Therapy in Men: An Update
Laurence Katznelson, M.D.
in men is manifested typically by symptoms of hypogonadism, including
decreases in erectile function and libido. Testosterone also has
an important role in the regulation of normal growth, bone metabolism
and body composition. Specifically, testosterone deficiency is an
important risk factor for osteoporosis and fractures in men. In
men older than 65 years of age, the incidence of hip fracture is
4-5/1000 and approximately 30% of all hip fractures occur in men.
Men with testosterone deficiency have significant decreases in
bone density, particularly in the trabecular bone compartment. Testosterone
deficiency has been reported in over half of elderly men with a
history of hip fracture. Men with testosterone deficiency also have
alterations in body composition that include an increase in body
Using quantitative CT scans to assess fat distribution, we have
shown that testosterone deficiency is associated with an alteration
in site-specific adipose deposition with increased deposits in all
areas, particularly in the subcutaneous and muscle areas.
Because truncal fat correlates with glucose intolerance and cardiovascular
risk, hypogonadism may have important implications with regard to
overall health and mortality. In one study, the alteration in skeletal
muscle composition was associated with a decrease in muscle strength.
Therefore, testosterone deficiency is associated with an enhanced
risk for osteoporosis, altered body composition including increases
in truncal fat, and, possibly, decreases in muscle performance.
Administration of adequate testosterone replacement therapy leads
to improvements in libido and erectile function. Following testosterone
replacement, men note an increase in energy and mood, which may
reflect either direct behavioral effects of androgens, and/or, an
elevation of hematocrit due to rising testosterone levels. Testosterone
therapy also leads to important beneficial effects on the skeleton
and lean tissue mass. Testosterone replacement increases bone density
in hypogonadal men with the most dramatic effects seen in the trabecular
These effects may be seen as early as 6 months following initiation
of testosterone therapy. In one recent study of the long-term benefits
of testosterone therapy, the greatest benefits in trabecular bone
were seen in the first several years of therapy. With regard to
body composition, testosterone replacement therapy results in a
dramatic reduction in adipose content, with the greatest effects
seen in the subcutaneous and skeletal muscle areas.
Androgen therapy leads to a significant increase in lean skeletal
muscle mass and strength. Therefore, there are beneficial effects
of testosterone replacement on body composition and bone mineral
density in adult hypogonadal men that may serve as indications for
therapy in addition to libido and sexual function.
Because testosterone levels decline with age, and aging is accompanied
by body changes including loss of muscle and increases in fat, there
is great interest in the potential benefits of testosterone administration
in elderly men.
In a recent study, Snyder et al. (1999) administered testosterone
via a scrotal patch in a randomized, placebo-controlled trial to
108 elderly men for 3 years. As shown in Figure 2, testosterone
administration resulted in beneficial effects on lean and fat mass.
Therefore, there may be a role for androgens in improving body composition
and function in elderly men.
Figure 2. Mean change from baseline in total
body mass, fat mass, and lean mass, as determined by DEXA, in
108 men over
65 yr of age. The decrease in fat mass (P < 0.005) and the
increase in lean mass (P < 0.001) in the testosterone-treated
subjects were significantly different from those in the placebo-treated
36 months. (Reproduced with permission from The Endocrine Society
- Snyder PJ, et al: The Journal of Clinical Endocrinology
& Metabolism 1999; 84:2647-2653).
Need Better Graphic
There are several modes of administration available for testosterone
replacement. Until recently, the traditional form of testosterone
therapy consisted of intramuscular injections of testosterone esters
given at 2 to 4 week intervals. This mode of therapy leads to an
increase in testosterone levels, but there are marked oscillations
in serum testosterone levels with an early peak, often to supraphysiologic
levels, followed by levels that fall in the subtherapeutic range.
Therefore, men may note an improvement in sexual function only
in the immediate period following the injection. Also, men may describe
mood swings and behavioral alterations that may reflect these changing
More recent advances have led to the development of novel delivery
systems for androgens such as transdermal preparations of testosterone.
These systems provide more physiologic testosterone replacement,
with serum testosterone levels in the normal range throughout the
day. Therefore, transdermal systems are considered the first line
therapy for men with hypogonadism. There are several patches currently
available. There are two non-scrotal transdermal systems, Testoderm
TTS and Androderm. Both of these patch systems are placed on the
skin daily, Testoderm TTS in the morning and Androderm at night.
Use of the patches leads to normal testosterone values, but Androderm
in particular may be associated with local skin irritation. Testoderm
TTS has an advantage because of a low incidence of skin irritation.
The typical dose is 5 mg applied daily.
A newly available non-patch, transdermal testosterone delivery
system is Androgel. Androgel comes as 2.5 or 5.0 gm testosterone
packets, applied daily. Normal testosterone levels are usually achieved
with 5.0 gm and there is a low incidence of skin irritation. This
system therefore is another option for testosterone replacement
therapy for men. Further studies are needed to assess long-term
compliance and efficacy of this form of replacement therapy.
There are several possible adverse effects of testosterone administration
that need to be closely monitored, including clinically significant
benign prostatic hypertrophy (BPH) and prostate cancer. Despite
the theoretical considerations that androgens will augment prostate
size, there is no evidence that androgen replacement in elderly
men will lead to the development of hyperplasia or aggravate its
clinical status. There is also a concern that prostate cancer may
develop during androgen therapy. There are no data available as
to whether androgen therapy will enhance the progression of preclinical
to clinical cancer.
However, androgens may stimulate the growth of already existing
prostate cancer. Therefore, prior to testosterone initiation, patients
should be screened for BPH and prostate cancer with a clinical history,
digital exam, and PSA (prostate specific antigen) level. Because
androgens may stimulate erythropoiesis and precipitate sleep-related
breathing disorders, a cbc should be followed and subjects queried
for the presence of sleep apnea. To assess efficacy of replacement
therapy using a transdermal system, a serum testosterone level should
This article was published with permission in fall of 2001