Male hypogonadism: More than just a low testosterone
ABSTRACTConfronted with a low serum testosterone level, physicians should not jump to the diagnosis of hypogonadism, as confirmation and thorough evaluation are warranted before making the diagnosis or starting therapy. This review discusses how to approach the finding of a low testosterone value, stressing the need to confirm the finding, the underlying pathophysiologic processes, drugs that can be responsible, and the importance of determining whether the cause is primary (testicular) or secondary (hypothalamic-pituitary).
KEY POINTS
- Blood samples for testosterone measurements should be drawn near 8 am.
- A low serum testosterone value should always be confirmed by a reliable reference laboratory.
- The definition of a low testosterone level varies from laboratory to laboratory. In general, values less than 200 or 250 ng/dL are considered low, and values between 250 and 350 ng/dL may be considered borderline low.
- If testosterone is low, determine if the cause is primary (testicular) or secondary (hypothalamic-pituitary).
- Acute illness and treatment with opioids, anabolic steroids, or corticosteroids can result in transient hypogonadism.
Acquired disorders that suppress gonadotrophs
Drugs. Long-term therapy with common medications such as opioids or corticosteroids can result in secondary hypogonadism.18–20 Others are GnRH analogues such as leuprolide (Lupron), which are used in treating advanced prostate cancer. The hypogonadism is usually transient and resolves after stopping the offending agent.
Obesity and related conditions such as obstructive sleep apnea, insulin resistance, and type 2 diabetes mellitus are associated with low testosterone levels.21 Treatment should be directed at these underlying conditions and should include lifestyle measures such as weight loss and exercise, rather than simple prescribing of testosterone supplementation, as these efforts may provide multiple health benefits in addition to raising testosterone levels.22
Insulin resistance. In the setting of obesity, the total testosterone level may be low but the bioavailable and free testosterone (active hormone) levels may be normal. This is due to the effect of hyperinsulinemia on the liver, which results in a reduction in SHBG production.23 Low levels of both total and free testosterone can be seen in morbid obesity,24 but the cause remains unclear.
Type 2 diabetes mellitus. Testosterone levels have been reported to be lower in obese men who have diabetes than in those with obesity alone.24 This decrement, comparable in magnitude to that seen with other chronic diseases, suggests that low testosterone may simply be a marker of poor health.22,25,26
Sleep apnea. Disturbances in the sleep cycle, regardless of the underlying cause, can result in decreases in serum testosterone levels. Often, correcting the underlying sleep disturbance can result in a normalization of serum testosterone levels.27,28 A caveat about testosterone therapy: a thorough evaluation for sleep apnea should be undertaken in patients at high risk, since testosterone replacement therapy can adversely affect ventilatory drive and induce or worsen obstructive sleep apnea.29
Aging. Most reports have shown an agerelated decline in both total and free serum testosterone levels (commonly referred to as “andropause”), particularly in men over 60 years of age. There also appears to be a loss of circadian rhythm,30 although not all reports agree.6 It appears that factors such as functional status and overall health may play a more important role in the pathophysiology of hypogonadism in men of advanced age than age alone.
Hemochromatosis. Iron overload, regardless of the cause, can result in hypogonadism via deposition of iron in the hypothalamus, pituitary, or testes. Hereditary hemochromatosis is a common autosomal recessive disease characterized by increased iron absorption. Although both primary and secondary hypogonadism can occur with long-standing iron overload, the latter is much more common.31 Some cases of hypogonadism have been reported to reverse with iron depletion therapy.32
Hyperprolactinemia. Recognized causes of hyperprolactinemia in men include medications (dopamine antagonists, antipsychotics, metoclopramide [Reglan]), pituitary adenomas (microadenomas < 10 mm, macroadenomas ≥ 10 mm), lactotroph hyperfunction (stalk compression interrupting or reducing the tonic suppression of prolactin secretion by dopamine), hypothyroidism, stress, chronic renal failure, cirrhosis, chest wall injury (trauma), and active herpes zoster. The ensuing hypogonadism may be due to the compressive effect of a sellar mass or the direct effect of the prolactin elevation alone, since prolactin disrupts the pulsatile release of GnRH from the hypothalamus,33 required for normal LH and FSH secretion.
Estrogen excess can be either exogenous (from exposure to estrogen-containing contraceptives and creams) or endogenous (from testicular34,35 or very rare adrenal36 estrogen-secreting tumors). Of note, some cases of testicular neoplasms may be detectable only with ultrasonography. Computed tomography may be performed if an adrenal lesion is suspected.
Anabolic steroid abuse. Exposure to anabolic steroids, deliberately or inadvertently, can result in secondary hypogonadism and testicular atrophy, both of which may persist for years after stopping the anabolic agents. If you suspect anabolic steroid abuse, a urine anabolic steroid screen can be obtained.
Anorexia nervosa is far less common in men than in women.37,38 Elements in the history that suggest this disorder include excessive exercise and a low body mass index. Chronic malnutrition (cachexia), regardless of the cause, can result in secondary hypogonadism.
Acute illness (gonadotroph sick syndrome). Hypogonadism is a relatively common finding in any critical illness (analogous to euthyroid sick syndrome with respect to the hypothalamic-pituitary-thyroid axis).8 Testosterone levels are invariably low, so that assessment of testosterone status is not recommended in this setting. The low testosterone phase is usually transient and resolves with resolution or improvement of the underlying medical condition, such as sepsis or myocardial infarction.
HIV. Human immunodeficiency virus (HIV) infection can result in primary or secondary hypogonadism. It can occur with active HIV infection, in patients in whom control of viral replication has been achieved with highly active antiretroviral therapy, and even in patients who have normalized CD4+ cell counts.39 Hypogonadism in HIV patients is multifactorial and may be related to weight loss, opportunistic infections of the pituitary-hypothalamus or testes, or medications such as opioids (licit or illicit), ganciclovir (Cytovene), ketoconazole, the appetite stimulant megestrol (Megace), or cyclophosphamide (Cytoxan). Testosterone replacement therapy does not adversely affect the HIV disease process and in fact may help to avoid complications.
Chronic medical conditions such as cirrhosis, renal failure, and rheumatoid arthritis commonly result in hypogonadism, the pathogenesis of which may involve dysfunction at all levels of the hypothalamic-pituitary-go-nadal axis.40–45 Hypogonadism in the setting of chronic disease is multifactorial, being due not only to the metabolic disturbances seen with these illnesses (uremia in renal failure, elevated circulating estrogens in liver cirrhosis), but also to recurrent acute illness and hospitalization for infection in these immuno-compromised hosts, either from the underlying medical condition or as a result of medications (corticosteroids).
Alcohol abuse. Alcohol can have adverse effects at all levels of the hypothalamic-pituitary-gonadal axis, resulting in low serum testosterone and reduced spermatogenesis.46
Severe chronic primary hypothyroidism, manifested by an extreme elevation of serum thyroid-stimulating hormone (TSH), can result in hypopituitarism. Pituitary function usually recovers with restoration of euthyroidism.47,48
Pubertal delay. Depending on the age of presentation, differentiating pubertal delay from permanent hypogonadotropic hypogonadism can be challenging.
