Is now the time to reconsider risks, benefits, and limitations of estrogen preparations as a treatment for menstrually related migraine?

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.

KEYWORDS:

• Estrogens
• menstrually related migraine
• migraine without aura
• migraine with aura
• combined hormonal contraception
• vascular risk
• chronic pelvic pain
• stroke

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.

Additional information

Funding

This manuscript has not been funded.