FERTILITYAND STERILITY~ Copyright
o 1997 American
Vol. 66, No. 5, November
Society for Reproductive
in U. 5’. A.
in monozygotic twins
Ruth M. Hadfield, B.Sc. Helen J. Mardon, D.Phil. David H. Barlow, F.R.C.O.G. Stephen H. Kennedy, M.R.C.O.G. Nuffield Department
University of Oxford, John Radcliffe Hospital,
Oxford, United Kingdom
Objective: To describe the occurrence of endometriosis in monozygotic twins. Design: Postal questionnaire plus confirmation of disease status. Setting: Twins were recruited via the American Endometriosis Association and the National Endometriosis Society of Great Britain and via British gynecologists. Result(s): Fourteen twin pairs were concordant for endometriosis, and two were discordant. Nine pairs of twins had moderate-severe endometriosis. Conclusion(s): These findings contribute to the growing body of literature that suggests (Fertil [email protected]
1997;68:941-2. 0 1997 by American endometriosis has a genetic basis. Society for Reproductive Medicine.) Key Words: Endometriosis, genetics, twins
It has been suggested that endometriosis has a genetic basis because of the strong familial tendency (1) and an increased prevalence in the first-degree relatives of afTect.edwomen compared with the general population (2). Concordance data from monozygotic and dizygotic twins would provide invaluable supportive data. However, the problems inherent in diagnosing endometriosis and the lack of large twin registers containing women in the 30-40 age group have made it dif&xlt to conduct such a study, and to date, only a collection of case reports has appeared in the literature (3). A group of twin pairs in whom disease severity was assessed by scrutiny of the surgical records was among sister pairs with endometriosis recruited for genetic linkage analysis; these data are presented here. MATERIALS AN-D METHODS
Sister pairs with endometriosis were recruited for genetic linkage analysis by advertising in the newsReceivedApril 14, 1997; revised and accepted July 22, 1997. Reprint requests: Stephen Kennedy, M.R.C.O.G., Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom (FAX: 44-1865-769141; e-mail: [email protected]
ACUK). Financial support: R.M.H. was supported by grant no. G9511653 from the Fundor Medical Research Council, London, United Kingdom. 0015-0282/97/$17.00 PI1 SOO15-0282(97)00359-Z
letters of the American Endometriosis Association and the United Kingdom Endometriosis Society, from the records of the John Radcliffe Hospital, Oxford, and with the help of British gynecologists. Twin sister pairs were never actively recruited for this study. Disease severity was assessed from the operative records as minimal-mild or moderate-severe by using the revised American Fertility Society (AFS) classification system (4). Where possible, histological evidence of endometriosis was also obtained. A revised standard questionnaire (5) was used to determine the zygosity of any twin pairs. This produces a correct classification in >95% of cases even if only one twin responds. We included questions about genotyping and Al30 and rhesus D blood group status. RESULTS
A total of 627 women responded, among whom there were 19 twin pairs. Zygosity was determined (monozygotic = 18, dizygotic = 1) on the basis of the response from both twins (n = 11) or one twin (n = 7) to the zygosity questionnaire or from DNA testing (n = 1). In the seven pairs of monozygotic twins where both reported their Al30 and rhesus blood group, full concordance was found. Disease status was inadequately documented in 2 941
monozygotic pairs who were excluded. Of the remaining 16 monozygotic pairs, 9 were concordant for stage III-IV endometriosis. In 5 pairs, one twin had stage I-II disease and the other had either stage III-IV (n = 4) or deeply infiltrating disease (n = 1). Two monozygotic pairs were discordant: both probands had stage III-IV disease, but their twin sisters either had no disease at laparoscopy or were asymptomatic, having had no gynecological surgery. Histological confirmation of disease was obtained for 22 of 30 women with a surgical diagnosis. Of the nine twin pairs with concordance for stage III-IV endometriosis, 8 of 9 (both sisters) had histological confirmation, Seventeen women (57%) reported that they had problems conceiving, although 7 (23%) had not attempted to conceive and 2 (7%) failed to respond to this question. Both twins without endometriosis reported that they had had difficulty conceiving. Three of the patients had adenomyosis, although no twin pairs were concordant for this finding. One monozygotic pair also had a nontwin sister with stage I-II endometriosis. The only dizygotic pair was concordant for endometriosis: one sister had stage III-IV disease, and the other stage I-II disease. DISCUSSION
Endometriosis may, like diabetes, asthma, and hypertension, be a multifactorial disease in which a susceptibility gene(s) interacts with the environment to produce the phenotype. Twin concordance studies would be invaluable to determine the relative effects of genetic and environmental factors, but they are difficult to conduct in patients with this disease. The only previously published study of endometriosis in monozygotic twins to date (3) reported 75% concordance in 8 monozygotic pairs; in our study, there was 87% concordance in 16 monozygotic pairs, of which 56% were concordant for moderatesevere endometriosis.
Hadfield et al.
In the two discordant monozygotic pairs, both twins without endometriosis were infertile. This observation leads us to speculate that endometriosis susceptibility genes may be associated with other genes that cause failure to conceive. There is inherent ascertainment bias in our method of data collection because we specifically recruited sister pairs with endometriosis. Furthermore, it is likely that monozygotic twins with disease would be highly motivated to participate in a genetic study, which may explain why surprisingly few dizygotic pairs responded. It has been estimated that the proportion of twin types in an unbiased study should be approximately 46% monozygotic and 54% dizygotic (6). However, in most studies in which twins volunteer, the proportion of monozygotic twins is higher than expected at approximately 62%. In comparison, of the 19 pairs of twins in our study, only one set was dizygotic. These findings support existing evidence suggesting that endometriosis may have a genetic basis. Acknowledgments. The authors thank the National Endometriosis Society of Great Britain, the American Endometriosis Association, Milwaukee, Wisconsin, and Ms. Mary-Lou Ballweg, in particular, for their invaluable help. REFERENCES Kennedy SH, Mardon HJ, Barlow DH. Familial endometriosis. J Assist Reprod Genet 1995; 12:32-4. Moen MH, Magnus P. The familial risk of endometriosis. Acta Obstet Gynecol Stand 1993;72:560-4. Moen MH. Endometriosis in monozygotic twins. Acta Obstet Gynecol Stand 1994;73:59-62. The American Fertility Society. Revised American Fertility Society classification of endometriosis: 1985. Fertil Steril 1985;43:351-2. 5. Magnus P, Berg K, Name WE. Predicting zygosity in Norwegian twin pairs born 1915-1960. Clin Genet 1983;24:10312. 6. Lykken DT, McGue M, Tellegen A. Recruitment bias in twin research: the rule of two-thirds reconsidered. Behav Genet 1987; 17:343-62.
Fertility and [email protected]