Histologic and Cytologic Detection of Endocrine and Reproductive Tract Effects of Exemestane in Female Rats Treated for up to Twenty-eight Days

Abstract

The objective of this study was to determine the shortest period of time necessary to detect histologic evidence of estrous cycle disruption in Sprague-Dawley rats treated for up to 28 days with the aromatase inhibitor exemestane at 1,000 mg/kg. Rats were evaluated on day 5, 8, 15, or 29. Vaginal mucification, uterine and cervical epithelial atrophy, uterine luminal epithelial vacuolation, decreased uterine granulocytes, and hypertrophy/hyperplasia of mammary ducts and alveoli were noted by day 5 and persisted throughout the study. From day 8 to day 29, absence of recent basophilic corpora lutea, increased atresia of antral follicles, interstitial cell hyperplasia, and increased luteinized follicles were present in the ovaries of treated rats. Vaginal smears detected persistent diestrus, confirming estrous cycle disruption between days 5 and 8. Ovary and uterine weights were largely unaffected. Serum hormone levels were not useful due to the study design employed. Other effects of exemestane included decreased adrenal weights and decreased cell size in both the adrenal zona fasciculata and the pituitary pars distalis. While early histologic changes were evident on day 5, only after 8 days of treatment were findings considered sufficient to clearly identify exemestane-induced estrous cycle disruption using microscopy alone.

Pituitary Aromatase P450 May Be Involved in Maintenance of the Population of Luteinizing Hormone-Positive Pituitary Cells in Mice

“…397 inhibitory feedback on pituitary gonadotroph cells. Although, inhibition of aromatase activity in females shows follicle ovarian dysfunction and atrophy [Liew et al, 2010;Mirsky et al, 2011], the effects of low levels of prolactin on the ovary may well be considered irrelevant.…”

Nonproliferative and Proliferative Lesions of the Rat and Mouse Female Reproductive System

“…31 Davis et al (1999), 53 Gaytan et al (2006), 66 Greaves (2012), 125 Mattheij and Swarts (1995), 129 Mirsky et al (2011), 172 Sato et al (2009b), 194 Tsubota et al (2009)…”

Impaired reproduction in adult male, but not female, rats following juvenile treatment with the aromatase inhibitor, exemestane

“…Exemestane‐treated female rats (100 mg/kg/week slow release formulation from PND 26 to 47) showed decreased ovarian weight and an increased incidence of ovarian cysts (van Gool et al, 2010b). The presence of ovarian cysts in adult females rats treated with exemestane has been noted to occur following as little as 8 days of treatment (Mirsky et al, 2011); therefore, the occurrence of ovarian cysts in female rats treated from PND 26 to 47 aligns with the adult female findigns and is not suggestive of a special sensitivity for peripubertal females.…”