The impact of endocrine-disrupting chemicals on stem cells: Mechanisms and implications for human health.

Endocrine-disrupting chemicals (EDCs) are compounds, either natural or man-made, that interfere with the normal functioning of the endocrine system. There is increasing evidence that exposure to EDCs can have profound adverse effects on reproduction, metabolic disorders, neurological alterations, and increased risk of hormone-dependent cancer. Stem cells (SCs) are integral to these pathological processes, and it is therefore crucial to understand how EDCs may influence SC functionality. This review examines the literature on different types of EDCs and their effects on various types of SCs, including embryonic, adult, and cancer SCs. Possible molecular mechanisms through which EDCs may influence the phenotype of SCs are also evaluated. Finally, the possible implications of these effects on human health are discussed. The available literature demonstrates that EDCs can influence the biology of SCs in a variety of ways, including by altering hormonal pathways, DNA damage, epigenetic changes, reactive oxygen species production and alterations in the gene expression patterns. These disruptions may lead to a variety of cell fates and diseases later in adulthood including increased risk of endocrine disorders, obesity, infertility, reproductive abnormalities, and cancer. Therefore, the review emphasizes the importance of raising broader awareness regarding the intricate impact of EDCs on human health.

Genome-wide analysis and identification of Carotenoid Cleavage Oxygenase (CCO) gene family in coffee (coffee arabica) under abiotic stress.

The coffee industry holds importance, providing livelihoods for millions of farmers globally and playing a vital role in the economies of coffee-producing countries. Environmental conditions such as drought and temperature fluctuations can adversely affect the quality and yield of coffee crops.Carotenoid cleavage oxygenases (CCO) enzymes are essential for coffee plants as they help break down carotenoids contributing to growth and stress resistance. However, knowledge about the CCO gene family in Coffee arabica was limited. In this study identified 21 CCO genes in Coffee arabica (C. arabica) revealing two subfamilies carotenoid cleavage dioxygenases (CCDs) and 9-cis-epoxy carotenoid dioxygenases (NCED) through phylogenic analysis. These subfamilies exhibited distribution patterns in terms of gene structure, domains, and motifs. The 21 CaCCO genes, comprising 5 NCED and 16 CCD genes were found across chromosomes. Promoter sequencing analysis revealed cis-elements that likely interact with plant stress-responsive, growth-related, and phytohormones, like auxin and abscisic acid. A comprehensive genome-wide comparison, between C. arabica and A. thaliana was conducted to understand the characteristics of CCO genes. RTqPCR data indicated that CaNCED5, CaNCED6, CaNCED12, and CaNCED20 are target genes involved in the growth of drought coffee plants leading to increased crop yield, in a conditions, with limited water availability. This reveals the role of coffee CCOs in responding to abiotic stress and identifies potential genes useful for breeding stress-resistant coffee varieties.

Greater sensitivity of the circadian system of women to bright light, but not dim-to-moderate light.

Women typically sleep and wake earlier than men and have been shown to have earlier circadian timing relative to the light/dark cycle that synchronizes the clock. A potential mechanism for earlier timing in women is an altered response of the circadian system to evening light. We characterized individual-level dose-response curves for light-induced melatonin suppression using a within-subjects protocol. Fifty-six participants (29 women, 27 men; aged 18-30 years) were exposed to a range of light illuminances (10, 30, 50, 100, 200, 400, and 2000 lux) using melatonin suppression relative to a dim control (<1 lux) as a marker of light sensitivity. Women were free from hormonal contraception. To examine the potential influence of sex hormones, estradiol and progesterone was examined in women and testosterone was examined in a subset of men. Menstrual phase was monitored using self-reports and estradiol and progesterone levels. Women exhibited significantly greater melatonin suppression than men under the 400-lux and 2000-lux conditions, but not under lower light conditions (10-200 lux). Light sensitivity did not differ by menstrual phase, nor was it associated with levels of estradiol, progesterone, or testosterone, suggesting the sex differences in light sensitivity were not acutely driven by circulating levels of sex hormones. These results suggest that sex differences in circadian timing are not due to differences in the response to dim/moderate light exposures typically experienced in the evening. The finding of increased bright light sensitivity in women suggests that sex differences in circadian timing could plausibly instead be driven by a greater sensitivity to phase-advancing effects of bright morning light.

The mediating role of steroid hormones in the relationship between bisphenol A and its alternatives bisphenol S and F exposure and preeclampsia.

Steroid hormone imbalance is believed to increase the odds of developing PE. Bisphenol A (BPA) and its substitutes (e.g., bisphenol S (BPS) and bisphenol F (BPF)) have estrogen-like effects, and its exposure may be related to the development of preeclampsia (PE). To explore the effects of bisphenol exposure on maternal serum steroid hormones and the potential mediating role of steroid hormones in the association between bisphenol exposure and developing PE, concentrations of bisphenols and steroid hormones in serum samples of 383 pregnant women were examined before delivery (including 160 PE cases and 223 control cases). Multivariable logistic and linear models were used to explore the associations of maternal serum bisphenols concentrations with both maternal steroid hormones and PE risk. Mediation modeling was employed to evaluate the mediating role of steroid hormones in the association between bisphenols and PE. Results showed that maternal serum BPS concentrations were positively associated with testosterone (T) concentrations. The mediation analyses suggested that approximately 10.17% of the associations between BPS concentrations and the development of PE might be mediated by maternal T. In conclusion, maternal exposure to BPS during pregnancy is linked to higher maternal T concentrations, which might increase the odds of developing PE. T might mediate the association between BPS exposure and the development of PE.

Hormonal basis of seasonal metabolic changes in mammalian species.

Seasonal changes in external conditions (photoperiod, meteorological conditions, diet) cause adaptive changes in both energy and substrate metabolism in the animals of mammalian species. In summer, long days and a rich diet contribute to relative elevation in the levels of thyroid hormones (TH), but warmer weather lowers their levels. In winter, short days and a poor diet inhibit TH synthesis, but low temperatures increase their secretion. In addition, the results of our meta-analyses revealed a significant role of atmospheric pressure in circannual fluctuations of metabolic parameters in humans. The changes in photoperiod are generally viewed as a major factor contributing to seasonal rhythm regulation However, numerous data show that season-dependent metabolic changes in mammals could be also accounted for by meteorological factors and diet.

Hormonal regulation in diabetes: Special emphasis on sex hormones and metabolic traits.

Diabetes constitutes a significant global public health challenge that is rapidly reaching epidemic proportions. Among the non-communicable diseases, the incidence of diabetes is rising at an alarming rate. The International Diabetes Federation has documented a 9.09% prevalence of diabetes among individuals aged between 20 and 79 years. The interplay of gonadal hormones and gender differences is critical in regulating insulin sensitivity and glucose tolerance, and this dynamic is particularly crucial because of the escalating incidence of diabetes. Variations in insulin sensitivity are observed across genders, levels of adiposity, and age groups. Both estrogen and testosterone are seen to influence glucose metabolism and insulin sensitivity. This chapter surveys the present knowledge of sex differences, sex hormones, and chromosomes on insulin imbalance and diabetes development. It further highlights the influence of metabolic traits in diabetes and changes in sex hormones during diabetic pregnancy. Notably, even stressful lifestyles have been acknowledged to induce hormonal imbalances. Furthermore, it discusses the potential of hormonal therapy to help stabilize sex hormones in diabetic individuals and focuses on the most recent research investigating the correlation between sex hormones and diabetes.

Thyroid hormone biosynthesis and its role in brain development and maintenance.

Thyroid hormones are critical modulators in the physiological processes necessary to virtually all tissues, with exceptionally fundamental roles in brain development and maintenance. These hormones regulate essential neurodevelopment events, including neuronal migration, synaptogenesis, and myelination. Additionally, thyroid hormones are crucial for maintaining brain homeostasis and cognitive function in adulthood. This chapter aims to offer a comprehensive understanding of thyroid hormone biosynthesis and its intricate role in brain physiology. Here, we described the mechanisms underlying the biosynthesis of thyroid hormones, their influence on various aspects of brain development and ongoing maintenance, and the proteins in the brain that are responsive to these hormones. This chapter was geared towards broadening our understanding of thyroid hormone action in the brain, shedding light on potential therapeutic targets for neurodevelopmental and neurodegenerative disorders.

Overlapping action of melatonin and female reproductive hormones-Understand the impact in pregnancy and menopause.

Melatonin is an indolamine secreted to circulation by the pineal gland according to a circadian rhythm. Melatonin levels are higher during nighttime, and the principal function of this hormone is to organize the temporal night and day distribution of physiological adaptive processes. Besides hormonal pineal production, melatonin is synthesized in various organs and tissues like the ovaries or the placenta for local utilization. In addition to its function as a circadian messenger, melatonin is also associated with many physiological functions. For example, melatonin has antioxidant properties and is involved in the regulation of energy and bone metabolism, and reproduction. Melatonin impacts several stages of reproduction and the action across the hypothalamus-pituitary-gonadal axis is well described. However, it is not well understood how those actions impact the female reproductive hormones secretion nor the consequent physiological outcomes. Thus, the first part of this chapter describes the regulation of female reproductive hormone synthesis by melatonin. Moreover, melatonin and female reproductive hormones have coincident physiological functions. Life stages like pregnancy or menopause are characterized by alterations in the reproductive hormones secretion that may be associated with certain physiological stages. Therefore, the second part discusses whether melatonin fluctuations could have an overlapping role with reproductive hormones in contributing to clinical outcomes associated with pregnancy and menopause.

Neurobiological characteristics associated with gender identity: Findings from neuroimaging studies in the Amsterdam cohort of children and adolescents experiencing gender incongruence.

This review has been based on my invited lecture at the annual meeting of the Society for Behavioral Neuroendocrinology in 2023. Gender incongruence is defined as a marked and persistent incongruence between an individual's experienced gender and the sex assigned at birth. A prominent hypothesis on the etiology of gender incongruence proposes that it is related to an altered or less pronounced sexual differentiation of the brain. This hypothesis has primarily been based on postmortem studies of the hypothalamus in transgender individuals. To further address this hypothesis, a series of structural and functional neuroimaging studies were conducted in the Amsterdam cohort of children and adolescents experiencing gender incongruence. Additional research objectives were to determine whether any sex and gender differences are established before or after puberty, as well as whether gender affirming hormone treatment would affect brain development and function. We found some evidence in favor of the sexual differentiation hypothesis at the functional level, but this was less evident at the structural level. We also observed some specific transgender neural signatures, suggesting that they might present a unique brain phenotype rather than being shifted towards either end of the male-female spectrum. Our results further suggest that the years between childhood and mid-adolescence represent an important period in which puberty-related factors influence several neural characteristics, such as white matter development and functional connectivity patterns, in both a sex and gender identity specific way. These latter observations thus lead to the important question about the possible negative consequences of delaying puberty on neurodevelopment. To further address this question, larger-scale, longitudinal studies are required to increase our understanding of the possible neurodevelopmental impacts of delaying puberty in transgender youth.

Contribution of testosterone and estradiol in sexual dimorphism of early-onset Parkinson's disease.

Early-onset Parkinson's disease (EOPD) occurs during the fertile life, when circulating neuroactive sex hormones might enhance the sexual dimorphism of the disease. Here, we aimed to examine how sex hormones can contribute to sex differences in EOPD patients. A cohort of 34 EOPD patients, 20 males and 14 females, underwent comprehensive clinical evaluation of motor and non-motor disturbances. Blood levels of estradiol, total testosterone, follicle-stimulating hormone, and luteinizing hormone were measured in all patients and correlated to clinical features. We found that female patients exhibited greater non-motor symptoms and a relatively higher rate of dystonia than males. In females, lower estradiol levels accounted for higher MDS-UPDRS-II and III scores and more frequent motor complications, while lower testosterone levels were associated with a major occurrence of dystonia. In male patients, no significant correlations emerged. In conclusion, this study highlighted the relevance of sex hormone levels in the sexual dimorphism and unique phenotype of EOPD.

The genetic effects of hormones modulated by the Pituitary-Thyroid/Adrenal/Gonadal axis on the risk of developing venous thromboembolism: a mendelian randomization study.

BACKGROUND: The aim of this study was to explore the genetic effects of hormones modulated through the pituitary-thyroid/adrenal/gonadal axis on the risk of developing venous thromboembolism (VTE) and to investigate the potentially causal relationships between them. METHODS: A two-sample Mendelian randomization (MR) design was used. The single-nucleotide polymorphisms (SNPs) used as instrumental variables for various hormones and hormone-mediated diseases were derived from published genome-wide association studies (GWASs). Summary statistics for the risk of developing VTE (including deep venous thrombosis [DVT] and pulmonary embolism [PE]) were obtained from the UK Biobank and the FinnGen consortium. Inverse-variance weighting (IVW) was applied as the primary method to analyse causal associations. Other MR methods were used for supplementary estimates and sensitivity analysis. RESULTS: A genetic predisposition to greater free thyroxine (FT4) concentrations was associated with a greater risk of developing DVT (OR = 1.0007, 95%CI [1.0001-1.0013], p = 0.0174) and VTE (OR = 1.0008, 95%CI [1.0002-1.0013], p = 0.0123). Genetically predicted hyperthyroidism was significantly associated with an increased risk of developing DVT (OR = 1.0685, 95%CI [1.0139-1.1261], p = 0.0134) and VTE (OR = 1.0740, 95%CI [1.0165-1.1348], p = 0.0110). According to the initial MR analysis, testosterone concentrations were positively associated with the risk of developing VTE (OR = 1.0038, 95%CI [1.004-1.0072], p = 0.0285). After sex stratification, estradiol concentrations were positively associated with the risk of developing DVT (OR = 1.0143, 95%CI [1.0020-1.0267], p = 0.0226) and VTE (OR = 1.0156, 95%CI [1.0029-1.0285], p = 0.0158) in females, while the significant relationship between testosterone and VTE did not persist. SHBG rs858518 was identified as the only SNP that was associated with an increased risk of developing VTE, mediated by estradiol, in females. CONCLUSIONS: Genetically predicted hyperthyroidism and increased FT4 concentrations were positively associated with the risk of developing VTE. The effects of genetically predicted sex hormones on the risk of developing VTE differed between males and females. Greater genetically predicted estradiol concentrations were associated with an increased risk of developing VTE in females, while the SHBG rs858518 variant may become a potential prevention and treatment target for female VTE.

Bilirubin Levels in Infancy and Their Associations with Body Weight, Levels of Iron-Related Parameters and Steroid Hormone Levels.

It is assumed that bilirubin is hormonally regulated and influences weight development by preventing weight gain. However, studies in healthy infants are limited. The present study established reference values for bilirubin and investigated whether bilirubin levels are significantly associated with body weight, levels of ferritin and transferrin as well as steroid hormone levels in a study population of three- and six-month-old healthy infants. Data from a total of 411 study visits from the LIFE Child study (Leipzig, Germany) were analyzed. Associations were examined using linear regression analyses. Besides laboratory parameters, anthropometric data were gathered. We found statistically significant associations between body weight and bilirubin levels. In girls, we observed additional associations between bilirubin levels and both ferritin and transferrin concentrations at three months of age. At six months, steroid hormone levels were significantly associated with concentrations of total and indirect bilirubin, with effects differing by sex. Our study thus confirms associations already reported from animal studies and studies in adult populations. Furthermore, we showed that these associations already exist in the first year of life, are influenced by sex and age and, further, depend on the bilirubin type. Our results provide reference values for bilirubin and assist, therefore, in interpreting bilirubin levels in infancy.

Total triiodothyronine level associated with disease severity for patients with emergent status.

Thyroid hormones are metabolic indicators to evaluate the physical condition of emergency hospitalized patients, while the relationship between total triiodothyronine and the severity of emergency inpatients is still unclear. To explore the thyroid function levels of inpatients in emergency ward and the status of combined Nonthyroidal illness syndrome (NTIS), and to emphasize the importance of thyroid hormone examination for non-endocrinology inpatients. According to thyroid function of inpatients in emergency ward, they were divided into NTIS group and non-NTIS group, the hematological characteristics and TH levels of each group were analyzed. Based on clinical diagnoses, the hospitalized patients were divided into three major groups, namely infection group, non-infection group and impaired organ function group. Among them, infection group was further divided into sepsis group, lung infection group and local infection group, altogether five groups. The thyroid function levels and low values in each group were evaluated, and the correlation between hormone levels and inflammatory factors, nutritional indicators and the relationship with the risk of death was discussed. The inpatient rate in emergency ward complicated with NTIS was 62.29%, T3 was the most sensitive index of NTIS, followed by FT3. Compared to non-NTIS group, the NTIS group had an increased risk of death. The sepsis group and impaired organ function group had the highest rates of complicated NTIS, reaching 83.33% and 78.12% respectively. Spearman's correlation analysis implied T3/T4/FT3 levels were positively correlated with ALb and PLT (except T4), and negatively correlated with CRP, D-Dimer, IL-6 and Fer. The Receiver Operating Curve (ROC) and Area under the curve (AUC) showed T3 levels alone were strongly associated with the risk of death (AUC 0.750; 95% CI 0.673-0.828; P < 0.001). T3 is the most sensitive indicator for emergency patients, followed by FT3. The decrease of T3 level has a good predictive value for mortality risk. Thyroid function should be monitored in critically ill patients.

Gut-Liver-Pancreas Axis Crosstalk in Health and Disease: From the Role of Microbial Metabolites to Innovative Microbiota Manipulating Strategies.

The functions of the gut are closely related to those of many other organs in the human body. Indeed, the gut microbiota (GM) metabolize several nutrients and compounds that, once released in the bloodstream, can reach distant organs, thus influencing the metabolic and inflammatory tone of the host. The main microbiota-derived metabolites responsible for the modulation of endocrine responses are short-chain fatty acids (SCFAs), bile acids and glucagon-like peptide 1 (GLP-1). These molecules can (i) regulate the pancreatic hormones (insulin and glucagon), (ii) increase glycogen synthesis in the liver, and (iii) boost energy expenditure, especially in skeletal muscles and brown adipose tissue. In other words, they are critical in maintaining glucose and lipid homeostasis. In GM dysbiosis, the imbalance of microbiota-related products can affect the proper endocrine and metabolic functions, including those related to the gut-liver-pancreas axis (GLPA). In addition, the dysbiosis can contribute to the onset of some diseases such as non-alcoholic steatohepatitis (NASH)/non-alcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC), and type 2 diabetes (T2D). In this review, we explored the roles of the gut microbiota-derived metabolites and their involvement in onset and progression of these diseases. In addition, we detailed the main microbiota-modulating strategies that could improve the diseases' development by restoring the healthy balance of the GLPA.

Evaluating Sex Steroid Hormone Neuroprotection in Spinal Cord Injury in Animal Models: Is It Promising in the Clinic?

The primary mechanism of traumatic spinal cord injury (SCI) comprises the initial mechanical trauma due to the transmission of energy to the spinal cord, subsequent deformity, and persistent compression. The secondary mechanism of injury, which involves structures that remained undamaged after the initial trauma, triggers alterations in microvascular perfusion, the liberation of free radicals and neurotransmitters, lipid peroxidation, alteration in ionic concentrations, and the consequent cell death by necrosis and apoptosis. Research in the treatment of SCI has sought to develop early therapeutic interventions that mitigate the effects of these pathophysiological mechanisms. Clinical and experimental evidence has demonstrated the therapeutic benefits of sex-steroid hormone administration after traumatic brain injury and SCI. The administration of estradiol, progesterone, and testosterone has been associated with neuroprotective effects, better neurological recovery, and decreased mortality after SCI. This review evaluated evidence supporting hormone-related neuroprotection over SCI and the possible underlying mechanisms in animal models. As neuroprotection has been associated with signaling pathways, the effects of these hormones are observed on astrocytes and microglia, modulating the inflammatory response, cerebral blood flow, and metabolism, mediating glutamate excitotoxicity, and their antioxidant effects. Based on the current evidence, it is essential to analyze the benefit of sex steroid hormone therapy in the clinical management of patients with SCI.

Association between FT3 Levels and Exercise-Induced Cardiac Remodeling in Elite Athletes.

BACKGROUND: Previous studies demonstrated that variations of fT3, even within the euthyroid range, can influence cardiac function. Our aim was to investigate whether thyroid hormones, even within the euthyroid range, are associated with the magnitude of exercise-induced cardiac remodeling in Olympic athletes. METHODS: We evaluated 1342 Olympic athletes (mean age 25.6 ± 5.1) practicing different sporting disciplines (power, skills, endurance, and mixed). Athletes underwent blood testing (thyroid stimulating hormone, fT3, and fT4), echocardiography, and exercise-stress testing. Athletes taking thyroid hormones, affected by thyroiditis, or presenting TSH out of ranges were excluded. RESULTS: The level of thyroid hormones varied according to the type of sporting discipline practiced: endurance athletes presented the lowest TSH (p < 0.0001), fT3 (p = 0.007), and fT4 (p < 0.0001) in comparison to the remaining ones. Resting heart rate (HR) was positively correlated to fT3 in athletes of different disciplines (power: p = 0.0002, R2 = 0.04; skill: p = 0.0009, R2 = 0.05; endurance: p = 0.007, R2 = 0.03; and mixed: p = 0.04, R2 = 0.01). The same results were seen for peak HR in the exercise-stress test in athletes engaged in power, skill, and endurance (respectively, p < 0.0001, R2 = 0.04; p = 0.01, R2 = 0.04; and p = 0.005, R2 = 0.02). Moreover, a positive correlation was observed with cardiac dimensions, i.e., interventricular septum (power: p < 0.0001, R2 = 0.11; skill: p = 0.02, R2 = 0.03; endurance: p = 0.002, R2 = 0.03; mixed: p < 0.0001, R2 = 0.04). Furthermore, fT3 was directly correlated with the left ventricle (LV) end-diastolic volume in skills (p = 0.04, R2 = 0.03), endurance (p = 0.04, R2 = 0.01), and mixed (p = 0.04, R2 = 0.01). CONCLUSIONS: Thyroid hormones, even within the euthyroid range, are associated with cardiac adaptive response to exercise and may contribute to exercise-induced cardiac remodeling.

Influence of endogenous and exogenous hormones on the cardiovascular response to lower extremity exercise and group III/IV activation in young females.

Oral contraceptive (OC) use can increase resting blood pressure (BP) in females as well as contribute to greater activation of group III/IV afferents during upper body exercise. It is unknown, however, whether an exaggerated BP response occurs during lower limb exercise in OC users. We sought to elucidate the group III/IV afferent activity-mediated BP and heart rate responses, while performing lower extremity tasks during early and late follicular phases in young, healthy females. Females not taking OCs (NOC: n=8; age: 25±4 years) and taking OCs (OC: n=10; age: 23±2 years) completed a continuous knee extension/flexion passive stretch (mechanoreflex) and cycling exercise with sub-systolic cuff occlusion (exercise pressor reflex), which was followed by a two-minute post-exercise circulatory occlusion (PECO) (metaboreflex). Data collection occurred on two occasions: once during the early follicular phase (days 1-4) and once during the late follicular phase (days 10-14) of their menstrual cycle (NOC), or during the placebo and active pill phases (OC). Resting mean arterial BP and heart rate were not different between phases in NOC and OC participants (p>0.05). Hemodynamic responses to metaboreflex, mechanoreflex, and collective exercise pressor reflex activation were not different between phases in both groups (p>0.05). In conclusion, although OCs are known to increase BP at rest, our findings indicate that neither endogenous nor exogenous (OC) sex hormones modulate BP during large, lower-limb muscle exercise, with or without group III/IV afferent activation in young, healthy females.

Exposure to Synthetic Endocrine-Disrupting Chemicals in Relation to Maternal and Fetal Sex Steroid Hormones: A Scoping Review.

PURPOSE OF REVIEW: Many synthetic endocrine-disrupting chemicals (EDCs) are ubiquitous in the environment and highly detected among pregnant people. These chemicals may disrupt maternal and/or fetal sex steroid hormones, which are critical to pregnancy maintenance and fetal development. Here, we review the epidemiological literature examining prenatal exposure to common synthetic EDCs in relation to maternal and fetal sex steroid hormones. RECENT FINDINGS: We performed a literature search using PubMed, SCOPUS, and Embase, ultimately identifying 29 articles for full review. Phenols, parabens, and persistent organic pollutants generally showed inverse associations with androgens, estrogens, and progesterone. Phthalates and per-and polyfluoroalkyl substances tended to be inversely associated with progesterone, while evidence regarding androgens and estrogens was mixed. Inconsistent, but noteworthy, differences by fetal sex and timing of exposure/outcome were observed. Overall, the literature suggests EDCs may disrupt maternal and fetal sex steroid activity, though findings are mixed. Given the pervasive, high-volume production of these synthetic chemicals and the critical functions sex steroid hormones play during gestation, additional research is warranted.

The association between maternal factors and milk hormone concentrations: a systematic review.

Background: Breast milk is the gold standard for infant feeding. It is a dynamic biological fluid rich in numerous bioactive components. Emerging research suggests that these components, including hormones, may serve as signals between mother and offspring. From an evolutionary perspective, maternal hormonal signals could allow co-adaptation of maternal and offspring phenotype, with implications for their Darwinian fitness. However, a series of steps need to be considered to establish the role of a component as a signal and this systematic review focuses on one step: 'Do maternal factors influence the concentration of milk hormones?' Objective: To systematically review human studies which analyze the association between maternal factors and the concentration of hormones in breast milk. Methods: Three databases were searched for studies reporting the association of maternal factors including body mass index (BMI), weight, fat mass, age, ethnicity, smoking with hormones such as adiponectin, leptin, insulin, ghrelin, and cortisol in breast milk. Results: Thirty-three studies were eligible for inclusion. Maternal BMI was positively associated with milk leptin (20/21 studies) and with milk insulin (4/6 studies). Maternal weight also displayed a positive correlation with milk leptin levels, and maternal diabetes status was positively associated with milk insulin concentrations. Conversely, evidence for associations between maternal fat mass, smoking, ethnicity and other maternal factors and hormone levels in breast milk was inconclusive or lacking. Conclusion: Current evidence is consistent with a signaling role for leptin and insulin in breast milk, however other steps need to be investigated to understand the role of these components as definitive signals. This review represents a first step in establishing the role of signaling components in human milk and highlights other issues that need to be considered going forward.

Menstrual cycle-driven hormone concentrations co-fluctuate with white and gray matter architecture changes across the whole brain.

Cyclic fluctuations in hypothalamic-pituitary-gonadal axis (HPG-axis) hormones exert powerful behavioral, structural, and functional effects through actions on the mammalian central nervous system. Yet, very little is known about how these fluctuations alter the structural nodes and information highways of the human brain. In a study of 30 naturally cycling women, we employed multidimensional diffusion and T1-weighted imaging during three estimated menstrual cycle phases (menses, ovulation, and mid-luteal) to investigate whether HPG-axis hormone concentrations co-fluctuate with alterations in white matter (WM) microstructure, cortical thickness (CT), and brain volume. Across the whole brain, 17ß-estradiol and luteinizing hormone (LH) concentrations were directly proportional to diffusion anisotropy (µFA; 17ß-estradiol: ß1 = 0.145, highest density interval (HDI) = [0.211, 0.4]; LH: ß1 = 0.111, HDI = [0.157, 0.364]), while follicle-stimulating hormone (FSH) was directly proportional to CT (ß1 = 0 .162, HDI = [0.115, 0.678]). Within several individual regions, FSH and progesterone demonstrated opposing relationships with mean diffusivity (Diso) and CT. These regions mainly reside within the temporal and occipital lobes, with functional implications for the limbic and visual systems. Finally, progesterone was associated with increased tissue (ß1 = 0.66, HDI = [0.607, 15.845]) and decreased cerebrospinal fluid (CSF; ß1 = -0.749, HDI = [-11.604, -0.903]) volumes, with total brain volume remaining unchanged. These results are the first to report simultaneous brain-wide changes in human WM microstructure and CT coinciding with menstrual cycle-driven hormone rhythms. Effects were observed in both classically known HPG-axis receptor-dense regions (medial temporal lobe, prefrontal cortex) and in other regions located across frontal, occipital, temporal, and parietal lobes. Our results suggest that HPG-axis hormone fluctuations may have significant structural impacts across the entire brain.