Treatment And Monitoring Of Hypogonadism In Men
O R I G I N A L A R T I C L E
Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men
Bruno Lunenfeld1, George Mskhalaya2, Michael Zitzmann3, Stefan Arver4, Svetlana Kalinchenko5, Yuliya Tishova5, and Abraham Morgentaler6
1Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel, 2Department of Andrology, Center for Reproductive Medicine MAMA, Moscow,
Russian Federation, 3
Centre for Reproductive Medicine and Andrology, University Clinics Muenster, Münster, Germany, 4
Centre for Andrology and Treatment And Monitoring Of Hypogonadism In Men
Sexual Medicine, Karolinska University Hospital and Karolinska Institutet Stockholm, Stockholm, Sweden, 5Clinical Endocrinology, Peoples’
Friendship University of Russia, Moscow, Russian Federation, and 6Men’s Health Boston, Harvard Medical School, Boston, MA, USA
Hypogonadism or Testosterone Deficiency (TD) in adult men as defined by low levels of serum testosterone accompanied by characteristic symptoms and/or signs as detailed further on can be found in long-recognized clinical entities such as Klinefelter syndrome, Kallmann syndrome, pituitary or testicular disorders, as well as in men with idiopathic, metabolic or iatrogenic conditions that result in testosterone deficiency. These recommendations do not encompass the full range of pathologies leading to hypogonadism (testosterone deficiency), but instead focus on the clinical spectrum of hypogonadism related to metabolic and idiopathic disorders that contribute to the majority of cases that occur in adult men.
Hypogonadism, late-onset, men, testosterone deficiency, testosterone
Received 25 December 2014 Accepted 26 December 2014 Published online 6 February 2015
The International Society for the Study of the Aging Male
(ISSAM) Hypogonadism panel consists of a multidisciplinary
group of experts, including urologists, endocrinologists,
andrologists and internists with various subspecialties. The
first recommendations were published in 2002 . Due to the
need for ongoing re-evaluation of the information presented in
the recommendations they were revised in 2005 . Clinical
guidelines present the best evidence available to the experts at
the time of writing, but as knowledge increased they were
again updated in 2009 . Since then a great amount of new
information accumulated which encouraged us in 2013 to
prepare a draft proposal for a further update . This proposal
was presented at the VII ISSAM congress in Moscow. A final
form was presented at the ISSAM congress in Almaty,
Kazakhstan, and the final version was accepted by consensus.
It must however be remembered that recommendations can
never replace clinical expertise. Treatment decisions, selec-
tion of treatment protocols or choice of products for
individual patients must take into account patients’ personal
needs and wishes. The multidisciplinary group of experts
received no corporate funding or remuneration for preparing
Hypogonadism or Testosterone Deficiency (TD) in adult
men as defined by low levels of serum testosterone
accompanied by characteristic symptoms and/or signs as
detailed further on can be found in long-recognized clinical
entities such as Klinefelter syndrome, Kallmann syndrome,
pituitary or testicular disorders, as well as in men with
idiopathic, metabolic or iatrogenic conditions that result in
testosterone deficiency. These recommendations do not
encompass the full range of pathologies leading to hypogonad-
ism (testosterone deficiency), but instead focus on the clinical
spectrum of hypogonadism related to metabolic and idiopathic
disorders that contribute to the majority of cases that occur in
adult men. Treatment And Monitoring Of Hypogonadism In Men
Recommendation 1: Definition
Hypogonadism (testosterone deficiency) in adult men is a
clinical and biochemical syndrome associated with low level
of testosterone, which may adversely affect multiple organ
functions and quality of life.
Although the clinical significance of hypogonadism in
adult men is becoming increasingly recognized, the extent of
its prevalence in the general population is underappreciated.
A large number of men with hypogonadism remain undiag-
nosed and untreated .
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
Address for correspondence: Dr George Mskhalaya, Department of Andrology, Center for Reproductive Medicine MAMA, Raskovoy str., 32, Moscow, Russian Federation. E-mail: firstname.lastname@example.org
Recommendation 2: Clinical diagnosis
The diagnosis of hypogonadism requires the presence of
characteristic symptoms and signs (Level 2, Grade A) in
combination with decreased serum concentration of
Symptoms of hypogonadism may be categorized as sexual
and non-sexual. Sexual symptoms include erectile dysfunc-
tion (ED), diminished frequency of morning erections  and
decrease in sexual thoughts (low libido) [7–9], as well as
difficulty in achieving orgasm and reduced intensity of
orgasm. Non-sexual symptoms include fatigue, impotence,
impaired concentration, depression and decreased sense of
vitality and/or wellbeing. Signs of hypogonadism also include
anemia, osteopenia and osteoporosis, abdominal obesity and
the metabolic syndrome .
Principally, the clinician has to distinguish between forms
of congenital hypogonadism that require lifelong substitution
and which can be congenital (e.g. Kallmann syndrome,
Klinefelter syndrome) or acquired (e.g. anorchia due to
trauma or orchiectomy, pituitary lesions/tumors, late-onset
hypogonadism (LOH)) and forms of hypogonadism that
might be reversible. The latter, potentially reversible forms of
hypogonadism are most often found in co-existence with
metabolic disorders such as obesity/type 2 diabetes mellitus
(T2DM), inflammatory diseases (e.g. chronic obstructive
pulmonary disease, chronic inflammatory bowel diseases) or
psychological problems such as depressive mood or stress.
Screening questionnaires on male symptomatic hypo-
gonadism, although sensitive, have low specificity. Morley
et al. compared the most commonly used questionnaires in
148 men using bioavailable testosterone (BT) as the bio-
chemical ‘‘gold standard’’ for the diagnosis of hypogonad-
ism, and found the sensitivity to be 97% for the ADAM
(Androgen Deficiency in the Aging Male questionnaire), 83%
for the AMS (Aging Male’s Symptoms scale) and 60% for the
MMAS (Massachusetts Male Aging Study questionnaire).
Specificity was 30% for the ADAM, 59% for the MMAS and
39% for the AMS  (now validated in many languages
[12,13]). Despite having low specificity, the AMS and other
male hypogonadism questionnaires may be useful to assess
the presence and severity of symptoms as a prerequisite for
initiating  and for monitoring the clinical response to
testosterone therapy [15–18].
Physical examination of patients with suspected hypo-
gonadism should include an assessment of the amount and
distribution of body hair (including beard growth and pubic
hair); presence of acanthosis nigricans, associated with insulin
resistance [19–22], presence and degree of breast enlarge-
ment; size and consistency of the testes; abnormalities in the
scrotum and size, appearance of the penis, presence of
subcutaneous plaque. The prostate should be examined in
older patients for size, consistency, symmetry and presence of
nodules or induration; it should be noted that the prostate may
be enlarged in older men, despite a low testosterone level
. Weight, height, body mass index (BMI) and waist
circumference should also be measured, since symptoms and
signs potentially indicative of testosterone deficiency in men
include height loss, reduced muscle bulk and strength and
increased body fat, in particular, abdominal fat accumulation
and BMI [24,25]. The greater the number of symptoms in a
man, the greater the probability that he truly has testosterone
deficiency . However, the presence of even one symptom
may raise suspicion of symptomatic hypogonadism. A high
prevalence of symptomatic hypogonadism has been observed
in populations of aging men, and those with diabetes mellitus
type 2, obesity , benign prostatic hyperplasia (BPH) and
lower urinary tract symptoms (LUTS) [28,29]. Treatment And Monitoring Of Hypogonadism In Men
The presence of symptoms alone does not constitute
testosterone deficiency. Symptoms must be accompanied by
decreased serum concentrations of total testosterone (TT) or
free T level to support a diagnosis of symptomatic hypo-
gonadism (Level 2, Grade A).
Various prospective studies have reported the occurrence
of hypogonadal symptoms as side effects of androgen-
deprivation therapy, including hot flashes, decreased libido
and ED [30,31]. Other complications of androgen-deprivation
therapy include osteoporosis, with increased risk of fractures,
and worsening of comorbidities such as diabetes mellitus,
cardiovascular disease and metabolic syndrome, as well as
physical, functional and cognitive impairment [32–35].
Based on the above and below mentioned data, we
recommend the investigation of hypogonadism in men with
the following conditions:
� Low libido � Poor morning erections � Erectile dysfunction � Depressed mood � Fatigue � Decreased vitality � Cognitive impairment � Insulin resistance � Obesity, abdominal obesity � Metabolic syndrome � Arterial hypertension � Diabetes mellitus type 2 � Decreased muscle mass and strength � Decreased bone mineral density and osteoporosis � Use of glucocorticoids, opioids, antipsychotics
Recommendation 3: Pathogenesis
The metabolic disorders such as obesity, T2DM, inflamma-
tory diseases and other co-morbidities mentioned above
modify the hypothalamic–pituitary–gonadal axis by suppress-
ing one or more of its components (decreased hypothalamic–
pituitary/decreased Leydig cell function) but not in a constant
fashion as in the permanent forms of hypogonadism where
one of the components has irrevocably lost function.
Age-related decrease in testosterone production (also
called Late-onset hypogonadism) is also related to an
impairment of hypothalamic–pituitary–gonadal axis ,
but in contrast may not be reversible.
Current opinion is that hypogonadism and the respective
co-morbidity reinforce each other and that a (potentially
transient) testosterone replacement therapy (TRT) can miti-
gate this vicious cycle.
Risk factors for hypogonadism may include chronic
illnesses, including T2DM, impaired thyroid gland function,
hyperprolactinemia, chronic obstructive lung disease,
6 B. Lunenfeld et al. Aging Male, 2015; 18(1): 5–15
rheumatoid arthritis, renal and HIV-related diseases, obesity,
metabolic syndrome , stress and hemachromatosis, vita-
min D deficiency [38–40]. Such chronic diseases should be
investigated and treated (Level 2, Grade A).
Though there is still a controversy in defining normal TSH
levels in the elderly [41–44], thyroid gland function impair-
ment should be excluded in all patients with hypogonadism,
as symptoms of hypothyroidism may overlap those of
TT levels have been reported to be lower in depressed men
compared with non-depressed men. TT is particularly low in
men with severe, treatment-resistant depression . TRT has
been shown to reduce depression symptoms in hypogonadal
men, including middle-aged men with hypogonadism and
those using antidepressants .
Drugs such as glucocorticoids, opioids, antipsychotics
induce TD [47–49]. Glucocorticoids are widely used as
anti-inflammatory drugs. However, prolonged use of gluco-
corticoids results in undesirable side effects, including
hypogonadism . It has also been reported that statins
may reduce TT .
Aloisi and colleagues  were the first to show that
morphine induces a dramatic and long-lasting decrease in
TT. This finding has now been corroborated by numerous
subsequent studies .
Recommendation 4: Laboratory diagnosis
In patients at risk or suspected of hypogonadism, a thorough
physical and biochemical work-up is recommended (Level 2,
The key laboratory tests to confirm the diagnosis of
hypogonadism are serum total and free testosterone. Note
should be made that transient decreases of serum T levels can
occur, due to acute illnesses , and this should be excluded
by careful clinical evaluation and repeated hormone
We recommend 12.1 nmol/L as a lower limit of normal for
TT level. However, due to individual differences in testoster-
one sensitivity some men may exhibit symptoms of hypo-
gonadism with TT concentrations above this threshold, and
may benefit from TRT. TRT may be reasonably offered to
symptomatic men with testosterone concentrations higher
than 12 nmol/L based on clinical judgment, and certainly if
free T concentrations are reduced.
Free T levels as low as 225 pmol/L (65 pg/mL)  or
243 pmol/L (70 pg/mL)  have been recommended as a
lower limit of normal range and together with the presence of
one or more hypogonadal symptoms can provide supportive
evidence for TRT (Level 2, Grade B). Others have proposed a
more generous threshold of 347 pmol/L (100 pg/mL or
10.0 ng/dL) as a lower threshold for free T level based on
clinical experience [55,56].
It is preferred to obtain a serum sample for TT determination
between 07.00 and 11.00 h  (Level 2a, Grade A), although
diurnal variation is substantially blunted in older men. In a
cross-sectional study of 3006 men with the mean age 60.3 years
presenting for prostate cancer screening, serum testosterone
concentrations were unchanged from 6 am to 2 pm, and then
decreased by only 13% between 2 pm and 6 pm .
It is our clinical impression that testosterone circadian
rhythms may be blunted in symptomatic hypogonadal men
regardless of age.
New data indicate that a glycaemic load may acutely
decrease testosterone . The clinical implications of this
observation have not been tested adequately to currently
recommend that blood testing for testosterone be performed
in a fasting state. Although this would make it possible to
permit to measure glucose and lipids at the same time and
help to discover co-morbidities.
The most widely accepted parameter to establish the
presence of hypogonadism is the measurement of TT.
Unfortunately, no consensus has been reached regarding the
lower TT threshold defining TD, and there are no generally
accepted lower limits of normal TT . This lack of
consensus follows from the fact that no studies have shown a
clear threshold for TT or free T that distinguishes men who
will respond to treatment from those who will not. In a recent
publication in NEJM the EMAS Group proposed 11 nmol/L
as a lower cut-off value for TT . Hypogonadism may be
considered if TT level is below 12.1 nmol/L based on LCMS/
MS (liquid chromatography–mass spectrometry) measure-
ments in three large cohorts comprising more than 10 000
men of various ages .
Meanwhile the number of CAG (cytosine–adenine–guan-
ine triplet) repeats in androgen receptor differs in men and
influences the androgen receptor activity [61–64] (Figure 1).
Hence testosterone sensitivity may vary in different individ-
uals. It has also been argued that the magnitude of the
decrease in serum T concentrations might be a better
predictor of hypogonadism than the actual concentrations of
TT and BT .
The same applies to androgen receptor gene CAG repeat
lengths 424 in the presence of symptoms and normal testosterone levels may be considered as a state of preclinical
The prevalence of hypogonadal symptoms increases with
TT levels below 12.1 nmol/L (350 ng/dL)  (Level 2b,
Grade A). However, Zitzmann et al. have shown that
testosterone deficiency symptoms may also be seen with TT
levels as high as 15 nmol/L. This study showed that the
prevalence of loss of libido or vigor increased at testosterone
concentrations below 15 nmol/L (p50.001), whereas depres- sion and T2DM (also in non-obese men) were significantly
more prevalent in men with TT concentrations below
10 nmol/L (p50.001). ED has been identified as a composite pathology of metabolic risk factors, smoking and depression,
whereas only TT concentrations below 8 nmol/L contributed
to that symptom (p¼0.003). Behre et al.  demonstrated that 6 months of TRT improved body composition and quality
of life in men aged 50–80 years with TT515 nmol/L and hypogonadal symptoms; these men showed further improve-
ments in body composition and quality of life over the
following 12 months of TRT. Lower TT levels have also been
shown to be associated with sub-threshold symptoms of
anxiety and depression . There is also a recent study
reporting increased hypogonadal symptoms in younger
men�40 years with TT below 400 ng/dL (13.9 nmol/L) . Free or bioavailable T should be considered when the
TT concentration does not correspond with clinical
DOI: 10.3109/13685538.2015.1004049 Hypogonadism in men 7
presentation, since individual variation in SHBG concen-
trations may influence total testosterone results. Free
or bioavailable T should also be particularly considered
in obese men. Equilibrium dialysis is the gold standard for
free T measurement but may not be routinely available
or may be too costly in some regions. Free T assays based
on analog displacement immunoassays are widely available
and have been used clinically with good success ,
but their reliability has been questioned by some authors
. Alternatively, measurement of serum SHBG together
with a reliable measurement of TT allows for the
determination of the calculated free T level  (Level
2b, Grade A).
Measurements of serum LH will assist in differentiating
between primary and secondary hypogonadism. All cases of
elevated LH level and testosterone below normal or in the
lower quartile range would indicate testicular failure and TRT
should be considered . A state of elevated LH in the
presence of normal testosterone but with hypogonadal
symptoms should be considered as hypogonadism.
Measurement of serum prolactin level is indicated when TT
is 55.2 nmol/L (150 ng/dL) [72,73] or when secondary
hypogonadism due to a pituitary tumor (like prolactinoma)
is suspected [24,74,75] (Level 2, Grade A).
In general, it is currently speculated that variable pheno-
types of androgen insensitivity exist, mainly owing to mutated
androgen receptors. A more subtle modulation of androgen
effects is related to the CAG repeat polymorphism (CAGn) in
exon 1 of the androgen receptor gene: transcription of
androgen-dependent target genes is attenuated with increasing
length of triplets. As a clinical entity, the CAG repeat
polymorphism can relate to variations of androgenicity in men
in various tissues and psychological traits: the longer the
CAGn, the less prominent is the androgen effect when
individuals with similar testosterone concentrations are
compared. A strictly defined threshold to hypogonadism is
likely to be replaced by a continuum spanned by genetics as
well as symptom specificity. In addition, effects of externally
applied testosterone can be markedly influenced by the CAGn
and respective pharmacogenetic implications are likely to
influence indications as well as modalities of testosterone
treatment of hypogonadal men.
The other recommended laboratory parameters should
include: LH, TSH, SHBG, prolactin and vitamin D.
Figure 1. Threshold continuum to hypogonadism.
8 B. Lunenfeld et al. Aging Male, 2015; 18(1): 5–15
Recommendation 5: Assessment of treatment outcome and decisions on continued therapy
Improvement in hypogonadal signs and symptoms occur at
different times for different organ systems .
Reduction in fat mass and increased lean body mass and
muscle strength occur within 12–16 weeks of starting TRT
and stabilize at 6–12 months, but can continue to improve
Significant improvement in libido is usually experienced
within 3–6 weeks of commencing TRT. Up to 12 months of
TRT may be required before significant improvement in
erectile and ejaculatory function is observed . Significant
improvement in quality of life (QoL) usually occurs within
3–4 weeks of starting TRT; longer-term TRT is required to
achieve maximum QoL benefit. Effects on depressive mood
become detectable after 3–6 weeks of starting TRT, with
maximum improvement occurring after 18–30 weeks.
Improvements in bone are detectable after 6 months of
TRT, while the full beneficial effect of TRT on bone mineral
density may take 2–3 years [78,79] or even 6 years as
suggested by Haider et al. .
Effects of TRT on lipids appear after 4 weeks, with
maximal effects being seen after 6–12 months of treatment.
Insulin sensitivity may improve within a few days of starting
TRT, but effects on glycaemic control become evident only
after 3–12 months. Failure to improve clinical symptoms
within a reasonable period of time should result in re-
evaluation of TRT with regard to dosage, compliance and
level of serum T achieved. Further investigation should be
undertaken to determine other causes of the symptoms (Level
1b, Grade A).
Recommendation 6: Body composition and mobility
In hypogonadal men, TRT improves body composition
(decrease of fat mass, increase of lean body mass). Meta-
analyses of randomized trials in middle-aged and older men
have demonstrated the beneficial effects of TRT in reducing
fat mass [81,82] (Level 1a, Grade A) with a significant
increase in lean body mass and grip strength.
Rodrıguez-Tolra et al. demonstrated clearly that TRT in
men with TD decreased fat mass overall, and to the greatest
extent in the android and gynecoid regions and caused
improvements in body composition, increasing lean mass,
primarily in arms and legs .
TRT is potentially an effective treatment in aging obese
men with TD . There is also some evidence that long-term
T may result in substantial and sustained reductions in body
weight, waist circumference and BMI in obese hypogonadal
men [84–86]. The successful achievement of weight loss, as
well as the consistent increase in lean mass lead to beneficial
effects on diabetes mellitus type 2 .
Higher free testosterone concentration is positively asso-
ciated with lower risk of developing mobility limitation and
progression of mobility limitations .
Recommendation 7: Bone density and fracture rate
Osteopenia, osteoporosis and fracture prevalence rates are
increased in younger and older hypogonadal men . In a
recent meta-analysis and in the FRAX algorithm hypogonad-
ism was identified as a known disorder strongly associated
with secondary osteoporosis [90,91]. According to the latest
Endocrine Society’s guidelines on osteoporosis total testos-
terone measurement is suggested in all men evaluated for
osteoporosis or considered for pharmacological treatment
with bone-active agents .
Bone density in hypogonadal men of all ages is increased
with TRT (Level 1b, Grade A).
In older men low testosterone levels are associated with
increased risk of falls . TRT has beneficial effects on
muscle mass and strength that may reduce propensity to fall
and therefore decrease fracture risk. Physical exercise,
including stretching and equilibrium exercises are mandatory
in combination with TRT.
Assessment of bone density at 2-year intervals is recom-
mended in aging, hypogonadal men with normal bone density.
In men with lowered bone mineral density receiving TRT,
stabilization or progress may be monitored with annual DXA.
This should be performed using DXA as a gold standard
method providing the largest amount of reliable data. It is
possible to use quantitative computer tomography (qCT) but
this is exposing patients to a high amount of radiation.
For clinical follow-up, methods of ultrasound measuring
bone density reflect the changes achieved by testosterone
substitution and may be used if other methods are not
available  Treatment And Monitoring Of Hypogonadism In Men
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