Effects of neonatal progestin exposure on female reproductive tract structure and function in the adult ewe

Endometrial glands are present in all mammalian uteri and produce secretion s that are hypothesized to support conceptus (i.e., embryo/fetus and placen tal membranes) survival and development. In sheep, endometrial gland morpho genesis occurs postnatally and can be epigenetically ablated by chronic neo natal exposure to a progestin from birth, thereby producing an adult uterin e gland knock-out (UGKO) phenotype. This study determined the long-term eff ects of neonatal progestin exposure on adult ovine reproductive tract struc ture and function. Neonatal ewes were exposed to norgestomet (Nor) from bir th to 32 wk of age. Unexposed ewes served as controls. After puberty, adult Nor-treated (n = 6) and control (n = 6) ewes were repeatedly bred at estru s (Day 0) to intact rams of proven fertility. In contrast to a pregnancy ra te of 80% for control ewes, pregnancy was never detected on Day 25 after ma ting (or thereafter) in bred UGKO ewes. Control and Nor-treated ewes were t hen bred and necropsied on Day 9. Similar numbers of hatched blastocysts we re present in uterine flushings from control and Nor-treated ewes. Weights of the ovaries and cervices were not affected by treatment. No histoarchite ctural differences between control and Nor-treated ewes were detected for o varies, oviducts, cervices, or vaginae. However, uterocervical and uterine weight as well as uterine horn length were less for Nor-treated ewes. The u teri of Nor-treated ewes were devoid of endometrial glands and lacked the s tromal delineation characteristic of intercaruncular endometrium in control ewes. Endometrial width, area, and lumenal epithelial length were decrease d in uteri from Nor-treated ewes, but myometrial width and morphology were not affected. Expression of a number of mRNAs that are expressed predominan tly in the endometrial epithelia was not different between uteri from contr ol and from Nor-treated ewes. Collectively, these results indicate that neo natal exposure of ewes to a progestin from birth appears to only affect dev elopment of the uterus and not any extrauterine reproductive tract tissues. The infertility of the UGKO ewes appears to result from a lack of endometr ial glands and, by extension, of their secretions that are required to supp ort growth and development of peri-implantation conceptuses.