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(See also Endocrine and Metabolic Disorders in Children: Male Hypogonadism in Children.)
Hypogonadism
is defined as testosterone deficiency with associated symptoms or
signs, deficiency of spermatozoa production, or both. It may result
from a disorder of the testes (primary hypogonadism) or of the hypothalamic-pituitary
axis (secondary hypogonadism). Both may be congenital or acquired
as the result of aging, disease, drugs, or other factors. Additionally,
a number of congenital enzyme deficiencies cause varying degrees
of target organ androgen resistance. Diagnosis is confirmed by hormone
levels. Treatment varies with etiology but typically includes testosterone
replacement.
Etiology
Primary hypogonadism involves failure of the testes to respond to follicle-stimulating hormone (FSH) and luteinizing hormone (LH). When primary hypogonadism affects testosterone production, testosterone is insufficient to inhibit production of FSH and LH; hence, FSH and LH levels are elevated. The most common cause of primary hypogonadism is Klinefelter's syndrome. It involves seminiferous tubule dysgenesis and a 47,XXY karyotype (see Chromosomal Anomalies: Klinefelter's Syndrome (47,XXY)).
Secondary hypogonadism is failure of the hypothalamus (or pituitary) to produce enough FSH and LH. With secondary hypogonadism, testosterone levels are low, but levels of FSH and LH are low or inappropriately normal. Any acute systemic illness can cause temporary secondary hypogonadism. Some syndromes of hypogonadism have both primary and secondary causes (mixed hypogonadism). Table 1: Male Reproductive Endocrinology: Causes of Hypogonadism* lists some common causes of hypogonadism by category.
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Table 1
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Causes of Hypogonadism*
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Type
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Congenital Causes
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Acquired Causes
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Primary (testicular)
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Klinefelter's syndrome
Anorchia (bilateral)
Cryptorchidism
Myotonic dystrophy
Enzymatic defects in testosterone synthesis
Leydig cell aplasia
Noonan's syndrome
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Chemotherapy/radiation therapy
Testicular infection (mumps, echovirus, flavivirus)
High doses of certain drugs (eg, cimetidine , spironolactone , ketoconazole , flutamide , cyproterone )
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Secondary (hypothalamic-pituitary)
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Kallmann's syndrome
Prader-Willi syndrome
Dandy-Walker malformation
Isolated luteinizing hormone deficiency
Idiopathic
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Any acute systemic illness
Hypopituitarism (tumor, infarction, infiltrative disease, infection, trauma, radiation-induced)
Hyperprolactinemia
Iron overload (hemochromatosis)
Certain drugs (eg, estrogens , psychoactives, metoclopramide , opioids, leuprolide )
Cushing's syndrome
Cirrhosis
Morbid obesity
Idiopathic
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Mixed
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Aging
Alcoholism
Systemic disease (uremia, liver failure, AIDS, sickle cell disease)
Drugs (ethanol, corticosteroids)
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*In approximate order of frequency.
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Some syndromes of hypogonadism (eg, cryptorchidism, some systemic disorders) affect spermatozoon production more than testosterone levels.
Symptoms and Signs
Age at onset of testosterone deficiency dictates the clinical presentation: congenital, childhood-onset, and adult-onset hypogonadism. Congenital hypogonadism may be of 1st-, 2nd-, or 3rd-trimester onset.
First-trimester onset results in inadequate male sexual differentiation. Complete absence of testosterone's effects results in normal-appearing female external genitals. Partial testosterone deficiency results in abnormalities ranging from ambiguous external genitals to hypospadias. Second- or 3rd-trimester onset of testosterone deficiency results in microphallus and undescended testes.
Childhood-onset testosterone deficiency (see Endocrine and Metabolic Disorders in Children: Male Hypogonadism in Children) has few consequences and usually is unrecognized until puberty is delayed. Untreated hypogonadism impairs development of secondary sexual characteristics. As adults, affected patients have poor muscle development, a high-pitched voice, a small scrotum, decreased phallic and testicular growth, sparse pubic and axillary hair, and an absence of body hair. They may develop gynecomastia and eunuchoidal body proportions (span > height by 5 cm and pubic to floor length > crown to pubic length by > 5 cm) because of delayed fusion of the epiphyses and continued long bone growth.
Adult-onset testosterone deficiency has varied manifestations depending on the degree and duration of the deficiency. Decreased libido; erectile dysfunction; decline in cognitive skills, such as visual-spatial interpretation; sleep disturbances; vasomotor instability (in acute, severe male hypogonadism); and mood changes, such as depression and anger, are common. Decreased lean body mass, increased visceral fat, testicular atrophy, osteopenia, gynecomastia, and sparse body hair typically take months to years to develop. Testosterone deficiency may increase the risk of coronary artery disease.
Diagnosis
Congenital and childhood-onset hypogonadism are often suspected because of developmental abnormalities or delayed puberty. Adult-onset hypogonadism should be suspected on the basis of symptoms or signs but is easily missed because these markers are insensitive and nonspecific. Klinefelter's syndrome should be considered in adolescent males in whom puberty is delayed, young men with hypogonadism, and all adult men with very small testes. Hypogonadism requires confirmatory testing (see Fig. 2: Male Reproductive Endocrinology: Laboratory Evaluation of Male Hypogonadism ).
Diagnosis
of primary and secondary hypogonadism:
Increases in FSH and LH are more sensitive for primary hypogonadism than are decreases in testosterone levels. Levels of FSH and LH also help determine whether hypogonadism is primary or secondary; high gonadotropin levels, even with low-normal testosterone levels, indicate primary hypogonadism, whereas gonadotropin levels that are low or lower than expected for the level of testosterone indicate secondary hypogonadism. Alternatively, in boys of short stature with delayed puberty, low testosterone plus low gonadotropin levels might result from constitutional delay of puberty. Elevation of serum FSH with normal levels of serum testosterone and LH often occurs when spermatogenesis is impaired but testosterone production is normal. The cause of hypogonadism is often evident clinically. Primary hypogonadism requires no further testing, although some clinicians perform a karyotype to definitively diagnose Klinefelter's syndrome.
Total (or calculated free and weakly bound) serum testosterone, serum FSH, and serum LH levels are measured simultaneously. The normal range for total testosterone is 300 to 1000 ng/dL (10.5 to .35 nmol/L). The initial screening testosterone level may be done at any time of day, but a second testosterone level should be drawn in the morning to confirm hypogonadism. Because of the increase in sex hormone–binding globulin (SHBG) with aging, total testosterone level is less sensitive for hypogonadism after age 50. Although serum free testosterone more accurately reflects functional testosterone levels, its measurement requires equilibrium dialysis, which is technically difficult and not widely available. Some commercially available kits, including the analog free testosterone assay, attempt to measure serum free testosterone levels, but the results are often inaccurate, particularly in conditions such as type 2 diabetes, obesity, and hypothyroidism that alter SHBG levels. Free testosterone levels can be calculated based on SHBG, albumin, and testosterone values: there are calculators available online. See the Free and Bioavailable
Testosterone Calculator. Because of the pulsatile secretion of FSH and LH, they are sometimes measured as a pooled sample of 3 venipunctures taken at 20-min intervals, but these pooled samples seldom add clinically important information compared with a single blood sample. Serum FSH and LH levels are usually ≤ 5 mIU/mL before puberty and between 5 and 15 mIU/mL in adulthood.
Sperm count can be useful and should be assessed in men who are seeking fertility treatment. In adolescents or adults, a semen sample collected by masturbation after 2 days of abstinence from ejaculation provides an excellent index of seminiferous tubular function. A normal semen sample has a volume of > 2.5 mL with > 20 million sperm/mL, of which 60% are of normal morphology and are motile (see also Infertility: Sperm Disorders).
Evaluation of
secondary hypogonadism:
Because any systemic illness can temporarily decrease levels of testosterone, FSH, and LH, secondary hypogonadism should be confirmed by measuring these levels again after at least a 4-wk interval after resolution of the systemic illness. To confirm secondary hypogonadism in adolescents, the gonadotropin-releasing hormone (GnRH) test is sometimes done. If, in response to IV GnRH, levels of FSH and LH increase, puberty is simply delayed. If levels do not increase, true hypogonadism is likely.
To help determine the cause of confirmed secondary hypogonadism, testing should include serum prolactin level and transferrin saturation (to screen for hemochromatosis—see Iron Overload: Primary Hemochromatosis). Sella imaging with MRI or CT is done to exclude a pituitary macroadenoma or other mass in men < 60 yr with no other identified cause for hypogonadism and in all men with very low total testosterone levels (< 200 ng/dL), elevated prolactin levels, or symptoms consistent with a pituitary tumor (eg, headache, visual symptoms). Also, if there are symptoms or signs of Cushing's syndrome, 24-h urine collection for free cortisol or a dexamethasone suppression test is done (see Adrenal Disorders: Cushing's Syndrome) If no abnormalities are identified, the diagnosis is acquired idiopathic secondary hypogonadism.
Treatment
Treatment is directed toward providing adequate androgen replacement conveniently and safely. Although patients with primary hypogonadism will not become fertile with any endocrine therapy, patients with secondary hypogonadism often become fertile with gonadotropin therapy. Testosterone formulations discussed here are those available in the US. Other formulations may be available in other countries.
Testosterone
therapy:
Males who have no signs of puberty and are near age 15 may be given long-acting testosterone enanthate 50 mg IM once/mo for 4 to 8 mo. These low doses cause some virilization without restricting adult height. Older adolescents with testosterone deficiency receive long-acting testosterone enanthate or cypionate at a dose that is increased gradually over 18 to 24 mo from 50 to 100 to 200 mg IM q 1 to 2 wk. Transcutaneous gel may also be used, although it is more expensive, could possibly be transferred to others during intimate contact, and is more difficult to accurately dose. It is reasonable to convert older adolescents to testosterone gel 1% at adult dosages when their IM dosage has reached the equivalent of 100 to 200 mg q 2 wk.
Adults with established testosterone deficiency may benefit from replacement therapy. Treatment prevents or attenuates osteopenia, muscle loss, vasomotor instability, loss of libido, and occasionally erectile dysfunction. Athough the effects of testosterone on coronary artery disease are not completely understood, testosterone replacement therapy may improve coronary artery blood flow and may decrease the risk of coronary artery disease. Options for replacement therapy include testosterone gel 1% (5 to 10 g daily to deliver 5 to 10 mg daily), IM testosterone enanthate or cypionate (100 mg q 7 days or 200 mg q 10 to 14 days), a buccal mucosal patch (30 mg bid), or a transdermal testosterone patch (5 to 10 mg daily). Testosterone gel maintains physiologic blood levels more consistently than other treatments, but IM or patch systems are sometimes used because of their lower cost.
Potential adverse effects of testosterone and its analogs include erythrocytosis (particularly in men > 50 yr receiving IM testosterone ), acne, gynecomastia, and very rarely prostatic enlargement or edema; prostatic obstructive symptoms are rare. Treatment may enhance growth of an existing prostate carcinoma but probably does not cause prostate cancer. Injectable or transdermal forms of testosterone are preferable to most oral formulations, which, except for testosterone undecanoate, carry a significant risk of hepatocellular dysfunction and hepatic adenoma.
Hct should be checked q 6 to 12 mo, and digital rectal examination and serum prostate-specific antigen (PSA) testing should be offered annually in men > 50. If Hct is ≥ 54%, the testosterone dose should be reduced by 1⁄4 or 1⁄3. With testosterone replacement, PSA levels increase to age-adjusted normal ranges. The increase is usually only 10 to 30% but may reach 100% without evidence of prostate cancer.
Treatment
of infertility due to hypogonadism:
Infertility, which has many possible causes other than hypogonadism, is discussed in full elsewhere (see Infertility). Infertility due to primary hypogonadism does not respond to hormonal therapy. Men with primary hypogonadism occasionally have a few intratesticular sperm that can be harvested with various microsurgical techniques and used to fertilize an egg by an assisted reproductive technique (eg, intracytoplasmic injection).
Infertility due to secondary hypogonadism usually responds to gonadotropin replacement therapy. Other symptoms of secondary hypogonadism respond well to testosterone replacement therapy alone. If secondary hypogonadism results from pituitary disease, gonadotropin replacement therapy usually is successful. Therapy begins with LH replacement. After all exogenous androgens are stopped, LH replacement is generally initiated using human chorionic gonadotropin (hCG). Doses begin at 375 to 750 IU sc 2 to 3 times/wk and are increased if necessary to 1000 to 2000 IU sc 2 to 3 times/wk. The dose is adjusted after 3 mo to achieve normal serum testosterone levels. Sperm counts are done monthly, but counts are not expected to increase for at least 4 mo. FSH replacement, which is expensive, begins if 6 to 12 mo of LH replacement does not stimulate spermatogenesis. FSH replacement uses human menotropic gonadotropin or human recombinant FSH, beginning with 75 to 150 IU 3 times/wk. The dose may be doubled if conception has not occurred within 6 mo of combination therapy with hCG. Many men become fertile with treatment despite sperm counts that do not usually result in fertility (eg, < 5 million/mL).
Secondary hypogonadism due to a hypothalamic defect (eg, Kallmann's syndrome) is treated initially with LH and FSH because of their ready availability; if these are ineffective, GnRH replacement therapy (q 2 h sc by a programmable minipump) might be more effective. Most (80 to 90%) of men respond successfully to these regimens.
Last full review/revision June 2007 by Bradley D. Anawalt, MD
Content last modified June 2007
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