1 Department of Obstetrics and Gynaecology, San Martino Hospital, University of Genoa, Largo R. Benzi 1 and 2 Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, via De Toni 5, 16132 Genoa, Italy
3 To whom correspondence should be addressed. Email: simone.ferrero{at}fastwebnet.it
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Abstract |
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Key words: endometriosis/headache/migraine/migraine with aura
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Introduction |
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Subjects with endometriosis are significantly more likely to have a number of additional distressing or disabling conditions than other women; these include a variety of autoimmune diseases, allergies, asthma, hypothyroidism, chronic fatigue syndrome and fibromyalgia (Sinaii et al., 2002). Clinical observations since the 1970s have suggested that women with endometriosis suffer headache significantly more often than those without endometriosis (Tervila and Marrtila, 1975
); however, to the best of our knowledge, no previous study has examined the prevalence and characteristics of headache in women with endometriosis by using the 1988 International Headache Society (IHS) criteria (Headache Classification Committee of the International Headache Society, 1988
). The IHS classification system is the standard clinical and research tool for categorizing headache disorders; this system has been found to be clinically applicable, exhaustive, reliable and valid (Iversen et al., 1990
; Rasmussen et al., 1991a
; Merikangas et al., 1993
; Granella et al., 1994
; Leone et al., 1994
; Olesen, 1996
).
In the current study, we sought to determine the prevalence and characteristics of headache in patients with endometriosis compared with women without this disease.
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Materials and methods |
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Age at headache onset, headache frequency, relationship to the menstrual cycle, duration of headache (unmedicated), pain intensity (scored on a 10-point ranked ordinal scale, from 0 = absence of pain to 10 = the worst possible pain) and disability were investigated. Specific questions were asked about headache features including the location and quality of pain, and the occurrence of nausea, vomiting, photophobia, phonophobia, and visual or sensorimotor aura. Subjects suffering headache were asked about usual treatment for their headache; they were also asked if they had ever consulted a physician for headache and, if so, if the physician was a headache specialist. The interview included questions on demographic (age) and health characteristics/behaviours (height, weight, smoking status, use of oral contraception). The neurologist who performed the interview was not aware of the gynaecological problems of the patients; in all cases, the interview was performed before surgery.
Data on the patient's primary gynaecological problem, full menstrual history, medical therapies and previous surgical treatments were collected. The presence of dysmenorrhoea, deep dyspareunia and chronic pelvic pain (>6 months) was investigated. The patients were asked to rate the intensity of the pain symptoms in the 3 months before surgery on a 10-point ranked ordinal scale (from 0 = absence of pain to 10 = the worst possible pain). During laparoscopy, the location and extension of endometriotic lesions were recorded. The extent of endometriosis was scored according to the revised classification of the American Fertility Society (rAFS) (American Fertility Society, 1985). The diagnosis of endometriosis was confirmed by the histological examination of specimens removed at surgery. All women who had used GnRH analogues in the year prior to surgery were excluded from the study. One schizophrenic patient was excluded from the study because of the inability to provide reliable data during the interview.
The study was approved by the local Institutional Review Board and each participant gave written informed consent.
Statistical analysis
Based on the results of a previous study investigating migraine prevalence in women (Lipton et al., 2001b), a power calculation indicated that
280 patients in each group would be necessary to detect a 10% difference in migraine prevalence between the two groups with a power of at least 80% at a 5% level of significance. The study was ended pre-term based on the results of an interim analysis.
Data were analysed by using Student's t-test, MannWhitney U-test, 2 x 2 2 test, and Fisher's exact test. The Spearman test was employed to evaluate the correlation between the intensity of migraine and the severity of pain symptoms. Statistical calculations were performed using the Statistical Package for the Social Sciences (SPSS) (version 10.0.5, SPSS Inc., Chicago, IL). A P-value <0.05 was considered statistically significant.
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Results |
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Table I shows demographic characteristics, health behaviours and indication for surgery of the women included in the study. Thirty-nine women had mild endometriosis (rAFS, stage III) and 94 severe endometriosis (rAFS, stage IIIIV). Among women with endometriosis, 117 (88.0%) subjects reported dysmenorrhoea, the mean (±SD) intensity of pain was 8.2±2.1; 83 (62.4%) patients complained of deep dyspareunia, the mean (±SD) intensity of pain was 6.3±2.0; and 58 (43.6%) women suffered chronic pelvic pain (>6 months), the mean (±SD) intensity of pain was 6.5±2.4. None of the patients included in the study reported previous cerebrovascular events (haemorrhagic or ischaemic stroke).
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Characteristics of migraine in women with and without endometriosis
Headache characteristics for the 51 women with endometriosis and 25 controls suffering migraine are displayed in Table III. The age at migraine onset was significantly lower in women with endometriosis than in controls (P=0.001); seven (13.7%) women with endometriosis and no control had experienced migraine onset before the age of 10 years; 30 (58.8%) women with endometriosis and 15 (60.0%) controls had experienced migraine onset between 10 and 20 years of age. The mean intensity of pain was similar in women with and without endometriosis; 41.2% (n=21) of women with endometriosis and 32.0% (n=8) of controls reported very high levels of pain (910 on a 10-point scale). No significant difference was observed in the migraine attack frequency between women with and without endometriosis; 64.7% (n=33) of women with endometriosis and 64.0% (n=16) of controls reported more than one migraine attack per month; 15.7% (n=8) of women with endometriosis and 16.0% (n=4) of controls reported one or more migraine attack per week.
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There was a trend for women with endometriosis to have longer unmedicated attacks owing to a higher percentage of subjects experiencing attacks of 48 h (10 out of 41, 24.4%) than in the control group (four out of 25, 16.0%).
Medical consultation and medication use
The majority (70.6% of women with endometriosis and 60.0% of controls) of migraine sufferers had consulted a physician at some time for headache; however, referral to a headache specialist was reported by only 27.4% of women with endometriosis and 24.0% of control subjects.
Preventive treatment was used by three women with endometriosis and one control. Analgesic (either alone or in combination) and non-steroidal anti-inflammatory drugs (NSAIDs) were the most frequently used medications for the acute treatment both among women with endometriosis (70.6%) and in the control group (72.0%). Only 7.8% of women with endometriosis and 4.0% of controls used triptans (Table III).
Disability
Of those who were employed (35 women with endometriosis and 22 controls), 51.4% of women with endometriosis and 22.7% of controls reported at least one missed day due to dysmenorrhoea or headache in the 3 months before surgery (P<0.032). When at work with migraine, the women with endometriosis and controls reported, respectively, a mean (±SD) reduction in work effectiveness of 46.7% (±18.7%) and 30.5% (±8.6%) (P<0.001).
Correlation between migraine characteristics and severity of endometriosis
No significant difference was observed in attack frequency and unmedicated headache duration between women with mild and severe endometriosis. The mean (±SD) migraine intensity was similar in women with mild (7.9±1.5) and severe endometriosis (8.1±1.8). No correlation was observed between the intensity of dysmenorrhea and the intensity of migraine (r=0.035, P=0.824, n=43). Among women with endometriosis, no significant difference was observed in the mean (±SD) intensity of dysmenorrhoea between subjects with and without migraine (8.2±2.2 and 8.2±2.0). The intensity of deep dyspareunia and chronic pelvic pain did not correlate with the intensity of migraine.
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Discussion |
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The findings of the current study raise some problems and concerns.
Headache classification depends on accurate diagnosis. Subjects suffering migraine often do not seek appropriate care and it has been reported that 82% of patients who consult a physician about their headaches do not visit a neurologist or headache specialist; instead, they consult their primary care practitioner, which, for many women is their gynaecologist (Lipton et al., 2001a; MacGregor et al., 2003
). About 60% of women notice an increase in the frequency of migraine attacks during the menstrual cycle, and this relationship may be the reason why these patients consult gynaecologists regarding their headaches (MacGregor, 1996
; Kornstein and Parker, 1997
).
Only 27.4% of women with endometriosis and 24.0% of control subjects had seen a headache specialist for their migraine; this low rate of migraine assessment by a specialist resulted in low rates of specific treatment. Most (98.0% of women with endometriosis and 96.0% of controls) of our patients with migraine had used medications to treat their headache, but the majority of the patients used symptomatic drugs; 70.6% of women with endometriosis and 72.0% of controls used analgesics or NSAIDs. Other symptomatic drugs, such as triptans and ergot derivatives, were taken by only a minority of patients. With these elements in mind, it seems reasonable to conclude that the rate of specialized care and adequate treatment of migraine in our sample is low.
It is well known that the physical health and the emotional well-being of many women of reproductive age are significantly affected by endometriosis when dysmenorrhoea, deep dyspareunia and chronic pelvic pain are present. When endometriosis and migraine are co-morbid, each exerts a significant and independent negative influence on health-related quality of life. Among the employed subjects included in the current study, women with endometriosis reported missing more working days (because of dysmenorrhoea or migraine) and to have a more severe reduction in work effectiveness (when at work with dysmenorrhoea or migraine) than controls.
The strengths of the current study consist of the fact that, during the study period, all patients examined by two investigators during the pre-operative clinic were approached for the study and the participation was almost complete.
Over 70% of women with endometriosis included in the current study had severe disease (rAFS, stage IIIIV). The high prevalence of severe endometriosis in our series can be explained by the fact that our institute represents a referral centre for the surgical treatment of endometriosis in our region, Liguria, in Northern Italy, and many cases of severe disease were referred to our institute from other centres. However, the high prevalence of severe endometriosis in the current series is unlikely to affect our findings because the prevalence and severity of migraine were similar among women with mild and severe endometriosis.
Previous studies showed that migraine prevalence declines after spontaneous menopause (Wang et al., 2003), while the sudden hormonal changes caused by surgical ovariectomy may worsen the migraine course (Neri et al., 1993
). Considering that, to the best of our knowledge, no previous study has examined the effect of GnRH analogue treatment on migraine course, no woman who had used this treatment in the year prior to surgery was included in the study.
Among women of reproductive age, migraine, particularly with aura, is an independent risk factor for ischaemic stroke (Tzourio et al., 1993; Carolei et al., 1996
; Donaghy et al., 2002
; Nightingale and Farmer, 2004
) and the relative risk is increased in subjects using combination oral contraceptives (Chang et al., 1999
; Curtis et al., 2002
).
Although the absolute risk of stroke is extremely low in young women suffering migraine (Tzourio et al., 1993), the presence of this condition should be investigated in subjects with endometriosis receiving hormonal treatments and a headache specialist should always perform the diagnosis. Changing or discontinuing the therapy may be prudent when patients develop migraine while under hormonal treatment or when the frequency, severity and duration of the attacks increase.
Our understanding of the link between endometriosis and migraine remains elusive; however, some biochemical mediators have been implicated in the molecular physiopathology of these two conditions. Different types of prostaglandins play a role in the pathogenesis of migraine (Stirparo et al., 2000; Sarchielli et al., 2000
) and increased levels of plasma prostaglandin E2 have been found during the pain phase in women with menstrual migraine (Nattero et al., 1989
). Interestingly, it has been shown that endometriosis is associated with a significant increase in prostaglandin production (Schenken and Asch, 1980
; De Leon et al., 1988
; Karck et al., 1996
); therefore, it is possible to hypothesize that the systemic spreading of prostaglandins produced by endometriotic lesions may contribute to the increased prevalence of migraine in this population. Similarly, an upregulation or disregulation of nitric oxide synthesis has been shown to have a role in the pathogenesis of both migraine (Sarchielli et al., 2000
; Stirparo et al., 2000
) and endometriosis (Osborn et al., 2002
; Khorram and Lessey, 2002
) and may contribute to the presence of this co-morbidity.
In conclusion, the present study shows that migraine is more frequent in women with endometriosis than in controls, but its presence and severity are not related to the stage of endometriosis. When endometriosis and migraine are co-morbid, the well-being of the patient may be significantly impaired, and their work performance may be significantly reduced. Although migraine cannot be cured or completely eliminated using currently available treatment, pain and associated symptoms can be controlled and disability can be greatly reduced with adequate diagnosis and treatment.
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Submitted on June 1, 2004; resubmitted on August 2, 2004; accepted on September 3, 2004.
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