Organokines and liver enzymes in adolescent girls with polycystic ovary syndrome during randomized treatments

Abstract

Introduction: Polycystic ovary syndrome (PCOS) is often associated with metabolic-associated fatty liver disease (MAFLD). MAFLD has been associated with altered hepatic function, systemic dysmetabolism, and abnormal circulating levels of signaling molecules called organokines. Here, we assessed the effects of two randomized treatments on a set of organokines in adolescent girls with PCOS and without obesity, and report the associations with circulating biomarkers of liver damage, which were assessed longitudinally in the aforementioned studies as safety markers.

Materials and methods: Liver enzymes [aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT)] were assessed as safety markers in previous randomized pilot studies comparing the effects of an oral contraceptive (OC) with those of a low-dose combination of spironolactone-pioglitazone-metformin (spiomet) for 1 year. As a post hoc endpoint, the organokines fibroblast growth factor-21 (FGF21), diazepam-binding protein-1 (DBI), and meteorin-like protein (METRNL) were assessed by ELISA after 6 months of OC (N = 26) or spiomet (N = 28). Auxological, endocrine-metabolic, body composition (using DXA), and abdominal fat partitioning (using MRI) were also evaluated. Healthy, age-matched adolescent girls (N = 17) served as controls.

Results: Circulating ALT and GGT levels increased during OC treatment and returned to baseline concentrations in the post-treatment phase; in contrast, spiomet treatment elicited no detectable changes in ALT and GGT concentrations. In relation to organokines after 6 months of treatment, (1) FGF21 levels were significantly higher in PCOS adolescents than in control girls; (2) DBI levels were lower in OC-treated girls than in controls and spiomet-treated girls; and (3) no differences were observed in METRNL concentrations between PCOS girls and controls. Serum ALT and GGT levels were directly correlated with circulating METRNL levels only in OC-treated girls (R = 0.449, P = 0.036 and R = 0.552, P = 0.004, respectively).

Conclusion: The on-treatment increase in ALT and GGT levels occurring only in OC-treated girls is associated with circulating METRNL levels, suggesting enhanced METRNL synthesis as a reaction to the hepatic changes elicited by OC treatment.

Clinical trial registration: https://doi.org, identifiers 10.1186/ISRCTN29234515, 10.1186/ISRCTN11062950.

Keywords: METRNL; PCOS; liver enzymes; metformin; oral contraceptives; organokines; pioglitazone; spironolactone.

Figure 1

Longitudinal results of aspartate aminotransferase (AST, A), alanine aminotransferase (ALT, B), and gamma-glutamyl transferase (GGT, C) concentrations in adolescent girls with polycystic ovary syndrome (PCOS) who received an oral contraceptive (OC, red circles, N = 26) or a low-dose combination of spironolactone–pioglitazone–metformin (spiomet, blue circles, N = 28) for 12 months and remained untreated for 12 months. The yellow area represents the active treatment phase. The dotted line represents the mean value in healthy controls (N = 17), and the shaded area represents the mean ± standard error in healthy controls. ^*P <0.05; ^**P <0.01; ^***P <0.001 for differences between subgroups at 6, 12, and 18 months. ^#P <0.05; ^##P <0.01, differences between controls and the OC subgroup. ⁺P <0.05, for differences between controls and spiomet subgroup.

Figure 2

Correlations between circulating meteorin-like (METRNL) levels and alanine aminotransferase (ALT, A) and gamma-glutamyl transferase (GGT, B) concentrations in adolescent girls with polycystic ovary syndrome (PCOS) after 6 months of treatment with an oral contraceptive (OC, red circles, N = 26) or a low-dose combination of spironolactone–pioglitazone–metformin (spiomet, blue circles, N = 28). P-values were adjusted for body mass index.