Hypothalamic Response to Kisspeptin-54 and Pituitary Response to Gonadotropin-Releasing Hormone Are Preserved in Healthy Older Men

Abbara, Ali; Narayanaswamy, Shakunthala; Izzi‐Engbeaya, Chioma; Comninos, Alexander; Clarke, Sophie; Malik, Zainab; Papadopoulou, Deborah; Clobentz, Ailish; Sarang, Zubair; Bassett, Paul; Jayasena, Channa N.; Dhillo, Waljit S.

doi:10.1159/000488452

Cited by 14 publications

(7 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous experimental data showed that kisspeptin administration induced gonadotropin secretion in the rat 17 , sheep 18 and human 19 . Recent pharmacological evidence also revealed that kisspeptin could potentially be used as a treatment for fertility disorders in humans 20,21 .…”

Section: Introductionmentioning

confidence: 98%

Recombinant B2L and Kisspeptin-54 DNA Vaccine Induces Immunity Against Orf Virus and Inhibits Spermatogenesis In Rats

Wassie

Zeng

Jiang

et al. 2019

Sci Rep

View full text Add to dashboard Cite

Orf is a highly contagious zoonotic disease of small ruminants caused by Parapoxvirus. Kisspeptin, encoded by the KISS1 gene with its cognate receptor GPR-54 is recognized as an upstream orchestrator in the hypothalamic-pituitary-gonadal axis. This study was designed to construct a DNA vaccine that produces a fused peptide composed of a major immunodominant protein of the orf virus (B2L) and kisspeptin-54, a neuropeptide with recognized roles in mammalian reproductive biology. The administration of this recombinant vaccine is shown to produce a significant antibody and cell-mediated immune response directed against B2L compared to the control group (p < 0.05). Furthermore, we found that rats inoculated with PBK-asd vaccine up-regulated antigen-mediated splenocyte proliferation and significantly raised antigen-specific tumor necrosis factor-alpha (TNFα-), interferon-gamma (IFN-ϒ) and interleukin (IL-2) compared to the control group (p < 0.05). This recombinant vaccine also stimulated antibody responses to kisspeptin and decreased serum luteinizing hormone and testosterone levels. Moreover, the current recombinant vaccine caused testicular atrophy and arrested spermatogenesis. It is concluded that this recombinant B2L and Kisspeptin-54 vaccine could be a promising approach for construction of bivalent orf virus and immunocastration vaccine. Furthermore, we concluded that the orf virus envelope protein (B2L) could be used as an immunomodulator for kisspeptin-54 to produce a strong antibody response.

show abstract

Section: Introductionmentioning

confidence: 98%

Recombinant B2L and Kisspeptin-54 DNA Vaccine Induces Immunity Against Orf Virus and Inhibits Spermatogenesis In Rats

Wassie

Zeng

Jiang

et al. 2019

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Further studies assessing whether MVT-602's more physiological endocrine profile translates to improved clinical outcomes during IVF treatment would be of great interest. Kisspeptin also offers potential for the treatment of functional hypogonadal disorders associated with hypothalamic dysfunction such as diabetes-induced secondary hypogonadism (41) and age-related hypogonadism (42). While the treatment of functional hypogonadal disorders using kisspeptin could thus repre-sent an attractive therapeutic intervention, these would require chronic stimulation protocols.…”

Section: Table 2 Pharmacokinetic and Pharmacodynamic Responses Of Kpmentioning

confidence: 99%

Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders

Abbara

Eng

Phylactou

et al. 2020

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

BACKGROUND. Kisspeptin is a key regulator of hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is essential for reproductive health. A specific kisspeptin receptor (KISS1R) agonist could significantly expand the potential clinical utility of therapeutics targeting the kisspeptin pathway. Herein, we investigate the effects of a KISS1R agonist, MVT-602, in healthy women and in women with reproductive disorders. METHODS. We conducted in vivo and in vitro studies to characterize the action of MVT-602 in comparison with native kisspeptin-54 (KP54). We determined the pharmacokinetic and pharmacodynamic properties of MVT-602 (doses 0.01 and 0.03 nmol/kg) versus KP54 (9.6 nmol/kg) in the follicular phase of healthy women (n = 9), and in women with polycystic ovary syndrome (PCOS; n = 6) or hypothalamic amenorrhea (HA; n = 6). Further, we investigated their effects on KISS1Rmediated inositol monophosphate (IP 1) and Ca 2+ signaling in cell lines and on action potential firing of GnRH neurons in brain slices. RESULTS. In healthy women, the amplitude of luteinizing hormone (LH) rise was similar to that after KP54, but peaked later (21.4 vs. 4.7 hours; P = 0.0002), with correspondingly increased AUC of LH exposure (169.0 vs. 38.5 IU•h/L; P = 0.0058). LH increases following MVT-602 were similar in PCOS and healthy women, but advanced in HA (P = 0.004). In keeping with the clinical data, MVT-602 induced more potent signaling of KISS1R-mediated IP 1 accumulation and a longer duration of GnRH neuron firing than KP54 (115 vs. 55 minutes; P = 0.0012). CONCLUSION. Taken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders. TRIAL REGISTRATION. International Standard Randomised Controlled Trial Number (ISRCTN) Registry, ISRCTN21681316.

show abstract

“…20 Additionally, responses to kisspeptin in healthy older men were also maintained. 21 Thus, in future, kisspeptin-based therapeutics could be developed for the treatment of functional hypogonadism such as diabetes, obesity, or age-related hypogonadism.…”

Section: Kisspeptin In Healthy Men and Womenmentioning

confidence: 99%

Clinical Translational Studies of Kisspeptin and Neurokinin B

Hunjan

Abbara

2019

Semin Reprod Med

Self Cite

View full text Add to dashboard Cite

Kisspeptin and neurokinin B (NKB) are hypothalamic neuropeptides that are vital for reproductive health. An absence of either kisspeptin or NKB signaling results in hypogonadotrophic hypogonadism and a failure to proceed through puberty. In recent years, several studies have demonstrated potential avenues for the clinical utility of medications that act through these pathways in the assessment and treatment of reproductive disorders. Kisspeptin acts to stimulate hypothalamic gonadotrophic-releasing hormone (GnRH) secretion from the hypothalamus. Kisspeptin induces gonadotrophin secretion in both healthy men and women, and in women with reproductive disorders such as hypothalamic amenorrhea (HA). Kisspeptin-based treatments hold promise for use during in vitro fertilization (IVF) treatment; a bolus of kisspeptin-54 induces an LH surge of 12 to 14 hours of duration sufficient to induce oocyte maturation, but with markedly reduced rates of the most significant complication of IVF treatment, ovarian hyperstimulation syndrome (OHSS). Kisspeptin could also be used chronically to restore reproductive health in patients with functional hypogonadism, such as those with HA. Furthermore, kisspeptin has potential as a diagnostic test of hypothalamic function; a “kisspeptin test” could be used in children with delayed puberty to identify the subset with genetically determined deficits in hypothalamic pathways (congenital hypogonadotrophic hypogonadism [CHH]). In addition to its role in hypothalamic GnRH pulse generation, NKB plays a critical role in the occurrence of one of the most troubling symptoms of the menopause, the “hot flush.” Neurokinin-3 receptor (NK3R) antagonists are highly effective as treatments for hot flushes in postmenopausal women, with several compounds now in late-phase development. Furthermore, NK3R antagonism leads to a reduction in LH secretion by reducing GnRH pulsatility in the hypothalamus and has been shown to reduce androgen levels in women with polycystic ovary syndrome (PCOS) (in whom GnRH pulsatility is often increased). In summary, although further detailed evaluation in several clinical settings is ongoing, medications based on kisspeptin and NKB pathways have prodigious potential in the assessment and treatment of reproductive disorders.

show abstract

Hypothalamic Response to Kisspeptin-54 and Pituitary Response to Gonadotropin-Releasing Hormone Are Preserved in Healthy Older Men

Cited by 14 publications

References 35 publications

Recombinant B2L and Kisspeptin-54 DNA Vaccine Induces Immunity Against Orf Virus and Inhibits Spermatogenesis In Rats

Recombinant B2L and Kisspeptin-54 DNA Vaccine Induces Immunity Against Orf Virus and Inhibits Spermatogenesis In Rats

Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders

Clinical Translational Studies of Kisspeptin and Neurokinin B

Contact Info

Product

Resources

About