Reduced recruitment and survival of primordial and growing follicles in GH receptor-deficient mice

Abstract

GH influences female fertility. The goal of the present study was to obtain more insight into the effect of loss of GH signalling, as observed in humans suffering from Laron syndrome, on ovarian function. Therefore, serial paraffin sections of ovaries of untreated and IGF-I-treated female GH receptor knock-out (GHR/GHBP-KO) mice were examined to determine the follicular reserve and the percentage of follicular atresia in each ovary. Our observations demonstrate that the amount of primordial follicles was significantly elevated in GHR/GHBP-KO mice, while the numbers of primary, preantral and antral follicles were lower compared with wild-type values. The reduced number of healthy growing follicles in GHR/GHBP-KO mice was accompanied by a significant increase in the percentage of atretic follicles. IGF-I treatment of GHR/GHBP-KO mice for 14 days resulted in a reduced number of primordial follicles, an increased number of healthy antral follicles, and a decreased percentage of atretic follicles. The results of the present study suggest that GH may play a role, either directly or indirectly, via for instance IGF-I, in the recruitment of primordial follicles into the growing pool. Furthermore, GH seems to protect antral follicles, directly or indirectly from undergoing atresia. Reproduction (2006) 131 525-532

Effect of growth hormone receptor gene disruption and PMA treatment on the expression of genes involved in primordial follicle activation in mice ovaries

“…Therefore, the higher expression of Foxo3a indicates that follicles could be trapped in the primordial stage. This hypothesis agrees with histological observations in long-living GH-resistant GHRKO mice, where a higher number of follicles in the primordial stage are observed concomitantly with fewer follicles in the primary, secondary, and tertiary stages (Slot et al 2006). A recent study has demonstrated that oocyte expression of a constitutively active form of Foxo3 in a transgenic mouse model is associated with the preservation of the ovarian reserve (Pelosi et al 2013) and, therefore, can be related to an ovarian phenotype characteristic of younger mice as observed in GHRKO mice in the current and previous studies (Sluczanowska- Fig.…”

“…This evidence suggests that GH is important for maximal reproductive efficiency; however, systemic IGF-I is essential for N follicle development, and females are not able to reproduce in its absence. Additionally, GHRKO females have an increased number of primordial follicles and a reduced number of healthy antral follicles Slot et al 2006), which can explain the reduced ovulation rate. However, treating GHRKO females with IGF-I decreases the number of primordial follicles and increases the number of healthy antral follicles (Slot et al 2006), suggesting that IGF-I-induced signaling promotes primordial follicle activation and antral follicle survival.…”

“…Additionally, GHRKO females have an increased number of primordial follicles and a reduced number of healthy antral follicles Slot et al 2006), which can explain the reduced ovulation rate. However, treating GHRKO females with IGF-I decreases the number of primordial follicles and increases the number of healthy antral follicles (Slot et al 2006), suggesting that IGF-I-induced signaling promotes primordial follicle activation and antral follicle survival. In addition, previous evidence indicates that GHRKO female mice have a prolonged reproductive lifespan, as indicated by the presence of ovarian activity at a later age (older than 20 months) when N mice have already depleted the ovarian follicular reserves (Sluczanowska-Glabowska et al 2012).…”

The hormonal action of IGF1 in postnatal mouse growth

“…Nevertheless, our data show that endocrine IGF1 is capable of supporting reproductive performance all by itself. Aside of mechanistic relationships, which will undoubtedly turn out to be very complex, our results in regard to female LIP reproduction are consistent with observations on female Ghr null mice (30). Although fertile, these mutants exhibit delayed sexual maturation and produce small-size litters, presumably because of reduced ovulation rates.…”

“…Their ovaries contain increased numbers of primordial and atretic follicles, while the numbers of healthy growing antral follicles is reduced. This defect was rescued, and the respective numbers of follicles were reversed, following IGF1 administration for two weeks (30).…”