Biological basis of follicle growth

Ovarian stimulation therapy is notoriously difficult to manage, partly because of the individual variability in response to exogenous hormones and hormone antagonists. The varied underlying pathophysiological conditions necessitating ovulation induction therapy were in great part causative of the different responses between patients. However, in-vitro fertilization therapy has provided a wider experience, particularly with ovarian stimulation in endocrinologically normal women. From these data, there is much inherent variability of response to exogenous gonadotrophins evident, even in these 'normal patients'. Furthermore, individual response types tend toward a consistent pattern from cycle to cycle, suggesting a constancy of physiological status, as opposed to a stoichastic response. In this study, we are seeking ways of reducing individual variability of responses to gonadotrophin therapy based on understanding the physiological origin. Our first objective is to identify the source of individual variability in the hypothalamic--pituitary ovarian axis. We developed a new experimental primate model, the reversible 'medical hypophysectomy', achieved by administration of a gonadotrophin-releasing hormone (GnRH) antagonist to negate endogenous gonadotrophin secretion. The second objective is to assess the validity of our model for medical hypophysectomy. Effective doses and regimens of the GnRH antagonist applications are determined. The third objective is to study the differential actions of follicle-stimulating hormone (FSH) treatment alone versus combined FSH/luteinizing hormone (LH) therapy on the ovary. In summary, it is concluded: (i) individual variation in ovarian response to gonadotrophin therapy in monkeys is, in large part, supra-ovarian in origin, although failure to respond to gonadotrophins was not negated by GnRH antagonist treatment. Furthermore, a milieu approaching 'medical hypophysectomy' using a potent GnRH antagonist deserves consideration as a clinically applicable strategy to reduce variability among responders, thereby improving patient management. (ii) In our monkey model, the GnRH antagonist promptly produced a relatively hypogonadotrophic state that was reversible. These findings have implications for both fertility and anti-fertility research. (iii) The two-cell theory requiring co-ordinate action of both FSH and LH to achieve ovarian steroidogenesis culminating in a dynamic oestrogen production, may be re-examined. Indeed, the importance credited to the ratios of these gonadotrophins is surely open to question.