Hypogonadism

Hypogonadism means diminished functional activity of the gonads—the testes in males or the ovaries in females—that may result in diminished sex hormone biosynthesis. In layman's terms, it is sometimes called interrupted stage 1 puberty. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estrogen (e.g., estradiol) as hypoestrogenism, and may occur as symptoms of hypogonadism in both sexes, but are generally only diagnosed in males and females respectively. Other hormones produced by the gonads that hypogonadism can decrease include progesterone, DHEA, anti-Müllerian hormone, activin, and inhibin. Spermatogenesis in males, and ovulation in females, may be impaired by hypogonadism, which, depending on the degree of severity, may result in partial or complete infertility.

Classification

Deficiency of sex hormones can result in defective primary or secondary sexual development, or withdrawal effects (e.g., premature menopause) in adults. Defective egg or sperm development results in infertility. The term hypogonadism usually means permanent rather than transient or reversible defects, and usually implies deficiency of reproductive hormones, with or without fertility 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 measure gonadotropins (LH and FSH) to distinguish primary from secondary hypogonadism. In primary hypogonadism the LH and/or FSH are usually elevated, meaning the problem is in the testicles, whereas in secondary hypogonadism, both are normal or low, suggesting the problem is in the brain.

Affected system

• Hypogonadism resulting from defects of the gonads is traditionally referred to as primary hypogonadism. Examples include Klinefelter syndrome and Turner syndrome. Mumps is known to cause testicular failure, and in recent years has been immunized against in the US. A varicocele can reduce hormonal production as well.
• Hypogonadism resulting from hypothalamic or pituitary defects are termed secondary hypogonadism or central hypogonadism (referring to the central nervous system).
  • Examples of hypothalamic defects include Kallmann syndrome.
  • Examples of pituitary defects include hypopituitarism.
• An example of a hypogonadism resulting from the lack of hormone response is androgen insensitivity syndrome, where there are inadequate receptors to bind the testosterone, resulting in a female appearance despite XY chromosomes.

Primary or secondary

• Primary - defect is inherent within the gonad: e.g. Noonan syndrome, Turner syndrome (45X,0), Klinefelter syndrome (47XXY), XY females with SRY gene-immunity
• Secondary - defect lies outside of the gonad: e.g. Polycystic ovary syndrome, and Kallmann syndrome, also called hypogonadotropic hypogonadism.^[1] Hemochromatosis and diabetes mellitus can be causes of this as well.

Congenital vs. acquired

• Examples of congenital causes of hypogonadism, that is, causes that are present at birth:
  • Turner syndrome in females, and Klinefelter syndrome in males. It is also one of the signs of CHARGE syndrome.
• Examples of acquired causes of hypogonadism:
  • Opioid Induced Androgen Deficiency (resulting from the prolonged use of opioid class drugs, e.g. codeine,Dihydrocodeine, morphine, oxycodone, methadone, fentanyl, hydromorphone, etc.)
  • Anabolic steroid-induced hypogonadism (ASIH)
  • Childhood mumps
  • Children born to mothers who had ingested the endocrine disruptor diethylstilbestrol for potential miscarriage
  • Traumatic brain injury, even in childhood
  • In males, normal aging causes a decrease in androgens, which is sometimes called "male menopause" (also known by the coinage "manopause"), late-onset hypogonadism (LOH), and andropause or androgen decline in the aging male (ADAM), among other names.
  • It is a symptom of Hereditary Hemochromatosis^[2]

Hormones vs. fertility

Hypogonadism can involve just hormone production or just fertility, but most commonly involves both.

• Examples of hypogonadism that affect hormone production more than fertility are hypopituitarism and Kallmann syndrome; in both cases, fertility is reduced until hormones are replaced but can be achieved solely with hormone replacement.
• Examples of hypogonadism that affect fertility more than hormone production are Klinefelter syndrome and Kartagener syndrome.

Signs and symptoms

Women with hypogonadism do not begin menstruating and it may affect their height and breast development. Onset in women after puberty causes cessation of menstruation, lowered libido, loss of body hair and hot flashes. In boys it causes impaired muscle and beard development and reduced height. In men it can cause reduced body hair and beard, enlarged breasts, loss of muscle, and sexual difficulties. A brain tumor (central hypogonadism) may involve headaches, impaired vision, milky discharge from the breast and symptoms caused by other hormone problems.^[3]

Hypogonadotrophic hypogonadism

The symptoms of hypogonadotrophic 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.

Diagnosis

Men

Low testosterone 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.^[4] However, low testosterone in the absence of any symptoms does not clearly need to be treated.

Normal total testosterone levels depend on the man's age but generally range from 240–950 ng/dL (nanograms per deciliter) or 8.3-32.9 nmol/L (nanomoles per liter).^[5] 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, particularly luteinizing 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).

Treatment is often prescribed for total testosterone levels below 230 ng/dL with symptoms.^[6] 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.

The standard range given is based off 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.^[7] In men, testosterone falls approximately 1 to 3 percent each year.^[8]

Blood testing

A position statement by the Endocrine Society expressed dissatisfaction with most assays for total, free, and bioavailable testosterone.^[9] In particular, research has questioned the validity of commonly administered assays of free testosterone by radioimmunoassay.^[9] The free androgen index, essentially a calculation based on total testosterone and sex hormone-binding globulin levels, has been found to be the worst predictor of free testosterone levels and should not be used.^[10] Measurement by equilibrium dialysis or mass spectroscopy is generally required for accurately results, particularly for free testosterone which is present normal in such small concentrations.

Women

Testing serum LH and FSH levels are often used to assess hypogonadism in women, particularly when menopause 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.

Hypogonadism is often discovered during evaluation of delayed puberty, but ordinary delay, which eventually results in normal pubertal development, wherein reproductive function is termed constitutional delay. It may be discovered during an infertility evaluation in either men or women.

Treatment

Male primary or hypergonadogropic hypogonadism is often treated with testosterone replacement therapy if they are not trying to conceive.^[6] Adverse effects of testosterone replacement therapy include increased cardiovascular events (including strokes and heart attacks) and death.^[11] The Food and Drug Administration (FDA) stated in 2015 that neither the benefits nor the safety of testosterone have been established for low testosterone levels due to aging.^[12][13] The FDA has required that testosterone pharmaceutical labels include warning information about the possibility of an increased risk of heart attacks and stroke.^[12][13]

Commonly used testosterone replacement therapies include transdermal (through the skin) using a patch or gel, injections, or pellets. Oral testosterone is no longer used in the U.S. because it is broken down in the liver and rendered inactive; it also can cause severe liver damage. Like many hormonal therapies, changes take place over time. It may take as long as 2–3 months at optimum level to reduce the symptoms, particularly wordfinding and cognitive dysfunction. Testosterone levels in the blood should be evaluated to ensure the increase is adequate. Levels between 400 and 700 ng/dL are considered appropriate mid-dose levels. Treatment usually starts with 200 mg intramuscular testosterone, repeated every 14 days.

While historically, men with prostate cancer risk were warned against testosterone therapy, that has shown to be a myth.^[14]

Other side effects can include an elevation of the hematocrit 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 that obstructive sleep apnea may worsen with testosterone therapy, and should be monitored.^[15]

Another treatment for hypogonadism is human chorionic gonadotropin (hCG).^[16] This stimulates the LH receptor, thereby promoting testosterone synthesis. This will not be effective in men who simply cannot make 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 suppress spermatogenesis like testosterone replacement therapy does.

For both men and women, an alternative to testosterone replacement is low-dose clomifene 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.^[17] This therapy has only been shown helpful for men with secondary hypogonadism. Recent studies have shown it can be safe and effective monotherapy for up to 2 years in patients with intact testicular function and impaired function of the HPTA(http://www.nature.com/ijir/journal/v15/n3/full/3900981a.html). Clomifene blocks estrogen from binding to some estrogen receptors in the hypothalamus, thereby causing an increased release gNRH and subsequently LH from the pituitary. Clomifene is a Selective Estrogen Reuptake Modulator (SERM). Generally clomifene does not have adverse effects at the doses used for this purpose. Clomifene at much higher doses is used to induce ovulation and has significant adverse effects in such a setting.

For women with hypogonadism, estradiol and progesterone are often replaced. Some types of fertility defects can be treated, others cannot. Some physicians also give testosterone to women, mainly to increase libido.

See also

References

External links

• Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency Overview at National Center for Biotechnology Information.
• MedlinePlus Encyclopedia Hypogonadism
• The Pituitary Foundation
• Hypogonadism at eMedicine