Table 2.

Justification for the dose of every component of SPIOMET

	No need for a higher dose in order to augment efficacy	No need for a lower dose in order to reduce side effects
SPI (50 mg/d)	SPI is a BAT activator [45] Circulating concentrations of CXCL14, a marker of BAT activity, are low in adolescent girls with PCOS, and this low SPI dose is enough to raise circulating CXCL14 towards normal [74]	> 50 years of experience do not point to safety concerns with doses ≤ 1 mg/kg/d 50 mg/d is at the lower limit of the recommended range (50–200 mg/d) [14]
PIO (7.5 mg/d)	HMW-adip is an adipokine with insulin-sensitising and anti-inflammatory properties Circulating concentrations of HMW-adip are low in adolescent girls with PCOS, and this low pioglitazone dose is enough to raise circulating HMW-adip towards normal concentrations, and even above normal [43]	> 25 years of experience do not point to safety concerns with a dose of 7.5 mg/d In adolescent girls with PCOS, a dose of 7.5 mg/d corresponds to approximately 0.1 mg/kg/d, whereas children are known to tolerate doses of 0.25, 0.50 and 0.75 mg/kg/d [58]
MET (850 mg/d)	Circulating GDF15 has been unmasked as a key mediator of metformin effects [60] In adolescent girls with PCOS, a metformin dose of 850 mg/d is enough to raise circulating GDF15 nearly threefold above the levels in healthy controls [61]	850 mg/d is at the lower limit of the recommended range (850–2000 mg/d) [14] EMA & FDA authorised the use of metformin in doses up to 2000 mg/d in children with type 2 diabetes

Abbreviations: BAT Brown adipose tissue, CXCL14 C-X-C motif chemokine ligand-14, EMA European Medicine Agency, FDA US Food and Drug Administration, GDF15 Growth-and-differentiation factor 15, HMW-adip High molecular weight adiponectin, MET Metformin, PCOS Polycystic ovary syndrome, PIO Pioglitazone, SPI Spironolactone