European Geriatric Medicine 3 (2012) 368373

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Hot topic in geriatric medicine

Andropause: A review of the denition and treatment

N. Samaras a,*, E. Frangos b, A. Forster a, P.-O. Lang c,d, D. Samaras e
a
Department of Internal Medicine, Rehabilitation and Geriatrics, Geneva University Hospitals, Chemin du Pont-Bochet 3, 1226 Thonex, Switzerland
b
Clinique de Jolimont, avenue Trembley 45, 1211 Geneva, Switzerland
c
Nescens Centre of preventive medicine, Clinic of Genolier, Genolier, Switzerland
d
Translational Medicine Research group, Craneld health, Craneld University, Craneld, United Kingdom
e
Department of medical specialties, unity of Clinical Nutrition, Geneva University Hospitals, rue Gabriel Perret-Gentil 4, 1211, Geneva, Switzerland

A R T I C L E I N F O A B S T R A C T

Article history: Testosterone levels decrease with age is well documented. It is related to abnormalities in the
Received 3 June 2012 hypothalamicpituitarytesticular axis, an age-related decline of Leydig cells mass and function, but also
Accepted 16 August 2012 to lifestyle factors such as obesity, physical activity, smoking and alcohol. Despite the relation between
Available online 14 September 2012
low testosterone and several age-related disorders it is rarely looked for in older individuals. In this
article, we review data on the denition and treatment modalities of andropause. We also look into the
Keywords: potential relation between testosterone replacement therapy and complications such as polycythemia,
Andropause
cardiovascular and prostate cancer. We nally present protocols of pretreatment evaluation and follow-
Treatment
up and argue the benets and risks of testosterone treatment in this age group.
Hormones
Elderly 2012 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.

1. Introduction disorders and anemia, making it important to recognize on a

Testosterone (T) is the major circulating androgen in men [1].
Other circulating androgens are androstenedione, dihydrotestos-
terone (DHT) (which is the most biologically active) and DHTs
metabolite androstanediol glucoronide, which is the marker for 5a
reductase activity [2]. T is mostly bound to sexual hormone
binding globulin (SHBG) (44%) (a steroid transporting protein
produced by the liver), albumin (50%) and cortisol-binding
globulin (4%). Two percent of total T (TT) is unbound or free
[1,3]. Albumins afnity for T is a 1000 times lower than SHBG and
albumin-bound T may easily disassociate and be available for
tissue uptake. Consequently, free testosterone (FT) and albumin-
bound T are also referred to as bioavailable T (BT) [4].
T levels decrease with age is now well documented [58]. Male
hypogonadism, or andropause, diagnosis requires the presence of
both clinical symptoms and low serum T levels [911]. Diagnosis in
geriatric populations is rather challenging since symptoms are
unspecic. The benet of testosterone replacement treatment
(TRT) in this age group is not yet clear and actual data do not
support a widespread screening policy [12]. Nevertheless, low T
has been related to various age-related diseases such as
sarcopenia, low bone mineral density, mood and cognitive
case-by-case basis [2,5,10,1317].
The aim of this article is to review recent data on late-onset
male hypogonadism pathophysiology, revisit its denition and
argue the benets and risks of TRT in elderly patients.
2. Epidemiology
The age-related TT decrease rate [18] is approximately 0.4 to 1%
per year [6,19,20] resulting to a 20 to 30% decrease from the age of
20 to the age of 80 [7]. Consequently, over 60 years around 20% of
healthy men have TT serum levels below the reference range for
young males (320 ng/dl or 11 nmol/liter) [7,12]. In a group of males
between 40 and 79 years, 17% had a TT level of less than 11 nmol/l
(320 ng/dl). The prevalence of late-onset hypogonadism dened by
TT serum levels below 11 nmol/l (320 ng/dl), FT below 220 pmol/l
(640 pg/dl) and three sexual symptoms, was of 2.1%. Prevalence
increased with age (0.1%, 0.6%, 3.2% and 5.1% for patients 40 to 49,
50 to 59, 60 to 69 and 70 to 79 years old respectively) [21].
3. Pathophysiology: age and lifestyle
3.1. Age

The highest concentrations for TT and FT are encountered

* Corresponding author. Tel.: +41 79 55 38 30 9; fax: +41 22 30 56 11 5.
E-mail addresses: nikolassamaras@hotmail.com (N. Samaras),
Emilia.Frangos@hcuge.ch (E. Frangos), alexandre.forster@hcuge.ch (A. Forster),
polang@nescens.com (P.-O. Lang), Dimitrios.Samaras@hcuge.ch (D. Samaras).
during the third decade of life [8]. SHBG, follicle stimulating
hormone (FSH) and luteinizing hormone (LH) levels tend to
increase with age, whereas FT, BT and TT decrease [57]. Lower TT
and higher LH levels suggest a decrease of Leydig cell mass or a

1878-7649/$ see front matter 2012 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
http://dx.doi.org/10.1016/j.eurger.2012.08.007
 N. Samaras et al. / European Geriatric Medicine 3 (2012) 368373
decreased capacity to produce T, as well as a decreased sensitivity
to LH [5,22]. Age-related FSH increase is even steeper and
independently related with further androgen decline (high FSH
levels have been related with low testicular volume) [7].
Consequently, a primary testicular defect seems most plausible
in andropause pathogenesis [7].
Age-related decrease of FT and BT is however steeper [6,23]. BT
decreases two times faster than TT [14] (4050% reduction
between age 40 and 70 [24]). Another study showed a 2% FT
decline in geometric mean concentration every 1.3 years compared
to 2.4 years for TT, which resulted to 25% and 30.2% of men over 70
years having low TT and FT respectively [8]. Indeed, lower TT levels
cause an increase of SHBG, which provokes a further decrease in BT
and FT [22].
3.2. Lifestyle
T levels are related to several lifestyle factors. Body mass index
(BMI) is inversely related to TT, BT, FT and SHBG [2,7,25]. This inverse
relationship between SHBG and BMI is probably due to inhibition of
SHBG hepatic synthesis by hyperinsulinemia [2]. SHBG reduction
secondarily induces a down-regulation of T synthesis in order to
maintain normal levels of FT. Lower T levels may also be related to
higher conversion to estrogen by aromatase in adipose tissue [2,25].
Higher estrogen also inhibits LH production and intratesticular
steroidogenesis through 17-a-hydroxylase and 17,20 lyase inhibi-
tion, further decreasing T levels [25].
Studies suggest a nonlinear relation between physical activity
and T. In fact, high physical activity is related to higher T and
extreme vigorous activity to lower T. No association was found
between T and moderate physical activity [26]. Alterations in the
hypothalamic-pituitary-gonadal axis caused by extreme activity
seem as the most plausible explanation [26].
Smoking is related to higher TT, BT [5] and FT levels [26],
probably through tobacco induced acute increases of LH [5]. Lower
body fat in smokers could also explain the positive relation
between smoking and SHBG [5]. On the other hand, a nonlinear
relation has been described between alcohol consumption and T.
Moderate alcohol consumption (up to 6 drinks/week) has been
related with an increase of TT and FT [26], contrarily to higher
alcohol consumption where a decrease in androgen levels is
observed, possibly secondary to Leydig cells damage or hypotha-
lamic-pituitary-gonadal axis impairment [27].
4. Clinical presentation and diagnostic criteria
4.1. Clinical presentation
Recent data challenge the perception of the asexual older
person. In a group of men aged between 75 and 95 years, 48.8%
declared sex to be important, 30.8% had at least one sexual
encounter during the past 12 months, of which 56.5% were
satised with the frequency of the activity [28]. On the other hand,
sexual disorders are highly prevalent in older patients, affecting up
to 72% of individuals between 75 and 95 years of age [28]. Sexual
symptoms such as diminished erectile quality (particularly
nocturnal erections), decreased libido, higher difculty for
achieving orgasms and reduced penis sensation, are also the most
usual presenting complaints in patients with low T [10,29]. Such
symptoms often appear below a threshold of 11 to 15 nmol/l
(320 ng/dl430 ng/dl) for TT [21,28] and 220 pmol/l (640 pg/dl) for
FT [21]. Nevertheless, particularly erectile dysfunction is more
frequently of non-hormonal etiology in older patients, low T
accounting approximately for 6 to 45% of cases depending on the
study [22]. Moreover, sexual symptoms improved by TRT in
hypogonadal men concern to a lesser extent erectile dysfunction
369
[30,31], even if androgens are known to improve structural and
functional components of penile erections [32]. Night sweats and
vasomotor disturbances may also occur occasionally [22].
Several age-related diseases have also been associated with low
plasma T, such as heart disease, metabolic syndrome and type
2 diabetes, osteoporosis and low trauma fractures, sarcopenia,
obesity, body hair and skin alterations, mood and cognition
disorders and anemia [2,5,10,1315,17].
4.2. Diagnostic criteria
Andropause diagnosis requires the presence of both clinical
symptoms and biochemical abnormalities [911]. Depending on
the study, the cut-off of serum TT for hypogonadism diagnosis
varies from 200 ng/dl to 300 ng/dl [9,30,33]. Wu FC et al. dened
hypogonadism as TT serum levels below 11 nmol/l (320 ng/dl), a FT
below 220 pmol/l(640 pg/dl) and three sexual symptoms [21].
Diagnosing andropause in geriatric patients is challenging.
Most symptoms related to low T levels are rather unspecic in this
age group. Moreover, TT levels interpretation is harder because of
the aforementioned inuence of lifestyle factors, as well as chronic
conditions more frequently encountered in older patients [34]. FT
measures are not considered as more reliable in elderly patients
whereas BT measures are more expensive and not widely available
[9]. Measuring FT is particularly recommended either when TT
levels are close to the lower limit of normal values, or in situations
where SHBG alterations are suspected (obesity, nephritic syn-
drome, hepatic cirrhosis, hepatitis, acromegaly, diabetes mellitus,
hypo- and hyperthyroidism, HIV, use of various drugs such as
glucocorticoides, progestins, androgenic steroids, estrogens, antic-
onvulsivants, etc.) [12]. Finally, for mildly decreased TT levels it is
recommended to repeat the measurement since in 30% of cases
they are nally normal [12].
Several tools have been developed for andropause diagnosis
such as the Saint Louis University Androgen Deciency in the Aging
Male (ADAM) questionnaire [35] (Appendix 1) and the Aging Male
Symptom (AMS) rating [36,37] (Appendix 2). Although sensitivity
was quite satisfying for both the ADAM and the AMS (88% and 96%
respectively) specicity was low (60% and 30% respectively) [35
37]. In fact, most of the symptoms on both tools may be due to
other age-related conditions such as depression, cognitive
disorders, heart disease etc. When both questionnaires were
studied more specically in geriatric populations, scores were
related to age but not to T levels [38]. Another study found a
correlation between T levels and only certain items of the ADAM
questionnaire [39]. Consequently, these instruments could be used
in order to help screening but not diagnosis of andropause in
elderly men.
5. Treatment
It has been estimated that two to four million men suffer from
hypogonadism in the United States, but only 5% receive appropri-
ate treatment [40]. Even though concerns for TRT safety are
common amongst physicians, serious adverse effects are rarely
observed if actual guidelines are followed and serum controls do
not exceed physiologic ranges [10]. Patients should undergo a
rather strict pretreatment control including [9]:
 a detailed medical history for sleep apnea, congestive heart
failure, low urinary tract symptoms, personal or family history of
prostate carcinoma;
 physical examination including a digital prostate examination;
 laboratory tests including hematocrit and prostate specic
antigen (PSA).
370 N. Samaras et al. / European Geriatric Medicine 3 (2012) 368373
In case of abnormal digital examination and/or high PSA
(> 4 ng/mL), transrectal ultrasound guided prostate biopsy should
be performed prior to TRT.
TRT is contraindicated in the following cases [30]:
 prostate cancer;
 PSA > 4 ng/mL, or PSA > 3 ng/mL in men at high risk of prostate
cancer (African Americans, men with a rst degree relative with
prostate cancer) without urological assessment;
 prostate nodule without urological assessment;
 severe symptoms of low urinary tract (International Prostate
Symptom Score [IPSS] > 19 [41]);
 hematocrit more than 50%;
 uncontrolled congestive heart failure;
 ischemic heart disease in the preceding six months (myocardial
infarction, acute coronary event, unstable angina, coronary
revascularization procedure);
 severe obstructive sleep apnea without treatment.
TRT should not be recommended to patients desiring fertility.
After treatment initiation patients should be evaluated every
three to six months during the rst year and annually thereafter in
order to assess symptoms, adverse effects and compliance. T serum
levels should be measured every three to six months [12].
5.1. Treatment modalities
5.1.1. Oral formulations
Absorption and bioavailability are rather poor with this
formulation. Oral 17a-alkylated T preparations (oxymesterone,
methyl-testosterone) should not be prescribed due to their high
hepatotoxicity and potential for lowering low-density lipoprotein
(LDL) [33,40]. On the other hand, oral T undecanoate is dissolved in
castor oil and has a lymphatic absorption bypassing the liver [9]. A
daily dosage of 2  40 mg to 2  80 mg of T undecanoate usually
sufces to bring serum T to normal levels [9]. T levels should be
monitored three to ve hours after intake in order to adapt dosage
[12].
5.1.2. Mucoadhesive buccal tablets
Sustained release mucoadhesive buccal T tablets should be
applied to the gum region every 12 hours. Initial posology is 30 mg
twice daily [12]. This form restores levels of T within four hours [9],
and patients reach a steady state within two to three days. T levels
should be measured in the morning, right before the morning dose.
Mucoadhesive buccal T tablets are generally well-accepted
formulations but may provoke gum irritation and taste alterations
[12,33].
5.1.3. Transdermal gel
Transdermal T gel (1% T in a hydroalcoholic gel) efciently and
rapidly increases T levels. It must be applied daily to intact, clean,
dry skin of the shoulders and upper arms, at the same hour (usually
in the morning). A single application is possible since the skin acts
as a reservoir gradually releasing T into systemic circulation [9].
Approximately 10% of the dose applied is nally absorbed. Gels are
generally well tolerated, with less skin irritations than patches [9].
However, there is a higher risk of gel transfer to other persons and
patients should cover the application zone with clothing [12,33].
Initial dosage is 5 g of gel daily, containing 50 mg of T [12]. Serum T
levels reach a steady state rapidly (3 to 4 days) and remain rather
stable thereafter [40]. T levels should be checked in the morning
right before gel application, and dosage may be increased to a
maximum of 10 g (100 mg of T) per day if necessary [12].
5.1.4. Transdermal patches
There are two types of patches, scrotal and non-genital, both
succeeding stable serum T levels and circadian patterns over time
[9,40]. T levels peak 4 to 8 hours post-application, to gradually
decrease over 24 hours [42]. Both patches should be applied in the
evening and left for 24 hours. T levels should be measured three to
12 hours after application [12]. Scrotal patches have been related
to higher levels of DHT due to high concentrations of 5a-reductase
in the scrotal skin. Non-scrotal patches are more frequently related
to skin reactions and application sites should be changed at least
once per week [9].
5.1.5. Intramuscular injections of long acting esters
Long acting intramuscular (IM) esters comprise T enanthate,
cypionate and undecanoate. T undecanoate allows for a prolonged
action of up to 8 to 12 weeks, leading to rather stable T plasma levels
[22]. Usual dosage is 1000 mg of T undecanoate every 12 weeks.
According to T plasma levels measured 12 weeks after the rst
injection, time interval between the following injections should be
adjusted (usually between 10 and 14 weeks) [12]. High rst-pass
effect and hepatotoxicity remain a serious issue with this form [9].
The pharmacokinetic proles of T enanthate and cypionate are
similar with a T peak 24 to 72 hours post-injection and a gradual
decline for the 2 to 3 following weeks. Treatment should be
initiated with an IM injection of 75 to 100 mg of T enanthate or
cypionate weekly, or 150 mg to 200 mg every 2 to 3 weeks [12]. T
levels should be checked midway between injections and should
be between 400 and 700 ng/dl (14.124.5nmol/l). Posology as well
as time intervals between injections should be adapted accord-
ingly [12]. T levels uctuations with these formulations should also
be looked for since they may create unpleasant symptom
uctuations characterized by periods of benet alternating with
periods of symptomatic hypogonadism [9,40]. Finally, IM for-
mulations may cause pain at injection site and coughing
immediately after the injection [33].
5.1.6. Subcutaneous pellets
Three 200 mg or six 100 mg pellets implanted subcutaneously
provide normal levels of T for approximately 6 months. T levels
should be measured at the end of the 6 months period [12]. This
form of therapy is rarely used since it requires a skin incision. They
are subject to infection, scarring and spontaneous extrusion [33].
5.2. Treatment complications
Several concerns about TRT safety have been put forward
regarding cardiovascular risk, prostate cancer, polycythemia and
worsening sleep apnea. Other secondary effects reported are acne,
oily skin, breast tenderness and gynecomastia, decreased testicular
size and decreased fertility [40].
5.2.1. Polycythemia
TRT increases hematocrit in a dose dependent manner [43]. The
main risk factor for polycythemia remains older age [9,30]. It also
occurs more frequently with IM formulations or in patients with
conditions already associated with a higher hematocrit [9].
Hematocrit should be measured every 6 months for the rst 18
months and yearly thereafter. If it exceeds 52% to 55%, treatment
should be decreased or discontinued, until it returns to values
under 50% [9,30].
5.2.2. Prostate cancer
There have been concerns about an increase of prostate cancer
risk under TRT. In a study, higher levels of T were related to higher
prostate cancer risk in older patients. Authors suggested that T
could promote typical growth and maturation of prostate cells in
 N. Samaras et al. / European Geriatric Medicine 3 (2012) 368373 371

younger, but malignant transformation in older patients [44].
Nevertheless, most studies including a recent meta-analysis have
not shown any association between androgen levels and prostate
cancer risk [4446]. Surprisingly studies have even suggested a
detrimental role of low T in benign prostate hypertrophy and
prostate cancer pathophysiology [22] and a rather protective role
of normal levels of T [47]. Indeed, worse clinical outcomes have
been related to low T levels (increased prostate cancer risk, worse
5-year biochemical relapse rate, higher Gleason scores, worse
pathological stages and higher risk for positive surgical margins)
[44,48].
Actual data support a rather satisfying safety prole of TRT
concerning benign hyperplasia and prostate cancer
[9,10,29,30,32,40]. TRT trials reporting higher prostate cancer
rates present a serious bias, since PSA increases in androgen
decient men following TRT which triggers higher rates of prostate
biopsies and diagnosis of subclinical prostate cancers [30]. Even so,
prostate cancer mean annual rate in TRT trials is around 1% [29],
which is not worse than cancer incidence in groups of men
undergoing a simple screening [49]. Hypogonadal men have lower
prostate volumes than age-matched controls. Even if TRT increases
prostate volume, it is rarely beyond normal limits [29] and without
worsening lower urinary tract symptoms [40]. A satisfying safety
prole of TRT was even reported in patients after radical
prostatectomy [30,32], brachytherapy [50] and external beam
radiation [51] for prostate cancer.
Even so, since TRT long-term safety is not yet well-established
[29], systematic follow-up of PSA levels is necessary [9,10]. Thus,
screening for low urinary tract symptoms and a digital rectal
examination should be performed every 6 to 12 months. PSA
should be measured every 3 to 6 months for the rst year and
annually thereafter. An annual PSA increase of 1.0 ng/dL is an
indication for prostate biopsy. PSA values should be followed every
3 to 6 months if annual increases of 0.7 to 0.9 ng/dl are observed
[9,40].
patients with recent ischemic CV events or uncontrolled conges-
tive heart failure should not receive TRT [30].
6. Conclusion
Despite its increasing prevalence with age, andropause remains
underdiagnosed in older men. Preconceived ideas on TRT safety
frequently prevent physicians from providing adequate treatment
for patients with overt andropause, not withstanding that actual
data suggest a rather satisfying safety prole. Given the relation
between low T and several geriatric syndromes, we believe that
andropause should be more frequently looked for in elderly
patients. Further studies should concentrate on better dening the
benet to risk ratio of TRT in well known geriatric syndromes such
as falls, sarcopenia, osteoporosis, cognitive and mood disorders.
Disclosure of interest
The authors declare that they have no conicts of interest
concerning this article.
Appendix 1. Saint Louis University ADAM Questionnaire
1. Do you have a decrease in libido (sex drive)?
2. Do you have a lack of energy?
3. Do you have a decrease in strength and/or endurance?
4. Have you lost height?
5. Have you noticed a decreased enjoyment of life?
6. Are you sad and/or grumpy?
7. Are your erections less strong?
8. Have you noted a recent deterioration in your ability to play sports?
9. Are you falling asleep after dinner?
10. Has there been a recent deterioration in your work performance?
A positive questionnaire result is dened as a yes answer to questions
1 or 7 or any 3 other questions. (adapted from Morley et al. [35] with
permission from Elsevier)

5.2.3. Cardiovascular risk

An increase of cardiovascular (CV) risk in men under TRT has
been evoked. A recent study of TRT in old frail men reported more
CV events in the treatment group [52]. Nevertheless, results from
Appendix 2. Aging males symptoms (AMS) scale. Which of
population-based prospective studies on CV mortality and low T
the following symptoms do you have currently? Between
have been inconsistent [5357]. Low T has even been related to
brackets you will nd examples that explain the symptoms.
increased markers of atherosclerosis (arterial stiffness and
Please check each symptom and give an intensity (mark one
intima-media thickness) [58], higher risk for abdominal aortic
appropriate box for each symptom). If you do not have the
aneurysm [59], coronary artery disease [60,61], stroke, transient
respective symptom, please mark no.
ischemic attack [62] and cardiovascular events [63,64]. Several
studies support direct anti-anginal properties of T [6567]. Intensity of symptoms
Moreover, low T has been related to metabolic syndrome and No Mild Moderate Severe Very
its components (insulin resistance, type 2 diabetes [T2D], severe
dyslipidemia, abdominal obesity and arterial hypertension)
1. Deterioration of general & & & & &
[18,22,6870]. well-being (health status,
TRT in hypogonadal men has been known to increase hepatic and perceived general situation)
lipoprotein lipase activity, inducing a decrease in high-density 2. Complaints in joints or muscles & & & & &
lipoprotein (HDL) levels [15]. Still, HDL reduction is mostly (pain in lower back, joints or legs)
3. Sweating (eruptions of & & & & &
encountered in patient with higher pretreatment T levels [31]. sweat, hot ushes)
IM TRT was related to smaller effects on HDL, probably through 4. Sleep disturbances (falling & & & & &
higher conversion to estradiol counteracting Ts effects on the asleep, continuing to sleep,
activity of lipoprotein lipase [71]. Non-aromatizable androgens waking too early
or tired, sleeplessness)
also decrease HDL cholesterol through the same mechanism [30]. A
5. Increased need for & & & & &
decrease in total cholesterol and LDL has also been reported [72]. sleep (often tired)
Overall, a rather neutral effect of T on lipid proles is supported by 6. Irritability (ill-humored, & & & & &
actual data [40]. irritated by minor causes,
Most data on TRT and CV disease seem to support a rather safe become angry or cross easily)
7. Nervousness (inner tension, & & & & &
prole, even if a recent study in older frail men showed the unrest, unable to stay
contrary [52]. Further studies specically in geriatric populations calm and relaxed)
are warranted. Moreover, until acute situations are better studied, 8. Anxiety (panic) & & & & &
372 N. Samaras et al. / European Geriatric Medicine 3 (2012) 368373

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