Kisspeptin 10

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Robert P. Millar - One of the best experts on this subject based on the ideXlab platform.

  • gametogenic and steroidogenic action of Kisspeptin 10 in the asian catfish clarias batrachus putative underlying mechanistic cascade
    Comparative Biochemistry and Physiology B, 2021
    Co-Authors: A Singh, Bechan Lal, Jyoti Parkash, Robert P. Millar
    Abstract:

    Unlike mammals, two Kisspeptins genes encoding, kiss1 and kiss2 are detected in fishes with highly varied and contradictory difference in their reproductive activities. The present study was undertaken to examine the direct action of Kisspeptin-10 and its role in gonadal activities in the gonadally quiescent Asian catfish using native mammalian Kisspeptin decapeptide (KP-10) involving in vivo and in vitro approaches. The in vivo KP-10 treatment caused precocious onset of gametogenesis and its rapid progression, as was evident from the appearance of advanced stages of ovarian follicles in ovary, and advanced germ cells (spermatocytes/ spermatids) in the testis of the treated Clarias batrachus in comparison to the control gonads. It also elevated the steroid levels in gonads of the catfish in vivo and in vitro conditions. Simultaneously, it increased the expressions of key steroidogenic enzymes like 3β-HSD, 17β-HSD, and StAR protein, responsible for transfer of cholesterol from outer to inner membrane of the mitochondria of steroidogenic cells. Concurrently, it augmented the activities of 3β-HSD and 17β-HSD in the ovarian explants. The expressions of MAPK component (pERK1/2 and ERK1/2) were also up-regulated by KP-10 in gonadal explants. Thus, the data suggest that Kisspeptin-10 stimulates gametogenesis by enhancing gonadal steroid production. The study also describes the putative mechanistic cascade of steroidogenic actions of Kisspeptin-10 in the catfish so much so in teleost fish. The study also suggests that, Kisspeptin may act locally to regulate gonadal activities in an autocrine/paracine manner, independent of known extra-gonadal factors in the catfish.

  • Kisspeptin and neurokinin b interactions in modulating gonadotropin secretion in women with polycystic ovary syndrome
    Human Reproduction, 2020
    Co-Authors: Karolina Skorupskaite, Jyothis T George, Robert P. Millar, Johannes D. Veldhuis, Richard A Anderson
    Abstract:

    STUDY QUESTION What is the role of the hypothalamic neuropeptide neurokinin B (NKB) and its interaction with Kisspeptin on GnRH/LH secretion in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER Administration of neurokinin 3 receptor antagonist (NK3Ra) for 7 days reduced LH and FSH secretion and LH pulse frequency in women with PCOS, whilst the stimulatory LH response to Kisspeptin-10 was maintained. WHAT IS KNOWN ALREADY PCOS is characterized by abnormal GnRH/LH secretion. NKB and Kisspeptin are master regulators of GnRH/LH secretion, but their role in PCOS is unclear. STUDY DESIGN, SIZE, DURATION The NK3Ra MLE4901, 40 mg orally twice a day, was administered to women with PCOS for 7 days (n = 8) (vs no treatment, n = 7). On the last day of NK3Ra administration or the equivalent day in those not treated, women were randomized to 7-h Kisspeptin-10 (4 µg/kg/h i.v.) or vehicle infusion. This was repeated with the alternate infusion in a subsequent cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS Subjects were women with PCOS, studied in a Clinical Research Facility. Reproductive hormones were measured before and after NK3Ra administration. On the last day of NK3Ra administration (or the equivalent cycle day in untreated women), all women attended for an 8-h frequent blood sampling to allow analysis of the pulsatile LH secretion. MAIN RESULTS AND THE ROLE OF CHANCE NK3Ra reduced LH secretion (4.0 ± 0.4 vs 6.5 ± 0.8 IU/l, P < 0.05) and pulse frequency (0.5 ± 0.1 vs 0.8 ± 0.1 pulses/h, P < 0.05); FSH secretion was also reduced (2.0 ± 0.3 vs 2.5 ± 0.4 IU/l, P < 0.05). Without NK3Ra pre-treatment, Kisspeptin-10 increased LH secretion (5.2 ± 0.5 to 7.8 ± 1.0 IU/L, P < 0.05), with a positive relationship to oestradiol concentrations (r2 = 0.59, P < 0.05). After NK3Ra administration, the LH response to Kisspeptin-10 was preserved (vehicle 3.5 ± 0.3 vs 9.0 ± 2.2 IU/l with Kisspeptin-10, P < 0.05), but the positive correlation with oestradiol concentrations was abolished (r2 = 0.07, ns. after NK3Ra). FSH secretion was increased by Kisspeptin-10 after NK3Ra treatment, but not without NK3Ra treatment. LIMITATIONS, REASONS FOR CAUTION The study did not explore the dose relationship of the effect of NK3R antagonism. The impact of obesity or other aspects of the variability of the PCOS phenotype was not studied due to the small number of subjects. WIDER IMPLICATIONS OF THE FINDINGS These data demonstrate the interactive regulation of GnRH/LH secretion by NKB and Kisspeptin in PCOS, and that the NKB system mediates aspects of oestrogenic feedback. STUDY FUNDING/COMPETING INTEREST(S) Wellcome Trust through Scottish Translational Medicine and Therapeutics Initiative (102419/Z/13/A) and MRC grants (G0701682 to R.P.M. and R.A.A.) and MR/N022556/1 to the MRC Centre for Reproductive Health. This work was performed within the Edinburgh Clinical Research Facility. J.T.G. has undertaken consultancy work for AstraZeneca and Takeda Pharmaceuticals and is an employee of Boehringer Ingelheim. R.P.M. has consulted for Ogeda and was CEO of Peptocrine. R.A.A. has undertaken consultancy work for Merck, Ferring, NeRRe Therapeutics and Sojournix Inc. J.D.V. and K.S. have nothing to disclose. TRIAL REGISTRATION NUMBER N/A.

  • hypothalamic pituitary ovarian axis reactivation by Kisspeptin 10 in hyperprolactinemic women with chronic amenorrhea
    Journal of the Endocrine Society, 2017
    Co-Authors: Jyothis T George, Robert P. Millar, Richard A Anderson, Charlotte Sonigo, Luigi Maione, Sylvie Braillytabard, Philippe Chanson, Nadine Binart, Jacques Young
    Abstract:

    Context: Hyperprolactinemia-induced hypogonadotropic amenorrhea (hPRL-HA) is a major cause of hypothalamic gonadotrophin-releasing hormone (GnRH) deficiency in women. In hyperprolactinemic mice, we previously demonstrated that hypothalamic Kisspeptin (Kp) expression was diminished and that Kp administration restored hypothalamic GnRH release, gonadotropin secretion, and ovarian cyclicity, suggesting that Kp neurons could also play a role in hPRL-HA. Objective: To study the effect of Kp-10 on the gonadotropic-ovarian axis in women with hPRL-HA. Patients: Two women (32 and 36 years old) with chronic hPRL-HA (prolactin: between 94 and 102 and 98 and 112 ng/mL, respectively) caused by cabergoline-resistant microprolactinomas. Interventions: Cabergoline was discontinued 6 months before inclusion. Blood samples were taken every 10 minutes for 12 hours during 2 consecutive days to evaluate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. Serum estradiol (E2), testosterone (T), and inhibin B (IB) levels were also measured. Vehicle or Kp-10 (1.5 μg/kg/h) was infused intravenously for 12 hours. Results: Kp-10 induced a significant increase in LH and FSH levels and increased LH pulses. E2, T, and IB serum levels were also significantly increased. Conclusions: In this exploratory study, we demonstrated that administration of Kp-10 reactivated gonadotropin secretion in women with hPRL-HA and increased ovarian activity. Our data suggest that, as in rodents, GnRH deficiency in hPRL-HA is also mediated by an impairment of hypothalamic Kp secretion. Kp-10 or its analogues could have therapeutic application as an alternative approach to restore ovarian function and fertility in women with hPRL-HA resistant to dopamine agonists and in whom pituitary surgery is not possible.

  • exploring the pathophysiology of hypogonadism in men with type 2 diabetes Kisspeptin 10 stimulates serum testosterone and lh secretion in men with type 2 diabetes and mild biochemical hypogonadism
    Clinical Endocrinology, 2013
    Co-Authors: Jyothis T George, Robert P. Millar, Johannes D. Veldhuis, Manuel Tenasempere, Richard A Anderson
    Abstract:

    Rationale Low serum testosterone is commonly observed in men with type 2 diabetes (T2DM), but the neuroendocrine pathophysiology remains to be elucidated. Objectives The hypothalamic neuropeptide Kisspeptin integrates metabolic signals with the reproductive axis in animal models. We hypothesized that administration of exogenous Kisspeptin-10 will restore luteinizing hormone (LH) and testosterone secretion in hypotestosteronaemic men with T2DM. Participants Five hypotestosteronaemic men with T2DM (age 33·6 ± 3 years, BMI 40·6 ± 6·3, total testosterone 8·5 ± 1·0 nmol/l, LH 4·7 ± 0·7 IU/l, HbA1c 7·4±2%, duration of diabetes <5 years) and seven age-matched healthy men. Experiment 1 Mean LH increased in response to intravenous administration of Kisspeptin-10 (0·3 mcg/kg bolus) both in healthy men (5·5 ± 0·8 to 13·9 ± 1·7 IU/l P < 0·001) and in men with T2DM (4·7 ± 0·7 to 10·7 ± 1·2 IU/l P = 0·02) with comparable ΔLH (P = 0·18). Experiment 2 Baseline 10-min serum sampling for LH and hourly testosterone measurements were performed in four T2DM men over 12 h. An intravenous infusion of Kisspeptin-10 (4 mcg/kg/h) was administered for 11 h, 5 days later. There were increases in LH (3·9 ± 0·1 IU/l to 20·7 ± 1·1 IU/l P = 0·03) and testosterone (8·5 ± 1·0 to 11·4 ± 0·9 nmol/l, P = 0·002). LH pulse frequency increased from 0·6 ± 0·1 to 0·9 ± 0 pulses/h (P = 0·05) and pulsatile component of LH secretion from 32·1 ± 8·0 IU/l to 140·2 ± 23·0 IU/l (P = 0·007). Conclusions Kisspeptin-10 administration increased LH pulse frequency and LH secretion in hypotestosteronaemic men with T2DM in this proof-of-concept study, with associated increases in serum testosterone. These data suggest a potential novel therapeutic role for Kisspeptin agonists in enhancing endogenous testosterone secretion in men with T2DM and central hypogonadism.

  • Kisspeptin 10 stimulation of gonadotrophin secretion in women is modulated by sex steroid feedback
    Human Reproduction, 2012
    Co-Authors: Jyothis T George, Robert P. Millar, Richard A Anderson
    Abstract:

    STUDY QUESTION Does sex-steroid feedback influence gonadotrophin responses to Kisspeptin-10? SUMMARY ANSWER Gonadotrophin response to Kisspeptin-10 is enhanced in sex-steroid deficient post-menopausal women and suppressed in women taking pharmacological doses of exogenous estrogen and progestogen. WHAT IS KNOWN ALREADY Kisspeptin, a novel hypothalamic neuropeptide, stimulates gonadotrophin secretion by stimulating GnRH secretion and has been shown in animal models to play a pivotal role in mediating sex steroid feedback. As estrogen feedback occurs at both the hypothalamus and the pituitary levels, we hypothesized that the stimulatory effect of Kisspeptin-10 in women would be dependent on prevailing sex steroid milieu. STUDY DESIGN, SIZE, DURATION An experimental study of a novel neuropeptide in women-10 in the early follicular phase, 6 post-menopausal and 8 taking sex-steroid contraceptives (combined pill, n = 4; progestogen implants, n = 4) with suppressed LH secretion. Gonadotrophin secretion was followed for 60 min after Kisspeptin administration. METHODS AND PARTICIPANTS The gonadotrophin response to intravenous Kisspeptin-10 (0.3 µg/kg) in women in the early follicular phase was compared with that in the presence of low endogenous sex steroids/high gonadotrophin secretion (post-menopausal women) and in women taking sex-steroid contraceptives (combined pill, n = 4; progestogen implants, n = 4) with suppressed LH secretion. Area under the curve (AUC) of gonadotrophin secretion sampled at 15 min intervals over 60 min before and after Kisspeptin-10 was analysed. MAIN RESULTS AND ROLE OF CHANCE Kisspeptin-10 stimulated LH secretion in follicular (ΔAUC 2.3 ± 0.8 IU/l h, P = 0.009), post-menopausal (5.3 ± 0.9 IU/l h P 0.002) and progestogen (2.6 ± 0.8 IU/l h P 0.05) groups but not in women taking combined pill (0.9 ± 0.4 IU/l h P 0.13). FSH secretion was significantly increased only in post-menopausal women (ΔAUC 2.6 ± 0.8 IU/l h P = 0.03) with changes of <0.5 IU/l h observed in the other three groups. Both LH and FSH responses in post-menopausal women were significantly larger than the other groups (one-way ANOVA analysis of ΔAUC; LH (P = 0.012) and FSH (P = 0.001)]. LIMITATIONS, REASONS FOR CAUTION This study only assessed acute responses to an intravenous bolus of Kisspeptin-10 administration, and the impact of continuous exposure to Kisspeptin-10 on LH pulse frequency in women remains to be studied to fully understand the translational potential. WIDER IMPLICATIONS OF THE FINDINGS Gonadotrophin secretion in women is stimulated by Kisspeptin-10. These results suggest that the pituitary gonadotrope is a functionally important locus of estrogen feedback in women and also inform potential translational applications of Kisspeptin in reproductive endocrine disorders. STUDY FUNDING Medical Research Council (UK). COMPETING INTERESTS None.

Richard A Anderson - One of the best experts on this subject based on the ideXlab platform.

  • Kisspeptin and neurokinin b interactions in modulating gonadotropin secretion in women with polycystic ovary syndrome
    Human Reproduction, 2020
    Co-Authors: Karolina Skorupskaite, Jyothis T George, Robert P. Millar, Johannes D. Veldhuis, Richard A Anderson
    Abstract:

    STUDY QUESTION What is the role of the hypothalamic neuropeptide neurokinin B (NKB) and its interaction with Kisspeptin on GnRH/LH secretion in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER Administration of neurokinin 3 receptor antagonist (NK3Ra) for 7 days reduced LH and FSH secretion and LH pulse frequency in women with PCOS, whilst the stimulatory LH response to Kisspeptin-10 was maintained. WHAT IS KNOWN ALREADY PCOS is characterized by abnormal GnRH/LH secretion. NKB and Kisspeptin are master regulators of GnRH/LH secretion, but their role in PCOS is unclear. STUDY DESIGN, SIZE, DURATION The NK3Ra MLE4901, 40 mg orally twice a day, was administered to women with PCOS for 7 days (n = 8) (vs no treatment, n = 7). On the last day of NK3Ra administration or the equivalent day in those not treated, women were randomized to 7-h Kisspeptin-10 (4 µg/kg/h i.v.) or vehicle infusion. This was repeated with the alternate infusion in a subsequent cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS Subjects were women with PCOS, studied in a Clinical Research Facility. Reproductive hormones were measured before and after NK3Ra administration. On the last day of NK3Ra administration (or the equivalent cycle day in untreated women), all women attended for an 8-h frequent blood sampling to allow analysis of the pulsatile LH secretion. MAIN RESULTS AND THE ROLE OF CHANCE NK3Ra reduced LH secretion (4.0 ± 0.4 vs 6.5 ± 0.8 IU/l, P < 0.05) and pulse frequency (0.5 ± 0.1 vs 0.8 ± 0.1 pulses/h, P < 0.05); FSH secretion was also reduced (2.0 ± 0.3 vs 2.5 ± 0.4 IU/l, P < 0.05). Without NK3Ra pre-treatment, Kisspeptin-10 increased LH secretion (5.2 ± 0.5 to 7.8 ± 1.0 IU/L, P < 0.05), with a positive relationship to oestradiol concentrations (r2 = 0.59, P < 0.05). After NK3Ra administration, the LH response to Kisspeptin-10 was preserved (vehicle 3.5 ± 0.3 vs 9.0 ± 2.2 IU/l with Kisspeptin-10, P < 0.05), but the positive correlation with oestradiol concentrations was abolished (r2 = 0.07, ns. after NK3Ra). FSH secretion was increased by Kisspeptin-10 after NK3Ra treatment, but not without NK3Ra treatment. LIMITATIONS, REASONS FOR CAUTION The study did not explore the dose relationship of the effect of NK3R antagonism. The impact of obesity or other aspects of the variability of the PCOS phenotype was not studied due to the small number of subjects. WIDER IMPLICATIONS OF THE FINDINGS These data demonstrate the interactive regulation of GnRH/LH secretion by NKB and Kisspeptin in PCOS, and that the NKB system mediates aspects of oestrogenic feedback. STUDY FUNDING/COMPETING INTEREST(S) Wellcome Trust through Scottish Translational Medicine and Therapeutics Initiative (102419/Z/13/A) and MRC grants (G0701682 to R.P.M. and R.A.A.) and MR/N022556/1 to the MRC Centre for Reproductive Health. This work was performed within the Edinburgh Clinical Research Facility. J.T.G. has undertaken consultancy work for AstraZeneca and Takeda Pharmaceuticals and is an employee of Boehringer Ingelheim. R.P.M. has consulted for Ogeda and was CEO of Peptocrine. R.A.A. has undertaken consultancy work for Merck, Ferring, NeRRe Therapeutics and Sojournix Inc. J.D.V. and K.S. have nothing to disclose. TRIAL REGISTRATION NUMBER N/A.

  • hypothalamic pituitary ovarian axis reactivation by Kisspeptin 10 in hyperprolactinemic women with chronic amenorrhea
    Journal of the Endocrine Society, 2017
    Co-Authors: Jyothis T George, Robert P. Millar, Richard A Anderson, Charlotte Sonigo, Luigi Maione, Sylvie Braillytabard, Philippe Chanson, Nadine Binart, Jacques Young
    Abstract:

    Context: Hyperprolactinemia-induced hypogonadotropic amenorrhea (hPRL-HA) is a major cause of hypothalamic gonadotrophin-releasing hormone (GnRH) deficiency in women. In hyperprolactinemic mice, we previously demonstrated that hypothalamic Kisspeptin (Kp) expression was diminished and that Kp administration restored hypothalamic GnRH release, gonadotropin secretion, and ovarian cyclicity, suggesting that Kp neurons could also play a role in hPRL-HA. Objective: To study the effect of Kp-10 on the gonadotropic-ovarian axis in women with hPRL-HA. Patients: Two women (32 and 36 years old) with chronic hPRL-HA (prolactin: between 94 and 102 and 98 and 112 ng/mL, respectively) caused by cabergoline-resistant microprolactinomas. Interventions: Cabergoline was discontinued 6 months before inclusion. Blood samples were taken every 10 minutes for 12 hours during 2 consecutive days to evaluate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. Serum estradiol (E2), testosterone (T), and inhibin B (IB) levels were also measured. Vehicle or Kp-10 (1.5 μg/kg/h) was infused intravenously for 12 hours. Results: Kp-10 induced a significant increase in LH and FSH levels and increased LH pulses. E2, T, and IB serum levels were also significantly increased. Conclusions: In this exploratory study, we demonstrated that administration of Kp-10 reactivated gonadotropin secretion in women with hPRL-HA and increased ovarian activity. Our data suggest that, as in rodents, GnRH deficiency in hPRL-HA is also mediated by an impairment of hypothalamic Kp secretion. Kp-10 or its analogues could have therapeutic application as an alternative approach to restore ovarian function and fertility in women with hPRL-HA resistant to dopamine agonists and in whom pituitary surgery is not possible.

  • exploring the pathophysiology of hypogonadism in men with type 2 diabetes Kisspeptin 10 stimulates serum testosterone and lh secretion in men with type 2 diabetes and mild biochemical hypogonadism
    Clinical Endocrinology, 2013
    Co-Authors: Jyothis T George, Robert P. Millar, Johannes D. Veldhuis, Manuel Tenasempere, Richard A Anderson
    Abstract:

    Rationale Low serum testosterone is commonly observed in men with type 2 diabetes (T2DM), but the neuroendocrine pathophysiology remains to be elucidated. Objectives The hypothalamic neuropeptide Kisspeptin integrates metabolic signals with the reproductive axis in animal models. We hypothesized that administration of exogenous Kisspeptin-10 will restore luteinizing hormone (LH) and testosterone secretion in hypotestosteronaemic men with T2DM. Participants Five hypotestosteronaemic men with T2DM (age 33·6 ± 3 years, BMI 40·6 ± 6·3, total testosterone 8·5 ± 1·0 nmol/l, LH 4·7 ± 0·7 IU/l, HbA1c 7·4±2%, duration of diabetes <5 years) and seven age-matched healthy men. Experiment 1 Mean LH increased in response to intravenous administration of Kisspeptin-10 (0·3 mcg/kg bolus) both in healthy men (5·5 ± 0·8 to 13·9 ± 1·7 IU/l P < 0·001) and in men with T2DM (4·7 ± 0·7 to 10·7 ± 1·2 IU/l P = 0·02) with comparable ΔLH (P = 0·18). Experiment 2 Baseline 10-min serum sampling for LH and hourly testosterone measurements were performed in four T2DM men over 12 h. An intravenous infusion of Kisspeptin-10 (4 mcg/kg/h) was administered for 11 h, 5 days later. There were increases in LH (3·9 ± 0·1 IU/l to 20·7 ± 1·1 IU/l P = 0·03) and testosterone (8·5 ± 1·0 to 11·4 ± 0·9 nmol/l, P = 0·002). LH pulse frequency increased from 0·6 ± 0·1 to 0·9 ± 0 pulses/h (P = 0·05) and pulsatile component of LH secretion from 32·1 ± 8·0 IU/l to 140·2 ± 23·0 IU/l (P = 0·007). Conclusions Kisspeptin-10 administration increased LH pulse frequency and LH secretion in hypotestosteronaemic men with T2DM in this proof-of-concept study, with associated increases in serum testosterone. These data suggest a potential novel therapeutic role for Kisspeptin agonists in enhancing endogenous testosterone secretion in men with T2DM and central hypogonadism.

  • Kisspeptin 10 stimulation of gonadotrophin secretion in women is modulated by sex steroid feedback
    Human Reproduction, 2012
    Co-Authors: Jyothis T George, Robert P. Millar, Richard A Anderson
    Abstract:

    STUDY QUESTION Does sex-steroid feedback influence gonadotrophin responses to Kisspeptin-10? SUMMARY ANSWER Gonadotrophin response to Kisspeptin-10 is enhanced in sex-steroid deficient post-menopausal women and suppressed in women taking pharmacological doses of exogenous estrogen and progestogen. WHAT IS KNOWN ALREADY Kisspeptin, a novel hypothalamic neuropeptide, stimulates gonadotrophin secretion by stimulating GnRH secretion and has been shown in animal models to play a pivotal role in mediating sex steroid feedback. As estrogen feedback occurs at both the hypothalamus and the pituitary levels, we hypothesized that the stimulatory effect of Kisspeptin-10 in women would be dependent on prevailing sex steroid milieu. STUDY DESIGN, SIZE, DURATION An experimental study of a novel neuropeptide in women-10 in the early follicular phase, 6 post-menopausal and 8 taking sex-steroid contraceptives (combined pill, n = 4; progestogen implants, n = 4) with suppressed LH secretion. Gonadotrophin secretion was followed for 60 min after Kisspeptin administration. METHODS AND PARTICIPANTS The gonadotrophin response to intravenous Kisspeptin-10 (0.3 µg/kg) in women in the early follicular phase was compared with that in the presence of low endogenous sex steroids/high gonadotrophin secretion (post-menopausal women) and in women taking sex-steroid contraceptives (combined pill, n = 4; progestogen implants, n = 4) with suppressed LH secretion. Area under the curve (AUC) of gonadotrophin secretion sampled at 15 min intervals over 60 min before and after Kisspeptin-10 was analysed. MAIN RESULTS AND ROLE OF CHANCE Kisspeptin-10 stimulated LH secretion in follicular (ΔAUC 2.3 ± 0.8 IU/l h, P = 0.009), post-menopausal (5.3 ± 0.9 IU/l h P 0.002) and progestogen (2.6 ± 0.8 IU/l h P 0.05) groups but not in women taking combined pill (0.9 ± 0.4 IU/l h P 0.13). FSH secretion was significantly increased only in post-menopausal women (ΔAUC 2.6 ± 0.8 IU/l h P = 0.03) with changes of <0.5 IU/l h observed in the other three groups. Both LH and FSH responses in post-menopausal women were significantly larger than the other groups (one-way ANOVA analysis of ΔAUC; LH (P = 0.012) and FSH (P = 0.001)]. LIMITATIONS, REASONS FOR CAUTION This study only assessed acute responses to an intravenous bolus of Kisspeptin-10 administration, and the impact of continuous exposure to Kisspeptin-10 on LH pulse frequency in women remains to be studied to fully understand the translational potential. WIDER IMPLICATIONS OF THE FINDINGS Gonadotrophin secretion in women is stimulated by Kisspeptin-10. These results suggest that the pituitary gonadotrope is a functionally important locus of estrogen feedback in women and also inform potential translational applications of Kisspeptin in reproductive endocrine disorders. STUDY FUNDING Medical Research Council (UK). COMPETING INTERESTS None.

  • Kisspeptin 10 is a potent stimulator of lh and increases pulse frequency in men
    The Journal of Clinical Endocrinology and Metabolism, 2011
    Co-Authors: Jyothis T George, Claire L. Newton, Antonia K. Roseweir, Elena Faccenda, Robert P. Millar, Johannes D. Veldhuis, Richard A Anderson
    Abstract:

    Context: Kisspeptins stimulate GnRH and thus gonadotropin secretion. Kisspeptin-10 is the minimal Kisspeptin sequence with full intrinsic bioactivity, but it has not been studied in man. Objective: We investigated our hypothesis that Kisspeptin-10 increases GnRH and thus LH pulse frequency. Design and Participants: The dose response of Kisspeptin-10 was investigated by administering iv bolus doses (0.01–3.0 μg/kg) and vehicle to healthy men. Effects on LH pulse frequency and size were determined by deconvolution analysis during infusion of Kisspeptin-10 for up to 22.5 h. Results: Intravenous bolus Kisspeptin-10 resulted in a rapid and dose-dependent rise in serum LH concentration, with maximal stimulation at 1 μg/kg (4.1 ± 0.4 to 12.4 ± 1.7 IU/liter at 30 min, P < 0.001, n = 6). Administration of 3 μg/kg elicited a reduced response vs. 1 μg/kg (P < 0.05). Infusion of Kisspeptin-10 at 4 μg/kg · h for 22.5 h elicited an increase in LH from a mean of 5.4 ± 0.7 to 20.8 ± 4.9 IU/liter (n = 4; P < 0.05) and ser...

Manuel Tenasempere - One of the best experts on this subject based on the ideXlab platform.

  • exploring the pathophysiology of hypogonadism in men with type 2 diabetes Kisspeptin 10 stimulates serum testosterone and lh secretion in men with type 2 diabetes and mild biochemical hypogonadism
    Clinical Endocrinology, 2013
    Co-Authors: Jyothis T George, Robert P. Millar, Johannes D. Veldhuis, Manuel Tenasempere, Richard A Anderson
    Abstract:

    Rationale Low serum testosterone is commonly observed in men with type 2 diabetes (T2DM), but the neuroendocrine pathophysiology remains to be elucidated. Objectives The hypothalamic neuropeptide Kisspeptin integrates metabolic signals with the reproductive axis in animal models. We hypothesized that administration of exogenous Kisspeptin-10 will restore luteinizing hormone (LH) and testosterone secretion in hypotestosteronaemic men with T2DM. Participants Five hypotestosteronaemic men with T2DM (age 33·6 ± 3 years, BMI 40·6 ± 6·3, total testosterone 8·5 ± 1·0 nmol/l, LH 4·7 ± 0·7 IU/l, HbA1c 7·4±2%, duration of diabetes <5 years) and seven age-matched healthy men. Experiment 1 Mean LH increased in response to intravenous administration of Kisspeptin-10 (0·3 mcg/kg bolus) both in healthy men (5·5 ± 0·8 to 13·9 ± 1·7 IU/l P < 0·001) and in men with T2DM (4·7 ± 0·7 to 10·7 ± 1·2 IU/l P = 0·02) with comparable ΔLH (P = 0·18). Experiment 2 Baseline 10-min serum sampling for LH and hourly testosterone measurements were performed in four T2DM men over 12 h. An intravenous infusion of Kisspeptin-10 (4 mcg/kg/h) was administered for 11 h, 5 days later. There were increases in LH (3·9 ± 0·1 IU/l to 20·7 ± 1·1 IU/l P = 0·03) and testosterone (8·5 ± 1·0 to 11·4 ± 0·9 nmol/l, P = 0·002). LH pulse frequency increased from 0·6 ± 0·1 to 0·9 ± 0 pulses/h (P = 0·05) and pulsatile component of LH secretion from 32·1 ± 8·0 IU/l to 140·2 ± 23·0 IU/l (P = 0·007). Conclusions Kisspeptin-10 administration increased LH pulse frequency and LH secretion in hypotestosteronaemic men with T2DM in this proof-of-concept study, with associated increases in serum testosterone. These data suggest a potential novel therapeutic role for Kisspeptin agonists in enhancing endogenous testosterone secretion in men with T2DM and central hypogonadism.

  • peripheral administration of the human Kisspeptin 10 and 26rf amide inhibits plasma testosterone levels in the adult male broiler breeder birds gallus domesticus
    Pakistan Journal of Zoology, 2012
    Co-Authors: Fazal Wahab, Manuel Tenasempere, Jérôme Leprince, Lubna Khan, Tanzeela Riaz, H Vaudry, Muhammad Shahab
    Abstract:

    Kisspeptin (KP), a family (belonging to the RFamide superfamily of peptides) of related-peptide hormones encoded by the KISS1 gene, is recently identified as the major player in the neuroendocrine regulation of the mammalian reproduction. Despite the well established role of KP in mammals not much is known about their action in non-mammalian species especially in the avian reproductive physiology. Therefore, the present study was designed to examine the effect of peripheral administration of human Kisspeptin-10 (KP10) on the plasma testosterone (T) concentration in the broiler breeder birds. Three different doses (11.5, 23, 38-nmol; intravenous injection) of KP10 were tested in the intact adult male broiler breeder birds under normal fed conditions. In addition, hCG (30IU) and vehicle (0.5 ml) were administered for control purposes. A single dose (38-nmol) of human 26RFamide (26RFa; another member of RFamide superfamily) was also tested. KP10 administration dose-dependently inhibited (P<0.05- 0.005) plasma T levels. Likewise, 26RFa administration also significantly decreased (P<0.05) plasma T concentration. Vehicle administration did not alter plasma T levels. hCG administration stimulated (P<0.01) plasma T levels. Thus, the present study demonstrated that human KP10 and 26RFa administration suppressed plasma T levels in the adult male broiler breeder birds. Our findings of the present study, therefore, assign a novel role to KP10 and 26RFa, as inhibitor of plasma T secretion in the broiler breeder birds. However, the mechanisms (receptor and intracellular signaling) by which KP10 and 26RFa suppressed the plasma T level in the broiler breeder birds are currently unknown.

  • ontogeny and mechanisms of action for the stimulatory effect of Kisspeptin on gonadotropin releasing hormone system of the rat
    Molecular and Cellular Endocrinology, 2006
    Co-Authors: J M Castellano, Victor M Navarro, R Fernandezfernandez, Justo P Castano, Maria M Malagon, E Aguilar, C Dieguez, Paolo Magni, L Pinilla, Manuel Tenasempere
    Abstract:

    Kisspeptins have recently emerged as essential regulators of gonadotropin secretion and puberty onset. These functions are primarily conducted by stimulation of hypothalamic gonadotropin-releasing hormone (GnRH) secretion. However, relevant aspects of KiSS-1 physiology, including the ontogeny and major signaling systems of its stimulatory action, remain to be fully elucidated. To cover these issues, the effects of Kisspeptin-10 on GnRH and LH secretion were monitored at early stages of postnatal maturation, and potential changes in the sensitivity to Kisspeptin were assessed along the pubertal transition in the rat. In addition, the signaling cascades involved in Kisspeptin-induced GnRH secretion were explored by means of pharmacological blockade using rat hypothalamic explants. Despite sexual immaturity, Kisspeptin-10 potently elicited GnRH release ex vivo and LH secretion in vivo at early stages (neonatal to juvenile) of postnatal development. Yet, LH responsiveness to low doses of Kisspeptin was enhanced in peri-pubertal animals. Concerning GnRH secretion, the stimulatory action of Kisspeptin-10 required activation of phospholipase-C, mobilization of intracellular Ca2+ and recruitment of ERK1/2 and p38 kinases, but was preserved after blockade of type 2 cyclo-oxygenase and prostaglandin synthesis. In summary, our present data document the ontogeny, sensitivity and intracellular signals for the stimulatory action of Kisspeptin on the GnRH/LH axis in the rat. Although LH responses to low doses of Kisspeptin appeared to be enhanced at puberty, Kisspeptin was able to readily activate the GnRH system at early stages of postnatal maturation. These observations further stress the essential role of Kisspeptin in normal, and eventually pathological, timing of puberty.

  • gpr54 and Kisspeptin in reproduction
    Human Reproduction Update, 2006
    Co-Authors: Manuel Tenasempere
    Abstract:

    Kisspeptins, the peptide products of the KiSS-1 gene, were identified in 2001 as natural ligands of the previously orphan G protein-coupled receptor, GPR54. They include, among others, metastin and Kisspeptin-10. The known biological functions of Kisspeptins were initially restricted to their ability to suppress tumour metastasis, hence the name of metastin. However, in late 2003, two groups independently reported that loss-of-function mutations of the GPR54 gene are linked to absence of puberty onset and hypogonadotrophic hypogonadism in humans—a phenotype that was reproduced in GPR54-null mice. Those seminal observations revealed a totally unexpected, fundamental role of the KiSS-1/GPR54 system in control of puberty and reproductive function and boosted an extraordinary interest for the characterization of these novel facets of Kisspeptin physiology. Indeed, in the last 2 years, metastin and Kisspeptin-10 have been demonstrated as very potent stimulators of the gonadotrophic axis, in a number of species and through different routes of administration. In addition, the hypothalamic KiSS-1/GPR54 system has been proven as an essential gatekeeper of GnRH neurons, involved in their activation at puberty and their regulation by gonadal steroids and (probably) metabolic factors. This review comprehensively examines the experimental evidence obtained to date supporting a pivotal role of Kisspeptins and GPR54 in the control of reproduction.

Jyothis T George - One of the best experts on this subject based on the ideXlab platform.

  • Kisspeptin and neurokinin b interactions in modulating gonadotropin secretion in women with polycystic ovary syndrome
    Human Reproduction, 2020
    Co-Authors: Karolina Skorupskaite, Jyothis T George, Robert P. Millar, Johannes D. Veldhuis, Richard A Anderson
    Abstract:

    STUDY QUESTION What is the role of the hypothalamic neuropeptide neurokinin B (NKB) and its interaction with Kisspeptin on GnRH/LH secretion in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER Administration of neurokinin 3 receptor antagonist (NK3Ra) for 7 days reduced LH and FSH secretion and LH pulse frequency in women with PCOS, whilst the stimulatory LH response to Kisspeptin-10 was maintained. WHAT IS KNOWN ALREADY PCOS is characterized by abnormal GnRH/LH secretion. NKB and Kisspeptin are master regulators of GnRH/LH secretion, but their role in PCOS is unclear. STUDY DESIGN, SIZE, DURATION The NK3Ra MLE4901, 40 mg orally twice a day, was administered to women with PCOS for 7 days (n = 8) (vs no treatment, n = 7). On the last day of NK3Ra administration or the equivalent day in those not treated, women were randomized to 7-h Kisspeptin-10 (4 µg/kg/h i.v.) or vehicle infusion. This was repeated with the alternate infusion in a subsequent cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS Subjects were women with PCOS, studied in a Clinical Research Facility. Reproductive hormones were measured before and after NK3Ra administration. On the last day of NK3Ra administration (or the equivalent cycle day in untreated women), all women attended for an 8-h frequent blood sampling to allow analysis of the pulsatile LH secretion. MAIN RESULTS AND THE ROLE OF CHANCE NK3Ra reduced LH secretion (4.0 ± 0.4 vs 6.5 ± 0.8 IU/l, P < 0.05) and pulse frequency (0.5 ± 0.1 vs 0.8 ± 0.1 pulses/h, P < 0.05); FSH secretion was also reduced (2.0 ± 0.3 vs 2.5 ± 0.4 IU/l, P < 0.05). Without NK3Ra pre-treatment, Kisspeptin-10 increased LH secretion (5.2 ± 0.5 to 7.8 ± 1.0 IU/L, P < 0.05), with a positive relationship to oestradiol concentrations (r2 = 0.59, P < 0.05). After NK3Ra administration, the LH response to Kisspeptin-10 was preserved (vehicle 3.5 ± 0.3 vs 9.0 ± 2.2 IU/l with Kisspeptin-10, P < 0.05), but the positive correlation with oestradiol concentrations was abolished (r2 = 0.07, ns. after NK3Ra). FSH secretion was increased by Kisspeptin-10 after NK3Ra treatment, but not without NK3Ra treatment. LIMITATIONS, REASONS FOR CAUTION The study did not explore the dose relationship of the effect of NK3R antagonism. The impact of obesity or other aspects of the variability of the PCOS phenotype was not studied due to the small number of subjects. WIDER IMPLICATIONS OF THE FINDINGS These data demonstrate the interactive regulation of GnRH/LH secretion by NKB and Kisspeptin in PCOS, and that the NKB system mediates aspects of oestrogenic feedback. STUDY FUNDING/COMPETING INTEREST(S) Wellcome Trust through Scottish Translational Medicine and Therapeutics Initiative (102419/Z/13/A) and MRC grants (G0701682 to R.P.M. and R.A.A.) and MR/N022556/1 to the MRC Centre for Reproductive Health. This work was performed within the Edinburgh Clinical Research Facility. J.T.G. has undertaken consultancy work for AstraZeneca and Takeda Pharmaceuticals and is an employee of Boehringer Ingelheim. R.P.M. has consulted for Ogeda and was CEO of Peptocrine. R.A.A. has undertaken consultancy work for Merck, Ferring, NeRRe Therapeutics and Sojournix Inc. J.D.V. and K.S. have nothing to disclose. TRIAL REGISTRATION NUMBER N/A.

  • hypothalamic pituitary ovarian axis reactivation by Kisspeptin 10 in hyperprolactinemic women with chronic amenorrhea
    Journal of the Endocrine Society, 2017
    Co-Authors: Jyothis T George, Robert P. Millar, Richard A Anderson, Charlotte Sonigo, Luigi Maione, Sylvie Braillytabard, Philippe Chanson, Nadine Binart, Jacques Young
    Abstract:

    Context: Hyperprolactinemia-induced hypogonadotropic amenorrhea (hPRL-HA) is a major cause of hypothalamic gonadotrophin-releasing hormone (GnRH) deficiency in women. In hyperprolactinemic mice, we previously demonstrated that hypothalamic Kisspeptin (Kp) expression was diminished and that Kp administration restored hypothalamic GnRH release, gonadotropin secretion, and ovarian cyclicity, suggesting that Kp neurons could also play a role in hPRL-HA. Objective: To study the effect of Kp-10 on the gonadotropic-ovarian axis in women with hPRL-HA. Patients: Two women (32 and 36 years old) with chronic hPRL-HA (prolactin: between 94 and 102 and 98 and 112 ng/mL, respectively) caused by cabergoline-resistant microprolactinomas. Interventions: Cabergoline was discontinued 6 months before inclusion. Blood samples were taken every 10 minutes for 12 hours during 2 consecutive days to evaluate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. Serum estradiol (E2), testosterone (T), and inhibin B (IB) levels were also measured. Vehicle or Kp-10 (1.5 μg/kg/h) was infused intravenously for 12 hours. Results: Kp-10 induced a significant increase in LH and FSH levels and increased LH pulses. E2, T, and IB serum levels were also significantly increased. Conclusions: In this exploratory study, we demonstrated that administration of Kp-10 reactivated gonadotropin secretion in women with hPRL-HA and increased ovarian activity. Our data suggest that, as in rodents, GnRH deficiency in hPRL-HA is also mediated by an impairment of hypothalamic Kp secretion. Kp-10 or its analogues could have therapeutic application as an alternative approach to restore ovarian function and fertility in women with hPRL-HA resistant to dopamine agonists and in whom pituitary surgery is not possible.

  • exploring the pathophysiology of hypogonadism in men with type 2 diabetes Kisspeptin 10 stimulates serum testosterone and lh secretion in men with type 2 diabetes and mild biochemical hypogonadism
    Clinical Endocrinology, 2013
    Co-Authors: Jyothis T George, Robert P. Millar, Johannes D. Veldhuis, Manuel Tenasempere, Richard A Anderson
    Abstract:

    Rationale Low serum testosterone is commonly observed in men with type 2 diabetes (T2DM), but the neuroendocrine pathophysiology remains to be elucidated. Objectives The hypothalamic neuropeptide Kisspeptin integrates metabolic signals with the reproductive axis in animal models. We hypothesized that administration of exogenous Kisspeptin-10 will restore luteinizing hormone (LH) and testosterone secretion in hypotestosteronaemic men with T2DM. Participants Five hypotestosteronaemic men with T2DM (age 33·6 ± 3 years, BMI 40·6 ± 6·3, total testosterone 8·5 ± 1·0 nmol/l, LH 4·7 ± 0·7 IU/l, HbA1c 7·4±2%, duration of diabetes <5 years) and seven age-matched healthy men. Experiment 1 Mean LH increased in response to intravenous administration of Kisspeptin-10 (0·3 mcg/kg bolus) both in healthy men (5·5 ± 0·8 to 13·9 ± 1·7 IU/l P < 0·001) and in men with T2DM (4·7 ± 0·7 to 10·7 ± 1·2 IU/l P = 0·02) with comparable ΔLH (P = 0·18). Experiment 2 Baseline 10-min serum sampling for LH and hourly testosterone measurements were performed in four T2DM men over 12 h. An intravenous infusion of Kisspeptin-10 (4 mcg/kg/h) was administered for 11 h, 5 days later. There were increases in LH (3·9 ± 0·1 IU/l to 20·7 ± 1·1 IU/l P = 0·03) and testosterone (8·5 ± 1·0 to 11·4 ± 0·9 nmol/l, P = 0·002). LH pulse frequency increased from 0·6 ± 0·1 to 0·9 ± 0 pulses/h (P = 0·05) and pulsatile component of LH secretion from 32·1 ± 8·0 IU/l to 140·2 ± 23·0 IU/l (P = 0·007). Conclusions Kisspeptin-10 administration increased LH pulse frequency and LH secretion in hypotestosteronaemic men with T2DM in this proof-of-concept study, with associated increases in serum testosterone. These data suggest a potential novel therapeutic role for Kisspeptin agonists in enhancing endogenous testosterone secretion in men with T2DM and central hypogonadism.

  • Kisspeptin 10 stimulation of gonadotrophin secretion in women is modulated by sex steroid feedback
    Human Reproduction, 2012
    Co-Authors: Jyothis T George, Robert P. Millar, Richard A Anderson
    Abstract:

    STUDY QUESTION Does sex-steroid feedback influence gonadotrophin responses to Kisspeptin-10? SUMMARY ANSWER Gonadotrophin response to Kisspeptin-10 is enhanced in sex-steroid deficient post-menopausal women and suppressed in women taking pharmacological doses of exogenous estrogen and progestogen. WHAT IS KNOWN ALREADY Kisspeptin, a novel hypothalamic neuropeptide, stimulates gonadotrophin secretion by stimulating GnRH secretion and has been shown in animal models to play a pivotal role in mediating sex steroid feedback. As estrogen feedback occurs at both the hypothalamus and the pituitary levels, we hypothesized that the stimulatory effect of Kisspeptin-10 in women would be dependent on prevailing sex steroid milieu. STUDY DESIGN, SIZE, DURATION An experimental study of a novel neuropeptide in women-10 in the early follicular phase, 6 post-menopausal and 8 taking sex-steroid contraceptives (combined pill, n = 4; progestogen implants, n = 4) with suppressed LH secretion. Gonadotrophin secretion was followed for 60 min after Kisspeptin administration. METHODS AND PARTICIPANTS The gonadotrophin response to intravenous Kisspeptin-10 (0.3 µg/kg) in women in the early follicular phase was compared with that in the presence of low endogenous sex steroids/high gonadotrophin secretion (post-menopausal women) and in women taking sex-steroid contraceptives (combined pill, n = 4; progestogen implants, n = 4) with suppressed LH secretion. Area under the curve (AUC) of gonadotrophin secretion sampled at 15 min intervals over 60 min before and after Kisspeptin-10 was analysed. MAIN RESULTS AND ROLE OF CHANCE Kisspeptin-10 stimulated LH secretion in follicular (ΔAUC 2.3 ± 0.8 IU/l h, P = 0.009), post-menopausal (5.3 ± 0.9 IU/l h P 0.002) and progestogen (2.6 ± 0.8 IU/l h P 0.05) groups but not in women taking combined pill (0.9 ± 0.4 IU/l h P 0.13). FSH secretion was significantly increased only in post-menopausal women (ΔAUC 2.6 ± 0.8 IU/l h P = 0.03) with changes of <0.5 IU/l h observed in the other three groups. Both LH and FSH responses in post-menopausal women were significantly larger than the other groups (one-way ANOVA analysis of ΔAUC; LH (P = 0.012) and FSH (P = 0.001)]. LIMITATIONS, REASONS FOR CAUTION This study only assessed acute responses to an intravenous bolus of Kisspeptin-10 administration, and the impact of continuous exposure to Kisspeptin-10 on LH pulse frequency in women remains to be studied to fully understand the translational potential. WIDER IMPLICATIONS OF THE FINDINGS Gonadotrophin secretion in women is stimulated by Kisspeptin-10. These results suggest that the pituitary gonadotrope is a functionally important locus of estrogen feedback in women and also inform potential translational applications of Kisspeptin in reproductive endocrine disorders. STUDY FUNDING Medical Research Council (UK). COMPETING INTERESTS None.

  • Kisspeptin 10 is a potent stimulator of lh and increases pulse frequency in men
    The Journal of Clinical Endocrinology and Metabolism, 2011
    Co-Authors: Jyothis T George, Claire L. Newton, Antonia K. Roseweir, Elena Faccenda, Robert P. Millar, Johannes D. Veldhuis, Richard A Anderson
    Abstract:

    Context: Kisspeptins stimulate GnRH and thus gonadotropin secretion. Kisspeptin-10 is the minimal Kisspeptin sequence with full intrinsic bioactivity, but it has not been studied in man. Objective: We investigated our hypothesis that Kisspeptin-10 increases GnRH and thus LH pulse frequency. Design and Participants: The dose response of Kisspeptin-10 was investigated by administering iv bolus doses (0.01–3.0 μg/kg) and vehicle to healthy men. Effects on LH pulse frequency and size were determined by deconvolution analysis during infusion of Kisspeptin-10 for up to 22.5 h. Results: Intravenous bolus Kisspeptin-10 resulted in a rapid and dose-dependent rise in serum LH concentration, with maximal stimulation at 1 μg/kg (4.1 ± 0.4 to 12.4 ± 1.7 IU/liter at 30 min, P < 0.001, n = 6). Administration of 3 μg/kg elicited a reduced response vs. 1 μg/kg (P < 0.05). Infusion of Kisspeptin-10 at 4 μg/kg · h for 22.5 h elicited an increase in LH from a mean of 5.4 ± 0.7 to 20.8 ± 4.9 IU/liter (n = 4; P < 0.05) and ser...

Mohammad A. Ghatei - One of the best experts on this subject based on the ideXlab platform.

  • Direct comparison of the effects of intravenous Kisspeptin-10, Kisspeptin-54 and GnRH on gonadotrophin secretion in healthy men
    Human Reproduction, 2015
    Co-Authors: Channa N. Jayasena, Alexander N Comninos, Julianne T Mogford, Zainab Malik, J. Calley, Shakunthala Narayanaswamy, Ali Abbara, Risheka Ratnasabapathy, Paul Bassett, Mohammad A. Ghatei
    Abstract:

    main results and the role of chance:Serum LH and FSH levels were � 3-fold higher during GnRH infusion when compared with Kisspeptin-10 and � 2-fold higher when compared with Kisspeptin-54 [mean area under the curve serum LH during infusion (in hours times international units per litre, h.IU/l): 10.81+ 1.73, 1.0 nmol/kg/h Kisspeptin-10; 14.43+ 1.27, 1.0 nmol/kg/h Kisspeptin-54; 34.06+ 5.18, 1.0 nmol/kg/h GnRH, P , 0.001 versus Kisspeptin-10, P , 0.01 versus Kisspeptin-54]. limitations, reasons for caution: This study had a small sample size. wider implications of the findings: Kisspeptin offers a novel means of stimulating the reproductive axis. Our data suggest that Kisspeptin stimulates gonadotrophin secretion less potently when compared with GnRH; however, Kisspeptin may stimulate gonadotrophins in a more physiological manner when compared with current therapies. Kisspeptin is emerging as a future therapeutic agent, so it is important to establish which Kisspeptin hormones could be used to treat patients with infertility. Results of this study suggest that either isoform has similar effects on reproductive hormone secretion in healthy men when administered intravenously. study funding/competing interests: This work is funded by grants from the MRC and NIHR and is supported by the NIHR

  • the effects of Kisspeptin 10 on reproductive hormone release show sexual dimorphism in humans
    The Journal of Clinical Endocrinology and Metabolism, 2011
    Co-Authors: Channa N. Jayasena, Alexander N Comninos, Gurjinder M K Nijher, Adam Januszewki, Meriel Vaal, Labosshy Sriskandarajah, Zohreh Farzad, Ali Abbara, Kevin G Murphy, Mohammad A. Ghatei
    Abstract:

    Background: Kisspeptin peptides are critical in human reproductive physiology and are potential therapies for infertility. Kisspeptin-10 stimulates gonadotropin release in both male and female rodents. However, few studies have investigated the effects of Kisspeptin-10 on gonadotropin release in humans, and none have investigated the effect in women. If Kisspeptin is to be useful for treating reproductive disease, its effects in both men and women must be established. Aim: To compare the effects of Kisspeptin-10 administration on reproductive hormone release in healthy men and women. Methods: Intravenous bolus Kisspeptin-10 was administered to men and women (n = 4–5 per group). Subcutaneous bolus and iv infusion of Kisspeptin-10 was also administered to female women (n = 4–5 per group). Circulating reproductive hormones were measured. Results: In healthy men, serum LH and FSH were elevated after iv bolus Kisspeptin-10, at doses as low as 0.3 and 1.0 nmol/kg, respectively. In healthy women during the folli...

  • A Kisspeptin-10 analog with greater in vivo bioactivity than Kisspeptin-10
    American Journal of Physiology-endocrinology and Metabolism, 2009
    Co-Authors: Annette E. Curtis, Jennifer H. Cooke, Jordan E. Baxter, James Richard C. Parkinson, A. Bataveljic, Mohammad A. Ghatei, Stephen R Bloom, Kevin Murphy
    Abstract:

    The Kisspeptins are neuropeptides that stimulate the hypothalamo-pituitary-gonadal (HPG) axis. The smallest endogenous Kisspeptin, Kisspeptin-10 (KP-10), binds to the receptor KISS1R with a similar...

  • an increase in Kisspeptin 54 release occurs with the pubertal increase in luteinizing hormone releasing hormone 1 release in the stalk median eminence of female rhesus monkeys in vivo
    Endocrinology, 2008
    Co-Authors: Kim L Keen, Frederick H Wegner, Mohammad A. Ghatei, Stephen R Bloom, Ei Terasawa
    Abstract:

    The G-protein coupled receptor GPR54 and its ligand, KiSS-1-derived peptide Kisspeptin-54, appear to play an important role in the mechanism of puberty. This study measures the release of Kisspeptin-54 in the stalk-median eminence (S-ME) during puberty and examines its potential role in the pubertal increase in LHRH-1 release in female rhesus monkeys. First, developmental changes in release of Kisspeptin-54 and LHRH-1 were assessed in push-pull perfusate samples obtained from the S-ME of prepubertal, early pubertal, and midpubertal female rhesus monkeys. Whereas LHRH-1 levels in 10-min intervals had been measured previously for other experiments, Kisspeptin-54 levels in 40-min pooled samples were newly measured by RIA. The results indicate that a significant increase in Kisspeptin-54 release occurred in association with the pubertal increase in LHRH-1 release and that a nocturnal increase in Kisspeptin-54 release was already observed in prepubertal monkeys and continued through the pubertal period. Second, we measured Kisspeptin-54 release in the S-ME of midpubertal monkeys at 10-min intervals using a microdialysis method. Kisspeptin-54 release in the S-ME was clearly pulsatile with an interpulse interval of about 60 min, and approximately 75% of Kisspeptin-54 pulses were correlated with LHRH-1 pulses. Finally, the effect of Kisspeptin-10 on LHRH-1 release was examined with the microdialysis method. Kisspeptin-10 infusion through a microdialysis probe significantly stimulated LHRH-1 release in a dose-dependent manner. Collectively, the results are consistent with the hypothesis that Kisspeptin plays a role in puberty.

  • central and peripheral administration of Kisspeptin 10 stimulates the hypothalamic pituitary gonadal axis
    Journal of Neuroendocrinology, 2004
    Co-Authors: Emily L Thompson, J F Todd, K Murphy, Waljit S Dhillo, Mohammad A. Ghatei, Kirsty L Smith, Michael Patterson, S.r. Bloom
    Abstract:

    Kisspeptin is the peptide product of the KiSS-1 gene and the endogenous agonist for the GPR54 receptor. Recent evidence suggests the Kisspeptin/GPR54 system is a key regulator of the reproductive system. We examined the effect of intracerebroventricular (i.c.v.) and peripheral administration of the active Kisspeptin fragment, Kisspeptin-10, on circulating gonadotrophins and total testosterone levels in adult male rats. The effect of Kisspeptin-10 in vitro on the release of hypothalamic peptides from hypothalamic explants and gonadotrophins from anterior pituitary fragments was also determined. The i.c.v. administration of Kisspeptin-10 dose-dependently increased plasma luteinizing hormone (LH) and increased plasma follicle stimulating hormone (FSH) and total testosterone at 60 min postinjection. In a separate study investigating the time course of this response, i.c.v. administered Kisspeptin-10 (3 nmol) significantly increased plasma LH at 10, 20 and 60 min, FSH at 60 min and total testosterone at 20 and 60 min postinjection. Kisspeptin-10 stimulated the release of luteinizing hormone-releasing hormone (LHRH) from in vitro hypothalamic explants. Peripheral administration of Kisspeptin-10 increased plasma LH, FSH and total testosterone. However, doses of 100–1000 nM Kisspeptin-10 did not influence LH or FSH release from pituitary fragments in vitro. Kisspeptin therefore potently stimulates the hypothalamic-pituitary-gonadal axis. These effects are likely to be mediated via the hypothalamic LHRH system.

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