Antiestrogens upregulate estrogen receptor β expression and inhibit adrenocortical H295R cell proliferation

Montanaro, Daniela; Maggiolini, Marcello; Recchia, Anna Grazia; Sirianni, Rosa; Aquila, Saveria; Barzon, Luisa; Fallo, Francesco; Andò, Sebastiano; Pezzi, Vincenzo

doi:10.1677/jme.1.01806

Cited by 72 publications

(58 citation statements)

References 45 publications

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“…An unexplored theoretical possibility would be that ER␣ activation antagonizes an unrecognized inhibitory (burst-abbreviating) effect of ER␤. This consideration arises because ER␤ is upregulated by depletion of ER␣ in some systems, and exerts countervailing transcriptional effects on certain gene promotors (21,34,35). The notion is consistent with the fact that both ER␣ and ER␤ are expressed in the human pituitary gland (6,39).…”

Section: Discussionmentioning

confidence: 69%

Peripheral estrogen receptor-α selectively modulates the waveform of GH secretory bursts in healthy women

Veldhuis¹,

Keenan²,

Bowers³

2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Veldhuis JD, Keenan DM, Bowers CY. Peripheral estrogen receptor-␣ selectively modulates the waveform of GH secretory bursts in healthy women. Am J Physiol Regul Integr Comp Physiol 293: R1514-R1521, 2007. First published August 8, 2007; doi:10.1152 doi:10. /ajpregu.00438.2007 drives growth hormone (GH) secretion via estrogen receptors (ER) located in the hypothalamus and pituitary gland. ER␣ is expressed in GH releasing hormone (GHRH) neurons and GH-secreting cells (somatotropes). Moreover, estrogen regulates receptors for somatostatin, GHR peptide (GHRP, ghrelin), and GH itself, while potentiating signaling by IGF-I. Given this complex network, one cannot a priori predict the selective roles of hypothalamic compared with pituitary ER pathways. To make such a distinction, we introduce an investigative model comprising 1) specific ER␣ blockade with a pure antiestrogen, fulvestrant, that does not penetrate the blood-brain barrier; 2) graded transdermal E 2 administration, which doubles GH concentrations in postmenopausal women; 3) stimulation of fasting GH secretion by pairs of GHRH, GHRP-2 (a ghrelin analog), and L-arginine (to putatively limit somatostatin outflow); and 4) implementation of a flexible waveform deconvolution model to estimate the shape of secretory bursts independently of their size. The combined strategy unveiled that 1) E 2 prolongs GH secretory bursts via fulvestrant-antagonizable mechanisms; 2) fulvestrant extends GHRH/GHRP-2-stimulated secretory bursts; 3) L-arginine/GHRP-2 stimulation lengthens GH secretory bursts whether or not E 2 is present; 4) E2 limits the capability of L-arginine/GHRP-2 to expand GH secretory bursts, and fulvestrant does not inhibit this effect; and 5) E 2 and/or fulvestrant do not alter the time evolution of L-arginine/GHRH-induced GH secretory bursts. The collective data indicate that peripheral ER␣-dependent mechanisms determine the shape (waveform) of in vivo GH secretory bursts and that such mechanisms operate with secretagogue selectivity. somatotropin; ghrelin; growth hormone releasing hormone; somatostatin; secretagogues; female; human GROWTH HORMONE (GH) secretion is at least 90% pulsatile in the healthy human and strongly controlled by sex steroid hormones (17,19). Individual GH secretory bursts are believed to reflect the concerted effects of somatotrope stimulation by GH-releasing hormone (GHRH), inhibition by somatostatin (SS), and amplification by the potent GHR peptide (GHRP) ghrelin (14,45). Estrogen supplementation stimulates pulsatile GH secretion in postmenopausal women and girls with ovarian dysgenesis (32, 38). Putative mechanisms include the capability of estradiol (E 2 ) to potentiate GHRH drive (reduce the halfmaximally stimulatory dose), augment GHRP stimulation (increase apparent efficacy), and antagonize SS inhibition (increase the half-maximally inhibitory dose) (2, 5, 41, 43). The topographic sites at which estrogen exerts such effects are not known (45). However, E 2 can upregulate pituitary SS-type 2 and hypothalamic GHRP receptors and...

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Section: Discussionmentioning

confidence: 69%

Peripheral estrogen receptor-α selectively modulates the waveform of GH secretory bursts in healthy women

Veldhuis¹,

Keenan²,

Bowers³

2007

American Journal of Physiology-Regulatory, Integrative and Comp

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“…However, expression of aromatase gene is very high in adrenocortical tumors, especially those secreting estrogens [29,47,48]. Moreover, functional aromatase was also identified in H295R cell line [49].…”

Section: Discussionmentioning

confidence: 99%

Expression of estrogen, estrogen related and androgen receptors in adrenal cortex of intact adult male and female rats

Trejter

Jopek

Celichowski

et al. 2015

Folia Histochem Cytobiol.

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Introduction. Adrenocortical activity in various species is sensitive to androgens and estrogens. They may affect adrenal cortex growth and functioning either via central pathways (CRH and ACTH) or directly, via specific receptors expressed in the cortex and/or by interfering with adrenocortical enzymes, among them those involved in steroidogenesis. Only limited data on expression of androgen and estrogen receptors in adrenal glands are available. Therefore the present study aimed to characterize, at the level of mRNA, expression of these receptors in specific components of adrenal cortex of intact adult male and female rats. Material and methods. Studies were performed on adult male and female (estrus) Wistar rats. Total RNA was isolated from adrenal zona glomerulosa (ZG) and fasciculate/reticularis (ZF/R). Expression of genes were evaluated by means of Affymetrix ® Rat Gene 1.1 ST Array Strip and QPCR. Results. By means of Affymetrix ® Rat Gene 1.1 ST Array we examined adrenocortical sex differences in the expression of nearly 30,000 genes. All data were analyzed in relation to the adrenals of the male rats. 32 genes were differentially expressed in ZG, and 233 genes in ZF/R. In the ZG expression levels of 24 genes were lower and 8 higher in female rats. The more distinct sex differences were observed in the ZF/R, in which expression levels of 146 genes were lower and 87 genes higher in female rats. Performed analyses did not reveal sex differences in the expression levels of both androgen (AR) and estrogen (ER) receptor genes in the adrenal cortex of male and female rats. Therefore matrix data were validated by QPCR. QPCR revealed higher expression levels of AR gene both in ZG and ZF/R of male than female rats. On the other hand, QPCR did not reveal sex-related differences in the expression levels of ERa, ERb and non-genomic GPR30 (GPER-1) receptor. Of those genes expression levels of ERa genes were the highest. In studied adrenal samples the relative expression of ERa mRNA was higher than ERb mRNA. In adrenals of adult male and female rats expression levels of estrogen-related receptors ERRa and ERRb were similar, and only in the ZF/R of female rats ERRg expression levels were significantly higher than in males. We also analyzed expression profile of three isoforms of steroid 5a-reductase (Srd5a1, Srd5a2 and Srd5a3) and aromatase (Cyp19a1) and expression levels of all these genes were similar in ZG and ZF/R of male and female rats. Conclusions. In contrast to Affymetrix microarray data QPCR revealed higher expression levels of AR gene in adrenal glands of the male rats. In adrenals of both sexes expression levels of ERa, ERb, non-genomic GPR30 (GPER-1), ERRa and ERRb receptors were comparable. The obtained results suggest that acute steroidogenic effect of estrogens on corticosteroid secretion may be mediated by non-genomic GPR30.

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“…In contrast, ERb levels were high, suggesting a more probable role. Montanaro et al (2005) demonstrated that the H295R adrenal carcinoma cell line produces more mRNA for ERb than for ERa. They also showed that 4-OH-tamoxifen (a selective estrogen receptor modulation (SERM)) and ICI 182 780 (a pure anti-estrogen) upregulate ERb and inhibit cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Expression of progesterone and estradiol receptors in normal adrenal cortex, adrenocortical tumors, and primary pigmented nodular adrenocortical disease

Crémoux

Rosenberg²,

Goussard³

et al. 2008

Endocrine Related Cancer

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Adrenal tumors occur more frequently in women and are the leading cause of Cushing's syndrome during pregnancy. We aimed to evaluate the potential role of sex steroids in the susceptibility of women to adrenocortical tumors. We evaluated the presence of the progesterone receptor (PR), estradiol receptors (ERs), and aromatase in 5 patients with primary pigmented nodular adrenal disease (PPNAD), 15 adrenocortical adenomas (ACAs) and adjacent normal tissues, 12 adrenocortical carcinomas (ACCs), and 3 normal adrenal glands (NA). The expression of PR and ERa was evaluated by enzyme immunoassays, real-time RT-PCR, immunohistochemistry, and cytosol-based ligand-binding assays. ERb and aromatase levels were evaluated by real-time RT-PCR. ERa concentrations were low in NA, in adrenal tissues adjacent to ACA (51G33), in ACC (53G78), and lower in ACA (11G11 fmol/mg DNA). Conversely, PR concentrations were high in NA and adrenal tissues adjacent to ACA, at 307G216 fmol/mg DNA, and were even higher in tumors -726G706 fmol/mg DNA in ACA and 1154G1586 fmol/mg DNA in ACC -and in isolated PPNAD nodules. Binding study results in four tumors were compatible with binding to a steroid receptor. In patients with PPNAD, a strong positive immunohistochemical signal was associated with the sole isolated nodular regions. ERb transcript levels were very high in all samples except those for two ACCs, whereas aromatase levels were low. PR and ERb are clearly present in normal adrenal glands and adrenal tumors. Further studies may shed light on the possible pathogenic role of these receptors in adrenal proliferation.

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Antiestrogens upregulate estrogen receptor β expression and inhibit adrenocortical H295R cell proliferation

Cited by 72 publications

References 45 publications

Peripheral estrogen receptor-α selectively modulates the waveform of GH secretory bursts in healthy women

Peripheral estrogen receptor-α selectively modulates the waveform of GH secretory bursts in healthy women

Expression of estrogen, estrogen related and androgen receptors in adrenal cortex of intact adult male and female rats

Expression of progesterone and estradiol receptors in normal adrenal cortex, adrenocortical tumors, and primary pigmented nodular adrenocortical disease

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