title: Involvement of bone morphogenetic protein activity in somatostatin actions on ovarian steroidogenesis.
abstract: Somatostatin is expressed in the hypothalamus, pancreas and gastrointestinal tracts and it inhibits the secretion of various hormones in vivo. In the rodent ovary, somatostatin receptor (SSTR) subtypes 2 and 5 are expressed in granulosa cells and oocytes. Somatostatin analogs have been clinically used for treatment of endocrine tumors. For this purpose, relatively high-dose or long-term treatments of somatostatin analogs are necessary; however, the direct and continuous impact of somatostatin analogs on gonadal functions has yet to be elucidated. In the present study, we investigated the effects of somatostatin analogs (octreotide and pasireotide) on ovarian steroidogenesis by rat primary granulosa cell culture. The expression levels of SSTR2 and SSTR5 in granulosa cells were upregulated by FSH treatment. Treatment with somatostatin analogs decreased FSH-induced estradiol production with reduction in aromatase mRNA expression, while the treatment also suppressed FSH-induced progesterone production with reduction of mRNAs levels of StAR, P450scc and 3βHSD2 in granulosa cells. This trend was also observed in a granulosa/oocyte co-culture condition. The effect of pasireotide was more potent than that of octreotide. FSH-induced synthesis of steroids and cAMP was also suppressed by somatostatin analog treatment. Notably, pretreatment with a BMP-binding protein, noggin reversed the suppressive effects of somatostatin analogs on progesterone and cAMP production, suggesting that the endogenous BMP system is functionally involved in the SSTR effects in granulosa cells. Treatment with BMP-2, -4, -6 and -7 decreased the mRNA expression of inhibitory Smads6 and 7, leading to enhancement of BMP actions detected by Id-1 transcription in granulosa cells. Collectively, the results revealed that SSTR activation modulates ovarian steroidogenesis by upregulating endogenous BMP activity in growing follicles.
authors.affiliation: 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.forename: Eri
authors.initials: E
authors.lastname: Nakamura
authors.forename: Fumio
authors.initials: F
authors.lastname: Otsuka
authors.forename: Kenichi
authors.initials: K
authors.lastname: Inagaki
authors.forename: Naoko
authors.initials: N
authors.lastname: Tsukamoto
authors.forename: Kanako
authors.initials: K
authors.lastname: Ogura-Ochi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Miyoshi
authors.forename: Kishio
authors.initials: K
authors.lastname: Toma
authors.forename: Masaya
authors.initials: M
authors.lastname: Takeda
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004958:Estradiol / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D006107:Granulosa Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015282:Octreotide / Q000494:pharmacology*; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010053:Ovary / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000235:genetics; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013256:Steroids / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D019485:Bone Morphogenetic Proteins; D017481:Receptors, Somatostatin; C115977:Sstr2 protein, rat; D013256:Steroids; D011374:Progesterone; D004958:Estradiol; D013004:Somatostatin; C094573:somatostatin receptor 5; D005640:Follicle Stimulating Hormone; C517782:pasireotide; D015282:Octreotide