Interaction between gut microbiota and sex hormones and their relation to sexual dimorphism in metabolic diseases.
Biology of sex differences
Metabolic diseases, such as obesity, metabolic syndrome (MetS) and type 2 diabetes (T2D), are now a widespread pandemic in the developed world. These pathologies show sex differences in their development and prevalence, and sex steroids, mainly estrogen and testosterone, are thought to play a prominent role in this sexual dimorphism. The influence of sex hormones on these pathologies is not only reflected in differences between men and women, but also between women themselves, depending on the hormonal changes associated with the menopause. The observed sex differences in gut microbiota composition have led to multiple studies highlighting the interaction between steroid hormones and the gut microbiota and its influence on metabolic diseases, ultimately pointing to a new therapy for these diseases based on the manipulation of the gut microbiota. This review aims to shed light on the role of sexual hormones in sex differences in the development and prevalence of metabolic diseases, focusing on obesity, MetS and T2D. We focus also the interaction between sex hormones and the gut microbiota, and in particular the role of microbiota in aspects such as gut barrier integrity, inflammatory status, and the gut-brain axis, given the relevance of these factors in the development of metabolic diseases.
10.1186/s13293-023-00490-2
Sex hormones, intestinal inflammation, and the gut microbiome: Major influencers of the sexual dimorphisms in obesity.
Frontiers in immunology
Obesity is defined as the excessive accumulation of body fat and is associated with an increased risk of developing major health problems such as cardiovascular disease, diabetes and stroke. There are clear sexual dimorphisms in the epidemiology, pathophysiology and sequelae of obesity and its accompanying metabolic disorders, with females often better protected compared to males. This protection has predominantly been attributed to the female sex hormone estrogen and differences in fat distribution. More recently, the sexual dimorphisms of obesity have also been attributed to the differences in the composition and function of the gut microbiota, and the intestinal immune system. This review will comprehensively summarize the pre-clinical and clinical evidence for these sexual dimorphisms and discuss the interplay between sex hormones, intestinal inflammation and the gut microbiome in obesity. Major gaps and limitations of this rapidly growing area of research will also be highlighted in this review.
10.3389/fimmu.2022.971048
Gut microbiota-gonadal axis: the impact of gut microbiota on reproductive functions.
Frontiers in immunology
The influence of gut microbiota on physiological processes is rapidly gaining attention globally. Despite being under-studied, there are available data demonstrating a gut microbiota-gonadal cross-talk, and the importance of this axis in reproduction. This study reviews the impacts of gut microbiota on reproduction. In addition, the possible mechanisms by which gut microbiota modulates male and female reproduction are presented. Databases, including Embase, Google scholar, Pubmed/Medline, Scopus, and Web of Science, were explored using relevant key words. Findings showed that gut microbiota promotes gonadal functions by modulating the circulating levels of steroid sex hormones, insulin sensitivity, immune system, and gonadal microbiota. Gut microbiota also alters ROS generation and the activation of cytokine accumulation. In conclusion, available data demonstrate the existence of a gut microbiota-gonadal axis, and role of this axis on gonadal functions. However, majority of the data were compelling evidences from animal studies with a great dearth of human data. Therefore, human studies validating the reports of experimental studies using animal models are important.
10.3389/fimmu.2024.1346035
Effect of exercise on the onset of puberty, gonadotropins, and ovarian inhibin.
Pellerin-Massicotte J,Brisson G R,St-Pierre C,Rioux P,Rajotte D
Journal of applied physiology (Bethesda, Md. : 1985)
Swimming 6 h/day from 11 days of age led to a significant delay of the onset of puberty of female rats compared with the sedentary group. Rats who were in contact with water but without the energy expenditure due to exercise (paddlers) had their vaginal opening in a middle point between control and exercising rats. Vaginal opening occurred at different ages but at a same body weight. Exercise and stress led to a marked decrease of the body weights between 19 and 40 days of age. Serum luteinizing hormone and follicle-stimulating hormone were increased with the exercise program at 30 days of age, whereas no significant differences between groups in serum gonadotropins were observed at 50 days of age. Only the anterior pituitary luteinizing hormone content was increased by exercise in adult rats. Total ovarian proteins were significantly reduced by stress and to a greater degree by exercise. Ovarian inhibin activity is not modified by exercise at 30 days of age, whereas it increased significantly in the exercising group at 50 days of age and to a lesser degree in paddlers. It is therefore suggested that the onset of puberty in rats is dependent on a critical weight and that exercise and stress can delay the onset of puberty. This delay could be explained by a deficiency of hormonal maturational process while exercising until sexual maturity alters the inhibin activity, which suggests that inhibin could play a major role for the normal reproductive function and this could possibly explain the menstrual disturbances in the female athlete.
10.1152/jappl.1987.63.3.1165
The Biological Basis of Sex Differences in Athletic Performance: Consensus Statement for the American College of Sports Medicine.
Medicine and science in sports and exercise
ABSTRACT:Biological sex is a primary determinant of athletic performance because of fundamental sex differences in anatomy and physiology dictated by sex chromosomes and sex hormones. Adult men are typically stronger, more powerful, and faster than women of similar age and training status. Thus, for athletic events and sports relying on endurance, muscle strength, speed, and power, males typically outperform females by 10%-30% depending on the requirements of the event. These sex differences in performance emerge with the onset of puberty and coincide with the increase in endogenous sex steroid hormones, in particular testosterone in males, which increases 30-fold by adulthood, but remains low in females. The primary goal of this consensus statement is to provide the latest scientific knowledge and mechanisms for the sex differences in athletic performance. This review highlights the differences in anatomy and physiology between males and females that are primary determinants of the sex differences in athletic performance and in response to exercise training, and the role of sex steroid hormones (particularly testosterone and estradiol). We also identify historical and nonphysiological factors that influence the sex differences in performance. Finally, we identify gaps in the knowledge of sex differences in athletic performance and the underlying mechanisms, providing substantial opportunities for high-impact studies. A major step toward closing the knowledge gap is to include more and equitable numbers of women to that of men in mechanistic studies that determine any of the sex differences in response to an acute bout of exercise, exercise training, and athletic performance.
10.1249/MSS.0000000000003300
Positive effect of combined exercise on adipokines levels and pubertal signs in overweight and obese girls with central precocious puberty.
Shokri Elnaz,Heidarianpour Ali,Razavi Zahra
Lipids in health and disease
BACKGROUND:The prevalence of precocious puberty is increasing. Obesity has been demonstrated to be associated with changes in the adipokine profile and incidence of early puberty in girls. This study assessed the pubertal signs, the levels of adiponectin, resistin, and tumor necrosis factor-alpha (TNF-α) after 12 weeks of combined exercise and 4 weeks of detraining in overweight and obese girls with precocious puberty. METHODS:Thirty overweight and obese girls (aged 7-9) with precocious puberty, who had received Triptorelin, were randomly divided into two groups (15 exercise and 15 control). Initially, serum levels of adiponectin, resistin, TNF-α, luteinising hormone (LH), and follicle-stimulating hormone (FSH) and the signs of puberty progression (bone age, uterine length, and ovarian volume) were measured. The exercise group performed 60 min of combined (aerobic and resistance) exercise three times/week for 12 weeks. The control group did not receive any exercise. 48 h after the last training session and after 4 weeks of detraining, all research variables were measured (also in the control group). The statistical method used for data analysis was repeated measures ANOVA. RESULTS:In the exercise group, adiponectin significantly increased and resistin significantly decreased after 12 weeks. After 4 weeks of detraining, adiponectin significantly decreased, but resistin significantly increased. TNF-α levels did not change significantly during the study. There was no significant difference in all of the factors in the control group. Throughout the 16-week study period, the rate of puberty and LH significantly decreased in both exercise and control groups, but FSH, LH/FSH and ovarian volume significantly decreased in the exercise group alone (P<0.05). CONCLUSIONS:Combined exercise increased adiponectin and decreased resistin and the rate of puberty. However, after 4 weeks of detraining, these effects diminished but did not disappear. TRIAL REGISTRATION:IRCT, IRCT56471. Registered 25 may 2021 - Retrospectively registered, https://fa.irct.ir/user/profile.
10.1186/s12944-021-01588-5
Effect of Exercise and Detraining on Signs of Puberty and Selected Inflammatory Markers in Girls with Precocious Puberty.
Medicine and science in sports and exercise
PURPOSE:We examined the effects of aerobic exercise and detraining on adiponectin, resistin, tumor necrosis factor alpha (TNF-α), white blood cell, and pubertal signs (uterine length, ovarian volume, luteinizing hormone [LH], and follicle-stimulating hormone [FSH]) in girls with central precocious puberty (CPP). METHODS:Thirty girls with CPP (7-9 yr old) were randomly divided into CPP and CPP + Exercise (EX) groups. Fifteen healthy age-matched girls without precocious puberty participated for comparison with CPP. Subjects in the CPP + EX group attended 12 wk of aerobic exercise protocol three sessions a week. In the baseline, after completing the exercise protocol and after 4 wk of detraining, all the parameters were measured. In the CPP and healthy groups, all the parameters were measured in all three stages. To measure adiponectin, resistin, and TNF-α, the ELISA method was used. LH and FSH were measured by electrochemiluminescence immunoassay. White blood cell counts were analyzed by an automated blood cell counter. Repeated-measures ANOVA was used to analyze the results. RESULTS:CPP girls have lower adiponectin ( P = 0.01) and higher TNF-α levels ( P = 0.001) than healthy girls. In the CPP + EX group, after 12 wk, body weight and fat mass decreased, and adiponectin increased significantly ( P = 0.02). Resistin ( P = 0.02), TNF-α ( P = 0.02), neutrophils ( P = 0.01), and signs of puberty significantly ( P < 0.05) decreased. After detraining, no significant change was observed except TNF-α, which increased significantly ( P = 0.03). In the CPP group, no significant change was observed in any of the parameters; only LH ( P = 0.0001) and uterine length and ovarian volume ( P = 0.003, P = 0.001) decreased after 12 and 16 wk, respectively. CONCLUSIONS:Aerobic exercise can have a positive effect on the state of inflammation and pubertal signs. Positive effects remain after 4 wk of detraining.
10.1249/MSS.0000000000003138
Changes in the Bile Acid Pool and Timing of Female Puberty: Potential Novel Role of Hypothalamic TGR5.
Endocrinology
CONTEXT:The regulation of pubertal timing and reproductive axis maturation is influenced by a myriad of physiologic and environmental inputs yet remains incompletely understood. OBJECTIVE:To contrast differences in bile acid isoform profiles across defined stages of reproductive maturity in humans and a rat model of puberty and to characterize the role of bile acid signaling via hypothalamic expression of bile acid receptor populations in the rodent model. METHODS:Secondary analysis and pilot studies of clinical cohorts, rodent models, ex vivo analyses of rodent hypothalamic tissues. Bile acid concentrations is the main outcome measure. RESULTS:Lower circulatory conjugated:deconjugated bile acid concentrations and higher total secondary bile acids were observed in postmenarcheal vs pre-/early pubertal adolescents, with similar shifts observed in infantile (postnatal day [PN]14) vs early juvenile (PN21) rats alongside increased tgr5 receptor mRNA expression within the mediobasal hypothalamus of female rats. 16S rRNA gene sequencing of the rodent gut microbiome across postnatal life revealed changes in the gut microbial composition predicted to have bile salt hydrolase activity, which was observed in parallel with the increased deconjugated and increased concentrations of secondary bile acids. We show that TGR5-stimulated GnRH release from hypothalamic explants is mediated through kisspeptin receptors and that early overexpression of human-TGR5 within the arcuate nucleus accelerates pubertal onset in female rats. CONCLUSION:Bile acid isoform shifts along stages of reproductive maturation are conserved across rodents and humans, with preclinical models providing mechanistic insight for the neuroendocrine-hepatic-gut microbiome axis as a potential moderator of pubertal timing in females.
10.1210/endocr/bqae098
Pubertal probiotic blocks LPS-induced anxiety and the associated neurochemical and microbial outcomes, in a sex dependent manner.
Murray Emma,Smith Kevin B,Stoby Karlene S,Thomas Bronwen J,Swenson Michael J,Arber Lauren A,Frenette Emilie,Ismail Nafissa
Psychoneuroendocrinology
Puberty is a critical period of neural development, and exposure to stress and inflammation during this period is thought to increase vulnerability to mental illness. The gut microbiome influences brain functioning and behavior and impacts mental health. Yet, the role of the gut microbiome during puberty, a period during which mental health conditions tend to onset, remains largely uninvestigated. We first examined age and sex differences in gut microbial changes among CD-1 mice exposed to an immune challenge (lipopolysaccharide; LPS) at 6 weeks of age (during the pubertal stress-sensitive period) or at 10 weeks of age (in adulthood) (Experiment 1). Compared to their adult counterparts, pubertal males and females showed more significant changes in gut microbial composition following LPS treatment, including the depletion of numerous bacterial genera such as Lactobacillus. Given the beneficial effects of Lactobacillus strains on stress and behaviour, we next investigated whether replenishment of the gut with the probiotic Lactobacillus reuteri (L. reuteri) throughout pubertal development would modulate LPS-induced sickness and enduring effects on memory dysfunction, anxiety-like behaviour and stress reactivity in adulthood (Experiment 2). LPS treatment at 6 weeks of age created enduring changes in anxiety-like behaviors among males only. Similarly, only males showed the protective effects of L. reuteri supplementation during puberty in preventing longstanding LPS-induced changes in anxiety-like behavior and stress-induced brain activation. These findings demonstrate that colonizing the gut with L. reuteri during puberty modulates sickness responses and enduring behavioural and neurochemical outcomes in a sex-specific manner. Therefore, colonizing the gut with beneficial microbes may protect against the development of mental illnesses in adulthood.
10.1016/j.psyneuen.2019.104481
Natural sweetener glycyrrhizin protects against precocious puberty by modulating the gut microbiome.
Life sciences
AIMS:Precocious puberty (PP) may lead to many adverse outcomes. Recent evidence suggests that PP is a gut-brain disease. On the other hand, the use of glycyrrhizin, a natural sweetener, has become popular in the past decade. Glycyrrhizin possesses various health benefits, but its impact on PP has yet to be investigated. We aimed to explore the protective effects of glycyrrhizin against PP in both humans (observational) and animals (interventional). MATERIALS AND METHODS:In the human cohort, we investigated the association between glycyrrhizin consumption and risk of PP. In the animal experiment, we observed puberty onset after feeding danazol-induced PP rats with glycyrrizin. Blood, fecal, and hypothalamic samples were harvested to evaluate potential mechanistic pathways. We also performed a fecal microbiota transplantation to confirm to causal relationship between glycyrrhizin and PP risk. KEY FINDINGS:Glycyrrhizin exhibited a protective effect against PP in children (OR 0.60, 95%CI: 0.39-0.89, p = 0.013), primarily driven by its significance in girls, while no significant effect was observed in boys. This effect was consistent with findings in rodents. These benefits were achieved through the modulation of the gut microbiome, which functionally suppressed the hypothalamic-pituitary-gonadal axis and prevented PP progression. A fecal microbiota transplantation indicated that the causal correlation between glycyrrhizin intake and PP is mediated by the gut microbiome alterations. SIGNIFICANCE:Our findings suggest that glycyrrhizin can protect against PP by altering the gut microbiome. Long term use of glycyrrhizin is safe and tolerable. Therefore, glycyrrhizin can serve as a safe and affordable complementary therapy for PP.
10.1016/j.lfs.2024.122789
Sexual dimorphism of gut microbiota at different pubertal status.
Yuan Xin,Chen Ruimin,Zhang Ying,Lin Xiangquan,Yang Xiaohong
Microbial cell factories
BACKGROUND:Accumulating evidence infer that gut microbiome-host relations are key mediators or modulators driving the observed sexual dimorphism in some disease onset and progression. To date, the sex-differences of gut microbiota at different pubertal status have not been reported. OBJECTIVE:To determine the characteristics of gut microbiota of both genders at different pubertal status. METHODS:Gut microbiota was analyzed in 89 Chinese participants aged 5-15 years. Participants were divided into pre-puberty and puberty groups for both male and female. The composition of gut microbiota was investigated by 16S rRNA-based metagenomics. Ecological representations of microbial communities were computed. The prediction of metagenomic functional content from 16S rRNA gene surveys was conducted. RESULTS:There were 49 males (9.76 ± 2.15 years) and 40 females (9.74 ± 1.63 years); 21 males and 26 females were at puberty. At genus level, Alistipes, Megamonas, Oscillospira and Parabacteroides were more prevalent in girls than in boys (p < 0.05). There were no significantly differences of alpha-diversity between genders, which was independent of pubertal status. The beta-diversity was significantly different in pubertal subjects between genders. Using statistical analyses, we assigned genera Dorea, Megamonas, Bilophila, Parabacteroides and Phascolarctobacterium as microbial markers for pubertal subjects. The predicted metabolic profiles differ in both pubertal and pre-pubertal groups between genders. CONCLUSION:This cross-sectional study revealed that sex differences in the gut microbiota composition and predicted metabolic profiles exist before puberty, which become more significant at puberty. The identification of novel puberty bacterial markers may disclose a potential effects of gender-related microbiota profiles on puberty onset.
10.1186/s12934-020-01412-2
Sleep deprivation alters pubertal timing in humans and rats: the role of the gut microbiome.
Sleep
STUDY OBJECTIVES:Evidence implied that sleeping duration is associated with the timing of puberty and that sleep deprivation triggers early pubertal onset in adolescents. Sleep deprivation can affect metabolic changes and gut microbiota composition. This study investigated the effects of sleep deprivation on pubertal onset and gut microbiota composition in animal models and a human cohort. METHODS:This study comprised 459 boys and 959 girls from the Taiwan Pubertal Longitudinal Study. Sleep duration was evaluated using the self-report Pittsburgh Sleep Quality Index questionnaire. Early sexual maturation was defined by pediatric endocrinologist assessments. Mediation analyses were done to examine the association between sleep parameters, obesity, and early sexual maturation. Besides, Sprague Dawley juvenile rats were exposed to 4 weeks of chronic sleep deprivation. Vaginal opening (VO) and preputial separation (PS) were observed every morning to determine pubertal onset in female and male rats. RESULTS:The sleep-deprived juvenile rats in the sleep-deprived-female (SDF) and sleep-deprived-male (SDM) groups experienced delayed VO (mean VO days: 33 days in control; 35 days in SDF; p-value < 0.05) and PS (mean PS days: 42 days in control; 45 days in SDM; p-value < 0.05), respectively. Relative to their non-sleep-deprived counterparts, the sleep-deprived juvenile rats exhibited lower body weight and body fat percentage. Significant differences in relative bacterial abundance at genus levels and decreased fecal short-chain-fatty-acid levels were identified in both the SDF and SDM groups. In the human cohort, insufficient sleep increased the risk of early sexual maturation, particularly in girls (OR, 1.44; 95% CI: 1.09 to 1.89; p-value < 0.01). Insufficient sleep also indirectly affected early sexual maturation in girls, with obesity serving as the mediator. CONCLUSIONS:Overall, sleep deprivation altered the timing of puberty in both animal and human models but in different directions. In the rat model, sleep deprivation delayed the pubertal onset in juvenile rats through gut dysbiosis and metabolic changes, leading to a low body weight and body fat percentage. In the human model, sleep deprivation led to fat accumulation, causing obesity in girls, which increased the risk of early puberty.
10.1093/sleep/zsad308
Precocious puberty and microbiota: The role of the sex hormone-gut microbiome axis.
Frontiers in endocrinology
Puberty is a critical phase of life associated with physiological changes related to sexual maturation, and represents a complex process regulated by multiple endocrine and genetic controls. Puberty is driven by hormones, and it can impact the gut microbiome (GM). GM differences between sex emerge at puberty onset, confirming a relationship between microbiota and sex hormones. In this narrative review, we present an overview of precocious pubertal development and the changes in the GM in precocious puberty (PP) in order to consider the role of the sex hormone-gut microbiome axis from the perspective of pediatric endocrinology. Bidirectional interactions between the GM and sex hormones have been proposed in different studies. Although the evidence on the interaction between microbiota and sex hormones remains limited in pediatric patients, the evidence that GM alterations may occur in girls with central precocious puberty (CPP) represents an interesting finding for the prediction and prevention of PP. Deepening the understanding of the connection between the sex hormones and the role of microbiota changes can lead to the implementation of microbiota-targeted therapies in pubertal disorders by offering a pediatric endocrinology perspective.
10.3389/fendo.2022.1000919