Cancer treatments can deplete the ovarian follicle reserve causing infertility and early menopause, with subsequent decline in cardiovascular, cognitive, and overall health. Medical measures to prevent this chemotherapy-induced ovarian damage are currently not available. Anti-Müllerian hormone (AMH) is important for preserving the ovarian follicle pool via downregulation of granulosa cell replication and function. Despite proven therapeutic ability to protect the ovarian follicle number in mice exposed to chemotherapy, AMH is not approved for human use. To overcome this gap, we created and patented a peptide designed to specifically bind to the AMH receptor, AMHR2 binding peptide (AMHR2BP), that could serve as an alternative therapeutic treatment. By activating the same downstream signaling and replicating the biological effects of natural AMH, we sought to investigate whether AMHR2BP could protect the follicle pool in both natural and accelerated ovarian aging mouse models. Here, we present a series of in vitro and in vivo translational studies to verify AMHR2BP’s affinity, specificity, mechanism of action, stability, and in vivo toxicity and efficacy. We performed immunofluorescence, immunoprecipitation, real-time RT-PCR, mass spectrometry, histological, and immunohistochemistry testing to validate our findings on two levels, gene activation and protein translation. We found that AMHR2BP activates the same SMAD signaling pathways as AMH and ultimately preserves the ovarian follicle pool by preventing the progression of primordial to antral follicles in naturally aging mice. Additionally, we demonstrated that AMHR2BP prevents follicle loss in an accelerated, chemotherapy-induced ovarian aging model, thereby effectively preventing identifiable ovarian damage. Importantly, AMHR2BP also portrays excellent plasma stability with no detectable toxicity. By mimicking the function of AMH, AMHR2BP represents a new medical therapeutic strategy to preserve fertility and reduce long-term reproductive and health risks from chemotherapy treatments.

AMH inhibits hormone production in luteinized granulosa cells (GCs) and stalls ovarian follicle development in vitro and in vivo. We sought to confirm AMH’s mechanism of action through SMAD activation and investigate AMH inhibition of follicle development and function, in vitro and in vivo. A primary culture of GCs isolated from follicular fluid was used, and cells were treated with recombinant AMH (rAMH) or placebo for 24 h. For the mouse model, 18-weeks old C57BL female mice were either euthanized at the beginning or treated with rAMH or normal saline for 3 weeks. Primordial (PDF), primary follicle (PRF), secondary (SEF), and tertiary follicles (TEF) were calculated. Real-time RT-PCR and ELISA were performed to quantify GC gene expression and protein translation of human SMAD 1, 5, and 8, FSH-R and mouse FSH-R, inhibin B, caspase 3, Ki67, BMP15, GDF9, and the epigenetic regulators miRNAa and b. In vitro, rAMH-treated GC showed activation of the SMAD 1, 5 and downregulation of SMAD 8, with greater magnitude at increasing rAMH doses (p < 0.04) and consequential control of downstream regulators. In vivo, the rAMH-treated mice showed increased SEFs and decreased PRFs while PDFs, TEFs, were unchanged compared with baseline. Compared with Placebo, the rAMH group showed increased PDFs, while PRFs, and TEFs were significantly decreased, and SEFs were unchanged. AMH caused SMAD activation in a dose-dependent manner, with downstream downregulation of cell function and replication, also through activation of miRNAs. These mechanisms were confirmed by the in vivo findings with ultimate downregulation of follicular development and preservation of the ovarian follicle number. Counteracting follicular depletion, AMH could be used to protect the ovarian follicle reservoir.

There is an urgent global need to improve in vitro fertilization success rates and expand access to services. Specific to the in vitro fertilization laboratory, challenges such as standardization and a shortage of trained embryologists hinder quality and limit service availability. Current standards for product approval rely on demonstrating comparable pregnancy rates, requiring extensive patient involvement and time-consuming trials, which may be further hindered by patient reluctance to participate in clinical trials. Efficient assessment of new protocols and devices for assessing human assisted reproductive technology requires considering intermediate endpoints and markers to complement conventional endpoints. This review explores blastocyst development as a potential surrogate marker for pregnancy. It examines the correlation between blastocyst development and implantation potential, evaluates how culture conditions and other factors affect outcomes, and discusses the evidence supporting an absence of adverse effects of embryo culture on perinatal and offspring health. The conclusion strongly suggests that blastocyst development could serve as a valuable surrogate for establishing equivalency of pregnancy and live births in new assisted reproductive technology protocols. This review underscores the need for a surrogate marker of quality and presents evidence supporting the utility of blastocyst use rate as a sufficient indicator. (F S Rev (R) 2025;6:100094. (c) 2025 by American Society for Reproductive Medicine.)

OBJECTIVE:Little is known about whether vitamin D binding protein (DBP) plays a role in reproductive outcomes. The few existing studies have largely presumed that any effects of DBP are due to its modulation of vitamin D bioavailability per the "free hormone theory" despite its many vitamin D-independent functions. This study, therefore, aimed to comprehensively evaluate the association between DBP concentration/haplotype and reproductive outcomes in patients with polycystic ovary syndrome or unexplained infertility undergoing ovarian stimulation. DESIGN:Retrospective cohort study, secondary analysis of randomized controlled trials Pregnancy in Polycystic Ovary Syndrome II and Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation. SUBJECTS:376 participants with polycystic ovary syndrome (Pregnancy in Polycystic Ovary Syndrome II), 505 participants with unexplained infertility (Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation). EXPOSURE:Vitamin D binding protein concentration and DBP Gc1f, Gc1s, and Gc2 haplotypes. MAIN OUTCOME MEASURES:Primary: live birth. Secondary: early pregnancy loss and composite of preterm delivery, preeclampsia, and fetal growth restriction. RESULTS:A total of 881 participants were included. There was no association between DBP concentration, Gc1s, or Gc2 and live birth. When adjusting for age, race, body mass index, 25-hydroxyvitamin D concentration, and treatment arm, the Gc1f haplotype was associated with increased odds of live birth (adjusted odds ratio [aOR], 1.49; 95% confidence interval [CI], 1.06-2.09) and decreased odds of early pregnancy loss (aOR, 0.46; 95% CI, 0.25-0.86). There was no association with obstetric complications (aOR, 0.76; 95% CI, 0.39-1.47). CONCLUSION:The Gc1f haplotype of DBP was associated with increased odds of live birth and decreased odds of early pregnancy loss independent of 25-hydroxyvitamin D and DBP concentration. Because Gc1f results in the DBP variant with the greatest binding affinity for vitamin D, these findings challenge the current narrative that associations between DBP and reproductive outcomes are primarily due to modulation of vitamin D bioavailability. Additional studies are needed to investigate other mechanisms for the role of DBP in reproductive outcomes.

ObjectiveTo determine whether improvements in metabolic syndrome before ovarian stimulation with intrauterine insemination affects live birth among women with obesity and unexplained infertility after fertility treatment.DesignSecondary analysis of the randomized controlled clinical trial Improving Reproductive Fitness Through Pretreatment With Lifestyle Modification in Obese Women With Unexplained Infertility (FIT-PLESE).SubjectsThree hundred seventy-nine women with obesity and unexplained infertility who underwent standard infertility treatment after a lifestyle intervention.InterventionThe FIT-PLESE trial evaluated whether prepregnancy lifestyle interventions (diet with weight loss medication and exercise vs. exercise alone) before ovarian stimulation with intrauterine insemination improved the live birth rate among women with obesity and unexplained infertility. Utilizing FIT-PLESE data, we compared the association between improved Metabolic Syndrome (by diagnostic criteria parameters and Metabolic Syndrome Z-scores) and live birth in a subset of women who have Metabolic Syndrome.Main Outcome MeasuresLive birth by groups were compared using chi-square and Fisher’s exact tests, and continuous variables were compared using Student’s t-tests. Logistic regression was used to assess Metabolic Syndrome Z-score difference and live birth.Results191 study participants were diagnosed with Metabolic Syndrome at baseline. Thirty of these women exhibited a decline in the number of metabolic syndrome parameters and 33 had decline in their Metabolic Syndrome Z-scores during the preconception lifestyle intervention phase. There were no statistically significant differences in live birth among those who exhibited decline in the number of metabolic parameters compared to those who had no decline (33.3% versus 19.9%; p=0.102). Those who improved their Metabolic Syndrome Z-score had a live birth rate of 17.2% compared to 20.8% of those whose Metabolic Syndrome Z-scores were worsened or unchanged (p=0.055).ConclusionAnalysis of the FIT-PLESE data was unable to demonstrate that women with improvement in Metabolic Syndrome prior to fertility treatment, as shown by decreased number of metabolic parameters and/or improved Metabolic Syndrome Z-scores, benefit with improved fertility and live birth outcomes.

BackgroundThe average age of childbearing has increased over the years contributing to infertility, miscarriages, and chromosomal abnormalities largely invoked by an age-related decline in oocyte quality. In this study, we investigate the role of nitric oxide (NO) insufficiency and protein nitration in oocyte chronological aging.MethodsMouse oocytes were retrieved from young breeders (YB, 8-14 weeks [w]), retired breeders (RB, 48-52w) and old animals (OA, 80-84w) at 13.5 and 17 hours after ovulation trigger. They were assessed for zona pellucida dissolution time (ZPDT); ooplasmic microtubule dynamics (OMD); cortical granule (CG) status and spindle morphology (SM), as markers of oocyte quality. Sibling oocytes from RB were exposed to NO supplementation and assessed for aging phenomena (AP). All oocyte cumulus complexes were subjected to fluorescence nitrotyrosine (NT) immunocytochemistry and confocal microscopy to assess morphology and protein nitration.ResultsAt 13.5 h from hCG trigger, oocytes from RB compared to YB had significantly increased ZPDT (37.8 ± 11.9 vs 22.1 ± 4.1 seconds [s]), OMD (46.9 vs 0%), CG loss (39.4 vs 0%), and decreased normal SM (30.3 vs 81.3%), indicating premature AP that worsened among oocytes from RB at 17 hours post-hCG trigger. When exposed to SNAP, RB AP significantly decreased (ZPDT: 35.1 ± 5.5 vs 46.3 ± 8.9s, OMD: 13.3 vs 75.0% and CG loss: 50.0 vs 93.3%) and SM improved (80.0 vs 14.3%). The incidence of NT positivity was significantly higher in cumulus cells (13.5 h, 46.7 ± 4.5 vs 3.4 ± 0.7%; 17 h, 82.2 ± 2.9 vs 23.3 ± 3.6%) and oocytes (13.5 h, 57.1 vs 0%; 17 h, 100.0 vs 55.5%) from RB compared to YB. Oocytes retrieved decreased with advancing age (29.8 ± 4.1 per animal in the YB group compared to 10.2 ± 2.1 in RB and 4.0 ± 1.6 in OA). Oocytes from OA displayed increased ZPDT, major CG loss, increased OMD and spindle abnormalities, as well as pronuclear formation, confirming spontaneous meiosis to interphase transition.Conclusion(s)Oocytes undergo zona pellucida hardening, altered spindle and ooplasmic microtubules, and premature cortical granule release, indicative of spontaneous meiosis-interphase transition, as a function of chronological aging. These changes are also associated with NO insufficiency and protein nitration and may be alleviated through supplementation with an NO-donor.

BACKGROUND: Few studies have directly compared different surgical procedures for uterine fibroids with respect to long-term health-related quality of life outcomes and symptom improvement.OBJECTIVE: We examined differences in change from baseline to 1-, 2-, and 3-year follow-up in health-related quality of life and symptom severity among patients who underwent abdominal myomectomy, laparoscopic or robotic myomectomy, abdominal hysterectomy, laparoscopic or robotic hysterectomy, or uterine artery embolization.STUDY DESIGN: The COMPARE-UF registry is a multiinstitutional prospective observational cohort study of women undergoing treatment for uterine fibroids. A subset of 1384 women aged 31 to 45 years who underwent either abdominal myomectomy (n=237), laparoscopic myomectomy (n=272), abdominal hysterectomy (n=177), laparoscopic hysterectomy (n=522), or uterine artery embolization (n=176) were included in this analysis. We obtained demographics, fibroid history, and symptoms by questionnaires at enrollment and at 1, 2, and 3 years posttreatment. We used the UFS-QoL (Uterine Fibroid Symptom and Quality of Life) questionnaire to ascertain symptom severity and health-related quality of life scores among participants. To account for potential baseline differences across treatment groups, a propensity score model was used to derive overlap weights and compare total health-related quality of life and symptom severity scores after enrollment with a repeated measures model. For this health-related quality of life tool, a specific minimal clinically important difference has not been determined, but on the basis of previous research, a difference of 10 points was considered as a reasonable estimate. Use of this difference was agreed upon by the Steering Committee at the time when the analysis was planned.RESULTS: At baseline, women undergoing hysterectomy and uterine artery embolization reported the lowest health-related quality of life scores and highest symptom severity scores compared with those undergoing abdominal myomectomy or laparoscopic myomectomy (P<.001). Those undergoing hysterectomy and uterine artery embolization reported the longest duration of fibroid symptoms with a mean of 6.3 years (standard deviation, 6.7; P<.001). The most common fibroid symptoms were menorrhagia (75.3%), bulk symptoms (74.2%), and bloating (73.2%). More than half (54.9%) of participants reported anemia, and 9.4% women reported a history of blood transfusion. Across all modalities, total health-related quality of life and symptom severity score markedly improved from baseline to 1-year with the largest improvement in the laparoscopic hysterectomy group (Uterine Fibroids Symptom and Quality of Life: delta= [+] 49.2; symptom severity: delta= [-] 51.3). Those undergoing abdominal myomectomy, laparoscopic myomectomy, and uterine artery embolization also demonstrated significant improvement in health-related quality of life (delta= [+]43.9, [+]32.9, [+] 40.7, respectively) and symptom severity (delta= [-]41.4, [-] 31.5, [-] 38.5, respectively) at 1 year, and the improvement persisted from baseline for uterine-sparing procedures during second (Uterine Fibroids Symptom and Quality of Life: delta= [+]40.7, [+]37.4, [+]39.3 SS: delta= [-] 38.5, [-] 32.0, [-] 37.7 and third year (Uterine Fibroids Symptom and Quality of Life: delta= [+] 40.9, [+]39.9, [+]41.1 and SS: delta= [-] 33.9, [-]36.5, [-] 33.0, respectively), posttreatment intervals, however with a trend toward decline in degree of improvement from years 1 and 2. Differences from baseline were greatest for hysterectomy; however, this may reflect the relative importance of bleeding in the Uterine Fibroids Symptom and Quality of Life, rather than clinically meaningful symptom recurrence among women undergoing uterus-sparing treatments.CONCLUSION: All treatment modalities were associated with significant improvements in health-related quality of life and symptom severity reduction 1-year posttreatment. However, abdominal myomectomy, laparoscopic myomectomy and uterine artery embolization indicated a gradual decline in symptom improvement and health-related quality of life by third year after the procedure.

By Lina Villar, Michael P. Diamond & 2 more. To assess the intrafollicular egg's quality, we monitor the follicle with an underlying assumption that its property, size, and estradiol production in some way reflects the quality of the oocyte.

Pregnancy loss among couples undergoing infertility treatment is not well characterized. Prior studies examining pregnancy loss in this population are limited by the inability to reliably detect early pregnancy and small sample sizes. In a prior study, our group evaluated the rate of pregnancy loss in a large, well-characterized cohort of over 3000 women with infertility. A pregnancy loss rate of 35.9% was identified; the majority of losses being biochemical (22.1%). This follow-up study examines risk factors for biochemical loss in a large cohort of couples undergoing treatment for infertility. Secondary analysis of six Reproductive Medicine Network randomized controlled trials (PPCOSI, PPCOSII, AMIGOS, MOXI, PhOx, and FIT-PLESE). Each trial enrolled women with an infertility diagnosis (PCOS in PPCOSI and II, unexplained infertility in AMIGOS and FIT-PLESE, male factor in MOXI, and various diagnoses in PhOx) and underwent various treatments (ovulation induction in PPCOSI and II, ovarian stimulation + IUI in AMIGOS, MOXI, and FIT-PLESE, and IVF in PhOx). Pregnancy outcome definitions were standardized across trials. Biochemical loss was defined as pregnancy that did not progress to cardiac activity on ultrasound. Variables examined as risk factors for biochemical loss included female factors (age, BMI, race, ethnicity, AMH), male factors (age, BMI), and duration of infertility. Risk ratios and 95% confidence intervals were estimated by modified Poisson regression. Additional covariates assessed for confounding included income, infertility diagnosis and treatment. 3662 participants across all trials were included. 1402 (38.3%) had a positive pregnancy test (defined as serum hCG > 5 mIU/mL) and 1314 (35.9%) achieved pregnancy (defined as any rise in hCG). After excluding multiple gestations and missing pregnancy outcomes, the biochemical loss rate was 23.3% (280/1201) among positive pregnancy tests and 17.3% (192/1113) among achieved pregnancies. Four trials had information regarding male characteristics (MOXI, PhOx, PPCOSII, and AMIGOS), so only participants from these studies were included in analyses adjusting for female and male factors (919 positive pregnancy tests, 838 achieved pregnancies). In adjusted models, female age (years: RR 1.07 [1.03, 1.11]) and male obesity (BMI ≥30 vs <25 kg/m2: RR 1.49 [1.08, 2.05]) were associated with increased risk of biochemical loss after a positive test. Among achieved pregnancies, female age was a significant risk factor for biochemical loss (RR 1.08 [1.03, 1.12]), but the magnitude and precision of the association with male obesity (RR 1.47 [0.98, 2.21]) were slightly attenuated. Regardless of the definition of biochemical loss, a positive association with female age was consistently observed, which persisted after controlling for male factors. Male obesity may also be an important risk factor for biochemical loss.

Pregnancy loss < 20 weeks gestations is the most common adverse event in early pregnancy, occurring in 10–20% of clinically recognized pregnancies. Given common occurrence, significant associated physical and psycho-social morbidities, it is imperative to identify patient and cycle characteristics that may lead to increased risk for miscarriage. In this study, we aimed to evaluate the association between FPL and EPL among women with unexplained infertility undergoing OS-IUI cycles. We hypothesized that women with short FPL may have increased risk of EPL due to inability to attain full oocyte maturation or inadequate development of the endometrium. Secondary analysis of a prospective, randomized, multicenter clinical trial investigating pregnancy, live-birth, and multiple pregnancy rates following OS-IUI, the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) trial. Among 2546 cycles from 869 AMIGOS participants, there were 320 achieved pregnancies defined by an initial rise in serum beta-hCG levels. FPL was evaluated as a categorical variable defined by quintiles (q1: ≤ 11 days, q2: 12 days, q3: 13 days, q4: 14-15 days, and q5: ≥16 days). EPL was defined as any achieved pregnancy that did not result in a live birth. Pattern of EPL by FPL quintile was evaluated using the Cochran Armitage trend test. Risk ratios (RR) and 95% confidence intervals (CI) were calculated using modified Poisson regression models with robust standard errors. Covariates evaluated in multivariable models included age, race/ethnicity, BMI, parity, duration of infertility, AMH, number of follicles >16 mm) and treatment group (clomiphene/letrozole vs gonadotropins). Age was the only covariate that changed the point estimates by more than 10% and thus adjusted models control only for age. Of the 320 achieved pregnancies, 10 were lost to follow up and excluded from the analysis. After excluding 3 cases who pursued induced abortion/selective reduction, there were overall 102 (33.3%) pregnancy losses. EPL was lowest for the 1st FPL quintile (≤ 11 days, 19.4%) and highest for 5th FPL quintile ( ≥16 days, 45.5%; trend test p=0.02), although rates did not monotonically rise with each increasing FPL quintile. When ≥16 days was used as the referent, FPL ≤ 11 days was associated with a 62% lower risk of EPL [adjusted aRR 0.38 (95% CI 0.21, 0.70)]. When stratified by treatment group, the 1st FPL quintile was similarly associated with reduced risk of EPL in the Clomiphene/Letrozole group [aRR 0.21 (95% CI 0.08, 0.75)] but this association was attenuated in the gonadotropin group [aRR 0.62, 95% CI 0.31, 1.24)]. Risk of EPL may be lowest in OS-IUI treatment cycles characterized by reduced FPL.

Both uterine endometrium and embryo contribute to implantation success. However, their relative role in the implantation success is still a matter for debate, as are the roles of endometrial receptivity analysis (ERA), endometrial scratch (ES), endometrial microbiome, and intrauterine or intravenous measures that are currently advocated to improve the implantation success. There is insufficient evidence to suggest that the endometrium is more important than the embryo in determining the implantation success and the utility of these measures, especially when euploid embryos are transferred is limited. Although embryo implantation on epithelium other than the endometrium is a very rare event, evidence suggests that embryo implantation and growth is not limited to the endometrium alone. Embryos can implant and develop to result in livebirths on epithelium that lacks the typical endometrial development present at implantation. Currently, the role of embryo euploidy in implantation success is underappreciated. At a minimum, it is the author’s opinion that until robust, definitive studies are conducted that demonstrate benefit, reproductive endocrinologists and infertility specialist should be prudent in the way they counsel patients about the utility of ERA, ES, and other measures in improving implantation success.

By Dmitri Dozortsev, Michael P. Diamond. "Minimal Stimulation," "Highly Individualized Egg Retrieval," and "Term Stimulation" as alternative strategies for improving egg quality in older patients undergoing ovarian stimulation.

Purpose To determine whether using progesterone as a trigger of a gonadotropin surge will induce ovulation and a competent corpus luteum. Methods Patients were administered 5 or 10 mg of progesterone intramuscularly when the leading follicle reached preovulatory size. Results We demonstrate that progesterone injections result in classical ultrasonographic hallmarks of ovulation about 48 h later and the formation of a corpus luteum competent to support pregnancy. Conclusion Our results support further exploration of using progesterone to trigger a gonadotropin surge in assisted human reproduction.

Abstract Disclosure: R.A. Roman: None. H. Liu: None. L.P. Chorich: None. Y. Li: None. J.E. Hall: None. M.P. Diamond: None. K.S. Korach: None. L.C. Layman: None. Objective: Estrogen receptor alpha (ERα), encoded by ESR1, is vital to human reproduction. DNA sequencing previously identified four ESR1 missense variants of uncertain significance in 197 cisgender women with well-characterized unexplained infertility, including a p.Thr313Met variant with impaired estrogen signaling in vitro. The p.His6Tyr, p.Ser118Pro, and p.Arg269Cys ESR1 variants did not affect estrogen signaling. We hypothesize that milder ESR1 variants could decrease ERα expression in women with unexplained infertility. Methods: Clinically identified ESR1 variant plasmids were constructed using site-directed mutagenesis and confirmed by Sanger sequencing. HepG2 cells were transiently transfected with either empty vector, wild type (WT) ESR1, p.His6Tyr, p.Ser118Pro, p.Arg269Cys, p.Thr313Met, or p.Gln375His (ESR1 missense variant control) estrogen receptor variant expression plasmids using Lipofectamine 3000 transfection reagent. Cell lysis was isolated from HepG2 cells 24 hours after transfection using RIPA lysis buffer. ERα expression was assessed by western blot fluorescence imaging and normalized to β-actin on LI-COR Odyssey DLx. Quantitative analysis was performed using Empiria Studio Software v.2. Results: Western blot analysis showed that the ESR1 p.His6Tyr variant had 87% decreased and the p.Ser118Pro variant had 75.6% decreased expression compared to WT ERα in vitro. The p.Arg269Cys, p.Thr313Met, and p.Gln375His variants had comparable expression to WT. Conclusion: Although the p.His6Tyr and p.Ser118Pro variant receptors have conserved estrogen signaling, our preliminary data show that they decrease ERα expression in vitro. This could be an underlying pathophysiologic mechanism affecting some women with unexplained infertility. Additional in vitro and in vivo analyses can further characterize their pathogenicity. Presentation: Friday, June 16, 2023

Objective: To compare 12-month post-treatment health-related quality of life (HR-QoL) and symptom severity (SS) changes among patients with symptomatic uterine fibroids (SUF) not seeking fertility and undergo a hysterectomy, abdominal myomectomy (AM), or uterine artery embolization (UAE). Materials and Methods: The Comparing Options for Management: Patient-Centered Results for Uterine Fibroids (COMPARE-UF) Registry is a multi-institutional prospective observational cohort study of patients treated for SUF. A subset of 1465 women 31-45 years of age, who underwent either hysterectomy (n = 741), AM (n = 446), or UAE (n = 155) were included in this analysis. Demographics, fibroid history, and symptoms were obtained by baseline questionnaires and at 1 year post-treatment. Results were stratified by all treatments and propensity score weighting to adjust for differences in baseline characteristics. Results: Women undergoing UAE reported the lowest baseline HR-QoL and highest SS scores (mean = 40.6 [standard deviation (SD) = 23.8]; 62.3 [SD = 24.2]) followed by hysterectomy (44.3 [24.3]; 59.8 [SD = 24.1]). At 12 months, women who underwent a hysterectomy experienced the largest change in both HR-QoL (48.7 [26.2]) and SS (51.9 [25.6]) followed by other uterine-sparing treatments. Propensity score weighting revealed all treatments produced substantial improvement, with hysterectomy patients reporting the highest HR-QoL score (92.0 [17.8]) compared with myomectomy (86.7 [17.2]) and UAE (82.6 [21.5]) (p < 0.0001). Similarly, hysterectomy patients reported the lowest SS scores (8.2 [15.1]) compared with myomectomy (16.5 [15.1]) and UAE (19.6 [17.5]) (p < 0.0001). Conclusion: All procedures showed improvement in HR-QoL and reduction in SS score at 12 months, hysterectomy showing maximum improvement. Of importance, at 12 months, patients who underwent either a myomectomy or UAE reported comparable symptom relief and HR-QoL. Clinicaltrials.Gov Identifier: NCT02260752.

Background: Intrauterine insemination with ovarian stimulation (IUI-OS) is a first-line treatment for couples with unexplained infertility. Individual participant data meta-analysis (IPD-MA) is the gold standard for evidence synthesis. Aim: To compare the effectiveness and safety of ovarian stimulation with gonadotrophin, Letrozole and clomiphene citrate (CC) and to explore treatment-covariate interactions for important baseline characteristics in women undergoing IUI. Method: We searched electronic databases including PubMed, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL). We included randomised controlled trials (RCTs) comparing IUI-OS with gonadotropins, Letrozole or CC among couples with unexplained infertility. We excluded dose comparing studies of the same drug. We contacted the authors of eligible RCTs to share the IPD and established the IUI IPD-MA collaboration. The primary effectiveness outcome was live birth and the primary safety outcome was multiple pregnancy. We used a one-stage approach using a random effects model. Results: Six RCTs (n= 2299) provided IPD. Gonadotropins increased the chance of a live birth compared to both CC (5 RCTs, 1946 women, RR 1.28, 95%CI 1.10 to 1.49, I2 = 25%, moderate-quality evidence) whereas there was insufficient evidence of a difference between Letrozole and CC (1 RCT, 599 women, RR 0.77 95%CI 0.58 to 1.03). Gonadotropins increased the risk of a multiple pregnancy compared to both CC (4 RCTs, 1696 women, RR 2.17, 95%CI 1.33 to 3.55, I2 = 69%, low-quality evidence) whereas there was insufficient evidence of a difference between Letrozole and CC (1 RCT, 599 women, RR 0.71, 95%CI 0.33 to 1.56). No strong evidence on the treatment-covariate interactions (female age, BMI or primary versus secondary infertility) was found. Conclusion: Gonadotropins increased the chance of a live birth compared to both CC and Letrozole but also increased the chance of a multiple pregnancy. Further RCTs comparing Letrozole and other interventions in couples with unexplained infertility are needed.

BACKGROUND:Women with obesity and infertility are counseled to lose weight prior to conception and infertility treatment to improve pregnancy rates and birth outcomes, although confirmatory evidence from randomized trials is lacking. We assessed whether a preconception intensive lifestyle intervention with acute weight loss is superior to a weight neutral intervention at achieving a healthy live birth. METHODS AND FINDINGS:In this open-label, randomized controlled study (FIT-PLESE), 379 women with obesity (BMI ≥ 30 kg/m2) and unexplained infertility were randomly assigned in a 1:1 ratio to 2 preconception lifestyle modification groups lasting 16 weeks, between July 2015 and July 2018 (final follow-up September 2019) followed by infertility therapy. The primary outcome was the healthy live birth (term infant of normal weight without major anomalies) incidence. This was conducted at 9 academic health centers across the United States. The intensive group underwent increased physical activity and weight loss (target 7%) through meal replacements and medication (Orlistat) compared to a standard group with increased physical activity alone without weight loss. This was followed by standardized empiric infertility treatment consisting of 3 cycles of ovarian stimulation/intrauterine insemination. Outcomes of any resulting pregnancy were tracked. Among 191 women randomized to standard lifestyle group, 40 dropped out of the study before conception; among 188 women randomized to intensive lifestyle group, 31 dropped out of the study before conception. All the randomized women were included in the intent-to-treat analysis for primary outcome of a healthy live birth. There were no significant differences in the incidence of healthy live births [standard 29/191(15.2%), intensive 23/188(12.2%), rate ratio 0.81 (0.48 to 1.34), P = 0.40]. Intensive had significant weight loss compared to standard (-6.6 ± 5.4% versus -0.3 ± 3.2%, P < 0.001). There were improvements in metabolic health, including a marked decrease in incidence of the metabolic syndrome (baseline to 16 weeks: standard: 53.6% to 49.4%, intensive 52.8% to 32.2%, P = 0.003). Gastrointestinal side effects were significantly more common in intensive. There was a higher, but nonsignificant, first trimester pregnancy loss in the intensive group (33.3% versus 23.7% in standard, 95% rate ratio 1.40, 95% confidence interval [CI]: 0.79 to 2.50). The main limitations of the study are the limited power of the study to detect rare complications and the design difficulty in finding an adequate time matched control intervention, as the standard exercise intervention may have potentially been helpful or harmful. CONCLUSIONS:A preconception intensive lifestyle intervention for weight loss did not improve fertility or birth outcomes compared to an exercise intervention without targeted weight loss. Improvement in metabolic health may not translate into improved female fecundity. TRIAL REGISTRATION:ClinicalTrials.gov NCT02432209.

Background: Quality of life (QOL) and psychological health has been reported to be decreased among women with gynecological conditions such as uterine fibroids (UFs). Materials and Methods: Women enrolled in the Comparing Options for Management: PAtient-centered REsults for Uterine Fibroids (COMPARE-UF) registry, receiving procedural therapy for symptomatic UFs, were eligible for this analysis if they completed a series of health-related QOL surveys administered at three time points (baseline, 6-12 weeks postprocedure, and 1 year postprocedure; n = 1486). Ethical approval for this study was obtained at each recruiting site and the coordinating center (NCT02260752, clinicaltrials.gov). Results: More than 26% (n = 393) of women reported moderate anxiety/depression on the baseline anxiety/depression domain of the Euro-QOL 5-dimension instrument. At both the 6-12 weeks and 1-year postprocedural follow-up, there was significant improvement in the UF QOL symptom severity score (p < 0.001, p < 0.001), the total UF symptom QOL score (p < 0.001, p < 0.001), and the Euro-QOL 5-dimension visual analog scale (p < 0.001, p = 0.004) compared with the preprocedural baseline scores. The reporting of anxiety/depression decreased by 66.4% among women who were at baseline, whereas 5.6% of women previously reporting no anxiety/depression reported anxiety/depression at the 1-year follow-up. Conclusion: UF symptoms were more severe among women reporting anxiety/depression at baseline. At the 1-year follow-up, health-related QOL scores improved among all women and the prevalence of anxiety/depression decreased in most, but not all women, whereas severity of anxiety/depression worsened in a small percentage of women (5.6%). Overall, these results suggest that UF treatment improves symptoms of anxiety/depression associated with symptomatic UFs.