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| Hypogonadism | |
|---|---|
| Other names | Interrupted stage 1 puberty, hypoandrogenism, hypoestrogenism |
| Specialty | Endocrinology |
Hypogonadism means diminished functional activity of thegonads—thetesticles or theovaries—that may result in diminishedproduction ofsex hormones. Lowandrogen (e.g.,testosterone) levels are referred to ashypoandrogenism and lowestrogen (e.g.,estradiol) ashypoestrogenism. These are responsible for the observed signs and symptoms in both males and females.
Hypogonadism, commonly referred to by the symptom "low testosterone" or "low T", can also decrease other hormones secreted by the gonads includingprogesterone,DHEA,anti-Müllerian hormone,activin, andinhibin.Sperm development (spermatogenesis) andrelease of the egg from the ovaries (ovulation) may be impaired by hypogonadism, which, depending on the degree of severity, may result in partial or completeinfertility.
In January 2020, theAmerican College of Physicians issued clinical guidelines fortestosterone treatment in adult men with age-related low levels of testosterone. The guidelines are supported by theAmerican Academy of Family Physicians. The guidelines include patient discussions regarding testosterone treatment forsexual dysfunction; annual patient evaluation regarding possible notable improvement and, if none, to discontinue testosterone treatment; physicians should consider intramuscular treatments, rather than transdermal treatments, due to costs and since the effectiveness and harm of either method is similar; and, testosterone treatment for reasons other than possible improvement of sexual dysfunction may not be recommended.[1][2]
Deficiency of sex hormones can result in defective primary or secondary sexual development, or withdrawal effects (e.g., prematuremenopause) in adults. Defective egg or sperm development results ininfertility. The term hypogonadism usually means permanent rather than transient or reversible defects, and usually implies deficiency of reproductive hormones, with or withoutfertility defects. The term is less commonly used for infertility without hormone deficiency. There are many possible types of hypogonadism and several ways to categorize them. Hypogonadism is also categorized by endocrinologists by the level of the reproductive system that is defective. Physicians measuregonadotropins (LH andFSH) to distinguish primary from secondary hypogonadism. In primary hypogonadism the LH and/or FSH are usually elevated, meaning the problem is in the testicles (hyper-gonatropic hypogonadism); whereas in secondary hypogonadism, both are normal or low, suggesting the problem is in the brain (hypo-gonatropic hypogonadism).[citation needed]
Hypogonadism can involve justhormone production or justfertility, but most commonly involves both.[citation needed]
Hypogonadism can occur in other conditions, likePrader–Willi syndrome.[citation needed]
Women with hypogonadism do not beginmenstruating and it may affect their height andbreast development. Onset in women afterpuberty causes cessation of menstruation, lowered libido, loss of body hair, andhot flashes. In men, it causes impaired muscle and body hair development,gynecomastia, decreased height,erectile dysfunction, and sexual difficulties. If hypogonadism is caused by a disorder of thecentral nervous system (e.g., abrain tumor), then this is known ascentral hypogonadism. Signs and symptoms of central hypogonadism may involve headaches, impaired vision,double vision,milky discharge from the breast, and symptoms caused by other hormone problems.[6]
The symptoms ofhypogonadotrophic hypogonadism, a subtype of hypogonadism, include late, incomplete, or lack of development at puberty, and sometimes short stature or the inability to smell; in females, a lack of breasts and menstrual periods, and in males a lack of sexual development, e.g., facial hair, penis, and testes enlargement, deepening voice.[citation needed]
Testing serumLH andFSH levels are often used to assess hypogonadism in women, particularly whenmenopause is believed to be happening. These levels change during a woman's normal menstrual cycle, so the history of having ceased menstruation coupled with high levels aids the diagnosis of being menopausal. Commonly, the post-menopausal woman is not called hypogonadal if she is of typical menopausal age. Contrast with a young woman or teen, who would have hypogonadism rather than menopause. This is because hypogonadism is an abnormality, whereas menopause is a normal change in hormone levels. In any case, the LH and FSH levels will rise in cases of primary hypogonadism or menopause, while they will be low in women with secondary or tertiary hypogonadism.[7]
Hypogonadism is often discovered during the evaluation ofdelayed puberty, but ordinary delay, which eventually results in normalpubertal development, wherein reproductive function is termedconstitutional delay. It may be discovered during aninfertility evaluation in either men or women.[8]
Lowtestosterone can be identified through a simple blood test performed by a laboratory, ordered by a health care provider. Blood for the test must be taken in the morning hours, when levels are highest, as levels can drop by as much as 13% during the day and all normal reference ranges are based on morning levels.[9][10]
Normal total testosterone levels depend on the man's age but generally range from 240 to 950 ng/dL (nanograms per deciliter) or 8.3–32.9 nmol/L (nanomoles per liter).[11] According to American Urological Association, the diagnosis of low testosterone can be supported when the total testosterone level is below 300 ng/dl.[12] Some men with normal total testosterone have low free or bioavailable testosterone levels which could still account for their symptoms. Men with low serum testosterone levels should have other hormones checked, particularlyluteinizing hormone to help determine why their testosterone levels are low and help choose the most appropriate treatment (most notably, testosterone is usually not appropriate for secondary or tertiary forms of male hypogonadism, in which the LH levels are usually reduced).[citation needed]
Treatment is often prescribed for total testosterone levels below 230 ng/dL with symptoms.[13] If the serum total testosterone level is between 230 and 350 ng/dL, free or bioavailable testosterone should be checked as they are frequently low when the total is marginal.[citation needed]
The standard range given is based on widely varying ages and, given that testosterone levels naturally decrease as humans age, age-group specific averages should be taken into consideration when discussing treatment between doctor and patient.[14] In men, testosterone falls approximately 1 to 3 percent each year.[15]
A position statement by the Endocrine Society expressed dissatisfaction with most assays for total, free, and bioavailable testosterone.[16] In particular, research has questioned the validity of commonly administered assays of free testosterone by radioimmunoassay.[16] The free androgen index, essentially a calculation based on total testosterone and sex hormone-binding globulin levels, is the worst predictor of free testosterone levels and should not be used.[17] Measurement by equilibrium dialysis or mass spectroscopy is generally required for accurate results, particularly for free testosterone which is normally present in very small concentrations.[citation needed]
Screening males who do not have symptoms of hypogonadism is not recommended as of 2018.[18]
Male primary orhypergonadotropic hypogonadism is often treated withtestosterone replacement therapy if they are not trying to conceive.[13]
In short- and medium-term testosterone replacement therapy the risk ofcardiovascular events (includingstrokes andheart attacks and other heart diseases) is not increased. The long-term safety of the therapy is not known yet.[19][20] Side effects can include an elevation ofhematocrit to levels that require blood withdrawal (phlebotomy) to prevent complications from excessively thick blood.Gynecomastia (growth of breasts in men) sometimes occurs. Finally, some physicians worry thatobstructive sleep apnea may worsen with testosterone therapy, and should be monitored.[21]
While historically, men with prostate cancer risk were warned against testosterone therapy, that has shown to be a myth.[22]
Another treatment for hypogonadism ishuman chorionic gonadotropin (hCG).[23] This stimulates the LH receptor, thereby promoting testosterone synthesis. This will not be effective in men whose testes simply cannot synthesize testosterone anymore (primary hypogonadism), and the failure of hCG therapy is further support for the existence of true testicular failure in a patient. It is particularly indicated in men with hypogonadism who wish to retain their fertility, as it does not suppressspermatogenesis (sperm production) as testosterone replacement therapy does.[citation needed]
For both men and women, an alternative to testosterone replacement is low-doseclomifene treatment, which can stimulate the body to naturally increase hormone levels while avoiding infertility and other side effects that can result from direct hormone replacement therapy.[24] Clomifene blocks estrogen from binding to some estrogen receptors in thehypothalamus, thereby causing an increased release ofgonadotropin-releasing hormone and subsequently LH from the pituitary. Clomifene is aselective estrogen receptor modulator (SERM). Generally, clomifene does not have adverse effects at the doses used for this purpose.
| Route | Medication | Major brand names | Form | Dosage |
|---|---|---|---|---|
| Oral | Testosteronea | – | Tablet | 400–800 mg/day (in divided doses) |
| Testosterone undecanoate | Andriol, Jatenzo | Capsule | 40–80 mg/2–4× day (with meals) | |
| Methyltestosteroneb | Android, Metandren, Testred | Tablet | 10–50 mg/day | |
| Fluoxymesteroneb | Halotestin, Ora-Testryl, Ultandren | Tablet | 5–20 mg/day | |
| Metandienoneb | Dianabol | Tablet | 5–15 mg/day | |
| Mesteroloneb | Proviron | Tablet | 25–150 mg/day | |
| Sublingual | Testosteroneb | Testoral | Tablet | 5–10 mg 1–4×/day |
| Methyltestosteroneb | Metandren, Oreton Methyl | Tablet | 10–30 mg/day | |
| Buccal | Testosterone | Striant | Tablet | 30 mg 2×/day |
| Methyltestosteroneb | Metandren, Oreton Methyl | Tablet | 5–25 mg/day | |
| Transdermal | Testosterone | AndroGel, Testim, TestoGel | Gel | 25–125 mg/day |
| Androderm, AndroPatch, TestoPatch | Non-scrotal patch | 2.5–15 mg/day | ||
| Testoderm | Scrotal patch | 4–6 mg/day | ||
| Axiron | Axillary solution | 30–120 mg/day | ||
| Androstanolone (DHT) | Andractim | Gel | 100–250 mg/day | |
| Rectal | Testosterone | Rektandron, Testosteronb | Suppository | 40 mg 2–3×/day |
| Injection (IMTooltip intramuscular injection orSCTooltip subcutaneous injection) | Testosterone | Andronaq, Sterotate, Virosterone | Aqueous suspension | 10–50 mg 2–3×/week |
| Testosterone propionateb | Testoviron | Oil solution | 10–50 mg 2–3×/week | |
| Testosterone enanthate | Delatestryl | Oil solution | 50–250 mg 1x/1–4 weeks | |
| Xyosted | Auto-injector | 50–100 mg 1×/week | ||
| Testosterone cypionate | Depo-Testosterone | Oil solution | 50–250 mg 1x/1–4 weeks | |
| Testosterone isobutyrate | Agovirin Depot | Aqueous suspension | 50–100 mg 1x/1–2 weeks | |
| Testosterone phenylacetateb | Perandren, Androject | Oil solution | 50–200 mg 1×/3–5 weeks | |
| Mixed testosterone esters | Sustanon 100, Sustanon 250 | Oil solution | 50–250 mg 1×/2–4 weeks | |
| Testosterone undecanoate | Aveed, Nebido | Oil solution | 750–1,000 mg 1×/10–14 weeks | |
| Testosterone buciclatea | – | Aqueous suspension | 600–1,000 mg 1×/12–20 weeks | |
| Implant | Testosterone | Testopel | Pellet | 150–1,200 mg/3–6 months |
| Notes: Men produce about 3 to 11 mg of testosterone per day (mean 7 mg/day in young men).Footnotes:a = Never marketed.b = No longer used and/or no longer marketed.Sources: See template. | ||||