madman
Super Moderator
The role of hormone therapy in urogenital health after menopause (2021)
Rossella E. Nappi, Laura Cucinella, Ellis Martini, Chiara Cassani
Menopause represents an endocrine challenge to urogenital health, as estrogens deprivation and androgens decline significantly contributes to age-related involution of vulvovaginal tissues and lower urinary tract. Genitourinary syndrome of menopause (GSM) is a clinical entity including the chronic and progressive condition of vulvovaginal atrophy (VVA) and encompassing both anatomical and functional consequences of menopause. The term GSM describes genital, sexual, and urinary symptoms with a detrimental impact on quality of life (QOL). Several treatment options are available, but many barriers are still present to adequately diagnose and treat GSM.
This review aims to present current evidence about epidemiology, etiology, diagnosis, and treatment of GSM, with a focus on prescription medications [low-dose local estrogen therapy (LET), prasterone (DHEA), and the SERM ospemifene] for urogenital symptoms in healthy postmenopausal women and in special populations, including women with premature ovarian insufficiency (POI) and breast cancer survivors (BCS).
Introduction
Urogenital health is a fundamental aspect of well-being after menopause with a great impact on quality of life (QOL) and sexual health [1]. Functional anatomy of urogenital tissues (vagina, vestibule, clitoris, bladder, urethra, and the pelvic floor) is under the influence of sex steroids [2,3].
Estrogen depletion with menopause, androgen decline with age and/or premature menopause, and effects of aging per se result in a series of signs and symptoms named Genitourinary Syndrome of Menopause (GSM) [4]. In 2014, the International Society for the Study of Women's Sexual Health (ISSWSH) and the North American Menopause Society (NAMS) proposed this new term with the aim to describe a variety of bothersome genital, sexual and urinary symptoms that can be either isolated or coexisting, and not related to other medical conditions [5]. GSM is a clinical entity, including the chronic and progressive condition of vulvovaginal atrophy (VVA) and encompassing a broader constellation of anatomical and functional consequences of menopause [6].
Early recognition of signs and symptoms at midlife and appropriate management through a long-term strategy is mandatory to preserve urogenital health at older age [7]. Despite available effective and safe treatments, findings from international surveys consistently showed that VVA was underreported, underdiagnosed, and undertreated [8]. That being so, healthcare providers (HCPs) should be proactive about discussing and providing interventions for GSM [9]
Here, we present a narrative overview on VVA/GSM (we used both terms according to the original publication) with a focus on prescription medications to manage the condition.
*Prevalence of urogenital symptoms after menopause
There is high variability in GSM prevalence, with women complaining of at least one symptom ranging from 14% to 87% [10]. The most commonly reported symptoms are vaginal dryness and dyspareunia, followed by irritation, burning, itching, and, less commonly, tenderness, discharge, and postcoital bleeding [10]. Dysuria and urgency commonly co-occur, and even the prevalence of urinary incontinence (UI) is high, varying between 23 and 50% [10]. Age, sexual activity, availability of a partner, and socio-cultural background, as well as awareness of the condition and willingness to discuss urogenital issues with HPCs, interfere with the estimation of the actual prevalence of GSM [10].
*Hormonal aspects of urogenital health
Estrogen deficiency and the changes of testosterone and its precursors [dehydroepiandrostenedione/dehydroepiandrostenedione sulphate (DHEA/DHEAS) and androstenedione] represent the main pathophysiological triggers of structural and functional changes at the urogenital level after menopause [27,28]. Both estrogen (ERs) and androgen (ARs) receptors are highly expressed during reproductive age in the vagina, vulva, bladder trigone, urethra, pelvic floor muscles, and endopelvic fascia. They become under-regulated after menopause and through aging [28,29]. Intracrinology possibly explains the variability in manifesting VVA/GSM, which is not only dependent on the decline of circulating sex hormone levels with menopause and age [30]. Indeed, the inactive precursor DHEA metabolized within the target cells represents the major local source of estrogen and androgen milieu to nourish urogenital tissues. Intracellular steroid-inactivating enzymes, especially glucuronyl transferases and sulfotransferases, are present within urogenital tissues to prevent the release of a biologically significant amount of sex hormones into the circulation [31]. The main effects of estrogen deprivation and androgen decline in urogenital tissues [32-34] are reported in Fig. 2.
It seems quite difficult to separate the effects of menopause from those of aging, as well as to identify the estrogen or androgen origin of specific signs and symptoms of VVA/GSM. The use of an estrogenic-androgenic symptom questionnaire in women (EASQ-W) attempted to explore items typically associated with low estrogens and some others possibly related to androgen insufficiency in a cross-sectional analysis [35].
*Clinical presentation and diagnosis of VVA/GSM
The process of care for sexual well-being following menopause should start with a conversation about several biopsychosocial contributors, but the recognition of VVA/GSM is a fundamental step in the management of urogenital health of women at midlife [36]. The clinical picture is highly heterogeneous and every woman may report her own constellation of symptoms and associated distress that in some cases do not correlate with objective signs at physical examination [37]. Symptoms may occur with sexual activity (dyspareunia, poor lubrication, post-coital bleeding, lack of sex drive, arousal/ orgasmic dysfunction, or even avoidance) or may arise spontaneously, with women reporting vulvar and/or vaginal dryness, soreness, itch, or malodorous discharges, as well as dysuria, urgency, UI and rUTI [6,9].
VVA/GSM is a clinical diagnosis based on a combination of a thorough interview and a careful physical examination, but supportive tools may be helpful [38]. In daily practice, rating scales of most bothersome symptoms are convenient, especially for the evaluation of response to treatment [7]. Objective measurements, including vaginal pH (>5, in absence of bleeding or infection) and vaginal cytology [vaginal maturation index (VMI) with less than 5% superficial cells or more than 75% parabasal cells)] confirm VVA [5]. The Vaginal Health Index (VHI) and Vulvar Health Index are useful tools to report findings from pelvic examination through score scales, in the attempt to quantify the condition objectively and to minimize the inter-individual variability among HCPs [7].
*General principles in the management of urogenital symptoms at menopause
Alleviation of symptoms represents the main goal of therapeutic intervention for GSM; this implies that finding of GSM signs at the physical examination in an asymptomatic woman does not always require specific treatment [39]. However, restoration of urogenital physiology is important to prevent the occurrence of urogenital symptoms over time [40] and the very crucial clinical dilemma is whether we should treat GSM when women report symptoms or when they manifest signs [41]. Interventions should be started as early as symptoms are reported [42] because appropriate treatments may be less effective when the clinical picture is already severe or women are over 60 years of age, even though it is never too late to obtain some meaningful effects [42,43]. The persistence of GSM symptoms may induce a vicious cycle predisposing to other manifestations, including hypertonic pelvic floor dysfunction and hypoactive sexual desire disorder (HSDD) [36], which may require their own management based on the biopsychosocial model [44].
Basic counseling represents the first therapeutic step when approaching sexual symptoms at menopause [45] and education is the key to informing women that urogenital symptoms are common and can be effectively treated [46]. Patients who discussed urogenital health with their HCPs were at least twice more likely to use VVA/GSM-specific treatments [47]. However, poor compliance and dissatisfaction were common findings [10], being possibly the consequence of unrealistic expectations and lack of awareness of the long-term evolution of the condition. Therefore, it should be emphasized that significant improvement may take time, especially when GSM is long-lasting. Moreover, under appropriate care, there are no limitations in terms of duration of treatment, as urogenital symptoms are likely to recur following discontinuation [39,40]. Tailored management should take into account distress, impact on QOL and relationship, ability to maintain an active sex life, as well as individual risk factors and health issues [9,41]. Women's needs should be reconsidered annually [48] and, after the first prescription, a follow-up at 8-12 weeks could be useful to assess response and reinforce adherence to a given treatment and eventually to prescribe another option or to perform further examinations [9].
Treatments approved for GSM-related symptoms include over-the-counter products (OTC) - vaginal lubricants and moisturizers - and prescription medications - local estrogen therapy (LET), intravaginal DHEA, and ospemifene, an oral selective estrogen receptor modulator (SERM) [49]. Intravaginal testosterone (T) may be a potential treatment in postmenopausal women but further studies are needed to establish both efficacy and safety [50]. Energy-based devices (laser and radiofrequency technologies) are promising non-hormonal treatment options but their long-term efficacy and safety are still under evaluation [51]. Even pelvic floor physical therapy (PFPT) may be useful [52] and deserves further investigation.
NAMS has recently suggested a step-up approach for optimal management of GSM, starting with non-hormonal local therapy and opting for prescription medications in case of inadequate response [39]. According to expert recommendations, vaginal moisturizers 2-3 times/week are effective in improving mild symptoms and even lubricants with sexual activity may help with a lower level of evidence [53]. However, moisturizers and lubricants merely mitigate symptomatology without addressing the underlying pathological mechanisms [54]. Despite a large amount of efficacy and safety data, rates of GSM therapeutic options use range from 13% to 78%, with a preference for OTC products rather than prescription medications [10], as fear of hormones, even at low doses and topically applied, still represents a major barrier [55].
*Finally, it is worth mentioning that urogenital symptoms are often part of the menopausal syndrome and, when systemic hormone therapy (HT) is prescribed to relieve vasomotor symptoms, VVA/GSM may be cured as well [39,40], with a 75% rate of improvement [56].
*Prescription medications for urogenital symptoms at menopause
Postmenopausal women with moderate to severe GSM and those who do not respond to lubricants and moisturizers have the possibility to use several safe and effective options with a Level A of evidence according to the last NAMS position statement [39].
A. Local estrogen therapy (LET)
Low-dose local estrogen therapy (LET) represents the first-line hormonal treatment for VVA/GSM providing adequate symptoms relief and restoring urogenital physiology with minimal systemic absorption [39,40,55]. LET can be used also in those women with persistent VVA/GSM symptoms under systemic HT [40]. LET availability is variable across different countries [57-59] and includes a wide range of products reported in Table 1. Applied locally at the manufacturer-recommended dose, starting daily for the first 1-3 weeks and then 1 to 3 times/week (with the exception of the ring which lasts 3 months), vaginal estrogens have few side effects (discharge, mycotic infection, bleeding, breast pain) and do not require the addition of progestogens to protect the endometrium [39,40,55]. NAMS did not recommend additional surveillance of endometrial thickness with ultrasound unless specific risk factors for endometrial hyperplasia exist [39]. Safety data from RCTs do not exceed 52 weeks [60], but a systematic review showed no evidence of increased endometrial hyperplasia or cancer risk with low-dose, unopposed vaginal estrogens [61]. Moreover, data from large prospective cohort studies indicated that chronic use of low-dose LET did not increase the risk of endometrial cancer, invasive breast cancer, venous thromboembolism, and cardiovascular diseases over a long-term follow-up [62,63]. That being so, it is fundamental to reassure women about safety even with long-term treatment, highlighting the different risk-benefit profiles of low-dose LET versus systemic HT in the context of the individual patient [46]. A working group on women's health and well-being in menopause and NAMS attempted to motivate the reasons for modifying the black box warning of low-dose LET [64], but FDA reconfirmed that all estrogen products have a class labeling. It is worth mentioning that any LET can cause systemic absorption but the dose is critical [64]. Ultralow dose (4 mcg inserts) and low dose oestradiol (10 mcg inserts) maintained circulating levels in the menopausal range [65]. Even ultra-low-dose vaginal oestriol gel (0.005%) caused a negligible increase [66], as well as promestriene, an estradiol analog, which was minimally absorbed [67]. The lowest effective dose to relieve symptoms should be used to minimize even minimal hormonal fluctuations that were more evident during the first 12 weeks of treatment, possibly because of increased absorption through the atrophic epithelium [60].
All vaginal estrogenic preparations are equally effective in relieving VVA, as evaluated through a variable combination of subjective symptoms, findings at physical examination, and changes in vaginal pH and VMI [68]. This seems to be true in spite of different molecules exerting peculiar influences on metabolism and affinity for ERs, with estriol displaying a 10 times lower affinity for ERa, highly expressed in endometrium and breast tissue, than estradiol [69]. Therefore, the choice of a particular LET formulation should take into account also preference, as compliance may matter more than type of prescription [46]
Interestingly enough, a double-blind controlled RCT comparing vaginal 10 mcg oestradiol tablet plus placebo gel, vaginal moisturizer plus placebo tablet, or dual placebo over a 12- week study period, showed a modest improvement in menopause-related QOL and sexual function domain scores in postmenopausal women with moderate-severe VVA symptoms [70]. No significant differences were observed among groups regarding overall improvement of sexual function and sexual frequency with LET [71], possibly because of the short duration of the study, confirming the importance of the biopsychosocial approach to FSD [36]. A recent review showed that vaginal estrogens had a more sustainable impact on subjective GSM symptoms up to 3-6 months, whereas objective GSM signs mostly deteriorated within approximately 4 weeks after vaginal estrogen treatment cessation [72]
Finally, evidence of low-dose LET superiority was more robust for vaginal dryness and dyspareunia rather than urinary symptoms as compared with placebo [73], possibly because of the effects on lower urinary tract symptoms (LUTs), including rUTI, urge UI (UUI) and stress UI (SUI), have been assessed in studies not specifically enrolling women with a diagnosis of GSM. Estrogen therapy was associated with less number of episodes in patients with rUTIs when administered locally but not systemically [1]. Clinical trials demonstrated a significant decrease in the number of episodes with LET compared to placebo, while contrasting results emerged from two trials comparing LET and antibiotic prophylaxis, an effective practice burdened by the increasing prevalence of antibiotic resistance [74]. Given the overall risk-benefit profile, the prophylactic use of LET in peri- and postmenopausal women with uncomplicated rUTI is included in guidelines from urology societies [75]. A Cochrane review of 34 trials conducted in postmenopausal patients with either SUI, UUI, or mixed UI showed an overall improvement with the use of LET and a possible worsening of symptoms with systemic HT [76]. Positive evidence with LET was more robust for UUI rather than SUI and even women with overactive bladder syndrome (OAB) could benefit from LET alone or in combination with anticholinergic load [77]. That being so, NAMS recently supported the use of LET in women with concomitant vulvovaginal and urinary symptoms but pointed to consider evidence-based therapies for urinary symptoms if there is no significant improvement following 3 months [39].
B. Intravaginal DHEA
Intravaginal DHEA, also known as prasterone, was approved for treating postmenopausal women with moderate-severe sexual pain related to VVA and with moderate-severe VVA in the US and Europe, respectively [78]. Three double-blind placebo-controlled RCTs confirmed the efficacy of daily applied DHEA 6.5 mg vaginal inserts in improving subjective symptoms and objective parameters (VMI, vaginal pH, and physical examination findings) [79]. Dyspareunia and vaginal dryness were reduced by 80% after 12 weeks of treatment, with a beneficial effect on other domains of sexual function (desire, lubrication, arousal, orgasm, and satisfaction) [80]. Given its dual estro-androgenic action, local DHEA use is promising for relieving urinary symptoms [41,73], but for now, it cannot be recommended to achieve such a goal. An open-label study over 52 weeks confirmed endometrial safety [81] supporting the intracrine action of DHEA [31]. In absence of comparative studies, intravaginal DHEA is considered an alternative to LET [39].
C. Ospemifene
Ospemifene is a SERM with agonist action on vaginal epithelium and bone, a partial agonistic effect on the endometrium, and a neutral to antagonist effect on breast tissue. It is currently the only oral treatment approved for dyspareunia and vaginal dryness due to VVA in the US and for moderate to severe VVA in women not candidates for LET in Europe [82]. At the dose of 60 mg daily, ospemifene significantly improved objective signs and subjective symptoms of VVA [83], as well as each domain of the sexual function, after 12 weeks of treatment, particularly in women reporting dyspareunia as the most bothersome symptom [84]. Indirect comparative data showed similarities between ospemifene and LET [85]. Interestingly, ospemifene seemed a useful option for treating OAB symptoms refractory to the first line of treatment with b3-agonists or antimuscarinic drugs in postmenopausal women with VVA [86]. A meta-analysis of RCTs showed high tolerability and good safety, with no significant estrogenic effects on the endometrium or breast following 1 year [87]. In a retrospective matched cohort study assessing breast safety, real-world data demonstrated a similar rate of breast cancer incidence and recurrence in ospemifene users compared to untreated women with VVA [88]. Even real-world data on venous thromboembolism (VTE) suggested a favorable safety profile for ospemifene in comparison to other SERMs (raloxifene, basedoxifene, or tamoxifen, for non-cancer indications) or no treatment [89]. Further long-term data are needed to offer postmenopausal women proper counseling in light of the boxed warning issued by the FDA on risks of endometrial cancer and cardiovascular disorders (CVD), as well as on the possibility to use ospemifene after completion of treatment of breast cancer, including adjuvant therapy, in Europe [82].
*Management of urogenital symptoms in special populations
Rossella E. Nappi, Laura Cucinella, Ellis Martini, Chiara Cassani
Menopause represents an endocrine challenge to urogenital health, as estrogens deprivation and androgens decline significantly contributes to age-related involution of vulvovaginal tissues and lower urinary tract. Genitourinary syndrome of menopause (GSM) is a clinical entity including the chronic and progressive condition of vulvovaginal atrophy (VVA) and encompassing both anatomical and functional consequences of menopause. The term GSM describes genital, sexual, and urinary symptoms with a detrimental impact on quality of life (QOL). Several treatment options are available, but many barriers are still present to adequately diagnose and treat GSM.
This review aims to present current evidence about epidemiology, etiology, diagnosis, and treatment of GSM, with a focus on prescription medications [low-dose local estrogen therapy (LET), prasterone (DHEA), and the SERM ospemifene] for urogenital symptoms in healthy postmenopausal women and in special populations, including women with premature ovarian insufficiency (POI) and breast cancer survivors (BCS).
Introduction
Urogenital health is a fundamental aspect of well-being after menopause with a great impact on quality of life (QOL) and sexual health [1]. Functional anatomy of urogenital tissues (vagina, vestibule, clitoris, bladder, urethra, and the pelvic floor) is under the influence of sex steroids [2,3].
Estrogen depletion with menopause, androgen decline with age and/or premature menopause, and effects of aging per se result in a series of signs and symptoms named Genitourinary Syndrome of Menopause (GSM) [4]. In 2014, the International Society for the Study of Women's Sexual Health (ISSWSH) and the North American Menopause Society (NAMS) proposed this new term with the aim to describe a variety of bothersome genital, sexual and urinary symptoms that can be either isolated or coexisting, and not related to other medical conditions [5]. GSM is a clinical entity, including the chronic and progressive condition of vulvovaginal atrophy (VVA) and encompassing a broader constellation of anatomical and functional consequences of menopause [6].
Early recognition of signs and symptoms at midlife and appropriate management through a long-term strategy is mandatory to preserve urogenital health at older age [7]. Despite available effective and safe treatments, findings from international surveys consistently showed that VVA was underreported, underdiagnosed, and undertreated [8]. That being so, healthcare providers (HCPs) should be proactive about discussing and providing interventions for GSM [9]
Here, we present a narrative overview on VVA/GSM (we used both terms according to the original publication) with a focus on prescription medications to manage the condition.
*Prevalence of urogenital symptoms after menopause
There is high variability in GSM prevalence, with women complaining of at least one symptom ranging from 14% to 87% [10]. The most commonly reported symptoms are vaginal dryness and dyspareunia, followed by irritation, burning, itching, and, less commonly, tenderness, discharge, and postcoital bleeding [10]. Dysuria and urgency commonly co-occur, and even the prevalence of urinary incontinence (UI) is high, varying between 23 and 50% [10]. Age, sexual activity, availability of a partner, and socio-cultural background, as well as awareness of the condition and willingness to discuss urogenital issues with HPCs, interfere with the estimation of the actual prevalence of GSM [10].
*Hormonal aspects of urogenital health
Estrogen deficiency and the changes of testosterone and its precursors [dehydroepiandrostenedione/dehydroepiandrostenedione sulphate (DHEA/DHEAS) and androstenedione] represent the main pathophysiological triggers of structural and functional changes at the urogenital level after menopause [27,28]. Both estrogen (ERs) and androgen (ARs) receptors are highly expressed during reproductive age in the vagina, vulva, bladder trigone, urethra, pelvic floor muscles, and endopelvic fascia. They become under-regulated after menopause and through aging [28,29]. Intracrinology possibly explains the variability in manifesting VVA/GSM, which is not only dependent on the decline of circulating sex hormone levels with menopause and age [30]. Indeed, the inactive precursor DHEA metabolized within the target cells represents the major local source of estrogen and androgen milieu to nourish urogenital tissues. Intracellular steroid-inactivating enzymes, especially glucuronyl transferases and sulfotransferases, are present within urogenital tissues to prevent the release of a biologically significant amount of sex hormones into the circulation [31]. The main effects of estrogen deprivation and androgen decline in urogenital tissues [32-34] are reported in Fig. 2.
It seems quite difficult to separate the effects of menopause from those of aging, as well as to identify the estrogen or androgen origin of specific signs and symptoms of VVA/GSM. The use of an estrogenic-androgenic symptom questionnaire in women (EASQ-W) attempted to explore items typically associated with low estrogens and some others possibly related to androgen insufficiency in a cross-sectional analysis [35].
*Clinical presentation and diagnosis of VVA/GSM
The process of care for sexual well-being following menopause should start with a conversation about several biopsychosocial contributors, but the recognition of VVA/GSM is a fundamental step in the management of urogenital health of women at midlife [36]. The clinical picture is highly heterogeneous and every woman may report her own constellation of symptoms and associated distress that in some cases do not correlate with objective signs at physical examination [37]. Symptoms may occur with sexual activity (dyspareunia, poor lubrication, post-coital bleeding, lack of sex drive, arousal/ orgasmic dysfunction, or even avoidance) or may arise spontaneously, with women reporting vulvar and/or vaginal dryness, soreness, itch, or malodorous discharges, as well as dysuria, urgency, UI and rUTI [6,9].
VVA/GSM is a clinical diagnosis based on a combination of a thorough interview and a careful physical examination, but supportive tools may be helpful [38]. In daily practice, rating scales of most bothersome symptoms are convenient, especially for the evaluation of response to treatment [7]. Objective measurements, including vaginal pH (>5, in absence of bleeding or infection) and vaginal cytology [vaginal maturation index (VMI) with less than 5% superficial cells or more than 75% parabasal cells)] confirm VVA [5]. The Vaginal Health Index (VHI) and Vulvar Health Index are useful tools to report findings from pelvic examination through score scales, in the attempt to quantify the condition objectively and to minimize the inter-individual variability among HCPs [7].
*General principles in the management of urogenital symptoms at menopause
Alleviation of symptoms represents the main goal of therapeutic intervention for GSM; this implies that finding of GSM signs at the physical examination in an asymptomatic woman does not always require specific treatment [39]. However, restoration of urogenital physiology is important to prevent the occurrence of urogenital symptoms over time [40] and the very crucial clinical dilemma is whether we should treat GSM when women report symptoms or when they manifest signs [41]. Interventions should be started as early as symptoms are reported [42] because appropriate treatments may be less effective when the clinical picture is already severe or women are over 60 years of age, even though it is never too late to obtain some meaningful effects [42,43]. The persistence of GSM symptoms may induce a vicious cycle predisposing to other manifestations, including hypertonic pelvic floor dysfunction and hypoactive sexual desire disorder (HSDD) [36], which may require their own management based on the biopsychosocial model [44].
Basic counseling represents the first therapeutic step when approaching sexual symptoms at menopause [45] and education is the key to informing women that urogenital symptoms are common and can be effectively treated [46]. Patients who discussed urogenital health with their HCPs were at least twice more likely to use VVA/GSM-specific treatments [47]. However, poor compliance and dissatisfaction were common findings [10], being possibly the consequence of unrealistic expectations and lack of awareness of the long-term evolution of the condition. Therefore, it should be emphasized that significant improvement may take time, especially when GSM is long-lasting. Moreover, under appropriate care, there are no limitations in terms of duration of treatment, as urogenital symptoms are likely to recur following discontinuation [39,40]. Tailored management should take into account distress, impact on QOL and relationship, ability to maintain an active sex life, as well as individual risk factors and health issues [9,41]. Women's needs should be reconsidered annually [48] and, after the first prescription, a follow-up at 8-12 weeks could be useful to assess response and reinforce adherence to a given treatment and eventually to prescribe another option or to perform further examinations [9].
Treatments approved for GSM-related symptoms include over-the-counter products (OTC) - vaginal lubricants and moisturizers - and prescription medications - local estrogen therapy (LET), intravaginal DHEA, and ospemifene, an oral selective estrogen receptor modulator (SERM) [49]. Intravaginal testosterone (T) may be a potential treatment in postmenopausal women but further studies are needed to establish both efficacy and safety [50]. Energy-based devices (laser and radiofrequency technologies) are promising non-hormonal treatment options but their long-term efficacy and safety are still under evaluation [51]. Even pelvic floor physical therapy (PFPT) may be useful [52] and deserves further investigation.
NAMS has recently suggested a step-up approach for optimal management of GSM, starting with non-hormonal local therapy and opting for prescription medications in case of inadequate response [39]. According to expert recommendations, vaginal moisturizers 2-3 times/week are effective in improving mild symptoms and even lubricants with sexual activity may help with a lower level of evidence [53]. However, moisturizers and lubricants merely mitigate symptomatology without addressing the underlying pathological mechanisms [54]. Despite a large amount of efficacy and safety data, rates of GSM therapeutic options use range from 13% to 78%, with a preference for OTC products rather than prescription medications [10], as fear of hormones, even at low doses and topically applied, still represents a major barrier [55].
*Finally, it is worth mentioning that urogenital symptoms are often part of the menopausal syndrome and, when systemic hormone therapy (HT) is prescribed to relieve vasomotor symptoms, VVA/GSM may be cured as well [39,40], with a 75% rate of improvement [56].
*Prescription medications for urogenital symptoms at menopause
Postmenopausal women with moderate to severe GSM and those who do not respond to lubricants and moisturizers have the possibility to use several safe and effective options with a Level A of evidence according to the last NAMS position statement [39].
A. Local estrogen therapy (LET)
Low-dose local estrogen therapy (LET) represents the first-line hormonal treatment for VVA/GSM providing adequate symptoms relief and restoring urogenital physiology with minimal systemic absorption [39,40,55]. LET can be used also in those women with persistent VVA/GSM symptoms under systemic HT [40]. LET availability is variable across different countries [57-59] and includes a wide range of products reported in Table 1. Applied locally at the manufacturer-recommended dose, starting daily for the first 1-3 weeks and then 1 to 3 times/week (with the exception of the ring which lasts 3 months), vaginal estrogens have few side effects (discharge, mycotic infection, bleeding, breast pain) and do not require the addition of progestogens to protect the endometrium [39,40,55]. NAMS did not recommend additional surveillance of endometrial thickness with ultrasound unless specific risk factors for endometrial hyperplasia exist [39]. Safety data from RCTs do not exceed 52 weeks [60], but a systematic review showed no evidence of increased endometrial hyperplasia or cancer risk with low-dose, unopposed vaginal estrogens [61]. Moreover, data from large prospective cohort studies indicated that chronic use of low-dose LET did not increase the risk of endometrial cancer, invasive breast cancer, venous thromboembolism, and cardiovascular diseases over a long-term follow-up [62,63]. That being so, it is fundamental to reassure women about safety even with long-term treatment, highlighting the different risk-benefit profiles of low-dose LET versus systemic HT in the context of the individual patient [46]. A working group on women's health and well-being in menopause and NAMS attempted to motivate the reasons for modifying the black box warning of low-dose LET [64], but FDA reconfirmed that all estrogen products have a class labeling. It is worth mentioning that any LET can cause systemic absorption but the dose is critical [64]. Ultralow dose (4 mcg inserts) and low dose oestradiol (10 mcg inserts) maintained circulating levels in the menopausal range [65]. Even ultra-low-dose vaginal oestriol gel (0.005%) caused a negligible increase [66], as well as promestriene, an estradiol analog, which was minimally absorbed [67]. The lowest effective dose to relieve symptoms should be used to minimize even minimal hormonal fluctuations that were more evident during the first 12 weeks of treatment, possibly because of increased absorption through the atrophic epithelium [60].
All vaginal estrogenic preparations are equally effective in relieving VVA, as evaluated through a variable combination of subjective symptoms, findings at physical examination, and changes in vaginal pH and VMI [68]. This seems to be true in spite of different molecules exerting peculiar influences on metabolism and affinity for ERs, with estriol displaying a 10 times lower affinity for ERa, highly expressed in endometrium and breast tissue, than estradiol [69]. Therefore, the choice of a particular LET formulation should take into account also preference, as compliance may matter more than type of prescription [46]
Interestingly enough, a double-blind controlled RCT comparing vaginal 10 mcg oestradiol tablet plus placebo gel, vaginal moisturizer plus placebo tablet, or dual placebo over a 12- week study period, showed a modest improvement in menopause-related QOL and sexual function domain scores in postmenopausal women with moderate-severe VVA symptoms [70]. No significant differences were observed among groups regarding overall improvement of sexual function and sexual frequency with LET [71], possibly because of the short duration of the study, confirming the importance of the biopsychosocial approach to FSD [36]. A recent review showed that vaginal estrogens had a more sustainable impact on subjective GSM symptoms up to 3-6 months, whereas objective GSM signs mostly deteriorated within approximately 4 weeks after vaginal estrogen treatment cessation [72]
Finally, evidence of low-dose LET superiority was more robust for vaginal dryness and dyspareunia rather than urinary symptoms as compared with placebo [73], possibly because of the effects on lower urinary tract symptoms (LUTs), including rUTI, urge UI (UUI) and stress UI (SUI), have been assessed in studies not specifically enrolling women with a diagnosis of GSM. Estrogen therapy was associated with less number of episodes in patients with rUTIs when administered locally but not systemically [1]. Clinical trials demonstrated a significant decrease in the number of episodes with LET compared to placebo, while contrasting results emerged from two trials comparing LET and antibiotic prophylaxis, an effective practice burdened by the increasing prevalence of antibiotic resistance [74]. Given the overall risk-benefit profile, the prophylactic use of LET in peri- and postmenopausal women with uncomplicated rUTI is included in guidelines from urology societies [75]. A Cochrane review of 34 trials conducted in postmenopausal patients with either SUI, UUI, or mixed UI showed an overall improvement with the use of LET and a possible worsening of symptoms with systemic HT [76]. Positive evidence with LET was more robust for UUI rather than SUI and even women with overactive bladder syndrome (OAB) could benefit from LET alone or in combination with anticholinergic load [77]. That being so, NAMS recently supported the use of LET in women with concomitant vulvovaginal and urinary symptoms but pointed to consider evidence-based therapies for urinary symptoms if there is no significant improvement following 3 months [39].
B. Intravaginal DHEA
Intravaginal DHEA, also known as prasterone, was approved for treating postmenopausal women with moderate-severe sexual pain related to VVA and with moderate-severe VVA in the US and Europe, respectively [78]. Three double-blind placebo-controlled RCTs confirmed the efficacy of daily applied DHEA 6.5 mg vaginal inserts in improving subjective symptoms and objective parameters (VMI, vaginal pH, and physical examination findings) [79]. Dyspareunia and vaginal dryness were reduced by 80% after 12 weeks of treatment, with a beneficial effect on other domains of sexual function (desire, lubrication, arousal, orgasm, and satisfaction) [80]. Given its dual estro-androgenic action, local DHEA use is promising for relieving urinary symptoms [41,73], but for now, it cannot be recommended to achieve such a goal. An open-label study over 52 weeks confirmed endometrial safety [81] supporting the intracrine action of DHEA [31]. In absence of comparative studies, intravaginal DHEA is considered an alternative to LET [39].
C. Ospemifene
Ospemifene is a SERM with agonist action on vaginal epithelium and bone, a partial agonistic effect on the endometrium, and a neutral to antagonist effect on breast tissue. It is currently the only oral treatment approved for dyspareunia and vaginal dryness due to VVA in the US and for moderate to severe VVA in women not candidates for LET in Europe [82]. At the dose of 60 mg daily, ospemifene significantly improved objective signs and subjective symptoms of VVA [83], as well as each domain of the sexual function, after 12 weeks of treatment, particularly in women reporting dyspareunia as the most bothersome symptom [84]. Indirect comparative data showed similarities between ospemifene and LET [85]. Interestingly, ospemifene seemed a useful option for treating OAB symptoms refractory to the first line of treatment with b3-agonists or antimuscarinic drugs in postmenopausal women with VVA [86]. A meta-analysis of RCTs showed high tolerability and good safety, with no significant estrogenic effects on the endometrium or breast following 1 year [87]. In a retrospective matched cohort study assessing breast safety, real-world data demonstrated a similar rate of breast cancer incidence and recurrence in ospemifene users compared to untreated women with VVA [88]. Even real-world data on venous thromboembolism (VTE) suggested a favorable safety profile for ospemifene in comparison to other SERMs (raloxifene, basedoxifene, or tamoxifen, for non-cancer indications) or no treatment [89]. Further long-term data are needed to offer postmenopausal women proper counseling in light of the boxed warning issued by the FDA on risks of endometrial cancer and cardiovascular disorders (CVD), as well as on the possibility to use ospemifene after completion of treatment of breast cancer, including adjuvant therapy, in Europe [82].
*Management of urogenital symptoms in special populations
