Estetrol is a natural estrogen with a favorable safety profile, showing minimal effects on liver proteins, blood clotting, and breast tissue, which may reduce the risks of blood clots and cardiovascular disease. This review presents the profile of estetrol in support of the rationale of two pivotal phase 3 clinical trials, E4COMFORT I and E4COMFORT II, as well as the design of those. E4COMFORT I and II are aimed at assessing the efficacy and safety of estetrol in the treatment of moderate to severe vasomotor symptoms in postmenopausal women. The E4COMFORT I and II trials were divided into an efficacy part (arms 1-3) and a safety part (arm 4). Efficacy was evaluated through a randomized, double-blind, placebo-controlled study examining two doses of estetrol (15 mg and 20 mg) in postmenopausal participants, both hysterectomized and non-hysterectomized, who experienced 7 or more moderate to severe vasomotor symptoms per day (or 50 or more per week). To comply with Food and Drug Administration and European Medicines Agency guidelines for long-term safety assessments in both groups, these trials evaluated the overall and endometrial safety of unopposed estetrol and of estetrol combined with natural progesterone. The total enrolment across the E4COMFORT I and II trials was 2576 participants. The results of these trials are expected to give a thorough understanding of estetrol 's potential as a new, distinctive treatment option for women with postmenopausal symptoms. CLINICALTRIALS REGISTRATION: NCT04209543 and NCT04090957.

OBJECTIVE:To assess the association of systolic and diastolic blood pressure (SBP and DBP) in recently menopausal women with white matter hyperintensity (WMH) volume later in life and determine whether short-term menopausal hormone therapy (mHT) modifies these associations. METHODS:Kronos Early Estrogen Prevention Study (KEEPS) was a multicenter, randomized, double-blinded, placebo-controlled 4-year mHT trial (oral conjugated equine estrogens or transdermal 17β-estradiol). KEEPS continuation was an observational follow-up of the participants 10 years after the end of mHT. The associations between KEEPS baseline blood pressure (BP) with KEEPS continuation WMH volume were examined adjusting for covariates in model 1 (age, total intracranial volume, study site, mHT type) and model 2 (additionally conventional CVD risk factors). Interaction terms (BP × mHT type) were added into the linear regression models. RESULTS:The mean ± SD ages of participants were 53 (±2) years at KEEPS baseline and 67 (±2) years at KEEPS continuation. Elevated BP at KEEPS baseline was associated with greater WMH volume measured 14 years later (model 1: SBP: β = 0.01 [95% CI, 0.001-0.01] and DBP: β = 0.01 [95% CI, 0.003-0.03]) and after additionally adjusting for CVD risk factors (model 2). We did not find any evidence that mHT versus placebo modified these associations. Topographically, higher BP was associated with greater periventricular WMH in the frontal and parietal lobes. CONCLUSION:Our findings suggest the importance of maintaining normal BP in recently postmenopausal women with low CVD risk, irrespective of short-term mHT usage, to potentially reduce the risk of WMH later in life.

BACKGROUND:Findings from Kronos Early Estrogen Prevention Study (KEEPS)-Cog trial suggested no cognitive benefit or harm after 48 months of menopausal hormone therapy (mHT) initiated within 3 years of final menstrual period. To clarify the long-term effects of mHT initiated in early postmenopause, the observational KEEPS Continuation Study reevaluated cognition, mood, and neuroimaging effects in participants enrolled in the KEEPS-Cog and its parent study the KEEPS approximately 10 years after trial completion. We hypothesized that women randomized to transdermal estradiol (tE2) during early postmenopause would show cognitive benefits, while oral conjugated equine estrogens (oCEE) would show no effect, compared to placebo over the 10 years following randomization in the KEEPS trial. METHODS AND FINDINGS:The KEEPS-Cog (2005-2008) was an ancillary study to the KEEPS (NCT00154180), in which participants were randomized into 3 groups: oCEE (Premarin, 0.45 mg/d), tE2 (Climara, 50 μg/d) both with micronized progesterone (Prometrium, 200 mg/d for 12 d/mo) or placebo pills and patch for 48 months. KEEPS Continuation (2017-2022), an observational, longitudinal cohort study of KEEPS clinical trial, involved recontacting KEEPS participants approximately 10 years after the completion of the 4-year clinical trial to attend in-person research visits. Seven of the original 9 sites participated in the KEEPS Continuation, resulting in 622 women of original 727 being invited to return for a visit, with 299 enrolling across the 7 sites. KEEPS Continuation participants repeated the original KEEPS-Cog test battery which was analyzed using 4 cognitive factor scores and a global cognitive score. Cognitive data from both KEEPS and KEEPS Continuation were available for 275 participants. Latent growth models (LGMs) assessed whether baseline cognition and cognitive changes during KEEPS predicted cognitive performance at follow-up, and whether mHT randomization modified these relationships, adjusting for covariates. Similar health characteristics were observed at KEEPS randomization for KEEPS Continuation participants and nonparticipants (i.e., women not returning for the KEEPS Continuation). The LGM revealed significant associations between intercepts and slopes for cognitive performance across almost all domains, indicating that cognitive factor scores changed over time. Tests assessing the effects of mHT allocation on cognitive slopes during the KEEPS and across all years of follow-up including the KEEPS Continuation visit were all statistically nonsignificant. The KEEPS Continuation study found no long-term cognitive effects of mHT, with baseline cognition and changes during KEEPS being the strongest predictors of later performance. Cross-sectional comparisons confirmed that participants assigned to mHT in KEEPS (oCEE and tE2 groups) performed similarly on cognitive measures to those randomized to placebo, approximately 10 years after completion of the randomized treatments. These findings suggest that mHT poses no long-term cognitive harm; conversely, it provides no cognitive benefit or protective effects against cognitive decline. CONCLUSIONS:In these KEEPS Continuation analyses, there were no long-term cognitive effects of short-term exposure to mHT started in early menopause versus placebo. These data provide reassurance about the long-term neurocognitive safety of mHT for symptom management in healthy, recently postmenopausal women, while also suggesting that mHT does not improve or preserve cognitive function in this population.

Objective This study aimed to determine long-term cardiometabolic effects of hormone therapies initiated within 3 years of onset of menopause after a 14-year follow-up study of participants of the Kronos Early Estrogen Prevention Study (KEEPS). Methods KEEPS was a multisite clinical trial that recruited recently menopausal women with good cardiovascular health for randomization to oral conjugated equine estrogens (Premarin, 0.45 mg/d) or transdermal 17β-estradiol (Climara, 50 μg/d) both with micronized progesterone (Prometrium, 200 mg/d) for 12 d/mo, or placebo pills and patch for 4 years. KEEPS continuation recontacted KEEPS participants 14 years after randomization and 10 years after the completion of the 4-year clinical trial to attend in-person clinic visits. Results Participants of KEEPS continuation (n = 299 of the 727 KEEPS participants; 41%) had an average age of 67 years (range, 58-73 y). Measurements of systolic and diastolic blood pressures, waist-to-hip ratio, fasting levels of glucose, insulin, lipid profiles, and homeostasis model assessment of insulin resistance were not different among the treatment groups at either KEEPS baseline or at KEEPS continuation visits, or for change between these two visits. The frequency of self-reported diabetes ( P = 0.007) and use of diabetes medications was higher in the placebo than the oral conjugated equine estrogens ( P = 0.045) or transdermal 17β-estradiol ( P = 0.02) groups, but these differences were not supported by the laboratory measurements of glycemia or insulin resistance. Conclusions There was no evidence of cardiovascular and/or metabolic benefits or adverse effects associated with 4 years use of oral or transdermal forms of hormone therapy by recently menopausal women with good cardiovascular health after 10 years.

AbstractBackgroundWomen have higher rates of hypertension at the time of menopausal transition than men. Although elevated systolic and diastolic blood pressures (SBP and DBP) are risk factors for white matter (WM) injury both in women and men, WM hyperintensities (WMH), a marker of WM injury, are more common in women than in men after the age of 60. Thus, women may be vulnerable to the effects of elevated BP on WM integrity during menopausal transition. We investigated the association of BP in recently postmenopausal women with good cardiovascular health with WMH volume assessed 13 years later.MethodWomen (n = 212; median age = 67; range 58‐72), who were previously enrolled in a multi‐site randomized menopausal hormone therapy trial, Kronos Early Estrogen Prevention Study (KEEPS), participated in the present observational KEEPS Continuation Study. SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59). Participants who were on antihypertensive medications at KEEPS baseline were excluded from the analysis (n = 34). Approximately 9 years after the end of KEEPS menopausal hormones versus placebo 4‐year interventions, WM integrity was assessed with automated WMH volume measurements from 3D‐FLAIR MRI. Associations of baseline SBP and DBP with logWMH volume measured 13 years later were tested by linear regression analyses. Model 1 was adjusted for age, study site, and total intracranial volume. Model 2 was adjusted for covariates of model 1, triglycerides, low density lipoproteins, and waist/hip ratio.ResultThe median SBP was 116 (range 83‐158) and DBP was 74 (range 56‐98). Higher SBP was associated with greater WMH volume (model 1:p = 0.005; model 2:p = 0.005). Similarly, higher DBP was associated with greater WMH volume (model 1:p = 0.008; model 2:p = 0.006) (Figure 1). Neither menopausal hormone therapies versus placebo, nor having high/low SBP (≥120/<120) modified these associations. Voxel‐based analyses demonstrate the association of BPs with the spatial distribution of WMHs (Figure 2).ConclusionHigher BPs in recently menopausal women were associated with greater WM injury more than a decade later after adjusting for CVD risk factors. Early postmenopausal stage is a critical time for BP control in women, which may reduce the risk of WM injury later in life.

OBJECTIVE:A phase 2 study showed that 15 mg estetrol (E4) alleviates vasomotor symptoms (VMS). Here, we present the effects of E4 15 mg on vaginal cytology, genitourinary syndrome of menopause, and health-related quality of life.METHODS:In a double-blind, placebo-controlled study, postmenopausal participants (n = 257, 40-65 y) were randomized to receive E4 2.5, 5, 10, or 15 mg or placebo once daily for 12 weeks. Outcomes were the vaginal maturation index and maturation value, genitourinary syndrome of menopause score, and the Menopause Rating Scale to assess health-related quality of life. We focused on E4 15 mg, the dose studied in ongoing phase 3 trials, and tested its effect versus placebo at 12 weeks using analysis of covariance.RESULTS:Least square (LS) mean percentages of parabasal and intermediate cells decreased, whereas superficial cells increased across E4 doses; for E4 15 mg, the respective changes were -10.81% ( P = 0.0017), -20.96% ( P = 0.0037), and +34.17% ( P < 0.0001). E4 15 mg decreased LS mean intensity score for vaginal dryness and dyspareunia (-0.40, P = 0.03, and -0.47, P = 0.0006, respectively); symptom reporting decreased by 41% and 50%, respectively, and shifted to milder intensity categories. The overall Menopause Rating Scale score decreased with E4 15 mg (LS mean, -3.1; P = 0.069) and across doses was associated with a decreasing frequency and severity of VMS ( r = 0.34 and r = 0.31, P < 0.001).CONCLUSIONS:E4 demonstrated estrogenic effects in the vagina and decreased signs of atrophy. E4 15 mg is a promising treatment option also for important menopausal symptoms other than VMS.

Introduction: Estrogens used in women's healthcare have been associated with increased risks of venous thromboembolism (VTE) and breast cancer. Estetrol (E4), an estrogen produced by the human fetal liver, has recently been approved for the first time as a new estrogenic component of a novel combined oral contraceptive (E4/drospirenone [DRSP]) for over a decade. In phase 3 studies, E4/DRSP showed good contraceptive efficacy, a predictable bleeding pattern, and a favorable safety and tolerability profile. Areas covered: This narrative review discusses E4MODIFIER LETTER PRIMEs pharmacological characteristics, mode of action, and the results of preclinical and clinical studies for contraception, as well as for menopause and oncology. Expert opinion: Extensive studies have elucidated the properties of E4 that underlie its favorable safety profile. While classical estrogens (such as estradiol) exert their actions via both activation of nuclear and membrane estrogen receptor alpha (ER alpha), E4 presents a specific profile of ER alpha activation: E4 binds and activates nuclear ER alpha but does not induce the activation of membrane ER alpha signaling pathways in specific tissues. E4 has a small effect on normal breast tissue proliferation and minimally affects hepatic parameters. This distinct profile of ER alpha activation, uncoupling nuclear and membrane activation, is unique.

Polycystic Ovary Syndrome (PCOS) represents a heterogeneous disorder and, using Rotterdam diagnostic criteria, four main phenotypes (A, B, C, and D) have been distinguished. However, it remains unclear whether lean versus obesity status influences findings in the various phenotypes of women with PCOS. 274 women with PCOS were consecutively assessed. Among these women, there were 149 with phenotype A, 24 with phenotype B, 94 with phenotype C, and 7 with phenotype D. We found normal body weight to be very common (65%) in phenotype C patients, common (43%) in phenotype A and D patients, and less represented (but still 25%) in phenotype B patients. Obesity was common in phenotype B (54%) and phenotype A (33%) patients and uncommon in phenotype C (only 11%) and phenotype D (14%) patients. Obese and lean patients of each phenotype were compared. Compared to the phenotype C PCOS patients, both phenotype A and B patients had higher total testosterone circulating values and higher luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio (p < 0.01) while anti-Mullerian hormone (AMH) levels were higher only in phenotype A PCOS patients. Instead, in the three obese PCOS phenotypes no differences in serum insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) calculation, and lipid blood values were observed. Analysis of data of lean patients gave similar results. Compared to the phenotype C PCOS patients, both phenotype A and B patients had higher total testosterone circulating values and higher LH/FSH ratio (p < 0.01) while AMH levels were higher only in phenotype A PCOS patients. However, no differences were observed in the circulating insulin levels, HOMA-IR calculation, or blood lipids between the three groups of lean PCOS patients. We conclude that Rotterdam phenotypes express the differences between PCOS patients in terms of ovulatory pattern and androgen secretion but fail to differentiate between obese patients with altered metabolic patterns and lean patients with normal metabolic patterns. A new classification of PCOS patients is needed and it should consider the influence of body weight on the metabolic patterns of PCOS patients.

Research on menopausal hormone therapy (MHT) for the reduction/prevention of cognitive decline or Alzheimer’s disease has been inconsistent. The Women’s Health Initiative Memory Study (WHIMS) revealed elevated incident cognitive impairment for women starting MHT after age >65 with oral conjugated equine estrogens (o‐CEE) treatment, especially among women with diabetes. Subsequently, the Cognitive and Affective substudy of the Kronos Early Estrogen Prevention Study (KEEPS‐Cog) found that MHT initiated soon after menopause caused neither cognitive benefit nor harm. Waist‐to‐hip ratio (WHR) is a measure of central adiposity and a surrogate marker for insulin resistance/prediabetes. To explore effects of MHT in insulin‐resistant states, in younger women, we analyzed WHR as a predictor of cognitive response to MHT in KEEPS‐Cog.

OBJECTIVE:To describe the prevalence of metabolic disturbances in a large cohort of women with polycystic ovary syndrome (PCOS) in southeastern Brazil and to compare the findings with other cohorts of Brazilian women with PCOS.METHODS:A retrospective study analyzing clinical and laboratory data of 462 women with PCOS treated at an outpatient clinic in a tertiary hospital in southeastern Brazil. Prevalence of insulin resistance, glucose intolerance, type 2 diabetes, dyslipidemia, central obesity, hypertension, and metabolic syndrome was compared to that of other cohorts of age and body mass index-matched Brazilian women with PCOS.RESULTS:Women with PCOS had a median age of 25.0 (21.0-29.0) years and BMI of 28.7 (23.9-34.0) kg/m2 . Prevalence of insulin resistance, glucose intolerance, and type 2 diabetes varied from 39.6% to 55.0%, 7.2% to 28.1%, and 2.0% to 4.1%, respectively. Prevalence of central obesity, dyslipidemia due to decreased high-density lipoprotein cholesterol, hypertriglyceridemia, and metabolic syndrome ranged from 57.8% to 66.4%, 54.1% to 70.4%, 22.9% to 35.1%, and 27.4% to 38.3%, respectively, which did not differ among regions in Brazil.CONCLUSION:Prevalence of metabolic disturbances was high among Brazilian women with PCOS. This study suggests that, from a public health perspective, authorities in Brazil should be aware of and encourage screening for metabolic dysfunction in women with PCOS in all regions of the country.

Elevated systolic blood pressure (SBP) and diastolic blood pressure (DBP) are risk factors for white matter (WM) injury associated with cognitive decline and dementia. White matter hyperintensities (WMH) on MRI, markers of WM injury, increase with aging and are more common in women than in men after the age of 60. We examined SBP and DBP in relation to WMH volume and diffusion MRI measures of WM integrity in postmenopausal women.

OBJECTIVE:The aim of this study was to select the minimum effective dose of estetrol (E4) for the treatment of vasomotor symptoms in postmenopausal women. METHODS:This was a multicenter, randomized, double-blind, placebo-controlled study. Postmenopausal women (n = 257, of whom 32 were hysterectomized) aged 40 to 65 years, with ≥7 moderate to severe hot flushes (HFs) per day, or 50 or more moderate to severe HFs weekly, received 2.5, 5, 10, or 15 mg E4, or placebo once-daily for a period of 12 weeks. Efficacy was assessed by recording the frequency and severity of HFs. Overall safety was assessed by recording adverse events, measuring endometrial thickness, and monitoring bleeding patterns. Treatment groups were compared using analysis of covariance. RESULTS:The frequency of moderate to severe HFs decreased with all E4 doses. The difference in the percentage change of weekly HF frequency was significant for 15 mg E4 versus placebo at both W4 (-66% vs -49%, P = 0.032) and W12 (-82% vs -65%, P = 0.022). The decrease in severity of HFs was significantly more pronounced for 15 mg E4 than for placebo at both W4 (-0.59 vs -0.33, P = 0.049) and W12 (-1.04 vs -0.66, P = 0.049); the other doses failed to achieve statistical significance. In nonhysterectomized women, endometrial thickness increased during treatment and normalized following progestin treatment at study completion. No endometrial hyperplasia was observed. CONCLUSIONS:Estetrol 15 mg is considered to be the minimum effective daily oral dose for treatment of vasomotor symptoms. Its current seemingly favorable safety profile is further to be confirmed in phase 3 clinical development. : Video Summary:http://links.lww.com/MENO/A591.

Polycystic ovary syndrome (PCOS) affects 6% to 20% of reproductive age women and is the most frequent cause of anovulatory infertility. Its physiopathology may result in part from hypothalamic alterations in the pulsatile secretion of gonadotropin-releasing hormone (GnRH). The neuropeptide kisspeptin participates in the mechanism through stimulation of the hormone's production. The purpose of this study was to review the articles which compared kisspeptin levels in women with PCOS with those of controls. A systematic review of observational studies was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) recommendations. The selected studies encompassed a population of patients with PCOS and controls, whose serum kisspeptin levels were evaluated. The studies were retrieved from the Medline, Cochrane, and Embase databases, and four of them were chosen for the review. In most studies, the serum kisspeptin levels were higher in women with PCOS than in controls notwithstanding the BMI. One of the articles showed that circulating plasma levels of kisspeptin were significantly higher in women with PCOS whose BMI was lower than 25 than in obese and overweight women. Our data suggest a higher concentration of serum kisspeptin in women with PCOS irrespective of their BMI. Further experimental and clinical studies are needed to ascertain the role of kisspeptin in PCOS.

Human preimplantation embryos show abnormal nucleation and DNA damage, compromising cell cycle progression and developmental potential. The molecular mechanisms and timing of these abnormalities are unknown. We identified endogenous DNA damage and repair mechanisms in human embryos and developed a murine model to study developmental consequences of replication stress in preimplantation embryos. Prospective laboratory study of human and mouse embryos Endogenous DNA damage and repair pathways were evaluated in humans using donated oocytes (n=25) and embryos (n=20). Immunofluorescent staining detected DNA damage (γH2AX, RPA), repair (RPAS33, RPA S4/S8, Rad51, 53BP1), and micronucleation. Consequences of genomic instability were studied in a murine model using aphidicolin, a DNA polymerase inhibitor that increases endogenous chromosome fragility1. Mouse zygotes (n=500) were briefly exposed to aphidicolin in the first cell cycle, then evaluated at 1-cell, 2-cell, 4-8-cell and blastocyst stage. Immunofluorescent staining detected DNA damage and repair. Cleavage progression, blastulation and embryo quality were assessed versus controls. Human and mouse karyotypes were determined with NGS. Human preimplantation embryos show endogenous DNA damage, demonstrated by γH2AX, RPA and abnormal nucleation. Cleavage embryos had significantly greater foci and micronucleation vs blastocysts (γH2AX cleavage mean 2.3 vs blastocyst 1.0, p <0.0001; RPA cleavage mean 1.7 vs 0.3, p<0.0001; abnormal nucleation cleavage mean 15.9% vs blastocyst 4.2%, p<0.0001). DNA damage foci coincided with RPAS33, indicating RPA phosphorylation by G2 checkpoint kinase ATR, Rad51, indicating repair by homologous recombination, and 53BP1, indicating unrepaired DNA is passed to daughter cells. Aphidicolin-induced replication delay resulted in DNA damage (γH2AX and RPA), and RPAS33, indicating an ATR-dependent G2 checkpoint. Additional DNA repair mechanisms included Rad51 and 53BP1, similar to human embryos. Though some unreplicated DNA is tolerated in mitosis and compatible with euploidy, aphidicolin-induced under replication in the first cell cycle precipitated instability in later cell cycles, leading to decreased blastulation (45% after 8h aphidicolin vs 91.8% control, p<0.0001), and poor quality embryos as evidenced by significantly fewer total cells and inner cell mass with significantly greater DNA damage and micronucleation with increasing duration of aphidicolin exposure compared to controls. DNA damage responses to incomplete replication in G2 (ATR and Rad51), and the G1 response to unreplicated DNA (53BP1) mirror endogenous repair activity in human preimplantation embryos. Developmental consequences of replication stress likely persist beyond the preimplantation stage and may contribute to failed implantation or miscarriage. The murine model of genomic instability enables further study of these processes and the development of targeted therapeutics.

Introduction: Estetrol (E4) is a native estrogen with selective action in tissues. Previous data have demonstrated no effects on biomarkers of hemostasis, on triglycerides, and on breast cell stimulation. Its capacity to alleviate symptoms of menopause was tested here.

Changes in pituitary-ovarian hormones across the menopausal transition have multiple physiological consequences. However, little is known about how the major types of postmenopausal hormone therapy (HT) affect pituitary-ovarian hormonal relationships. This study evaluated these relationships in recently menopausal women (52.45 ± 2.49 yr of age) in the Kronos Early Estrogen Prevention Study (KEEPS) who were compliant to randomized, double-blinded treatment with oral conjugated equine estrogen (o-CEE; n = 109), transdermal 17β-estradiol (t-E2; n = 107), or placebo ( n = 146). Androstenedione, testosterone, 17β-estradiol, estrone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured in serum before (baseline) and 48 mo after randomization to treatment. Descriptive summaries of hormone levels were performed, and multiple regression analyses were used to examine the effects of o-CEE, t-E2, and placebo on these hormone levels at 48 mo, adjusting for baseline levels. A network analysis examined the covariance of changes in hormone levels over the 48 mo within treatment groups. As expected, at 48 mo of treatment, hormone levels differed between women in the two active treatment groups compared with placebo, and network analysis indicated stronger relationships among hormone levels in the t-E2 and o-CEE groups compared with placebo. Associations among testosterone, 17β-estradiol, FSH, and LH differed between the o-CEE group compared with t-E2 and placebo groups. Thus, two common HT regimens differentially alter pituitary-ovarian hormone levels, altering feedback cycles and interhormonal associations in recently menopausal women. These interactions provide the basis for future studies investigating the impact of hormonal modulation of aging, including cognitive decline in women.

OBJECTIVE:To evaluate efficacy, endometrial safety, and overall safety of a single-capsule 17β-estradiol-progesterone (TX-001HR) for treating menopausal moderate-to-severe vasomotor symptoms.METHODS:REPLENISH was a phase 3, 12-month, randomized, double-blind, placebo-controlled, multicenter trial. Women (aged 40-65 years) with vasomotor symptoms and a uterus were randomized to daily estradiol (mg)-progesterone (mg) (1/100, 0.5/100, 0.5/50, or 0.25/50), and women in the vasomotor symptoms substudy (women with moderate-to-severe hot flushes [seven or greater per day or 50 or greater per week]) to those estradiol-progesterone doses or placebo. The primary safety endpoint was endometrial hyperplasia incidence at 12 months in all women (the total population), and the primary efficacy endpoints were frequency and severity changes (from daily diaries) in moderate-to-severe vasomotor symptoms with estradiol-progesterone compared with placebo at weeks 4 and 12 in the vasomotor symptoms substudy. A sample size of 250 women in each active treatment arm with two or less endometrial hyperplasia cases would result in 1% or less annual incidence (upper bound 2.5% or less, one-sided 95% CI).RESULTS:One thousand eight hundred forty-five women were enrolled and randomized from August 2013 to October 2015; 1,835 received medication (safety population); 1,255 were eligible for the endometrial safety population; 726 comprised the vasomotor symptoms substudy; their mean age and body mass index were 55 years and 27, respectively; one third were African American. No endometrial hyperplasia was found. Frequency and severity of vasomotor symptoms significantly decreased from baseline with 1 mg estradiol and 100 mg progesterone and 0.5 mg estradiol and 100 mg progesterone compared with placebo at week 4 (frequency: by 40.6 and 35.1 points [1 mg and 100 mg and 0.5 mg and 100 mg, respectively] vs 26.4 points [placebo]; severity: by 0.48 and 0.51 vs 0.34 points) and week 12 (by 55.1 and 53.7 vs 40.2; severity: by 1.12 and 0.90 vs 0.56); 0.5 mg estradiol and 50 mg progesterone improved (P<.05) frequency and severity at week 12, and 0.25 mg estradiol and 50 mg progesterone frequency but not severity at weeks 4 and 12.CONCLUSION:No endometrial hyperplasia was observed while single-capsule estradiol-progesterone provided clinically meaningfully improvements in moderate-to-severe vasomotor symptoms. This estradiol-progesterone formulation may represent a new option, using naturally occurring hormones, for the estimated millions of women using nonregulatory-approved, compounded hormone therapy.CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov, NCT01942668.

IMPORTANCE Sexual dysfunction, an important determinant of women's health and quality of life, is commonly associated with declining estrogen levels around the menopausal transition.OBJECTIVE To determine the effects of oral or transdermal estrogen therapy vs placebo on sexual function in postmenopausal women.DESIGN, SETTING, AND PARTICIPANTS Ancillary study of the Kronos Early Estrogen Prevention Study (KEEPS), a 4-year prospective, randomized, double-blinded, placebo-controlled trial of menopausal hormone therapy in healthy, recently menopausal women. Of 727 KEEPS enrollees, 670 agreed to participate in this multicenter ancillary study. Women were 42 to 58 years old, within 36 months from last menstrual period. Data were collected from July 2005 through June 2008 and analyzed from July 2010 through June 2017.INTERVENTIONS Women were randomized to either 0.45 mg/d oral conjugated equine estrogens (o-CEE), 50 mu g/d transdermal 17 beta-estradiol (t-E-2), or placebo. Participants also received 200 mg oral micronized progesterone (if randomized to o-CEE or t-E-2) or placebo (if randomized to placebo estrogens) for 12 days each month.MAIN OUTCOMES AND MEASURES Aspects of sexual function and experience (desire, arousal, lubrication, orgasm, satisfaction, and pain) were assessed using the Female Sexual Function Inventory (FSFI; range, 0-36 points; higher scores indicate better sexual function). Low sexual function (LSF) was defined as an FSFI overall score of less than 26.55. Distress related to low FSFI score (required for the diagnosis of sexual dysfunction) was not evaluated.RESULTS The 670 participants had a mean (SD) age of 52.7 (2.6) years. The t-E-2 treatment was associated with a significant yet moderate improvement in the FSFI overall score across all time points compared with placebo (average efficacy, 2.6; 95% CI, 1.11-4.10; adjusted P = .002). With o-CEE treatment, there was no significant difference in FSFI overall score compared with placebo (mean efficacy, 1.4; 95% CI, -0.1 to 2.8; adjusted P = .13). There was no difference in FSFI overall score between the t-E-2 and o-CEE groups on average across 48 months (adjusted P=.22). In the individual domains of sexual function, t-E-2 treatment was associated with a significant increase in mean lubrication (0.61; 95% CI, 0.25-0.97; P = .001) and decreased pain (0.67; 95% CI, 0.25-1.09; P = .002) compared with placebo. Overall, the proportion of women with LSF was significantly lower after t-E-2 treatment compared with placebo (67%; 95% CI, 55%-77% vs 76%; 95% CI, 67%-83%; P = .04). For o-CEE there was no significant reduction in the odds of LSF.CONCLUSIONS AND RELEVANCE Treatment with t-E-2 modestly improved sexual function in early postmenopausal women, but whether it relieved symptoms of distress is not known.