Reproductive Health in the Spotlight

The Journey to Male Contraceptives: Where Are We Now? Proteomics in Endometriosis: A Less Invasive Path to Diagnosis What Drives Ovarian Aging and Fertility Decline? REPRODUCTIVE HEALTH IN THE SPOTLIGHT Credit: Technology Networks. CONTENTS 4 Environmental Pollutants: A Growing Concern for Reproductive Health 8 Fetal Therapy Could Offer a Lifeline for Children With Genetic Disorders 12 “Once a Parent, Always a Parent”: How Pregnancy Leaves Lasting Brain Changes 17 Proteomics in Endometriosis: A Less Invasive Path to Diagnosis 22 The Journey to Male Contraceptives: Where Are We Now? 27 What Drives Ovarian Aging and Fertility Decline? REPRODUCTIVE HEALTH IN THE SPOTLIGHT 3 TECHNOLOGYNETWORKS.COM FOREWORD Reproductive health impacts all stages of life. Not only is it necessary for procreation, but reproductive system changes occur throughout a person's life span, most notably during adolescence and menopause. Our understanding of reproductive well-being is evolving rapidly alongside advances in the diagnosis and treatment of reproductive system conditions and diseases. This eBook brings together a series of articles exploring the latest developments in reproductive health research, spanning topics such as ovarian aging, genetic fetal therapies, endometriosis diagnostics, and the effects of environmental pollutants on fertility. Through expert insights, this collection highlights practical applications, emerging challenges, and areas of ongoing research in this critical aspect of overall well-being. The Technology Networks editorial team 4 REPRODUCTIVE HEALTH IN THE SPOTLIGHT Environmental Pollutants: A Growing Concern for Reproductive Health Alexander Beadle For the past several decades, fertility rates have been in decline. In 1950, the global total fertility rate was around 4.8, meaning that the average woman could expect to have 4–5 children during her lifetime. By 2021, this fertility rate had more than halved to 2.3—just narrowly above the 2.1 figure needed for population size to remain stable. There are many potential reasons for this large shift in fertility rate over the past 70 years. Changes in lifestyle, economic conditions, improved access to contraception, and progress in women’s rights and autonomy are all important social factors. But scientists have also noticed a rise in male and female infertility in recent years. The increasing prevalence and incidence of other reproductive disorders, such as endometriosis and reduced sperm count, are also a concern. Again, multiple factors could be at play here. General awareness of reproductive health conditions is considerably higher now than it was many decades ago, and medical diagnostic technology has also improved. However, a growing body of evidence suggests that exposure to environmental toxins is also a key contributor to this rise in reproductive health issues. Credit: Technology Networks. TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 5 The health burden of environmental pollution Environmental pollutants have already been linked to a wide array of chronic and acute health conditions. Air pollution from automobile emissions, burning waste, and volcanic eruptions can disrupt the respiratory system, cardiovascular system, and has been linked to an increased risk of cancers. Long-term exposure to lead—a common environmental contaminant due to its long use as a component in old paints and pipes—can lead to chronic kidney disease and neurological issues. Now, research is beginning to shed light on the associations between environmental exposure to common pollutants and negative impacts on reproductive health and fertility. “Comprehensive reviews connect environmental exposures to early puberty, endometriosis, polycystic ovary syndrome (PCOS), early menopause, longer time-to-pregnancy (when actively trying to conceive), higher odds of being infertile (not able to conceive within 12 months), irregular cycles, lower quality of eggs and embryos, lower ovarian response to hormone stimulations during IVF treatments, and higher risk of miscarriage,” Prof. Pauliina Damdimopoulou, a professor of reproductive biology at the Karolinska Institutet, told Technology Networks. PFAS and POPs: A long-lasting threat Per- and polyfluoroalkyl substances (PFAS) are a family of thousands of highly fluorinated chemicals. PFAS found widespread use in the mid-20th century as a component in commercial grease- and waterproof coatings, and as an agent in industrial firefighting foams. While their extreme chemical stability made them useful for these purposes, the stability of PFAS also presents a stark environmental challenge; their relative inability to degrade naturally in the environment means that they easily move through soils and water, where they can contaminate drinking water sources and fishing grounds. Select PFAS—such as PFOS, PFOA, PFHxS—have been phased out of use, in recognition of their potential harms. However, thousands of other PFAS compounds remain with no restrictions on their production or use. Legacy PFAS and emerging PFAS alternatives also continue to pose risks to the environment, aquatic life, and human health. In terms of the risk these compounds may pose to reproductive health, studies have linked both longchain and short-chain PFAS to female reproductive health problems, including PCOS, premature ovarian failure, endometriosis, reproductive system tumors, and pregnancy complications. Under the Stockholm Convention, PFAS are classified as persistent organic pollutants (POPs). Like PFAS, many other POPs have been linked to reproductive health issues. Persistent organic pollutants (POPs) As defined by the Stockholm Convention on Persistent Organic Pollutants, POPs are carbon-based chemical substances that: remain intact in the environment for many years; can become widely distributed in the environment via natural processes; accumulate inside living organisms; and are toxic to humans and wildlife. “Persistent chemicals are particularly concerning as their half-lives are so long in our bodies. If we stop all use today (there are no signs that this will happen), they will still remain in our bodies, pass on to our fetuses, and contaminate our food chain for decades to come,” Damdimopoulou said. “The longer we allow toxic persistent chemicals on the market, the longer down the generations the problems are passed.” TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 6 Endocrine-disrupting chemicals (EDCs) and female fertility PFAS and many other POPs also belong to another much larger class of chemicals, known as endocrinedisrupting chemicals (EDCs). EDCs can impact the body through a number of different mechanisms. Some EDCs are “hormone mimics” that trick the body into reacting to them, while others actively block the body's naturally produced hormones. Other EDCs make their effects felt by affecting how hormones are made, broken down, or stored in the body, which in turn can dramatically affect the levels of hormones circulating in the bloodstream. “Chemicals that disrupt the hormonal system are no good. They can interfere with the development of the ovaries and eggs in the uterus, which translate to reproductive health consequences later in life, and they can affect the functioning of the ovary in adulthood (hormone production, egg production),” Damdimopoulou explained. Damdimopoulou’s research focuses on understanding how different mixtures of EDCs impact women’s fertility, with a special emphasis on how these chemicals affect the ovary. “My studies have found complex mixtures of POPs, phthalates, parabens, and air pollution particles in serum and/or ovarian follicular fluid of reproductive age women living in Sweden. Further, we have seen that these chemicals pass the placenta and can be detected in vital organs of fetuses,” Damdimopoulou said. “We have seen significant associations between the mixture exposures in women and the size of her ovarian reserve (how many eggs the woman has left), how the follicles that house the eggs grow to ovulation, the quality of the embryos that the eggs become, the time it takes for her to get pregnant, and her risk of being diagnosed with infertility.” Using cell and tissue culture models, Damdimopoulou’s research group can closely study the effects of environmental pollutants on human endometrial cells and reproductive system tissue, and in turn, learn more about how these pollutants exert their effects. “When we study some of these chemicals further in the laboratory, using donated small pieces of ovarian tissue in culture, we can confirm that phthalates and POPs disrupt energy balance in the tissue, leading to increased death of the follicles,” Damdimopoulou said. “Furthermore, the exposures appear to disrupt the structure of the cells as well as lipid metabolism. We have learned that chemicals act in multiple different ways; EDCs can also disrupt energy and cell structures, not only hormone signaling.” The rise of microplastics Microplastics can be found in almost every corner of the planet—from the depths of the Mariana Trench to the peaks of remote mountain ranges. Despite their large footprint, the tiny size of microplastics has meant that the damage these particles cause to local ecosystems and to public health has only now started to become clear. “Despite the several technical limitations in methods to quantify micro- and nanoplastics precisely, these particles are found everywhere, including our reproductive tissues,” said Damdimopoulou. Human exposure to nano- and microplastics can happen through many routes, including inhaling airborne particles, eating contaminated fish or other foods, and through contact with contaminated materials, such as soil. The accumulation of plastic particles in the placenta has been linked to inflammation, oxidative stress, diminished microbiome diversity, reduced birthweights, and worse fetal growth and development. In addition to the physical accumulation of microplastics in the body, these plastics also present a chemical toxicity risk. As they move through the environment, microplastics can act as a vehicle for other chemical contaminants, which may carry their TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 7 own health risks. Recent studies also suggest that some chemical additives used in plastics production can leach out of microplastics and enter the body via dermal contact. “As plastics are inseparably connected to chemicals (no registries exist, but estimates suggest that ca. 16,000 chemicals are used in the production of plastics, out of which 4,200 are of concern due to being persistent, bioaccumulative, mobile, and/or toxic), microplastics also carry chemical additives and contaminants with them,” said Damdimopoulou. “No one knows what this combination of tiny particles and problematic chemicals does to us—or the environment.” “Experimental studies across multiple types of animals from fish and waterfleas to rodents suggest negative health effects, including reduced fertility in males and females,” Damdimopoulou added. How can research help to safeguard reproductive health? Experimental evidence has shown clear links between exposure to EDCs and the development of reproductive disorders. Early results with microplastics show similar effects, with the plastic particles either acting as a “Trojan Horse” for EDCs or through their physical accumulation in tissues. Exposure to these environmental pollutants is considered a contributing factor to the broader rise in the prevalence of reproductive disorders. To safeguard public health, researchers stress the need for tighter regulations on chemical testing, with more consideration given to potential reproductive health risks. “The solution is to introduce legislation that requires chemicals to be thoroughly tested before they are allowed on the market. Sadly, this is currently not the case. An additional solution is to introduce clear rules for chemicals that already are on the market; if they are found to be endocrine-disruptive or toxic to reproduction, they should be phased out across all pieces of legislation,” Damdimopoulou suggested. “Finally, when chemicals are tested, the methods should be appropriate; sensitive and human-relevant, and measuring the right things.” “Due to limited access to samples (and perhaps limited interest), we are only now mapping the key female reproductive organs, like the ovaries and endometrium, to understand what cells they are made of, how they respond to hormones, and what goes wrong in diseases like endometriosis and PCOS,” Damdimopoulou continued. “In order to protect women, we need detailed knowledge on these key organs so that we can develop human-relevant and sensitive test methods for assessment of reproductive toxicity in women.” ABOUT THE INTERVIEWEE: Prof. Pauliina Damdimopoulou is a professor of reproductive biology in the Department of Women’s and Children’s Health at the Karolinska Institutet, Sweden. Her research focuses on effects of environmental exposures on female fertility. In the Damdimopoulou Lab, researchers use primary human ovarian tissue to study the cellular and chemical composition of the ovary, age-related changes, and the effects of environmental stressors and gonadotoxic therapies on ovarian function. 8 REPRODUCTIVE HEALTH IN THE SPOTLIGHT Fetal Therapy Could Offer a Lifeline for Children With Genetic Disorders Blake Forman Genetic disorders with onset before birth are a leading cause of death in infants and children. Thanks to advances in imaging and genetic diagnostic technologies, clinicians can now detect many of these disorders in the womb. This has opened the door to fetal therapies that allow clinicians to intervene before irreversible damage occurs. Fetal therapies have evolved from invasive open surgical procedures to investigational therapies that utilize advanced technologies such as stem cells and gene editing. This transformation has drastically changed the possibilities for treating genetic disorders in utero. Intervening before birth could preempt early organ damage and improve perinatal outcomes. Natural fetal immune tolerance, coupled with high cellular turnover, could even enhance therapeutic impact. Despite the many potential benefits of fetal therapies, there has historically been a lack of appetite among pharmaceutical companies to invest in research for therapies that are used during pregnancy. This is often rooted in fears of maternal-fetal complications, lack of guidance on how to conduct clinical trials involving pregnant women, and the legal implications of treating both fetus and mother simultaneously. Against this backdrop, can fetal therapy redefine the standard of care for rare genetic disorders? Credit: Technology Networks. TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 9 A new era for fetal therapies Key drivers advancing fetal therapies towards the clinic include developments in prenatal imaging and next-generation sequencing (NGS), which have enabled clinicians to identify and characterize genetic disorders in utero. “Improvements in 3D USS [ultrasound] and MRI [magnetic resonance imaging] (especially superresolution reconstruction techniques for MRI) are improving our ability to make an informed prenatal diagnosis,” Prof. Anna David, a professor of obstetrics and maternal fetal medicine at University College London (UCL), told Technology Networks. Advances in imaging have not only improved diagnosis but have also enabled the safe delivery of therapeutics to the fetus. “With current ultrasound technology, it is very straightforward and extremely safe to administer drugs, as well as cell and gene therapies, to the fetus by a simple percutaneous injection, similar to amniocentesis,” Prof. Graça Almeida-Porada, a professor of regenerative medicine at the Wake Forest Institute for Regenerative Medicine, told Technology Networks. These improvements, combined with the ability to use NGS approaches during pregnancy, such as gene panels, exome sequencing, and whole genome sequencing, mean it's now possible to detect a range of rare genetic disorders in the womb. Alongside improved diagnostics, therapies themselves are advancing. In gene therapy, new vectors and more targeted delivery technologies are being developed, leading to safer and more precise therapeutics. “Gene editing platforms have advanced tremendously in recent years, as the field has moved from CRISPR/ Cas-based editing that requires induction of doublestrand breaks within the DNA to base editors, and more recently to the most advanced platform prime editors,” Prof. Christopher Porada, a professor at the Wake Forest Institute for Regenerative Medicine, told Technology Networks. “As the field has evolved, each new technology has become more precise and has promised ever-higher specificity with a lower risk of off-target effects. Each of these improvements in the safety and precision of gene editing has brought the possibility of using such treatments in the fetus closer to clinical reality,” Porada continued. Deadly disorders treated in utero for the first time Technological advances in prenatal diagnostics and treatment aren’t just theoretical. An increasing number of real-world cases are emerging of fetal therapies being used to treat patients in the womb. In February 2025, it was reported that a child diagnosed with spinal muscular atrophy (SMA) had no identifiable features of SMA two years after in utero treatment with the small molecule drug risdiplam. SMA is caused by recessive loss-of-function mutations in the SMN1 gene, leading to a lack of the survival motor neuron protein. This protein is important for development, particularly in the third trimester and the first three months after birth. Early intervention is therefore critical to managing symptom severity. The risdiplam case study demonstrates the safety and feasibility of treating SMA in utero using an orally administered drug. The same year, a team of researchers found that antisense oligonucleotides (ASOs) delivered via amniotic fluid injection could improve treatment outcomes of SMA in mouse models. The ASOs restore production of full-length SMN protein by repairing the splicing of the mRNA encoded by the SMN2 gene, which is retained in SMA patients but normally produces only truncated, nonfunctional SMN protein. The researchers are now looking to optimize the ASOs to find one suitable for clinical trials. Outside of rare genetic disorders, gene therapy approaches have also been proposed to treat fetal growth restriction (FGR), using adenoviral vectors. “The gene therapy that we are proposing is a short-term increased expression of the VEGF protein locally in the TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 10 uteroplacental circulation,” said David. “Gene therapy allows a targeted approach in this condition, where we know that there is reduced availability of the VEGF protein at the level of the uterine circulation. “Early studies in two preclinical models of FGR have shown that this approach increases fetal growth without any evidence of harm to the fetus, neonate, or mother. There is a spread of the vector to the maternal tissues, especially the liver, where the vector is broken down. But importantly, there is no spread to the fetal tissues, especially none in the fetal gonads, which is reassuring for safety.” David and colleagues have since interviewed stakeholders and parents who have experienced severe early-onset FGR about the possibility of a clinical trial of maternal VEGF gene therapy. “The response was positive, with parents especially welcoming a potential treatment to improve their baby’s outcome,” David said. Beyond gene therapy, fetal stem cell therapies that leverage the functional immaturity of the fetal immune system hold promise. “At UCL, we are developing gene editing approaches to correct fetal stem cells ex vivo, using amniotic fluid stem cells collected via amniocentesis and then injecting the gene-corrected cells back into the fetus for therapeutic effect,” said David. In utero stem cell approaches have the advantage of targeting cells or organs inaccessible in adult life, while avoiding sequestration of stem cells in the lungs after injection into the umbilical vein. In addition, the small size of the fetus reduces the number of stem cells required for treatment. “Many barriers that preclude efficient drug and gene delivery in the postnatal patient (e.g., the blood-brainbarrier, the mucous barrier in the airway, specifically in the setting of cystic fibrosis) are either not present or are still forming, allowing efficient delivery of therapeutics to these cells/tissues,” Almeida-Porada stated. “The fetus is also suspended in amniotic fluid, which it is constantly swallowing/breathing during development. This serves as a unique and facile delivery route for therapeutics that need to reach the airways and the GI tract.” Enzyme replacement therapy—whereby functional, manufactured enzymes are administered to a patient to replace missing or deficient enzymes—also holds promise as a fetal therapy. A study, published in the New England Journal of Medicine, reported successful treatment of infantile-onset Pompe disease by initiating enzyme replacement therapy during fetal development. The child, Ayla, was given six prenatal enzyme replacement treatments. As a result, Ayla was born at term and at 16 months of age was reported to have normal cardiac and motor function. Clinical trial challenges hold back progress Despite promising results in preclinical models and case studies, moving fetal therapies into clinical trials has required years of work. One of the challenges was the lack of definitions for what constitutes an adverse event in the mother and baby. David now believes this challenge has been addressed: “When we first looked at how to assess safety, such as adverse events in clinical trials, we were shocked to discover that the usual terminology systems, such as CTCAE [Common Terminology Criteria for Adverse Events] or DAIDS [Division of AIDS], only had a “The biology of the fetus makes it a far better recipient for cell and gene therapy than an adult, child, or even an infant,” explained Almeida-Porada. TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 11 handful of adverse event definitions for maternal or fetal complications that might result from drug treatments. This meant that it was impossible to accurately assess the safety of any intervention—be it drug or device—in pregnancy.” Maternal Fetal Adverse Event Terminology [MFAET] was launched by David and team in 2021 with 38 new definitions of safety signals observed in the mother and fetus. David explains that this is the “first and only terminology to address improving the safety of clinical trials in pregnancy, describing adverse events in the mother and fetus.” Not only has a lack of definitions held back clinical trial progress, but Porada believes that “the preconceived notion that treatments must first be tested in adults, then in children” has plagued the advancement of fetal cell and gene-based therapies. “While this paradigm of testing first in adults often works when trying to develop therapeutics for adolescents, and in some cases for children, it is often completely invalid in the case of in utero therapies, which are specifically designed to be age-bespoke, taking advantage of the distinctive physiology and immunology of the fetal recipient, and the unique opportunities they create,” said Porada. Even with these barriers, progress has been made, and today, various clinical trials are underway to investigate the effects of fetal therapies. “At present, in utero stem cell transplantation has already been performed, on a compassionate use basis, on over 50 human patients for more than a dozen genetic disorders, and 3 clinical trials are being performed,” stated Almeida-Porada. The next steps for fetal medicine The outlook for fetal therapies is improving thanks to emerging tools for prenatal diagnosis. Porada envisions that further advances in digital PCR could pave the way for the validation and widespread acceptance of prenatal diagnosis for most genetic disorders. This could be performed by drawing blood from the pregnant woman and analyzing the cell-free fetal DNA present. While resistance still exists to the application of genebased therapies to fetal recipients, further advances in cell-targeting and specificity could help overcome uncertainties regarding the risk of off-target effects. More robust data on the mutagenesis risk will allow regulatory agencies to make more informed riskto- benefit calculations when evaluating proposed trials using these therapies. The path to getting these therapies into the clinic may be difficult. But Almeida- Porada hopes that “ongoing trials will help to change the entire paradigm for how we diagnose and treat most genetic disorders within the coming years.” MEET THE INTERVIEWEES Prof. Anna David is an academic obstetrician and maternal fetal medicine specialist in the UK. David is director of the Elizabeth Garrett Anderson Institute for Women’s Health at University College London (UCL) and an honorary consultant in obstetrics and maternal fetal medicine at UCL Hospital (UCLH). Clinically, she specializes in fetal medicine, early-onset fetal growth restriction, and prevention of preterm birth. Her research is in translational medicine and prenatal therapy. Her lab is developing novel prenatal therapies using stem cells and gene therapy for life-threatening disorders such as single-gene disorders and obstetric complications such as fetal growth restriction. Prof. Christopher Porada is a professor at the Wake Forest Institute for Regenerative Medicine. For the past 25 years, his research has focused on developing safer and more efficient means of accomplishing gene transfer into clinically relevant cell types in vivo. His goal is to help develop safe, effective treatments for monogenic diseases that could be administered shortly after or prior to birth. Porada holds a PhD from the University of Nevada. Prof. Graça Almeida-Porada is a professor of regenerative medicine at the Wake Forest Institute for Regenerative Medicine (WFIRM), and a professor in the Department of Cancer Medicine, Section of Hematology and Oncology, and in the School of Biomedical Engineering and Sciences at the Wake Forest School of Medicine. She founded and leads the Fetal Research and Therapy Program at WFIRM, which is aimed at pursuing basic and translational research to develop prenatal treatments for genetic disorders and other life-threatening conditions. Her research focuses on the development of cellular and gene delivery platforms to treat genetic and immune-mediated diseases. She is particularly interested in improving the outcome of stem cell transplantation and gene therapy in prenatal recipients and children with genetic disorders, to cure diseases before they start. 12 REPRODUCTIVE HEALTH IN THE SPOTLIGHT “Once a Parent, Always a Parent”: How Pregnancy Leaves Lasting Brain Changes Rhianna-lily Smith Pregnancy is often described in terms of hormones, physical symptoms, and bodily changes. But one of the most significant organs undergoing transformation is the brain. Recently, neuroscience research has begun to reveal that pregnancy represents one of the most dramatic periods of adult neuroplasticity outside of adolescence. Rather than being passively affected by shifting hormones, the brain appears to be actively reorganizing itself—structurally and functionally—in preparation for caregiving. These changes unfold over time, with early pregnancy, late pregnancy, and the postpartum period each involving distinct neural processes, forming what researchers describe as a coordinated brain transition. “We know that the brain changes significantly across pregnancy and the postpartum period,” said Dr. Jodi Pawluski, a neuroscientist and author passionate about the neuroscience of motherhood and perinatal mental health. Dr. Elseline Hoekzema, the head of the Pregnancy Brain Lab at the Amsterdam University Medical Center, whose neuroimaging research has mapped structural changes across pregnancy, agreed: “I think in general pregnancy is now considered a period of great brain plasticity.” Credit: Technology Networks. TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 13 Technology Networks spoke with Pawluski and Hoekzema to understand the processes behind this transformation. Early pregnancy: Opening a window of plasticity In early pregnancy, hormonal levels begin to rise rapidly. Estrogen, progesterone, and human chorionic gonadotropin increase in concentration, and the brain is one of their primary targets. Estrogen and progesterone bind to receptors widely distributed throughout the brain, which influences synaptic growth, neuronal excitability, and gene expression, particularly in regions involved in emotion and stress regulation, such as the amygdala and hypothalamus. However, hormones are not simple switches that dictate behavior. “We love to talk about hormones and how they rule our worlds, especially as women,” Pawluski said. “But we don't have the data that shows that there's a clear relationship between hormonal shifts, except for a lot of correlative data.” Instead, researchers are starting to think of these hormones as modulators of plasticity—biological signals that open a window during which neural circuits can reorganize. “In early pregnancy, hormonal shifts are still relatively subtle, and so are the brain changes,” Hoekzema explained. Even so, early pregnancy appears to prime the brain for adaptation. Emotional sensitivity can shift, vigilance and threat detection may increase, and attention and motivation begin to change, which may reflect the brain beginning to reprioritize. “What we see in those individuals who have experienced pregnancy is that pregnancy itself has a significant impact on the brain structure, as well as function,” Pawluski said. “There is some research showing that there's an association between the increases in estradiol and progesterone and the decreases in brain structure across pregnancy,” Pawluski noted. But she cautioned against oversimplification: “We don't know at what level hormone shifts in humans play a role in the brain. We don't have a clear story, and so I think we have to be very careful not to assume that hormones are responsible for all brain changes at various points in a woman's life.” In rodent models, hormonal priming during pregnancy alters neural responsiveness to offspring. “We know from animal research that hormones play a role in how the brain is becoming better prepared to respond to offspring,” Pawluski said. “Lab rats who have not given birth take longer to respond to young than maternal rats who have been pregnant; they respond rapidly—that rapid response to young has to do with the priming of the brain.” In other words, early pregnancy may set the stage for the more dramatic remodeling that follows. Late pregnancy: Refinement and neural specialization By the third trimester, brain changes become more robust and measurable. Longitudinal MRI studies have shown consistent reductions in gray matter volume in specific brain regions. “[Brain changes] are most strongly observed in late pregnancy,” Hoekzema said. “We have also found strong associations between the changes in brain structure and different types of estrogens (estradiol and estriol) in the third trimester of pregnancy.” These changes occur primarily in neural networks involved in social cognition and the default mode network—regions such as the medial prefrontal cortex and temporoparietal junction. TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 14 Default mode network A network of interconnected brain regions that becomes active when the mind is at rest and during introspection. Although the idea of gray matter reduction sounds alarming, neuroscientists interpret these changes as refinement rather than damage—akin to synaptic pruning during adolescence, when neural circuits become more efficient. “I think one of the biggest misconceptions is that this must be a pure degenerative process, as if becoming a mother would only result in function loss,” Hoekzema said. “That preparing to care for a child would be preceded merely by neural degenerations that may actually impede this process.” Pawluski echoes this interpretation: “In late pregnancy, the research is showing that structurally, there seems to be a consistent decrease,” she said. “The structure of the whole brain is fine-tuned, or diminished in size, but these changes are also associated with an increase in sensitivity.” Hoekzema’s research has linked structural changes to a mother’s neural and emotional responses to infants. “We have found associations between changes in brain structure and function and a mother’s neural, physiological, and emotional response to infants,” she said. “This also includes changes within the brain’s reward system, which are associated with a stronger reward response to infants.” These adaptations seem to begin before birth: “Similar to other mammals, these brain changes seem to influence the way a woman’s body and brain respond to infant cues,” Hoekzema said. “We have observed associations with nesting behavior (e.g., feeling an intense urge to clean the house).” Evidence is still emerging on how late-stage pregnancy brain adaptations influence behavior. “I think we need more research on this,” Pawluski added. “Essentially, I don't think we have a lot of information that can tell us that brain changes late in pregnancy are associated with improving caregiving demands before birth.” Subtle cognitive shifts observed in late pregnancy may reflect reprioritization rather than decline. “Pregnant women have enhanced memory for parenting-related objects,” Pawluski noted. “This speaks to the idea that perhaps the brain is picking and choosing what it's going to attend to and what it is going to remember.” The late-pregnancy brain appears to be narrowing its focus—becoming more efficient at processing information relevant to caregiving. Postpartum: Experience, bonding, and continued plasticity Birth does not end this process. If anything, it accelerates it. “In the postpartum period, interaction with the infant continues to shape the brain and further adjust maternal brain circuits,” Hoekzema said. Hormones such as oxytocin, which surge during childbirth and breastfeeding, also interact with dopamine pathways in the brain’s reward system. Together, these signals may help reinforce caregiving behaviors and increase sensitivity to infant cues. Between four and six months postpartum, some brain regions, including parts of the prefrontal cortex, show volume increases. “When looking at structural changes, it's quite dynamic in the postpartum period,” Pawluski explained. “There seems to be a bit of an increase in the volume of certain brain areas in the early postpartum period, and this increase in structures is associated with how well a parent feels they're performing as a parent.” TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 15 “But then after that period, there's been consistent research showing that it's back to this kind of diminished size that occurs up to two to six years postpartum,” Pawluski said. “There seems to be this shrinkage of the brain, or fine-tuning of the brain, for a long time that starts in pregnancy and continues.” However, diminished size does not mean diminished capacity. “This doesn't mean that the brain's being pruned and you're losing synapses,” Pawluski said. “There could be either increases in synapses, or that the neurons that are there are becoming more efficient, and you don't need as many.” Some of these changes appear to persist for years. “We have found that these [permanent changes] persist until at least six years postpartum,” Hoekzema said. New research suggests that these neural adaptations may not simply reset between pregnancies. Hoekzema and colleagues found that a second pregnancy continued to remodel the brain, but in a different way than the first. While the initial transition to motherhood strongly affected networks involved in social cognition, subsequent pregnancies showed greater changes in attention and somatomotor systems—regions linked to responding to sensory cues and coordinating physical actions. The postpartum brain is also shaped by experience. Repeated exposure to infant cries, facial expressions, and scent may further shape neural circuits through experiencedependent plasticity, strengthening connections in sensory and emotional processing networks. “Parenting impacts, or marks, the brain,” Pawluski said. “You can tell if someone's been pregnant or not through looking at brain scans.” “Once a parent, always a parent,” she added. TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 16 Rethinking “pregnancy brain” Despite persistent cultural narratives about “pregnancy brain,” evidence for global cognitive decline is weak. “So far, we have not found clear indications of memory declines with pregnancy,” Hoekzema said. “Some women will report that they feel their brain isn't working as it should,” Pawluski added. “However, if they're brought into a lab and asked to perform on memory tests, they often perform exactly or just as well as a non-pregnant or a non-maternal female.” In one study, pregnant participants were more likely to fail memory tasks when completing them at home— amid distractions—than in controlled laboratory settings. That suggests the so-called “mom brain” may reflect cognitive load and environmental demands rather than dysfunction. “The transition to motherhood socially is fraught with a whole bunch of pressures,” Pawluski said. “However, if they're given the opportunity to perform memory tasks in an environment that's conducive to concentration and reduced distractions, they can perform quite well.” For Pawluski, the biggest misconception is that pregnancy renders the brain dysfunctional. “This is adaptive, normal, and this is healthy,” she said. “This is supposed to happen.” Pregnancy and postpartum represent not decline, but transformation—a coordinated recalibration of structure, connectivity, and sensitivity in service of caregiving. Far from diminishing the brain, motherhood reveals its capacity for profound and enduring change. ABOUT THE INTERVIEWEES: Dr. Jodi Pawluski is a neuroscientist, therapist, and science communicator specializing in the neuroscience of motherhood and perinatal mental health. Her work centers around understanding and providing care for brain changes during the transition to motherhood and maternal mental health conditions. Dr. Elseline Hoekzema is the head of the Pregnancy Brain Lab in the Amsterdam University Medical Center. Her research has shown that becoming a mother renders changes in the grey matter structure and neural activity in women’s brains. Recently, her group has also tracked changes in first-time and second-time mothers for the first time. Her work is funded primarily by the European Research Council and the Netherlands Organization for Scientific Research. 17 REPRODUCTIVE HEALTH IN THE SPOTLIGHT Proteomics in Endometriosis: A Less Invasive Path to Diagnosis Laura Elizabeth Lansdowne Diagnosing endometriosis has traditionally been a slow and difficult process. In the United States and the United Kingdom, clinical guidance now acknowledges that relying solely on surgery to confirm the condition has contributed to long delays, often spanning many years. To improve this, clinicians are now encouraged to suspect and manage endometriosis based on an individual’s symptoms, medical history, and imaging, rather than delaying care until it’s confirmed by invasive laparoscopic surgery. Public awareness has grown in recent years, helped by celebrities speaking openly about their experiences. Comedian Amy Schumer, for example, described endometriosis as “a lonely, lonely disease” and shared that doctors removed 30 lesions and her appendix during surgery—highlighting how severe the condition can be despite being invisible from the outside. What is endometriosis? Endometriosis is a chronic, progressive condition where tissue similar to the lining of the uterus grows outside of it—often forming patches of tissue (known as lesions) on the ovaries, fallopian tubes, and the lining of the pelvis. These lesions respond to hormonal changes that can lead to inflammation, pain, and scarring. Credit: Technology Networks. TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 18 The increase in awareness and changes to clinical practice coincide with efforts from patient advocacy groups, the scientific community, and government agencies to better understand what is happening inside the body. For example, in 2024, the National Institutes of Health launched the RADx® Tech ACT ENDO Challenge to accelerate the development of noninvasive diagnostic tools for endometriosis. Researchers now recognize that endometriosis is an estrogen-dependent, chronic, whole-body inflammatory condition—not just tissue growing where it shouldn’t. It is characterized by elevated inflammatory markers, which can fluctuate with the menstrual cycle. Unlike many other inflammatory diseases, this inflammation is closely linked to hormonal activity, impacting the timing and severity of symptoms. New technologies—especially proteomics, the study of proteins—are helping scientists uncover the biological processes driving the disease and its symptoms. These insights could help speed up diagnosis and lead to more targeted treatment options. Why is diagnosing endometriosis so difficult? Endometriosis doesn’t look the same for everyone. Symptoms can include severe bloating, painful periods, pelvic pain, pain during or after sexual intercourse, bowel or bladder symptoms, fatigue, and fertility challenges— many of which overlap with other conditions. Associate Professor Sarah Holdsworth-Carson, research manager at the Moyna Fox Fertility Research Centre, focuses on improving the diagnosis and classification of endometriosis through translational research that connects laboratory findings with patient care. “There are so many symptoms linked to endometriosis, and people with the condition can have a combination of these symptoms or be completely asymptomatic… Education at the community and medical level is critical to improving recognition,” she explained. Like many, she has lived experience of the condition but was fortunate to receive an early diagnosis at the age of 19, during her undergraduate degree. This, she notes, strongly influenced her decision to pursue research in women’s health. “As my knowledge about endometriosis grew, I became fascinated by the heterogeneity of the condition, both at the symptom level and the appearance of lesions,” she added. The wide range of symptoms—combined with social stigma—explains why diagnosis is typically delayed. “As a society, we are not very good at talking to peers, family, or health professionals about menstrual health and painful periods or intercourse. There is a normalization of pain associated with menstruation, and many people do not seek help,” she said. Findings from an online survey of > 3,000 people diagnosed with endometriosis, conducted by Endometriosis UK, showed that, on average, it took 3.5 years from first noticing symptoms to seeking medical help. Even then, many did not feel heard: 83% of respondents reported being told their symptoms were normal, that they were “making a fuss about nothing”, or experienced similar dismissal from a healthcare professional. In a video intended to raise awareness and encourage others to seek help, Schumer said : "You know, for months, I had been complaining of pain…it was just this pain you can't see. And, you know, there is the inclination to always think a woman is just being dramatic. We have to advocate for ourselves; we have to speak up.” When you combine repeated dismissive experiences with the vast array of physical symptoms, it’s understandable that mental health can suffer. A large study from Yale School of Medicine, analyzing > 8,200 individuals with endometriosis and 194,000 controls, found significantly higher rates of depression, anxiety, and eating disorders among those with the condition. TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 19 “Early detection and therefore more timely treatment of endometriosis could theoretically reduce the risk of developing chronic pain symptoms and infertility,” emphasized Holdsworth‑Carson. What biology is revealing about the disease Although the exact cause of endometriosis remains unknown, scientists have identified several key processes that help explain why the disease persists and causes pain. These include chronic inflammation, immune system changes, new blood vessel growth (angiogenesis), and nerve growth. “Immune dysregulation is likely responsible for the establishment and progression of lesions, and the resulting inflammatory environment,” said Holdsworth- Carson. Endometriosis involves both the innate immune system and the adaptive immune system. Innate immune activity promotes an inflammatory environment, while adaptive immune dysfunction reduces the body’s ability to clear abnormal cells. “There are many unanswered questions… but a focus on the heterogeneity of endometriosis lesions is needed to develop more meaningful disease stratification and personalized treatment options,” she added. Different lesion types (i.e., superficial, deep infiltrating, ovarian) show distinct biology and behavior, with differences in molecular profiles, depth of invasion, and related symptoms. The role of angiogenesis in endometriosis Endometriotic lesions require a blood supply to survive. Angiogenesis—the formation of new blood vessels—is normally tightly regulated by a balance between pro-angiogenic and anti-angiogenic signals. In endometriosis, excess pro-angiogenic signals, particularly via vascular endothelial growth factor (VEGF) signaling, trigger the sprouting of new vessels. This provides oxygen and nutrients to lesions, allowing them to establish and grow outside the uterus. “Angiogenesis plays an essential role in the growth and survival of endometriotic lesions in endometriosis,” explained Professor Ronald Wang, division head of the Department of Obstetrics & Gynaecology at The Chinese University of Hong Kong. Wang’s research focuses on reproduction and development. Lymphatic vessels also play a role, facilitating the spread of endometrial cells and supporting immune cell trafficking, which, together, contribute to the chronic inflammatory environment. This process is closely linked to immune dysregulation. Pro-inflammatory cytokines stimulate the production of vascular growth factors, creating a feedback loop that sustains inflammation and lesion growth. Many of the proteins involved in these pathways— including VEGF family members—are measurable in biological fluids, making them attractive candidates for proteomics-based diagnostics. One key molecule is vascular endothelial growth factor C (VEGF-C), which is elevated in ectopic endometrial tissue. VEGF-C promotes endothelial cell activity, increases vascular permeability, and supports both angiogenesis and lymphangiogenesis—the formation of new lymphatic vessels. As Wang explains, “because VEGF-C is involved in disease progression, it holds promise as a potential biomarker and therapeutic target. Detecting or modulating this pathway could open new avenues for both diagnosis and treatment.” “Our studies suggested VEGF-C as a potential biomarker of angiogenesis and a target of antiangiogenesis therapy for endometriosis. How specifically and sensitively VEGF-C can be detected by biochemical, molecular, or imaging methods—and how it can be targeted by new or existing pharmaceuticals for diagnosis and treatment of endometriosis—may require further studies,” said Wang. TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 20 Biomarkers like VEGF-C can be measured using techniques such as enzyme-linked immunosorbent assay and liquid chromatography–mass spectrometry (MS). Emerging approaches, including AI-assisted drug discovery, may also help identify promising therapies that can target angiogenesis pathways. Why we still don’t have a reliable blood test Despite decades of research, there is currently no widely approved, clinically validated biomarker test that can definitively diagnose endometriosis on its own. Blood tests that focus on cancer antigen 125 (a protein sometimes elevated in endometriosis) can be measured, but they’re not specific or sensitive enough to diagnose or rule out disease by themselves, and levels can be elevated by other conditions, such as ovarian cancer. Some countries are exploring alternative diagnostic tools; for example, researchers in France have developed a saliva‑based test, which has been supported by the French government. A lot of Holdsworth-Carson’s research had originally focused on the genomics/transcriptomics of endometriosis, and as she puts it, “frustratingly, these avenues don’t really reflect the dynamic nature of the disease, whereas a large‑scale proteomics approach gives a real‑time functional snapshot.” Proteomic studies can identify hundreds of proteins that differ between people with and without endometriosis. One study, involving Wang, used proteomic profiling to reveal diverse protein patterns across clinical samples. By systemically integrating and analyzing these data, it highlighted potential biomarkers that could support earlier, non-invasive diagnosis and offered insights into novel therapeutic targets. A promising step toward non-invasive diagnostics came from researchers at the University of Melbourne and the Royal Women’s Hospital, in collaboration with Proteomics International Laboratories. Using a proteomics workflow, the team analyzed plasma samples to identify and validate protein biomarkers associated with endometriosis. This approach goes beyond single-marker testing by capturing a broader snapshot of disease biology. Speaking about the development of this blood test —the Promarker®Endo—which utilizes precision MS technology, Holdsworth-Carson explained: “I was interested in two factors: 1) non-invasively diagnosing endometriosis, avoiding the need for invasive or intimate procedures (such as surgery and vaginal ultrasound), which a routine blood test could offer, and 2) applying a technology that better illustrates the real-time functional snapshot of disease mechanisms, progression and differences relevant to disease changes and treatment response, which a large-scale proteomics approach could do.” She emphasized that endometriotic lesions are highly heterogeneous and dynamic, with appearances changing over time, and that intra-individual variation adds complexity: “A biomarker for endometriosis would need to accommodate these potential differences. As proteomics can capture real-time biological state, this approach [PromarkerEndo] holds a lot of promise.” The study, which involved Holdsworth-Carson, demonstrated that panels of circulating proteins could distinguish individuals with endometriosis from those without it. Wang noted: “Proteomics is good to provide functional insights, discover biomarkers, and more direct clinical applications”, but cautioned that it also “has a wide dynamic analytical range leading to high detection variability.” Because endometriosis is so heterogeneous, combining proteins, genes, and metabolites—known as multiomics—may reveal a clearer picture. TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 21 Three goals for the future Holdsworth‑Carson outlined three key goals for the future application of proteomics in endometriosis: ∙ Better classification of the disease: akin to molecular staging in breast cancer, allowing individuals to receive tailored treatment. ∙ Routine monitoring: capturing how the disease changes over time using non-invasive tests—such as blood, urine, or other bodily fluids—so management and treatment can be adjusted based on realtime profiles. ∙ Integration with multiomics: combining proteomics with other ‘omics technologies and patient-specific clinical data to build a multidimensional diagnostic framework. As proteomics and multiomics methods advance, the hope is that earlier diagnosis, individualized treatment, and better long-term management will become possible. ABOUT THE INTERVIEWEES: Dr. Ronald Chi Chiu Wang is professor, division head, and deputy director of the Prenatal Genetic Diagnosis Centre, Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong. He earned his MBBS with honors in 1994, a PhD in surgical sciences in 1998, and a PhD in genetics in 2011. His research focuses on reproduction and development, with over 340 publications in leading journals and 22 patents. Associate Prof. Sarah Holdsworth-Carson is the research manager of the Moyna Fox Fertility Research Centre. With a PhD in obstetrics and gynecology from the University of Melbourne and an established track record in endometriosis and gynecological research. Holdsworth-Carson has an established publication record in high-impact journals such as Nature, BMC Medicine, Human Reproduction, and Reproductive Sciences, contributing to advances in our understanding of endometrial biology. 22 REPRODUCTIVE HEALTH IN THE SPOTLIGHT The Journey to Male Contraceptives: Where Are We Now? Izzy Hirst For women, the debut of the first contraceptive pill was, at the time, revolutionary—they gained greater control over if-and-when they had children, which broadened access to opportunities outside of family life and transformed societal views on gender norms. Freedom brought opportunity, but also the weight of reproductive responsibility. Six decades later, this burden still largely remains with women. The limitations of modern contraceptives affect the individual—with half of women changing methods due to intolerability, and some discontinuing them altogether—the couple, due to the emotional and financial toll of unplanned pregnancy, and ultimately, poses broader socioeconomic consequences for society. With over one-third of unplanned pregnancies resulting from inconsistent or incorrect use of contraceptives, current methods are simply insufficient. Despite this, progress to date has remained limited. Women have just a handful of options, and choices for men remain unchanged from those available 50 years ago: condoms, which have high real-world failure rates; withdrawal, equally risky; and vasectomy, an invasive procedure with inconsistent reversibility. However, views on family planning and gender roles are ever-changing, and increased demand for novel male contraceptives has provided the perfect opportunity to address these shortfalls. Just as the pill granted Credit: Technology Networks. TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 23 women freedom, researchers hope that with improved male contraceptive options, men can share more of the burden of reproductive responsibility. From concept to capsule: Oral candidates in human trials Vitamin A discovery leads to viable birth control: YCT-529 Several oral male contraceptive candidates are being investigated. YCT-529 is a daily, non-hormonal, male contraceptive pill among the most advanced options, currently in Phase 1b/2a clinical trials. The pill was developed by YourChoice Therapeutics (YCT) in collaboration with Prof. Gunda Georg, regent’s professor of Medicinal Chemistry at the University of Minnesota. The science behind YCT-529 dates to research conducted in the 1930s, when pharmacologists identified the importance of vitamin A in sperm production. After placing mice on a vitamin A-deficient diet, they became infertile. Adding vitamin A back into the mice’s diet also restored fertility in some cases. “In the testis and other organs, vitamin A is converted to retinoic acid (RA). RA binds to retinoic acid receptors (RARs) and initiates processes that are important for sperm development inside the testis,” Georg explained. The team developed a strategy to introduce a “decoy” molecule into this process—one structurally similar to RA that could take its place and block its function. After 5 years and 300–400 molecules, the team identified the potential of YCT-529. YCT later conducted animal studies that laid the groundwork for commencing first-in-human trials. Dr. Mannowetz, chief scientific officer and co-founder of YCT, co-authored the study, which found that the compound reduced sperm counts and was 99% effective at preventing pregnancy in mice. Crucially, it was also found to be reversible. Mannowetz explained that “once males stop taking the pill, sperm production resumes. We have shown this mechanism in several animal species.” Phase 1 clinical studies demonstrated a strong safety profile, attributed to YCT-529’s specificity for RARα, a receptor required for sperm production. While the trial supported previous findings, it was a single-ascendingdose trial rather than an assessment of ongoing use. The drug has now progressed to Phase 1b/2a clinical trials, where long-term use, efficacy, and reversibility will be tested in humans for the first time. Akash Bakshi, chief executive officer and co-founder of YCT, spoke about his hopes for male contraceptives: “Societally, women should be able to trust men to take responsibility for family planning. That will bring about a shift in which men take on responsibility for both women's health and their own health.” One pill, two hormones: Dimethandrolone undecanoate (DMAU) DMAU is also a once-daily pill, but it differs in its mechanism as a hormonal contraceptive. In males, hormonal contraceptives generally rely on interruption of the hypothalamic-pituitary-gonadal (HPG) axis. The HPG axis This is the communication system between the brain and reproductive organs. The hypothalamus releases gonadotropinreleasing hormone, stimulating the pituitary gland to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In males, LH stimulates testicular testosterone production, while FSH supports spermatogenesis. The process is regulated via negative feedback – increased levels of testosterone act on the hypothalamus and pituitary gland to reduce the release of GnRH, FSH, and LH. TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 24 “DMAU is a modified androgen that incorporates both androgen (testosterone) and progestin activities into a single molecule,” explained Dr. Stephanie Page, chief of the division of Metabolism, Endocrinology, and Nutrition at the University of Washington. These properties enable DMAU to trigger the negative feedback loop and suppress endogenous testosterone production. Additionally, it acts as a progestin, further suppressing the HPG axis. This combined effect lowers the hormonal signals required for spermatogenesis. Phase 1 trial results showed that the pill was welltolerated, although oral DMAU had poor bioavailability and was best taken with high-fat meals to achieve effective serum concentrations. The pill has now entered early Phase 2 trials. A sister compound: 11β‑MNTDC 11β‑MNTDC was developed after DMAU by the same Washington research team. While it exerts contraceptive effects through the same broad mechanism, it has a slightly different structure, which alters its affinity to androgen and progesterone receptors. Although both compounds showed similar user acceptability, the structural change is expected to result in slightly different side effect profiles. In small, early-stage trials, 11β-MNTDC caused a slight increase in LDL-C, or “bad cholesterol,” compared with placebo, while DMAU was associated with a decrease in adiponectin, a protein hormone associated with obesity, type 2 diabetes, and cardiovascular disease. However, the same study found no significant differences in compound-specific effects when compared head-to-head. As with DMAU, bioavailability has remained an issue and, in some cases, has impacted adherence—variants are in development to address this while 11β-MNTDC is evaluated in Phase 1 trials. Two existing drugs, one new purpose: NLS‑133 NLS-133 is an investigational non-hormonal, ondemand male contraceptive, combining two FDAapproved drugs: silodosin, used to treat benign prostate hyperplasia, and guanfacine, indicated for ADHD and blood pressure treatment. At present, there are no peer-reviewed clinical results, and the mechanism of action has not been publicized. NLS-133 is thought to primarily act through alpha-1- adrenergic receptor antagonism. This receptor plays a vital role in sperm motility through promoting vas deferens contraction, which is crucial for sperm transport. By inhibiting this mechanism, it is hypothesized that the number of sperm in semen should decrease, though this effect has not yet been demonstrated. NEXT Life Sciences is currently assessing the effects of the pill on semen volume and sperm parameters within Phase 2a clinical trials. Vas deferens The vas deferens is a fibromuscular tube in the male reproductive system that transports sperm from the epididymis, which is connected to the testicle, to the ejaculatory duct. The male reproductive tract has two vas deferens, one for each testis; these are referred to as the vasa deferentia. TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 25 Injectable candidates provide an alternative route Injectable DMAU: Every few weeks, not every day Long-acting injectable DMAU was developed to address limitations identified during the development of the oral version and is currently in Phase 1 trials. It works through the same mechanism as oral DMAU but, as Page explained,“the injectable is longer lasting, similar to long-lasting testosterone injections given every 8–12 weeks.” Injectable DMAU has been tested both intramuscularly and subcutaneously and aims to address bioavailability concerns, offering men with daily compliance challenges an alternative. Studies in non-human primates have demonstrated safety, efficacy across surrogate endpoints, and reversal potential with testosterone and spermatogenesis indicators returning to baseline following end-of-treatment. Plan A’s promise: Set it and forget it Plan A refers to the combination of a patented delivery system and a long-acting, reversible hydrogel, termed Vasalgel®, injected directly into the vas deferens. Dr. Darlene Walley, chief executive officer at NEXT Life Sciences, explained how the technology works: “Vasalgel is placed in the center of the vas deferens, preventing the flow of sperm while still allowing normal flow of other fluids.” NEXT Life Science’s claim that the patented delivery system allows clinicians to accurately deliver the gel into the small center of the vas deferens. Thus far, the technology has been successful in preventing conception and achieving azoospermia in animal studies with rhesus monkeys and rabbits. Reported side effects have been mild and transient, broadly comparable to those associated with vasectomy. Vasalgel is designed to be reversible on demand, with Walley telling Technology Networks that, “the mechanism and reversibility [are] supported by animal and ex-vivo data, the latter of which is yet to be published.” This mechanism is yet to be demonstrated in humans. As Plan A enters Phase 2 trials, Walley is hopeful about the future of male contraceptives, stating, “Several technologies are progressing through clinical pathways to finally meet this need and should be available in the next three to five years.” The inspiration: Reversible inhibition of sperm under guidance (RISUG®) RISUG is also injected into the vas deferens, but it works through a different mechanism. The polymer gel acts as a contraceptive through electrostatic interactions that disrupt sperm cell membranes, leading to in-transit inactivation. To date, RISUG has shown efficacy in clinical trials, achieving high rates of azoospermia and reasonable tolerability, with mild, transient side effects such as scrotal swelling reported by the majority of participants. Robust reversibility data for RISUG remain limited to animal studies, and reviews recommend that broader studies and in-human reversibility data are required before widespread adoption. Although the technology was first conceptualized in the 1970s, the development journey of RUSIG has been slow. Trials, based in India, were academically led and received no pharmaceutical funding; thus, development progressed under regulatory and funding conditions different than typical Western pathways. Therefore, although currently being evaluated in Phase 3 trials, the technology would require new studies for widespread approval and adoption. However, RUSIG is recognized for inspiring other technologies, including Plan A. TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 26 Topical solutions: A hands-on approach One of a kind: The Nestorone/Testosterone (NES/T) gel NES/T is the only transdermal male contraceptive gel currently in clinical trials. Theoretically, the gel works through the same fundamental hormonal mechanism as DMAU. Although NES/T uses a synthetic progestin and testosterone, DMAU is a single agent that mimics the effects of both hormones. The topical route was a conscious choice, affording stable hormone levels, avoiding toxicity associated with oral anabolic steroid intake, and providing user convenience. One limitation may be the time to sperm suppression from the first administration onwards, which is approximately 8–16 weeks. Page, also principal investigator for NES/T, explained: “This is because the cycle of human sperm production takes 72 days, and sperm that have reached a certain stage of maturation are not blocked by these methods and must exit the reproductive track prior to the method being effective.” She emphasized that any method relying on spermatogenesis suppression, including non-hormonal methods, will face the same challenge. Following completion of large-scale Phase 2b trials, the details of which are yet to be released, NES/T is considered the most advanced hormonal male contraceptive in development as it progresses toward Phase 3 clinical trials. Having worked on numerous male contraceptive options, Page was hopeful regarding the changes we may observe in the coming years, stating that “The goal is to get novel, reliable, and user-friendly, reversible male contraceptives to the market within the next decade.” ABOUT THE INTERVEWEES Akash Bakshi completed an MSc in biotechnology in 2011, with a background in biochemistry and cell biology. In 2018, Akash cofounded YCT. Since then, he has served as chief executive officer (CEO) with the vision of developing non-hormonal contraceptives for men and women. Dr. Darlene R. Walley is currently the chief executive officer of NEXT Life Sciences, focusing on reproductive healthcare. Walley has over 30 years of life science business experience, having served as an executive at Procter & Gamble, Gillette/Oral-B laboratories, and Arm & Hammer. Prof. Gunda Georg earned a bachelor’s degree in pharmacy and a PhD in medicinal chemistry from Marburg University, Germany. Her main research interests are medicinal chemistry, drug discovery, contraception, and cancer. She is the co-inventor of one marketed drug and three drugs currently in clinical trials. She has published 280 articles and has trained over 100 students, postdocs, and visiting scientists. Dr. Mannowetz co-founded YCT with the goal of developing non-hormonal family planning tools for men and women, after developing YCT-529, a novel, male contraceptive compound. Dr. Mannowetz has made multiple contributions to science, including revealing important bicarbonate-mediated pathways of early sperm activation and characterizing the principal potassium channel of human sperm cells. Dr. Page is chief of the division of Metabolism, Endocrinology, and Nutrition at the University of Washington. Her research focuses on male reproduction, the development of reversible male contraceptives, and the effects of testosterone on aging, metabolic health, and disease risk. 27 REPRODUCTIVE HEALTH IN THE SPOTLIGHT What Drives Ovarian Aging and Fertility Decline? Katie Brighton The ovaries are critical for maintaining female reproductive and endocrine function. They are known to age faster than other organs, and few effective methods exist to slow this aging. Ovarian aging decreases fertility, increases the risk of pregnancy complications, and ultimately leads to menopause. Beyond reproductive health, ovarian aging and the accompanying fluctuations in estrogen and progesterone influence bone health, cardiovascular function, the immune system, cognitive abilities, sleep, and energy metabolism. Characterizing ovarian aging Women are born with a finite stock of follicleenclosed oocytes in the ovary, which are depleted over time. Historically, reproductive decline was thought to be determined by the ovarian reserve, which is the number of remaining follicles. “Recent evidence indicates that there are other important players in reproductive aging, such as ovarian inflammation and fibrosis, which increase with age,” Prof. Augusto Schneider, associate professor at the Federal University of Pelotas, told Technology Networks. Schneider’s research has shown that Western and highfat diets do not affect the number of ovarian follicles but instead promote other hallmarks of aging, such as inflammation. “Even though the follicle count remained stable, the quality of the oocytes was impaired by high-fat and western diets, also reducing pregnancy rates,” he said. “This suggests that declining fertility with reproductive aging isn't just about the number of follicles; it can be impaired via different pathways depending on the trigger.” Credit: Technology Networks. TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 28 Separate research has identified that fibrosis within the ovarian stromal compartment impairs the release of oocytes, preventing ovulation and therefore pregnancy. Fibrosis develops in response to tissue damage or inflammation and is characterized by excessive extracellular matrix deposition and the expansion of connective tissue. In the study, researchers found that fibrotic extracellular matrix deposition contributed to age- and obesity-induced ovarian dysfunction and pinpointed mitochondrial dysfunction as a trigger of fibrosis. They also found that antifibrosis drugs could be used to remove fibrotic collagen and restore ovulation in reproductively old mice and mice with obesity. Creating a timeline of biological aging In using follicle depletion as a measure of ovarian aging, it appears that there is a slow, steady decline that mirrors chronological aging. “When we look at other hallmarks of ovarian aging, such as inflammation and fibrosis, the timeline is different,” Schneider explained. During early reproductive life, inflammation and fibrosis increase, which some studies propose is linked to repeated ovulation, causing minor tissue damage that needs to be repaired. In mice, which usually reproduce until around 12–14 months, inflammation and fibrosis peak from around 6–9 months in age, whereas ovarian follicle reserve depletion is most significant at 12 months, Schneider explained. “We still need more research to fully map out exactly how these different aging timelines interact,” said Schneider. An ecosystem that changes with age The surrounding cells and tissues of the ovary also change with age and play a key role in how quickly fertility declines. “It is not just a matter of fertility when we talk about preventing ovarian aging.” — Prof. Augusto Schneider What happens to follicleenclosed oocytes over time? In the ovary, oocytes are dormant in the primordial follicles. They can undergo one of the following processes: 1. Primordial follicle activation: occurs when individual follicles are recruited to leave their dormant state and enter a growth phase, moving through maturation steps to reach ovulation, where the oocyte is released. 2. Atresia: a form of apoptotic cell death as the ovarian follicles degenerate. This may be a protective mechanism to remove poor-quality oocytes. 3. Remain quiescent. TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 29 Using 3D imaging of mouse and human ovaries, researchers from the University of California, San Francisco (UCSF) profiled what normal aging looks like. They found that, in human ovaries, egg cells cluster in “pockets.” “These pockets suggest that even within one ovary, the environment around an egg may influence how long it lasts and how well it matures,” said Dr. Diana Laird, professor of obstetrics, gynecology, and reproductive sciences at UCSF and senior author of the study. A role for the nervous system in ovarian health The research also pinpointed key support cells in the ovaries, including glial cells, which are typically associated with the nervous system. They were frequently found in association with sympathetic nerves involved in “fight or flight” responses, which formed dense networks that became denser with age. Ablation of these nerves in mice increased the number of eggs in reserve. However, fewer of these matured, indicating that the nervous system is involved in promoting follicle recruitment and may therefore play a role in ovarian aging. “This all points to a brand-new line of inquiry about how nerves, blood vessels, and other cell types communicate with eggs,” Laird said. “It tells us that ovarian aging is not just about the egg cells but about their whole ecosystem.” Immune cells also contribute to aging Research from Northwestern University has also identified immune cells that are linked to ovarian aging. Multinucleated giant cells (MNGCs), which are derived from macrophages, are associated with chronic inflammation throughout the body, but they also appear in the aging ovary. The researchers found that these MNGCs likely play a role in clearing cellular debris—they had molecular signatures related to cell degradation, immune function, and high metabolic activity. “These cells are likely in the aging ovary to compensate for defects in normal processes that are needed to clear out cellular debris. However, MNGCs may have additional consequences because they have a unique immune profile,” said lead author of the study, Dr. Aubrey Converse. “I think this is one of the most interesting aspects of this biology—the MNGCs may be trying to maintain homeostasis initially, but then they may have detrimental consequences to the tissue.” Creating a “roadmap” of how the ovary and its surrounding tissues change with age offers a starting place from which to study the influence of different environments, conditions, or dietary interventions on ovarian aging. Could caloric restriction influence ovarian aging? Calorie restriction—the controlled reduction of calorie intake by around 30% without malnutrition—has been widely shown to extend lifespans and prevent ageassociated disease in multiple species. Calorie restriction is known to alter mitochondrial activity through inhibiting mammalian target of rapamycin (mTOR) and insulin-like growth factor 1, activating the sirtuin family of proteins and AMP‑dependent kinase. It also decreases oxidative damage and has anti-inflammatory effects. “In the ovary specifically, calorie restriction reduces the activation of primordial follicles in mice regardless of what age the diet is started,” said Schnieder. This helps to maintain the follicle reserve. After calorie restriction was stopped and the mice returned to feeding freely, the follicle reserve remained elevated, effectively extending the reproductive lifespan. TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 30 “Our recent unpublished data suggest that this is not dependent on any macronutrient specifically, and may be dependent both on the restriction of calories itself and the fasting window,” said Schneider. “We also found that calorie restriction reduces inflammation and fibrosis in the ovary.” There is a downside to caloric restriction, Schneider warns: “While mice are on the calorie restriction diet, ovulation and cyclicity are suppressed. So, while calorie restriction preserves the ovarian reserve, it makes it very hard for mice to conceive as they are not ovulating regularly.” Translating aging research into humans Although calorie restriction slows ovarian aging in the lab, applying the same intervention to humans in a realworld setting presents numerous challenges. “I think the ultimate goal is to translate our findings to clinical trials to understand how diet impacts ovarian aging in humans,” said Schneider. “However, strict calorie restriction is incredibly difficult for humans to maintain long-term.” “If we can delay ovarian aging, we don't just extend fertility; we delay menopause and protect women's longterm metabolic health.” — Prof. Augusto Schneider TECHNOLOGYNETWORKS.COM REPRODUCTIVE HEALTH IN THE SPOTLIGHT 31 Schneider’s research in mice highlights that the effects of caloric restriction on ovarian aging are more evident over long periods of time, which would translate to decades in humans. Although weight loss generally improves fertility, extreme dieting over such a long period of time may reduce ovulation and negatively impact fertility. “There is also a gap in our knowledge regarding obesity effects in ovarian aging and approaches to prevent or reverse this damage,” Schneider noted. Most of his work on caloric restriction uses lean mice, but obese mice may respond differently to this intervention. “This is critical right now because women are postponing motherhood, and obesity rates are rising. This combination can be very detrimental to fertility,” he said. Understanding aging mechanisms Future research might focus on decoupling follicle activation and ovulation, enabling the follicle reserve to be maintained while allowing for ovulation and pregnancy. By identifying the mechanisms that regulate follicle activation, pharmacological treatments can be designed to combat ovarian aging and potentially extend fertility. “We have observed that rapamycin, an mTOR inhibitor, has promising effects for preventing ovarian aging,” Schneider said. In mice, Schneider and colleagues compared rapamycin treatment with a 30% caloric restriction, finding that both interventions increased the number of primordial follicles compared to a control. “If we can figure out how to control the activation of primordial follicles without stopping ovulation, we could prevent ovarian aging without compromising fertility and have something that can be translated to humans,” Schneider explained. ABOUT THE INTERVIEWEE: Prof. Augusto Schneider is an associate professor at the Nutrition College at the Federal University of Pelotas. The main focus of his research is the interface between reproduction, nutrition, and aging biology. Particularly, he seeks to understand how aging and obesity-related metabolic dysfunction accelerates the loss of fertility in females and alternatives to prevent this damage. His research has also focused on understating ovarian primordial follicle activation and its consequence for reproductive longevity. Schneider holds a degree in veterinary medicine and a master's degree and a doctorate in biotechnology from the Federal University of Pelotas. REPRODUCTIVE HEALTH IN THE SPOTLIGHT 32 TECHNOLOGYNETWORKS.COM CONTRIBUTORS Alexander Beadle Alexander Beadle is a science writer and editor for Technology Networks. He holds a masters degree in Materials Chemistry from the University of St Andrews, Scotland. Blake Forman Blake pens and edits breaking news, articles, and features on a broad range of scientific topics. He earned an honors degree in chemistry from the University of Surrey. Blake also holds an MSc in chemistry from the University of Southampton. 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She holds an honors degree in biomedicine from the University of East Anglia and a masters degree in microbiology. Before joining Technology Networks she researched maternal health and the microbiome.