The estrogen-injected female mouse: new insight into the etiology of PCOS

Abstract

BackgroundFemale mice and rats injected with estrogen perinatally become anovulatory and develop follicular cysts. The current consensus is that this adverse response to estrogen involves the hypothalamus and occurs because of an estrogen-induced alteration in the GnRH delivery system. Whether or not this is true has yet to be firmly established. The present study examined an alternate possibility in which anovulation and cyst development occurs through an estrogen-induced disruption in the immune system, achieved through the intermediation of the thymus gland.Methods, Results and ConclusionA putative role for the thymus in estrogen-induced anovulation and follicular cyst formation (a model of PCOS) was examined in female mice by removing the gland prior to estrogen injection. Whereas all intact, female mice injected with 20 ug estrogen at 5–7 days of age had ovaries with follicular cysts, no cysts were observed in animals in which thymectomy at 3 days of age preceded estrogen injection. In fact, after restoring immune function by thymocyte replacement, the majority of thymectomized, estrogen-injected mice had ovaries with corpora lutea. Thus, when estrogen is unable to act on the thymus, ovulation occurs and follicular cysts do not develop. This implicates the thymus in the cysts' genesis and discounts the role of the hypothalamus. Subsequent research established that the disease is transferable by lymphocyte infusion. Transfer took place between 100-day-old estrogen-injected and 15-day-old naïve mice only when recipients were thymectomized at 3 days of age. Thus, a prerequisite for cyst formation is the absence of regulatory T cells. Their absence in donor mice was judged to be the result of an estrogen-induced increase in the thymus' vascular permeability, causing de facto circumvention of the final stages of regulatory T cell development. The human thymus has a similar vulnerability to steroid action during the fetal stage. We propose that in utero exposure to excessive levels of steroids such as estrogen has a long-term effect on the ability of the thymus to produce regulatory T cells. In female offspring this can lead to PCOS.

MECHANISMS IN ENDOCRINOLOGY: Thyroid and polycystic ovary syndrome

“…When estrogen was unable to exert influence upon the thymus during its development, and adult thymic cells were provided later, the ovulation occurred and follicular cysts did not appear. Furthermore, estrogen-injected mice with intact thymus had significantly fewer number of thymocytes than controls (60). The absence of Tregs owing to estrogen-affected thymus was supposed to be a prerequisite for estrogen-induced cyst formation, thus supporting the autoimmune etiology of PCOS (60).…”

“…Furthermore, estrogen-injected mice with intact thymus had significantly fewer number of thymocytes than controls (60). The absence of Tregs owing to estrogen-affected thymus was supposed to be a prerequisite for estrogen-induced cyst formation, thus supporting the autoimmune etiology of PCOS (60). Similarly, in women prenatally exposed to diethylstilbestrol (DES), a potent synthetic estrogen, which was prescribed in the USA from 1940 to 1971, the highest rate of infertility was found when they were exposed to DES from gestational weeks 9 to 12 (61).…”

Polycystic Ovary Morphology (PCOM) in Estradiol Valerate Treated Mouse Model

“…These changes in ovarian morphological features are similar to those of PCOS women (9). The polycystic ovarian morphology in PCOS is presented by an excessive amount of growing follicles (13). In the present study we aimed to develop PCOM model through the EV-treated mice.…”

Interactions Between Reproductive and Immune Systems During Ontogeny: Roles of GnRH, Sex Steroids, and Immunomediators

“…In addition, excess sex steroids cause disturbances in mammal immune system. In particular, they suppress differentiation of regulatory and cytotoxic T cells in the thymus, with consequent increase in the numbers of immature lymphocytes in the circulation, and cause an impairment of negative selection mechanisms, which results in the formation of selfreactive T cells (Chapman et al, 2009). Estrogens also stimulate an increase in the numbers of self-reactive B lymphocytes and the level of circulating autoantibodies (Olsen & Kovacs, 1996;Tanriverdi et al, 2003).…”

“…Estradiol and testosterone injected to female mice during the neonatal period induce the development of infertility, whereas their injection on postnatal day 7 causes no disturbances in the reproductive system. Hydrocortisone injected together with estradiol prevents the development of infertility (Chapman et al, 2009). Sex hormones also modulate the development of lymphoid organs, the thymus being their main target in the immune system.…”