Effects of melatonin in polycystic ovary syndrome: is there Hippo pathway crosstalk?

Abstract

Objective: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder among reproductive women, characterized by hyperandrogenism, oligo-ovulation and polycystic ovarian morphology. Incorporating complementary medicine alongside traditional lifestyle therapies for PCOS may offer additional benefits for affected women. Melatonin (MT), a hormone secreted by the pineal gland, has emerged as a potential treatment for regulating ovarian function in PCOS. However, the specific effects and underlying mechanisms of MT on PCOS need to be elucidated.

Methods: This review consolidates evidence from randomized controlled trials, original research articles, systematic reviews, and meta-analyses regarding MT supplementation in PCOS, with a particular focus on its interaction with the Hippo pathway, to provide a comprehensive overview of current knowledge.

Results: Current evidence suggests that MT plays a role in modulating PCOS through various mechanisms and is associated with the Hippo pathway. However, several uncertainties and key limitations in the existing literature must be addressed before these treatments can be integrated into standard clinical practice.

Clinical trial number: Not applicable.

Keywords: Hippo; Melatonin; Ovary; PCOS; YAP.

Fig. 1

Schematic representation of the pathophysiological mechanisms, risk factors, and complications associated with PCOS. Insulin resistance (IR) and the hyperinsulinemia (HA) are central mechanisms that perpetuate anovulation. Abbreviations: HHOA: hypothalamus-hypophysis-ovary axis; GnRH: gonadotropin-releasing hormone; FSH: follicle-stimulating hormone; LH: luteinizing hormone; SHBG: sex hormone-binding globulin; ↑: indicates increase in protein level or activity; ↓: indicates decrease in protein level or activity; →: indicates unchanged in protein level or activity

Fig. 2

Schematic representation of Melatonin ameliorates ovarian dysfunction in PCOS. Abbreviations: MT: melatonin; MT 1, 2: melatonin receptor 1, 2; G: G-protein coupled receptor; ROS: reactive oxygen species; AC: adenylyl cyclase; PLC: phospholipase C; ATP: adenosine triphosphate; cAMP: cyclic Adenosine Monophosphate; PI3K: phosphatidylinositol-3 kinase; PKC: protein kinase C; Akt: protein kinase B; MAPK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase; Bcl-2: B-cell lymphoma-2; Bax: Bcl-2-accociated X protein; IL-18: interleukin-18; TNF-α: tumor necrosis factor-α; NF-κB: nuclear factor kappa B; iNOS: inducible nitric oxide synthetase; NO: nitric oxide; NOX2: the oxidant-encoding gene (NADPH oxidase 2); MDA: malondialdehyde; SIRT1: NAD-dependent deacetylase sirtuin-1; PINK1: PTEN-induced kinase-1; FSH: follicle-stimulating hormone; LH: luteinizing hormone; T: testosterone; A: Aromatase activity; CYP19A1: cytochrome P450 family 19 subfamily A member 1; E₂: 17β-estradiol; BMP: bone morphogenic protein; GDF: growth differentiation factor; LC 3B- II: light chain 3B-II; SOD: superoxide dismutase; GSH: glutathione; CAT: catalase; GPX: glutathione peroxidase; IR: Insulin resistance; HA: hyperinsulinemia;↑: indicates increase in protein level or activity; ↓: indicates decrease in protein level or activity

Fig. 3

Disruption of the ovarian Hippo pathway through actin polymerization, resulting in increased nuclear YAP expression and contributing to PCOS formation. Abbreviations:↑ indicates increase in protein level or activity; ↓ indicates decrease in protein level or activity; YAP: Yes-associated protein; TAZ: PDZ-binding motif; MST 1/2: mammalian STE20-like protein kinase 1/2; SAV1: salvador homologue 1; LATS1/2: large tumor suppressor 1 and 2; MOB1A: MOB kinase activator 1

Fig. 4

Melatonin-regulated GPCR signaling interacts with GPCR signal-regulated Hippo pathway. Abbreviations:↑ indicates increase in protein level or activity; ↓ indicates decrease in protein level or activity; ┨: indicates inhibition in protein level or activity; MT: melatonin; MT 1: melatonin receptor 1; GPCR: G-protein coupled receptor; Gαi: inhibitory guanine triphosphate-binding protein α-subunit; Gαs: stimulatory guanine triphosphate-binding protein α-subunit; cAMP: cyclic adenosine monophosphate; AC: adenylyl cyclase; PKC: protein kinase C; PKA: Protein Kinase A; LATS1/2: large tumor suppressor 1 and 2; MOB1A: MOB kinase activator 1; TEAD: TEA domain family member; YAP: Yes-associated protein; TAZ: PDZ-binding motif (also known as WW domain-containing transcription regulator protein 1, WWTR1); NF-κB: nuclear factor-κB

Fig. 5

Interaction between melatonin, insulin, and the Hippo pathway. Abbreviations: Gαs: stimulatory guanine triphosphate-binding protein α-subunit; cAMP: cyclic adenosine monophosphate; cAMP: cyclic guanosine monophosphate; LATS1/2: large tumor suppressor 1 and 2; YAP: Yes-associated protein; IGF-I: insulin-like growth factor; IRS-1: insulin receptor substrate-1