The effect of gonadotrophins on follicular development and subsequent oocyte competence

Abstract

The growth and development of the ovarian follicle is a long and complex process. Throughout this process the oocyte maintains close contact with the surrounding somatic cells and through bi-directional communication acquires the developmental programs necessary for fertilisation and embryonic development. During the latter phase of follicular development the signals between oocyte and the somatic cells are dependent on stimulation by the gonadotrophin hormones, FSH and LH. The precise and individual role that FSH and LH play in this tightly co-ordinated process has yet to be determined. Despite this, exogenous administration of gonadotrophin preparations is used extensively in clinical and agricultural settings as a means of obtaining a large number of oocytes for use in ART. However, the basic question as to what affects gonadotrophins have on oocyte development within the follicle prior to ovulation remains to be answered. The main aim of this thesis was to use an animal model, the mouse, to begin to address this question.

In an attempt to distinguish between intra follicular and inter follicular/extra ovarian effects, experiments were performed using both in vitro and in vivo models. The results obtained using the hypogonadal mouse as an in vivo model were limited. However they did show that stimulation by both gonadotrophins might be necessary to induce sufficient ovarian oestrogen production to prime the reproductive tract prior to pregnancy. After optimising the in vitro system, which gave interesting insights into the nutritional aspects of follicular development, the results obtained indicated that elevation of LH during the follicular growth phase affected the ability of the oocyte to complete pre-implantation development.

Manipulation of gonadotrophins resulted in alterations in the production of the sex steroids. Both androgens and oestrogens are potential mediators of gonadotrophin action. Using a different experimental paradigm this was investigated directly by elevating androgens, oestrogens or both steroids in vitro. It was found that the fertilisation rates of the oocytes was adversely affected by elevating oestrogens but positively correlated in the presence of elevated androgens.

Whether oestrogen plays an obligatory role within the ovary is controversial. The finding that two receptors exist for this steroid has complicated the issue. Investigations using the ERKO transgenic mouse and in vitro techniques have gone some way towards clarifying this situation. Lack of the ERa receptor does not impair follicular development or developmental competence of the oocyte. Observations made during these experiments and those using the hypogonadal mouse suggest that oestrogen may facilitate the ovulatory process.

In conclusion the findings presented in this thesis have demonstrated that androgens, independently of oestrogens, are a necessary component of the signalling system in follicular development and subsequent oocyte maturation. Additionally, alterations in the pattern of intra-follicular steroid production either directly, or as a result of manipulating gonadotrophin levels such as occurs during ovulation induction, can influence the viability and developmental potential of the oocyte.