From adolescent PCOS to adult MAFLD: opposing effects of randomised interventions

Abstract

Asfari et al reported that nonalcoholic fatty liver disease (NAFLD) is fourfold more prevalent in women with than without PCOS, and concluded that ‘further studies are needed to assess if specific PCOS treatments can affect NAFLD progression’. In the meantime, an international consensus has replaced NAFLD by metabolic dysfunctionassociated fatty liver disease (MAFLD). In the absence of overweight and obesity, the definition of MAFLD requires not only that steatosis be present, but also that at least two markers point to metabolic dysfunction, for example, a circulating concentration of C reactive protein (CRP) >2.0 mg/L, and an Homeostasis Model AssessmentInsulin Resistance (HOMAIR) value ≥2.5. Adolescent polycystic ovary syndrome (PCOS) is a prevalent condition (≈10% of girls and women between 2 and 8 years postmenarche) that is characterised by androgen excess and menstrual irregularity (as a proxy of oligoanovulation) but seems to be driven by ectopic lipid accumulation in the liver, essentially resulting from a mismatch between (reduced) prenatal weight gain and (augmented) postnatal weight gain. 5 Adolescent PCOS is increasingly viewed as a state of metabolic dysfunction, often with lowgrade inflammation (by CRP) and/or insulin resistance (by HOMAIR); a polycystic appearance of the ovaries is no longer a diagnostic criterion of PCOS in adolescence. 4 6 The new definitions of MAFLD and adolescent PCOS have led to the insight that there may be an overlap between both entities, and that interventions for PCOS in late adolescence could indeed influence the prevalence of MAFLD in early adulthood. We investigated the latter possibility by taking advantage of recent data from randomised pilot studies in nonobese adolescents with PCOS. These studies compared the effects of a widely recommended treatment (targeting the ovaries) to those of a new treatment (targeting ectopic fat), each on top of lifestyle measures. The recommended treatment was an oestroprogestagen contraceptive (OC; 20 μg ethinylestradiol plus 100 mg levonorgestrel for 21/28 days, and placebo for 7/28 days) that silences the gonadotropic axis, thereby reducing the androgen excess and ensuring anovulation. 8 The new treatment was a lowdose combination of three generics (SPIOMET), namely spironolactone 50 mg/day (to activate brown adipose tissue), pioglitazone 7.5 mg/day (to double highmolecularweight adiponectinaemia, and to prioritise subcutaneous adipogenesis) and metformin 850 mg/day (to triple the circulating concentrations of appetiteattenuating GDF15). SPIOMET does not elicit a loss of body weight, but redistributes body fat from ectopic to subcutaneous depots, thereby conferring more broadly normalising benefits than OC, in particular on liver fat (by MRI) and on posttreatment androgen excess and ovulation rate 13 (online supplemental table 1). Here, we highlight the effects of OC versus SPIOMET intervention on a key MAFLD ensemble in nonobese young women with PCOS, namely the triad of hepatic fat, HOMAIR and circulating CRP. Figure 1 shows that the randomised interventions were accompanied by opposing influences on these MAFLD components, so that the prevalence of the MAFLD triad increased from 13% to 35% during OC treatment, and decreased from 13% to 0% during SPIOMET treatment (p<0.001 for betweengroup difference at 6 and 12 months, by χ test). Mean body mass index increased over 12 months on OC (from 24.2 to 24.9 kg/m; p≤0.01) but did not change detectably on SPIOMET (from 24.2 to 23.9 kg/ m). In conclusion, the new MAFLD concept unmasks that the widely recommended OC therapy for PCOS does not attenuate the underpinning problem of metabolic dysfunction, and that approximately onethird of OCtreated nonobese adolescents with PCOS become young women with MAFLD. SPIOMET treatment represents a more pathophysiological approach: it is a weightlossmimicking intervention that normalises liver fat, HOMAIR and circulating CRP, and that may be particularly preferable in adolescent settings of sexual abstinence, where contraception is not at stake. PCOS in adolescent girls and young women is, in essence, a postmenarcheal or pregestational central obesity syndrome (PCOS) that should not only be treated from Department of Development and Regeneration, KU Leuven University Hospitals Leuven, Leuven, Belgium Department of Endocrinology, Hospital Sant Joan de Déu, Barcelona, Spain