Persistent depression? Low libido? Androgen decline may be to blame

Total testosterone includes protein-bound and unbound testosterone and is a good measure of testosterone synthesis (Box).¹⁵ Normal circulating total testosterone levels are:

• 325 to 1,000 ng/dL in men
• 25 to 90 ng/dL in women (approximately 10% of male levels).

Testosterone assays are usually insensitive in the lower concentration ranges. This makes establishing testosterone deficiency difficult in women.

When total testosterone level is equivocal or low, repeat total testosterone levels once or twice and measure free testosterone, which is the biologically active form. More than 95% of circulating testosterone is bound to plasma proteins, including SHBG and albumin. Also measure free testosterone during the initial screen when you suspect testosterone deficiency.

In cycling women, sex hormone concentrations spike during ovulation and are low when the follicular phase begins. Although longitudinal evaluation is more accurate, the more practical crosssectional screen (AMblood) in the late follicular or late luteal phase is usually adequate.

Evaluating women taking oral contraceptives is biochemically straightforward, as exogenous estrogen suppresses ovarian sex hormone production and induces steady testosterone concentrations.

Postmenopausal women can be screened for sex hormone concentrations on virtually any morning, although perimenopausal women (within 5 years of last menstrual period) are, like premenopausal women, best studied longitudinally. DHEA and DHEA-S concentrations are perhaps more important to measure in women than in men because these sex steroids are responsible for a comparatively much larger component of circulating testosterone in women.

Follow-up tests. If testosterone deficiency is established, measure circulating pituitary hormones LH, FSH, and prolactin to determine if hypogolnadism is primary (gonadal) or secondary to another abnormality (of the brain or pituitary):

• Elevated LH and/or FSH levels are seen in primary hypogonadism, as the pituitary attempts to compensate for poorly functioning or sluggish gonads by increasing their stimulation.
• Diminished or inappropriately normal LH levels during testosterone deficiency (when high levels should be seen) are consistent with central or secondary hypogonadism.
• A combination of primary and secondary hypogonadism is common with advanced age.

Measure serum prolactin concentrations when evaluating hypogonadism because hyperprolactinemia is a common cause.

If the patient is testosterone-deficient, also assess other endocrine systems. If one fails or becomes inflamed, other glands or hormone systems often show insufficiency or inflammation as well, perhaps because of a common pathologic process. Circulating testosterone levels may be normal or elevated in testosterone insensitivity or hyposensitivity syndromes.

Correcting deficiency

Testosterone deficiency can often be corrected without using androgens, such as by changing or supplementing a medication.

Hyperprolactinemia is a common cause of central hypogonadism and testosterone deficiency in psychiatric patients, often as an adverse effect of psychotropics (particularly antipsychotics). Hyperprolactinemia suppresses GnRH and, in turn, LH and gonadal synthesis of testosterone. Hyperprolactinemia depresses libido and causes infertility in both sexes and amenorrhea in women.

Medication changes can usually correct psychotropic-induced hyperprolactinemia. Elevated prolactin levels from other causes (such as a pituitary prolactinoma) usually respond to dopamine agonists such as bromocriptine or cabergoline.

Zinc deficiency can lower testosterone levels. Zinc is highly enriched in the testes and prostate, where it accumulates via a zinc uptake system. The cerebral cortex is also zinc-enriched.

Zinc’s recommended daily allowance (RDA) is 15 mg for men and 12 mg for women. Mild zinc deficiency is common, affecting, for example, about 30% of healthy older men in Detroit¹⁶ and many depressed patients.¹⁷

Remarkably, dietary zinc restriction (to one-third of the RDA) in healthy young men reduces serum testosterone levels by 75% after 5 to 6 months. Conversely, giving a zinc supplement, 30 mg/d, to marginally zinc-deficient older men nearly doubled their serum testosterone concentrations after 6 months.¹⁸

Because serum zinc concentrations do not reliably reflect zinc status, the most expedient clinical approach is to supplement with the RDA—found in widely available multivitamins. Zinc is generally considered low-risk for toxicity, although high doses should be avoided. Much is unknown about zinc’s role in the CNS, where it apparently can be neuroprotective or neurotoxic.

Androgen suppressants. Cholesterol-lowering agents—whether they inhibit cholesterol biosynthesis or absorption—can sometimes lower serum androgen levels. Included are antihyperlipidemic pharmaceuticals and plant sterols that compete with cholesterol for gut absorption. Plant sterols such as beta-sitosterol are marketed as cholesterol-lowering food supplements.

Volatile and fatty oils of the saw palmetto berry (Seranoa repens or Sabal serrulata)—a frequently used over-the-counter phytotherapy for benign prostatic hypertrophy—have antiandrogen properties. They inhibit 5-alpha reductase types I and II, reducing testosterone’s conversion to dihydrotestosterone.¹⁹ Flaxseed oil (linseed oil), another over-the-counter herbal supplement, also may alter testosterone levels.

Table 2

Recommended testosterone-replacement preparations