la Marca, A., Morgante, G., Palumbo, M., Cianci, A., Petraglia, F., & De Leo, V. (2002). Insulin-lowering treatment reduces aromatase activity in response to follicle-stimulating hormone in women with polycystic ovary syndrome. Fertility and Sterility, 78(6), 1234-1239. https://doi.org/10.1016/s0015-0282(02)04346-7
la Marca A, Morgante G, Palumbo M, Cianci A, Petraglia F, De Leo V. Insulin-lowering treatment reduces aromatase activity in response to follicle-stimulating hormone in women with polycystic ovary syndrome. Fertil Steril. 2002;78(6):1234-1239. doi:10.1016/s0015-0282(02)04346-7
la Marca, Antonio, et al. "Insulin-lowering treatment reduces aromatase activity in response to follicle-stimulating hormone in women with polycystic ovary syndrome." Fertility and Sterility, vol. 78, no. 6, 2002, pp. 1234-1239.
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Metformin was followed by lower FSH-driven aromatase activity in PCOS
After metformin, 15 women with PCOS made less estrogen in response to FSH. This 2002 Italian study gave FSH shots before and after 35 to 40 days of metformin. Two hormone ratios that indicate aromatase activity in response to FSH were lower afterward. Aromatase is the enzyme that turns androgens into estrogen.
Key Findings
Twenty women aged 18 to 26 with PCOS were recruited. Complete results came from 15; 5 ovulated during metformin treatment and were excluded.
After 35 to 40 days of metformin, free testosterone, fasting insulin and insulin response to an oral glucose test were significantly lower than before. Body mass index did not change significantly.
The estradiol response to FSH, at its peak and over the 24-hour sampling period, was significantly smaller after metformin than before.
Aromatase activity after FSH, measured as ratios of the estradiol response to the androstenedione and testosterone responses, was significantly lower, with mean reductions of 48% and 36%.
A larger fall in insulin response to the glucose test went with a larger fall in estradiol response to FSH. Body mass index showed no significant correlation with the fall in estradiol.
Interpretation
This prospective study followed 15 women with PCOS, comparing each woman's own hormone levels before and after metformin. The women were 18 to 26 years old with irregular or absent periods and high androgens. The authors describe the link between metformin and lower aromatase activity as an association. The findings support larger studies of this approach.
RRM Context
The authors conclude that insulin affects production of both androgen and estrogen. Restorative reproductive medicine looks for the root cause of ovulation problems. PCOS is now renamed polyendocrine metabolic ovarian syndrome (PMOS). These results point to insulin as one candidate driver.
Our editorial summary of this paper, not the article's abstract.
Abstract
Objective
To investigate the effects of reduction of insulin resistance and hyperinsulinemia associated with the polycystic ovary syndrome (PCOS) on FSH-stimulated ovarian aromatase activity.
Design
Prospective study.
Setting
Academic health center, Siena, Italy.
Patients
Twenty women 18 to 26 years of age in whom PCOS was diagnosed on the basis of oligomenorrhea or amenorrhea and hyperandrogenemia.
Interventions
Recombinant FSH was administered. The next day, therapy with metformin (500 mg t.i.d.) was begun. After 35 to 40 days of treatment, the pretreatment protocol was repeated.
Main Outcome Measures
Plasma levels of estradiol (E(2)), androstenedione (A), and testosterone (T). The ratios of basal levels and areas under the curve (AUCs) of products and substrates were compared before and after metformin administration to detect differences in aromatase activity.
Results
Metformin treatment was associated with significant reduction in basal free testosterone plasma levels, insulin plasma levels, and insulin response to oral glucose tolerance testing. Administration of FSH was followed by a significantly lesser E(2) response after metformin therapy than before this therapy. The ratios of AUC(E2) to AUC(A) and to AUC(T), indicative of aromatase activity in response to FSH, were significantly lower after metformin therapy than before.
Conclusions
Metformin therapy in women with PCOS is associated with a reduction in aromatase activity in response to FSH. Insulin affects production of both androgen and estrogen. Insulin therefore plays a central role in regulating the activity of thecal and granulosa cells.
