Ovarian anti-Mullerian hormone: what does it do in the normal ovary and why is it so high in polycystic ovary syndrome?

In the womb, boy babies develop part of their reproductive system because of the actions of a hormone called anti-Mullerian hormone (AMH). Interestingly, this hormone has now been shown to play a part in adult women in that it is involved in the working of the ovary. In the ovary each month an egg is grown and released. We have found that only those eggs which have got rid of AMH manage to grow. This is important because we have also found that the levels of this hormone are very high in a common condition which causes infertility. We now need to find out why the levels are high in these women and what exactly AMH does in the ovary. We hope that this will allow us to help these women to have better fertility in the future.

The male fetal sexual differentiative factor anti-Mullerian hormone is a potentially important signalling molecule in the adult ovary. Although much of this information was derived from knock-out mice, AMH is increasingly being heralded as a clinical marker of ?fertility?. Very little is known about its production or action in human ovary. We have discovered that, although AMH is high in human follicles of 2-6 mm, it is absent from follicles progressing beyond selection. Preliminary results indicate that this is because it inhibits FSH-stimulated aromatase, an inhibition which would limit continued folliculogenesis. We now wish to elucidate the mechanism of this inhibition. This work will be carried out in human granulosa cells and we will focus on the function of specific SMADs using siRNAs, dominant negatives and overexpression. We will then determine which aromatase promoter II-associated transcription factors are altered by AMH treatment and gel shift assay. In parallel with this candidate approach we will screen for other differentially expressed genes in granulosa and theca cells from normal ovaries exposed to AMH using microarray.
Our observation that AMH levels in cells from polycystic ovaries are 75 times higher than those from normal has important implications for fertility in these women. Our second aim therefore is to elucidate the molecular basis for the upregulated AMH expression. We will investigate alterations in transcriptional regulation of the gene by investigating promoter activity in granulosa cells from PCO and normal ovaries. In this way we will distinguish between the failure to repress versus the acquisition of promiscuous activation in PCOS. It is also conceivable that the upregulation reflects alterations in AMH protein turnover which we will investigate by measuring the half-life of tagged versions of AMH in the two types of granulosa cells. This will also permit us to understand the normal mechanism of the control of AMH production in the developing follicle.
If AMH is to be used as an important clinical marker then we need to understand its production and actions. Determining how and why AMH levels are tightly controlled in the follicle at the critical time of selection will add fundamental knowledge to this key process. Anovulation is an important consequence of PCOS for many women and yet the cause remains unknown and treatments are far from perfect. As AMH is only made by granulosa cells, elucidating its role in inhibition of follicle progression may make it an ideal target for treatment.