Selective estrogen receptor modulators (SERMs) have the potential to treat 
estrogen sensitive diseases such as uterine leiomyoma and endometriosis, which 
are prevalent in reproductive age women. However, SERMs also increase the risk 
of developing ovarian cysts in this population, a phenomenon that is not seen in 
postmenopausal women. It is believed that current SERMs partially block 
estradiol's ability to downregulate gonadotropin-releasing hormone (GnRH) 
secretion from the hypothalamus thereby interfering with estradiol's negative 
feedback, leading to increased ovarian stimulation by gonadotropins, and cyst 
formation. It has been postulated that a SERM with poor brain exposure would 
have less negative effect on the HPO axis, therefore reducing the risk of 
developing ovarian cysts. In order to test this hypothesis, we identified an 
early marker of SERM-dependent ovarian effects: upregulation of Cyp17a1 mRNA. 
SERMs known to cause ovarian cysts upregulate Cyp17a1 after only 4 days of 
dosing and suppression of the HPO axis prevented this regulation, indicating 
that ovarian expression of Cyp17a1 was secondary to SERM's effect on the brain. 
We then characterized three SERMs with similar binding affinity and antagonist 
effects on the uterus for their relative brain/plasma exposure and ovarian 
effects. We found that the degree of brain exposure correlated very well with 
Cyp17a1 expression.