1. No category

I
Seminar
@ ® Male hypogonadism
Cross Mark
Sh ehzad Basaria
l ancet 2014; 383:1250-63
Published Online
October 10, 2013
http://dx.doi.org/10.1016/
S0140-6736(13)61126-s
Section on Men's Health, Aging
and Metabolism, Division of
Endocri nology, Brigham and
Wome n's Hospital, Harvard
Medical School, Boston, MA,
USA (S Basa ria)
Correspondence to:
Dr Shehzad Basaria, Section on
Male hypogonadism is a clinical syndrome that results from failure to produce physiological concentrations of
testosterone, normal amounts of sperm, or both. Hypogonadism may arise from testicular disease (primary
hypogonadism) or dysfunction of the hypothalamic-pituitary unit (secondary hypogonadism). Clinical presentations
vary dependent on the time of onset of androgen deficiency, whether the defect is in testosterone production or
spermatogenesis, associated genetic factors, or history of androgen therapy. The clinical diagnosis of hypogonadism
is made on the basis of signs and symptoms consistent with androgen deficiency and low morning testosterone
concentrations in serum on multiple occasions. Several testosterone-replacement therapies are approved for
treatment and should be selected according to the patient's preference, cost, availability, and formulation-specific
properties. Contraindications to testosterone-replacement therapy include prostate and breast cancers, uncontrolled
congestive heart failure, severe lower-urinary-tract symptoms, and erythrocytosis. Treatment should be monitored for
benefits and adverse effects.
Men's Health, Aging and
Metabolism, Division
of Endocrinology, Brigham
and Women 's Hospital,
Harvard Medical School,
221 Longwood Avenue, BLI-541,
Boston, MA 02115, USA
[email protected]
Introduction
Physiological functioning of the testes is important for
virilisation, physical strength, behaviour, and reproduction. In men testes have two seminal functions:
production of testosterone and spermatogenesis. Testosterone, which is the predominant circulating androgen, is
produced by the Leydig cells and is crucial for virilisation
and maintenance ofthe male phenotype. Spermatogenesis
takes place within the seminiferous tubules and is essential for male fertility. Male hypogonadism refers to impairment of one or both of these functions.' Disorders of
androgen action due to mutations in the androgen
receptor also constitute a rare cause of hypogonadism.'
In this Seminar, I provide an overview of the causes,
diagnosis, and treatment of male hypogonadism. Extensive discussion of age-related decline in testosterone
concentrations (late-onset hypogonadism) and infertility,
however, is beyond the scope of this seminar.
Physiology of the hypothalamic-pituitarygonadal axis
The gonadal axis is regulated by a nexus of hypothalamic
neurons (hypothalamic pulse generator) in the mediabasal hypothalamus that responds to stimulation by the
peptide hormone kisspeptin. Gonadotropin-releasing
hormone (GnRH) is released in pulses every 60- 90 min
Search strategy and selection criteria
I searched Medline and PubMed for full-text,
English-language articles published from january, 1970, to
December, 2012. I used the search terms "male
hypogonad ism", "male androgen deficiency", and
"testosterone" in combination with "physiology",
"pathophysiology", "diagnosis", "treatment", "benefits", and
"adverse effects". I also manually searched the reference lists
of selected papers for further re levant publications. The
search focused mainly on orig inal research articles, but I also
selected reviews and meta-analyses published in the past
5 years and frequently referenced important older articles.
1250
(figure 1) ,'-4 which stimulates the pulsatile release of the
gonadotropins luteinising hormone (LH) and folliclestimulating hormone (FSH) into the bloodstream. LH
stimulates Leydig cells to produce testosterone, and FSH,
in conjunction with intratesticular testosterone, acts on
Sertoli cells and seminiferous tubules to stimulate
spermatogenesis. Testes produce 3-10 mg of testosterone
daily, which roughly corresponds to concentrations of
10 ·4--34·7 nmoljL in serum that peak in the morning.
Testosterone acts directly via androgen receptors and via
its conversion into two active metabolites, dihydrotestosterone by the enzyme 5-a reductase or oestradiol by
the enzyme aromatase (figure 2). Testosterone and
oestradiol feedback negatively to the hypothalamus and
pituitary to suppress gonadotropin secretion.
Classification of hypogonadism
Male hypogonadism is a clinical syndrome that arises
from disruption of the hypothalamic-pituitary-gonadal
axis at any level. In primary hypogonadism, where the
testes are primarily affected, testosterone concentrations
in serum are substantially lowered, spermatogenesis is
impaired, and concentrations of gonadotropins are
raised (hypergonadotropic h ypogonadism) . Secondary
hypogonadism is characterised by low testosterone
concentrations in serum, reduced spermatogenesis
and low or inappropriately normal concentrations of
gonadotropins (hypogonadotropic hypogonadism).
Both forms may arise from numerous congenital and
acquired disorders (table 1). In primary hypogonadism,
impairment of spermatogenesis is generally greater
than that of testosterone production, whereas in secondary hypogonadism both functions are affected to the
same degree.
The different types of hypogonadism have different
therapeutic implications and, therefore, accurate classification of patients is important. In men with primary
hypogonadism, fertility cannot be restored by hormonal
therapy because the seminiferous tubules are damaged.
Use of donor sperm, assisted reproductive technologies
and adoption could be considered instead. By contrast,
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Seminar
fertility in secondary hypogonadism can frequently be
restored by pulsatile GnRH therapy (in patients with an
intact pituitary) and with gonadotropin therapy.' Men
with secondary hypogonadism generally need additional
rule out hyperdiagnostic
investigations to
prolactinaemia, hypercortisolism, pituitary adenoma,
and infiltrative diseases.
A rare form of hypogonadism results from mutations
in androgen receptors, and phenotype is based on partial
or complete resistance to androgens. 2
A Normal HPG axis
B Primary hypogonadism
I
C Secondary hypogonadism
Hypothalamus
Posterior
pituitary
LH lFSH
LH lFSH
LH lFSH
Causes of primary hypogonadism
Klinefelter's syndrome
Klinefelter's syndrome is the most common genetic
cause of hypogonadism and occurs in one per
600 livebirths. 6 The clinical manifestations vary and are
the consequence of an extra X chromosome that results
from non-disjunction of sex chromosomes during
meiosis. The most common genotype is 47, XXY, but
mosaicism 46, XY/47, XXY is frequently seen. Patients
have small firm testes and are generally infertile because
of tubular damage. Testosterone concentrations in serum
are low, but patients might present with concentrations
at the lower end of the normal range and have a normal
male phenotype. Some men with mosaicism have
normal testicular size and spermatogenesis at puberty,
but germ cells are progressively lost over time.' Diagnosis
of Klinefelter's syndrome is confirmed by karyotyping.
Data from the Danish Klinefelter's syndrome registry
indicate that most men remain undiagnosed during
their lifetime.' Men with Klinefelter's syndrome have
increased incidence of cryptorchidism, psychosocial
abnormalities, and learning disabilities.' The risks of
breast cancer and non-Hodgldn lymphoma are raised,
although the absolute rates remain low.' Testosterone.replacement therapy successfully induces and maintains
virilisation but has no effect on fertility. Some patients
respond to assisted-reproduction techniques. 10
Mumps-related orchitis
With the widespread use of vaccinations, the presentation
of orchitis related to mumps has shifted from children to
young adults. Orchitis is seen in 15-30% of men with
parotitis 11 and presents as painful testicular enlargement.
Seminiferous tubules are predominantly affected, with
30% of patients experiencing testicular atrophy. 12 Fertility
is generally preserved and low testosterone concentrations
in serum are rarely seen.
Chemotherapy and radiation
Allcylating chemotherapeutic agents (eg, cyclophosphamide and procarbazine) lead to the worst gonadal
toxic effects and the degree of harm correlates with the
cumulative dose. Postpubertal testes are the most susceptible to damage. The germinal epithelium of the
seminiferous tubules is more vulnerable than are the
Leydig cells. Suppression of spermatogenesis might
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00
00
j \
j \
B
I
Sperm
tbd)
j
I
\
B
Figure 1: Hypothalamic-pituitary-gonadal axis
{A) Normal physiology, (B) primary hypogonadism, and (C) secondary hypogonadism. The size of the arrows
reflects the concentration ofthe hormones. GnRH=gonadotropin-releasing hormone. LH=Ieuteinising hormone.
FSH=follicle-stimulating hormone.
·External genitalia
• Sebum production
· Prostate development
and growth
·Skin
• Hairfollicles
- Epiphyseal fusion
• Accrual of bone mass
·Some sexual behaviour
·Verbal memory
• Plasma lipids
Figure 2 : Production and metabolism of testosterone into its active
metabolites, dihydrotestosterone and oestradiol
occur as early as 2 weeks after the start of treatment and
azoospermia might be seen within 8-12 weeks.ll Recovery
depends on the viability of the stem cells (spermatogonia).
If viability is preserved, spermatogenesis might resume
within 12 weeks after the end of treatment." Testosterone
concentrations in serum might decline in some cases.
The germinal epithelium is also sensitive to radiationinduced damage. Sperm cryopreservation should be
offered before chemotherapy and pelvic radiation therapy
are started. Prophylactic suppression of the gonadal axis
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Seminar
Congenital
Acquired
Primary hypogonadism
Klinefelter's syndrome, Y-chromosome
microdeletions, mutations in LH and
FSH receptors, myotonic dystrophy,
cryptorchidism
Testicular trauma or torsion, testicular radiation, orchitis (mumps), chemotherapy with
alkylating agents, treatment with ketoconazole, autoimmune testicular failure,
infiltrative disease (haemochromatosis), varicocele, sickle-cell disease, cirrhosis,
excessive alcohol intake
Secondary hypogonadism
Isolated hypogonadotropic
hypogonadism (Kallmann's syndrome),
Prader-Willi syndrome, mutations in
~subunit of LH and FSH
Hyperprolactinaemia (from any cause), pituitary damage from tumours, apoplexy,
infection (tuberculosis) or infiltrative disease (haemochromatosis, sarcoidosis, or
histiocytosis), head trauma (causing stalk injury), acute systemic illness, medications
(opioids, glucocorticoids, GnRH agonists or antagonists), sickle-cell disease, morbid
obesity or diabetes, eating disorders, excessive exercise, cirrhosis, idiopathic
hypogonadotropic hypogonadism
LH = Iuteinising hormone. FSH =follide~stimulating hormone. GnRH=gonadotropin-releasing hormone.
Table 1: Causes of primary and secondary hypogonadism
with GnRH analogues or exogenous testosterone has not
been shown to prevent gonadal toxic effects .15
Testicular trauma and torsion
Testes are predisposed to trauma because of their external
location. Blunt trauma leads to atrophy in around half of
cases." Testicular torsion results in interruption of
testicular perfusion. Surgical correction within 6-8 h
preserves testicular viability."
Varicocele
Some evidence suggests that varicoceles negatively affect
spermatogenesis and testosterone production. Improvements in testosterone concentrations and fertility have
been repmted after varicocelectomy."·"
Medications
Although an important cause of secondary hypogonadism, glucocorticoids in supraphysiological doses
occasionally cause reversible primary hypogonadism.
Ketoconazole also directly and reversibly inhibits testicular steroidogenesis.20
Y-chromosome microdeletions
Microdeletions in the male-specific region on the long
arm of the Y chromosome are the most common genetic
cause of male infe1tility after Klinefelter's syndrome.
This region has a locus (azoospermia factor) that contains essential genes for spermatogenesis. Azoospermic
men have more microdeletions than those with oligozoospermia." Larger deletions result in complete tubular
atrophy, with only Sertoli cells being visible on testicular
biopsy (Sertoli-cell-only syndrome) . Concentrations of
testosterone and LH in serum are generally normal, but
FSH concentration is raised because of decreased
production of inhibin B and loss of negative feedback."
Causes of secondary hypogonadism
Isolated congenital gonadotropin deficiency
This disorder is due mainly to isolated GnRH deficiency; other pituitary axes remain intact. Kallmann's
syndrome, which is characterised by anosmia or
1252
hyposmia, is the most common cause (60% of cases) ."
Patients might present with cleft palate, red-green
colour blindness, and synkinesis. Although most
patients have no identifiable genetic defects, mutations
in ICA.Ll, FGFRl, PROK2, and PROKR2 have been
reported. 21
Hyperprolactinaemia
Hyperprolactinaemia leads to secondary hypogonadism
through suppression ofGnRH synthesis and secretion."·"
Unless gonadotrophs are damaged by mass effect from a
pituitary macroadenoma, the gonadal axis generally
recovers after normalisation of prolactin concentrations.
Dopamine agonists are used to treat prolactinomas and
idiopathic hyperprolactinaemia.
Medications
Glucocorticoids in supraphysiological doses lead to
androgen deficiency by inhibition of GnRH synthesis.
Prednisone in daily doses of 15 mg or higher can
suppress testosterone concentrations in serum within
3 days, with the magnitude of suppression being
directly related to the glucocorticoid dose ."·" Opioid
analgesics also suppress GnRH synthesis and
testosterone concentrations, which occasionally decline
into the castrate range," and result in reduced quality
of life and bone loss ." Agents that are agonists of
v-opioid receptors (eg, methadone and morphine)
potently suppress the gonadal axis . Such effects are
infrequently encountered with drugs that are partial
agonists of ]l-opioid receptors and antagonists of
K-opioid receptors (eg, buprenorphine). 29 Uncontrolled
studies of testosterone-replacement therapy have
shown improved quality of life in men with opioidinduced androgen deficiency.30
Pituitary damage
Tumours, radiation, infiltrative diseases , apoplexy, surgery, h ead trauma, and subarachnoid haemorrhage might
result in gonadotropin deficiency.31 Haemochromatosis
might lead to isolated central hypogonadism, which, if
diagnosed early, can be reversed by phlebotomy."
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Seminar
Critical illness and starvation
Hypogonadotropic hypogonadism is frequently seen in
acutely ill men" but is generally transient. Testosterone
concentrations in serum are inversely related to the
severity of illness and sometimes decrease into the castrate
range.34 Proposed mechanisms include reduced GnRH
synthesis, hypercortisolaemia, and hyperoestrogenaemia
(owing to increased aromatisation) . Severe caloric restriction might also result in central hypogonadism."
Signs and symptoms of hypogonadism•
+
Measure total testosterone concentration in
serum in the morning with a reliable assay
Idiopathic
Adult-onset idiopathic hypogonadotropic hypogonadism
is increasingly being recognised in men who have.
undergone normal pubertal development and have even
fathered children." Pituitary imaging is g~nerally normal. Decreased activity of the GnRH pulse generator has
been proposed as an underlying mechanism."
I
I
I
+
+
I
Total testosterone <9·7-10·4 nmoi/Lt
Normal testosterone
Repeat measurement oftotal testosterone
and measure free testosterone if SHBG
and follow up
+
+
Hypogonadism unlikely; reassure patient
variations expected
~
Total testosterone <9-7-10-4 nmoi/L,
free testosterone <0·17-0·31 nmoi/Lt
~
Measure LH and FSH
Epidem iology
The incidence and prevalence of male hypogonadism in
the general population are unknown, although crude
estimates are available from epidemiological studies and
outpatient practices. Population studies done so far have
had several limitations: the populations studied have been
mainly middle-aged and older men; multiple numerical
definitions ofhypogonadism have been used;"-" symptoms
have not been talcen into account;" and standard testosterone assays have not been used. 37•40·" Mass spectrometry
is the gold standard method for measurement of testosterone concentrations."·" Although symptoms such as
sexual dysfunction, decreased vitality, and reduced physical
function have been associated with low testosterone
concentrations in serum, many men are asymptomatic
and some symptomatic men have normal testosterone
concentrations."·"-# The crude prevalence of androgen
deficiency in the USA is around 6%. 40·41 An outpatient
clinic survey showed 38 · 7% prevalence on the basis of
testosterone concentrations lower' than 10·4 nmolfL (but
not symptoms)." Around 500000 men per year in the USA
are diagnosed as having androgen deficiency, and prevalence is higher among those with specific comorbidities,
such as obesity, diabetes mellitus, and HIV.'·46
Diagnosis
The diagnosis of male hypogonadism is based on assessment of signs and symptoms and on low testosterone
concentrations in serum in the morning on at least two
occasions, assessed by a reliable assay (figure 3) .' Diagnosis of hypogonadism should not be attempted during
acute illness . Systemic illness, eating disorders, drug
misuse, and excessive exercise should be excluded. Use
of opioid analgesics, glucocorticoids, and ketoconazole
should be ascertained.
Signs and symptoms
The signs and symptoms of hypogonadism vary dependent on age of onset, severity of testosterone deficiency,
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+
High LH/FSHconcentrations
(primary hypogonadism)
l
+
Low or inappropriately normal
LH/FSH concentrations
(secondary hypogonadism)
+
Further testing:
• Iron studies
• Karyotyping (to rule out
Klinefelter's syndrome)
+
Further testing:
• Prolactin
• Iron studies
·Other pituitary llormones
·MRit
- Exclude use of opioids/
glucocorticoids
Figure 3: Diagnosis of male hypogonadism
SHBG=sex-hormone-binding globulin. LH=Iuteinising hormone. FSH=follicle-stimulating hormone. *Postpone
assessment if the patient has been recently admitted to hospital, is recovering from an acute or subacute illness,
has reversible systemic illness, or has severe nutritional deficiency. tReference values are based on those used by
some commercial and reference-laboratory ranges. Clinicians should use values from their own reference
laboratories if they differ. tMRI of the pituitary is indicated in men with hypenprolactinaemia, symptoms of a mass
effect from a sellar lesion, and mu ltiple pituitary hormone deficiencies; in patients withoutthese clinical
characteristics, the decision to obtain an MRI should be made on an individual basis'
androgen sensltl.Vlty of an individual, and previous
use of testosterone-replacement therapy (panel 1). Prenatal or prepubertal onset leads to delayed or incomplete sexual development, eunuchoidal proportions, and
small testes. In men with postpubertal onset, galactorrhoea might rarely be seen in thos.e with prolactinomas.
Laboratory diagnosis
Testosterone is secreted according to a circadian
rhythm, with peaks in the morning and troughs during
evening hours, although this rhythm is blunted in
some older men (older than 60 years)." Testosterone
concentrations in serum should be measured in the
morning because even in healthy men evening troughs
can be below the lower limit of normal.
Total testosterone is 58% loosely bound to albumin,
40% tightly bound to sex-hormone-binding globulin, and
the remaining 0 ·5-2· 0% circulates in free form (free
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Seminar
Panel 1: Clinical manifestations of male hypogonadism
Prepubertal onset
Testes volume <5 em'
Micropenis
Cryptorchidism
Anosmia (Kallmann's syndrome)
Hypopigmented scrotum
Lack of scrotal rugae
Gynaecomastia
Eunuchoidal proportions
Decreased body hair
High-pitched vo ice
Low hair line
Decreased libido
Decreased bone mass
Decreased muscle mass
Visual-field defects (pituitary lesion)
Small prostate
Postpubertal onset*
Decreased libido
Decreased spontaneous erections
Decrease in testicular volume
Gynaecomastia
Hot flashes
. Decreased bone mass
Height loss or minimum-trauma fracture
Decreased pubic and axillary hair
Decreased frequency of shaving
Galactorrhoea (prolactinoma; rare)
Visual-field defects (pituitary lesion)
Decreased muscle mass
Decreased energy and motivation
*These patients have normal skeletal proportions, penile length, voice, and prostate size.
Panel 2: Conditions that alter concentrations of
sex-hormone-binding globulin in serum
Increased concentrations
Ageing
Hyperthyroidism
Hyperoestrogenaemia
Liver disease
HIV
Use of anticonvulsants
Decreased concentrations
Obesity
Insulin resistance and diabetes
Hypothyroidism
Growth-hormone excess
Glucocorticoids
Androgens
Progestins
Nephrotic syndrom'e
1254
testosterone, which is the fraction taken to be biologically
active). 48 Bioavailable testosterone refers to free plus
albumin-bound testosterone; because testosterone is
loosely bound to albumin, it is thought to dissociate
during tissue transit and become bioavailable." Total
testosterone concentrations cannot be accurately
measured if concentrations of sex-hormone-binding
globulin are affected by other conditions (panel 2). 50 In
most circumstances, measurement of total testosterone
by immunoassays can reliably distinguish hypogonadal
from eugonadal men, 51 but mass spectrometry is the
preferred method to measure testosterone and is now
available in some commercial laboratories.
Initial assessment of hypogonadism
The best screening test for the diagnosis of hypogonadism
is measurement of total testosterone in serum in a
morning sample, preferably with mass spectrometry
(figure 3). 50 Low concentrations of testosterone in semm
should be confirmed by repeat measurement. Although
the concentrations below which hypogonadal symptoms
occur remains unclear, some studies suggest that
10-4 nmoljl is a useful threshold.'2....,52 In some commercial laboratories, the lower limit ranges from 9 · 7 to
10 · 4 nmoljL. Although still arbitrary, such concentrations
suggest hypogonadism in symptomatic men. If abnormalities in concentrations of sex-hormone-binding globulin
are suspected, measurement of free or bioavailable
testosterone is indicated. Equilibrium dialysis is the
reference method for measurement of free testosterone
and ammonium-sulphate precipitation is the gold standard for measurement of bioavailable testosterone.48 ·49
These methods are technically challenging and are not
widely available in laboratories for high throughput
screening. Thus concentrations are generally calculated
from total testosterone, sex-hormone-binding globulin,
and albumin concentrations with use of the law of mass
action equations.48•53 Calculated free testosterone concentrations de1ived from total testosterone measured with a
reliable assay provide a convenient and reasonable alternative to equilibrium dialysis, although some equations
overestimate values. 54 Tracer analogue displacement
assays available in many hospital laboratories are inaccurate and their use is not recommended. 1 In some
laboratories, lower thresholds for free testosterone range
from 0-17 to 0 · 31 nmoljL. In men presenting with
infertility, semen analysis should be done.
Further assessments
After the initial diagnosis, whether patients have
primary or secondary hypogonadism must be established by measurement of gonadotropins (figure 3).
Raised gonadotropin concentrations suggest primary
testicular failure. Karyotyping should be used to exclude
Klinefelter's syndrome. If gonadotropin concentrations are low or inappropriately normal, diagnosis of
secondary hypogonadism should be considered. Semm
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Seminar
prolactin and other pituitary hormones (if indicated)
should be measured and iron studies done. If suspected,
Cushing's syndrome should be excluded. Patients with
hyperprolactinaemia, symptoms of a mass effect (headaches , peripheral vision disturbances, etc), and panhypopituitarism should undergo MRI of the sella
turcica. Many men of middle age and older and those
with diabetes and metabolic syndrome have biochemical
features of secondary hypogonadism, but only a small
proportion have sellar lesions."·" Obese men in whom
biochemical features indicate secondary hypogonadism,''·" presumably owing to negative feedback by
oestrogens, generally also have normal MRI results.
Therefore, for patients without panhypopituitarism,
hyperprolactinaemia, or mass effects, whether to do
MRI should be decided on an individual basis." Use of
bone densitometry is reasonable in men with minimumtrauma fractures, height loss, or known low bone mass.
When common causes of secondary hypogonadism are
excluded, a diagnosis of isolated hypogonadotropic hypo·
gonadism remains. The disorder could be idiopathic or
associated with a genetic syndrome. Recognition of
specific features, such as small testes plus anosmia and
cleft palate (Kallmann's syndrome), short stature (eg,
contiguous gene deletions of chromosome X), and
primary adrenal insufficiency (NROBl mutation) can
facilitate recognition of specific syndromes.
Population screening and case detection
Population-level screening for hypogonadism is not
recommended because its cost-effectiveness and effect
on public health are unclear. Screening tools are being
developed, but performance characteristics have not yet
been rigorous ly established. " By contrast, case detection
by measurement of testosterone concentrations might
be appropriate in symptomatic men with suspected
hypogonadism, such as those with sexual symptoms,"
minimal-trauma fracture ," and those talcing glucocorticoids or opioids .28 Symptomatic men with disorders
such as HIV," chronic obstructive pulmonary disease,"
renal disease," and type 2 diabetes," which are associated with low testosterone concentrations , could also
be tested.
Testosterone-replacement therapy
Testosterone-replacement therapy should only be started
in men who have a confirmed diagnosis ofhypogonadism.
The goal of treatment is to establish and maintain
secondary sexual characteristics, sexual function, body
composition, and quality of life. Testosterone-replace·
ment therapy is contraindicated in men with hormoneresponsive tumours, such as prostate or breast cancers
(panel 3).' Men with prostate abnormalities on digital
rectal examination or abnormal prostate-specific-antigen
concentrations should be assessed further before
testosterone-replacement therapy is started. Although
testosterone has been administered to men with prostate
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cancer in uncontrolled studies,"·66 no randomised trial
supports such a recommendation. Testosterone-replacement therapy can worsen polycythaemia, untreated
obstructive sleep apnoea, and uncontrolled congestive
heart failure.
Several formulations are available for testosterone·
replacement therapy. The pros and cons of each should,
therefore, be discussed with the patient (table 2) .
Although target testosterone concentrations in serum
might be individualised, generally the aim should be to
achieve those in the mid-normal range provided by a
local laboratory.
Injectable treatments
Esters
Testosterone esters have been used for decades. The
kinetics of testosterone enantate and cipionate are
similar, whereas testosterone propionate has a shorter
half.life. An ultra-long-acting injectable ester, testos·
terone undecylate, is available in Europe but is not
approved for clinical use in the USA. Esterification of
the testosterone molecule at the 17~-hydroxyl position
slows its release into the aqueous compartment from its
oil depot in the skeletal muscle . After intramuscular
injection of 200 mg testosterone enantate' or cipionate,
testosterone concentrations in serum rise into the
supraphysiological range within 24---48 h and gradually
decline into the low-normal range over 2 weeks."
This pharmacokinetic variability might lead to fluctuations in the patient's mood, libido, and energy level.
Administration of 100 mg weeldy yields physiological
concentrations, but requires four injections per month.
One injection of testosterone undecylate maintains
testosterone concentrations in serum in the normal
range for up to 10-12 weeks with a lesser degree of
fluctuation ." 8•6' This drug, however, is administered in a
large volume of oil, which might cause pain after
injection. A transient cough, presumably secondary to
oil embolisation, has been reported in a few patients
immediately after injection.••
Panel 3 : Contraindi cat ions t o t estost erone t herapy
Prostate cancer
Breast cancer
Nodu le or indu ration on prostate examination (unless
biopsy is negative)
Prostate-specific-antigen concentration >4·0 j.lg/L, or
>3·0 j.lg/L in high-risk men (eg, African Americans,
first-degree relatives of men with prostate cancer) unless
urological assessment is negative
Severe lower-urinary-tract symptoms (international
prostate symptom score >19)
Haematocrit >50%
Untreated severe sleep apnoea
Uncontrolled congestive heart fa ilure
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Seminar
Route of
delivery
Regimen
Intramuscular
25-50 mg 2-3 times per week
Monitoring oftestosterone
Advantages
Disadvantages
Inexpensive, corrects
Highly variable pharmacokinetics (not
with testosterone undecylate),
fluctuations in libido and mood (not
with testosterone undecylate), pain at
injection site, coughing episodes after
injection, polycythaemia (mainly in
elderly men), contraindicated in
patients with bleeding disorders
concentrations in serum
Testosterone esters
Testosterone propionate
Midway between injections
hypogonadal symptoms,
could be self-administered
Testosterone e nantate
Intramuscular
75-100 mg every week or 200 mg
every 2 weeks
Midway between injections
Testosterone cipionate
Intramuscular
75-100 mg everyweekor200 mg
every 2 weeks
Midway between injections
Testosterone undecylate•
Intramuscular
1000 mg bolus, followed by 1000 mg
at 6 weeks, then 1000 mg every
1Q-14weeks
Before each 10-14 week
40-80 mg 2-3 times daily with meals
3-5 h after dose
injection
Testosterone undecylate
tablets•
Oral
Testosterone patch
Transdermal
3-12 h after application
4-8 mg daily (patches are 2 or 4 ·mg)
applied nightly to skin of upper arm,
back, or thigh in non-pressure locations
Problems with adherence due to
rhythm, corrects hypogonadal sweating, skin irritation in up to
symptoms
66% of men
Testosterone gel
Transdermal
5-10 g daily of1% gel containing
50-100 mg testosterone applied to
no n-genital skin
After 1 week oftreatment,
any time of day
Potential of transfer to partners or
rhythm, corrects hypogonadal children, skin irritation (but affects
symptoms, good skin
<10% of men), supraphysiological
tolerability
dihydrotestosterone concentrations,
need to cover application site and wash
hands after application
Buccal testosterone
Buccal
30 mg controlled-release bioadhesive
tablets every 12 h
Before application of tablet
Corrects hypogonadal
symptoms, physiological
Convenient
Variable testosterone concentrations,
variable clinical response, nausea, high
DHT:T ratio, frequent administration
Convenient, mimics circadian
Convenient, mimics circadian
Alteration in taste, gum irritation
(10-15% men), twice-daily dosing
testosterone concentrations
achievable
Axillary testosterone
solution
Axilla
60-120 mg 2%topical solution
applied in axillae
2-8 h after application
Corrects hypogonadal
symptoms, physiological
Skin irritation, erythema (5-7% men)
testosterone concentrations
achievable
Testosterone pellets•
Subcutaneous
implant
600-1200 mg every 4-6 monthst
Testosterone
Transdermal
Two 2x60 em' patches on non-genital After24 h
skin every 2 days (delivers 4·8 mg
testosterone)
adhesive-matrix patch*
Before insertion of the new
pellets to help dose
adjustment
Corrects hypogonadal
symptoms
Requires surgical incision, possibility of
infection, risk of spontaneous pellet
Convenient
Skin irritation (19% men)
extrusion, fibrosis
DHT:T ratio= ratio of dihydrotestosterone to testosterone. *These products are unavailable in the USA. tEach pellet is 200 mg, but doses vary by formulation .
Table 2: Types of testosterone-replacement therapy
Pellets
C1ystalline testosterone pellets are surgically inserted
into the subcutaneous tissue. Each 200 mg implant
releases 1· 3 mg testosterone daily through surface erosion. The starting dose is 800 mg, which can maintain
testosterone concentrations in the normal range for up to
6 months." Spontaneous exhusion, infection, and fibrosis at the inse1tion site are disadvantages.
Transdermal treatments
Patches
Transdermal patches containing 2 or 4 mg testosterone
are applied on non-scrotal skin. After 4-12 h testosterone
and oestradiol concentrations in serum reach the midnormal range and physiological concentrations of
dihydrotestosterone are achieved. 71 In some men, one
4 mg patch might not be sufficient to raise testosterone
concentrations and a higher dose might be required. The
1256
patches are associated with a high frequency (19-66%) of
skin irritation, which leads to discontinuation in 5-10%
of patients.I.7I Pretreatment with 0-1% triamcinolone
cream at the application site reduces the risk of irritation
without affecting testosterone absorption."
Gels
Two transdermal gels are commercially available. 5 g of a
1% gel contains 50 mg and delivers 5 mg testosterone
into the circulation over 24 h. Daily application of 5-10 g
raises serum testosterone concentrations into the midnormal range;" around 25% of patients require more than
5 g daily to achieve target testosterone concentrations.
One of these gels is available in a metered pump.
Each pump actuation dispenses 1· 25 g gel, which leads
to greater flexibility in dose titration. A concentrated
formulation (1· 62%) of this gel is also available. Another
gel has become available in the USA with a starting dose
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Seminar
of 40 mg daily (maximum dose 70 mg), but it is not yet
available in other countries.
Substantial variation in testosterone concentrations
in serum has been reported within and ·between
individuals receiving transdermal gel and, therefore,
follow-up measurements of testosterone concentrations
are required. 7-10% of men report skin irritation."·"
Transfer of testosterone to partners or children via
direct skin contact is a risk. The US Food and Drug
Administration issued a black-box warning after cases
of precocious pseudopuberty were reported in children.
In Europe and Australia, a dihydrotestosterone gel is
also available.
Axillary solution
A fragrance-free, ethanol-based 2% solution of topical
testosterone has been approved, although only in North
Ame1ica and Australia. It is applied to the axillae. The
starting dose is 60 mg testosterone daily and the maximum
recommended dose is 120 mg daily." The solution comes in
a metered pump, and each actuation of 1· 5 mL contains
30 mg testosterone. With 60 mg daily around 85% of patients
achieve testosterone concentrations in serum in the nmmal
range." Skin irritation is seen in S-7% of patients.
Oral treatments
Buccal tablets
Bioadhesive, controlled-release tablets applied to the
buccal mucosa raise testosterone concentrations in serum
into the normal range." The tablets are placed in the
depression in the gums above the incisors. Testosterone is
released into the systemic circulation after being absorbed
across the buccal mucosa and, therefore, bypasses firstpass hepatic metabolism. Peale concentrations are reached
in 30 min." Twice daily application, gum irritation, altered
taste, and poor adhesion to buccal mucosa are disadvantages of this treatment.
Pills
Oral testosterone undecylate, although not available in
the USA, has been used in other parts of the world for
many years. When administered in capsules filled with
oleic acid, testosterone undecylate is absorbed into the
systemic circulation through the lymphatic system and
bypasses first-pass hepatic metabolism. Oral testosterone
undecylate must be taken soon after meals to enable
lymphatic absorption. Pills taken with a meal containing
around 19 g lipids is sufficient to raise testosterone
concentrations in serum." An increased ratio of dihydrotestosterone to testosterone in serum, 80 administration
multiple times per day, and variation in testosterone
concentrations are disadvantages of this treatment.
End-organ effects
Testosterone exerts a wide range of effects on various
organ systems. This section summarises the benefits of
testosterone on main systems. Although most studies
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I
discussed here enrolled men with pathological causes of
hypogonadism, some outcomes have only been assessed
in men older than 60 years with late-onset hypogonadism,
which will be specified where applicable.
Sexual function
Testosterone-replacement therapy affects libido, sexual
thoughts, and attention to erotic stimuli."·"·"·" Treatment
also increases frequency and duration of nocturnal penile
erections and improves erectile function. 83 •84 Men with
testosterone concentrations in serum lower than
10 · 4 nmoljL at diagnosis generally respond better than
those with higher concentrations. A meta-analysis
showed that testosterone-replacement therapy improved
sexual motivation, number of successful intercourses,
erectile function scores, and overall sexual satisfaction in
men with baseline serum testosterone concentrations
lower than 12 · 0 nmoljL, whereas no effect was seen in
eugonadal men." By contrast, another meta-analysis
found that testosterone-replacement therapy did not
improve overall sexual satisfaction." In men older than
60 years with late-onset hypogonadism, testosterone
concentrations in serum do not strongly correlate with
erectile function, which suggests other causes for their
condition." Positive effects of testosterone-replacement
therapy on libido have been seen more consistently than
those on erectile function. Some small trials showed
benefits with combined testosterone-replacement therapy
and phosphodiesterase-S inhibitors in men resistant to
phosphodiesterase-S inhibitors alone."·" In a later large
randomised, controlled trial, however, no additional
benefit was seen when testosterone-replacement therapy
was added to an optimised dose of sildenafil."
Bone
Compared with controls, hypogonadal men have
reduced cortical and spinal bone densities ." Small trials
in men with unequivocal organic hypogonadism have
shown that testosterone-replacement therapy is associated with increases in spinal and hip bone-mineral
density of S-8% and 4%, respectively, with maximum
improvement seen by 24 months.92 m Improvement in
trabecular microarchitecture has also been shown. 94 A
meta-analysis showed that intramuscular but not
transdermal testosterone-replacement therapy increased
lumbar spine bone-mineral density, but effects on
femoral neck were inconclusive." Higher concentrations
of testosterone in serum achieved with intramuscular
formulations might explain this observation." No trial
has assessed the effect of testosterone-replacement
therapy on the risk of incident fractures.
Body composition, muscle strength, and physical function
Testosterone-replacement therapy is associated with
increased fat-free mass and decreased fat mass.''·"·" In
some studies, improvements in lean mass have translated
into improved muscle strength,"·"-" although other
1257
I
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studies have not confirmed these findings." A metaanalysis showed that testosterone-replacement therapy
resulted in a 1· 6 kg increase in lean mass, a 1· 6 kg
decrease in fat mass, and improved lower-extremity and
dominant-arm strength.'00 Studies in frail men older than
60 years with late-onset hypogonadism have reported
improvements in some aspects of physical function."·"
therapy,' 05 but another showed that supraphysiological
testosterone concentrations negatively affected cognitive
function. 106 Association of increased regional cerebral
blood flow (in areas critical for memory and attention)
with endogenous free testosterone concentrations have
led to the hypothesis that testosterone affects cognition
by this mechanism.'07
Quality of life and mood
The role of testosterone-replacement therapy on quality
of life remains unclear. Some studies have reported
improvement in the physical-function domain of quality
of life, but others have reported no benefits.'" Some
studies have shown improvements in mood, energy,
and wellbeing."·''' In a meta-analysis, testosteronereplacement therapy resulted in greater improvements
in depression scores than did placebo. 10 '
Insulin sensitivity and diabetes
Cognition
Whether testosterone-replacement therapy affects cognition remains unclear because most trials have been
small and results have been mixed. Improvements in
spatial and verbal memory have been seen after treatment
in men older than 60 years who have late-onset hypogonadism. The latter is mainly influenced by aromatisation of testosterone to oestradiol.''' A sh01t-term study
in men with cognitive impairment showed improvement in spatial memory with testosterone-replacement
Monitoring plan
General health
Assess for efficacy and adverse effects at 3 and 6 months after the start of
treatment and annually thereafter if stable; check for formulation-specific
adverse effects
Testosterone concentration
Adjust dose to maintain testosterone concentrations in serum in the
mid·normal range (according to local laboratory reference)
Digital rectal examination
No data available about benefits in healthy men younger than 40 years
Perform at baseline in men aged 40-49 years who are African American,
have first-degree relatives of men with prostate cancer, or who have
baseline PSA concentrations >0·6 [Jg/L
Perform at baseline in all men older than 50 years
Repeat 3-6 months after the start oftherapy and annually thereafter;
discontinue therapy if nodules or induration are detected
PSA concentration
Check at baseline in all men older than 40 years
Check at 3-6 months after the start oftherapy and annually thereafter;
discontinue therapy and assess further if PSA concentration increases by
>1-4 [Jg/L in a 1·yearperiod or PSA velocity is >0-4 [Jg/L per year (applicable
if>2 years of data are available, with the 6-month value taken as reference)
Lower-urinary-tract symptoms
Discontinue therapy and assess if the patient complains of severe
symptoms or ifthe international prostate symptom score is >19
Haematocrit
Check at baseline to exclude sleep apnoea, hypoxaemia, and
haematological disorders
Check at 3-6 months after the start of therapy and annually thereafter;
discontinue therapy if haematocrit >54%; ifthe value reverts to normal,
treatment can be restarted at a lower dose
Sleep apnoea
Assess symptoms of sleep apnoea (snoring, daytime somnolence, etc)
Bone density
Measure baseline bone·mineral density if indicated (minimum-trauma
fracture, osteoporosis, height loss, etc) and repeat every 1-2 years
PSA=prostate-specific antigen.
Table 3: Methods for monitoring oftreatment
1258
Low testosterone concentrations are associated with
insulin resistance and diabetes, 10'·"' which are also
more prevalent in men with prostate cancer undergoing
androgen-deprivation therapy than in those not receiving this treatment.'" Although a few trials have investigated the effects of testosterone-replacement therapy
on insulin sensitivity and diabetes, they have been
small and have yielded conflicting results .m.m A large
trial of testosterone-replacement therapy with a 2% gel
in men with type 2 diabetes, metabolic syndrome, or
both, showed a slight improvement in insulin sensitivity, but concentrations of glycated haemoglobin A,,
did not improve. 113 In another study of a gel, no
improvement was seen in either glycated haemoglobin
A,, concentrations or insulin sensitivity in men
receiving testosterone-replacement therapy.'" On the
. basis of the available data, it is prudent not to start
testosterone therapy in men with diabetes solely for the
purpose of improving metabolic control if they show no
signs and symptoms of hypogonadism.
Adverse effects and treatment monitoring
Formulation-specific adverse effects are summarised in
table 2 and methods for assessment during treatment are
shown in table 3. Adverse effects in different organ
systems are discussed below.
Erythrocytosis
Erythrocytosis is the most frequent adverse event related
to testosterone-replacement therapy. Men randomised
to testosterone in studies are five times more likely to
develop erythrocytosis than those receiving placebo. 115
This disorder is more frequently seen in men who
receive intramuscular injections than treatment by
other routes, and in men older than 60 years, probably because of reduced testosterone clearance.'"
Testosterone-replacement therapy generally leads to a
mean increase in haematocrit of 3 ·18%.' 17 The frequency
of erythrocytosis with injections is higher than that with
transdermal administration (44% vs 15%), probably
because higher testosterone concentrations in serum
are achieved with the former." Whether the risk of
erythrocytosis is greater in men with comorbid disorders
that predispose to hypoxia, such as chronic obstructive
pulmonary disease or obstructive sleep apnoea, is
unclear.'" Testosterone promotes erythropoiesis via
erythropoietin production, bone-marrow stimulation,
and suppression of hepcidin, a regulatory protein
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Seminar
whose inhibition increases iron availability."'·"' The
haematocrit cutoff for increased risk of neuro-occlusive
events is unknown, but such events have been reported
in men taking testosterone-replacement therapy. 121
If haematocrit is higher than 50% testosteronereplacement therapy should not be started without
further assessment.' If haematocrit rises to more than
54% during therapy, treatment should be stopped (or
phlebotomy could be done)' and disorders that cause
hypoxia should be investigated. Once haematocrit
normalises, the restarting of treatment at a lower dose
might be considered.
Prostate
The prostate is an androgen-dependent tissue, but epidemiological stUdies have shown no consistent relation
between endogenous testosterone concentrations and
the risk of prostate cancer.122 Many men older than
60 years harbour microscopic foci of prostate cancer and,
therefore, there is a theoretical concern that testosteronereplacement therapy could stimulate growth of these
clinically dormant tumours. 123 Testosterone can be safely
administered to men with benign prostatic hypertrophy
who have mild to moderate lower-urinary-tract symptoms, but in men with severe lower-urinary-tract symptoms, careful monitoring is required because even a
small increase in prostate volume could exacerbate
obstructive symptoms .'
In hypogonadal men the prostate is small and, therefore, concentrations of prostate-specific antigen are
expected to increase during testosterone-replacement
therapy.' 24 Because prostate biopsy is generally triggered
by such an increase in concentration of prostate-specific
antigen, men taldng testosterone-replacement therapy
are more likely to undergo this investigation than men
receiving placebo. Additionally, concentrations of prostatespecific antigen fluctuate over time because of interassay
variability, age effects, and subclinical prostatitis,125 ·"6 and
increases do not always suggest underlying malignant
disease. A meta-analysis showed that men treated with
testosterone-replacement therapy had higher rates of
combined prostate events (mainly driven by increased
concentration of prostate-specific antigen and prostate
biopsy), but the rates of prostate cancer did not differ from
those in men receiving placebo. 115 In 36-month trials of
testosterone-replacement therapy in men older than
60 years, the changes in prostate-specific-antigen concentrations in serum did not differ significantly between
placebo and treatment groups.'"·"'
During testosterone-replacement therapy, increments
in prostate-specific-antigen concentrations in hypogonadal men are generally lower than 0 · 5 jlgjL, therefore
increments greater than 1· 0 }lg/L over a 3-6 month period
are deemed unusual.'" In the placebo arm of a large trial
that investigated finasteride treatment for benign prostatic
hypertrophy, the 90% CI for change in prostate-specificantigen concentrations over 3-6 months was 1·4Jlg/L.' 30 A
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I
change of this magnitude within any 12-month period has
been suggested to warrant further assessment."' When
sequential measurements of prostate-specific antigen
concentration are available for more than 2 years, prostatespecific-antigen velocity might be useful to assess. A
velocity of more than 0 · 4 }lg/L per year warrants assessment. Large long-term intervention trials are needed to
definitively address the issue of prostate safety.
Cardiovascular
Long-term safety of testosterone therapy in relation to
the cardiovascular system remains uncertain because no
adequately powered trial has investigated the effects of
testosterone on cardiovascular events. 131 For decades,
testosterone-replacement therapy was believed to
increase the risk of heart disease, a theoretical i:wtion
based mainly on anecdotal rep01ts of cardiac events in
athletes taking anabolic steroids."' Epidemiological
studies show an inverse association between testosterone concentrations and cardiovascular disease and
mortality.",_135 A previous meta-analysis showed that men
randomised to testosterone were nearly twice as likely to
experience cardiovascular events as those receiving
placebo." 6 This issue has received further attention since
the publication of a randomised trial (the TOM trial" )
that was stopped early because of an increased frequency
of cardiovascular events in the testosterone arm. Men in
this trial, however, were older than 65 years and had a
high prevalence of underlying cardiovascular disease at
baseline. A meta-analysis of controlled trials that did not
include the TOM trial did not confirm the findings from
the previous meta-analysis."' Small short-term studies of
testosterone treatment in men with stable angina and
congestive heart failure have shown some benefits.m·'"
The cardiovascular safety of testosterone-replacement
therapy needs to be investigated specifically in large,
adequately powered controlled trials.
lipids
Effects of androgen administration on plasma lipids
vary by dose, route of administration, and whether the
androgen can be aromatised. Orally administered and
non-aromatisable androgens have consistently been
associated with decreased concentrations ofHDL cholesterol,"' whereas treatment with testosterone, which is
aromatised, has been associated with no or only slight
decreases in HDL-cholesterol concentrations.117•136 The
effects of testosterone-replacement therapy on total
cholesterol, LDL-cholesterol, and triglyceride concentrations have been mixed.
Sleep apnoea
An association between obstructive sleep apnoea and
testosterone-replacement therapy has arisen from
anecdotal reports and small studies that used supraphysiological doses of intramuscular testosterone-"'·'"
Since upper-airway dimensions do not change,
1259
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testosterone is thought to affect respiratory centres. More
research is needed, but in the meantime it seems prudent
not to start testosterone-replacement therapy in men
with untreated severe obstructive sleep apnoea.'
Other effects
Exogenous testosterone is a potent contraceptive because
it inhibits spermatogenesis."' This effect deserves
consideration before testosterone-replacement therapy
is sta1ted in men with slightly low testosterone concentrations who plan to start a family in the near future.
Acne and increased sebum production are frequently
encountered in young men taking intramuscular formulations . Hepatotoxic effects, such as peliosis hepatitis and
adenomas, are seen in men taking oral 17-a-allcylated
androgens'" and these drugs should not be used in the
treatment ofhypogonadism.'
Conclusions
Over the past two decades important advances have been
made in the diagnosis and treatment of male hypogonadism. These include the discovery of novel genetic
causes of hypogonadism, the availability of sensitive
testosterone assays, and development of testosteronereplacement treatments that are convenient and yield
physiological concentrations. Although the benefits of
testosterone-replacement therapy outweigh the risks in
young men with organic hypogonadism, long-term
efficacy and risks of treatment, especially to the prostate
and cardiovascular system in men older than 60 years
who have pathological hypogonadism, remain unclear.
These features comprise the challenge for the next
decade, which can be overcome only by the unde1taking
oflarge, controlled trials.
Conflicts of interest
I have previously received research support for investigator-initiated
studies from Abbott Pharmaceuticals and consulted for Eli Lilly.
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