Postnatal androgenization induces premature aging of rat ovaries

In the present paper, we report that ovaries of adult rats treated with tes tosterone propionate (TP) on a critical postnatal Day 5 exhibit histologic and immunohistochemical findings which resemble those of the anovulatory ov aries in middle-aged female rats. The sterile rat model has been long known whereas ovarian failure seems to be a reason for anovulation wi th normal hypothalamo-pituitary-gonadotropin background. Appropriate function of ovar ian steroidogenic cells is also regulated by mesenchymal cells. To characte rize the ovarian failure, we studied the histology, luteinizing hormone rec eptor (LHR) expression, and characterized changes of vascular pericytes, T cells, and dendritic cells in ovarian steroidogenic compartments consisting of interstitial cells (ISC) of ovarian interstitial glands, and granulosa and theca interna cells of ovarian follicles. Normal adult ovaries containe d 63% of mature interstitial glands. The mature ISC exhibited moderate cyto plasmic and strong surface LHR expression and fine (<5 mu m) cytoplasmic va cuoles (ISC of 'luteal type'). They originated from young ISC of 'thecal ty pe,' which exhibited strong cytoplasmic LHR expression. Remaining 37% were aged interstitial glands, which consisted of aged ISC (increased cytoplasmi c vacuolization, nuclear pyknosis, and reduced surface LHR expression) and regressing ISC tweak cytoplasmic and no surface LHR expression). However, n o mature ISC of 'luteal type' were detected in anovulatory ovaries of adult rats 45- and 60-day-old) injected with TP (100 or 500 mu g) on postnatal D ay 5 (TP rats). Their ovaries contained 96% of aged interstitial glands wit h aged and regressing ISC. Remaining 4% were abnormal interstitial glands w ith direct transition of young ISC of 'thecal type' into aged ISC (young/ag ed glands). Lack of mature ISC, and similar amount of aged (96%) and young/ aged interstitial glands (4%) was also detected in anovulatory ovaries of u ntreated persistently estrous middle-aged (IO-month-old) females (aging PE mts). The aging process in TP and aging PE rats was accompanied by regressi on of vascular pericytes, T cells, and dendritic cells within the interstit ial glands. In addition, anovulatory ovaries of TP rats and aging PE female s contained mature follicles exhibiting LHR overexpression by granulosa cel ls, and aged (cystic) follicles with reduced layers of granulosa cells lack ing LHR expression. In contrast, when the mts were injected with 500 mu g o f TP later, on postnatal Day 10, the adult females exhibited estrous cycles and normal ovaries with corpora lutea. These results show that injection o f TP during the critical postnatal period causes a lack of mature and prepo nderance of aged ISC in adult ovaries, accompanied by degeneration of mesen chymal cells. We suggest that mesenchymal cells regulate qualitative aspect s of tissue-specific cells, and this function of mesenchymal cells is progr ammed during the critical period of development. (C) 2000 Elsevier Science Inc. An rights reserved.