1 Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, NIH, 10 Center Drive, Building 10, Room 9D42, MSC 1583, Bethesda, MD 20892-1583, 2 Department of Epidemiology and Biostatistics, School of Public Health and Health Services, The George Washington University, 2300 I Street N.W., Ross 120B, Washington, DC 20037 and 3 Endometriosis Association, International Headquarters, 8585 N. 76th Place, Milwaukee, WI 53223, USA
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Abstract |
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Key words: autoimmune/chronic fatigue syndrome/endocrine/endometriosis/fibromyalgia
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Introduction |
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If immune surveillance is altered in women with endometriosis, then these women might have autoimmune diseases, such as Hashimotos thyroiditis, systemic lupus erythematosus (SLE), Sjögrens syndrome (SS), rheumatoid arthritis (RA) and multiple sclerosis (MS). Since degranulating eosinophils and eotaxin have been reported in those with endometriosis (Blumenthal et al., 2000; Hornung et al., 2000
), atopic diseases, such as allergies, asthma and eczema may also be more common with endometriosis. Additionally, others have reported the occurrence of fibromyalgia in women with endometriosis (Clauw and Chrousos, 1997
), although population-based studies have not been done. Thus, women with endometriosis who have pelvic pain may have chronic generalized pain and fatigue, i.e. fibromyalgia and chronic fatigue syndrome.
The goal of this study was to examine whether the prevalence of autoimmune and endocrine diseases, fibromyalgia, chronic fatigue syndrome and atopic disorders were more common in women with endometriosis than in the general female population. There are no such previous population-based studies. In 1998, the Endometriosis Association surveyed members in the USA and Canada to characterize the symptoms associated with endometriosis. Based on anecdotal reports to the Endometriosis Association and observations by some endometriosis clinicians, this survey also sought to describe the frequency of autoimmune and related diseases among women with endometriosis. We report on the symptoms of pain and infertility described by these women, the prevalence of common autoimmune and endocrine diseases, chronic pain and fatigue states, and familial history of endometriosis and other diseases. We compare these reports of diagnosed diseases with published rates in women in the USA.
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Materials and methods |
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Measures
Ethnicity/race, education level, familys total annual income and date of birth were tabulated. Because endometriosis is most accurately diagnosed by surgery, only those women with endometriosis diagnosed by laparoscopy (n = 3199) or laparotomy (n = 481) were included in analyses (n = 3680). The age at diagnosis was calculated by subtracting the year of diagnosis from each respondents birth year. The age of first pelvic symptoms included categories for ages <15 and 1545 years divided into 5 year age groups, and age >45 years.
The existence, location and severity of endometriosis-related pain were described. Pain severity was graded as mild, mild to moderate, mild to severe, moderate, moderate to severe, and severe. The duration of incapacitation was categorized by time intervals varying from <24 h to weeks (<24 h, 12 days, 23 days, 36 days, 12 weeks, 23 weeks, 4 weeks, and not specified).
Reproductive history, including infertility and the number of miscarriages and ectopic pregnancies, was summarized. Women who did not describe their pregnancy history (n = 2023) and those who were pregnant (n = 53) were excluded from reproductive history analyses.
Diseases diagnosed by a physician were categorized as (i) autoimmune inflammatory diseases, including systemic lupus erythematosus (SLE), Sjögrens syndrome (SS), rheumatoid arthritis (RA) and multiple sclerosis (MS), (ii) endocrine diseases, including diabetes mellitus (DM), hypothyroidism and hyperthyroidism, and (iii) fibromyalgia and chronic fatigue syndrome. MS was included as an autoimmune inflammatory disease although there is some question whether it has an autoimmune origin (Chabas et al., 2001). Also, the survey did not distinguish between insulin-dependent and insulin-resistant diabetes, although most women probably had insulin resistance rather than insulin dependence due to the mean age at diagnosis of diabetes (35.5 years). In addition, women may not have recognized the name Hashimoto or Graves, or may not have been told they had these conditions when they were diagnosed with hypothyroidism or hyperthyroidism. Hashimotos thyroiditis was combined with hypothyroidism and Graves disease with hyperthyroidism. Thus, the category of endocrine diseases was a mixture of autoimmune endocrine, such as Graves disease, Hashimotos thyroiditis and insulin-dependent diabetes, and general endocrine diseases, such as insulin-resistant diabetes.
Subjects reported asthma, eczema and allergies, although the method of diagnosis was not ascertained. Those reporting at least one allergy to pollens, dust, trees, paint, grasses, cigarette smoke, perfumes/fragrances, cleaning products, foods and environmental chemicals were considered to have allergies.
Family history of endometriosis indicated which family member was affected, and included mother, sister(s), daughter(s), maternal and paternal grandmothers, nieces, aunts and cousins. Only relatives reported to have diagnosed endometriosis were used in analyses (n = 1610). Family history of autoimmune inflammatory, endocrine, or fibromyalgia or chronic fatigue syndrome included the relative for each disease. While each woman had one mother and two grandmothers, the total number of affected and unaffected relatives was not known.
Ascertainment of prevalence estimates in the general population
PubMed and Medline were searched from 1969 to 2001 to obtain prevalence estimates in the general female population for the selected diseases. Reports identified by key words such as epidemiology, prevalence, incidence or disease susceptibility were reviewed. Disease prevalence (rate per 100 000 women) was compared with prevalence estimates in the general female population calculated from review articles (Jacobson et al., 1997; Reyes et al., 1997
; Lawrence et al., 1998
) or from the USA Census Bureau data (United States Census Bureau, 2001
). Rates of diabetes among reproductive-aged women were obtained from the CDC Diabetes Surveillance Report (Geiss, 1997
). The infertility rate was obtained from the National Survey of Family Growth (Abma et al., 1997
), and rates for allergies and asthma were obtained from the NHANES I Epidemiologic Follow-up Study of 1992 (Idler et al., 2000
).
Data analysis
Age, education level, income and ethnicity/race were compared with the general USA female population in 1998 using Z-tests. Prevalence estimates of diagnosed diseases among women with endometriosis were calculated and compared with rates in the general population using a series of Z-tests. We used t-tests to compare the severity of pain, median age of first pelvic symptoms, age at endometriosis diagnosis, and age at diagnosis of autoimmune inflammatory or endocrine disorder, or fibromyalgia and chronic fatigue syndrome in women with endometriosis alone and those with the co-morbid conditions. Z-tests and 2-tests evaluated differences in rates for allergies, asthma and eczema. The association of endometriosis with co-morbid diseases among relatives was assessed by
2-tests. Those respondents with family members with diagnosed endometriosis and co-morbid diseases were compared with respondents with family members with diagnosed endometriosis and no other conditions.
To limit confounding of analyses, only those women indicating a disease in only one categoryautoimmune inflammatory diseases, endocrine diseases, or fibromyalgia or chronic fatigue syndromewere compared for associations with other conditions. Also, for all analyses, those who did not indicate a yes or no answer were excluded for that particular question. However, if a woman was only asked to check the applicable item, no included all who answered no and those who skipped the question.
In order to determine the effect of misclassification of either the study sample or the general population, a sensitivity analysis was done. Models were developed to determine a threshold for an overestimation of disease rates for the study sample and an underestimation of true prevalence in the general population such that the difference between the two groups would disappear.
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Results |
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Among the general USA population, 22% of women report an inability to carry on normal work during menses (Campbell et al., 1997). By comparison, 81% of survey respondents were unable to work, including doing household chores, because of pelvic pain. Although 73% usually recovered within 3 days, almost 10% reported at least a few weeks of debilitation and 87% complained of fatigue or low energy.
All women with fibromyalgia or chronic fatigue syndrome reported pain (n = 320). Pain was more severe in those with fibromyalgia (P < 0.01) compared with those with endometriosis alone. Forty-two women (1%) reported having been diagnosed with both fibromyalgia and chronic fatigue syndrome. Another 21 women reported having both fibromyalgia and chronic fatigue syndrome in addition to an endocrine (n = 11) or autoimmune inflammatory disease (n = 10).
Infertility and reproductive history
Overall, 41% reported infertility (Table II), a 4-fold greater risk than the USA reproductive-aged population (Abma et al., 1997
; Stephen and Chandra, 1998
). Of the 1604 women who described their pregnancy history, 21% (n = 329) had at least one miscarriage and 2% (n = 37) reported at least one ectopic pregnancy. The USA population rates for miscarriage and ectopic pregnancy are 14 and 1% respectively (Saraiya et al., 1999
).
Figure 1 shows infertility rates for those with endometriosis alone, autoimmune inflammatory diseases, endocrine disorders, or fibromyalgia or chronic fatigue syndrome. The infertility rates for women with endometriosis alone were similar to those with endometriosis and at least one co-morbid disease in all age groups, except for significantly lower rates in 2534 year olds with endocrine diseases and fibromyalgia or chronic fatigue syndrome (P < 0.01), and higher rates in 3544 year olds with endocrine disorders (P < 0.05). All infertility rates among women in the sample were significantly higher than the USA population (P < 0.001). When those with diseases from more than one category were included, the infertility rates were not significantly altered (data not shown).
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Chronology (age of first pelvic symptoms, age at endometriosis diagnosis and age at diagnosis of co-morbid diseases)
Table V presents the age of first pelvic symptoms, age at endometriosis diagnosis and age at diagnosis of co-morbid diseases, excluding those reporting more than one co-morbid disease. Women who had pelvic symptoms at a younger age were more likely to develop SLE, RA, SS or chronic fatigue syndrome (P < 0.05). All women, those with endometriosis alone or those with endometriosis and another disease, had about a 10 year delay in the diagnosis of endometriosis after the onset of pelvic symptoms. Endometriosis diagnosis aged >30 years was more common for those with SS (P < 0.01), any thyroid disease (P < 0.01) and fibromyalgia (P < 0.01). Other diseases were usually diagnosed
4 years after the diagnosis of endometriosis, except for RA (P < 0.001), hypothyroidism (P < 0.05) and hyperthyroidism (P < 0.05), which were all diagnosed before age 30 years.
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Familial endometriosis and familial co-morbid diseases
Two-thirds of subjects stated that relatives had diagnosed (n = 1610) or suspected (n = 2404) endometriosis, suggesting a familial tendency for endometriosis (Table VI). One-fourth knew (n = 298) or suspected (n = 819) that their mother had endometriosis, and twice the number of maternal relatives were affected compared with paternal relatives.
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Discussion |
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The delay in endometriosis diagnosis is significant and has been previously reported (Laufer et al., 1997). Since women appear to develop symptoms shortly after menarche and are not diagnosed with endometriosis for years, it is unknown whether endometriosis actually develops at menarche as others have reported (Hadfield et al., 1996
; Reese et al., 1996
), or if endometriosis develops over time. It also is unclear whether treating pain early could prevent chronic pelvic pain from developing in these women. Thus, attempts should be made to diagnose and treat endometriosis in adolescent women. In this sample, endometriosis was generally diagnosed after rheumatoid arthritis and thyroid diseases, which were diagnosed in the 20s, a younger age than usually seen in the USA population. By contrast, the diagnosis of endometriosis preceded the other autoimmune inflammatory diseases.
The early onset of thyroid disease and rheumatoid arthritis, as well as the higher rate of autoimmune inflammatory diseases, supports our hypothesis of an immunological aspect to endometriosis. Moreover, the high rate of physician-diagnosed fibromyalgia in women with chronic pain from endometriosis suggests an association among different aspects of chronic pain. The co-existence of allergies, asthma, eczema and autoimmune disease in women with fibromyalgia or chronic fatigue syndrome may also suggest an underlying role for the immune system in fibromyalgia and chronic fatigue syndrome. Whereas fibromyalgia has been associated with endometriosis, the association of chronic fatigue syndrome with endometriosis has not been reported (Clauw and Chrousos, 1997).
The strength of this study is its statistical power due to the large sample size. About 50% of those surveyed responded to the questionnaire, an above-average response rate. By only analysing responses from those with surgically diagnosed endometriosis and physician-diagnosed diseases, the likelihood of each diagnosis is more certain. By restricting the analysis of co-morbid diseases to women having only one other disease, the likelihood of confounding is limited.
One limitation of this type of study is selection bias. Almost all the members of the Endometriosis Association completing this survey reported pain, with two-thirds experiencing moderate to severe pain and significant debility. Since the Endometriosis Association provides education and support services, as well as research, perhaps most joined the Association to seek support for pain. Thus, these respondents may over-represent endometriosis-related pain and under-represent women with other symptoms, such as infertility, though the prevalence of infertility in the sample is nonetheless high. Women with infertility may seek support for their infertility first, perhaps through other patient support groups. Thus, the findings of this study may not apply to women with endometriosis and no pain. Also, members of the Endometriosis Association pay annual fees and may be more likely to join if they have more knowledge and resources. This may explain why white and educated women from a higher socioeconomic level are over-represented compared with the general population, especially since other studies have shown that endometriosis does not occur only in white, educated women of higher socioeconomic status (Chatman, 1976; Miyazawa, 1976
; Houston et al., 1988
). The demographic observations in this sample may also reflect a diagnostic bias, since educated women with a higher income may be more likely to be diagnosed with endometriosis.
The fact that these data derive from a self-reported survey has several limitations (Hook and Regal, 1992; Warnecke et al., 1997
; Bergmann et al., 1998
; Lawrence et al., 1998
). Women may misinterpret questions, may not recognize the name of specific diseases or may not accurately report conditions experienced by family members (Warnecke et al., 1997
; Bergmann et al., 1998
; Lawrence et al., 1998
). Recall and reporting errors may also occur (Warnecke et al., 1997
), especially when trying to remember the age of medical events or medical diseases for relatives. Also, it is possible that some diseases were not recognized by physicians and were never diagnosed (Jacobson et al., 1997
). Other limitations include incomplete or missing data from respondents who skipped questions (Hook and Regal, 1992
).
In addition, because of the younger age of women in the study sample, prevalence estimates obtained from other reports, which may have included a broader age range, may not be appropriate for comparison. For example, hypothyroidism is common in older, often postmenopausal, women (Canaris et al., 2000). By contrast, most women responding to this survey were of reproductive age.
Study limitations also may result from misclassification for diseases in the general population depending on whether they were diagnosed by a clinician or self-reported. Prevalence rates for many of the diseases were calculated from pooled disease rates from dozens of published articles using standardized medical definitions, and included clinical and laboratory evaluation (Jacobson et al., 1997). Due to insufficient data from the USA, the prevalence estimates for Sjögrens syndrome and Hashimotos thyroiditis/hypothyroidism also included data from international studies. Chronic fatigue syndrome (Reyes et al., 1997
) was rigorously defined using a combination of patient interviews, laboratory testing and a physician diagnosis. Fibromyalgia prevalence was derived from a population-based study in which a large proportion were examined by a clinician (Lawrence et al., 1998
). Diabetes diagnoses were based on a self-reported survey conducted by the Centers for Disease Control and Prevention (Geiss, 1997
) surveillance system.
We presented the prevalence odds ratio with 95% confidence intervals and the sensitivity analysis to address the misclassification of diseases in both populations. The sensitivity analysis confirms that even if the disease prevalence is underestimated in the general population and overestimated in the study sample, the rates reported in women with endometriosis are significantly higher and the differences appear real.
In conclusion, the present study is the first to provide data on the characteristics and co-morbid states of women with pain from endometriosis. Women with endometriosis frequently suffer from autoimmune inflammatory diseases, hypothyroidism, fibromyalgia, chronic fatigue syndrome, allergies and asthma. It is evident that women with pelvic pain are not diagnosed as having endometriosis for many years, suggesting that physicians, especially those taking care of adolescents, should consider the diagnosis. These data suggest a strong association between endometriosis and autoimmune disorders and indicate the need to consider the coexistence of other co-morbid conditions in women with endometriosis.
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Acknowledgements |
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Notes |
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References |
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Submitted on March 27, 2002; accepted on May 30, 2002.