What causes Polycystic Ovary Syndrome (PCOS)?

What Causes Polycystic Ovary Syndrome (PCOS)?

PCOS is a complex multifactorial disorder with an unclear etiology that involves genetic predisposition, environmental factors, and metabolic dysregulation, primarily characterized by altered hypothalamic-pituitary-ovarian function interacting with hyperinsulinemia and insulin resistance to promote androgen excess. [@2-7@, 1]

Core Pathophysiologic Mechanisms

The fundamental pathogenesis involves several interconnected pathways [@2-7@]:

• Accelerated pulsatile GnRH secretion leading to abnormal gonadotropin release [@2-7@]
• Insulin resistance and hyperinsulinemia with downstream metabolic dysregulation [@2-7@, 1]
• Hypersecretion of luteinizing hormone (LH) causing ovarian theca stromal cell hyperactivity [@2-7@]
• Hypofunction of the FSH-granulosa cell axis resulting in follicular arrest and ovarian acyclicity [@2-7@]

These abnormalities manifest as hyperandrogenism, hirsutism, and chronic anovulation [@2-7@].

Genetic Factors

PCOS is considered a polygenic trait resulting from interaction of susceptibility and protective genomic variants under environmental influence 2, 3:

• Familial clustering demonstrates hereditary involvement, though no single "PCOS gene" has been identified 2, 3
• Candidate genes include those related to:
  • Steroid hormone biosynthesis (CYP11A, CYP17, CYP19) 3
  • Insulin secretion and action (INS VNTR, insulin receptor genes, IRS1-2) 3
  • Gonadotropin and gonadal hormone action (androgen receptor, FSH receptor) 3
  • Obesity and energy regulation 2, 3

The INS VNTR minisatellite, particularly class III alleles, may determine predisposition to anovulatory PCOS and concomitant diabetes risk 3.

Environmental and Metabolic Triggers

Weight gain is a major trigger for PCOS development in genetically susceptible women [@2-7@]:

• Physical inactivity and unhealthy eating habits play vital roles in PCOS progression 4
• Obesity exacerbates insulin resistance and favors progression to diabetes 2
• The association between obesity and PCOS is complex and bidirectional, with obesity genes noted in PCOS genetic studies 1

Prenatal and Developmental Factors

Alterations during prenatal development may contribute to PCOS etiology 4:

• Exposure to excess anti-Müllerian hormone (AMH) or androgens during fetal development 4
• Exposure to environmental toxins (bisphenol-A, endocrine disruptors) 4

Insulin Resistance as Central Mechanism

Abnormal serine phosphorylation in the insulin receptor impairs signal transduction, creating a post-binding defect in insulin action 3:

• This same serine phosphorylation is involved in regulating 17,20-lyase activity (CYP17) 3
• There may be a common etiology for both insulin resistance and hyperandrogenism through this shared pathway 3
• Insulin resistance is present in most women with PCOS, both obese and lean 3

Inflammatory Component

Chronic low-grade inflammation is intrinsically linked to PCOS pathogenesis 4:

• Proinflammatory genotypes and phenotypes are associated with obesity, insulin resistance, and PCOS 2
• Advanced glycation end products (AGEs) exaggerate PCOS symptoms and relate to ovarian dysfunction 4
• Oxidative stress and ROS formation contribute to disease progression 4

Drug-Induced PCOS

Certain medications can trigger or exacerbate PCOS [@2-7@]:

• Valproate (antiepileptic drug) is associated with PCOS development [@2-7@]
• Older antiepileptic drugs (carbamazepine, phenobarbital, phenytoin) alter sex hormone metabolism through hepatic enzyme induction [@2-7@]

Important Clinical Caveat

PCOS should not be confused with isolated polycystic ovaries (polycystic morphology without symptoms or hormonal abnormality), which occurs in 17-22% of the general population [@2-7@]. Only some women with polycystic ovaries develop full PCOS with chronic oligomenorrhea/amenorrhea and elevated androgens [@2-7@].