It is estimated that four to five million American men may not produce enough testosterone. Most discouraging, research finds that most men know very little about testosterone, the potential consequences of having low testosterone levels, and the availability of therapies to increase testosterone and overall health.
A 1998 survey completed by Roper Starch Worldwide of 1,000 men found that 68 percent of participants could not name a symptom or condition associated with low testosterone. In addition, half of the participants admitted some knowledge of hormone replacement therapy, but only seven percent knew that it could be used in men.
This guide seeks to improve your awareness of testosterone, testosterone deficiency, and testosterone replacement therapy. Section 1, Testosterone Overview, provides comprehensive information on the hormone, its function, the diagnosis of low testosterone, and other related factors. Section 2, Benefits and of Testosterone Replacement Therapy (TRT) discusses some of the physical and psychological benefits associated with restoring testosterone. Section 3, Treatments for Low Testosterone, outlines treatment options that are available to increase testosterone levels. Section 4, Potential Risks of Testosterone Replacement Therapy, outlines the risks associated with prolonged testosterone therapy. Section 5, Overview of Clinical Trials, presents highlights of recent clinical studies evaluating testosterone and testosterone replacement therapy. Finally, Section 6, Frequently Asked Questions and Section 7, Glossary of Terms provide additional information and resources.
Testosterone and Its Function
Testosterone is the most important sex hormone (otherwise known as androgen)
produced in the male body. It is the hormone that is primarily responsible for
producing and maintaining the typical adult male attributes. At puberty, testosterone
stimulates the physical changes that characterize the adult male, such as enlargement
of the penis and testes, growth of facial and pubic hair, deepening of the voice,
an increase in muscle mass and strength, and growth in height. Throughout adult
life, testosterone helps maintain sex drive, the production of sperm cells,
male hair patterns, muscle mass, and bone mass.
Testosterone is produced mostly in the testes and a small amount of testosterone is produced from steroids secreted by the outer layer of the adrenal glands (called the adrenal cortex); in females, small amounts of testosterone are produced by the ovaries. While it is commonly perceived that testosterone is not a major factor in prepubescent male development, testosterone is active long before puberty begins. For example, while a fetus is still in the womb, testosterone and a product of its metabolism, dihydrotestosterone, cause the male genitalia to form.
Testosterone Production
The body carefully controls the production of testosterone. Chemical signals
from two locations — the pituitary gland at the base of the brain, and
a part of the brain called the hypothalamus — tell the testes how much
testosterone to produce.
The hypothalamus controls hormone production in the pituitary gland by means of gonadotropin-releasing hormone (GnRH). This hormone tells the pituitary gland to make follicle-stimulating hormone (FSH) and luteinizing hormone (LH). LH signals the testes to produce testosterone. If the testes begin producing too much testosterone, this is sensed by the brain which sends signals to the pituitary to make less LH. This, in turn, slows the production of testosterone. If the testes begin producing too little testosterone, the brain senses this and sends signals to the pituitary gland telling it to make more LH, which stimulates the testes to make more testosterone.
Physical Symptoms Related to Low Testosterone
Signs of low testosterone in men may include decreased sex drive, poor erections
by the penis [erectile dysfunction (ED)], lowered sperm count and reduced fertility,
or increased breast size. Men also may have symptoms similar to those seen during
menopause in women — hot flashes, increased irritability, inability to
concentrate, and depression.
Some men may have a prolonged and severe decrease in testosterone production. As a result, they may experience loss of body hair and reduced muscle mass, their bones may be more brittle and prone to fracture, and their testes may become smaller and softer. In younger men, low testosterone production may reduce the development of body and facial hair, muscle mass, and genitals. In addition, their voices also may fail to deepen.
Conditions That Could Cause Low Testosterone
There are a number of specific medical conditions that can cause low testosterone. Often, such conditions are most evident in younger men and men with extremely low testosterone levels. Some of these conditions are associated with diseases or abnormalities of the testes, pituitary gland and hypothalamus. Other men experience low testosterone levels as a result of various genetic factors.
The Effects of Aging on Testosterone Production — Andropause
As men age, their ability to produce testosterone declines. Also, some men's
production of LH decreases with aging, which lowers testosterone production.
Moreover, a protein that binds up and holds onto testosterone called sex hormone
binding globulin (SHBG) increases in older men. This reduces the amount of free
(unbound) testosterone in the blood that is available to tissues, such as muscles.
Aging also causes changes in the daily cycle of testosterone production. For
example, younger men show a peak of testosterone in the morning, but this finding
is blunted in older men.
The decrease in testosterone production as men age and symptoms associated with testosterone deficiency are sometimes referred to as andropause.
Testes-Based Conditions
Men whose testosterone deficiency is caused by an abnormality in the testes
often display increased FSH levels, increased LH levels, and impaired sperm
production. These conditions include:
Trauma — A direct physical injury to the testes may damage the cells that
produce testosterone.
Castration — Surgical removal of the testes, e.g., for testicular cancer, results in severe reduction in testosterone production.
Orchitis — Testicular inflammation can occur after a post-puberty bout with the mumps (there is a higher risk of risk of infertility than low testosterone).
Radiation treatment or chemotherapy — These therapies for other diseases may damage the testosterone-producing cells of the testes.
Testicular tumors — Treatment of testicular tumors may directly affect
testosterone production.
Pituitary/Hypothalamus-Based Conditions
Men whose low testosterone levels result from defects in the pituitary or hypothalamus
generally have a low or low-normal FSH level and low or low-normal levels of
LH. These conditions include:
Pituitary tumors The growth of abnormal tissue in the pituitary can disrupt
the gland's normal functioning and interfere with hormone production. Some tumors
produce hormones that can interfere with LH production.
>High prolactin levels High levels of the pituitary hormone prolactin from
a hypothalamic or pituitary tumor, certain medications, and other causes inhibit
LH and FSH production, resulting in low testosterone levels.
Medications — Certain drugs used to treat medical conditions that affect
the brain (e.g., opiate pain medications such as morphine) and hormones (e.g.,
cortisone-like medications such as prednisone, and anabolic steroids) may inhibit
LH and FSH secretion by the pituitary, and in turn, testosterone production
by the testes.
HIV/AIDS — Viruses or other infectious agents may directly or indirectly affect the hypothalamus, pituitary or testes and can decrease testosterone levels; as many as 50 percent of men infected with the human immunodeficiency virus (HIV) may have low testosterone. Severe malnutrition that occurs with AIDS and other wasting conditions may also inhibit LH and FSH production, resulting in low testosterone levels.
Immune and Inflammatory Pituitary Disease — Conditions such as sarcoidosis,
tuberculosis, fungal infection, and autoimmune disease may also impair the pituitary's
ability to make hormones.
Genetically-Based Conditions
Men may have low testosterone as a result of chromosomal abnormalities or genetically-based
conditions. These conditions include:
Klinefelter's syndrome — A genetic condition in which an extra X chromosome is present (about one in every 400 men have this); testosterone production is low to low normal; men with this syndrome also may have markedly reduced bone density and learning disabilities.
Hemochromatosis — A common genetic disorder in which there is excessive depositing of iron into body tissues, most notably the liver, pancreas, heart, skin, and pituitary gland, resulting in reduced functioning of these organs. Iron deposition in the pituitary gland causes impaired production of LH and FSH, which results in decreased testosterone production.
Kallmann's syndrome — Usually a recessive genetic disorder associated with the X chromosome, which occurs in about one of every 10,000 men. A deficiency of gonadotropin releasing hormone (GnRH) impairs the release of LH and FSH, which decreases testosterone production; men with the syndrome lack the sense of smell; testes do not enlarge at puberty.
Prader-Willi syndrome — A genetic disorder characterized by decreased muscle tone in infancy that improves with age, underdeveloped genitals (including undescended testes in boys) and low sex hormone levels. An obsession with food and compulsive eating, also linked with this disorder, may begin before the age of six.
Myotonic dystrophy — The most common adult form of muscular dystrophy,
this genetic condition only occurs in men and is carried on the Y chromosome;
because testicular failure usually occurs around the age of 30 to 40, men may
have sons at risk for the disease.
Diagnosing Low Testosterone
Importance of the Medical History
Sometimes physical symptoms can suggest a medical problem. For example, a man
who, as he ages, has a progressive decrease in muscle mass, loss of libido,
erectile dysfunction (ED) or reduced sperm count may have low testosterone.
Similarly, a teenager who still has the appearance of a young boy — small
testes, penis and prostate; scant pubic and body hair; and a high-pitched voice
— shows clear signs of someone with inadequate testicular function. There
are cases, though, that may involve some medical detective work. Therefore,
it is extremely important to provide the doctor with a detailed medical history.
Things that should be discussed include:
past or present major illnesses;
all prescription and nonprescription drugs currently being taken;
family/relationship problems, such as sexual problems; and
any major life events or changes that have occurred.
A family history also may help the doctor to pinpoint a genetic basis for the
problem. The doctor can use these clues to identify the correct diagnosis.
Physical Examination
During the physical examination, the doctor will look at:
the amount and distribution of body hair;
presence and degree of breast enlargement;
size and consistency of the testes;
abnormalities in the scrotum;
size of the penis; and
the ability to see in all directions (visual field test)
Measuring Hormone Levels
Testosterone levels vary from hour to hour, so the time at which blood is drawn
for testing can affect the results. However, the generally acceptable range
of values is 300 to 1,200 nanograms per deciliter (ng/dl) for total testosterone.
Generally, the highest testosterone levels occur in the early morning hours;
therefore, doctors will often measure testosterone levels at this time.
Testosterone circulates in the blood in three forms:
About 40 percent of testosterone is bound tightly to a protein called sex hormone
binding globulin (SHBG), and is not available to body tissues for action;
About 58 percent is weakly bound to another protein called albumin and is available
to many tissues for action;
About two percent circulates freely in the bloodstream.
Determination of low testosterone may require more than one blood test. A normal
total testosterone reading may not necessarily indicate that a man has normal
levels of free testosterone. For example, some men with increased levels of
SHBG and low blood levels of free testosterone may have normal levels of total
testosterone. Therefore, labs often measure the total testosterone levels and
its components.
Other Tests
Because low testosterone levels may affect bone mass, the doctor may want to
assess any bone loss with bone density testing.
Genetic testing can confirm the presence of an inherited condition.
If tests cause the doctor to suspect a problem within the pituitary gland, he/she
may want to examine the gland to see if a tumor is present. Two examination
procedures are most common, and neither penetrates the skin. A computed tomography,
or CT, is a computer-assisted X-ray process. Magnetic resonance imaging, or
MRI, uses a combination of radio waves, high intensity magnetic fields, and
computer technology to produce images of the body's interior. The MRI is often
the preferred procedure; both tests are usually done before and after a minute
amount of dye is injected into a vein.
Men with low levels of testosterone generally complain of sexual and mood problems. Testosterone replacement therapy has been proven to improve both physical and psychological functioning.
Sexual Interest
Testosterone replacement has been shown to increase sexual interest and the
frequency of spontaneous erections.
Erectile Function
Testosterone replacement restores erectile function in androgen deficient men
in the absence of other diseases (such as blood vessel and nerve diseases that
occur commonly in older men) that affect erectile dysfunction.
Mood
Men whose condition makes them depressed, angry, tired, or confused prior to
therapy may feel better after receiving supplemental testosterone.
Masculine Characteristics
Men taking testosterone can maintain masculine characteristics such beard growth
and pubic hair.
Bone Density and Muscle Mass
Testosterone therapy can increase lean muscle mass and bone density in men and
improve grip and leg strength.
There are four delivery methods of testosterone that have been approved by the U.S. Food and Drug Administration (FDA). Supplemental testosterone is typically used in one of the following forms:
Pills Manufacturer Dosing Administration
Andriol* (testosterone undecanoate) Organon 80-160 mg daily Orally
*Available in Canada, Mexico, and Europe
Injections Manufacturer Dosing Administration
Depo-Testosterone® (brand of testosterone cypionate) Pharmacia Corporation
150-200 mg, every 10-21 days Intramuscular injection
Delatestryl® (testosterone enanthate injection) BTG Pharmaceuticals 150-200
mg, every 10-21 days Intramuscular injection
Patches Manufacturer Dosing Administration
Testoderm® Alza Pharmaceuticals 4mg/day, 40cm2 Applied daily to
patch or 6mg/day, 60cm2 patch scrotum
Androderm® (testosterone transdermal system) Watson Pharmaceuticals 5 mg/day,
using two 2.5 mg, 37 cm2 patches, or one 5 mg, 44 cm2 patch Applied daily to
back, abdomen, upper arms, or thighs
Gel Manufacturer Dosing Administration
AndroGel® 1% (testosterone gel) Unimed Pharmaceuticals/Solvay 5-10 g/day,
using clear, colorless, water/alcohol mixture Applied daily to shoulders and
upper arms and/or abdomen
Testim® Auxilium Pharmaceuticals 5-10 g/day, using clear, colorless, water/alcohol
mixture Applied daily to shoulders and upper arms and/or abdomen
Buccal Manufacturer Dosing Administration
Striant® (testosterone buccal system gel) Columbia Laboratories, Inc. Single
dose/strength; no dose titration required Applied to the buccal mucosa (where
the gum meets the upper lip)
Once a doctor has diagnosed low testosterone on the basis of physical symptoms
and medical test results, he/she should determine if the low testosterone levels
are due to testicular, pituitary, or hypothalamic etiology. Individuals with
low testosterone and normal or low serum LH levels may require further evaluation.
After resolving these issues, treatment with supplemental testosterone can begin.
Many studies have demonstrated improved function with testosterone replacement.
Investigators have found that treatment resulted in increased sexual interest
and an increased number of spontaneous erections. Men taking testosterone replacement
therapy also were less depressed, angry, and fatigued.
As seen in the accompanying chart, testosterone replacement therapy can be offered in a variety of forms. Together, the patient and his physician can select a mode of acceptable treatment.
Pills
Although methyl testosterone is manufactured in capsule or pill form, it is
not recommended for testosterone replacement in men because it is a weak androgen
and not as effective as other preparations, and it has potentially serious adverse
effects on the liver and lipids. When capsules/pills are swallowed and absorbed
into the bloodstream, they are quickly broken down by the liver and do not achieve
high enough blood levels to be useful unless given in large doses (40-50 mg/day).
At these doses, they may cause adverse changes in blood lipids (fats) and liver
damage. Testosterone undecanoate is moderately effective, but it must be given
in capsular form three times daily. It has unique properties that reduce rapid
metabolism by the liver and has not been associated with serious adverse effects
on the liver.
Injections
Deep muscle injections do not have to be taken daily but are instead given every
7-21 days. With injections, blood levels peak about two to three days after
dosing and slowly decline during the next one to two weeks. The injections are
painful, and fluctuations in serum levels of testosterone may be accompanied
by changes in mood and a sense of well being. Injectable therapy usually is
the least expensive way to provide testosterone replacement, and it requires
the least patient motivation and compliance.
Transdermal (through the skin) Delivery Systems
Gel and patch systems offer other advantages. Both are easy-to-apply systems
that provide continuous delivery of testosterone. The water/alcohol mixture
in the gel system dries quickly and the testosterone is readily absorbed into
the skin, which serves as a reservoir for the sustained release of testosterone
into the bloodstream. The site of application should be covered, or direct contact
with women and children should be avoided. Skin reactivity with the gel seems
to be limited in studies at the present time. Patches may cause local reactions
in some patients. Most common complaints consist of itching or irritation and
rarely blister formation at the application site and they may fall off when
the individual sweats.
Buccal Testosterone Delivery System
A recently approved system, buccal testosterone treatment, provides a controlled
and sustained release of testosterone through the buccal mucosa (tablet adheres
to gum surface), where it is absorbed into the bloodstream. Tablets are replaced
about every 12 hours. This system may cause gum or mouth irritation, bitter
taste, gum pain or tenderness, headache, and taste perversion, but the majority
of side effects were resolved within one to 14 days. Insignificant amounts of
testosterone are present in the saliva, so transfer of testosterone to women
and children in contact with saliva (e.g., with kissing or sharing of eating
utensils) is negligible.
With any testosterone delivery system, prolonged use may result in breast enlargement or increased risk of prostate enlargement or cancer in older men. Men receiving testosterone replacement therapy should be monitored carefully for prostate cancer, e.g., with a rectal examination and prostate specific antigen. In addition, patients with preexisting heart, kidney, or liver disease may experience fluid accumulation with or without heart failure. Men with breast cancer or known or suspected prostate cancer should not receive testosterone therapy. The patch and gel products are not indicated for use in women. Testosterone may cause fetal harm.
Physicians should instruct men taking testosterone to report any of the following:
Breathing disturbances, especially those associated with sleep
Too frequent or persistent erection
in men with the AIDS wasting syndrome. A randomized, double-blind, placebo-controlled
trial — S. Grinspoon et al. Annals of Internal Medicine 1998; 129(1):18-26.
Fifty-one HIV-positive men with a mean age of 42 who had wasting and low testosterone
were randomly assigned to receive testosterone or placebo every three weeks
for six months. Testosterone-treated men gained fat-free mass, lean body mass
and muscle mass. These men also reported they felt better, had an improved quality
of life and improved appearance. (Design of Study: Double-blind, randomized,
placebo-controlled trial of testosterone versus placebo therapy in HIV-infected
men with AIDS wasting syndrome.)
What is testosterone?
Testosterone is the primary sex hormone produced in men's bodies. Testosterone
stimulates the development of the penis and testes, growth of facial and pubic
hair, deepening of the voice, changes in body-shape, growth of bones, and increased
muscle mass and strength. It helps maintain sex drive and the production of
sperm cells, and it may play a role in balding. Mood is also affected by testosterone,
and low levels of the hormone can cause severe and prolonged depression as well
as fatigue. Testosterone is produced mostly in the testes and a small amount
is produced from steroids secreted from the outer part of the adrenal glands
called the adrenal cortex. Women's ovaries also produce a small amount of testosterone.
The testes receive chemical signals from the pituitary gland, which is located
at the base of the brain. The pituitary gland receives signals from the hypothalamus.
The hypothalamus secretes gonadotropin-releasing hormone (GnRH). This signals
the pituitary gland to produce and secrete follicle-stimulating hormone (FSH)
and luteinizing hormone (LH). LH signals the testes to produce testosterone.
If the testes begin producing too much testosterone, the body sends signals
to the pituitary telling it to make less LH. This, in turn, slows down the production
of testosterone.
Doctors check to see if a man's blood testosterone level falls into a generally
acceptable range of values. Testosterone levels vary from hour to hour, so fluctuations
can be seen in men with no apparent problems. Generally, the highest testosterone
levels occur in the early morning hours, so measurements should be taken at
this time. Normal ranges are determined in normal, healthy men between the ages
of 20 and 40 or 45.
If a doctor suspects someone is not producing enough testosterone, he/she will
check if the total blood testosterone level falls into the acceptable range.
The doctor also may instruct the laboratory to measure the amount of free or
loosely bound testosterone (about 40 percent of the total testosterone is strongly
bound to a protein called sex hormone binding globulin, known as SHBG; about
58 percent is weakly bound to another protein called albumin) and the amount
of free testosterone (only about two percent circulates freely in the blood).
Blood levels of SHBG increase with age, so older men may have a higher percentage
of bound testosterone and a lower percentage of free testosterone. Bioavailable
testosterone includes the non-SHBG bound testosterone or the sum of the testosterone,
which is bound to albumin and free (unbound) testosterone.
Not only does the amount of testosterone produced decline with age, the morning
spike of testosterone seen in young men is blunted in older men. The pituitary
glands of older men also may produce less luteinizing hormone (LH), which decreases
testosterone production. Testosterone in aging men is more likely to bind to
sex hormone binding globulin (SHBG), which reduces the amount of bioavailable
or freely circulating testosterone that is available to the body. However, aging
also is frequently associated with increasing obesity, and obesity is associated
with decreased SHBG levels. Thus, measurement of non-SHBG bound testosterone
may be needed in aging, obese men.
Yes. Certain genetic conditions such as Klinefelter's syndrome, Kallmann's syndrome,
and Prader-Willi syndrome can cause lowered testosterone production in boys
and young men. In addition, testosterone production can be lowered by bilateral
cryptochid testes injury, inflammation, and tumors. Chemotherapy and radiation
therapy also may damage testosterone-producing cells. Finally, many patients
who are HIV+ have low testosterone levels.
If someone has a low testosterone level, how do they get it increased?
Supplemental preparations of testosterone currently are available in gel and
patch forms that deliver it through the skin, as pills, or as preparations that
have to be injected into deep muscle about every 7 to 21 days.
An endocrinologist is a doctor who is a medical expert in treating diseases
with abnormal hormone secretion and tumors of glands that secrete hormones.
Board-certified endocrinologists are ideally suited to evaluate, diagnose, and
identify a wide spectrum of medical, physical and psychiatric abnormalities
responsible for causing male sexual dysfunction including a low testosterone
level. To find an endocrinologist near you, visit The Hormone Foundation's "Find
an Endocrinologist" physician referral directory at www.hormone.org (The
directory is comprised of over 2,500 members of The Endocrine Society, the parent
organization of The Hormone Foundation and the largest organization of endocrinologists
in the world.)