Exogenous glucocorticoids suppress DHEA release by negative feedback suppression of adrenocorticotropic hormone (ACTH) at the anterior pituitary. To protect against sex hormone deficiency, give DHEA in replacement doses whenever more than a few glucocorticoid doses are given. This applies particularly to postmenopausal women, in whom DHEA is the major source of circulating androgens.
Testosterone replacement
Preliminary data suggest that correcting testosterone deficiency in depressed men can have an antidepressant effect, especially in men who respond inadequately to standard antidepressants. Moreover, like antidepressants, testosterone replacement therapy can induce hypomania or mania in some individuals.
Depression and/or anxiety associated with sustained, irreversible serum testosterone deficiency—usually with other signs of testosterone deficiency (Table 1)—is the major psychiatric indication for testosterone replacement. Borderline biochemical testosterone deficiency and psychiatric symptoms in a “treatment-resistant” patient—especially one at risk for suicide—may justify an empirical testosterone replacement trial. Do not continue such a trial indefinitely without compelling reasons, however, because gonadal function recovery can be delayed for months after even a 12-week testosterone trial.20
Recommended agents for testosterone replacement are shown in Table 2. In men, testosterone preparations are normally used to increase testosterone levels. In women, I prescribe DHEA (discussed below). In young men and women with secondary hypogonadism, pulsatile use of gonadotropins may be necessary to induce spermatogenesis or ovulation—interventions outside the scope of psychiatric practice.
Contraindications to androgen replacement include hyperandrogenism, prostate cancer, antisocial personality, current mania, pedophilia, hypersexuality, and any psychiatric syndrome characterized by violent or predatory behavior. Pregnant patients (or women without a reliable birth control method) should not receive testosterone. Use caution when replacing androgens in patients with benign prostatic hypertrophy, hypomania, or a history of mania or hypomania.
An antidepressant response to adequate exogenous testosterone (enough to raise free testosterone levels to mid-normal range) is generally seen within 4 weeks. If psychological improvement is not observed, testosterone replacement may still prove beneficial if reversing hypogonadism improves the efficacy of subsequent antidepressants.
Dosage forms for men. Transdermal testosterone patches are normally applied to clean, dry skin on the upper arms, abdomen, thigh, or back and rotated among sites to avoid dermal irritation. When the nonscrotal patch is applied at night, testosterone concentrations mimic the circadian pattern seen in young men without causing supraphysiologic transients.21
Testosterone gel is applied every morning—also in a rotating manner—to clean, dry, intact skin and allowed to dry. Absorption is rapid, with measurable testosterone increases within 30 minutes. Approximately 10% of the testosterone is absorbed, delivering 5 to 10 mg/d into the circulation after 5 to 10 grams of gel (containing 50 to 100 mg of testosterone) is applied. Steady-state concentrations are achieved within 2 to 3 days, so dosages can be adjusted quickly.
Some patients regard 10 grams of gel as too messy to apply comfortably. Testosterone gel residuals can be washed from the skin with soap and water. Prolonged coated-skin contact with another person, such as a sex partner, can increase testosterone concentrations in the untreated individual.
Oral testosterone is absorbed poorly (often requiring high dosages) and cleared rapidly (half-life: 10 to 100 minutes). Only 10-mg capsules of methyltestosterone preparations are readily available—a dose too small for most men and too large for women. Many pharmacists can formulate other dosages for individual patients. Twice-daily doses are often used. Gum irritation and altered taste can occur when using buccal mucoadhesive testosterone.
Oil-based testosterone injections (such as IM testosteroneenanthate) are absorbedslowly and cannot reproduce normal circadian testosterone rhythms and concentrations. In some cases, however, the long-acting effectsof IM testosteroneare beneficial.
DHEA acutely increases testosterone and estrogens in both men and women after a single physiologic dose. During maintenance DHEA replacement, however, clinically significant increases in both sex hormones are seen only in women. DHEA is preferred to increase testosterone levels in women, as it is converted to appropriate proportions of androgens and estrogens by endogenous steroidogenic enzymes.
Table 3
Potential adverse effects of testosterone replacement therapy
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DHEA, which occurs in yams, is available over-the-counter as a “food supplement” or “nutritional supplement.” However, many of these preparations, which are not regulated by the FDA, are unreliable because of poor quality control.22
Aromatase inhibitors were developed as antibreastcancer agents but also may treat testosterone deficiency. Testosterone administration increases circulating estrogens because testosterone is metabolized by the enzyme aromatase to estradiol. Aromatase inhibitors may prevent excessive estradiol levels—and associated adverse effects, such as gynecomastia—that are sometimes seen during testosterone replacement therapy in men. Available aromatase inhibitors include anastrozole, exemestane, and letrozole.