A. Hypogonadotropic Hypogonadism (Low Testosterone with Normal or Low Lh)

A deficiency in FSH and LH may be isolated or associated with other pituitary hormonal abnormalities. (See Hypopituitarism.) Hypogonadotropic hypogonadism can be primary, defined as failure to enter puberty by age 14, or it can be acquired. Causes of primary hypogonadotropic hypogonadism include hypopituitarism, isolated hypogonadotropic hypogonadism, or simple constitutional delay of growth and puberty. Causes of acquired hypogonadotropic hypogonadism include genetic conditions (eg, Kallmann syndrome or PROKR2 mutations, X-linked congenital adrenal hypoplasia, 17-ketosteroid reductase deficiency, Prader-Willis syndrome), which account for about 40% of cases of isolated and idiopathic disease with a serum testosterone level less than 150 ng/dL (5.2 nmol/L) (Table 28-13. Causes of Male Hypogonadism).

Partial male hypogonadotropic hypogonadism is defined as a serum testosterone in the range of 150-300 ng/dL (5.2-10.4 nmol/L). The main causes of acquired partial male hypogonadotropic hypogonadism include obesity, poor health, or normal aging, such that it is termed age-related hypogonadism. However, other causes need to be excluded, including pituitary or hypothalamic tumors. Spermatogenesis is usually preserved.

B. Hypergonadotropic Hypogonadism (Testicular Failure with High Lh)

A failure of the testicular Leydig cells to secrete adequate testosterone causes a rise in LH and FSH. Acquired conditions that can cause testicular failure are listed in Table 28-13. Causes of Male Hypogonadism. Male hypergonadotropic hypogonadism can be caused by XY gonadal dysgenesis, partial 17-ketosteroid reductase deficiency, and a congenital partial deficiency in the steroidogenic enzyme CYP17 (17-hydroxylase). Abiraterone acetate, a drug for prostate cancer, inhibits CYP17. In men who have had a unilateral orchiectomy for cancer, the remaining testicle frequently fails, even in the absence of radiation or chemotherapy.

Klinefelter syndrome (47,XXY and its variants) is the most common chromosomal abnormality among males, with an incidence of about 1:500 (see Chapter 42). It is caused by the expression of an abnormal karyotype, classically 47,XXY. Other karyotypes occur, eg, 46,XY/47,XXY mosaicism, 48,XXYY, 48,XXXY, or 46,XX males. The manifestations of Klinefelter syndrome are variable and diagnosed in less than 25% of patients. Testes feel normal during childhood, but during adolescence they usually become firm, fibrotic, small, and nontender to palpation. Affected children have an increased risk of cryptorchidism, decreased penile size, delayed speech, learning disabilities, psychiatric disturbances, and mediastinal malignancies. Up to 75% of affected boys experience some gynecomastia at puberty. Although puberty occurs at the normal time, the degree of virilization is variable. Serum testosterone is usually low and gonadotropins are elevated. Adult men usually have somewhat reduced facial and pubic hair. Over 95% have azoospermia or severe oligospermia, although some sperm production is often present in their early teens. Men with 46,XY/47,XXY mosaicism may have spontaneous fertility. Some men may be fertile with the use of in vitro fertilization using intracytoplasmic sperm injection (ICSI). Other common findings include tall stature and abnormal body proportions that are unusual for hypogonadal men (eg, height more than 3 cm greater than arm span). Patients with multiple X or Y chromosomes are more apt to have mental deficiency and other abnormalities such as clinodactyly or synostosis. They may also exhibit problems with coordination and social skills. Other problems include a higher incidence of breast cancer, chronic pulmonary disease, varicosities of the legs, osteoporosis, and diabetes mellitus (8% of patients) and impaired glucose tolerance (in another 19%). The diagnosis of Klinefelter syndrome is confirmed by karyotyping or by determining the presence of RNA for X-inactive-specific transcriptase (XIST) in peripheral blood leukocytes by PCR. On semen analysis, most men (about 95%) with classic Klinefelter syndrome have azoospermia.

XY gonadal dysgenesis describes several conditions that result in the failure of the testes to develop normally. SRY is a gene on the Y chromosome that initiates male sexual development. Mutations in SRY result in testicular dysgenesis. Affected individuals lack testosterone, which results in sex reversal: female external genitalia with a blind vaginal pouch, no uterus, and intra-abdominal dysgenetic gonads. Affected individuals appear as normal girls until their lack of pubertal development and amenorrhea leads to the diagnosis. Intra-abdominal rudimentary testes have an increased risk of developing a malignancy and are usually resected. Patients who are considered women receive estrogen replacement therapy.

C. Androgen Insensitivity

Partial resistance to testosterone is a rare condition in which phenotypic males have variable degrees of apparent hypogonadism, hypospadias, cryptorchism, and gynecomastia. Serum testosterone levels are normal.

A. Symptoms and Signs

Hypogonadism that is congenital or acquired during childhood presents as delayed puberty. Men with acquired hypogonadism have variable manifestations, known as "testosterone deficiency syndrome." Most men experience decreased libido. Others complain of erectile dysfunction, poor morning erection, or hot sweats. Men often have depression, fatigue, or decreased ability to perform vigorous physical activity. The presenting complaint may also be infertility, gynecomastia, headache, fracture, or other symptoms related to the cause or result of the hypogonadism. The patient's history often gives a clue to the cause (Table 28-13. Causes of Male Hypogonadism).

Physical signs associated with hypogonadism may include decreased body, axillary, beard, or pubic hair, but only after years of severe hypogonadism (eFigure 28-23. Boy, 15-Years-Old with Kallmann Syndrome). Men with hypogonadism lose muscle mass and gain weight due to an increase in subcutaneous fat. Examination should include measurements of arm span and height. Testicular size should be assessed with an orchidometer (normal volume is about 10-25 mL; normal length is 3-5 cm). Testicular size may decrease but usually remains within the normal range in men with postpubertal hypogonadotropic hypogonadism, but it may be diminished with testicular injury or Klinefelter syndrome. The testes must be palpated for masses, since Leydig cell tumors may secrete estrogen and present with hypogonadism, and examined for evidence of trauma, infiltrative lesions (eg, lymphoma), or infection (eg, leprosy, tuberculosis).

B. Laboratory Findings

Serum testosterone circulates as ‘free' hormone and hormone bound to sex hormone-binding globulin. Serum total and free testosterone levels in men are highest at age 20-30 years. Thereafter, serum testosterone levels decline variably by an average of 1-2% annually; serum free testosterone levels decline even faster since sex hormone-binding globulin increases with age. Serum levels of free testosterone are lower in men aged 40-70 compared with younger men, without any increase in serum LH. In evaluating laboratory values for total and free testosterone, it is important to compare with age-adjusted reference ranges. Normal ranges for serum testosterone have been derived from non-fasting morning blood specimens, which tend to be the highest of the day.

The evaluation for hypogonadism begins with a morning (before 10 AM) blood draw for serum "ultrasensitive" total testosterone and free testosterone measurement. Serum total testosterone normal reference ranges vary with the lab and assay. Serum total testosterone levels are considered low if they are less than 300 ng/dL (8.3 nmol/L); levels between 300 ng/dL and 350 ng/dL (12 nmol/L) are considered borderline low. Serum free testosterone levels are considered low if they are less than 35 pg/mL (120 pmol/L); levels between 35 pg/mL and 40 pg/mL (140 pmol/L) are considered borderline low. A low serum testosterone or free testosterone should be verified with a repeat morning non-fasting assay, along with serum LH and PRL levels.

Seasonal variations in serum total testosterone levels have been observed in Korea, with the lowest mean level in May and the highest mean level in January.

In men over age 40, serum testosterone and free testosterone reference ranges are influenced by a large percentage of men with symptomatic hypogonadism. The main comorbid conditions that contribute to a decline in serum testosterone with aging include type 2 diabetes, obesity, metabolic syndrome, CVD, COPD, renal insufficiency, cancer, and opioids. After age 70, LH levels tend to rise, indicating a contribution of primary gonadal dysfunction. Testing for serum free testosterone is especially important for detecting hypogonadism in older men, who generally have high levels of sex hormone binding globulin. Most radioimmunoassays and ELISAs for testosterone are inaccurate when serum testosterone levels are less than 300 ng/dL (10.4 nmol/L). "Ultrasensitive" assays for serum testosterone assays are more accurate and use extraction and chromatography, followed by mass spectrometry. Serum LH levels are high in patients with hypergonadotropic hypogonadism but low or inappropriately normal in men with hypogonadotropic hypogonadism or normal aging. High serum estradiol levels are seen in men with obesity-related hypogonadotropic hypogonadism.

Testosterone stimulates erythropoiesis in men, causing the normal RBC range to be higher in men than in women; mild anemia is common in men with hypogonadism. For men with long-standing severe male hypogonadism, osteoporosis is common, so bone densitometry is recommended.

A. Therapies for Male Hypogonadism

B. Benefits of Testosterone Replacement Therapy

Testosterone therapy given for the indications listed under Treatment, above, usually benefits men with low serum testosterone and at least three manifestations of hypogonadism. Replacement testosterone therapy can improve overall mood, sense of well-being, sexual desire, and erectile function. It also increases physical vigor and muscle strength. Testosterone replacement improves exercise endurance and stair climbing ability. Long-term testosterone replacement causes significant weight loss and a reduction in waist circumference. After 2 years of testosterone replacement, muscle mass increases about 4.5%, while fat mass decreases by about 9.1%. Appropriate testosterone replacement therapy also appears to improve longevity.

C. Risks of Testosterone Replacement or Stimulation Therapy

Testosterone therapy does not appear to increase the risk of prostate cancer or BPH above that of normal men, provided serum testosterone levels are maintained in the normal reference range. However, testosterone therapy is contraindicated in the presence of active prostate cancer. Hypogonadal men who have had a prostatectomy for low-grade prostate cancer, and who have remained in complete remission for several years, may have testosterone therapy given cautiously while monitoring serum PSA levels.

Erythrocytosis is more common with intramuscular injections of testosterone enanthate than with transcutaneous testosterone. Testosterone replacement has not been considered to significantly increase the risk of thromboembolic events in most hypogonadal men. However, one large medical database study has found a correlation between testosterone therapy and thromboembolic events, particularly in men with a prior history of vascular events and in men being prescribed testosterone without proper documentation of hypogonadism.

Testosterone therapy tends to aggravate sleep apnea in older men, likely through CNS effects. Surveillance for sleep apnea is recommended during testosterone therapy and a formal evaluation is recommended for all high-risk patients with snoring, obesity, partner's report of apneic episodes, nocturnal awakening, unrefreshing sleep with daytime fatigue, or hypertension.

Testosterone therapy frequently increases acne that is usually mild and tolerated; topical antiacne therapy or a reduction in testosterone replacement dosage may be required. Increases in intraocular pressure have occurred during testosterone therapy. During the initiation of testosterone replacement therapy, gynecomastia develops in some men, which usually is mild and tends to resolve spontaneously; switching from testosterone injections to testosterone transdermal gel may help this condition.

D. Risks of Performance-Enhancing Anabolic Steroids

Performance-enhancing agents, particularly androgenic anabolic steroids, are used by up to 2% of young athletes and by 20-65% of power sport athletes. They are often used as part of a "stacking" polypharmacy that may include nandrolone decanoate, dimethandrolone, testosterone propionate, or testosterone enanthate. These androgens are usually illegal, often contaminated by toxic substances (such as arsenic), and can produce toxic hepatitis, dependence, aggression, depression, dyslipidemias, gynecomastia, acne, male pattern baldness, hepatitis, thromboembolism, and cardiomyopathy. Arsenic contamination can cause multiorgan failure and death.