Histologic changes in ovary, uterus, vagina, and mammary gland of mature beagle dogs treated with the SERM idoxifene.
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 > or = 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).


CONCLUSIONS
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.
Rehm
Sabine
S
GlaxoSmithKline, King of Prussia, Pennsylvania 19406-0939, USA. Sabine.Rehm@gsk.com
Solleveld
Henk A
HA
Portelli
Samm T
ST
Wier
Patrick J
PJ
D000818:Animals; D004285:Dogs; D004717:Endometrium / Q000166:cytology / Q000187:drug effects; D004965:Estrogen Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000187:drug effects* / Q000473:pathology; D010053:Ovary / Q000187:drug effects* / Q000473:pathology; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D014599:Uterus / Q000187:drug effects* / Q000473:pathology; D014621:Vagina / Q000187:drug effects* / Q000473:pathology
D004965:Estrogen Antagonists; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; C071362:idoxifene