The effects of atamestane and toremifene alone and in combination compared with letrozole on bone, serum lipids and the uterus in an ovariectomized rat model

• Published in: Breast cancer research and treatment 2007-07, Vol.103 (3), p.293-302
• Main Authors: GOSS, Paul E, SHANGLE QI, HAIQING HU, CHEUNG, Angela M
• Format: Article
• Language: English
• Subjects: Androstenedione - administration & dosage; Androstenedione - analogs & derivatives; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Biological and medical sciences; Breast cancer; Cancer research; Cancer therapies; Chemotherapy; Disease Models, Animal; Female; Gynecology. Andrology. Obstetrics; Humans; Lipids; Lipids - chemistry; Mammary gland diseases; Medical sciences; Models, Chemical; Nitriles - administration & dosage; Organ Size; Ovariectomy; Rats; Rats, Sprague-Dawley; Rodents; Steroids; Toremifene - administration & dosage; Triazoles - administration & dosage; Tumors; Uterus - drug effects; Uterus - pathology
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-006-9381-y

We compared the effects of atamestane (ATA) and toremifene (TOR) alone and in combination, with letrozole (LET) on bone, serum lipids and the uterus in ovariectomized (OVX) rats after 16 weeks of treatment. Compared to OVX controls lumbar vertebral and femoral BMD as well as mechanical strength and trabecular bone volume were significantly greater in animals given ATA, TOR or ATA + TOR. The effects of ATA were not reversed by the androgen receptor blocker, flutamide (FLT). Serum cholesterol, low-density lipoprotein cholesterol and triglycerides were reduced by TOR and ATA + TOR whereas they remained unchanged in animals receiving ATA, ATA + FLT, and LET. The uterine epithelium in OVX animals was equally stimulated by TOR and ATA + TOR and unaffected by ATA or LET. Intact animals had significant atrophy of the uterine epithelium when receiving ATA. In summary, TOR alone or in combination with ATA had a predictable stimulatory effect on bone and the uterine epithelium while reducing key parameters of lipid metabolism. In contrast, ATA but not LET had an unexpected stimulatory effect on the OVX rat's bone and this was not reversed by the anti-androgen FLT leaving this finding unexplained for now. ATA is distinct from LET on end-organ function and this favorable profile makes clinical testing of this steroidal aromatase inhibitor of interest in the clinical setting.