Role of Mevalonate Pathway on Ovarian Function

Principal Investigator: Professor Antoni Duleba, M.D.

Funding for the project: National Institute of Health, R01

Appropriate ovarian development and function require mechanisms regulating growth and steroidogenesis of theca-interstitial cells. Under pathological conditions such as polycystic ovary syndrome (PCOS), theca-interstitial compartment is hyperplastic and produces excessive amounts of androgens. We postulate that mevalonate pathway affects theca-interstitial cells by: (i) altering isoprenylation of small GTPases such as Ras and Rho affecting thus signal transduction pathways regulating growth, (ii) modulating the availability of substrates for steroidogenesis, and (iii) altering the level of oxidative stress, which, in turn, affects growth and steroidogenesis. Ultimately, we propose that, inhibtion of the mevalonate pathway by agents such as statins may correct major features of PCOS including excessive growth of theca-interstitial cells, excessive androgen production and oxidative stress. Our preliminary studies have shown that moderate oxidative stress increases and statins inhibit proliferation and steroidogenesis of theca-interstitial cells while blocking ERK1/2 phosphorylation. We have also completed a first clinical trial and we found that simvastatin decreases testosterone and luteinizing hormone in women with PCOS.

The specific aims of this project are to study in depth the role of the mevalonate pathway in theca-interstitial cells on: (i) growth, (ii) steroidogenesis and (iii) oxidative stress. In long term, this project may shed new light on the pathophysiology of PCOS and provide an impetus towards the development of new therapeutic approaches, such as clinical use of statins.