Possible benefits of androgen replacement in women

To examine the possible benefits of androgen replacement in women, it may be best to use the complications of the male hypogonadotropic state as a template, reviewing the evidence in that particular area in regards to women. Some provisos need to be noted: the state of the art of androgen replacement in women is rapidly changing, so the existing data is confounded by multiple modalities of androgen replacement, most of which are not physiological regimens. Some studies use surgically menopausal subjects while others do not. Much of the data is also based on cross-sectional studies of endogenous androgen levels and outcomes, with all the limitations of non-randomized epidemiologic data.

17.4.1 Testosterone replacement and sexual function

Multiple studies demonstrate clear evidence that testosterone replacement enhances sexual function in hypogonadal men. In women, there is also strong data in this regard. The best-known study demonstrating a beneficial effect of androgen replacement on sexual function in women was published in 1987 (Sherwin and Gelfand 1987). This trial, although non-randomized and unblinded, did demonstrate increased arousal, fantasy, coitus and orgasm in postmenopausal women given monthly intra-muscular testosterone enanthate (150 mg) and 10 mg of E2 valerate. However, mean serum testosterone levels noted in this study were well over 200 ng/dl, at least five times the physiological range seen in naturally post-menopausal women. Accordingly, a later study reported that prolonged use of this preparation resulted in virulizing effects in a number of women (Urman et al. 1991).

More sexuality data exists with testosterone replacement via subcutaneous (SQ) testosterone pellets, with or without concomitant E2. These pellets consist of 50 and 100 mg of crystalline testosterone with or without E2, and are the best characterized form of non-oral testosterone replacement to date. An early series reported a beneficial effect of these implants on sexual function (Cardozo et al. 1983), although other data showed no additional benefit of testosterone over E2 alone (Dow and Hart 1983). As seen inFig. 17.9,Davis etal. demonstrated that placement of the pellets improved multiple parameters of sexual function in postmenopausal women on HRT (Davis 1995). While the circulating testosterone levels attained were again relatively high, no adverse androgenization was reported.

Oral testosterone androgenic preparations have also been assessed in terms of sexual function in postmenopausal women. A carefully designed trial (Myers 1990) demonstrated only a slight improvement in parameters of sexual function (self-stimulating behavior) with the addition of 5 mg methyltestosterone (MT) over estrogen alone. The subjects were not selected for decreased libido. Another study using lower doses of MT did not see an improvement in sexual function (Barrett-Conner et al. 1999). In contrast, a more recent study by Lobo et al. (2003) and colleagues demonstrated that a much lower dose of MT (1.25 mg/day), in conjuc-tion with esterified estrogens, did improve various parameters of sexual function in postmenopausal women with extant hypoactive sexual desire. Because circulating MT is not easily measured, it is not clear what dose of this compound best mimics physiologic replacement therapy. In the latter study there was an adverse change in serum lipids (HDL) and decreases in SHBG levels seen with MT therapy indicating that the androgenic effect achieved to maintain this level of improvement in sexual function may have been supraphysiologic. Another two-year study with the same preparation of MT and esterified estrogen demonstrated that adverse androgenization indeed frequently occurs (Watts etal. 1995).

Sexuality Score Summary Statistics

Libido -

Activity -

Satisfaction -

Sexuality Scale Pleasure -

Fantasy -Orgasm -

Relevancy -

Sexuality Score Summary Statistics

Libido -

Activity -

Satisfaction -

Sexuality Scale Pleasure -

Fantasy -Orgasm -

Relevancy -

Fig. 17.9 Two years of subcutaneous placement of 50 mg testosterone pellets improves multiple parameters of sexual function in postmenopausal women on HRT (adapted from Davis 1995).

Another oral androgen preparation, testosterone undecanoate, has been assessed in one recent study (Floter et al. 2002) in terms of sexual function. This study was well designed, and showed improvements in well-being, self-esteem, and sexual function in these women, compared to estrogen replacement alone.

What about the effect of transdermal testosterone administration and sexual function? Perhaps the best study in this area was published by Shifrin etal. (2000). This multi-center, randomized, controlled, and blinded study assessed the effect of 150 and 300 |xg transdermal testosterone patches on sexual function in surgically menopausal women who had hypoactive sexual desire. It demonstrated improved sexual function and sense of well-being with restitution of a physiologic serum testosterone milieu. As seen in Fig. 17.10, however, the difference was not dramatic as compared to estrogen patches alone.

In all, the weight of the studies assessing the effect of various forms of androgen replacement on sexual function in women demonstrate a modest benefit in a fashion similar to, but not as pronounced as, that seen in hypogonadal men given testosterone replacement. The fact that improvement in sexual function is not dramatic may point to the relative complexity of sexual response in women, or be

Composite Score

Thoughts/Desires Arousal Frequency Initiation

Pleasure/Orgasm

Relationship Satisfaction

Problems

70 80 90 % Normative Mean

Fig. 17.10 A multi-center, randomized, controlled, and blinded study assessed the effect of 150 and 300 ^g transdermal testosterone patches on sexual function in surgically menopausal women who had hypoactive sexual desire, and demonstrated improved sexual function and sense of well being (adapted from Shifren 2000).

a reflection of study limitations, particularly in the measurement of female sexual response.

17.4.2 Testosterone and insulin sensitivity in women

In hypogonadal men, testosterone supplementation certainly does not adversely affect and may mildly enhance parameters of insulin sensitivity. One epidimio-logic study has demonstrated an association between low endogenous testosterone levels in men and subsequent development of type 2 diabetes (Oh etal. 2002). In contrast, in women, testosterone is commonly thought to increase insulin resistance. This dogma is based primarily on the observation that women with hyper-androgenic anovulation and elevated testosterone levels (polycystic ovarian syndrome, or PCOS) are frequently hyperinsulinemic. Recently, as the thoughts about hyperandrogenic anovulation have shifted, it is now recognized that an antecedent hyperinsulinemia likely results in a secondary elevation of ovarian androgen secretion with resultant hyperandrogenemia. The thought that increased testosterone causes insulin resistance in women has been further eroded by studies demonstrating that intravenous testosterone infusion does not worsen insulin resistance, and that GNRH analog suppression of hyperandrogenemia in PCOS patients does not improve insulin sensitivity (Dunaif et al. 1990). Indeed, some tantalizing data demonstrates that DHEA replacement (with resultant elevations in circulating DHEAS, A4A, and testosterone), may actually improve insulin sensitivity (Casson 1975) (Fig. 17.10).

In female testosterone replacement studies to date, very few measurements of insulin sensitivity have been measured. In a recent testosterone patch study (Schifrin et al. 2000) fasting insulin and glucose did not change. The issue of whether physiologic testosterone replacement in an androgen-deficient woman may actually improve insulin sensitivity has not been yet addressed with sensitive insulin resistance endpoints.

17.4.3 Is testosterone cardioprotective in women?

In hypogonadal men, testosterone replacement may indeed be cardioprotective. In normal men, some epidemiologic studies have demonstrated that low testosterone may adversely affect parameters of insulin sensitivity and lipoproteins, both important contributors to cardiovascular disease (Oh etal. 2002; Simon 1997). A further possible cardioprotective effect of testosterone in men may also be the observed negative correlation between serum levels and increasing intraabdominal fat (Tsai 2000). Another beneficial effect may be a short-term direct coronary vasodilator effect as demonstrated by Rosano etal. (1999). Finally, testosterone may beneficially alter blood viscosity (Basaria etal. 2002).

Are androgens actually cardioprotective in women? The few epidemiologic studies that look at correlations between elevated endogenous testosterone levels in women and heart disease show a positive association, but that may be because elevated testosterone is a marker for the metabolic syndrome associated with PCOS. One interesting study may circumferentially address the issue of the possible cardiopretective effect of testosterone in women. In an assessment of the Rancho-Bernardo cohort (Kritz-Silverstein etal. 1997) postmenopausal oophorec-tomy may actually worsen dyslipidemia and insulin resistance, both contributors to increased risk for cardiovascular disease. Intriguingly, the possibility exists that physiologic testosterone replacement in androgen deficiency may not worsen, and possibly protect, against cardiovascular disease. Obviously, given the recent results of the Women's Health Initiative and other studies regarding the effect of HRT on cardiovascular disease on postmenopausal women, such a contention with respect to androgens is highly speculative, but it must be noted that HRT clearly reduces endogenous testosterone levels. (for further discussion also see Chapter 10).

17.4.4 Testosterone replacement and body morphology in women

Multiple studies have demonstrated that testosterone replacement in hypogonadal men positively impacts lean body mass and parameters of muscle strength. Data in

1 21 1 21

Fig. 17.11 Data demonstrating that three weeks of 50 mg of DHEA replacement (with resultant elevations in circulating DHEAS, A4A, and testosterone), may actually improve insulin sensitivity, as measured by testosterone-lymphocyte insulin binding and degradation (Casson 1995).

Fig. 17.11 Data demonstrating that three weeks of 50 mg of DHEA replacement (with resultant elevations in circulating DHEAS, A4A, and testosterone), may actually improve insulin sensitivity, as measured by testosterone-lymphocyte insulin binding and degradation (Casson 1995).

this regardwith respect to women is scant. If oral DHEA replacement is considered a modified form of androgen replacement in women (a reasonable assumption, given that DHEA elevates serum testosterone), several studies in women using this form of replacement have demonstrated improvements in muscle strength and exercise tolerance. We have recently demonstrated that the V02 (maximal exercise tolerance) of postmenopausal women increases with DHEA replacement and that this may be independent of cardiac output (Fig. 17.11) (Burger et al. 2003). Certainly, several

Effect of DHEA on VO2 Peak

25 20

Fig. 17.12 One year of physiologic dehydroepiandrosterone replacement in postmenopausal women increases V02 (maximal exercise tolerance) independent of cardiac output, compared to placebo (Burger 2003). There was no significant change in weight or lean body mass by DEXA scan.

studies have demonstrated DHEA replacement in women improves lean body mass. The idea that physiologic testosterone replacement in women may improve lean body mass, increase muscle mass and increase exercise tolerance is, of course, an exciting prospect, not without basis, and worthy of further investigation.

17.4.5 Testosterone replacement and bone mass in women

Testosterone replacement clearly increases bone mineral density in hypogonadal men. Does the same effect occur in women who are given testosterone replacement? Two randomized, controlled trials exist addressing this issue. Davis et al. (1995) demonstrated a substantial improvement in vertebral and trochanteric bone mineral density in postmenopausal women given E2-testosterone pellet replacement versus E2 alone over a period of two years. Additionally, oral MT replacement improves bone mineral density over two years, although the effect seen in this study was not dramatic and at the expense of adverse androgenization, including dyslipidemia (Watts etal. 1995). In summary, there is strong evidence that androgen replacement may have a beneficial effect on postmenopausal bone, above that seen with estrogen alone.

P< O.Ol

DHEA Group Placebo Group

DHEA Group Placebo Group

The limited data existing regarding the extra reproductive effects of testosterone replacement in women indicates that there are strong parallels between men and women in this area. Testosterone replacement in women, although imperfect, clearly improves sexual function, likely improves bone mineral density (more so than estrogen alone), may improve insulin sensitivity, and finally may have a cardioprotective effect. Certainly, the concept of multi-system benefits of testosterone replacement in women is worthy of further investigation, particularly since the adverse physiologic changes seen with menopause on bone mineral density, cardiovascular disease, and lean body mass and strength significantly impact a large portion of our society.

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