Elsevier

Contraception

Volume 88, Issue 3, September 2013, Pages 369-375
Contraception

Original research article
Effect of a contraceptive pill containing estradiol valerate and dienogest (E2V/DNG) in women with menstrually-related migraine (MRM)

https://doi.org/10.1016/j.contraception.2013.02.001Get rights and content

Abstract

Background

Combined hormonal contraception might worsen migraine in sensitive women, especially during the free-hormone interval, and raise concerns about the vascular risk. The characteristics of a contraceptive pill containing estradiol valerate/dienogest (E2V/DNG) might be of potential benefit in women with menstrually related migraine (MRM) who choose to use oral contraception for birth control.

Study design

This was a prospective diary-based pilot study. Thirty-two women (age > 35 years) [n= 18 who had never used combined oral contraceptives (COCs) and n= 14 who had previously used COCs] diagnosed with MRMs according to the International Headache Society criteria were included. During the observational period, women filled in a diary with the clinical characteristics of migraine attacks. After a three-cycle run-in period, each subject received a COC containing E2V/DNG (Qlaira®/Natazia®; Bayer HealthCare, Berlin, Germany) administered using an estrogen step-down and progestogen step-up approach. Follow-up evaluations were scheduled at the last cycle of run-in and at the third and sixth cycles of treatment.

Results

The number of migraine attacks was significantly reduced at the third (p<.001) and sixth cycles (p<.001) in comparison with the run-in period. A similar result was evident for the duration (p<.001 at the third and p<.001 at the sixth cycle) as well as for the severity of head pain (p<.001 at the third and p<.001 at the sixth month). Indeed, a significantly lower number of analgesics were used at the third cycle (p<.001) in comparison with baseline, and a further decrease was evident at the sixth cycle (p<.001) in comparison with the third cycle of E2V/DNG use. Interestingly, duration and severity of head pain were significantly correlated with the number of days of dysmenorrhea at the third cycle (r= .89, p=.000 and r= .67, p=.02; respectively) and at the sixth cycle (r= .76, p=.000 and r= .62, p=.04; respectively) in women without complete remission of menstrual cramps during the study period.

Conclusions

The present diary-based pilot study indicates that the use of a pill containing EV2/DNG for six cycles has a positive effect in women with MRM and suggests an association between dysmenorrhea with COCs use as a potential feature of refractory head pain.

Introduction

Hormonal fluctuations in women are highly relevant to the clinical expression of menstrually related migraine (MRM) during the entire reproductive life span [1]. The International Headache Society (IHS) criteria define MRM as attacks of head pain with migraine characteristics occurring on day 1 of menstruation ± 2 days in at least two out of three menstrual cycles associated with attacks occurring at other times during the cycle [2]. The recognition of a 5-day menstrual migraine window [3] is based on clinical data [4], [5] and on the early observations that a period of several days of exposure to high estrogen levels is necessary before estrogen withdrawal can result in migraine at the time of menstruation [6]. Many clinicians are under the impression that migraine attacks related to menses are more severe, long-lasting and refractory to both acute and prophylactic treatments [4], [7], [8]. Indeed, migraine attacks may cover the entire perimenstrual period, from day − 2 to day + 7, because head pain lasts longer and is less responsive to acute treatment [8]. Migraine at menstruation is different in terms of severity from nonmenstrual attacks, even within individuals, and the highest severity is evident on days 1 to 3 when menstrual bleeding starts [3].

Prescribers of combined hormonal contraceptives (CHCs) should be aware that hormonal compounds may trigger the occurrence of migraine and/or tension-type headache (TTH) or exacerbate preexisting attacks, especially around the time of menstruation [9], [10]; this is a condition that is also codified in the IHS classification as hormonally associated headaches (exogenous hormone-induced headache and estrogen-withdrawal headache) [2]. Recognizing that the headaches are triggered by estrogen withdrawal, transdermal estradiol supplementation has been proposed for the management of MRM and other hormonally associated headaches [11], [12], [13]. For CHCs users reporting estrogen-withdrawal headache during the 7-day free-hormone interval, a different approach has been to shorten the interval from 7 to 4 days or to administer low-dose combined oral contraceptives (COCs) in extended/flexible regimens [14], [15]. However, in spite of the considerable advances in terms of safety and tolerability of CHCs in migraine sufferers [16], their use is still questioned especially in women with additional risk factors for stroke, including smoking, hypertension, diabetes, hyperlipidemia and thrombophilia, aged over 35 years [17]. For example, the US Medical Eligibility Criteria rate initiating of estrogen-containing contraceptives as a category 4 for any migraineur over the age of 35 years.

The recent availability of COCs containing natural estrogens, either estradiol valerate (E2V) or 17β-estradiol (E2), may offer new perspectives in women with migraine without aura in light of the evidence of a neutral metabolic and hemostatic impact which may be relevant in those cases at higher risk for the potential negative effects of ethinyl estradiol [18]. On the other hand, data on the vascular safety of progestins in migraine sufferers are inconsistent and deserve further research [16]. However, taking into account the estrogen-withdrawal theory in the occurrence of severe MRM, the peculiar dynamic dosing regimen of the combination of E2V with dienogest (DNG), a hybrid progestogen with strong progestational activity in vivo and antiandrogenic properties without estrogenic, glucocorticoid and androgenic activities [19], may influence the course of head pain during its use and at the time of scheduled bleeding. Indeed, E2V/DNG is administered with a very short free-hormone interval (only 2 days) in an estrogen step-down, progestogen step-up manner, which results in stable E2 levels during the period of intake and also at the time of withdrawal bleeding [20]. In addition, the evidence that when assuming E2V/DNG-containing pill women report lighter bleeding [21], [22] and less symptoms related to estrogen withdrawal [23] may be an additional potential benefit to minimize menstrual-related pain conditions [24].

In this study, we prospectively investigated the effect of a COC containing E2V/DNG on the characteristics (frequency, duration and intensity) of headache with migraine characteristics in women with MRM at baseline who choose to use oral contraception for birth control. In addition, this diary-based study explored the relationship between bleeding profile and dysmenorrhea and the course of head pain during six cycles of E2V/DNG use.

Section snippets

Materials and methods

This prospective, diary-based study was carried out at the University Consortium for Adaptive Disorders and Head Pain and at the Research Center for Reproductive Medicine, Department of Obstetrics and Gynecology, IRCCS S. Matteo Foundation, University of Pavia, Italy. The study protocol was approved by the local university Ethical Committees.

Thirty-two women suffering from MRM diagnosed according to the IHS criteria [3] entered the present study after they had signed informed consent. To be

Results

The mean (± SD) age of the study sample was 40.6±3.5 years and the mean (± SD) BMI was 24.4±1.9 kg/m2, without significant differences between previous COCs users (age 40.1±4.1 years, BMI 24.5±1.8 kg/m2) and never COC users (age 41.0±3.0 years, BMI 24.3±2.1 kg/m2). The clinical characteristics of headache attacks collected by diaries and by a structured interview according to the IHS criteria at baseline are reported in Table 1, as well as the duration and length of the menstrual cycle and the

Discussion

This prospective diary-based pilot study showed that, in women with MRM, the use of COC containing EV2/DNG for six cycles significantly reduced the number of attacks, duration and severity of head pain, and analgesics intake. Interestingly, duration and severity of headache with migraine characteristics were significantly correlated with the number of days of dysmenorrhea in those women who experienced persistent (but reduced) menstrual cramps. Our results suggest that a pill containing EV2/DNG

Acknowledgments

This study was supported by a grant of the Italian Ministry of Public Health RC2010-2011 assigned to a project entitled “Migraine and reproductive life: the role of sexual hormones.”

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    Conflicts of interest: During the past 2 years, Professor R.E. Nappi had a financial relationship (lecturer, member of advisory boards and/or consultant) with Bayer-Schering Pharma, Eli Lilly, Gedeon Richter, Merck Sharpe & Dohme, Novo Nordisk, Pfizer Inc. and Teva/Theramex.

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