Testosterone Restoration, the Gut Microbiome, and Systems Outcomes in Men and Women

Abstract 

Testosterone restoration therapy (TRT) is increasingly used in men and, when clinically indicated, in women. Emerging evidence shows bidirectional crosstalk between sex steroids and the gut microbiome, with implications for metabolic, neuropsychiatric, and inflammatory outcomes. This brief synthesises current data to guide clinicians on integrating gut assessment and modulation with TRT.  

Key takeaways:  

(1) sex hormones shape microbial composition and function, and microbes metabolise/steward steroid bioavailability;  

(2) low testosterone states associate with dysbiosis and inflammatory taxa;  

(3) sex-dimorphic microbiome–disease patterns extend to the gut–brain axis; and  

(4) microbiota-directed adjuncts (e.g., probiotics/synbiotics) show early signals of benefit in hyperandrogenic states such as PCOS.  

1) Physiological Background 

Sex steroids (testosterone, estradiol, progesterone) modulate immune tone, musculoskeletal anabolism, neurocognition, and cardio-metabolic risk across the lifespan. The intestinal microbiome participates in steroid metabolism (deconjugation, oxidation/reduction) and thereby influences enterohepatic recirculation and tissue exposure. Contemporary reviews emphasise a bidirectional sex hormone–microbiome axis that evolves with age, diet, medication exposure, and host factors.  

2) Sexual Dimorphism & Disease Patterns 

Across preclinical and human data, sex differences in obesity and metabolic disease are partly explained by interactions among sex hormones, intestinal inflammation, and the gut microbiome. These dimorphisms likely contribute to divergent disease trajectories and heterogeneous treatment responses by sex.  

Gut–brain axis: Large cohort data show that associations between specific gut taxa and psychological symptom severity (depression, anxiety/stress, sleep/fatigue, cognitive complaints) are sex-dependent, reinforcing the need to consider sex hormones when interpreting psychobiotic signatures.  

3) Low Testosterone & Dysbiosis 

Observational clinical data in men with type 2 diabetes demonstrate that low serum testosterone associates with reduced microbial diversity and enrichment of opportunistic/gram-negative taxa linked to inflammatory and metabolic perturbations. These patterns provide a mechanistic rationale for gut assessment in hypogonadal phenotypes and suggest potential microbial mediators of TRT outcomes.  

4) Women’s Health: Hyperandrogenism & Microbiota 

In PCOS, multiple systematic reviews/meta-analyses indicate that probiotic/synbiotic adjuncts can improve glycaemic indices and show modest reductions in total testosterone, supporting microbiota-targeted strategies alongside endocrine management. While effect sizes vary, the signal is consistent enough to warrant clinical consideration when insulin resistance and low-grade inflammation coexist.  

5) Clinical Implications for TRT at Levitas 

When to assess the gut in TRT: 

• Persistent fatigue, brain fog, visceral adiposity or glycaemic instability despite dose-appropriate TRT 

• GI symptoms (bloating, irregularity), recurrent antibiotics, proton-pump inhibitor use 

• Elevated hs-CRP, ferritin (as inflammatory surrogate), or ALT; or features of metabolic syndrome 

Integrated pathway (Levitas Gut Health × Hormone for Life): 

1. Baseline profiling: CBC, CMP, lipids, HbA1c, insulin/HOMA-IR, hs-CRP; total & free T, SHBG, estradiol (E2), progesterone (women), DHEA-S; thyroid panel. Consider stool microbiome diversity/richness indices and calprotectin if indicated. 

2. Foundations: Mediterranean-leaning, fibre-replete diet; polyphenols; resistance training; sleep optimisation; alcohol moderation; medication reconciliation (e.g., PPIs). 

3. TRT initiation/titration: 

4. Men: aim mid-physiological free T with attention to SHBG; monitor hematocrit, PSA, BP. 

5. Women (selected cases: hypoactive sexual desire disorder, premature ovarian insufficiency, surgical menopause): low-dose transdermal T with symptom- and level-guided titration; monitor lipids, LFTs, hirsutism/acne. 

6. Gut-directed adjuncts: Time-limited, strain-specific probiotics/synbiotics (e.g., Bifidobacterium/Lactobacillus complexes) when dysbiosis/metabolic features or PCOS are present; prebiotic fibres; selective use of short-chain fatty acid precursors.  

7. Re-evaluation (8–12 weeks): symptoms, body composition, glycaemic markers, hs-CRP, lipids; adjust TRT and microbiome plan accordingly. 

8. Neurocognitive/mental health: consider gut–brain axis when anxiety/sleep/cognition are prominent; combine behavioural sleep interventions with anti-inflammatory diet and TRT optimisation.  

6) Safety & Governance 

• Follow established TRT safety monitoring: hematocrit, PSA (men), breast health and androgenic side-effects (women), BP, lipids, LFTs. 

• Screen for secondary causes of hypogonadism (pituitary disease, medications, OSA, severe obesity). 

• Microbiome therapeutics are adjuncts; avoid over-promising and counsel on variable response. 

• Document shared decision-making; anchor interventions to symptoms, objective biomarkers, and function. 

7) Research Priorities (Levitas Academy) 

1. Prospective cohort: microbiome signatures predicting TRT symptom/biomarker response in men vs women. 

2. Pragmatic RCT: TRT ± standardised synbiotic in hypogonadal men with metabolic syndrome; endpoints: HOMA-IR, hs-CRP, diversity indices, PROMs. 

3. PCOS subtyping: microbiome-informed phenotypes to tailor anti-androgen strategies and metabolic care. 

4. Neurobehavioral outcomes: gut–brain markers mediating mood/sleep improvements under TRT.  

How this informs Levitas care 

For clinicians across Levitas Clinics (Knightsbridge – The HVN; Mayfair; Guildford; Esher): pair TRT with structured gut assessment, deploy time-limited microbiome adjuncts in dysbiosis/metabolic phenotypes, and monitor multi-system endpoints (metabolic, inflammatory, neurocognitive) to capture the full therapeutic signal of hormone restoration.