Transcript testosterone

Primary Male Hypogonadism
and Testosterone Therapy
By: Dr Salehidoost
Assistant Prof. of Endocrinology
Isfahan University Of Medical Sciences
Development of the male reproductive
system
Male sexual development starts between the 7th and 12th
week of gestation.
The undifferentiated gonads develop into a fetal testis
through expression of the sex-determining region Y gene
(SRY), a gene complex located on the short arm of the Y
chromosome .
The fetal testis produces two hormones: testosterone and
anti-Müllerian hormone (AMH).
Jungwirth A,et al.Eur Urol. 2012 Feb.
Development of the male reproductive
system
Testosterone is needed for the development of the
Wolffian ducts, resulting in formation of the epididymis,
vas deferens and seminal vesicle.
AMH activity results in regression of the Müllerian ducts.
Under the influence of intratesticular testosterone, the
number of gonocytes per tubule increases threefold during
the fetal period.
Jungwirth A,et al.Eur Urol. 2012 Feb.
Development of the male reproductive
system
Testosterone is needed for development of the prostate,
penis and scrotum.
However, in these organs testosterone is converted into
the more potent metabolite dihydrotestosterone (DHT) by
the enzyme 5a-reductase .
The enzyme is absent in the testes, which explains why 5areductase inhibitors do not have a marked effect on
spermatogenesis.
Jungwirth A,et al.Eur Urol. 2012 Feb.
Development of the male reproductive
system
Intratesticular testosterone is needed to maintain the spermatogenic
process and to inhibit germ cell apoptosis .
The seminiferous tubules of the testes are exposed to concentrations of
testosterone 25-100 times greater than circulating levels.
Suppression of gonadotrophins (e.g. through excessive testosterone
abuse) results in a reduced number of spermatozoa in the ejaculate and
hypospermatogenesis .
Complete inhibition of intratesticular testosterone results in full cessation of
meiosis up to the level of spermatids .
Jungwirth A,et al.Eur Urol. 2012 Feb.
Hypogonadism
Hypogonadism is defined as “inadequate gonadal function, as
manifested by deficiencies in gametogenesis and/or the secretion of
gonadal hormones.”
These abnormalities usually result from disease of the testes (primary
hypogonadism) or disease of the pituitary or hypothalamus (secondary
hypogonadism).
In occasional cases, a defect in the ability to respond to testosterone is
the cause of hypogonadism.
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
Hypergonadotropic Hypogonadism
Patients with hypergonadotropic hypogonadism may
have some or all of the following characteristic findings:
• Increased FSH level
• Increased LH level
• Low testosterone level
• Impaired production of sperm
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
Hypogonadotropic Hypogonadism
The condition of hypogonadotropic hypogonadism is
generally associated with the following findings:
• Low or low-normal FSH level
• Low or low-normal LH level
• Low testosterone level
• Impaired production of sperm
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
Hypogonadism
Primary hypogonadism differs from secondary hypogonadism in two
ways:
●Primary hypogonadism is more likely to be associated with a
decrease in sperm production than in testosterone production.
Although many testicular diseases damage both the seminiferous
tubules and the Leydig cells, they usually damage the seminiferous
tubules to a greater degree. As a consequence, the sperm count may
be low, and the serum FSH concentration normal or high, yet the
serum testosterone concentration remains normal.
In contrast, in secondary hypogonadism, there is a proportionate
reduction in testosterone and sperm production.
UpToDate 2015, Causes of primary hypogonadism in males
Hypogonadism
Primary hypogonadism differs from secondary hypogonadism in
two ways:
●Primary hypogonadism is more likely to be associated with
gynecomastia, presumably due to the stimulatory effect of the
supranormal serum FSH and LH concentrations on testicular
aromatase activity. This results in increased conversion of
testosterone to estradiol .
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General Manifestations
Symptoms of hypogonadism depend primarily on the age of the male patient
at the time of development of the condition.
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
General Manifestations
When hypogonadism develops before the age of puberty, the manifestations are
those of impaired puberty:
 • Small testes, phallus, and prostate
 • Scant pubic and axillary hair
 • Disproportionately long arms and legs (from delayed epiphyseal closure)
 • Reduced male musculature
 • Gynecomastia
 • Persistently high-pitched voice
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
General Manifestations
In men in whom androgen deficiency develops after completion of pubertal
maturation, symptoms of androgen deficiency include:
 reduced sexual desire and activity,
 decreased spontaneous erections,
 loss of body hair and reduced frequency of shaving,
 infertility,
 reduced muscle bulk and strength,
 hot flushes and sweats,
 height loss due to atraumatic fracture,
 small or shrinking testes,
 breast enlargement or tenderness
Less-specific symptoms include decreased energy, motivation, and initiative; sad
or blue feelings, depressed mood, dysthymia; poor concentration and memory;
sleep disturbance and increased sleepiness; increased body fat; and diminished
physical or work capacity.
General Manifestations
Postpubertal loss of testicular function results in slowly
evolving subtle clinical symptoms and signs.
In aging men, these symptoms and signs may be difficult
to appreciate because they are often attributed to “getting
older.”
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
General Manifestations
The growth of body hair usually slows.
The voice and the size of the phallus usually remain unchanged.
Prostate size may decrease in hypogonadal men, but the amount of
change is related to the severity of testosterone deficiency.
Typical temporal hair recession and balding usually do not occur,
and if they did, these manifestations would not be expected to
prompt a patient to seek medical attention.
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
Physical Examination
The amount and distribution of body hair, including beard
growth, axillary hair, and pubic hair, should be noted, as should the
presence of a male pattern escutcheon.
The presence and degree of gynecomastia should be recorded. The
presence of galactorrhea would suggest pronounced
hyperprolactinemia, usually associated with some degree of
hyperestrogenism.
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
Physical Examination
The testes should be measured (length and width) by using a Prader
orchidometer or calipers.
Some testicular disorders may selectively affect production of sperm without
influencing production of testosterone. These disorders may sometimes be
detected by careful physical examination, including determination of testicular
size and consistency.
Because approximately 85% of testicular mass consists of germinal tissue, a
reduced germinal cell mass would be associated with a reduced testicular size and
a soft consistency.
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
Physical Examination
Testicular consistency should be noted.
If the germinal epithelium was damaged before puberty, the testes are generally
small and firm.
If postpubertal damage occurred, the testes are usually small and soft.
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
Physical Examination
On examination of the scrotum, the presence of any masses or varicoceles should be
noted for further evaluation. For assessment of any potentially significant varicocele,
the patient should be asked to perform a Valsalva maneuver, and the scrotal contents
should be examined.
The stretched penis should be measured (length and width) .
With prepubertal onset of hypogonadism, the stature may assume eunuchoid
proportions, with a crown-to-pubis divided by a pubis-to-floor ratio of <0.92 and an
arm span more than 3 cm greater than the height.
A nonpalpable prostate suggests low testosterone levels. A prostate that is normal for
age suggests reasonably normal testosterone levels. Of note, an enlarged prostate may
not substantially diminish if once-normal testosterone levels have decreased.
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
Differential Diagnosis
Klinefelter's syndrome
Klinefelter's syndrome is the most common congenital abnormality
causing primary hypogonadism, occurring in approximately 1 in 1000
live male births .
This syndrome is the clinical manifestation of a male who has an extra
X chromosome. The most common genotype is 47,XXY ,but greater
and lesser numbers of X chromosomes have also been reported,
resulting in karyotypes such as 48,XXXY and 46,XY/46,XXY mosaicism .
46,XX males also have Klinefelter's syndrome; the development of
testes in this setting is presumably due to translocation of a small
portion of chromosomal material containing the testis-determining
factor to an X chromosome.
UpToDate 2015, Causes of primary hypogonadism in males
Klinefelter's syndrome
The 47,XXY genotype results from nondisjunction of the sex
chromosomes of either parent during meiotic division.
While mosaicism probably results from nondisjunction during
mitotic division after conception.
The greater the number of extra X chromosomes, the greater
the phenotypic consequences, both gonadal and extragonadal.
UpToDate 2015, Causes of primary hypogonadism in males
Klinefelter's syndrome
Damage to the seminiferous tubules and, usually, damage to the
Leydig cells as well.
The gonadal manifestations include almost invariably small, firm
testes, severely subnormal sperm count, infertility, elevated (FSH)
and (LH) concentrations, variably subnormal serum testosterone
concentration and decreased virilization .
The damage may be increased if the patient also has cryptorchidism,
the incidence of which is increased in Klinefelter's .
A psychosocial abnormality, unrelated to the hypogonadism, which
causes difficulty in social interactions throughout life and has been
characterized by "marked lack of insight, poor judgment, and
impaired ability to learn from adverse experience" .
UpToDate 2015, Causes of primary hypogonadism in males
Klinefelter's syndrome
Predisposition to develop morbidities later in life that are unrelated to testosterone
deficiency .
These include:
 pulmonary diseases such as chronic bronchitis, bronchiectasis, and emphysema ;
 cancers, including germ cell tumors (particularly extragonadal tumors involving
the mediastinum) ,breast cancer ,and possibly non-Hodgkin lymphoma ;
 varicose veins, leading to leg ulcers ;
 systemic lupus erythematosus, probably due to the extra X chromosome ;
 and diabetes mellitus
Mortality from breast cancer has been reported to be much higher in Klinefelter
syndrome than in the general population but that from prostate cancer lower.
UpToDate 2015, Causes of primary hypogonadism in males
Klinefelter's syndrome
Diagnosis of Klinefelter's syndrome usually can be made by determining the
karyotype of the peripheral leukocytes.
Testosterone deficiency and the resulting hypogonadism, if present, can be
treated with testosterone .
Hormone replacement is unlikely to improve the other abnormalities.
Fertility has been achieved with assisted reproductive technologies , but
there are important genetic implications of these procedures .
UpToDate 2015, Causes of primary hypogonadism in males
Other Chromosomal Abnormalities
●The 46,XY/XO karyotype leads to a syndrome characterized by short
stature and features typical of Turner syndrome. The gonads vary from
streak to dysgenetic to normal testes; as a result, the sexual phenotype
varies from complete female to complete male. If the patient has both a
streak gonad and a dysgenetic testis ("mixed gonadal dysgenesis"), the
risk of gonadoblastoma is about 20 percent .Gonadectomy should
therefore be performed in these patients.
●The 47,XYY karyotype was initially thought to be associated with
hypogonadism, but subsequent reports have not confirmed this relation.
●Microdeletions in specific regions of the long arm of the Y chromosome
are occur in up to 20 percent of men with azoospermia or severe
oligospermia. Some of these men have no other testicular lesions, but
others have cryptorchidism .
Mutation in the FSH and LH receptor genes
Another rare cause of primary hypogonadism is a mutation in
the FSH receptor gene .One report described five men found to
be homozygous for an inactivating mutation of the FSH
receptor. These subjects had variably low sperm counts and
inhibin B concentrations and high serum FSH concentrations.
LH receptor mutations result in Leydig cell hypoplasia and
testosterone deficiency in the first trimester in utero, resulting in
varying degrees of male pseudohermaphroditism.
Cryptorchidism
Cryptorchidism refers to testes that are undescended. Unilateral or bilateral
cryptorchidism can occur.
The incidence of this condition is 3 to 4% at birth, but most testes ultimately descend.
Thus, the 1-year incidence is about 0.8%.
Because normal testicular descent requires normal pituitary function and
dihydrotestosterone levels, the incidence of cryptorchidism is increased in patients
with Kallmann’s syndrome.
Generally, the objective is to bring the undescended testicle into the scrotum before 1 to
2 years of age to improve fertility potential.
Because a slight risk of a malignant lesion is associated with undescended testicles,
surgical placement into the scrotum offers the opportunity for thorough examination.
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
Cryptorchidism
Cryptorchidism may affect one or both testes. Some clinical
consequences of cryptorchidism depend upon whether one or both
testes are cryptorchid:
●If only one testis is undescended, the sperm count will be subnormal
in 25 to 33 percent, and the serum FSH concentration will be slightly
elevated. The presence of these abnormalities suggests that both
testes are abnormal, perhaps congenitally, even though only one fails
to descend.
●If both testes are undescended, the sperm count will usually be
severely subnormal and the serum testosterone may also be reduced.
UpToDate 2015, Causes of primary hypogonadism in males
Disorders of androgen biosynthesis
A congenital decrease in testosterone synthesis and secretion can
result from mutations of the genes that encode the enzymes
necessary for testosterone biosynthesis.
These mutations, all rare, involve the cholesterol side chain cleavage
enzyme, 3 beta-hydroxysteroid dehydrogenase, and 17 alphahydroxylase, both of which are present in the adrenal glands as well
as the testes, and 17 beta-hydroxysteroid dehydrogenase, which is
present only in the testes.
Each of these mutations results in decreased testosterone secretion,
beginning in the first trimester of pregnancy, and therefore in
incomplete virilization.
Myotonic Dystrophy
Classically, myotonic dystrophy is an autosomal dominant disorder,
characterized by hypogonadism, muscle weakness, and frontal balding, that
occurs only in male patients.
Testicular failure usually occurs after age 40 years; thus, patients often have
children at risk for the disease. Testosterone levels may be variably decreased
in the setting of azoospermia and high gonadotropin levels.
Small testes and decreased sperm production are more common than
decreased serum testosterone levels.
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
Vanishing Testes Syndrome (Congenital Anorchism or
Prepubertal Functional Castrate)
The initial manifestation of the vanishing testes syndrome is sexual immaturity in a
male patient. The cause is unclear, but the syndrome may be due to testicular torsion
during fetal life after sufficient testosterone exposure to produce masculinization of the
reproductive tract.
Impalpable testes suggest the possibility of cryptorchidism. FSH and LH levels are
increased, and testosterone levels are low. If the LH levels are only minimally
increased, hCG stimulation testing of the gonad should be done. With vanishing testes
syndrome, no response would be demonstrated.
A response to hCG stimulation would raise the possibility of intra-abdominal testes,
which would necessitate further evaluation because of the potential for malignant
transformation. In this setting, MRI is recommended to assess the possibility of a
retained intraabdominal dysgenetic gonad because this would be associated
with an increased risk of a malignant lesion and would necessitate removal.
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
Varicocele
Varicosity of the venous plexus within the scrotum, called a
varicocele, has long been considered a possible cause of damage
to the seminiferous tubules and thereby of infertility.
UpToDate 2015, Causes of primary hypogonadism in males
Infections — Mumps orchitis
Mumps orchitis is the infection most closely associated with
testicular damage. Orchitis is a much more common
manifestation when mumps occurs in adulthood than in
childhood. The median age of men who got mumps orchitis in
one study was 29.
Testicular involvement of mumps causes painful swelling of the
testes, followed by atrophy.
The seminiferous tubules are almost always severely affected,
often resulting in infertility, especially when both testes are
involved; the Leydig cells also may be damaged, resulting in
decreased testosterone production.
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Radiation
Direct radiation to the testes, as in treatment for leukemia, will
damage the testes .
Even indirect radiation to the testes when they are shielded (as
with radiation to the inguinal lymph nodes for lymphoma) will
damage the seminiferous tubules .
The degree of damage is proportionate to the amount of
radiation exposure.
Radioactive iodide has been reported to cause a decrease in the
sperm count when doses of several hundred mCi are
administered to treat thyroid cancer.
UpToDate 2015, Causes of primary hypogonadism in males
• Trauma — Trauma to the testes can be sufficiently severe to
damage both seminiferous tubules and Leydig cells.
• Testicular torsion — Testicular torsion is one of the
most common reasons for the loss of a testicle before puberty.
Testicular torsion is a twisting of the testis on the spermatic cord,
which results in acute loss of the blood supply to the testis. Torsion
lasting more than eight hours can lead to sufficient damage to the
seminiferous tubules to lower the sperm count .
• Bilateral orchiectomy — Orchiectomy is standard
treatment for testicular cancer, which is often bilateral, although it
often occurs at different times on each side.
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Alkylating and antineoplastic agents
Alkylating agents, such as cyclophosphamide, chlorambucil,
cisplatin, and busulfan can damage the seminiferous tubules to
a degree sufficient to cause azoospermia and markedly elevated
serum follicle-stimulating hormone (FSH) concentrations
.Concurrent administration of testosterone might protect
against long-term gonadal injury in adults.
UpToDate 2015, Causes of primary hypogonadism in males
Drugs
• Ketoconazole — The antifungal drug directly inhibits
testosterone biosynthesis, thereby causing
testosterone deficiency .
• Glucocorticoids — Chronic glucocorticoid use can
also lower testosterone levels by about one-third;
the mechanism is not clear, but inhibition may occur
at both the testis and pituitary.
UpToDate 2015, Causes of primary hypogonadism in males
Autoimmune Syndromes
Anti-Leydig cell antibody-associated disorders or conditions associated with
anti-sperm antibodies are autoimmune syndromes related to hypogonadism.
The hypogonadism that accompanies autoimmune polyglandular disease is
also characterized by hypothyroidism and hypoadrenalism.
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
Chronic systemic diseases
•
Many chronic, systemic illnesses cause hypogonadism both
by a direct testicular effect and by decreasing gonadotropin
secretion.
• Cirrhosis
• Chronic renal failure
• HIV
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
Hemochromatosis
Iron overload may lead to primary gonadal failure or
hypothalamic-pituitary dysfunction that results in secondary
gonadal failure .
The diagnosis is made in the setting of associated findings of
hemochromatosis in conjunction with an increased ferritin level.
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
Idiopathic
Primary hypogonadism may be idiopathic, whether it is
severe, resulting in testosterone deficiency and
azoospermia, or mild, resulting only in
oligospermia/azoospermia and an elevated FSH.
Laboratory Studies
Testosterone
Testosterone concentrations may be affected by illness and certain
medications (e.g. opiates and glucocorticoids).
Total testosterone concentrations are also influenced by alterations in
SHBG concentrations.
Serum testosterone levels exhibit a circadian variation with peak
values in the morning; this circadian rhythm is blunted with aging .
Because of this circadian variation in testosterone levels and the fact
that normal ranges for serum testosterone are usually established
using morning blood samples, testosterone measurement for the
diagnosis of androgen deficiency should be performed in the
morning.
J Clin Endocrinol Metab, June 2010, 95(6):2536–2559
Testosterone
It is important to confirm low testosterone concentrations in men
with an initial testosterone level in the mildly hypogonadal range
because 30% of such men may have a normal testosterone
level on repeat measurement .
Also, 15% of healthy young men may have a testosterone level
below the normal range in a 24-h period (day-to-day variations)
Single testosterone measurements were inadequate to
characterize an individual’s levels, and at least two
testosterone measurements were needed to diagnose
androgen deficiency with greater confidence.
J Clin Endocrinol Metab, June 2010, 95(6):2536–2559
Testosterone
Serum total testosterone concentration represents the sum of
unbound and protein-bound testosterone in circulation.
Most of the circulating testosterone is bound to SHBG and to
albumin ;only 0.5–3% of circulating testosterone is unbound or
“free. ”
The term “bioavailable testosterone” refers to unbound
testosterone plus testosterone bound loosely to albumin.
Free or bioavailable testosterone concentrations should be
measured when total testosterone concentrations are close to
the lower limit of the normal range and when altered SHBG
levels are suspected, e.g. in older men and in men with obesity,
diabetes mellitus, chronic illness, or thyroid disease.
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Gonadotropins
Both FSH and LH are secreted in short pulses. FSH has a longer half-life than
does LH and is more likely to provide adequate results on a single blood
sample.
Because LH has a shorter half-life than does FSH, errors may be introduced in
measurements made on single samples.
Pooled samples for LH done 20 to 30 minutes apart are more accurate than
single-sample determinations (albeit less convenient).
Persistent borderline values may be further evaluated with dynamic endocrine
testing.
These tests may include the GnRH stimulation test, the clomiphene stimulation
test, and the human chorionic gonadotropin (hCG) stimulation test.
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
Semen Analysis
A semen analysis is the primary test to assess the fertility potential of
the male patient. Semen should be collected by masturbation after 2 to
5 days of abstinence and evaluated within 2 hours.
Variability between specimens is common; with low or borderline
samples, follow-up consisting of evaluation of three or more samples
should be done during a 3-month period.
A fructose test should be done on a semen sample showing
azoospermia. Because fructose is secreted by the seminal vesicles,
absence of fructose may indicate complete obstruction of the
ejaculatory ducts or congenital absence of both vasa deferens and
both ejaculatory ducts.
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
Genetic Studies
Patients with hypergonadotropic hypogonadism and impaired
pubertal development associated with small, firm testes and often
with gynecomastia are likely to have Klinefelter’s syndrome or a
variant.
Classically, a buccal smear was done to establish the diagnosis by
revealing Barr bodies.
We currently recommend genetic karyotype testing to confirm
the diagnosis .
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
Testicular Biopsy and Scrotal Exploration
Since the advent of sensitive FSH assays, germinal cell
function is now most often assessed through the FSH assay alone
rather than testicular biopsy.
Men with azoospermia, normal FSH levels, and normal testicular
size should usually undergo testicular biopsy and scrotal
exploration to determine whether a germinal cell abnormality, an
obstruction, or a congenital abnormality of the vasa is present.
AACE Hypogonadism Guidelines, Endocr Pract. 2002;8(No. 6)
Diagnosis
We recommend making a diagnosis of androgen deficiency
only in men with consistent symptoms and signs and
unequivocally low serum testosterone levels between 8
and 10 AM on at least two occasions.
.
J Clin Endocrinol Metab, June 2010, 95(6):2536–2559
Diagnosis
If a single 8 to 10 AM value is well within the normal
range, testosterone production can be assumed to be
normal.
If a single 8 to 10 AM value is low or borderline low or
does not fit with the clinical findings, the
measurement should be repeated once or twice
before making the diagnosis of hypogonadism.
The normal range in adult men in most laboratories is about
300 to 800 ng/dL.
Diagnosis
We suggest the measurement of morning total testosterone
level as the initial diagnostic test.
We recommend confirmation of the diagnosis by repeating
measurement of total testosterone.
We suggest measurement of free or bioavailable testosterone
level, using an accurate and reliable assay, in some men in
whom total testosterone concentrations are near the lower limit
of the normal range and in whom alterations of SHBG are
suspected.
We suggest that an evaluation of androgen deficiency should not
be made during an acute or subacute illness.
J Clin Endocrinol Metab, June 2010, 95(6):2536–2559
Case finding
Case finding
In men with chronic diseases such as diabetes mellitus,
end-stage renal disease, and chronic obstructive lung
disease, measurement of testosterone may be indicated
by symptoms such as sexual dysfunction, unexplained
weight loss, weakness, or mobility limitation.
In men with some other conditions, such as a pituitary
mass, HIV-associated weight loss, low trauma fracture,
or treatment with medications that affect testosterone
production, measurement of testosterone may be
indicated regardless of symptoms.
J Clin Endocrinol Metab, June 2010, 95(6):2536–2559
Testosterone Therapy
We recommend testosterone therapy for symptomatic men
with classical androgen deficiency syndromes aimed at
inducing and maintaining secondary sex characteristics
and at improving their sexual function, sense of well-being,
and bone mineral density.
J Clin Endocrinol Metab, June 2010, 95(6):2536–2559
Testosterone Therapy
We suggest that when clinicians prescribe testosterone
therapy, the therapeutic target should be to raise serum
testosterone levels into a range that is mid-normal for
healthy, young men.
In men receiving testosterone enanthate or cypionate,
serum testosterone levels vary during the dosing interval;
We suggest aiming for testosterone levels between 400
and 700 ng/dl midway between injections.
J Clin Endocrinol Metab, June 2010, 95(6):2536–2559
Monitoring men receiving testosterone therapy
Evaluate the patient 3 to 6 months after treatment initiation and then annually
to assess whether symptoms have responded to treatment and whether the
patient is suffering from any adverse effects.
Monitor testosterone level 3 to 6 months after initiation of testosterone
therapy:
Therapy should aim to raise serum testosterone level into the mid-normal
range.
Injectable testosterone enanthate or cypionate: measure serum
testosterone level midway between injections. If testosterone
is 700 ng/dl (24.5 nmol/liter) or 400 ng/dl (14.1 nmol/liter), adjust dose or
frequency.
Transdermal patches: assess testosterone level 3–12 h after application of
the patch; adjust dose to achieve testosterone level in the mid-normal range.
J Clin Endocrinol Metab, June 2010, 95(6):2536–2559
Monitoring men receiving testosterone therapy
Buccal testosterone bioadhesive tablet: assess level immediately before or
after application of fresh system.
Transdermal gels: assess testosterone level any time after patient has been
on treatment for at least 1 wk; adjust dose to achieve serum testosterone level
in the mid-normal range.
Testosterone pellets: measure testosterone levels at the end of the dosing
interval. Adjust the number of pellets and/or the dosing interval to achieve
serum testosterone levels in the normal range.
Oral testosterone undecanoatea: monitor serum testosterone level 3 to 5 h
after ingestion.
Injectable testosterone undecanoate: measure serum testosterone level just
prior to each subsequent injection and adjust the dosing interval to maintain
serum testosterone in mid-normal range.
J Clin Endocrinol Metab, June 2010, 95(6):2536–2559
Monitoring men receiving testosterone therapy
Check hematocrit at baseline, at 3 to 6 months, and
then annually. If hematocrit is 54%, stop therapy until
hematocrit decreases to a safe level; evaluate the patient
for hypoxia and sleep apnea; reinitiate therapy with a
reduced dose.
Measure bone mineral density of lumbar spine and/or
femoral neck after 1–2 yr of testosterone therapy in
hypogonadal men with osteoporosis or low trauma fracture,
consistent with regional standard of care.
J Clin Endocrinol Metab, June 2010, 95(6):2536–2559
Monitoring men receiving testosterone therapy
In men 40 yr of age or older with baseline PSA greater than 0.6 ng/ml,
perform digital rectal examination and check PSA level before initiating
treatment, at 3 to 6 months, and then in accordance with guidelines for
prostate cancer screening depending on the age and race of the patient.
Obtain urological consultation if there is:
 An increase in serum PSA concentration 1.4 ng/ml within any 12month period of testosterone treatment.
 A PSA velocity of 0.4 ng/ml yr using the PSA level after 6 months of
testosterone administration as the reference (only applicable if PSA
data are available for a period exceeding 2 yr).
 Detection of a prostatic abnormality on digital rectal examination.
 An AUA/IPSS of 19.
J Clin Endocrinol Metab, June 2010, 95(6):2536–2559
Testosterone therapy in men with sexual
dysfunction
We suggest that clinicians offer testosterone therapy to
men with low testosterone levels and low libido to
improve libido and to men with ED who have low
testosterone levels after evaluation of underlying causes of
ED and consideration of established therapies for ED.
Guidelines for Testosterone Therapy in Androgen-Deficient Men J Clin Endocrinol Metab, June
2010, 95(6):2536–2559
HIV-infected men with weight loss
We suggest that clinicians consider short-term
testosterone therapy as an adjunctive therapy in HIVinfected men with low testosterone levels and weight
loss to promote weight maintenance and gains in LBM and
muscle strength.
Guidelines for Testosterone Therapy in Androgen-Deficient Men J Clin Endocrinol Metab, June
2010, 95(6):2536–2559
Glucocorticoid-treated men
We suggest that clinicians offer testosterone therapy to
men receiving high doses of glucocorticoids who
have low testosterone levels to promote preservation of
LBM and bone mineral density.
Guidelines for Testosterone Therapy in Androgen-Deficient Men J Clin Endocrinol Metab, June
2010, 95(6):2536–2559
Time course of effects
The time course of the effects of testosterone
replacement is variable.
Increases in fat-free mass, prostate volume,
erythropoiesis, energy, and sexual function occurred
within the first three to six months.
In contrast, the full effect on bone mineral density
(BMD) did not occur until 24 months.
In general, the benefits of TRT are more consistent in
men with very low testosterone concentrations than in
those with concentrations just below the normal range.
Health care professionals should make patients aware
of the possible increased cardiovascular risk when
deciding whether to start or continue a patient on
testosterone therapy.
TRT should not be provided to men who have
untreated or metastatic prostate cancer or breast
cancer.
Testosterone and Cardiovascular Risk, Endocr Prac. 2015;21(No. 9)
Relative contra-indications include :
 untreated severe sleep apnea,
 a hematocrit >50%,
 severe lower urinary tract symptoms with an International
Prostate Symptom Score above 19,
 uncontrolled or poorly controlled heart failure,
 a MI or cerebrovascular accident within the past 6 months,
 a personal or family history of a procoagulant state,
 or a personal history of thromboembolism
Testosterone and Cardiovascular Risk, Endocr Prac. 2015;21(No. 9)