shown androgens alone are capable of altering thestructure of the brain,[18] but identification of which alterations in neuroanatomy stem from androgens or estrogens is difficult, because of their potential for conversion.
Evidence fromneurogenesis (formation of new neurons) studies on male rats has shown that thehippocampus is a useful brain region to examine when determining the effects of androgens on behavior. To examineneurogenesis, wild-type male rats were compared with male rats that hadandrogen insensitivity syndrome, a genetic difference resulting in complete or partial insensitivity to androgens and a lack of externalmale genitalia.
Neural injections ofbromodeoxyuridine (BrdU) were applied to males of both groups to test forneurogenesis. Analysis showed thattestosterone anddihydrotestosterone regulated adulthippocampalneurogenesis (AHN). Adult hippocampal neurogenesis was regulated through theandrogen receptor in the wild-type male rats, but not in the TMF male rats. To further test the role of activated androgen receptors on AHN,flutamide, anantiandrogen drug that competes with testosterone and dihydrotestosterone for androgen receptors, and dihydrotestosterone were administered to normal male rats. Dihydrotestosterone increased the number of BrdU cells, while flutamide inhibited these cells. Moreover, estrogens had no effect. This research demonstrates how androgens can increase AHN.[19]
Researchers also examined how mild exercise affected androgen synthesis which in turn causes AHN activation ofN-methyl-D-aspartate (NMDA) receptors.NMDA induces a calcium flux that allows for synaptic plasticity which is crucial for AHN.
Researchers injected both orchidectomized (ORX) (castrated) and sham castrated male rats withBrdU to determine if the number of new cells was increased. They found that AHN in male rats is increased with mild exercise by boosting synthesis ofdihydrotestosterone in thehippocampus. Again it was noted that AHN was not increased via activation of theestrogen receptors.[20]
AgainBrdU was injected into both groups of rats in order to see if cells were multiplying in the living tissue. These results demonstrate how the organization of androgens has a positive effect onpreadolescenthippocampalneurogenesis that may be linked with lowerdepression-like symptoms.[21]
Reduced ability of anXY-karyotype fetus to respond to androgens can result in one of several conditions, including infertility and several forms ofintersex conditions.
Determined by consideration of all biological assay methods (c. 1970):[7]
Androgen
Potency (%)
Testosterone
40
5α-Dihydrotestosterone (DHT)
100
Androstenediol
.0008
Androstenedione
.04
Dehydroepiandrosterone
.02
Androsterone
.06
5α-Dihydrotestosterone (DHT) was 2.4 times more potent than testosterone at maintaining normal prostate weight and duct lumen mass (this is a measure of epithelial cell function stimulation). Whereas DHT was equally potent as testosterone at preventing prostate cell death after castration.[24]One of the 11-oxygenated androgens, namely 11-ketotestosterone, has the same potency as testosterone.[25]
Androgens aresynthesized fromcholesterol and are produced primarily in thegonads (testicles and ovaries) and also in theadrenal glands. The testicles produce a much higher quantity than the ovaries. Conversion of testosterone to the more potent DHT occurs inprostate gland,liver,brain and skin.
Notes: "Theconcentration of a steroid in the circulation is determined by the rate at which it is secreted from glands, the rate of metabolism of precursor or prehormones into the steroid, and the rate at which it is extracted by tissues and metabolized. Thesecretion rate of a steroid refers to the total secretion of the compound from a gland per unit time. Secretion rates have been assessed by sampling the venous effluent from a gland over time and subtracting out the arterial and peripheral venous hormone concentration. Themetabolic clearance rate of a steroid is defined as the volume of blood that has been completely cleared of the hormone per unit time. Theproduction rate of a steroid hormone refers to entry into the blood of the compound from all possible sources, including secretion from glands and conversion of prohormones into the steroid of interest. At steady state, the amount of hormone entering the blood from all sources will be equal to the rate at which it is being cleared (metabolic clearance rate) multiplied by blood concentration (production rate = metabolic clearance rate × concentration). If there is little contribution of prohormone metabolism to the circulating pool of steroid, then the production rate will approximate the secretion rate."Sources: See template.
A low testosterone level (hypogonadism) in men may be treated with testosterone administration. Prostate cancer may be treated by removing the major source of testosterone: testicle removal (orchiectomy); or agents which block androgens from accessing their receptor:antiandrogens.
^Moini J (2015).Fundamental Pharmacology for Pharmacy Technicians. Cengage Learning. p. 338.ISBN978-1-30-568615-1.Androgen is the generic term for any natural or synthetic compound, usually a steroid hormone, which stimulates or controls the development of masculine characteristics by binding to androgen receptors.
^abBriggs MH, Brotherton J (3 February 1970).Steroid Biochemistry and Pharmacology. London: Academic Press.ISBN978-0-12-134650-8.
^abAbraham GE (August 1974). "Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle".The Journal of Clinical Endocrinology and Metabolism.39 (2):340–346.doi:10.1210/jcem-39-2-340.PMID4278727.
^Cooke B, Hegstrom CD, Villeneuve LS, Breedlove SM (October 1998). "Sexual differentiation of the vertebrate brain: principles and mechanisms".Frontiers in Neuroendocrinology.19 (4):323–362.doi:10.1006/frne.1998.0171.PMID9799588.S2CID14372914.
^Costantino A, Cerpolini S, Alvisi S, Morselli PG, Venturoli S, Meriggiola MC (14 February 2013). "A prospective study on sexual function and mood in female-to-male transsexuals during testosterone administration and after sex reassignment surgery".Journal of Sex & Marital Therapy.39 (4):321–335.doi:10.1080/0092623X.2012.736920.PMID23470169.S2CID34943756.
^Johnson JM, Nachtigall LB, Stern TA (1 November 2013). "The effect of testosterone levels on mood in men: a review".Psychosomatics.54 (6):509–514.doi:10.1016/j.psym.2013.06.018.PMID24016385.
