Doxycycline Mediated MMP Inhibition Blocks LH-induced Steroidogenesis and Promotes Cycling in a Mouse Model for Polycystic Ovary Syndrome

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 548-560-Hyperandrogenic Disorders
Basic/Clinical
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-556
Allison Light*1 and Stephen R Hammes2
1University of Rochester, NY, 2University of Rochester, Rochester, NY
Doxycycline Mediated MMP Inhibition Blocks LH-induced Steroidogenesis and Promotes Cycling in a Mouse Model for Polycystic Ovary Syndrome

Allison Light and Stephen R. Hammes

G Protein-Coupled Receptor/Epidermal Growth Factor Receptor crosstalk is a key event in the gonads (i.e., ovaries and testes) and adrenals for the production of steroid in response to LH or ACTH, respectively. Notably, the ovary uniquely employs an extracellular mechanism of crosstalk that is dependent on matrix metalloproteinases (MMP’s). In brief, we and others have demonstrated that LH triggered activation of its GPCR on theca and mural granulosa cells signals MMPs to cleave and release membrane bound EGFR ligands.  These ligands in turn stimulate cumulus granulosa cells, and possibly mural granulosa cells and theca cells, to promote steroidogenesis.  Using freshly isolated mouse ovarian follicles, we found that doxycycline, a common antibiotic and also a known MMP inhibitor, significantly reduced LH-induced progesterone and androgen production.  Administration of doxycycline to female mice similarly reduced LH-triggered steroidogenesis by approximately 50% in-vivo.  Given these observations, we proposed that doxycycline might offer a means of normalizing steroid levels in Polycystic Ovary Syndrome (PCOS), a disorder of ovarian androgen excess, consequently improving ovulation and fertility.  Interestingly, in a pilot study using a mouse model of PCOS, a two-week treatment with oral doxycycline improved cycling, and this improvement continued for several weeks after stopping the drug.  Since treatment options for women with PCOS are limited and do not always address the spectrum of associated symptoms, further characterization of the MMPs involved in LH-induced steroidogenesis, as well as additional studies assessing the effects of their inhibition in a PCOS mouse model, could lead to novel treatments.

Nothing to Disclose: AL, SRH

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm