ABSTRACT
Introduction
Estrogen fluctuations modulate pain threshold and play a pivotal role in the central and peripheral pathogenesis of menstrually related migraine (MRM). Estrogen-withdrawal during the perimenstrual phase of a spontaneous menstrual cycle or the hormone-free interval (HFI) of hormonal treatments seems to be the culprit.
Area covered
The authors report the most relevant data on risks, benefits, and limitations of exogenous estrogens as a treatment for MRM considering gynecological comorbidities associated with chronic pelvic pain that may be effectively managed by the use of combined hormonal contraception (CHC). Given that migraine and CHC are both currently known as independent risk factors for stroke, levels of evidence contraindicate CHC in women with migraine with aura, whereas quality of evidence is low in women with migraine without aura, including MRM. Continuous/extended/flexible CHC regimens, shorter HFI, or estrogens supplementation during the HFI/perimenstrual spontaneous phase may be beneficial in women with MRM.
Expert opinion
Safety is a main issue, and it is mandatory to investigate the impact of CHC containing natural estrogens, instead of ethinylestradiol, on clinical pattern of MRM and cardiovascular associated risk. Reproductive characteristics may be relevant and should be considered in a multidisciplinary approach to increase the power of endocrine management in MRM.
Article highlights
Estrogens influence the nociceptive and inflammatory pathogenetic mechanisms of migraine by acting on brain circuitries and pelvic function in women.
Menstrually related migraine (MRM) is attributable to estrogen withdrawal during the perimenstrual phase of a spontaneous menstrual cycle or during the hormone-free interval (HFI) of hormonal treatments.
Combined hormonal contraception (CHC) and migraine are independent risk factors for stroke, but data on their association are weak and mainly influenced by the presence of aura, which contraindicates the use of exogenous estrogens.
The European Headache Federation/European Society of Contraception (EHF/ESC) expert consensus recommends CHC use in women with migraine without aura requiring contraception or to prevent estrogen withdrawal migraine. CHC with continuous/extended/flexible regimens or shorter HFI may be beneficial in women with MRM.
Estrogen supplementation during the perimenstrual phase of a spontaneous menstrual cycle or during the HFI of CHC is a valid short-term preventive strategy for MRM in women not requiring or with contraindication to CHC.
CHC containing natural estrogens, which display less cardio-metabolic impact in comparison to ethinyl estradiol, may become the best option for women with migraine, including MRM.
List of abbreviations
CGRP | = | calcitonin gene related peptide |
CHC | = | combined hormonal contraception |
COCs | = | combined oral contraceptives |
DNG | = | dienogest |
E2 | = | estradiol |
E2V | = | estradiol valerate |
E4 | = | estetrol |
EE | = | ethinylestradiol |
ER | = | estrogen receptor |
GABA | = | gamma-aminobutyric acid |
HFI | = | hormone-free interval |
ICHD | = | International Classification of Headache Disorders |
MA | = | migraine with aura |
MM | = | menstrual migraine |
MO | = | migraine without aura |
MRM | = | menstrually-related migraine |
PMM | = | pure menstrual migraine |
PGs | = | prostaglandins |
WHO | = | World Health Organization |
Declaration of interest
RE Nappi has had past financial relationships (lecturer, member of advisory boards, and/or consultant) with Boehringer Ingelheim, Eli Lilly and Company, Endoceutics, Exceltis, Merck Sharp & Dohme, Palatin Technologies, Pfizer Inc, Procter & Gamble Co, TEVA Women’s Health Inc, and Zambon SpA. Furthermore, she currently has a financial relationship with Astellas, Bayer HealthCare AG, Fidia, Gedeon Richter, HRA Pharma, Merck Healthcare, Novo Nordisk, Organon & Co, Shionogi Limited, and Theramex, outside of this submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.