Abstract
Premature ovarian insufficiency (POI) occurs in 1% of reproductive-age women. The ovarian manifestation ranges from the presence of a variable population of follicles (follicular) to the absence of follicles (afollicular), and in the majority of cases the cause is unknown. A transgenic mouse model of follicular POI, the Double Mutant (DM), arises from oocyte-specific deletion of Mgat1 and C1galt1 required for the generation of O- and N-glycans. DM females are subfertile at 6 weeks, infertile by 9 weeks and exhibit POI by 12 weeks of age. In this study we investigate the cause of the reduced fertility at 6 weeks and infertility at 9 weeks of DM females. Ovary sections were used to analyse follicle and corpora lutea (CL) numbers, apoptosis, and levels of laminin and 3β-hydroxysteroid dehydrogenase using immunohistochemistry. After POI, DM females unexpectedly remained sexually receptive. At both 6 and 9 weeks, DM ovaries contained more primary follicles, however, at 9 weeks DM follicles were proportionally healthier, revealed by TUNEL analysis compared with Controls. In 9 week DM ovaries (collected post-mating), secondary follicles had theca and basal lamina structure abnormalities, whilst preovulatory follicles failed to ovulate resulting in the presence of numerous luteinised unruptured follicles, indicative of ovulation failure. Finally, DM ovaries contained more regressing CL with decreased luteal cell apoptosis indicative of a defect in CL regression. Identifying these follicular modifications have provided insight into the aetiology of a model of POI and highlight targets to investigate with the hope of developing new fertility treatments.
Highlights
Follicle development starts with the activation and development of quiescent primordial follicles that develop through primary, secondary, preantral and antral follicle stages before they ovulate a fertilisable oocyte, many follicles undergo atresia and die (Greenwald 1972, Hirshfield 1991)
Since Double Mutant (DM) females have a normal ovulation rate but decreased fertility at 6 weeks of age, which declines dramatically by 9 weeks of age, and are infertile by 3 months of age (Williams et al 2007, Williams & Stanley 2011, Grasa et al 2012), we investigated the aetiology of Premature ovarian insufficiency (POI)
DM females did not have any litters after the first litter at 9 weeks of age they remained sexually receptive as all DM females mated frequently throughout the study period; the period between the plugs could be divided into three separate groups (Fig. 1C)
Summary
Follicle development starts with the activation and development of quiescent primordial follicles that develop through primary, secondary, preantral and antral follicle stages before they ovulate a fertilisable oocyte, many follicles undergo atresia and die (Greenwald 1972, Hirshfield 1991). At the primary follicle stage, the oocyte and its supporting cuboidal granulosa cells (GCs) are encapsulated by a basal lamina (BL) composed of extracellular matrix (ECM). At the secondary follicle stage, theca cells are recruited from the surrounding stromal tissue (Young & McNeilly 2010) and the GCs proliferate, resulting in the formation of a preantral follicle. This preantral follicle develops an antrum to become an antral follicle, which develops further to become a large preovulatory follicle from which the mature oocyte will ovulate. Complex interactions between the oocyte, the granulosa and theca cells orchestrate follicle development with oocytespecific proteins and glycoproteins playing an active role
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