Kisspeptin Levels in Girls with Precocious Puberty: A Systematic Review and Meta-Analysis

Abstract

<b><i>Background/Aims:</i></b> Kisspeptin (KP) is a key player in the regulation of the release of gonadotropin-releasing hormone (GnRH), which increases the secretion of gonadotropin during puberty to establish reproductive function and regulate the hypothalamic-pituitary-gonadal axis. Premature activation of GnRH secretion leads to idiopathic/central gonadotropin-dependent precocious puberty (CPP). We aimed to compare the blood KP concentrations in girls with CPP and healthy controls. <b><i>Methods:</i></b> A systematic review and meta-analysis was performed. We searched MEDLINE, EMBASE, The Cochrane Library, and SciELO. Random-effects model and standardized mean difference (SMD) were used. Heterogeneity was assessed through <i>I</i><sup>2</sup>. Meta-regression considered patient age, KP fraction, and analytical method for KP measurement. <b><i>Results:</i></b> The 11 studies included comprised 316 CPP patients and 251 controls. Higher KP levels in the CPP group were found (SMD 1.53; CI 95% = 0.56–2.51). Subgroup analysis revealed association with patient age (<i>p</i> = 0.048), indicating a positive correlation between elevation in KP concentration and age in CPP group. A group of patients with precocious thelarche (PT) from 5 of the included studies comprising 121 patients showed higher levels of KP (1.10; −0.25–2.45: CI 95%) and high heterogeneity (<i>I</i><sup>2</sup> = 91%). The CPP/PT ratio for KP level indicates KP 36% higher on CPP than PT patients. <b><i>Conclusions:</i></b> A consistent difference in KP levels between girls with CPP and controls was identified. While there are important limitations in KP assays which argue against its use as a diagnostic tool, the KP levels in CPP versus control and PT children are consistent with the predicted mechanisms and pathophysiology of CPP.

Kisspeptin regulates the proliferation and apoptosis of ovary granulosa cells in polycystic ovary syndrome by modulating the PI3K/AKT/ERK signalling pathway

“…Kisspeptin is an essential regulator of reproductive function and its expression is closely associated with precocious puberty [ 28 ]. Kisspeptin expression is also considered a marker for PCOS diagnosis.…”

The Role of Genetics in Central Precocious Puberty: Confirmed and Potential Neuroendocrine Genetic and Epigenetic Contributors and Their Interactions with Endocrine Disrupting Chemicals (EDCs)

“…For instance, in one CPP study describing proteomic profiles, the authors conclude that the "altered members of the metabolic signaling are valuable and potential novel therapeutic targets of central precocious puberty" [137]. As we learn more about the neuroendocrine signaling, it may be possible to measure the protein molecules in the blood (e.g., kisspeptin or MKRN3) to make the diagnosis of CPP without the need for more expensive and complicated analysis [138,139].…”

Female reproductive functions of the neuropeptide PACAP

“…Recent data have provided evidence that PACAP might be a central regulator of puberty and female hormonal cycles, via interactions with the kisspeptin-GnRH system. The clinical importance of kisspeptin in several diseases has been highlighted in recent publications ( 161 , 162 ). Studies summarized in the present review prove that PACAP is both a central and peripheral modulator of reproductive functions and call for further investigations to elucidate the exact role in some processes and to evaluate the potential diagnostic and/or therapeutic use of PACAP in biological fluids as a biomarker, as it has been also shown for the other players in these complex regulatory mechanisms.…”