Angela Ferrer

Early Puberty: Rapid Progression and Reduced Final Height in Girls With Low Birth Weight

Objective. To assess whether, in girls with early onset of puberty, low birth weight is a risk factor for rapid progression to menarche and for short adult stature. Design. Longitudinal clinical assessment of 54 Catalan (Northern Spanish) girls followed from early onset of puberty (onset of breast development between 8.0 and 9.0 years of age) to final height. The timing of menarche and the final height were analyzed a posteriori according to birth weight, the cutoff level between normal and low birth weight subgroups being −1.5 standard deviation (SD; ∼2.7 kg at term birth). Results. Normal and low birth weight girls had similar target heights and characteristics at diagnosis of early puberty. However, menarche occurred on average 1.6 years earlier in low versus normal birth weight girls (11.3 ± .3 years vs 12.9 ± .2 years), and final height was >5 cm shorter in low birth weight girls (parental adjusted height SD: −.6 ± .2 cm vs .3 ± .2 cm). Conclusion. The timing of menarche and the level of final height in Catalan girls with early onset of puberty was found to depend on prenatal growth. Girls with normal birth weight tend to progress slowly through puberty with a normal timing of menarche and normal final height. In contrast, girls with low birth weight tend to progress relatively rapidly to an early menarche and to a reduced final height. If these findings are confirmed in other ethnic and/or larger groups, then a subgroup has been identified that will most likely benefit from any therapeutic intervention aiming at a delay of pubertal development and/or an increase of final height.

Anovulation in eumenorrheic, nonobese adolescent girls born small for gestational age: Insulin sensitization induces ovulation, increases lean body mass, and reduces abdominal fat excess, dyslipidemia, and subclinical hyperandrogenism

Adolescent girls who were small for gestational age when born are, even if not obese, at risk for numerous abnormalities, including hyperinsulinism, subnormal ovarian responsiveness to FSH, subclinical hyperandrogenism, areduced rate of ovulation, and abnormal blood lipids. Hyperinsulinemic insulin resistance has been suggested as an important pathogenetic factor. The authors tested this possibility by determining the effects of insulin sensitization in 13 such girls. They were not obese and had normal menses, but they did not ovulate and had central adiposity and dyslipidemia. In addition, subclinical hyperandrogenism was documented. All had weighed below 2 standard deviations at term birth and had a body mass index less than 25 kg/m 2 . The participants, 14 to 18 years of age at the time of study, had begun menstruating 3 to 6 years earlier. Metformin was given in a dose of 850 mg daily for 3 months. Blood levels of insulin, androgens, triglycerides, and FSH were elevated in these girls, but fasting insulin levels and androgens declined when metformin was given, and the lipid profile became less atherogenic in all cases. Initially the waist-to-hip ratio was high with excess fat, especially abdominally, and a reduced lean body mass. After 3 months on metformin, all of these abnormalities were less evident. The most marked changes were a reduction in abdominal fat mass and an increase in lean body mass (Fig. 1). Body weight remained unchanged. Six of the 13 girls (46%) began ovulating about 6 weeks after the start of treatment, and within 11 weeks, 69% were ovulating. The increase in lean body mass that followed from metformin therapy raises the question of whether it reduces growth hormone secretion in adolescent girls with hyperinsulinemic hyperandrogenism. If so, this would reinforce the importance of insulin sensitivity in maintaining a normal body shape and ovulatory function.

Sensitization to Insulin Induces Ovulation in Nonobese Adolescents With Anovulatory Hyperandrogenism

Even nonobese girls with precocious pubarche may develop a variant of polycystic ovary syndrome (PCOS) characterized by hyperinsulinism, hyperandrogenism, abnormal lipids, and persistent anovulation. Insulin-sensitizing treatment has limited hyperinsulinism and hyperandrogenism and restored eumenorrhea in women with PCOS. Extrapolating from observations in obese women with PCOS who receive an insulin-sensitizing agent such as metformin or troglitazone and become more likely to ovulate, this study examined the effects of metformin in 18 nonobese adolescent girls with a mean age of 16½ years who were 3 to 7 years past menarche. All were anovulatory and met clinical and hormonal criteria for ovarian hyperandrogenism. The participants also had a history of precocious pubarche caused by exaggerated adrenarche. All the girls were hyperinsulinemic but had normal glucose tolerance. Anovulation was confirmed twice by obtaining four consecutive serum progesterone levels below 4 ng/ml at 1-week intervals. Metformin was given for 6 months in a daily dose of 1275 mg. Hirsutism scores decreased with metformin therapy, as did levels of fasting serum insulin, luteinizing hormone, total testosterone, androstenedione, dehydroepiandrosterone sulfate, and the free androgen index. Serum levels of sex hormone-binding globulin increased at the same time, and the lipid profiles became less atherogenic. There were no changes in body mass index, fasting glycemia, or serum levels of estradiol or follicle-stimulating hormone. All but 2 of the 18 girls reported regular menses within 4 months of the start of metformin therapy and, after 6 months, all were eumenorrheic. Ovulation induction failed in 4 of the 18 girls (Fig. 1), including the 2 with the most severe hyperandrogenism. Abdominal discomfort in 4 girls resolved spontaneously within 2 weeks. Metformin treatment tends to normalize endocrine-metabolic function in nonobese adolescent girls with anovulatory hyperandrogenism and induces ovulation in many of them.