Biosynthesis of Sexual Steroids by Hyperplastic Adrenal Glands of Castrated Female C<sub>3</sub>H/Ep Mice

Rosner, Jorge M.; Houssay, Alberto B.; Epper, C E

doi:10.1210/endo-79-4-681

Cited by 15 publications

(5 citation statements)

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“…7), it seems that the absence of B cells in intact TG females could be due to the low serum concentrations of LH and possible presence of other gonadal factors such as inhibin. According to previous reports, post-GDX A cells appear first in the adrenal cortex, and later under prolonged LH stimulation the LHCGR-positive lipid-laden B cells (Rosner et al, 1966;Murthy et al, 1970;Bielinska et al, 2003). It has been suggested that the process of A and B cell formation represents metaplasia of stem/progenitor cells in the adrenal cortex, which under the influence of unopposed gonadotropins transform into tissue resembling gonadal stroma (Dunn, 1970;Russfield, 1975;Bielinska et al, 2003).…”

Section: Discussionmentioning

confidence: 97%

“…DBA/2J, C3H and CE mouse strains have been found to be genetically susceptible to develop gonadotropin-dependent adrenocortical hyperplasia or tumors, whereas such responses do not occur in non-susceptible C57BL/6 or FVB/N mice (Bielinska et al, 2003;Vuorenoja et al, 2007;Bernichtein et al, 2008). DBA/2J and C3H adrenocortical tumors are composed of spindle-shaped A cells that proliferate in the subcapsular region (Hofmann et al, 1960;Murthy et al, 1970), and steroidogenically active lipidladen B cells that appear later within patches of A cells in adrenal cortex (Rosner et al, 1966). In several transgenic models of adrenocortical tumorigenesis, such as inhibin alpha-subunit promoter/simian virus 40 T-antigen (inha/Tag) mice, or inhibin a knockout mice (inha2/2), one of the driving forces for tumorigenesis seems to be the elevated serum LH (Risma et al, 1995;Kero et al, 2000;Mikola et al, 2003;Looyenga et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Transgenic GATA-4 expression induces adrenocortical tumorigenesis in C57Bl/6 mice

Chruściel

Vuorenoja

Mohanty

et al. 2013

Journal of Cell Science

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SummaryA link between elevated luteinizing hormone (LH) levels, GATA-4 and LH receptor (LHCGR) expression and gonadotropin-dependent adrenocortical tumorigenesis in humans and mice has been shown. To assess the mechanistic tumorigenic interrelationships between these factors, we transgenically expressed Gata4 under the 21-hydroxylase promoter (Cyp21a1, 21-OH) in C57Bl/6N mice. There was a gradual age-dependent increase of GATA-4 expression only in 21-OH-GATA-4 (TG) female adrenals, in association with slowly progressing neoplasia of non-steroidogenic spindle-shaped A cells in the subcapsular cortex. Gonadectomy (GDX), apparently through direct action of elevated serum LH, markedly enhanced the adrenocortical neoplasia, which now also appeared in GDX TG males. The neoplastic areas of the post-GDX TG adrenals contained, besides A cells, larger lipid-laden, steroidogenically active and LHCGRpositive B cells. Prolonged (.10 months) exposure to elevated post-GDX LH levels resulted in formation of adrenocortical adenomas in the TG mice. Intact and GDX TG mouse adrenals displayed elevated FOG-2 and decreased GATA-6 expression. Additionally, increased expression/activation of components of the Inhbb-Acvr2a-Acvr1c-Smad2/3 signaling system was observed in 12-month-old GDX TG adrenals. Our findings show that two distinct GATA-4-dependent populations of neoplastic adrenocortical cells form: non-steroidogenic LH-independent A cells and steroidogenic LH-dependent B cells.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Transgenic GATA-4 expression induces adrenocortical tumorigenesis in C57Bl/6 mice

Chruściel

Vuorenoja

Mohanty

et al. 2013

Journal of Cell Science

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“…As progesterone is a precursor of corticosterone, it is not surprising that the adrenal gland contributes to circulating progesterone in mice (8). In mice, gonadectomy has been reported to induce expression of P450c17 and thereby androgen synthesis in the adrenal cortex (30,(32)(33)(34), possibly explaining the low but measurable levels of testosterone and DHT in ovx female mice in the present study The potential role of the adrenals as a contributing endocrine gland to circulating testosterone and DHT in female rodent should be further evaluated by analyzing the tissue-specific sex steroid profile of the adrenal gland in gonadal intact and ovx rodents.…”

Section: Discussionmentioning

confidence: 99%

Measurement of a Comprehensive Sex Steroid Profile in Rodent Serum by High-Sensitive Gas Chromatography-Tandem Mass Spectrometry

et al. 2015

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Accurate measurement of sex steroid concentrations in rodent serum is essential to evaluate mouse and rat models for sex steroid-related disorders. The aim of the present study was to develop a sensitive and specific gas chromatography-tandem mass spectrometry (GC-MS/MS) method to assess a comprehensive sex steroid profile in rodent serum. A major effort was invested in reaching an exceptionally high sensitivity for measuring serum estradiol concentrations. We established a GC-MS/MS assay with a lower limit of detection for estradiol, estrone, T, DHT, progesterone, androstenedione, and dehydroepiandrosterone of 0.3, 0.5, 4.0, 1.6, 8, 4.0, and 50 pg/mL, respectively, whereas the corresponding values for the lower limit of quantification were 0.5, 0.5, 8, 2.5, 74, 12, and 400 pg/mL, respectively. Calibration curves were linear, intra- and interassay coefficients of variation were low, and accuracy was excellent for all analytes. The established assay was used to accurately measure a comprehensive sex steroid profile in female rats and mice according to estrous cycle phase. In addition, we characterized the impact of age, sex, gonadectomy, and estradiol treatment on serum concentrations of these sex hormones in mice. In conclusion, we have established a highly sensitive and specific GC-MS/MS method to assess a comprehensive sex steroid profile in rodent serum in a single run. This GC-MS/MS assay has, to the best of our knowledge, the best detectability reported for estradiol. Our method therefore represents an ideal tool to characterize sex steroid metabolism in a variety of sex steroid-related rodent models and in human samples with low estradiol levels.

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“…Since then, further studies have identified other susceptible mouse strains that develop adrenal tumors with near complete penetrance following GDX (DBA/2J, CE/J, C3H, NU/J, BALB/c and B6D2F1), as well as resistant strains (C57BL/6 and FVB/N) (Bielinska et al, 2003, Johnsen et al, 2006, Krachulec et al, 2012, Rosner et al, 1966, Woolley, 1945). Further characterization of GDX-induced adrenal neoplasias showed that tumorigenesis, while predicted to result from loss of a gonadal factor and /or increase in pituitary gonadotropins, was also mediated by intrinsic genetic attributes of susceptible lines (Bielinska et al, 2005, Bielinska et al, 2006, Röhrig et al, 2015).…”

Section: Mouse Models Of Gonadectomy-induced Adrenocortical Neoplasiamentioning

confidence: 99%

Mouse models of adrenocortical tumors

Basham

Hung

Lerário

et al. 2016

Molecular and Cellular Endocrinology

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The molecular basis of the organogenesis, homeostasis, and tumorigenesis of the adrenal cortex has been the subject of intense study for many decades. Specifically, characterization of tumor predisposition syndromes with adrenocortical manifestations and molecular profiling of sporadic adrenocortical tumors have led to the discovery of key molecular pathways that promote pathological adrenal growth. However, given the observational nature of such studies, several important questions regarding the molecular pathogenesis of adrenocortical tumors have remained. This review will summarize naturally occurring and genetically engineered mouse models that have provided novel tools to explore the molecular and cellular underpinnings of adrenocortical tumors. New paradigms of cancer initiation, maintenance, and progression that have emerged from this work will be discussed.

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Biosynthesis of Sexual Steroids by Hyperplastic Adrenal Glands of Castrated Female C₃H/Ep Mice

Cited by 15 publications

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Transgenic GATA-4 expression induces adrenocortical tumorigenesis in C57Bl/6 mice

Transgenic GATA-4 expression induces adrenocortical tumorigenesis in C57Bl/6 mice

Measurement of a Comprehensive Sex Steroid Profile in Rodent Serum by High-Sensitive Gas Chromatography-Tandem Mass Spectrometry

Mouse models of adrenocortical tumors

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Biosynthesis of Sexual Steroids by Hyperplastic Adrenal Glands of Castrated Female C3H/Ep Mice

Cited by 15 publications

References 0 publications

Transgenic GATA-4 expression induces adrenocortical tumorigenesis in C57Bl/6 mice

Transgenic GATA-4 expression induces adrenocortical tumorigenesis in C57Bl/6 mice

Measurement of a Comprehensive Sex Steroid Profile in Rodent Serum by High-Sensitive Gas Chromatography-Tandem Mass Spectrometry

Mouse models of adrenocortical tumors

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Biosynthesis of Sexual Steroids by Hyperplastic Adrenal Glands of Castrated Female C₃H/Ep Mice