Hypogonadism in Men

Hypogonadism in men
Straight to the point of care
Last updated: May 01, 2018

Table of Contents
Overview 3
Summary 3
Definition 3
Theory 4
Epidemiology 4
Aetiology 4
Pathophysiology 5
Classification 6
Case history 6
Diagnosis 8
Approach 8
History and exam 12
Risk factors 14
Investigations 16
Differentials 19
Management 21
Approach 21
Treatment algorithm overview 24
Treatment algorithm 25
Patient discussions 34
Follow up 35
Monitoring 35
Complications 36
Prognosis 37
Guidelines 38
Diagnostic guidelines 38
Treatment guidelines 39
References 41
Images 47
Disclaimer 48
Hypogonadism in men Overview
Summary
May present with features of testosterone deficiency and/or infertility.
When caused by pituitary macro-adenoma, patients may have additional symptoms due to mass effects,
OVERVIEW
such as headaches or peripheral visual disturbance. There may also be signs and symptoms of other
pituitary hormone deficiencies.
Early morning serum total testosterone level below 10.4 nanomol/L (<300 nanograms/dL) on at least two
separate occasions in a symptomatic man generally confers the diagnosis of hypogonadism.
Testosterone should be measured in all men with erectile dysfunction.
Measurement of the gonadotrophins (LH and FSH) distinguishes between a primary and a secondary cause.
The aim of testosterone therapy is to achieve serum testosterone levels within the normal physiological range
with dose adjustment to have the maximum effect on alleviation of symptoms.
Definition
Hypogonadism in males is a clinical syndrome that comprises symptoms and/or signs, along with
biochemical evidence of testosterone deficiency.[1]
The male gonads (testes) have 2 primary functions: testosterone production (by the Leydig cells) and
spermatogenesis (by the spermatogenic and Sertoli cells in the seminiferous tubules). Hypogonadism in
men occurs where there is dysfunction in the normal physiological mechanism of the hypothalamic-pituitary-
gonadal axis that results in a decreased ability to carry out either of these functions.
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Hypogonadism in men Theory
Epidemiology
The prevalence of hypogonadism increases with age. About a quarter of the US male population have total
testosterone levels that are below 10.4 nanomol/L (<300 nanograms/dL) (considered by many experts to
THEORY
be the lower end of normal).[4] It is estimated that there are approximately 2.4 million American men with
androgen deficiency, and that the incidence of hypogonadism in American men between the ages of 40
and 69 years is approximately 481,000 new cases per year.[5] The European Male Aging Study (EMAS)
reports a prevalence of late-onset hypogonadism of 2.1% in men aged between 40 and 79 years.[6]It is now
recognised that there is a higher prevalence of hypogonadism in men with diabetes, HIV, coronary heart
disease, or renal disease, or receiving opiate or glucocorticoid therapy.[7]
Aetiology
In primary hypogonadism, the defect lies at the level of the testes ('testicular failure'). This condition is
associated with low testosterone and elevated gonadotrophins. The most common causes are:
• Klinefelter syndrome: the most common congenital cause of hypogonadism. It affects 1 in 500 live
births, but 75% remain undiagnosed in life.[8] [9] Most patients have 47,XXY genotype anomaly;
however, mosaicism is also seen.
• Noonan syndrome: phenotypic and genotypic males with physical signs of classic female Turner
syndrome. Condition may be sporadic or familial, inherited as an autosomal dominant.
• Cryptorchidism (undescended testes), but may also occur in secondary hypogonadism that has
occurred prior to puberty (e.g., Kallmann syndrome).
• Infections: orchitis related to mumps is the most common infection. Spermatogenesis is more affected
than androgen production.
• Drugs: alkylating agents, such as cyclophosphamide and chlorambucil, are the most notable
examples. The seminiferous tubules are usually the main site of damage, although testosterone
production can also be affected.[10] Ketoconazole also decreases testosterone production. Men
undergoing therapy with alkylating agents should be given the option of sperm banking.
• Testicular trauma, torsion, or irradiation.
• Varicocele: rarely causes hypogonadism but does cause increased temperature and/or accumulation
of tissue metabolites in the testes.
• Myotonic dystrophy: presence of CTG repeats have been associated with hypogonadism.
• Auto-immune orchitis: a rare cause of primary hypogonadism.
• Radiation exposure.
• Environmental toxins (e.g., heavy metals, chemical, pesticides).
• Excessive alcohol consumption.
• Human immunodeficiency virus (HIV).
• Y-chromosome microdeletion: usually spermatogenesis is affected. Testosterone levels are normal in
the majority of patients.
• Idiopathic: cause not identified.
In secondary hypogonadism, the defect lies at the level of the hypothalamic-pituitary axis and is associated
with low testosterone and low (or inappropriately normal) gonadotrophins. The common disorders affecting
the hypothalamic-pituitary axis are:
• Combined pituitary hormone deficiency (CPHD): progressive stepwise onset of pituitary dysfunction
during childhood or even adult life.
4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 01, 2018.
• Isolated hypogonadotrophic hypogonadism (IHH): caused by a complete or partial failure of GnRH
secretion from the hypothalamus, leading to a reduction in FSH and LH release. Many genetic
mutations may result in IHH, Kallmann syndrome (causing IHH with anosmia) being the most well-
known.[11]
THEORY
• Hyperprolactinaemia: elevated prolactin level (from any cause) suppresses GnRH.
• Pituitary tumours and pituitary apoplexy: causes compression of gonadotrophs (basophilic cells of the
anterior pituitary specialised to secrete FSH or LH).
• Parasellar tumours: e.g., meningioma, craniopharyngioma, Rathke's cleft cyst, metastases.
• Empty or partial empty sella syndrome.
• Drugs: opioids, high-dose glucocorticoids, GnRH analogues, exogenous oestrogens or androgens.
• Infiltrative diseases (e.g., haemochromatosis, sarcoidosis, histiocytosis): destruction of the
gonadotrophs is considered to be the mechanism of action.
• Irradiation.
• Severe systemic illness: this can suppress the hypothalamic-pituitary-gonadal axis; when the illness
resolves, the axis usually recovers.
• Head injury: trauma, surgery.
• Chronic disease: common examples include diabetes/insulin resistance, coronary artery disease
and HTN, uraemia, sickle cell disease, thalassaemia, obesity, COPD, HIV, renal disease, rheumatoid
arthritis or other inflammatory disorder, or liver cirrhosis.
• Glucocorticoids: Cushing syndrome or exogenous glucocorticoid use cause suppression of GnRH
synthesis.
• Idiopathic: cause not identified.
Late-onset hypogonadism is a clinical and biochemical syndrome associated with advancing age and
characterised by symptoms and a deficiency in serum testosterone levels (below the young healthy reference
range). This condition may result in significant detriment to quality of life and adversely affect the function
of multiple organ systems.[2] [3] This diagnosis can only be made when classical causes of hypogonadism
are excluded. The diagnosis can include hypogonadism associated with comorbidities/chronic diseases as
above.
Pathophysiology
Pathology at any level of the hypothalamic-pituitary-gonadal axis may result in hypogonadism. The
causes include genetic diseases, head or testicular trauma, tumours, radiation injury, alkylating agents,
hyperprolactinaemia, and infiltrative diseases. Determining the aetiology and location of injury to the
hypothalamic-pituitary-gonadal axis is important because the prognosis and treatment options vary with
these factors.
Primary hypogonadism is an end organ disease. It occurs due to pathology of either Leydig cells or
seminiferous tubules or both. Injury to Leydig cells results in decreased testosterone production, while
seminiferous tubule involvement results in decreased or absent spermatogenesis. The majority of the
conditions causing testicular injury predominantly involve tubules. Gonadotrophins are elevated due to loss of
negative feedback.
Secondary hypogonadism is a central disease. Causes include genetic mutations (resulting in

maldevelopment of GnRH neurons), hyperprolactinaemia (causing suppression of GnRH), or destruction/
compression of the gonadotrophs (by tumour, trauma, infiltrative diseases, pituitary apoplexy). Chronic
diseases such as metabolic syndrome and diabetes can lead to secondary hypogonadism.[12] In secondary
5
hypogonadism gonadotrophin levels are decreased or inappropriately normal, and this results in decreased
testicular stimulation, causing decreased spermatogenesis and androgen production. Prolonged secondary
hypogonadism leads to testicular atrophy.
THEORY
Obesity is associated with low testosterone levels, but not all obese men have hypogonadal symptoms.
Adipocytokines and estradiol produced by adipose tissue inhibits the hypothalamic-pituitary-testicular axis,
impairing testosterone secretion.[12]
Classification
Clinical classification
Hypogonadism is broadly classified as primary or secondary, according to the site of physiological
dysfunction:
• Primary hypogonadism: dysfunction of the testes resulting in failure of spermatogenesis and/or

testosterone production.
• Secondary hypogonadism: dysfunction of the hypothalamus and/or the pituitary gland causing failure
to secrete GnRH, LH, or FSH.
Late-onset hypogonadism (LOH) is a clinical and biochemical syndrome associated with advancing age, and
characterised by typical symptoms and a deficiency in serum testosterone levels. It may result in significant
detriment to the quality of life and adversely affect the function of multiple organ systems.[2] [3]
Case history
Case history #1
A 27-year-old man presents for evaluation of infertility. He had a normal birth and early development, but
did not undergo puberty. He has developed none of the typical male secondary sexual characteristics.
He reports diminished libido, although he occasionally gets early morning erections. He is able to get an
erection during sexual activity, provided he is sufficiently aroused. He married 3 years ago, but attempts
to father a child have been unsuccessful. His wife has normal menstrual cycles and her gynaecological
examination is normal. On examination, the patient has sparse facial hair and low hair line. Minimal
bilateral, non-tender gynaecomastia is present. The patient has a normal penis and scrotum, but the
testes are small and firm with an estimated volume of 4 mL each.
Case history #2
A 42-year-old man presents with a 4-month history of frontal headaches and decreased libido. The
symptoms started gradually. In addition to decreased libido, the patient also complains of gradual loss
of early morning erections. He has been married for 12 years and has 3 children. He denies any head or
testicular injury. He also denies gynaecomastia or galactorrhoea. The only abnormality on his physical
examination is bitemporal hemianopia on visual field testing.
Other presentations
Men with secondary hypogonadism may present with anosmia, headache, bitemporal hemianopia,
diplopia, gynaecomastia, erectile dysfunction, or, occasionally, galactorrhoea.
THEORY
7
Hypogonadism in men Diagnosis
Approach
Hypogonadism is a common condition, but it is frequently unrecognised and undiagnosed because signs and
symptoms may be non-specific, or overlap with other common conditions (such as depression). It can occur
at all stages of life from infancy to old age, and the exact clinical features depend on the time of onset of
testosterone deficiency, the testicular functions involved (testosterone production and/or spermatogenesis),
and the site of dysfunction along the hypothalamic-pituitary-gonadal axis. Diagnosis requires both the
presence of clinical symptoms with or without signs and laboratory confirmation through appropriate
laboratory testing on two occasions.[13] [14]
DIAGNOSIS
An approach for the diagnostic evaluation of adult men suspected of having androgen deficiency
Adapted from Endocrine Society Guidelines, with permission
History
If hypogonadism started before puberty, adult patients typically report delayed or absent puberty/
development of secondary male characteristics; infertility; and diminished libido. They may give a history
of decreased body and facial hair and a high-pitched voice compared with peers. They may complain
of having a short penis and may have noted small testes or gynaecomastia. These complaints may
be confirmed by examination, when lack of scrotal hyper-pigmentation, little or no scrotal rugae, and a
small prostate may also be noted. Frequently, they have unusually long limbs and eunuchoid proportions
(i.e., arm span >2 cm greater than height), due to delayed pubertal closure of the epiphyses of the long
bones.[13]
When hypogonadism occurs after a normal puberty, the presentation is frequently less formulaic. The
main presenting symptoms are loss or reduction in libido, fatigue, erectile dysfunction, and reduced
physical strength/sarcopenia. However, it can sometimes involve problems of infertility. The penis,
scrotum, and prostate can appear normal in these patients.[13] There may be a history of testicular
trauma or torsion, radiotherapy, treatment with alkylating agents, mumps, or cryptorchidism, which would
suggest primary hypogonadism.
The signs and symptoms that are particularly indicative of testosterone deficiency include:
• Incomplete sexual development, eunuchoidism, azoospermia

• Loss of libido
• Decrease in spontaneous early morning erections
• Erectile dysfunction
• Inability to father children, low or zero sperm count
• Decreased muscle mass and strength
• Loss of height, low trauma fracture, low bone mineral density/osteoporosis
• Hot flushes, sweats
• Breast discomfort and gynaecomastia
• Loss of axillary and pubic hair; reduced shaving
• Very small or shrinking testes (especially <5 mL each).
Other more general signs and symptoms that may also be associated with testosterone deficiency
include:
• Decreased energy, motivation, or initiative

• Diminished physical or work performance
• Feeling sad or blue, depressed mood
• Irritability, grumpy or bad temper
DIAGNOSIS
• Poor concentration and memory
• Sleep disturbance
• Increased body fat, increased BMI, central obesity
• Mild, normochromic, normocytic anaemia.
Examination
When a diagnosis of hypogonadism is suspected, a thorough and careful examination should be
undertaken, focused on the features discussed above.
• General examination should focus on the body habitus of the patient. Tall men should be carefully
evaluated for eunuchoid proportions (i.e., arm span >2 cm greater than height). These proportions
develop due to a delay in the fusion of the epiphyses of the long bones, caused by a deficiency of
estradiol arising as a result of testosterone deficiency.[15] These men also have relatively long legs,
resulting in an increased lower-to-upper body ratio. Absence of facial hair and a lower hair line may
also be noted in many men with hypogonadism. Some men may have a high-pitched voice.
• Evaluation of visual fields and extra-ocular movements may be important because a pituitary
tumour may compress the optic chiasm. Assessing visual fields by confrontation may reveal
9
bitemporal hemianopia, but more formal testing by ophthalmic testing is much more accurate and
picks up small changes.
• Cleft lip, cleft palate, or anosmia may point towards a genetic cause of central hypogonadism (e.g.,
various forms of IHH).[16]
• Gynaecomastia may be present. This is firm, ductal tissue that is mainly sub-areolar. It is more
commonly seen in primary hypogonadism.[17] It should be differentiated from adipose tissue in
obese patients (often termed lipomastia or pseudo-gynaecomastia).
• Fine wrinkling of facial skin, especially adjacent to mouth and eyes, occurs in more severe forms of
hypogonadism.
• Genital examination should evaluate for micro-penis, under-developed scrotum, or bifid scrotum.
Evaluate for cryptorchidism. Normal testes measure 20 to 25 mL on the Prader orchidometer (5
to 7 cm in length). Small, firm testes measuring less than 5 mL are seen in men with Klinefelter
syndrome. Presence of the vas deferens can be confirmed by palpation of the spermatic cord.
Men with small, firm testes and infertility may have Klinefelter syndrome. Men with severe
oligozoospermia or azoospermia and normal testosterone levels may have Y-chromosome
microdeletions.[18] Men with secondary hypogonadism may present with anosmia (typical of Kallmann
syndrome), headache, bitemporal hemianopia, diplopia, gynaecomastia, erectile dysfunction, or,
occasionally, galactorrhoea.
Measurement of serum testosterone levels

Laboratory investigation of hypogonadism focuses on evaluating serum testosterone levels and
performing seminal fluid analysis, guided by presenting symptoms and whether fertility and/or
androgenisation is the treatment goal.
The vast majority of circulating testosterone is bound to protein.[13] Approximately 60% is strongly bound
to sex hormone-binding globulin (SHBG) and is not bio-active. A further approximate 40% of testosterone
is weakly bound to albumin; this portion can rapidly dissociate from the albumin and so is bio-active.
Approximately 2% is unbound (free testosterone) and is also bio-active. The albumin-bound and free
testosterone are collectively known as bio-available testosterone. The half-life of free testosterone is only
DIAGNOSIS
10 minutes.
A number of tests are available for measuring these various components:
• Total serum testosterone (free and bound) can be determined by enzyme-linked immunosorbent
assay (ELISA) or mass spectroscopy. This test is readily available, reliable, and is comparatively
inexpensive. It is generally considered the first-line investigation in the evaluation of suspected
hypogonadism.
• Bio-available testosterone (i.e., non-SHBG-bound and free testosterone) can be measured using
a 50% ammonium sulphate precipitation technique, but this test is cumbersome and unsuited to
routine use.
• Free testosterone can be measured by equilibrium dialysis, which is a complex technique unsuited
to routine use. Free testosterone measured by ELISA is not acceptable as SHBG effects persist.
• Calculated free and bioavailable testosterone levels can be performed using validated equations
based on the total testosterone, SHBG, and, in some equations, the albumin level. The Vermeulen
equation for free testosterone is the most commonly used.
Total serum testosterone is the usual first-line test as it is more widely available, although evaluating free
or bio-available testosterone levels may be necessary in some patients. Conditions that cause elevated or
decreased levels of SHBG can produce levels of free testosterone that are not commensurate with total
testosterone levels. For example, older men often have increasing levels of SHBG with increasing age,
which causes a low free testosterone with a normal-appearing total testosterone.[13]
The timing of sampling is important, especially in younger men. Testosterone levels follow a circadian
rhythm, reaching a maximum at 8 a.m. and declining to a minimum at 10 p.m. (this pattern is less marked
in older men, although some older men do maintain a normal rhythm). Because reference ranges are
based on peak levels in normal young men, it is best if samples are taken between 6 a.m. and 8 a.m.
However, for practical reasons, a sample taken up to 11 a.m. is acceptable. Total testosterone should
be measured on at least two occasions, one week apart.[1] The testes normally produce 3 to 10 mg of
testosterone daily, resulting in serum levels of 10.4 to 34.7 nanomol/L (300 to 1000 nanograms/dL). Many
experts and guidelines take 10.4 nanomol/L (300 nanograms/dL) as the threshold level for hypogonadism
because studies have shown that below this level there is evidence of bone loss and increased fat
accumulation. However, normal ranges differ between laboratories, assay kits, and populations. One set
of guidelines on late-onset hypogonadism recommend that a total testosterone level <8 nanomol/L (<230
nanograms/dL) is consistent with hypogonadism, whereas a level >12 nanomol/L (>350 nanograms/dL) is
not.[3] A symptomatic patient with a total testosterone between 8 and 12 nanomol/L (230-350 nanograms/
dL) could be hypogonadal and a trial of testosterone therapy considered.
Guidelines from the Endocrine Society in the US, and other international guidelines, recommend
repeating the measurement of morning total serum testosterone along with SHBG and, in some
patients, measuring or calculating free or bio-available testosterone level to confirm the diagnosis of
hypogonadism.[3] [7] [19] [20] The guidelines also note that it is important to confirm low testosterone
concentrations in men with an initial testosterone level in the mildly hypogonadal range, because 30% of
such patients may have a normal testosterone level on repeat measurement. In addition, 15% of healthy
young men have a testosterone level below the normal range in a 24-hour period. Taking testosterone
samples during periods of acute illness should also be avoided as acute illness can suppress the
hypothalamic-pituitary-testes axis and so cause inaccuracies in evaluation.
Measurement of gonadotrophins
DIAGNOSIS
If testosterone levels are found to be consistently low by any of the testing methods described, LH
and FSH levels should be measured to determine whether the patient has primary or secondary
hypogonadism.
• Low testosterone level accompanied by elevated gonadotrophin levels suggests primary

hypogonadism. In these patients, particularly if there is azoospermia, small testes, and eunuchoid
proportions, karyotyping can be considered to evaluate for Klinefelter syndrome. Iron studies
(including serum transferrin saturation) can be performed to rule out haemochromatosis.
• Low testosterone level accompanied by low or inappropriately normal gonadotrophin levels
suggests secondary hypogonadism. These patients should have TSH and prolactin levels
measured, along with iron studies. If hypopituitarism is suspected, 9 a.m. blood samples for free
thyroxine and cortisol should be taken (i.e., a short synacthen test). In addition, MRI of the pituitary
can be performed to rule out a mass lesion. The yield of MRI is highest when total testosterone
levels are below 5.2 nanomol/L (<150 nanograms/dL). Hence, MRI should be considered in
patients with these values. MRI could also be obtained in men with higher values if clinically
indicated or if there are concerning signs and symptoms.
11
Semen analysis
Semen analysis is performed in men who have low testosterone levels and are complaining of infertility
or who express a desire to start a family in the future. Normal sperm concentration in semen is 50
to 200 million/mL, with more than 50% motile and above 4% with normal morphology by Kruger
strict criteria. Two semen analyses (each with 2-5 days of abstinence) are recommended to make an
accurate diagnosis. Seminal fructose levels can be measured to help make the diagnosis of obstructive
azoospermia or oligospermia with the obstruction commonly being seen distal to the seminal vesicles,
but a diminished semen volume (less than 1mL) is highly suggestive of obstruction. If a semen volume
of less than 1mL is seen on analysis, the patient should be questioned to ensure that the entire sample
was collected in the cup. The World Health Organization now considers 15 million/mL to be oligospermic,
although many practitioners still use the historical 20 million/mL; a count of below 5 million/mL suggests
severe oligozoospermia.[21]
Men with azoospermia should undergo karyotyping to evaluate for Klinefelter syndrome. Testicular biopsy
shows hyalinisation of the seminiferous tubules. Men with severe oligozoospermia (non-obstructive)
should be evaluated for Y-chromosome microdeletions. Genetic analysis for the the KAL-1 gene can also
aid in the diagnosis of Kallmann syndrome.
History and exam

Key diagnostic factors
decreased libido (common)
• Strongly indicative of testosterone deficiency.
loss of spontaneous morning erections (common)

• Strongly indicative of testosterone deficiency.
erectile dysfunction (common)

DIAGNOSIS
• A fair indicator of testosterone deficiency.

• Can also have a psychogenic basis, associated with depression or a result of vascular or neurological
conditions.
gynaecomastia (common)
• Firm ductal tissue that is mainly sub-areolar. It should be differentiated from adipose tissue in obese
patients (often termed lipomastia or pseudo-gynaecomastia).
• Gynaecomastia is more commonly seen in primary hypogonadism.[17]
infertility (common)
• A common presenting issue in men with hypogonadism. Three semen analyses may be needed to
make an accurate diagnosis. Seminal fructose levels should also be measured to rule out obstructive
azoospermia in men with a low semen volume.
galactorrhoea (uncommon)
• Strongly indicative of hyperprolactinaemia.
micro-penis (uncommon)
• Short penis (often in association with lack of scrotal hyper-pigmentation and rugae) is indicative of
hypogonadism that occurred before puberty.
small testes (uncommon)

• Very small or shrinking testes (especially <5 mL volume) are indicative of testosterone deficiency.
bifid scrotum (uncommon)

• A manifestation of testosterone deficiency in utero.
cryptorchidism (uncommon)
• A manifestation of testosterone deficiency in utero.
eunuchoid proportions (uncommon)

• Indicated by an arm span more than 2 cm greater than height; occurs when hypogonadism occurs
before puberty and causes delayed pubertal closure of the epiphyses of the long bones.[13]
bitemporal hemianopia (uncommon)

• Indicative of a space-occupying intra- or para-sellar lesion, which may be causing secondary
hypogonadism.
low trauma fractures (uncommon)

• Long-standing hypogonadism is associated with osteoporosis that can result in fractures occurring with
unusually low levels of trauma.
loss of height (uncommon)

• May be indicative of spinal compression fractures associated with low bone mineral density and
osteoporosis secondary to hypogonadism.
anosmia (uncommon)
• May be noted in patients with some genetic forms of central hypogonadism, such as Kallmann
DIAGNOSIS
syndrome.
Other diagnostic factors

decreased energy and fatigue (common)
• Non-specific finding that may be reported in patients with hypogonadism, who may complain of
physical exhaustion and lack of vitality.
delayed puberty (uncommon)

• If hypogonadism occurred prior to puberty, patients may report delayed or absent puberty.
lack of scrotal hyper-pigmentation and rugae (uncommon)

• Indicative of hypogonadism that started before puberty.
decreased muscle mass and strength (uncommon)

• Non-specific. A good tool in research but limited value in clinical practice.
loss of axillary and pubic hair (uncommon)
13
• Non-specific finding that may be reported in patients with hypogonadism.
lack of facial hair (uncommon)

• Absence of facial hair and a lower hair line may be noted in many men with hypogonadism.
poor concentration and memory (uncommon)

depressed mood (uncommon)

sleep disturbance (uncommon)

• Severe hypogonadism may be associated with hot flushes that may influence sleep quality.
hot flushes and sweats (uncommon)

• Severe hypogonadism may be associated with hot flushes that may influence sleep quality.
increasing BMI (uncommon)

• Obesity may result in hypogonadism by suppressing hypothalamic-pituitary axis due to increased
oestrogens.
tall stature (uncommon)

• Some males with hypogonadism may be tall with eunuchoid proportions ( i.e., arm span >2 cm greater
than height), due to delay in fusion of the epiphyses of the long bones.
fine wrinkling of facial skin (uncommon)

• May be noted in some patients with hypogonadism.
Risk factors
DIAGNOSIS
Strong
genetic anomaly
• Klinefelter syndrome is the most common congenital cause of primary hypogonadism.[9] It affects 1 in
1000 live births.[8] Most patients have 47,XXY genotype anomaly; however, mosaicism is commonly
seen.
• Y-chromosome microdeletion usually causes reduction in spermatogenesis with testosterone levels
being normal in the majority of patients.
• Many genetic mutations may result in isolated hypogonadotrophic hypogonadism (IHH), Kallmann
syndrome being the most well-known.[11]
type 2 diabetes mellitus

• A high prevalence of hypogonadism is recognised in men with type 2 diabetes. Secondary
hypogonadism is most commonly found, although primary hypogonadism also occurs.
use of alk ylating agents, opioids, or glucocorticoids
• Can be a cause of both primary and secondary hypogonadism.
• Alkylating agents such as cyclophosphamide and chlorambucil can cause primary hypogonadism,
the seminiferous tubules usually being the main site of damage, although testosterone production by
Leydig cells can also be affected.[10] Men undergoing therapy with alkylating agents should be given
the option of sperm banking.
• High-dose glucocorticoids can cause primary hypogonadism by influencing Leydig cells, and
secondary hypogonadism by inhibiting GnRH synthesis.
• Opioids reduce gonadal function mainly via direct effects on the hypothalamic-pituitary axis
(suppressing GnRH synthesis).
use of exogenous sex hormones and GnRH analogues

• GnRH analogues (e.g., goserelin, leuprorelin, nafarelin, buserelin), exogenous oestrogens, and
exogenous androgens can all cause hypogonadism. GnRH analogues cause down-regulation of
receptors for gonadotrophins, while exogenous androgens suppress hypothalamic-pituitary unit by
negative feedback.
hyperprolactinaemia
• Elevated prolactin level (from any cause) suppresses GnRH.
pituitary tumour or apoplex y

• Causes compression of gonadotrophs (basophilic cells of the anterior pituitary specialised to secrete
FSH or LH), resulting in secondary hypogonadism.
critical illness
• Severe systemic illness can suppress the hypothalamic-pituitary-gonadal axis, resulting in decreased
GnRH secretion and secondary hypogonadism; the hypothalamic-pituitary-gonadal axis usually
recovers when the illness resolves.
testicular damage
DIAGNOSIS
• Can occur as a result of torsion, direct trauma, or irradiation. With torsion, the likelihood of damage is
increased with duration of unrelieved torsion.
Weak
varicocele
• Causes increased temperature and/or accumulation of tissue metabolites in the testes, which can
result in primary hypogonadism.
auto-immune testicular damage

• It is unclear whether antibodies against testicular tissue are pathogenic.
15
Investigations
1st test to order
Test Result
serum total testosterone less than 10.4 nanomol/
• Check between 6 a.m. and 8 a.m. ideally; sample taken up to 11 a.m. L (<300 nanograms/dL)
is generally accepted as
is acceptable.
indicating hypogonadism
• May not be accurate in obese and ageing men, in which case other
confirmatory measures of testosterone levels may be required.
DIAGNOSIS
Other tests to consider
Test Result
serum sex hormone binding globulin (SHBG) increased or decreased
(normal range in adult
• Should be checked in men with an equivocal or borderline
males is 10-57 nanomol/L)
total testosterone, and can be used to calculate the serum free
testosterone, which is generally more accurate than values run on
serum samples.[19] [20]
• Altered SHBG levels are suspected in older men and in men with
underlying conditions, such as obesity, diabetes mellitus, nephrotic
syndrome, or liver or thyroid disease.[7]
serum free testosterone below 0.2 nanomol/L (<5
• Check between 6 a.m. and 8 a.m. ideally; sample taken up to 11 a.m. nanograms/dL) generally
indicates hypogonadism
acceptable.
• The equilibrium dialysis method should be used if possible,
although this may not be available in all centres. The calculated free
testosterone (using serum SHBG and an online calculator) is a more
accepted approach due to laboratory inaccuracies for serum free
testosterone.
serum bioavailable testosterone below 2.4 nanomol/L (<70
• Check between 6 a.m. and 8 a.m. ideally; sample taken up to 11 a.m. nanograms/dL) generally
indicates hypogonadism
acceptable.
• The ammonium sulphate precipitation method should be used if
possible, although this may not be available in all centres.
• Calculate bioavailable testosterone.
serum LH/FSH in patients with low
testosterone, elevated
• Check once the diagnosis of hypogonadism is established based on
levels indicate primary
testosterone levels.
hypogonadism; decreased
or normal levels indicate
secondary hypogonadism
serum prolactin above 783 picomol/
DIAGNOSIS
L (>18 nanograms/
• Check fasting levels because meals can elevate prolactin levels.
• Prolactin is measured if results of testosterone and gonadotrophin mL or 18 micrograms/
L) is considered
testing suggest secondary hypogonadism (i.e., low testosterone,
elevated, although
accompanied by low or inappropriately normal gonadotrophins).
much higher levels are
generally present with
a symptomatic pituitary
adenoma
serum Fe, TIBC, and ferritin elevated ferritin and iron

saturation confirms
• Check in patients with either primary or secondary hypogonadism.
haemochromatosis
• Iron studies (including serum transferrin saturation) should also be
performed to rule out haemochromatosis.
MRI pituitary mass greater than 10 mm
• Obtain if gonadotrophins (LH/FSH) are low or inappropriately normal. in size confirms macro-
adenoma; mass <10 mm
• Men with serum levels of total testosterone below 5.2 nanomol/L
in size confirms micro-
(<150 nanograms/dL) may benefit from pituitary imaging.[13]
adenoma; alternatively,
may show empty or
17
Test Result
partially empty sella, or a
parasellar mass
semen analysis sperm count below 5

million/mL indicates
• Check if fertility is an issue.
severe oligozoospermia
• Determines motility, anatomy, and progression of spermatozoa.
• Include seminal fructose levels to rule out obstructive
oligozoospermia in select men.
• Sample obtained after 2 to 5 days of abstinence.
genetic testing 47,XXY confirms
Klinefelter syndrome
• Karyotype will check for Klinefelter syndrome if azoospermia and
(may be mosaic)
small testes detected.
• Evaluate for Y-chromosome microdeletions if severe
oligozoospermia.
serum TSH hypothyroidism can result
in hyperprolactinaemia
• Hypothyroidism can result in hyperprolactinaemia because TRH
stimulates prolactin secretion. In such instances, restoration of
euthyroidism results in resolution of hyperprolactinaemia.
dual-energy X-ray absorptiometry (DEXA or DXA) hypogonadism can
cause a decrease in bone
• Long term suppressed levels of testosterone (with correspondingly
density
low oestrogen) can lead to compromised bone health in men
DIAGNOSIS
Differentials
Condition Differentiating signs / Differentiating tests

symptoms
Pituitary macro-adenoma • Headache and bitemporal • Low LH and FSH levels with
hemianopia symptoms pituitary macro-adenoma.
related to other pituitary • Possible low TSH, growth
hormonal deficiencies; for hormone, and cortisol
example, weight loss and deficiency.
nausea due to adrenal • MRI of the pituitary reveals
insufficiency, or cold pituitary lesion.
intolerance and constipation
due to hypothyroidism.
Prolactinoma • Headache, bitemporal • MRI of the pituitary reveals

hemianopia, and occasional pituitary lesion.
galactorrhoea. • Serum prolactin elevated.
Hyperprolactinaemia • Galactorrhoea may be • Elevated prolactin levels.

present. Hypothyroidism and
• Headache may be present medicines such as dopamine
if hyperprolactinaemia is antagonists should be
secondary to prolactinoma. excluded.
Depression • Depression resulting in • With depression, hormonal

reduced libido. tests may be normal.
• Psychogenic erectile • Normal early morning
dysfunction. erections will still occur
if erectile dysfunction is
psychogenic.
Screening
DIAGNOSIS
The Endocrine Society in the US recommends against screening for androgen deficiency in the general
population.[7] However, they suggest that clinicians consider case detection by measurement of total
testosterone levels in men with the following clinical disorders, in which the prevalence of low testosterone
levels is high or for whom testosterone therapy is suggested or recommended:
• Sellar mass, radiation to the sellar region, or other diseases of the sellar region
• Treatment with medicines that affect testosterone production or metabolism: for example,
glucocorticoids, ketoconazole, and opioids
• HIV-associated weight loss
• Withdrawal from long-term anabolic-androgenic steroid use
• Infertility
• Osteoporosis or low trauma fracture, especially in a young man
• Men with decreased libido, erectile dysfunction, gynaecomastia, and osteoporosis are candidates
for screening of total testosterone, as treatment with testosterone results in improvement in libido,
impotence (especially younger men), resolution of gynaecomastia, and improvement in bone mineral
density
• Men complaining of infertility should also undergo screening by semen analysis, using 2 samples
obtained after 2 to 5 days of abstinence.
19
The European Association of Urology recommends assessing testosterone in all men with erectile
dysfunction.[22] Men with low testosterone may have a poor response to phosphodiesterase type-5
inhibitors, which can be improved with appropriate testosterone supplementation.[23] [24] [25]
DIAGNOSIS
Hypogonadism in men Management
Approach
For most men with hypogonadism, treatment aims to restore serum testosterone levels to the normal
physiological range by the administration of testosterone therapy. The specific choice of type and route of
administration is guided by efficacy, patient preference, ease of use, and cost. The adequacy of testosterone
therapy is assessed by clinical symptoms and serum hormone levels.[1] [2] [26] [27] Patients require close
follow-up to ensure compliance, assess effectiveness, adjust dosing, and monitor for side effects. Patients
should be reviewed at regular intervals during the first year of treatment and then annually thereafter.[3]
[7]Haematocrit and PSA should also be checked at these visits, along with hormone studies to ensure
adequate response to treatment.
There are 2 specific subsets of men with hypogonadism who are not treated with testosterone therapy:
• The first is men in whom hypogonadism is due to a prolactinoma (micro-adenoma or macro-

adenoma). These patients receive a dopamine agonist such as cabergoline or bromocriptine, rather
than testosterone therapy. The vast majority (90% to 95%) of these patients achieve eugonadism
within 6 months of achieving normal prolactin levels. In patients with a micro-adenoma, a trial
withdrawal of the dopamine agonist may be considered after a few years of treatment, as the
recurrence of hyperprolactinaemia has been reported as being as low as 30% in the 5 years following
withdrawal. Patients with macro-adenomas usually require lifelong treatment. The small percentage
of patients who do not respond to a dopamine agonist can be treated with testosterone therapy to
improve symptoms of hypogonadism. Surgery is considered for patients who are resistant or have
partial resistance to dopamine agonist therapy. Surgery (as with dopamine agonist therapy) may
lead to some reversal of the hypogonadism, but this would be less likely after surgery than with drug
therapy as larger tumours are likely to cause more permanent damage. Also, surgery itself may cause
damage to normal pituitary tissue.
• The second group is men with isolated hypogonadotrophic hypogonadism (IHH) who desire fertility.
Exogenous testosterone therapy is not helpful in restoring fertility in this group of patients and will
in fact decrease sperm counts. These men may be treated with a selective oestrogen receptor
modulator such as clomifene or tamoxifen, or an aromatase inhibitor (AI) such as anastrozole (if
IHH is secondary to obesity and their hypothalamic-pituitary unit is intact) or with human chorionic
gonadotrophin (alone or in combination with FSH) or with pulsatile GnRH (if their hypothalamic-
pituitary unit is inadequate). These treatment regimens result in stimulation of the testes and secretion
of endogenous testosterone.[28] Note that the use of selective oestrogen receptor modulators and AIs
is an off-label indication in men.[29] For all of these treatments, oestradiol levels should be monitored
as levels may change with selective oestrogen receptor modulators or AIs. If current or future fertility is
not desired, then exogenous testosterone therapy is sufficient for androgenisation.
Testosterone therapy
Apart from the 2 specific patient groups outlined above, the remainder of men with hypogonadism
are treated with testosterone therapy. The class effect of testosterone therapy compared with placebo
is to improve quality of life, depression, erectile function, and libido.[30] However, for most individual
MANAGEMENT
treatments, improvements are not significantly better than placebo, and there are few differences between
the treatments when compared to each other.[30] The specific choice of type and route of administration
is guided by efficacy, patient preference, ease of use, and cost. The aim of testosterone therapy is to
achieve normal physiological testosterone levels, usually to the mid-normal range, to reverse hypogonadal
symptoms and signs.
21
Topical and transdermal preparations:
• Formulations include gels, solution, and transdermal patch.[31] These require once-daily
application and can achieve physiological serum levels with dose adjustment.
• Local skin irritation is the main side effect and is seen in 30% of men using the patch, but is much
less frequent if the gel preparation is used.[32] Application of triamcinolone ointment and then
later application of the patch over it helps to prevent allergic reaction in many men. Triamcinolone
ointment is not used in conjunction with gel preparations.
• Transfer of testosterone from patient to partner or child through skin-to-skin contact has been
reported in patients using gel or cream preparations.[33] [34] [35] Showering, swimming, and
sexual activity should be avoided for 4 hours after application.
• Testosterone levels can be checked to see if they have reached therapeutic levels after initiating
transdermal products, to ensure that adequate treatment has been given. It is advised that the
testosterone level should be measured 2 to 4 hours after gel application as this gives the peak
value.
• In the minority of patients who have severe local skin irritation from a transdermal preparation
that cannot be managed by triamcinolone ointment, use of an intramuscular preparation can be
considered.
Intramuscular preparations:
• Injections are normally administered every 1 to 2 weeks, but alternative injection schedules are
commonly used. Although intramuscular injections do achieve the goal of androgenisation and
maintenance of secondary sexual characteristics, the serum levels of testosterone achieved are
highly variable in the time after injection due to medication decay. When using intramuscular
preparations, testosterone levels can either be adjusted based on a mid-cycle value or based on
peak/trough values.
• Immediately after injection, supra-physiological levels of serum testosterone may occur. Levels then
decline, reaching near hypogonadal levels after 2 weeks post-injection.
• A long-acting formulation, intramuscular testosterone undecanoate, can be given every 10 to 14
weeks to maintain testosterone levels within normal physiological range. Testosterone levels should
be measured just prior to an injection (i.e., trough level) to ensure concentration is near the low-
normal range. If the patient experiences a return or persistence of symptoms and testosterone
is low once established on therapy, then the frequency of injection can be increased as the dose
cannot be changed. If trough testosterone is greater than mid-normal range, injection frequency
should be reduced. Peak or post-injection levels should also be considered in men without
symptomatic improvement.
• All intramuscular preparations of testosterone should be warmed to body temperature and
administered slowly to reduce discomfort. Long-acting intramuscular testosterone undecanoate
should be administered over a 2-minute period to reduce injection pain and the risk of pulmonary oil
microembolism (POME). Patients who receive testosterone undecanoate should be monitored for
30 minutes after injection in the clinic for clinical symptoms of embolisation, such as cough or chest
pain.
MANAGEMENT
• Polycythaemia and gynaecomastia (due to high estradiol levels resulting from aromatisation
of testosterone) occur more commonly with intramuscular injections than with transdermal
preparations.
Buccal preparations:
• Buccal testosterone tablets (which adhere to the buccal mucosa) may be applied twice daily.
Testosterone levels achieved using this preparation are within the normal physiological range.
Intranasal gel:
• After blowing the nose, the dose is applied to the inside of each nostril. Most patients achieve
normal physiological range testosterone levels.
Implantable pellets:
• Implantable subcutaneous pellets containing testosterone; usually placed into the subcutaneous
tissue of the buttocks. This is a clinic-based procedure, with treatment effects lasting 3 to 4 months
based on the number of pellets implanted. A serum testosterone level approximately 1 month after
insertion, along with a level before the next insertion, are used to determine the number of pellets
inserted and the interval of insertion.
Contraindications, side effects, and monitoring:
• Contraindications to testosterone therapy include unmonitored prostate or breast cancer; untreated,

uncontrolled, or severe congestive cardiac failure; untreated, severe lower urinary tract symptoms
associated with benign prostatic hypertrophy (as indicated by the American Urological Association
prostate symptom score or an International Prostate Symptom Score [IPSS] >19); and untreated
sleep apnoea.[7] [36]
• In men successfully treated for breast or prostate cancer, after a prudent interval with no evidence
of residual cancer confirmed by the specialist managing the cancer, testosterone therapy can be
considered. The risks and benefits must be discussed with the patient, and treatment in these
circumstances would only be considered in patients who have symptoms that are significantly
affecting their quality of life. Strict follow-up of these patients is particularly important.[2] [3]
• Testosterone therapy has been shown to be of benefit in men with moderate chronic cardiac
failure.[37] [38]
• In men with cardiovascular disease, testosterone replaced to the mid-normal range has not been
shown to adversely impact on cardiovascular events or mortality. Use of doses of testosterone
higher than those recommended may, however, lead to a greater risk of cardiovascular-related
events.[39] Men with low testosterone have been shown to be at greater risk of cardiovascular
events and mortality in some studies. Randomised placebo-controlled trials of testosterone therapy
in men with coronary heart disease, cardiac failure, or diabetes, and in frail men, where standard
testosterone therapy is to the normal range have not shown any increase in adverse cardiovascular
events.[37] [38] [40] [41] [42] [43] A retrospective review of more than 83,000 men found that
normalisation of testosterone levels reduces myocardial infarction and mortality in men, with those
receiving treatment but not achieving normal levels still being at risk.[44] A retrospective cohort
study reported an increased risk of cardiovascular events and mortality in men who underwent
angiography; however, a proportion of the population only picked up one prescription and the
mean level of testosterone on treatment was suboptimal at the lower end of the normal range.[45]
The results of this study should be interpreted with caution. The risks and benefits of testosterone
therapy in men with hypogonadism and cardiovascular disease should be carefully reviewed with
MANAGEMENT
the patient. Patients who receive treatment must be carefully monitored, with the aim of replacing
testosterone to the mid-normal range.
• In addition to the side effects specific to each of the modes of administration discussed above, all
forms of testosterone therapy can cause polycythaemia, oily skin, and acne.
23
• Testosterone therapy has not been shown to cause prostate cancer (although there have been no
long-term placebo-controlled trials to verify this). Testosterone therapy may, however, unmask a
prostate cancer that was not evident prior to starting treatment, or it may aggravate pre-existing
prostate cancer. Hence, PSA should be monitored at baseline, intermittently throughout the first
year of treatment, and then annually. History of prostate cancer was previously considered an
absolute contraindication to testosterone therapy, but this stance has recently been challenged.
• Research has shown that testosterone therapy is neutral (if not beneficial) with regard to a
patient's lipid profile and does not cause exacerbations of sleep apnoea.[40] [46] [47] In addition,
testosterone therapy has been shown to have beneficial effects on insulin resistance, cholesterol,
and lipoprotein(a), as well as sexual health in men with type 2 diabetes.[42] [48] [49] Men with
low serum testosterone levels have been found to have elevated markers for cardiovascular
disease.[50]
• Pulmonary oil microembolism (POME) may occur with intramuscular injections of long-acting
testosterone undecanoate and less commonly with other oil-based intramuscular testosterone
injections. Symptoms may include cough, dyspnoea, throat tightening, chest pain, dizziness,
and syncope. These episodes typically occur within 30 minutes of administration and resolve
spontaneously. POME is much less frequent if the injection is given over a 2-minute period.
• Changes in lower urinary tract symptoms should be monitored. While outdated dogma states that
testosterone use in men worsens urinary symptoms related to benign prostatic hyperplasia, recent
work has largely reported that this concern is unfounded.[51] [52]
Treatment algorithm overview

Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Ongoing ( summary )
primary
1st testosterone therapy
secondary
due to prolactinoma 1st dopamine agonist
adjunct testosterone therapy
adjunct surgery
isolated 1st testosterone therapy

hypogonadotrophic
hypogonadism (IHH): not
desiring fertility
isolated 1st fertility treatment

hypogonadotrophic
MANAGEMENT
hypogonadism (IHH):
desiring fertility
Treatment algorithm
Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
MANAGEMENT
25
Ongoing
primary
1st testosterone therapy

Primary options
» testosterone topical: (gel or solution) apply

equivalent of 50-60 mg of testosterone
initially and adjust dose to achieve target
testosterone level
OR
» testosterone transdermal: 2.5 to 5 mg/day

patch applied once daily
OR
» testosterone buccal: 30 mg buccally every

12 hours
OR
» testosterone nasal: (5.5 mg/dose) 1 dose

(actuation) in each nostril three times daily
OR
» testosterone: (75 mg/pellet) 150-450 mg

implanted subcutaneously every 3-6 months;
doses of up to 750 mg have been used
OR
» testosterone cipionate: 200 mg

intramuscularly every 2 weeks, or 100 mg
intramuscularly once weekly initially; titrate
dose as necessary
OR
» testosterone enantate: 200 mg

dose as necessary
OR
» testosterone undecanoate: 750 mg

MANAGEMENT
intramuscularly initially, repeat in 4 weeks,

then every 10 weeks thereafter; adjust
interval as needed
» The goal is to restore serum testosterone

levels to the mid-normal range. Choice of route
Ongoing
of administration is guided by patient preference,
ease of use, and cost. The adequacy of
testosterone therapy is assessed by clinical
symptoms and serum hormone levels.[26] [27]
» Patients require close follow-up to ensure

compliance, assess effectiveness, adjust dosing,
and monitor for side effects. Dose titration
may be required to attain adequate circulating
testosterone levels. Patients should be reviewed
at regular intervals after initiation of testosterone,
and annually thereafter.[3] [7] Haematocrit
and PSA should also be checked at these
visits. Transfer of testosterone from patient to
partner or child through skin-to-skin contact has
been reported in patients using gel or cream
preparations.[33] [34] [35]
» Intramuscular dosing may cause intermittent

supra-physiological testosterone levels with
resulting fluctuations in mood and sexual
behaviour, polycythaemia, gynaecomastia,
and over-stimulation of the prostate. When
using intramuscular preparations, levels may
either be checked mid-cycle between injections
or as peak and trough levels. Testosterone
levels can be checked to see if they have
reached therapeutic levels after 1 week of using
transdermal products. Showering, swimming,
and sexual activity should be avoided for 4 hours
after application.
» All intramuscular preparations of testosterone

should be warmed to body temperature and
administered slowly to reduce discomfort. Long-
acting intramuscular testosterone undecanoate
should be administered over a 2-minute period to
reduce injection pain and the risk of pulmonary
oil microembolism (POME).
» Local skin irritation is the main side effect

of transdermal testosterone preparations and
is seen in 30% of men using the patch, but
is much less frequent if the gel preparation
is used.[32] Application of 1% triamcinolone
ointment and then application of the patch over
it helps to prevent allergic reaction in many
men. Triamcinolone ointment is not used in
conjunction with gel preparations.
secondary
MANAGEMENT
due to prolactinoma 1st dopamine agonist

Primary options
» cabergoline: 0.25 to 1 mg orally twice

weekly
27
Ongoing
Secondary options
» bromocriptine: 2.5 to 10 mg orally once

daily
» Cases of hypogonadism due to prolactinoma

(micro-adenoma or macro-adenoma) are treated
with dopamine agonists.
» Cabergoline is more potent than bromocriptine,

has a better side effect profile, and only
needs to be taken twice weekly. It is a
selective dopamine-2 agonist, compared with
bromocriptine, which is a combined dopamine-1/
dopamine-2 agonist.
» The vast majority (90% to 95%) of patients

achieve eugonadism within 6 months of
achieving normal prolactin levels. The small
percentage of patients who do not respond
to a dopamine agonist can be treated with
testosterone therapy.
adjunct testosterone therapy
Treatment recommended for SOME patients in
selected patient group
Primary options

testosterone level
OR

OR

12 hours
OR

OR
MANAGEMENT

OR
Ongoing

dose as necessary
OR

dose as necessary
OR

interval as needed
» The vast majority (90% to 95%) of patients

respond to treatment with a dopamine agonist,
which is the first-line treatment in this group of
patients. The small percentage of patients who
do not respond to a dopamine agonist can be
treated with testosterone therapy. Postsurgical
patients may also need testosterone therapy.


and annually thereafter.[3] [7] Haematocrit

MANAGEMENT
behaviour, polycythaemia, gynaecomastia, and

over-stimulation of the prostate. When using
intramuscular preparations, levels may either
be checked mid-cycle between injections or
checked as peak and trough levels. Testosterone
29
Ongoing
after application.


adjunct surgery
Treatment recommended for SOME patients in
selected patient group
» Surgery is considered for patients who are
resistant or have partial resistance to dopamine
agonist therapy. Surgery (as with dopamine
agonist therapy) may lead to some reversal of
the hypogonadism, but this would be less likely
after surgery than with drug therapy, as larger
tumours are likely to cause more permanent
damage. Also, surgery itself may cause damage
to normal pituitary tissue.
isolated 1st testosterone therapy
hypogonadotrophic
Primary options
hypogonadism (IHH): not
desiring fertility
testosterone level
OR

OR
MANAGEMENT

12 hours
OR
Ongoing

OR

OR

dose as necessary
OR

dose as necessary
OR

interval as needed


and annually thereafter.[3] [7]Haematocrit
MANAGEMENT

behaviour, polycythaemia, gynaecomastia, and
over-stimulation of the prostate. When using
31
Ongoing
intramuscular preparations, levels may either
be checked mid-cycle between injections or
checked as peak and trough levels. Testosterone
after application.


isolated 1st fertility treatment
hypogonadotrophic
Primary options
hypogonadism (IHH):
desiring fertility
» clomifene: 25-50 mg orally once daily or
three times weekly; consult specialist for
further guidance on dose
OR
» tamoxifen: consult specialist for guidance

on dose
OR
» anastrozole: consult specialist for guidance

on dose
OR
» human chorionic gonadotrophin: 1500 units

intramuscularly/subcutaneously twice weekly
Dose may need to be increased up to
5000 units twice weekly to attain normal
MANAGEMENT
OR
» human chorionic gonadotrophin: 1500 units

intramuscularly/subcutaneously twice weekly
Ongoing
Dose may need to be increased up to
5000 units twice weekly to attain normal
--AND--
» urofollitropin: 75-150 units subcutaneously
three times weekly
FSH.
-or-
» follitropin alfa: 150 units subcutaneously
three times weekly
Recombinant FSH.
-or-
» follitropin beta: 150 units subcutaneously
three times weekly
Recombinant FSH.
Secondary options
» pulsatile GnRH: consult specialist for

guidance on dose
» Sperm production cannot be stimulated in men

with primary hypogonadism (i.e., damage to the
seminiferous tubules). However, infertility due to
secondary hypogonadism (i.e., damage to the
hypothalamic-pituitary axis) can be treated in
many instances.
» For men with IHH who desire current or

future fertility, exogenous testosterone therapy
is not helpful in restoring fertility. These
men are treated with a selective oestrogen
receptor modulator such as clomifene or
tamoxifen, or an aromatase inhibitor (AI) such
as anastrozole (if IHH is secondary to obesity
and the hypothalamic-pituitary unit is intact), or
with human chorionic gonadotrophin (alone or in
combination with FSH), or with pulsatile GnRH
(if the hypothalamic-pituitary unit is damaged).
These treatment regimens result in stimulation
of the testes and secretion of endogenous
testosterone.[28] Note that the use of clomifene
and other selective oestrogen modulators is an
off-label indication in men.[29]
» Estradiol levels should be monitored

in men receiving a selective oestrogen
receptor modulator, an AI, or human chorionic
gonadotrophin.
» If fertility is not desired, then exogenous

MANAGEMENT
testosterone therapy is sufficient for

androgenisation.
33
Patient discussions
Patients applying transdermal gels should not wear a shirt for at least 10 minutes after application, and
should ensure adequate drying before putting on a shirt. Sexual activity, showering, and swimming
should be avoided for 4 hours after gel application. Gel should be applied on the shoulder, upper arm, or
abdomen for better absorption.
MANAGEMENT
Hypogonadism in men Follow up
Monitoring
Monitoring
FOLLOW UP
Transdermal preparations: testosterone level should be checked 2 to 4 hours after testosterone gel
application, when peak absorption level is attained. Testosterone levels can be checked to see if they
have reached therapeutic levels as early as 1 to 2 weeks after initiation of transdermal products, to ensure
that adequate treatment has been given.
Intramuscular preparations administered every 2 weeks: serum total testosterone levels should be
checked 1 week after an injection of testosterone to assess whether levels are therapeutic (13.9-24.3
nanomol/L [400-700 nanograms/dL]). Levels should be checked periodically.
Intramuscular preparations administered every week: serum total testosterone levels should be checked
either at mid-cycle or as a peak and trough value to assess whether levels are therapeutic. Levels should
be checked periodically.
Long-acting testosterone undecanoate: testosterone levels should be measured just prior to an injection
(i.e., trough level) to ensure concentration is in the low-normal range.
Haematocrit and PSA should be checked at regular intervals after initiation of therapy and then annually.
A digital rectal examination should be a frequent part of the examination. An evaluation of benefits and
side effects is advised and cessation of treatment should be considered in men without therapeutic
benefit.
35
Complications
Complications Timeframe Likelihood

FOLLOW UP
pulmonary oil microembolism (POME) short term low
Pulmonary oil microembolism (POME) may occur with intramuscular injections of long-acting testosterone
undecanoate and less commonly with other oil-based intramuscular testosterone injections. Symptoms
may include cough, dyspnoea, throat tightening, chest pain, dizziness, and syncope. These episodes
typically occur within 30 minutes of administration and resolve spontaneously. POME is much less
frequent if the injection is given over a 2-minute period.
skin irritation from testosterone patch variable high
Occurs in up to 30% of patients using the patch.
Permeation enhancers in the patch are thought to be responsible.
Application of 1% triamcinolone cream before application of the patch prevents irritation.
polycythaemia variable medium
This is particularly common with intramuscular testosterone preparations.
If haematocrit greater than 54%, decrease testosterone dose, consider changing from an intramuscular to
a transdermal preparation, and/or consider venesection. Venesection may need to be performed at regular
intervals according to clinical need.
skin irritation from testosterone gels variable low
Occurs less frequently than in patch users; the mechanism is unclear.
increase in PSA variable low
Obtain urology consultation if: PSA increases to above 4.0 micrograms/L (>4.0 nanograms/mL); PSA
velocity is above 0.4 micrograms/L/year (>0.4 nanograms/mL/year); there is an increase in PSA above 1.4
micrograms/L (>1.4 nanograms/mL) within a 12-month period of testosterone treatment.
PSA elevation may occur from causes other than testosterone therapy: for example, exercise (in particular
cycling), urinary tract infection (check urine), prostatitis, benign prostatic hypertrophy, urinary retention,
urinary catheterisation, digital rectal examination, sigmoidoscopy/colonoscopy, inflammatory bowel
disease, ejaculation, anal intercourse, and recent surgery.
testicular shrinkage variable low
Some patients, especially those treated with intramuscular preparations, experience testicular shrinkage
as a result of negative feedback of testosterone secretion on gonadotrophin secretion.
subfertility variable low
Complications Timeframe Likelihood

Reduction in sperm count may occur on testosterone therapy. This may lead to subfertility. This is more
FOLLOW UP
likely to occur with intramuscular testosterone preparations. Sperm count may be abnormal as part of
hypogonadal condition. If fertility is required, if possible taking into account the underlying cause of the
hypogonadism, then transdermal preparations are less likely to suppress spermatogenesis.
Prognosis
Many men with permanent causes of hypogonadism (e.g., genetic causes, testicular damage, pituitary
injury) require lifelong therapy. Men with hypogonadism related to critical illness or medicine use recover
after resolution of the illness or discontinuation of the medication that causes low testosterone (e.g., opiates,
glucocorticoids). Marked weight loss in men with obesity (e.g., with bariatric surgery) may lead to recovery of
eugonadal state.
37
Hypogonadism in men Guidelines
Diagnostic guidelines
United Kingdom
Guidelines on the management of sexual problems in men: the role of

androgens (ht tp://bssm.org.uk/resources)
Published by: British Society for Sexual Medicine Last published: 2010
Europe
Guidelines on male hypogonadism (ht tp://uroweb.org/individual-guidelines/

non-oncology-guidelines)
Published by: European Association of Urology Last published: 2018
GUIDELINES
International
Recommendations on the diagnosis, treatment and monitoring of

hypogonadism in men (ht tp://www.issam.ch/loh.asp)
Published by: International Society for the Study of the Aging Male Last published: 2015
The International Society for Sexual Medicine's process of care for the
assessment and management of testosterone deficiency in adult men (ht tp://
www.ncbi.nlm.nih.gov/pubmed/26081680)
Published by: International Society for Sexual Medicine Last published: 2015
North America
Evaluation and management of testosterone eficiency: AUA guideline (ht tps://

www.auanet.org/guidelines?q=&filters=&ContentType=Clinical_Guidelines)
Published by: American Urological Association Last published: 2018
Testosterone therapy in adult men with androgen deficiency syndromes

(ht tps://www.endocrine.org/guidelines-and-clinical-practice/clinical-practice-
guidelines)
Published by: The Endocrine Society Last published: 2018
Treatment guidelines
United Kingdom
Guidelines on adult testosterone deficiency, with statements for UK Practice

(ht tp://www.bssm.org.uk/resources)
Published by: British Society for Sexual Medicine Last published: 2017
Fertility problems: assessment and treatment (ht tps://www.nice.org.uk/

guidance/CG156)
Published by: National Institute for Health and Care Excellence Last published: 2017
Europe
Guidelines on male hypogonadism (ht tp://uroweb.org/individual-guidelines/
GUIDELINES
non-oncology-guidelines)
Guidelines on male infertility (ht tp://uroweb.org/individual-guidelines/non-

oncology-guidelines)
International
Recommendations on the diagnosis, treatment and monitoring of

hypogonadism in men (ht tp://www.issam.ch/loh.asp)
Published by: International Society for the Study of the Aging Male Last published: 2015
The International Society for Sexual Medicine's process of care for the
assessment and management of testosterone deficiency in adult men (ht tp://
www.ncbi.nlm.nih.gov/pubmed/26081680)
Published by: International Society for Sexual Medicine Last published: 2015
39
North America
Evaluation and management of testosterone eficiency: AUA guideline (ht tps://

www.auanet.org/guidelines?q=&filters=&ContentType=Clinical_Guidelines)
Published by: American Urological Association Last published: 2018
Testosterone therapy in adult men with androgen deficiency syndromes

(ht tps://www.endocrine.org/guidelines-and-clinical-practice/clinical-practice-
guidelines)
Published by: The Endocrine Society Last published: 2018
Adult onset hypogonadism (ht tp://www.smsna.org/V1/about/position-

statements)
Published by: Sexual Medicine Society of North America (SMSNA) Last published: 2015
GUIDELINES
Hypogonadism in men References
Key articles
• Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and management of testosterone deficiency:
REFERENCES
AUA Guideline. J Urol. 2018 Mar 28. pii: S0022-5347(18)42817-0. [Epub ahead of print] Full text
(https://www.auanet.org/guidelines/evaluation-and-management-of-testosterone-deficiency)
• Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in
men. J Clin Endocrinol Metab. 2007 Nov;92(11):4241-7. Full text (https://academic.oup.com/
jcem/article/92/11/4241/2598366) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/17698901?
tool=bestpractice.bmj.com)
• Araujo AB, O'Donnell AB, Brambilla DJ, et al. Prevalence and incidence of androgen deficiency
in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin
Endocrinol Metab. 2004 Dec;89(12):5920-6. Full text (https://academic.oup.com/jcem/
article/89/12/5920/2844159) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/15579737?
• Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An
Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018 Mar 17. [Epub ahead of
print] Full text (https://academic.oup.com/jcem/advance-article/doi/10.1210/jc.2018-00229/4939465)
Abstract (http://www.ncbi.nlm.nih.gov/pubmed/29562364?tool=bestpractice.bmj.com)
• Wang C, Jackson G, Jones TH, et al. Low testosterone associated with obesity and the metabolic
syndrome contributes to sexual dysfunction and cardiovascular disease risk in men with type
2 diabetes. Diabetes Care. 2011 Jul;34(7):1669-75. Full text (http://care.diabetesjournals.org/
content/34/7/1669.long) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/21709300?
• Snyder PJ, Bhasin S, Cunningham GR, et al; Testosterone Trials Investigators. Effects of testosterone
treatment in older men. N Engl J Med. 2016 Feb 18;374(7):611-24. Full text (http://www.nejm.org/doi/
full/10.1056/NEJMoa1506119#t=article) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/26886521?
References
1. Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and management of testosterone deficiency:
AUA Guideline. J Urol. 2018 Mar 28. pii: S0022-5347(18)42817-0. [Epub ahead of print] Full text
(https://www.auanet.org/guidelines/evaluation-and-management-of-testosterone-deficiency)
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5. Araujo AB, O'Donnell AB, Brambilla DJ, et al. Prevalence and incidence of androgen deficiency
in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin
Endocrinol Metab. 2004 Dec;89(12):5920-6. Full text (https://academic.oup.com/jcem/
article/89/12/5920/2844159) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/15579737?
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Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018 Mar 17. [Epub ahead of
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male hypogonadism. Expert Opin Pharmacother. 2007 Dec;8(17):2991-3008. Abstract (http://
28. Spratt DI, Finkelstein JS, O'Dea LS, et al. Long-term administration of gonadotropin-releasing
hormone in men with idiopathic hypogonadotropic hypogonadism. A model for studies of the
hormone's physiologic effects. Ann Intern Med. 1986 Dec;105(6):848-55. Abstract (http://
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medroxyprogesterone acetate/percutaneous testosterone contraception. Lancet. 1984 Feb
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statement. J Androl. 2006 Mar-Apr;27(2):133-4. Full text (https://onlinelibrary.wiley.com/doi/
full/10.1002/j.1939-4640.2006.tb01177.x) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/16474019?
37. Malkin CJ, Pugh PJ, West JN, et al. Testosterone therapy in men with moderate severity heart failure:
a double-blind randomized placebo controlled trial. Eur Heart J. 2006 Jan;27(1):57-64. Full text
(https://academic.oup.com/eurheartj/article/27/1/57/608065) Abstract (http://www.ncbi.nlm.nih.gov/
38. Caminiti G, Volterrani M, Iellamo F, et al. Effect of long-acting testosterone treatment on functional
exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly
patients with chronic heart failure: a double-blind, placebo-controlled, randomized study. J Am Coll
Cardiol. 2009 Sep 1;54(10):919-27. Full text (http://www.onlinejacc.org/content/54/10/919) Abstract
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administration. N Engl J Med. 2010 Jul 8;363(2):109-22. Full text (http://www.nejm.org/doi/
40. Carson CC 3rd, Rosano G. Exogenous testosterone, cardiovascular events, and cardiovascular
risk factors in elderly men: a review of trial data. J Sex Med. 2012 Jan;9(1):54-67. Abstract (http://
41. English KM, Steeds RP, Jones TH, et al. Low-dose transdermal testosterone therapy improves
angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-
controlled study. Circulation. 2000 Oct 17;102(16):1906-11. Full text (http://circ.ahajournals.org/
42. Jones TH, Arver S, Behre HM, et al; TIMES2 Investigators. Testosterone replacement in hypogonadal
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43. Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of testosterone on muscle strength,
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46. Malkin CJ, Pugh PJ, Jones RD, et al. The effect of testosterone replacement on endogenous
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48. Haider A, Haider KS, Saad F. Remission of type 2 diabetes in a hypogonadal man under long-term
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Hypogonadism in men Images
Images
IMAGES
Figure 1: An approach for the diagnostic evaluation of adult men suspected of having androgen deficiency
Adapted from Endocrine Society Guidelines, with permission
47
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49
Contributors:
// Authors:
Charles Welliver, MD
Assistant Professor of Surgery
Division of Urology, Albany Medical College, Albany, NY
DISCLOSURES: CW has worked as a consultant for Coloplast, and as an investigator for Auxilium
Pharmaceuticals, Mereo BioPharma, PROCEPT BioRobotics, and Repros; and he is a paid reviewer at
Oakstone Publishing and BMJ Best Practice. CW also has a family member who is an employee at Bristol-
Myers Squibb.
// Acknowledgements:
Dr Charles Welliver would like to gratefully acknowledge Matthew Aoun for his help with updating this topic.
He would also like to acknowledge Dr T. Hugh Jones, Dr Milena Braga-Basaria, and Dr Shehzad Basaria,
previous contributors to this monograph. THJ and SB are authors of references cited in this topic. MB
declared that she had no competing interests.
// Peer Reviewers:
Randal J. Urban, MD
Professor
Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX
DISCLOSURES: RJU declares that he has no competing interests.
Niki Karavitaki, MBBS, MSc, PhD

Consultant Endocrinologist
Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
DISCLOSURES: NK declares that she has no competing interests.

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Hypogonadism in men

Straight to the point of care

Last updated: May 01, 2018

Testosterone should be measured in all men with erectile dysfunction.

Secondary hypogonadism is a central disease. Causes include genetic mutations (resulting in

• Primary hypogonadism: dysfunction of the testes resulting in failure of spermatogenesis and/or

• Incomplete sexual development, eunuchoidism, azoospermia

• Decreased energy, motivation, or initiative

Measurement of serum testosterone levels

A number of tests are available for measuring these various components:

• Low testosterone level accompanied by elevated gonadotrophin levels suggests primary

History and exam

loss of spontaneous morning erections (common)

erectile dysfunction (common)

• A fair indicator of testosterone deficiency.

small testes (uncommon)

bifid scrotum (uncommon)

eunuchoid proportions (uncommon)

bitemporal hemianopia (uncommon)

low trauma fractures (uncommon)

loss of height (uncommon)

Other diagnostic factors

delayed puberty (uncommon)

lack of scrotal hyper-pigmentation and rugae (uncommon)

decreased muscle mass and strength (uncommon)

loss of axillary and pubic hair (uncommon)

lack of facial hair (uncommon)

poor concentration and memory (uncommon)

depressed mood (uncommon)

sleep disturbance (uncommon)

hot flushes and sweats (uncommon)

increasing BMI (uncommon)

tall stature (uncommon)

fine wrinkling of facial skin (uncommon)

type 2 diabetes mellitus

use of exogenous sex hormones and GnRH analogues

pituitary tumour or apoplex y

auto-immune testicular damage

Other tests to consider

serum prolactin above 783 picomol/

serum Fe, TIBC, and ferritin elevated ferritin and iron

semen analysis sperm count below 5

Condition Differentiating signs / Differentiating tests

Prolactinoma • Headache, bitemporal • MRI of the pituitary reveals

Hyperprolactinaemia • Galactorrhoea may be • Elevated prolactin levels.

Depression • Depression resulting in • With depression, hormonal

• The first is men in whom hypogonadism is due to a prolactinoma (micro-adenoma or macro-

• Contraindications to testosterone therapy include unmonitored prostate or breast cancer; untreated,

Treatment algorithm overview

1st testosterone therapy

due to prolactinoma 1st dopamine agonist

adjunct testosterone therapy

isolated 1st testosterone therapy

isolated 1st fertility treatment

1st testosterone therapy

» testosterone topical: (gel or solution) apply

» testosterone transdermal: 2.5 to 5 mg/day

» testosterone buccal: 30 mg buccally every

» testosterone nasal: (5.5 mg/dose) 1 dose