Migraine and endometriosis are common conditions that mainly affect females of reproductive age. Both can cause significant pain and have a strong impact on the quality of life. Increasing evidence suggests that these two conditions often occur together, and that females who have both may experience more severe symptoms than those with only one of them. However, the reasons why migraine and endometriosis are linked are still not well understood.

Some biological factors may help explain this connection. One of them is a molecule called calcitonin gene-related peptide (CGRP), which plays an important role in migraine and may also be involved in pain and inflammation in endometriosis. In addition, hormonal changes during the menstrual cycle, especially fluctuations in estrogen levels, may influence symptoms in both conditions. Genetic and epigenetic factors may also contribute to this association.

The main hypothesis of this study is that females who have both migraine and endometriosis have a distinct clinical and biological profile compared to females who have only migraine or only endometriosis. In particular, it is expected that differences will be observed in CGRP levels and hormonal patterns across the menstrual cycle.

The FEMININE study is a prospective observational study that will follow females over several menstrual cycles. It will include three groups: females with both migraine and endometriosis, females with migraine only, and females with endometriosis only. Participants will record their symptoms in diaries and will provide blood samples at specific times of the menstrual cycle.

The main goal of the study is to compare CGRP levels between groups. Additional goals include describing differences in symptoms, menstrual-related migraine, hormonal levels, and selected genetic and epigenetic markers.

By improving the understanding of how migraine and endometriosis are related, this study aims to support better diagnosis and more personalized care for females affected by these conditions.

Inclusion Criteria:

1. Adult females (≥18 years old).
2. Diagnosis of migraine according to ICHD-3 criteria confirmed by a headache specialist (for MIG-O and MIG-EDM groups).
3. Confirmed diagnosis of endometriosis based on clinical symptoms and imaging or surgical criteria according to ESHRE guidelines (for EDM-O and MIG-EDM groups).
4. Signed informed consent.

Exclusion Criteria:

1. Individuals diagnosed with secondary headache according to the ICHD-3.
2. Individuals with a severe disease (e.g., major psychiatric disorder, severe cardiovascular conditions).
3. History of, treatment for, or evidence of, alcohol or drug abuse within the past 12 months.
4. Pregnant or breastfeeding females.

Participants of female sex assigned at birth with reproductive potential

Participants will be recruited from prospectively maintained clinical databases at Vall d'Hebron University Hospital (Headache Unit and Gynecology Unit) and from outpatient clinics specialized in migraine and endometriosis. The study population consists of adult females of reproductive age with a diagnosis of migraine, endometriosis, or both, who are receiving routine clinical care at a tertiary referral center.

Access to de-identified individual participant data may be granted to researchers upon reasonable request, pending ethical approval and the execution of appropriate data sharing agreements.