What is the diagnostic workup for hypogonadism (hypogonadism is a condition in which the testes or ovaries do not produce enough sex hormones, specifically testosterone in men and estrogen in women)?

From the Guidelines

A hypogonadism workup should begin with a thorough history and physical examination, followed by laboratory testing to confirm low testosterone levels, as recommended by the American College of Physicians 1. Initial testing should include morning total testosterone measurements on two separate occasions, as levels fluctuate throughout the day. If testosterone is low (<300 ng/dL), additional tests should include:

• Luteinizing hormone (LH)
• Follicle-stimulating hormone (FSH)
• Prolactin
• Complete blood count
• Comprehensive metabolic panel
• Thyroid function tests High LH and FSH levels suggest primary hypogonadism (testicular failure), while low or normal levels indicate secondary hypogonadism (pituitary or hypothalamic dysfunction). For secondary hypogonadism, additional testing may include pituitary MRI, especially if prolactin is elevated. Semen analysis should be performed if fertility is a concern. Bone density testing is recommended for men with prolonged hypogonadism to assess for osteoporosis. Genetic testing (karyotype) may be indicated in cases of suspected Klinefelter syndrome or other genetic disorders. This comprehensive approach helps distinguish between primary and secondary causes, which is crucial for determining appropriate treatment. Primary hypogonadism typically requires testosterone replacement therapy, while secondary hypogonadism might be addressed by treating the underlying condition or with gonadotropin therapy if fertility is desired, as supported by the Endocrine Society guidelines 1. In patients with obesity, treatment with testosterone-replacement therapy should be considered when the morning free testosterone by equilibrium dialysis is frankly low on at least 2 separate assessments, and the hypogonadism workup has been completed to rule out an etiology of hypogonadism unrelated to obesity, as suggested by the Gastroenterology study 1. The method of testosterone replacement should be individualized for each patient, with transdermal testosterone preparations being a common choice due to their convenience and ability to produce normal serum testosterone concentrations, as noted in the Gastroenterology study 1. Testosterone levels should be monitored to determine that normal serum testosterone concentrations are being achieved, with testing 2 to 3 months after treatment initiation, and/or after any dose change, as recommended by the Gastroenterology study 1. The safety of testosterone therapy has been a concern, with the FDA requiring a labeling change to inform both health care professionals and patients of a possible increased risk of heart attack and stroke with the use of testosterone preparations to treat age-related hypogonadism, as reported by the FDA and supported by the Gastroenterology study 1. However, multiple associations, societies, and agencies support the use of testosterone in hypogonadal men, citing the cardiometabolic benefits of testosterone replacement therapy, as noted in the Gastroenterology study 1. In men with diabetes, a morning serum total testosterone level should be measured using an accurate and reliable assay, and free or bioavailable testosterone levels should also be measured in men with diabetes who have total testosterone levels close to the lower limit, given expected decreases in sex hormone–binding globulin with diabetes, as recommended by the Diabetes Care study 1. In HIV-infected men, a total testosterone level that is below the lower limit of normal should be confirmed by repeat testing, and further testing by measuring luteinizing hormone and follicular stimulating hormone should be considered to determine whether it is primary source (testicular failure) or central source (hypothalamic or pituitary dysfunction), as recommended by the Clinical Infectious Diseases study 1. Overall, a comprehensive hypogonadism workup is essential for determining the underlying cause of low testosterone levels and guiding appropriate treatment, as supported by the American College of Physicians 1 and other studies 1.

From the FDA Drug Label

Prior to initiating testosterone gel, 1. 62%, confirm the diagnosis of hypogonadism by ensuring that serum testosterone has been measured in the morning on at least two separate days and that these concentrations are below the normal range.

The workup for hypogonadism involves measuring serum testosterone levels in the morning on at least two separate days to confirm the diagnosis, with concentrations below the normal range indicating hypogonadism 2.

From the Research

Hypogonadism Workup

• The diagnosis of hypogonadism is based on clinical signs and symptoms plus laboratory confirmation via the measurement of low morning testosterone levels on two different occasions 3.
• Serum luteinizing hormone and follicle-stimulating hormone levels distinguish between primary (hypergonadotropic) and secondary (hypogonadotropic) hypogonadism 3.
• A systematic approach to diagnose hypogonadism initially establishes the presence of symptoms/signs of testosterone deficiency, considers other potential causes of manifestations, and excludes conditions that transiently suppress testosterone 4.
• Hypogonadism is confirmed by measuring fasting serum total testosterone in the morning on at least 2 separate days, or free testosterone by equilibrium dialysis or calculated free testosterone in men with conditions that alter sex hormone-binding globulin or serum total testosterone near lower limit of normal 4.

Laboratory Tests

• Measurement of serum prolactin, LH, and FSH is necessary to rule out secondary hypogonadism 5.
• Sex hormone-binding globulin (SHBG) result is also important, as it corresponds to 30.5% of those potentially hypogonadal 5.
• Estimated free testosterone is negatively associated with BMI, and total testosterone is also negatively associated with BMI in the over 50s 5.

Testosterone Replacement Therapy

• All approved testosterone replacement methods, when used according to recommendations, can restore normal serum testosterone concentrations and relieve symptoms in most hypogonadal men 6.
• Selection of the method depends on the patient's preference with advice from the physician, and dose adjustment is possible with most delivery methods 6.
• Testosterone treatment induces reversible suppression of spermatogenesis, and if fertility is desired in the near future, human chronic gonadotropin, selective estrogen receptor modulator, estrogen antagonist, or an aromatase inhibitor that stimulates endogenous testosterone production may be used 6.