Med Clin N Am 90 (2006) 1005–1023

Andropause: A Quality-of-Life Issue

in Older Males
Matthew T. Haren, PhDa,b, Moon Jong Kim, MDc,
Syed H. Tariq, MDa,b, Gary A. Wittert, MB, BChd,
John E. Morley, MD, BCha,b,*
a
Division of Geriatric Medicine, Saint Louis University School of Medicine,
1402 South Grand Boulevard, M238, St. Louis, MO 63104, USA
b
Veterans Affairs Medical Center, GRECC, #1 Jefferson Barracks
Dr., St. Louis, MO 63125, USA
c
Department of Family Medicine, Pochon CHA University, 351 Yatup-dong, Bundang-gu,
Sungnam-si, Kyonggi-do, 463-712, Seoul, South Korea
d
Department of Medicine, University of Adelaide, Royal Adelaide Hospital, North Terrace,
Adelaide, South Australia 5000

Introduction
Andropause or androgen deficiency in aging men is a condition in which
low levels of testosterone in an older man are associated with a decrease in
sexual satisfaction or a decline in a feeling of general well-being [1–3].
Cross-sectional and longitudinal studies have demonstrated that testoster-
one levels decline at a rate of approximately 1% per year after the age of
30 years [4–9]. Because of the increase of sex hormone-binding globulin
(SHBG) levels with aging there is an even greater decline in the free or bio-
available testosterone levels with aging. In this article we discuss the path-
ophysiology of testosterone decline with aging; the problems in the
determination of biochemically meaningful testosterone deficiency; testos-
terone’s relationship to sexual activity, sarcopenia, physical function, and
cognitive function; the development of diagnostic questionnaires; and the
methods of treatment of male hypogonadism. It should be recognized
that this is a complex and controversial syndrome with limited numbers
of studies. Thus, all conclusions should be considered tentative until the
completion of larger studies [10].

* Corresponding author. Division of Geriatric Medicine, Saint Louis University School

of Medicine, 1402 South Grand Boulevard, M238, St. Louis, MO 63104.
E-mail address: morley@slu.edu (J.E. Morley).

0025-7125/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.mcna.2006.06.001 medical.theclinics.com
1006 HAREN et al

The pathophysiology of late-onset hypogonadism

In young people the most common form of hypogonadism is testicular
failure characterized by a decrease in testosterone and an increase in lutei-
nizing hormone (LH). In older people testosterone levels decrease but rarely
to the levels seen in primary hypogonadism in young men. This decrease is
associated with only a small increase in LH, except late in life [4,11]. The
prevalence of hypogonadism has been estimated to be between 2% to 5%
at 40 years of age and 30% to 70% by 70 years of age [12]. It is estimated
that at least 5 million men in the United States have hypogonadism, with
less than 10% receiving hormone replacement.
The causes of late-life hypogonadism are multifactorial [13–15]. Defects
have been shown to occur at the level of gonadotrophin-releasing hormone
(GnRH) pulse generator in the hypothalamus, the pituitary, and the testes.
With aging there is a decrease in Leydig cells and the testicular response to
stimulation with human chorionic gonadotropin. The negative feedback of
testosterone at the pituitary level increases with aging. There is a decreased
pulse generation of GnRH, with the pulses being generated more chaoti-
cally. It is the combination of these factors that leads to the age-related de-
cline in testosterone level. In addition, with aging the normal circadian
rhythm of testosterone secretion is lost [16].
Testosterone circulates in a free form and bound to albumin and SHBG.
In general, it is believed that the testosterone that is free and bound to albu-
min is available to tissues (bioavailable) whereas that bound to SHBG is not
capable of entering tissues. The exception to this is reproductive tissues,
where megalin is a receptor for SHBG that may then allow testosterone
to penetrate cells. With aging an increase in SHBG decreases the amount
of bioavailable testosterone.
After entering cells, either testosterone itself or dihydrotestosterone binds
to a receptor in the cytoplasm. This receptor then dimerizes and is carried
along filamin into the nucleus. This testosterone-receptor complex then binds
to androgen response elements (AREs) on DNA with its action being modu-
lated by several coactivators and corepressors. Binding to the DNA results in
generation of messenger RNA and proteins. The function of the testosterone
receptor is regulated by the number of CAG repeats. When there are a large
number of CAG repeats the receptor functions less well than when there are
fewer CAG repeats. Finally, testosterone also has several nongenomic, mem-
brane-mediated effects. The effects of aging on these complex intracellular
actions of testosterone have not been studied. Fig. 1 summarizes these age-
related changes in the male hypothalamic-pituitary-testicular axis.

Biochemical determination of testosterone

Although the measurement of testosterone is relatively simple, the devel-
opment of a large number of kits for platform assays has made it into
 ANDROPAUSE 1007

Fig. 1. Age-related changes in hypothalamic-pituitary-testes axes. DHT, dihydrotestosterone;

FSH, follicle-stimulating hormone; LH, luteinizing hormone; MRNA, messenger RNA;
SHBG, sex hormone-binding globulin.

a jungle. There is a large variability in the values for each of these assays
[17,18]. This variability makes it essential that normal values, and not the
manufacturers’ values, are determined for each laboratory. This procedure
entails obtaining three pooled values in the morning on at least two occa-
sions from at least 40 healthy men between 20 and 40 years of age. Most lab-
oratories use a value between 250 to 350 ng/dl as the lower limit of normal.
Many authorities believe that especially with the older person free or bio-
available (albumin-bound þ free) testosterone should be obtained [19,20].
Most laboratories offer an analog free-testosterone assay, which generally
is believed to be of no value. Salivary testosterone provides a reasonable
approximation of free testosterone levels.

Testosterone and sexuality

It generally is believed that testosterone is a prime driver of libido. People
with a low libido generally have lower testosterone levels than those with
a normal libido, but there is a marked overlap in testosterone levels in peo-
ple with normal and abnormal libido [21]. Hajjar and colleagues [22] showed
that testosterone replacement leads to a marked increase in libido, but this
effect also can be seen with placebo [23]. A meta-analysis has confirmed that
1008 HAREN et al

testosterone increases enthusiasm for sex and sexual activity [24]. The pla-
cebo effect seen on sexuality is equivalent to that seen in people with depres-
sion, with the testosterone effect being of the same magnitude as that seen
with antidepressant treatment.
Testosterone levels are particularly low in people with diabetes mellitus
[25], and low libido and erectile dysfunction commonly are associated
with diabetes [26].

Erectile dysfunction and lower urinary tract symptoms

Epidemiology
The prevalence of erectile dysfunction (ED) is difficult to estimate be-
cause of the assumed underreporting of the problem. Various age-dependent
estimates have been made from population-based studies [27–29]. Pinnock
and colleagues [27] reported that erections inadequate for intercourse
affected 3% of men in their 40s and increased to 64% of men in their
70s in an Australian community sample. In another Australian sample of
consecutive male attendees to general medical practices, Chew and co-
workers [28] reported the prevalence of complete ED to be 2% of men in
their 40s and 50% of men in their 70s. Data on the incidence of ED from
the Massachusetts Male Aging Study report an increase from 12.4 cases
per 1000 man-years for men in their 40s to 29.8 per 1000 man-years for
men in their 50s and 46.4 per 1000 man-years for men in their 60s [30].
The prevalence of lower urinary tract symptoms (LUTS), such as ur-
gency, frequency, nocturia, incontinence, and reduced urine flow, increase
with age [31,32], from approximately 26% in men 18 to 64 years old to
48% in those more than 65 years old. These symptoms often significantly
affect quality of life and sexual functioning. Benign prostatic hyperplasia
(BPH) also increases with age, being present in as many as 50% of men
aged 50 and in nearly 90% of autopsies in men aged more than 80 [33].
LUTS and ED are strongly associated with aging and numerous small epi-
demiologic studies have postulated an association between the two condi-
tions but have failed to show a direct relation after the effect of aging has
been accounted for. In a large, multi-center study (United Kingdom [Bir-
mingham], The Netherlands [Boxmeer], France [Auxere], and Korea
[Seoul]) men who had an International Prostate Symptom Scale (IPSS) score
of 8 to 35 were more likely to have ED, based on a score of 0 to 4 on the
Sexual Function Inventory of O’Leary and colleagues [34], after adjusting
for age and country (odds ratio [OR] 1.39, 95% CI 1.10–1.74) [35]. Men
who had diabetes (OR 1.57, 95% CI 1.09–2.25) and high blood pressure
(OR 1.38, 95% CI 1.09–1.75) also were more likely to have an ED score
of 0 to 4.
Associations between serum testosterone levels and ED have not been
clear in epidemiologic studies. Serum free-testosterone concentrations corre-
late with impaired relaxation of cavernous endothelial and corporeal
 ANDROPAUSE 1009

smooth muscle in response to vasoactive challenge, independent of age [36].

Factors that may be associated with both ED and low T levels include de-
terminants of health (age, education, occupation, ethnicity), behavioral
and lifestyle (quality of life, alcohol intake, smoking, diet, and physical ac-
tivity), clinical (diabetes, heart disease, hypertension, and drug therapies),
and psychologic factors, including depression and anxiety [29,37]. There is
a strong positive relationship between ED and cardiovascular risk factors
[29] and depression (the probability of ED is w90% in men who have severe
depression but only 25% in men who have mild depression) [37]. The causal
relationship is unclear and possibly occurs through mechanisms involving
reduced testosterone levels [38]. A longitudinal study of the evolution of
ED, associated factors, and comorbidities will provide this much-needed data.
Haidinger and colleagues [32] reported that age was the single most influ-
ential predictor of LUTS, as measured by the IPSS, in 1557 Viennese men
aged 40 to 96 years. It usually is assumed that BPH is responsible for
LUTS, particularly when the urine flow is reduced. Numerous cross-
sectional studies have shown either no or inconsistent relationships between
LUTS, BPH, and urine flow [39,40]. Moreover, urine flow may be low in
young men without symptoms. Concomitant detrusor instability [41] or
other factors may predict LUTS in men who have BPH. The longitudinal
rate of change in maximal urine flow rate may correlate more strongly
with symptom scores than the flow rate at any given time in cross-sectional
studies.
Prostate volume was not significantly related to circulating testosterone
levels, but increased with increasing age and body mass index and decreased
with increasing levels of SHBG in African American men [42]. Neither ele-
vated testosterone nor dihydrotestosterone predisposes men to BPH [38].
Prostate-specific antigen (PSA) is a glycoprotein produced by prostatic ep-
ithelium. Serum levels of PSA correlate positively with age. PSA screening
for prostate cancer remains controversial because of problems associated
with sensitivity and specificity of cutoff values in predicting prostate cancer.
Recent reports suggest that a lower threshold level of PSA for recommend-
ing prostate biopsy may improve the clinical value of the PSA test for pros-
tate cancer. Meigs and coworkers [43] reported that elevated free PSA levels
predicted BPH, independent of total PSA levels, in 1019 men without pros-
tate cancer at 9-year followup.

Biochemistry
In animal studies, androgen deprivation alters the functional responses
and structure of erectile tissue [44]. Penile tissue possesses high concentra-
tions of locally synthesized androgens and thus androgen-dependent func-
tions need not reflect circulating androgen levels [45]. It is well
documented in rats that testosterone is required for adequate function of ni-
tric oxide synthase, which produces nitric oxide necessary for relaxation of
cavernosal endothelial and corporeal smooth muscle resulting in erection
1010 HAREN et al

[46]. There are also possible non-nitric oxide–dependent effects of testoster-

one on penile erection that involve stimulation of cyclic GMP synthesis [47].
In animals, testosterone has been shown to inhibit detrusor muscle contrac-
tion [48] and therefore low testosterone levels may promote unstable function
of the detrusor muscle and LUTS, particularly in men who have concomitant
BPH. The prostate is androgen dependent, in particular to dihydrotestoster-
one that is produced within the gland by way of 5a-reduction from testoster-
one. The relative contribution of changes in androgens to LUTS is unclear.

Intervention
In the absence of significant hypogonadism, testosterone treatment does
not have an effect on erectile function but it does improve the response to
sildenafil [49]. Aversa and colleagues [35] showed that in men who had erec-
tile dysfunction, low free testosterone levels, independent of age, correlated
with impaired relaxation of cavernous endothelial and corporeal smooth
muscle cells. Moreover, a follow-up study in men who had arteriogenic erec-
tile dysfunction, testosterone levels in the lower quartile of the normal
range, and who were nonresponsive to sildenafil treatment after six at-
tempts, demonstrated that 1 month of transdermal testosterone supplemen-
tation improved erectile response to sildenafil [50]. Several other studies
have suggested enhanced strength or maintenance of erections following
testosterone or dihydrotestosterone replacement in older men [23,51–55].
Furthermore, a meta-analysis of the usefulness of androgen replacement
for erectile dysfunction showed that testosterone-treated patients improve
significantly more than placebo-treated patients and that patients with pri-
mary testicular failure respond better to treatment than those with second-
ary testicular failure. Moreover, transdermal therapy is more effective than
oral or intramuscular therapy [56].
Of great clinical importance is the independent association between
LUTS and ED. Both conditions can have profound but variable levels of
bothersomeness in aging men and it has been estimated that more than
60% of Australian men bothered by LUTS do not seek medical help [31].
These coexisting conditions raise interesting management issues and it is rec-
ommended that older men presenting with one condition also be investi-
gated for the other.

Skeletal muscle mass and strength

Epidemiology
Muscle mass decreases and fat mass increases with increasing age. In the
New Mexico Ageing Process Study the best predictor of loss of muscle mass
and strength (sarcopenia) was free testosterone. Other predictors included
age, caloric intake, physical activity, and insulinlike growth factor- (IGF)
1 [57,58]. Sarcopenia leads to frailty, an important precursor of subsequent
functional deterioration and death. Frailty has been defined objectively by
the criteria of weight loss, exhaustion, weakness (grip strength), slow
 ANDROPAUSE 1011

walking speed, and low physical activity [57,59]. Several hormones are be-
lieved to play a role in the pathophysiology of frailty. People who have di-
abetes mellitus are at high risk for developing premature frailty. Weight loss,
which can be because of sarcopenia, anorexia, cachexia, or dehydration, is
a hallmark of frailty. In men, obesity, particularly when the fat is distributed
within the abdomen (visceral), is associated with low plasma testosterone
[60–62]. Conversely, decreased testosterone levels in men are associated
with increased accumulation of visceral fat [63,64] and are reversible on tes-
tosterone administration [65,66].
Van den Beld and coworkers [67] reported inverse cross-sectional associ-
ations between total, free, and bioavailable testosterone and total fat mass in
403 community-dwelling men aged 73 to 94 years. Moreover, both total and
bioavailable testosterone were positively associated with handgrip strength.
Denti and colleagues [68] showed an age-independent, inverse association
between SHBG and whole body fat percentage estimated from four skinfold
measurements using the Durnin-Wormsely and Siri equations in 206 healthy
volunteers aged 18 to 95 years. In a longitudinal study it was shown that
people who have lost muscle mass but remain obese (sarcopenic obesity)
have an extremely high rate of future disability and death [69]. It has been
shown that sarcopenia is strongly related to the loss of hormones, such as tes-
tosterone and IGF-1, and to mild increases in cytokines, such as TNF-a and
IL-6 [57,70,71]. Other causes of sarcopenia include diminished neuronal in-
put to muscle, decreased food intake (particularly protein and creatine),
and peripheral vascular disease [72].
Low levels of gonadal steroids and changes in the activity of the IGF axis
therefore may be markers of the metabolic syndrome associated with in-
creasing age, visceral obesity, impaired glucose tolerance and insulin signal-
ing, and cardiovascular disease, resulting in accelerated frailty and death.

Biochemistry
Changes in the IGF/insulin signaling pathway with aging are likely to
play a central role in regulation of skeletal muscle mass. Skeletal muscle is
responsible for the production of 25% of circulating IGF-1. There are
two muscle isoforms, one similar to liver IGF-1 and the other (IGF-IEc: me-
chanogrowth factor [MGF]) having local actions on muscle [73]. Exercise
(stretch) leads to upregulation of the mRNA for both muscle isoforms
and reduced muscle IGF-1 signaling leads to muscle atrophy. Hormones
(growth hormone, testosterone, insulin, and vitamin D) and exercise regu-
late muscle IGF-1 [74]. It is the decline in the muscle isoforms of IGF-1 (liv-
erlike and MGF) [73] that are likely to contribute most to age-related
sarcopenia. Moreover, age-related decline in testosterone and growth hor-
mone may lead to increased myostatin expression and dissociation in
IGF-1 autocrine effects on protein synthesis in skeletal muscle [70].
Recent research has focused on the testosterone and IGF-1 stimulation of
myogenic satellite cell activity in aged skeletal muscle. Satellite cells are
1012 HAREN et al

responsible for muscle regeneration and repair after injury or atrophy. Older
muscle exhibits a reduced number and proliferative capacity of satellite cells,
but this is amenable to change with the nature of the systemic environment
[75]. In rats, IGF-1 enhances muscle growth partially by increasing satellite
cell proliferation [76] and electroporation of IGF-1 stimulates muscle fiber
hypertrophy [77]. IGF-IEc also stimulates protein synthesis in muscle [78].
A localized IGF-IEc transgene prevented age-related muscle atrophy and
allowed older animals to develop a proliferative response to muscle injury
similar to that seen in younger animals [79].
The mechanisms by which testosterone, growth hormone, IGF-1, and
other growth factors interact with receptor activity, myostatin gene expres-
sion, and satellite cell function in aged skeletal muscle to influence muscle
protein synthesis warrant further vigorous research.

Intervention
Testosterone replacement in young hypogonadal men [80,81] and supra-
physiologic treatment in eugonadal young men [82] have been shown to in-
crease muscle mass and strength. In older men who have low bioavailable
testosterone [83] or low-normal total testosterone levels [84,85], intramuscu-
lar testosterone increases muscle mass and strength. Numerous studies of
oral and transdermal testosterone in older men who have low-normal total
testosterone levels, however, show significant increases in lean mass without
improvements in muscle strength [86–88]. In the study by Wittert and col-
leagues [88] it was shown that change in lean mass correlated with change
in quadriceps strength from baseline to month 12 in the testosterone but
not in the placebo group. Urban and coworkers reported that intramuscu-
lar testosterone increases muscle IGF-1 mRNA and Snyder and colleagues
[86] reported an increase in serum IGF-1 in men receiving testosterone by
transdermal patch. Oral testosterone undecanoate had no effect on serum
IGF-1 levels [88]. Bhasin and coworkers [89] have shown that the muscle re-
sponse to testosterone in young men is related to dose. The use of muscle
function testing in the elderly is confounded by wide variability in most mea-
sures. Motivation, tolerance to pain, and potential learning effects may be
some of the major factors limiting the ability of these tests to identify differ-
ences between the treatment groups in interventional studies. Accordingly,
large study groups may be required to determine small treatment benefits [90].

Testosterone and bone

Men fracture their hips approximately 10 years later than women do [91].
Men have a higher mortality rate than women when they fracture their hips.
Minimal trauma hip fracture is associated with low testosterone levels
[92,93]. The relationship of testosterone to bone is less clear in men.
Several studies have shown that testosterone treatment can increase bone
mineral density [94,95]. This effect of testosterone is not blocked by the
 ANDROPAUSE 1013

5-alpha-reductase inhibitor. It would seem that aromatization of testoster-

one to estrogen is the major cause of the positive effects of testosterone
on bone. This effect has been demonstrated clearly in people with congenital
aromatase deficiency [96]. Testosterone also seems to have direct effects on
the osteoblast.

Testosterone and cognition

Low bioavailable testosterone levels are correlated with poor cognition,
especially visuospatial cognition [97–99]. Some studies have demonstrated
that testosterone replacement may improve visuospatial cognition [100].
This has not been a universal finding, however [101].
The SAMP8 mouse has poor cognition, which is attributable to overpro-
duction of amyloid-beta protein associated with increased oxidative damage
[102–107]. The SAMP8 mouse has low testosterone levels. Testosterone re-
placement in this mouse model of Alzheimer disease improves learning
and memory [108]. Testosterone treatment decreased amyloid precursor
protein.
Low testosterone levels are associated with an increased likelihood of de-
veloping Alzheimer disease [109,110]. Patients with Alzheimer disease have
low testosterone levels in brain tissue compared with controls [111]. Testos-
terone replacement has been shown to produce small improvements in cog-
nition in people who have Alzheimer disease [100,112].

Testosterone and health-related quality of life

Health-related quality of life (HRQOL) is a complex and abstract con-
cept that includes physical, psychologic, social, and other domains of func-
tioning specific to a given health condition. It focuses on the ways in which
a disease modifies the happiness and satisfaction of an individual. It repre-
sents the patient’s viewpoint of the effects of treatment. It generally has sev-
eral domains, including symptoms, function, emotional stability, social
functioning, and general satisfaction with life. In the case of hypogonadism,
decreased energy levels and impaired sexual performance appear to be the
most important quality-of-life areas.
Lowering testosterone levels in patients who have prostate cancer results
in deterioration in the HRQOL [113]. The effects of testosterone replacement
on HRQOL in older hypogonadal men have been less dramatic (Table 1)
[86,114–119,125]. Overall testosterone has had an effect on the physical
performance scale of the SF-36 (a quality-of-life questionnaire). Of the eight
trials that have examined quality of life involving 390 patients, only four
studies (193 patients) showed positive effects. In a small study of men
who had prostate cancer, there was a significant increase in the hormone do-
main of the extended prostate inventory composite HRQOL [117]. There is
a need to develop better HRQOL scales for hypogonadal men.
1014 HAREN et al

Table 1
Testosterone and quality of life
Study n Age (years) Effect (scale)
[86] 108 72 Physical (SF-36)
[114] 22 65þ None (SF-36)
[118] 46 62 Physical (SF-36)
[115] 29 52 None (Endicott)
[116] 39 d Improved (PNUH QoL)
[101] 60 60–78 None (Visual analog)
[117] 10 59–69 Improved (Hormone Domain
of Extended Prostate
Inventory Composite [HRQOL]
[119] 76 64 None (MLHF)
Abbreviations: SF-36, short form-36; PNUH Qol, Puson National University Hospital Qual-
ity of Life; MLHF, Minnesota Living with Heart Failure Questionnaire.

Diagnosis of hypogonadism in older men

The diagnosis of hypogonadism in older men requires the presence of
a constellation of signs and symptoms and a demonstrated low total testos-
terone or preferably free or bioavailable testosterone level [120,121]. Several
questionnaires have been developed to help screen for andropause and to
provide an objective measure of treatment response [122–127]. Two of these
have excellent specificity: the Saint Louis University ADAM questionnaire
and the Aging Male Survey. Unfortunately, neither questionnaire has very
good sensitivity [128]. Nevertheless, they can be considered a reasonable ap-
proach to symptom identification. Because of the multiple causes of symp-
toms similar to the male hypogonadism in older men, it is unlikely that any
questionnaire will perform much better.
A simplified algorithmic approach to diagnosing late-life hypogonadism
is presented in Box 1. This approach is compatible with recent consensus
recommendations [121,129,130].

Testosterone treatments
Several different methods of testosterone treatments have been developed
[131]. Testosterone can be given as injections every 1 to 3 weeks. The major
problem with this approach is that the levels of testosterone vary from
supraphysiologic to low over each treatment period. This approach has
been used successfully, however, for more than 70 years. A long-acting tes-
tosterone undecanoate injection has been developed in Asia and Europe and
should be available in the United States within the next year [132]. This
treatment is similar to testosterone pellet implant therapy, which can be im-
planted every 4 to 6 months.
 ANDROPAUSE 1015

Box 1. St. Louis University Androgen Deficiency in Aging Male

(ADAM) questionnaire
A positive screen for hypogonadism includes a ‘‘Yes’’
response to numbers 1 and 7, or any other 3 questions.
Do you have a decrease in libido (sex drive)?
Do you have a lack of energy?
Do you have a decrease in strength and/or endurance?
Have you lost height?
Have you noticed a decreased enjoyment of life?
Are you sad and/or grumpy?
Are your erections less strong?
Have you noticed a recent deterioration in your ability to play
sports?
Are you falling asleep after dinner?
Has there been a recent deterioration in your work performance?

Testosterone patches have a high rate of skin irritation because of alcohol

being part of the vehicle. Hydroalcoholic gels containing 1% testosterone
have become popular in the United States. They have a lower rate of skin
irritation and a better patient acceptance. Doses vary from 50 to 100 mg
of gel daily. Three-year safety data for this form of treatment have been
reported [133]. This study showed continued positive results of treatment
on muscle, bone, fat, and libido in men aged 19 to 67 years. Two forms
of testosterone gel, AndroGel and Testim, are available in the United States.
A buccal delivery form of testosterone (Striant) has had little success in the
United States [134].
Oral testosterone undecanoate is absorbed mainly through the lymphatic
system, thus avoiding the effects of high-dose testosterone on the liver
during the first pass. It has been used widely throughout the world and
10-year safety data have been reported [135]. It is not available in the United
States. Because of the high concentrations of 5-alpha-reductase in gut
epithelium, its administration is associated with high serum levels of
dihydrotestosterone.
A nasal delivery form of testosterone (baccaltestosterone) has been devel-
oped. It has adequate bioavailability and does not increase dihydrotestoster-
one. In rabbit studies it did not damage the nasal mucosa. At present it is
undergoing the FDA approval process in the United States.
There is little evidence to recommend the use of dehydroepiandrosterone
as an androgen replacement [136–138]. Nandrolone, an injectable androgen,
has been used successfully to improve strength in men and women [139].
Several oral selective androgen receptor molecules have been developed in
hopes that they will be useful for the treatment of sarcopenia. Some
1016 HAREN et al

authorities have suggested that dihydrotestosterone may be an alternative

approach to testosterone replacement, but in view of potential effects on
the prostate this is unlikely [140]. Human chorionic gonadotropin, which
stimulates testicular secretion of testosterone, also has been used to treat
andropause [141].

Testosterone and the cardiovascular system

Low testosterone levels are correlated with increased atherosclerosis and
an increased carotid-intima media thickness [142,143]. Testosterone de-
creases angina and decreases ST depression [118,144]. It has minimal effects
on cholesterol. Testosterone improves walking speed in people with conges-
tive heart failure [119]. Overall, these small studies suggest a beneficial effect
of testosterone on heart disease.

Side effects
The major side effect of testosterone is an excessive increase in hemato-
crit. When the hematocrit increases to more than 55, testosterone therapy
should be withheld. Testosterone also can be associated with worsening
sleep apnea [145]. Testosterone therapy can be associated with the develop-
ment of gynecomastia related to the aromatization of testosterone to estro-
gen. Parenteral testosterone administration has minimal deleterious effects
on the liver.
Testosterone therapy increases PSA levels slightly. Testosterone may
increase prostate size, worsening BPH. The effects of testosterone on the
development or the acceleration of prostate cancer are uncertain [51]. There
is a need for a large study to determine these effects. At present the prudent
physician should follow PSA levels and conduct a rectal examination every
6 to 12 months.

Summary
Testosterone deficiency occurs commonly in men as they grow older. This
deficiency often is associated with a decline in sexual activity and a loss of
muscle mass. Testosterone replacement can reverse many of these effects.
At present, no ideal form of testosterone replacement is available. Like
the phosphodiesterase-5 inhibitors, testosterone replacement in older men
is a quality of life issue.

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