Testosterone and the heart

Forget clothes. In a very real sense, testosterone makes the man.

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, or sex drive, as well as for normal erections and sexual performance. Testosterone stimulates the growth of the genitals at puberty and is responsible for sperm production throughout adult life.

Although testosterone acts directly on many tissues, some of its least desirable effects don't occur until it is converted into another male hormone, 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 adolescence but contributing to benign prostatic hyperplasia (BPH) and possibly even prostate cancer in many older men.

Testosterone is the major male hormone; it belongs to the family of hormones that doctors call androgens, an appropriate name that derives from the Greek words for man-maker. But while testosterone's effects on many organs are well established, research is challenging old assumptions about how the hormone affects a man's heart, circulation, and metabolism.

Early worries

A direct association between testosterone and heart disease has never been established, but for many years, doctors have suspected that a link exists. The reasoning goes like this: men have much more testosterone than women, and they develop heart disease about 10 years before their female counterparts. Like other muscles, cardiac cells have receptors that bind male hormones. Animals that are given testosterone develop enlarged hearts. Athletes who abuse testosterone and other androgenic steroids have a sharply increased risk of high blood pressure, heart attack, and stroke. And in high doses, testosterone can have a negative effect on cardiac risk factors, including HDL ("good") cholesterol levels.

Cardiovascular disease is but one of the many things that should keep athletes from abusing steroids. But the fact that large amounts of testosterone harm the heart and metabolism doesn't necessarily mean that physiological amounts are also harmful. In fact, research is challenging these old dogmas.

Testosterone and erectile dysfunction

Erectile dysfunction (ED) becomes more common as men age. Testosterone levels decline with age. Many men with ED blame their sagging performance on sagging hormone levels. But are they correct?

To find out, the Massachusetts Male Aging Study surveyed 625 randomly selected men between the ages of 40 and 70. Forty-one percent of the men had moderate to severe erectile dysfunction, but there was no link between ED and levels of total testosterone, bioavailable testosterone, and sex hormone–binding proteins.

Doctors in Australia approached the question from the other direction, by measuring testosterone levels in 1,455 men who were referred for evaluation of ED. Fewer than 6% of the men had low testosterone levels.

ED is much, much more likely to result from cardiovascular disease, diabetes, and medication side effects than from testosterone deficiency.

Complex relationships

It's hard for scientists to study heart disease. One reason is that there are so many cardiac risk factors, including family history, age, gender, blood pressure, cholesterol, blood sugar, obesity, smoking, exercise, and personality.

It's also hard for scientists to study testosterone. There is an exceptionally wide range of normal values. Healthy men can have testosterone levels between 270 and 1,070 nanograms per deciliter (ng/dL). Levels vary during the day, with peak values in the early morning. The hormone travels in the blood in three ways: on its own as free testosterone, while tightly bound to the protein sex hormone–binding globulin, or while weakly bound to the protein albumin. Testosterone levels change during life; total testosterone falls by about 1% a year starting around age 40, while free and weakly bound testosterone (which are collectively known as bioavailable testosterone) fall by almost 2% a year. Testosterone levels are temporarily boosted by exercise, but levels are decreased by excessive body fat, particularly abdominal fat. Finally, some of a man's testosterone is converted to estradiol, an estrogen that affects blood vessel function and metabolism in both men and women.

Heart disease and testosterone are mighty complex on their own, and studies that evaluate the two together are more complex still. Scientists who undertake these daunting investigations must account for all the things that influence heart disease and all the variables that affect testosterone. They must also decide whether to study men with normal testosterone levels or men who have low levels (called hypogonadism), either because of natural factors or because of androgen-deprivation therapy for prostate cancer. And doctors who investigate the effects of testosterone therapy can do so either in healthy men or in patients with cardiovascular disease. Finally, even if results suggest that testosterone might help the heart, the effects of hormone therapy on the rest of the body would also have to be considered.

With all these pitfalls, it's not surprising that more research is needed to fill in all the blanks. Still, even if current information can't tell us if testosterone can protect a man's heart, it can dispel fear that physiologic levels of the hormone are toxic.

Raging hormones?

Testosterone gets the credit — and blame — for everything from road rage and a 90-mile-an-hour fastball to prostate cancer. But can it also explain wild swings in the stock market?

To find out, researchers in England measured testosterone and cortisol (a stress hormone) in saliva samples from 17 male stock traders twice a day for eight days. They found that a high testosterone level in the morning was linked to a successful, money-making trading day. In contrast, high cortisol levels were recorded during volatile, up-and-down trading sessions.

It's just one small, preliminary study. But if testosterone is linked to male aggression, it could explain risk-taking investment practices. Be aware, though, that aggressive trading can trigger losses as well as gains.

Testosterone and cardiac risk factors

In high doses, androgens tend to raise LDL ("bad") cholesterol levels and lower HDL cholesterol levels. That's one of the things that gave testosterone its bad reputation. But in other circumstances, the situation is very different. Men who receive androgen-deprivation therapy for prostate cancer drop their testosterone levels nearly to zero, and when that happens, their cholesterol levels rise. Even within the normal range, men with the lowest testosterone levels tend to have the highest cholesterol levels. And when doctors from the Mayo Clinic reviewed 30 trials of testosterone-replacement therapy, they did not find any overall effect of hormone treatment on cholesterol levels, for good or ill.

Diabetes is another important cardiac risk factor. Androgen-deprivation therapy produces insulin resistance and increases the risk of diabetes. Obesity increases the risk of both diabetes and heart disease. Men with low testosterone have more body fat and more of the abdominal fat that's most harmful than men with higher hormone levels, but since obesity itself reduces testosterone, it's not clear which is the cause and which the effect.

Peripheral artery disease (PAD) is an important form of atherosclerosis in its own right, and it also signals an increased risk for heart disease. A Swedish study of over 3,000 men with an average age of 75 linked low testosterone and high estradiol levels to an increased risk of PAD.

There is less information about the relationship between testosterone and other cardiac risk factors. At present, the hormone does not appear linked to hypertension or inflammatory markers.

Symptoms of testosterone deficiency

Red flags

Low libido (sex drive)
Osteoporosis or low-trauma fractures
Hot flashes and night sweats
Infertility

Less specific symptoms

Decreased spontaneous erections
Loss of height
Loss of muscle bulk
Fatigue or lethargy
Depression
Anemia
Breast enlargement
Reduced facial or body hair
Shrinking or very small testicles
Diminished physical function

Testosterone therapy and cardiovascular function

Low testosterone levels have been linked to various cardiac risk factors, but that doesn't prove that low levels actually cause heart disease. Still, if testosterone therapy could help men with heart disease, it would bolster the argument that testosterone may be safe for the heart. Only a few small, short-term studies have been published to date, and the results offer mixed support for this theory.

Blood vessels and heart muscle cells have receptors that latch on to testosterone. Men who undergo androgen-deprivation therapy develop abnormally stiff arteries. In men with atherosclerosis and normal testosterone levels, short-term treatment with testosterone improves vascular reactivity and blood flow.

If testosterone helps blood vessels widen, it might be able to improve angina in men with coronary artery disease. A 2000 trial evaluated 46 men with stable angina and low-normal blood testosterone levels who were randomly assigned to 12 weeks of treatment with a testosterone patch or a placebo. Each man underwent a standard exercise stress test before and after treatment. Compared with the placebo-treated subjects, men on testosterone displayed improved exercise tolerance at the end of the trial — but the difference was slight, amounting to an average gain of just 26 seconds.

A similar 2004 study compared testosterone injections with placebo in 10 men with angina and low testosterone levels. One month of treatment produced a 74-second gain in exercise tolerance without changing HDL or LDL cholesterol levels. In another 2004 trial, 20 men with heart failure were given testosterone injections or placebo. After 12 weeks, testosterone produced a 33% increase in the distance the men were able to walk on a treadmill as well as a decrease in symptoms.

A 2008 study administered an oral testosterone preparation or a placebo to 22 men with coronary artery disease and low testosterone levels. Hormone therapy produced a modest increase in blood flow to the heart muscle by widening healthy, but not partially blocked, coronary arteries. Testosterone also boosted heart muscle contractions. However, treatment had no effect on the pain of angina, and it did reduce HDL cholesterol levels.

Testicular transplants

Testicular transplantation has intrigued doctors for centuries — mostly, one suspects, older male doctors.

Dr. John Hunter performed the first successful animal experiments in the mid-18th century, transplanting the testicles from a rooster to a hen. In the 19th century, doctors began to experiment with animal-to-human transplantation, but their attempts to rejuvenate aging men were uniformly unsuccessful. That didn't stop thousands of men from submitting to the operation in the 1920s; it was a fad that rejuvenated only its promoters. Fortunately, the "goat-gland operation" was exposed as quackery, bringing similar ventures to a well-deserved halt.

In 1935, doctors discovered the male hormone testosterone. Testosterone therapy quickly became the standard treatment for men with low levels of the hormone, or hypogonadism, though its role for aging men with normal testicular function remains highly debatable.

Testosterone therapy makes it unnecessary to consider testicular transplantation to boost virility, but it doesn't resolve the question of transplants for infertility. American surgeons achieved success in this area in 1977, when they transplanted a testicle from a healthy man to his identical twin who was born without testicles. More recently, surgeons in Russia and China have experimented with transplants between unrelated men. They have reported some success, but only in recipients who were treated with powerful immunosuppressive medications.

Testicular transplantation is technically possible, but the operation should not be considered except in extremely rare circumstances.

There must be an easier way to treat testosterone deficiency. And there is.

Cardiac events and mortality

Four small, brief trials of testosterone's effect on treadmill performance in men with heart disease hint that the hormone may be helpful. Clearly, though, it's much more important to see if testosterone therapy can change the risk of actual clinical cardiovascular events. The Mayo Clinic scientists who reviewed 30 placebo-controlled trials of testosterone therapy identified only six that reported clinical events. Together, these studies evaluated 147 men who received placebo and 161 who received testosterone for up to three years; testosterone did not appear to change the incidence or severity of cardiovascular events, though there was a trend toward more heart problems in the men who got the hormone.

The most important cardiovascular event is death from heart disease. The Massachusetts Male Aging Study linked high free testosterone levels with a modest increase in risk of death from coronary artery disease, but other studies report the opposite, finding that low testosterone levels are associated with an increased risk of cardiac death. None of these observational studies establish causality, and none can tell us if testosterone therapy is heart-healthy or -harmful; more research is needed.

Are we the men we were?

Testosterone levels decline slowly as men age. But a 2007 study suggests that since 1987, the hormone's levels have fallen in American men independent of age. Researchers measured testosterone levels in 1,532 randomly selected men during three time periods, 1987–89, 1995–97, and 2002–04. There was a slow but steady decline in average testosterone levels over the study period. In all, an average, healthy 65-year-old in 2002 had about 15% less testosterone than a similar 65-year-old in 1987. Since smoking boosts testosterone levels, and obesity has the opposite effect, the scientists checked to see if the change could be explained by a decline in smoking or an increase in obesity, but neither possibility held up. More research is needed to find out why testosterone levels have declined.

Testosterone-replacement controversy

Heart disease is the number one killer of American men, but most men who receive testosterone therapy are taking the drug to treat other organs. Testosterone therapy may be safe for the heart, but how about the rest of the body?

Testosterone deficiency affects about 6% of American men; most are in the older age groups. Although the problem is relatively common, it is underdiagnosed. According to one survey, only 12% of men with androgen deficiency were receiving treatment.

Experts do not recommend routine testing for testosterone deficiency. But you should request a test if you have symptoms such as those listed above.

If you have your testosterone levels measured, try to have the blood drawn between 7 a.m. and 10 a.m. But since normal levels vary so widely, how do you know if your results are really low? As a rule of thumb, if your total testosterone is above 300 ng/dL, your free testosterone is above 5 ng/dL, or your bioavailable testosterone is above 150 ng/dL, true deficiency is unlikely.

But even if your levels are low, you may benefit from a period of observation and repeat testing before starting treatment. That's because a report from the Massachusetts Male Aging Study found that over half the men with symptomatic testosterone deficiency improved without any treatment at all.

Causes of testosterone deficiency 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.

Men with hypogonadism should receive testosterone-replacement therapy. Exceptions include patients who have had prostate or breast cancer, unexplained high PSA levels, prostate nodules or severe BPH, elevated high red blood cell counts or abnormally viscous ("thick") blood, untreated obstructive sleep apnea (respiratory pauses during sleep that may increase the risk of high blood pressure, heart attack, and stroke), or severe heart failure.

Until recently, men who needed testosterone required injections of the hormone every one to three weeks. Now, most men use skin patches (Testoderm, Androderm), gels (AndroGel, Testim), or tablets that are placed on the surface of the gums (Striant). All these products require a doctor's prescription and, except for injections, all are expensive. A safe testosterone pill has not yet been approved in the U.S.

Women and children beware

The FDA has received reports of premature puberty and behavioral changes in children who have inadvertently come into contact with a man's testosterone gel. The FDA advises women and children to avoid contact with application sites on the skin of men who use these gels. Men should wash their hands with soap and water after each application. They should also cover the application site with clothing after the gel dries, and then wash the area with soap and water before any skin-to-skin contact with another person.

Testosterone tinkering

If the FDA'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?

Heart disease is not the only thing that is related to age. As the years pile on, men lose muscle mass and bone density; the red blood cell counts sag; sexual ardor declines; mood, energy, and memory drift down; and body fat increases. In theory, at least, testosterone therapy might blunt or reverse each of these woes.

That makes testosterone sound pretty good, and it's why so many men are turning to the drug. But the theoretical benefits should be balanced against the theoretical risks.

The most serious long-term complications of testosterone therapy include an increased risk of prostate diseases, both BPH and possibly prostate cancer. Other potential side effects include polycythemia (an excessive number of red blood cells), sleep apnea, gynecomastia (benign breast enlargement), acne, and liver disease. Cholesterol abnormalities and heart disease were once on that list, but they now appear unlikely.

Do the potential gains of testosterone treatment outweigh the possible pains? Nobody knows. To date, only small, short-term studies have been completed. They report few side effects, but benefits are decidedly mixed. For example, a study of 237 healthy 60- to 80-year-old men with low-normal testosterone levels found that six months of treatment produced an increase in muscle mass but did not reduce abdominal fat or improve bone density, mental function, or physical performance. The study did not evaluate heart disease, but it did find that testosterone reduced HDL cholesterol levels. A smaller study of 81 testosterone-deficient men with an average age of 57 reported that 36 months of testosterone replacement produced subjective improvement in symptoms and reduced the average cholesterol level from 204 mg/dL to 167 mg/dL — but 5% of the men were diagnosed with prostate cancer after an average of 33 months of therapy.

More research is needed to learn how testosterone affects the heart and the rest of a man's body and mind. That's where women stood before the Women's Health Initiative turned medical "wisdom" on its ear when researchers reported that hormone therapy does more harm (breast cancer, heart attacks, and strokes) than good, particularly for older women. But because federal funding agencies are worried about the possible risks of long-term testosterone therapy, a "Men's Health Initiative" is not in the works.

Without good data, what's a guy to do? The best advice is to protect your heart and your body by taking care of known risk factors, such as cholesterol, blood pressure, diabetes, obesity, and tobacco exposure. And don't forget that diet and exercise remain the keys to reducing the risk of heart disease: shedding body fat and building up muscles and bones; improving memory, mood, and vigor; and slowing the aging process.

Testosterone makes the man, but a good lifestyle makes him healthy.

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