A case where drug therapy was to blame
Jed G is a 61-year-old man who reported decreased libido and erectile dysfunction. Examination revealed normal male external genitalia and prostate. Gynecomastia was not present. Laboratory results were: total testosterone, 159 ng/dL (normal, 241-827); free testosterone, 40 pg/mL (47-244); follicle-stimulating hormone (FSH), 9.1 mIU/mL (1.4-18.1); luteinizing hormone (LH), 3.4 mIU/mL (1.5-9.3); prolactin, 2.8 ng/mL (2.1-17.7); and normal values for ferritin and iron. His prostate-specific antigen (PSA) level was 0.8 ng/mL (normal, 0.00-4.00 ng/mL).
Mr. G was started on testosterone 1% gel at 5 g/d. The repeat total testosterone measurement was 215 ng/dL, and free testosterone was 82 pg/mL. The patient discontinued the testosterone gel a few months later due to the medication’s high cost.
Several years later, his total testosterone level had fallen to 110 ng/dL, and he continued to complain of fatigue, decreased libido, and erectile dysfunction. We initiated testosterone enanthate 100 mg IM every 3 weeks, which increased his testosterone level to 285 mg/dL. However, hemoglobin increased to 18.3 g/dL, and he noted bilateral nipple tenderness since the start of the injections. Small bilateral gynecomastia about 1 cm in diameter was noted. Testosterone injections were discontinued due to the erythrocytosis. The breast tenderness and gynecomastia resolved 4 months later.
Mr. G had idiopathic hypogonadism. The breast tenderness and gynecomastia he developed were most likely a result of peripheral aromatization of testosterone. This is similar to gynecomastia commonly observed during early puberty and would likely have regressed with continued therapy. However, as noted above, the testosterone injections had to be stopped due to significant erythrocytosis.
The history may also uncover significant weight gain, because obesity is associated with increased aromatase activity resulting in a relative increase in estrogens systemically and locally in the breast. When obesity is the cause of gynecomastia, the breast examination reveals firm, rubbery tissue (unlike the findings in pseudogynecomastia, where there is a soft enlargement of the breast). Alternatively, a history of weight loss is important because it can lead to hypothalamic dysfunction and a decrease in gonadotropin (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) secretion, resulting in decreased testosterone levels.8
Also inquire about prior diagnoses of liver cirrhosis or thyrotoxicosis or the presence of symptoms suggestive of these disorders, such as fatigue, jaundice, bloating, heat intolerance, or heart palpitations. These conditions can alter the metabolism of sex steroids and their binding proteins. A history of decreased libido and erectile dysfunction is suggestive of low testosterone levels, also known as hypogonadism. Headaches, visual disturbances, and behavioral abnormalities suggest a hypothalamic or pituitary disorder resulting in decreased FSH and LH levels and secondary hypogonadism. A family history of gynecomastia is elicited in half the patients with persistent pubertal gynecomastia.9
Physical examination. For all patients (except newborns), calculate the BMI and measure arm span and upper and lower body segments. A eunuchoid proportion—arm span 2 cm or greater than height—is associated with early-onset hypogonadism that precedes fusion of the epiphyses.3 Thus, you’ll need to consider congenital disorders of the testes, such as Klinefelter syndrome, as well as hypothalamic or pituitary disease, such as Kallmann syndrome, resulting in deficient FSH and LH production.
As noted earlier, you’ll need to examine the breasts to determine if true gynecomastia exists, as opposed to increased adipose tissue or the presence of a suspicious mass. A hard or irregular mass outside the areola, especially if associated with skin changes such as dimpling or retraction, should raise the possibility of breast carcinoma. Promptly arrange for diagnostic mammography and possible biopsy in this setting.
Carefully examine the secondary sexual characteristics, including body hair distribution and muscle mass. Inspect the external genitalia, penile development, and position of the urethral meatus. Note testicular size and consistency. Small, firm testes are suggestive of dysgenetic gonads found in patients with Klinefelter syndrome (47 XXY), whereas small, soft testes suggest secondary hypogonadism. A unilateral testicular mass raises suspicion of a neoplasm. Palpate the prostate in older men, especially if contemplating androgen therapy, which could exacerbate a preexisting focal prostate cancer.
Look for signs of hyperthyroidism, such as goiter, exophthalmos, tachycardia, and hyper-reflexia. Examine the abdomen for masses, hepato- or splenomegaly, and signs of cirrhosis, such as ascites and venous congestion. The examination should also include visual fields, cranial nerves, and fundoscopy for possible pituitary (or other) central nervous system lesions. Look for spider angiomas and palmar erythema (as occur in cirrhosis); warm, moist skin and myxedema (as in Graves’ disease); and mucocutaneous lentigines (as in Peutz-Jeghers syndrome).10
When laboratory and radiologic testing may help