Virilizing Adrenocortical Adenoma Responsive to Gonadotrophin

Blichert-Toft, M; Vejlsted, H.; Kehlet, Henrik; Albrechtsen, Reidar

doi:10.1530/acta.0.0780077

Cited by 32 publications

(11 citation statements)

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“…Cushing's syndrome due to spontaneously formed LHand hCG-sensitive adrenal tumors during pregnancy and menopause causes secretion of higher levels of glucocorticoids and androgens [13][14][15][16][17][52][53][54][55][56][57][58][59][60][61]. It is possible that these tumors may arise in part from the changes in sensitivity and/or zonal distribution of normal adrenal LH/hCG receptors.…”

Section: Discussionmentioning

confidence: 99%

Functional Luteinizing Hormone/Chorionic Gonadotropin Receptors in Human Adrenal Cortical H295R Cells

Rao

Zhou

Lei

2004

Biology of Reproduction

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Previous studies have suggested that activation of normal human adrenal and adrenal tumor luteinizing hormone (LH)/chorionic gonadotropin (hCG) receptors results in an increased secretion of steroid hormones. Since it is not feasible to test this suggestion on normal human adrenal cells, we used human adrenal cortical carcinoma H295R cells, which are similar in some respects to normal adrenal cortical cells. These cells contained LH/hCG receptor transcripts and receptor protein that can bind (125)I-hCG in a hormone-specific manner. Culturing the cells with highly purified hCG resulted in a time- and dose-dependent significant increase in dehydroepiandrosterone sulfate (DHEAS) secretion as compared with the controls. The DHEAS response was hormone as well as steroid specific. Since hCG treatment did not increase DHEA secretion, we suspected that the hCG might increase DHEA sulfotransferase (ST). Consistent with this possibility, hCG treatment increased steady-state DHEA-ST mRNA levels. The hCG effects require its receptors, as inhibition of their synthesis by treatment with antisense phosphorothioate oligodeoxynucleotides (ODN) made from the LH/hCG receptor sequence resulted in loss of DHEA-ST and DHEAS responses. The findings that 1) hCG treatment increased cAMP levels and activated protein kinase A (PKA), 2) 8-bromo cAMP mimicked hCG, and 3) blocking PKA activation prevented hCG as well as 8-bromo cAMP from increasing both DHEA-ST mRNA and DHEAS levels suggested that cAMP/PKA signaling was involved in the hCG actions. In conclusion, H295R cells contain LH/hCG receptors, which are coupled to increasing DHEAS secretion through upregulating the ST enzyme mRNA level. This action is mediated by the cAMP/PKA signaling pathway. These findings support the concept that adrenal function in normal and pathological conditions could be influenced by LH and hCG.

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Section: Discussionmentioning

confidence: 99%

Functional Luteinizing Hormone/Chorionic Gonadotropin Receptors in Human Adrenal Cortical H295R Cells

Rao

Zhou

Lei

2004

Biology of Reproduction

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“…Many studies have indicated that high-amplitude GH pulses in rats and humans, mean blood GH secretion in rats, and integrated GH values in humans diminish during aging (33)(34)(35)(36)(37)(38)(39)(40)(41). The mechanisms involved are unknown but may be due to alterations in the release of GRF and/or SRIF from the hypothalamus.…”

Section: Discussionmentioning

confidence: 99%

Levels of human and rat hypothalamic growth hormone-releasing factor as determined by specific radioimmunoassay systems.

Audhya¹,

Manzione²,

Nakane³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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Polyclonal antibodies to synthetic human pancreatic growth hormone-releasing factor )NH2] and rat hypothalamic growth hormone-releasing factor [rhGRF(1-43)OHJ were produced in rabbits by injecting these weak immunogens, coupled to thyroglobulin and emulsified with complete Freund's adjuvant in the presence of activated charcoal, directly into the spleen. A subsequent booster in-jection by the conventional intramuscular route resulted in high-titer antibodies, which at a 1:20,000 dilution were used to develop highly sensitive and specific radioinmunoassays for these peptides. By using antibodies with an apparent K. of 3.3x 10-12 (human) and 7.7 x 10-11 (rat), the sensitivity of these assays in both human and rat was found to be <1 fmol. The antibody to hpGRF(1-44)NH2 is directed against the COOHterminal region of the molecule, as shown by its crossreactivity with various hpGRF analogues: 140% with hpGRF(30-44)NH2; 1%-2% with hpGRF(1-37)OH, hpGRF(140)OH, and hpGRF(1-40)NH2; and none with hpGRF(1-29)NH2. Serial dilutions of human and rat hypothalamic extracts demonstrated parallelism with the corresponding species-specific standard and 12,5-labeled tracer. There was no crossreactivity with other neuropeptides, gastrointestinal peptides, or hypothalamic extracts of other species. The hypothalamic content in fmol/mg (wet weight) of tissue was 3.6 ± 0.2 for the human and 11.1 ± 5.5 for the rat. Age-related changes in hypothalamic GRF content were present in rats, with a gradual increase from 2 to 16 weeks and a correlation between increasing body weight and GRF content. These radioimmunoassays winl serve as important tools for understanding the regulation of growth hormone secretion in both human and rat.Since 1959 (1), it has been known that the hypothalamus is involved in the control of growth hormone (GH) secretion. Experimental and clinical evidence has since indicated that the hypothalamus performs a dual function in the regulation of GH secretion from the anterior pituitary (2-4). Inhibition of GH release is accomplished by an inhibitory peptide, somatostatin (SRIF), which in 1972 was isolated from ovine hypothalami, purified, and characterized as a tetradecapeptide (5). In contrast, as suggested by physiological evidence (2-4) and GH-releasing activity in hypothalamic extracts (6-8), stimulation of GH release is accomplished by a stimulatory peptide, GH-releasing factor (GRF). Until 1982, howev-er, the isolation and characterization of GRF remained elusive. The difficulty in its characterization had been due to the minute quantities of the peptide in hypothalamic tissue, the large quantities of SRIF that interfere in the bioassay, and the fact that the methodology used for peptide sequencing and purification has only recently become available (9-12).The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. 2970Many investigators have reported the presenc...

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“…As plasma LH was found to be relatively suppressed in some of these patients, the role of endogenous LH in maintaining androgen production may be uncertain. In other cases, estrogens were unsuccessful in depressing androgen production (264,269,270). In other cases, estrogens were unsuccessful in depressing androgen production (264,269,270).…”

Section: E Lh-dependent Adrenal Androgen-secreting Tumorsmentioning

confidence: 99%

Ectopic and Abnormal Hormone Receptors in Adrenal Cushing’s Syndrome*

et al. 2001

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The mechanism by which cortisol is produced in adrenal Cushing's syndrome, when ACTH is suppressed, was previously unknown and was referred to as being "autonomous." More recently, several investigators have shown that some cortisol and other steroid-producing adrenal tumors or hyperplasias are under the control of ectopic (or aberrant, illicit, inappropriate) membrane hormone receptors. These include ectopic receptors for gastric inhibitory polypeptide (GIP), beta-adrenergic agonists, or LH/hCG; a similar outcome can result from altered activity of eutopic receptors, such as those for vasopressin (V1-AVPR), serotonin (5-HT4), or possibly leptin. The presence of aberrant receptors places adrenal cells under stimulation by a trophic factor not negatively regulated by glucocorticoids, leading to increased steroidogenesis and possibly to the proliferative phenotype. The molecular mechanisms responsible for the abnormal expression and function of membrane hormone receptors are still largely unknown. Identification of the presence of these illicit receptors can eventually lead to new pharmacological therapies as alternatives to adrenalectomy, now demonstrated by the long-term control of ectopic P-AR- and LH/hCGR-dependent Cushing's syndrome by propanolol and leuprolide acetate. Further studies will potentially identify a larger diversity of hormone receptors capable of coupling to G proteins, adenylyl cyclase, and steroidogenesis in functional adrenal tumors and probably in other endocrine and nonendocrine tumors.

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Virilizing Adrenocortical Adenoma Responsive to Gonadotrophin

Cited by 32 publications

References 0 publications

Functional Luteinizing Hormone/Chorionic Gonadotropin Receptors in Human Adrenal Cortical H295R Cells

Functional Luteinizing Hormone/Chorionic Gonadotropin Receptors in Human Adrenal Cortical H295R Cells

Levels of human and rat hypothalamic growth hormone-releasing factor as determined by specific radioimmunoassay systems.

Ectopic and Abnormal Hormone Receptors in Adrenal Cushing’s Syndrome*

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