Epigenetic modifications of primordial reproductive tract. A common etiologic pathway for Mayer-Rokitansky-Kuster-Hauser Syndrome and endometriosis?

Dear Editor, we read with great interest the paper by Alcolado [1], published in your prestigious Journal. This work conforms ‘‘the fetal basis of adult disease’’ hypothesis, which proposes that prenatal exposure to certain forms of environmental stress can cause increased susceptibility to clinical disorders, modulating the gene expression later in life (the so-called ‘‘epigenetic imprinting”). During embryogenesis, it was already shown that homeobox (Hox) genes are strictly involved in the differentiation of the paramesonephric duct into the mature female reproductive system [2]. Two weeks after birth, Hoxa9, Hoxa10, Hoxa11 and Hoxa13 develop their characteristic spatial distribution throughout the Müllerian ducts [3]. Moreover, it was demonstrated that the loss of Hoxa10 function provokes dysregulation during decidualization and implantation, resulting in female infertility [4]. Although clear data about the role of Hoxa gene clusters in infertility remain to be elucidated, we know that Hoxa10 specifically mediates the progesterone regulation of two prostaglandin E2 receptors (EP3 and EP4) in uterine stroma [5]. Moreover, another well-known family of genes that influence remarkably the organogenesis of the Müllerian reproductive tract is Wnt (wingless-type MMTV integration site family). Failures in Wnt signaling are associated with infertility, endometriosis, endometrial cancer and gestational trophoblastic disease such as choriocarcinomas [6]. Basing on these data, it is possible that epigenetic disturbance(s) during the Müllerian reproductive tract development may lead to modified intercellular communications, dysregulation of common downstream targets and, finally, to defect of organogenesis. Considering that the dysregulation of Wnt and/or Hox genes may affect cell migration during organogenesis and differentiation of Müllerian structures of the female reproductive tract, these altered pathways can underlie the well-known Mayer-Rokitansky-Kuster-Hauser Syndrome [7], clinically characterized by a physiological development of the secondary sexual characters and by a normal female karyotype 46 XX, with a congenital aplasia of the uterus and of 2/3 superior parts of vagina. A similar etiologic machinery was already hypothesized for endometriosis [8], a gynecological condition characterized by the breakdown of peritoneal immune homeostasis [9–11] and related symptoms and signs [12–14] due to the pro-inflammatory profile of pelvic as well as intrauterine microenvironment.