Histologic Changes in Ovary, Uterus, Vagina, and Mammary Gland of Mature Beagle Dogs Treated With the SERM Idoxifene

  • Publication Date :
  • Publication Type : Journal Article
  • Author(s) : Rehm S, Solleveld HA, Portelli ST, Wier PJ
  • Journal Name : Birth Defects Research Part B: Developmental and Reproductive Toxicology

Birth Defects Research Part B: Developmental and Reproductive Toxicology. 2007;80(3):225-232

Background: Idoxifene is a selective estrogen receptor modulator similar to tamoxifen but is no longer in pharmaceutical development due to adverse genitourinary effects in the clinic. Histologic observations of the reproductive system and mammary glands are presented from female dogs treated with idoxifene for up to 12 months.

Methods: Studies were conducted as part of regulatory requirements to support clinical development. Idoxifene was given orally by capsule, once daily, for 1, 6, or 12 months to female Beagle dogs (n = 3 or 4/group) aged 11–14 months (start of dosing) at dosages 0, 0.03, 0.3, 1.5, or 3 mg/kg/day. Evaluations included the following: clinical observations, hematology, hemostasis, chemistry, toxicokinetics, and histology.

Results: Dose- and time-dependent findings were present in dogs given ≥0.03 mg/kg/day and included abnormal vaginal discharge, minor increases of platelet and neutrophil counts, and microscopic observations in the ovary (atrophy and mesothelial [ovarian surface epithelium] hyperplasia), endometrium (edema, inflammation, glandular atrophy, squamous metaplasia, increased collagen), myometrium (edema, increased collagen), vagina (squamous hyperplasia, keratinization), and mammary gland (atrophy).

Conclusion: Dogs given idoxifene exhibited estrogenic effects in ovary, uterus(), and vagina but antiestrogenic effects in endometrial and mammary glands consistent with several observations in clinical trials in post-menopausal women treated with triphenylethylenes.

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