Development of an early biomarker for the ovarian liability of selective estrogen receptor modulators in rats.
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.
Harris
Heather A
HA
Women's Health and Musculoskeletal Biology, Wyeth Research, Collegeville, PA 19426, USA. harrish@wyeth.com
Chennathukuzhi
Vargheese M
VM
Zhang
Xiaochun
X
Mekonnen
Belew
B
Jelinsky
Scott A
SA
Schelling
Scott H
SH
Patel
Vikram S
VS
Huselton
Christine
C
Negahban
Andre
A
Azam
Farooq
F
Winneker
Richard C
RC
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D009281:Naphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D010048:Ovarian Cysts / Q000378:metabolism* / Q000473:pathology; D010053:Ovary / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D020849:Raloxifene Hydrochloride / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013254:Steroid 17-alpha-Hydroxylase / Q000096:biosynthesis*; D015854:Up-Regulation
D015415:Biomarkers; D047628:Estrogen Receptor alpha; C504960:LY2066948; D009281:Naphthalenes; D010880:Piperidines; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; D013254:Steroid 17-alpha-Hydroxylase