Measurements of serum LH will assist in differentiating

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Aging Male, 2015; 18(1): 5–15 ! 2015 The Author(s). Published by Taylor & Francis. DOI: 10.3109/13685538.2015.1004049

ORIGINAL ARTICLE

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, 3Centre for Reproductive Medicine and Andrology, University Clinics Muenster, Münster, Germany, 4Centre for Andrology and

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

Abstract

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.

Keywords

Hypogonadism, late-onset, men, testosterone deficiency, testosterone

History

Received 25 December 2014 Accepted 26 December 2014 Published online 6 February 2015

Introduction

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 [1]. Due to the

need for ongoing re-evaluation of the information presented in

the recommendations they were revised in 2005 [2]. 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 [3]. Since then a great amount of new

information accumulated which encouraged us in 2013 to

prepare a draft proposal for a further update [4]. 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

these recommendations.

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.

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 [5].

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: mskhalaya@mail.ru

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

testosterone.

Symptoms of hypogonadism may be categorized as sexual

and non-sexual. Sexual symptoms include erectile dysfunc-

tion (ED), diminished frequency of morning erections [6] 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 [10].

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 [11] (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 [14] 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

[23]. 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 [26]. 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 [27], benign prostatic hyperplasia (BPH) and

lower urinary tract symptoms (LUTS) [28,29].

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 [36],

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 [37], 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

hypogonadism.

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 [45]. TRT has

been shown to reduce depression symptoms in hypogonadal

men, including middle-aged men with hypogonadism and

those using antidepressants [46].

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 [49]. It has also been reported that statins

may reduce TT [50].

Aloisi and colleagues [51] 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 [52].

Recommendation 4: Laboratory diagnosis

In patients at risk or suspected of hypogonadism, a thorough

physical and biochemical work-up is recommended (Level 2,

Grade A).

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 [53], and this should be excluded

by careful clinical evaluation and repeated hormone

measurement.

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) [54] or

243 pmol/L (70 pg/mL) [10] 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 [57] (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 [58].

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 [59]. 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 [60]. 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 [6]. 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 [60].

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 [65].

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

hypogonadism [66].

The prevalence of hypogonadal symptoms increases with

TT levels below 12.1 nmol/L (350 ng/dL) [26] (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 (p¼ 0.003). Behre et al. [14] 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 [67]. 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) [68]. 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 [69],

but their reliability has been questioned by some authors

[56]. Alternatively, measurement of serum SHBG together

with a reliable measurement of TT allows for the

determination of the calculated free T level [70] (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 [71]. A state of elevated LH in the