Cedars, Marcelle I.

Background With improvements in in vitro culture techniques, there has been a steady shift in practice to transfer in vitro fertilisation (IVF) embryos at the blastocyst-stage to increase pregnancy rates per embryo transfer (ET) and reduce the risk of multiple pregnancy. In patients with fewer embryos (≤5 zygotes), fresh cleavage-stage ET is still commonly performed to reduce the risk of cycle cancellation if no embryo survives to the blastocyst-stage in vitro. However, evidence for improved outcomes with cleavage-stage embryo transfer in this subgroup of patients is lacking. We will compare blastocyst-stage to cleavage-stage ET with regard to cumulative live birth rates (CLBR) per oocyte retrieval and other patient-centred cycle outcomes in patients with ≤5 zygotes. Methods and analysis Multicentre, randomised pragmatic comparative effectiveness trial with superiority design comparing blastocyst-stage to cleavage-stage ET in patients with ≤5 zygotes. This trial will enrol and randomise 1126 women aged 18–44 undergoing IVF to either fresh cleavage-stage or blastocyst-stage ET at eleven IVF centres. Surplus embryos will be vitrified at the blastocyst-stage. The primary outcome is the CLBR per oocyte retrieval. Secondary outcomes include: multiple pregnancy, pregnancy loss <20 weeks and cycle cancellation. Exploratory outcomes include: live birth per fresh ET, ectopic pregnancy, time to pregnancy, stillbirth, preterm birth, financial burden, patient distress and facilitators and barriers for patient involvement and implementation. All primary analyses will be conducted according to the intent-to-treat principle. We also will report per-protocol analyses as a sensitivity analysis. A multidisciplinary stakeholder team, including a 5-patient stakeholder panel, will participate in study design, conduct and oversight. Ethics and dissemination The Institutional Review Board at Beth Israel Deaconess Medical Center (BIDMC) provides central regulatory oversight. Results will inform timing of embryo transfer in patients with ≤5 zygotes and will be disseminated through academic publications, meeting presentations and communications to advocacy groups and patient participants. Trial registration number NCT06746129 .

Abstract INTRODUCTION Associations of short‐term use of menopausal hormone therapy (mHT) with Alzheimer's disease (AD) and structural magnetic resonance imaging (MRI) biomarkers were investigated 10 years after an mHT trial. METHODS Recently menopausal women with good cardiovascular health were randomized to oral conjugated equine estrogens (oCEE) or transdermal 17β‐estradiol (tE2) and micronized progesterone, or placebo for 4 years. Amyloid beta (Aβ) on positron emission tomography, hippocampal atrophy, and dorsolateral prefrontal cortex thickness on MRI were assessed 10 years after completion of the mHT trial ( n = 266). RESULTS Aβ and structural MRI biomarkers were not different in the oCEE and tE2 groups compared to placebo. Apolipoprotein E ε4 status did not modify the findings. DISCUSSION There was no evidence of adverse effects or benefits associated with 4 years of use of oral or transdermal mHT on Aβ and structural MRI biomarkers in relatively healthy women, 10 years after mHT. Findings support the long‐term safety of short‐term use of mHT on brain health. CLINICAL TRIALS REGISTRATION NCT00154180 Kronos Early Estrogen Prevention Study (KEEPS) Highlights There were no menopausal hormone therapy–related adverse effects or benefits on amyloid beta and magnetic resonance imaging biomarkers in the long term. Apolipoprotein E ε4 carrier status did not modify these findings. Findings align with neutral cognitive and cerebrovascular outcomes in this cohort.

Objective: To determine associations between central adiposity, cognitive function, and randomized menopausal hormone therapy (MHT) in a reanalysis of the Kronos Early Estrogen Prevention Study-Cognitive and Affective (KEEPS-Cog) sub-study participants. Methods: KEEPS randomized 727 women (ages 42-58) who were <36 months postnatural menopause to oral conjugated equine estrogens (o-CEE), transdermal 17-β-estradiol (t-E2), or placebo for 48 months. Participants with diabetes, body mass index >35 kg/m 2 , coronary artery calcium score >50 Agatston Units, and other cardiometabolic disease risk indicators were excluded from enrollment. In the ancillary KEEPS-Cog study, cognitive tests were completed at baseline, 18-, 36-, and 48-month post-randomization. In these analyses, cognitive variables were summarized as four cognitive domain-specific factor scores: verbal learning and memory, auditory attention and working memory, visual attention and executive function, and speeded language and mental flexibility. Waist-hip-ratio (WHR), an indicator of central adiposity, was measured at screening (baseline) and modeled as a covariate in linear latent growth models assessing associations of MHT with cognitive functions at baseline and over time. Results: Higher baseline WHR was associated with poorer performance on all domain-specific cognitive outcomes at baseline and with changes in visual attention and executive function across time. Models including interaction effects were not significant for either o-CEE x WHR or t-E2 x WHR. Conclusion: Central adiposity is a risk factor for domain-specific cognitive decline, and thus, cognitive health effects should be investigated in early postmenopausal women, even in women with low cardiovascular risk statuses.

Objectives: To assess the long-term effects of 4 years of menopausal hormone therapy (mHT) on the brain’s white matter architecture in women who initiated mHT within 3 years of menopause onset. Methods: The Kronos Early Estrogen Prevention Study (KEEPS) was a multicenter, double-blind, randomized, placebo-controlled 4-year mHT trial with treatment arms of oral conjugated equine estrogens (oCEE), transdermal 17β-estradiol (tE2), and placebo in recently postmenopausal women. KEEPS Continuation was an observational follow-up of KEEPS participants. White matter integrity was evaluated in KEEPS Continuation participants 10 years after KEEPS completion using white matter hyperintensity volume, diffusion magnetic resonance imaging (dMRI) techniques, and cerebral infarcts. Linear regression models were fitted for each brain region to evaluate if there were differences in white matter between KEEPS treatment arms. Results: There was no evidence to suggest the long-term effects of 4 years of mHT on brain white matter in KEEPS Continuation participants [n=266, mean age 67 (58-73)]. No differences in dMRI metrics were found in each of the treatment arms (oCEE n=70; tE2 n=79) when compared to placebo (n=94), following a false discovery rate adjustment for multiple comparisons. There were no statistically significant differences in white matter hyperintensity volume or infarct occurrence when comparing each of the treatment arms to placebo. Conclusions: We found no evidence of the long-term effect of 4-year mHT on white matter integrity when compared to placebo, consistent with emerging evidence of the safety of short-term use of mHT in recently postmenopausal women.

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

Abstract STUDY QUESTION How should premature/primary ovarian insufficiency (POI) be diagnosed and managed based on the best available evidence from published literature? SUMMARY ANSWER The current guideline provides 145 recommendations on symptoms, diagnosis, causation, sequelae, and treatment of POI. WHAT IS KNOWN ALREADY Premature ovarian insufficiency (POI) presents a significant challenge to women’s health, with far-reaching implications, both physically and emotionally. The potential implications include adverse effects on quality of life; fertility; and bone, cardiovascular, and cognitive health. Although hormone therapy (HT) can mitigate some of these effects, many questions still remain regarding the optimal management of POI. STUDY DESIGN, SIZE, DURATION The guideline was developed according to the structured methodology for development of ESHRE guidelines. Key questions were determined by a group of experts and informed by a scoping survey of women and health care professionals. Literature searches and assessments were then performed. Papers published up to 30 January 2024 and written in English were included in the guideline. An integrity review was conducted for the randomized controlled trials (RCTs) on POI included in the guideline. PARTICIPANTS/MATERIALS, SETTING, METHODS Based on the collected evidence, recommendations were formulated and discussed within the guideline development group until consensus was reached. Women with lived experience of POI informed the recommendations in general, and particularly on those on provision of care. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline development group and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE New data indicate a higher prevalence of POI, 3.5%, than was previously thought. This guideline aims to help health care professionals to apply best practice care for women with POI. The recent update of the POI guideline covers 40 clinical questions on diagnosis of the condition, the different sequelae, including bone, cardiovascular, neurological and sexual function, fertility and general well-being, and treatment options, including HT. The list of clinical questions was expanded from the previous iteration of the guideline (2015) based on the scoping survey and appreciation of emerging knowledge of POI. Questions were added on the role of anti-Müllerian hormone (AMH) in the diagnosis of POI, fertility preservation, muscle health, and specific considerations for HT in iatrogenic POI. Additionally, the topic on complementary treatments was extended with specific focus on non-hormonal treatments and lifestyle management options. Significant changes from the previous 2015 guideline include the recommendations that only one elevated FSH &gt;25 IU is required for diagnosis of POI, and guidance that AMH testing, repeat FSH measurement, and/or AMH may be required where there is diagnostic uncertainty. Recommendations were also updated regarding genetic testing, estrogen doses and regimens, use of the combined oral contraceptive and testosterone therapy. Women with lived experience of POI informed the recommendations on provision of care. LIMITATIONS, REASONS FOR CAUTION The guideline describes different management options, but it must be acknowledged that for most of these options, supporting evidence is limited for POI. WIDER IMPLICATIONS OF THE FINDINGS The guideline provides health care professionals with clear advice on best practice in POI care, based on the best evidence currently available. In addition, a list of research recommendations is provided to guide further studies in POI. STUDY FUNDING/COMPETING INTEREST(S) The guideline was developed and funded by ESHRE, American Society for Reproductive Medicine (ASRM), Centre for Research Excellence in Women's Health in Reproduction Life (CRE-WHiRL), and International Menopause Society (IMS), covering expenses associated with the guideline meetings, literature searches, and dissemination of the guideline. The guideline group members did not receive payments. N.P. declared grants from Bayer Pharma (research and consultancy) and NIHR—research POISE; consulting fees from Abbott, Astellas, Bayer, Besins, Lawley, Mithra, Theramex, Viatris; honoraria from Astellas, Bayer, Besins, Gedeon Richter, Theramex, Viatris; support for attending meetings and/or travel from Astellas, Bayer, Theramex, Viatris; President, International Menopause Society, Medical Advisory Committee member, British Menopause Society, Patron Daisy Network. A.J.V. declared grants from Amgen Australia, Australian NHMRC, and Australian MRFF; consulting fees from IQ Fertility; honoraria from the Australasian Menopause Society; participation on a Data Safety Monitoring Board or Advisory Board of Astellas; Board Member of the International Menopause Society (2020 to current) and Past president of the Australasian Menopause Society (2017–2019); R.A.A. declared grants from Roche (Research support, to institution), and participation on a Data Safety Monitoring Board of Bayer. M.C. declared grants from NHI; payments or honoraria from Up-to-Date (as editor/reviewer); Board Member of American Society of Reproductive Medicine, and of American Gynecological and Obstetrical Society. M.D. declared (NIHR—HTA Reference Number: NIHR133461; NIHR—HTA Reference Number: NIHR128757; Action Medical Research and Borne: GN2818) consulting fees from a small personal medical practice, support for attending meetings and/or travel from ESHRE, Bayer and UCLH special Trustees; Participation on the Advisory Board of the British Menopause Society, UKSTORE project, the Progress Educational Trust, and the Turner Syndrome Support Society UK; Leadership or fiduciary roles in the British Fertility Society (Trustee), Elizabeth Garrett Anderson Hospital Charity (chair of Trustees), and the Essex Wynter charitable trust (Trustee). C.E. declared being Chair of a SIG from the Royal Australian College of General Practitioners Integrative Medicine Specific Interest Group and Program Lead for Next Practice Western Sydney Integrative Health. C.H.G. declared grants from Novo Nordisk Foundation (Nos. NNF15OC0016474 and NNF20OC0060610), sygesikringen danmark (No 2022-0189), and the Independent Research Fund Denmark (Nos. 0134-00406 and 0134-00130B); consulting fees from Novo Nordisk, Merck, and Astra Zeneca. S.K. declared grants from Roche diagnostics. A.K. declared grants from NIH R01 5R01HD101475; consulting fees as Medical Reviewer for Flo and for Healthline; honoraria as Medical Consultant for Summus; support for attending meetings from the Reproductive Scientist Development Program; Society for Reproductive Investigation Council Member and Society for Assisted Reproduction Registry/Validation Chair; R.E.N. declared consulting fees from Astellas, Bayer Pharma, Besins Healthcare, Fidia, Theramex; honoraria from Abbott, Astellas, Exeltis, Fidia, Gedeon Richter, Merck & Co, Novo Nordisk, Shionogi Limited, Theramex, Viatris; payment for expert testimony from Vichy Laboratories; Participation in Data Safety Monitoring Board of Advisory board from Astellas and Bayer Healthcare; President elect of the International Menopause Society (IMS). H.T. declared a grant from NHMRC Centre for Research Excellence for women’s health in reproductive life. A.B. declared being chair of the Daisy Network Charity. The other authors have no conflicts of interest to declare. DISCLAIMER This guideline represents the views of ESHRE, ASRM, CRE-WHiRL, and IMS, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgement to each individual presentation, nor variations based on locality and facility type. The collaborating societies make no warranty, expressed or implied, regarding the clinical practice guidelines and specifically exclude any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.)

Abstract Premature ovarian insufficiency (POI) presents a significant challenge to women's health, with significant implications both physically and emotionally. Despite its life-altering impact, there remain substantial unknowns in the causes this condition and how to optimally manage its various sequelae While such unknows provide direction for future research, they also underscore the need for clinical guidance. In 2015, under the auspices of ESHRE, a group of experts evaluated the existing best evidence and published the first European guideline on the management of premature ovarian insufficiency. The update of this Guideline was performed in an international collaboration of experts representing American Society for Reproductive Medicine (ASRM), International Menopause Society (IMS), and the Centre for Research Excellence in Women’s Health in Reproductive Life (CRE WHiRL). The recent update of the POI guideline covers 40 clinical questions on diagnosis of the condition, the different sequelae, including musculoskeletal health, cardiovascular health, neurological health, sexual function and general well being, and treatment options, including hormone therapy. The list of clinical questions was expanded from the questions included in the guideline from 2015. Based on a scoping survey and appreciation of emerging knowledge of POI, questions were added on the role of AMH in the diagnosis of POI, fertility preservation, muscle health, and specific considerations for hormone treatment in iatrogenic POI. Additionally, the topic on complementary treatments was extended with specific focus on non-hormonal treatments and lifestyle management options. The draft guideline published for stakeholder review includes a total of 142 recommendations. One third of these recommendations were formulated as good practice points. Of the evidence-based recommendations, almost 80% were formulated as strong recommendations, even if the evidence base for most evidence-based recommendations was limited to observational data (level very low or low), supporting a call for future research. The guideline group hope that the new POI Guideline will improve the clinical management of this devastating condition.

AbstractBackgroundHigher blood pressure (BP) is associated with greater white matter hyperintensity (WMH) volume, but research is limited in recently menopausal and postmenopausal women. Postmenopausal women have a greater burden of WMH than men and premenopausal women, but whether hormone therapy (HT) modifies the association between systolic and diastolic BP (SBP, DBP) and WMH is unknown. We investigated the association of SBP and DBP in recently postmenopausal women who participated in an HT trial with WMH volumes measured 14 years later and explored whether HT modified the results.MethodWomen with good cardiovascular (CV) health, who were previously enrolled in a randomized placebo‐controlled HT trial, the Kronos Early Estrogen Prevention Study (KEEPS), participated in the current observational KEEPS continuation (n = 212; median age = 67; range 58‐72). SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59) and continuation. Antihypertensive users were excluded (baseline, n = 34; continuation, n = 61). Approximately 10 years after the end of KEEPS HT versus placebo 4‐year interventions, automated WMH volumes were measured from 3D‐FLAIR MRI. Associations of KEEPS baseline and continuation SBP and DBP with log WMH volume at KEEPS continuation were tested using linear regression analyses adjusting for covariates in model 1 (age, total intracranial volume, study site) and model 2 (model 1 plus cardiovascular risk factors (CVRF)).ResultHigher KEEPS baseline SBP and DBP were associated with greater WMH volume measured 14 years later, and after adjusting for CVRF (p≤0.01). Similarly, in KEEPS continuation, higher SBP and DBP were associated with greater WMH volume measured concurrently and after adjusting for CVRF (p<0.001). We did not find statistically significant evidence that HT versus placebo modified these associations. Topographically, higher SBP and DBP were associated with greater periventricular WMH in the frontal and parietal lobes after adjusting for age (Figure).ConclusionHigher SBP and DBP in recently menopausal women with good CV health were associated with greater WMH volumes more than a decade later after adjusting for CVRF, independent of randomization to HT. Our results show the importance of blood pressure control in recently menopausal women, that may reduce the white matter injury later in life.

AbstractBackgroundHigher blood pressure (BP) is associated with greater white matter hyperintensity (WMH) volume, but research is limited in recently menopausal and postmenopausal women. Postmenopausal women have a greater burden of WMH than men and premenopausal women, but whether hormone therapy (HT) modifies the association between systolic and diastolic BP (SBP, DBP) and WMH is unknown. We investigated the association of SBP and DBP in recently postmenopausal women who participated in an HT trial with WMH volumes measured 14 years later and explored whether HT modified the results.MethodWomen with good cardiovascular (CV) health, who were previously enrolled in a randomized placebo‐controlled HT trial, the Kronos Early Estrogen Prevention Study (KEEPS), participated in the current observational KEEPS continuation (n = 212; median age = 67; range 58‐72). SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59) and continuation. Antihypertensive users were excluded (baseline, n = 34; continuation, n = 61). Approximately 10 years after the end of KEEPS HT versus placebo 4‐year interventions, automated WMH volumes were measured from 3D‐FLAIR MRI. Associations of KEEPS baseline and continuation SBP and DBP with log WMH volume at KEEPS continuation were tested using linear regression analyses adjusting for covariates in model 1 (age, total intracranial volume, study site) and model 2 (model 1 plus cardiovascular risk factors (CVRF)).ResultHigher KEEPS baseline SBP and DBP were associated with greater WMH volume measured 14 years later, and after adjusting for CVRF (p = 0.01). Similarly, in KEEPS continuation, higher SBP and DBP were associated with greater WMH volume measured concurrently and after adjusting for CVRF (p<0.001). We did not find statistically significant evidence that HT versus placebo modified these associations. Topographically, higher SBP and DBP were associated with greater periventricular WMH in the frontal and parietal lobes after adjusting for age (Figure).ConclusionHigher SBP and DBP in recently menopausal women with good CV health were associated with greater WMH volumes more than a decade later after adjusting for CVRF, independent of randomization to HT. Our results show the importance of blood pressure control in recently menopausal women, that may reduce the white matter injury later in life.