Investigating the regulatory role of Anti-Müllerian Hormone in the growing follicles of a monovulatory species

Elfituri, Abdullatif (2016) Investigating the regulatory role of Anti-Müllerian Hormone in the growing follicles of a monovulatory species. PhD thesis, University of Nottingham.

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Abstract

Evidence from recent research suggests that folliculogenesis is regulated by stage specific locally produced growth factors and hormones including mediators of proliferation, differentiation and angiogenesis. AMH has been identified as one of these potentially important local factors and in polyovulatory species has been implicated in the regulation of the follicles growth, throughout its developmental stages. However in monovulatory species, despite its circulating levels being use as a marker of ovarian reserve and its suggested link to the aetiology of PCOS, little is known about its role and the means of its control in the growing follicle. Using the sheep model, the over-riding objective of this research project was the further elucidation of the roles of AMH during the antral stages of follicular development in monovulatory species. It was hoped the work would also provide valuable insights into the aetiology of PCOS. The study has focussed on four main research goals: characterisation of GC and TCs in terms of AMH and AMHR2 expression; confirmation of the utilisation of a SMAD signal transduction pathway in GC and TCs; an androgen involvement in AMH production; and the elucidation of two putative mechanisms of AMH regulation.

Both AMH and AMHR2 were found to be expressed in ovine GC and TCs, although levels of AMH mRNA in TCs were very low and may not be biologically relevant. The outcomes also confirmed that in both ovine GC and TCs, AMH binds to a receptor complex containing the type 2 AMH receptor and that this mediates transduction of an intra-cellular signal via the SMAD 1/5/8 pathway. This finding in TCs indicates that GCs derived AMH may act in a paracrine way on TCs, disputing the long held belief of AMH only functioning in an autocrine manner.

The effect of androgens on AMH production in FSH-stimulated GCs was previously not clarified but in this present study a significant increase in steroidogenesis in the presence of a non-aromatisable androgen now suggests that androgens may have a direct role in the regulation of AMH production, and thus at least in part, be involved in the modulation of folliculogenesis.

The final aspect of this project was to study novel inter-ovarian interactions. This focussed on the hypothesis that VEGF, a potent ovarian angiogenic factor, and SOX8, a member of the SOX family of transcription factors, could be involved in AMH regulation in GCs. Results indicate that the two VEGF variants associated with growing follicles (VEGF120 and VEGF164) may have direct roles in AMH regulation. While on the other hand, SOX8 may have a role in regulating folliculogenesis and altering oestradiol production, however, it was not shown that this effect was mediated via AMH regulation.

In conclusion this present study, not only supports earlier work showing TCs responsiveness to AMH, but for the first time in a monovulatory species, provides compelling evidence that AMH signal transduction in TCs is via receptor complexes containing AMHR2. Collectively these studies indicate a probable regulatory loop between GC produced AMH and TC produced androgens. From these outcomes it seems likely that the AMH regulatory loop may involve fine-tuning by external stimuli. A further novel finding has been that the VEGF variants particularly associated with growing follicles, and the transcription factor SOX8 appear to have some involvement in a complex system of AMH regulation. These findings should help in the design of future studies to elucidate how perturbations in this complex configuration may be involved in the aetiology of common forms of anovulatory infertility.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Marsters, P.
Campbell, B.
Keywords: Folliculogenesis, Hormones, Follicular development, Ovarian follicle
Subjects: Q Science > QL Zoology
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID: 33570
Depositing User: Elfituri, Abdullatif
Date Deposited: 19 Jul 2016 06:40
Last Modified: 15 Sep 2016 13:45
URI: http://eprints.nottingham.ac.uk/id/eprint/33570

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