Familial risk among Japanese patients with endometriosis

International Journal of Gynecology and Obstetrics 84 (2004) 61–64

Article

Familial risk among Japanese patients with endometriosis K. Kashimaa,*, T. Ishimarub, H. Okamurac, H. Suginamid, K. Ikumae, T. Murakamif, M. Iwashitag, K. Tanakaa a

Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan b Department of Obstetrics and Gynecology, Nagasaki University School of Medicine, Nagasaki, Japan c Department of Obstetrics and Gynecology, Kumamoto University School of Medicine, Kumamoto, Japan d Department of Obstetrics and Gynecology, Kyoto National Hospital, Kyoto, Japan e Department of Obstetrics and Gynecology, Takarazuka City Hospital, Hyogo, Japan f Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Miyagi, Japan g Department of Obstetrics and Gynecology, Kyorin University School of Medicine, Tokyo, Japan Received 26 March 2003; received in revised form 24 July 2003; accepted 30 July 2003

Abstract Objectives: This study was designed to examine the prevalence of endometriosis among female siblings of patients with endometriosis in Japan. Methods: A total of 339 patients with endometriosis were questioned about endometriosis in their sisters. The control group consisted of 284 Japanese healthy fertile women with no history of endometriosis. Similarly, the controls were interviewed about their sisters. Results: We detected sisters with endometriosis in 8.8% of cases and 1.5% of the control population. The relative risk of endometriosis in female siblings was 5.7. However, a significant difference was not seen in age at diagnosis and clinical stage between patients with or without a family history of endometriosis. Conclusions: These data demonstrate a familial tendency for endometriosis and suggest that endometriosis has a genetic factor in the pathogenesis. 䊚 2003 International Federation of Gynecology and Obstetrics. Published by Elsevier Science Ireland Ltd. All rights reserved. Keywords: Endometriosis; Female siblings; Japan

1. Introduction Endometriosis is one of the most common gynecological disorders observed in approximately 2– 10% of women of reproductive age w1,2x. Women *Corresponding author. Tel.: q81-25-227-2320; fax: q8125-227-0789. E-mail address: [email protected] (K. Kashima).

with endometriosis may have a variety of symptoms including severe pelvic pain and infertility. Although little is known about its etiology and pathogenesis, it is likely to have a genetic basis. Because a number of studies have demonstrated a 3- to 9-fold increased risk for mothers or sisters of patients for developing the disease w3–5x. More recently, studies of twins have showed that concordance in monozygotic twins exceeded that in dizygotic twins by two times w6x.

0020-7292/04/$30.00 䊚 2003 International Federation of Gynecology and Obstetrics. Published by Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0020-7292(03)00340-0

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Table 1 Characteristics of patients with endometriosis Variable Age at diagnosis Mean 10–19 20–29 30–39 40–49 50–59 Clinical stage Revised ASRM stage III Revised ASRM stage IV Chief complaints Dysmenorrhea Abdominal pain Sterility Menarche mean Cycle length mean Menstruation duration mean Marital status Married Single No. of live births (married) 0 1F Therapy of sterility (married) Done Not done

(ns339) 32.3"7.4 5 134 135 63 2

(years) (1.5%) (39.5%) (39.8%) (15.6%) (0.6%)

202 137

(59.6%) (40.4%)

217 102 76

(64.0%) (30.1%) (22.4%)

12.2"1.2

(years)

27.1"3.7

(days)

6.0"1.4

(days)

246 93

(72.6%) (27.4%)

142 104

(57.7%) (42.3%)

90 156

(36.6%) (63.4%)

ASRM, American Society for Reproductive Medicine.

Hospital, Nagasaki University Hospital, Kumamoto University Hospital, Kyoto National Hospital, Takarazuka City Hospital, Tohoku University Hospital, Kyorin University Hospital, and several hospitals in Niigata Prefecture. A total of 339 unrelated patients with endometriosis diagnosed at laparoscopy or laparotomy were investigated in this study. All patients were hospitalized for diagnosis and treatment, and informed consent was obtained by explaining the details of this study. None refused to participate in this study. The enrollment questionnaire was designed to obtain information on the patient’s symptoms, menstrual cycle characteristics, reproductive history, and endometriosis in their female siblings. The information was obtained by an interview at the hospital. Medical records of the patients were reviewed to obtain information on chief complaints, methods of diagnosis, and history of treatment. 2.2. Controls The control group consisted of 284 Japanese healthy fertile women with no history of endometriosis who had undergone an annual health examination in Niigata. The mean age was 56.3"7.6 years. The controls were asked directly about endometriosis in their sisters, and none refused to give information.

The incidence of endometriosis among Japanese women has been reported to be twice that of Caucasian women w7x. Moreover, other investigators suggested that endometriosis is more common in Asian women than in Caucasian women w8,9x. However, the prevalence of endometriosis among the female siblings of Japanese patients with endometriosis has not been reported. In this study, we reported the results of a questionnaire study about family history of endometriosis among 339 women with endometriosis and 284 healthy fertile women in Japan with no history of endometriosis.

The relative risk of having affected female siblings for cases compared with the control population was estimated as follows: the relative risk is the risk for the female siblings of the affected individual divided by the risk for the female siblings of the control population. Student’s t-test and chi-square test were used to test differences between patients with or without a family history.

2. Materials and methods

3. Results

2.1. Patients The patients with endometriosis were registered between 2000 and 2002 at Niigata University

2.3. Statistical methods

The characteristics of the patients with endometriosis, including age at diagnosis and clinical stage, are shown in Table 1. Endometriosis was

K. Kashima et al. / International Journal of Gynecology and Obstetrics 84 (2004) 61–64 Table 2 Proportions of endometriosis in female sibs Cases (ns339) (%)

n

Controls (ns284) n

(%)

Total no. of female siblings 251 262 Female siblings with endometriosis 22 (8.8) 4 (1.5)

staged according to the Revised American Society for Reproductive Medicine (ASRM) classification w10x: 202 women with endometriosis had stage III and 137 had stage IV. The mean values of age at diagnosis, menarche, cycle length, and menstruation duration was 32.3"7.4 years, 12.2"1.2 years, 27.1"3.7 days, and 6.0"1.4 days respectively. The patients had the following chief complaints: dysmenorrhea in 64.0%, abdominal pain in 30.1% and sterility in 22.4%. Among the married patients, sterility therapy had been performed in 36.6%. Of the 339 patients with endometriosis, 198 patients had female siblings. We detected 22 patients with endometriosis among the 251 female siblings (8.8%) (Table 2). All 22 sisters with endometriosis were confirmed by medical records, and they were diagnosed by laparoscopy or laparotomy. However, we observed four sisters with endometriosis among 262 female siblings of the

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control group (1.5%) (Table 2), and three cases were confirmed by medical records. In one case, no medical records could be obtained, but the medical history gave substantial evidence of the diagnosis. The relative risk of endometriosis in female siblings was 5.7. Table 3 demonstrates the differences in clinical characteristics between cases with or without a family history of endometriosis. A significant difference was not seen in age at diagnosis and the Revised ASRM stage. 4. Discussion Endometriosis is increasingly recognized as a complex trait, the development of which is influenced by interactions between multiple genes and environmental factors. A number of studies have demonstrated a 3.9- to 8.1-fold increased risk for mothers and 3.8- to 5.8-fold increased risk for sisters of patients for developing the disease w3– 5x. A prevalence in the USA of 5.8% w3x and in Norway of 4.8% w5x has been reported in female siblings of affected probands. Furthermore, six sisters were affected among the 81 patients with endometriosis in Brazil w11x. In this study, we registered 339 patients and detected 22 cases of endometriosis among 251 female siblings (8.8%).

Table 3 Comparison of clinical characteristics between cases with a positive and a negative family history of endometriosis

Age at diagnosis (years) Clinical stage Revised ASRM stage III Revised ASRM stage IV Chief complaints Dysmenorrhea Abdominal pain Sterility Marital status Married Single No. of live births (married) 0 1F

Family history Positive (ns22)

Family history Negative (ns176)

P-value

31.7"7.4

32.7"8.1

N.S.

18 10

(64.3%) (35.7%)

99 77

(56.3%) (43.8%)

N.S.

18 8 8

(64.3%) (28.6%) (28.6%)

115 52 37

(65.3%) (29.5%) (21.0%)

N.S.

21 7

(75.0%) (25.0%)

128 48

(72.7%) (27.3%)

N.S.

12 9

(57.1%) (42.9%)

77 51

(60.2%) (39.8%)

N.S.

ASRM, American Society for Reproductive Medicine.

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Our data were higher than the past data and suggested that heritable genetic factors contribute to the development of endometriosis in Japan. Moen et al. have reported that severe manifestations of endometriosis were found more often among patients with a positive family history w5x. However, a significant difference in the Revised ASRM stage was not seen between the patients with and without a family history of endometriosis in this study. The population prevalence of endometriosis is not known exactly, because laparoscopy or laparotomy is required for diagnosis. However, endometriosis has been estimated to be prevalent in approximately 2–10% of women of reproductive years w1,2x. In this study, the prevalence of endometriosis of the female siblings in the control population was 1.5%. Therefore, the relative risk for sisters was calculated to be 5.7. Although the genetic risk may be due to a single highly penetrant gene, it is more likely due to a number of genes each responsible for a small increase in risk. Previous association studies implicated glutathione S-transferase M1 w12–14x, Nacetyltransferase 2 w13,15x and estrogen receptor a w16,17x genes as possible disease susceptibility genes. However, the exact genes that play a role in the susceptibility of development and progression of endometriosis are unknown. In conclusion, our current study suggests that a genetic factor is responsible for endometriosis. The identification of genes conferring susceptibility to endometriosis may lead to a better understanding of disease etiology, improved therapeutic strategies, and diagnostic methods. References w1x Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am 1997;24:235 –258. w2x Moen MH, Schei B. Epidemiology of endometriosis in a Norwegian county. Acta Obstet Gynecol Scand 1997;76:559 –562.

w3x Simpson JL, Elias S, Malinak LR, Buttram VC Jr.. Heritable aspects of endometriosis. I. Genetic studies. Am J Obstet Gynecol 1980;137:327 –331. w4x Lamb K, Hoffmann RG, Nichols TR. Family trait analysis: a case-control study of 43 women with endometriosis and their best friends. Am J Obstet Gynecol 1986;154:596 –601. w5x Moen MH, Magnus P. The familial risk of endometriosis. Acta Obstet Gynecol Scand 1993;72:560 –564. w6x Treloar SA, O’Connor DT, O’Connor VM, Martin NG. Genetic influences on endometriosis in an Australian twin sample. Fertil Steril 1999;71:701 –710. w7x Miyazawa K. Incidence of endometriosis among Japanese women. Obstet Gynecol 1976;48:407 –409. w8x Arumugam K, Templeton AA. Endometriosis and race. Aust New Zealand J Obstet Gynaecol 1992;32:164 – 165. w9x Sangi-Haghpeykar H, Poindexter AN 3rd. Epidemiology of endometriosis among parous women. Obstet Gynecol 1995;85:983 –992. w10x American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997;67:817 –821. w11x dos Reis RM, de Sa MF, de Moura MD, Nogueira AA, Ribeiro JU, Ramos ES, et al. Familial risk among patients with endometriosis. J Assist Reprod Genet 1999;16:500 –503. w12x Baranova H, Bothorishvilli R, Canis M, Albuisson E, Perriot S, Glowaczower E, et al. Glutathione S-transferase M1 gene polymorphism and susceptibility to endometriosis in a French population. Mol Hum Reprod 1997;3:775 –780. w13x Baranova H, Canis M, Ivaschenko T, Albuisson E, Bothorishvilli R, Baranov V, et al. Possible involvement of arylamine N-acetyltransferase 2, glutathione S-transferases M1 and T1 genes in the development of endometriosis. Mol Hum Reprod 1999;5:636 –641. w14x Baxter SW, Thomas EJ, Campbell IG. GSTM1 null polymorphism and susceptibility to endometriosis and ovarian cancer. Carcinogenesis 2001;22:63 –65. w15x Nakago S, Hadfield RM, Zondervan KT, Mardon H, Manek S, Weeks DE, et al. Association between endometriosis and N-acetyl transferase 2 polymorphisms in a UK population. Mol Hum Reprod 2001;7:1079 –1083. w16x Georgiou I, Syrrou M, Bouba I, Dalkalitsis N, Paschopoulos M, Navrozoglou I, et al. Association of estrogen receptor gene polymorphisms with endometriosis. Fertil Steril 1999;72:164 –166. w17x Kitawaki J, Obayashi H, Ishihara H, Koshiba H, Kusuki I, Kado N, et al. Oestrogen receptor-alpha gene polymorphism is associated with endometriosis, adenomyosis and leiomyomata. Hum Reprod 2001;16:51 –55.