Male contraception: narrative review of ongoing research.

BACKGROUND: Since the release of the combined oral contraceptive pill in 1960, women have shouldered the burden of contraception and family planning. Over 60 years later, this is still the case as the only practical, effective contraceptive options available to men are condoms and vasectomy. However, there are now a variety of promising hormonal and non-hormonal male contraceptive options being studied. The purpose of this narrative review is to provide clinicians and laypeople with focused, up-to-date descriptions of novel strategies and targets for male contraception. We include a cautiously optimistic discussion of benefits and potential drawbacks, highlighting several methods in preclinical and clinical stages of development. RESULTS: As of June 2023, two hormonal male contraceptive methods are undergoing phase II clinical trials for safety and efficacy. A large-scale, international phase IIb trial investigating efficacy of transdermal segesterone acetate (Nestorone) plus testosterone gel has enrolled over 460 couples with completion estimated for late 2024. A second hormonal method, dimethandrolone undecanoate, is in two clinical trials focusing on safety, pharmacodynamics, suppression of spermatogenesis and hormones; the first of these two is estimated for completion in December 2024. There are also several non-hormonal methods with strong potential in preclinical stages of development. CONCLUSIONS: There exist several hurdles to novel male contraception. Therapeutic development takes decades of time, meticulous work, and financial investment, but with so many strong candidates it is our hope that there will soon be several safe, effective, and reversible contraceptive options available to male patients.

RéSUMé: CONTEXTE: Depuis la sortie de la pilule contraceptive orale combinée en 1960, les femmes ont assumé le fardeau de la contraception et de la planification familiale. Plus de 60 ans plus tard, c'est toujours le cas, car les seules options contraceptives pratiques et efficaces disponibles pour les hommes sont les préservatifs et la vasectomie. Cependant, il existe maintenant une variété d'options contraceptives masculines hormonales et non hormonales prometteuses qui sont à l'étude. Le but de cette revue narrative est de fournir aux cliniciens et aux profanes des descriptions ciblées et à jour de nouvelles stratégies et cibles pour la contraception masculine. Nous incluons une discussion prudemment optimiste sur les avantages et les inconvénients potentiels, en soulignant plusieurs méthodes aux stades précliniques et cliniques du développement. RéSULTATS: En juin 2023, deux méthodes contraceptives masculines hormonales faisaient l'objet d'essais cliniques de phase II pour leur innocuité et leur efficacité. Un essai international de phase IIb à grande échelle, portant sur l'efficacité de l'acétate de ségestérone transdermique (Nestorone) et du gel de testostérone, a recruté plus de 460 couples et devrait être achevé pour la fin de 2024. Une seconde méthode hormonale, l'undécanoate de diméthandrolone, fait l'objet de deux essais cliniques axés sur l'innocuité, la pharmacodynamique, la suppression de la spermatogenèse et des hormones; le premier de ces deux essais devrait être achevé en décembre 2024. Il existe également plusieurs méthodes non hormonales à fort potentiel aux stades précliniques de développement. CONCLUSIONS: Il existe plusieurs obstacles à la nouvelle contraception masculine. Le développement thérapeutique nécessite des décennies de temps, un travail méticuleux et un investissement financier ; mais avec autant de candidats solides, nous espérons qu'il y aura bientôt plusieurs options contraceptives sûres, efficaces et réversibles, disponibles pour les hommes.

COVID-19 Vaccine Hesitancy in Rural Midwestern Infertility Patients: A Cross-Sectional Survey.

BACKGROUND: Pregnant patients with COVID-19 experience higher rates of maternal mortality, pregnancy loss, and other severe comorbidities. Despite these well-characterized risks, this group displayed a high level of vaccine hesitancy that contributed to their slow acceptance of the COVID-19 vaccinations and greater maternal mortality during the pandemic. The rural Midwest was no exception to this unfortunate trend, so here we sought to determine attitudes, beliefs, and perceptions in these women and their partners associated with vaccine hesitancy to better address uncertainties and improve vaccination rates. METHODS: We used a cross-sectional survey of rural Midwestern infertility patients. Study population included both women and men, ranging from 21 to 53 years old. We evaluated vaccination status, hesitancy or refusal for COVID-19 vaccination, sociodemographic factors, sources and types of medical information, employer vaccination requirements, and specific attitudes, beliefs, and perceptions towards vaccines using questions guided by the Health Belief Model. RESULTS: We surveyed 390 Midwestern patients with pre-existing clinic appointments who were being evaluated for infertility and/or trying to conceive. Vaccine-hesitant patients held significant concerns of rushed vaccine development, safety, and benefits not outweighing potential risks. Patients were significantly more likely to obtain the vaccine if it was recommended by their physician. They were also more likely to receive the vaccine if they were given written resources or if required by their employer. CONCLUSIONS: Survey results identified specific concerns and strategies that may be used to address vaccine hesitancy in this at-risk population. Addressing vaccine hesitancy may improve vaccination rates and in turn reduce maternal mortality and morbidity, particularly in rural populations.

Impact of Prenatal Exposure to Maternal Diabetes and High-Fat Diet on Postnatal Myocardial Ketone Body Metabolism in Rats.

Infants exposed to diabetic pregnancy are at higher risk of cardiomyopathy at birth and early onset cardiovascular disease (CVD) as adults. Using a rat model, we showed how fetal exposure to maternal diabetes causes cardiac disease through fuel-mediated mitochondrial dysfunction, and that a maternal high-fat diet (HFD) exaggerates the risk. Diabetic pregnancy increases circulating maternal ketones which can have a cardioprotective effect, but whether diabetes-mediated complex I dysfunction impairs myocardial metabolism of ketones postnatally remains unknown. The objective of this study was to determine whether neonatal rat cardiomyocytes (NRCM) from diabetes- and HFD-exposed offspring oxidize ketones as an alternative fuel source. To test our hypothesis, we developed a novel ketone stress test (KST) using extracellular flux analyses to compare real-time ß-hydroxybutyrate (ßHOB) metabolism in NRCM. We also compared myocardial expression of genes responsible for ketone and lipid metabolism. NRCM had a dose-dependent increase in respiration with increasing concentrations of ßHOB, demonstrating that both control and combination exposed NRCM can metabolize ketones postnatally. Ketone treatment also enhanced the glycolytic capacity of combination exposed NRCM with a dose-dependent increase in the glucose-mediated proton efflux rate (PER) from CO2 (aerobic glycolysis) alongside a decreased reliance on PER from lactate (anaerobic glycolysis). Expression of genes responsible for ketone body metabolism was higher in combination exposed males. Findings demonstrate that myocardial ketone body metabolism is preserved and improves fuel flexibility in NRCM from diabetes- and HFD-exposed offspring, which suggests that ketones might serve a protective role in neonatal cardiomyopathy due to maternal diabetes.

Mitochondrial Transfer Improves Cardiomyocyte Bioenergetics and Viability in Male Rats Exposed to Pregestational Diabetes.

Offspring born to diabetic or obese mothers have a higher lifetime risk of heart disease. Previously, we found that rat offspring exposed to late-gestational diabetes mellitus (LGDM) and maternal high-fat (HF) diet develop mitochondrial dysfunction, impaired cardiomyocyte bioenergetics, and cardiac dysfunction at birth and again during aging. Here, we compared echocardiography, cardiomyocyte bioenergetics, oxidative damage, and mitochondria-mediated cell death among control, pregestational diabetes mellitus (PGDM)-exposed, HF-diet-exposed, and combination-exposed newborn offspring. We hypothesized that PGDM exposure, similar to LGDM, causes mitochondrial dysfunction to play a central, pathogenic role in neonatal cardiomyopathy. We found that PGDM-exposed offspring, similar to LGDM-exposed offspring, have cardiac dysfunction at birth, but their isolated cardiomyocytes have seemingly less bioenergetics impairment. This finding was due to confounding by impaired viability related to poorer ATP generation, more lipid peroxidation, and faster apoptosis under metabolic stress. To mechanistically isolate and test the role of mitochondria, we transferred mitochondria from normal rat myocardium to control and exposed neonatal rat cardiomyocytes. As expected, transfer provides a respiratory boost to cardiomyocytes from all groups. They also reduce apoptosis in PGDM-exposed males, but not in females. Findings highlight sex-specific differences in mitochondria-mediated mechanisms of developmentally programmed heart disease and underscore potential caveats of therapeutic mitochondrial transfer.

Age and Sex Influence Mitochondria and Cardiac Health in Offspring Exposed to Maternal Glucolipotoxicity.

Infants of diabetic mothers are at risk of cardiomyopathy at birth and myocardial infarction in adulthood, but prevention is hindered because mechanisms remain unknown. We previously showed that maternal glucolipotoxicity increases the risk of cardiomyopathy and mortality in newborn rats through fuel-mediated mitochondrial dysfunction. Here we demonstrate ongoing cardiometabolic consequences by cross-fostering and following echocardiography, cardiomyocyte bioenergetics, mitochondria-mediated turnover, and cell death following metabolic stress in aged adults. Like humans, cardiac function improves by weaning with no apparent differences in early adulthood but declines again in aged diabetes-exposed offspring. This is preceded by impaired oxidative phosphorylation, exaggerated age-related increase in mitochondrial number, and higher oxygen consumption. Prenatally exposed male cardiomyocytes have more mitolysosomes indicating high baseline turnover; when exposed to metabolic stress, mitophagy cannot increase and cardiomyocytes have faster mitochondrial membrane potential loss and mitochondria-mediated cell death. Details highlight age- and sex-specific roles of mitochondria in developmentally programmed adult heart disease.

Maternal High Fat Diet and Diabetes Disrupts Transcriptomic Pathways That Regulate Cardiac Metabolism and Cell Fate in Newborn Rat Hearts.

Background: Children born to diabetic or obese mothers have a higher risk of heart disease at birth and later in life. Using chromatin immunoprecipitation sequencing, we previously demonstrated that late-gestation diabetes, maternal high fat (HF) diet, and the combination causes distinct fuel-mediated epigenetic reprogramming of rat cardiac tissue during fetal cardiogenesis. The objective of the present study was to investigate the overall transcriptional signature of newborn offspring exposed to maternal diabetes and maternal H diet. Methods: Microarray gene expression profiling of hearts from diabetes exposed, HF diet exposed, and combination exposed newborn rats was compared to controls. Functional annotation, pathway and network analysis of differentially expressed genes were performed in combination exposed and control newborn rat hearts. Further downstream metabolic assessments included measurement of total and phosphorylated AKT2 and GSK3ß, as well as quantification of glycolytic capacity by extracellular flux analysis and glycogen staining. Results: Transcriptional analysis identified significant fuel-mediated changes in offspring cardiac gene expression. Specifically, functional pathways analysis identified two key signaling cascades that were functionally prioritized in combination exposed offspring hearts: (1) downregulation of fibroblast growth factor (FGF) activated PI3K/AKT pathway and (2) upregulation of peroxisome proliferator-activated receptor gamma coactivator alpha (PGC1α) mitochondrial biogenesis signaling. Functional metabolic and histochemical assays supported these transcriptome changes, corroborating diabetes- and diet-induced cardiac transcriptome remodeling and cardiac metabolism in offspring. Conclusion: This study provides the first data accounting for the compounding effects of maternal hyperglycemia and hyperlipidemia on the developmental cardiac transcriptome, and elucidates nuanced and novel features of maternal diabetes and diet on regulation of heart health.

Diabetic Pregnancy and Maternal High-Fat Diet Impair Mitochondrial Dynamism in the Developing Fetal Rat Heart by Sex-Specific Mechanisms.

Infants born to diabetic or obese mothers are at greater risk of heart disease at birth and throughout life, but prevention is hindered because underlying mechanisms remain poorly understood. Using a rat model, we showed that prenatal exposure to maternal diabetes and a high-fat diet caused diastolic and systolic dysfunction, myocardial lipid accumulation, decreased respiratory capacity, and oxidative stress in newborn offspring hearts. This study aimed to determine whether mitochondrial dynamism played a role. Using confocal live-cell imaging, we examined mitochondrial dynamics in neonatal rat cardiomyocytes (NRCM) from four prenatally exposed groups: controls, diabetes, high-fat diet, and combination exposed. Cardiac expression of dynamism-related genes and proteins were compared, and gender-specific differences were evaluated. Findings show that normal NRCM have highly dynamic mitochondria with a well-balanced number of fusion and fission events. Prenatal exposure to diabetes or a high-fat diet impaired dynamism resulting in shorter, wider mitochondria. Mechanisms of impaired dynamism were gender-specific and protein regulated. Females had higher expression of fusion proteins which may confer a cardioprotective effect. Prenatally exposed male hearts had post-translational modifications known to impair dynamism and influence mitophagy-mediated cell death. This study identifies mitochondrial fusion and fission proteins as targetable, pathogenic regulators of heart health in offspring exposed to excess circulating maternal fuels.

Placental lipid processing in response to a maternal high-fat diet and diabetes in rats.

BackgroundDiabetes and obesity during pregnancy have an impact on the health of both mothers and developing babies. Prevention focuses on glycemic control, but increasing evidence implicates a role for lipids. Using a rat model, we showed that a maternal high-fat (HF) diet increased perinatal morbidity and mortality, but lipid processing across the maternal-placental-fetal triad remained unstudied. We hypothesized that HF diet would disrupt placental lipid processing to exaggerate fuel-mediated consequences of diabetic pregnancy.MethodsWe compared circulating lipid profiles, hormones, and inflammatory markers in dams and rat offspring from normal, diabetes-exposed, HF-diet-exposed, and combination-exposed pregnancies. Placentae were examined for lipid accumulation and expression of fuel transporters.ResultsMaternal HF diet exaggerated hyperlipidemia of pregnancy, with diabetes marked dyslipidemia developed in dams but not in offspring. Placentae demonstrated lipid accumulation and lower expression of fatty acid (FA) transporters. Diet-exposed offspring had a lower fraction of circulating essential FAs. Pregnancy loss was significantly higher in diet-exposed but not in diabetes-exposed pregnancies, which could not be explained by differences in hormone production. Although not confirmed, inflammation may play a role.ConclusionMaternal hyperlipidemia contributes to placental lipid droplet accumulation, perinatal mortality, and aberrant FA profiles that may influence the health of the developing offspring.

Prenatal Exposure to a Maternal High-Fat Diet Affects Histone Modification of Cardiometabolic Genes in Newborn Rats.

Infants born to women with diabetes or obesity are exposed to excess circulating fuels during fetal heart development and are at higher risk of cardiac diseases. We have previously shown that late-gestation diabetes, especially in conjunction with a maternal high-fat (HF) diet, impairs cardiac functions in rat-offspring. This study investigated changes in genome-wide histone modifications in newborn hearts from rat-pups exposed to maternal diabetes and HF-diet. Chromatin-immunoprecipitation-sequencing revealed a differential peak distribution on gene promoters in exposed pups with respect to acetylation of lysines 9 and 14 and to trimethylation of lysines 4 and 27 in histone H3 (all, false discovery rate, FDR < 0.1). In the HF-diet exposed offspring, 54% of the annotated genes showed the gene-activating mark trimethylated lysine 4. Many of these genes (1) are associated with the "metabolic process" in general and particularly with "positive regulation of cholesterol biosynthesis" (FDR = 0.03); (2) overlap with 455 quantitative trait loci for blood pressure, body weight, serum cholesterol (all, FDR < 0.1); and (3) are linked to cardiac disease susceptibility/progression, based on disease ontology analyses and scientific literature. These results indicate that maternal HF-diet changes the cardiac histone signature in offspring suggesting a fuel-mediated epigenetic reprogramming of cardiac tissue in utero.

Maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancy through metabolic stress and mitochondrial dysfunction.

Offspring of diabetic pregnancies are at risk of cardiovascular disease at birth and throughout life, purportedly through fuel-mediated influences on the developing heart. Preventative measures focus on glycemic control, but the contribution of additional offenders, including lipids, is not understood. Cellular bioenergetics can be influenced by both diabetes and hyperlipidemia and play a pivotal role in the pathophysiology of adult cardiovascular disease. This study investigated whether a maternal high-fat diet, independently or additively with diabetes, could impair fuel metabolism, mitochondrial function, and cardiac physiology in the developing offspring's heart. Sprague-Dawley rats fed a control or high-fat diet were administered placebo or streptozotocin to induce diabetes during pregnancy and then delivered offspring from four groups: control, diabetes exposed, diet exposed, and combination exposed. Cardiac function, cellular bioenergetics (mitochondrial stress test, glycolytic stress test, and palmitate oxidation assay), lipid peroxidation, mitochondrial histology, and copy number were determined. Diabetes-exposed offspring had impaired glycolytic and respiratory capacity and a reduced proton leak. High-fat diet-exposed offspring had increased mitochondrial copy number, increased lipid peroxidation, and evidence of mitochondrial dysfunction. Combination-exposed pups were most severely affected and demonstrated cardiac lipid droplet accumulation and diastolic/systolic cardiac dysfunction that mimics that of adult diabetic cardiomyopathy. This study is the first to demonstrate that a maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancies through metabolic stress and serves as a critical step in understanding the role of cellular bioenergetics in developmentally programmed cardiac disease.