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.

Photoperiod-dependent modulation of anti-Müllerian hormone in female Siberian hamsters, Phodopus sungorus

“…However, luteinized granulosa cells have not been reported in the ovaries of FORKO mice, and this may reflect differences in the hormonal milieu when compared with SD hamsters. Plasma LH was elevated in FORKO mice relative to wild type and plasma estradiol was undetectable Balla et al (2003). Conversely, serum LH concentration has been reported to be much lower in SD than in LD female hamsters (Dodge & Badura 2002), but E 2 concentration does not appear to be consistently lower in SD when compared with LD hamsters (van den Hurk et al 2002, Scotti et al 2007; but see Moffatt-Blue et al 2006).…”

“…The uterus, a highly estrogen sensitive organ, weighs significantly less in female hamsters raised in SD when compared with LD (Ebling 1994 Scotti et al (2007) found no significant effect of photoperiod on serum E 2 concentration; however, their SD hamsters were adults that had been transferred from LD to SD, whereas van den Hurk et al (2002) transferred hamsters from LD to SD at birth. Because E 2 has been purported to both inhibit (Baarends et al 1995, Balla et al 2003 and stimulate (Ikeda et al 2002) ovarian AMH expression, it will be important to determine whether P450arom is expressed by luteinized granulosa cells and whether hamsters raised in SD in fact have higher serum E 2 concentrations than females reared in LD. Unfortunately, sample volume limitations precluded us from measuring serum E 2 in the present study.…”

“…Baarends et al 1995, noted a decrease in ovarian Amh expression following the administration of human recombinant FSH to rats, and Balla et al (2003) reported an up-regulation of AMH in ovarian granulosa cells in the follitropin receptor knockout (FORKO) mouse. Similar to SD hamsters in which antral follicles are rare (present study) or absent (Place et al 2004, Timonin et al 2006, FORKO mice lack ovarian follicles that develop beyond the preantral stage.…”

“…The similarities and differences in the ovarian phenotype of SD hamsters with that of GDF9 deficient and FORKO mice should help direct future investigations to determine the mechanisms/signals that underlie the luteinization of granulosa cells and the up-regulation of AMH in SD ovaries. Logical starting points will be to examine SD ovary expression of GDF9 as well as GATA4, which mediates the inhibition of AMH via the FSH receptor (Tremblay & Viger 2001, Balla et al 2003.…”

BAX is involved in regulating follicular growth, but is dispensable for follicle atresia in adult mouse ovaries

“…Conversely, activin A is a negative regulator of preantral follicle growth, promoting these follicles to remain dormant and blocking follicle stimulating hormone (FSH)-induced granulosa cell proliferation (Mizunuma et al 1999). FSH is critical for the transition of follicles to the antral stage (Kumar et al 1997, Balla et al 2003, and for the follicle survival beyond the early antral stage (Hirshfield 1986, 1988. On the other hand, FAS/FASL and tumor necrosis factor a (TNFa) promote follicle atresia (Kaipia et al 1996, Hu et al 2001, Morrison & Marcinkiewicz 2002, Sasson et al 2002, Abdo et al 2003.…”