Is There a “Male Menopause”: Will Hormones Help?
a “Male Menopause”: Will Hormones
(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?
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.
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
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).
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
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.
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
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.
- Genetic errors such as Kleinfelter’s
- Mumps (when it affects both testicles)
- Severe trauma
- Cancer chemotherapy
- Tumors (usually benign)
- Brain trauma
- Surgical treatment of pituitary disease
- 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 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.
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
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
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
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
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
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
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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