Menopausal Status and the Androgen Milieu

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The correlation between menopausal status and sexual health among diabetic women has been poorly investigated. Data seem to suggest, however, that the postmenopausal condition does not cause a significantly negative impact on women's sexuality particularly because of the diabetes mellitus itself (9, 23, 37, 38, 40).

Similarly, the potential associations among the circulating androgen milieu [total and free testosterone, dehydroepiandrosterone (DHEA), DHEA sulphate (DHEAS), and A4-androstenedione (A4A)] and SF in diabetic women have been scarcely analysed, especially when studies adequately segregating both the type of diabetes and the pre- vs. postmenopausal population are considered. In contrast, several studies have analysed the concept that endogenous sex hormones may have a role in sex-dependent aetiologies of DM2, such that hyperandrogenism may increase risk in women while decreasing risk in men (55-63). In their comprehensive review, Ding et al. (56) reported that cross-sectional studies indicated that testosterone level was significantly lower in DM2 men but higher in DM2 women than in controls (p < 0.001, for sex difference). Similarly, prospective studies showed that men with higher testosterone levels had a 42% lower risk of DM2 (RR: 0.58; 95% CI: 0.39-0.87), while there was suggestion that testosterone increased risk in women (p = 0.06, for sex difference). These authors concluded that endogenous sex hormones may differentially modulate glycaemic status and risk of DM2 in men and women (56). Likewise, data from the cross-sectional Multi-Ethnic Study of Atherosclerosis on 1973 postmenopausal women not taking hormone replacement therapy showed that endogenous bioavailable testosterone, estradiol, and DHEA were positively associated, whereas sex hormone-binding globulin was negatively associated with insulin resistance (57). Moreover, Korytkowski et al. (58) showed that DM2 postmenopausal women have both clinical and biochemical evidence of androgen excess that may contribute to more adverse cardiovascular risk profiles. Similarly, Phillips et al. (62) analysed the correlation between androgens and coronary heart disease among DM2 postmenopausal Hispanic women. These patients had both hyperandrogenemia and hyperestrogenemia, with total or free testosterone positively correlated with a greater risk for coronary heart disease. Thus, Phillips et al. concluded that hyperandrogenemia may be a link between diabetes and coronary heart disease in women (62). Indeed, hypoandrogenism, coronary heart disease, and diabetes are all significant independent predictors of sexual disorders in men. Thus, the actual pathophysiology of the relationship between diabetes mellitus, menopause and women's SF certainly needs to be adequately investigated.

The role of endogenous androgens in women's SF among the general population is still controversial (23, 64-66). Androgens play a key role in determining sexual desire and satisfaction, as well as in conditioning mood, energy and psychological well-being (64, 67). Androgens are necessary for the development of female reproductive function and hormonal homeostasis, and they are the immediate precursors of estrogens. In pre- and postmenopausal women, a low serum-free testosterone level has been proposed as a diagnostic marker of the female androgen insufficiency syndrome, which is characterized by reduced libido, diminished well-being and depressed mood (64, 66-68). There is increasing awareness of the impact of low androgen levels on the emotional, social, psychological and sexual well-being of women. Several studies have shown that testosterone substitution therapy in women may improve sexual desire, orgasm and satisfaction after either physiological (65, 66, 69, 70) or surgical menopause (65, 66, 70-75).

However, the diagnosis of female androgen insufficiency syndrome is not unequivocal, because there is currently no reliable and inexpensive assay to measure circulating levels of free testosterone in the range observed in women (23, 76), nor is there agreement on the serum-free testosterone threshold that defines the hypoandrogenism associated with impaired SF (23, 77, 78). In addition, we must note that the levels of circulating androgens associated with symptomatic hypoandrogenism have not been unequivocally defined even for men (23, 76, 79-81).

Moreover, recent data show that endogenous androgens are not independent predictors of well-being in postmenopausal women. Only DHEAS is associated with greater vitality in premenopausal women (78). In addition, a recent community-based, cross-sectional study including more than 1,400 women failed to show a relationship between low serum levels of either free or total testosterone or A4A and low psychometric scores for SF. Interestingly, the same study demonstrated that among premenopausal women low DHEAS levels were associated with lower scores for sexual desire, sexual arousal, and sexual responsiveness (82). The Endocrine Society recently recommended against diagnosing androgen deficiency in women because a widely accepted definition of female androgen insufficiency syndrome and normative total or free testosterone levels in women throughout their lifespan are still not available (23, 65).

Labrie et al. (83, 84) demonstrated that steroid hormones can be produced within cells in peripheral target tissues, where they can exert effects without release into systemic circulation, thus making unreliable the measurement of serum testosterone as a marker of total androgenic activity. This implies that serum levels of androgenic hormone might not accurately reflect the actual androgenic activity in tissue (84). This may have implications for women with androgen deficiency involving osteoporosis, obesity, DM2, SD or a loss of muscular strength. Therefore, the role of androgens in both glucose homeostasis and SF in postmenopausal women requires further study.

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