The selective estrogen receptor modulator SCH 57068 prevents bone loss, reduces serum cholesterol and blocks estrogen-induced uterine hypertrophy in ovariectomized rats

Goss, Paul E.; Qi, Shangle; Cheung, Angela M.; Hu, Haijun; Mendes, Maria; Pritzker, Kenneth P.H.

doi:10.1016/j.jsbmb.2004.05.009

Cited by 18 publications

(8 citation statements)

References 40 publications

(38 reference statements)

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“…In this study, the expression of both lipid transport-and metabolism-related genes is decreased and then later increased by E2, which has not been observed in other studies. Interestingly, it has been suggested, although not significantly, that E2 could potentially downregulate triglycerides in liver, although it significantly induces serum triglycerides, while serum high-density lipoproteins seem to be slightly reduced in ovariectomized rats (23,35,53).…”

Section: Discussionmentioning

confidence: 99%

Temporal analysis of E2 transcriptional induction of PTP and MKP and downregulation of IGF-I pathway key components in the mouse uterus

Ivanga

Labrie

Calvo

et al. 2007

Physiological Genomics

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Temporal analysis of E2 transcriptional induction of PTP and MKP and downregulation of IGF-I pathway key components in the mouse uterus. Physiol Genomics 29: 13-23, 2007; doi:10.1152 doi:10. /physiolgenomics.00291.2005 is well known to be associated with uterine cancer, endometriosis, and leiomyomas. Although insulin-like growth factor I (IGF-I) has been identified as a mediator of the uterotrophic effect of E2 in several studies, this mechanism is still not well understood. In the present study, identification of the genes modulated by a physiological dose of E2, in the uterus, has been done in ovariectomized mice using Affymetrix microarrays. The E2-induced genomic profile shows that multiple genes belonging to the IGF-I pathway are affected after exposure to E2. Two phases of regulation could be identified. First, from 0 to 6 h, the expression of genes involved in the cell cycle, growth factors, protein tyrosine phosphatases, and MAPK phosphatases is quickly upregulated by E2, while IGF-I receptor and several genes of the MAPK and phosphatidylinositol 3-kinase pathways are downregulated. Later, i.e., from 6 to 24 h, transporters and peptidases/ proteases are stimulated, whereas defense-related genes are differentially regulated by E2. Finally, cytoarchitectural genes are modulated later. The present data show that a physiological dose of E2 induces, within 24 h, a series of transcriptional events that promote the uterotrophic effect. Among these, the E2-mediated activation of the IGF-I pathway seems to play a pivotal role in the uterotrophic effect. Furthermore, the protein tyrosine phosphatases and MAPK phosphatases are likely to modulate the estrogenic uterotrophic action by targeting, at different steps, the IGF-I pathway.17␤-estradiol; 17␤-estradiol modulation; ovariectomized mice; oligonucleotide microarray; protein tyrosine phosphatase IN MAMMALS, THE UTERUS of a mature female undergoes multiple changes during the estrous cycle that reflect modifications of the uterine endometrium in continuous preparation for embryo implantation. Since the majority of cycles are not associated with conception, they often lead to endometrial degeneration and menstrual bleeding. The endometrium thus exhibits a cyclic pattern of growth, regression, disruption, bleeding, and regeneration throughout reproductive life. These changes are mainly under the control of estrogens, progesterone, and androgens. Disregulation of the uterine vasculature has been found to accompany different sex steroid disturbances (28).17␤-Estradiol (E2) is well known to play the key role in mammalian endometrial physiology, since the proliferation of endometrial cells and the extension of spiral vessels that occur during the proliferative phase of the menstrual cycle are controlled by E2 (20, 46). Estrogen is also frequently associated with endometrial cancer, which comprises two subtypes: endometrioid carcinomas (type I) related to estrogen exposure and nonendometrioid carcinomas (type II), which are independent of E2 action (16). Type I cancers ar...

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Section: Discussionmentioning

confidence: 99%

Temporal analysis of E2 transcriptional induction of PTP and MKP and downregulation of IGF-I pathway key components in the mouse uterus

Ivanga

Labrie

Calvo

et al. 2007

Physiological Genomics

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“…However, in the rat, both HDL and LDL cholesterol are reduced, because rat HDL contains apoprotein E (not found in human HDL), which also binds to the hepatic LDL receptor [33]. In the rat, as opposed to humans, HDL cholesterol is a predominant form of circulating cholesterol, and estrogen therapy lowers both HDL and LDL levels [34][35][36][37]. Thus the reduction in both HDL and LDL seen with TOR treatment in the OVX rat is in the expected direction.…”

Section: Discussionmentioning

confidence: 99%

The effects of atamestane and toremifene alone and in combination compared with letrozole on bone, serum lipids and the uterus in an ovariectomized rat model

Goss

et al. 2006

Breast Cancer Res Treat

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We compared the effects of atamestane (ATA) and toremifene (TOR) alone and in combination, with letrozole (LET) on bone, serum lipids and the uterus in ovariectomized (OVX) rats after 16 weeks of treatment. Compared to OVX controls lumbar vertebral and femoral BMD as well as mechanical strength and trabecular bone volume were significantly greater in animals given ATA, TOR or ATA + TOR. The effects of ATA were not reversed by the androgen receptor blocker, flutamide (FLT). Serum cholesterol, low-density lipoprotein cholesterol and triglycerides were reduced by TOR and ATA + TOR whereas they remained unchanged in animals receiving ATA, ATA + FLT, and LET. The uterine epithelium in OVX animals was equally stimulated by TOR and ATA + TOR and unaffected by ATA or LET. Intact animals had significant atrophy of the uterine epithelium when receiving ATA. In summary, TOR alone or in combination with ATA had a predictable stimulatory effect on bone and the uterine epithelium while reducing key parameters of lipid metabolism. In contrast, ATA but not LET had an unexpected stimulatory effect on the OVX rat's bone and this was not reversed by the anti-androgen FLT leaving this finding unexplained for now. ATA is distinct from LET on end-organ function and this favorable profile makes clinical testing of this steroidal aromatase inhibitor of interest in the clinical setting.

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“…A number of SERMs have followed, including lasofoxifene [138], bazedoxifene [139], ospemifene [140], SCH 57068 [141], SP500263 [142], and HMR-3339 [143]. Clearly, all SERMs do not behave identically.…”

Section: F Tissue Selective Estrogensmentioning

confidence: 99%

Regulation of Bone Cell Function by Estrogens

Komm¹,

Cheskis²,

Bodine³

2008

Osteoporosis

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The selective estrogen receptor modulator SCH 57068 prevents bone loss, reduces serum cholesterol and blocks estrogen-induced uterine hypertrophy in ovariectomized rats

Cited by 18 publications

References 40 publications

Temporal analysis of E2 transcriptional induction of PTP and MKP and downregulation of IGF-I pathway key components in the mouse uterus

Temporal analysis of E2 transcriptional induction of PTP and MKP and downregulation of IGF-I pathway key components in the mouse uterus

The effects of atamestane and toremifene alone and in combination compared with letrozole on bone, serum lipids and the uterus in an ovariectomized rat model

Regulation of Bone Cell Function by Estrogens

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