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Yuriy Kirichok - One of the best experts on this subject based on the ideXlab platform.
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disruption of the principal Progesterone activated sperm ca2 channel in a catsper2 deficient infertile patient
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: James F Smith, Yuriy Kirichok, Olga Syritsyna, M Fellous, Catherine Serres, Nadja Mannowetz, Polina V. LishkoAbstract:The female steroid hormone Progesterone regulates ovulation and supports pregnancy, but also controls human sperm function within the female reproductive tract. Progesterone causes elevation of sperm intracellular Ca2+ leading to sperm hyperactivation, acrosome reaction, and perhaps chemotaxis toward the egg. Although it has been suggested that Progesterone-dependent Ca2+ influx into human spermatozoa is primarily mediated by cationic channel of sperm (CatSper), the principal flagellar Ca2+ channel of sperm, conclusive loss-of-function genetic evidence for activation of CatSper by Progesterone has yet to be provided. Moreover, it is not clear whether the responsiveness of CatSper to Progesterone is an innate property of human spermatozoa or is acquired as the result of exposure to the seminal plasma. Here, by recording ionic currents from spermatozoa of an infertile CatSper-deficient patient, we demonstrate that CatSper is indeed the principal Ca2+ channel of human spermatozoa, and that it is strongly potentiated by Progesterone. In addition, by recording CatSper currents from human epididymal and testicular spermatozoa, we show that CatSper sensitivity to Progesterone arises early in sperm development and increases gradually to a peak when spermatozoa are ejaculated. These results unambiguously establish an important role of CatSper channel in human sperm nongenomic Progesterone signaling and demonstrate that the molecular mechanism responsible for activation of CatSper by Progesterone arises early in sperm development concurrently with the CatSper channel itself.
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Progesterone activates the principal ca2 channel of human sperm
Nature, 2011Co-Authors: Polina V. Lishko, Inna L. Botchkina, Yuriy KirichokAbstract:The female steroid hormone Progesterone is produced by the ovaries and the placenta, and supports gestation and embryogenesis through its actions on a well-characterized nuclear Progesterone receptor. But Progesterone released by cells surrounding the egg also stimulates sperm cells within the Fallopian tubes and increases their fertilizing ability, and the mechanism of this action of Progesterone has remained elusive. Two independent research groups now report that Progesterone potently activates CatSper, the principal Ca2+ channel of the sperm flagellum. Their data demonstrate that the CatSper channel or a directly associated membrane protein serves as a novel Progesterone receptor that can mediate a fast, non-genomic effect of Progesterone at the level of the sperm plasma membrane. These results should help to define the physiological role of Progesterone and CatSper in sperm, and could lead to the development of new classes of non-hormonal contraceptives. Progesterone stimulates an increase in Ca2+ levels in human sperm, but the underlying signalling mechanism is poorly understood. Two studies now show that Progesterone activates the sperm-specific, pH-sensitive CatSper calcium channel, leading to a rapid influx of Ca2+ ions into the spermatozoa. These results should help to define the physiological role of Progesterone and CatSper in sperm, and could lead to the development of new classes of non-hormonal contraceptives. Steroid hormone Progesterone released by cumulus cells surrounding the egg is a potent stimulator of human spermatozoa. It attracts spermatozoa towards the egg and helps them penetrate the egg’s protective vestments1. Progesterone induces Ca2+ influx into spermatozoa1,2,3 and triggers multiple Ca2+-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the egg4,5,6,7,8. As an ovarian hormone, Progesterone acts by regulating gene expression through a well-characterized Progesterone nuclear receptor9. However, the effect of Progesterone upon transcriptionally silent spermatozoa remains unexplained and is believed to be mediated by a specialized, non-genomic membrane Progesterone receptor5,10. The identity of this non-genomic Progesterone receptor and the mechanism by which it causes Ca2+ entry remain fundamental unresolved questions in human reproduction. Here we elucidate the mechanism of the non-genomic action of Progesterone on human spermatozoa by identifying the Ca2+ channel activated by Progesterone. By applying the patch-clamp technique to mature human spermatozoa, we found that nanomolar concentrations of Progesterone dramatically potentiate CatSper, a pH-dependent Ca2+ channel of the sperm flagellum. We demonstrate that human CatSper is synergistically activated by elevation of intracellular pH and extracellular Progesterone. Interestingly, human CatSper can be further potentiated by prostaglandins, but apparently through a binding site other than that of Progesterone. Because our experimental conditions did not support second messenger signalling, CatSper or a directly associated protein serves as the elusive non-genomic Progesterone receptor of sperm. Given that the CatSper-associated Progesterone receptor is sperm specific and structurally different from the genomic Progesterone receptor, it represents a promising target for the development of a new class of non-hormonal contraceptives.
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Progesterone activates the principal Ca 2+ channel of human sperm
Nature, 2011Co-Authors: Polina V. Lishko, Inna L. Botchkina, Yuriy KirichokAbstract:Steroid hormone Progesterone released by cumulus cells surrounding the egg is a potent stimulator of human spermatozoa. It attracts spermatozoa towards the egg and helps them penetrate the egg's protective vestments. Progesterone induces Ca(2+) influx into spermatozoa and triggers multiple Ca(2+)-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the egg. As an ovarian hormone, Progesterone acts by regulating gene expression through a well-characterized Progesterone nuclear receptor. However, the effect of Progesterone upon transcriptionally silent spermatozoa remains unexplained and is believed to be mediated by a specialized, non-genomic membrane Progesterone receptor. The identity of this non-genomic Progesterone receptor and the mechanism by which it causes Ca(2+) entry remain fundamental unresolved questions in human reproduction. Here we elucidate the mechanism of the non-genomic action of Progesterone on human spermatozoa by identifying the Ca(2+) channel activated by Progesterone. By applying the patch-clamp technique to mature human spermatozoa, we found that nanomolar concentrations of Progesterone dramatically potentiate CatSper, a pH-dependent Ca(2+) channel of the sperm flagellum. We demonstrate that human CatSper is synergistically activated by elevation of intracellular pH and extracellular Progesterone. Interestingly, human CatSper can be further potentiated by prostaglandins, but apparently through a binding site other than that of Progesterone. Because our experimental conditions did not support second messenger signalling, CatSper or a directly associated protein serves as the elusive non-genomic Progesterone receptor of sperm. Given that the CatSper-associated Progesterone receptor is sperm specific and structurally different from the genomic Progesterone receptor, it represents a promising target for the development of a new class of non-hormonal contraceptives.
Polina V. Lishko - One of the best experts on this subject based on the ideXlab platform.
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disruption of the principal Progesterone activated sperm ca2 channel in a catsper2 deficient infertile patient
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: James F Smith, Yuriy Kirichok, Olga Syritsyna, M Fellous, Catherine Serres, Nadja Mannowetz, Polina V. LishkoAbstract:The female steroid hormone Progesterone regulates ovulation and supports pregnancy, but also controls human sperm function within the female reproductive tract. Progesterone causes elevation of sperm intracellular Ca2+ leading to sperm hyperactivation, acrosome reaction, and perhaps chemotaxis toward the egg. Although it has been suggested that Progesterone-dependent Ca2+ influx into human spermatozoa is primarily mediated by cationic channel of sperm (CatSper), the principal flagellar Ca2+ channel of sperm, conclusive loss-of-function genetic evidence for activation of CatSper by Progesterone has yet to be provided. Moreover, it is not clear whether the responsiveness of CatSper to Progesterone is an innate property of human spermatozoa or is acquired as the result of exposure to the seminal plasma. Here, by recording ionic currents from spermatozoa of an infertile CatSper-deficient patient, we demonstrate that CatSper is indeed the principal Ca2+ channel of human spermatozoa, and that it is strongly potentiated by Progesterone. In addition, by recording CatSper currents from human epididymal and testicular spermatozoa, we show that CatSper sensitivity to Progesterone arises early in sperm development and increases gradually to a peak when spermatozoa are ejaculated. These results unambiguously establish an important role of CatSper channel in human sperm nongenomic Progesterone signaling and demonstrate that the molecular mechanism responsible for activation of CatSper by Progesterone arises early in sperm development concurrently with the CatSper channel itself.
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Progesterone activates the principal ca2 channel of human sperm
Nature, 2011Co-Authors: Polina V. Lishko, Inna L. Botchkina, Yuriy KirichokAbstract:The female steroid hormone Progesterone is produced by the ovaries and the placenta, and supports gestation and embryogenesis through its actions on a well-characterized nuclear Progesterone receptor. But Progesterone released by cells surrounding the egg also stimulates sperm cells within the Fallopian tubes and increases their fertilizing ability, and the mechanism of this action of Progesterone has remained elusive. Two independent research groups now report that Progesterone potently activates CatSper, the principal Ca2+ channel of the sperm flagellum. Their data demonstrate that the CatSper channel or a directly associated membrane protein serves as a novel Progesterone receptor that can mediate a fast, non-genomic effect of Progesterone at the level of the sperm plasma membrane. These results should help to define the physiological role of Progesterone and CatSper in sperm, and could lead to the development of new classes of non-hormonal contraceptives. Progesterone stimulates an increase in Ca2+ levels in human sperm, but the underlying signalling mechanism is poorly understood. Two studies now show that Progesterone activates the sperm-specific, pH-sensitive CatSper calcium channel, leading to a rapid influx of Ca2+ ions into the spermatozoa. These results should help to define the physiological role of Progesterone and CatSper in sperm, and could lead to the development of new classes of non-hormonal contraceptives. Steroid hormone Progesterone released by cumulus cells surrounding the egg is a potent stimulator of human spermatozoa. It attracts spermatozoa towards the egg and helps them penetrate the egg’s protective vestments1. Progesterone induces Ca2+ influx into spermatozoa1,2,3 and triggers multiple Ca2+-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the egg4,5,6,7,8. As an ovarian hormone, Progesterone acts by regulating gene expression through a well-characterized Progesterone nuclear receptor9. However, the effect of Progesterone upon transcriptionally silent spermatozoa remains unexplained and is believed to be mediated by a specialized, non-genomic membrane Progesterone receptor5,10. The identity of this non-genomic Progesterone receptor and the mechanism by which it causes Ca2+ entry remain fundamental unresolved questions in human reproduction. Here we elucidate the mechanism of the non-genomic action of Progesterone on human spermatozoa by identifying the Ca2+ channel activated by Progesterone. By applying the patch-clamp technique to mature human spermatozoa, we found that nanomolar concentrations of Progesterone dramatically potentiate CatSper, a pH-dependent Ca2+ channel of the sperm flagellum. We demonstrate that human CatSper is synergistically activated by elevation of intracellular pH and extracellular Progesterone. Interestingly, human CatSper can be further potentiated by prostaglandins, but apparently through a binding site other than that of Progesterone. Because our experimental conditions did not support second messenger signalling, CatSper or a directly associated protein serves as the elusive non-genomic Progesterone receptor of sperm. Given that the CatSper-associated Progesterone receptor is sperm specific and structurally different from the genomic Progesterone receptor, it represents a promising target for the development of a new class of non-hormonal contraceptives.
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Progesterone activates the principal Ca 2+ channel of human sperm
Nature, 2011Co-Authors: Polina V. Lishko, Inna L. Botchkina, Yuriy KirichokAbstract:Steroid hormone Progesterone released by cumulus cells surrounding the egg is a potent stimulator of human spermatozoa. It attracts spermatozoa towards the egg and helps them penetrate the egg's protective vestments. Progesterone induces Ca(2+) influx into spermatozoa and triggers multiple Ca(2+)-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the egg. As an ovarian hormone, Progesterone acts by regulating gene expression through a well-characterized Progesterone nuclear receptor. However, the effect of Progesterone upon transcriptionally silent spermatozoa remains unexplained and is believed to be mediated by a specialized, non-genomic membrane Progesterone receptor. The identity of this non-genomic Progesterone receptor and the mechanism by which it causes Ca(2+) entry remain fundamental unresolved questions in human reproduction. Here we elucidate the mechanism of the non-genomic action of Progesterone on human spermatozoa by identifying the Ca(2+) channel activated by Progesterone. By applying the patch-clamp technique to mature human spermatozoa, we found that nanomolar concentrations of Progesterone dramatically potentiate CatSper, a pH-dependent Ca(2+) channel of the sperm flagellum. We demonstrate that human CatSper is synergistically activated by elevation of intracellular pH and extracellular Progesterone. Interestingly, human CatSper can be further potentiated by prostaglandins, but apparently through a binding site other than that of Progesterone. Because our experimental conditions did not support second messenger signalling, CatSper or a directly associated protein serves as the elusive non-genomic Progesterone receptor of sperm. Given that the CatSper-associated Progesterone receptor is sperm specific and structurally different from the genomic Progesterone receptor, it represents a promising target for the development of a new class of non-hormonal contraceptives.
J. C. Prior - One of the best experts on this subject based on the ideXlab platform.
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Effects of Progesterone therapy on serum sclerostin levels in healthy menopausal women: a 3-month randomized, placebo-controlled clinical trial
Osteoporosis International, 2020Co-Authors: Y. B. Yang, A. Goshtasebi, A. H. Van Lierop, D. Kalidasan, C. L. Hitchcock, J. C. PriorAbstract:Sclerostin, a natural hormone made in bone, suppresses bone formation. Sclerostin is also decreased by estrogen. Progesterone, estrogen’s menstrual partner, stimulates bone formation. It is unclear whether Progesterone influences sclerostin. This study showed that Progesterone did not change sclerostin using serum remaining from a randomized Progesterone hot flush therapy trial. Introduction Progesterone and sclerostin are both endogenous hormones acting through osteoblast-origin cells and promote or suppress bone formation, respectively. Estradiol suppresses sclerostin, but Progesterone, its menstrual cycle partner hormone, has unclear sclerostin relationships. We postulated that Progesterone therapy would influence serum sclerostin levels. Methods We obtained sclerostin levels for an ethics-approved post hoc analysis. Fasting sclerostin was measured in all remaining sera from a previous 12-week randomized controlled trial (RCT) of oral micronized Progesterone (Progesterone) for menopausal (> 1 year after last flow) vasomotor symptoms (VMS). Women in the RCT took 300 mg Progesterone at bedtime or placebo (1:1) in a trial showing Progesterone significantly decreased VMS. Results Participants were healthy menopausal, primarily Caucasian (91.2%) community-dwelling women (± SD), 55.2 ± 4.6 years old with BMI 24.9 ± 2.9 kg/m^2. The baseline sclerostin level in 60 women was 28.41 ± 10.47 pmol/L. Baseline sclerostin was not correlated with the run-in VMS score ( r = 0.143, P = 0.294). Paired baseline and 12-week RCT data for 52 women showed serum sclerostin levels did not change related to experimental therapy ( P = 0.504). Changes in final sclerostin values adjusted for baseline were Progesterone (− 1.07 ± 7.96 pmol/L) and placebo (− 2.64 ± 8.70 pmol/L). In observational data ( n = 60), baseline sclerostin levels correlated with the General Framingham Cardiovascular (CVD) Risk score ( r = − 0.398, P = 0.003) and self-reported health by SF-36 quality of life instrument (QoL, r = − 0.331, P = 0.016). Conclusion Physiological oral micronized Progesterone did not stimulate nor suppress serum sclerostin levels based on post hoc analysis of RCT data. Exploratory results, however, showed sclerostin negatively correlated with CVD risk and QoL. ClinicalTrials.gov #NCT0146469.
W Van Den Broeck - One of the best experts on this subject based on the ideXlab platform.
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immunolocalization of Progesterone receptors in the canine ovary and their relation to sex steroid hormone concentrations
Reproduction, 2001Co-Authors: Hildegarde Vermeirsch, Paul Simoens, M Coryn, W Van Den BroeckAbstract:The aim of the present study was to describe the normal cellular distribution of Progesterone receptors in the canine ovary at different stages of the oestrous cycle. Samples of both ovaries were obtained from 75 healthy adult bitches of various breeds and ages, including five pregnant bitches and three bitches that had just delivered. The presence of Progesterone receptors was visualized by immunohistochemistry on paraffin wax sections using a monoclonal antibody. Nuclear staining for Progesterone receptors was observed in the surface epithelium, cortical tubules, rete ovarii, follicle cells, thecal cells, luteal cells, granulosa cell cords and ovarian stroma. The staining intensity for Progesterone receptors in the follicle cells increased with the stage of follicle development, indicating an intrafollicular role of Progesterone in the mechanism of ovulation and luteinization. The stronger staining intensities for Progesterone receptors in thecal cells compared with follicle cells may be explained by the fact that thecal cells mediate some effects of steroid hormones on the follicle cells in secondary and tertiary follicles. Little correlation was found between the expression of Progesterone receptors in follicle cells and oestradiol, Progesterone or testosterone concentrations. This finding indicates a different regulating mechanism for Progesterone receptors in canine ovarian follicles compared with other tissues of the genital tract. During pregnancy all groups of ovarian cells had lower staining intensity scores than during the oestrous cycle, although the sex steroid hormone concentrations in pregnant bitches were similar to those in non-pregnant bitches during the luteal phase of the oestrous cycle. The lower expression of Progesterone receptors during pregnancy may be due to higher tissue concentrations of Progesterone that are not reflected in the serum because of haemodilution and increased metabolism and clearance during pregnancy.
Y. B. Yang - One of the best experts on this subject based on the ideXlab platform.
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Effects of Progesterone therapy on serum sclerostin levels in healthy menopausal women: a 3-month randomized, placebo-controlled clinical trial
Osteoporosis International, 2020Co-Authors: Y. B. Yang, A. Goshtasebi, A. H. Van Lierop, D. Kalidasan, C. L. Hitchcock, J. C. PriorAbstract:Sclerostin, a natural hormone made in bone, suppresses bone formation. Sclerostin is also decreased by estrogen. Progesterone, estrogen’s menstrual partner, stimulates bone formation. It is unclear whether Progesterone influences sclerostin. This study showed that Progesterone did not change sclerostin using serum remaining from a randomized Progesterone hot flush therapy trial. Introduction Progesterone and sclerostin are both endogenous hormones acting through osteoblast-origin cells and promote or suppress bone formation, respectively. Estradiol suppresses sclerostin, but Progesterone, its menstrual cycle partner hormone, has unclear sclerostin relationships. We postulated that Progesterone therapy would influence serum sclerostin levels. Methods We obtained sclerostin levels for an ethics-approved post hoc analysis. Fasting sclerostin was measured in all remaining sera from a previous 12-week randomized controlled trial (RCT) of oral micronized Progesterone (Progesterone) for menopausal (> 1 year after last flow) vasomotor symptoms (VMS). Women in the RCT took 300 mg Progesterone at bedtime or placebo (1:1) in a trial showing Progesterone significantly decreased VMS. Results Participants were healthy menopausal, primarily Caucasian (91.2%) community-dwelling women (± SD), 55.2 ± 4.6 years old with BMI 24.9 ± 2.9 kg/m^2. The baseline sclerostin level in 60 women was 28.41 ± 10.47 pmol/L. Baseline sclerostin was not correlated with the run-in VMS score ( r = 0.143, P = 0.294). Paired baseline and 12-week RCT data for 52 women showed serum sclerostin levels did not change related to experimental therapy ( P = 0.504). Changes in final sclerostin values adjusted for baseline were Progesterone (− 1.07 ± 7.96 pmol/L) and placebo (− 2.64 ± 8.70 pmol/L). In observational data ( n = 60), baseline sclerostin levels correlated with the General Framingham Cardiovascular (CVD) Risk score ( r = − 0.398, P = 0.003) and self-reported health by SF-36 quality of life instrument (QoL, r = − 0.331, P = 0.016). Conclusion Physiological oral micronized Progesterone did not stimulate nor suppress serum sclerostin levels based on post hoc analysis of RCT data. Exploratory results, however, showed sclerostin negatively correlated with CVD risk and QoL. ClinicalTrials.gov #NCT0146469.
