Leader vs follower in the tango of polycystic ovary syndrome: Insulin resistance vs androgen excess
Francis de Zegher, Lourdes Ibáñez
Abstract
In their Nordic perspective on the recommendations from the 2023 polycystic ovary syndrome (PCOS) guideline, Forslund et al.1 confirm that androgen excess is a criterion to diagnose PCOS and they omit the original statement that “insulin resistance is recognized as a key feature of PCOS”.2 In their section on PCOS diagnosis, these eminent authors discuss clinical and biochemical hyperandrogenism, but they remain silent on insulin resistance.1 Such omissions or silences generate the perception that these experts view androgen excess as “leader” and insulin resistance as “follower” in the “tango of PCOS”, thereby joining the opinion of many PCOS patients who are primarily concerned about their hirsutism, acne, seborrhea and/or alopecia, and who may not even be aware of their insulin resistance. If androgen excess were indeed the tango's leader, then a marked lowering of free androgenemia (for example, with a combined oral contraceptive pill [COCP], as recommended1, 2) should be followed by a net reduction of insulin resistance and its correlates. Time and again, however, such reduction fails to occur, even when COCPs are given in the early stages of adolescent PCOS.3-6 This hypothesis should thus be abandoned, given that the proposed leader is simply not followed. If insulin resistance is the tango's leader, then an insulin-sensitizing intervention (for example, with a low-dose combination of spironolactone [as anti-mineralocorticoid rather than as anti-androgen], pioglitazone and metformin4-6) should be followed by a net fall of free androgenemia, as is indeed consistently the case. Such intervention can even revert the entire PCOS phenotype, if given to adolescent girls without obesity.4-6 In 2019, Samuel & Shulman wrote that “insulin resistance probably encompasses heterogeneous subtypes with discrete mechanisms, but in most clinical situations it ultimately reflects ectopic lipid accumulation in insulin-responsive organs”.7 Therefore, the current view is that PCOS is, in essence, driven by ectopic fat which, in turn, results from a mismatch between adipogenesis and lipogenesis in subcutaneous adipose tissue.6 The CO in the center of PCOS could thus stand for Central Obesity.6 In conclusion, insulin resistance is the leader in the tango of PCOS, and androgen excess is the follower. As in real-life tangos, however, the follower (androgen excess) does sometimes attract more attention than the leader.