Shared Pathophysiological Mechanisms and Genetic Factors in Early Menarche and Polycystic Ovary Syndrome

Abstract

Early age at menarche (early AAM) and polycystic ovary syndrome (PCOS) are reproductive and metabolic disorders with overlapping pathophysiological and genetic features. Epidemiological studies suggest a link between these two conditions, both of which are characterized by dysregulation of the neuroendocrine pathways that control pulsatile gonadotropin-releasing hormone secretion, thus affecting gonadotropin release, particularly luteinizing hormone secretion. A common pathophysiology involving positive energy balance and abnormal metabolic status is evident in both disorders. Genetic and epigenetic factors influence the onset of puberty and reproductive outcomes. Genome-wide association studies have identified common genetic variants associated with AAM and PCOS, particularly in genes related to the neuroendocrine axis (e.g., FSHB) and obesity (e.g., FTO). In addition, high-throughput sequencing has revealed rare loss-of-function variants in the DLK1 gene in women with central precocious puberty (CPP), early menarche, and PCOS, who experienced adverse metabolic outcomes in adulthood. This review explores the shared pathophysiological mechanisms between CPP/early AAM and PCOS, examines potential genetic and epigenetic factors that may link these neuroendocrine reproductive conditions, and offers insights into future research and treatment strategies. Understanding these connections may provide new targets for therapeutic interventions and improve outcomes for individuals with these reproductive disorders.

Keywords: early menarche; genetic variants; metabolic outcomes; neuroendocrine pathways; polycystic ovary syndrome; precocious puberty.

Figure 1.

Neuroendocrine regulation of GnRH secretion: the interplay between metabolism, kisspeptin, and pubertal onset. An increase in the frequency and amplitude of GnRH pulses triggers the release of LH and FSH from the anterior pituitary gland, with an increase in the LH/FSH ratio. LH stimulates androgen production and ovulation in ovarian theca cells, while FSH promotes ovarian follicle development in granulosa cells. The kisspeptin system is the main stimulatory factor of GnRH neurons, through both kisspeptin neurons located in the AVPV nucleus and KNDy neurons located in the ARC. Estradiol, secreted from granulosa cells after enzymatic conversion, acts as a positive feedback mediator in the AVPV and a negative feedback mediator in the ARC. GnRH neuron activity is regulated by a balance of excitatory (green arrows) and inhibitory (orange arrows) hypothalamic factors. The predominance of excitatory factors over inhibitory ones, indicated by the different arrow widths, leads to the pubertal onset, considered precocious if it occurs in girls younger than 8 years. Hypothalamic neurons controlling hunger (AgRP/NPY neurons) and satiety (POMC/CART neurons) act, respectively, as inhibitors and activators of ARC kisspeptin neurons in response to body energy reserves. Additionally, cellular energy sensors AMPK and mTOR, respectively, inhibit and stimulate ARC kisspeptin secretion based on circulating nutrient levels. Peripheral factors, such as leptin and insulin, appear to facilitate kisspeptin release, whereas ghrelin acts to inhibit kisspeptin secretion. DLK1 is an inhibitor of adipogenesis that links metabolism and reproduction, though its precise target and mechanisms are not yet fully understood. AgRP/NPY, agouti-related peptide/neuropeptide Y; AMPK, AMP-activated protein kinase; ARC, arcuate nucleus; AVPV, anteroventral periventricular nucleus; DHT, dihydrotestosterone; DLK1, Delta-like noncanonical Notch ligand 1; FSH, follicle-stimulating hormone; GnRH, hypothalamic gonadotrophin-releasing hormone; KNDy, kisspeptin neurokinin B/dynorphin; LH, luteinizing hormone; POA, preoptic area; mTOR, mammalian target of rapamycin; POMC/CART, proopiomelanocortin/cocaine amphetamine-regulated transcript.

Figure 2.

Metabolic disruption in PCOS: the interactions between GnRH pulsatility, androgen excess, and insulin resistance. An increase in the frequency of hypothalamic GnRH pulses leads to a preferential secretion of LH over FSH from the anterior pituitary gland. This elevated LH/FSH ratio results in increased androgen production in ovarian theca cells. AMH levels are elevated due to an increased number of small and immature follicles in the ovaries and increased production by each granulosa cell. The elevated AMH levels perpetuate ovarian dysfunction by inhibiting FSH-dependent follicular maturation, as well as by inhibiting the conversion of androgens to estradiol via aromatase activity in granulosa cells. Additionally, AMH increases GnRH-dependent LH pulsatility and secretion. Hyperandrogenism is linked with insulin resistance and adipose tissue dysfunction in PCOS. The adipose tissue can generate testosterone from its precursor androstenedione through the enzyme AKR1C3, whose expression is increased by insulin. Testosterone promotes lipogenesis and suppresses lipid β-oxidation and lipolysis in the adipose tissue, leading to lipid accumulation. This results in fatty acid overspill, which increases insulin resistance and secretion. Additionally, excess testosterone may reduce the hypothalamic–pituitary negative feedback from ovarian steroid hormones, presumably via KNDy neurons located in the ARC. The central and peripheral metabolic factors that regulate GnRH activity may be unbalanced in PCOS, with a predominance of excitatory (green arrows) over inhibitory (orange arrows) factors, as indicated by the different arrow widths. DLK1 may play a role in the physiopathology of PCOS as a link between metabolism and reproduction, though its precise targets and mechanisms of action remain unclear. AgRP, agouti-related protein; AKR1C3, aldoketoreductase type 1C3; AMPK, AMP-activated protein kinase; ARC, arcuate nucleus; AVPV, anteroventral periventricular nucleus; DHT, dihydrotestosterone; DLK1, Delta-like noncanonical Notch ligand 1; FSH, follicle-stimulating hormone; GnRH, hypothalamic gonadotrophin-releasing hormone; KNDy, kisspeptin/neurokinin B/dynorphin; LH, luteinizing hormone; POA, preoptic area; mTOR, mammalian target of rapamycin; POMC/CART, proopiomelanocortin/cocaine amphetamine-regulated transcript.

Figure 3.

Genetic and epigenetic influences on the pathophysiology of CPP. Gain-of-function variants in the KISS1 and KISS1R genes lead to activation of the kisspeptin system and represent rare causes of CPP. MKRN3, a paternally expressed gene, suppresses KISS1 and TAC3 promoter activities, and loss-of-function mutations in this gene are the most common cause of familial CPP. DLK1, also a mly expressed gene, known for its role in inhibiting adipogenesis, has been linked to CPP with adverse metabolic outcomes, though its role in pubertal regulation remains to be fully understood. Common epigenetic changes associated with CPP include histone modifications, methylation of genes repressing GnRH, and alterations in miRNA expression, all of which contribute to the complex regulation of the pubertal onset.

Figure 4.

Genetic and epigenetic influences on the pathophysiology of PCOS. FSHB polymorphisms are associated with higher circulating LH and/or lower circulating FSH levels, while FSHR polymorphisms can affect receptor sensitivity to FSH, with variations in response observed among different ethnic groups. The higher expression of LHCGR in the ovaries of women with PCOS suggests that polymorphisms in this gene can increase ovarian sensitivity to LH. At least one INSR polymorphism has been linked to decreased insulin sensitivity in the peripheral tissue, represented here by adipocytes, though its role in the ovaries is not yet fully understood. AMH variants that impair signaling showed a reduced ability to inhibit CYP17A1 expression in vitro, contributing to increased androgen synthesis in the ovaries. A specific polymorphism in AMHR2 has been linked to lower LH levels and a reduced LH-to-FSH ratio, although the mechanism underlying this association remains unclear. DENND1A encodes two transcripts, DENND1A.V1 and DENND1A.V2, produced through alternative splicing. In PCOS, DENND1A.V2 is upregulated in theca cells and linked to increased expression of steroidogenic enzyme genes, leading to enhanced androgen biosynthesis. Therefore, it is plausible that DENND1A variants associated with PCOS may promote the expression of DENND1A.V2 over DENND1A.V1. A rare DLK1 variant has been identified in patients with PCOS, suggesting that DLK1 may function as a peripheral signal of metabolic status, influencing reproductive function through mechanisms that remain largely unknown. Epigenetic alterations in PCOS have been most extensively studied in the ovarian tissue, where histone modifications, dysregulated expression of ncRNAs, and predominant hypomethylation patterns have all been implicated in the disorder's pathophysiology.

Figure 5.

Common and distinct genetic variants associated with CPP and PCOS. The Venn diagram represents common and distinct genetic variants associated with CPP and PCOS. Genes with shared genetic variants between the two conditions are shown in the overlapping section, while key genes specifically implicated in CPP and PCOS are displayed in their respective sections, with only genes discussed in the text included. The size of each gene name reflects the strength of genetic evidence. Genes shown in gray are supported by GWAS evidence, while genes in black indicate that rare variants have been associated with the condition.