Peptides for men vs. women: how biology shapes research outcomes

One of the most underappreciated variables in peptide research is biological sex. Differences in hormonal milieu, body composition, receptor expression, and enzymatic activity between male and female subjects can produce substantially different outcomes for the same compound at the same dose. Understanding these differences is essential for designing reproducible studies and interpreting results with appropriate context.

Why sex-specific differences matter in peptide research

Biological sex influences peptide pharmacology at multiple levels simultaneously. At the receptor level, expression density can vary by 15–30% for several key receptors involved in metabolic and regenerative signalling. At the pharmacokinetic level, differences in renal clearance, hepatic enzyme activity, and body fat distribution alter drug exposure profiles. At the downstream signalling level, estrogen and testosterone modulate second messenger systems and gene expression in ways that affect cellular responses to peptide ligands.

Historically, preclinical studies have relied heavily on male animal models, partly to avoid the confounding influence of the oestrous cycle. This has left significant gaps in our understanding of how peptides behave in female biology — gaps that are increasingly being addressed as the field matures.

Key areas where differences are documented

Metabolic peptides (GLP-1 agonists, NNMT inhibitors)

GLP-1 receptor density in pancreatic islet cells is consistently higher in female subjects across mammalian models — approximately 15–20% greater expression compared to males. This translates to differential dose-response relationships when studying incretin mimetics such as Semaglutide or Tirzepatide. Female models tend to show greater glucose-lowering response per unit dose, while male models show more pronounced effects on gastric motility.

For NNMT inhibitors such as 5-Amino-1MQ, the interaction with estrogen signalling is particularly relevant. Estrogen independently suppresses NNMT expression, meaning female models typically start from a lower baseline NNMT activity. This narrows the apparent effect size of NNMT inhibitors in female cohorts — not because the compound is less effective, but because the baseline is already partially modulated.

Tissue repair peptides (BPC-157, TB-500, GHK-Cu)

Estrogen plays a well-documented role in collagen synthesis and inflammatory regulation. In female models, BPC-157 administered in conditions of normal estrogen levels shows enhanced tissue repair compared to male controls, an effect that diminishes significantly in ovariectomised models. This suggests that the peptide and estrogen operate through partially shared or cooperative pathways — a clinically relevant finding for recovery research.

TB-500 (Thymosin Beta-4) appears less subject to sex-hormone modulation, with more consistent effects across male and female models. Its primary mechanism — actin G/F ratio regulation and cell migration promotion — operates through pathways with relatively lower sex-hormone dependence, making it a reliable compound across cohorts.

GHK-Cu shows differentiated research profiles by intended target tissue. In skin remodelling studies, female-biased models demonstrate more pronounced collagen upregulation, consistent with baseline differences in dermal fibroblast activity and estrogen-mediated collagen synthesis support. For systemic antioxidant and anti-inflammatory endpoints, sex differences are less pronounced.

Growth hormone axis peptides (CJC-1295, Ipamorelin, Sermorelin)

GH secretion patterns differ significantly between sexes. Males exhibit higher amplitude, lower frequency GH pulses; females show more frequent, lower amplitude pulses with higher baseline IGF-1 levels in reproductive years. These baseline differences affect how GH-releasing peptides are studied.

Ipamorelin research in female rodent models demonstrates more frequent but smaller GH pulses in response to the same dose, compared to larger single spikes in male models. For research concerned with muscle preservation and recovery, this distinction matters: the female GH secretion pattern tends to produce more sustained IGF-1 elevation, which may actually be advantageous for some research endpoints.

Cognitive peptides (Selank, Semax)

GABAergic and BDNF signalling — the primary targets of Selank and Semax respectively — are both subject to modulation by sex hormones. Estrogen upregulates BDNF expression in hippocampal tissue, which may create a higher baseline in female models and compress the apparent magnitude of Semax's BDNF-elevating effect. Progesterone interacts with GABA-A receptors through its neurosteroid metabolites, complicating interpretation of Selank's anxiolytic effects in female models without hormonal cycle control.

Practical implications for study design

These differences translate into several concrete recommendations for researchers working with peptide compounds:

• Stratify cohorts by sex from the outset. Post-hoc stratification of mixed-sex data is insufficient — power calculations and randomisation must account for sex as a primary variable.
• Document hormonal status in female subjects. For rodent models, oestrous cycle phase at the time of compound administration and sample collection should be recorded and controlled.
• Report sex-disaggregated data. Combined-sex averages obscure potentially significant directional differences that are relevant to downstream research.
• Adjust starting doses thoughtfully. Where pharmacokinetic data supports sex-specific differences in clearance, dose scaling from male-derived data to female subjects requires adjustment — a flat dose equivalence assumption is not appropriate.
• Interpret effect sizes in context. A smaller effect size in female models for estrogen-modulated pathways does not necessarily reflect compound inferiority — it may reflect a biology that is already partially optimised.

The research gap and what's changing

The NIH's 2016 mandate requiring the inclusion of female subjects in preclinical research has begun to shift the literature. More recent peptide studies include both sexes, and several research groups are publishing primary sex-comparison data. As this body of evidence grows, the picture of peptide biology will become progressively more nuanced and applicable across the full spectrum of human biology.

Treating biological sex as a confounding variable to be controlled away, rather than a dimension of biology to be understood, has left significant gaps in peptide research. Closing those gaps will strengthen the field.

References

• Clayton, J.A. & Collins, F.S. (2014). Policy: NIH to balance sex in cell and animal studies. Nature, 509, 282–283.
• Mauvais-Jarvis, F. et al. (2020). Sex and gender: modifiers of health, disease, and medicine. The Lancet, 396(10250), 565–582.
• Veldhuis, J.D. et al. (2006). Differential impact of age, sex steroid hormones, and obesity on basal versus pulsatile growth hormone secretion. Journal of Clinical Endocrinology & Metabolism, 91(3), 800–809.