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Testosterone Deficiency
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Testosterone production declines naturally with age.
Testosterone deficiency (TD) may result from disease or damage
to the hypothalamus, pituitary gland, or testicles that
inhibits hormone secretion and testosterone production, and is
also known as hypogonadism. Depending on age, insufficient
testosterone production can lead to abnormalities in muscle
and bone development, underdeveloped genitalia, and diminished
virility.
Testosterone is the androgenic hormone primarily responsible
for normal growth and development of male sex and reproductive
organs, including the penis, testicles, scrotum, prostate, and
seminal vesicles. It facilitates the development of secondary
male sex characteristics such as musculature, bone mass, fat
distribution, hair patterns, laryngeal enlargement, and vocal
chord thickening. Additionally, normal testosterone levels
maintain energy level, healthy mood, fertility, and sexual
desire.
The testes produce testosterone regulated by a complex chain
of signals that begins in the brain. This chain is called the
hypothalamic-pituitary-gonadal axis. The hypothalamus secretes
gonadotropin-releasing hormone (GnRH) to the pituitary gland
in carefully timed pulses (bursts), which triggers the
secretion of leutenizing hormone (LH) from the pituitary
gland. Leutenizing hormone stimulates the Leydig cells of the
testes to produce testosterone. Normally, the testes produce
4–7 milligrams (mg) of testosterone daily.
Incidence and Prevalence
Testosterone production increases rapidly at the onset of
puberty and decreases rapidly after age 50 (to 20–50% of peak
level by age 80). Recent estimates show that approximately 13
million men in the United States experience testosterone
deficiency and less than 10% receive treatment for the
condition.
Studies also have shown that men with obesity, diabetes, or
hypertension may be twice as likely to have low testosterone
levels.
Types and Causes
Testosterone deficiency (hypogonadism) may be present at birth
(congenital) or may develop later (acquired). It is classified
by the location of its cause along the hypothalamic-pituitary-gonadal
axis:
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Primary,
disruption in the testicles
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Secondary,
disruption in the pituitary
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Tertiary,
disruption in the hypothalamus
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The most common congenital cause is
Klinefelter's syndrome. This condition, which is caused by an
extra X chromosome, results in infertility, sparse facial and
body hair, abnormal breast enlargement (gynecomastia), and
small testes.
Congenital hormonal disorders such as leutenizing
hormone-releasing hormone (LHRH) deficiency and gonadotropin-releasing
hormone (GnRH) deficiency (e.g., Kallmann's syndrome) also may
cause testosterone deficiency.
Other congenital causes include absence of the testes (anorchism;
also may be acquired) and failure of the testicles to descend
into the scrotum (cryptorchidism).
Acquired causes of testosterone deficiency include the
following:
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Chemotherapy
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Damage
occurring during surgery involving the pituitary gland,
hypothalamus, or testes
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Glandular
malformation
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Head trauma
that affects the hypothalamus
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Infection
(e.g., meningitis, syphilis, mumps)
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Isolated LH
deficiency (e.g., fertile eunuch syndrome)
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Radiation
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Testicular
trauma
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Tumors of the
pituitary gland, hypothalamus, or testicles
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Signs and Symptoms
Signs depend on the age of onset and the duration of hormonal
deficiency. Congenital testosterone deficiency is generally
characterized by underdeveloped genitalia (testes that do not
descend into the scrotum) and, occasionally, undeterminable
genitalia. Acquired testosterone deficiency that develops near
puberty can result in enlargement of breast tissue (gynecomastia),
sparse or absent pubic and body hair, and underdeveloped
penis, testes, and muscle. Adult men may experience diminished
libido, erectile dysfunction, muscle weakness, loss of body
hair, depression, and other mood disorders.
Complications
Testosterone deficiency has been linked to muscle weakness and
osteoporosis. In one study, proximal and distal muscle
weakness was detected in 68% of men with primary or secondary
hypogonadism. Spinal, trabecular, and radial cortical bone
density may also be significantly reduced in
testosterone-deficient men. Thirty percent of men with spinal
osteoporosis have long-standing testosterone deficiency, and
one-third of men have subnormal bone density that puts them at
risk for fracture.
Diagnosis
Serum and blood testing is done to determine the availability
of testosterone and levels of leutenizing and gonadotropin-releasing
hormones in the body. Men with low testosterone in whom normal
or high gonadotropin levels are found typically have primary
testosterone deficiency, which stems from a problem in the
testicles. Secondary and tertiary types, caused by problems of
the hypothalamus or pituitary gland, often result in low
testosterone and low gonadotropin levels.
Other tests involve injecting GnRH or clomiphene citrate (an
estrogen) to stimulate a diagnostic response within the
hypothalamic-pituitary gonadal axis.
Rarely, testicular biopsy is done, usually in cases where
sperm is absent from ejaculate despite normal testicle
development. Biopsy, which involves using a needle to collect
a sample of testicular tissue, may detect a malfunction in
sperm production.
Treatment
Treatment involves hormone replacement therapy. The method of
delivery is determined by age and duration of deficiency. Oral
testosterone (methyltestosterone, Testred®) is associated with
liver toxicity and liver tumors and so is prescribed
sparingly.
Treatment for adults is aimed at maintaining secondary sex
characteristics, improving energy, strength, mood, and
feelings of well-being, and preventing bone degeneration.
Modes of delivery include transdermal, mucoadhesive, and
intramuscular injection.
Transdermal delivery (i.e., through the skin) with a
testosterone patch is becoming the most common method of
treatment for testosterone deficiency in adults. It
establishes and maintains adequate serum levels in as many as
92% of men treated, without causing significant side effects.
A patch is worn, either on the scrotum or elsewhere on the
body, and testosterone is released through the skin at
controlled intervals. Patches are typically worn for 12 or 24
hours and can be worn during exercise, bathing, and strenuous
activity. Two transdermal patches that are available are
Androderm® (nonscrotal) and Testoderm® (scrotal).
The Androderm® patch is applied to the abdomen, lower back,
thigh, or upper arm and should be applied at the same time
every evening between 8 p.m. and midnight. If the patch falls
off before noon, replace it with a fresh patch until it is
time to reapply a new patch that evening. If the patch falls
off after noon, do not replace it until you reapply a new
patch that evening.
The most common side effects associated with transdermal patch
therapy include itching, discomfort, and irritation at the
site of application. Some men may experience fluid retention,
acne, and temporary abnormal breast development (gynecosmastia).
AndroGel® and Testim™ are transdermal gels that are applied
once daily to the clean dry skin of the upper arms or abdomen.
When used properly, these gels deliver testosterone for 24
hours. The gel must be allowed to dry on the skin before
dressing and must be applied at least 6 hours before showering
or swimming. Gels cannot be applied to the genitals.
AndroGel® is available in a metered-dose pump, which allows
physicians to adjust the dosage of the medication. Side
effects of transdermal gels include adverse reactions at the
site of application, acne, headache, and hair loss (alopecia).
Mucoadhesive delivery allows testosterone to enter the
bloodstream directly, bypassing the gastrointestinal tract and
the liver.
Striant™ (testosterone buccal system) mucoadhesive CIII is a
hormone-replacement treatment that delivers testosterone twice
daily through a tablet-like buccal system that adheres to the
gum or cheek. It is placed in the mouth where the gum meets
the upper lip and dissolves into a gel that remains in place
for 12 hours. As the product absorbs moisture, it gradually
releases testosterone directly into the bloodstream, bypassing
the gastrointestinal tract and the liver. In clinical trials,
approximately 87% of patients obtained normal testosterone
levels using Striant™.
Side effects are usually mild and transient (i.e., come and
go) and resolve within 2 weeks. They include gum or mouth
irritation, pain, and swelling (edema); bitter taste, and
headache. Abnormal breast development (gynecomastia) may also
occur. Patients should report persistent gum abnormalities to
their physician.
Striant™ should not be used in men with prostate or breast
cancer and should be used with caution in patients with
chronic heart, kidney, liver, or lung disease. It may cause
edema, congestive heart failure, and sleep apnea, and may
increase the risk for enlarged prostate and prostate cancer.
Patients taking the medication must undergo regular digital
rectal examinations (DRE) and prostate-specific antigen (PSA)
tests to monitor for signs of the disease.
Intramuscular injection (IM) is used less frequently because
it is associated with erratic testosterone levels. The primary
adverse effect associated with injected testosterone involves
fluctuating mood, energy level, and libido caused by
testosterone levels that rise rapidly upon injection and then
fall too low before the next dose.
Kallmann's syndrome may be treated with chorionic gonadotropin,
which can correct undescended testicles (cryptorchidism) and
infertility. Gonoadotropin releasing hormone (GnRH) therapy
can trigger secretion of testosterone and other sex steroids,
initiate virilization, and may establish fertility.
Children and adolescents with low testosterone and delayed
puberty may be treated with low doses of testosterone through
intramuscular injection to induce puberty. Adolescents may
receive gradually increasing doses that last longer in the
body, because, with age, there is less risk for affecting
normal growth patterns.
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