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SUMMARY
Two women, who had undergone bilateral ovariectomy and adrenalectomy for carcinomatosis secondary to primary growths of the breast, received 100 mg progesterone in arachis oil intramuscularly for 3 days. Estimations of pregnane-3(α):20(α)-diol, total 17-ketosteroids and dehydroisoandrosterone and its derivatives were made on 24 hr urine specimens collected for a control period, while the patients received progesterone, and for 3 days afterwards. Both patients excreted increased amounts of pregnane-3(α):20(α)-diol and one excreted increased amounts of 17-ketosteroids and dehydroisoandrosterone and its derivatives.
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The 5,7-dienes, 3β-hydroxy-5,7-pregnadien-20-one and 3β-hydroxy-5,7-androstadien-17-one were extracted from fetal horse gonads and purified by solvent partition, thin-layer chromatography and high performance liquid chromatography. The isolated steroids were identified by comparison with the synthetic steroids using ultraviolet and mass spectroscopy and by gas chromatography–mass spectroscopy. The identification of these compounds as endogenous steroids, together with the data on their biosynthesis reported previously, support the proposal that in the fetal horse gonad there is a 5,7-diene pathway biosynthesizing 3β-hydroxy-5,7-androstadien-17-one, which is the proposed precursor for equilin in the placenta.
Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California 94305-5317, USA
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Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California 94305-5317, USA
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Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California 94305-5317, USA
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Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California 94305-5317, USA
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Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California 94305-5317, USA
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In addition to gonadotropins, steroidogenesis and proliferation of granulosa cells during follicular development are controlled by a number of intraovarian factors including growth differentiation factor-9 (GDF-9), bone morphogenetic protein-4 (BMP-4), and IGF-I. The objective of this study was to determine the effect of GDF-9 and BMP-4 and their interaction with IGF-I and FSH on ovarian granulosa cell function in cattle. Granulosa cells from small (1–5 mm) and large (8–22 mm) follicles were collected from bovine ovaries and cultured for 48 h in medium containing 10% fetal calf serum and then treated with various hormones in serum-free medium for an additional 48 h. We evaluated the effects of GDF-9 (150–600 ng/ml) and BMP-4 (30 ng/ml) during a 2-day exposure on hormone-induced steroidogenesis and cell proliferation. In FSH plus IGF-I-treated granulosa cells obtained from small follicles, 300 ng/ml GDF-9 reduced (P<0.05) progesterone production by 15% and 600 ng/ml GDF-9 completely blocked (P<0.01) the IGF-I-induced increase in progesterone production. In comparison, 300 and 600 ng/ml GDF-9 decreased (P<0.05) estradiol production by 27% and 71% respectively, whereas 150 ng/ml GDF-9 was without effect (P>0.10). Treatment with 600 ng/ml GDF-9 increased (P<0.05) numbers (by 28%) of granulosa cells from small follicles. In the same cells treated with FSH but not IGF-I, co-treatment with 600 ng/ml GDF-9 decreased (P<0.05) progesterone production (by 28%), increased (P<0.05) cell numbers (by 60%), and had no effect (P>0.10) on estradiol production. In FSH plus IGF-I-treated granulosa cells obtained from large follicles, GDF-9 caused a dose-dependent decrease (P<0.05) in IGF-I-induced progesterone (by 13–48%) and estradiol (by 20–51%) production. In contrast, GDF-9 increased basal and IGF-I-induced granulosa cell numbers by over 2-fold. Furthermore, treatment with BMP-4 also inhibited (P<0.05) steroidogenesis by 27–42% but had no effect on cell numbers. To elucidate downstream signaling pathways, granulosa cells from small follicles were transfected with similar to mothers against decapentaplegics (Smad) binding element (CAGA)- or BMP response element (BRE)-promoter reporter constructs. Treatment with GDF-9 (but not BMP-4) activated the Smad3-induced CAGA promoter activity, whereas BMP-4 (but not GDF-9) activated the Smad1/5/8-induced BRE promoter activity. We have concluded that bovine granulosa cells are targets of both GDF-9 and BMP-4, and that oocyte-derived GDF-9 may simultaneously promote granulosa cell proliferation and prevent premature differentiation of the granulosa cells during growth of follicles, whereas theca-derived BMP-4 may also prevent premature follicular differentiation.
Inpharmatica Ltd, London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK
Biomedical Research Institute, Department of Biological Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
Cancer Research-UK Labs and Section of Cancer Cell Biology, Department of Cancer Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
Endokrinologikum Hamburg, Falkenried 88, 20251 Hamburg, Germany
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Inpharmatica Ltd, London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK
Biomedical Research Institute, Department of Biological Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
Cancer Research-UK Labs and Section of Cancer Cell Biology, Department of Cancer Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
Endokrinologikum Hamburg, Falkenried 88, 20251 Hamburg, Germany
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Inpharmatica Ltd, London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK
Biomedical Research Institute, Department of Biological Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
Cancer Research-UK Labs and Section of Cancer Cell Biology, Department of Cancer Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
Endokrinologikum Hamburg, Falkenried 88, 20251 Hamburg, Germany
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Inpharmatica Ltd, London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK
Biomedical Research Institute, Department of Biological Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
Cancer Research-UK Labs and Section of Cancer Cell Biology, Department of Cancer Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
Endokrinologikum Hamburg, Falkenried 88, 20251 Hamburg, Germany
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Inpharmatica Ltd, London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK
Biomedical Research Institute, Department of Biological Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
Cancer Research-UK Labs and Section of Cancer Cell Biology, Department of Cancer Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
Endokrinologikum Hamburg, Falkenried 88, 20251 Hamburg, Germany
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Inpharmatica Ltd, London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK
Biomedical Research Institute, Department of Biological Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
Cancer Research-UK Labs and Section of Cancer Cell Biology, Department of Cancer Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
Endokrinologikum Hamburg, Falkenried 88, 20251 Hamburg, Germany
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Inpharmatica Ltd, London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK
Biomedical Research Institute, Department of Biological Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
Cancer Research-UK Labs and Section of Cancer Cell Biology, Department of Cancer Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
Endokrinologikum Hamburg, Falkenried 88, 20251 Hamburg, Germany
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Inpharmatica Ltd, London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK
Biomedical Research Institute, Department of Biological Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
Cancer Research-UK Labs and Section of Cancer Cell Biology, Department of Cancer Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
Endokrinologikum Hamburg, Falkenried 88, 20251 Hamburg, Germany
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Inpharmatica Ltd, London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK
Biomedical Research Institute, Department of Biological Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
Cancer Research-UK Labs and Section of Cancer Cell Biology, Department of Cancer Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
Endokrinologikum Hamburg, Falkenried 88, 20251 Hamburg, Germany
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Inpharmatica Ltd, London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK
Biomedical Research Institute, Department of Biological Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
Cancer Research-UK Labs and Section of Cancer Cell Biology, Department of Cancer Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
Endokrinologikum Hamburg, Falkenried 88, 20251 Hamburg, Germany
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Inpharmatica Ltd, London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK
Biomedical Research Institute, Department of Biological Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
Cancer Research-UK Labs and Section of Cancer Cell Biology, Department of Cancer Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
Endokrinologikum Hamburg, Falkenried 88, 20251 Hamburg, Germany
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Rapid non-genomic actions of progesterone are implicated in many aspects of female reproduction. Recently, three human homologues of the fish membrane progestin receptor (mPR) have been identified. We combined bioinformatic analysis with expression profiling to define further the role of these mPRs in human reproductive tissues. Sequence analysis confirmed that the mPRs belong to a larger, highly conserved family of proteins, termed ‘progestin and adiponectin receptors’ (PAQRs). A comparison of the expression of mPR transcripts with that of two related PAQR family members, PAQRIII and PAQRIX, in cycling endometrium and pregnancy tissues revealed markedly divergent expression levels and profiles. For instance, endometrial expression of mPRα and γ and PAQRIX was cycle-dependent whereas the onset of parturition was associated with a marked reduction in myometrial mPRα and β transcripts. Interestingly, mPRα and PAQRIX were most highly expressed in the placenta, and the tissue expression levels of both genes correlated inversely with that of the nuclear PR. Phylogenetic analysis demonstrated that PAQRIX belongs to the mPR subgroup of proteins. We also validated a polyclonal antibody raised against the carboxy-terminus of human mPRα. Immunohistochemical analysis demonstrated more intense immunoreactivity in placental syncytiotrophoblasts than in endometrial glands or stroma. The data suggest important functional roles for mPRα, and possibly PAQRIX, in specific reproductive tissues, particularly those that express low levels of nuclear PR.
