Hypogonadism in Male Adults

Background

• Hypogonadism is a clinical syndrome due to disrupted activity of ≥ 1 hormone levels of the hypothalamic-pituitary-testicular axis resulting in low serum testosterone and/or reduced spermatozoa levels in male adults.
• Given that testosterone levels slowly fall with advancing age, hypogonadism is more common in older patients.
• Hypogonadism is associated with reduced sexual function, including low libido and erectile dysfunction, reduction in muscle mass, osteoporosis, anemia, and less specific symptoms, such as reduced exercise tolerance, fatigue, poor concentration, depressed mood, and sleep disturbance.
• Hypogonadism can be classified according to the location of the dysfunction along the hypothalamic-pituitary-testicular axis.
  • Primary hypogonadism (hypergonadotropic hypogonadism) is caused by primary testicular failure due to impaired Leydig cell function and results in low testosterone levels, impairment of spermatogenesis, and elevated gonadotropin levels.
  • Secondary hypogonadism (hypogonadotropic hypogonadism) is caused by central defects of the hypothalamus or pituitary gland and results in low testosterone levels, impairment of spermatogenesis, and low or inappropriately normal gonadotropin levels (inadequate gonadotropic stimulation of Leydig cells).
  • Combined primary and secondary hypogonadism is caused by combined primary and secondary testicular failure and results in low testosterone levels, impaired spermatogenesis, and variable gonadotropin levels (depending on whether primary or secondary testicular failure is predominant).

Evaluation

• Establishing the diagnosis of hypogonadism:
  • When testosterone deficiency is suspected, document symptoms, and perform physical exam to identify signs and comorbid conditions (Strong recommendation).
  • Specific signs and symptoms of hypogonadism in male adults include incomplete or delayed sexual development, and small, soft, or shrinking testes (normal testes are 3.5 to 5.5 cm in length which corresponds to 15-30 mL).
  • Suggestive signs and symptoms include reduced sexual desire and activity, reduced spontaneous erections, loss of body hair, gynecomastia, eunuchoidal body proportions, infertility, low-trauma fracture, and low bone density.
  • Testosterone level measurement:
    • Consider testing for total serum testosterone if patient presents with:
      • signs and symptoms of testosterone deficiency
      • condition or treatment in which testosterone deficiency is prevalent, including
        • obesity
        • metabolic syndrome
        • sexual dysfunction
        • type 2 diabetes mellitus
        • pituitary mass, following radiation involving the sellar region and other diseases in hypothalamic and sellar region
        • moderate-to-severe chronic obstructive lung disease
        • infertility
        • osteoporosis or low-trauma fractures
        • HIV infection with sarcopenia
        • treatment with medications that cause suppression of testosterone levels, such as corticosteroids and opiates
    • Measure total testosterone level while fasting in the early morning (Strong recommendation).
    • Repeat fasting, early morning total testosterone to confirm the diagnosis (Strong recommendation).
    • Normal range for serum total and free testosterone may vary according to laboratory and type of assay performed.
      • Centers for Disease Control and Prevention (CDC) harmonized lower limit of normal total testosterone level for healthy young male adults without obesity is 264 ng/dL (9.2 nmol/L).
      • Professional organizations vary in their specific recommendations for interpretation of total testosterone measurement, but most suggest a diagnosis of testosterone deficiency can be made if levels are around < 12 nmol/L (346 ng/dL) with measurement repeated on ≥ 2 fasting early morning occasions to confirm diagnosis.
  • Diagnosis of hypogonadism is confirmed if symptoms or signs are present and serum total testosterone and/or free testosterone concentrations are consistently low (for example, on ≥ 2 fasting early morning occasions) (Strong recommendation).
  • Routine screening of men in the general population for hypogonadism is not recommended (Strong recommendation).
• Differentiating primary and secondary hypogonadism:
  • When testosterone level is low on ≥ 2 occasions, measure luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels to distinguish between primary and secondary hypogonadism (Strong recommendation).
  • Interpretation of results and next steps:
    • Elevated levels of LH and FSH suggest primary hypogonadism.
      • Consider checking karyotype in patients with unknown cause to exclude Klinefelter syndrome (especially in those with testicular volume < 6 mL) (Weak recommendation).
      • Checking for karyotype in men with evidence of prepubertal onset of hypogonadism is also suggested.
    • Low or normal levels of LH and FSH suggest secondary hypogonadism. Consider additional testing in these patients, such as (Weak recommendation):
      • further blood testing, including measurement of serum prolactin level to detect hyperprolactinemia, iron saturation to detect hemochromatosis, and pituitary function tests to detect other pituitary hormone deficiencies
      • magnetic resonance imaging of sella turcica to identify causes of hypothalamic and/or pituitary dysfunction if serum total testosterone is < 150 ng/dL (5.2 nmol/L)
    • LH and FSH may be high, low, or normal in combined primary and secondary hypogonadism, depending on predominant underlying process.
    • Patient is considered to have compensated hypogonadism if serum LH is elevated despite normal serum testosterone level. It is not clear if these patients should be treated or not.
• Consider measuring sex hormone binding globulin (SHBG) concentration in older male adults, male adults with borderline total testosterone levels but persistent signs and symptoms of low testosterone, or with suspicion of having altered SHBG level (Weak recommendation).

Management

• Investigate and treat chronic illnesses associated with high prevalence of hypogonadism such as diabetes mellitus type 2, impaired thyroid gland function, hyperprolactinemia, chronic obstructive pulmonary disease, rheumatoid arthritis, kidney and HIV-related illness, obesity, and metabolic syndrome (Strong recommendation).
• Testosterone therapy is the primary treatment modality for male adults with hypogonadism, with a goal of restoring testosterone levels to physiological range to maintain secondary sexual characteristics and improve sense of well-being, sexual function, and bone mineral density.
• Administration of testosterone therapy:
  • Goal of testosterone therapy is to restore testosterone levels to physiological range to maintain secondary sexual characteristics and improve sense of well-being, sexual function, and bone mineral density.
  • Clinical indications for testosterone therapy for male adults with low serum testosterone level include sexual dysfunction (low libido or erectile dysfunction), decreased muscle mass or strength, decreased bone mineral density, or presence of metabolic syndrome.
  • Contraindications and relative contraindications for testosterone therapy include breast cancer, prostate cancer, severe urinary tract symptoms due to benign prostatic hypertrophy, hematocrit > 48% (> 50% if living at high altitude), severe chronic heart failure, untreated obstructive sleep apnea, or desire for children.
  • In older male adults, evaluate comorbidities, and risks versus benefits prior to considering treatment and offer on a case by case basis (Strong recommendation).
  • Administer currently available safe and effective options for treatment, including intramuscular injections, implantable pellets, transdermal (patch or gel), oral (may be limited in availability), or buccal preparations of natural testosterone (Strong recommendation).
• While on testosterone therapy, periodically monitor response to treatment, adverse effects, and compliance with treatment regimen (such as every 3-6 months for the first year and then annually).
• Adverse events of testosterone therapy include erythrocytosis, progression of preexisting prostate cancer, acne, oily skin, decreased spermatogenesis and fertility, gynecomastia, male pattern balding, growth of breast cancer, worsening of sleep apnea, and emotional lability such as irritability and hostility.
• Consider alternatives to testosterone, such as human chorionic gonadotropin (hCG) or antiestrogens, for male adults with secondary hypogonadism who desire fertility in the near future.