Polycystic ovary syndrome in adolescent girls: treatment oriented to pathophysiology and new markers of effciacy

[eng] Polycystic ovary syndrome (PCOS) could begin with a mismatch between prenatal (reduced) and postnatal (increased) growth, causing an excess of hepato-visceral fat. Dysfunction of adipose tissue, alteration of the intestinal microbiota, thyroid disorders and altered circulating levels of signaling molecules (organocins), can contribute to the pathogenesis of PCOS. There is currently no drug approved for the treatment of this syndrome, although an oral contraceptive (OCA) is usually prescribed. Recently, a new treatment based on the low-dose combination of spironolactone, pioglitazone and metformin (SPIOMET) has been proposed. Although the evidence is still limited, a pilot study carried out in a population of adolescents with PCOS and without obesity (N=34) has described that treatment with SPIOMET provides more normalizing effects than treatment with ACOs. HYPOTHESIS: In a larger study population of adolescents with PCOS, SPIOMET treatment will be confirmed to have more beneficial effects than treatment with ACOs. OBJECTIVES: - To compare the effects of treatment with SPIOMET or ACOs in a larger cohort of adolescents with PCOS and without obesity - To characterize circulating levels of CXCL14 [C-X-C motif chemokine ligand 14, a protein secreted by brown adipose tissue (TAM)] in adolescents with PCOS and to assess whether divergent changes occur after one year of treatment with SPIOMET or ACOs. To determine the effects of the drugs that make up SPIOMET on the expression and release of CXCL14 in a cellular model of human adipocytes. - To study the composition of the intestinal microbiota in stool samples from adolescents with PCOS and to determine the effects of treatment for one year with SPIOMET or ACOs. - To determine whether thyrotropin (TSH) levels are elevated in adolescents with PCOS and to study whether these levels are reduced after one year of treatment with SPIOMET or ACOs and whether they remain low 1 year after discontinuation of treatment. - To evaluate the effects of 6 months of treatment with SPIOMET or ACOs on a set of organocins [fibroblast growth factor 21 (FGF21), diazepam-binding protein 1 (DBI) and meteorin-like (METRNL)] in adolescents with PCOS and to identify associations with circulating biomarkers of liver damage [aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT)] evaluated as safety parameters in pilot studies.