Rossella E. Nappi, MD, PhD, Research Center for Reproductive Medicine, Department of Morphological, Eidological and Clinical Sciences, & Gynecological Endocrinology Unit— Department of Internal Medicine & Endocrinology, IRCCS S. Maugeri Foundation, University of Pavia, Via Ferrata 8—27100 Pavia, Italy. Tel: +39 0382 592201; Fax: +39 0382 520070; E-mail: email@example.com
Introduction. Estrogen is relevant to women's well-being including sexual functioning.
Aim. The goal of this Continuing Medical Education article was to provide a comprehensive review of the effect of exogenous estrogen use on women's sexual function.
Main Outcome Measures. We present a literature review.
Methods. The medical literature was accurately searched (1990–2008) with regard to estrogen therapy in menopausal women by using several terms related to and including the terms “estrogen” and “sexual function.”
Results. A review of the studies most useful to guide menopausal practice.
Conclusions. Estrogen decline is one of the key factors contributing to sexual functioning during menopausal transition and beyond. Systemic estrogen treatments are associated with significant benefits in some domains of menopausal sexual function, especially when estradiol is delivered transdermally, whereas local estrogens are effective in preventing urogenital aging. Even tibolone, a selective tissue estrogenic activity regulator, displays positive effects in postmenopausal women with sexual complaints. However, a tailored approach to the individual woman is always needed. Nappi RE, and Polatti F. The use of estrogen therapy in women's sexual functioning. J Sex Med 2009;6:603–616.
A direct link between sex hormones and sexual functioning remains elusive because of the multitude of intrapersonal and interpersonal factors influencing human sexual behavior. However, the hormonal environment is certainly relevant to sexual function given the evidence that sex hormones, estrogens and androgens, modulate cortical coordinating and controlling areas interpreting what sensations are to be perceived as sexual and issuing appropriate commands to the rest of the nervous system. In addition, sex hormones affect the threshold of sensitivity of both nongenital and genital organs and of hypothalamic-limbic structures where they elicit conscious perception and pleasurable reactions by influencing the release of specific neurotransmitters and neuromodulators [1,2]. Estrogens especially represent the core of womanliness and play a critical role in maintaining the physiological function of many tissues, including the central nervous system and the genital apparatus, and of organs relevant to general health .
Sexual complaints and problems in women are prevalent during the entire reproductive life span, but women attending menopause clinics may be more vulnerable to develop female sexual dysfunction (FSD) because of a complex interplay of peculiar individual factors variably affecting the sense of well-being, including endocrine changes . Based on cross-sectional studies, the average age of natural menopause can be estimated between 50 and 52 with a wider range of normal extending from the 30s to 60s . Menopause occurs with the permanent cessation of menstruation following the loss of ovarian activity as a result of the natural aging process throughout a period of neuroendocrine transition. Estradiol levels progressively decline, particularly during the late menopausal transition phase, and estrone, in spite of its reduced secretion, remains the predominant estrogen postmenopausally because of the peripheral conversion of pre-androgens and testosterone of ovarian and adrenal origin . Therefore, natural menopause represents a good model to understand the role of estradiol deprivation in women's physical and mental well-being, including sexual function. On the other hand, the iatrogenically removal of both ovaries, the so-called “surgical menopause” which may occur well before the age of natural menopause, represents a suitable clinical model in order to explore the effects of acute estrogen and even androgen deprivation in several domains of sexual function and general well-being . Indeed, testosterone levels significantly decline with age, independently from the menopausal transition, because of a progressive reduction of adrenal production, but the menopausal ovary is still capable of producing a variable amount of androgens with relevant effects on women's health, depending on the bioavailability of sexual hormones within target tissues [8,9].
Endogenous Estrogens and Sexual Functioning
Sexual function involves a successful integration of neural, vascular, and muscular circuitries critically modulated by the endocrine system. The paramount importance of estrogens over a lifetime is clearly evident in vulvovaginal tissues  and the sexual implication of estradiol in mental awareness, genital receptivity, and general responsiveness has been largely investigated especially in the spontaneous menopausal model . Even the use of aromatase inhibitors in order to diminish estrogen synthesis in women with breast cancer gives origin to symptoms similar to that seen with the natural events of aging, confirming the essential role of estrogen in quality of life and sexual well-being . Briefly, estrogen deficiency induces a neuroendocrine adaptation which involves a complex rearrangement of a vast array of neurotransmitters, neuromodulators, and other neuroactive mediators relevant namely to thermoregulation, mood, pain threshold, and cognition . Indeed, estrogen exerts both organizational and activational effects at multiple levels of the nervous system, and its actions are mediated by nongenomic as well as direct and indirect genomic pathways. In addition to affecting the hypothalamus and other brain areas related to reproduction, estrogen are involved in a multitude of nonreproductive brain functions and therefore, estrogen withdrawal after natural or surgical menopause can lead to a host of changes in brain function and behavior . Menopausal symptomatology may be variably expressed in every single woman and may also include sexual symptom such as modification of sexual desire, impairment of central arousal, and reduced perception of orgasm and satisfaction. On the other hand, estrogen deficiency significantly contributes to urogenital and vaginal involution by reducing epithelial cell proliferation, paracellular permeability, and smooth muscle content, and by inducing vascular remodeling and changes in innervation. Vaginal pH shifts from acidic to alkaline and vaginal secretion are reduced, contributing to genital symptoms of dryness, irritation/burning, pruritis, and recurrent vaginitis. In addition, urinary symptoms, such as frequency, urgency, nocturia, dysuria, incontinence, and postcoital/recurrent urinary infection, may be present. Over time, vaginal vault becomes pale in appearance and less elastic with loss of rugation and tissue friability followed by progressive shortening and narrowing, while the clitoris gets fibrosed and the vulvar and labial tissues lose fullness .
The proportion of urogenital aging is significantly high following menopause and women will spend more than one-third of their life in condition of hypoestrogenism. A cross-sectional analysis based on N = 98,705 postmenopausal women (age range: 50–79 years) enrolled in the US-based Women's Health Initiative observational study and clinical trials displayed a prevalence rates for dryness of 27.0%, for irritation or itching of 18.6%, for discharge of 11.1%, and for dysuria of 5.2% . The significance of such symptoms in terms of sexual function is strongly dependent on age and level of sexual activity, given the evidence that pain during intercourse is generally less reported later in life mainly because older women are less likely to still have a spousal or other intimate relationship . In 349 sexually active community-based women, aged 20–65 years, who self-identified as being either satisfied or dissatisfied with their sexual life, postmenopausal satisfied women reported less sexual thoughts, days with sexual activity, and sexual events per month compared with premenopausal satisfied women . In any case, when urogenital atrophy is present, sensation, vasocongestion, and lubrication are highly damaged; thus, in sexually active postmenopausal women genital arousal may be impaired and sexual pain disorders (dyspareunia and vulvodynia) may frequently occur. In brief, estrogen highly orchestrates the entire hemodynamic process leading to vaginal vasocongestion and increased lubrication by affecting alone, or in association with androgens, the complex cascade of mediators involved in genital arousal [2,19,20]. The inadequate hormonal-dependent genital receptivity is likely to cause other sexual symptoms which contribute to amplify pain during coital and noncoital activity. Indeed, it is extremely common to observe a lack of mental arousal and a decline of sexual desire following a history of sexual pain; the consequent reduction of orgasmic capacity may, then, reduce sexual satisfaction which, in turn, negatively influences sexual motivation, activity, and couple's relationship. That being so, there is a high degree of comorbidity among sexual symptoms in menopausal women and it is important to recognize timely the “leader” symptom to avoid such cascade of negative events and to establish appropriate treatments. Indeed, if hypoactive sexual desire disorder (HSDD) is present, as the result of androgen insufficiency related to the removal of the ovaries or to other medical conditions, it is likely that the entire sexual response may be compromised, regardless of the presence of urogenital symptoms. On the other hand, an adequate treatment of the estrogen-dependent consequences of urogenital aging may significantly maintain sexual desire over time in postmenopausal women . Finally, it is likely that the “domino” effect of other menopausal symptoms, namely hot flushes and mood swings, can modulate the clinical expression of FSD [4,22].
During the normal menstrual cycle, circulating estradiol levels are comprised mostly between 50 and 400 pg/mL (180–1,400 pmol/L), being lower during the menstrual phase and higher during the ovulatory phase. At menopause, estradiol levels are normally low, between 10 and 20 pg/mL (40–70 pmol/L) . At a level of estradiol less than 50 pg/mL (180 pmol/L), women reported more vaginal dryness, increased frequency and intensity of dyspareunia, pain with penetration and deep insertion, and burning . Other studies indicated that perimenopausal women with higher levels of estradiol did not report any complaints related to sexual desire, response, or satisfaction, while estradiol levels below 35 pg/mL (130 pmol/L) were associated with reduced coital frequency [4,24]. In a sample of sexually active elderly postmenopausal women (average age: 65 years), subjects with very low levels of E2 (<20 pmol/L; <5.4 pg/mL) had significantly greater discomfort and inability to relax compared with women with E2 ≥ 20 pmol/L (5.4 pg/mL). After 3 years, women with E2 ≥ 20 pmol/L (5.4 pg/mL) had significantly less decline in sexual enjoyment, satisfaction, sexual comfort, and sexual feelings summary score, when compared with women who had E2 levels <20 pmol/L (<5.4 pg/mL) .
The longest duration population-based study, the Melbourne Women's Midlife Health Project, found a significant decrease of women's desire, arousal, orgasm, and frequency of sexual activity and a significant increase in vaginal dryness/dyspareunia with a rate of sexual dysfunction from 42% to 88% throughout the menopausal transition. Both age and declining estradiol had significant detrimental effects on sexual functioning, desire, and sexual responsiveness (arousal, sexual pleasure, and orgasm) [26,27]. Interestingly enough, by investigating the relative effects of hormonal and relationship factors in sexual function during the natural menopausal transition, Dennerstein et al.  demonstrated that the best predictors of sexual function were prior level of sexual function, change in partner status, feelings for partner, and estradiol level (R2 = 0.65). Moreover, the minimum effective dose of estradiol needed to increase sexual response by 10% (700 pmol/L; 190.7 pg/mL) is twice that needed to decrease dyspareunia, supporting the notion that other hormonal-mediated mechanisms, modulating physical and mental well-being more broadly, are involved in sexual functioning across the menopause. Indeed, data from a US community-based sample of 441 women aged 45–54 years who stated that they were sexually active at the time of the study showed that the experiencing of depressive symptoms and the reporting of poor overall health were important correlates of sexual dysfunction . On the other hand, it is critical to keep in mind that circulating levels of estradiol may not reflect estrogenic activity within the target tissues (brain, vagina, etc.) and other estrogen metabolites may be as well important. Finally, it is worth to remember that every woman possesses her own threshold to hormonal variation depending on several factors, from genetic disposition to lifestyle and personal experiences, and a wide range of individual responses may be observed at physical and behavioral level following hormonal manipulations .
In this short review, we reported the studies most useful to guide menopausal practice regarding the role of estrogens administered either systemically or locally for prevention and treatment of FSD. In addition, we tried to critically discuss the type of estrogen therapy in the context of sexual functioning. The medical literature was accurately searched (1990–2008) with regard to estrogen therapy in menopausal women by using several terms related to and including the terms “estrogen” and “sexual function.”
Exogenous Estrogens and Sexual Functioning
The management of sexual symptoms at menopause should be individualized and tailored on women's history and current needs to obtain meaningful and long-lasting results in clinical practice.
“Pills” are not everything in the field of FSD and offering unrealistic expectations may be extremely frustrating for women and their partners and can be a real “boomerang” for the clinician. Indeed, intrapersonal and interpersonal factors need to be addressed and adequately treated with basic counseling and psychosexual interventions. However, a well-balanced view of the biological components conditioning the most common complaints such as vaginal dryness and painful sex, low sexual desire, poor sexual orgasm, and satisfaction, and of the psycho-relational aspects amplifying or initiating some of these symptoms, is always very helpful and those women who are effectively distressed by FSD may gain great benefits by using medical treatments [31,32].
Hormone therapy (HT) with estrogen alone (ET), as it is indicated in hysterectomized menopausal women, and with estrogen-progestin (EPT), as it is currently used in menopausal women with intact uterus, has been the first-line hormonal treatment for women reporting menopausal symptoms (mainly hot flushes) across menopausal transition and beyond. Recent guidelines support the initiation of HT around the time of menopause to treat menopause-related symptoms and/or to reduce the risk of osteoporosis or fractures in selected population of peri- and postmenopausal women. The benefit–risk ratio for menopausal HT is favorable during the years close to menopause (the so-called “window of opportunity”) but decreases with aging and with time since menopause in previously untreated women [33,34]. Other strategies, including alternative nonprescription remedies and/or nonhormonal prescription options, can be used, if effective, for mild vasomotor symptoms, taking into account the scientific uncertainties of such therapeutic options . In a recent workshop on menopause and aging, quality of life, and sexuality, the panel concluded that the administration of individualized hormonal therapies in women suffering from relevant climacteric symptoms clearly improves quality of life and sexuality and should therefore be recommended whenever necessary and at the dose and for the time that are necessary to improve symptoms and to get back to the woman a satisfying quality of life and sexual function . The value of the different interventions which have the potential to impact the development or progression of chronic diseases, such as cancer, cardiovascular disease, or osteoporosis, should be weighted both for efficacy and cost-effectiveness but also for the potential to modulate quality of life and sexual function .
Systematic reviews including all randomized and placebo-controlled trials of treatment for FSD in postmenopausal women concluded that many HTs that are used in practice are not supported by adequate evidence [30,37]. Even though ET/EPT may be an effective treatment for vaginal atrophy, increasing vaginal lubrication, and reducing dyspareunia, it has not been shown to increase consistently sexual desire or activity and many women with FSD remain unresponsive. There is a significant subgroup of women with sexual symptoms who respond initially to ET/EPT but subsequently revert to their initial problems, especially when symptoms include loss of sexual desire, as it is frequent in surgical menopause in which the addition of androgen treatments has proved to be helpful both at supraphysiological and physiological levels [23,38,39]. However, the interpretation of the results available on ET/EPT needs to be expanded, taking into account the differences existing among various schemes of conventional HTs in terms of type of molecules, dosage, regimen, routes of administration, mechanism of action, and metabolism. The type of estrogen modulates both the amount of bioavailable sexual hormones at target tissues and the ovarian and adrenal androgenic milieu, while the association of progestins can oppose the positive effects of estrogens and lead to a recurrence of dryness and dyspareunia [40–42]. In this context, it is relevant to focus the attention on the role of sex hormone-binding globulin (SHBG), a glycoprotein synthesized and released by the liver, which is the principal carrier of sexual hormones. Circulating levels of SHBG influence the dynamic equilibrium existing between bound and free fractions and modify the amount of sexual hormones available to cells. Several factors modulate SHBG production and activity, including circulating estrogen (high levels increase it) and androgen (high levels decrease it), changes in body weight, thyroid function, physical activity, alcohol intake, etc. Across menopause, SHBG levels are slightly decreased (around 50 nmol/L) and are variably affected by the biochemical properties of HT [6,8,9] (Figure 1). Indeed, it has been shown that SHBG strongly increased by using conjugated equine estrogens (CEE, 0.625 mg/day), moderately increased with micronized estradiol (1 mg/day) and slightly increased with transdermal estradiol (TDE2, 0.05 mg/day) . This piece of information has been recently corroborated by a randomized, open-label crossover study by Shifren et al.  comparing the effect of oral vs. transdermal estrogen therapy (plus oral micronized progesterone 100 mg/day, continuously) on serum sexual, thyroid, and adrenal hormones in naturally menopausal women. TDE2 (0.05 mg/day), which avoids first-pass metabolism by liver and enzymatic degradation by gastrointestinal tract, displayed a very mild effect on SHBG levels (+12%), while CEE (0.625 mg/day) significantly increased circulating SHBG (+132.2%) after 12 weeks in comparison with baseline. The amount of free estradiol was almost double in women treated with TDE2, while free estrone was significantly higher in women taking CEE. Free testosterone was significantly reduced (−32.7%) in women on CEE, while it was almost unchanged in women on TDE2 (+1%). DHEAS levels significantly increased under both treatments, with a higher change in TDE2 (+35.1%) in comparison with CEE (+21.8%). Even on free thyroxine, the two treatments behaved differently, with a significant reduction (−10%) in women on CEE in comparison with those on TDE2 (+0.3%). Thus, there is a striking difference between CEE and TDE2 in terms of hormonal bioavailability with significant implications in clinical efficacy, potential side effects, and risk profile of diverse HT options. By avoiding first-pass hepatic metabolism, TDE2 maintains high effectiveness even at lower doses (0.0375, 0.025, and 0.015 mg/day) with greater tolerability, as side effects (breast tenderness, vaginal bleeding, etc.) are generally dose-related. TDE2 induces a less pronounced effect on hepatic protein synthesis, such as markers of coagulation and fibrinolysis, while oral estrogen has more pronounced hyper-coagulant effects and increases synthesis of C-reactive protein and fibrinolytic markers . Recent epidemiological data identified differences in the risk of venous thromboembolism (VTE) between oral and transdermal HT and as a function of oral estrogen dose [46,47]. It remains unclear whether reduced doses of estrogen or the transdermal route display a better safety profile in terms of atherosclerotic cardiovascular diseases or breast cancer risk, also as a consequence of the possibility of reducing the exposure to progestins for endometrium protection .
The diverse effect of TDE2 on vascular homeostasis may be relevant also to sexual function, given the importance of estrogen in modulating the hemodynamic process of genital arousal. That being so, the data from Nathorst-Boos et al. on sexual function  deserve attention because they were obtained by using TDE2 against placebo in naturally menopausal women. A Swedish version of “McCoy's Sex Scale Questionnaire” (MFSQ), a validated scale designed to measure aspects of female sexuality likely to be affected by changing sexual hormone levels, was used. Following 12 weeks, items regarding “satisfaction with frequency of sexual activity, sexual fantasies, degree of enjoyment, vaginal lubrication and pain during intercourse” were positively influenced in the TDE2 group compared with the placebo group. Items not affected were “frequency of orgasm and sexual arousal.” By using the Swedish version of the Women's Health Questionnaire (WHQ), a patient-based measure of postmenopausal complaints including sexual symptoms, Wiklund et al.  showed an increase in feelings of physical attraction, sexual satisfaction, and sexual life and a decrease in sexual problems following TSDE2 vs. placebo. In line with the new trend of lowering the HT dose as much as possible particularly in elderly women, a very recent multicenter, randomized, double-blind, placebo-controlled trial assessed sexual function by validated instruments in 417 older postmenopausal women treated for 24 months with ultralow-dose TDE2 (0.014 mg/day) . Ultralow-dose TDE2 resulted in a modest improvement of sexual function related to vaginal pain and dryness but not in other domains of sexual function (desire, satisfaction, problems, or orgasm). A randomized double-blind controlled trial by using CEE (0.625 or 1.25 mg for days 1–25) plus medroxyprogesterone acetate (MAP 5 mg from days 15–25) published several years ago in naturally menopausal women was the only study demonstrating positive effects of oral estrogen treatment on sexual desire and arousal and the relevance of the estrogen/progestin dose ratio on sexual well-being. However, the Daily Menopausal Rating Scale used in this trial was not well validated . Even though we have clearly shown that CEE has a detrimental effect on circulating testosterone and therefore may be potentially harmful to sexual function, it is worth to remember that such compound gives origin to several forms of estrogens which are biologically active and may exert per se a positive influence on sexuality. Moreover, the availability of lower CEE doses, equally effective on climacteric symptoms , offers an additional option in the management of postmenopausal women with less impact on androgen milieu and vascular homeostasis. A recent study evaluated the safety and efficacy of CEE (0.3 mg/day) for 12 weeks in the treatment of vulvovaginal atrophy in symptomatic, postmenopausal women (mean age 58.6 years). A significant improvement was seen in vaginal maturation index, vaginal pH, and severity of vaginal dryness and pain during intercourse from baseline to the end of treatment .
The addition of progestins seems problematic in terms of sexual functioning, and we still lack well-designed studies to address this issue. Their biochemical properties and the route of administration are likely to be critical because of peculiar effects on SHBG and of the nature of metabolites . For example, norethisterone acetate (NETA), a progestin with some estrogenic and androgenic activity, administered orally or transdermally has been used in comparative studies as the best competitor to try to demonstrate the superiority of other compounds with respect to EPT [55,56]. On the other hand, new progestins with antiandrogenic properties, such as drospirenone and nomegestrol acetate, in doses used in HRT do not appear to have a negative effect on sexual function and have the potential of not counteracting the beneficial effects of estrogen .
Collectively, these data allow us to reasonably state that transdermal estradiol seems to be the more logical choice to treat peri- and postmenopausal women with FSD, because it avoids a further reduction of circulating androgens without significantly affecting vascular homeostasis. Taking into account a risk–benefit ratio, the dose more adequate in early postmenopausal women with FSD appears to be 0.05 mcg/day (Table 1). However, on the basis of the existing literature, which comprises only a paucity of well-designed studies with EPT by using validated sexual instruments, and on clinical experience, we cannot exclude that other combinations of EP molecules, as well as their mode of administration and dosages, may be equally effective on sexual functioning of the individual woman. Indeed, we should always try to use the lowest effective dose of HT either by oral or non-oral formulations as the first-line treatment because of the better safety profile and the highest tolerability.
Table 1. Randomized controlled studies on the effects of transdermal estradiol (TDE2) on sexual function in naturally postmenopausal women
N = 223 50 µg Transdermal estradiol patch vs. placebo
• Sexual problems ↓ • Feeling of physical attractiveness ↑ • Sexual satisfaction ↑ • Sex life ↑
To prevent urogenital and vaginal aging is critical for maintaining sexual function across the menopausal transition and beyond. Sexual symptoms related to vaginal atrophy are even possible in other clinical conditions characterized by hypoestrogenism such as breast-feeding and secondary amenorrhea. Topical estrogen (ET) is the basic treatment for urogenital symptoms and may be administered alone or in combination with systemic ET/EPT, when needed [58,59]. It has the advantage that can be used in women of any age and low doses are highly effective to maintain vaginal tropism, as confirmed by cytology. When the vaginal epithelium is atrophic, the degree of systemic absorption is low initially but it increases over time due to the estrogen-mediated improvement in vascularity . Several studies have compared a large number of treatment options including creams, tablets, suppositories, pessaries, and rings and in carefully controlled trial, no specific treatment regimens have been shown to be superior to others at menopause. Topical ET includes CEE, estriol (E3) (not available in the US market), and estradiol (E2) to be used at the recommended doses to avoid significant systemic absorption, particularly in women with a history of breast cancer or other estrogen-dependent diseases . Vaginal E2 use is, however, contraindicated in women with breast cancer taking aromatase inhibitors because of the small but significant increase of circulating E2 levels, at least in the short term .
In healthy women, the efficacy and safety of vaginal E2 tablets (25 mcg) were assessed and compared with CEE vaginal cream (1.25 mg) for the relief of menopausal-derived atrophic vaginitis resulting from estrogen deficiency in a multicenter, open-label, randomized, parallel-group study. Both treatment regimens were equivalent in relieving symptoms of atrophic vaginitis in postmenopausal women, but vaginal tablet therapy resulted in greater patient acceptance and lower withdrawal rates compared with vaginal cream therapy, without appreciable systemic estradiol increases or estrogenic side effects . A similar result was evident by comparing vaginal estradiol tablets with estriol vagitories (0.5 mg) in postmenopausal women . A recent prospective, randomized study in which women were assigned to a continuous low-dose E2-releasing vaginal ring (2 mg) and to vaginal E2 tablet confirmed no statistical difference in the alleviation of symptoms and signs of urogenital estrogen deficiency with equivalent endometrial safety at 48 weeks . Thus, it is not recommended to perform annual endometrial surveillance in asymptomatic women using vaginal ET. Other alternative and complementary therapies exerting local effects similar to estrogens are available but their efficacy and safety are questionable. Collectively, the results indicate that all of the low-dose vaginal estrogen products approved for treatment of vaginal atrophy are equally effective at the doses recommended in labeling. The choice of therapy should be guided by clinical experience and patient preference and vaginal ET should be continued for women as long as distressful symptoms remain. When a history of hormone-dependent cancer is present, management recommendations are dependent upon each woman's preference in consultation with her oncologist .
Other HTs with Systemic Estrogenic Activity
Estrogen-containing HT is the most widely prescribed and well-established therapeutic approach for menopausal symptoms. However, other medications with systemic estrogenic activity (namely SERMs and tibolone) displaying peculiar risk/benefit profiles have been studied over the years for prevention and treatment of estrogen deprivation [66,67].
SERMs include a relatively large number of compounds, each with different profiles of estrogenic/antiestrogenic actions in target tissues. SERMs have effects on tissues containing estrogen receptors, such as the breast, bone, uterine and genitourinary tissues, and brain, and on markers of cardiovascular risk. Current evidence indicates that each SERM has a unique array of clinical activities and, contrary to their well-established positive effects in osteoporosis prevention, SERMs do not seem to have a class-specific effect on the neuroendocrine system and the genitourinary tract. Therefore, sexual functioning may be differently affected according to the peculiar pattern of action and any conclusion on SERMs should be established in appropriate clinical trials. Many SERMs have entered clinical development very recently and there is a great hope for therapeutic options tailored on the specific needs of women in terms of preventive medicine. Early SERMs include clomiphene citrate, used for the treatment of ovulation induction, and tamoxifen which is widely used in the treatment of patients with breast cancer and for chemoprophylaxis in high-risk women . Tamoxifen results in a spectrum of abnormalities involving the genital tract, including pain, burning, or discomfort with intercourse , in spite of its ability to increase the vaginal maturation index . However, the study of the sexual side effects of any kind of chemotherapy is a complicated issue because of the complexity of intrapersonal and interpersonal factors involved in the burden of breast cancer . Sexual dysfunction occurred more frequently in women who had received chemotherapy (all ages), and in younger women who were no longer menstruating, while in women older than 50 years, tamoxifen therapy was unrelated to sexual functioning . The association of other hormonal chemotherapies, such as GnRH analogs and aromatase inhibitors, to tamoxifen significantly worsened sexual symptoms , while the addition of tamoxifen to GnRH analogs reduced sexual fears and symptoms in premenopausal women probably as a consequence of the estrogenic action on the genital tract .
Raloxifene is a second-generation SERM that functions as an estrogen antagonist on breast and uterine tissues, and an estrogen agonist on bone. It is available in many countries worldwide for the treatment and prevention of osteoporosis in postmenopausal women, and has also been approved in the United States for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis or postmenopausal women at increased risk of invasive breast cancer . Unfortunately, raloxifene (60 mg/day) is not effective on climacteric syndrome and by measuring changes in quality of life (WHQ), postmenopausal women treated with conventional continuous combined EPT reported significantly greater mean improvements in memory, vasomotor symptoms, and sexual behavior . In a recent double-blind, randomized phase 3 prevention trial designed to evaluate the relative efficacy of raloxifene vs. tamoxifen in reducing the incidence of invasive breast cancer in high-risk postmenopausal women quality of life, depression and sexual function (Medical Outcomes Study Sexual Activity Questionnaire) were assessed. No significant differences existed between the tamoxifen and raloxifene groups in patient-reported outcomes for physical health, mental health, and depression, although the tamoxifen group reported better sexual function. Although mean symptom severity was low among these postmenopausal women, those in the tamoxifen group reported more gynecological problems, vasomotor symptoms, leg cramps, and bladder control problems, whereas women in the raloxifene group reported more musculoskeletal problems, dyspareunia, and weight gain . In older postmenopausal women with osteoporosis, there were no differences in sexual desire or frequency of sexual activity between raloxifene and placebo after 3 years . In a 3-month case-control study, raloxifene did not appear to adversely affect mood, well-being, and indices of sexual activity . In addition, in another case-control study in postmenopausal women (average age 69 years), raloxifene taken long term did not appear to adversely affect urinary incontinence or prolapse . Interestingly enough, concomitant administration of raloxifene did not alter the effects of the E2 ring on alleviating signs and symptoms of genitourinary atrophy  and did not counteract the improvement of vaginal atrophy observed by using either low-dose conjugated estrogen cream or nonhormonal moisturizer in postmenopausal women .
Therefore, on the basis of the available data, raloxifene may be used in association with vaginal estrogens with no substantial harm to sexual functioning in elderly postmenopausal women with osteoporosis in the absence of vasomotor symptoms.
In Europe, a long-term experience for the treatment of climacteric symptoms, including mood and sexual dysfunction, is available with tibolone (not present in the US market), a selective tissue estrogenic activity regulator (STEAR) which is metabolized in the gastrointestinal tract to the 3α and 3β metabolites . These compounds circulate predominantly in their inactive sulfated form and become estrogenically active when desulfated in the target tissues . The global effect of tibolone is, therefore, estrogenic. However, tibolone itself and its 3β metabolite can be converted to a Δ4-isomer which is able to bind and transactivate the progesterone receptor with a concomitant protection of the endometrium . In addition, the intrinsic capacity of the Δ4-isomer to activate the androgen receptor  and the ability of tibolone to reduce SHBG and, hence, to increase bioavailable T and even E2 and DHEAS  have received much attention in the context of sexual functioning. Tibolone exerts positive neuroendocrine effects by improving the opioidergic and serotoninergic tone to the same extent observed with conventional ET/EPT  and significantly increase allopregnanolone, a steroid with sedative and anxiolytic properties, without reducing, unlike estrogen-based therapy, the DHEA milieu in the menopause . On the other hand, tibolone increases the vaginal maturation index and enhances vaginal health as it occurs with EPT [87,88]. In randomized studies against placebo  or oral E2 (2 mg/day) plus NETA (1 mg/day) , tibolone treatment (2.5 mg/day) alleviates vaginal dryness and dyspareunia, ameliorating sexual desire, arousal, and sexual satisfaction in postmenopausal women significantly more than conventional EPT. Moreover, tibolone shows a positive effect on sexuality which is superimposable to that observed with estro-androgenic preparations . These data, together with the observation that 6 months of tibolone treatment significantly increased vaginal pulse amplitude at baseline and following erotic stimulation against placebo  and modulated clitoral circulation in postmenopausal women with desire and arousal disorders , further support the notion that such tissue-specific compound may be considered a good therapeutic option to relief FSD in naturally postmenopausal women because of both its estrogenic and androgenic properties (Figure 2). In addition, tibolone may be even useful in surgical menopause by improving mood, sexual desire, and somatic symptoms to a greater extent than estrogen therapy alone  and its progestogenic activity may be useful when surgical menopause is consequent to estrogen-dependent conditions to avoid the risk of recurrence or malignant transformation related to the use of unopposed estrogens .
In older postmenopausal women, half-dose tibolone (1.25 mg/day) treatment has shown a trend toward an improvement in quality of life and sexuality when compared with raloxifene (60 mg/day) in a double-blind, randomized study conducted in osteopenic but otherwise healthy, postmenopausal women (mean age 66 years) treated for 2 years. No difference could be assessed between the tibolone and raloxifene group in mean total score and separate domains' scores of the MFSQ, except for the vaginal lubrication domain . Very recently, a multicenter, double-blind, randomized clinical trial was performed to compare the efficacy on sexual function of tibolone (2.5 mg) with continuous combined transdermal E2/NETA (50 mcg/140 mcg) in naturally postmenopausal women with sexual dysfunction (mean age 56 years). Both treatments resulted in improved overall sexual function, as determined by scores on the Female Sexual Function Index (FSFI), an increase in the frequency of sexual events, and a reduction in sexuality-related personal distress. The bleeding profile was better with tibolone in comparison with E2/NETA. In the per-protocol analysis but not in the intent-to-treat analysis, the change from baseline for the composite sub-score of the arousal, desire, and satisfaction domains was significantly larger in the tibolone group when compared with the E2/NETA patch group at week 24 .
An international multidisciplinary panel of experts recently proposed a number of subgroups of postmenopausal women with vasomotor symptoms in whom tibolone might have added value, including women with sexual dysfunction, mood disorders, fibroids, and urogenital complaints, as well as those with breast tenderness or high mammographic breast density with EPT use . However, in a randomized placebo-controlled trial (LIFT study) , low-dose tibolone (1.25 mg) significantly reduced the risk of fracture and breast cancer and possibly colon cancer but significantly increased the risk of stroke in older women (between 60 and 85 years of age) with osteoporosis during a median of 34 months of treatment. This evidence has induced some concerns on the safety profile of tibolone, even though we should take into account that this drug has a behavior similar to EPT and it should not be started many years after the time of menopause to avoid the risk of the late exposure to estrogen compounds in older women.
Estrogen decline plays a pivotal role in women's sexual functioning across the entire reproductive life span, and natural menopause is the best clinical model to investigate the effect of estrogen deprivation over time both at neuroendocrine and urogenital levels. Genital receptivity may be significantly impaired when estradiol levels are low, leading to sexual pain disorders and other FSD.
Systemic estrogen treatments are associated with significant benefits in some domains of menopausal sexual function, especially when estradiol is delivered transdermally, whereas local estrogens are effective in preventing urogenital aging. Even tibolone, a selective tissue estrogenic activity regulator, displays positive effects in postmenopausal women with sexual complaints. When signs and symptoms of estrogen deprivation are present in women reporting FSD, it is mandatory to propose tailored hormonal strategies to address the need of the individual woman, after a careful assessment of the risk–benefit profile.