Natural hair color and the incidence of endometriosis

Transcription

1 Natural hair color and the incidence of endometriosis Stacey A. Missmer, Sc.D., a,b,c Donna Spiegelman, Sc.D., c,d Susan E. Hankinson, Sc.D., a,c Susan Malspeis, S.M., a,c Robert L. Barbieri, M.D., c and David J. Hunter, M.B.B.S., Sc.D. a,c,e a Channing Laboratory, Department of Medicine, and b Department of Obstetrics, Gynecology, and Reproductive Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts; and c Department of Epidemiology, d Department of Biostatistics, and e Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts Objective: To investigate a previously hypothesized relation between natural hair color and endometriosis. Design: Prospective cohort study. Setting: Nurses Health Study II with 10 years of follow-up. Participant(s): A total of 90,065 women, years old, who had never been diagnosed with endometriosis, infertility, or cancer at baseline in Main Outcome Measure(s): Incidence of laparoscopically confirmed endometriosis according to natural hair color. Result(s): During 379,422 person-years of follow-up, 1,130 cases of laparoscopically confirmed endometriosis were reported among women with no past infertility. After adjusting for age, calendar time, parity, race, and body mass index at age 18, we observed no association overall. However, compared with women with any other hair color, we observed an increased rate of endometriosis among women with naturally red hair who had never been infertile (incidence rate 1.3, 95% confidence interval [CI] ), but a decreased rate among women with naturally red hair among women who were infertile (incidence rate 0.4, 95% CI ); P value, test for heterogeneity.03. Conclusion(s): Overall, we did not observe a significant relation between red hair color and the rate of endometriosis, however this prospective cohort study suggests that the relation may differ by infertility status. (Fertil Steril 2006;85: by American Society for Reproductive Medicine.) Key Words: Endometriosis, epidemiology, cohort, hair color Endometriosis is the third leading cause of gynecologic hospitalization in the United States (1). Despite the high morbidity and health care costs associated with endometriosis, the etiology of endometriosis has not been fully delineated. The pathophysiology likely includes hormonal, anatomic, genetic, and immune factors. Risk may be associated with factors that increase the volume, frequency, and duration of retrograde menstruation and promote implantation and growth of endometrial plaques (2). Women with naturally red hair have been hypothesized to have altered coagulation (3 5) and immune function (6, 7). Cross-sectional studies have suggested that the proportion of women with naturally red hair is greater among those with endometriosis compared with the general population (8 10). Using data collected from the Nurses Health Study II, an ongoing, prospective cohort study of premenopausal U.S. nurses that began in 1989, we have investigated the relation between hair color and laparoscopically confirmed endometriosis. Received April 29, 2005; revised and accepted December 5, Supported by NICHD grant HD40882 and NIH grant CA Reprint requests: Stacey A. Missmer, Sc.D., Channing Laboratory, Brigham and Women s Hospital, 181 Longwood Avenue, Boston, Massachusetts (FAX: or ; stacey.missmer@channing.harvard.edu). MATERIALS AND METHODS Study Population and Data Collection Data for these analyses were collected in the Nurses Health Study II cohort from September 1989 to June Questionnaires requesting information on incident diseases and demographic, biologic, environmental, and lifestyle risk factors are updated and mailed biennially. A total of 116,678 female registered nurses ranging in age from 25 to 42 and residing in 1 of 14 states in the United States completed the baseline questionnaire. Follow-up of this cohort in each 2-year interval has been consistently 90%. The Institutional Review Board of the Harvard School of Public Health approved this research. Case Ascertainment and Analytic Definition In 1993, the women were first asked if they had ever had physician-diagnosed endometriosis. If yes, they were asked to report when the diagnosis had occurred (before September 1989, September 1989 May 1991, and June 1991 May 1993, which correspond to the follow-up periods) and if it had been confirmed by laparoscopy a standard surgical method for diagnosing endometriosis (11, 12). These questions were asked again in each subsequent questionnaire. In March 1994, we conducted a study to validate selfreported endometriosis diagnosis within the Nurses Health Study II prospective cohort. Supplementary questionnaires 866 Fertility and Sterility Vol. 85, No. 4, April /06/$32.00 Copyright 2006 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert

2 were mailed to 200 women who were randomly selected from the then 1,766 cases who had reported incident diagnosis. Among those who reported laparoscopic confirmation and for whom records were received and reviewed (n 105), a diagnosis of endometriosis was confirmed in 89%. However, among those women without laparoscopic confirmation (n 26), evidence of clinical diagnosis was found in only 54% of the records. Severity data (based on the 1996 revised American Society for Reproductive Medicine [ASRM] classification system) (13) suggested that the majority of laparoscopically confirmed cases (61%) had minimal or mild disease. Requests for permission to review medical records were also sent to any woman who indicated that she had had a hysterectomy during the 2-year interval of reported endometriosis diagnosis. A diagnosis of endometriosis at time of surgical procedure was confirmed in 80% (n 144/181) of the records received. However, endometriosis was the primary indication for hysterectomy in only 6% (n 9/163) of women for whom indication information was available. On the basis of these validation results, self-reported physician-diagnosed endometriosis without laparoscopic confirmation may be misclassified substantially. In addition, allowing women who report endometriosis and a hysterectomy in the same follow-up period to be cases might yield spurious results, because it would be unclear if the associated risk factors are related to endometriosis or to the pathology for which the hysterectomy was performed. Therefore, to reduce the magnitude of misclassification and prevent confounding by indication for hysterectomy, analyses of incident diagnosis of endometriosis were restricted to those women who reported laparoscopic confirmation of their diagnosis. Within this restricted case definition, the relation between endometriosis and infertility status is complex. At baseline, the prevalence of infertility (defined as attempting to become pregnant for 1 year without success) was greater among women with laparoscopic confirmation (20%) than among those who were clinically diagnosed without laparoscopic confirmation (4%), potentially resulting in oversampling those with asymptomatic disease. Approximately 20% of all infertile women are found to have endometriosis (14). Had these women not attempted to become pregnant, a large proportion may never have received a laparoscopic diagnosis of endometriosis. We may also assume that women with no infertility who have had a laparoscopic diagnosis are symptomatic. Otherwise, a surgical evaluation would not have been conducted. Because endometriosis with infertility may be indicative of asymptomatic disease secondary to other primary causes of infertility, the risk factors for endometriosis with infertility could differ from those for endometriosis without concurrent infertility. Thus, we looked at risk factors separately by two subtypes of endometriosis: [1] cases with neither past nor concurrent infertility, and [2] cases with concurrent infertility. Within this cohort, self-reported infertility was validated in a study of 100 randomly selected women who reported ovulatory infertility 95% of the selfreports were confirmed through medical record review (15). Assessment of Exposure Hair color was assessed with the question What was the natural color of your hair at age 18? Response categories included red, blonde, light brown, dark brown, and black. Statistical Analysis Exclusion Criteria. Those who reported the diagnosis of endometriosis or a history of infertility before September 1989 were excluded from all analyses. Analyses were also restricted to those who were premenopausal and had intact uteri, because the occurrence of endometriosis after hysterectomy or in postmenopausal women is rare. Women with prior cancer diagnoses other than nonmelanoma skin cancer also were excluded. Person-Time Calculation. Woman-months at risk were calculated from entry into the cohort until independently confirmed death or cancer diagnosis (other than nonmelanoma skin cancer), or self-reported laparoscopically confirmed endometriosis diagnosis, hysterectomy, or the onset of menopause. Women who reported physician-diagnosed endometriosis with no laparoscopic confirmation were censored at the time of that report but were allowed to reenter the analysis population if they reported laparoscopic confirmation on a subsequent questionnaire. In addition, because infertility is so strongly correlated with diagnosis of endometriosis via laparoscopy, we censored at self-report of infertility. Therefore, in all analyses our comparison group consists of women with neither diagnosed endometriosis nor infertility, allowing for a more homogeneous comparison group as we have previously described in detail (16). Relative Risk Estimation. Incidence rates for each exposure category were computed as the number of incident cases divided by the woman-time accumulated. Time-varying Cox proportional hazards models treating age in months and 2-year questionnaire period as the time scale were used to estimate multivariate (MV) incidence rate ratios (RR) and to calculate 95% confidence intervals (CI), after adjusting simultaneously for confounding variables. Tests for trend were calculated by creating a variable in which ordinal numbering for each hair color category was assigned to all participants in that group. Tests comparing the effect of natural hair color in relation to the incidence of endometriosis with no infertility to the effect of natural hair color in relation to the incidence of endometriosis with concurrent infertility were conducted with a Wald statistic referred to a 2 distribution with 1 degree of freedom (17). To evaluate effect modification, stratified analyses were conducted, and likelihood ratio tests comparing the model with both the main effects and the interaction terms to that with the main effects only were calculated. Confounding Variables. We considered other possible risk factors for endometriosis as potential confounders if addition Fertility and Sterility 867

3 of that variable to the model changed the rate ratio by 10% or greater (18). If a factor was identified as a confounder of any estimated main effect, it was kept in all models. On the basis of these criteria, risk factors not observed to confound the relation with hair color included: age at menarche; time to menstrual cycle regularity; menstrual cycle length during college; menstrual cycle pattern during college; duration of lactation; current body mass index; current alcohol use; current smoking status; woman s birth weight; if the woman was breast fed as an infant; if she was one of a multiple gestation; or health care use through a proxy variable created from the answers to several questions that asked if the nurse had a clinical physical exam, Papanicolaou smear, pelvic exam, or breast exam in the past 2 years (categorized as no exam, exam for screening, exam for symptoms). RESULTS After baseline exclusions, a total of 90,065 women contributed 379,422 person-years of follow-up; 1,130 incident cases of laparoscopically confirmed endometriosis with no past infertility were reported. These included 900 cases with no past or current infertility and 228 cases reporting an infertility evaluation during the same follow-up period as laparoscopic confirmation of endometriosis. At baseline, the cohort prevalence of red hair was 4% (n 2,985) (data not shown). Among all women, we observed no effect of red hair on the rate of laparoscopic diagnosis of endometriosis (multivariate rate ratio [MV RR] 1.1 compared with all other natural hair colors, 95% CI ) (Table 1). This effect was not modified by nulliparity, ever use of oral contraceptives, or having had a recent gynecologic exam (data not shown). However the effect of red hair did differ by infertility status with an increased risk for natural red hair observed among those with no infertility (MV RR 1.3, 95% CI ) but a decreased risk among those with concurrent infertility (MV RR 0.4, 95% CI ); P value, test for heterogeneity.03. DISCUSSION In this prospective study among premenopausal women, we observed that the incidence rate of diagnosis of laparoscopically confirmed endometriosis was similar comparing women with naturally red hair to those with other hair colors. However, among women who never reported infertility, we observed a 30% increased rate; in contrast, among concurrently infertile cases, we observed a decreased rate. The literature contains data from two cross-sectional studies that suggest that endometriosis may be associated with natural red hair color (8 10). Among 143 women ranging in age from 23 to 41 who were undergoing laparoscopic investigation for infertility, Woodworth and colleagues observed that 83% of the women with naturally red hair (n 10/12), whereas only 42% of the women with other hair colors (n 55/131), were found to have endometriosis; P value.03 (8). Additionally, in a study of nearly 4,000 college graduates ranging in age from approximately 35 80, Wyshak and colleagues observed that women with naturally red hair were twice as likely to report having endometriosis compared with women with other hair colors (odds ratio after adjustment for age, participation in college athletics, and infertility history 2.04, 95% CI ) (9, 10). A gene associated with red hair (coding for pheomelanin pigmentation) is located on chromosome 4 (19), whereas a gene for brown pigmentation (eumelanin) is located on chromosome 19 (20). Red hair is inherited not through a dominance of pheomelanin but through a deficit of eumelanin resulting from a mutation in the melanocortin-1 receptor gene (MC1-R) (21 24). Several hypotheses underlying an association between red hair and endometriosis have been posited. The gene associated with red hair on chromosome 4 is proximal to a cluster of genes associated with fibrinogen (25), and there has long been anecdotal belief that patients with red hair color exhibit decreased coagulation / increased risk of hemorrhage during surgical procedures (3, 5, 10). In a recent study comparing nine red-haired women with nine dark -haired women (all Caucasian and comparable in height, weight, and age), the red-haired women exhibited a significant decrease in platelet function but no absolute differences in platelet numbers or coagulation factors (4). It is possible that these blood component differences are related to the volume or components of retrograde menstruation in red-haired women. In addition, the inheritance of red hair color has been linked to immune system deficits in the third component of complement, coded on chromosome 19 (6, 7). Woodworth suggested that it is therefore possible that phenotypic expression of red hair color reflects immune pathology that diminishes the clearance of retrograde menstrual fragments, thus increasing the likelihood of extrauterine implantation (8). In fact, several studies have reported an increased concentration of leukocytes, particularly macrophages, T lymphocytes, and natural killer cells, in the peritoneal fluid of women with endometriosis (26 28). Halme et al. compared the peritoneal macrophage secretions of women with and without endometriosis and found that cases demonstrated increased secretion of growth factors and proinflammatory cytokines (29). Overall, we observed no association between natural hair color and the rate of laparoscopically confirmed endometriosis. Although we did observe an increased risk associated with red hair color among women with no history of infertility, the magnitude of the effect (RR 1.3) did not approach that of the two previous cross-sectional studies (8 10). It did, however, fall within the 95% confidence interval reported by Wyshak and Frisch (10). The relation with natural hair color, if present, is likely modest and may differ by the infertility status of the study 868 Missmer et al. Hair color and endometriosis Vol. 85, No. 4, April 2006

4 Fertility and Sterility TABLE 1 Hair color and the incidence of laparoscopically confirmed endometriosis among premenopausal women by infertility status. All women (no past infertility) f Case definition No past or concurrent infertility a Concurrent infertility a Cases Age-adjusted RR MV RR (95% CI) b (95% CI) c Cases MV RR (95% CI) c Cases MV RR (95% CI) c P value e Natural hair color Red ( ) ( ) ( ).06 Blonde ( ) ( ) ( ) Light brown ( ) ( ) ( ) Dark brown (referent) 1.0 (referent) (referent) (referent) Black ( ) ( ) ( ) P value d.48 P value d.86 P value d.89 P value d.96 Red hair ( ) ( ) ( ).03 All others 1, (referent) 1.0 (referent) (referent) (referent) Note: RR rate ratio; CI confidence interval; MV RR multivariate rate ratio. a Infertility is defined as attempting to become pregnant for 1 year without success. Cases with no past or concurrent infertility are women who never reported infertility. Cases with concurrent infertility are women who reported an infertility evaluation in the same follow-up cycle as laparoscopic confirmation of endometriosis. b Adjusted for age (months) and calendar time. c Adjusted for age (months), calendar time, race (Caucasian, other race/ethnicities [African American, Hispanic, Asian]), parity (0, 1, 2, 3, 4 ), and body mass index at age 18 ( 19, , , , , 30 kilograms/meters 2 ). d P value, test for trend. e P value, test for heterogeneity comparing the effect of red hair color among women with no past or current infertility to those with concurrent infertility. f The total number of cases among all women with no past infertility is greater than the sum of cases among women with no past or concurrent infertility and those with concurrent infertility, because some cases were missing data on infertility evaluation and could not be separated. Missmer. Hair color and endometriosis. Fertil Steril

5 population. We may assume that cases with no infertility with a laparoscopic diagnosis are symptomatic, whereas those with infertility may be indicative of asymptomatic disease. However, the differential path to diagnosis highlighted by this potential heterogeneity is not correlated with disease stage as defined by the revised ASRM classification system (13), and therefore cannot be assumed to approximate a difference in the relation with natural hair color due to disease stage. In addition, among concurrently infertile women, our population consisted of only four cases with natural red hair. Further investigation into the potential linkage between red hair color and coagulation or immune dysfunction may explain the observed difference in the association between hair color and endometriosis with concurrent infertility vs. endometriosis without infertility. REFERENCES 1. Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am 1997;24: Oral E, Arici A. Pathogenesis of endometriosis. Obstet Gynecol Clin North Am 1997;24: Chua MV, Tsueda K, Doufas AG. Midazolam causes less sedation in volunteers with red hair. Can J Anaesth 2004;51: Liem EB, Hollensead SC, Lenhardt R, Sessler DI. Decreased platelet function in people with red hair. Anesthesiology 2003;99:A Loefler IJ. Pigmentation, melanocortins and red hair. QJM 1999;92: Eiberg H, Mohr J, Nielsen LS, Simonsen N. Genetics and linkage relationships of the C3 polymorphism: discovery of C3-Se linkage and assignment of LES-C3-DM-Se-PEPD-Lu synteny to chromosome 19. Clin Genet 1983;24: Bannatyne RM, Skowron PN, Weber JL. Job s syndrome a variant of chronic granulomatous disease. Report of a case. J Pediatr 1969;75: Woodworth SH, Singh M, Yussman MA, Sanfilippo JS, Cook CL, Lincoln SR. A prospective study on the association between red hair color and endometriosis in infertile patients. Fertil Steril 1995;64: Frisch RE, Wyshak G, Albert LS, Sober AJ. Dysplastic nevi, cutaneous melanoma, and gynecologic disorders. Int J Dermatol 1992;31: Wyshak G, Frisch RE. Red hair color, melanoma, and endometriosis: suggestive associations. Int J Dermatol 2000;39: Duleba AJ. Diagnosis of endometriosis. Obstet Gynecol Clin North Am 1997;24: Pardanani S, Barbieri RL. The gold standard for the surgical diagnosis of endometriosis: visual findings or biopsy results? Journal of Gynecologic Techniques 1998;4: The American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: Fertil Steril 1997;67: Tanahatoe S, Hompes PG, Lambalk CB. Accuracy of diagnostic laparoscopy in the infertility work-up before intrauterine insemination. Fertil Steril 2003;79: Rich-Edwards JW, Goldman MB, Willett WC, Hunter DJ, Stampfer MJ, Colditz GA, et al. Adolescent body mass index and infertility caused by ovulatory disorder. Am J Obstet Gynecol 1994;171: Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Marshall LM, Hunter DJ. Incidence of laparoscopically confirmed endometriosis by demographic, anthropometric, and lifestyle factors. Am J Epidemiol 2004;160: Prentice RL, Kalbfleisch JD, Peterson AV Jr, Flournoy N, Farewell VT, Breslow NE. The analysis of failure times in the presence of competing risks. Biometrics 1978;34: Greenland S. Modeling and variable selection in epidemiologic analysis. Am J Public Health 1989;79: Eiberg H, Mohr J. Major locus for red hair color linked to MNS blood groups on chromosome 4. Clin Genet 1987;32: Eiberg H, Mohr J. Major genes of eye color and hair color linked to LU and SE. Clin Genet 1987;31: Rees JL, Flanagan N. Pigmentation, melanocortins and red hair. Qjm 1999;92: Schioth HB, Phillips SR, Rudzish R, Birch-Machin MA, Wikberg JE, Rees JL. Loss of function mutations of the human melanocortin 1 receptor are common and are associated with red hair. Biochem Biophys Res Commun 1999;260: Valverde P, Healy E, Jackson I, Rees JL, Thody AJ. Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nat Genet 1995;11: Healy E, Jordan SA, Budd PS, Suffolk R, Rees JL, Jackson IJ. Functional variation of MC1R alleles from red-haired individuals. Hum Mol Genet 2001;10: McKusick VA. Mendelian inheritance in man. 8th ed. Baltimore: Johns Hopkins Press, Hill JA. Immunology and endometriosis. Fact, artifact, or epiphenomenon? Obstet Gynecol Clin North Am 1997;24: Rier SE, Yeaman GR. Immune aspects of endometriosis: relevance of the uterine mucosal immune system. Semin Reprod Endocrinol 1997; 15: Witz CA, Schenken RS. Pathogenesis. Semin Reprod Endocrinol 1997; 15: Halme J, Becker S, Haskill S. Altered maturation and function of peritoneal macrophages: possible role in pathogenesis of endometriosis. Am J Obstet Gynecol 1987;156: Missmer et al. Hair color and endometriosis Vol. 85, No. 4, April 2006