NEW ORLEANS — Metformin appeared to reverse the features of polycystic ovary syndrome when given to prepubertal girls with a history of low birth weight and precocious puberty in two small randomized studies.
When metformin was withdrawn from these girls after puberty, however, the beneficial changes were reversed within 6 months, Lourdes Ibanez, M.D., said at the annual meeting of the Endocrine Society.
Dr. Ibanez of the University of Barcelona, Spain, reported on two small randomized studies of metformin treatment in girls with a combined history of low birth weight and precocious puberty. The first study randomized 33 prepubertal girls to either no therapy or to 425 mg of metformin daily for 6 months. The second was a randomized crossover trial: 24 postpubertal girls received either no therapy or 850 mg metformin daily for 12 months, after which the groups switched treatments for 6 months.
In the first study, all girls were 8 years old and prepubertal. Birth weight averaged 2.4 kg and BMI, 18.5. All had precocious puberty secondary to exaggerated adrenarche, high circulating levels of interleukin-6 and dehydroepiandrosterone sulfate (DHEAS), and low adiponectin.
In untreated girls, these parameters continued to diverge from normal levels during the 6-month study, Dr. Ibanez said. Their DHEAS levels rose from about 105 μg/dL to 115 μg/dL; interleukin-6 rose from about 1,050 femtogram/mL to 1,100 fg/mL, and adiponectin decreased from about 10.5 μg/mL to 9 μg/mL. The girls continued to increase their abdominal fat over the 6 months, gaining an average of about 300 g.
All these parameters improved in the treated girls, Dr. Ibanez said. In this group, the DHEAS levels remained stable, the interleukin-6 level dropped from about 1,000 fg/mL to abut 800 fg/mL, and the adiponectin increased from about 10 μg/mL to about 11 μg/mL. Abdominal fat decreased in these girls by an average of 300 g.
The crossover trial contained 24 girls who were 6-12 months beyond menarche at the study outset. These girls were also low birth weight (average 2.4 kg). Their average age was 12 years and their average BMI was 21.
All of these girls showed precursor features of polycystic ovary syndrome (PCOS): They had hyperinsulinemia, hyperandrogenemia, increased truncal fat, decreased lean body mass, and dyslipidemia
The girls were randomized to either no treatment or 850 mg of metformin daily for 12 months. At the end of that period, the treated girls stopped therapy, and the untreated girls began therapy.
After 12 months, the untreated girls experienced increases in markers associated with incipient PCOS, Dr. Ibanez said. Their BMI increased from 21 to 21.6; their insulin sensitivity declined; and levels of testosterone, androstenedione, and DHEAS all increased. Their LDL cholesterol and triglycerides increased, while their HDL cholesterol decreased. The girls gained about 2 kg of truncal fat and lost about 1 kg of lean body mass.
Although not fully normalized by the end of 12 moths, these parameters all improved in the treated girls. BMI stayed stable, but the girls lost 0.5 kg of truncal fat and gained about 2 kg of lean body mass. Their insulin sensitivity increased, while their testosterone and androstenedione levels decreased. There was no significant effect on DHEAS.
The girls' lipid levels improved as well, with decreases in LDL cholesterol and triglycerides and an increase in HDL cholesterol.
After 12 months, the groups switched treatments. Within 6 months, the girls who stopped therapy lost almost all of their improvements in weight, hormones, and lipids, while the girls who began therapy made significant gains in these areas.
After 6 months of stopping metformin, the previously treated girls experienced a drop in insulin sensitivity (100% to about 65%) and adiponectin (from 14 μg/mL to 12 μg/mL) and an increase in interleukin-6 (from about 900 fg/mL to 1,300 fg/mL).
After 6 months of treatment, the previously untreated girls experienced an increase in insulin sensitivity (from 60% to about 85%) and adiponectin (from about 12 fg/mL to 13 fg/mL), and a decrease in interleukin-6 (from about 1,400 fg/mL to about 900 fg/mL).