ABSTRACT
BACKGROUND: The bone morphogenetic proteins (BMPs) are growth factors involved in the folliculogenesis. Alteration in their expression may compromise the reproductive process in disease such as the polycystic ovary syndrome (PCOS). This study investigated the expression and role of granulosa cell (GC) BMP from normal cycling and PCOS women. METHODS AND RESULTS: This prospective study was performed in GCs obtained from 14 patients undergoing IVF: i) six women with normal ovulatory cycles and tubal or male infertility and ii) eight women with PCOS. BMP2, BMP4, BMP5, BMP6, BMP7, and BMP8A and their receptors BMPR1A, BMPR1B, and BMPR2 were identified by RT-PCR in GCs from normally cycling and PCOS women. BMP4, BMP6, and BMP7 expressions were confirmed by immunohistochemistry. Quantitative transcript analysis showed the predominant expression of BMP6. In GCs from PCOS women, an overexpression of BMP6 (P<0.01) and BMPR1A mRNA (P<0.05) was observed. GC culture experiments demonstrated that basal estradiol (E2) production was threefold higher but FSH-induced E2 increment was twofold lower in PCOS compared with controls. In PCOS, BMP6 and BMP7 exerted a stimulatory effect on basal E2 production while BMP4 and BMP6 inhibited FSH-induced E2 production. FSH receptor and aromatase expression were not different between both groups. CONCLUSION: The BMP system is expressed in human GCs from normal cycling and PCOS women. The BMP may be involved in reproductive abnormalities found in PCOS.
Subject(s)
Bone Morphogenetic Protein Receptors/metabolism , Bone Morphogenetic Proteins/metabolism , Gene Expression Regulation , Granulosa Cells/metabolism , Polycystic Ovary Syndrome/metabolism , Steroids/metabolism , Adult , Bone Morphogenetic Protein 4/genetics , Bone Morphogenetic Protein 4/metabolism , Bone Morphogenetic Protein 6/genetics , Bone Morphogenetic Protein 6/metabolism , Bone Morphogenetic Protein 7/genetics , Bone Morphogenetic Protein 7/metabolism , Bone Morphogenetic Protein Receptors/genetics , Bone Morphogenetic Proteins/genetics , Cells, Cultured , Estradiol/metabolism , Female , Follicle Stimulating Hormone, Human/metabolism , Granulosa Cells/pathology , Humans , Immunohistochemistry , Polycystic Ovary Syndrome/pathology , Prospective Studies , Protein Isoforms/genetics , Protein Isoforms/metabolism , RNA, Messenger/metabolism , Young AdultABSTRACT
Gonadotrophin-releasing hormone (GnRH) agonists and antagonists have been widely used to prevent premature LH surge during ovarian stimulation. However, studies have shown a significantly lower serum oestradiol concentration on the day of human chorionic gonadotrophin administration for cycles using GnRH antagonist. This study compared aromatase gene expression in granulosa lutein cells from 50 women randomly assigned to receive either GnRH agonist (group 1, n=28) or GnRH antagonist (group 2, n=22). The cellular mechanism involved in the observed effects was also investigated. GnRH antagonist treatment significantly affected serum oestradiol concentration (1894+/-138 versus 1074+/-63 pg/ml; P < or = 0.001), follicular-fluid oestradiol concentration in large follicles (18,565+/-2467 versus 10,184+/-1993 pg/ml; P < or = 0.05), aromatase activity (9600+/-1179 versus 5376+/-997 fmol/10(6) cells/h; P < or = 0.05) and mRNA aromatase/mRNA glyceraldehyde 3-phosphate dehydrogenase (15+/-3 versus 6+/-1; P < 0.05). Protein kinase C (PKC) activity in granulosa lutein cells from the GnRH antagonist group was 2.5-fold higher than in the GnRH agonist group. In-vitro experiments showed that selective down-regulation of PKC was only observed in GnRH-desensitized granulosa lutein cells. This report suggests that, in granulosa lutein cells, the modulation of the FSH-induced protein kinase A pathway by PKC was different in agonist versus antagonist cycles.
