Recommended measurement instruments for genitourinary symptoms associated with menopause: the COMMA (Core outcomes in menopause) consortium.

OBJECTIVE: The aim of the study is to identify appropriate definitions and patient-reported outcome measures (PROMs) for each of the eight core outcomes previously selected for genitourinary symptoms associated with menopause: pain with sex, vulvovaginal dryness, vulvovaginal discomfort or irritation, discomfort or pain when urinating, change in most bothersome symptom, distress, bother or interference of genitourinary symptoms, satisfaction with treatment, and side effects. METHODS: We conducted a systematic review to identify possible definitions and PROMs, including their measurement properties. Identified definitions and relevant PROMs with acceptable measurement properties were entered into an international consensus process involving 28 participants from 10 countries to achieve final recommendations for each core outcome. RESULTS: A total of 87 publications reporting on 34 PROMs were identified from 21,207 publications screened. Of these 34 PROMs, 29 were not considered to sufficiently map onto the core outcomes, and 26 of these also had insufficient measurement properties. Therefore, only five PROMs corresponding to two core outcomes were considered for recommendation. We recommend the PROMIS Scale v2.0 - Sexual Function and Satisfaction: Vaginal Discomfort with Sexual Activity to measure the outcome of "pain with sexual activity" and the Day-to-Day Impact of Vaginal Aging (DIVA) Questionnaire to measure "distress, bother or interference" from genitourinary symptoms. Six definitions of "side effects" were identified and considered. We recommend that all trials report adverse events in study participants, which is a requirement of Good Clinical Practice. CONCLUSIONS: Suitable PROMs and definitions were identified to measure three of eight core outcomes. Because of the lack of existing measures, which align with the core outcomes and have evidence of high-quality measurement properties, future work will focus on developing or validating PROMs for the remaining five core outcomes.

Oral lasofoxifene's effects on moderate to severe vaginal atrophy in postmenopausal women: two phase 3, randomized, controlled trials.

OBJECTIVE: The aim of this study was to demonstrate whether lasofoxifene improves vaginal signs/symptoms of genitourinary syndrome of menopause. METHODS: Two identical, phase 3 trials randomized postmenopausal women with moderate to severe vaginal symptoms to oral lasofoxifene 0.25 or 0.5 mg/d, or placebo, for 12 week. Changes from baseline to week 12 in most bothersome symptom, vaginal pH, and percentages of vaginal parabasal and superficial cells were evaluated. These coprimary endpoints were analyzed using analysis of covariance, except superficial cells, which were analyzed by the nonparametric, rank-based Kruskal-Wallis test. RESULTS: The two studies enrolled 444 and 445 women (mean age, ~60 y), respectively. Coprimary endpoints at week 12 improved with lasofoxifene 0.25 and 0.5 mg/d greater than with placebo (P < 0.0125 for all). Study 1: most bothersome symptom (least square mean difference from placebo: -0.4 and -0.5 for 0.25 and 0.5 mg/d, respectively), vaginal pH (-0.65, -0.58), and vaginal superficial (5.2%, 5.4%), and parabasal (-39.9%, -34.9%) cells; study 2: most bothersome symptom (-0.4, -0.5), vaginal pH (-0.57, -0.67), and vaginal superficial (3.5%, 2.2%) and parabasal (-34.1%, -33.5%) cells. Some improvements occurred as early as week 2. Most treatment-emergent adverse events were mild or moderate and hot flushes were most frequently reported (lasofoxifene vs placebo: 13%-23% vs 9%-11%). Serious adverse events were infrequent and no deaths occurred. CONCLUSIONS: In two phase 3 trials, oral lasofoxifene 0.25 and 0.5 mg/d provided significant and clinically meaningful improvements in vaginal signs/symptoms with a favorable safety profile, suggesting beneficial effects of lasofoxifene on genitourinary syndrome of menopause.

Recommended measurement instruments for menopausal vasomotor symptoms: the COMMA (Core Outcomes in Menopause) consortium.

OBJECTIVE: The aim of the study is to identify suitable definitions and patient-reported outcome measures (PROMs) to assess each of the six core outcomes previously identified through the COMMA (Core Outcomes in Menopause) global consensus process relating to vasomotor symptoms: frequency, severity, distress/bother/interference, impact on sleep, satisfaction with treatment, and side effects. METHODS: A systematic review was conducted to identify relevant definitions for the outcome of side-effects and PROMs with acceptable measurement properties for the remaining five core outcomes. The consensus process, involving 36 participants from 16 countries, was conducted to review definitions and PROMs and make final recommendations for the measurement of each core outcome. RESULTS: A total of 21,207 publications were screened from which 119 reporting on 40 PROMs were identified. Of these 40 PROMs, 36 either did not adequately map onto the core outcomes or lacked sufficient measurement properties. Therefore, only four PROMs corresponding to two of the six core outcomes were considered for recommendation. We recommend the Hot Flash Related Daily Interference Scale to measure the domain of distress, bother, or interference of vasomotor symptoms and to capture impact on sleep (one item in the Hot Flash Related Daily Interference Scale captures interference with sleep). Six definitions of "side effects" were identified and considered. We recommend that all trials report adverse events, which is a requirement of Good Clinical Practice. CONCLUSIONS: We identified suitable definitions and PROMs for only three of the six core outcomes. No suitable PROMs were found for the remaining three outcomes (frequency and severity of vasomotor symptoms and satisfaction with treatment). Future studies should develop and validate PROMs for these outcomes.

A Contemporary View of Menopausal Hormone Therapy.

Enthusiasm for the use of hormones to ameliorate symptoms of perimenopause and menopause has waxed and waned over the years. Both treatment for symptoms and training of women's health care practitioners in the management of menopause have sharply declined since publication of the Women's Health Initiative initial results in 2002. Findings from that trial, which treated a population of older, asymptomatic patients, have been extrapolated over the past 21 years to all estrogen products, all menopausal women, and all delivery mechanisms. Our patients deserve a more nuanced, individualized approach. Conjugated equine estrogens and medroxyprogesterone acetate are no longer the predominant medications or medications of choice available for management of menopausal symptoms. All hormones are not equivalent any more than all antiseizure medications or all antihypertensives are equivalent; they have different pharmacodynamics, duration of action, and affinity for receptors, among other things, all of which translate to different risks and benefits. Consideration of treatment with the right formulation, at the right dose and time, and for the right patient will allow us to recommend safe, effective, and appropriate treatment for people with menopausal symptoms.

Efficacy, tolerability, and endometrial safety of ospemifene compared with current therapies for the treatment of vulvovaginal atrophy: a systematic literature review and network meta-analysis.

IMPORTANCE: Ospemifene is a novel selective estrogen receptor modulator developed for the treatment of moderate to severe postmenopausal vulvovaginal atrophy (VVA). OBJECTIVE: The aim of the study is to perform a systematic literature review (SLR) and network meta-analysis (NMA) to assess the efficacy and safety of ospemifene compared with other therapies used in the treatment of VVA in North America and Europe. EVIDENCE REVIEW: Electronic database searches were conducted in November 2021 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomized or nonrandomized controlled trials targeting postmenopausal women with moderate to severe dyspareunia and/or vaginal dryness and involving ospemifene or at least one VVA local treatment were considered. Efficacy data included changes from baseline in superficial and parabasal cells, vaginal pH, and the most bothersome symptom of vaginal dryness or dyspareunia, as required for regulatory approval. Endometrial outcomes were endometrial thickness and histologic classifications, including endometrial polyp, hyperplasia, and cancer. For efficacy and safety outcomes, a Bayesian NMA was performed. Endometrial outcomes were compared in descriptive analyses. FINDINGS: A total of 44 controlled trials met the eligibility criteria ( N = 12,637 participants). Network meta-analysis results showed that ospemifene was not statistically different from other active therapies in most efficacy and safety results. For all treatments, including ospemifene, the posttreatment endometrial thickness values (up to 52 wk of treatment) were under the recognized clinical threshold value of 4 mm for significant risk of endometrial pathology. Specifically, for women treated with ospemifene, endometrial thickness ranged between 2.1 and 2.3 mm at baseline and 2.5 and 3.2 mm after treatment. No cases of endometrial carcinoma or hyperplasia were observed in ospemifene trials, nor polyps with atypical hyperplasia or cancer after up to 52 weeks of treatment. CONCLUSIONS AND RELEVANCE: Ospemifene is an efficacious, well-tolerated, and safe therapeutic option for postmenopausal women with moderate to severe symptoms of VVA. Efficacy and safety outcomes with ospemifene are similar to other VVA therapies in North America and Europe.

Symptoms and associated impact in pre- and postmenopausal women with sexual arousal disorder: a concept elicitation study.

BACKGROUND: Approximately 26% of adult women in the United States suffer from female sexual arousal disorder (FSAD), yet little has been done to compare the experience of FSAD in pre- and postmenopausal women, which is critical to enhance the current understanding of FSAD and inform the development and assessment of treatment options for these patient populations. AIM: To explore the experience of condition-associated symptoms and the relative importance of FSAD symptoms, including their severity, bother, and impact, on participants' health-related quality of life (HRQoL) in pre- and postmenopausal women with FSAD. METHODS: In-depth, qualitative, semistructured concept elicitation interviews were conducted with premenopausal (n = 23) and postmenopausal (n = 13) women who were clinically diagnosed with FSAD by a trained sexual medicine clinician. All interviews were audio recorded and transcribed verbatim by a professional transcription company. Thematic analysis was performed with the assistance of NVivo qualitative analysis software. OUTCOMES: Outcomes included qualitative interview data about FSAD symptoms and HRQoL, as well as a comparison between pre- and postmenopausal populations. RESULTS: The most frequently reported symptom in both cohorts was "inability or difficulty with orgasm" (premenopausal, n = 21; postmenopausal, n = 13). The symptom that premenopausal women most desired to have treated was lubrication, and for postmenopausal women, it was a lack of lubrication or wetness and loss of feeling/sensation. In total, 21 of 23 premenopausal women and all 13 postmenopausal women reported a lack of feeling or sensation in the genitals. The most frequently reported HRQoL impact in both groups was decreased confidence. CLINICAL IMPLICATIONS: Results from this study suggest that the manifestation and experience of FSAD are similar in pre- and postmenopausal women and that the unmet need for an FSAD treatment in the postmenopausal population is just as great as that of the premenopausal population. STRENGTHS AND LIMITATIONS: This study involved in-depth qualitative interviews with a relatively small group of women (N = 36) recruited from only 5 study sites across the United States. CONCLUSION: The analysis of qualitative data from the concept elicitation interviews revealed a substantial physical and emotional burden of FSAD, underscoring the need for Food and Drug Administration-approved treatment options for pre- and postmenopausal women with FSAD.

Efficacy and safety of elinzanetant, a selective neurokinin-1,3 receptor antagonist for vasomotor symptoms: a dose-finding clinical trial (SWITCH-1).

OBJECTIVE: Neurokinin (NK)-3 and NK-1 receptors have been implicated in the etiology of vasomotor symptoms (VMS) and sleep disturbances associated with menopause. This phase 2b, adaptive, dose-range finding study aimed to assess the efficacy and safety of multiple doses of elinzanetant (NT-814), a selective NK-1,3 receptor antagonist, in women experiencing VMS associated with menopause, and investigate the impact of elinzanetant on sleep and quality of life. METHODS: Postmenopausal women aged 40 to 65 years who experienced seven or more moderate-to-severe VMS per day were randomized to receive elinzanetant 40, 80, 120, or 160 mg or placebo once daily using an adaptive design algorithm. Coprimary endpoints were reduction in mean frequency and severity of moderate-to-severe VMS at weeks 4 and 12. Secondary endpoints included patient-reported assessments of sleep and quality of life. RESULTS: Elinzanetant 120 mg and 160 mg achieved reductions in VMS frequency versus placebo from week 1 throughout 12 weeks of treatment. Least square mean reductions were statistically significant versus placebo at both primary endpoint time points for elinzanetant 120 mg (week 4: -3.93 [SE, 1.02], P < 0.001; week 12: -2.95 [1.15], P = 0.01) and at week 4 for elinzanetant 160 mg (-2.63 [1.03]; P = 0.01). Both doses also led to clinically meaningful improvements in measures of sleep and quality of life. All doses of elinzanetant were well tolerated. CONCLUSIONS: Elinzanetant is an effective and well-tolerated nonhormone treatment option for postmenopausal women with VMS and associated sleep disturbance. Elinzanetant also improves quality of life in women with VMS.

Effects of Flibanserin on Subdomain Scores of the Female Sexual Function Index in Women With Hypoactive Sexual Desire Disorder.

INTRODUCTION: Flibanserin treatment increases sexual desire and satisfying sexual events while decreasing distress in certain women diagnosed with acquired, generalized hypoactive sexual desire disorder (HSDD). Additional aspects of sexual function and the time course of response have not been fully characterized. AIM: To evaluate changes in sexual function assessed by the subdomains of the Female Sexual Function Index (FSFI) in women with HSDD treated with flibanserin. METHODS: FSFI data pooled from 3 pivotal flibanserin trials in premenopausal women (flibanserin = 1,165; placebo = 1,203) and FSFI data from one complete flibanserin trial in postmenopausal women (flibanserin = 432; placebo = 463) were subjected to post-hoc analyses. For each FSFI subdomain, least squares mean change from baseline was calculated at each assessment visit (treatment weeks 4, 8, 16, 24) and treatment groups were compared using analysis of covariance. Standardized effect size (Cohen's d) was also determined for each FSFI subdomain. MAIN OUTCOME MEASURE: Changes from baseline in FSFI subdomains. RESULTS: Compared to placebo, both premenopausal (P < .02) and postmenopausal (P < .045) patients in the flibanserin group reported significantly greater increases over baseline in the FSFI subdomain scores of desire, arousal, lubrication, orgasm, and satisfaction. In premenopausal patients, significant improvements were observed at the first assessment of response (week 4) and were maintained through week 24. In postmenopausal patients, significant improvements were observed at week 4 for desire and arousal, while significant improvements in lubrication, orgasm, and satisfaction were observed at week 8. At week 24, excluding the pain subdomain, standardized effect sizes ranged from 0.18 to 0.28 in the premenopausal cohort and 0.12 to 0.29 in the postmenopausal cohort. In both pre- and postmenopausal patients, improvements in pain were smaller and largely undifferentiated between treatment groups. CLINICAL IMPLICATIONS: While variations in time to response should be taken into consideration, on average, the beneficial impact of flibanserin on overall sexual function occurs within the first month of treatment. The data also suggest that the response to flibanserin is sustained for the duration of treatment. STRENGTHS AND LIMITATIONS: Sexual function assessments were performed in a large cohort of 2,368 premenopausal women and 895 postmenopausal women. However, the FSFI assesses changes over a 1-month period and time points earlier than 4 weeks could not be assessed. CONCLUSION: These analyses suggest that assessment of benefit of flibanserin in HSDD should include improvements across all domains of sexual function, not only desire. Simon JA, Clayton AH, Goldstein I, et al. Effects of Flibanserin on Subdomain Scores of the Female Sexual Function Index in Women With Hypoactive Sexual Desire Disorder. Sex Med 2022;10:100570.

Review of menopausal hormone therapy with estradiol and progesterone versus other estrogens and progestins.

Objective: The objective of the present document was to review/summarize reported outcomes compared between menopausal hormone therapy (MHT) containing estradiol (E2) versus other estrogens and MHT with progesterone (P4) versus progestins (defined as synthetic progestogens).Methods: PubMed and EMBASE were systematically searched through February 2021 for studies comparing oral E2 versus oral conjugated equine estrogens (CEE) or P4 versus progestins for endometrial outcomes, venous thromboembolism (VTE), cardiovascular outcomes, breast outcomes, cognition, and bone outcomes in postmenopausal women.Results: A total of 74 comparative publications were identified/summarized. Randomized studies suggested that P4 and progestins are likely equally effective in preventing endometrial hyperplasia/cancer when used at adequate doses. E2- versus CEE-based MHT had a similar or possibly better risk profile for VTE and cardiovascular outcomes, and P4- versus progestin-based MHT had a similar or possibly better profile for breast cancer and cardiovascular outcomes. E2 may potentially protect better against age-related cognitive decline and bone fractures versus CEE; P4 was similar or possibly better versus progestins for these outcomes. Limitations are that many studies were observational and some were not adequately powered for the reported outcomes.Conclusions: Evidence suggests a differential effect of MHT containing E2 or P4 and those containing CEE or progestins, with some evidence trending to a potentially better safety profile with E2 and/or P4.

Sexual Dysfunction as a Harbinger of Cardiovascular Disease in Postmenopausal Women: How Far Are We?

BACKGROUND: Female sexual dysfunction (FSD) affects 40-50% of women in the general population, resulting from the interaction among organic, psychological, sociocultural and relational factors; differently from men, in women definitive clinical evidence suggesting a connection between cardiovascular (CV) diseases (CVDs) and female sexual function is still lacking. AIM: To focus on the current scientific support for an association between CV diseases and/or risk factors and FSD, focused primarily on postmenopausal women. METHODS: This is a narrative review based on an extensive literature search of peer-reviewed publications on the associations between CV diseases and/or risk factors and FSD and their underlying mechanisms, which was performed using the PubMed database. OUTCOMES: We present a summary of the evidence from clinical and preclinical studies and discuss the possible mechanisms providing the pathophysiologic bases of vasculogenic FSD. RESULTS: Growing evidence shows that female sexual function, especially arousal, is significantly affected by genital vascular impairment, which can lead to FSD. For many cardiometabolic risk factors and diseases, such as hypertension, diabetes, dyslipidemia and metabolic syndrome, an adverse impact on endothelial function as well as an association with FSD have been recognized. In this scenario, similarly to penile Doppler blood flow studies in men, clitoral Doppler ultrasound can represent an innovative and useful tool to early reveal the presence of CV risk factors and sexual dysfunction. Notably, although the prevalence of CVDs as well as of FSD increases as a function of menopause and aging, middle-aged women have shown a higher prevalence of distressing sexual problems than older and younger women. CLINICAL IMPLICATIONS: It becomes clinically relevant to assess particularly postmenopausal women for FSD and CVDs, since both disorders still remain underdiagnosed and sub-optimally untreated. Clitoral Doppler ultrasound could represent a useful technique to diagnose the presence of underlying CVD, which along with risk factors could predict sexual dysfunction in women. STRENGTHS & LIMITATIONS: This review focuses on a very important and innovative topic, providing a context for describing, elaborating and evaluating the relevant theory that sexual dysfunction could be a harbinger for CVDs also in women. However, its narrative nature as well as the lack of specifically designed studies to assess a definitive association between FSD and CVDs represent the principle limitations of this paper. CONCLUSION: Postmenopausal women, particularly those in the middle-age range, should be assessed for CV risk factors and FSD, so that both CVDs and sexual problems do not persist unnoticed. Cipriani S, Simon JA. Sexual Dysfunction as a Harbinger of Cardiovascular Disease in Postmenopausal Women: How Far Are We? J Sex Med 2022;19:1321-1332.

Individual Benefits and Risks of Intravaginal Estrogen and Systemic Testosterone in the Management of Women in the Menopause, With a Discussion of Any Associated Risks for Cancer Development.

ABSTRACT: Several formulations of intravaginal oestrogen are available for the treatment of genitourinary syndrome of menopause (GSM). These are safe and effective treatments for the symptoms of GSM. Licensed doses of intravaginal oestrogen do not elevate systemic estradiol levels above the normal postmenopausal range with long term use and there is no evidence of an increased risk of coronary heart disease, stroke, thromboembolism, colorectal cancer, endometrial cancer, breast cancer or breast cancer recurrence with their use. This should reassure both women and their healthcare professionals and should lead to more women receiving these localised, vaginally administered hormonal treatments. Available evidence also suggests a positive safety profile for transdermal testosterone treatment when delivered at physiological concentrations.

Assessing the Burden of Illness Associated with Acquired Generalized Hypoactive Sexual Desire Disorder.

Background: Hypoactive sexual desire disorder (HSDD), which affects ∼10% of women in the United States, is defined as the persistent or recurrent deficiency/absence of sexual desire accompanied by personal distress. Although HSDD impacts patient quality of life and interpersonal relationships, the disorder often goes unaddressed or untreated. Recent studies of the burden of illness in women with HSDD, especially premenopausal women, are limited. Materials and Methods: A 45-minute web-based survey was designed to investigate the experience of women seeking treatment for HSDD and the impact of this disorder on several psychosocial aspects of women's lives. Women were recruited from an online panel of patients who participated in research studies for compensation. Validated questionnaires assessed sexual function (Female Sexual Function Index) and health-related quality of life (12-Item Short Form Survey [SF-12]), including mental and physical component scores. Results: A total of 530 women, aged ≥18 years, diagnosed with acquired generalized HSDD were included in the study. Premenopausal women indicated greater overall HSDD symptom burden compared with postmenopausal women. Patients with HSDD reported lower SF-12 scores compared with the general population. A multivariable regression analysis demonstrated that psychosocial factors influencing the burden of HSDD, including interference with their relationship with their partner (ß = -0.18; p < 0.005), mental and emotional well-being (ß = -0.23; p < 0.005), and household and personal activities (ß = -0.23; p = 0.02), negatively affected SF-12 mental component scores. Conclusions: HSDD symptom burden was found to be negatively and statistically significantly associated with patients' mental health; the impact was greater among premenopausal women compared with postmenopausal women.

Prespecified and Integrated Subgroup Analyses from the RECONNECT Phase 3 Studies of Bremelanotide.

Background: Hypoactive sexual desire disorder (HSDD), the most prevalent female sexual dysfunction, is characterized as persistent diminished desire for sexual activity accompanied by distress. The efficacy and safety of bremelanotide, a melanocortin receptor agonist approved by the U.S. Food and Drug Administration for treatment of acquired generalized HSDD in premenopausal women, were established in the phase 3 RECONNECT studies, two identically designed double-blind randomized placebo-controlled studies with an optional 52-week open-label extension. This report investigates efficacy of bremelanotide versus placebo according to prespecified subgroups (age, weight, body mass index [BMI], and bioavailable testosterone) in the RECONNECT studies. Materials and Methods: Patients self-administered bremelanotide 1.75 mg or placebo subcutaneously using an autoinjector, as needed, before sexual activity for 24 weeks. Efficacy was assessed using change from baseline to end-of-study for Female Sexual Function Index desire domain and Female Sexual Distress Scale-Desire/Arousal/Orgasm Item 13 for bremelanotide versus placebo. Results: Among 1202 patients included in the integrated and subgroup analyses, bremelanotide achieved statistically significant improvements in measures of increased desire and decreased distress associated with low desire across all age, weight, and BMI subgroups, and all baseline bioavailable testosterone quartiles, with few exceptions. Bremelanotide was further associated with statistically significant increases in reported sexual desire (p < 0.05) in patients not taking hormonal contraceptives, and with a numerical advantage in those taking hormonal contraceptives. Patients treated with bremelanotide experienced decreased distress compared with those in the placebo group at levels of statistical significance (p < 0.05) regardless of hormonal contraceptive use. Statistically significant improvements were observed in the presence or absence of decreased arousal, and regardless of HSDD duration. Conclusions: Bremelanotide was associated with statistically significant improvements in sexual desire and reduced distress across several prespecified subgroups, with few exceptions.

Safety Profile of Bremelanotide Across the Clinical Development Program.

Background: Bremelanotide, a melanocortin receptor agonist, is Food and Drug Administration (FDA)-approved for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder. Methods: Review of bremelanotide's safety profile from the clinical development program (phases 1 through 3). Results: The clinical development program comprised 3500 subjects in 43 completed studies. In the phase 3 studies, subjects took bremelanotide for up to 18 months. The most common adverse events (AEs) were nausea (40.0% vs. 1.3%), flushing (20.3% vs. 1.3%), headache (11.3% vs. 1.9%), and injection site reactions (5.4 vs. 0.5), bremelanotide versus placebo groups, respectively, in the integrated double-blind portion of the phase 3 studies (N = 1247). Nausea was the most common reason for bremelanotide discontinuation. There were no deaths; a few subjects experienced serious AEs. Focal hyperpigmentation was rare when bremelanotide was dosed in accordance with label recommendations, but it occurred in more than one-third of subjects following up to 16 consecutive daily dosings. Small and transient but statistically significant blood pressure increases were observed during ambulatory blood pressure monitoring. Most drug-drug interactions were not clinically significant, except for interactions that lowered plasma concentrations of indomethacin and naltrexone. In the double-blind portion of the integrated phase 3 studies, 70% of the bremelanotide group proceeded to the open-label phase of the studies versus 87% of those on placebo. Conclusions: The AEs associated with bremelanotide are mostly mild to moderate. Although not deemed clinically important, bremelanotide should be used with caution in patients at risk of cardiovascular disease, and blood pressure should be well controlled during treatment. Clinical Trial Registration number: NCT02333071 [Study 301] and NCT02338960 [Study 302].

Clinically Meaningful Benefit in Women with Hypoactive Sexual Desire Disorder Treated with Flibanserin.

BACKGROUND: The efficacy of flibanserin in treating hypoactive sexual desire disorder (HSDD) is based upon statistically significant improvements in sexual desire, satisfying sexual events, and distress. However, clinically meaningful benefit has not been well characterized. AIM: Evaluate clinically meaningful benefit of flibanserin. METHODS: Data were pooled from 3 pivotal trials evaluating flibanserin 100 mg qhs in premenopausal women (flibanserin, n = 1192; placebo, n = 1215). Flibanserin trial data in postmenopausal women (flibanserin, n = 450; placebo, n = 476) were analyzed separately. Clinically meaningful benefit was evaluated by the Patient Global Impression of Improvement (PGI-I). Responders were determined through anchor-based analyses that used the PGI-I for key efficacy endpoints: satisfying sexual events (SSE), desire domain of the Female Sexual Function Index (FSFI-d), and distress associated with decreased sexual desire (FSDS-R13). Odds ratios were calculated to assess effect size and Kaplan-Meier analyses were performed to estimate onset time for treatment benefit. OUTCOMES: PGI-I, anchor-based analyses for key efficacy endpoints (SSE, FSFI-d, FSDS-R13), odds ratios, onset time for treatment benefit. RESULTS: Based on the PGI-I, more patients reported clinically meaningful benefit with flibanserin treatment versus placebo (49.8% vs 33.6%, premenopausal cohort; 40.5% vs 28.7%, postmenopausal cohort). In anchor-based analyses, responder rates were significantly higher for premenopausal women on flibanserin (46.1%-55.2%) than placebo (34.1%-44.2%) for all 3 key efficacy endpoints (P < .0001). Responder rates for postmenopausal women on flibanserin were higher compared to placebo for SSE (29.8% vs 22.9%; P = .015) and FSFI-d (38.9% vs 26.3%; P = .0001). Odds ratios for key endpoints indicated that premenopausal women were 2.0-2.4 times as likely to be responders with flibanserin treatment compared to placebo. Postmenopausal women were 1.6 times as likely to be responders with flibanserin for FSFI-d. Kaplan-Meier analyses indicated significant separation between flibanserin and placebo for the key endpoints in both premenopausal and postmenopausal cohorts (log-rank tests P < .01) with earlier median response times among patients receiving flibanserin. CLINICAL IMPLICATIONS: Patient-reported benefit assessments such as the PGI-I capture the patient's perspective and may be a useful approach in assessing overall clinical meaningfulness for sexual dysfunction therapies. STRENGTHS AND LIMITATIONS: Strengths include a well-powered study with large enrollment, use of validated instruments, and self-assessment of treatment benefit. Limitations include pooling of trial data in premenopausal women with slightly different study designs and use of an endpoint (SSE) indirectly related to HSDD. CONCLUSION: Assessment of clinically meaningful benefit and additional responder analyses provide further support for flibanserin's efficacy beyond numerical improvements in endpoint measures. Simon JA, Clayton AH, Kim NN, et al. Clinically Meaningful Benefit in Women with Hypoactive Sexual Desire Disorder Treated with Flibanserin. Sex Med 2022;10:100476.

Androgen therapy for women after menopause.

BACKGROUND: Androgens are essential hormones in women. Yet, androgen therapy is understudied and underutilized despite showing improvement in postmenopausal hypoactive sexual desire disorder (HSDD) and the genitourinary syndrome of menopause (GSM). Additionally, regulatory concerns have left a significant gap in commercially available testosterone preparations, formulated specifically for women, in most countries. This has led to off-label use of male formulations and compounded therapies which are under-regulated. Beyond HSDD and GSM, testosterone likely influences the brain, breast, cardiovascular and musculoskeletal systems. These effects are not well studied, and therefore it is difficult to counsel patients on testosterone therapy when used for these endpoints. Ultimately, further study is needed to elucidate these effects, create a fuller picture of the risks and benefits, and encourage product development specifically designed for women.

Bone Mineral Density Changes Associated With Pregnancy, Lactation, and Medical Treatments in Premenopausal Women and Effects Later in Life.

Bone mineral density (BMD) changes during the life span, increasing rapidly during adolescence, plateauing in the third decade of life, and subsequently entering a phase of age-related decline. In women, menopause leads to accelerated bone loss and an increase in fracture risk. Between peak bone mass attainment and menopause, BMD is generally stable and the risk of fracture is typically low. This time period is marked by life events such as pregnancy and lactation, which transiently decrease BMD, yet their long-term effects on fracture risk are less certain. BMD may also be altered by exposure to medications that affect bone metabolism (e.g., contraceptives, glucocorticoids, antidiabetic medications, antiepileptic drugs). Although oral contraceptives are often believed to be neutral with regard to bone health, depot medroxyprogesterone acetate (DMPA) and gonadotropin-releasing hormone (GnRH) agonists have been associated with decreases in BMD. Development of newer medical therapies, principally GnRH antagonists (e.g., ASP1707, elagolix, linzagolix, relugolix), for treatment of endometriosis-associated pelvic pain and heavy menstrual bleeding due to uterine fibroids has renewed interest in the short- and long-term impacts of changes in BMD experienced by premenopausal women. It is important to understand how these drugs influence BMD and put the findings into context with regard to measurement variability and naturally occurring factors that influence bone health. This review summarizes what is known about the effects on bone health pregnancy, lactation, and use of DMPA, GnRH agonists, and GnRH antagonists in premenopausal women and potential consequences later in life. ClinicalTrials.gov identifier: NCT03213457.