How does Metformin (metformin) lower testosterone levels in women with Polycystic Ovary Syndrome (PCOS)?

How Metformin Lowers Testosterone in Women with PCOS

Metformin lowers testosterone levels in women with PCOS primarily by improving insulin sensitivity, which reduces insulin levels and subsequently decreases ovarian androgen production. 1, 2

Mechanism of Action

• Metformin, a biguanide medication, improves insulin sensitivity in peripheral tissues, leading to decreased circulating insulin levels 2
• High insulin levels directly stimulate ovarian theca cells to produce androgens; when insulin decreases, this stimulation is reduced 2, 3
• Improved insulin sensitivity leads to increased sex hormone binding globulin (SHBG) production by the liver, which binds free testosterone, reducing bioavailable testosterone levels 1, 4
• Metformin decreases both total testosterone and free androgen index (FAI) in women with PCOS 5, 3
• The medication may also have direct effects on ovarian steroidogenesis, independent of its insulin-sensitizing properties 2

Clinical Effects on Androgen Levels

• Studies show metformin significantly reduces testosterone levels (from 2.9 to 1.8 nmol/L) and free androgen index (from 9.1 to 5.3) in women with PCOS 5
• Metformin therapy leads to decreased dehydroepiandrosterone sulfate (DHEAS) levels in some women with PCOS 5, 3
• The medication's effect on androgen levels is most pronounced in women with PCOS who have obesity or insulin resistance 2
• Clinical improvements in hyperandrogenism symptoms (hirsutism, acne) typically follow the biochemical improvements in androgen levels 3

Metabolic Improvements Contributing to Androgen Reduction

• Metformin significantly reduces HOMA-IR (from 4.6 to 2.3) and insulin area under the curve, demonstrating improved insulin sensitivity 5
• The medication helps normalize glucose metabolism, with studies showing decreased 2-hour glucose levels (from 117 to 90 mg/dL) 5
• Metformin tends to decrease weight in women with PCOS, unlike thiazolidinediones which tend to increase weight 1
• Even modest weight loss (5% of initial weight) improves both metabolic and reproductive abnormalities in PCOS, enhancing metformin's effects 1, 6

Clinical Response Variability

• There is considerable heterogeneity in clinical response to metformin therapy among women with PCOS 7
• Genetic factors may play a significant role in predicting response to metformin therapy in PCOS 7
• Women with elevated DHEAS levels may respond differently to metformin compared to those with normal DHEAS levels 3
• The medication's effectiveness in lowering testosterone appears most pronounced in women with higher baseline insulin resistance 2, 4

Additional Reproductive Benefits

• Metformin restores menstrual cyclicity in many women with PCOS, with studies showing normalization of cycles in up to 66.7% of patients 5
• The medication can improve ovulation rates in women with PCOS, though it is not considered first-line therapy for ovulation induction 6, 2
• Metformin may enhance fertility when combined with other treatments for women attempting to conceive 2

Important Clinical Considerations

• Metformin is not FDA-approved specifically for PCOS treatment, though it is widely used off-label for this purpose 1
• The American College of Obstetricians and Gynecologists (ACOG) notes that interventions improving insulin sensitivity, including metformin, may positively impact risk factors for diabetes and cardiovascular disease in women with PCOS 1
• Metformin should be considered particularly in women with PCOS who have cardiometabolic features such as abdominal obesity and insulin resistance 1
• The medication's effects on testosterone levels typically begin within weeks of starting therapy but may continue to improve over several months 3, 4