Prolactin and CGRP Create Female-Specific Migraine Pathways, Suggesting Sex-Based Treatment Strategies | Research

The takeaway

Prolactin sensitizes female sensory neurons and enhances CGRP release in a female-selective manner across mice, primates, and humans, and clinical data suggest CGRP-receptor antagonists may be more effective in women than men.

Female-selective across 3 species
Prolactin-driven CGRP sensitization conserved in mice, primates, and humans — exclusively affecting female pain pathways

What the researchers found

Prolactin produces female-selective sensory neuron sensitization and enhanced CGRP release across species (mice, primates, humans), and clinical data indicate CGRP-receptor antagonists may be preferentially effective in women for acute migraine.

Why it matters

Migraine affects 3x more women than men, yet treatments are rarely sex-stratified. Understanding that female-specific hormonal pathways drive migraine through CGRP could lead to more effective, personalized treatment strategies and better clinical trial design.

The numbers in context

Migraine is approximately 3 times more common in women than men. Prolactin circulates at higher levels in females.

How the study worked

Narrative review integrating preclinical data (mouse, non-human primate, human tissue studies), post-mortem analyses, and publicly available clinical trial data on sex differences in CGRP antagonist efficacy.

Who was studied

Women with migraine (preclinical and clinical evidence)

What this study cannot tell us

Much of the evidence is preclinical. The clinical data suggesting sex differences in gepant efficacy comes from publicly available datasets, not prospective sex-stratified trials. The degree to which prolactin-CGRP interactions drive migraine in clinical practice is not fully quantified.

How to read the evidence

Moderate evidence combining consistent preclinical findings across species with suggestive clinical data. The evolutionary conservation strengthens the translational relevance.

When this study was published

Published in 2024. Contributes to the rapidly growing understanding of sex differences in pain and migraine.

The bigger picture

This work represents a paradigm shift in migraine biology — from assuming migraine works the same way in both sexes to recognizing qualitatively different underlying mechanisms. If treatments are tailored by sex, millions of migraine patients could receive more effective care.

Questions still open

Should migraine clinical trials be designed with sex-specific primary endpoints?
Would anti-prolactin therapies combined with CGRP drugs offer superior migraine prevention in women?
What drives the minority of male migraine patients — is it the same prolactin-CGRP pathway or a different mechanism?

Common questions

Why do women get migraines more than men?

This review reveals that prolactin — a hormone at higher levels in females — directly sensitizes pain neurons and triggers CGRP release specifically in females. This creates a female-selective pathway for migraine that doesn't exist in the same way in males.

Should women and men take different migraine drugs?

The research suggests this could be beneficial. Clinical data hint that CGRP-receptor blocking drugs (gepants) may work better in women. While sex-stratified prescribing isn't yet routine, this evidence supports the idea that personalized migraine treatment based on sex could improve outcomes.

Read the original research

Female-selective mechanisms promoting migraine.

The journal of headache and pain, 25(1), 63

View on PubMed ↗Publisher’s paper ↗

Citation

Singh, Shagun; Kopruszinski, Caroline M; Watanabe, Moe; Dodick, David W; Navratilova, Edita; Porreca, Frank. (2024). Female-selective mechanisms promoting migraine.. The journal of headache and pain, 25(1), 63. https://doi.org/10.1186/s10194-024-01771-w