Abstract
This thesis comprises a series of published works arising out of research on the
regulation of ovarian function undertaken by myself since receiving the degree of
Ph.D. from the University of Wales in 1975. Eighty-three publications are submitted,
reporting work that falls into three interrelated categories, as summarised below.
Basic Experimental Studies Publications 1-35 deal mainly with the use of
cultured rat and marmoset monkey granulosa cells to study endocrine and paracrine
mechanisms underlying gonadotrophin action on the ovaries. Primary cell cultures
were used to define the roles of FSH and LH in controlling granulosa cell function and
to assess the intrafollicular functions of sex steroids and putative nonsteroidal
regulatory factors, such as inhibin. A particular contribution was the demonstration
that androgens produced by thecal cells exert specific (receptor-mediated) modulation
of granulosa cell differentiation - notably expression of aromatase, the enzyme
uniquely responsible for oestrogen synthesis. Synthesis of inhibin and expression of
messenger RNA species encoding inhibin and activin subunits in granulosa cells were
also shown to be under gonadotrophs control and modulated by sex steroids, leading
to the suggestion that the androgen/oestrogen and inhibin/activin axes of the ovarian
paracrine system are functionally interlinked.
Basic Clinical Studies Publications 36-56 are concerned with in vitro
research on 'normal' ovarian tissues obtained from women undergoing elective
surgical procedures. Techniques and experience acquired from experimental work on
animal ovarian tissues were used to study the regulation of steroid hormone synthesis
in human follicular and luteal cells. This work demonstrated that granulosa cells are
primary cellular sites of oestradiol biosynthesis in the human ovary. It also confirmed
the potential that theca-derived androgens have to modulate FSH-induced granulosa
cell function, including aromatase activity and inhibin production. Conversely,
androgen production by thecal cells was shown to be promoted by inhibin. Based on
these findings it is postulated that an intrafollicular positive feedback loop exists
mediated by theca-derived androgen and granulosa-derived inhibin, which may
underpin preovulatory follicular 'selection' and oestrogen synthesis in the human
menstrual cycle.
Applied Clinical Studies Papers 57-83 deal with the practical relevance of
ovarian endocrinology to the treatment of human infertility. Protocols for stimulating
ovarian function in infertile women were evaluated, with monitoring based on serial
measurements of ovarian steroids in blood and urine. Oocytes collected from such
women were used for in-vitro fertilisation (IVF) and embryo transfer. Oocytes,
granulosa cells and follicular fluids aspirated from IVF patients were studied to obtain
information on steroid dynamics and other metabolic changes in ovarian follicles in
relation to IVF outcome. Results highlighted the potential that endogenously produced
steroids and exogenously administered steroid analogues have to interfere with human
fertilisation, embryonic development and implantation. Alternative strategies are
proposed for the induction of single or multiple ovulation (superovulation) in infertile
women, based on the selective use of 'pure' FSH and LH to manipulate the ovarian
paracrine system.
