Effect of CGS 20267 on ovarian aromatase and gonadotropin levels in the rat
Abstract
Aromatase catalyzes the rate limiting step that converts androgens to estrogens. Postmenopausal women with hormone dependent breast cancer respond to first generation aromatase inhibitors such as aminoglutethimide with a marked suppression of circulating estradiol levels. In contrast, premenopausal women appear to be resistant to first generation aromatase inhibitors. The inability to block ovarian aromatase results from the low affinity of first generation inhibitors for the active site of the enzyme. Under these circumstances, the high substrate levels in the premenopausal ovary compete effectively with these inhibitors and do not allow binding of inhibitor to the active site of the enzyme. Second and third generation aromatase inhibitors with higher affinity for aromatase have now been developed and potentially could block ovarian aromatase. To test this possibility, we administered CGS 20267 (letrozole), a highly potent aromatase inhibitor, to cycling female rats. A dose dependent inhibition of uterine weight occurred with maximum effects produced by the 5 mg/kg/day dosage. During a period of 4 weeks, uterine weight was reduced to levels induced by ovariectomy. Ovarian tissue estradiol levels were inhibited by approximately 80%. As a reflection of inhibition of ovarian aromatase activity, the levels of androstenedione in the ovary increased by an order of magnitude. Both LH and FSH plasma levels increased but not to those observed after ovariectomy. The rise in gonadotropin levels induced a statistically significant but relatively small increase in ovarian weights. These results demonstrate the ability to persistently block ovarian aromatase activity in cycling rats with a potent aromatase inhibitor. This study provides a rationale for clinical trials of potent aromatase inhibitors in pre-menopausal women with breast cancer.
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In normally cycling female rats, letrozole resulted in greater than 80% suppression of ovarian E2 levels and caused a marked increase in LH and FSH, with a 35% increase in ovarian weights within 1 week of treatment.
“When administered to normally cycling female rats, letrozole resulted in greater than 80% suppression of ovarian E 2 levels and caused a marked increase in LH and FSH, with a 35% increase in ovarian weights within 1 week of treatment (19).”
From A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women (2002) · cites this paper as [19]
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- Authors
- Sinha, S., Kaseta, J., Santner, S. J., Demers, L. M., Bremmer, W. J., & Santen, R. J.
- Affiliations
- Pennsylvania State University (US)
- ORCID
- Santen, R.J.
- Venue
- Breast Cancer Research and Treatment
- Published
- 1998-03
- Volume
- 48
- Issue
- 1
- Pages
- 45-51
- ISSN
- 0167-6806 (ISSN-L)
- 1573-7217
- OpenAlex
- W1977481280
- Cited by
- 48
- References
- 17
- Citations by year
- 2026: 1 · 2025: 1 · 2021: 1 · 2020: 2 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 2 · 2013: 3
- FWCI
- 0.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Breast Cancer Research and Treatment (publishedVersion)
- PubMed (publishedVersion)
- ResearchWorks at the University of Washington (University of Washington) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Keywords
- letrozole, aromatase inhibitors, ovarian aromatase, estradiol, gonadotropins, luteinizing hormone, follicle-stimulating hormone, uterine weight, androstenedione, premenopausal breast cancer, ovariectomy
- MeSH terms
- Letrozole, Animals, Antineoplastic Agents, Enzyme Inhibitors, Female, Gonadotropins, Pituitary, Nitriles, Organ Size, Ovary, Triazoles, Rats, Sprague-Dawley, Aromatase Inhibitors, Rats
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