Adolescent polycystic ovary syndrome without obesity: HOTAIR rs1443512 genotype relates to fat mass and to the redistribution of fat mass on low-dose pioglitazone.

Abstract

Adolescent polycystic ovary syndrome (PCOS) is characterized by androgen excess and oligo-amenorrhea, and often results from ectopic lipid storage due to a mismatch between early adipogenesis and later lipogenesis. Endogenous HOX transcript antisense RNA (HOTAIR) and exogenous pioglitazone are enhancers of subcutaneous adipogenesis, particularly in the gluteofemoral region. The A allele of HOTAIR rs1443512 is an equivalent of a natural knock-down and is, thus, a candidate to influence the distribution of fat mass, and also the redistribution of fat mass by pioglitazone in adolescent PCOS-without-obesity. We performed two post hoc analyses by HOTAIR rs1443512 genotype. In the first, we analyzed the pooled pre-treatment data (auxology; endocrinology; body composition by dual X-ray absorptiometry; abdominal fat distribution by magnetic resonance imaging) of 65 adolescent girls with PCOS-without-obesity in three reported studies (ISRCTN45546616; ISRCTN29234515; ISRCTN11062950). In the second, we analyzed the results of 24 adolescent girls with PCOS-without-obesity, who received pioglitazone (7.5 mg/d for 1 year) as part of a randomized combination treatment (with spironolactone and metformin) in two reported studies (ISRCTN29234515; ISRCTN11062950). All data had been obtained in a blinded-to-genotype way. The pre-treatment data disclosed that the girls-with-A-allele of HOTAIR rs1443512 had developed PCOS with a lower BMI (22.3 ± 2.3 kg/m2; N = 17) than the other girls (24.1 ± 2.7 kg/m2; N = 48), this difference being essentially attributable to a lower fat mass (mean difference 4.6 kg; P < 0.01). On low-dose pioglitazone, girls-with-A-allele (N = 12) raised their fat mass while the other girls (N = 12) did not (total fat mass + 2.2 ± 1.8 kg vs - 0.9 ± 2.2 kg; P < 0.001), particularly in the gynoid area (gluteofemoral fat + 0.6 ± 0.4 kg vs - 0.1 ± 0.5 kg; hip circumference + 2.3 ± 1.9 cm vs - 1.7 ± 3.1 cm; both P < 0.001). The present findings suggest that the HOTAIR rs1443512 genotype influences not only the distribution of fat mass in adolescent girls with PCOS-without-obesity but also the redistribution of fat mass during prolonged treatment with low-dose pioglitazone. ISRCTN45546616 ( https://doi.org/10.1186/ISRCTN45546616 ). ISRCTN29234515 ( https://doi.org/10.1186/ISRCTN29234515 ). ISRCTN11062950 ( https://doi.org/10.1186/ISRCTN11062950 ).