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Insulin Sensitization for Girls with Precocious Pubarche and with Risk for Polycystic Ovary Syndrome: Effects of Prepubertal Initiation and Postpubertal Discontinuation of Metformin Treatment

Endocrinology Unit (L.I.) and Hormonal Laboratory (C.V.), Hospital Sant Joan de Déu, University of Barcelona, 08950 Esplugues, Barcelona, Spain; Endocrinology Unit, Hospital de Terrassa (M.V.M.), 08227 Terrassa, Barcelona, Spain; Department of Pediatrics, University of Cambridge (K.O., D.B.D.), Cambridge, United Kingdom CB2 2QQ; and Department of Pediatrics, University of Leuven (F.d.Z.), 3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Dr. Lourdes Ibáñez, 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

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Among girls with precocious pubarche (PP), those with low birth weight (LBW) are, even if nonobese, at risk for progression to polycystic ovary syndrome (PCOS) including hyperinsulinemic hyperandrogenism, dyslipidemia, dysadipocytokinemia, and central fat excess. Recently, we disclosed the efficacy of insulin sensitization with metformin to disrupt progression from PP to PCOS in formerly LBW girls who were postmenarche. In LBW-PP girls, we have now extended the exploration of early insulin sensitization therapy in two directions: 1) metformin therapy was started before puberty; and 2) we assessed the effects of metformin discontinuation in girls who had started metformin treatment after menarche. Prepubertal LBW-PP girls (n = 33; mean age, 8.0 yr; body mass index, 18.5 kg/m²) were randomly assigned to remain untreated or to receive metformin (425 mg/d) for 6 months. Postpubertal LBW-PP girls (n = 24; age, 12.4 yr; body mass index, 21.0 kg/m²) had been randomized (at –12 months) to remain untreated or to receive metformin (850 mg/d) for 12 months, at which time (0 month) a treatment cross-over was performed for 6 months. Fasting blood glucose and serum insulin, SHBG, dehydroepiandrosterone sulfate, androstenedione, testosterone, lipid profile, IL-6, and adiponectin were assessed at 0 and 6 months, as was body composition (by dual x-ray absorptiometry). In the prepubertal study (group A), comparisons of untreated vs. treated girls disclosed normalizing effects of metformin on SHBG, androstenedione, dehydroepiandrosterone sulfate, low and high density lipoprotein cholesterol, triglycerides, IL-6, adiponectin, total and abdominal fat mass, and lean body mass. In the postpubertal study (group B), treatment cross-over at 0 month was in each subgroup followed by a striking reversal in the course of the endocrine-metabolic state, adipocytokinemia, and body composition; all changes pointed to normalizing effects of metformin treatment. In conclusion, these two studies provide the first evidence that 1) prepubertal metformin therapy has normalizing effects on PCOS features in high risk girls with a combined history of LBW and PP; and 2) in adolescence, metformin’s normalizing effects are reversed as soon as metformin therapy is discontinued.

	Introduction

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AMONG GIRLS WITH precocious pubarche (PP; defined as pubic hair at <8 yr), those with low birth weight (LBW) are, even if nonobese, at high risk for progression to developing a variant of polycystic ovary syndrome (PCOS) with hyperinsulinemic hyperandrogenism, dyslipidemia, dysadipocytokinemia, central fat excess, and a deficit of lean body mass (1, 2, 3, 4, 5). The mechanisms underpinning this sequence are incompletely understood, but hyperinsulinemic insulin resistance of prepubertal onset has been proposed as a key pathogenetic factor (4, 6, 7, 8, 9, 10). Recently, we disclosed the efficacy of insulin sensitization with metformin to disrupt progression from PP to PCOS in formerly LBW girls who were 6–12 months postmenarche, with hyperinsulinemia and hyperandrogenemia, but without other signs or symptoms of androgen excess (11). In LBW-PP girls, we have now extended the exploration of early insulin sensitization therapy in two directions: in the first study, the onset of metformin therapy was advanced well into the prepubertal age range, and in the second study, we assessed the effects of postpubertal metformin discontinuation. Here, we report that metformin therapy delays or reverses hyperandrogenemia, hypoadiponectinemia, hypertriglyceridemia, and body adiposity in prepubertal LBW-PP girls, and that postpubertal discontinuation of metformin therapy is accompanied by renewed progression of PCOS features within 6 months.

	Subjects and Methods

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Prepubertal study

The population of this study consisted of 33 LBW-PP girls (Table 1). The inclusion criteria were 1) PP attributed to exaggerated adrenarche, based on high serum androstenedione and/or dehydroepiandrosterone sulfate (DHEAS) levels (12); 2) birth weight for gestational age below –1.5 SD, which corresponds to approximately 2.7 kg in term Catalunyan girls; this level of prenatal growth restraint is associated in PP girls with ovarian hyperandrogenism in adolescence (2); 3) body mass index (BMI) less than 21 kg/m²; and 4) prepubertal state (Tanner breast stage 1).

The population of this follow-up study was that of the original study in which metformin therapy was initiated postmenarche (11). In brief, the original cohort (Table 2) consisted of 24 girls (mean age, 12.4 ± 0.2 yr; range, 10.6–13.9 yr) who were small at birth and who presented with PP to Barcelona Hospital. In all girls, PP was attributed to exaggerated adrenarche (12). At the start of the original study (–12 months), all girls were 6–12 months (mean, 7.9 ± 0.6 months) beyond menarche; the clinical characteristics and adrenal androgen levels were: height, 155.1 ± 1.4 cm; weight, 50.9 ± 1.6 kg; BMI, 21.0 ± 0.4 kg/m²; onset of puberty (Tanner breast stage 2), 9.4 ± 0.1 yr; DHEAS, 126 ± 7 µg/dl; and post-ACTH 17-hydroxyprogesterone, 235 ± 23 ng/dl. For none of these baseline indexes were there significant differences between the original subpopulations (11).

Prepubertal and postpubertal studies

None of the girls had a family or personal history of diabetes mellitus or presented evidence for thyroid dysfunction, Cushing syndrome, hyperprolactinemia, glucose intolerance (14), late-onset congenital adrenal hyperplasia (15, 16), or signs and symptoms of androgen excess (17); none was receiving an oral contraceptive or a medication known to affect gonadal function or carbohydrate metabolism. Data on birth weight and gestational age were obtained from hospital records and transformed into SD scores, as previously described (2). The study protocols were approved by the institutional review board of Barcelona University, Hospital of Sant Joan de Déu. Informed consent was obtained from parents, and assent was obtained from the girls.

Study design

The prepubertal and postpubertal studies were each open-labeled, and their treatment subgroups were assembled by randomization (1:1 ratio). An assignment list was produced before the start of each study by the Gran Mos program from Barcelona’s Medical Research Institute; the investigators followed the sequence in this list, and patients were consecutively included as either untreated or treated according to their positions on this list. At the time of deciding about a patient’s inclusion, the investigators had no access to the next treatment assignment in the sequence.

Prepubertal study

Girls were randomized to remain untreated or to be treated with metformin (425 mg/d) once daily at dinner time for 6 months. Fasting blood glucose and serum insulin, SHBG, DHEAS, androstenedione, testosterone, lipid profile, IL-6, and adiponectin were assessed at 0 and 6 months, as was body composition. Baseline levels were compared with references from a local population matched for gender, age, and pubertal stage (4, 11, 18).

Postpubertal study

Each of the subgroups had been followed for 12 months (–12 to 0 months) as reported previously (11) and were then followed for an additional 6 months (0–6 months), with a treatment cross-over in between (at 0 months). The girls had been randomized to either be first untreated (–12 to 0 months) and then receive metformin for 6 months (untreated/metformin; n = 12) or to first receive metformin (850 mg once daily at dinner time) and remain then untreated (metformin/untreated; n = 12).

Fasting glucose, insulin, lipid profile, SHBG, DHEAS, androstenedione, testosterone, adiponectin, and IL-6 were assessed at –12, 0, and 6 months, as was body composition. Baseline hormonal assessments were performed in the follicular phase (d 3–7) of the cycle or after 2 months of amenorrhea. Baseline levels were compared with references from a local population matched for gender, age, and pubertal stage (10, 12).

Body composition

Body composition was assessed by dual energy x-ray absorptiometry with a Lunar Prodigy coupled to Lunar software (Lunar Corp., Madison, WI). Absolute (kilograms) whole body fat, and lean mass were assessed as well as fat content in the abdominal region, which was defined as the area between the dome of the diaphragm (cephalad limit) and the top of the great throcanter (caudal limit) (19). The total radiation dose for each examination was 0.1 milliSievert. Coefficients of variation (CVs) for scanning precision are estimated to be 2.0% and 2.6% for fat and lean body masses (Hologic, Waltham, MA) with an intraindividual CV for abdominal fat mass of 0.7%. Normal references for body composition were obtained from healthy Catalan schoolgirls matched for age, pubertal status, and body size, who were living in the same area.

Hormone assays, calculations, and statistics

Serum glucose was measured by the glucose oxidase method. Immunoreactive insulin was assayed by IMX (Abbott Diagnostics); the mean intra- and interassay CVs were 4.7% and 7.2%, respectively. Serum DHEAS, androstenedione, testosterone, and SHBG were assayed as previously described (10). IL-6 was measured by immunochemiluminescence (IMMULITE 2000, Diagnostic Products, Los Angeles, CA), with a lower detection limit of 100 fg/ml; the intra- and interassay CVs were 3.5% and 5.1%, respectively. Adiponectin was measured by RIA (Linco Research, Inc., St. Charles, MO); the intra- and interassay CVs were 6.2% and 6.9%, respectively. Samples were kept frozen at –20 C until assay.

Fasting insulin sensitivity was estimated from fasting insulin and glucose levels using the homeostasis model assessment (HOMA-CIGMA Calculator program, version 2.00) (20).

Two-sided t tests were performed to compare baseline data between the references and the total study population and between the two treatment subgroups; t tests were also performed to compare in each study the changes within each treatment subgroup and between the two subgroups. For uniformity, all results are expressed as the mean ± SEM. The level of statistical significance was set at P < 0.05. Although numerous outcome variables were tested, these features of PCOS risk are highly interrelated, and therefore, the use of corrections for multiple testing was not considered necessary.

	Results

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Prepubertal study

Table 3 summarizes the clinical, endocrine-metabolic, adipocytokine, and body composition results in the untreated and metformin-treated study groups. At baseline, compared with height- and weight-matched normal girls (reference group), the total study population showed reduced serum SHBG, increased androgen levels, abnormal lipid profiles, elevated serum IL-6, reduced adiponectin concentrations, and an augmented total and abdominal fat mass, consistent with a pre-PCOS state.

View larger version (11K): [in this window] [in a new window]   FIG. 1. Serum DHEAS, IL-6, and adiponectin concentrations (mean and SEM) in the prepubertal study group (A). Girls had been randomized to remain untreated (; n = 17) or to be treated with metformin (425 mg/d; n = 16) for 6 months. Broken lines indicate mean reference levels. Metformin treatment was accompanied by changes toward normal (*, P < 0.01). See Table 3 for values (also of reference levels) and for statistics. To convert to Systeme International units, multiply the concentration of DHEAS by 0.02714.

View larger version (12K): [in this window] [in a new window]   FIG. 2. Absolute changes (0–6 months) in abdominal fat mass (grams) in the prepubertal study group. Girls (mean age, 8 yr) had been randomized to remain untreated (; n = 17) or to be treated with metformin (425 mg/d; n = 16). Metformin treatment is consistently accompanied by loss of abdominal fat excess, as judged by dual x-ray absorptiometry. See Table 3 for values and statistics.

Postpubertal study

Table 4 summarizes the clinical, endocrine-metabolic, adipocytokine, and body composition indexes in the treatment subgroups from –12 to 0 months and, after cross-over, to 6 months. The study variables of the subgroups were not detectably different at baseline (–12 months). Between –12 and 0 months, the untreated subgroup showed significant increases in endocrine-metabolic and body composition abnormalities, all further away from the normal reference, whereas the metformin-treated subgroup showed significant improvements in all of these parameters, and insulin resistance was normalized (11). Subsequent treatment cross-over at 0 months in each subgroup was followed by a striking reversal in the course of insulin sensitivity, androgen levels, cholesterol and triglyceride levels, adipocytokinemia, total body and central fat, and lean body mass, all in favor of metformin therapy (Fig. 3).

View larger version (11K): [in this window] [in a new window]   FIG. 3. Serum testosterone, IL-6, and adiponectin concentrations (mean and SEM) in the postpubertal study group (B). Girls had first been randomized to remain untreated (; n = 12) or to be treated with metformin (850 mg/d; n = 12) from –12 to 0 months; treatment cross-over was performed at 0 months for a duration of 6 months. Broken lines indicate mean reference levels. Cross-over of metformin treatment was followed by cross-over of testosterone, IL-6, and adiponectin concentrations; in the treated subgroup, metformin treatment was accompanied by changes toward normal. See Table 4 for values (also of reference levels) and statistics. To convert to Systeme International units, multiply the concentrations of testosterone by 0.03467.

	Discussion

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In the development of a preventive treatment to be given in childhood and adolescence, there are at least three steps to explore. The first step is to identify children and adolescents at high risk for an adverse outcome (21). Previous studies showed that nonobese Catalunyan girls with PP before puberty were at increased risk for developing PCOS (1), in particular if they were born small (birth weight below –1.5 SD), presumably because prenatal growth restraint is associated with a degree of insulin resistance and abdominal fat excess, especially when postnatal weight gain has been excessive (2, 22, 23). We therefore selected such girls for these intervention studies; additional inclusion criteria were biochemical evidence of hyperinsulinemia and hyperandrogenemia, but no girl had other signs or symptoms of androgen excess. The baseline assessments, including IL-6 and adiponectin, shed further light on the pathogenesis of PCOS and also of the long-term cardiovascular disease risk associated with PCOS. Furthermore, in the untreated study girls, the significant deterioration in all of the main endocrine, metabolic, adipocytokine, and body composition variables confirms that the prepubertal and early postpubertal years are indeed dynamic phases in the evolution to PCOS after LBW and PP (24). Although their BMIs were normal, these young girls had increased total and abdominal body fat and reduced lean mass.

The second step is to establish short-term efficacy and safety. In contrast to the untreated group, the metformin-treated group presented consistent improvements in all biochemical and body composition variables and did so without changes in BMI and without instructions regarding lifestyle. This normalizing effect of metformin on the body composition of LBW-PP girls indicates that their endocrine-metabolic-adipocytokine state governs their body composition, rather than the reverse, and it suggests that hyperinsulinemic insulin resistance (without reduced ß-cell capacity) is a key pathogenic component, presumably together with its correlates, such as dyslipidemia, hyperandrogenism, and hypersomatotropism (11, 25). In these studies metformin monotherapy failed to fully normalize fat mass, serum androgens, SHBG, IL-6, and adiponectin, which are interrelated variables (4, 26, 27, 28, 29, 30, 31) that might be further normalized by adding an androgen receptor blocker to metformin therapy (11, 32, 33). Given the absence of severe hyperandrogenemia at baseline, we preferred to study metformin monotherapy in PCOS prevention; metformin proved to have a good efficacy/safety profile in adolescents with PCOS (7, 8) and is available at low cost.

The third step is to establish whether the preventive treatment needs to be continuous. We now report that the endocrine-metabolic-adipocytokine state and the body com-position of the girls, who were commenced on metformin, reverted back toward baseline values within 6 months off metformin. These findings are in line with previous reports indicating that the benefits of metformin therapy are limited to the duration of its actual administration in nonobese adolescents or young women with PCOS regardless of whether metformin is given in monotherapy (7, 8) or in combination with an androgen receptor blocker (33). These findings imply that metformin is likely to prevent progression of PCOS features more effectively when given continuously rather than discontinuously.

Because an open-label design implies potential limitations in the interpretation of the results, we emphasize that the body weight changes of untreated and treated girls did not diverge, that no significant changes were reported in diet or behavior in any group during the follow-up period, and, finally, that the main outcome variables were measured without knowledge of treatment allocation.

To explore the effects of insulin sensitization on a broad range of PCOS features and cardiovascular risk factors, our subjects were assessed using a comprehensive array of biochemical and body composition variables, and this would increase the potential for a false positive finding. However, many of these outcome variables are highly interrelated, and we therefore did not consider the use of corrections for multiple testing to be necessary. Indeed, we saw significant changes in the majority of outcomes, all consistently indicative of a beneficial effect of therapy, suggesting that a false positive effect is highly unlikely.

In conclusion, these two studies provide the first evidence that 1) prepubertal metformin therapy has normalizing effects on PCOS features in high risk girls with a combined history of LBW and PP; and 2) in adolescence, metformin’s normalizing effects are reversed as soon as metformin therapy is discontinued. Future studies need to address not only the safety of longer-term early metformin therapy and its possible effects on pubertal growth and development, but also its potential to more fully reverse/prevent abnormalities in body composition and risk of PCOS in LBW-PP girls and in other high risk groups, for example, in obese adolescents and genetically predisposed girls (21).

	Acknowledgments

 
We thank Montserrat Gallart for hormone measurements.

	Footnotes

 
This work was supported by Grant PI/021013 from the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (Madrid, Spain), and an Eli Lilly grant from the Spanish Society for Pediatric Endocrinology. F.d.Z. is a Clinical Investigator with the Fund for Scientific Research (Flanders, Belgium).

Abbreviations: BMI, Body mass index; CV, coefficient of variation; DHEAS, dehydroepiandrosterone sulfate; LBW, low birth weight; PCOS, polycystic ovary syndrome; PP, precocious pubarche.

Received March 11, 2004.

Accepted June 8, 2004.

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