What are the causes of polycystic ovarian syndrome (PCOS) in women of reproductive age?

What Causes Polycystic Ovarian Syndrome (PCOS)?

PCOS is fundamentally caused by accelerated pulsatile GnRH secretion that drives excessive LH production, combined with insulin resistance and hyperinsulinemia, creating a self-amplifying hormonal and metabolic cascade—though the ultimate trigger for this neuroendocrine dysregulation remains unknown and likely involves genetic predisposition activated by environmental and lifestyle factors. 1

The Core Pathophysiological Mechanism

The central pathogenic driver involves a specific hormonal cascade:

• Accelerated GnRH pulsatility initiates the entire process, causing disordered gonadotropin secretion with the LH/FSH ratio typically exceeding 2:1 2, 1
• Excessive LH secretion directly stimulates ovarian theca stromal cells to massively overproduce androgens, particularly testosterone 2, 1
• FSH-granulosa cell axis hypofunction develops simultaneously, with FSH levels remaining relatively low or normal, preventing proper follicular maturation and causing follicular arrest 2, 1
• This results in hyperandrogenism, hirsutism, and ovarian acyclicity as the downstream manifestations 2

The Metabolic Amplification Loop

Insulin resistance creates a vicious cycle that perpetuates and worsens PCOS:

• Hyperinsulinemia directly stimulates ovarian theca cells to produce even more androgens, independent of LH stimulation 1
• Insulin suppresses hepatic production of sex hormone-binding globulin (SHBG), increasing the fraction of free testosterone circulating in the blood 1
• This metabolic dysregulation is present in the majority of PCOS patients, independent of obesity status 3

Genetic Predisposition

While no single gene causes PCOS, genetic factors play a substantial role:

• PCOS inheritance was historically considered autosomal dominant, but recent investigations reveal it as a multigene origin disease 4
• Genome-wide association studies (GWAS) have identified different genetic loci and specific genes associated with disease development and progression 4
• The genetic variance contributes to four phenotypic variants of PCOS: classic, ovulatory, non-hyperandrogenic, and other types 4

Environmental and Lifestyle Triggers

Multiple modifiable factors can trigger or worsen PCOS in genetically susceptible women:

• Weight gain is a major trigger for PCOS development and symptom progression 2, 3
• Abdominal obesity exacerbates metabolic, reproductive, and psychological features, with obesity prevalence in PCOS increasing from 51% in the 1990s to 74% in recent decades 3
• Environmental pollutants may predispose females to PCOS 5
• Gut dysbiosis may play a pathogenic role in PCOS development 5
• Lifestyle or diet factors contribute to the risk of developing PCOS 5

Medication-Induced PCOS

Certain medications can trigger or exacerbate PCOS:

• Valproate (an antiepileptic drug) can cause PCOS or worsen PCOS-like symptoms, including hirsutism 2, 1, 6
• The prevalence of PCOS in patients with temporal lobe epilepsy ranges between 10% and 25% even without antiepileptic drugs, suggesting a complex relationship 2

Secondary PCOS: Treatable Underlying Causes

A concept of secondary PCOS describes conditions that create a PCOS phenotype but are potentially curable when the underlying cause is treated:

• These well-defined factors are completely treatable, making secondary PCOS potentially curable unlike primary PCOS 7
• It is advisable to actively look for these conditions including thyroid disease, hyperprolactinemia, non-classical congenital adrenal hyperplasia, Cushing's syndrome, and androgen-secreting tumors 6, 7

The Inflammatory Component

PCOS involves systemic inflammation:

• Chronic inflammation is a key pathophysiological disturbance in PCOS females 5, 8
• PCOS is characterized as a polygenic, polyfactorial, systemic, inflammatory, dysregulated steroid state 8
• Some evidence suggests PCOS may have autoimmune disease characteristics 8

Critical Clinical Context

• PCOS affects approximately 4–6% of women in the general population 2
• The syndrome is polygenic and multifactorial, meaning no single cause explains all cases 5, 8
• We still do not know the exact ultimate cause of primary PCOS, which is why it cannot be completely cured, only controlled 7
• Neuroendocrine alterations at the hypothalamic level appear to be the initiating event, but what triggers these alterations remains unclear 5