Effect of Hormone Therapy on Lipoprotein Subfractions in Early and Late Postmenopausal Women.

CONTEXT: The Early vs Late Intervention Trial with Estradiol (ELITE) showed that hormone therapy (HT) reduced atherosclerosis progression among early but not late postmenopausal women (PMW). OBJECTIVE: Determined by time-since-menopause (1) HT effects on lipids and lipoprotein particle subfractions (LPs), (2) associations of estradiol (E2) level with lipids and LPs, (3) associations of lipids and LPs with atherosclerosis progression. DESIGN: Randomized controlled trial stratified by time-since-menopause. SETTING: Academic institution. PARTICIPANTS: Healthy postmenopausal women. INTERVENTION: Oral E2 with/without sequential vaginal progesterone. MAIN OUTCOME MEASURES: Standard lipids and 21 LPs quantitated by ion mobility every 6 months. RESULTS: Among 562 PMW (240 early, 322 late), HT significantly increased total triglycerides (TG), high-density lipoprotein (HDL) cholesterol, small low-density lipoproteins (LDL), large HDL, and TG/C ratio in LDL and HDL and decreased LDL-cholesterol, total very low density lipoproteins (VLDL), small VLDL, intermediate-density lipoproteins, large LDL, and LDL peak diameter. HT showed no lipid or LP differences between time-since-menopause. Associations of E2 level with lipids and LPs explained the HT effects. Despite the nonsignificant P interaction by time-since-menopause, we observed that very small LDL and total HDL LPs were associated with atherosclerosis progression in late PMW. CONCLUSION: HT effects on standard lipids and LPs are consistent with the literature. HT has similar effect on lipids and LPs in early and late PMW. Novel findings include discordant effects of HT on TG and VLDL particles, which can be explained by increased catabolism of atherogenic remnants of TG-rich lipoproteins. Our findings extend the well-known HT effects on standard lipids and LPs that may contribute to the beneficial effects on atherosclerosis progression in PMW.

Benefits of the Enhanced Recovery After Surgery (ERAS) Pathway With Quadratus Lumborum Blocks for Minimally Invasive Gynecologic Surgery Patients: A Retrospective Cohort Study.

STUDY OBJECTIVE: This study aimed to determine the effect of the implementation of the Enhanced Recovery After Surgery (ERAS) protocol among patients receiving minimally invasive gynecologic surgery. DESIGN AND SETTING: This retrospective cohort study was performed in a tertiary care hospital. PATIENTS: A total of 328 females who underwent minimally invasive gynecologic surgeries requiring at least one overnight stay at Keck Hospital of University of Southern California (USC), California, USA, from 2016 to 2020 were included in this study. INTERVENTIONS: The institutional ERAS protocol was implemented in late 2018. A total of 186 patients from 2016 to 2018 prior to the implementation were compared to 142 patients from 2018 to 2020 after the implementation. Intraoperatively, the ERAS group received a multimodal analgesic regimen (including bilateral quadratus lumborum (QL) blocks) and postoperative care geared toward a satisfactory, safe, and expeditious discharge. MEASUREMENTS AND MAIN RESULTS: The two groups were similar in demographics, except for the shorter surgical time noted in the ERAS group. The median opioid use was significantly less among the ERAS patients compared with the non-ERAS patients on postoperative day 1 (7.5 vs. 14.3 mg; p<0.001) and throughout the hospital stay (17.4 vs. 36.2 mg; p<0.001). The ERAS group also had a shorter median hospital length of stay compared to the non-ERAS group (p<0.01). Among patients with a malignant diagnosis, patients in the ERAS group had significantly less postoperative day 1 and total opioid use and a shorter hospital stay (p<0.01). Within the ERAS group, 20% of the patients did not end up receiving a QL block. Opioid use and length of stay were similar between patients who did and did not receive the QL block. CONCLUSIONS: The ERAS pathway was associated with a reduction in opioid use postoperatively and a shorter length of hospital stay after minimally invasive gynecologic surgery. There was a more significant decrease in opioid use and hospital length of stay for patients with malignant diagnoses compared to patients with benign diagnoses. Further research can be done to fully delineate the effect of QL blocks in ERAS protocols.

The Positive Predictive Value of Hospital Discharge Data for Identifying Severe Maternal Morbidity With and Without Blood Transfusion.

BACKGROUND: Blood transfusion is 1 of the 21 indicators for severe maternal morbidity (SMM) as defined by the Centers for Disease Control and Prevention (CDC) using administrative data. The CDC SMM definition is being prepared to measure hospital quality of care; however, transfusion coding reliability has been questioned. The authors assessed the positive predictive value (PPV) of administrative data for identifying gold standard SMM using the CDC SMM definition, with and without the transfusion indicator. METHODS: A retrospective cohort study of one hospital's childbirth admissions (2016-2019) was performed. Data were screened for CDC SMM, and subgroups were created for those with transfusion as the sole indicator for SMM (transfusion-only SMM) versus those with at least one other SMM indicator (other SMM). Medical chart review classified CDC SMM cases based on gold standard SMM criteria. Gold standard SMM was defined by validated indicators identified by internal hospital quality reviews and confirmed by expert consensus. The PPV was calculated for all CDC SMM cases and the subgroups. RESULTS: Of 4,212 eligible people, 278 (6.6%) had CDC SMM. Chart review identified 110 gold standard SMM cases among screen-positive cases, yielding an overall PPV of the CDC SMM definition for gold standard SMM of 39.6%. CDC SMM cases identified solely by administrative coding for transfusion were half as likely to meet gold standard criteria, compared to cases identified by other SMM administrative codes (25.9% vs. 49.4%). CONCLUSION: Blood transfusion, coded as an independent risk factor, had a poor PPV for gold standard SMM. Given efforts to use CDC SMM for quality comparisons, more research is needed to reliably identify cases of SMM without relying on blood transfusion codes.

Family Planning, Fertility, and Medical School: A Survey of Students' Plans and Perceptions of Institutional Support.

Background Deciding when to pursue parenthood can be difficult for medical trainees and infertility is more common in the physician population. However, few studies have examined the views of very early career trainees. The goal of this study was to assess premedical and medical student plans for family building, knowledge of fertility, and thoughts on assisted reproductive technology, as well as institutional support for parenthood in medical school and fertility curriculum. Methods Web-based cross-sectional survey on Qualtrics distributed through social media and school organization-based networks. Responses were reported as frequency and percent and compared across subgroups of population with χ2 tests. Results The study had a total of 605 premedical and medical students respondents. Most students (78%) do not have children but plan to have children in the future. Almost two-thirds (63%) of students would consider using assisted reproductive technology. More than 80% of respondents have considered or would consider oocyte cryopreservation for themselves or their partners. A majority (95%) of students are worried about balancing parenthood and a career in medicine and about their fertility declining while they complete medical training (84%). The most frequently cited barriers to family planning during medical school and residency were: limited time off during training (84%), demands of training (82%), cost of having a child (59%), and stigma of having a child during training (45%). Less than half of medical students had formal education on infertility. Conclusions Premedical and medical students are worried about fertility declining in training and about balancing parenthood and medical careers, but gaps in knowledge and institutional support exist.

The association of hysterectomy with or without ovarian conservation with subclinical atherosclerosis progression in healthy postmenopausal women.

OBJECTIVE: While the deleterious associations of surgical menopause after bilateral oophorectomy with cardiovascular disease are documented, less is specifically known concerning subclinical atherosclerosis progression. METHODS: We used data from 590 healthy postmenopausal women randomized to hormone therapy or placebo in the Early versus Late Intervention Trial with Estradiol (ELITE), which was conducted from July 2005 to February 2013. Subclinical atherosclerosis progression was measured as annual rate of change in carotid artery intima-media thickness (CIMT) over a median 4.8 years. Mixed-effects linear models assessed the association of hysterectomy and bilateral oophorectomy compared with natural menopause with CIMT progression adjusted for age and treatment assignment. We also tested modifying associations by age at or years since oophorectomy or hysterectomy. RESULTS: Among 590 postmenopausal women, 79 (13.4%) underwent hysterectomy with bilateral oophorectomy and 35 (5.9%) underwent hysterectomy with ovarian conservation, a median of 14.3 years before trial randomization. Compared with natural menopause, women who underwent hysterectomy with and without bilateral oophorectomy had higher fasting plasma triglycerides while women who underwent bilateral oophorectomy had lower plasma testosterone. The CIMT progression rate in bilaterally oophorectomized women was 2.2 µm/y greater than natural menopause ( P = 0.08); specifically, compared with natural menopause, the associations were significantly greater in postmenopausal women who were older than 50 years at the time of bilateral oophorectomy ( P = 0.014) and in postmenopausal women who underwent bilateral oophorectomy more than 15 years before randomization ( P = 0.015). Moreover, the CIMT progression rate in hysterectomized women with ovarian conservation was 4.6 µm/y greater than natural menopause ( P = 0.015); in particular, compared with natural menopause, the association was significantly greater in postmenopausal women who underwent hysterectomy with ovarian conservation more than 15 years before randomization ( P = 0.018). CONCLUSIONS: Hysterectomy with bilateral oophorectomy and ovarian conservation were associated with greater subclinical atherosclerosis progression relative to natural menopause. The associations were stronger for later age and longer time since oophorectomy/hysterectomy. Further research should continue to examine long-term atherosclerosis outcomes related to oophorectomy/hysterectomy.

Quantitation of 5α-androstanedione in normal women and women with PCOS.

In vitro studies show that 5α-androstane-3,17-dione (5α-A) is an important intermediate in the formation of dihydrotestosterone (DHT) from androstenedione (A) in women and men. Many studies involving hyperandrogenism, hirsutism, and polycystic ovary syndrome (PCOS) have measured A, testosterone (T), and DHT, but not 5α-A due to lack of a readily available assay to quantify this androgen. We have developed a specific and sensitive radioimmunoassay to measure 5α-A levels, together with A, T, and DHT, in both serum and genital skin. The present study involves 2 cohorts. Cohort 1 included 23 mostly postmenopausal women who provided both serum and genital skin to measure those androgens. In cohort 2, serum androgen levels were compared between women with PCOS and non-PCOS controls. Tissue-to-serum ratios were significantly higher for 5α-A and DHT as compared to A and T. None of the androgens showed a significant correlation between serum and genital tissue. In serum, 5α-A was significantly correlated with A, T, and DHT. In cohort 2, A, T, and DHT were significantly higher in the PCOS group compared to the control group. In contrast, 5α-A levels were similar between the 2 groups. Our findings support the view that 5α-A is an important intermediate in DHT formation in genital skin. Also, the relatively low levels of 5α-A in PCOS women suggest that it may play a more important intermediate role in the conversion of A to androsterone glucuronide.

Postpartum Glucose Tolerance Testing Among Patients With Gestational Diabetes During the Coronavirus Disease 2019 Pandemic.

Introduction The impact of the coronavirus disease (COVID-19) COVID-19 pandemic on the care of pregnant patients with gestational diabetes (GDM) is largely unreported. The objective of this study was to compare the completion of postpartum oral glucose tolerance testing (GTT) prior to and during the COVID-19 pandemic among patients with GDM. Methods This was a retrospective review of patients diagnosed with GDM between April 2019 and March 2021. Medical records of patients diagnosed with GDM prior to and during the pandemic were compared. The primary outcome was the difference in the completion of postpartum GTT prior to and during the COVID-19 pandemic. Completion was defined as testing between four weeks to six months postpartum. Secondary objectives were: 1) to compare maternal and neonatal outcomes prior to and during the pandemic among patients with GDM, and 2) to compare pregnancy characteristics and outcomes by compliance with postpartum GTT. Results There were 185 patients included in the study, of whom 83 (44.9%) delivered prior to the pandemic and 102 (55.1%) delivered during the pandemic. There was no difference in completion of postpartum diabetes testing prior, compared to during the pandemic (27.7% vs 33.3%, p=0.47). Postpartum diagnosis of pre-diabetes and type two diabetes mellitus (T2DM) did not differ between groups (p=0.36 and p=1.00, respectively). Patients who completed postpartum testing were less likely to have preeclampsia with severe features compared to patients who did not (OR 0.08, 95% CI 0.01-0.96, p=0.02). Conclusion Completion of postpartum testing for T2DM remained poor prior to and during the COVID-19 pandemic. These findings underscore the need for the adoption of more accessible methods of postpartum testing for T2DM among patients with GDM.

Does male fertility-related quality of life differ when undergoing evaluation by reproductive urologist versus reproductive endocrinologist?

The female infertility experience is well-described, but the male experience is less explored. We sought to understand if fertility motivations and quality of life differ for males undergoing fertility evaluation by a reproductive urologist (RU) versus a reproductive endocrinologist (RE). A cross-sectional study of 201 males undergoing fertility evaluation at an academic centre, by either a RU or RE, over a 2-year period, was performed. A survey was administered, with demographic, medical, and fertility motivations questions, and the validated Fertility Quality of Life (FertiQoL) questionnaire. Responses were compared by provider type using descriptive statistics, chi-square, and t-test. Most men (91.1%) pursued evaluation because of a mutual desire for children. RE evaluated males were older, earned higher incomes, and were more likely to pursue IVF versus those RU evaluated (p < 0.05). Men evaluated by RUs had lower FertiQoL scores, (p < 0.05), which correlated with having known male factor infertility (p < 0.05). Nearly all (96.2%) men evaluated by RUs indicated this was helpful for understanding their infertility. Our findings provide new insight into the male fertility evaluation experience. Despite the lower QoL seen by men seeing a RU, nearly all men reported that a RU evaluation was helpful for understanding their infertility experience.

Changes in concentrations of cervicovaginal immune mediators across the menstrual cycle: a systematic review and meta-analysis of individual patient data.

BACKGROUND: Hormonal changes during the menstrual cycle play a key role in shaping immunity in the cervicovaginal tract. Cervicovaginal fluid contains cytokines, chemokines, immunoglobulins, and other immune mediators. Many studies have shown that the concentrations of these immune mediators change throughout the menstrual cycle, but the studies have often shown inconsistent results. Our understanding of immunological correlates of the menstrual cycle remains limited and could be improved by meta-analysis of the available evidence. METHODS: We performed a systematic review and meta-analysis of cervicovaginal immune mediator concentrations throughout the menstrual cycle using individual participant data. Study eligibility included strict definitions of the cycle phase (by progesterone or days since the last menstrual period) and no use of hormonal contraception or intrauterine devices. We performed random-effects meta-analyses using inverse-variance pooling to estimate concentration differences between the follicular and luteal phases. In addition, we performed a new laboratory study, measuring select immune mediators in cervicovaginal lavage samples. RESULTS: We screened 1570 abstracts and identified 71 eligible studies. We analyzed data from 31 studies, encompassing 39,589 concentration measurements of 77 immune mediators made on 2112 samples from 871 participants. Meta-analyses were performed on 53 immune mediators. Antibodies, CC-type chemokines, MMPs, IL-6, IL-16, IL-1RA, G-CSF, GNLY, and ICAM1 were lower in the luteal phase than the follicular phase. Only IL-1α, HBD-2, and HBD-3 were elevated in the luteal phase. There was minimal change between the phases for CXCL8, 9, and 10, interferons, TNF, SLPI, elafin, lysozyme, lactoferrin, and interleukins 1ß, 2, 10, 12, 13, and 17A. The GRADE strength of evidence was moderate to high for all immune mediators listed here. CONCLUSIONS: Despite the variability of cervicovaginal immune mediator measurements, our meta-analyses show clear and consistent changes during the menstrual cycle. Many immune mediators were lower in the luteal phase, including chemokines, antibodies, matrix metalloproteinases, and several interleukins. Only interleukin-1α and beta-defensins were higher in the luteal phase. These cyclical differences may have consequences for immunity, susceptibility to infection, and fertility. Our study emphasizes the need to control for the effect of the menstrual cycle on immune mediators in future studies.

Effect of menopausal hormone therapy on methylation levels in early and late postmenopausal women.

BACKGROUND: Cardiovascular disease (CVD) remains the leading cause of death among postmenopausal women but standard primary prevention strategies in women are not as effective as in men. By comparison, the Early versus Late Intervention Trial with Estradiol (ELITE) study demonstrated that hormone therapy (HT) was associated with significant reduction in atherosclerosis progression in women who were within six years of menopause compared to those who were 10 or more years from menopause. These findings are consistent with other studies showing significant reductions in all-cause mortality and CVD with HT, particularly when initiated in women younger than 60 years of age or within 10 years since menopause. To explore the biological mechanisms underlying the age-related atheroprotective effects of HT, we investigated changes in methylation of blood cells of postmenopausal women who participated in ELITE. RESULTS: We first validated the epigenetic data generated from blood leukocytes of ELITE participants by replicating previously known associations between smoking and methylation levels at previously identified CpG sites, such as cg05575921 at the AHRR locus. An epigenome-wide association study (EWAS) evaluating changes in methylation through interactions with time-since-menopause and HT revealed two significantly associated CpG sites on chromosomes 12 (cg19552895; p = 1.1 × 10-9) and 19 (cg18515510; p = 2.4 × 10-8). Specifically, HT resulted in modest, but significant, increases in methylation levels at both CpGs but only in women who were 10 or more years since menopause and randomized to HT. Changes in carotid artery intima-media thickness (CIMT) from baseline to 36 months after HT were not significantly correlated with changes in methylation levels at either cg19552895 or cg18515510. Evaluation of other previously identified CpG sites at which methylation levels in either blood or vascular tissue were associated with atherosclerosis also did not reveal any differences in methylation as a function of HT and time-since-menopause or with changes in CIMT. CONCLUSIONS: We identified specific methylation differences in blood in response to HT among women who were 10 or more years since menopause. The functional consequence of these change with respect to atherosclerosis progression and protective effects of HT remains to be determined and will require additional studies.

Effect of menopausal hormone therapy on arterial wall echomorphology: Results from the Early versus Late Intervention Trial with Estradiol (ELITE).

OBJECTIVE: To evaluate the effect of hormone therapy (HT) on arterial wall composition by ultrasound. BACKGROUND: The effect of HT on the progression of subclinical atherosclerosis has been well-described using measurements of common carotid artery (CCA) wall thickness. However, it is unknown whether the change in arterial wall anatomic structure is accompanied by an effect of HT on arterial wall composition. METHODS: A total of 643 healthy postmenopausal women divided into two strata according to the time since menopause (<6 years, the early-postmenopause group; or >10 years, the late-postmenopause group) were randomized to receive either active treatment or placebo. For hysterectomized women, the active treatment was oral micronized 17ß-estradiol 1 mg/day; for women with a uterus, 4% vaginal micronized progesterone gel 45 mg/day for 10 days each month was added to the estradiol regimen. Gray-scale median of the CCA intima-media complex (IM-GSM), a (unitless) measurement of arterial wall composition based on echogenicity, was determined by high-resolution B-mode ultrasonography. Lower IM-GSM, or less echogenicity, indicates more atherosclerosis. IM-GSM and serum estradiol (E2) concentration were assessed every 6 months over a median 4.8-year trial period. Linear mixed effects regression models were used for all analyses. RESULTS: Overall, IM-GSM progression/year had a negative trajectory, reflecting reduction in echogenicity over time (worsening atherosclerosis). HT effects on IM-GSM progression/year differed by postmenopause strata (interaction p-value = 0.02). IM-GSM progression/year (95% CI) in the early postmenopause group randomized to HT was -0.50 (-0.82, -0.18)/year compared with -1.47 (-1.81, -1.13)/year among those randomized to placebo (p-value <0.0001). In the late postmenopause group, the annual IM-GSM progression rate did not significantly differ between HT and placebo (p = 0.28). Higher mean on-trial E2 (pg/ml) levels were associated with higher IM-GSM progression, indicating less atherosclerosis progression in all women (ß (95% CI) = 0.006 (0.0003, 0.01), p = 0.04). For each pg/dl E2, IM-GSM progression/year was 0.007 ((-0.0002, 0.01), p = 0.056) in the early and 0.003 ((-0.006, 0.01), p = 0.50) in the late postmenopause group (interaction p-value = 0.51). CIMT progression rate (µm/year) was significantly inversely associated with the IM-GSM progression (ß (95% CI) = -4.63 (-5.6, -3.7), p < 0.001). CONCLUSIONS: HT, primarily with oral estradiol, reduced atherogenic progression of arterial wall composition in healthy postmenopausal women who were within 6 years from menopause. TRIAL REGISTRATION NUMBER: NCT01553084.

A Systematic Review and Meta-Analysis of Smoking and Circulating Sex Hormone Levels Among Premenopausal Women.

INTRODUCTION: It is established that higher prediagnostic circulating androgen and estrogen levels are associated with increased breast cancer risk in premenopausal and postmenopausal women. Pooled analyses in postmenopausal women report higher androgen and estrogen levels in current heavy cigarette smokers compared to nonsmokers. However, evidence among premenopausal women has been inconsistent. AIMS AND METHODS: We conducted a systematic review and meta-analysis to estimate differences in standardized mean hormone levels among current premenopausal smokers compared to nonsmokers. We reviewed and collated publications with sex hormone levels by smoking status among healthy, premenopausal women who were nonusers of exogenous hormones, including oral contraceptives, using PubMed through December 2019. A random effects meta-analysis was conducted to combine the standardized mean differences (SMD) and 95% confidence intervals (CIs) for estradiol, progesterone, testosterone, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and sex hormone-binding globulin by smoking status. Findings were summarized by menstrual cycle phase and overall. RESULTS: Nineteen published peer-reviewed articles were included. Significantly increased testosterone levels among smokers compared to nonsmokers were identified from cross-sectional studies with varied menstrual phase timing (SMD 0.14; 95% CI 0.0005, 0.29) and significantly increased dehydroepiandrosterone-sulfate levels were found over all phases (SMD 0.12; 95% CI 0.01, 0.22). However, substantial heterogeneity existed in these studies. CONCLUSIONS: This meta-analysis suggests that smoking may increase blood androgen levels in healthy premenopausal women which may increase breast cancer risk; however, the differences were modest. Larger and covariate-adjusted studies with standardized collection over the menstrual cycle are needed to better understand this relationship and to reduce heterogeneity. IMPLICATIONS: Existing research has described associations between high prediagnostic estradiol and androgen levels with breast cancer risk among premenopausal women and has established active smoking as a breast cancer risk factor. However, the smoking and circulating sex hormone associations among premenopausal women remain inadequately studied. In this meta-analysis, we identified an association between smoking and higher mean testosterone and dehydroepiandrosterone-sulfate levels with consideration of menstrual phase, providing additional information on smoking's potential pathway to premenopausal breast cancer.

Concentrations of endogenous sex steroid hormones and SHBG in healthy postmenopausal women.

Studies reporting age-specific reference ranges of endogenous sex steroid hormones in postmenopausal women are relatively scarce. If levels differ by age, dosing and treatment regimens should vary among postmenopausal women accordingly. Our objective was to establish reference ranges for sex steroid hormones and sex hormone binding globulin (SHBG) by age group and overall, and to investigate their association with demographic characteristics. Serum samples were obtained from 1207 healthy postmenopausal women aged 41-92, not using hormone therapy, at the baseline visit of 3 clinical trials. Estrone (E1), estradiol (E2), and total testosterone (T) were measured by radioimmunoassay with preceding purification steps; SHBG was measured by direct chemiluminescent immunoassay. Free T (FT) was calculated. Women were categorized by 5-year age groups. There was little change in the mean estrogen levels among the different age groups (E2: 9-12 pg/mL; E1: 33-35 pg/mL). Mean total T levels increased gradually with age from 19.9-26.2 ng/dL, but FT mean levels were relatively constant (3.7-4.6 pg/mL). Mean SHBG levels increased with age from 43-68 nmol/L. A generalized linear model tested the association of each demographic characteristic with the hormones and SHBG. A significant association was derived. Our study provides valuable insight into the profiles of serum sex steroid hormones and SHBG in different healthy postmenopausal women aged 41-92 years.

Use of oral estradiol plus vaginal progesterone in healthy postmenopausal women.

OBJECTIVES: To compare the effect of oral estradiol (E2) plus vaginal progesterone (P4) against placebo on endometrial thickness, endometrial biopsy pathology, cervical cytology and total cancer incidence among healthy postmenopausal women. STUDY DESIGN: This study is a sub-analysis of the Early versus Late Intervention Trial with Estradiol (ELITE), a randomized, double-blinded, placebo-controlled trial that previously demonstrated that hormone therapy (HT) was associated with less progression of subclinical atherosclerosis than placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. This sub-analysis included only ELITE participants with an intact uterus, who were randomized to either daily oral micronized 17-beta-E2 1 mg/day with 4% vaginal micronized P4 gel 45 mg/day for 10 days each month or placebo. MAIN OUTCOME MEASURES: Participants were evaluated at baseline and annually during a median follow-up of 4.8 years for endometrial thickness as determined by pelvic transvaginal ultrasound followed by an endometrial biopsy when indicated, and cervical cytology and cancer incidence. RESULTS: Over up to 80 months of follow-up, participants randomized to oral E2 plus vaginal P4 had progressive and statistically significant increases in endometrial thickness (p<0.001), underwent more endometrial biopsies and had a higher rate of endometrial hyperplasia on endometrial biopsy compared with the placebo group. Due to the close follow-up of participants in the trial protocol, these abnormal findings were effectively treated. CONCLUSION: Our results suggest that 10 days of vaginal P4 45 mg/day is insufficient to completely oppose the effect of oral E2 1 mg/day on the endometrium. Further studies are needed to test alternative doses or frequencies of administration of vaginal P4 for adequate endometrial protection from E2 therapy among postmenopausal women. ClinicalTrials.gov registration NCT00114517.

Does timing matter when initiating elagolix in a natural menstrual cycle?

OBJECTIVE: To investigate the efficacy of elagolix when administered at different time points in a menstrual cycle. DESIGN: Clinical case series. SETTING: Academic reproductive endocrinology center. PATIENTS: Ovulatory women not desiring pregnancy. INTERVENTIONS: Six doses of elagolix 200 mg were administered over 4 days, starting at 3 different points in a menstrual cycle: early follicular; late follicular; and midluteal. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and progesterone (P) concentrations were measured at baseline, during elagolix administration, and 1 day after the last dose. Transvaginal ultrasounds were performed to monitor follicle sizes. MAIN OUTCOME MEASURES: Serum FSH, LH, E2, and P. RESULTS: Twelve women, four per group, completed the study. Subjects were 23-42 years of age. Demographics and ovarian reserve parameters were similar among participants. Elagolix suppressed FSH, LH, E2, and P when administered in the early follicular and midluteal phases but had mixed results when administered in the late follicular phase. Two participants demonstrated suppression of all four hormones. One participant ovulated, indicated by an increase in P concentration and development of a corpus luteum. A second participant did not ovulate yet demonstrated an increase in E2 concentration with growth of a dominant follicle. There were no significant differences in median percent change of hormone concentrations across study groups. CONCLUSIONS: The results of this study suggest that elagolix can suppress the hypothalamic-pituitary-ovarian axis when initiated at different points in a menstrual cycle. Optimal dosing and treatment window for consistent hormone suppression have yet to be determined. CLINICAL REGISTRATION NUMBER: NCT04060992.

Association of bioavailable inhibin B and oocyte yield in controlled ovarian stimulation.

OBJECTIVE: To determine if the biologically active or bioavailable inhibin B (bio-inhB) correlated with the oocyte yield in controlled ovarian stimulation (COS). DESIGN: Cross-sectional study. SETTING: Academic center. PATIENTS: Women undergoing oocyte cryopreservation. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Serum of women were sampled to measure bio-inhB at three points: baseline ("start"); middle ("mid"); and end of COS. A validated, highly specific enzyme-linked immunosorbent assay (Ansh Labs, Webster, TX) measured bio-inhB. The Spearman tests analyzed correlations between bio-inhB and other ovarian reserve markers, including age, follicle-stimulating hormone (FSH), antral follicle count (AFC), and antimüllerian hormone (AMH), and correlations between these markers and oocyte yield. RESULTS: A total of 144 women were included. Bioavailable inhibin B at the mid and end of COS, plus its delta, were strongly correlated with other ovarian reserve markers. As the bio-inhB concentration increased, the AFC and AMH levels also increased, whereas the FSH concentration and age decreased. Bioavailable inhibin B values, except at the start of COS, were more strongly correlated with oocyte yield than the FSH concentration (r = 0.72-0.82 vs. r = -0.44) and correlated similarly to the AFC and AMH concentration (r = 0.79 and 0.81, respectively). These correlations strengthened in those with diminished ovarian reserve, specifically age ≥35 years or AMH concentration <2 ng/mL (r = 0.71-0.86 vs. r = 0.49-0.67). CONCLUSIONS: Predicting COS outcome is imperfect. When using a highly specific enzyme-linked immunosorbent assay, bio-inhB correlated with the oocyte yield similar to or more strongly than traditionally used ovarian reserve markers. These correlations strengthened in cases of diminished ovarian reserve. Bioavailable inhibin B provides physicians with an additional clinical tool for estimating COS outcome.

Effect of oral contraceptives on total and bioavailable 25-hydroxyvitamin D.

Studies show an increase in circulating levels of 25-hydroxyvitamin D [25(OH)D] in women using combined oral contraceptives (COCs). 25(OH)D is a quantitatively important metabolite and widely used clinical marker of vitamin D status and is regulated by vitamin D binding protein (VDBP). However, studies have not identified the type of formulations used by the women, and there are no data on the effect of progestins on 25(OH)D levels. Our study objective was to compare the effects of two COC formulations [ethinyl estradiol (EE)/norethindrone acetate (NETA) vs. EE/levonorgestrel (LNG)] as well as LNG alone on total and bioavailable (free plus albumin-bound) 25(OH)D levels in serum samples collected at baseline, mid treatment, and end of treatment. Total 25(OH)D and VDBP were measured by immunoassay, and bioavailable 25(OH)D was calculated. The results show that with the EE/NETA formulation, total and bioavailable 25(OH)D and VDBP levels increased non-significantly by 7.4 %, 14.9 %, and 10 %, respectively, from baseline to end of treatment. In contrast, the corresponding changes with EE/LNG showed an increase of 4.4 % in total 25(OH)D but a significant decrease of 18.2 % in bioavailable 25(OH)D and increase of 19.1 % in VDBP. When LNG was administered alone, no significant changes were observed in total and bioavailable 25(OH)D or VDBP levels during the course of treatment. Our findings show considerably different effects on total and bioavailable 25(OH)D levels, as well as VDBP levels, with different oral contraceptive formulations. LNG may have a suppressive effect on VDBP, similar to its well-known androgenic effect on SHBG. Further studies are needed to determine the effect of hormonal contraceptive formulations on vitamin D status and its potential impact on women's health.

Factors Associated With Serum Estradiol Levels Among Postmenopausal Women Using Hormone Therapy.

OBJECTIVE: To identify factors associated with serum estradiol (E2) levels among healthy postmenopausal women using hormone therapy (HT). METHODS: This is an unplanned post hoc analysis of data from ELITE (Early versus Late Intervention Trial with Estradiol), a randomized controlled trial of 1 mg oral E2 with or without vaginal progesterone in healthy early compared with late (<6 years compared with 10 or more years since menopause) postmenopausal women. We included results from visits when women reported at least 80% compliance with HT. Mixed-effects linear models identified factors associated with serum E2 levels while participants were taking HT, assessed every 6 months over a median follow-up of 4.8 years and adjusted for baseline E2 level, visit, and reduced E2 dose. Possible correlates evaluated included demographics, clinical characteristics, medication use, and biomarkers of liver and kidney metabolic function. RESULTS: The analysis included 2,160 E2 measurements in 275 postmenopausal women. Mean±SD age was 55.4±3.9 vs 64.4±5.5 years, and mean±SD time since menopause was 3.6±1.8 vs 16.0±5.6 years for early vs late postmenopausal women. Adjusted for pretreatment E2 level, visit, and reduced dose indicator, higher serum E2 levels were associated with higher body mass index (BMI), higher weight, surgical menopause, alcohol use, and antihypertensive medication use. Current and past smoking and antifungal medication use were associated with lower serum E2 levels. In the multivariable model, higher BMI and alcohol use were associated with higher serum E2 levels, whereas current and past smoking were associated with lower serum E2 levels. These factors were similar between early and late postmenopausal women. CONCLUSION: Factors associated with serum E2 levels among postmenopausal women taking HT include BMI, alcohol use, and smoking. As serum E2 levels relate to HT effect, achievement of desirable E2 levels may be maximized through personalized intervention. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00114517.

Effects of Estradiol Dose and Serum Estradiol Levels on Metabolic Measures in Early and Late Postmenopausal Women in the REPLENISH Trial.

Background: To identify the association of estradiol (E2) dose and serum E2 levels with metabolic measures in early (<6 years) compared with late (≥10 years) postmenopausal women from the REPLENISH trial. Material and Methods: This is a post hoc analysis of a multicenter randomized clinical trial in the United States. Four doses of TX-001HR, an oral combination of E2 and progesterone (P4), and placebo were tested. This analysis included a total of 1,216 early and 297 late postmenopausal women. Linear mixed-effects models tested the association of E2 dose and serum E2 levels with changes in metabolic parameters; total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and glucose (GLUC) levels from six visits over 12 months, adjusted for the serum P4 level. Results: A higher E2 dose was significantly associated with lower TC (p = 0.02) and LDL-C (p = 0.002) and higher HDL-C (p = 0.04) levels in early, but not late, postmenopause. With longer time since menopause, the inverse association of E2 dose with TC and LDL-C and positive association with HDL-C were attenuated (interaction p < 0.05). Higher serum E2 levels were significantly associated with lower TC (p = 0.004), LDL-C (p = 0.0001), and fasting blood GLUC (p = 0.003) and higher TG (p = 0.002) levels in early postmenopause. Conclusion: E2 dose differentially affects metabolic measures among early compared with late postmenopausal women. No significant main effect of the serum P4 level was found. As the metabolic parameters studied are risk factors for cardiovascular events, these results support the timing hypothesis of E2 therapy and its cardiovascular benefits.