Sex Hormones and the Gut Microbiome

Vital throughout the lifespan, androgens, estrogen, and progesterone not only stimulate reproductive organ function and influence body system development during puberty but these gonadal steroid hormones are also known regulators of immune responses and integral to optimal health as we age, from the bone to the brain.^1-4 What about the gut microbiome connection? Research indicates that commensal gut bacteria metabolize steroid hormones through the stimulation of different enzymes.⁵ As one example, gut microbes mediate enzymatic processes that deconjugate conjugated estrogen metabolites that had been marked for excretion but are then returned in active form to enterohepatic circulation.⁶

As the hormone-gut relationship continues to be explored, a growing evidence base indicates a sexual dimorphism of gut microbiota, with sex hormones helping to shape microbiota composition and to influence function.^7-9 What is the relationship between a patient’s serum levels of sex hormones and their gut microbial landscape? This area of developing research adds to the complex relationship between hormones, intestinal health, and chronic disease, as well as another clinical consideration for personalized gut and hormone-balancing interventions. 

Gut Microbiota & Sex Hormone Interactions: Chronic Disease Impact

Sexual dimorphisms in the composition of the gut microbiota and the potential role this plays in chronic disease development and treatment is an evolving area of research.^10,11 As studies continue to investigate steroid hormone impacts on intestinal microbiome composition and function, researchers have suggested a potentially bidirectional sex hormone/gut microbiota interaction in relation to any sex-specific pathophysiology of disease. For example, a 2022 review summarized preclinical and clinical evidence for the sexual dimorphisms in obesity and suggested that the interplay between systemic sex hormones, the gut’s microbes, and the intestinal inflammatory response plays a role in the complex disease development.¹² A 2023 review investigated the known sex differences seen in the development and prevalence of other metabolic diseases, including metabolic syndrome and type 2 diabetes.¹³ In this context, the researchers also reported evidence highlighting the observed sex differences in gut microbiota composition and also suggested that the interaction between steroid hormones and the gut microbes may influence metabolic disease pathologies.¹³

Illustrating the progression of this research field, a 2022 observational study (n=46 men; 18 with low testosterone levels; 28 with normal) investigated the association between testosterone levels in men with type 2 diabetes and their gut microbiota composition.¹⁴ Overall, investigators found that the low testosterone and normal testosterone groups had statically significant differences in gut microbiota, and testosterone insufficiency indicated more severe gut dysbiosis manifested as an increase in opportunistic pathogens and gram-negative bacteria linked to worse disease biomarkers.¹⁴

Gut-brain axis: the sex hormone influence

Both animal and human studies have indicated that reciprocal interactions between sex-specific factors, such as gonadal steroid hormones and the gut microbiota, may influence the gut-brain axis and be relevant in understanding and treating mental health, neuropsychiatric, or neurodegenerative conditions.^15,16 In this expanding field of research, a 2022 cross-sectional retrospective study (n=1,143 males and 3,467 females) explored the associations between gut microbiota species and psychological symptom expression across four focused areas that included depression, neurocognition, stress and anxiety, and sleep and fatigue for both males and females.¹⁷ Results indicated that the microbial composition was similar between males and females; however, the associations between gut microbiota and psychological symptom severity varied in a sex-dependent manner for all four measured symptoms, with females reporting greater severities.¹⁷

Influencing Microbial Diversity: Testosterone & Estrogen Levels

Measuring the abundance of specific commensal gut bacteria among different populations while also measuring their sex hormone levels has been one avenue used to further investigate the molecular mechanisms at play within the sex hormone/gut microbiota bidirectional relationship. A 2022 systematic review (n=13 observational studies; 852 total participants; 91% female) explored the interactions and associations between gonadal steroid hormones and gut microbiota diversity in humans.¹⁸ The participants ranged from healthy men and women (pre- and postmenopausal) to participants who were obese or those with diagnosed polycystic ovary syndrome (PCOS), breast cancer, osteopenia, or osteoporosis. The measured sex hormones included testosterone and estrogen. A narrative synthesis of study results included the following:¹⁸

• In healthy women, higher estrogen levels were associated with a higher abundance of Bacteroidetes, a lower abundance of Firmicutes, and increased microbial diversity. (Note: A lower Firmicutes to Bacteroidetes ratio has been linked to healthy gut homeostasis and a lower BMI). 
• In healthy men, higher testosterone levels were positively correlated with Ruminococcus, Acinetobacter, and an increased microbial diversity. Levels of Ruminococcus, a key symbiont in the conversion of complex sugars to host nutrients, were the most sensitive to testosterone levels.
• In healthy women, elevated testosterone levels were correlated with Escherichia and several species of pathogenic Shigella, whereas several species of beneficial Ruminococcus were negatively associated with elevated testosterone levels. 
• Those women with altered testosterone/estrogen profiles had a differing gut microbiota compared to healthy women, with a negative correlation between testosterone levels and microbial diversity in women with PCOS. 

While the studies included in this review support the evident sexually dimorphic relationship between testosterone and estrogen and gut microbiota diversity, researchers discussed the limited understanding of those molecular mechanisms that mediate the effect of sex hormones on microbial populations (and vice versa), especially for testosterone.¹⁸

Clinical Applications & Continuing Research

Studies continue to investigate the hormone-gut relationship to determine if sex hormone variability drives gut microbiota variability, if the reverse relationship predominately occurs, or if both directions equally impact system balance. As this field of research expands,^19,20 increased opportunities emerge to further customize personalized interventions that not only tailor hormone-balancing therapies to benefit gut health and intestinal integrity but that also support the gut microbial composition and diversity that will most benefit an individual patient’s gonadal steroid hormone health. 

Clinical trials have started to evaluate the benefits of probiotic interventions on sex hormone balance. A 2023 umbrella review of 28 meta-analyses of randomized controlled trials (RCT) evaluated nutritional interventions for women with PCOS.²¹ Some of these interventions included the use of probiotics or synbiotics (a combination of probiotics and prebiotics). The combined results from three meta-analyses indicated with moderate certainty that among women with PCOS, probiotic/synbiotic supplementation helped to not only reduce fasting plasma glucose, fasting insulin, and insulin resistance but also to significantly reduce total testosterone levels by 0.14 ng/mL (95% CI −0.21 ng/mL to −0.08 ng/mL).²¹

Awareness of developing hormone/gut research may help focus clinical interventions by considering both the support of gut microbial richness as a treatment component for sex hormone balance and the support of optimal sex hormone levels as a treatment component for healthy gut balance. Join functional medicine experts at IFM’s Hormone Advanced Practice Module (APM) for a deeper dive into the latest hormone-related research and learn more about assessing hormone dysfunction and those clinical tools that help identify points of leverage for effective personalized interventions.