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The kisspeptin system in and beyond reproduction: exploring intricate pathways and potential links between endometriosis and polycystic ovary syndrome

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Abstract

Endometriosis and polycystic ovary syndrome (PCOS) are two common female reproductive disorders with a significant impact on the health and quality of life of women affected. A novel hypothesis by evolutionary biologists suggested that these two diseases are inversely related to one another, representing a pair of diametrical diseases in terms of opposite alterations in reproductive physiological processes but also contrasting phenotypic traits. However, to fully explain the phenotypic features observed in women with these conditions, we need to establish a potential nexus system between the reproductive system and general biological functions. The recent discovery of kisspeptin as pivotal mediator of internal and external inputs on the hypothalamic–pituitary–gonadal axis has led to a new understanding of the neuroendocrine upstream regulation of the human reproductive system. In this review, we summarize the current knowledge on the physiological roles of kisspeptin in human reproduction, as well as its involvement in complex biological functions such as metabolism, inflammation and pain sensitivity. Importantly, these functions are known to be dysregulated in both PCOS and endometriosis. Within the evolving scientific field of “kisspeptinology”, we critically discuss the clinical relevance of these discoveries and their potential translational applications in endometriosis and PCOS. By exploring the possibilities of manipulating this complex signaling system, we aim to pave the way for novel targeted therapies in these reproductive diseases.

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Abbreviations

PCOS:

Polycystic ovary syndrome

HPG:

Hypothalamic–pituitary–gonadal

KP:

Kisspeptin

GnRH:

Gonadotropin Releasing Hormone

SANRA:

Scale for the Assessment of Narrative Review Articles

KPR:

Kisspeptin receptor

KISS1:

Kisspeptin (gene)

KISS1R:

Kisspeptin receptor (gene)

RF-amide peptide:

Arginine-Phenylalanine amide peptide (sequence at C-terminus)

GPR54:

G protein-coupled receptor 54

PLC:

Phospholipase C

DAG:

Diacylglycerol

IP3:

Inositol-(1,4,5)-triphosphate

LH:

Luteinizing hormone

FSH:

Follicle stimulating hormone

KNDy:

Kisspeptin-Neurokinin B-Dynorphin neurons

NKB:

Neurokinin B

E2:

Estradiol

POA:

Preoptic area

POI:

Premature ovarian insufficiency

AMH:

Anti-Mullerian hormone

KO:

Knockout

GCs:

Granulosa cells,

CCs:

Cumulus cells

ESCs:

Endometrial stromal cells

LIF:

Leukemia inhibitory factor

MMPs:

Matrix metalloproteinases

VEGFA:

Vascular endothelial growth factor A

BMI:

Body mass index

EP:

Ectopic pregnancy

PTB:

Preterm birth

FGR:

Fetal growth restriction

HDP:

Hypertensive disorders of pregnancy

GDM:

Gestational diabetes mellitus

GTD:

Gestational trophoblastic disease

CH:

Chronic hypertension

PIH:

Pregnancy induced hypertension

PE:

Pre-eclampsia

GSIS:

Glucose‐stimulated insulin secretion

LPS:

Lipopolysaccharide

TNF:

Tumor necrosis factor

WHR:

Waist-to-hip ratio

NK3Ra:

Neurokinin-3-receptor antagonists

BBB:

Blood-brain-barrier

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Funding

This study was (partially) funded by Italian Ministry of Health- Current research IRCCS.

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Authors and Affiliations

  1. Gynecology and Obstetrics Unit, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy

    Noemi Salmeri, Paolo Cavoretto & Massimo Candiani

  2. Infertility Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via M. Fanti 6, 20122, Milan, Italy

    Paola Viganò

  3. Gynecology & Obstetrics, University of Ferrara, 44121, Ferrara, Italy

    Roberto Marci

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  1. Noemi Salmeri
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  3. Paolo Cavoretto
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  5. Massimo Candiani
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Contributions

Conceptualization, N.S. and P.V.; methodology, N.S.; software, N.S.; validation, N.S., P.V., P.C., R.M., M.C; investigation, N.S.; resources, N.S.; data curation, N.S.; writing—original draft preparation, N.S.; writing—review and editing, P.V, P.C.; visualization, N.S., P.V., P.C., R.M., M.C; supervision, P.V.; project administration, N.S. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Paola Viganò.

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Salmeri, N., Viganò, P., Cavoretto, P. et al. The kisspeptin system in and beyond reproduction: exploring intricate pathways and potential links between endometriosis and polycystic ovary syndrome. Rev Endocr Metab Disord 25, 239–257 (2024). https://doi.org/10.1007/s11154-023-09826-0

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