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Is There a “Male Menopause”: Will Hormones Help?

Is There a “Male Menopause”: Will Hormones Help?

(This article was first printed in the June 2001 issue of the Harvard Men’s Health Watch. For more information or to order, please go to http://www.health.harvard.edu/mens.)

How things have changed. At the beginning of the 20th century, Freud coined the term “penis envy” to account for psychic differences between men and women. At the beginning of the 21st century, though, the tables have turned: many American men seem to be experiencing “hormone replacement envy” as they watch record numbers of their female peers take estrogens and progesterones in the hope that treatment will help them prevent disease and retain at least some attributes of youth.

Time marches on as surely for men as for women, but where hormones are concerned, the two sexes march to different tunes. What’s the score for hormone replacement in men?

Women’s World

There’s no mystery about menopause; it’s an inevitable part of the aging process that occurs at about age 50 in the average American woman. Menopause is built into female anatomy. At birth, the ovaries contain about one million egg follicles. At puberty, the follicles begin producing estrogens, the female hormones that cause enlargement of the breasts and uterus along with other female sex characteristics. But each follicle has a finite lifespan, and they begin to die off even before birth. By puberty, women have only about 400,000 follicles, and by about 50 virtually all the follicles are gone. Without follicles, estrogen production declines sharply, menstruation ceases, the reproductive capacity ends, and menopause has arrived.

Although menopause is normal and natural, it has adverse consequences, including hot flashes, deteriorating cholesterol levels, and reductions in bone calcium that can lead to osteoporosis and fractures. Hormone replacement therapy can help avert these problems, and it may also reduce a woman’s risk of colon cancer and Alzheimer’s disease. But estrogen replacement has been a disappointment for preventing heart attacks and strokes, and it has risks of its own, including breast cancer and blood clots.

As men age, they too face increasing risks of heart disease, stroke, and osteoporosis—to say nothing of colon cancer and Alzheimer’s. Much as men may envy women, they can’t take estrogens, which actually increase the risk of heart disease in men while producing many unacceptable side effects. But can men benefit from taking the male hormone testosterone?

In the Beginning

The fundamental difference between males and females resides in their genes. All humans have 46 chromosomes, two of which are sex chromosomes. In women, the two sex chromosomes are both X chromosomes; in men one is an X, the other a Y. The Y chromosome is one of the smallest human chromosomes, being only about a third the size of the X—but what a difference it makes. In fact, the difference between men and women appears to reside on just one gene in the Y chromosome, the sex-determined region Y (SRY). SRY is the tiny bit of DNA that’s required for the production of testosterone, and without testosterone, every fetus would be born looking like a girl even if it had a Y chromosome.

Male Hormones

Although testosterone is the most potent male hormone, it is only one of a large family of male hormones known as androgens. The ancient Greeks provided the name, and they chose well: androgen comes from the word 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 before traveling to another part to 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 response to GnRH, the pituitary secretes two additional hormones, follicle stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH were named for their effects on ovaries, but they are every bit as important for men; both act on the testicles, where 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 as the building block of all sex hormones, male and female. After several intermediate steps, cholesterol is converted into androstenedione, the hormone that is readily available to Mark McGwire and other athletes 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. It also has crucial, if incompletely understood, effects on male behavior; it contributes to aggressiveness and is essential for the libido or sex drive, as well as for normal erection and sexual performance. Testosterone stimulates the growth of the genitals at puberty, and it is responsible for sperm production throughout adulthood. Finally, and for most men unhappily, testosterone also acts on the liver, raising the production of LDL (“bad”) cholesterol.

Although testosterone acts directly on many other 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 from the scalp. Male pattern baldness is one thing, prostate disease quite another—and DHT also stimulates the growth of prostate cells, producing normal growth in adolescence but contributing to benign prostatic hyperplasia (BPH) 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 the adrenal glands. Women also make testosterone in their adrenal glands; in both sexes, adrenal hormone production is independent of LH and FSH. In both men and women, cholesterol is the basis for adrenal androgen production—and in both, an important precursor of testosterone is dehydroepiandrosterone (DHEA), another hormone that is widely popular as a non-prescription dietary supplement.

Testosterone metabolism has a final complexity; in its last throes, the 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).

Medical Uses for Androgens

Men with hypogonadism should receive testosterone, but men with age-related symptoms should not, at least until research clarifies the benefits and risks of therapy. But doctors are already using testosterone and other androgens to treat a variety of serious medical conditions. Examples include the wasting syndrome of advanced AIDS and the pronounced muscle wasting sometimes associated with prolonged cortisone therapy and debilitating illnesses, such as severe emphysema, cirrhosis, and burns. Androgens can also be helpful for men and women with rare conditions that cause severe anemia (aplastic anemia, Fanconi’s syndrome) or life-threatening tissue swelling (hereditary angioedema). Finally, some women with severe endometriosis benefit from androgen therapy, but its side effects limit the duration of treatment.

Testosterone and the Life Cycle

In males, testosterone production begins very early indeed, usually at the start of the seventh week of embryonic development, when boys become boys. Testosterone levels remain high throughout fetal life but 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, and they stay low until puberty.

At puberty, a surge in GnRH and LH fire up testosterone production, and testosterone stimulates the growth of bones and muscles, the production of red blood cells, the enlargement of the voice box, the growth of facial and body hair, the enlargement of the genitals, and the 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 7 mg 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, however, the decline in men is gradual, averaging just over 1% a year. A 1% yearly drop in testosterone production is imperceptible at first, but by the age of 70, the average man’s testosterone production is 30% below its peak. Still, even with the usual decline, 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 even beyond.

What’s Normal?

It’s a simple question with a complex answer. Instead of a single normal level for testosterone, there is a wide range; in most cases, healthy adult men have testosterone levels between 270 and 1,070 ng/ml (nanograms per milliliter). 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 consistent time, usually first thing in the morning. Timing is particularly important in testing older men; because age takes a greater toll on the morning peak of testosterone production than on the afternoon plateau, a late-day level can look deceptively normal, but a feeble morning surge can still leave a man’s total production low.

The aging process introduces a final complexity. Testosterone travels in the blood in one of two forms, either bound to protein or free and unbound. Only the free hormone is biologically active. The sex hormone binding protein rises with age, so an older man may have a normal total testosterone but still be low where it counts, in free testosterone.

It may not be important for a man to understand all the ins and outs of testosterone metabolism, but he should understand that these complexities account for important flaws in much of the medical research on testosterone replacement therapy. And if you need to know where you stand, you should ask to have both your total and free testosterone levels measured, preferably early in the morning.

Major Causes of Hypogonadism

  • Genetic errors such as Kleinfelter’s syndrome
  • Mumps (when it affects both testicles)
  • Severe trauma
  • Alcoholism
  • Cancer chemotherapy
  • Radiation
  • Medication
  • Tumors (usually benign)
  • Brain trauma
  • Surgical treatment of pituitary disease
  • Medication
  • Hereditary disorders
  • Iron excess
  • Starvation or massive obesity

As the Clock Ticks

Most senior citizens agree that aging is not what it’s cracked up to be. It’s not all bad, of course, and with good health habits, competent medical care, and a bit of luck, most men can remain healthy and active at an age that would have astounded their grandparents. But without good fortune and good preventive care, aging men lose 12 to 20 pounds of muscle, 15% of bone density, and almost 2 inches of height. Red blood cell counts also drift down as the years pile up. Sexual activity also tends to diminish over the years, but the impotence that afflicts about 50% of American men over 75 is the product of disease, not normal aging. In fact, testosterone deficiency is a rare cause of impotence, accounting for erectile dysfunction much less often than atherosclerosis, diabetes, hypertension, medications, treatments for prostate disease, and psychological disorders.

Can Testosterone Help?

There is no question about it: testosterone can help men with hypogonadism, abnormally low testosterone production due either to testicular failure or to disorders affecting the pituitary gland. Hypogonadism, though, is uncommon. When the problem lies in the inability of the testicles to produce testosterone, genetic abnormalities may be responsible; Kleinfelter’s syndrome is the most common, but these genetic abnormalities occur in only one of every 400 men. Other things that can impair testosterone synthesis include infections (mumps in adulthood, HIV, leprosy), severe trauma, radiation, and medications, such as ketoconazole (Nizoral) and spironolactone (Aldactone). Pituitary causes of hypogonadism, even less common, include hereditary disorders, infections, tumors, medications (cortisone), starvation or massive obesity, iron excess (hemochromatosis), and autoimmune disorders.

Adult men with true hypogonadism lack libido, but their problems go far beyond sexual dysfunction. They have smallish muscles, reduced bone density, diminished body and facial hair, and increased body fat, particularly around the hips. Men with hypogonadism also have small penises and small, soft testicles and prostate glands.

Testosterone can correct all these manifestations of hypogonadism, but doctors should reserve treatment for men with truly low testosterone levels and clear evidence of hypogonadism. To be sure, doctors should check pituitary hormone levels (FSH, LH, andprolactin) as well as liver and thyroid function tests; they should also measure free and total testosterone levels on several occasions, preferably in the morning.

Testosterone Replacement

Testosterone therapy is far from new; testosterone extracts were first used in 1889, and in the 1930s scientists synthesized the hormone itself, winning the Nobel Prize for their feat.

Athletic Abuses of Androgens

It’s a problem of epidemic proportion; in the U.S. alone, at least one million people are current or former androgen abusers. Most are competitive athletes or body builders, but some simply want to “look good.” Despite attempts to ban the abuse of “performance enhancing” steroids, the illicit practice appears to be increasing in both men and women. Most individuals take large amounts, sometimes consuming 100 times the doses used for testosterone replacement therapy.

Some androgens can increase muscle mass and strength, but others, like androstenedione (Andro), do not appear effective. But all illicit androgens can have major side effects, including cosmetic changes (acne, abnormal hair growth), liver disorders (inflammation, benign and malignant tumors), sexual dysfunction (shrunken testicles, infertility), breast enlargement, behavioral problems (aggression, mood disorders), and abnormal cholesterol levels (high LDL, low HDL). High blood pressure, heart attacks, strokes, liver cancer, and psychosis have all been linked to androgen abuse.

Victory at any cost? Not when the price is health.


Testosterone Preparations for Replacement Therapy

Until recently, injections have been the mainstays of testosterone replacement therapy. Several forms are available, including testosterone propionate (100 mg every week),testosterone enthanate (200 mg every two weeks), and testosterone cypionate (200–400 mg every three weeks).

Injections have two disadvantages: they are injections, and they produce roller-coaster testosterone levels, abnormally high at first but undesirably low later. To eliminate these problems, researchers have developed transdermal testosterone preparations, which deliver steady levels of the drug through the skin. Several types of patches are now available in the U.S.; they are applied once a day, mimicking the daily fluctuation in testosterone levels that occur in healthy young men.

Two types, Androderm and Testoderm TTS, are placed on the upper arm, thigh, back, or abdomen each evening; Testoderm TTS delivers 5 mg of testosterone, Androderm half as much, so men usually apply two patches at once. Skin irritation is the major side effect, so the patch should be moved to a new location each day. The third patch, Testoderm, comes in 4 and 6 mg strengths; it is less irritating to the skin, but since it will only deliver the medication through porous skin, it must be applied to the scrotum, which requires shaving. The scrotal patch produces higher levels of DHT, the testosterone derivative that stimulates the prostate, but doctors don’t yet know if this will be harmful. All the patches are expensive, costing dollars a day instead of pennies a day for injections.

The newest preparation is a testosterone gel, AndroGel, which is applied once a day to the shoulders, upper arms, or abdomen. It raises testosterone levels within 30 minutes to 4 hours, and levels remain steady during the course of a day as the hormone is slowly released from the gel. AndroGel is convenient, and it allows doctors to adjust the testosterone dose, but it is very expensive, about 50% more than the testosterone patches.

Much has changed in the past 75 years, but one thing has not: testosterone is not suitable for long-term use in pill form. That’s because after oral testosterone is absorbed by the intestines, the blood carries it straight to the liver, where the large amounts of the hormone impair cholesterol metabolism and may lead to liver tumors, both benign and malignant. Scientists are working on new oral preparations that may be safe and effective; chemists have already produced many related androgens that are effective in pill form but are not so safe—unfortunately, many athletes abuse such anabolic steroids, risking their health in the quest for enhanced muscular strength and athletic performance. But although men who need testosterone don’t have the convenience of a safe oral preparation, they have a rapidly expanding menu of options for testosterone replacement, ranging from injections to patches and, the newest of all, a gel.

Testosterone for Aging?

Men with hypogonadism will be grateful for the new treatment options, but should healthy men consider testosterone therapy to reverse some of the changes that occur with aging?

It’s an important question, but there’s no good answer yet. That’s because scientists have not conducted long-term studies of testosterone in healthy men. Small, short-term studies, though, illustrate the potential for testosterone therapy as well as its possible perils. For example, researchers in Seattle administered weekly injections of 100 mg of testosterone enthanate to 13 healthy 57- to 76-year-old men with low or borderline testosterone levels. Three months of treatment produced an increase in muscle mass and red blood cell counts. It also produced an increase in the men’s feelings of well-being, but it did not reduce body fat; surprisingly, perhaps, it seemed to improve blood cholesterol levels. But there was also a dark side to this brief trial: prostate-specific antigen (PSA) levels rose, indicating stimulation of prostate cells. PSA levels also rose slightly in 54 healthy men over 65 who used the testosterone patch for a three years; there was no overall improvement in bone density during the trial, but men whose initial testosterone levels were low appeared to benefit.

Testosterone has potential advantages: it can increase muscle mass and strength; it can improve bone density, and it can boost red blood cell counts. It’s far from clear, though, if it will improve libido, erectile function, or sexual performance in older men; several small studies have been disappointing thus far. And long-term therapy has potential risks, including abnormal cholesterol levels and possibly heart disease, liver damage, excessive red blood cell counts (polycythemia), sleep apnea, and prostate stimulation, which could increase the risk of BPH and prostate cancer.

Despite the obvious appeal of testosterone replacement for older men, most doctors advise against it; on balance, the risks seem to outweigh the benefits. But that doesn’t mean men have to accept the down side of aging. Far from it; in fact, there are simple ways to get many of the benefits of testosterone without 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. Taking adequate calcium (1,200 mg a day) and vitamin D (400–600 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 impotence in older men.

It’s never too late to start living young, and it’s never too early, either. Men who take good care of themselves won’t have much reason to envy women for their hormone replacement options—and women who do the right things will also find hormones optional.

(This article was first printed in the June 2001 issue of the Harvard Men’s Health Watch. For more information or to order, please go to http://www.health.harvard.edu/mens.)

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Harvard Men's Health Watch

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