Control of steroidogenesis in Leydig cells

Cooke, Brian A.; Choi, Mi Hyun; Dirami, Ghenima; López-Ruiz, M.P.; West, Anthony P.

doi:10.1016/0960-0760(92)90083-u

Cited by 29 publications

(10 citation statements)

References 30 publications

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“…Consistent with a previous study showing that, in the human adrenal cortex, the LH/hCG receptor is almost exclusively expressed by zona reticularis (26), we did not observe any effect of hCG on cortisol production by normal adrenocortical cells. In one hyperplasia, the attenuation of the cortisol response observed with high concentrations of hCG suggests the occurrence of a desensitization phenomenon of the receptor, as previously shown in Leydig cells (27,28). The molecular mechanisms involved in the prolonged stimulation of cortisol production evoked by a single pulse of hCG in perifused hyperplasia fragments remain unclear.…”

Section: Discussionmentioning

confidence: 77%

In Vivo and in Vitro Screening for Illegitimate Receptors in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Causing Cushing’s Syndrome: Identification of Two Cases of Gonadotropin/Gastric Inhibitory Polypeptide-Dependent Hypercortisolism

Bertherat

Contesse

Louiset

et al. 2005

The Journal of Clinical Endocrinology &Amp; Metabolism

100

106

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In ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing Cushing's syndrome, cortisol production can be controlled by illegitimate membrane receptors. The aim of the present study was to evaluate in vivo and in vitro the sensitivity of AIMAH to various regulatory factors to detect the expression of illegitimate receptors by the tissues. Four consecutive patients with AIMAH and hypercortisolism (H1-H4) preoperatively underwent a series of pharmacological and/or physiological tests. After adrenalectomy, in vitro studies were conducted to investigate the cortisol responses of cultured cells, derived from hyperplastic tissues, to various membrane receptor ligands. The adrenal tissues of the two patients who responded in vivo to food intake (H2 and H4) were stimulated in vitro by gastric inhibitory polypeptide. GnRH and human chorionic gonadotropin, but not FSH, stimulated cortisol secretion in patients H2 and H4. In these two cases, human chorionic gonadotropin but not GnRH stimulated cortisol production from cultured adrenocortical cells. Cisapride induced a significant increase in cortisol levels in patient H1. In addition, serotonin (5-HT) was more efficient to stimulate cortisol production in H1 cells than in normal adrenocortical cells. Upright stimulation test provoked an increase in cortisol levels in patients H1, H2, and H3. H1 and H2 cells were more sensitive to the stimulatory action of angiotensin II than normal cells. Similarly, arginine vasopressin (AVP) more efficiently activated steroidogenesis in H1 cells than in normal cells. In H1 tissue, immunohistochemical studies revealed the presence of 5-HT- and AVP-like immunoreactivities within clusters of steroidogenic cells, suggesting that these two factors acted through an autocrine/paracrine mechanism to stimulate cortisol secretion. The present study provides the first demonstration of primary adrenal Cushing's syndrome dependent on both gonadotropin and gastric inhibitory polypeptide. Our data also show a hyperresponsiveness of hyperplastic adrenal tissues to 5-HT, angiotensin II, and AVP. Finally, they reveal for the first time the presence of paracrine regulatory signals in adrenal hyperplasia tissues.

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Section: Discussionmentioning

confidence: 77%

In Vivo and in Vitro Screening for Illegitimate Receptors in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Causing Cushing’s Syndrome: Identification of Two Cases of Gonadotropin/Gastric Inhibitory Polypeptide-Dependent Hypercortisolism

Bertherat

Contesse

Louiset

et al. 2005

The Journal of Clinical Endocrinology &Amp; Metabolism

100

106

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“…The increase in intracellular cAMP activates cAMP-dependent protein kinase A (PKA) and results in the phosphorylation of protein(s), involved in steroidogenesis [139][140][141]. Hormonal regulation of steroid biosynthesis requires de novo protein synthesis, as inhibition of protein synthesis has been shown to ablate the steroidogenic response [6,7].…”

Section: Hormonal Regulation Of Starmentioning

confidence: 99%

Regulation of the Steroidogenic Acute Regulatory Protein Expression: Functional and Physiological Consequences

Manna

Stocco²

2005

curr drug targets immune endocr metabol disord

125

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Steroid hormones are synthesized in steroidogenic cells of the adrenal, ovary, testis, placenta and brain and are essential for normal reproductive function and bodily homeostasis. The rate-limiting and regulated step in steroid biosynthesis is the intramitochondrial transport of cholesterol, a process that is mediated by the steroidogenic acute regulatory (StAR) protein. The importance of StAR has been illustrated by analyses of patients with lipoid congenital adrenal hyperplasia (lipoid CAH), an autosomal recessive disorder that markedly disrupts the synthesis of all gonadal and adrenal steroids. Molecular and physio-pathological analyses have demonstrated that alterations in the StAR gene are the only known cause of lipoid CAH. Furthermore, StAR knockout mice have been generated and display a phenotype that is essentially identical to the human condition. Recent advances in tissue-specific and hormone-induced expression of the StAR protein provide insights into a number of human endocrinological health issues including developmental and reproductive abnormalities. Several factors and processes have been demonstrated to influence StAR expression in steroidogenic cells and there is increasing evidence that a transcription factor-binding site-rich region present in the proximal region of the StAR promoter is highly instrumental in StAR gene expression. In this review we focus on the significant findings that have been made with regards to the regulation of StAR expression and also on the clinical and endocrinological consequences of a non-functioning StAR gene.

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“…Regulation of various Leydig cell functions, including steroidogenesis, are predominantly mediated by luteinizing hormone/chorionic gonadotropin (LH/CG) through the involvement of multiple signaling pathways (Dufau 1988, Cooke et al 1992, Saez 1994, Ascoli et al 2002. The steroidogenic responsiveness of Leydig cells has been shown to be regulated not only by LH/CG but also by peptide and non-peptide hormones, including locally produced factors, prostaglandins, and steroids through endocrine, paracrine, and autocrine events (Saez 1994, Cooke 1999.…”

Section: Introductionmentioning

confidence: 99%

cAMP-independent signaling regulates steroidogenesis in mouse Leydig cells in the absence of StAR phosphorylation

Manna¹,

Chandrala²,

Jo³

et al. 2006

Journal of Molecular Endocrinology

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In the regulation of steroid biosynthesis, a process mediated by the steroidogenic acute regulatory (StAR) protein, both cAMP-dependent and -independent pathways are involved. While the cAMP-dependent regulatory events represent, by far, the most robust increase in steroid synthesis and are well established, the knowledge regarding cAMP-independent mechanisms is lacking. The present investigation was designed to elucidate the potential involvement of the latter in regulating StAR expression and steroidogenesis in mouse Leydig tumor cells (mLTC-1 cells). Treatment of mLTC-1 cells with a number of factors including insulin-like growth factor-I (IGF-I), epidermal growth factor (EGF), fibroblast growth factor, transforming growth factor (TGF)a, interleukin-1 (IL-1), and colony-stimulating factor-1, increased the levels of StAR mRNA, StAR protein, and progesterone to varying degrees and utilized signaling pathways that are not associated with elevations in intracellular cAMP levels. Importantly, phosphorylation of StAR in response to these stimuli was undetectable, which is in marked contrast to observations with human chorionic gonadotropin (hCG), indicating factors that do not alter intracellular cAMP, regulate the steroid biosynthesis in a StAR phosphorylation-independent manner. In addition, the roles for factors involved in cross-talk between the protein kinase pathways, PKA and PKC, were demonstrated. Further characterization of signaling by one such cAMP-independent factor, TGFa, demonstrated that the mechanism, whereby it increased StAR expression and steroid synthesis, was dependent on de novo protein synthesis and mediated via activation of the EGF receptor. TGFa was also able to augment hCG-stimulated cAMP synthesis, StAR protein and StAR phosphorylation, and influence hCG binding and LH receptor mRNA expression. Furthermore, TGFa increased phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and cAMP-response element-binding protein (CREB), processes inhibited by the mitogen-activated protein kinase/ERK inhibitor U0126 and by expression of non-phosphorylatable CREB-M1 respectively. Inhibition of ERK activity enhanced TGFa-mediated StAR protein expression (but not its phosphorylation) and decreased progesterone synthesis, events correlated with the expression of dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene 1 (DAX-1) and scavenger receptor class B type 1 (SR-B1). Collectively, these findings demonstrate that, in mouse Leydig cells, cAMPindependent signaling events regulate steroidogenesis in a StAR phosphorylation-independent manner.

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Control of steroidogenesis in Leydig cells

Cited by 29 publications

References 30 publications

In Vivo and in Vitro Screening for Illegitimate Receptors in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Causing Cushing’s Syndrome: Identification of Two Cases of Gonadotropin/Gastric Inhibitory Polypeptide-Dependent Hypercortisolism

In Vivo and in Vitro Screening for Illegitimate Receptors in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Causing Cushing’s Syndrome: Identification of Two Cases of Gonadotropin/Gastric Inhibitory Polypeptide-Dependent Hypercortisolism

Regulation of the Steroidogenic Acute Regulatory Protein Expression: Functional and Physiological Consequences

cAMP-independent signaling regulates steroidogenesis in mouse Leydig cells in the absence of StAR phosphorylation

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