Human chorionic gonadotropin (hCG) regulates the expression of Steroidogenic acute regulatory protein (StAR) via the ERK1/2 pathway

We have previously found that cyclooxygenase-2 (COX-2), a key enzyme in the biosynthesis of prostaglandins (PGs), is present in the testicular interstitial cells of infertile men, whereas it is absent in human testes with no evident morphological changes or abnormalities. To find an animal model for further investigating COX-2 and its role in testicular steroidogenesis, we screened testes from adult species ranging from mice to monkeys. By using immunohistochemical assays, we found COX-2 expression only in Leydig cells of the reproductively active (peripubertal, pubertal, and adult) seasonal breeder Syrian hamster. COX-2 expression in hamster Leydig cells was confirmed by RT-PCR. In contrast, COX-1 expression was not detected in hamster testes. Because COX-2 expression implies PG synthesis, we investigated the effect of various PGs on testosterone production and found that PGF2α stood out because it significantly reduced human chorionic gonadotropin-stimulated testosterone release from isolated hamster Leydig cells in a dose-dependent manner. This mechanism involves a decreased expression of testicular steroidogenic acute regulatory protein and 17β-hydroxysteroid dehydrogenase. Testicular concentration and content of PGF2α in reproductively active hamsters as well as production of PGF2α from isolated hamster Leydig cells were also determined. Moreover, PGF2α receptors were localized in Leydig cells of hamsters and testicular biopsies from patients with Sertoli cell only and germ arrest syndromes. Thus, in this study, we described a COX-2-initiated pathway that via PGF2α production, PGF2α receptors, steroidogenic acute regulatory protein, and 17β-hydroxysteroid dehydrogenase represents a physiological local inhibitory system of human chorionic gonadotropin-stimulated testosterone production in the Syrian hamster testes.

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The Steroidogenic Response and Corpus Luteum Expression of the Steroidogenic Acute Regulatory Protein after Human Chorionic Gonadotropin Administration at Different Times in the Human Luteal Phase

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2002-021916 ◽

2003 ◽

Vol 88 (7) ◽

pp. 3421-3430 ◽

Cited By ~ 29

Author(s):

Paulina Kohen ◽

Olga Castro ◽

Alberto Palomino ◽

Alex Muñoz ◽

Lane K. Christenson ◽

...

Keyword(s):

Corpus Luteum ◽

Chorionic Gonadotropin ◽

Human Chorionic Gonadotropin ◽

Luteal Phase ◽

Regulatory Protein ◽

Steroidogenic Acute Regulatory Protein ◽

Steroidogenic Acute Regulatory

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Human Chorionic Gonadotropin Induces an Inverse Regulation of Steroidogenic Acute Regulatory Protein Messenger Ribonucleic Acid in Theca Interna and Granulosa Cells of Equine Preovulatory Follicles*

Endocrinology ◽

10.1210/endo.140.2.6499 ◽

1999 ◽

Vol 140 (2) ◽

pp. 667-674 ◽

Cited By ~ 16

Author(s):

Abdurzag Kerban ◽

Derek Boerboom ◽

Jean Sirois

Keyword(s):

Chorionic Gonadotropin ◽

Granulosa Cells ◽

Human Chorionic Gonadotropin ◽

Ribonucleic Acid ◽

Regulatory Protein ◽

Steroidogenic Acute Regulatory Protein ◽

Messenger Ribonucleic Acid ◽

Preovulatory Follicles ◽

Theca Interna ◽

Steroidogenic Acute Regulatory

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Extracellular Signal-Regulated Kinases Are Involved in the Acute Activation of Steroidogenesis in Immature Rat Leydig Cells by Human Chorionic Gonadotropin

Endocrinology ◽

10.1210/en.2004-0496 ◽

2004 ◽

Vol 145 (10) ◽

pp. 4629-4634 ◽

Cited By ~ 61

Author(s):

N. Martinelle ◽

M. Holst ◽

O. Söder ◽

K. Svechnikov

Keyword(s):

Protein Kinase ◽

Chorionic Gonadotropin ◽

Human Chorionic Gonadotropin ◽

Protein Phosphatase ◽

Leydig Cells ◽

Regulatory Protein ◽

Steroidogenic Acute Regulatory Protein ◽

Immature Rat ◽

Phosphatase 2A ◽

Steroidogenic Acute Regulatory

Abstract We studied the involvement of the ERK cascade in human chorionic gonadotropin (hCG)-induced steroidogenesis by primary cultures of immature rat Leydig cells. Our findings indicate that protein kinase A and protein kinase C function as upstream kinases in connection with transduction of the signal from the gonadotropin receptor to the ERK cascade. These MAPKs enhance the stimulatory effects of hCG on the de novo synthesis of the steroidogenic acute regulatory protein and the activity of protein phosphatase 2A, which are associated with increased androgen production by the Leydig cell. Specific inhibition of ERK1/2 by Uo126 suppressed all of these cellular responses to hCG. In contrast, steroidogenesis from 22OHC (a cell-permeable form of cholesterol) is not inhibited by Uo126, suggesting that cholesterol delivery to mitochondria is being affected by this compound. We propose that the ERK cascade is an important part of the signal transduction pathway involved in the rapid hormonal responses of Leydig cells to trophic hormones. In hCG-activated Leydig cells, these MAPKs may play a role in controlling the biosynthesis of the steroidogenic acute regulatory protein as well as regulating protein phosphatase 2A activity, thereby governing cholesterol transport across the mitochondrial membrane.

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Luteinizing Hormone/Human Chorionic Gonadotropin-Mediated Activation of mTORC1 Signaling Is Required for Androgen Synthesis by Theca-Interstitial Cells

Molecular Endocrinology ◽

10.1210/me.2012-1106 ◽

2012 ◽

Vol 26 (10) ◽

pp. 1732-1742 ◽

Cited By ~ 22

Author(s):

Murugesan Palaniappan ◽

K. M. J. Menon

Keyword(s):

Chorionic Gonadotropin ◽

Regulatory Protein ◽

Steroidogenic Acute Regulatory Protein ◽

Steroidogenic Enzymes ◽

Steroidogenic Enzyme ◽

S6 Kinase ◽

Ribosomal Protein S6 ◽

Mtorc1 Signaling ◽

Steroidogenic Acute Regulatory ◽

I Cells

Abstract LH triggers the biosynthesis of androgens in the theca-interstitial (T-I) cells of ovary through the activation of a cAMP-dependent pathway. We have previously shown that LH/human chorionic gonadotropin (hCG) activates mammalian target of rapamycin complex 1 (mTORC1) signaling network, leading to cell proliferation. In the present study, we provide evidence that the LH/hCG-mediated activation of the mTORC1 signaling cascade is involved in the regulation of steroidogenic enzymes in androgen biosynthesis. Treatment with LH/hCG increased the expression of downstream targets of mTORC1, ribosomal protein S6 kinase 1, and eukaryotic initiation factor 4E as well as steroidogenic enzymes. LH/hCG-mediated stimulation of the steroidogenic enzyme mRNA was blocked by the mTORC1 inhibitor, rapamycin. This inhibitory effect was selective because rapamycin failed to block hCG-mediated increase in the expression of Star mRNA levels. Furthermore, pharmacological targeting of mTORC1 with rapamycin also blocked LH/hCG- or forskolin-induced expression of cAMP response element-binding protein (CREB) and steroidogenic enzymes (P450 side-chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase type 1, and 17α-hydroxylase/17,20 lyase) but produced no effect on steroidogenic acute regulatory protein levels. These results were further confirmed by demonstrating that the knockdown of mTOR using small interfering RNA selectively abrogated the LH/hCG-induced increase in steroidogenic enzyme expression, without affecting steroidogenic acute regulatory protein expression. LH/hCG-stimulated androgen production was also blocked by rapamycin. Furthermore, the pharmacological inhibition of mTORC1 or ribosomal protein S6 kinase 1 signaling prevented the LH/hCG-induced phosphorylation of CREB. Chromatin immunoprecipitation assays revealed the association of CREB with the proximal promoter of the Cyp17a1 gene in response to hCG, and this association was reduced by rapamycin treatment. Taken together, our findings show for the first time that LH/hCG-mediated activation of androgen biosynthesis is regulated by the mTORC1 signaling pathway in T-I cells.

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Von Hermaphroditos der griechischen Mythologie bis zu DSD der Moderne

Praxis ◽

10.1024/1661-8157.98.1.31 ◽

2008 ◽

Vol 98 (1) ◽

pp. 31-34

Author(s):

Oestmann ◽

Mullis ◽

Stanga

Keyword(s):

Regulatory Protein ◽

Steroidogenic Acute Regulatory Protein ◽

Sich Eine ◽

Fand Sich ◽

Steroidogenic Acute Regulatory

Wir berichten über eine heute 34-jährige Frau, die im Alter von 6 Monaten wegen rezidivierendem Erbrechen hospitalisiert werden musste. Als Ursache fand sich eine Nebenniereninsuffizienz mit Verminderung sämtlicher Hormone der Steroidhormonbiosynthese. Die weiteren Abklärungen ergaben bei dem phänotypisch weiblichen Säugling eine lipoide kongenitale adrenale Hyperplasie mit 46,XY DSD. 24 Jahre später konnte in der DNS-Sequenzanalyse ein homozygoter, in der Schweiz vorkommender Basenaustausch des steroidogenic acute regulatory protein-Gens gefunden werden, welcher zu einem Aminosäurenaustausch Leucin 260 Prolin (L260P) führt.

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