Of Mice and Men: The Many Guises of Estrogens

Simpson, Evan R.; Jones, Morris

doi:10.1007/2789_2006_016

Cited by 15 publications

(14 citation statements)

References 92 publications

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“…Although we investigated only two genetic backgrounds, previous reports have indicated clear genetic regulation in the response of uterus (7, 8), vagina (8, 9), mammary gland (8), and bone (27, 28) to E 2 across several strains of mice. Therefore, genetics clearly plays a role in phenotypic variation observed in response to natural, synthetic, and environmental estrogens (36, 41, 42). In addition, our findings lay the groundwork for important and relevant experiments that could provide insight into mechanisms underlying genetic variation in other highly relevant E 2 ‐regulated processes in humans, including bone loss in postmenopausal women (43, 44), premature ovarian failure (45), fertility (41, 46), and libido (41), success rate of fertility treatments (42, 47), and sensitivity to environmental endocrine disrupters (36).…”

Section: Discussionmentioning

confidence: 99%

Genetic control of estrogen‐regulated transcriptional and cellular responses in mouse uterus

Wall¹,

Hewitt

Liu

et al. 2013

FASEB j.

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The uterotropic response of the uterus to 17β-estradiol (E2) is genetically controlled, with marked variation observed depending on the mouse strain studied. Previous genetic studies from our laboratory using inbred mice that are high [C57BL/6J (B6)] or low [C3H/HeJ (C3H)] responders to E2 led to the identification of quantitative trait (QT) loci associated with phenotypic variation in uterine growth and leukocyte infiltration. The mechanisms underlying differential responsiveness to E2, and the genes involved, are unknown. Therefore, we used a microarray approach to show association of distinct E2-regulated transcriptional signatures with genetically controlled high and low responses to E2 and their segregation in (C57BL/6J×C3H/HeJ) F1 hybrids. Among the 6664 E2-regulated transcripts, analysis of cellular functions of those that were strain specific indicated C3H-selective enrichment of apoptosis, consistent with a 7-fold increase in the apoptosis indicator CASP3, and a 2.4-fold decrease in the apoptosis inhibitor Naip1 (Birc1a) in C3H vs. B6 following treatment with E2. In addition, several differentially expressed transcripts reside within our previously identified QT loci, including the ERα-tethering factor Runx1, demonstrated to enhance E2-mediated transcript regulation. The level of RUNX1 in uterine epithelial cells was shown to be 3.5-fold greater in B6 compared to C3H. Our novel insights into the mechanisms underlying the genetic control of tissue sensitivity to estrogen have great potential to advance understanding of individualized effects in physiological and disease states.

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Section: Discussionmentioning

confidence: 99%

Genetic control of estrogen‐regulated transcriptional and cellular responses in mouse uterus

Wall¹,

Hewitt

Liu

et al. 2013

FASEB j.

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“…Given the role of adipose tissue aromatase in estrogen levels within the adipose tissue, aromatase knockout animals have also been evaluated. These mice, regardless of sex, develop hypercholesterolemia, and male knockout mice exhibited elevated triglycerides and fatty liver disease [33, 34]. …”

Section: Animal Models Identify Sex Differences In Adipose Tissue Biomentioning

confidence: 99%

Gender and Sex Differences in Adipose Tissue

2018

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There is evidence related to the sex dichotomy in obesity in a variety of areas including adipocyte function, sex hormone effects, genetics, and metabolic inflammation leading to critical differences in adipose tissue biology. The sex and gender difference in adipose tissue is a factor that should be considered when studying an individuals' risk for obesity and metabolic dysfunction. This understanding is important for strategizing treatment and prevention measures.

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“…Moreover, the relative contributions of testosterone vs its active metabolite estradiol on metabolism have not been differentiated in most intervention studies to date. Importantly, men deficient in aromatase, the enzyme responsible for the conversion of testosterone to estradiol, have severe metabolic derangements including insulin resistance and dyslipidemia that are corrected by the administration of estradiol 13 …”

Section: Introductionmentioning

confidence: 99%

Acute testosterone deprivation reduces insulin sensitivity in men

Rubinow¹,

Snyder²,

Amory³

et al. 2012

Clinical Endocrinology

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Objective In men with prostate cancer, androgen deprivation reduces insulin sensitivity; however, the relative roles played by testosterone and estradiol are unknown. To investigate the respective effects of these hormones on insulin sensitivity in men, we employed a model of experimental hypogonadism with or without hormone replacement. Design Placebo-controlled, randomized trial. Participants 22 healthy male volunteers, 18–55 years old. Methods Following screening, subjects received the gonadotropin releasing hormone antagonist acyline plus one of the following for 28 days: Group 1, placebo transdermal gel and placebo pills; Group 2, transdermal testosterone gel 10g/day plus placebo pills; Group 3, transdermal testosterone gel 10 g/day plus the aromatase inhibitor anastrozole 1 mg/day to normalize testosterone while selectively reducing serum estradiol. Fasting insulin, glucose, adipokines and hormones were measured bi-weekly. Results With acyline administration, serum testosterone was reduced by >90% in all subjects in Group 1. In these men, mean fasting insulin concentrations were significantly increased compared with baseline (p=0.02) at 28 days, despite stable body weight and no changes in fasting glucose concentrations. Decreased insulin sensitivity also was apparent in the insulin sensitivity indices HOMA-IR (p=0.03) and QUICKI (p=0.04). In contrast, in Groups 2 and 3, testosterone concentrations remained in the physiologic range, despite significant reduction in mean estradiol in Group 3. In these groups, no significant changes in insulin sensitivity were observed. Conclusions Acute testosterone withdrawal reduces insulin sensitivity in men independent of changes in body weight, whereas estradiol withdrawal has no effect. Testosterone appears to maintain insulin sensitivity in normal men.

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Of Mice and Men: The Many Guises of Estrogens

Cited by 15 publications

References 92 publications

Genetic control of estrogen‐regulated transcriptional and cellular responses in mouse uterus

Genetic control of estrogen‐regulated transcriptional and cellular responses in mouse uterus

Gender and Sex Differences in Adipose Tissue

Acute testosterone deprivation reduces insulin sensitivity in men

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