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Editorial: Increasing Complexity and Challenges in the Diagnosis and Treatment of Male Hypogonadism

Fifty years ago, the diagnosis and treatment of male hypogonadism was limited mostly to younger men with diseases of the hypothalamic-pituitary-testicular (HPT) axis, such as Kallmann syndrome, hypopituitarism and Klinefelter syndrome (organic causes of hypogonadism). Men with these disorders presented with clinical manifestations of severe androgen deficiency, such as prominent sexual dysfunction, gynecomastia and infertility, eunuchoidism (poor sexual development), loss of male body hair and small testes. There was a greater reliance on history and physical examination because measurements of testosterone were only available initially in research and specialty laboratories. Hypogonadal men were treated with intramuscular injections of testosterone and treatment resulted in marked clinical improvements in the manifestations of androgen deficiency.

Over time, there has been an increasing recognition that in men with chronic illnesses, obesity and certain medications that suppress the hypothalamic-pituitary-testicular axis and in aging men who demonstrate a progressive decline in testosterone levels, serum testosterone levels may be reduced into the hypogonadal range. As in women with functional amenorrhea, the degree of suppression of reproductive function serves as a barometer of illness severity. Many of these men manifest non-specific symptoms that are consistent with androgen deficiency associated with low testosterone levels, expanding the population of men with hypogonadism to older men with less severe androgen deficiency due to functional rather than organic etiologies.

Developments in assay methodology increased the rapidity and efficiency, and permitted automation and more widespread availability of testosterone assays in clinical laboratories, contributing to an increased reliance on testosterone levels and reduced attention to symptoms and physical examination to diagnose hypogonadism. More recently, heavily-marketed, transdermal testosterone formulations became available for clinical use, providing a more convenient and patient-friendly method of testosterone treatment than injections. This together with a worldwide increase in testing for testosterone has resulted in an increased number of men diagnosed and treated with testosterone.

These developments over the last 50 years have uncovered and highlighted a number of challenges that have increased the complexity of the diagnosis and treatment of male hypogonadism that are now beginning to be addressed but need continued investigation in the future. But, how does a clinician deal with them now?

As recommended in the Endocrine Society clinical practice guidelines, the diagnosis of hypogonadism should only be made in men with symptoms and signs of androgen deficiency and repeatedly low serum testosterone levels. In men with comorbid illness, clinicians should be aware that non-specific symptoms of androgen deficiency might be caused predominantly by conditions such as depression and underlying illness or medications that may respond to treatment of the underlying condition or discontinuation of the offending medication. However, some signs of severe androgen deficiency are relatively specific, such as eunuchoidism (pathognomonic of prepubertal androgen deficiency), small or reduced testes size, or loss of male body hair. Recent results from both the European Male Aging Study (EMAS) and The Testosterone Trials suggested that sexual symptoms, in particular loss of libido, are important symptoms of androgen deficiency, so that their absence should lead one to question (but not exclude) the diagnosis of hypogonadism.

The most dramatic and disturbing developments that have profoundly affected the diagnosis of hypogonadism are the extreme assay-to-assay variability and lack of accuracy-based standardization, accuracy and harmonization of most of the testosterone assays used by clinicians today. The Centers for Disease Control and Prevention (CDC) Hormone Standardization (HoSt) Program has recently provided a mechanism to standardize and harmonize testosterone assays, similar to its highly successful standardization programs for cholesterol and hemoglobin A1c. Also, together with CDC, the Partnership for the Accurate Testing of Hormones (PATH) is completing a program to generate a harmonized reference range for testosterone levels in a number of cohorts of community-dwelling adult men. However, while many large reference laboratories participate in the CDC standardization program, manufacturers of most testosterone assays whose platform kits are used by local laboratories do not participate in the CDC program. Clearly, until the goal of complete accuracy-based standardization and harmonization of testosterone assays is achieved, the accuracy and consistency of testosterone measurements used to confirm the diagnosis of hypogonadism will be compromised, to the detriment of clinical care and research and public health. State-of-the-art mass-spectrometry-based testosterone assays have much greater accuracy, precision, sensitivity and specificity. But, their use remains limited to large reference and research laboratories, until the cost of instrumentation is reduced and expertise in clinical laboratories is developed.

It is preferable albeit not always feasible to measure testosterone levels in CDC-certified laboratories for which there will soon be a harmonized reference range. However, at present, most clinicians will likely continue to use non-standardized testosterone assays in local laboratories to confirm a diagnosis of hypogonadism. In this instance, it is particularly important for a clinician to make a clinical judgment regarding the likelihood of hypogonadism and use testosterone levels only to confirm their clinical impression. When there is a discrepancy between their clinical impression and locally performed testosterone levels, repeat testosterone measurements using a CDC-certified laboratory may be helpful.

Recent studies have documented a substantial day-to-day biological variability of testosterone levels, such that up to 30% of low testosterone values are normal on repeat testing. Therefore, it is important to have consistently low testosterone levels on at least two occasions to confirm a diagnosis of hypogonadism and committing a patient to testosterone treatment. Other studies have confirmed that conditions that lower sex hormone-binding globulin (SHBG) levels (such as moderate obesity) may lower total testosterone levels without affecting free testosterone levels. At present, it is prudent, as suggested by Endocrine Society guidelines to measure free testosterone using an accurate method (i.e. equilibrium dialysis) to assess circulating androgen status in clinical situations where low SHBG levels might occur or when serum total testosterone levels are only slightly below the reference limit. Recent results from EMAS found that androgen deficiency symptoms occurred in men with normal total testosterone and low free testosterone levels, but not in those with low total testosterone and normal free testosterone levels, supporting the utility of free testosterone levels to avoid over-diagnosis of symptomatic hypogonadism, particularly in the setting of obesity.

Once the diagnosis of hypogonadism is established, it is important to establish whether the etiology is organic, i.e., a congenital, structural or destructive lesion of the HPT axis that is largely irreversible, or caused by a functional suppression of an otherwise intact HPT axis that may be reversible or treatable without T treatment. Future studies of testosterone treatment of functional causes of hypogonadism that are not reversible (such as in individuals with chronic intractable pain or narcotic addiction who are unable to discontinue chronic opioid medications) need to be conducted.

The recent report of initial results from The Testosterone Trials found that testosterone treatment for one year in older men with clinical androgen deficiency improved sexual function and possibly depressive symptoms and mood, but not vitality or physical function. Together with results of the cognitive function, bone, anemia and cardiovascular trials in future reports, The Testosterone Trials will help to inform decisions regarding testosterone treatment of older men with low testosterone levels for no apparent reason other than age.

Despite conflicting observational studies and relatively small randomized treatment trials, concerns regarding the possible cardiovascular safety of testosterone treatment led to new Food and Drug Administration (FDA) labeling for testosterone formulations and have pervaded the clinical care of hypogonadal men. These concerns will linger until large, long-term randomized controlled trials are conducted that investigate the effects of testosterone treatment on clinically meaningful outcomes, such as fractures, major cardiovascular events and prostate cancer. A study analogous to the Women’s Health Initiative is needed to address these important clinical outcomes. A large, long-term cardiovascular safety study conducted by a consortium of industry sponsors that was requested by the FDA may shed light on the cardiovascular safety of testosterone treatment. In the absence of long-term randomized controlled clinical outcome trials, the overall clinical benefits and risks of testosterone treatment in men’s health will remain unclear.

For now, the diagnosis and treatment of male hypogonadism will remain relatively straightforward for men with severe androgen deficiency due to diseases of the HPT axis (organic causes of hypogonadism), but more complex and challenging in men with functional and age-related androgen deficiency. For optimal men’s health, management of the latter individuals in particular will require a good understanding of existing evidence-base, a broader, more holistic approach to patient management, good clinical judgment, the best testosterone assays available, and ascertainment of realistic patient goals and informed consent given the uncertainties regarding the long-term benefits and risks of testosterone treatment.

Alvin M. Matsumoto, MD
Associate Editor, The Journal of Clinical Endocrinology & Metabolism

R. Paul Robertson, MD
Editor-in-Chief, The Journal of Clinical Endocrinology & Metabolism

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