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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

Endocrinology Unit (L.I., A.F., F.R.-H.), Hospital Sant Joan de Déu, University of Barcelona, 08950 Barcelona, Spain; Hormonal Laboratory (N.P.), Hospital Materno-Infantil Vall d’Hebron, 08035 Barcelona, Spain; Endocrinology Unit (M.V.M.), Consorci Hospitalari de Terrassa, 08227 Terrassa, Spain; and Department of Pediatrics (F.d.Z.), University of Leuven, 3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Lourdes Ibáñez, M.D., Ph.D., Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Passeig de Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. E-mail: libanez{at}hsjdbcn.org.

Abstract

Adolescent girls born small for gestational age (SGA) are at risk for anovulation, hyperinsulinism, subclinical hyperandrogenism, dyslipidemia, and central adiposity. Hyperinsulinemic insulin resistance has been proposed as a key pathogenetic factor underpinning these associations.

We have tested this hypothesis in an intervention study by assessing the effects of insulin sensitization (metformin treatment, 850 mg/d for 3 months) in eumenorrheic, nonobese, anovulatory SGA adolescents [n = 13; mean birth weight, 2.3 kg; age, 15 yr; body mass index (BMI), 20.5 kg/m²; 3 yr post-menarche] who were in a steady state (over 6 months) for BMI, hyperinsulinism, subclinical hyperandrogenism, and dyslipidemia, and who presented a deficit of lean body mass and an excess of (truncal and abdominal) fat mass.

Metformin treatment was accompanied by a drop in fasting insulin and serum androgens and by a less atherogenic lipid profile (all P 0.01). After 3 months on metformin, all identified aberrations in body composition were attenuated, the most marked changes (P < 0.0001) being a reduction of the excess in abdominal fat and of the deficit in lean body mass; BMI remained unaltered. Finally, 6 of 13 girls became ovulatory after about 6 wk on metformin, and 9 of 13 (69%) ovulated within 11 wk on metformin.

In conclusion, these observations corroborate the notion that anovulation, an excess of abdominal fat mass, and a deficit of lean mass in nonobese SGA adolescents are essentially underpinned by hyperinsulinemic insulin resistance, and that sensitization to insulin is an effective approach to correct these abnormalities and, conceivably, to prevent them.

ADOLESCENT GIRLS BORN small for gestational age (SGA) are at risk for hyperinsulinism, ovarian hyporesponsiveness to FSH, subclinical hyperandrogenism (adrenal and/or ovarian origin), reduced ovulation rate, central adiposity, and dyslipidemia, even when nonobese (Refs. 1, 2, 3, 4, 5, 6, 7 8A ). The mechanisms underpinning these associations are incompletely understood, but hyperinsulinemic insulin resistance has been proposed as a key pathogenetic factor (5, 9, 10). We have now tested this hypothesis by conducting an intervention study in which the effects of insulin sensitization were assessed in eumenorrheic, nonobese adolescent SGA girls with anovulation, central adiposity, dyslipidemia, and subclinical hyperandrogenism.

Subjects and Methods

Subjects

The study population consisted of 13 girls (age, 15.1 ± 0.4 yr; range, 14–18 yr) who were recruited, as described (8), among healthy relatives of hospital staff (n = 3) or among asymptomatic girls who attended the pediatric endocrine clinic for evaluation of thyroid function (n = 1), timing of pubertal development (n = 1), or postmenarcheal growth status (n = 8). In the latter 10 girls, we documented, respectively, euthyroidism, normal variation in timing of pubertal development, and final height within (n = 4) or below (n = 4) target height range. Ten of the 13 girls belonged to the cohort of SGA adolescents in whom the high prevalence of anovulation was originally described (8).

The inclusion criteria were: 1) weight below -2 SD at term birth (37–41 wk); 2) menarche 3–6 yr before study; 3) menstrual cycles (25–35 d) with a variation of 5 d (7); 4) body mass index (BMI) below 25 kg/m²; and 5) persisting anovulation, recently documented (see Ovulation assessment below).

The exclusion criteria were: evidence for a syndromatic, chromosomal, or infectious etiology of low birth weight; hirsutism [defined as a score 8 on Ferriman and Gallwey scale (11)]; a history of precocious pubarche (12) or precocious puberty (13); thyroid dysfunction, Cushing syndrome, hyperprolactinemia; previous or current use of oral contraceptives; and a family or personal history of diabetes mellitus.

Birth weight and gestational age data were obtained from hospital records or from the girls’ pediatricians and transformed into SD scores, as described (3).

Study design

After documenting the anovulatory state, all girls received metformin (Dianben, Andreu Roche, Barcelona, Spain) in a daily dinner-time dose of 850 mg for 3 months. Blood was sampled in fasting state and in the early follicular phase (range, cycle d 5 ± 3), firstly before documenting the anovulatory state; secondly, before starting metformin; and finally, after 3 months on metformin therapy. Blood glucose was measured, together with serum insulin, low-density lipoprotein (LDL) and high-density lipoprotein (HDL)-cholesterol, triglycerides, LH, FSH, estradiol, dehydroepiandrosterone-sulfate (DHEAS), androstenedione, testosterone, and SHBG; the free androgen index (FAI), an index of free testosterone, was calculated [FAI = testosterone (nmol/liter) x 100/SHBG (nmol/liter)] as described (14). Blood count and screening tests for liver and kidney function were also performed before and after 3 months of treatment, as additional safety variables.

Endocrine-metabolic variables were compared with those of a control group consisting of healthy girls who had an appropriate weight at term birth; recruitment characteristics were the same as for the SGA subgroup, as described (8).

Methods

Serum glucose was measured by the glucose oxidase method. Immunoreactive insulin was assayed by IMX (Abbott Diagnostics, Santa Clara, CA). The mean intra- and interassay coefficients of variation (CV) were 4.7% and 7.2%, respectively. LH and FSH were measured by immunochemiluminescence (IMMULITE 2000; Diagnostic Products, Los Angeles, CA), with CV of 3.5% and 5.0% for LH and 4.6% and 6.3% for FSH. Serum estradiol, DHEAS, androstenedione, testosterone, and SHBG were assayed as previously described (9, 10). Serum samples were kept frozen at -20 C until assay.

Ovulation assessment

Before starting metformin treatment, persisting anovulation was documented in all girls for 3 consecutive months by progesterone measurements in blood that was weekly collected after a finger-stick and that was placed on filter paper, starting on d 21 of the first menstrual cycle of the study (8). Anovulation was inferred by filter paper progesterone concentrations below 0.7 ng/ml in all pretreatment samples (8).

Ovulatory function was similarly assessed over 3 months on metformin, starting 1 wk after initiation of therapy. Ovulation was considered to have occurred if progesterone concentration was greater than 1.0 ng/ml in a filter paper sample obtained 5–8 d before onset of menses (8).

Waist to hip ratio (WHR) and body composition

Waist circumference was measured at the end of expiration to the nearest 0.5 cm, using a measuring tape placed around the waist at the level of the umbilicus. Hip circumference was also measured to the nearest 0.5 cm, at the level of maximal anteroposterior excursion. Waist and hips were each measured three times, and the mean of each of these was used for ratio calculations and subsequent analyses.

Body composition was assessed by dual-energy x-ray absorptiometry using a Lunar Prodigy machine. All studies were performed using Lunar software programs (versions 3.4 and 3.5, Lunar Corp., Madison, WI; Ref. 15). Absolute fat and lean mass (in kilograms) were assessed for the whole body and also by specific body regions. The truncal region was defined as the tissue area bordered by a horizontal line below the chin, vertical borders lateral to the ribs, and oblique lines passing through the femoral necks. The abdominal region was defined as the area encompassed between the dome of the diaphragm (cephalad limit) and the top of the greater throcanter (caudal limit; Ref. 16). The total radiation dose in each examination was 0.1 mSv. The CV for scanning precision, calculated from 30 consecutive scans of an external hydroxyapatite, luciate, and high-density polyethylene Hologic phantom (Hologic, Inc., Waltham, MA), were 2.0% and 2.6% for fat and lean body mass, respectively (17). The intra-individual CV for abdominal fat mass was 0.7%, as assessed by 3 consecutive scans of 14 persons.

Sixteen healthy schoolgirls volunteered to serve as body composition controls; these girls had the same Catalan origin, were living in the same area, and were matched for age, pubertal status, and body size.

Statistical analysis and ethics

Results are expressed as mean ± SEM. Two-sided t test was used for statistical comparisons, unless mentioned otherwise; significance level was set at P value less than 0.05.

The study protocol was approved by the Institutional Review Board of Barcelona University Hospital of Sant Joan de Déu. Informed consent was obtained from parents and/or study subjects, with assent being obtained from minors.

Results

Table 1 summarizes the clinical characteristics and endocrine-metabolic results. Anovulatory SGA adolescents were found to have high insulin, triglyceride, androgen, and FSH levels; this condition remained stable until the start of metformin treatment. This intervention was accompanied by a drop in fasting insulin and serum androgens and by a less atherogenic lipid profile (all P 0.01).

View larger version (11K): [in this window] [in a new window]   Figure 1. Changes in the abdominal fat and lean body mass of 13 anovulatory SGA adolescents, as judged by dual x-ray absorptiometry, before vs. after 3 months on metformin treatment. Loss of abdominal fat mass was consistently accompanied by gain of lean body mass.

The adolescent girls participating in this study were essentially selected according to two consecutive criteria: firstly, a low birth weight for gestational age and, secondly, anovulatory cycling in the absence of obesity. These adolescents also presented hyperinsulinemia, abdominal fat excess, and a high serum LDL/HDL ratio with elevated triglyceride, androgen, and FSH levels, as previously reported in adolescent SGA girls who had been selected through other criteria, e.g. low birth weight only (5, 7, 18), precocious pubarche (3 8A, 19), early puberty and/or short stature (2, 20). In addition, this anovulatory cohort of SGA adolescents was documented to have a reduced lean body mass. The most innovative findings of this study relate to the concomitant effects of metformin treatment on gonadal function and body composition: ovulation was induced whereas both abdominal fat and lean body mass evolved toward normalization, and this without changes in BMI and without particular instructions regarding diet, exercise, or other lifestyle habits.

The increment in ovulation rate after the start of metformin treatment was swift and synchronized, half of the cohort becoming ovulatory after about 6 wk on metformin. This ovulatory response to metformin in SGA adolescents is even more homogeneous and faster than that evidenced in older, nonobese adolescents with hyperandrogenism after precocious pubarche (14). These observations suggest that the SGA-associated anovulation is underpinned by hyperinsulinemic insulin resistance rather than by primarily adrenal or ovarian hyperandrogenism, and that the hyporesponsiveness to FSH, if any, can be overcome, at least as judged by ovulation rate at this age.

The body composition of nonobese, anovulatory SGA adolescents was found to be characterized by a reduced lean body mass and by a relative excess of fat, in particular in the abdominal region. These observations fit well into a longitudinal perspective in which firstly, SGA infants with catch-up growth maintain a reduced muscle mass (21) and become insulin-resistant (22); subsequently, prepubertal SGA children are insulin-resistant (1, 23) and become prone to abdominal fat excess (24); and ultimately, lean women with polycystic ovary syndrome have both reduced lean and excessive fat mass (25).

Metformin treatment was found to augment lean mass and to reduce fat mass (in particular abdominally) within 3 months, without changes in BMI and without particular instructions regarding lifestyle. This normalizing effect of metformin on the silhouette and body composition of anovulatory SGA adolescents indicates that the endocrine-metabolic setting governs the body composition of these girls, rather than vice versa, and it suggests that hyperinsulinemic insulin resistance is a key component of this setting, presumably together with its correlates, such as dyslipidemia and hyperandrogenism.

The observation that lean body mass did augment in the face of both attenuated hyperinsulinemia and hyperandrogenemia was unexpected, in particular because any reduction of hyperinsulinemia in SGA individuals is also expected to reduce the associated hypersecretion of GH (26). Hence, one of the next questions to answer is whether metformin treatment indeed reduces GH secretion in adolescent girls with hyperinsulinemic hyperandrogenism. If it does, then this would corroborate the novel concept that the endocrine key to obtaining or maintaining the normal silhouette, body composition, and ovulation rate of a young woman is an insulin-sensitive state without either hyperandrogenism or hypersomatotropism.

Acknowledgments

We are grateful to the girls and families who contributed to this study. We thank Carme Valls, M.D., Montserrat Gallart, and Maria Jesús Gras for hormone measurements, and Diagnostic Products España SA (Madrid, Spain) for providing the progesterone assay and blood specimen collection cards for progesterone analysis.

Footnotes

This work was supported by a Visiting Fellowship from the European Society for Pediatric Endocrinology. F.d.Z. is a Clinical Research Investigator of the Fund for Scientific Research (Flanders, Belgium).

Abbreviations: BMI, Body mass index; CV, coefficient(s) of variation; DHEAS, dehydroepiandrosterone sulfate; FAI, free androgen index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SGA, small for gestational age; WHR, waist to hip ratio.

Received June 13, 2002.

Accepted September 12, 2002.

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