Arch Gynecol Obstet (2009) 280:395–400 DOI 10.1007/s00404-009-0927-1 123 ORIGINAL ARTICLE Polymorphisms in estrogen metabolism and estrogen pathway genes and the risk of miscarriage S. Cupisti · Peter A. Fasching · A. B. Ekici · P. L. Strissel · C. R. Loehberg · R. Strick · J. Engel · R. Dittrich · M. W. Beckmann · T. W. Goecke Received: 25 July 2008 / Accepted: 3 January 2009 / Published online: 18 January 2009  Springer-Verlag 2009 Abstract Purpose This study investigated genetic variations in the estrogen pathway and their association with miscarriages. Methods A total of 483 patients were recruited from a comprehensive control group for case–control studies. Three variants of the CYP19A1 gene (rs10046, rs4646 and rs700519) and one variant each of the estrogen (ESR1) and progesterone (PGR) receptor genes (rs3020314 and rs1042838) were investigated using polymorphism geno- typing. The chi-squared test and one-way analysis of varia- tion (ANOVA) were used for statistical analysis. Results For rs10046 (CYP19A1), the C/C genotype was associated with a greater frequency of miscarriages (P = 0.017). The other genotypes were not found to be associated with recurrent miscarriage. Conclusions This is the Wrst study that has identiWed a single-nucleotide polymorphism in the aromatase gene that suggests a signiWcant association between genotypes and miscarriage. As aromatase is an essential enzyme in the estrogen pathway, it may be speculated that variations in the aromatase gene in some way give rise to diVerent condi- tions in the endocrine environment that can lead to impaired fertility. Keywords Miscarriage · Estrogen · Estrogen pathway · CYP19A1 polymorphisms Introduction Recurrent miscarriage, deWned as three or more abortions, is a problem that aVects nearly 1% of women [1]. The etiol- ogy is varied, and the condition is not often identiWed in clinical practice. It has been suggested that genetic causes, anatomical abnormalities, and thrombophilic factors may be associated with recurrent miscarriage [2, 3]. In recent years, increasing eVorts have been made to describe genetic causes of recurrent miscarriage at the molecular level. There have been reports of associations between recurrent miscarriages and genetic polymorphism in the immune sys- tem [4–6], variations in the factor V gene [7] and variations in the plasminogen activator inhibitor 1 gene [8]. There is evidence that estrogen and progesterone signal- ling is important throughout pregnancy, particularly in the Wrst trimester [9, 10], and that it may contribute to the maintenance of pregnancy. Genetic variations capable of causing alterations in the estrogen pathway might therefore inXuence the course of pregnancies. A few studies have investigated the role of genetic varia- tions in the sex hormone signalling pathway. One study reported no association between recurrent miscarriage and polymorphisms in estrogen receptor genes 1 and 2 (ESR1 and ESR2) [11]. However, ESR1 and ESR2 polymorphisms have been linked to a higher risk of unexplained infertility and to the outcome of controlled ovarian stimulation [12], as well as to the ovarian response to FSH [13]. ESR1 polymorphisms are thought to be related to pheno- typic markers of ovarian aging, suggesting a possible role for this gene in the timing of the transition to menopause S. Cupisti and P. A. Fasching contributed equally to this work. S. Cupisti · P. A. Fasching (&) · P. L. Strissel · C. R. Loehberg · R. Strick · J. Engel · R. Dittrich · M. W. Beckmann · T. W. Goecke Department of Gynecology and Obstetrics, Erlangen University Hospital, Universitaetsstrasse 21–23, 91054 Erlangen, Bavaria, Germany e-mail: peter.fasching@uk-erlangen.de A. B. Ekici Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany