Women’s sexuality after menopause: What role for androgens?

Androgens in postmenopausal women 

The major androgens in women include dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, and dihydrotestosterone (DHT). However, DHEA, DHEAS, and androstenedione are considered pro-androgens because they must be converted to testosterone in order to express their effects. Androgen biosynthesis occurs in the ovary and the adrenal under stimulation by luteinizing hormone and adrenocorticotropic hormone, respectively, along with intraglandular paracrine and autocrine regulatory mechanisms. Plasma testosterone levels fall slowly with age,2 and both free testosterone and androstenedione are produced in less quantity at midcycle in older women,3 without significant changes in testosterone during the menopausal transition.4

Starting from the third decade of life, independent of menopausal transition, circulating Δ-5 androgen levels fall linearly with age. At physiologic menopause, the cessation of follicular activity is characterized by a significant decline in ovarian production of androstenedione, more so than testosterone. The progressive fall of plasma testosterone concentrations is thus the consequence of the reduced peripheral conversion from its major precursor5 and from DHEA and DHEAS, which also decline with age. Indeed, plasma testosterone and androstenedione levels among women in their 60’s are about half those in women aged 40. And after age 70, levels of DHEA and DHEAS are 20% or less of their maximum plasma concentrations.6

As far as surgical menopause is concerned, bilateral oophorectomy both premenopausally and postmenopausally leads to a sudden 50% fall in circulating testosterone levels.7 Recent data suggest that during postmenopause, virtually 100% of active sex steroids derive from the peripheral conversion of precursors, mainly DHEA and DHEAS, to estrogens and androgens.8 These data support the concept that target tissues may represent a local source of testosterone and estradiol starting from circulating ovarian and adrenal precursors. Finally, it is important to note that oral estrogens substantially increase circulating sex steroid hormone-binding globulin (SHBG), the protein that binds circulating testosterone, with a consequent fall in free testosterone concentrations,9 while transdermal estrogens exert minimal effects on circulating androgens.10

Androgens in the etiology of desire disorders 

Gonadal steroids play a crucial role in maintaining the anatomic and functional integrity of all the structures involved in feminine sexual response. Circulating testosterone levels are aromatized to estrogen within the CNS and bind to androgen-receptor, following conversion to DHT.11 Testosterone, together with estrogen, modulates cortical coordinating and controlling centers, interpreting what sensations are to be perceived as sexual, and issuing appropriate commands to the rest of the nervous system. In addition, sex steroids affect the sensitivity of both genital organs and hypothalamic-limbic structures, where they elicit conscious perception and pleasurable reactions by influencing the release of specific neurotransmitters and neuromodulators.12 Indeed, androgens modulate vaginal and clitoral physiology by influencing the muscular tone of erectile tissue and vaginal walls.

The androgenic facilitation of vaginal smooth muscle relaxation occurs especially in the proximal vagina, producing distinct physiologic responses in comparison with estradiol.13, 14 Androgens down-regulate arginase activity by reducing L-arginine concentrations, a substrate for nitric oxide synthase (NOS), a crucial enzyme for vaginal lubrication and genital sensation. In addition, androgens interact with the synthesis and release of NOS in the proximal vagina by facilitating vaginal and clitoral smooth muscle relaxation to electric field stimulation.

Inadequate hormone-dependent vaginal receptivity is the precipitating factor of dyspareunia and other sexual symptoms that amplify pain during coital activity. A decline in libido is extremely common following a history of dyspareunia. The consequent reduction of orgasmic capacity may reduce sexual satisfaction, negatively influencing sexual motivation and creating a self-sustaining “loop.” This model clearly explains the high degree of comorbidity displayed by sexual symptoms in women.

Studies conducted in the fertile age report an increase in establishing interpersonal relationships and exchanging sexual pleasure during the periovulatory period, corresponding to the plasma androgenic peak, even though no clear correlation has been reported between plasma androgen levels and sexual response. In addition, we should keep in mind that the strong motivation to sexual activity at the time of ovulation may be due to a peak in estrogen.15, 16

Estrogen-progestin use, particularly in a monophasic regimen, seems to interfere with the spontaneous expression of sexual desire, but even the effects of the pill on mental wellbeing may play a role in sexual motivation.17, 18 Several authors have reported that serum testosterone levels are related to genital response and to subjective physical sensation (lubrication and breast sensitivity) in response to visual erotic stimulation both in premenopause and postmenopause.19 Moreover, antiandrogen administration has been associated with low libido in females.20 Further evidence suggests that circulating free testosterone relates to sexual desire and masturbation in young women.21 Finally, 5 α-reductase activity is significantly impaired in target tissues in those women reporting low libido following menopause,22 while a significant correlation has been found between high levels of circulating testosterone and androstenedione and a lower index of vaginal atrophy.23

Especially during menopause, sexual symptoms are highly expressed in women with psychologic symptoms.24 The high degree of co-morbidity complicates every attempt to correctly diagnose and treat sexual dysfunction throughout reproductive life. There is no doubt that surgical menopause is associated with the so-called androgen deficiency syndrome, an increasingly accepted clinical entity characterized by low libido, persistent and inexplicable fatigue, blunted motivation, and a reduced sense of well-being.

The treatment options 

Tibolone 

It is worth mentioning the therapeutic use of tibolone (Livial), a synthetic steroid, for climacteric symptoms and low mood and libido.26, 27 Tibolone can be selectively metabolized by individual tissues to its estrogenic, progestrogenic, or androgenic metabolites and hence exhibits tissue-specific hormonal effects. It exerts an estrogenic effect at the vaginal tissues and a mild androgenic effect within the CNS. These data support the notion that such a tissue-specific compound is a good therapeutic option to relieve sexual symptoms at menopause because of its estrogenic and androgenic properties.

Recent data also have demonstrated that circulating levels of DHEA decrease progressively and significantly during 12 months of treatment using various estrogen or estrogenprogestin molecules, regimens, and routes of administration (Figure 1).28 Interestingly, tibolone administration does not induce a reduction in circulating levels of DHEA (article in press). Unlike estrogen-based therapy, tibolone does not affect the androgen milieu in postmenopausal women and does not aggravate the physiologic androgen deficiency syndrome.

View Large Image Download to PowerPoint

Figure 1. Dehydroepiandrosterone (DHEA) circulating levels in response to 12 months of treatment using various estrogen and/or progestin molecules, regimens, and routes of administration.28 TE, transdermal estradiol; MPA, medoxyprogesterone acetate; E2, estradiol; NETA, norethisterone acetate; CEE, conjugated equine estrogens Adapted from Bernardi F et al. Gynecol Endocrinol 2003;17:65–77.28

These observations let us speculate that the increase in well-being, libido, sexual pleasure, and arousal observed in postmenopausal women treated with tibolone stem not only from the direct effect of its active metabolites in specific brain areas but also, probably, from the lack of reduction of endogenous DHEA synthesis/release and from the lack of increase of SHBG levels as seen with oral estrogen therapy.29

Δ-5 androgens: a new piece of the mosaic 

Although the majority of studies related to androgen replacement have been performed using testosterone therapy in selected patients, the age-related decline of DHEA has prompted research on its experimental replacement in women. Epidemiologic data suggest a link between decreases in DHEA levels and declines in cognition and immune function and increases in insulin resistance and the incidence of neoplasia.30 Conversely, the administration of DHEA improves physical and psychological well-being, sexuality, and cognitive performance in aged subjects.31

It is of great relevance to remember that DHEA and DHEAS also are considered “neurosteroids” because they are produced in the CNS and may directly affect central functions. The concentrations of DHEA and DHEAS in the CNS are 5–10 times greater than in plasma levels.32 Experimental evidence suggests that the effects of DHEA and DHEAS on the CNS also occur directly through specific binding to the γ-aminobutyric acidA (GABAA) receptor, with a resulting increase in neuronal excitability.

At present, however, it is unknown whether changes in circulating levels of DHEA and DHEAS, or treatment with DHEA, can directly affect CNS functions. In experimental animals, DHEA treatment has induced a memory-enhancing effect. In vitro studies suggest a neurotrophic effect on neurons and glial cells.

On the basis of these animal studies, DHEA has been administered in women. It was tested recently as a 25 mg/d oral therapy for 12 months in early and late postmenopausal women. Throughout the course of treatment, progressive and significant increases occurred in levels of DHEA, DHEAS, androstenedione, testosterone, DHT, estrone, estradiol, progesterone, 17 OH-progesterone, allopregnanolone, β-endorphin, and growth hormone. The levels reached were similar to those observed in fertile women, without significant differences between the two groups. While testosterone showed slightly supraphysiologic levels after one year of therapy, SHBG levels did not show significant modification. On the contrary, cortisol and gonadotropin levels progressively decreased in all groups.33

These data indicate that DHEA supplementation induces a dose-related modulation on endocrine and neuroendocrine parameters and that a low dose (25 mg/d) is effective in restoring physiologic levels. On the other hand, 12 months of 25 mg/d DHEA therapy did not change endometrial thickness. This fact might be ascribed to the threefold DHEA-induced increase in circulating progesterone concentrations. Therefore, the effect of DHEA at the endometrial level seems to be similar to that induced by continuous combined hormone therapy.

Thus DHEA is active as a prehormone, inducing modifications that counteract the phenomena occurring during menopause and aging. The use of low doses of DHEA is effective to positively modulate the endocrine and neuroendocrine milieu. Its beneficial effects on quality of life and in reverting aging processes may be related to the increase in anxiolytic (allopregnanolone and β-endorphin), anabolic (androstenedione, testosterone, DHT), and estrogenic molecules, and a favorable blunt in cortisol levels.

Summing up 

Ideally, physicians will be able to translate the gathering evidence about gonadal steroids into an increasing ability to improve women’s sexual health. We must move from the mechanics and psychobiology of female sexual function and dysfunction to a more comprehensive view of patients as sexual human beings, satisfying the ultimate goals of better health and improved quality of life. □