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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

Instituto de Investigaciones Materno Infantil y Departamento de Obstetricia y Ginecología, Facultad de Medicina, Universidad de Chile, Hospital Clínico San Borja-Arriarán (P.K., O.C., A.P., A.M., L.D.); and Instituto de Nutrición y Tecnología de Alimentos, Universidad de Chile (W.S.), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile (P.C.), CP 6519100 Santiago, Chile; and Center for Research on Reproduction and Women’s Health, University of Pennsylvania (L.K.C., J.F.S.), Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: Dr. Luigi Devoto, Instituto de Investigaciones Materno Infantil y Departamento de Obstetricia y Ginecología, Facultad de Medicina, Universidad de Chile. P.O. Box 226-3, PC 6519100 Santiago, Chile. E-mail: ldevoto{at}machi.med.uchile.cl.

This study was designed 1) to assess corpus luteum (CL) steroidogenesis in response to exogenous human chorionic gonadotropin (hCG) at different times during the luteal phase, 2) to examine the effect of hCG on steroidogenic acute regulatory protein (StAR) expression within the CL, 3) to correlate StAR expression and luteal steroidogenic responses to hCG, and 4) to determine whether endogenous LH regulates ovarian steroidogenesis in the early luteal phase. Blood was collected before and after hCG treatment for steroid and hCGß determinations. CL were obtained at the time of surgery to assess StAR gene and protein expression. During the early luteal phase various women received the GnRH antagonist for 24–48 h; some of them also received hCG 24 h after the GnRH antagonist. A slight steroidogenic response to hCG was observed in early luteal phase; 17-hydroxyprogesterone, but not progesterone (P4), levels were significantly increased 8 h post-hCG, indicating a differential response by the granulosa and theca-lutein cells. The 1.6- and 4.4-kb StAR transcripts and the 37-kDa preprotein and 30-kDa mature StAR protein did not change post-hCG administration in early luteal phase CL.

In contrast, the StAR 4.4- and 1.6-kb transcripts diminished significantly (P < 0.05) after the antagonist treatment. Immunohistochemical staining for StAR protein was weak, particularly in granulosa-lutein cells. Treatment with hCG restored StAR mRNA and protein and plasma P4 levels within 24 h in antagonist-treated women. hCG stimulated the highest plasma concentrations of P4 and estradiol in the midluteal phase, indicating its greatest steroidogenic capacity. Midluteal tissue StAR gene and protein expression increased by 1.6- and 1.4-fold after 24 h of hCG treatment, respectively. Administration of hCG resulted in the greatest increment in plasma P4 (4-fold) and 17-hydroxyprogesterone (3-fold) levels over baseline in the late luteal phase. This was associated with an increase in StAR mRNA (3.5-fold) and protein (1.8-fold).

Collectively, these data indicate that 1) the hCG-stimulated steroidogenic response is dependent on the age of the CL; 2) the early luteal phase CL is relatively insensitive to exogenous hCG in the presence of normal pituitary gonadotropin support, but becomes responsive when the latter is withdrawn; 3) the hCG-stimulated steroidogenic response in the mid- and late luteal phase is correlated with increased StAR mRNA and protein abundance; and 4) there are differential responses of small and large luteal cells to hCG stimulation that depend upon the age of the CL.

This work was supported in part by CONICYT/FONDECYT-Programa Fondap Grant 15010006 and NIH Grants TW-001485 and HD-06274.

Abbreviations: AUC, Area under the curve; CL, corpus luteum; E2, estradiol; hCG, human chorionic gonadotropin; 17OHP, 17-hydroxyprogesterone; P4, progesterone; SSC, standard saline citrate; StAR, steroidogenic acute regulatory protein; T, testosterone.

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