SAT389 Reproductive And Metabolic Characterization of Mice Overexpressing CYP17 in Ovarian Theca Cells

Abstract

Abstract Disclosure: S. Joseph: None. V. Ubba: None. M. K DSilva: None. S. Wu: None. Androgens, in physiological levels are important to normal ovarian function. However, excess androgens are detrimental to ovarian function, and is seen in PCOS, Congenital Adrenal Hyperplasia and Transgender Males undergoing testosterone therapy. Current models of androgen excess in females, mostly involve external administration of the causative agent. Hence, we developed an endogenous model of excess testosterone in female mice. To achieve this, a Triple mutant (TM) mouse was developed using the doxycycline inducible tet- on system, which involved RTTA, Cyp17 Cre and teto operator specifically inserted into CYP17 gene (purpose- double secure CYP17 specifically expressed in theca cells). These mice were fed with Doxycycline 625 mg/kg at 2 months of age. The TM mice showed significantly increased testosterone levels and Cyp17 protein expression in the ovaries. Estradiol, progesterone was unchanged. Reproductive characterization of the mice showed impaired estrous cyclicity and reduced fertility (number of pups and litters). Ovarian histology showed increased number of atretic follicles, with no changes in the number of developmental follicles and corpus leuteum. In the pituitary, mRNA expression of LHβ was significantly decreased, while GnRHR and FSHβ was unchanged. GnRH stimulation showed a decrease in LH levels in the TM mice. Immunoblotting showed increased expression of Androgen Receptor (Ar). Although increased androgens in females is associated with metabolic dysfunction, we did not observe any changes in Glucose, pyruvate and insulin tolerance in TM mice. Comprehensive Laboratory Animal Monitoring System (CLAMS) did not show any changes in the Respiratory Exchange Ratio, heat production and ambulatory movement. These studies show a unique strategy to develop an endogenous excess testosterone producing transgenic mice with decreased fertility. Presentation Date: Saturday, June 17, 2023