Changing the Perspective on Fertility Preservation for Women with Metastatic or Advanced Stage Cancer.

PURPOSE OF REVIEW: In this Perspective we share the personal story of a 33-year-old patient diagnosed with metastatic breast cancer and her journey through fertility preservation, surrogacy, and eventually motherhood, highlighting misconceptions about fertility preservation in this population. RECENT FINDINGS: There are nearly 1 million women under the age of 50 diagnosed and living with cancer in the USA. These patients are met with life-altering decisions, including those that may limit their reproductive ability. While there have been tremendous advances and advocacy in the field of oncofertility, there has been limited focus on patients with advanced stage or metastatic cancer. We describe five key misconceptions surrounding fertility preservation in patients with advanced stage cancer, offering a review of the literature and our approach to challenging topics like desiring fertility preservation in the face of Stage 4 disease, the safety and timing of ovarian stimulation during cancer treatment, and passing away following fertility preservation. We review the importance of assessing perceptions of fertility preservation in patients with metastatic cancer and highlight the lack of research in this area as a call to action.

Metabolic and endocrine status associate with obstructive sleep apnea risk among patients with polycystic ovary syndrome.

STUDY OBJECTIVES: Risk of obstructive sleep apnea (OSA) appears to be increased among patients with polycystic ovary syndrome (PCOS), but the underlying physiology is unclear. We sought to identify predictors of OSA risk among patients with PCOS. METHODS: A cross-sectional analysis of patients evaluated for PCOS at a single tertiary center from 2017-2022 was completed. Inclusion criteria included patients 18-44 years of age who had Rotterdam criteria for PCOS and had completed a Berlin Questionnaire (BQ) for OSA risk assessment. All patients underwent standardized anthropometric, ultrasound, endocrine, and metabolic phenotyping. RESULTS: Of the 572 patients screened during the study period, 309 patients with PCOS met inclusion criteria, and 104 (33.7%) had a high-risk BQ. Those with a high-risk BQ, compared with those without, had significantly (P < .05) higher waist:hip ratio, low-density-lipoprotein cholesterol, triglycerides, fasting insulin, 2-hour insulin, fasting glucose, 2-hour glucose, homeostatic model assessment for insulin resistance, hemoglobin A1C, C-reactive protein, free testosterone, and free androgen index and had lower high-density-lipoprotein cholesterol and sex hormone binding globulin. In multivariable modeling controlling for all significantly differing variables in univariate analyses, hemoglobin A1C (ß [standard error] 1.05 [0.45], P = .02), C-reactive protein (0.09 [0.04], P = .01), and sex hormone binding globulin (-0.02 [0.01], P = .02) associated with high-risk BQ. CONCLUSIONS: Dysglycemia, inflammation, and androgen status independently associate with predicted OSA risk by BQ. Future studies are needed to comprehensively assess the impact of treatment of OSA on these outcomes among patients with PCOS to better clarify the directionality and clinical implications of these associations. CITATION: Christ JP, Shinkai K, Corley J, Pasch L, Cedars MI, Huddleston HG. Metabolic and endocrine status associate with obstructive sleep apnea risk among patients with polycystic ovary syndrome. J Clin Sleep Med. 2024;20(6):871-877.

Antimullerian Hormone, a Marker of Ovarian Reserve, Is Protective Against Presence and Severity of NASH in Premenopausal Women.

BACKGROUND & AIMS: Antimüllerian hormone (AMH) is a marker of ovarian reserve with emerging data linking lower levels to some metabolic and inflammatory diseases in women. Whether AMH levels influence nonalcoholic fatty liver disease (NAFLD) is unknown. METHODS: Leveraging the NASH Clinical Research Network we determined the association of AMH levels within 6 months of liver biopsy with presence and severity of histologic measures of NAFLD in premenopausal women. Outcomes included presence of nonalcoholic steatohepatitis (NASH), presence and severity of fibrosis, and NAFLD Activity Score and its components. Logistic and ordinal logistic regression models were adjusted for age, race/ethnicity, homeostatic model assessment for insulin resistance, body mass index, dyslipidemia, polycystic ovary syndrome, estrogen-progestin use, and menstrual cyclicity. RESULTS: Median cohort age was 35 years; 73% were white and 24% Hispanic. Thirty-three percent had diabetes, 81% had obesity, and 95% had dyslipidemia. On biopsy 71% had NASH, 68% had any fibrosis, and 15% had advanced fibrosis. On adjusted analysis (n = 205), higher AMH quartiles were inversely associated with NAFLD histology including prevalent NASH (adjusted odds ratio [AOR], 0.64; 95% confidence interval [CI], 0.41-1.00), NAFLD Activity Score ≥5 (AOR, 0.52; 95% CI, 0.35-0.77), Mallory hyaline (AOR, 0.54; 95% CI, 0.35-0.82), and higher fibrosis stage (AOR, 0.70; 95% CI, 0.51-0.98). The protective effects of AMH were more pronounced among women without polycystic ovary syndrome (n = 164), including lower odds of NASH (AOR, 0.53; 95% CI, 0.32-0.90) and any NASH fibrosis (AOR, 0.54; 95% CI, 0.32-0.93). CONCLUSIONS: AMH may reflect a unique biomarker of NASH in premenopausal women and findings suggest a novel link between reproductive aging and histologic severity of NAFLD in women.

Cardiometabolic outcomes in Kronos Early Estrogen Prevention Study continuation: 14-year follow-up of a hormone therapy trial.

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 17ß-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 17ß-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.

Presence of Fibroids on Transvaginal Ultrasonography in a Community-Based, Diverse Cohort of 996 Reproductive-Age Female Participants.

Importance: Fibroids are benign uterine tumors that can cause significant morbidity. Knowledge on fibroid prevalence, especially in the asymptomatic population and in Asian and Hispanic or Latina individuals, is limited, and a better understanding of affected groups will improve timely diagnosis and motivate appropriate recruitment in clinical trials to reduce health disparities. Objective: To estimate the prevalence of fibroids in a diverse cohort of female individuals. Design, Setting, and Participants: This cross-sectional study included female individuals not seeking treatment for fertility or other conditions who were prospectively recruited in an academic medical center in San Francisco, California. Effort was made to recruit an equal proportion of participants from 4 large racial and ethnic groups in the United States (Asian-Chinese, Black or African American, Hispanic or Latina, and White) and across 4 equal age groups between 25 and 45 years. All participants reported regular menses (21-35 days), had not used estrogen- or progestin-containing medications in the 3 months prior to enrollment, and denied history of pelvic surgery. The assessment of ultrasonography results was part of an ongoing longitudinal cohort, with initial recruitment from October 2006 to September 2012. Data analysis was performed in April to September 2022. Main Outcomes and Measures: Fibroid presence and burden as assessed by transvaginal ultrasonography. Results: A total of 996 female participants were included in the analysis, including 229 (23.0%) Asian-Chinese, 249 (25.0%) Black or African American, 237 (23.8%) Hispanic or Latina, and 281 (28.2%) White individuals. Mean (SD) age was 34.8 (5.7) years in Asian-Chinese participants, 35.4 (6.1) years in Black or African American participants, 34.8 (5.3) years in Hispanic or Latina participants, and 35.3 (5.0) years in White participants. Fibroids were present in 21.8% (95% CI, 16.7%-27.8%) of Asian-Chinese participants, 35.7% (95% CI, 29.8%-42.0%) of Black or African American participants, 12.7% (95% CI, 8.7%-17.6%) of Hispanic or Latina participants, and 10.7% (95% CI, 7.3%-14.9%) of White participants. Black or African American and Asian-Chinese participants were more likely to have fibroids than White participants (Black or African American: adjusted odds ratio [OR], 4.72 [95% CI, 2.72-8.18]; P < .001; Asian-Chinese: adjusted OR, 3.35 [95% CI, 1.95-5.76]; P < .001). In those with fibroids, the proportion with multiple fibroids were 48.3% in Black or African American participants, 33.3% in White participants, 33.3% in Hispanic or Latina participants, and 26.0% in Asian-Chinese participants (P = .06). The largest mean (SD) fibroid diameter was 3.9 (1.9) cm in Black or African American participants, 3.2 (1.6) cm in Asian-Chinese participants, 3.2 (1.6) cm in White participants, and 3.0 (1.4) cm in Hispanic or Latina participants (P = .03). Conclusions and Relevance: In this study of female participants in a nonclinical setting, Black or African American and Asian-Chinese participants were disproportionately affected by uterine fibroids. Hispanic or Latina participants had similar fibroid burden to White participants.

B-cell lymphoma 6 expression significantly differs by the uterine preparation method used for frozen embryo transfer.

OBJECTIVE: To determine whether B-cell lymphoma 6 (BCL6), an endometriosis-associated marker postulated to predict poor pregnancy outcomes, is differentially expressed in the window of implantation with various uterine preparation regimens commonly used for frozen embryo transfers. DESIGN: A retrospective cohort study. SETTING: An academic center. PATIENT(S): Patients with infertility who underwent endometrial biopsy for BCL6 evaluation INTERVENTION(S): Exogenous estradiol and/or progesterone. MAIN OUTCOME MEASURE(S): Endometrial BCL6 histological score (HSCORE) and overexpression (HSCORE >1.4) RESULT(S): Two hundred and forty-four patients were included in the analysis: 76 patients were sampled in a natural menstrual cycle without exogenous hormone exposure (NC), 25 under a modified natural cycle embryo transfer protocol with choriogonadotropin alfa injection followed by luteal phase vaginal progesterone supplementation (mNC), and 143 under a programmed cycle embryo transfer protocol, with estradiol administration followed by addition of intramuscular progesterone-in-oil injections (PC). Median HSCORE (interquartile range) was the highest in NC (3.0 [1.8-3.6]). BCL6 expression was significantly lower in mNC (1.1 [0.4-2.1]) and PC groups (0.8 [0.3-1.3]) compared with NC. In addition, BCL6 overexpression (HSCORE >1.4) was observed in 80.3% of NC, 40.0 % of mNC, and 23.1 % of PC. After adjusting for covariates, the endometrium exposed to exogenous progesterone had significantly lower odds of BCL6 overexpression than that of a natural menstrual cycle (adjusted odds ratio, 0.12 [95% CI 0.04-0.35] for mNC; and odds ratio, 0.08 [95% CI 0.04-0.17] for PC). CONCLUSION(S): BCL6 expression differs by the type of uterine preparation method, with lower levels observed with exogenous progesterone exposure. The validity and utility of BCL6 testing under medicated endometrial state warrants further investigation.

Associations between pituitary-ovarian hormones and cognition in recently menopausal women independent of type of hormone therapy.

OBJECTIVES: To examine associations of pituitary-ovarian hormone levels with cognition before and after different formulations of hormone therapy (HT) or placebo independent of treatment group. METHODS: Recently menopausal, healthy women were randomized to 0.45 mg/day oral conjugated equine estrogens (o-CEE, n = 109), 50 µg/day transdermal 17ß (tE2, n = 107) or placebo pills and patches (n = 146); women on active treatment received oral 200 mg/day micronized progesterone for 12 days per month. Levels of estrone, 17ß-estradiol, follicle stimulating hormone, luteinizing hormone, androstenedione, and testosterone were determined prior to and after 48 months of study participation. Neuropsychological testing was administered at baseline, and months 18, 36 and 48. Latent growth curve models controlling for education level, age, APOE allele status, waist circumference, and treatment examined the trajectories of each cognitive domain after accounting for the effect of hormone levels at baseline and months 18, 36 and 48. A linear multivariate mixed model examined the effect of changes in hormone levels on changes in trajectories of complex attention tasks with varying degrees of difficulty. RESULTS: All women were adherent to treatment at month 48. Higher baseline estrone levels were associated with poorer global cognition, auditory attention and working memory, visual attention, and executive function, but not working memory. Higher levels of baseline 17ß-E2 were associated with poorer cognitive performance, with marginal significance at baseline in speeded language and mental flexibility (p = 0.013). Other hormone levels were not associated with cognition. Controlling for all treatments, hormone levels at baseline and at month 48 did not have any significant correlation with cognitive trajectories over time. SUMMARY: In healthy, recently menopausal women, baseline estrone levels were inversely associated with selected cognitive factors independent of two types of HT or placebo during 4 years of follow-up. Baseline levels of the other pituitary-ovarian hormones studied were not associated with baseline cognition, nor were changes in any hormones associated with changes in cognition during the study. The marginal association between estradiol levels and cognitive factors warrants further investigation. GOV NUMBERS: NCT00154180, NCT00623311.

Polycystic ovary syndrome is associated with nonalcoholic steatohepatitis in women of reproductive age.

Polycystic ovary syndrome (PCOS) occurs in approximately 10% of all reproductive-age women, with over 50% of these patients having imaging-confirmed nonalcoholic fatty liver disease (NAFLD). Whether PCOS increases the risk for more clinically relevant disease, such as nonalcoholic steatohepatitis (NASH), is unclear. Such findings are relevant to prognosticating risk of progressive liver disease in the growing population of young adults with NAFLD. Using weighted discharge data from the United States National Inpatient Sample from 2016 to 2018, we evaluated the association of PCOS with the presence of NASH among reproductive-age women with NAFLD. The association of PCOS with NASH was assessed by logistic regression, adjusting for demographic and comprehensive metabolic comorbidities. Other causes of hepatic steatosis and chronic liver diseases were excluded. Our analysis included 189,440 reproductive-age women with NAFLD, 9415 of whom had PCOS. Of those with PCOS, 1390 (15%) had a distinct code for NASH. Women with PCOS were younger (median age, 33 vs. 40 years; p < 0.001) and more likely to have diabetes (37.0% vs. 34.0%), obesity (83.0% vs. 58.0%), dyslipidemia (26.0% vs. 21.0%), and hypertension (38.0% vs. 35.0%) (all p ≤ 0.01). On adjusted analysis accounting for these metabolic comorbidities, PCOS remained independently associated with an increased prevalence of NASH (adjusted odds ratio, 1.22; 95% confidence interval, 1.05-1.42; p = 0.008). Conclusions: Among reproductive-age women with NAFLD, metabolic risk factors were more common in those with PCOS. Despite adjustment for these metabolic comorbidities, PCOS remained associated with a 22% higher odds of having NASH. These findings support efforts to increase NAFLD screening in young women with PCOS and highlight the potential "head start" in progressive liver disease among young women with PCOS.

Triggering with 1,500 IU of human chorionic gonadotropin plus follicle-stimulating hormone compared to a standard human chorionic gonadotropin trigger dose for oocyte competence in in vitro fertilization cycles: a randomized, double-blinded, controlled noninferiority trial.

OBJECTIVE: To assess if triggering with 1,500 IU of human chorionic gonadotropin (hCG) with 450 IU of follicle-stimulating hormone (FSH) induces noninferior oocyte competence to a standard dose of hCG trigger used in in vitro fertilization (IVF). The alternative trigger will be considered noninferior if it is at least 80% effective in promoting oocyte competence. DESIGN: Randomized, double-blinded, controlled noninferiority trial. SETTING: Academic infertility practice. PATIENTS: Women aged 18-41 undergoing IVF with antral follicle count ≥8, body mass index ≤30 kg/m2, and no history of ≥2 IVF cycles canceled for poor response were enrolled. Participants with a serum estradiol >5,000 pg/mL on the day of trigger were excluded because of high risk of ovarian hyperstimulation syndrome. INTERVENTIONS: Participants were randomized to receive an alternative trigger of 1,500 IU of hCG plus 450 IU of FSH or a standard trigger dose of hCG (5,000 or 10,000 IU) for final oocyte maturation. MAIN OUTCOME MEASURES: The primary outcome was total competent proportion, defined as the probability of 2 pronuclei from an oocyte retrieved. The alternative trigger will be considered noninferior to the standard trigger if a 1-sided 95% confidence interval (CI) of the relative risk (RR) is not <0.8. Secondary outcomes included oocyte recovery and maturity, intracytoplasmic sperm injection fertilization, embryo quality, pregnancy rates, as well as serum and follicular hormones. Secondary outcomes were compared using a 2-sided superiority test. Outcomes were analyzed by intention-to-treat and per-protocol. RESULTS: A total of 105 women undergoing IVF were randomized from May 2015 to June 2018. The probability of the primary outcome was 0.59 with the alternative trigger and 0.65 with the standard trigger, with a RR of 0.91 and a 1-sided 95% CI of 0.83. Noninferiority of the alternative trigger was demonstrated. Live birthrate from all fresh transfers in the alternative trigger group vs. standard trigger was 46.9 vs. 46.4% (RR, 1.01; 95% CI, 0.62-1.62), respectively. Live birthrate per randomized participant was 48.1% in the alternative trigger group vs. 62.7% with the standard trigger (RR, 0.73; 95% CI, 0.48-1.11). No participants had a failed retrieval. CONCLUSION: Triggering with 1,500 IU of hCG plus 450 IU of FSH promoted noninferior oocyte competence compared to a standard hCG trigger dose. TRIAL REGISTRATION: NCT02310919.

Cardiometabolic measures and cognition in early menopause - Analysis of baseline data from a randomized controlled trial.

OBJECTIVE: The relationships between cardiometabolic indices and cognition were examined in recently menopausal women. METHODS: Cross-sectional analysis of baseline data from the KEEPS (Kronos Early Estrogen Prevention Study)-Cognitive ancillary study (n = 621). Cognitive performance was assessed by the Modified Mini Mental Status (3MS) score (primary outcome). Physical cardiometabolic indices included body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and blood pressure (BP). Biochemical cardiometabolic indices included serum levels of high sensitivity C-reactive protein (hs-CRP), total cholesterol (TC), low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), non-HDL (non-HDL-C), triglycerides (TG), fasting serum glucose (FSG), and insulin resistance (HOMA-IR). Socio-demographic variables included age, race/ethnicity, education, and lifestyle (physical activity, smoking). Central adiposity was defined as WC > 88 cm (>35 in) and WHR > 0.8. Separate stepwise multivariable analyses (GLM, ordinal logistic regression and logistic regression) assessed relationships between 3MS scores (as continuous, in tertiles and dichotomized at 90 respectively) with the measures of central adiposity (predictor variables); socio-demographic variables (age, time since menopause, race, educational status and lifestyle) and cardiometabolic variables (BP, lipids, FSG, HOMA-IR and hs-CRP) were examined as covariates. The final multivariable models included time since menopause, race, ethnicity, educational status, strenuous exercise, BMI ≥30 kg/m2, non-HDL-C and hs-CRP as covariates. Due to the high collinearity between the two indices of central adiposity, within each analytic strategy, separate models examined the respective associations of WC > 88 cm and WHR > 0.8 with 3MS score. RESULTS: On adjusted analyses, indices of central adiposity were independent predictors of significantly lower 3MS scores (p < 0.05). Consistency in this relationship was observed across the three different multivariable regression analytic approaches (GLM, ordinal and logistic regression). CONCLUSIONS: Among recently menopausal women, WC > 88 cm and WHR > 0.8 were associated with significantly lower cognitive function, as reflected by lower 3MS scores. The mechanisms that might explain the observed negative implications of central adiposity for cognitive function warrant further study.

Breast cancer grade and stage do not affect fertility preservation outcomes.

PURPOSE: To investigate if breast cancer stage and grade affect fertility preservation outcomes. METHODS: We performed a retrospective cohort study that included premenopausal women with breast cancer undergoing fertility preservation diagnosed between January 2011 and January 2019. The primary outcome measure was the number of mature oocytes (MII) per antral follicle count (AFC). Secondary outcome measures included total oocytes retrieved, total mature oocytes retrieved, and greater than 10 mature oocytes preserved. Univariate and multivariate models were used to assess the association of low vs. high stage (low stage I-II and high stage III-IV) and grade I vs. grade II/III with each outcome, with adjustment for confounders. RESULTS: A total of 267 premenopausal breast cancer patients undergoing fertility preservation were included in our study, with the majority presenting with low stage (N = 215, 80.5%), grade II/III (N = 235, 88.1%) disease. Baseline AFC, total gonadotropin dose, days of stimulation, and follicles [Formula: see text] 13 mm on the day of trigger did not differ by stage or grade. After adjusting for age, BMI, and baseline AFC, we found that the mean MII per AFC did not differ by stage (1.0 vs. 1.1, P = 0.3) or grade (1.0 vs. 1.0, P = 0.92). Similarly, total oocytes retrieved, total MII retrieved, and percentage of patients who were able to preserve greater than 10 MII did not differ by breast cancer stage or grade (all P > 0.2). CONCLUSION: Breast cancer grade and stage do not impact ovarian stimulation or fertility preservation outcome.

Autologous platelet-rich plasma treatment for moderate-severe Asherman syndrome: the first experience.

PURPOSE: Treatment of Asherman syndrome (AS) presents a significant clinical challenge. Based on our in vitro data showing that PRP could activate endometrial cell proliferation and migration, we hypothesized that intrauterine infusion of autologous platelet-rich plasma (PRP) may improve endometrial regeneration and fertility outcomes in patients with moderate-severe AS. MATERIALS AND METHODS: Subjects with moderate-severe AS were randomized to PRP or saline control administered following hysteroscopic adhesiolysis. Due to relative inability to randomize patients to the control group, after initial randomization of 10 subjects (6 in PRP and 4 in control groups), the remainder were prospectively enrolled in PRP group (n = 9), with 11 historic controls added to control group, for a total of 30 subjects (PRP n = 15; saline control n = 15). Right after hysteroscopy, 0.5-1 mL of PRP or saline was infused into the uterus via a Wallace catheter, followed by estrogen therapy. The primary outcomes were changes in endometrial thickness (EMT, checked in 3 weeks) and in menstrual flow; secondary outcomes were pregnancy and live birth rates. EMT and menstrual bleeding pattern were assessed before and after the intervention. Pregnancy was assessed over a 6-month period. RESULTS: There were no statistically significant differences in age, gravidity/parity, cause of AS, preoperative menses assessment, AS hysteroscopy score, and intrauterine balloon placement between the groups. There was no statistically significant difference (p = 0.79) in EMT pre-PRP infusion for control (5.7 mm, 4.0-6.0) and study arm (5.3 mm, 4.9-6.0). There was no statistically significant change (p = 0.78) in EMT after PRP infusion (1.4 mm, - 0.5-2.4) vs saline (1.0 mm, 0.0-2.5). Patients tolerated the procedure well, with no adverse effects. There was no difference in the predicted likelihood of pregnancy (p = 0.45) between the control (0.67, 0.41-0.85) and study arm (0.53, 0.29-0.76). CONCLUSIONS: PRP was well accepted and tolerated in AS patients. However, we did not observe any significant EMT increase or improved pregnancy rates after adding PRP infusion, compared to standard treatment only. The use of intrauterine PRP infusion may be a feasible option, and its potential use must be tested on a larger sample size of AS patients.

Concomitant tamoxifen or letrozole for optimal oocyte yield during fertility preservation for breast cancer: the TAmoxifen or Letrozole in Estrogen Sensitive tumors (TALES) randomized clinical trial.

PURPOSE: To determine whether concomitant tamoxifen 20 mg with gonadotropins (tamoxifen-gonadotropin) versus letrozole 5 mg with gonadotropins (letrozole-gonadotropin) affects mature oocyte yield. METHODS: Open-label, single-institution, randomized trial. Inclusion criteria included the following: females, ages 18-44 years old, with new diagnosis of non-metastatic breast cancer, who were undergoing fertility preservation with either oocyte or embryo cryopreservation. Those with estrogen-receptor-positive (ER+) breast cancer were randomized to tamoxifen-gonadotropin or letrozole-gonadotropin. Another group with estrogen-receptor-negative (ER-) breast cancer was recruited, as a prospectively collected comparison arm who took neither letrozole nor tamoxifen (gonadotropin only). The primary outcome was the number of mature oocytes obtained from the cycle. The randomized groups were powered to detect a difference of three or more mature oocytes. RESULTS: Forty-five patients were randomized to tamoxifen-gonadotropin and fifty-one to letrozole-gonadotropin. Thirty-eight patients completed gonadotropin only. Age, antral follicle count, and body mass index were similar between the randomized groups. Our primary outcome of mature oocyte yield was similar between the tamoxifen-gonadotropin and letrozole-gonadotropin groups (12±8.6 vs. 11.6±7.5, p=0.81, 95%CI of difference =-2.9 to 3.7). In a pre-specified secondary comparison, mature oocyte yield was also similar with tamoxifen-gonadotropin or letrozole-gonadotropin versus gonadotropin only (12±8.6 vs. 11.6±7.5 vs. 12.4±7.2). There were no serious adverse events in any of the groups. CONCLUSIONS: Tamoxifen-gonadotropin and letrozole-gonadotropin produced a similar number of mature oocytes. Women who received either tamoxifen-gonadotropin or letrozole-gonadotropin had a similar number of oocytes to the gonadotropin-only group. TRIAL REGISTRATION: NCT03011684 (retrospectively registered 1/5/2017, after 9% enrolled).

Association of obstructive sleep apnea risk with depression and anxiety symptoms in women with polycystic ovary syndrome.

STUDY OBJECTIVE: To determine whether obstructive sleep apnea (OSA) risk is associated with depression and anxiety symptoms in women with polycystic ovary syndrome (PCOS). METHODS: This is a cross-sectional study of women with PCOS, by the Rotterdam criteria, seen at a single academic center between June 2017 and June 2020. Depression symptoms, anxiety symptoms, and OSA risk were assessed with the self-administered Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and Berlin questionnaires, respectively. Univariate and multivariate logistic regression analyses were used to determine the odds of moderate/severe symptoms of depression (PHQ-9 ≥ 10) and anxiety (GAD-7 ≥ 10) in the high-risk vs low-risk OSA groups. The primary multivariate model adjusted for age, body mass index, free testosterone, and insulin resistance. RESULTS: Of the 200 participants, the mean age was 28.0 years and 38% screened high risk for OSA. Women who screened high-risk OSA had > 3 times the odds of moderate/severe depression (odds ratio [OR]: 3.19; 95% confidence interval [CI]: 1.76-5.78; P < .001) and > 2 times the odds of having moderate/severe anxiety (OR: 2.49; 95% CI: 1.34-4.64; P = .004). These associations were only slightly attenuated in the adjusted models: the adjusted OR for moderate/severe depression was 3.06 (95% CI: 1.36-6.88; P = .01) and the aOR for moderate/severe anxiety was 2.39 (95% CI: 1.03-5.59; P = .04). CONCLUSIONS: Among women with PCOS, those at high risk of OSA experienced elevated depression and anxiety symptoms compared with those at low risk for OSA, independent of the effects of age, body mass index, hyperandrogenism, and insulin resistance. CITATION: Zhou X, Jaswa E, Pasch L, Shinkai K, Cedars MI, Huddleston HG. Association of obstructive sleep apnea risk with depression and anxiety symptoms in women with polycystic ovary syndrome. J Clin Sleep Med. 2021;17(10):XXX-XXX.

Uterine synechiae after intrauterine device use: a case series.

PURPOSE: The intrauterine device (IUD) is one of the most effective and safe contraceptive methods. Substantial literature suggests an overall return to normal fertility following IUD removal. However, there are no studies to date that evaluate endometrial function specifically in nulliparous women after levonorgestrel IUD use. METHODS: We present three nulliparous women with a history of levonorgestrel IUD use who were evaluated for uterine dysfunction at the University of California, San Francisco Center for Reproductive Health. These patients had no other known risk factors or history of uterine manipulation, including prior uterine surgery, pelvic radiation, intrauterine infection, hypothalamic amenorrhea, or uterine anomaly. RESULTS: Upon evaluation, these patients were found to have uterine synechiae concerning for Asherman syndrome. All three patients were eventually able to conceive through assisted reproductive technology or natural conception. CONCLUSION: This case series is the first to suggest a possible effect of endometrial dysfunction on fertility resumption following levonorgestrel IUD removal in nulliparous patients. It is possible that a small subset of patients may be at risk for Asherman syndrome after IUD use. Larger prospective trials are needed to explore this possible association.

Predictors of adequate physical activity within a multiethnic polycystic ovary syndrome patient population: a cross-sectional assessment.

BACKGROUND: Physical activity is a cornerstone for treatment of women with polycystic ovary syndrome (PCOS), but there are limited data on their exercise behaviors. A previous study identified PCOS patients of non-White ethnicity to be at higher risk for inadequate physical activity. Further data is needed to identify groups that would benefit from additional counseling in achieving adequate physical activity (APA). Therefore, this study examined correlates of APA within a multiethnic PCOS patient population. METHODS: Cross-sectional assessment of exercise behaviors within a multiethnic PCOS patient population was performed using the International Physical Activity Questionnaire (IPAQ). Kruskal-Wallis test was used to compare metabolic equivalents from physical activity among racial/ethnic groups. APA was defined as at least 150 min of moderate-intensity, or 75 min of vigorous-intensity, or an equivalent combination of moderate- and vigorous-intensity activity per week. Logistic regression analyses were performed to identify correlates of APA. RESULTS: Four hundred and sixty-five women of various racial/ethnic backgrounds were included in analysis: 62% (n = 287) self-identified as White, 15% (n = 71) as Hispanic, 11% (n = 52) as East/Southeast Asian, 7% (n = 32) as South Asian, and 5% (n = 23) as Black/African American. Significant differences were observed in metabolic equivalents (METs) from vigorous-intensity and total (moderate plus vigorous-intensity) exercise across racial/ethnic groups (p < 0.01); South Asian patients had the lowest metabolic expenditure in moderate-intensity, vigorous-intensity, and total exercise. Overall prevalence of APA was 66%; South Asian patients exhibited the lowest prevalence (46.9%). Ethnicity was a predictor for APA when controlled for age (p = 0.01); this finding was attenuated in logistic regression models that also controlled for age and body mass index (p = 0.05) as well as education level and parity (p = 0.16). CONCLUSIONS: South Asian patients with PCOS exhibited the lowest metabolic expenditure and frequency of APA in our cohort. Differences in frequency of APA across racial/ethnic groups appear to be influenced by anthropometric and sociodemographic factors. Our findings present an opportunity for women's health providers to be cognizant and provide additional counseling regarding physical exercise to at-risk PCOS patients to improve their known higher risk for adverse long-term metabolic outcomes.

Conception after chemotherapy: post-chemotherapy method of conception and pregnancy outcomes in breast cancer patients.

PURPOSE: As the paradigm shifts towards improving cancer survivorship, an important concern for reproductive-aged women diagnosed with cancer is how their disease and its treatment will affect their future fertility. We sought to characterize pregnancy attempts and outcomes in breast cancer patients following chemotherapy. METHODS: We conducted a prospective cohort study of women diagnosed with breast cancer seen between 2010 and 2019. A questionnaire was administered following cancer treatment with questions regarding oncologic and reproductive history and attempts and method of conception. RESULTS: Of 181 participants, 46 (25.4%) attempted to conceive following chemotherapy. Thirty-five patients (76.1%) had return of ovarian function. Of those, 34 patients (mean age 32.8 years) first attempted to conceive by intercourse, and 22 (64.7%) became pregnant, resulting in 17 live births. Of the remaining 12 who did not successfully conceive through intercourse, eight went on to try other methods, resulting in five additional pregnancies and one live birth. Twelve patients (mean age 34.6 years) proceeded directly to ART; of those, eight (66.7%) became pregnant, resulting in six live births. CONCLUSION: In breast cancer patients with return of ovarian function after chemotherapy, half were able to conceive by intercourse alone. In order to maximize reproductive potential in patients who have return of ovarian function, providers should offer natural conception as a reasonable option prior to the use of cryopreserved tissue. For those who did not attempt to conceive on their own, the use of pre-treatment cryopreserved eggs or embryos had a high likelihood of success.

Diminished ovarian reserve is associated with reduced euploid rates via preimplantation genetic testing for aneuploidy independently from age: evidence for concomitant reduction in oocyte quality with quantity.

OBJECTIVE(S): To determine whether women with diminished ovarian reserve (DOR) (quantitatively) had lower rates of euploid blastocysts, as a proxy for oocyte quality. DESIGN: Retrospective cohort study. SETTING: University reproductive health clinic. PATIENT(S): A total of 1,152 women aged 19-42 years underwent 1,675 IVF cycles yielding 8,073 blastocysts for biopsy from 2010 to 2019. INTERVENTIONS(S): Preimplantation genetic testing for aneuploidy. MAIN OUTCOME MEASURE(S): Euploid rates, defined as the number of euploid blastocysts divided by the number of biopsied blastocysts per cycle. RESULT(S): A total of 225 women (20%) had DOR as infertility diagnosis per the Bologna criteria. Age was higher among the women with DOR (39.5 y vs. 37.0 y). Euploid rates were lower among women with vs. without DOR (29.0% vs. 44.9%). In generalized linear models controlling for age, women with DOR had 24% reduced odds of a biopsied blastocyst being euploid versus women without DOR. In a secondary analysis assigning DOR status to women producing the lowest quartile of age-adjusted mature oocyte yield, this relationship remained. No differences were identified in live birth rates between women with and without DOR after euploid single-embryo transfer independently from age (n = 944 transfers; 56.8% vs. 54.8%, respectively). CONCLUSION(S): Blastocysts from women with DOR are less likely to be euploid than those from women without DOR after adjustment for age. Given the concomitant reduction in euploid rates with quantity of oocytes observed in this study, quantitative ovarian reserve assessments (i.e., follicular machinery) may yield insight into relative ovarian aging.

Highly elevated level of antimüllerian hormone associated with preterm delivery in polycystic ovary syndrome patients who underwent ovulation induction.

OBJECTIVE: To determine the relationship between high antimüllerian hormone (AMH) levels and increased preterm delivery risk in populations of women with polycystic ovary syndrome (PCOS) or unexplained infertility undergoing ovulation induction. DESIGN: Secondary analysis of data from two multicenter randomized clinical trials: Pregnancy in Polycystic Ovary Syndrome II (PPCOS II); and Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS). SETTING: Not applicable. PATIENTS: Live births at ≥24 weeks' gestation from both the PPCOS II (n = 172) and AMIGOS (n = 222) cohorts were evaluated, and those at risk for iatrogenic preterm delivery including placental conditions, fetal growth restriction, multiple gestations, hypertensive diseases of pregnancy, and pre-gestational diabetes were excluded. The final analysis included 118 women with PCOS from the PPCOS II cohort and 146 women with unexplained infertility from the AMIGOS cohort. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Spontaneous preterm delivery. RESULTS: In the PCOS population, median AMH overall was 5.5 ng/dL (interquartile range 2.9-9.3 ng/dL). In all, 62% of participants who delivered preterm had AMH levels above the 75th percentile. When comparing clinical covariates between the preterm and term deliveries, women with PCOS who delivered preterm had notably higher AMH than their term counterparts (11.1 vs. 5.4 ng/mL). In the univariate logistic regression analysis, each unit increase in AMH raised the odds of preterm delivery by 14% (odds ratio 1.14, 95% confidence interval 1.02-1.26). The effect was magnified only after adjusting for age, race, body mass index, smoking status, testosterone, homeostatic model assessment for insulin resistance, and treatment randomization group (adjusted odds ratio 1.25, 95% confidence interval 1.06-1.49). Unlike in the PCOS population, the unexplained infertility cohort had no significant difference in AMH levels between those with or without preterm delivery (2.3 vs. 2.6 ng/mL). CONCLUSIONS: Our findings suggest that women with PCOS and high AMH who conceived after ovulation induction represent a high-risk group for preterm delivery. These data indicate that closer monitoring in the third trimester of pregnancies in PCOS patients with early first trimester AMH levels above 9.3 ng/mL may be warranted. CLINICAL TRIAL REGISTRATION NUMBER: NCT01044862.