Estrogens are lipophilic hormones derived from cholesterol and synthetized primarily in the granulosa cells of ovaries. They also derive from the aromatization of androgens in peripheral tissues and within the brain. Estrogens achieve physiological effects through the activation of various estrogen receptors (ERs). Animal studies have revealed that numerous brain areas involved in pain processing express ERs.
Genetic studies have explored a possible role for ER variants in the pathogenesis of migraine. Estrogens can modulate the activity of several neurotransmitter systems involved in the pathophysiology of migraine and the pain network pathways. The serotonergic system is enhanced by estrogens and has a protective role toward migraine attacks. An estrogen-mediated mechanism contributes to cortical spreading depression (CSD), a characteristic feature of migraine with aura consisting of a strong wave of neuronal depolarization with glial and vascular activation. (Nappi et al, 2022) The natural course of migraine throughout the lifetime suggests a contribution from hormonal changes, from puberty to pregnancy to menopause/post-menopause. Estrogen withdrawal is a known trigger for migraine. (Ahmad & Rosendale, 2022)
Menstruation is listed as a precipitating factor for tension type headache by 39% to 60% of women. A retrospective study showed that menstrual tension-type headache was more severe and less likely to respond to treatment than non menstrual headache. The initiation of tension-type headache in girls with adolescence, and subsequent changes in relation to menses, pregnancy, and menopause, suggests an important headache-modulating role for sex hormones. Female sex hormones modify pain and headache activity and perception. Estrogen changes can be most closely linked to chronic headache activity. Estrogen affects headache activity because of direct effects on neurotransmitters. Estrogen increases neurotransmitter levels or activity important for tension-type headache, including serotonin, GABA, and enkephalin/ endorphin. (Marcus, 2001)
Nappi RE, Tiranini L, Sacco S, De Matteis E, De Icco R, Tassorelli C. Role of Estrogens in Menstrual Migraine. Cells. 2022 Apr 15;11(8):1355. doi: 10.3390/cells11081355. PMID: 35456034; PMCID: PMC9025552.
Ahmad SR, Rosendale N. Sex and Gender Considerations in Episodic Migraine. Curr Pain Headache Rep. 2022 Jul;26(7):505-516. doi: 10.1007/s11916-022-01052-8. Epub 2022 Jun 9. PMID: 35679008; PMCID: PMC9325838.
Marcus DA. Estrogen and tension-type headache. Curr Pain Headache Rep. 2001 Oct;5(5):449-53. doi: 10.1007/s11916-001-0056-4. PMID: 11560810.