GUIDELINES ON

MALE HYPOGONADISM

G.R. Dohle (chair), S. Arver, C. Bettocchi, S. Kliesch, M. Punab,

W. de Ronde

Introduction
Male hypogonadism is a clinical syndrome caused by andro-
gen deficiency. It may adversely affect multiple organ func-
tions and quality of life. Androgens play a crucial role in the
development and maintenance of male reproductive and
sexual functions. Low levels of circulating androgens can
cause disturbances in male sexual development, resulting
in congenital abnormalities of the male reproductive tract.
Later in life, this may cause reduced fertility, sexual dysfunc-
tion, decreased muscle formation and bone mineralisation,
disturbances of fat metabolism, and cognitive dysfunction.
Testosterone levels decrease as a process of ageing: signs
and symptoms caused by this decline can be considered a
normal part of ageing. However, low testosterone levels are
also associated with several chronic diseases, and sympto-
matic patients may benefit from testosterone treatment.

Androgen deficiency increases with age; an annual decline

in circulating testosterone of 0.4-2.0% has been reported.
In middle-aged men, the incidence was found to be 6%. It is
more prevalent in older men, in men with obesity, those with
co-morbidities, and in men with a poor health status.

Aetiology and forms

Male hypogonadism can be classified in 4 forms:
1. Primary forms caused by testicular insufficiency.
2. Secondary forms caused by hypothalamic-pituitary
dysfunction.

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3. Late onset hypogonadism.
4. Male hypogonadism due to androgen receptor
insensitivity.
The main causes of these different forms of hypogonadism
are highlighted in Table 1.

The type of hypogonadism has to be differentiated, as this has

implications for patient evaluation and treatment and enables
identification of patients with associated health
problems.

Table 1: Different forms of male hypogonadism and main

causes
Primary forms Main causes
(testicular insufficiency)
Congenital forms Klinefelter syndrome
Testicular dysgenesis
(cryptorchidism)
Congenital anorchia
Acquired forms Testicular malignancy
Orchitis
Medications (chemotherapy)
Systemic diseases
Acquired anorchia
Secondary forms Main causes
(hypothalamic-pituitary
dysfunctions)
Congenital forms Kallmann syndrome
Idiopathic
hypogonadotrophic
hypogonadism (IHH)

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 Acquired forms Pituitary tumour
(prolactinoma)
Drugs
Systemic disease (renal
failure, haemochromatosis,
hypothyroidism, trauma,
infections)
Abuse of anabolic steroids
Morbid obesity
Radiotherapy
Late onset hypogonadism Ageing
(Combined testicular and Obesity
hypothalamic pituitary Chronic diseases
insufficiency) Poor health status
Androgen receptor Partial androgen insensitivity
insensitivity syndrome (PAIS)

Diagnosis
The diagnosis of male hypogonadism is based on clinical
symptoms and signs of androgen deficiency (Tables 2 and 3),
together with consistently low serum testosterone levels.

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Table 2: Signs and symptoms suggesting prepubertal-onset
hypogonadism
Small testes
Cryptorchidism
Gynaecomastia
High voice
Unclosed epiphyses
Linear growth into adulthood
Eunuchoid habitus
Sparse body/facial hair
Infertility
Low bone mass
Sarcopenia
Reduced sexual desire/activity

Table 3: Signs and symptoms associated with late-onset

hypogonadism
Loss of libido
Erectile dysfunction
Sarcopenia
Low bone mass
Depressive thoughts
Changes in mood, fatigue and anger
Sleep disturbances
Loss of body hair
Hot flushes
Loss of vigour
Insulin resistance
Metabolic syndrome
Visceral obesity
Gynaecomastia

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 Diminished cognitive functions

Routine screening for testosterone deficiency is not indi-

cated. However, testosterone assessment should be done in
men with:
• Pituitary mass, following radiation involving the sellar
region and other diseases in the hypothalamic and sellar
region.
• End-stage renal disease receiving haemodialysis.
• Treatment with medications that cause suppression of
testosterone levels e.g. corticosteroids and opiates;
• Moderate to severe chronic obstructive lung disease;
• Infertility.
• Osteoporosis or low-trauma fractures.
• Human immunodeficiency virus (HIV) infection with sarco-
penia.
• Type 2 diabetes.

Acquired hypogonadotropic hypogonadism (secondary forms)

can be caused by some drugs, hormones, anabolic steroids
and by tumours of the pituitary gland. Imaging (CT or MRI)
of the sellar region and complete endocrine work-up is
requested when a pituitary tumour is suspected.

Recommendations for screening GR

Screening for testosterone deficiency is only recom- C
mended in adult men with consistent and preferably
multiple signs and symptoms, listed in Tables 2 and 3.
Adult men with established severe hypogonadism B
should be screened for concomitant osteoporosis.
Total testosterone assessment should be repeated at A
least on two occasions with a reliable method.

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- In men with total testosterone levels close to the
lower normal range (8-12 nmol/l), the free testoste-
rone level should be measured to strengthen the
laboratory assessment.
- In men with suspected or known abnormal sex
hormone-binding globulin (SHBG) levels, free
testosterone should also be included.

Treatment
The aim of treatment is to restore testosterone levels to the
physiological range and thereby improve the patient’s quality
of life. Indications and contraindications are listed in Tables 4
and 5.

Table 4: Indications for testosterone treatment

Adult men with consistent and preferably multiple signs and
symptoms of hypogonadism (listed in Tables 2 and 3) and
low testosterone
Delayed puberty (idiopathic, Kallmann syndrome)
Klinefelter syndrome with hypogonadism
Sexual dysfunction and low testosterone
Low muscle strength and bone mass in hypogonadism
Hypopituitarism
Testicular insufficiency and symptomatic hypogonadism

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 Table 5: Contraindications against testosterone treatment
Prostate cancer
Prostate-specific antigen (PSA) > 4 ng/mL
Male breast cancer
Severe sleep apnoea
Male infertility
Haematocrit > 50%
Severe lower urinary tract symptoms due to benign
prostatic enlargement

Choice of treatment
Testosterone replacement therapy (TRT) is safe and effective
and the agents are available as oral preparations, intramuscu-
lar injections, and transdermal gel or patches (Table 6).

Table 6: Testosterone preparations for replacement

therapy
Formulation Administration Advantages Dis-
advantages
Testosterone Oral; 2-6 cps Absorbed Variable
undecanoate every 6 h through the levels of
lymphatic testosterone
system, with above and
consequent below the
reduction of mid-range.
liver involve- Need for
ment several doses
per day with
intake of
fatty food

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Testosterone Intramuscular; Short-acting Possible
cypionate one injection preparation fluctuation of
every 2-3 weeks that allows testosterone
drug with- levels
drawal in
case of onset
of side effects
Testosterone Intramuscular; Short-acting Possible
enanthate one injection preparation fluctuation of
every 2-3 weeks that allows testosterone
drug with- levels
drawal in
case of onset
of side effects
Testosterone Intramuscular; Steady-state Long-acting
undecanoate one injection testosterone preparation
every 10-14 levels without that cannot
weeks fluctuation allow drug
withdrawal
in case of
onset of side
effects
Transdermal Gel or skin Steady-state Skin irritation
testosterone patches; daily testosterone at the site of
application level without application
fluctuation and risk of
interpersonal
transfer

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 Sublingual Sublingual; daily Rapid absorp- Local irrita-
testosterone doses tion and tion
achievement
of physiologi-
cal serum
level of testo-
sterone
Buccal Buccal tablet; Rapid absorp- Irritation and
testosterone two doses per tion and pain at the
day achievement site of appli-
of physiologi- cation
cal serum
level of testo-
sterone
Subdermal Subdermal Long duration Risk of infec-
depots implant every 5-7 and constant tion and
months serum testo- extrusion of
sterone level the implants

In patients with secondary hypogonadism, anti-oestrogens

or hormonal stimulation with hCG and FSH or alternatively
GnRH can restore testosterone production.

Recommendations GR
The patient should be fully informed about expected A
benefits and side effects of each treatment option. The
selection of the preparation should be a joint decision
by an informed patient and the physician.
Short-acting preparations may initially be preferred to B
long-acting depot administration when starting treat-
ment. Patients can switch to a long-acting depot if
preferred and side effects are absent or minimal.

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Human chorionic gonadotrophin (hCG) treatment can B
only be recommended for hypogonadal patients who
are receiving simultaneous fertility treatment.

Risk factors in testosterone treatment

• C ase reports and small cohort studies point to a possible
correlation between TRT and the onset of breast cancer,
but there is as yet a lack of strong evidence for this rela-
tionship.
• Randomised controlled trials support the hypothesis that
TRT does not result in changes in prostatic histology.
However, there are not yet data available that show long-
term prostatic safety of TRT.
• Testosterone therapy is not related to the development
of de novo cardiovascular events. However, patients with
severe cardiovascular diseases should be screened first by
a cardiologist before TRT is initiated.

Recommendations for initiation of treatment GR

Haematological, cardiovascular, breast and prostatic A
assessment should be performed before the start of
treatment.
Men with severe cardiovascular co-morbidity should C
be assessed by a cardiologist before TRT is initiated
and there should be close cardiovascular monitoring
during TRT.
Prostate health should be assessed by digital rectal A
examination (DRE) and PSA before the start of TRT.
In patients treated for localised prostate cancer C
and without signs of prostate cancer recurrence,
testosterone therapy should not start before at least 1
year of follow-up.

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 Recommendations for monitoring GR
The response to treatment (symptoms and C
testosterone serum levels) should be assessed 3, 6 and
12 months after the onset of treatment, and thereafter
annually.
In men with an abnormal bone mineral density (BMD), C
BMD measurements should be repeated 6 and 12
months after the start of TRT and thereafter annually.
Haematocrit should be monitored at 3, 6 and 12 C
months and thereafter annually. The testosterone
dosage should be decreased, or therapy discontinued
if the haematocrit increases above normal levels.
Prostate health should be monitored by PSA testing at C
3, 6 and 12 months and thereafter annually.
Routine screening of potential cardiovascular side A
effects is not indicated in men receiving TRT.

This short booklet text is based on the more comprehensive EAU

guidelines (978-90-79754-83-0), available to all members of the
European Association of Urology at their website,
http://www.uroweb.org.

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