Abstract
Although uterine development is considered independent of sex steroids, alteration to circulating oestrogen, progestin and androgen concentrations result in abnormal uterine phenotypes. Polycystic ovary syndrome (PCOS) and endometriosis are common reproductive diseases that feature dysregulated hypothalamic-pituitary-gonadal axis and sex steroids. Exposure to high prenatal androgens (PNA) and low PNA are suggested causal factors for PCOS and endometriosis, respectively. However, individuals who are diagnosed with both diseases contradict this theory. As such, this thesis explores the impact of differential PNA exposure on uterine development.
Histology and immunohistochemistry techniques were used to assess the impact of increased PNA on the timing and extent of endometrial and myometrial differentiation. Newborn, prepubertal, and adult ovariectomised and estrogen-treated (Ovx + E) uteri from a mouse model of PCOS were examined. Additionally, a protocol was designed to investigate the effects of low PNA on myometrial and endometrial development in mice.
There were no statistically significant differences in epithelial height, mesenchyme width and total uterine width between newborn PNA-treated and control mice. Myometrial development, vascular density and cellular proliferation were not significantly affected by increased PNA. In prepubertal mice, endometrial stroma width, myometrial width and total uterine width were not significantly different between treatment groups. Glandular density, vascular density, and cellular proliferation were also not significantly different. However, there was a significant increase in epithelial height of PNA-treated uteri compared to controls. Width measurements of individuals within the same treatment group were also significantly different in newborn and prepubertal mice. No significant differences were observed in adult Ovx + E uteri, although abnormal phenotypes were observed across both treatment groups.
The recommendations for decreasing PNA in mice to examine its influence on uterine development were informed by current literature and lessons learned from the PCOS mouse model. Pregnant dams should be treated with 200mg/kg of antiandrogen flutamide. Basic health parameters of the pups should be assessed, alongside a histological examination of uteri collected at birth, before puberty and in adulthood. As an initial protocol, further experiments are likely required.
Excess prenatal androgen did not significantly affect the timing or extent of differentiation in the myometrium at birth and before puberty. However, the increase in epithelial height of prepubertal, but not newborn, PNA-treated mice suggests a subtle effect of increased PNA on uterine development. These findings indicate a need to further investigate the general mechanisms behind uterine development and the role of PNA in this process.