The Masters Men's Clinic Radio

Get Healthy!

Start Taking High Quality Omega 3s

For Increased Vitality & Quality of Life Try The New

Dr. Komer, MD Recommended Liquid Muti-Vitamin

Protect Your Heart

Dr. Komer, MD Recommended Cardiac Defense

Hormone Replacement Therapy

Diagnosis of androgen deficiency in elderly males. As the
clinical symptoms of hormone deficiency in elderly males
are rather vague and aspecific and as a substantial number of
elderly men have (F)T levels within the normal range for
young adults, we can state that hormone replacement therapy (HRT) is only warranted in the presence both of clinical symptoms suggestive of hormone deficiency and of decreased hormone levels. Moreover, eventually present primary causes of the decreased androgen levels should be
adequately treated before starting HRT.

How do we define hypogonadism in elderly males? Clinical
signs of relative androgen deficiency in elderly men most
easy to objectify are a decrease of muscle mass and strength,
a decrease of bone mass and osteoporosis, and an increase in central body fat. Other signs such as a decrease in libido and sexual desire, forgetfulness, loss of memory, difficulty in
concentration, insomnia, as well as a decreased sense of well
being are rather subjective impressions that are more difficult
to measure and differentiate from hormone-independent
aging.

As to subnormal (F) T levels, it should be realized that it is
still unknown whether the requirements of elderly males are
identical with the requirements of younger men. There is
some evidence for increased sensitivity to androgens in elderly males, for example, at the level of the feedback system
(82-85), whereas several (86-91), but not all (92, 93), studies
show a decrease of the androgen receptor (AR) concentration in tissues of elderly animals and men, suggesting a saturation of the receptor sites at a lower T concentration and a decrease of the maximal genomic effect of T. Also, changes in the CAG repeat length of the AR gene may be involved in the age-related decline of plasma T levels. The latter appear to decline more rapidly in subjects with a lower number of CAG repeats (7). This is possibly the consequence of a higher androgen sensitivity; a large number of CAG repeats as in the Kennedy syndrome are accompanied by androgen resistance and increased T levels.

Moreover, even in the young men, it is not clear whether T
concentrations in the normal range are required for full
androgenic effects in the different androgen-responsive organs. It has been reported repeatedly that T levels at half the concentration found in young males, are appropriate for
sustaining normal libido and sexual activity (94).

In fact, there is no clinically useful biological parameter
reflecting androgen activity. It has been suggested that
SHBG capacity might be such a parameter (95) but, whereas
the decrease of SHBG after T treatment indicates androgen
activity, a single basal SHBG level is difficult to interpret;
the level is determined by several hormonal and
nonhormonal factors, such as GH, insulin, thyroid hormones,
obesity, and medications.

It should be realized, finally, that normal hormone levels
do not imply per se normal physiological effects; indeed, the
interaction of the ligand with the hormone receptor as well as
the presence of coactivators and coinhibitors will determine
the biological effects.

Because there is no generally accepted cut off value of
plasma T for defining androgen deficiency, and in the absence of convincing evidence for an altered androgen requirement in elderly men, we consider the normal range of (F)T levels in young males also valid for elderly men. In our healthy male nonobese population 20-40 yr of age (n = 150), the mean of log-transformed early morning T levels was 21.8 nmol/L (627 ng/dL), the mean - 2 SD was 12.5 nmol/L (365 ng/dL), and the mean — 2.5 SD was 11 nmol/L (319 ng/dL). For FT, measured by equilibrium dialysis or calculated from T and SHBG levels (96), the mean was 0.5 nmol/L (14 ng/ dL), the mean - 2 SD was 0.26 nmol/L (7.4 ng/dL), and the mean — 2.5 SD was 0.225 nmol/L (6.5 ng/dL). If we take as the lower normal limit and threshold of partial androgen deficiency, a conservative value of 11 nmol/L for T and 0.225 nmol/L for FT, which represent the lower 1% value of healthy young males, then it appears that more than 30% of men over 75 yr old have subnormal (F)T levels. Most authors use rather similar values (1, 2, 9, 13, 97, 98). It should bementioned that direct FT assays using a T analog, do not yield a reliable estimate of FT (96). The age-associated decline in (F)T levels has both a testicular (decreased Leydig cell number) and central origin, the latter being characterized by a decrease in the amplitude of LH pulses in elderly men.

Hence, many elderly men have normal LH levels and we do
not consider an increase in LH levels to be required for the
diagnosis of hypogonadism in elderly men (84). As already
mentioned, in the absence of a reliable, clinically useful biological parameter of androgen action, these criteria of hypogonadism of the aging men are somewhat arbitrary.

The treatment aims at restoring hormone levels in the
normal range of young adults and, more importantly, at
alleviating the symptoms suggestive of the hormone deficiency. However, the ultimate goals are to maintain or regain the highest quality of life, to reduce disability, to compress major illnesses into a narrow age range, and to add life to years.

What are the effects of androgen supplementation in elderly
man with subnormal (F)T levels? Before discussing the
beneficial effects of androgen supplementation in elderly
males, it should be stressed that the number of well
controlled studies is still small; the number of patients having
been involved in such studies is limited to a few hundred.
Hence the experience is limited and the clinical results
should be interpreted critically.

There is no doubt that in young androgen-deficient men T
supplementation increases fat free mass and muscle strength
and decreases body fat, with improvement of insulin
sensitivity (98, 99-104). Androgens induce their specific response via the AR, which regulates the androgenresponsive target genes.

Following androgen treatment, Sheffield-Moore et al. (105) observed an increase in AR messenger RNA in healthy young men, and in older men long-term androgen administration increased AR transcription at 1 month with a return to base line levels after 6 months (105, 106). Androgen administration to healthy older men increased insulin-like growth factor 1 messenger RNA; decreased the concentration of the inhibitory insulinlike growth factor binding protein 4 (107); and, increasing protein synthesis (99, 105-107), induced myotrophic effects in skeletal muscle (104, 105).

After androgen supplementation to elderly men, generally at a biweekly dose of 200 mg T enanthate, several authors (1, 2,106,108) reported a significant, albeit often relatively modest, increase in muscle mass (±2 kg) (1) and/or arm circumference and generally of grip strength, whereas fat mass generally is decreased modestly (106, 109). Also Urban et al. (106) reported that T administration to elderly men increases skeletal muscle strength. A recent study of Snyder et al. (97), on the other hand, reported an increase in lean body mass (LBM) but without increase in strength of knee extension or flexion, whereas Clague et al. (110) after a 12-week administration of T, found neither an increase of LBM nor muscle strength.

Bhasin et al. (Ill) stresses that although muscle strength is
an important aspect of muscle function, it is not the most
important. Muscle power, defined as the rate of power development is strongly correlated to performance of functional activities such as rising from a chair, stair climbing, etc.; such an increase, more specifically of the lower limb
muscles, would be important, improving mobility and
stability and preventing falls and, hence, fractures (110).

As to osteoporosis, all studies show that in hypogonadal
men androgen supplementation increases bone mass (100,
102, 103, 112), although normal adult bone mass is not
reached (113). Also in eugonadal men with osteoporosis, T
esters (250 mg/2 weeks) increased BMD (114). Again, the
effects in elderly men are less convincing. Morley et al. (2)
observed an increase in osteocalcin levels, an index of osteoblast activity, whereas Tenover (1) reported a decrease of hydroxyproline excretion, an index of bone resorption, and
more recently (Tenover J. S., personal communication) in a
3-yr study involving 70 elderly men, an increase in BMD at
all measured sites. However, neither Orwoll and Klein (14)
nor Sih et al. (108) could observe any effect of T supplementation on biochemical parameters of bone turnover. Snyder et al. (115), in a study involving 108 elderly subjects, observed that HRT increased BMD of the lumbar spine, but not of the hip, in patients with clearly subnormal T levels, but not in the whole elderly population studied, which included, all subjects with a T level below 16.5 nmol/L (475 ng/dL), a va

On the other hand, it is evident that morbidity of osteoporosis relates essentially to hip fractures! It may be of interest to mention that in orchidectomized aged rats, the threshold concentration of T, necessary for prevention of loss of both bone and LBM is clearly lower than for prostate and seminal vesicles (116). Whether this applies also to the aged man requires further research, but would explain that the effects of T on BMD of elderly men, are limited to men with clearly decreased (F)T levels.

Finally, HRT only makes sense when other causes of osteoporosis, such as insufficient calcium or vitamin D intake
have been excluded (117). As to the effects of T replacement on sexual activity, the effects in young hypogonadal men are spectacular (98, 101, 103), but supraphysiological doses of T administered to young healthy men for contraceptive purposes did apparently not affect frequency of intercourse, kissing, or fondling (118).

Anderson et al. (119), injected 200 mg T enanthate weekly for 8 weeks to normal men and observed a significant increase in sexual interest, awareness, and arousal, which was, however, not reflected in modification of overt sexual behavior, which they suggest may be more determined by social factors.

Morley et al. (2) as well as Hajjar et al. (120) observed that also in elderly men T replacement improves libido substantially. Wang et al. (98, 121) also reported improvement
of sexual function; however, their data suggests that there is a threshold level of T above which there is no further enhancement of response. Interestingly, Carani et al.
(122), in a patient with aromatase deficiency, reported evidence that estrogen might have a role in male sexual activity, but not in sex orientation.

Most authors (98, 106, 123) observed that androgen substitution in hypogonadal males improved mood, energy, sense of well being, and friendliness, whereas T levels were
negatively correlated with nervousness and irritability. These
significant correlations with T levels were only observed
when T levels were below the normal range, which suggests
that once a minimally adequate T/dihydrotestosterone (DHT)
level was achieved, further increase did not further contribute
to improvement of mood (98, 123).

Similarly in elderly males, androgen replacement therapy
has been reported to increase the sense of well being (2, 124,
125). Androgen supplementation in elderly hypogonadal men
improves also spatial cognition (1, 126) and verbal fluency
(127, 128), but no effect was seen on memory (108).

As to the influence on plasma lipids, atherosclerosis, and
cardiovascular disease, it is well known that administration
of T to surgically or chemically castrated males, or female to
male transsexuals (129), as well as supraphysiological T levels in men (40,129-131) induce a decrease of HDL-C and an
increase of triglyceride levels. But administration of 250 mg
T im once per week for 6 months to young healthy men
resulted in a decrease of total and LDL-C, as well as in a
slight, nonsignificant decrease of HDL-C and in a decrease
of lipoprotein(a) levels (132).

Most (1, 2,125,133), but not all (134), studies on androgen
replacement in elderly men report a fall in total and LDL-C,
with no significant effect on HDL-C and an improvement of
insulin sensitivity (127,135-137). Moreover, a tendency to a
fall of arterial blood pressure has been reported (135). The
mechanism of this fall in lipids might be related to the decrease in the visceral abdominal fat mass (124) under the
influence of androgens, which inhibit lipoproteinlipase activity and increase lipolysis (138, 139) with improvement of
insulin sensitivity and mobilization of triglycerides from abdominal fat tissue (140).

As to the influence of androgen supplementation on cardiovascular disease, Alexandersen et al. (141) reviewing the outcome of 30 cross-sectional studies in men, reported that most studies suggest either a favorable or neutral effect of normal T levels on cardiovascular disease in men, and they
conclude that low androgen levels increase the risk of cardiovascular disease in men.

It should be remembered that the beneficial effects of
physiological androgen levels on the lipid profile are limited
to aromatizable androgens and that the effects of androgens
on the vascular system are not limited to their indirect effects
on the plasma lipids, but that T decreases lipoprotein(a) (8)
and has complex effects on platelet aggregation (51), blood
coagulation, and fibrinolysis, respectively (142,143).
Moreover, it has been shown that administration of T in
physiological concentration increases coronary blood flow in
patients with coronary heart disease (144, 145), whereas
beneficial effects on endothelial function (146) and
myocardial ischemia have also been demonstrated (147,
148).Unfortunately, notwithstanding its favorable effects of T
supplementation on the lipidogram, so far no influence on
cardiovascular mortality has been reported (45, 46).

In summary, androgen supplementation in aging males
with subnormal T levels seems to have beneficial effects on
muscle mass and strength, BMD, plasma lipids and insulin
sensitivity, mood, libido, and sense of well being, but generally only in men with subnormal (F)T levels; no effects are generally seen above a certain threshold level of T.
Moreover, beneficial effects on clinically relevant parameters
such as bone fracture rates, falls, infarction rates, or
cardiovascular mortality, so far, have not been reported, and
the clinical significance of the observed effects remains
questionable.

Surveying the data available, on one hand, one is struck by
the fact that the beneficial effects of T supplementation are
much more pronounced in young hypogonadal males than in
elderly men, and, on the other hand, by the fact that although
almost a decade has elapsed since the first clinical studies on
androgen supplementation in elderly men were published, the number of elderly subjects having participated in controlled studies of androgen supplementation are very limited. We are awaiting eagerly the results of large long-term controlled studies on androgen supplementation in elderly men.

As to the first problem, this might indicate either that the
elderly men receiving androgen supplementation had higher
T levels at the start than the young hypogonadal men and
were not really hypogonadal, which was probably the case in
some studies, or that, due to a reduction of their tissue
receptors, their possible response to androgens is limited.
However, this is less likely as moderately supraphysiological
doses appear to induce sometimes polycythemia as well as an atherogenic lipid profile. It is not unlikely that the response
to androgen supplementation of the oldest men, who
generally have the lowest endogenous androgen levels,
would be comparable to the response of young hypogonadal
men. Whether higher doses of T via nongenomic effects
might be more effective is still an open question.

VERMEULEN 2384 JCE & M • 2001
Vol. 86 • No. 6

Bhasin et al. (149) as well as Young et al. (150) observed that
supraphysiological doses of T (600 mg/week im)
administered for 6 weeks to normal men increased free fat
mass, muscle size, and strength. As to the limited number of studies available, this is probably related to the fear of serious side effects, more specifically, stimulation of the development of an undiagnosed prostatic carcinoma and its possible legal consequences.