Acute and subacute effects of a synthetic kisspeptin analog, C6, on serum concentrations of luteinizing hormone, follicle stimulating hormone, and testosterone in prepubertal bull calves.

Kisspeptin (KP) is a neuropeptide integral in regulating puberty and gonadotropin releasing hormone. Compound 6 (C6), a KP analog, is more potent in vitro, has a longer half-life, and may have greater therapeutic applications than KP. To determine the acute and subacute effects of KP and C6 on serum concentrations of luteinizing hormone (LH), follicle stimulating hormones (FSH), and testosterone (T), prepubertal bull calves [12.1 ±â€¯1.1 (SD) weeks of age; 91.2 ±â€¯10.8 kg BW] were assigned to one of three treatment groups [Saline (n = 4), KP (n = 4; 20 nmoles), or C6 (n = 4; 20 nmoles). Treatments were administered intramuscularly once daily for four consecutive days. Blood samples were collected every 15 min for 6 h immediately following treatment administration on Day 1 (acute) and Day 4 (subacute). Serum concentrations of LH, FSH, and T were determined by radioimmunoassay. For each day, effects of treatment, time, and interactions on LH and FSH concentrations and pulse parameters were analyzed using procedures for repeated measures with JMP Software (SAS Inst. Inc., Cary, NC). There was a treatment × time interaction during Day 1 (P < 0.0001) and Day 4 (P = 0.02) such that LH concentrations were greatest following administration of C6 (albeit diminished during Day 4). Number of LH pulses were least (P = 0.02) and LH nadirs were highest (P = 0.04) following administration of C6 (P = 0.02). There was no effect of treatment (P = 0.95) or treatment × time interaction (P = 0.10) on serum FSH concentrations during Day 1. During Day 4 FSH concentrations (P = 0.02) and number of FSH pulses (P = 0.02) were least following administration of C6. There was no effect of treatment (P = 0.33), time (P = 0.19) or treatment × time interaction (P = 0.44) on T concentrations. In conclusion, acute and subacute C6 increased LH concentrations and subacute C6 decreased FSH concentrations and pulse parameters. Despite suppression of FSH with subacute daily administration of C6, altered frequency and timing of treatment with KP analogs may have application to affect the onset of puberty in livestock.

A synthetic kisspeptin analog that triggers ovulation and advances puberty.

The neuropeptide kisspeptin and its receptor, KiSS1R, govern the reproductive timeline of mammals by triggering puberty onset and promoting ovulation by stimulating gonadotrophin-releasing hormone (GnRH) secretion. To overcome the drawback of kisspeptin short half-life we designed kisspeptin analogs combining original modifications, triazole peptidomimetic and albumin binding motif, to reduce proteolytic degradation and to slow down renal clearance, respectively. These analogs showed improved in vitro potency and dramatically enhanced pharmacodynamics. When injected intramuscularly into ewes (15 nmol/ewe) primed with a progestogen, the best analog (compound 6, C6) induced synchronized ovulations in both breeding and non-breeding seasons. Ovulations were fertile as demonstrated by the delivery of lambs at term. C6 was also fully active in both female and male mice but was completely inactive in KiSS1R KO mice. Electrophysiological recordings of GnRH neurons from brain slices of GnRH-GFP mice indicated that C6 exerted a direct excitatory action on GnRH neurons. Finally, in prepubertal female mice daily injections (0.3 nmol/mouse) for five days significantly advanced puberty. C6 ability to trigger ovulation and advance puberty demonstrates that kisspeptin analogs may find application in the management of livestock reproduction and opens new possibilities for the treatment of reproductive disorders in humans.