Kisspeptin

[Michael Scally MD]

Comninos A, Anastasovska J, Sahuri-Arisoylu M, Li X, Li S, et al. Kisspeptin signaling in the amygdala modulates reproductive hormone secretion. Brain Structure and Function. 2015;1-13. http://link.springer.com/article/10.1007/s00429-015-1024-9/fulltext.html

Kisspeptin (encoded by KISS1) is a crucial activator of reproductive function. The role of kisspeptin has been studied extensively within the hypothalamus but little is known about its significance in other areas of the brain.

KISS1 and its cognate receptor are expressed in the amygdala, a key limbic brain structure with inhibitory projections to hypothalamic centers involved in gonadotropin secretion. We therefore hypothesized that kisspeptin has effects on neuronal activation and reproductive pathways beyond the hypothalamus and particularly within the amygdala.

To test this, we mapped brain neuronal activity (using manganese-enhanced MRI) associated with peripheral kisspeptin administration in rodents. We also investigated functional relevance by measuring the gonadotropin response to direct intra-medial amygdala (MeA) administration of kisspeptin and kisspeptin antagonist.

Peripheral kisspeptin administration resulted in a marked decrease in signal intensity in the amygdala compared to vehicle alone. This was associated with an increase in luteinizing hormone (LH) secretion. In addition, intra-MeA administration of kisspeptin resulted in increased LH secretion, while blocking endogenous kisspeptin signaling within the amygdala by administering intra-MeA kisspeptin antagonist decreased both LH secretion and LH pulse frequency.

We provide evidence for the first time that neuronal activity within the amygdala is decreased by peripheral kisspeptin administration and that kisspeptin signaling within the amygdala contributes to the modulation of gonadotropin release and pulsatility.

Our data suggest that kisspeptin is a ‘master regulator’ of reproductive physiology, integrating limbic circuits with the regulation of gonadotropin-releasing hormone neurons and reproductive hormone secretion.

 

[barbelle]

This is very interesting, but it sounds like no lifter would want to experiment with this for at least another 5 to 10 years. Too early, too little known, serious potential to fuck you up for life if it can cause GnRH-releasing cells to start migrating.

I'm guessing it already sells pretty well.

 

[Michael Scally MD]

Kisspeptin Neurons Mediate Negative Feedback in the Male Reproductive Axis
https://endo.confex.com/endo/2015endo/webprogram/Paper20017.html

Pulsatile neurosecretion of gonadotropin-releasing hormone (GnRH) maintains the activity of hypothalamic-pituitary-gonadal axes of both sexes.

In males, homeostatic negative feedback regulation within the axis is conveyed by testosterone (T), which suppresses GnRH pulsatility and thereby restrains luteinizing hormone (LH) secretion. These effects are mediated by activation of the androgen receptor (AR) by T and/or estrogen receptor alpha (ERα) by estrogens derived from aromatization of T. Since GnRH neurons do not express appreciable AR or ERa, both actions are likely exerted in first- or multi-order neuronal afferents controlling pulsatile GnRH neurosecretion.

Kisspeptin (Kiss1) neurons have been implicated in the transmission of gonadal steroid feedback, as they innervate GnRH neurons, stimulate GnRH release, and express ERα and AR. Moreover, Kiss1 expression in the arcuate nucleus (ARC) of the hypothalamus is increased following castration and suppressed by T replacement.

We tested the hypothesis that negative feedback in the male mouse reproductive axis is dependent upon activation of either AR or ERα in kisspeptin neurons. Male kisspeptin cell-specific AR knockout (KARKO) mice, kisspeptin cell-specific ERα knockout (KERKO) mice, and control Cre- wild-type (WT) mice were generated and their hormone responses to sham surgery (SS), castration (Cx) + vehicle (V), Cx + T, Cx + 17b-estradiol (E2), or Cx + dihydrotestosterone (non-aromatizable androgen; DHT) were compared.

Results: Serum LH levels were low following SS, and elevated in all genotypes following Cx + V, although the post-Cx rise in LH was moderately attenuated in KARKO mice.

T was fully effective in suppressing LH in all genotypes. However, E2 exerted full feedback suppression in WT and KARKO, but was only partially suppressive in KERKO mice; by contrast DHT exerted full feedback suppression in WT and KERKO mice, but was only partially effective in KARKO mice.

Measurement of Kiss1 mRNA in the ARC by qPCR revealed differences in Kiss1 expression among groups and treatments that were strikingly similar to those observed for effects on serum LH.

Conclusions: These results demonstrate that ERα in kisspeptin neurons mediates negative feedback elicited by E2, while AR in kisspeptin neurons is required for a portion of the negative feedback actions exerted by androgens. Our observations are consistent with the idea that ERa and AR in kisspeptin neurons convey parallel and mutually compensatory feedback actions of T in the male reproductive axis.

 

[Michael Scally MD]

Jayasena CN, Abbara A, Narayanaswamy S, Comninos AN, Ratnasabapathy R, et al. Direct comparison of the effects of intravenous kisspeptin-10, kisspeptin-54 and GnRH on gonadotrophin secretion in healthy men. Hum Reprod. http://humrep.oxfordjournals.org/content/early/2015/06/17/humrep.dev143.full

STUDY QUESTION: How potently does the novel hypothalamic stimulator of reproduction, kisspeptin, increase gonadotrophin secretion when compared with GnRH in healthy men?

SUMMARY ANSWER: At the doses tested, intravenous administration of either of two major kisspeptin isoforms, kisspeptin-10 and -54, was associated with similar levels of gonadotrophin secretion in healthy men; however, GnRH was more potent when compared with either kisspeptin isoform.

WHAT IS KNOWN ALREADY: Kisspeptin-10 and -54 are naturally occurring hormones in the kisspeptin peptide family which potently stimulates endogenous GnRH secretion from the hypothalamus, so have the potential to treat patients with reproductive disorders. Rodent studies suggest that kisspeptin-54 is more potent when compared with kisspepitn-10; however, their effects have not previously been directly compared in humans, or compared with direct pituitary stimulation of gonadotrophin secretion using GnRH.

STUDY DESIGN, SIZE AND DURATION: A single-blinded placebo controlled physiological study was performed from January to December 2013. Local ethical approval was granted, and five participants were recruited to each dosing group.

PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthy men were administered vehicle, kisspeptin-10, kisspeptin-54 and GnRH intravenously for 3 h on different study days. Each hormone was administered at 0.1, 0.3 and 1.0 nmol/kg/h doses (n = 5 subjects per group). Regular blood sampling was conducted throughout the study to measure LH and FSH. Study visits were conducted at least a week apart.

MAIN RESULTS AND THE ROLE OF CHANCE: Serum LH and FSH levels were approximately 3-fold higher during GnRH infusion when compared with kisspeptin-10 and approximately 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 Imperial Biomedical Research Centre Funding Scheme. C.N.J. is supported by an NIHR Clinical Lectureship. A.A. is supported by Wellcome Trust Research Training Fellowships. A.N.C. is supported by Wellcome Trust Translational Medicine Training Fellowship. W.S.D. is supported by an NIHR Career Development Fellowship.

 

[Michael Scally MD]

There is Kisspeptin - And Then There is Kisspeptin

Trends
· Kisspeptin and its class I G protein-coupled receptor KISS1R regulate not only (i) puberty and fertility but also (ii) glucose homeostasis, locomotor activity, and body-weight control.
· Glucagon stimulates liver kisspeptin production. Kisspeptin inhibits insulin secretion via activating KISS1R located on pancreatic β cells.
· In the absence of KISS1R signaling, locomotor activity is profoundly reduced, accompanied by a slight reduction in food intake and energy expenditure, leading to adiposity.
· An absence of KISS1R signaling results in increased body weight and impaired glucose homeostasis in female but not male mice.

Hussain MA, Song WJ, Wolfe A. There is Kisspeptin - And Then There is Kisspeptin. Trends Endocrinol Metab. 2015;26(10):564-72. https://www.sciencedirect.com/science/article/pii/S1043276015001411

While kisspeptin was initially found to function as a metastasis suppressor, after identification of its receptor KISS1R and their expression profiles in tissues such as the hypothalamus and adrenals, kisspeptin and KISS1R were predominantly assigned endocrine functions, including regulating puberty and fertility through their actions on hypothalamic gonadotropin releasing hormone production.

More recently, an alter ego for kisspeptin has emerged, with a significant role in regulating glucose homeostasis, insulin secretion, as well as food intake and body composition, and deficient kisspeptin signaling results in reduced locomotor activity and increased adiposity.

This review highlights these recent observations on the role of kisspeptin in metabolism as well as several key questions that need to be addressed in the future.

 

[Michael Scally MD]

Chan YM, Lippincott MF, Butler JP, et al. Exogenous kisspeptin administration as a probe of GnRH neuronal function in patients with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2014;99(12):E2762-71. http://press.endocrine.org/doi/10.1210/jc.2014-2233

CONTEXT: Idiopathic hypogonadotropic hypogonadism (IHH) results from defective synthesis, secretion, or action of GnRH. Kisspeptin is a potent stimulus for GnRH secretion.

OBJECTIVE: We probed the functional capacity of the GnRH neuronal network in patients with IHH.

PARTICIPANTS: Eleven subjects with congenital IHH (9 men and 2 women) and one male subject who underwent reversal of IHH were studied. Six of the twelve subjects had an identified genetic cause of their IHH: KAL1 (n = 1), FGFR1 (n = 3), PROKR2 (n = 1), GNRHR (n = 1).

INTERVENTION: Subjects underwent q10 min blood sampling to measure GnRH-induced LH secretion at baseline and in response to intravenous boluses of kisspeptin (0.24 nmol/kg) and GnRH (75 ng/kg) both pre- and post-six days of treatment with exogenous GnRH (25 ng/kg sc every 2 h). RESULTS: All subjects with abiding IHH failed to demonstrate a GnRH-induced LH response to exogenous kisspeptin. In contrast, the subject who achieved reversal of his hypogonadotropism demonstrated a robust response to kisspeptin.

CONCLUSIONS: The functional capacity of the GnRH neuronal network in IHH patients is impaired, as evidenced by their inability to respond to the same dose of kisspeptin that effects a robust GnRH-induced LH response in healthy men and luteal-phase women. This impairment is observed across a range of genotypes, suggesting that it reflects a fundamental property of GnRH neuronal networks that have not been properly engaged during pubertal development. In contrast, a patient who had experienced reversal of his hypogonadotropism responded to exogenous kisspeptin.

 

[Michael Scally MD]

[Open Access] The Role of Kisspeptin Signalling In the Hypothalamic-Pituitary-Gonadal Axis - Current Perspective

The discovery of kisspeptins in the recent past remoulded current understanding of the neuroendocrine axis relating to the regulation of human puberty and reproduction.

Kisspeptins have been recognised to act upstream of GnRH and have been shown to play a vital role in the control of the hypothalamic-pituitary-gonadal axis via regulation of gonadotrophin secretion, onset of puberty, and control of fertility.

KNDy (kisspeptin/neurokinin-B/dynorphin) neurons have been suggested to modulate GnRH pulsatile secretion, which is required to support reproductive function in both sexes.

They have also been involved in mediating both positive and negative sex steroid feedback signals to GnRH neurons and serve as a vital connection between reproduction and metabolic status of the body.

When kisspeptin is administered to healthy humans, and in patients with reproductive disorders, it strongly and directly stimulates GnRH and subsequent LH secretion and enhances LH pulse frequency.

These observations suggest that kisspeptins are a potential novel therapeutic approach for treating disorders with either pathologically reduced or augmented gonadotrophins pulsatile secretion and is currently a focus of translational research.

Kisspeptins have also been identified in several peripheral reproductive organs, indicating their role in modulation of ovarian function, embryo implantation, and placentation, but a great deal of work remains to be done to explore further in this regard, and the evidence is only available from studies done on animal models.

In this review we will mainly focus on current available evidence related to the role of kisspeptins in controlling GnRH pulse frequency, specifically their role in puberty, fertility, and reproduction. We will also be appraising other factors that regulate the kiSS1/Kisspeptin/GPR-54 system.

Javed Z, Qamar U, Sathyapalan T. The role of kisspeptin signalling in the hypothalamic-pituitary-gonadal axis - current perspective. Endokrynol Pol 2015;66(6):534-47. The role of kisspeptin signalling in the hypothalamic–pituitary–gonadal axis — current perspective | Javed | Endokrynologia Polska

Diagrammatic representation of the relationship between kisspeptin neurons, KNDy neurons, and GnRH neurons in humans.

POA — preoptic area of hypothalamus; KNDy neuron — kisspeptin neurokinin dynorphin neuron; GPR54 — G-protein coupled receptor 54 (GPCR); GnRH — gonadotrophin releasing hormone; GnRHR-1 — gonadotrophin releasing hormone receptor 1, LH — luteinizing hormone, FSH — follicle stimulating hormone, ERα — oestrogen receptor alpha, PR — progesterone receptor, NKB — neurokinin-B, Dyn — dynorphin, + stimulatory, – inhibitory.

 

[Dr JIM]

I just came across an article online that was published last year about a protein called kisspeptin that is key in triggering puberty and sexual maturation in teens.
It seems to directly stimulate GnRH.

The first link is the article. The second two links are medical abstracts.


http://www.gestion.uco.es/gestion/comunica/dossier/mostrar/prensa/dossier/20050722/13.pdf
Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54
Kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis in adult male rats following central and peripheral administration

Holy peptide Batman, finally a PEP with efficacy based on legitimate evidence!

NICE POST

 

[Dr JIM]

Jayasena CN, Abbara A, Narayanaswamy S, Comninos AN, Ratnasabapathy R, et al. Direct comparison of the effects of intravenous kisspeptin-10, kisspeptin-54 and GnRH on gonadotrophin secretion in healthy men. Hum Reprod. Direct comparison of the effects of intravenous kisspeptin-10, kisspeptin-54 and GnRH on gonadotrophin secretion in healthy men

STUDY QUESTION: How potently does the novel hypothalamic stimulator of reproduction, kisspeptin, increase gonadotrophin secretion when compared with GnRH in healthy men?

SUMMARY ANSWER: At the doses tested, intravenous administration of either of two major kisspeptin isoforms, kisspeptin-10 and -54, was associated with similar levels of gonadotrophin secretion in healthy men; however, GnRH was more potent when compared with either kisspeptin isoform.

WHAT IS KNOWN ALREADY: Kisspeptin-10 and -54 are naturally occurring hormones in the kisspeptin peptide family which potently stimulates endogenous GnRH secretion from the hypothalamus, so have the potential to treat patients with reproductive disorders. Rodent studies suggest that kisspeptin-54 is more potent when compared with kisspepitn-10; however, their effects have not previously been directly compared in humans, or compared with direct pituitary stimulation of gonadotrophin secretion using GnRH.

STUDY DESIGN, SIZE AND DURATION: A single-blinded placebo controlled physiological study was performed from January to December 2013. Local ethical approval was granted, and five participants were recruited to each dosing group.

PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthy men were administered vehicle, kisspeptin-10, kisspeptin-54 and GnRH intravenously for 3 h on different study days. Each hormone was administered at 0.1, 0.3 and 1.0 nmol/kg/h doses (n = 5 subjects per group). Regular blood sampling was conducted throughout the study to measure LH and FSH. Study visits were conducted at least a week apart.

MAIN RESULTS AND THE ROLE OF CHANCE: Serum LH and FSH levels were approximately 3-fold higher during GnRH infusion when compared with kisspeptin-10 and approximately 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 Imperial Biomedical Research Centre Funding Scheme. C.N.J. is supported by an NIHR Clinical Lectureship. A.A. is supported by Wellcome Trust Research Training Fellowships. A.N.C. is supported by Wellcome Trust Translational Medicine Training Fellowship. W.S.D. is supported by an NIHR Career Development Fellowship.

Nice study design using healthy HUMAN volunteers as a comparison .
CME credit should be offered for this one

The combination is just great stuff IMO DOC

 

[Michael Scally MD]

The diagram shows that
(a) kisspeptin (Kp) stimulates gonadotrophin-releasing hormone (GnRH) secretion and subsequently gonadotrophin release. Testosterone (T) is aromatised to oestrogen (E), which exerts negative feedback on the anterior pituitary gland and hypothalamus.
(b) E exerts negative feedback on GnRH via Kp neurons in the arcuate nucleus (ARC).
(c) E exerts positive feedback on GnRH via Kp neurons in the anteroventral periventricular nucleus (AVPV).

FSH: follicle-stimulating hormone; LH: luteinising hormone


Tng EL. Kisspeptin signalling and its roles in humans. Singapore Med J 2015;56(12):649-56. Kisspeptin signalling and its roles in humans

Kisspeptins are a group of peptide fragments encoded by the KISS1 gene in humans. They bind to kisspeptin receptors with equal efficacy. Kisspeptins and their receptors are expressed by neurons in the arcuate and anteroventral periventricular nuclei of the hypothalamus.

Oestrogen mediates negative feedback of gonadotrophin-releasing hormone secretion via the arcuate nucleus. Conversely, it exerts positive feedback via the anteroventral periventricular nucleus. The sexual dimorphism of these nuclei accounts for the differential behaviour of the hypothalamic-pituitary-gonadal axis between genders.

Kisspeptins are essential for reproductive function. Puberty is regulated by the maturation of kisspeptin neurons and by interactions between kisspeptins and leptin. Hence, kisspeptins have potential diagnostic and therapeutic applications.

Kisspeptin agonists may be used to localise lesions in cases of hypothalamic-pituitary-gonadal axis dysfunction and evaluate the gonadotrophic potential of subfertile individuals.

Kisspeptin antagonists may be useful as contraceptives in women, through the prevention of premature luteinisation during in vitro fertilisation, and in the treatment of sex steroid-dependent diseases and metastatic cancers.

 

[Michael Scally MD]

[Mice] Direct Actions of Kisspeptins on GnRH Neurons Permit Attainment of Fertility but are Insufficient to Fully Preserve Gonadotropic Axis Activity

Kisspeptins, ligands of the receptor, Gpr54, are potent stimulators of puberty and fertility.

Yet, whether direct kisspeptin actions on GnRH neurons are sufficient for the whole repertoire of their reproductive effects remains debatable.

To dissect out direct vs. indirect effects of kisspeptins on GnRH neurons in vivo, we report herein the detailed reproductive/gonadotropic characterization of a Gpr54 null mouse line with selective re-introduction of Gpr54 expression only in GnRH cells (Gpr54(-/-)Tg; rescued).

Despite preserved fertility, adult rescued mice displayed abnormalities in gonadal microstructure, with signs of precocious ageing in females and elevated LH levels with normal-to-low testosterone secretion in males.

Gpr54(-/-)Tg rescued mice showed also altered gonadotropin responses to negative feedback withdrawal, while luteinizing hormone responses to various gonadotropic regulators were variably affected, with partially blunted relative (but not absolute) responses to kisspeptin-10, NMDA and the agonist of tachykinin receptors, NK2R.

Our data confirm that direct effects of kisspeptins on GnRH cells are sufficient to attain fertility. Yet, such direct actions appear to be insufficient to completely preserve proper functionality of gonadotropic axis, suggesting a role of kisspeptin signaling outside GnRH cells.

Leon S, Barroso A, Vazquez MJ, et al. Direct Actions of Kisspeptins on GnRH Neurons Permit Attainment of Fertility but are Insufficient to Fully Preserve Gonadotropic Axis Activity. Sci Rep 2016;6:19206. Direct Actions of Kisspeptins on GnRH Neurons Permit Attainment of Fertility but are Insufficient to Fully Preserve Gonadotropic Axis Activity : Scientific Reports

 

[Michael Scally MD]

Lippincott MF, Chan Y-M, Delaney A, Morales DR, Butler JP, Seminara SB. Kisspeptin Responsiveness Signals Emergence of Reproductive Endocrine Activity: Implications for Human Puberty. The Journal of Clinical Endocrinology & Metabolism. http://press.endocrine.org/doi/abs/10.1210/jc.2016-1545

Context: Some patients with idiopathic hypogonadotropic hypogonadism (IHH) undergo spontaneous activation of their hypothalamic-pituitary-gonadal axis resulting in normalization of steroidogenesis and/or gametogenesis, a phenomenon termed reversal.

Objective: To assess the responsiveness of the GnRH neuronal network to exogenous kisspeptin administration in IHH patients who have undergone reversal.

Participants: Six men with congenital IHH and evidence for reversal.

Intervention: Subjects underwent q10 min blood sampling to measure GnRH-induced LH secretion at baseline and in response to intravenous boluses of kisspeptin (0.24 – 2.4 nmol/kg) and GnRH (75 ng/kg).

Results: Individuals with sustained reversal of their hypogonadotropism (spontaneous LH pulses) responded to exogenous kisspeptin with a GnRH-induced LH pulse. Individuals who had reversal but then subsequently suffered relapse of their IHH (loss of spontaneous LH pulsatility) did not respond to kisspeptin.

Conclusions: The ability of kisspeptin to stimulate a GnRH-induced LH pulse correlates with the presence of endogenous LH pulses. This data suggests that reversal of hypogonadotropism, and by extension, sexual maturation, may be due to the acquisition of kisspeptin responsiveness.

 

[Michael Scally MD]

Vargas Trujillo M, Kalil B, Ramaswamy S, Plant TM. Estradiol Up-Regulates Kisspeptin Expression in the Pre-Optic Area of Both the Male and Female Rhesus Monkey (Macaca mulatta): Implications for the Hypothalamic Control of Ovulation in Highly Evolved Primates. Neuroendocrinology. http://www.karger.com/Article/Abstract/448520

The aim of this immunohistochmical study was to evaluate the distribution of kisspeptin neurons in the pre-optic area (POA) of gonadally intact adult male and female rhesus monkeys, and to determine whether imposition of an estradiol (E2) positive feedback signal in the castrate male increased kisspeptin in the POA.

Additionally, kisspeptin in POA of the intact female was examined during an LH surge induced prematurely by E2 administered in the early follicular phase. The number of kisspeptin neurons in POA of males and females was similar.

Immunoactive kisspeptin perikarya were not observed in the POA of castrate adult males but such neurons in these animals were present within 12 h of imposing an increment in circulating E2 concentrations, that in a screening study conducted 4-6 weeks earlier elicited an LH surge. As expected, premature induction of an LH surge by E2 early in the follicular phase was associated with up-regulation of kisspeptin in POA.

These results represent the first description of immunoreactive kisspeptin cell bodies in POA of the macaque brain and provide further support for the view that
(1) kisspeptin neurons in POA of the female monkey are a target for the positive feedback action of E2 and
(2) the hypothalamic mechanism, which mediates this action of E2 in primates, is not subjected to perinatal programming by testicular testosterone.

MOREOVER, OUR FINDINGS INDICATE THAT MAINTENANCE OF KISSPEPTIN CONTENT IN POA OF INTACT MALE MONKEYS REQUIRES THE ACTION OF E2, PRESUMABLY GENERATED BY AROMATIZATION OF TESTICULAR TESTOSTERONE AT THE HYPOTHALAMIC LEVEL.

 

[Dr JIM]

Very interesting @Michael Scally MD

 

[lntense]

Sorry to bump an old thread. But has anyone had any experience with this? or have any new studies on it, I find this peptide very interesting

 

[Michael Scally MD]

George JT, Hendrikse M, Veldhuis JD, Clarke IJ, Anderson RA, Millar RP. Effect of gonadotropin inhibitory hormone (GnIH) on luteinizing hormone secretion in humans. Clinical Endocrinology. Effect of gonadotropin inhibitory hormone (GnIH) on luteinizing hormone secretion in humans

Gonadotropin inhibitory hormone (GnIH, human homologue of RFRP-3) suppresses gonadotropin secretion in animal models, but its effects have not been studied in the human.

Objective: We tested the hypotheses that exogenous GnIH inhibits LH secretion
a) in postmenopausal women, and
b) in men concurrently administered exogenous kisspeptin.

Design: Following in vitro and in vivo pre-clinical studies to functionally characterize the GnIH peptide, a dose-finding study (human GnIH 1.5 to 150 μg/kg/h, iv for 3h) was undertaken, and 50 μg/kg/h selected for further evaluation.

Five postmenopausal women were administered 50 μg/kg/h iv infusion for 3h or vehicle on two separate days.

Four men were administered kisspeptin-10 (0.3 μg/kg iv bolus) with simultaneous infusion of GnIH (50 μg/kg/h, iv for 3h) or vehicle.

Participants: Healthy postmenopausal women (mean age 58±2 years, LH: 30.8±2.9 IU/L, FSH: 78.7±6.4 IU/L, estradiol: <50 pmol/L) and men (39.8±2.1 years, mean total testosterone 12.1±1.8 nmol/L, LH 2.2±0.2 IU/L).

Primary Outcome: Change in area-under-curve of LH during GnIH vs. vehicle.

Results: During GnIH administration in postmenopausal women, LH secretion decreased (Δ AUC -9.9±1.8 IU/3h) vs. vehicle (Δ AUC -0.5±1.7 IU/3h) (P= 0.02).

Kisspeptin-10 stimulated LH responses in men was not affected by GnIH co-administration (60-min AUC of LH 6.2±0.8 IU/h with kisspeptin-10 alone, 6.3±1.0 IU/h, kisspeptin-10 with GnIH, P = 0.72).

Exogenous GnIH was well tolerated, with no adverse events reported.

Conclusions: GnIH decreased LH secretion in postmenopausal women in this first-in-human study. Kisspeptin-stimulated LH secretion in men was not inhibited during concomitant administration of GnIH.

 

[Michael Scally MD]

Liu PY. Assessing new peptides that may be involved in the physiological regulation of the gonadal axis in humans: gonadotropin inhibitory hormone. Clinical Endocrinology. http://onlinelibrary.wiley.com/doi/10.1111/cen.13328/abstract

The hypothalamo-pituitary-testicular (HPT) and hypothalamo-pituitary-ovarian (HPO) axes are integrated networks that regulate androgenization or estrogenization (including embryonic, infantile, pubertal and adult sexual maturation), male or female sexual behavior, and spermatogenesis or ovulation, respectively.

Dysregulation of the HPT axis, for example, results in pubertal delay, eunuchism, impaired spermatogenesis, and reduced systemic androgen exposure; and may also contribute to some of the features of male aging, impair recovery from protracted critical illness, and induce visceral adiposity, sarcopenia, osteopenia, and insulin resistance.

Furthering knowledge of how the gonadal axes are regulated will thereby inform important and diverse pathophysiological processes.

 

[Michael Scally MD]

Abbara A, Narayanaswamy S, Izzi-Engbeaya C, et al. Hypothalamic response to kisspeptin and pituitary response to GnRH are preserved in healthy older men. Neuroendocrinology 2018. Hypothalamic response to kisspeptin and pituitary response to GnRH are preserved in healthy older men

Background: Male testosterone levels decline by 1% per year from the age of 40yrs. Whilst a primary testicular deficit occurs, hypothalamic or pituitary dysregulation may also coexist. This study aimed to compare the hypothalamic response to kisspeptin and the pituitary response to GnRH of older men with those of young men.

Methods: Following 1 hour of baseline sampling, healthy older men (n=5, mean age 59.3±2.9yrs) received a 3 hour intravenous infusion (IVI) of either: vehicle, kisspeptin-54 0.1, 0.3, 1.0nmol/kg/h, or GnRH 0.1nmol/kg/h on 5 different study days. Serum gonadotropins and total testosterone were measured every 10 minutes and compared to young men (n=5/group) (mean age 28.9±2.0yrs) with a similar BMI (24 kg/m2) who underwent the same protocol.

Results: Kisspeptin and GnRH significantly stimulated serum gonadotropin release in older men compared to vehicle (P<0.001 for all groups). Gonadotropin response to kisspeptin was at least preserved in older men when compared with young men. At the highest dose of kisspeptin (1.0nmol/kg/h), a significantly greater LH (P=0.003) response was observed in older men. The FSH response to GnRH was increased in older men (P=0.002), but the LH response was similar (P=0.38). Serum testosterone rises following all doses of kisspeptin (P≤0.009) were reduced in older men.

Conclusions: Our data suggests that healthy older men without late onset hypogonadism (LOH) have preserved hypothalamic response to kisspeptin and pituitary response to GnRH, but impaired testicular response. Further work is required to investigate the use of kisspeptin to identify hypothalamic deficits in men with LOH.

 

[Michael Scally MD]

[OA] Lehman MN, Coolen LM, Steiner RA, et al. The 3(rd) World Conference on Kisspeptin, "Kisspeptin 2017: Brain and Beyond": Unresolved questions, challenges and future directions for the field. Journal of neuroendocrinology 2018:e12600. https://onlinelibrary.wiley.com/doi/abs/10.1111/jne.12600

The 3(rd) World Conference on Kisspeptin, "Kisspeptin 2017: Brain and Beyond" was held March 30-31 at the Rosen Centre Hotel in Orlando, Florida, providing an international forum for multidisciplinary scientists to meet and share cutting-edge research on kisspeptin biology and its relevance to human health and disease.

The meeting built upon previous world conferences focused on the role of kisspeptin and associated peptides in the control of gonadotropin-releasing hormone (GnRH) secretion and reproduction. Based on recent discoveries, the scope of this meeting was expanded to include functions of kisspeptin and related peptides in other physiological systems including energy homeostasis, pregnancy, ovarian and uterine function, and thermoregulation.

In addition, discussions addressed the translation of basic knowledge of kisspeptin biology to the treatment of disease, with the goal of seeking consensus about the best approaches to improve human health.

The two-day meeting featured a non-traditional structure, with each day starting with poster sessions followed by lunch discussions and facilitated large-group sessions with short presentations to maximize the exchange of new, unpublished data. Topics were identified by a survey prior to the meeting, and focused on major unresolved questions, important controversies, and future directions in the field.

Finally, career development activities provided mentoring for trainees and junior investigators, and networking opportunities for those individuals with established researchers in the field.

Overall, the meeting was rated as a success by attendees and covered a wide range of lively and provocative discussion topics on the changing nature of the field of "kisspeptinology" and its future.

 

[Michael Scally MD]

[OA] Kisspeptin and Metabolism

Apart from the well-established role of kisspeptin (Kp) in the regulation of reproductive functions, recent data described its action in the control of metabolism. Of particular interest for the review is the population of Kp neurons localized in the arcuate nucleus (ARC) of the hypothalamus, the site of the brain where reproductive and metabolic cross talk occurs.

However, within the hypothalamus Kp does not work alone, but rather interacts with other neuropeptides, e.g., neurokinin B, dynorphin A, proopiomelanocortin, the cocaine- and amphetamine-regulated transcript, agouti-related peptide, and neuropeptide Y. Beyond the brain, Kp is expressed in peripheral tissues involved in metabolic functions.

In this review, we will mainly focus on the local action of this peptide in peripheral organs such as the pancreas, liver, and the adipose tissue. We will concentrate on dysregulation of the Kp system in cases of metabolic imbalance, e.g., obesity and diabetes. Importantly, these patients besides metabolic health problems often suffer from disruptions of the reproductive system, manifested by abnormalities in menstrual cycles, premature child birth, miscarriages in women, decreased testosterone levels and spermatogenesis in men, hypogonadism, and infertility.

We will review the evidence from animal models and clinical data indicating that Kp could serve as a promising agent with clinical applications in regulation of reproductive problems in individuals with obesity and diabetes. Finally, emerging data indicate a role of Kp in regulation of insulin secretion, potentially leading to development of further therapeutic uses of this peptide to treat metabolic problems in patients with these lifestyle diseases.

Dudek M, Ziarniak K, Sliwowska JH. Kisspeptin and Metabolism: The Brain and Beyond. Frontiers in endocrinology 2018;9:145. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911457/