Recurrent Pregnancy Loss and Inappropriate Local Immune Response to Sex Hormones Alek M. Itsekson 1 , Daniel S. Seidman 1 , Matityahu Zolti 1 , Anneta Lazarov 2 , Howard J.A. Carp 1 1 Department of Obstetrics & Gynecology, Sheba Medical Center, Tel Hashomer, Israel 2 Dermatology Clinic Meir Hospital, Sapir Medical Center, Kfar Saba, Israel Introduction Recurrent pregnancy loss is defined as three or more consecutive miscarriages. Despite exhaustive investi- gation, the cause often remains undiagnosed. 1 Var- ious therapeutic regimens have been used, often with no consensus as to their efficacy, due to the imprecise nature of the diagnosis of cause. The cor- pus luteum plays an essential role in maintenance of pregnancy by producing progesterone, estrogen and possibly other hormones. Lutectomy early in preg- nancy is known to precipitate abortion. 2 Abortion can be induced by progesterone receptor antagonists such as mifepristone. 3 Estrogen antagonists such as tamoxifen (in combination with misoprostol) are also associated with a 92% abortion. 4 Corpus luteum deficiency has long been suspected to be a cause of miscarriage, 5,6 and numerous reports have attempted to raise the live birth rate in women with recurrent miscarriage by administering progesterone supple- ments. However, the results have been controversial. Most investigators consider progesterone supple- ments to be unwarranted. Progesterone is also known to accelerate autoim- mune processes. 7 Autoantibodies to progesterone and 17a-hydroxyprogesterone have been found in Keywords Estrogen, progesterone, recurrent miscarriage, skin testing, spontaneous abortion Correspondence A. Itsekson, Department of Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer 52621, Israel. E-mail: itsekson@netvision.net.il Submitted August 3, 2006; revised September 29, 2006; accepted November 22, 2006. Citation Itsekson AM, Seidman DS, Zolti M, Lazarov A, Carp HJA. Recurrent pregnancy loss and inappropriate local immune response to sex hormones. Am J Reprod Immunol 2007; 57:160–165 doi:10.1111/j.1600-0897.2006.00461.x Problem The cause of recurrent miscarriage is often unknown. Recurrent miscar- riage may be associated with inappropriate responses to progesterone and estrogen. We examined whether the condition may be diagnosed by skin testing. Method of study In a longitudinal prospective study, the weal and flare reaction after in- tradermal injection of estradiol and progesterone was compared in 29 women with recurrent miscarriage to the response in 10 healthy women. Reactions were evaluated after 20 min, 24, and 48 hr and 5 days later. Results Estrogen hypersensitivity was found in 23 patients, and progesterone hypersensitivity in 20 patients. No patient in the control group demon- strated sex hormone hypersensitivity. Conclusion Recurrent pregnancy loss may be associated with inappropriate local immune responses to sex hormones. Further research is necessary into the mechanisms of hypersensitivity to estrogen and progesterone and their interactions with other systems. ORIGINAL ARTICLE American Journal of Reproductive Immunology 57 (2007) 160–165 ª 2007 The Authors 160 Journal compilation ª 2007 Blackwell Munksgaard