Headache Medicine 2021, 12(1) p-ISSN 2178-7468, e-ISSN 2763-6178
23
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DOI: 10.48208/HeadacheMed.2021.5
Headache Medicine
© Copyright 2021
Original
Migraine and premenstrual syndrome: comorbid disorders?
Eliana Meire Melhado Tulio Ruiz Eschiapati Jessica Bidurin Picolo Mariana Arantes Santos
Guilherme Martins Tahan Rafael Dias Maria Ana Clara Volpato de Matos
Medical School of Catanduva, Medicine, Catanduva, São Paulo, Brazil
Abstract
Introduction
Headache is a common symptom among women, including during the menstrual cycle. The
migraine frequency in women who present migraine associated with the menstrual period ranges
from 50% to 70%. Premenstrual syndrome (PMS) is prevalent among women, affecting 80% to
90% of them throughout their lives.
Objective
The objectives of this study were to verify PMS prevalence and its characteristics among women
who present with cephalalgia in the neurology ambulatory care unit and show the prevalence of
headache and its association with PMS in the gynecology ambulatory care unit.
Methods
It is a descriptive and qualitative study which was carried out at Emilio Carlos Teaching Hospital
in the neurology and gynecology ambulatory care units with women aged 18 to 52 years old.
Eighty-seven questionnaires were distributed and self-applied throughout the year of 2018 for
data collection. Each questionnaire consisted of 27 questions about the life cycle of the women
and their headache episodes. The diagnostic criteria for headache and migraine from the Inter-
national Headache Society were used. Criteria for PMS were met according to the quality of life
questionnaire.
Results
In gynecology unit group, 9% of the women did not present headache, 76% had PMS and 94%
presented with headache during PMS. In neurology, 79% of the women had PMS and 79% of
the women who presented with cephalalgia also had PMS.
Conclusion
There is a large percentage of PMS in both groups, i.e. neurological unit and gynecological unit,
showing it is not a spurious correlation.
Tulio Ruiz Eschiapati
tulioeschiapati@hotmail.com
Edited by
Mario Fernando Prieto Peres
Marcelo Moraes Valença
Keywords:
Premenstrual syndrome
Headache
Neurology
Gynecology
Migraine
Smoking
Aura
Received: February 5, 2021
Accepted: March 30, 2021
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Melhado EM, Eschiapati TR, Picolo JB, Santos MA, Tahan GM, Maria RD, Matos ACV
Migraine and premenstrual syndrome: comorbid disorders?
Introduction
H
eadache consists of any pain in the cephalic segment,
which happens quite often, and it happens to women two
or three times more often compared to men.
1
Cephalalgia
prevalence is similar among boys and girls and its incidence
in girls increases after the menarche due to hormonal uc-
tuations.
2,3
The migraine that happens during the menstrual
period is known as menstrual migraine or headache and it
can be considered to be a premenstrual migraine associated
with the premenstrual syndrome (PMS) when it happens about
a week before the menstrual period.
In women who present with migraine, clinical trials show that
the frequency of the migraine episodes associated with their
menstrual period ranges from 50% to 70%.
4
One of the main
causes of this association is the cyclic production of ovarian
hormones which can affect the clinic expression of migraine
according to scientic evidences that correlate the inuence
of these hormones with the nociceptive pathways (trigeminal
ones), which change in periods such as pregnancy, menstru-
ation and premenstrual period and menopause.
5,6,7
The denition for migraine diagnosis related to menstruation
is widely discussed and diverges about the preceding and
consequent menstrual period between the authors.
8,9,10
The
International Headache Society (IHS) considers a diagnosis
if 90% of the crises happen between two days before the
beginning of the period and until three days after it.
11
PMS is prevalent among women, 80% to 90% of them can
suffer from it throughout their lives.
12
It is a cyclical disorder
with several symptoms which start in the luteal phase and
nish on the rst days of the menstrual cycle.
13
The association between women who suffer from menstru-
al migraine and premenstrual syndrome is probably high;
however, it has not been clearly conrmed by clinical trials.
The aim of this study was to analyze the association between
PMS and migraine, verifying the prevalence of PMS in women
who present with cephalalgia in the neurology ambulatory
care and showing the prevalence of cephalalgia and PMS
in women in the gynecology ambulatory care at the same
hospital.
It also intended to analyze if headache and PMS are comor-
bid disorders among those women.
Methods
The study was an observational cross-sectional study, which
was carried out at Emilio Carlos Teaching Hospital (ECTH),
in both neurology and gynecology ambulatory care units,
with women aged 18 to 52 years old.
The research was submitted to the Ethics and Research Com-
mittee of Centro Universitário Padre Albino (UNIFIPA) connect-
ed to Plataforma Brasil (CAAE: 84943718.0.0000.5430).
Data were collected through 100 self-applied questionnaires
which consisted of 27 questions related to the women’s cycli-
cal life and to the headaches and were distributed throughout
the year of 2018. It was made clear to the women from the
neurology and gynecology ambulatory care units the objec-
tives and the purposes of the study, assuring them that they
would be guaranteed anonymity and that the information
would only be used for the research. After they had agreed,
they signed the Informed Consent Form.
The diagnostic criteria for headache and migraine were the
ones from the International Headache Society from 2018.
14
The premenstrual syndrome criteria were met according to the
2003 Apolinario’s study.
14
There were 87 women enrolled in
the study who: were aged 18-52 years old, took birth control
pills, were or were not undergoing premenstrual syndrome
or headache treatment and had or did not have comorbid-
ities such as hypertension, diabetes
mellitus
(DM), asthma,
controlled hypothyroidism and other clinically well-controlled
conditions.
Inclusion criteria: women aged 18-52; taking birth control
pills or not; undergoing premenstrual and/or headache
treatment or not; no problems if presented with comorbidities
such as hypertension, diabetes mellitus, asthma, controlled
hypothyroidism and other clinically well-controlled conditions.
Exclusion criteria: diseases such as tuberculosis, HIV, cancer,
lupus (or diseases similar to it); endocrine disorders which
cause relevant hormonal alterations; uncontrolled cardiovascu-
lar or kidney disease; other autoimmune diseases or the ones
associated with immunosuppression; use of chemotherapy
drugs or hormones; pregnancy; and menopause.
After the questionnaires had been collected, data were insert-
ed in an Excel spreadsheet and were analyzed by using the
Fisher’s exact test, odds ratio, the chi-square test and the t-test.
Fisher's exact and chi-square tests were used to verify whether
women with PMS from gynecology unit had more headache
and women with headache from neurology unit had more
PMS.
Odds ratio was used to compare the occurrence of PMS in
those who have migraine or the occurrence of migraine in
those who have PMS in the whole group.
Chi-square and Fisher's exact tests were used to test whether
women with PMS from gynecology unit have more menstrually
related migraine (MRM) and women from neurology unit
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Melhado EM, Eschiapati TR, Picolo JB, Santos MA, Tahan GM, Maria RD, Matos ACV
Migraine and premenstrual syndrome: comorbid disorders?
with MRM have more MRM. Fisher's exact test was used
for association between smoking prevalence in women from
Gynecology and Neurology units, for migraine with aura
and smoking, for smoking and PMS, for association between
types of migraine and use of contraceptives, and to compare
the HIT scale with PMS.
Student t-test was used to compare the age of menarche with
PMS and MRM.
Chi-square test was used to compare the number of PMS
symptoms with MRM.
Results
Eighty-seven women were enrolled in the study, 42 women in
the neurology ambulatory care unit presented with headache
and 45 women complained about several gynecological
problems in the gynecology ambulatory care unit. Only 4 out
of 45 (9%) women in gynecology unit did not present with
headache. In neurology unit group, 33 out of 42 (79%) wom-
en had PMS and 32 out of 34 women in gynecology (91%)
presented with headache (Figures 1 and 2). The average
age of the women in the study was 31.29 years old and the
median age was 30 years old. The average age of menarche
was 12.32 years old and the median age was 12 years old.
Among the women who presented with PMS and migraine:
13 gynecology patients present with menstrual migraine (MM)
statistically signicant comparing to non-MM 10 (p<0.05);
22 neurology unit group patients present signicantly with
more MM comparing to the 6 women who do not have MM
(p<0.05). Women who have PMS also have more MM.
Figure 1. Headache and premenstrual syndrome (PMS) in
gynecology unit group
There is no signicant difference in chances (odds ratio) of
a woman who has PMS presenting with migraine or who
has migraine presenting with PMS compared to the one who
Figure 2. Headache and premenstrual syndrome (PMS) in the
neurology unit group.
does not have PMS or migraine respectively in both groups
(p=0.225). However, the chance of a woman who has PMS
having MM and a woman who presents with MM having PMS
is 6.57 times greater (95%CI 1.72 – 25.11) than not having
MM and PMS, respectively (p=0.005). There is a signicant
difference when comparing the occurrence of MM in women
who have PMS and the occurrence of PMS in women who
have MM comparing to the ones who do not present with
PMS and MM, respectively (p=0.005).
Headache has signicantly less impact on the gynecology
group than on the neurology group (p=0.036) according to
the Headache Impact test-6 (HIT-6) (Figure 3).
Figure 3. Impact of cephalalgia on gynecology and neurology
unit groups.
HIT: Little or no impact = HIT-6 score 49 or less. Some impact = HIT-
6 score 50–55. Substantial impact = HIT-6 score 56–59. Severe
impact = HIT-6 score ≥ 60.
Figure shows little + no+ some in blue= NO or LOW IMPAC and
substantial+severe in orange=HIGH IMPACT
The international classication of headache disorders accord-
ing to IHS 2018 can be found in the following table (Table 1).
There is a prevalence of migraine without aura in both groups.
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Melhado EM, Eschiapati TR, Picolo JB, Santos MA, Tahan GM, Maria RD, Matos ACV
Migraine and premenstrual syndrome: comorbid disorders?
Table 1. Classication of headaches in the women in the study according to IHS 2018.
Classication of Headaches n % Neurology Unit (n) % Gynecology Unit (n) %
Migraine without aura 46 55.0 29 69.0 17 41.0
Migraine with aura 29 35.0 12 28.6 17 41.0
Probable migraine 4 4.8 4 9.7
Tension-type headache 4 4.8 1 2.4 3 7.3
Total 83 100 42 100 41 100
In addition, other variables were compared using statistical tests (Table 2).
Table 2. Results of other variables.
Smoking
There are signicantly more smokers in the gynecology group (p= 0.016 - Fisher’s exact test).
The chance of a woman in the gynecology group being a smoker is 9.25 times higher (95%CI 1.24 to
84.88) than the chance of a woman in the neurology group being a smoker.
There are not signicantly more smokers in the group of women who have migraine with aura than in the
group of women who have migraine without aura (p=0.248).
There are not signicantly more smokers in the group of women who have PMS than in the group of women
who do not have PMS (p=0.443, Fisher’s exact test).
Contraceptives
Women in gynecology taking contraceptives do not present with signicantly more migraine with aura than
the ones who do not take contraceptives (p=0.700 – Fisher’s exact test).
Women in neurology group who take contraceptives do not present with signicantly more migraine with
aura than the ones who do not take contraceptives (p>0.99- Fisher’s exact test).
Women in gynecology who take contraceptives do not present with signicantly more migraine with aura
than the women in neurology who take contraceptives (p>0.999, Fisher’s exact test).
Age of Menarche
There is no statistically signicant difference in the ages of menarche of patients who have or do not have
PMS (p=0.253).
There is no statistically signicant difference in the ages of menarche of patients who present and do not
present with MM (p=0.662).
Discussion
The present study is innovative because it shows the patho-
logical association between PMS and migraine, mainly mi-
graine in general (disregarding migraines associated with
the menstrual cycle at a rst moment).
Studies analyzed the relation between MM and mood disor-
ders, such as PMS, premenstrual dysphoric disorder (PMDD)
and major depression, trying to determine an in common
pathogenic mechanism. The comorbidity may be related to
the ovary hormone uctuations: those disorders are more
frequent during periods of estrogen deprivation (such as in
postpartum period and PMS). Furthermore, the prodromal
phase of migraine is associated with dopaminergic symptoms
and the mood disorders are characterized by the dopamine
imbalance.
15
In our study, PMS did not make MM worse, different from
previous studies which show menstrual headache as inca
pacitating, limiting daily activities.
16
A study showed that the number of prodromal symptoms in
the group of women who presented with MM was larger than
in the non-MM group. Researchers classied the episodes of
PMS migraine into the premenstrual period (-2 and -1 days)
(46 patients), menstrual period (from day 1 to day 3) (90
patients) and late menstrual period (day 4 to day 7) (19 pa-
tients). The duration of more intense headache and several
symptoms frequently associated with it were observed and it
was suggested that it could reect an increase in excitability
and/or susceptibility in these patients’ brains.
17
However, despite more prodromal symptoms, Merle and
Diamond demonstrated that the clinical characteristics of MM
are similar to non-MM.
18
About the research on comorbidity, when the menstrual
migraine fraction was separated, it was observed that there
is neither comorbidity nor risk factor for PMS. Nonetheless,
PMS is a risk factor for and comorbid for MM which makes
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Melhado EM, Eschiapati TR, Picolo JB, Santos MA, Tahan GM, Maria RD, Matos ACV
Migraine and premenstrual syndrome: comorbid disorders?
it a unilateral comorbidity.
The aw in this study is the small sample size which has not
allowed an assessment of the menstrual migraine duration.
It conrms Fettes’s work
19
which states that the cause of men-
strual migraine is different from PMS. A migraine episode that
happens between 7 and 2 days before the menstrual cycle
is considered premenstrual and associated with PMS, which
does not correspond to MacGregor’s denition of migraine
that states it happens between 2 and 3 days before the men-
strual cycle.
19
However, it contradicts others who claim the
existence of an association without stating it categorically that
there is comorbidity and also that some neuroendocrinologi-
cal ndings are shared by both problems (MM and PMS).
20
There is no MM interference in PMS symptom in our study
and there were no data for comparison.
Women who have migraine with aura smoke as much as the
ones who have migraine without aura. Migraine with aura is
a serious risk factor for stroke in young women and it shows
that these patients do not know about it, which indicates
problems in the anti-smoking campaigns of health programs.
These agencies should advise this group to stop smoking,
practice exercises and attend support groups.
The study also showed that PMS is not related to smoking. It
was believed that stress could lead to female smoking, but
there are not scientic data about it.
To sum up, the strengths of this study were the following: pa-
tients in two different areas (neurology and gynecology) and
the questionnaire that identied details about the menstrual
cycle and possible comorbidities. The aws were the small
sample size, because it was difcult to keep women focused
on answering the questionnaire until the end, and also be-
cause the PMS diagnosis was based on a questionnaire from
a textbook and not on the DSM-5.
Despite the limitations, it was possible to identify interesting
results to improve future researches on this subject whose
objective is general women’s health, which must be treated
with dignity in order to have a better quality of life through
government actions and health care.
Conclusions
The prevalence of migraine in gynecology unit and PMS in
neurology unit is high and the relation between PMS and
migraine is signicant in both groups. Migraine and PMS
are, therefore, bilaterally associated disorders. In spite of that,
PMS indicates a risk for MM, but MM does not indicate a
risk for PMS, which is not comorbid in this way.
In clinical practice, it is observed that women look for a
neurologist because migraine is more incapacitating than
PMS. Thus, it can be concluded that it is really necessary to
advise gynecologists to refer their patients to have access
to specialized treatment for cephalalgia and neurologists
need to refer their patients to gynecologists occasionally to
treat PMS symptoms.
Financing: No
Conflict of interests: No
Author Contributions: Author Contributions: EMM and TRE - Statisti-
cal Analysis, Writing, Reviewing and Editing; JBP - Data Collection
and Writing; MAS, GMT, RDM and ACVM – Conceptualization
and Writing
Eliana Meire Melhado
https://orcid.org/0000-0003-3699-1064
Túlio Ruiz Eschiapati
https://orcid.org/0000-0002-1762-9097
Jéssica Bidurin Pícolo
https://orcid.org/0000-0003-1901-8254
Mariana Arantes Santos
https://orcid.org/0000-0001-8107-7250
Guilherme Martins Tahan
https://orcid.org/0000-0001-8920-8665
Rafael Dias Maria
https://orcid.org/0000-0002-5251-9678
Ana Clara Volpato De Matos
https://orcid.org/0000-0002-4723-3499
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