The challenge of when and whether to treat hypogonadism is a common issue in medical practice. Is hypogonadism a natural part of aging? What are the limitations of diagnostic measures? What are the risks and benefits of treatment, and what treatments are available?
Testosterone was first chemically elucidated and chemically synthesized in the 1930s. It was subsequently used to treat conditions associated with fatigue, erectile dysfunction and the “male climacteric.” Oral testosterone was first approved by the U.S. Food and Drug Administration (FDA) in 1972, with transdermal testosterone receiving FDA approval in 1995. The past decade has seen a substantial increase in prescriptions for testosterone replacement therapy (TRT).
Hypogonadism is estimated to affect 20 percent of men older than 60 and 30–40 percent of men older than 80. The majority of men with hypogonadism are left untreated. Symptoms attendant with decreased androgens include depression, loss of energy and sexual dysfunction. Testosterone secretion is under the influence of the hypothalamic-pituitary axis, and it is important to be aware of gonadotropic disturbances (e.g., prolactinoma).
Diagnosis of hypogonadism is based on signs, symptoms and laboratory confirmation of diminished androgens. Each of these three components of diagnosis is subject to lack of specificity and imprecision of clinical measures.
The symptoms of hypogonadism are not specific, and other etiologies for these complaints, including hypothyroidism, vascular disease and diabetes, need to be considered. Multiple questionnaires have been developed (e.g., the Aging Males’ Symptoms Scale, the Androgen Deficiency in Aging Males questionnaire, the Massachusetts Male Aging Study questionnaire, the Hypogonadism Related Symptoms Scale and the Androtest questionnaire). These questionnaires have variable specificity and sensitivity, and they can be a useful adjunct in diagnosing hypogonadism. They are generally not recommended to be the sole basis of diagnosis, however.
The laboratory evaluation of testosterone (and other androgens) is subject to diurnal, seasonal and age-related changes. Additionally, chronic illness, glucocorticoids and opiate use are all known to diminish testosterone levels. Different assays can be used in the measurement of testosterone (e.g., radioimmunoassays, enzyme-linked immunoassays, liquid chromatography-tandem mass spectroscopy and equilibrium dialysis), with different levels of precision, sensitivity, reproducibility and linearity of assay.
Generally, a testosterone level below 300 ng/dL is accepted as hypogonadal. The American Society of Andrology recommends that testosterone levels above 350 ng/dL do not require treatment, while levels below 230 ng/dL do.
Testosterone is usually found in the circulatory system bound to other molecules. Approximately 44 percent of testosterone is strongly bound to sex hormone-binding globulin (SHBG). The remainder (56 percent) is termed “bioavailable,” with approximately 2 percent of total testosterone being unbound or “free” and the rest being bound to albumin or cortisol (50 percent and 4 percent, respectively). The importance of total over bioavailable testosterone in the efficacy and management of hypogonadism is an ongoing debate.
SHBG increases with age, hyperthyroidism and hepatic cirrhosis; it decreases with obesity, diabetes mellitus and glucocorticoid use.
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) should be evaluated to distinguish between primary (testicular) and secondary (pituitary-hypothalamic) hypogonadism.
There are longitudinal studies (e.g., Longitudinal Aging Study Amsterdam) that show a correlation of decreasing androgen levels with frailty, and other (but not all) studies demonstrate a correlation of low androgen levels with a propensity for osteoporosis, fractures, impaired mobility and decreased muscle mass. Additionally, there are studies demonstrating a correlation between hypogonadism and metabolic syndrome. However, longitudinal studies about the long-term effect of TRT are more limited.
Potential adverse effects of testosterone replacement include erythrocytosis, detection of subclinical prostate cancer, growth of metastatic prostate cancer, reduced sperm production and fertility, gynecomastia, male pattern balding, growth of breast cancer, worsening of obstructive sleep apnea, and acne. Further, testosterone may worsen benign prostatic hyperplasia (BPH) symptoms. Intramuscular injections of testosterone (enanthate, cypionate or undecanoate) are more often associated with fluctuation in mood or libido — possibly because of more variable hormone levels — and with pain at the injection site. Transdermal patches can be associated with skin reactions at the application site. Transdermal gels can also cause skin reactions and the potential risk of transfer to another person. Buccal testosterone tablets may cause alterations in taste or irritation of the gums. Lastly, pellet implants risk infection or expulsion of the pellet.
Alternatives to exogenous testosterone need to be considered in patients who desire to protect future fertility potential. Clomiphene citrate, an estrogen receptor blocker, raises serum FSH and LH levels. It is less effective than testosterone in the setting of primary testicular failure in raising androgen levels. Another alternative is Arimidex, an aromatase inhibitor. Long-term suppression of estradiol may increase the risk of osteopenia/osteoporosis. Injections of human chorionic gonadotropin, an LH analog stimulating Leydig cell production of testosterone, can also be used, though they are expensive and often not covered by insurers.
Treatment goals should be a restoration of testosterone to mid-normal range, with serial evaluation of prostate-specific antigen, liver function tests and hematocrit. Testosterone is generally not advised for treatment of erectile dysfunction in the absence of laboratory-evidenced hypogonadism. A rising PSA or the development of induration/nodularity of the prostate gland may warrant urologic referral.
Gerald L. Albert, MD, Wichita Urology Group, received his medical degree from the University of Texas Medical Branch at Galveston after completing a doctorate in physics. He completed his internship and residency in the specialties of surgery and urology at the University of Tennessee Health Science Center in Memphis. Dr. Albert is certified by the American Board of Urology and has been in practice since 2003.