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Grumpy No More: Testosterone Deficiency & Depression

Does DHEA Raise The Levels Of Bioavailable Testosterone In Men?

August 2002


Postmenopausal depression and cognitive dysfunction in older women have received much attention. Many studies have established a positive impact of estrogen on mood and memory, motor coordination, alertness and cerebral blood flow. But what about depression in hormone-deficient older men? Is the "grumpy old man" syndrome just one of those jokes about aging, like the countless jokes about memory loss and waning sexual potency? Depression is no joke, but research shows that it can be treated.

No one wants to be depressed, but it seems depression scores tend to rise with age. Depression is finally being recognized as a widespread and serious problem, not only among the elderly, but also among midlife men (we used to call it "the midlife crisis," but is now referred to as "andropause"). The "grumpy old man" syndrome is only now coming to the fore as a serious, debilitating condition that is potentially easily corrected-not with antidepressants such as Prozac (notorious for causing sexual dysfunction), but with testosterone.

Clinical and anecdotal experience indicates that testosterone is an excellent antidepressant, capable of restoring a lethargic "grump" to his former cheerful, active self. Delighted wives speak of irritable mates turning sweet-tempered again, of couch potatoes rising from their slough of despond and beginning to putter in the garage, whistling as they work. The ad for the new Testoderm patch states, "enhances mood, energy, libido and sexual function." Note that "mood" is mentioned first. "Men who take testosterone typically report that they feel happier, more energetic and more full of life," explained Dr. William Regelson, author of The Superhormone Promise. One reason it is so difficult to do placebo-controlled testosterone studies is that men taking the active substance quickly note an enhanced sense of well-being (as well as youthful changes such as more color in the face and lips due to increased red blood cell production).

As testosterone replacement for women is becoming increasingly commonplace, women too report not just restored libido, but also improved mood and greater energy, less anxiety and more assertiveness. The very fact that depression has a large female predominance hints that testosterone may be protecting men against this debilitating disorder. But is there enough research to validate the widely accepted testosterone-mood connection?

Free testosterone and depression

Image with Caption
Testosterone is an excellent
antidepressant, capable of restoring
a lethargic "grump" to his former
cheerful, active self.

A major study was published in the February 1999 issue of the Journal of Clinical and Experimental Endocrinology and Metabolism, one of the most respected biomedical journals. Dr. Elizabeth Barrett-Connor, a famous name in the field of hormone replacement research, headed the study. This was part of the Rancho Bernardo Study that yielded much valuable information about postmenopausal women. Now the attention has turned to men.

The subjects in Barrett-Connor's study were 856 men aged 50 to 89, not on testosterone replacement, living in the suburban community of Rancho Bernardo near San Diego. The average age was 70. They completed the Beck Depression Inventory; several physiological variables were measured, including total testosterone and free testosterone, dihydrotestosterone (DHT), total estradiol and free estradiol. The study found a very pronounced drop in free testosterone with age, a smaller drop in free estradiol, a relatively small, statistically insignificant decrease in total testosterone and total estradiol; DHT stayed the same (with possible slight trend toward increase with age).

Depression score went up with age, in parallel with the drop in free testosterone. Age, loss of weight (the authors note: "Depressed men, in contrast to depressed women, are likely to lose weight"), and lack of exercise also correlated with the depression score. The strongest connection that emerged was the one between low free testosterone and depression. The researchers state, "After adjustment for age, a significant negative trend in BDI [depression] score was seen only for bioavailable testosterone; the association persisted after additional adjustment for change of body weight and regular exercise." In other words, age alone did not reliably predict depression as assessed by the standard depression inventory; low levels of free testosterone were the best predictor of depression, regardless of age.

Furthermore, it turned out that 25 men in this group suffered from clinical depression (some were actually taking antidepressants). Was this reflected in their levels of free testosterone? The study provided a resounding yes: "These men had lower levels of bioavailable testosterone than all other men." On the average, free testosterone levels were 17% lower in the 25 clinically depressed men.

It is interesting to note that Barrett-Connor and colleagues speculate that the actual correlation between free testosterone and depression scores is even higher than revealed by their study; they suspect that many depressed men were not inclined to participate in this research project. Both depression and declining testosterone are psychologically difficult areas; unlike women, who tend to be much more aware of the hormonal connection, aging men are less likely to be open about their problems.

Discussing their results, the authors point out that in the brain testosterone is partly converted to estradiol and DHT. The improvement in memory and cognitive function associated with testosterone replacement is generally regarded as a consequence of aromatization (when the body converts excess testosterone into estrogen) of testosterone to estradiol. Could it be that the improvement in mood is really due to higher estradiol levels? Barrett-Connor does not think so; after all, the study showed no correlation between depression and free estradiol.

The mood-improving action of testosterone is more likely to be due to the direct action of testosterone on the brain-possibly through raising the levels of dopamine, a very important "reward" neurotransmitter. In addition, a sufficient amount of free testosterone is important for mitochondrial energy production, since some of the Krebs cycle enzymes depend on testosterone. (The Krebs cycle is a series of enzymatic reactions in aerobic organisms that lead to the production of high-energy phosphate compounds.) Like thyroid, testosterone enhances aerobic metabolism. This improved overall energy production may also play a role in creating better mood. (Note that hypothyroidism is also linked to depression.)

Some have also raised the cause-and-effect issue. Could it be that depression comes first, and depressed men produce less testosterone? We know that as cortisol rises, testosterone levels tend to drop. Thus, there seems to be a constant tug-of-war between stress and testosterone. A vicious circle is also likely: lower testosterone leads to depressed mood, depressed mood leads to less exercise and social activity, and also further lowers testosterone production, which in turn leads to more depression.

The Importance of Maintaining Youthful Levels of Free Testosterone

A positive development in endocrinology has been the introduction of tests for "free" hormones, not bound to a protein (in this case, SHBG, the sex hormone-binding globulin). It is the levels of free steroids that matter, since only free hormones are biologically active. This discovery has changed our picture of what really happens to men's testosterone levels as they age. While the levels of total testosterone may remain quite adequate, the levels of free testosterone have been found to decline by as much as 40% between the ages of 40 and 70.

Basically, the drop begins at some point in mid-twenties, but becomes really notable in midlife ("andropause"). This decline in free testosterone is due partially to the increase in sex hormone-binding globulin (SHBG), a protein on which most steroids "ride" in the bloodstream. This rise in SHBG parallels the age-related increase in body fat. As body fat (and thus SHBG) increases, we see more depression, memory problems, atherosclerosis, osteoporosis (yes, men lose bone mass too, especially in the spine), muscle loss and declining sexual function; and yes, we do see more prostate cancer (which is not surprising, considering the rising ratio of free estradiol to free testosterone). Stress, with concomitant conversion of pregnenolone to cortisol rather than testosterone, is also a great enemy of testosterone, as is elevated insulin.

Some (Dr. Barry Sears in The Anti-Aging Zone, for example) argue that if men manage to preserve muscle mass while keeping the percentage of body fat as low as it used to be in the early twenties, they should not need testosterone replacement. Others point out that some free-radical damage to the testes is inevitable over the course of aging, and that sooner or later the production of testosterone is bound to decline.