title: Mutual regulation of growth hormone and bone morphogenetic protein system in steroidogenesis by rat granulosa cells.
abstract: GH induces preantral follicle growth and differentiation with oocyte maturation. However, the effects of GH on ovarian steroidogenesis and the mechanisms underlying its effects have yet to be elucidated. In this study, we investigated the actions of GH on steroidogenesis by rat granulosa cells isolated from early antral follicles by focusing on the ovarian bone morphogenetic protein (BMP) system. We found that GH suppressed FSH-induced estradiol production with reduction in aromatase expression and, in contrast, GH increased FSH-induced progesterone level with induction of steroidogenic acute regulatory protein, side chain cleavage cytochrome P450, and 3β-hydroxysteroid dehydrogenase. The effects of GH on steroidogenesis by granulosa cells were enhanced in the presence of the BMP antagonist noggin. Coculture of GH with oocytes did not alter GH regulation of steroidogenesis. Steroid production induced by cAMP donors was not affected by GH treatment and the GH effects on FSH-induced steroid production were not accompanied by changes in cAMP synthesis, suggesting that GH actions were not directly mediated by the cAMP-protein kinase A pathway. GH exerted synergistic effects on MAPK activation elicited by FSH, which regulated FSH-induced steroidogenesis. In addition, GH-induced signal transducer and activator of transcription phosphorylation was involved in the induction of IGF-I expression. GH increased IGF-I, IGF-I receptor, and FSH receptor expression in granulosa cells, and inhibition of IGF-I signaling restored GH stimulation of FSH-induced progesterone production, suggesting that endogenous IGF-I is functionally involved in GH effects on progesterone induction. BMP inhibited IGF-I effects that increased FSH-induced estradiol production with suppression of expression of the GH/IGF-I system, whereas GH/IGF-I actions impaired BMP-Sma and Mad related protein 1/5/8 signaling through down-regulation of the expression of BMP receptors. Thus, GH acts to modulate estrogen and progesterone production differentially through endogenous IGF-I activity in granulosa cells, in which GH-IGF-I interaction leads to antagonization of BMP actions including suppression of FSH-induced progesterone production. Mutual balance between GH/IGF-I and BMP signal intensities may be a key for regulating gonadotropin-induced steroidogenesis in growing follicles.
authors: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama City, 700-8558, Japan.
authors: Eri
authors: E
authors: Nakamura
authors: Fumio
authors: F
authors: Otsuka
authors: Kenichi
authors: K
authors: Inagaki
authors: Tomoko
authors: T
authors: Miyoshi
authors: Yoshinori
authors: Y
authors: Matsumoto
authors: Kanako
authors: K
authors: Ogura
authors: Naoko
authors: N
authors: Tsukamoto
authors: Masaya
authors: M
authors: Takeda
authors: Hirofumi
authors: H
authors: Makino
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism / Q000494:pharmacology; D018920:Coculture Techniques; D004958:Estradiol / Q000096:biosynthesis; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D013006:Growth Hormone / Q000378:metabolism* / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008954:Models, Biological; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011374:Progesterone / Q000096:biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000235:genetics; D011962:Receptors, FSH / Q000235:genetics; D011986:Receptors, Somatotropin / Q000235:genetics; D013256:Steroids / Q000096:biosynthesis*; D000099176:Noggin Protein
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D004958:Estradiol; D005640:Follicle Stimulating Hormone; D013006:Growth Hormone; D007334:Insulin-Like Growth Factor I; D011374:Progesterone; D012333:RNA, Messenger; D017526:Receptor, IGF Type 1; D011962:Receptors, FSH; D011986:Receptors, Somatotropin; D013256:Steroids; D000099176:Noggin Protein