Ep. 1: Genetic and Hormonal Components of Sex Differences in Alzheimer's Disease

September 10, 2024

In the kickoff episode of the 2024 Women's Health Series, Dr. Rachel Buckley, Associate Professor of Neurology at Massachusetts General Hospital, presents her research on sex differences in Alzheimer's disease risk, showing across multiple independent cohorts that women exhibit elevated levels of tauopathy in the brain relative to men even as they are often underdiagnosed with dementia due to outperforming men on many neuropsychological tests. She explores whether sex steroid hormones and the X chromosome help drive these differences, and closes by making the case for sex disaggregation in observational research and clinical trials, outlining a working framework for where the field stands and the gaps that remain.

Key Highlights

• Dr. Buckley's work has consistently shown, across many independent cohorts, that women exhibit elevated levels of tauopathy in the brain relative to men.
• Women are frequently underdiagnosed with dementia because they tend to perform better than men on many neuropsychological tests, masking underlying pathology.
• Buckley examines whether sex steroid hormones and the X chromosome moderate Alzheimer's disease risk, and argues for sex disaggregated findings in both observational research and clinical trials.

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Ep. 2: Metabolic Mechanisms that Contribute to Pregnancy-Induced Cardiac Growth and its Reversal

October 16, 2024

Dr. Helen E. Collins, Assistant Professor in the Division of Environmental Medicine at the University of Louisville's Center for Cardiometabolic Science, addresses the rising maternal mortality crisis in the United States, where cardiovascular disease is the leading cause of death and pregnancy-related cardiovascular complications raise both all-cause and cardiovascular mortality in women later in life. Using multi-omics approaches, her NIH-funded laboratory examines the metabolic mechanisms driving pregnancy-induced cardiac growth and its reversal, including the contributions of ancillary biosynthetic pathways of glucose metabolism that supply building blocks for cardiac growth and the role of myocardial ketone body metabolism in sustaining mitochondrial energetics in the maternal heart. Dr. Collins also reviews the cardiovascular adaptations that occur during a healthy pregnancy alongside the risk factors for pregnancy-associated cardiovascular disease.

Key Highlights

• Maternal mortality rates in the United States are at an all-time high and continue to rise, with cardiovascular disease as the leading cause of death.
• Dr. Collins' NIH-funded research uses multi-omics approaches to identify the metabolic mechanisms, including ancillary biosynthetic pathways of glucose metabolism, that contribute to pregnancy-induced cardiac growth.
• Her lab has also identified myocardial ketone body metabolism as a key contributor to maintaining mitochondrial energetics in the maternal heart during pregnancy-induced cardiac growth and its reversal.

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Ep. 3: Effects of Ovarian Failure on Muscle Form and Function

October 29, 2024

Parastoo Mashouri, MSc, a PhD candidate in Human Health and Nutritional Sciences at the University of Guelph, uses the VCD (4-vinylcyclohexene diepoxide) model of chemically induced ovarian failure, which mimics the gradual, time-course nature of menopause more closely than the traditional ovariectomy (OVX) model, to study how perimenopause and menopause affect skeletal muscle. She presents findings on contractile properties of skeletal muscle at the single fiber level alongside morphological changes such as fatty infiltration and fibrosis following ovarian failure, and discusses the role of estrogen in maintaining muscle function. Mashouri emphasizes the importance of studying perimenopause as a dynamic transitional phase rather than a single timepoint, pointing toward strategies for mitigating menopause's negative effects on women's muscle health. Sponsored by Aurora Scientific, Inc.

Key Highlights

• Parastoo Mashouri uses the VCD model of chemically induced ovarian failure to capture the gradual, time-course nature of menopause, offering advantages over the traditional ovariectomy model.
• Her research shows that ovarian failure alters the contractile properties of skeletal muscle at the single fiber level and drives morphological changes including fatty infiltration and fibrosis.
• Mashouri highlights the importance of studying perimenopause as a dynamic transitional process, arguing this approach can lead to more accurate research findings and new strategies for mitigating menopause-related muscle decline.

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Ep. 4: Sympathetic Regulation in Human Pregnancy

November 12, 2024

Dr. Qi Fu, Professor at UT Southwestern Medical Center's Institute for Exercise and Environmental Medicine and Director of the Women's Heart Health Lab, draws on more than 27 years of research in autonomic circulatory control to examine the sympathetic neural mechanisms thought to drive the dramatic maternal hemodynamic changes seen in normal pregnancy, changes detectable as early as 4 weeks of gestation and that plateau in the second trimester. She reviews sympathetic neural control in both normotensive and hypertensive pregnancy, an area where the role of the sympathetic nervous system in blood pressure regulation remains largely unclear, and discusses how maternal obesity versus gestational weight gain differentially affects sleep apnea risk, sympathetic reactivity, and pregnancy outcomes. Sponsored by Finapres Medical Systems.

Key Highlights

• Maternal hemodynamic changes can be detected as early as 4 weeks of gestation and reach a plateau in the second trimester, with sympathetic neural mechanisms proposed as a key driver.
• Dr. Qi Fu, who has authored more than 170 papers on autonomic circulatory control, reviews how sympathetic neural control differs between normotensive and hypertensive pregnancy, an area where mechanisms remain largely unclear.
• Fu's research distinguishes the effects of maternal obesity from gestational weight gain on sleep apnea risk and sympathetic reactivity, with implications for pregnancy outcomes.

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Ep. 5: Preeclampsia: From Hippocrates to Contemporary Research

November 19, 2024

Dr. Stella Goulopoulou, Associate Professor in the Lawrence Longo Center for Perinatal Biology at Loma Linda University, traces preeclampsia from its first description by Hippocrates in Ancient Greece through to contemporary research, noting that the multisystem hypertensive disorder still affects 5 to 8 percent of all pregnancies and significantly raises the risk of long-term cardiovascular disease-related maternal mortality and morbidity despite its etiology remaining unknown. Her research examines how the placenta contributes to circulating cell-free mitochondrial DNA in preeclampsia, and characterizes the resulting vasoactive and inflammatory effects on maternal vascular physiology.

Key Highlights

• Preeclampsia affects 5 to 8 percent of all pregnancies and remains a leading cause of maternal deaths, with its etiology still unknown more than two millennia after Hippocrates first described the condition.
• Dr. Goulopoulou's research identifies the placenta as a key contributor to circulating cell-free mitochondrial DNA levels in preeclampsia.
• Her work characterizes the inflammatory and vasoactive effects of this circulating cell-free mitochondrial DNA, linking placental biology to the vascular dysfunction seen in preeclampsia.

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Ep. 6: Pathophysiology of Endometriosis: Current Concepts and Clinical Translations

December 3, 2024

Dr. Rick Burney, MD, MSc, Director of the Division of Reproductive Endocrinology and Infertility at the University of Alabama at Birmingham, reviews the pathogenesis of endometriosis, a prevalent gynecologic condition defined by endometrial glands and stroma outside the uterus, most notably in the pelvic peritoneum, ovaries, and rectovaginal space, causing pelvic pain and infertility. He discusses molecular hallmarks of the disease including estrogen dependence, attenuated progesterone action, neuroangiogenesis, chronic inflammation, and fibrosis, and addresses persistent clinical gaps in diagnosis, the implications of endometriosis for fertility treatment, and a two-pronged approach to managing endometriosis-associated pain.

Key Highlights

• Endometriosis is defined by endometrial glands and stroma outside the uterus, most commonly in the pelvic peritoneum, ovaries, and rectovaginal space, driving both pelvic pain and infertility.
• Dr. Burney identifies estrogen dependence, attenuated progesterone action, neuroangiogenesis, chronic inflammation, and fibrosis as the molecular hallmarks underlying endometriosis pathophysiology.
• Despite these advances, significant clinical gaps remain in diagnosing endometriosis, prompting Burney to outline a two-pronged approach for managing endometriosis-associated pain alongside implications for fertility treatment.

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Ep. 7: Polycystic Ovarian Syndrome and Cardiovascular Disease

December 10, 2024

Dr. Licy Yanes Cardozo, Professor in the Departments of Pharmacology and Medicine/Endocrinology at the University of Mississippi Medical Center, examines cardiovascular disease in women with Polycystic Ovary Syndrome (PCOS), noting that CVD caused 310,661 female deaths in 2021 alone, about 1 in every 5 deaths among women, according to CDC data. She explains that hyperandrogenemia, present in roughly 80% of PCOS patients, is linked to worse cardiometabolic outcomes than non-androgenic PCOS, and that a large retrospective analysis of electronic health records found significantly elevated cardiovascular event risk in PCOS women averaging just 26 years of age compared with BMI and age matched controls. Yanes Cardozo reviews the mechanisms underlying these risk factors and the limited current and emerging therapeutic options for managing cardiometabolic complications in this population.

Key Highlights

• Cardiovascular disease caused 310,661 deaths among women in 2021, about 1 in every 5 female deaths, according to the CDC's National Center for Health Statistics.
• Hyperandrogenemia affects roughly 80% of women with PCOS, and hyperandrogenic PCOS patients show worse cardiometabolic complications than their non-androgenic counterparts.
• A large retrospective analysis of electronic health records found significantly increased cardiovascular event risk in PCOS women averaging only 26 years old compared with BMI and age matched controls, underscoring the need for aggressive early management given the current shortage of targeted therapeutic agents.

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Ep. 8: Migraine: Past, Present, and Future

January 21, 2025

Dr. Amaal J. Starling, Associate Professor of Neurology at Mayo Clinic and Program Director for its Headache Medicine Fellowship, reviews migraine as a highly prevalent neurologic disease affecting approximately 12% of the global population and disproportionately impacting women, with 1 in 5 women, 1 in 11 children, and 1 in 16 men affected, and notes that migraine is the leading cause of years lived with disability for women in their most productive years. She explains that migraine pathophysiology involves complex interactions between genetic and environmental factors alongside abnormal neurologic function, highlighting neuropeptides such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase activating polypeptide as key drivers of disease and novel drug targets. Starling also reviews current acute and preventive treatment options, including neuromodulation, and identifies persistent gaps in migraine diagnosis and treatment.

Key Highlights

• Migraine affects approximately 12% of the global population and disproportionately impacts women, with 1 in 5 women, 1 in 11 children, and 1 in 16 men living with the disease.
• Migraine is the number one leading cause of years lived with disability for women during their most productive years, according to Dr. Starling.
• Neuropeptides including calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase activating polypeptide play critical roles in migraine pathophysiology and have become novel targets for acute and preventive drug therapies, alongside emerging neuromodulation approaches.

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Ep. 9: Hormonal and Chromosomal Influences on Autoimmunity and Lupus

January 28, 2025

Dr. Betty Diamond, Professor and Director of the Institute of Molecular Medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, and Dr. Melissa Cunningham, Associate Professor of Medicine at the Medical University of South Carolina, examine why autoimmune diseases, which affect over 8% of the population and cluster in families, preferentially affect women, showing that both hormonal and chromosomal influences contribute. They focus on nuclear hormone action, particularly estrogen receptor alpha (ERalpha), and how B cell maturation and selection are altered by hormonal milieu, with Dr. Cunningham's research specifically examining how estrogen receptor alpha variants modulate Toll-like receptor signaling and inflammatory responses in lupus, a disease Dr. Diamond has long studied through the induction and pathogenicity of anti-DNA antibodies in Systemic Lupus Erythematosus.

Key Highlights

• Autoimmune diseases affect over 8% of the population and preferentially affect women, a pattern the speakers show is driven by both hormonal and chromosomal influences rather than one or the other.
• Dr. Diamond's research has focused on the induction and pathogenicity of anti-DNA antibodies in Systemic Lupus Erythematosus, a hallmark autoantibody response contributing to tissue injury in the disease.
• Dr. Cunningham's research shows that estrogen receptor alpha (ERalpha) variants modulate Toll-like receptor signaling and inflammatory responses in lupus, and that B cell maturation and selection are altered by the hormonal milieu.

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Ep. 10: Challenges and Opportunities for Treatment of Metastatic Breast Cancer

February 4, 2025

Dr. Marsha Rosner, Charles B. Huggins Distinguished Service Professor in the Ben May Department for Cancer Research at the University of Chicago, addresses the challenges of eliminating metastatic breast cancer, with particular attention to triple-negative breast cancer (TNBC), a clinically aggressive subtype with high rates of metastasis and recurrence that disproportionately affects women of African descent and carriers of germline BRCA and PALB2 mutations. She notes that among younger patients, TNBC is associated with higher pathologic stage and worse long-term survival, and that despite advances in earlier diagnosis and targeted therapy, chemotherapy remains the mainstay treatment for metastatic TNBC. Drawing on her own research, Rosner presents novel strategies for targeting metastatic breast cancer beyond current chemotherapy-based approaches.

Key Highlights

• Triple-negative breast cancer (TNBC) is a clinically aggressive subtype with high rates of metastasis and recurrence that disproportionately affects women of African descent and carriers of germline BRCA and PALB2 mutations.
• Among younger breast cancer patients, the TNBC subtype is associated with higher pathologic stage and worse long-term survival compared with other subtypes.
• Despite progress from earlier diagnosis and targeted therapy, chemotherapy remains the mainstay treatment for metastatic TNBC, and Dr. Rosner presents novel strategies from her own research for more effectively targeting metastatic disease.

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Ep. 11: New Treatments for Vasomotor Symptoms Due to Menopause

February 18, 2025

Dr. JoAnn V. Pinkerton, Mamie Jessup Professor of Obstetrics and Gynecology at the University of Virginia School of Medicine and founder of the Midlife Health Center at UVA Health, reviews vasomotor symptoms (VMS), reported by up to 80% of women during the menopausal transition and among the leading reasons women seek medical care, with one-third of menopausal women experiencing severe hot flashes and night sweats alongside sleep disruption and mood changes that can persist for 10 years or more. She explains that VMS arise from hyperactivation of the thermoregulatory pathway driven by hypertrophy of kisspeptin, neurokinin B, and dynorphin (KNDy) neurons in the hypothalamus, which are normally inhibited by estrogen and stimulated by the neuropeptide neurokinin B, and reviews treatment options ranging from menopausal hormone therapy and off-label nonhormonal agents such as low-dose antidepressants and gabapentinoids to the newer neurokinin receptor antagonists.

Key Highlights

• Up to 80% of women report vasomotor symptoms during the menopausal transition, with one-third experiencing severe hot flashes and night sweats that can persist for 10 years or more.
• Dr. Pinkerton explains that VMS result from hyperactivation of the thermoregulatory pathway driven by hypertrophy of KNDy (kisspeptin, neurokinin B, dynorphin) neurons in the hypothalamus, which are normally inhibited by estrogen and stimulated by neurokinin B.
• While menopausal hormone therapy remains the most effective treatment, neurokinin receptor antagonists have emerged as an effective new nonhormonal option alongside off-label agents like low-dose antidepressants and gabapentinoids.

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Ep. 12: Hypertension and Hypothalamic Changes in a Mouse Model of Menopause

February 25, 2025

Dr. Teresa Milner, Professor of Neuroscience at the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine, uses an accelerated ovarian failure (AOF) mouse model, induced by 4-vinylcyclohexene diepoxide (VCD), to isolate the role of estrogen in menopausal hypertension within the hypothalamic paraventricular nucleus (PVN), a key brain region for blood pressure regulation. Her work shows that slow-pressor angiotensin II infusion produces hypertension in peri-AOF and post-AOF female mice, along with distinct changes in glutamatergic NMDA (GluN1) and AMPA (GluA1) receptor distribution in estrogen receptor beta (ERbeta) containing PVN neurons, and that hypertensive peri-AOF mice show heightened GluN1 signaling and reactive oxygen species production in ERbeta containing PVN dendrites. Milner further demonstrates that cyclic administration of an ERbeta agonist reduces hypertension and suppresses NMDA receptor signaling in angiotensin II treated peri-AOF females, but not in males, pointing to a therapeutic window during the menopause transition. Sponsored by ALZET.

Key Highlights

• In the AOF mouse model, slow-pressor angiotensin II infusion produces hypertension in peri-AOF and post-AOF female mice and in male mice, but not in young female mice, isolating estrogen's protective role.
• Hypertensive peri-AOF mice show heightened GluN1 (NMDA receptor) signaling and reactive oxygen species production in estrogen receptor beta containing PVN dendrites, alongside distinct changes in GluN1 and GluA1 receptor distribution.
• Cyclic administration of an estrogen receptor beta agonist reduced hypertension and suppressed NMDA receptor signaling in angiotensin II treated peri-AOF female mice, but not in males, revealing a sex-specific therapeutic window for managing menopausal hypertension.