When a patient exhibits depressed mood, low energy, anxiety, insomnia, and low libido, do you consider major depression related to testosterone deficiency? Psychiatrists who don’t look for hypogonadism may miss a reversible cause of depression, especially in patients whose affective symptoms don’t respond to antidepressants.
Evidence is revealing how below-normal androgen levels may affect behavior and psychopathology in both men and women. This article describes:
- possible causes and effects of hypogonadism
- how to recognize and treat depression related to testosterone deficiency
- which lab tests provide the most clinically useful measures of testosterone
- potential benefits and adverse effects of testosterone replacement therapy.
Low testosterone and depression
Testosterone deficiency is particularly common in men with treatment-resistant depression. In one study, hypogonadism (total AMtestosterone contrations ≤350 ng/dL) was detected in 24 (43%) of 56 middle-aged men with treatment-resistant depression.1
Table 1
Signs and symptoms of testosterone deficiency
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Symptoms. Although most depressed patients are not hypogonadal, testosterone deficiency can cause depressed mood, low self-confidence, timidity, fearfulness, irritability, low libido, and impaired sexual function in men1-6 and most likely in women.7
Conversely, robust androgen secretion usually promotes good mood, self-confidence, boldness, dominant behavior, and strong libido. Men’s normally higher testosterone levels may relate to this sex’s lower frequency of depression and generally more violent aggression, compared with women.
Increased male aggression is associated with elevated gonadal steroid levels—from overelaboration of endogenous hormone or, more commonly, use of exogenous anabolic steroids.8 Less well-appreciated is that testosterone deficiency in men is frequently associated with irritability,9 particularly in response to stress. Correcting testosterone deficiency can improve control of hostile feelings and lead to higher self-esteem and less impulsivity.2
In general, correcting hypogonadism improves mood in men,10,11 including those with refractory depression.1,12
Depression in women. Evidence is conflicting and limited on a possible link between testosterone deficiency and depression in women. Psychological well-being in postmenopausal women given exogenous estrogens appears to improve when low-dose testosterone is added. In a recent placebo-controlled trial, testosterone cream, 10 mg/d—sufficient to bring total testosterone to the upper normal range—significantly improved mood in premenopausal women with low libido.13
Diagnosing hypogonadism
Hypogonadism is usually diagnosed by clinical and biochemical findings. Testosterone deficiency’s common signs and symptoms are shown in Table 1. Treated diabetes and obesity are significantly related to testosterone deficiency, as are—to a lesser extent—headaches, age >60, not smoking, treated asthma, low dominance rating, and sleeping <5 hr/night.14
Laboratory evaluation. Measuring total serum testosterone concentrations in blood withdrawn before 9 AMis a useful initial screen for testosterone deficiency. Circulating testosterone concentrations show diurnal variation in both sexes, with higher levels in early morning—typically 7 to 8 AM—and lowest levels in the evening—typically 7 to 8 PM. Morning concentrations of serum and salivary testosterone decline an average 50% to 60% from zenith to nadir.
Sex hormones’ effect on body and brain
In men, 90 to 95% of circulating sex hormones originate in the testes; transformation from adrenal-derived DHEA accounts for only about 5 to 10%. In ovulatory women, the ovaries and adrenals (via conversion from DHEA) contribute approximately equally to circulating androgens and estrogens.
Relative concentrations of sex hormones in circulation, CSF, and tissues depend on the concentrations and function of steroidogenic enzymes, whose sexual divergences largely account for differences between men’s and women’s androgen and estrogen levels.
The brain controls sex hormone synthesis and release and is also an important target organ for sex hormone action. Gonadotropin-releasing hormone (GnRH) released from the hypothalamus is the primary brain regulator of gonadal function, via the so-called hypothalamic-pituitary-gonadal (HPG) axis. Pulsatile GnRH stimulates the anterior pituitary to release luteinizing hormone (LH) and follicular-stimulating hormone (FSH). LH and FSH in turn regulate spermatogenesis, ovulation, and synthesis and release of estrogens and androgens.
The brain also regulates adrenal sex hormone synthesis and release but by the hypothalamicpituitary-adrenal (HPA) axis, via pituitary adrenocorticotropic hormone (ACTH). Unlike cortisol, which is also regulated by ACTH, negative feedback suppression of ACTH by DHEA, if it occurs at all, is not significant.
Testosterone begins to decline with age in men after the third decade and in women after menopause. Approximately 90% of men in their 80s have biochemical hypogonadism (testosterone or free testosterone <2.5th percentile for young men), as do 35% of men in their 60s.15 Age-related increases in sex hormone-binding globulin (SHBG) compound the effects of diminishing total testosterone synthesis. Thus, free testosterone decreases with aging proportionately faster than total testosterone.