Letrozole increases ovarian growth and CYP17A1 gene expression

Capsule:
Letrozole increases ovarian size and androgen production and upregulates Cyp17a1 messenger RNA expression in the rat ovary.

Authors:
Israel Ortega, M.D., Anna Sokalska, M.D. Ph.D., Jesus A. Villanueva Ph.D., Amanda B. Cress, B.S., Donna H. Wong, Ph.D., Elisabet Stener-Victorin, Ph.D., Scott D. Stanley, Ph.D., Antoni J. Duleba, M.D.

Volume 99, Issue 3, Pages 889-896, 1 March 2013

Abstract:

Objective:
To evaluate the effects of letrozole on ovarian size and steroidogenesis in vivo, as well on proliferation and steroidogenesis of theca-interstitial cells alone and in co-culture with granulosa cells using an in vitro model.

Design:
In vivo and in vitro studies.

Setting:
Research laboratory.

Animal(s):
Immature Sprague-Dawley female rats.

Intervention(s):
In vivo effects of letrozole were studied in intact rats receiving either letrozole (90-day-continuous-release sc pellets, 400 μg/day) or placebo pellets (control group). In in vitro experiments, theca cells were cultured alone or in co-culture with granulosa cells in the absence or presence of letrozole.

Main Outcome Measure(s):
DNA synthesis was determined by thymidine incorporation assay; steroidogenesis by mass spectrometry; steroidogenic enzyme mRNA expression by PCR.

Result(s):
In vivo, letrozole induced an increase in ovarian size compared to the control group and also induced a profound increase of androgen, LH levels and Cyp17a1 mRNA expression. Conversely, a decrease in Star, Cyp11a1 and Hsd3b1 transcripts was observed in letrozoleexposed rats. In vitro, letrozole did not alter either theca cell proliferation or Cyp17a1 mRNA expression. Similarly, letrozole did not affect Cyp17a1 transcripts in granulosa-theca co-cultures.

Conclusion(s):
These findings suggest that letrozole exerts potent, but indirect, effect on growth of rat ovary and dramatically increases androgen levels and Cyp17a1 mRNA expression, the key enzyme regulating androgen biosynthesis pathway. The present findings reveal novel mechanisms of action of letrozole in the rat ovary.

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