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.