What is the mechanism of hyperandrogenism in women with Polycystic Ovary Syndrome (PCOS)?

Mechanism of Hyperandrogenism in PCOS

Hyperandrogenism in PCOS results from accelerated GnRH pulsatility driving excessive LH secretion, which directly stimulates ovarian theca cells to overproduce androgens (particularly testosterone), while hyperinsulinemia amplifies this process by independently stimulating androgen production and suppressing SHBG, creating a self-perpetuating cycle of elevated free testosterone. 1

The Primary Ovarian Mechanism (Functional Ovarian Hyperandrogenism)

Functional ovarian hyperandrogenism (FOH) is the dominant mechanism, present in approximately 70% of PCOS patients. 2, 3

The Neuroendocrine Cascade

• Accelerated GnRH pulsatility initiates the entire hormonal cascade, leading to disordered gonadotropin secretion with an LH/FSH ratio typically exceeding 2:1, which is both diagnostically significant and mechanistically critical. 1

• Excessive LH secretion directly stimulates ovarian theca stromal cells, causing massive overproduction of androgens, particularly testosterone and 17-hydroxyprogesterone. 1, 2

• FSH-granulosa cell axis dysfunction occurs simultaneously, with FSH levels remaining relatively low or normal, preventing proper follicular maturation and creating the characteristic polycystic ovarian morphology. 1

Intrinsic Theca Cell Dysregulation

• Theca cells from polycystic ovaries have an intrinsic steroidogenic dysregulation that persists even in long-term culture, demonstrating this is not merely a response to hormonal signals but a fundamental cellular abnormality. 3

• Overexpression of steroidogenic enzymes, particularly cytochrome P450c17 (which has both 17-hydroxylase and 17,20-lyase activities), represents the rate-limiting step in androgen biosynthesis that becomes dysregulated in PCOS. 2, 3

• This dysregulation is characterized by excessive secretion of 17-hydroxyprogesterone in response to GnRH agonist or hCG stimulation, and failure of dexamethasone to suppress plasma free testosterone normally despite adequate adrenocortical suppression. 2

The Metabolic Amplification Loop

Hyperinsulinemia creates a vicious cycle that dramatically amplifies ovarian androgen production through two distinct mechanisms. 1, 4

• Direct stimulation of ovarian theca cells by insulin occurs independent of LH stimulation, causing even greater androgen production beyond what LH alone would trigger. 1

• Suppression of hepatic SHBG production by insulin increases the fraction of free (bioavailable) testosterone circulating in the blood, as SHBG normally binds and inactivates testosterone. 1

• Obesity worsens insulin resistance, creating compensatory hyperinsulinemia that has tissue-selective effects, including aggravation of hyperandrogenism, forming a self-perpetuating cycle. 1, 3

The Adrenal Contribution (Functional Adrenal Hyperandrogenism)

Functional adrenal hyperandrogenism contributes to total androgen excess in approximately 20-30% of PCOS patients, though it is not the primary mechanism. 5

• Increased adrenal sensitivity to ACTH at the level of the adrenal gland causes excessive secretion of DHEA and DHEAS in response to normal ACTH stimulation. 2, 5

• The mechanism involves exaggerated secretory response of the adrenal cortex for DHEA and androstenedione, but not altered pituitary responsivity to CRH or increased sensitivity to ACTH stimulation. 6

• DHEAS is elevated in only 8-33% of PCOS patients when age-adjusted reference ranges are used, making it a secondary rather than primary contributor to hyperandrogenism. 7

• Adrenal androgens may be elevated in at-risk girls from childhood through menopause, suggesting these androgens are clinically relevant across the lifespan and may play a role in PCOS development. 5

Clinical Manifestations and Diagnostic Implications

Hyperandrogenism is present in 75% of PCOS cases and serves as both a diagnostic criterion and central pathogenic driver. 8, 1

• Total testosterone (TT) and free testosterone (FT) measured by LC-MS/MS should be first-line tests, with TT having 74% sensitivity and 86% specificity, and FT having 89% sensitivity and 83% specificity. 7

• Calculated free androgen index (FAI = total testosterone/SHBG ratio) can be used when LC-MS/MS is unavailable, as SHBG fluctuations affect interpretation and are influenced by age, weight, and medications. 7, 1

• Second-line testing with androstenedione (A4) and DHEAS should only be performed if TT and FT are not elevated but clinical suspicion remains high, noting their poorer specificity (A4: 75% sensitivity, 71% specificity; DHEAS: 75% sensitivity, 67% specificity). 7

Important Clinical Caveats

• Weight gain is a major trigger for PCOS development and worsening symptoms in genetically susceptible women, making lifestyle intervention essential to break the insulin-androgen cycle. 1

• Certain medications, particularly valproate, can exacerbate PCOS and trigger or worsen PCOS-like symptoms, including hyperandrogenism. 1

• Rapid-onset or severe hyperandrogenism with virilization (deepening voice, clitoromegaly) suggests an androgen-secreting tumor rather than PCOS and demands immediate aggressive workup with imaging. 7, 1

• The heterogeneity of PCOS means that hyperandrogenism is not the only pathogenic factor, and distinct phenotypes exist based on the presence or absence of ovarian versus adrenal androgen excess. 4, 5