Letter to the Editor: Tackling NAFLD in Adolescent Polycystic Ovary Syndrome: Reducing Liver Fat to Mimic Weight Loss
Authors: Francis de Zegher, Lourdes Ibáňez
Journal: Hepatology (2020)

Potential conflict of interest: Nothing to report. TO THE EDITOR: Adolescent girls with polycystic ovary syndrome (PCOS) fit in at least two of the target populations wherein Wegermann et al. propose to tackle nonalcoholic fatty liver disease (NAFLD).(1) Diagnostic features of adolescent PCOS are androgen excess (clinical and biochemical) and menstrual irregularity, but ectopic lipid accumulation in the liver is emerging as a key pathogenic mechanism, apparently driven by a mismatch between (reduced) prenatal weight gain and (augmented) postnatal weight gain.(2) The latter mismatch implies that adolescents with PCOS may have NAFLD without being overweight or obese, particularly in regions such as South Asia,(3) where prenatal weight gain and subcutaneous adipogenesis tend to be low.(2) For those adolescents, it is notoriously difficult to achieve a sustained loss of body weight. In 1998, this fact prompted a search for weight loss–mimicking interventions in adolescents with PCOS who are not obese.(4) Two decades later, this search has led to a low‐dose combination of generics (spironolactone‐pioglitazone‐metformin [SPIOMET]) consisting of spironolactone (50 mg/day, to activate brown adipose tissue, as judged by circulating chemokine [C‐X‐C motif] ligand 14), pioglitazone (7.5 mg/day, to double circulating high‐molecular‐weight adiponectin), and metformin (850 mg/day, to triple the circulating concentrations of appetite‐attenuating GDF15).(5) In the absence of weight loss, SPIOMET intake was associated with a marked reduction of hepatic fat and a disappearance of PCOS features, including a normalization of ovulation rate (Fig. 1). The same figure also shows that the lowering of androgen excess with an estro‐progestogen contraceptive failed to reduce liver fat: NAFLD is thus a cause rather than a consequence of androgen excess. Our pilot evidence remains to be corroborated in double‐blind multicenter studies of larger and more diverse populations. In the meantime, the future armamentarium to tackle NAFLD is anticipated to include not only measures and medications that aim at weight loss—as explained by Wegermann et al.—but also weight loss–mimicking strategies that reduce ectopic adiposity without lowering body weight.Fig. 1: Reduction of liver fat—without changing body weight—is followed by more ovulations in adolescent girls with PCOS. Longitudinal changes in the hepatic fat fraction (by magnetic resonance imaging) are shown in adolescents with PCOS, first on treatment (0‐12 months) and then after treatment (12‐24 months). The dotted line indicates the average percentage of hepatic fat in healthy control girls. The adolescents with PCOS (mean age 16 years) were randomized to receive an oral estro‐progestogen contraceptive (OC; red circles/bar) or a low‐dose combo of SPIOMET (blue circles/bar). Both treatments reduced the androgen excess within 12 months toward normal without changing body weight or lean mass. Treatment with OC failed to reduce the hepatic fat excess and was followed by a rebound of the androgen excess. In contrast, treatment with SPIOMET was accompanied by a normalization of hepatic adiposity and insulin resistance that extended beyond the time window of active treatment. The annualized number of ovulations after treatment was nearly 3‐fold higher after SPIOMET than after OC treatment (results are shown as mean and SEM; n = 31 in each treatment group). P < 0.001 for between‐group differences in on‐treatment changes of hepatic fat, hepatic fat fractions after treatment, and ovulation rates after treatment. Original data are from reference Ibáñez et al.( 5 )