Workshop summary: National Institutes of Health (NIH) 2022 scientific workshop on gender and health.

In this manuscript, we summarize the goals, content, and impact of the Gender and Health: Impacts of Structural Sexism, Gender Norms, Relational Power Dynamics, and Gender Inequities workshop held by the National Institutes of Health (NIH) Office of Research on Women's Health (ORWH) in collaboration with 10 NIH Institutes, Centers, and Offices. Specifically, we outline the key points emerging from the workshop presentations, which are the focus of the collection of articles in this supplement. The overarching goals of the workshop were to convene NIH staff, the external scientific community, and the public to discuss methods, measurement, modifiable factors, interventions, and best practices in health research on gender as a social and cultural variable and to identify opportunities to advance research and foster collaborations on these key topics. Themes emerging from the workshop include the need for intersectional measures in research on gender and health, the role of multilevel interventions and analyses, and the importance of considering gender as a social and structural determinant of health. Careful, nuanced, and rigorous integration of gender in health research can contribute to knowledge about and interventions to change the social and structural forces that lead to disparate health outcomes and perpetuate inequities.

Maternal Morbidity and Mortality: Are We Getting to the "Heart" of the Matter?

Cardiovascular disease (CVD), including hypertensive disorders of pregnancy (HDP) and peripartum cardiomyopathy, is a leading cause of pregnancy-related death in the United States. Women who are African American or American Indian/Alaskan Native, have HDP, are medically underserved, are older, or are obese have a major risk for the onset and/or progression of CVD during and after pregnancy. Paradoxically, women with no preexisting chronic conditions or risk factors also experience significant pregnancy-related cardiovascular (CV) complications. The question remains whether substantial physiologic stress on the CV system during pregnancy reflected in hemodynamic, hematological, and metabolic changes uncovers subclinical prepregnancy CVD in these otherwise healthy women. Equally important and similarly understudied is the concept that women's long-term CV health could be detrimentally affected by adverse pregnancy outcomes, such as preeclampsia, gestational hypertension, and diabetes, and preterm birth. Thus, a critical life span perspective in the assessment of women's CV risk factors is needed to help women and health care providers recognize and appreciate not only optimal CV health but also risk factors present before, during, and after pregnancy. In this review article, we highlight new advancements in understanding adverse, pregnancy-related CV conditions and will discuss promising strategies or interventions for their prevention, diagnosis, and treatment.

Dysglycemia in Pregnancy and Maternal/Fetal Outcomes.

Maternal dysglycemia-including diabetes, impaired glucose tolerance, and impaired fasting glucose-affects one in six pregnancies worldwide and represents a significant health risk to the mother and the fetus. Maternal dysglycemia is an independent risk factor for perinatal mortality, major congenital anomalies, and miscarriages. Furthermore, it increases the longer-term risk of type 2 diabetes mellitus, metabolic syndrome, cardiovascular morbidity, malignancies, and ophthalmic, psychiatric, and renal diseases in the mother. The most commonly encountered form of maternal dysglycemia is gestational diabetes. Currently, international consensus does not exist for diagnostic criteria defining gestational diabetes at 24-28 weeks gestation, and potential diagnostic glucose thresholds earlier in gestation require further investigation. Likewise, recommendations regarding the timing and modality (e.g., lifestyle or pharmacological) of treatment vary greatly. Because a precise diagnosis determines the appropriate treatment and outcome of the pregnancy, it is imperative that a better definition of maternal dysglycemia and its treatment be achieved. This article will address some of the controversies related to diagnosing and managing maternal dysglycemia. In addition, the article will discuss the impact of maternal dysglycemia on complications experienced by the mother and infant, both at birth and in later life.

Sex Differences in Diabetic Kidney Disease.

While the global prevalence of both type 1 and type 2 diabetes mellitus is similar in men and women, the consequences of diabetes on associated end-organ complications, including diabetic kidney disease appear to be more sex-specific. Particularly, women with diabetes have higher mortality rates for diabetes-related deaths, and higher prevalence of diabetic kidney disease risk factors such as hypertension, hyperglycemia, obesity, and dyslipidemia. However, the evidence for the impact of sex on diabetic kidney disease prevalence and disease progression is limited and inconsistent. Although most studies agree that the protective effect of the female sex against the development of kidney disease is diminished in the setting of diabetes, the reasons for this observation are unclear. Whether or not sex differences exist in the risk of diabetic kidney disease is also unclear, with studies reporting either higher risk in men, women, or no sex differences. Despite the remaining controversies, some of the factors that associate with sex differences in the risk of diabetic kidney disease are age at onset, and type and duration of diabetes. There is growing appreciation of the importance of sex hormones in the regulation of renal function, with estrogens generally considered to be renoprotective. Although some progress has been made towards better understanding of the mechanisms by which sex hormones play a role in the pathophysiology of diabetic kidney disease, the translational potential of this knowledge is still underappreciated. A better understanding of sex differences in diabetic kidney disease may provide basis for personalized and sex-specific treatment of diabetic kidney disease.

Sex and the kidneys: current understanding and research opportunities.

Concerns regarding sex differences are increasingly pertinent in scientific and societal arenas. Although biological sex and socio-cultural gender are increasingly recognized as important modulators of renal function under physiological and pathophysiological conditions, gaps remain in our understanding of the mechanisms underlying sex differences in renal pathophysiology, disease development, progression and management. In this Perspectives article, we discuss specific opportunities for future research aimed at addressing these knowledge gaps. Such opportunities include the development of standardized core data elements and outcomes related to sex for use in clinical studies to establish a connection between sex hormones and renal disease development or progression, development of a knowledge portal to promote fundamental understanding of physiological differences between male and female kidneys in animal models and in humans, and the creation of new or the development of existing resources and datasets to make them more readily available for interrogation of sex differences. These ideas are intended to stimulate thought and interest among the renal research community as they consider sex as a biological variable in future research projects.

Implementing the National Heart, Lung, and Blood Institute's Strategic Vision in the Division of Cardiovascular Sciences.

As we commemorate the 70th Anniversary of the National Heart, Lung, and Blood Institute (NHLBI) and celebrate important milestones that have been achieved by the Division of Cardiovascular Sciences (DCVS), it is imperative that DCVS and the Extramural Research community at-large continue to address critical public health challenges that persist within the area of Cardiovascular Diseases (CVD). The NHLBI's Strategic Vision, developed with extensive input from the extramural research community and published in 2016, included overarching goals and strategic objectives that serve to provide a general blueprint for sustaining the legacy of the Institute by leveraging opportunities in emerging scientific areas (e.g., regenerative medicine, omics technology, data science, precision medicine, and mobile health), finding new ways to address enduring challenges (e.g., social determinants of health, health inequities, prevention, and health promotion), and training the next generation of heart, lung, blood, and sleep researchers. DCVS has developed a strategic vision implementation plan to provide a cardiovascular framing for the pursuit of the Institute's overarching goals and strategic objectives garnered from the input of the broader NHLBI community. This plan highlights six scientific focus areas that demonstrate a cross-cutting and multifaceted approach to addressing cardiovascular sciences, including 1) addressing social determinants of cardiovascular health (CVH) and health inequities, 2) enhancing resilience, 3) promoting CVH and preventing CVD Across the lifespan, 4) eliminating hypertension-related CVD, 5) reducing the burden of heart failure, and 6) preventing vascular dementia. These priorities will guide our efforts in Institute-driven activities in the coming years but will not exclude development of other novel ideas or the support of investigator-initiated grant awards. The DCVS Strategic Vision implementation plan is a living document that will evolve with iterative dialogue with the NHLBI community and adapt as the dynamic scientific landscape changes to seize emerging opportunities.

Portfolio analysis on preeclampsia and pregnancy-associated hypertension research funded by the National Heart, Lung, and Blood Institute.

Chronic hypertension and preeclampsia are the most common complications of pregnancy. To clarify the contributions of the National Heart, Lung, and Blood Institute (NHLBI) to the field and identify potential research gaps, we performed portfolio analysis of awards related to preeclampsia and pregnancy-associated hypertension. A list of National Institutes of Health (NIH)-funded awards between fiscal years 2008-present was obtained through an NIH RePORTER search using the following terms: "preeclampsia" and "pregnancy-associated hypertension." More in-depth analyses were performed on currently active awards supported by the NHLBI. The NHLBI is the lead institute at the NIH in funding research related to pregnancy-associated hypertension and second leading in funding research related to preeclampsia. The NHLBI currently supports 38 awards related to preeclampsia and six awards related to pregnancy-associated hypertension, with a combined total dollar investment of $21 million. Of the currently active, NHLBI-supported awards on preeclampsia and pregnancy-associated hypertension combined, 47% are related to basic science research, 30% to clinical, 14% to clinical trials, and 9% to early translational research. The focus of NHLBI-funded awards is primarily on vascular mechanisms and short and long-term cardiovascular complications of preeclampsia and pregnancy-associated hypertension. Despite steady funding for research on preeclampsia and pregnancy-associated hypertension, several gaps in knowledge exist. NHLBI held a workshop entitled Predicting, Preventing and Treating Preeclampsia to address some of these gaps and inform future research directions for the institute.

Sex differences in micro- and macro-vascular complications of diabetes mellitus.

Vascular complications are a leading cause of morbidity and mortality in both men and women with type 1 (T1DM) or type 2 (T2DM) diabetes mellitus, however the prevalence, progression and pathophysiology of both microvascular (nephropathy, neuropathy and retinopathy) and macrovascular [coronary heart disease (CHD), myocardial infarction, peripheral arterial disease (PAD) and stroke] disease are different in the two sexes. In general, men appear to be at a higher risk for diabetic microvascular complications, while the consequences of macrovascular complications may be greater in women. Interestingly, in the absence of diabetes, women have a far lower risk of either micro- or macro-vascular disease compared with men for much of their lifespan. Thus, the presence of diabetes confers greater risk for vascular complications in women compared with men and some of the potential reasons, including contribution of sex hormones and sex-specific risk factors are discussed in this review. There is a growing body of evidence that sex hormones play an important role in the regulation of cardiovascular function. While estrogens are generally considered to be cardioprotective and androgens detrimental to cardiovascular health, recent findings challenge these assumptions and demonstrate diversity and complexity of sex hormone action on target tissues, especially in the setting of diabetes. While some progress has been made toward understanding the underlying mechanisms of sex differences in the pathophysiology of diabetic vascular complications, many questions and controversies remain. Future research leading to understanding of these mechanisms may contribute to personalized- and sex-specific treatment for diabetic micro- and macro-vascular disease.

A Systematic Review of Obesity Disparities Research.

CONTEXT: A review of interventions addressing obesity disparities could reveal gaps in the literature and provide guidance on future research, particularly for populations with a high prevalence of obesity and obesity-related cardiometabolic risk. EVIDENCE ACQUISITION: A systematic review of clinical trials in obesity disparities research that were published in 2011-2016 in PubMed/MEDLINE resulted in 328 peer-reviewed articles. Articles were excluded if they had no BMI, weight, or body composition measure as primary outcome or were foreign (n=201); were epidemiologic or secondary data analyses of clinical trials (n=12); design or protocol papers (n=54); systematic reviews (n=3); or retracted or duplicates (n=9). Forty-nine published trials were summarized and supplemented with a review of ongoing obesity disparities grants being funded by the National, Heart, Lung and Blood Institute. EVIDENCE SYNTHESIS: Of the 49 peer-reviewed trials, 27 targeted adults and 22 children only or parent-child dyads (5 of 22). Interventions were individually focused; mostly in single settings (e.g., school or community); of short duration (mostly ≤12 months); and primarily used behavioral modification (e.g., self-monitoring) strategies. Many of the trials had small sample sizes and moderate to high attrition rates. A meta-analysis of 13 adult trials obtained a pooled intervention effect of BMI -1.31 (95% CI=-2.11, -0.52, p=0.0012). Institutional review identified 140 ongoing obesity-related health disparities grants, but only 19% (n=27) were clinical trials. CONCLUSIONS: The reviews call for cardiovascular-related obesity disparities research that is long term and includes population research, and multilevel, policy, and environmental, or "whole of community," interventions.

Shifting Demographics among Research Project Grant Awardees at the National Heart, Lung, and Blood Institute (NHLBI).

The present study was initiated because of concerns expressed by NHLBI-funded mid-career investigators regarding perceived difficulties in the renewal of their grant awards. This led us to ask: "Are mid-career investigators experiencing disproportionate difficulties in the advancement of their professional careers?" Our portfolio analysis indicates that there has been a significant and evolving shift in the demographics of research project grant (RPG) awardees at NHLBI. In 1998, mid-career (ages 41-55) investigators constituted approximately 60% of all investigators with the remaining 40% being equally divided between early-stage (ages 24-40) investigators and established (ages 56 to 70 and older) investigators. However, since 1998, the proportion of established RPG awardees has been increasing in a slowly progressive and strikingly linear fashion. At the same time the proportion of early-stage awardees fell precipitously until 2006 and then stabilized. During the same period, the proportion of mid-career awardees, which had been relatively stable through 2006, began to fall significantly. In examining potential causes of these demographic shifts we have identified certain inherent properties within the RPG award system that appear to promote an increasingly more established awardee population and a persistent decrease in the proportion of mid-career investigators. A collateral result of these demographic shifts, when combined with level or declining funding, is a significant reduction in the number of RPG awards received by NHLBI mid-career investigators and a corresponding decrease in the number of independent research laboratories.

Age at menarche and the risk of diabetic microvascular complications in patients with type 1 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the relationship among age at onset of diabetes, age at onset of menarche and risk of diabetic nephropathy and laser-treated retinopathy in type 1 diabetes. METHODS: Data related to age at menarche were collected through questionnaires and were available for 1,304 women who participated in the Finnish Diabetic Nephropathy Study (FinnDiane). A possible association between age at menarche and diabetic nephropathy and retinopathy was investigated. RESULTS: There was an inverse relationship between the age at onset of diabetes and age at menarche: the younger the age at onset of diabetes, the higher the age at menarche (p < 0.0001). A non-linear relationship between the age of menarche and risk of diabetic microvascular complications was found in patients with diabetes onset before menarche, but there was no such association in patients with diabetes onset after menarche. Women with delayed menarche (> mean age + 2 years) had a 2.30 (95% CI 1.27, 4.17; p < 0.006) times higher risk of nephropathy compared with the women who underwent menarche at the mean age ± 2 years. Delayed menarche also increased the risk of retinopathy (OR 2.34 [95% CI 1.36, 4.01]). After excluding patients with nephropathy, the OR for retinopathy was 2.11 (95% CI 1.15, 3.90). Earlier menarche (< mean age - 2 years) did not have any effect on this risk. CONCLUSIONS/INTERPRETATION: Delayed menarche was associated with an increased risk of diabetic nephropathy and retinopathy, whereas early menarche was not. Delayed menarche may be used as a new tool to identify women at risk of diabetic microvascular complications.

Physiological effects and therapeutic potential of proinsulin C-peptide.

Connecting Peptide, or C-peptide, is a product of the insulin prohormone, and is released with and in amounts equimolar to those of insulin. While it was once thought that C-peptide was biologically inert and had little biological significance beyond its role in the proper folding of insulin, it is now known that C-peptide binds specifically to the cell membranes of a variety of tissues and initiates specific intracellular signaling cascades that are pertussis toxin sensitive. Although it is now clear that C-peptide is a biologically active molecule, controversy still remains as to the physiological significance of the peptide. Interestingly, C-peptide appears to reverse the deleterious effects of high glucose in some tissues, including the kidney, the peripheral nerves, and the vasculature. C-peptide is thus a potential therapeutic agent for the treatment of diabetes-associated long-term complications. This review addresses the possible physiologically relevant roles of C-peptide in both normal and disease states and discusses the effects of the peptide on sensory nerve, renal, and vascular function. Furthermore, we highlight the intracellular effects of the peptide and present novel strategies for the determination of the C-peptide receptor(s). Finally, a hypothesis is offered concerning the relationship between C-peptide and the development of microvascular complications of diabetes.

Preventing autoimmunity protects against the development of hypertension and renal injury.

Several studies suggest a link between autoimmunity and essential hypertension in humans. However, whether autoimmunity can drive the development of hypertension remains unclear. The autoimmune disease systemic lupus erythematosus is characterized by autoantibody production, and the prevalence of hypertension is increased markedly in this patient population compared with normal healthy women. We hypothesized that preventing the development of autoimmunity would prevent the development of hypertension in a mouse model of lupus. Female lupus (NZBWF1) and control mice (NZW) were treated weekly with anti-CD20 or immunoglobulin G antibodies (both 10 mg/kg, IV) starting at 20 weeks of age for 14 weeks. Anti-CD20 therapy markedly attenuated lupus disease progression as evidenced by reduced CD45R+ B cells and lower double-stranded DNA autoantibody activity. In addition, renal injury in the form of urinary albumin, glomerulosclerosis, and tubulointerstitial fibrosis, as well as tubular injury (indicated by renal cortical expression of neutrophil gelatinase-associated lipocalin) was prevented by anti-CD20 therapy in lupus mice. Finally, lupus mice treated with anti-CD20 antibody did not develop hypertension. The protection against the development of hypertension was associated with lower renal cortical tumor necrosis factor-α expression, a cytokine that has been previously reported by us to contribute to the hypertension in this model, as well as renal cortical monocyte chemoattractant protein-1 expression and circulating T cells. These data suggest that the development of autoimmunity and the resultant increase in renal inflammation are an important underlying factor in the prevalent hypertension that occurs during systemic lupus erythematosus.

Impact of ovarian function on cardiovascular health in women: focus on hypertension.

Arterial blood pressure levels and the prevalence of hypertension are generally lower in premenopausal women compared with age-matched men. The lower blood pressure levels in premenopausal women are associated with a lower risk of the development and progression of cardiovascular disease. In contrast, menopause, a state characterized by a physiologic reduction in ovarian hormone levels, is associated with progressive increases in blood pressure and an overall increase in the risk of cardiovascular disease. These observations suggest an association between blood pressure regulation and changes in ovarian hormone levels, estrogens in particular. In addition to menopause, the risk of hypertension and cardiovascular disease is also dramatically increased in premenopausal women with chronic diseases such as diabetes and systemic lupus erythematosus. Studies suggest that these chronic diseases may be associated with an imbalance in ovarian hormones, which may explain the increased risk of hypertension and cardiovascular disease in these women. However, the use of hormone therapy to manage the risk and prevent the development of hypertension and cardiovascular diseases in women remains controversial. The precise mechanisms by which estrogens contribute to the regulation of blood pressure are still not completely understood. However, accumulating evidence suggests that modulating the activity of locally active hormone systems is one of the major mechanisms by which estrogens exert their effects on target organs, including the vasculature, kidneys, and immune system. In particular, the interaction between estrogens and the renin-angiotensin system has been implicated in the regulation of blood pressure and cardiovascular function in both humans and experimental models. This review summarizes our current understanding of the mechanisms by which estrogens regulate blood pressure and the potential use of hormone therapy in prevention of hypertension and consequent cardiovascular risk.