Dynamics of ovarian development in the FORKO immature mouse: structural and functional implications for ovarian reserve

Abstract

Adult Follitropin Receptor Knockout (FORKO) female mice are infertile and estrogen deficient. In order to understand the peri/postnatal developmental changes, we have now characterized the structural and molecular aberrations by comparing several markers of follicular development in 2-, 10-, and 24-day-old wild-type and FORKO females. By Day 24, FORKO mice have 40%-50% smaller uteri and vaginas. Estradiol is undetectable but testosterone and LH levels are already elevated at this age. FORKO ovaries are 45% smaller, indicating a postnatal or perinatal deficit consequent to FSH receptor ablation. This is attributable to decreased numbers of growing follicles and reduced diameter. Developmental markers, such as Müllerian inhibiting substance, GATA-4, estrogen receptor beta, and androgen receptor, were differentially expressed in granulosa cells. In the 2-day-old mutant neonates, a faster recruitment process was noted that later slowed down, impeding development of follicles. This is noteworthy in light of the controversy regarding the direct role of FSH/receptor system as a determinant of small and preantral follicle development in rodents. As the pool of nongrowing primordial follicles specifies the duration of female fertility and timing of reproductive senescence, we believe that the postnatal FORKO female mouse could help in exploring the signals that impact on early folliculogenesis. In addition, our data suggest that the FSH/receptor system is a major contributor to the formation and recruitment of the nongrowing pool of follicles as early as Postnatal Day 2 in the mouse.