1 LITHUANIAN UNIVERSITY OF HEALTH SCIENCES
FACULTY OF MEDICINE
Department of Gynecology and Obstetrics
Title of Master’s Thesis:
THE IMPACT OF HORMONAL CONTRACEPTIVES ON WOMEN WITH MIGRAINE:
A REVIEW OF THE EVIDENCE
Author:
Georgia Christodoulou
Supervisor:
Jonas Ulevičius M.D
Kaunas
2018-2019
2
TABLE OF CONTENTS
Summary ... 3
Acknowledgements... 5
Conflict of interest ... 6
Abbreviations ... 6
Chapter 1: Introduction ... 7
Chapter 2: Aims and Objectives ... 8
Chapter 3: Literature Review……….9
Chapter 4: Research Methodology and Methods……….13
Chapter 5: Results and their Discussion………14
Chapter 6: Conclusions ………...20
Chapter 7: Practical Recommendations………22
Chapter 8: Literature List……….23
3
SUMMARY
Author name: Georgia Christodoulou
Research title: The impact of hormonal contraceptives on women with migraine: a review of the evidence
Aim: To explore the impact of hormonal contraceptives on women with migraine Objectives:
1. To estimate the impact of hormonal contraceptives use on migraine headaches.
2. To explore the impact of hormonal contraceptives on the different types of migraine and headache
3. To compare the impact on migraine between the uses of combined hormonal contraceptives and progestin only contraceptive on women with migraine.
Methodology: This was a Literature review where searches were conducted using Medline (PubMed), Science direct publications and Google Scholar. The search terms used were
“hormonal contraceptives” “progestin-only pill”, “migraine" “migraine treatment” and “headache”.
Literature was searched from September 2018 until December 2018.The articles and studies were selected for inclusion in this thesis based on their relevance on the topic.The studies which were selected and included are studies that used low dose formulations of Combined Hormonal Contraceptives (CHC) and Progestin-Only Pill (POP). The classification of migraines according to the International Classification of Headache Disorders was used utilized in order to carry out this literature review.
Results:Eleven studies in total met the inclusion criteria. Six studies that evaluated the influence of CHC on women with different types of migraines were included. The two out of six studies that reported a negative influence are studies on women suffering from migraine with aura (MA) and migraine without aura (MO), in both groups the migraine worsened. The four out of six of the studies that reported a positive influence (prevention and reduction of the severity, intensity and frequency of migraine headaches) are studies on women with menstrual-related migraine (MRM), pure menstrual migraine (PMM), and unspecified type of headache. Three studies that evaluated the influence of POP on women suffering from MA and MO were used. All three studies showed a positive influence of POP, significant reductions in headache days and intensity. Two studies included in this review made a comparison between CHC and POP on women suffering from MO.
4 The Authors suggest POP alone improves migraine therapy patterns, reduces the pain severity, the duration and number of attacks and POP has a more positive impact over oral CHC.
Conclusions: Combined hormonal contraceptives in a number of cases seem to aggravate the course of migraine and in particular in women diagnosed with MA and MO. In the case of MRM and PMM, CHCs seem to have a positive impact. CHCs are contraindicated to women suffering from MA and MO with additional risk factors. POP is a safe and effective alternative over CHCs to use. The comparison between the two regimens, POP and CHCs on women with MO showed a greater positive impact of POP over the oral CHCs.
5
ACKNOWLEDMENTS
I would first like to thank my thesis supervisor Dr. Jonas Ulevičius for always being available whenever I had a question about my research or writing. He consistently allowed this thesis to be my own work, but steered me in the right the direction whenever he thought I needed it.
I dedicate this thesis to the memory of my father who would have been happy to see me accomplishing my goals.
I also dedicate this thesis to my mother and I would like to thank her for providing me with unfailing support and continuous encouragement throughout my study years. Thank you.
6
CONFLICT OF INTEREST
The author reports no conflicts of interest during the study.
ABBREVIATIONS
OCs Oral Contraceptives
COCs Combined Oral Contraceptives MA Migraine with Aura
MO Migraine without Aura
CHCs Combined hormonal contraceptives IHS International Headache Society
EE Ethinyl Estradiol
PMM Pure Menstrual Migraine MRM Menstrual-Related Migraine
ICHD International Classification of Headache Disorders DRSP/EE Drospirenone/ Ethinyl Estradiol
HFI Hormone Free Interval
MIDAS Migraine Disability Assessment POP Progestin-only Pill
7
CHAPTER 1: INTRODUCTION
Oral contraceptives (OCs) use is nowadays a widespread method of birth control among women, due to its safety and high effectiveness. In addition to high contraceptive efficacy, they add some non-contraceptive, health benefits such as protection against ovarian and endometrial cancer, pelvic inflammatory disease and ectopic pregnancy. [1] Nonetheless, it is commonly believed that COCs can initiate or aggravate headaches, in particular migraine. [2]
It is estimated that 18% of women, which rises to 24% between 30 and 39 years of age, and 6% of men suffers from migraine with a female/male prevalence ratio of around 3 to 1. [7]
Approximately 60% of women with migraine reported an association between menstruation and the occurrence of migraine attacks. [8] The high prevalence of migraine in females, its correlation with the menstrual cycle and with the use of hormonal contraceptives suggest that the female hormones are implicated in the attacks. [7]
Primary headaches are relatively common in reproductive-aged women. Because hormonal contraceptive use is also prevalent in this group, clinicians are often questioned about the use of hormonal birth control in women with coexisting headaches. [11] The term “headache” and the term “migraine” are often, in literature used as synonyms.
Recently, there have been a number of studies done to assess the influence of hormonal contraceptives in migraine sufferers. The aim of this thesis is to review the available scientific evidence and attempt to provide a better understanding on whether hormonal contraceptives have a negative or a positive impact on migraines. In addition we will compare the impact on migraines between the use of combined hormonal contraceptives and the progestin-only preparations. By doing this we could make a conclusion to what the most suitable regimen is for women suffering from different types of migraines and headaches.
8
CHAPTER 2: AIMS AND OBJECTIVES
Aim: To explore the impact of hormonal contraceptives on women with migraine
Objectives:
1. To estimate the impact of hormonal contraceptives use on migraine.
2. To explore the impact of hormonal contraceptives on the different type of migraines and headaches.
3. To compare the impact on migraine between the uses of combined hormonal contraceptives and progestin-only contraceptives on women with migraine.
9
CHAPTER 3: LITERATURE REVIEW
Types of Hormonally Related Migraines and Headaches in Females
Migraine is a primary headache disorder, defined as a unilateral, pulsatile headache of moderate to severe intensity that lasts 4-72 hours. It may be associated with sensitivity to sounds or photophobia, nausea and vomiting and occasionally with simultaneous focal neurologic or visual symptoms known as auras. [8] Clinically, there are two main forms of migraine: migraine with aura (MA) and migraine without aura (MO).
As a matter of fact, headache is among the most common side effects reported with the utilization of COCs, frequently leading to their use being discontinued. [1]
Perceiving the need for accurate diagnosis the International Headache Society (IHS) generated a comprehensive guide for differentiating between the different headaches subtypes. The establishment of these guidelines has facilitated suitable diagnosis and treatment of headaches and, more importantly for prescribers of contraception, it has become a useful tool for identifying women who have migraines.
The International Classification of Headache Disorders (ICHD), identifies at least two entities that can evidently be related to OCs use. One entity is “exogenous hormone induced headache” and the other “estrogen-withdrawal headache”. An “exogenous hormone-induced headache” could be triggered by intake of OCs. In the diagnostic criteria of the first entity we can distinct two for our interest:
- Headache or migraine develops or markedly worsens within three months of commencing exogenous hormones.
- Headache or migraine resolves or reverts to its previous pattern within three months after total discontinuation of exogenous hormones. [2]. In year 2008 a considerable change was presented where the diagnosis of headache induced by exogenous hormones requires the presence of headache for at least fifteen days per month. [13] The classification and criteria of headaches and migraines are summarized in table 2.
Many of the previous studies in adult women and COC use are old and dealt with oral contraceptive using higher doses of Ethinylestradiol as high as 50 g or more. [6] Oral contraceptives has progressively reduced the estrogen content throughout the years: The earliest preparations of OCs contained 100 μg EE or even more. In 1970s Ethynilestradiol (EE) content reduced to 35 μg, and now it has been reduced to 15 μg in some formulations. [10] Despite the
10 dose content of EE, clinical evidence suggests that, also with the newest formulations, OCs can sometimes modify the pattern of the individual migraine attacks. We aim to review the latest studies using the newest formulations with the reduced content of estrogens and progestogens.
Estrogen withdrawal headache is defined as the headache that develops within 5 days after last use of estrogen or resolves within 3 days. Menstruation is reported to be a trigger for migraine by about 60 % of female migraineurs. [10]
Another entry of the International Headache Society identifies two different type of migraine associated with the menstrual cycle: The one of which is “pure menstrual migraine” and the other
“menstruation/menstrual-related migraine. [8] Menstrual migraines are a subset category of migraines without aura.[21]Pure menstrual migraine (PMM) is defined as migraine attacks arising on or between day 1 of menstruation +/- 2 days (i.e., on or between days -2 to +3 of the cycle in at least two of three cycles, with no migraine at other times of the cycle. On the other hand, menstruation-related migraine (MRM) is defined as up to four attacks of migraine per month, of which one must occur at other times in addition to day 1±2 of the menstrual cycle. [8, 10].Both, MRM and PMM were forms of migraine without aura, along with non-menstrual MO or migraine with aura (MA) in the case of MRM but since 2018, in the Appendix of the classification, PMM with aura and MRM with aura are new entries. [13] The possible combinations of menstrual migraines forms are summarized and presented in table 1.
Table 1-Possible combinations of migraine forms
MA MO
PMM PMM+MA PMM+MO
MRM MRM+MA MRM+MO
11 Table 2-Hormonally associated headache classification: International Classification of headache Disorders criteria for hormonally associated headache
From The International Classification of Headache Disorders, 2nd edition. [30]
Hormones affecting pain
The sum of data on hormone levels and menstrual or hormonally related migraine indicate that falling estrogen levels or estrogen withdrawal after periods of sustained higher levels can trigger migraine. This is in line with the observation that migraines are most likely to occur in the late luteal phase of the menstrual cycle when serum estradiol levels are falling, during the hormone-free interval of estrogen-containing contraceptive regimens, and around menopause when estradiol levels are unstable and unpredictable.[5,21] Besides that, migraines usually improve during pregnancy, when estradiol levels are high or rising, and have the tendency to regress with aging,
Menstrual Migraine
-Pure Menstrual migraine: migraine attacks that occur exclusively 2 days before to 3 days after the onset of menses, in at least 2 out of 3
menstrual cycles and at no other of the cycle
-Menstrual-related migraine: migraine attacks that occur 2 days before to 3 days after the onset of menses and additionally at other times of the cycle
Exogenous hormone-induced headache
-Headache or migraine that develops or worsens within 3 months of starting exogenous hormones
-Headache or migraine that resolves or reverts to its previous pattern within 3 months after discontinuing exogenous hormones.
-Headache or migraine lasting for at least 15 days per month (Criterion added in 2018)
Estrogen withdrawal headache
-Headache or migraine that develops within 5 days after use of estrogen -Headache or migraine that resolves within 3 days
12 when estradiol levels are low or stable. [5] In what way estrogen or progesterone may influence the occurrence or course of migraine?
The suspected mechanism behind estrogen withdrawal headache, which is in fact the rapid drop of estrogen level in blood is that fluctuations of estrogen levels may have direct or indirect effects on serotonergic and opiatergic neurotransmitter systems, which are considered to be important regulators of the trigeminal pain pathways. [12, 22] Sex steroid hormones, whether endogenous or exogenously administered, can possibly affect pain in general and migraine in particular through a variety of neurovascular mechanisms. They have neuroactive properties that seem to alter the threshold for migraine in susceptible women [10]. Estradiol, progesterone, and testosterone are synthesized and metabolized by the brain. They can induce rapid anesthetic, sedative/hypnotic, and anticonvulsant effects in the brain and through genomic effects, sex hormones can alter receptor expression and modulate the synthesis, release, and transport of neurotransmitters involved in pain and inflammation [10]. Estrogen and progesterone fluctuations therefore have widespread effects on opioid, serotonergic, noradrenergic, beta-adrenergic, dopaminergic, and GABAergic systems which may affect the expression of migraine. [10]
13
CHAPTER 4: RESEARCH METHODOLOGY AND METHODS
Methodology: For this literature review the electronic medical database Medline (PubMed), Science direct publications and Google Scholar were used. The keywords and terms searched are “combined oral contraceptives”, “hormonal contraceptives” “progestin-only pill”,
“migraine" “migraine treatment” and “headache”.Literature was searched from September 2018 until December 2018. Article types that were searched, were reviews, systematic reviews and studies. The articles and studies were selected for inclusion in this thesis based on their relevance on the topic. The studies which were selected and included are studies that used low dose formulations of COC and POP. The titles and abstract associated with these searches were reviewed for references to the topic, and if found relevant, full texts of those articles were retrieved.
The classification of migraines according to the International Classification of Headache Disorders was used utilized in order to carry out this literature review.
14
CHAPTER 5: RESULTS AND DISCUSSION
Combined Hormonal Contraceptives
In a separate analysis on the types of migraine with and without aura in contraceptive pill users, F. Granella et al. evaluated 39 women with migraine with aura and 83 women with migraine without aura taking COC in a case–control study. The diagnosis of MA and MO was made according to the ICHD criteria. The Authors reported exacerbation in both groups. The use of OCs worsened the headache more frequently in MA than in MO subjects (MA=56.4%, MO=25.3%). In both forms a small number of patients, in contrast, reported an improvement in their headache.
The rates of improvement in the two groups were 5.1% in the group with aura and 7.2% in the group without aura. [11].These results are in agreement with the study of R.B. Machado et al. who evaluated 480 women in a cross-sectional design study, 80 of them were diagnosed with migraine according to ICHD and 400 were classified as having other type of headache. In the migraine group 13 out of the 80 women fulfilled the criteria for the presence of aura, which all had aura before starting COC. Migraines, but not other types of headache, were significantly affected by COCs. Following COC use, headaches worsened in 32.5% and 19.3% and improved in 30% and 13.8% in the “migraine” and “non-migraine” groups, respectively. In the migraine group, the presence of aura tended to be associated with an exacerbation in the intensity and/or frequency of migraine episodes during contraceptive use; however, this correlation was not statistically significant. In the migraine group only, headache episodes occurred predominantly during or around the hormone-free interval. [4] Since estrogen-containing hormonal contraceptives are contraindicated for women who have migraine with aura the number of studies evaluating the influence of COC on women with MA are limited. Taking into account the available evidence regarding the influence of COC on MA the situation seems to worsen and an aggravation of the symptoms has been observed in these cases. [4, 17, 26] Nevertheless, Loder et al. who conducted a systematic review [24] reported that, regardless of its cause, headache associated with COCs use tends to improve or disappear with continued use, even in new-onset headaches attributable to OCs use.
Sulak et al. performed an open label single-center prospective analysis of headaches in 114 women with and without headache. [12] The diagnosis was not made following the criteria of ICHD and women with MA were excluded. COC’s influence on migraines typically tends to occur during
15 the pill-free (placebo) week. The Authors compared a standard 21/7 day combined pill (estrogen+progestin) cycle for 3 months followed by a 168-day extended placebo-free regimen.
The Authors found that compared to a 21/7 OC regimen the 168 extended placebo-free regimen with DRSP/EE led to a decrease in headache severity. As hormonal fluctuations are thought to likely play a role in migraine pathophysiology, and estrogen withdrawal is probably one of the more important triggers, the finding of this study demonstrate that the removal of placebo interval and thus the hormonal fluctuations improved, severe headaches seen throughout the entire 28 days of the standard 21/7 regimen.
Calhoun and Ford performed a retrospective review of 229 consecutive women seen in follow- up for hormonal prevention of MRM. [13] They administered COCs with low-dose supplementation with ethinyl estradiol during the placebo week, an extended cycle regimen with COCs with supplemental estrogen, and natural cycles with perimenstrual application of an estradiol patch.
The authors found that in 229 adult women the resolution of menstrually related migraines correlated with the conversion of chronic migraines to an episodic pattern. In addition the Authors found that there was also a significant reduction in medication use such as Triptans.
Similarly in a double-blind, randomized, placebo-controlled pilot study that was done by Coffee et al. in 32 suffering with MRM without aura diagnosed according to modified ICHD-II criteria.[14]
Participants were initiated on 21/7 extended combined oral contraceptives (containing levonogestrel and ethinyl estradiol) and others were not on hormonal contraceptives . During the HFI participants were given Triptan for the management of migraine. Analyses compared headache scores during pre-study baseline cycles to those in a 168-day extended regimen with placebo versus Triptan treatments during HFIs. The pre-treatment observation was menstrual cycles. The Authors reported that the daily headache scores decreased during the extended HC regimen as compared to baseline and MIDAS scores also decreased as compared to baseline in the users of extended OCs as compared to baseline.
As it is demonstrated in the two mentioned studies, the extended or continuous administration of estrogen has been associated with an overall reduction in migraine severity and frequency. [21]
Nappi et al. performed a prospective diary-based pilot study with 32 women [n=18 had never used (COCs) and n=14 had previously used COCs, diagnosed with MRMs according to the International Headache Society.[15] The number of migraine attacks was significantly reduced at the 3rd and
16 6th cycles in comparison with the run-in period. The present diary-based pilot study indicates that the use of COC for six cycles has a positive effect in women with MRM.
De Leo et al. studied 60 women affected by PMM without aura and evaluated two therapeutic approaches after randomization: EE 20 lg/DRSP 3 mg in formulations of 21/7 or 24/4 were administered for 3 months. Although both groups had a significant reduction in both intensity and duration of attacks, the group on the 24/4 regimen had the most benefits as from the first cycle.
The 24/4 regimen was superior with regard to the intensity and duration of menstrual migraine attacks, compared with the 21/7 regimen. [8]
Extended-cycle COC regimens and shortened hormonal free intervals are associated with decreases in hormone-withdrawal symptoms, such as menstrual related headaches but also cyclic mood swings, pelvic pain, and dysmenorrhea. [8]
Nowadays, new formulations with other extended regimens, such as Ethinyl E2 20 mg plus Drospirenone 3 mg administered 24/4, are developed. This new formulation is associated with a decrease in days without estrogen, which was claimed to decrease or prevent the modification of certain neurotransmitters such as dopamine, serotonin, and norepinephrine and consequently the improvement in migraine attacks caused by vasodilation and increased prostaglandin secretion.
[8]
De Leo et al. concluded that, the use of the 24/4 regimen, with a shortened 4-day pill-free interval, and with a progestin such as Drospirenone, could be the regimen of choice for women suffering from menstrual migraines. This regimen guarantees a longer presence of estrogen and the associated antiandrogens and antimineralocorticoid of Drospirenone. [8]
Despite of the considerable advances in terms of safety and tolerability of the new hormonal contraceptive formulations, exogenous estrogen use may be remarkably associated with cerebrovascular diseases in migraine sufferers, especially under certain clinical conditions, including smoking, hypertension, diabetes, hyperlipidemia and thrombophilia and in women over 35 years old.[16] There is a general consensus that combined hormonal contraceptives are relatively contraindicated in women with migraine with aura because of the increased risk of ischemic stroke.[10,16] The same is true when aura symptoms appear in COCs users with MO.
A working group consisting of headache experts, gynecologists, stroke experts, and epidemiologists developed a first consensus document about the safety of hormonal
17 contraceptives (HCs) in females suffering from migraines in reproductive age. [17] According to the recommendations of the European Headache Federation (EHF)/ European Society of Contraception and Reproductive Health (ESCRH) consensus group, CHCs should not be used in all women with MA and women with MO who have additional risk factors. [17]
Progestin-only pill
A very recent study investigating the changes of quality of life in migraineurs 3 months after start of the progestin-only pill Desogestrel 75 μg intake demonstrates a highly significant reduction in MIDAS Score and MIDAS grades. Merki-Feld et al. analyzed retrospectively the effect of 3 month course of the progestogen-only pill (POP) containing 75 μ g desogestrel (Cerazette ®; Merck Sharp & Dohme AG, Luzern, Switzerland) on 37 migrainous women. [18]. Desogestrel was associated with significant reductions in headache days and intensity and the MIDAS migraine disability score improved significantly (from 27.4 to 11.1 points) 25 of the 37 women (68%) experienced a decrease of at least one grade.
Another study by Merki-Feld et al. on the effect of Desogestrel 75 μg included women with MA (n°=6) and with MO (n°=32) and evaluated migraine days, pain score and pain medication [19].
An improvement of each parameter was observed during 3 months use of Desogestrel 75 μg in comparison to a three months pre-treatment interval. A sub-analyses of the effect on 32 women with MO revealed significant improvements in number of migraine days, pain medication and pain intensity. The authors conclude that in order to avoid estradiol withdrawal and high estradiol levels, an estradiol- free pill like Desogestrel 75 mg could be regarded as suitable because it is used without hormone-free phases, inhibits ovulation and prevents hormone withdrawal.
Estrogen levels released from the ovary during its use are steady and low. Another explanation to the potential positive effects of Desogestrel 75 mg focusses on direct effects of the progestin.
Although the dosage of 75 mg Desogestrel is rather low, the biological effects are significant because the complex steroid structure of this ethyl-gonane delays liver metabolism and prolongs the half-life of the substance. Progestins are known to antagonize estrogen actions in reproductive tissues and the brain by lowering estrogen receptor expression. [19]
18 Their findings are in line with the findings of the study of Nappi et al. which evaluated the effects of progestin-only contraception on migraine.[20] The study evaluated 30 women with MA (n=15 who have never used COCs and n=15 who had previously used COCs were diagnosed according to the International Headache Society criteria. The use of Desogestrel 75 μg resulted in a significant reduction in MA attacks and in the duration of aura symptoms, already after three months of observation. Interestingly, the beneficial effect of Desogestrel 75 μg on visual and other neurological symptoms of aura was significantly present only in those women in whom MA onset was related to previous COCs treatment. These findings propose that the reduction in estrogen levels may be relevant to the amelioration of MA, but do not exclude a direct effect of the progestin on cortical spreading depression. On the other hand in both above mentioned studies there were few dropouts of women experiencing more migraine after starting contraception with this progestin, indicating that progestin can probably also deteriorate migraine in few cases.
The above mentioned studies show that this POP might not only improve migraines, but can also act as a trigger for more headaches in a few hormone- sensitive migraineurs. Altogether during the the studies a broad variety of reactions on Desogestrel 75 mg but besides a few cases with worsening, the improvement of migraine frequency ranged from 20% to 100%. [19]
Progestin-only-contraceptives are not associated with an increased risk of thromboembolic events [18] it is surprising that their use is not frequently recommended to women suffering from migraine.
The question that rises again after the studies show positive impact of progestin-only pill is: What is the possible mechanism that Progestogen influences the occurrence or the course of migraines?
Progestogen appears to be protective against migraine attacks because of its increase during medium-luteal phase and the evocation of anovulatory cycles in continuous formulations.
Progesterone may also influence the central nervous system, by reducing the nociceptive activation in the trigeminal-vascular system and down-regulating the estrogen receptors. [7]
19
Desogestrel progestogen-only pill versus extended regimen of combined oral contraceptives
Morotti et al. compared data of 31 women with MO who were treated with Desogestrel 75 μg/day and 22 women with MO who were treated with continuous Ethinylestradiol (EE) 20 μg/day + Desogestrel 150 μg/day [25]. The authors found that Desogestrel 75 μg/day as compared to the continuous EE 20 μg/day + Desogestrel 150 μg/day was associated with a decline in the number of days with pain medication. There was no difference between the two group in migraine days, headache days, headache intensity, days with headache score 3 and Triptan use. The Authors suggest that their preliminary data confirm that POP therapy improves migraine patterns and quality of life after 6 months’ treatment in women with migraine without aura and it decreases the analgesic consumption with respect to an extended COC therapy.
Another study of Morotti et al. compared data of 62 women with MO who were treated with Desogestrel 75 μg/day and 82 women with MO who were treated with continuous EE 20 μg/day + Desogestrel 150 μg/day for 6 months [26]. The authors found that Desogestrel 75 μg/day as compared to the continuous EE 20 μg/day + Desogestrel 150 μg was associated with a reduction in pain severity, duration of attacks and number of attacks.
Although these available data suggest a greater benefit from Desogestrel over the oral CHC but evidence is too preliminary to draw firm conclusions.
According to the results of this literature review which hormonal contraceptives a woman selects can greatly influence her course of migraine. Traditionally, neurologists are not trained in the hormonal management of hormonally related migraines and headaches and most training in gynecology, does not deal with the hormonal management of neurologic disorders. [31]
20
CHAPTER 6: CONCLUSIONS
In conclusion, hormonal contraceptives and especially CHCs may trigger or worsen migraine, but their correct use may even prevent or reduce some forms of migraine, like estrogen withdrawal headache and exogenous hormone-induced migraine induced by COC’s. [7] Evidence suggested that stable estrogen levels have a positive effect, minimizing or eliminating the estrogenic drop and consequently prevent, reduce the severity, intensity or reduce the frequency of migraines in women diagnosed also with MRM, PMM and MO. [7, 12, 13]
Several contraceptive strategies may act in this way: extended cycle CHCs, CHCs with shortened hormone-free interval (HFI), progestin-only contraceptives, CHCs containing new generation estrogens and estrogen supplementation during the HFI. [7]
In addition to the fact that women suffering from MA and women suffering from MO with additional risk factors (e.g., age over 35 years, tobacco use, hypertension, obesity, and diabetes) are contraindicated to the use of CHC, studies show that CHC exacerbate MA and aura symptoms in most cases. In this case POP could be used as an alternative. [20, 26, 27] Potentially, the maintenance of stable estrogen level by the administration of progestins in ovulation inhibiting dosages may have a positive influence of nociceptive threshold in women with migraine.
Preliminary evidences based on headache diaries in migrainous women suggest that the progestin-only pill containing Desogestrel 75 μg has a positive effect on the course of both MA and MO in the majority of women, reducing the number of days with migraine, the number of analgesics and the intensity of associated symptoms. [27]
In studies comparing the two regimens and in particular the use of extended combined hormonal contraceptives compared to the use of progestin-only pill, a positive influence of Desogestrel on migraine not only in women who switched from CHCs to Desogestrel, but also in those who had not used hormones for over 6 months before starting it. [29]
Nevertheless, it is not facile to evaluate the influence of hormonal contraceptives on the clinical evolution of migraine. A number of studies performed on the course of migraine during hormonal intake are observational in nature and a number of them do not provide a clear description and classification of migraines and headaches. In addition to that, the number of studies are generally limited in number and one of the reasons could be that combined hormonal contraceptives are relatively contraindicated in women with migraine with aura because of the increased risk of
21 ischemic stroke andthe appears to be true when aura symptoms appear in COCs users with MO.
Another reason may be that neurologists do not usually delve into the female hormonal aspect of the migraines and headaches and gynecologists do not delve into the female hormonal management of neurologic disorders, therefore it remains unexplored. We can likewise note that a very few studies distinguish between the combined CHCs and the progestin-only pill. Many of the Authors suggest that their data are preliminary to draw a definite conclusion. The role of hormonal contraceptives on migrainous women deserves to be further investigated.
The Author declares that certain notes and recommendations in this review are not directly covering raised objectives, but have been written because of their relevance to the topic.
22
CHAPTER 7: PRACTICAL RECOMMENDATIONS
1. In case of MA or MO with additional risk factors, CHCs should be avoided.
2. In case of MRM, PMM and MO, CHCs maybe be used with preference to extended cycle CHCs, CHCs with shortened hormone-free interval (HFI), progestin-only contraceptives, CHCs containing new generation estrogens and estrogen supplementation during the HFI.
3. POP may be an alternative to CHCs.
4. It is recommended that the cooperation between gynecologist and neurologist is
established for the selection of appropriate treatment in women suffering from migraines.
23
LITERATURE LIST
1. Allais, G., De Lorenzo, C., Mana, O. and Benedetto, C. (2004). Oral contraceptives in women with migraine: balancing risks and benefits. Neurological Sciences, 25(S3), pp.s211-s214.
2. Allais, G., Castagnoli Gabellari, I., De Lorenzo, C., Mana, O. and Benedetto, C. (2011).
Oral contraceptives in migraine therapy. Neurological Sciences, 32(S1), pp.135-139.
3. Morotti, M., Remorgida, V., Venturini, P. and Ferrero, S. (2018). Progestin-only contraception compared with extended combined oral contraceptive in women with migraine without aura: a retrospective pilot study.
4. Machado, R., Pereira, A., Coelho, G., Neri, L., Martins, L. and Luminoso, D. (2010).
Epidemiological and clinical aspects of migraine in users of combined oral contraceptives.
Contraception, 81(3), pp.202-208.
5. Shuster, L., Faubion, S., Sood, R. and Casey, P. (2011). Hormonal Manipulation Strategies in the Management of Menstrual Migraine and Other Hormonally Related Headaches. Current Neurology and Neuroscience Reports, 11(2), pp.131-138.
6. Pakalnis, A. and Gladstein, J. (2010). Headaches and Hormones. Seminars in Pediatric Neurology, 17(2), pp.100-104.
7. Allais, G., Chiarle, G., Sinigaglia, S., Airola, G., Schiapparelli, P., Bergandi, F. and Benedetto, C. (2017). Treating migraine with contraceptives. Neurological Sciences, 38(S1), pp.85-89.
8. De Leo, V., Scolaro, V., Musacchio, M., Di Sabatino, A., Morgante, G. and Cianci, A.
(2011). Combined oral contraceptives in women with menstrual migraine without aura.
Fertility and Sterility, 96(4), pp.917-920.
9. Allais, G., Castagnoli Gabellari, I., De Lorenzo, C., Mana, O. and Benedetto, C. (2011).
Oral contraceptives in migraine therapy. Neurological Sciences, 32(S1), pp.135-139.
10. Faubion, S., Casey, P. and Shuster, L. (2012). Hormonal Contraception and Migraine:
Clinical Considerations. Current Pain and Headache Reports, 16(5), pp.461-466.
24 11. Granella, F., Sances, G., Pucci, E., Nappi, R., Ghiotto, N. and Nappi, G. (2000). Migraine
with aura and reproductive life events: a case control study. Cephalalgia, 20(8), pp.701- 707.
12. Sulak, P., Willis, S., Kuehl, T., Coffee, A. and Clark, J. (2007). Headaches and Oral Contraceptives: Impact of Eliminating the Standard 7-Day Placebo Interval. Headache:
The Journal of Head and Face Pain, 47(1).
13. Calhoun, A. and Ford, S. (2008). Elimination of Menstrual-Related Migraine Beneficially Impacts Chronification and Medication Overuse. Headache: The Journal of Head and Face Pain, 48(8), pp.1186-1193
14. Coffee, A., Sulak, P., Hill, A., Hansen, D., Kuehl, T. and Clark, J. (2014). Extended Cycle Combined Oral Contraceptives and Prophylactic Frovatriptan During the Hormone-Free Interval in Women with Menstrual-Related Migraines. Journal of Women's Health, 23(4), pp.310-317
15. Nappi, R., Terreno, E., Sances, G., Martini, E., Tonani, S., Santamaria, V., Tassorelli, C.
and Spinillo, A. (2013). Effect of a contraceptive pill containing estradiol valerate and dienogest (E2V/DNG) in women with menstrually-related migraine (MRM). Contraception, 88(3), pp.369-375.
16. Nappi, R., Sances, G., Allais, G., Terreno, E., Benedetto, C., Vaccaro, V., Polatti, F. and Facchinetti, F. (2011). Effects of an estrogen-free, desogestrel-containing oral
contraceptive in women with migraine with aura: a prospective diary-based pilot study.
Contraception, 83(3), pp.223-228
17. Sacco, S., Merki-Feld, G., Ægidius, K., Bitzer, J., Canonico, M., Gantenbein, A., Kurth, T., Lampl, C., Lidegaard, Ø., Anne MacGregor, E., MaassenVanDenBrink, A., Mitsikostas, D., Nappi, R., Ntaios, G., Paemeleire, K., Sandset, P., Terwindt, G., Vetvik, K. and Martelletti, P. (2018). Effect of exogenous estrogens and progestogens on the course of migraine during reproductive age: a consensus statement by the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESCRH). The Journal of Headache and Pain, 19(1)
18. Merki-Feld, G., Imthurn, B., Seifert, B., Merki, L., Agosti, R. and Gantenbein, A. (2013).
Desogestrel-only contraception may reduce headache frequency and improve quality of life in women suffering from migraine. The European Journal of Contraception &
Reproductive Health Care, 18(5), pp.394-400.
25 19. Merki-Feld GS, Imthurn B, Langner R, Sandor PS, Gantenbein AR (2013) Headache
frequency and intensity in female migraineurs using desogestrel only contraception: a retrospective pilot diary study. Cephalalgia 33:340–346
20. Nappi, R., Sances, G., Allais, G., Terreno, E., Benedetto, C., Vaccaro, V., Polatti, F. and Facchinetti, F. (2011). Effects of an estrogen-free, desogestrel-containing oral
contraceptive in women with migraine with aura: a prospective diary-based pilot study.
Contraception, 83(3), pp.223-228
21. Harris, M. and Kaneshiro, B. (2009). An evidence-based approach to hormonal contraception and headaches. Contraception, 80(5), pp.417-421.
22. Lieba-Samall, D., Wöberl, C., Frantall, S., Brannathl, W., Schmidtl, K., Schrolnbergerl, C.
and Wöber-Bingöll, Ç. (2011). Headache, menstruation and combined oral
contraceptives: A diary study in 184 women with migraine. European Journal of Pain, 15(8), pp.852-857
23. Allais, G., Castagnoli Gabellari, I., Airola, G., Borgogno, P., Schiapparelli, P. and Benedetto, C. (2009). Headache induced by the use of combined oral contraceptives.
Neurological Sciences, 30(S1), pp.15-17.
24. Cupini LM, Matteis M, Troisi E, Calabresi P, Bernardi G, Silvestrini M. Sex-hormone- related events in migrainous females. A clinical comparative study between migraine with aura and migraine without aura. Cephalalgia 1995;15:140-4. Oslo. ISSN 0333-1024
25. Loder, E., Buse, D. and Golub, J. (2005). Headache as a side effect of combination estrogen-progestin oral contraceptives: A systematic review. American Journal of Obstetrics and Gynecology, 193(3), pp.636-649.
26. Morotti, M., Remorgida, V., Venturini, P. and Ferrero, S. (2014). Progestin-only contraception compared with extended combined oral contraceptive in women with migraine without aura: a retrospective pilot study. European Journal of Obstetrics &
Gynecology and Reproductive Biology, 183, pp.178-182.
27. Morotti, M., Remorgida, V., Venturini, P. and Ferrero, S. (2014). Progestogen-only contraceptive pill compared with combined oral contraceptive in the treatment of pain symptoms caused by endometriosis in patients with migraine without aura. European Journal of Obstetrics & Gynecology and Reproductive Biology, 179, pp.63-68.
26 28. Nappi, R., Merki-Feld, G., Terreno, E., Pellegrinelli, A. and Viana, M. (2013). Hormonal
contraception in women with migraine: is progestogen-only contraception a better choice?
The Journal of Headache and Pain, 14(1).
29. Gabriele S. Merki-Feld, Bruno Imthurn, Raghvendran Dubey, Peter S. Sándor &
Andreas R. Gantenbein (2017) Improvement of migraine with change from combined hormonal contraceptives to progestin-only contraception with desogestrel: How strong is the effect of taking women off combined contraceptives?, Journal of Obstetrics and Gynaecology, 37:3, 338-341
30. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 24 Suppl 1: 9–160, 2004
31. Faubion, S., Batur, P. and Calhoun, A. (2018). Migraine throughout the Female Reproductive Life Cycle. Mayo Clinic Proceedings, 93(5), pp.639-645.
