Testosterone, aging, and the mind

A look at testosterone's role in the male body, and whether or not hormone replacement therapy is a good idea.
Testosterone, aging, and the mind
By Harvard Medical International
Tue 25 Mar 2008 04:00 AM

A look at testosterone's role in the male body, and whether or not hormone replacement therapy is a good idea.

When men (and, for that matter, women) think about the powers of testosterone, they are not likely to consider mental processes. Indeed, the male hormone has much more obvious roles in a man's body. Still, new research suggests that testosterone may have a surprising role in masculine mentality.

Doctors don’t know if the theoretical benefits of testosterone can be realised in practice.

Before you consider how testosterone affects the mind - and before you even begin to think about hormone therapy - you should know how testosterone is produced, how it affects the body, how it changes with age, and how it's measured.

The testosterone connection

Although testosterone is the most potent male hormone (androgen), it is only one of many. When the ancient Greeks provided the name, they chose well: "androgen" comes from the words for "man-maker," and, indeed, androgens make the man, or at least his characteristic male traits.

Androgen production requires a complex chain of events. It all begins in the brain, where the hypothalamus produces gonadotropin-releasing hormone (GnRH, also known as luteinizing hormone-releasing hormone, LHRH). Hormones are chemicals that are produced in one part of the body, then travel to another part where they do their work. GnRH is a true hormone, but it doesn't have a long commute; it acts on a nearby part of the brain, the pituitary gland.

In turn, the pituitary secretes two additional hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH were named for their effects on women's ovaries, but they are every bit as important for men, since they act on the testicles: LH triggers testosterone production, and FSH, acting with testosterone, stimulates sperm production.

Testosterone is produced by the Leydig cells of the testicles. The starting point is cholesterol, notorious for its effects on the heart but critical for its role as the building block of all sex hormones, both male and female.

After several intermediate steps, cholesterol is converted into androstenedione, the hormone made infamous by Mark McGwire as the unregulated "dietary supplement" andro. Whether androstenedione comes from the body or a bottle, it is rapidly converted into testosterone.

Testosterone has many direct effects on the male anatomy and metabolism. It is responsible for the deep voice, increased muscle mass, and strong bones that characterize the gender. It stimulates the production of red blood cells by the bone marrow.

The hormone also has crucial, if incompletely understood, effects on male behavior: It contributes to aggressiveness, and it is essential for the libido (sex drive), as well as for normal erections and sexual performance.

Testosterone stimulates the growth of the genitals at puberty, and it is responsible for sperm production throughout adult life. Finally, it influences cholesterol metabolism, but scientists are still not sure how that affects health.

Although testosterone acts directly on many tissues, some of its least desirable effects don't occur until it is converted into another androgen, dihydrotestosterone (DHT). DHT acts on the skin, sometimes producing acne, and on the hair follicles, putting hair on the chest but often taking it off the scalp.

Male-pattern baldness is one thing, but prostate disease quite another: DHT also stimulates the growth of prostate cells, producing normal growth in adolescents but contributing to benign prostatic hyperplasia and prostate cancer in many older men.

About 95% of a man's testosterone is produced in the testicles under the control of LH. The remaining 5% is produced in his adrenal glands. Women also make testosterone in their adrenal glands.

In both sexes, adrenal hormone production does not depend on LH or FSH, and in both sexes, an important precursor of testosterone is dehydroepiandrosterone (DHEA), another hormone that is widely popular as a nonprescription "dietary supplement.

Testosterone metabolism has a final complexity. In its last throes, this quintessential male hormone is converted to estradiol, a major female hormone.

Most of this final conversion takes place in fat cells, which is why obese men and women have higher estrogen levels than lean men and women.

Testosterone and the life cycle

In males, testosterone production begins very early indeed, usually at the start of the seventh week of embryonic development. Testosterone levels remain high throughout fetal life, but they fall just before birth, so they're only slightly higher in newborn boys than girls.

Baby boys experience a blip in testosterone production between three and six months of age, but by a year their levels are back down. Between six and eight years of age, adrenal androgen production rises, triggering a transient growth spurt and a bit of body hair but no sexual development.

At puberty, a surge in GnRH and LH fire up testosterone production, and testosterone goes on to stimulate the growth of bones and muscles, the production of red blood cells, an enlargement of the voice box, the growth of facial and body hair, an enlargement of the genitals, and an awakening of sexual function and reproductive capacity.

In most young men, testosterone production reaches its maximum at about age 17, and levels remain high for the next two to three decades. On average, healthy young men produce about six milligrams of testosterone a day.
In some men, testosterone levels remain high throughout life, but in most they begin to decline at about age 40. Unlike the precipitous drop in hormones that women experience at menopause, however, the decline in men is gradual, averaging just over 1% a year.

This drop is imperceptible at first, but by age 70, the average man's testosterone production is 30% below its peak. Still, testosterone levels remain within the normal range in at least 75% of older men, which is why many men can father children in their 80s and beyond.

Men tend to be less social and more independent, less communicative and more active.

And older men who worry about declining testosterone may be reassured by a study that found no link between low testosterone levels and the risk of erectile dysfunction, as well as by another that found no relationship between an older man's testosterone level and his mortality rate.

What's normal?

It's a simple question with a complex answer. Instead of a single normal level for testosterone, normal men exhibit a wide range, with testosterone levels between 270 and 1,070 nanograms per deciliter (ng/dL).

But, like so many biological functions, testosterone production waxes and wanes over a 24-hour cycle; production is highest at 8 a.m. and lowest at 9 p.m. For measurements to be meaningful, they should be obtained at a standard time, usually first thing in the morning.

Timing is particularly important when testing older men; because age takes a greater toll on the morning peak production than on the afternoon plateau, a late-day level can look normal, but a feeble morning surge can still leave a man's 24-hour production low.

The aging process introduces a final complexity. Testosterone travels in the blood in one of two forms, either bound to one of two proteins or free and unbound. The hormone binds tightly to sex hormone-binding globulin but only weakly to the second protein, albumin. Only the free and albumin-bound forms of testosterone are biologically active; together, they are known as bioavailable testosterone.

The sex hormone-binding protein rises with age, so an older man may have a normal total testosterone level but still be low where it counts, in bioavailable testosterone. A man may not need to know all of the ins and outs of testosterone metabolism, but he should understand that these complexities account for important flaws in much of the research on testosterone replacement therapy.

If you need to know where you stand, you should ask to have your total testosterone and free or bioavailable testosterone levels measured, preferably early in the morning. The table below shows the testosterone levels observed in one study of healthy men between 40 and 79 years of age.

Mars and Venus

Both men and women are Earthbound, but sometimes it seems they really are from different planets. The biologic model of gender identity attributes the difference to hormones and genes, while the social model examines cultural, educational, and familial influences. In fact, both factors contribute to the behavioral differences, which remain pronounced even as our society becomes more egalitarian.

As a rule, men tend to be less social and more independent, less communicative and more active. Men take more risks and are more aggressive. Men may thank these traits for their political dominance and economic success, but they also contribute to the occupational injuries, accidents, substance abuse, and violence that cost so many men their lives.

The problem is particularly acute in young men. Among 15- to 24-year-old Americans, for example, the death rate of males is three times that of females. Motor vehicle accidents and homicides account for much of the difference, but suicide is also more common in teenage boys than girls.

Cultural expectations and peer pressures certainly account for many behavioral differences between the sexes. But hormones also play a role; in particular, testosterone contributes to aggressive behavior, especially in high doses.

Neuroscientists are also beginning to assemble data pointing to structural and functional differences in the brains of men and women. For example, scientists in Germany reported that men and women use different parts of their brains to navigate their way out of a maze - and that men are about 28% faster at navigation.

It's an interesting observation, but the researchers didn't offer any explanation for the legendary male reluctance to ask for directions when their navigational skills fail. Men tend to perform better on certain spatial tasks, but women excel at certain manual tasks requiring precision.

Men outperform women on tests of mathematical reasoning, but women do better on arithmetical calculation tests. Males tend to have superior musical and mathematical skills; women, enhanced verbal abilities.

These distinctions, of course, are far from absolute, and it is far from clear if they depend on biology or culture, nature or nurture. Still, new research suggests that testosterone may play an important role in cognitive function.
Testosterone and the mind

All the body's attributes change with age, and mental function is no exception. Memory is the most fragile mental function. With age, new learning is slower, new information is processed less carefully, and details often slip.

Men tend to be less social and more independent, less communicative and more active.

Short-term memory typically weakens, but long-term memory is well preserved. These changes give rise to "the senior moment" in healthy elders and to cognitive impairment and dementia in those who are not so lucky. Testosterone levels decline with age, just when memory begins to slow. Might falling hormone levels account for some of the problem?

Perhaps. The data are far from conclusive, but some studies suggest a link:

• A 2005 study of 565 World War II veterans found that higher testosterone levels in midlife were linked to better preservation of brain tissue in some, but not all, regions of the brain in late life.

• A 2004 study of 400 men between the ages of 40 and 80 found that higher testosterone levels were associated with better cognitive performance in older men. No link was observed in younger individuals.

• A 2004 report from the Baltimore Longitudinal Study of Aging evaluated 574 men over a 19-year period. Low free testosterone levels predicted an increased risk of developing Alzheimer's disease, even after other dementia risk factors were taken into account.

• A 2002 study of 310 men with an average age of 73 found that higher levels of bioavailable testosterone were associated with better scores on three tests of cognitive function.

• A 2002 study of 407 men between the ages of 51 and 91 found that men with higher free testosterone levels achieved higher scores on four cognitive function tests, including visual and verbal memory.

• A 1999 study of 547 men between the ages of 59 and 89 found that high testosterone levels in older men were associated with better performance on several cognitive function tests.

If high testosterone levels are indeed linked to better mental function, will treatments that reduce hormone levels lead to cognitive decline? Androgen deprivation therapy is an effective treatment for advanced prostate cancer and a useful adjunct to radiation therapy for locally advanced prostate cancer.

Three studies published in 2005 and 2006 linked androgen deprivation therapy with impaired performance on various cognitive function tests. The effects were modest, however, and certainly should not deter men who need androgen deprivation therapy from receiving it.

Now for the $64,000 question: Can testosterone therapy improve mental function in older men who are healthy or in those with cognitive impairment? Only a few small, short-term studies have examined this question. Subtle improvements on cognitive function tests have been reported, but a 2006 trial found no benefit for healthy older men or Alzheimer's patients.

And in laboratory experiments, high levels of testosterone can trigger apoptosis, the process of cell self-destruction. Until more research is available, men should not use testosterone or any other androgen to improve mental function.

Testosterone and mood

Studies of testosterone and mood are in their infancy. Some research suggests that men with abnormally low testosterone levels, either because of hypogonadism (see below) or androgen deprivation therapy, have an increased incidence of depression, but other studies disagree.

Small, short-term studies suggest that testosterone therapy may help alleviate symptoms of depression in some men but that very high doses may promote aggressive or manic behavior. The bottom line is familiar: More research is needed.
Testosterone therapy

Men who are truly testosterone deficient should receive replacement therapy. The Institute of Medicine estimates that four to five million men are in this category but that only 5% of them are receiving testosterone.

Testosterone deficiency is called hypogonadism. Causes include testicular failure due to genetic errors, mumps, severe trauma, alcoholism, and cancer chemotherapy and radiation.

In other cases, the problem originates in the pituitary gland of the brain; causes include tumors (almost all benign), head trauma, brain surgery, various medications, some hereditary disorders, severe malnutrition, and chronic illnesses.

How do doctors diagnose testosterone deficiency? According to the Endocrine Society, men over 50 years of age who have total testosterone levels of 200 ng/dL or lower are hypogonad; they require an evaluation of pituitary function before beginning testosterone therapy.

Men with testosterone levels between 200 and 400 ng/dL are borderline and should have additional testing before considering therapy, and men with levels above 400 ng/dL don't need further tests or therapy. Until recently, men who needed testosterone required injections of the hormone every one to three weeks. That's changed dramatically.

Now, most men use skin patches (Testoderm, Androderm), gels (AndroGel, Testim), or tablets that are placed on the surface of the gum, where they form a gel that releases the hormone so it can be absorbed across the mouth's membranes (Striant). All these products require a doctor's prescription and, except for injections, all are expensive. A safe testosterone pill has not yet been developed.

Testosterone tinkering

If the Institute of Medicine's estimates are correct, about 250,000 American men are receiving testosterone for hypogonadism, the only condition for which the hormone is approved. But some 1.75 million prescriptions for testosterone products were written by American doctors in 2002, at a cost of $400 million - and the numbers have continued to soar. Why are all these men taking testosterone? And should they?

Memory is not the only thing that declines with age. Men also lose muscle mass and bone density; the red blood cell count drifts down; sexual ardor declines; and body fat increases. In theory, at least, testosterone therapy might attenuate or reverse each of these changes.

Unfortunately, doctors don't know if the theoretical benefits of testosterone can be realized in practice; well-designed, long-term studies have not been performed. And because federal funding agencies think the potential risks of testosterone therapy may outweigh the potential benefits, those studies may be a long time in coming.

The most serious long-term risks of testosterone therapy are prostate diseases, both benign prostatic hyperplasia and prostate cancer.

Other potential side effects include polycythemia (an excessive number of red blood cells), sleep apnea (respiratory pauses during sleep that may increase the risk of high blood pressure, heart attack, and stroke), gynecomastia (benign breast enlargement), acne, and liver disease. Cholesterol abnormalities and heart disease were once on that list, but they now appear less likely.

Doctors will have to start at the beginning, with small, short-term trials of testosterone in older men. If the benefits appear to outweigh the risks, the next step will be larger, longer trials in younger men. Only then will men know if testosterone therapy is effective or safe.

It will take time. Meanwhile, men who are really hypogonad should receive testosterone, but other men should not. The experience of millions of American women who took hormone replacement therapy before studies showed that it did more harm than good should help men resist temptation. But that doesn't mean you should sit back and wait for science to tell you what to do.

Keep your mind young and supple with mental activity, physical exercise, good nutrition, and regular medical care. And you can also get many of the purported benefits of testosterone for your body without any of its risks.

Along with a healthy amount of dietary protein, resistance exercises and other forms of strength training will help preserve muscle mass and strength, bone density, and musculoskeletal function.

A reasonable consumption of calcium (1,200 milligrams a day) and vitamin D (800 international units a day) will help prevent osteoporosis. Above all, perhaps, a program of regular exercise and a low-fat, high-fiber, vegetable- and fruit-rich diet will help prevent atherosclerosis, hypertension, and diabetes - the three major causes of illness, disability, and erectile dysfunction in older men.

And since illness and obesity accelerate the age-related decline in testosterone levels, healthy living may actually make your testosterone levels 10 years younger. It's never too late to start thinking young and living young - and it's never too early, either.

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