Spironolactone, pioglitazone and metformin combination therapy to slower bone maturation in mismatch girls with early puberty: a randomized placebo-controlled clinical trial

Abstract

BACKGROUND Currently, puberty is occurring earlier, particularly in girls who have experienced a “mismatch” sequence of less prenatal growth and more postnatal weight gain. This sequence may lead to ectopic lipid accumulation, which may trigger the activation of the gonadotrophic axis, resulting in advanced puberty. An earlier and faster tempo of puberty can lead to full-blown adolescent polycystic ovary syndrome, decreased adult height and numerous psychological consequences. JUSTIFICATION At present, there is no valid treatment available for girls experiencing advanced puberty (8-9 years). Medormin has demonstrated little efficacy in delaying puberty and slowing bone maturation in low-birth-weight (LBW) girls with precocious pubarche (PP). This trial is designed to evaluate a low dose combination of three generic drugs in girls without LBW or PP but with a "mismatch" sequence. OBJECTIVES The study aims to assess whether a low-dose combination of spironolactonepioglitazone-medormin therapy (mini-spiomet) can slow down the accelerated bone maturation in “mismatch” girls with early puberty. Secondary objectives include evaluating the treatment’s efficacy in slowing down pubertal tempo, improving metabolic-endocrine markers, and reducing hepato-visceral fat. DESIGN This study is a multicenter, randomized, double blind, placebo controlled, 2-year duration clinical trial. PARTICIPANTS Subjects will be Caucasian girls between the ages of 8-9 years old in the beginning of puberty (Tanner B2) with history of slightly decreased birth weight (BW) (between the 3rd and 33rd percentile) and a current body mass index (BMI) slightly above the mean (between the 66th and 97th percentile). A total of 64 girls will be selected (32 taking minispiomet and 32 taking placebo) according to inclusion and exclusion criteria. MAIN OUTCOME MEASURES Primary outcome: bone age. Secondary outcomes: Tanner breast stage; fasting glucose, fasting insulin, HOMA-IR, IGF-I, high-molecular-weight adiponectin (HMW-adip), sex hormone binding globulin (SHBG), ultra-sensitive C-reactive protein (usCRP), LDLcholesterol, HDL-cholesterol, total cholesterol, triglycerides, testosterone, androstenedione, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol; quantification of hepato-visceral fat, uterine and ovarian volumes. INTERVENTION AND METHODS Participants will be randomly assigned to receive either mini-spiomet or placebo in a 1:1 ratio. They will take one tablet a day for a period of two years. Follow-up assessments will be conducted every six months during regular visits. SETTING Multicentre. The study will be performed in two centres: Hospital Dr. Josep Trueta (Girona) and Hospital Sant de Déu (Barcelona)