Dataset Information

Skeletal and Uterotrophic Effects of Endoxifen in Female Rats.

ABSTRACT: Endoxifen, the primary active metabolite of tamoxifen, is currently being investigated as a novel endocrine therapy for the treatment of breast cancer. Tamoxifen is a selective estrogen receptor modulator that elicits potent anti-breast cancer effects. However, long-term use of tamoxifen also induces bone loss in premenopausal women and is associated with an increased risk of endometrial cancer in postmenopausal women. For these reasons, we have used a rat model system to comprehensively characterize the impact of endoxifen on the skeleton and uterus. Our results demonstrate that endoxifen elicits beneficial effects on bone in ovary-intact rats and protects against bone loss following ovariectomy. Endoxifen is also shown to reduce bone turnover in both ovary-intact and ovariectomized rats at the cellular and biochemical levels. With regard to the uterus, endoxifen decreased uterine weight but maintained luminal epithelial cell height in ovariectomized animals. Within luminal epithelial cells, endoxifen resulted in differential effects on the expression levels of estrogen receptors ? and ? as well as multiple other genes previously implicated in regulating epithelial cell proliferation and hypertrophy. These studies analyze the impact of extended endoxifen exposure on both bone and uterus using a Food and Drug Administration-recommended animal model. Although endoxifen is a more potent breast cancer agent than tamoxifen, the results of the present study demonstrate that endoxifen does not induce bone loss in ovary-intact rats and that it elicits partial agonistic effects on the uterus and skeleton in ovariectomized animals.

SUBMITTER: Gingery A

PROVIDER: S-EPMC5659691 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Skeletal and Uterotrophic Effects of Endoxifen in Female Rats.

Gingery Anne A Iwaniec Urszula T UT Subramaniam Malayannan M Turner Russell T RT Pitel Kevin S KS McGovern Renee M RM Reid Joel M JM Marler Ronald J RJ Ingle James N JN Goetz Matthew P MP Hawse John R JR

Endocrinology 20171001 10

Endoxifen, the primary active metabolite of tamoxifen, is currently being investigated as a novel endocrine therapy for the treatment of breast cancer. Tamoxifen is a selective estrogen receptor modulator that elicits potent anti-breast cancer effects. However, long-term use of tamoxifen also induces bone loss in premenopausal women and is associated with an increased risk of endometrial cancer in postmenopausal women. For these reasons, we have used a rat model system to comprehensively charact ...[more]

PMID: 28977607

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Project description:BackgroundMaternal obesity (MO) impairs maternal and offspring health. Mechanisms and interventions to prevent adverse maternal and offspring outcomes need to be determined. Human studies are confounded by socio-economic status providing the rationale for controlled animal data on effects of maternal exercise (MEx) intervention on maternal (F0) and offspring (F1) outcomes in MO.HypothesisMO produces metabolic and endocrine dysfunction, increases maternal and offspring glucocorticoid exposure, oxidative stress and adverse offspring outcomes by postnatal day (PND) 36. MEx in part prevents these outcomes.MethodsF0 female rats ate either control or obesogenic diet from weaning through lactation. Half of each group wheel ran (from day 90 of life through pregnancy beginning day 120) providing four groups (n=8/group)--(i) controls, (ii) obese, (iii) exercised controls and (iv) exercised obese. After weaning, PND 21, F1 offspring ate a control diet. Metabolic parameters of F0 prepregnancy and end of lactation and F1 offspring at PND 36 were analyzed.ResultsExercise did not change maternal weight. Before breeding, MO elevated F0 glucose, insulin, triglycerides, cholesterol, leptin, fat and oxidative stress. Exercise completely prevented the triglyceride rise and partially increases glucose, insulin, cholesterol and oxidative stress. MO decreased fertility, recovered by exercise. At the end of lactation, exercise returned all metabolic variables except leptin to control levels. Exercise partially prevented MO elevated corticosterone. F1 offspring weights were similar at birth. At PND 36, MO increased F1 male but not female offspring leptin, triglycerides and fat mass. In controls, exercise reduced male and female offspring glucose, prevented the offspring leptin increase and partially the triglyceride rise.ConclusionsMEx before and during pregnancy has beneficial effects on the maternal and offspring metabolism and endocrine function occurring with no weight change in mothers and offspring indicating the importance of body composition rather than weight in evaluations of metabolic status.

Project description:There is a complex collection of neuroendocrine function during the postpartum period. Prolactin (PRL) released by suckling stimulus and its PRL receptors (PRL-R) in the central nervous system (CNS) are involved in hyporesponsiveness of the hypothalamic-pituitary-adrenal (HPA) axis in lactating mammals including rodents and humans. It is not clear how long it takes to reestablish the attenuated HPA axis activity of lactating rats to a pre-pregnancy state after pup separation. We first tested the hypothesis that HPA axis activity in response to an acute stress in postpartum rats would return to a pre-pregnancy state after pup separation. Restraint stress for 30 min was performed at the end of pup separation as an acute stressor. Plasma levels of corticosterone (CORT) were measured following restraint stress or no-stress (control) in virgin rats and postpartum rats housed with their pups or with pup removal for different periods of time of one hour, 24 h, or eight days. We then tested the hypothesis that circulating PRL level and CNS PRL-R gene expression were involved in mediating the acute stress response in postpartum rats. Plasma levels of PRL and PRL-R mRNA levels in the choroid plexus of the CNS were determined in both no-stress and stress, virgin rats, and postpartum rats housed with their pups or with pup removal for various periods, and their correlation with plasma CORT levels was assessed. The results demonstrated that PRL levels declined to virgin state in all postpartum rats separated from their pups, including the dams with one-hour pup separation. Stress-induced HPA activity dampened in lactating rats housed with pups, and returned to the pre-pregnancy state after 24 h of pup separation when both circulating PRL level and CNS PRL-R expression were restored to a pre-pregnancy state. Additionally, basal plasma CORT and CNS PRL-R expression were significantly correlated in rats with various pup status. This study suggested that stress-induced HPA activation occurred when PRL-R expression was similar to the level of virgin females, indicating that PRL-R upregulation contributes to an attenuated HPA response to acute stress. Understanding neuroendocrine responses to stress during the postpartum period is critical to understand postpartum-related neuropsychiatric illnesses and to maintain mental health in postpartum women.

Dataset Information

Skeletal and Uterotrophic Effects of Endoxifen in Female Rats.

Publications

Skeletal and Uterotrophic Effects of Endoxifen in Female Rats.

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