Is the Estrogen–CGRP Relationship Relevant to Migraine?

Calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology, and recent studies have identified interactions between ovarian steroid hormones, CGRP, and the trigeminovascular system, according to a review published online ahead of print October 30, 2017, in Cephalalgia.

“Numerous animal and human studies have shown that cyclic fluctuations of ovarian hormones (mainly estrogen) modulate CGRP in the peripheral and central trigeminovascular system; this [effect] is especially relevant now that novel antibodies directed against CGRP or its receptor are currently in clinical trials,” said Alejandro Labastida-Ramírez of the Division of Vascular Medicine and Pharmacology at Erasmus University Medical Center in Rotterdam, the Netherlands, and colleagues.

The relationship between estrogen and CGRP seems to be “a key factor involved in the higher prevalence of migraine in women,” the authors said. “Future studies should focus on how fluctuations of gonadal hormones influence migraine pathophysiology in both genders…. Hopefully, these sex-related differences may contribute to the development of gender-specific therapies.”

Interplay of Hormones and CGRP

A clinical study by Stevenson et al in 1986 was one of the first to discover a relationship between female sex hormones and CGRP. In this study, concentrations of immunoreactive plasma CGRP in healthy women were significantly increased throughout pregnancy and decreased after delivery. A 1990 study by Valdemarsson et al found that in healthy subjects, immunoreactive plasma CGRP levels were significantly higher in females than in males. “The use of combined contraceptive pills was associated with even higher levels of immunoreactive CGRP in plasma,” said the review authors. “Accordingly, in postmenopausal women, decreased estradiol serum levels were positively correlated with decreased plasma immunoreactive CGRP concentrations, [suggesting] that the CGRP system could be influenced directly by endogenous or exogenous ovarian steroid hormones.”

Ibrahimi et al in 2017 used an experimental model to explore gender differences in CGRP-dependent dermal blood flow in healthy subjects and migraineurs. Dermal blood flow in males did not vary over time and was comparable between healthy subjects and migraineurs. In healthy women, fluctuations of ovarian steroid hormones influenced CGRP-dependent dermal blood flow. “Interestingly, in female migraine patients, dermal blood flow responses were elevated, compared to healthy subjects, but these responses were independent of the menstrual cycle,” the review authors noted.

Therapeutic Trials

Three humanized monoclonal antibodies targeting CGRP and one fully human monoclonal antibody targeting the CGRP receptor are in development.

While trials indicate that CGRP blockade is effective for treating migraine, further studies are needed to “elucidate whether these novel drugs are safe in individuals with cardiovascular risk factors, if there are any consequences of chronic CGRP inhibition in young reproductive women with a normal menstrual cycle, and whether efficacy depends on the phase of the menstrual cycle,” the authors said.

—Jake Remaly

Suggested Reading

Ibrahimi K, Vermeersch S, Frederiks P, et al. The influence of migraine and female hormones on capsaicin-induced dermal blood flow. Cephalalgia. 2017;37(12):1164-1172.

Labastida-Ramírez A, Rubio-Beltrán E, Villalón CM, MaassenVanDenBrink A. Gender aspects of CGRP in migraine. Cephalalgia. 2017 Oct 30 [Epub ahead of print].

Stevenson JC, Macdonald DW, Warren RC, et al. Increased concentration of circulating calcitonin gene related peptide during normal human pregnancy. Br Med J (Clin Res Ed). 1986;293(6558):1329-1330.

Valdemarsson S, Edvinsson L, Hedner P, Ekman R. Hormonal influence on calcitonin gene-related peptide in man: effects of sex difference and contraceptive pills. Scand J Clin Lab Invest. 1990;50(4):385-388.