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.

Ospemifene for the treatment of menopausal vaginal dryness, a symptom of the genitourinary syndrome of menopause.

Introduction: Vulvovaginal atrophy (VVA), a component of the genitourinary syndrome of menopause, is a progressive condition due to decline in estrogen leading to vaginal and vulvar epithelial changes. Accompanying symptoms of dryness, irritation, burning, dysuria, and/or dyspareunia have a negative impact on quality of life. Ospemifene is a selective estrogen receptor modulator (SERM) approved by the FDA for moderate to severe dyspareunia and vaginal dryness due to postmenopausal VVA. Areas covered: PubMed was searched from inception to March 2019 with keywords ospemifene and vulvar vaginal atrophy to review preclinical and clinical data describing the safety and efficacy of ospemifene for vaginal dryness and dyspareunia due to VVA. Covered topics include efficacy of ospemifene on vaginal cell populations, vaginal pH, and most bothersome VVA symptoms; imaging studies of vulvar and vaginal tissues; effects on sexual function; and safety of ospemifene on endometrium, cardiovascular system, and breast. Expert opinion: Ospemifene is significantly more effective than placebo in all efficacy analyses studied, working through estrogen receptors and possibly androgen receptors. Safety as assessed by adverse events was generally comparable to that with placebo and to other SERMs, and/or adverse events were not clinically meaningful. No cases of endometrial or breast cancer were reported.

Efficacy of the 1-year (13-cycle) segesterone acetate and ethinylestradiol contraceptive vaginal system: results of two multicentre, open-label, single-arm, phase 3 trials.

BACKGROUND: A ring-shaped, contraceptive vaginal system designed to last 1 year (13 cycles) delivers an average of 0·15 mg segesterone acetate and 0·013 mg ethinylestradiol per day. We evaluated the efficacy of this contraceptive vaginal system and return to menses or pregnancy after use. METHODS: In two identically designed, multicentre, open-label, single-arm, phase 3 trials (one at 15 US academic and community sites and one at 12 US and international academic and community sites), participants followed a 21-days-in, 7-days-out segesterone acetate and ethinylestradiol contraceptive vaginal system schedule for up to 13 cycles. Participants were healthy, sexually active, non-pregnant, non-sterilised women aged 18-40 years. Women were cautioned that any removals during the 21 days of cyclic use should not exceed 2 h, and used daily paper diaries to record vaginal system use. Consistent with regulatory requirements for contraceptives, we calculated the Pearl Index for women aged 35 years and younger, excluding adjunctive contraception cycles, as the primary efficacy outcome measure. We also did intention-to-treat Kaplan-Meier life table analyses and followed up women who did not use hormonal contraceptives or desired pregnancy after study completion for 6 months for return to menses or pregnancy. The trials are registered with ClinicalTrials.gov, numbers NCT00455156 and NCT00263341. FINDINGS: Between Dec 19, 2006, and Oct 9, 2009, at the 15 US sites, and between Nov 1, 2006, and July 2, 2009, at the 12 US and international sites we enrolled 2278 women. Our overall efficacy analysis included 2265 participants (1130 in the US study and 1135 in the international study) and 1303 (57·5%) participants completed up to 13 cycles. The Pearl Index for the primary efficacy group was 2·98 (95% CI 2·13-4·06) per 100 woman-years, and was well within the range indicative of efficacy for a contraceptive under a woman's control. The Kaplan-Meier analysis revealed the contraceptive vaginal system was 97·5% effective, which provided further evidence of efficacy. Pregnancy occurrence was similar across cycles. All 290 follow-up participants reported return to menses or became pregnant (24 [63%] of 38 women who desired pregnancy) within 6 months. INTERPRETATION: The segesterone acetate and ethinylestradiol contraceptive vaginal system is an effective contraceptive for 13 consecutive cycles of use. This new product adds to the contraceptive method mix and the 1-year duration of use means that women do not need to return to the clinic or pharmacy for refills every few months. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, the US Agency for International Development, and the WHO Reproductive Health Research Department.

Women's experience of vulvovaginal symptoms associated with menopause.

OBJECTIVE: This study describes women's experiences of the genitourinary syndrome of menopause (GSM) elicited through focus groups and cognitive debriefing sessions during development of a novel patient-reported outcome measure (PROM) designed for use in both clinical care and research. METHODS: A draft questionnaire to identify and assess bothersome genitourinary symptoms associated with estrogen deficiency in menopausal women was developed in five discrete phases from multiple sources of information in accordance with standards for PROM development. GSM was confirmed by report of symptoms in conjunction with a confirmatory pelvic examination and laboratory assessments. RESULTS: Qualitative content interviews were completed in 36 menopausal women with GSM. Cognitive testing of draft PROM items was performed in nine focus groups, including 26 menopausal women with and 15 without GSM. Participants reported a range of symptoms and described associated impacts on more than 15 quality-of-life domains. The majority of women reported that their symptoms impacted their sexual functioning and had a negative effect on their overall quality of life. GSM affected many aspects of menopausal women's lives beyond sexual function, with descriptions of pain when walking, urinating, wearing tight clothes, and with other activities of daily living. CONCLUSIONS: Women's own words methodically recorded and analyzed during qualitative interviews and cognitive debriefing focus groups illuminate the subjective experience of women with GSM. It is hoped that the PROM currently in development will provide an effective tool for increasing our understanding of the prevalence, predictors, and impact of GSM in menopausal women's lives.

Flibanserin in Postmenopausal Women With Hypoactive Sexual Desire Disorder: Results of the PLUMERIA Study.

BACKGROUND: Hypoactive sexual desire disorder (HSDD) is a common sexual disorder in younger and older women. Flibanserin is approved for the treatment of acquired generalized HSDD in premenopausal women only. The efficacy of flibanserin for postmenopausal women with HSDD was demonstrated in the first of two North American randomized, double-blinded, placebo-controlled trials (SNOWDROP). AIM: To evaluate the safety and efficacy of flibanserin in postmenopausal women with HSDD in a second randomized, double-blinded, placebo-controlled trial (PLUMERIA). METHODS: Naturally postmenopausal women were randomly assigned to receive flibanserin (100 mg/d) or placebo. Efficacy outcomes were assessed using the last-observation-carried-forward imputation method. OUTCOMES: Safety assessment included incidence of adverse events. Primary efficacy outcomes were the number of satisfying sexual events and the Female Sexual Function Index desire domain (FSFI-d) score. RESULTS: The study population (flibanserin, n = 376; placebo, n = 369) included primarily white women (84.7%), with a mean age of 56.1 years and a mean HSDD duration of 5.0 years. When the study was discontinued early by the sponsor, 45.3% of randomly assigned patients had completed week 16 (which served as the primary analysis time point). The most common adverse events in flibanserin-treated patients were insomnia (7.7%), somnolence (6.9%), and dizziness (6.4%). Improvement from baseline to week 16 (last-observation-carried-forward) in FSFI-d score was significantly greater for flibanserin compared with placebo (P = .011); however, the between-group comparison for satisfying sexual events did not reach statistical significance. CLINICAL IMPLICATIONS: Considered with the findings of the previous randomized controlled trial (SNOWDROP), the results of this study support the safety and efficacy of flibanserin in postmenopausal women. STRENGTHS AND LIMITATIONS: This was a well-designed randomized, placebo-controlled trial. A key limitation was early discontinuation by the study sponsor, which decreased the sample size. In addition, the validity of satisfying sexual events as a primary outcome measurement in HSDD studies has been called into question (but was required by the US Food and Drug Administration as a primary end point in studies of female sexual dysfunction at the time this study was conducted). CONCLUSION: Flibanserin was generally well tolerated in this population of naturally postmenopausal women. Despite the greatly decreased power to detect improvement compared with placebo on the efficacy measurements used, results suggest that flibanserin could be efficacious in postmenopausal women with HSDD. Portman DJ, Brown L, Yuan J, et al. Flibanserin in Postmenopausal Women With Hypoactive Sexual Desire Disorder: Results of the PLUMERIA Study. J Sex Med 2017;14:834-842.

Bremelanotide for female sexual dysfunctions in premenopausal women: a randomized, placebo-controlled dose-finding trial.

AIM: Evaluate efficacy/safety of bremelanotide (BMT), a melanocortin-receptor-4 agonist, to treat female sexual dysfunctions in premenopausal women. METHODS: Patients randomized to receive placebo or BMT 0.75, 1.25 or 1.75 mg self-administered subcutaneously, as desired, over 12 weeks. Primary end point was change in satisfying sexual events/month. Secondary end points included total score changes on female sexual function index and female sexual distress scale-desire/arousal/orgasm. RESULTS: Efficacy data, n = 327. For 1.25/1.75-mg pooled versus placebo, mean changes from baseline to study end were +0.7 versus +0.2 satisfying sexual events/month (p = 0.0180), +3.6 versus +1.9 female sexual function index total score (p = 0.0017), -11.1 versus -6.8 female sexual distress scale-desire/arousal/orgasm total score (p = 0.0014). Adverse events: nausea, flushing, headache. CONCLUSION: In premenopausal women with female sexual dysfunctions, self-administered, as desired, subcutaneous BMT was safe, effective, and well tolerated (NCT01382719).

Lack of effect of intravaginal dehydroepiandrosterone (DHEA, prasterone) on the endometrium in postmenopausal women.

OBJECTIVE: This study aims to evaluate the effects of intravaginal dehydroepiandrosterone (DHEA, prasterone) on the endometrium in postmenopausal women. METHODS: Intravaginal DHEA (6.5 mg) was administered daily for 52 weeks to 422 women who had endometrial biopsy at baseline and end of study, whereas 15 women were similarly treated for 26 to 52 weeks. Participants in three other studies received 3.25 mg (n = 126), 6.5 mg (n = 129), or 13 mg (n = 30) of DHEA for 12 weeks; women similarly had baseline and end-of-study biopsies. Endometrial biopsy samples were available for 668 women at baseline and end of study, with sufficient material for analysis. RESULTS: Endometrial atrophy or inactive endometrium (668 women) was found in all women treated with intravaginal DHEA. Similar atrophy was observed in 119 of 121 participants with sufficient material for analysis who received placebo. CONCLUSIONS: After cessation of estradiol secretion by the ovaries at menopause, the estrogens made by mechanisms of intracrinology are inactivated intracellularly at their site of formation and action, thus maintaining serum estradiol at biologically inactive concentrations to avoid stimulation of the endometrium. The absence of enzymes that are able to transform DHEA into estrogens in the endometrium explains the typical endometrial atrophy in all normal postmenopausal women in the presence of variable concentrations of circulating endogenous DHEA. According to these mechanisms, the inactive sex steroid precursor DHEA administered intravaginally acts exclusively in the vagina, whereas all serum sex steroids remain well within the biologically inactive postmenopausal reference range, thus avoiding any stimulation of the already atrophic endometrium.

Treatment of pain at sexual activity (dyspareunia) with intravaginal dehydroepiandrosterone (prasterone).

OBJECTIVE: This study aims to confirm the local effects of intravaginal prasterone on moderate to severe dyspareunia, a symptom of vulvovaginal atrophy (VVA) associated with menopause. METHODS: In a prospective, randomized, double-blind, placebo-controlled phase III clinical trial, we examined the effects of daily intravaginal prasterone (6.5 mg) on four co-primary objectives, namely, percentage of vaginal parabasal cells, percentage of vaginal superficial cells, vaginal pH, and moderate to severe dyspareunia identified by women as the most bothersome VVA symptom. RESULTS: After daily intravaginal prasterone administration for 12 weeks, the percentage of parabasal cells decreased by 45.8% compared with placebo (P < 0.0001), the percentage of superficial cells increased by 4.7% over placebo (P < 0.0001), and vaginal pH decreased by 0.83 pH units compared with placebo (P < 0.0001). The severity of most bothersome dyspareunia decreased by 46% over placebo (P = 0.013) at 12 weeks, whereas moderate to severe vaginal dryness decreased by 0.43 severity score units (or 42%) compared with placebo (P = 0.013). On gynecologic evaluation, a 14.4% to 21.1% improvement in vaginal secretions, epithelial integrity, epithelial surface thickness, and color over placebo (P = 0.0002 to P < 0.0001) was observed. Serum steroids, in agreement with the physiology of intracrinology and menopause, remained well within reference postmenopausal concentrations. All endometrial biopsies at 12 weeks have shown atrophy. CONCLUSIONS: Daily intravaginal prasterone (0.50%; 6.5 mg) treatment has clinically and statistically significant beneficial effects on the four co-primary objectives of VVA, according to US Food and Drug Administration guidelines. No significant drug-related adverse effect in line with the strictly local action of treatment has been reported, thus providing a high benefit-to-risk ratio for intravaginal prasterone.

Prasterone has parallel beneficial effects on the main symptoms of vulvovaginal atrophy: 52-week open-label study.

OBJECTIVE: An objective was to analyze the time course of efficacy of daily intravaginal administration of 0.5% (6.5mg) DHEA (prasterone) for 52 weeks on the moderate to severe (MS) symptoms and signs of vulvovaginal atrophy (VVA). METHOD: Five hundred twenty-one postmenopausal women were enrolled and received daily intravaginal administration of 0.5% DHEA in an open-label phase III study. The severity of the VVA symptoms examined in detail in the different groups. RESULTS: A parallel improvement of pain at sexual activity was observed in women who had moderate to severe (MS) dyspareunia as their most bothersome symptom (MBS) (n=183) or not MBS (n=240) and MS without being MBS (n=57) with a 1.70 severity unit change in the MBS group for a decrease of 66.1% from baseline (p<0.0001 versus baseline) over 52 weeks. A further improvement of dyspareunia, namely 0.33 severity unit (19.4%), was observed with continuing treatment from 12 weeks to 52 weeks. Similar results were observed on vaginal dryness and irritation/itching. Highly significant beneficial effects (p<0.0001 versus baseline for all) were observed at gynecological examination on vaginal secretions, color, epithelial integrity and epithelial surface thickness. CONCLUSION: The present study shows, in addition to the parallel benefits on the three symptoms of VVA, that the choice of any of the MS symptoms as being or not being MBS by women has no influence on the observed therapeutic effect (NCT01256671).

Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and the North American Menopause Society.

INTRODUCTION: The terminology for the genitourinary tract symptoms related to menopause was vulvovaginal atrophy, which does not accurately describe the symptoms nor is a term that resonates well with patients. AIM: In 2012, the Board of Directors of the International Society for the Study of Women's Sexual Health (ISSWSH) and the Board of Trustees of The North American Menopause Society (NAMS) acknowledged the need to review current terminology associated with genitourinary tract symptoms related to menopause. METHODS: The two societies cosponsored a terminology consensus conference, which was held in May 2013. MAIN OUTCOME MEASURE: The development of a new terminology that more accurately described the genitourinary tract symptoms related to menopause. RESULTS: Members of the consensus conference agreed that the term genitourinary syndrome of menopause (GSM) is a medically more accurate, all-encompassing, and publicly acceptable term than vulvovaginal atrophy. GSM is defined as a collection of symptoms and signs associated with a decrease in estrogen and other sex steroids involving changes to the labia majora/minora, clitoris, vestibule/introitus, vagina, urethra, and bladder. The syndrome may include but is not limited to genital symptoms of dryness, burning, and irritation; sexual symptoms of lack of lubrication, discomfort or pain, and impaired function; and urinary symptoms of urgency, dysuria, and recurrent urinary tract infections. Women may present with some or all of the signs and symptoms, which must be bothersome and should not be better accounted for by another diagnosis. CONCLUSION: The term GSM was presented and discussed at the annual meeting of each society. The respective Boards of NAMS and ISSWSH formally endorsed the new terminology--genitourinary syndrome of menopause--in 2014.

Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and the North American Menopause Society.

BACKGROUND: In 2012, the Board of Directors of the International Society for the Study of Women's Sexual Health (ISSWSH) and the Board of Trustees of The North American Menopause Society (NAMS) acknowledged the need to review current terminology associated with genitourinary tract symptoms related to menopause. METHODS: The 2 societies cosponsored a terminology consensus conference, which was held in May 2013. RESULTS AND CONCLUSIONS: Members of the consensus conference agreed that the term genitourinary syndrome of menopause (GSM) is a medically more accurate, all-encompassing, and publicly acceptable term than vulvovaginal atrophy. GSM is defined as a collection of symptoms and signs associated with a decrease in estrogen and other sex steroids involving changes to the labia majora/minora, clitoris, vestibule/introitus, vagina, urethra and bladder. The syndrome may include but is not limited to genital symptoms of dryness, burning, and irritation; sexual symptoms of lack of lubrication, discomfort or pain, and impaired function; and urinary symptoms of urgency, dysuria and recurrent urinary tract infections. Women may present with some or all of the signs and symptoms, which must be bothersome and should not be better accounted for by another diagnosis. The term was presented and discussed at the annual meeting of each society. The respective Boards of NAMS and ISSWSH formally endorsed the new terminology--genitourinary syndrome of menopause (GSM)--in 2014.

Efficacy and safety of an ascending-dose, extended-regimen levonorgestrel/ethinyl estradiol combined oral contraceptive.

OBJECTIVE: To evaluate the efficacy and safety of an ascending-dose, extended-regimen (ADER) combined oral contraceptive consisting of levonorgestrel (LNG) 150 mcg/ethinyl estradiol (EE) 20 mcg for 42 days, LNG 150 mcg/EE 25 mcg for 21 days, LNG 150 mcg/EE 30 mcg for 21 days and EE 10 mcg for 7 days. STUDY DESIGN: This was a multicenter, open-label, phase 3, single-arm study. Sexually active women aged 18-40 years were enrolled and received ADER for up to 1 year (4 consecutive 91-day cycles). Participants kept diaries to record adherence, bleeding/spotting and other contraceptive use. Efficacy was measured using the Pearl Index and the life-table method; safety and tolerability were assessed through reported adverse events (AEs). RESULTS: A total of 3701 women were enrolled and 2144 completed the study. The Pearl Index was 3.19 [95% confidence interval (CI), 2.49-4.03], based on 70 pregnancies that occurred after ADER initiation and ≤ 7 days after the last LNG/EE or EE-only pill in women aged 18-35 years, excluding cycles in which another contraceptive method was used. Life-table pregnancy rate was 2.82% (95% CI, 2.23%-3.57%) for all users aged 18-35 years. Unscheduled bleeding/spotting decreased with increasing EE doses within each cycle and decreased after cycle 1. No unexpected AEs or changes in laboratory parameters were reported. CONCLUSION: This study demonstrated that ADER effectively prevented pregnancy with a favorable safety and tolerability profile.

Effects of low-dose paroxetine 7.5 mg on weight and sexual function during treatment of vasomotor symptoms associated with menopause.

OBJECTIVE: Two phase 3, randomized, placebo-controlled trials demonstrated that low-dose paroxetine 7.5 mg reduced the frequency and severity of vasomotor symptoms (VMS) associated with menopause and had a favorable tolerability profile. The impact of paroxetine 7.5 mg on body weight and sexual function was evaluated in a pooled analysis. METHODS: Postmenopausal women aged 40 years or older who had moderate to severe VMS were randomly assigned to receive paroxetine 7.5 mg or placebo once daily for 12 or 24 weeks. Assessments included changes in body mass index (BMI) and weight, Arizona Sexual Experiences Scale score, Hot Flash-Related Daily Interference Scale sexuality subscore, and adverse events related to weight or sexual dysfunction. RESULTS: Pooled efficacy and safety populations comprised 1,174 and 1,175 participants, respectively. Baseline values were similar for median weight (∼75 kg), median BMI (∼28 kg/m), and the proportion of women with sexual dysfunction (∼58%). No clinically meaningful or statistically significant changes from baseline in weight or sexual function assessments occurred in the paroxetine 7.5 mg group. Small but statistically significant increases in weight and BMI were observed in the placebo group only on week 4. No significant difference between treatment groups was observed in the proportion of participants who had 7% or higher gain in body weight on week 4, 12, or 24. Rates of adverse events suggestive of sexual dysfunction were low and similar in both treatment groups. CONCLUSIONS: Paroxetine 7.5 mg does not cause weight gain or negative changes in libido when used to treat menopause-associated VMS in postmenopausal women.

Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials.

OBJECTIVE: The efficacy and safety of low-dose paroxetine 7.5 mg for the treatment of menopausal vasomotor symptoms were evaluated in two multicenter, double-blind, placebo-controlled, phase 3 studies of 12 and 24 weeks' duration. METHODS: Postmenopausal women were randomly assigned 1:1 to receive paroxetine 7.5 mg or placebo once daily. The four primary efficacy endpoints included mean changes in the frequency and severity of moderate to severe vasomotor symptoms on weeks 4 and 12; an additional endpoint was persistence of treatment benefit on week 24. RESULTS: Five hundred ninety-one participants were randomly assigned to treatment with paroxetine 7.5 mg, and 593 participants were randomly assigned to treatment with placebo. All primary endpoints were met in the 24-week study; three of four primary endpoints were met in the 12-week study. In both studies, paroxetine 7.5 mg significantly reduced the mean weekly vasomotor symptom frequency compared with placebo on week 4 (P < 0.0001 for both studies) and week 12 (P = 0.0090, 12-wk study; P = 0.0001, 24-wk study). Mean weekly reduction in vasomotor symptom severity was significantly greater for paroxetine 7.5 mg than for placebo on week 4 (P = 0.0048) in the 12-week study and on week 4 (P = 0.0452) and week 12 (P = 0.0114) in the 24-week study. Persistence of treatment benefit was demonstrated in the 24-week study. Most treatment-emergent adverse events were mild or moderate in severity. No clinically significant changes in laboratory values or vital signs were noted, and no short-term discontinuation of symptoms followed treatment cessation. CONCLUSIONS: Paroxetine 7.5 mg is well-tolerated, is effective in reducing the frequency and severity of menopausal vasomotor symptoms, and demonstrates persistence of treatment benefit through 24 weeks of treatment.

Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy.

OBJECTIVE: The aim of this work was to study the role of ospemifene, a novel selective estrogen receptor modulator, in the treatment of vulvar and vaginal atrophy in postmenopausal women with moderate to severe dyspareunia and physiological vaginal changes. METHODS: This multicenter phase 3 study used a randomized, double-blind, parallel-group design to compare the efficacy, safety, and tolerability of oral ospemifene 60 mg/day versus placebo. A total of 605 women aged 40 to 80 years who self-reported a most bothersome symptom of dyspareunia and had a diagnosis of vulvar and vaginal atrophy were randomized to take a once-daily dose of ospemifene (n = 303) or placebo (n = 302) for 12 weeks. RESULTS: Analysis of the intent-to-treat (n = 605) population found the efficacy of ospemifene to be significantly greater than that of placebo for each of the following coprimary endpoints: percentages of parabasal and superficial cells, vaginal pH, and severity of dyspareunia. With ospemifene, the percentage of parabasal cells and vaginal pH significantly decreased; the percentage of superficial cells significantly increased; and dyspareunia was significantly reduced versus placebo (all P < 0.0001, except for dyspareunia: P = 0.0001). Among the randomized women, 186 (61.4%) in the ospemifene group and 154 (51.0%) in the placebo group reported at least one treatment-emergent adverse event. Hot flushes were the most frequently reported treatment-related adverse event (ospemifene 6.6% vs placebo 3.6%); only one participant discontinued in each group. As determined by the investigators, no serious adverse events related to the study drug were reported. CONCLUSIONS: In this study, once-daily oral ospemifene 60 mg was effective for the treatment of vulvar and vaginal atrophy in postmenopausal women with dyspareunia.

Adding low-dose estrogen to the hormone-free interval: impact on bleeding patterns in users of a 91-day extended regimen oral contraceptive.

BACKGROUND: A cross-study analysis of contraceptive clinical trials for two different 91-day oral contraceptive (OC) regimens was performed to examine the impact on bleeding patterns when supplementing the 7-day hormone-free interval with 10 mcg ethinyl estradiol (EE) daily. STUDY DESIGN: Two separate 1-year Phase 3 clinical programs were conducted using similar study designs. The percentages of subjects reporting bleeding and spotting using electronic diaries for each 91-day cycle were compared. RESULTS: Scheduled bleeding with the EE regimen was less than that reported with the regimen utilizing placebo during Days 85-91, with significant differences noted for all four 91-day cycles. Unscheduled bleeding decreased more quickly with the 91-day regimen containing low-dose EE in place of placebo, with significant differences noted during the third cycle. CONCLUSIONS: This cross-study comparison suggests that the administration of low-dose estrogen in place of placebo in a 91-day extended regimen OC improves the bleeding profile.

A retrospective managed care claims data analysis of medication adherence to vaginal estrogen therapy: implications for clinical practice.

OBJECTIVES: This study sought to assess refill-based treatment duration and adherence to vaginal estrogen therapy (VET) in clinical practice and to compare treatment duration in women prescribed vaginal tablets (VT) or vaginal creams (VC) in clinical trials with that in clinical practice. METHODS: Adults initiating VET between January and June 2004 were identified in 57 commercial health plans in the United States and followed for up to 10 months after treatment initiation. Treatment duration (Kaplan-Meier analysis) and adherence (medication possession ratio [MPR]) were examined for VC and VT cohorts and compared with a weighted average of treatment duration calculated for seven clinical trials identified in the literature. RESULTS: Of 13,074 women (mean age 54 +/- 9.1 years) identified, patients on VT had significantly longer treatment duration compared with patients on VC (149.1 +/- 101.1 days vs. 91.6 +/- 30.0 days, p < 0.01). Among 5,599 patients receiving multiple prescriptions, higher treatment durations were observed for both VT-treated and VC-treated patients (198.5 +/- 82.4 days vs. 177.1 +/- 86.7 days, p < 0.01) compared with 165 days observed in clinical trials. Medication adherence (MPR > or = 80%) was significantly higher among VT users compared with VC users (74% +/- 27% vs. 52% +/- 32%], p < 0.01); OR, 3.24, 95% CI 2.84-3.70). CONCLUSIONS: Duration of VET among patients receiving multiple prescriptions was longer in real-world clinical practice than in clinical trials. Newly treated patients initiating VT were more likely to continue treatment for longer periods and exhibited greater medication adherence than did those on VC.

A randomized, double-blind, placebo-controlled, multicenter study that assessed the endometrial effects of norethindrone acetate plus ethinyl estradiol versus ethinyl estradiol alone.

OBJECTIVE: The purpose of this study was to determine the incidence of endometrial hyperplasia in subjects who receive continuous norethindrone acetate and ethinyl estradiol combinations versus unopposed ethinyl estradiol. STUDY DESIGN: Nine hundred forty-five postmenopausal women were randomly selected for 12 months of treatment with one of six blinded norethindrone acetate/ethinyl estradiol combinations (milligrams of norethindrone acetate/micrograms of ethinyl estradiol: 0/5, 0.25/5, 1/5, 0/10, 0.5/10, or 1/10) or to open-label 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate. Endometrial hyperplasia and endometrial proliferation were assessed by biopsy at screening, months 6 and 12. RESULTS: Endometrial hyperplasia developed in 26 subjects: Placebo, 0/5 and 0.25/5 (1 subject each) and 0/10 (23 subjects). Significantly less endometrial proliferation was measured in the 1/5 norethindrone acetate/ethinyl estradiol and other norethindrone acetate/ethinyl estradiol combination groups and in the 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate group, than in unopposed ethinyl estradiol groups (6 months: P <.004; 12 months: P <.001). Treatment with 1/5 norethindrone acetate/ethinyl estradiol and with other norethindrone acetate/ethinyl estradiol combinations significantly reduced endometrial proliferation compared with 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate (6 and 12 months: P <.02). CONCLUSION: Norethindrone acetate protects the endometrium from estrogen-induced hyperplasia and changes in proliferative status. In addition, norethindrone acetate/ethinyl estradiol-treated subjects had significantly less endometrial proliferation compared with 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate-treated subjects.