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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-0336
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 8 2888-2891
Copyright © 2006 by The Endocrine Society

Metformin Treatment to Prevent Early Puberty in Girls with Precocious Pubarche

Lourdes Ibáñez, Ken Ong, Carme Valls, Maria Victoria Marcos, David B. Dunger and Francis de Zegher

Endocrinology Unit (L.I.) and Hormonal Laboratory (C.V.), Hospital Sant Joan de Déu, University of Barcelona, 08950 Esplugues, Barcelona, Spain; Department of Paediatrics (K.O., D.B.D.), University of Cambridge, Cambridge CB2 2QQ, United Kingdom; Medical Research Council Epidemiology Unit (K.O.), Cambridge CB1 8RN, United Kingdom; Endocrinology Unit (M.V.M.), Hospital de Terrassa, 08227 Terrassa, Barcelona, Spain; and Department of Woman and Child (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
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context and Objective: Girls with precocious pubarche (PP, pubic hair at < 8 yr of age) are at high risk for early onset and rapid progression of puberty, in particular if their prenatal growth was restrained, i.e. low birth weight (LBW), and followed by rapid postnatal catch-up of weight gain. We postulated that insulin resistance contributes to early onset and rapid progression of puberty in LBW-PP girls and thus explored the puberty-delaying effects of insulin sensitization with metformin initiated shortly after PP diagnosis.

Setting, Design, and Patients: The study population consisted of 38 prepubertal LBW girls with PP attributed to exaggerated adrenarche [mean body weight, 2.4 kg; age, 7.9 yr; body mass index (BMI), 18.4 kg/m2]. These girls were randomly assigned to remain untreated (n = 19) or to receive metformin (n = 19; 425 mg/d) for 2 yr.

Main Outcome Measures: Pubertal staging, age at menarche, body composition by absorptiometry, fasting insulin, glucose, lipids, leptin, IGF-I, IGF-binding protein-1, testosterone, dehydroepiandrosterone sulfate, and SHBG were the main outcome measures.

Results: Metformin treatment was associated with a less adipose body composition (and lower serum leptin levels) and with a 0.4-yr delay in the clinical onset of puberty (Tanner B2; 9.5 vs. 9.1 yr; P < 0.01). These findings were corroborated by a delay of at least 1 yr in the puberty-associated rise of circulating IGF-I (P < 0.01). Available results also point to a metformin-associated delay of menarche (P < 0.02). Gain in height and lean mass was not divergent between study subgroups.

Conclusion: The efficacy of early metformin treatment in PP girls is here extended to include not only a less adipose body composition after 2 yr but also a less advanced onset of puberty, whereas height gain is maintained. These findings open the perspective that, ultimately, metformin treatment may also prove to heighten the short adult stature of LBW-PP girls.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CATALAN GIRLS WITH precocious pubarche (PP; pubic hair at < 8 yr of age) because of exaggerated adrenarche are known to develop hyperinsulinemia of prepubertal onset and to present a rapidly progressive puberty with early-normal menarche (1, 2). The PP girls at highest risk for both an early onset of puberty and a fast transit to postmenarche are those who were thin as fetuses, i.e. low birth weight (LBW), and became adipose in childhood (2, 3). On average, these girls start puberty (Tanner breast stage 2, B2) at 9.4 yr and experience menarche at 11.5 yr (2). Among PP girls, those with LBW are also the most hyperinsulinemic and hyperleptinemic, and they have the lowest serum levels of SHBG and of IGF-I-binding protein-1 (IGFBP-1) (2, 4, 5).

Both insulin and leptin are thought to accelerate the timing of pubertal onset and to up-regulate the tempo of pubertal progression (6, 7). Hyperinsulinemia and -leptinemia are commonly present in obese girls and in LBW girls with early-normal onset of puberty (B2 at 8–9 yr) and may contribute to drive their rapid transit to postmenarche (8, 9, 10, 11).

We postulated that hyperinsulinemic insulin resistance contributes to early onset and rapid progression of puberty in LBW-PP girls, and thus explored the puberty-delaying effects of insulin sensitization with metformin initiated shortly after PP diagnosis.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects and ethics

The study population consisted of 38 LBW-PP girls (Table 1Go). The inclusion criteria were: 1) PP resulting from exaggerated adrenarche, as judged by high serum dehydroepiandrosterone sulfate (DHEAS) and/or androstenedione levels (12); 2) weight less than 2.9 kg at term birth (38–41 wk) or below –1 SD for gestational age at preterm birth (33–37 wk); 3) body mass index (BMI) less than 22 kg/m2; and 4) prepuberty (Tanner B1) (13).


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  		TABLE 1. Baseline characteristics of the study population

 
None of the girls had a family or personal history of diabetes mellitus or presented evidence for thyroid dysfunction, glucose intolerance (14), or late-onset congenital adrenal hyperplasia (15, 16), and none was receiving a medication known to affect gonadal function or carbohydrate metabolism.

The study protocol was registered under number ISRCTN84749320 and was approved by the Institutional Review Board of Barcelona University, Hospital of Sant Joan de Déu. Informed consent was obtained from parents and assent from the girls.

Study design and assessments

Girls were randomly assigned to remain untreated or to receive metformin (425 mg, once daily at dinner time) for 24 months. Additional follow-up is ongoing (metformin dose is 850 mg/d beyond 24 months). The randomization list (1:1 ratio) was produced before the start of the study (Gran Mos program; Barcelona Medical Research Institute, Barcelona, Spain), and the investigators followed the sequence in this list. Patients were consecutively included, as either untreated or treated, according to their position within this list. When deciding about a patient’s inclusion, the investigators had no access to the next treatment assignment in the sequence.

Clinical examination with pubertal staging was performed every 6 months, together with assessment of body composition, fasting blood glucose and serum insulin, SHBG, DHEAS, androstenedione, testosterone, and lipid profile. Serum leptin and IGFBP-1 were determined at 0 and 24 months. A single investigator (L.I.) assessed breast budding (B2) by palpation and, when appropriate, screened by history for an even more precise timing of B2 appearance within the 6 preceding months; age at menarche was derived by history.

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 trochanter (caudal limit), as described (3). Total radiation dose per examination was 0.1 mSv. Coefficients of variation for scanning precision are estimated to be 2.0 and 2.6% for fat and lean mass (Hologic, Waltham, MA) with an intraindividual coefficient of variation for abdominal fat mass of 0.7% (17). Indicative references for body composition are from 13 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. Serum immunoreactive insulin, DHEAS, androstenedione, testosterone, and SHBG were assayed as described (18). Serum leptin was measured by RIA (Linco, St. Louis, MO) (5), and IGFBP-1 was measured by quantitative immunometric assay (Medix-Biochemma, Oulu, Finland) (4). All methods had intra- and interassay coefficients of variation from 4–8% within the relevant concentration ranges. Fasting insulin sensitivity was estimated from fasting insulin and glucose levels using the homeostasis model assessment (HOMA-CIGMA Calculator program version 2.00) (19). Samples were kept frozen at –20 C until assay, and markers in both groups were assayed at the same time.

Data on birth weight and gestational age were obtained from hospital records and transformed into SD scores (12).

Two-sided t tests were performed to compare the total study population with the indicative references, and t tests were also performed to compare the changes within each treatment subgroup and the 0- to 24-month changes between the subgroups. Differences in longitudinal 6-monthly data between the two groups were tested by repeated-measures ANOVA. For uniformity, all results are expressed as mean ± SEM. The level of statistical significance was set at P < 0.05. Prepubertal, short-term results (0–6 months) of part of this study population (n = 33) have been reported previously (18).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 2Go summarizes the main results at 0 and 24 months. Baseline values of the study population were suggestive of insulin resistance, androgen excess, an atherogenic lipid profile, and an adipose body composition. After 24 months, metformin-treated girls displayed less insulin resistance and less androgen excess and had a less atherogenic lipid profile and a less adipose body composition than the untreated girls.


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  		TABLE 2. Clinical, endocrine-metabolic, and body composition indices in prepubertal girls (age, ~8 yr) with a combined history of low birth weight and PP

 
Figure 1Go highlights a selection of longitudinal findings. Between the subgroups, there is a striking difference in pubertal development, which is reflected in the respective IGF-I patterns. Despite a slower course into and through puberty, the metformin-treated girls maintained their gains in height and lean mass, whereas they attenuated their fat excess.


Figure 1
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  		FIG. 1. Pubertal stage, height, lean body mass, IGF-I levels, percent total body fat, and abdominal fat mass in low-birth-weight girls with precocious pubarche who remained untreated (n = 19) or received metformin (n = 19) for 24 months. Means ± 95% confidence interval (CI) are displayed. *, P < 0.01 for difference in rate of change between subgroups by repeated-measures ANOVA.

 
Metformin-treated girls entered into B2 approximately 0.4 yr after the untreated girls (9.5 ± 0.1 vs. 9.1 ± 0.1 yr; P < 0.01). Preliminary results during the third study year indicate that metformin treatment is also associated with a delay of menarche; five of 19 untreated girls already experienced menarche, whereas this was the case in none of the 19 metformin-treated girls (P = 0.016 by {chi}2).

Metformin treatment was well tolerated; indices of hepatic and renal function remained unchanged throughout treatment.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Longitudinal and cross-sectional studies have shown that LBW-PP girls are at risk for early onset of puberty and menses and, thereafter, for a relatively short stature and for further progression to anovulation and to hyperinsulinemic hyperandrogenism, which is a variant of polycystic ovary syndrome (2, 12, 20, 21, 22, 23). These sequential outcomes are thought to be partly attributable to hyperinsulinemic insulin resistance and its correlates, such as an adipose body composition (even in the absence of obesity), a proinflammatory state, high circulating leptin concentrations, adrenal hyperandrogenism, an atherogenic lipid profile, and low SHBG levels (1, 2, 3, 4, 5, 18, 23). Accordingly, insulin sensitization with metformin is under exploration as an approach not only to prevent postmenarcheal progression to polycystic ovary syndrome (24, 25, 26) but also to prevent earlier steps within this sequence. In prepubertal LBW-PP girls, metformin treatment is known to induce within 6 months a less adipose body composition, an attenuated adrenarche, a more favorable lipid profile, and a less proinflammatory state, as judged by normalization of the adipocytokine pattern and by a decrease in the neutrophil count (18, 27). The efficacy of metformin treatment in LBW-PP girls is here extended to include a less advanced onset of puberty and menses while height gain is maintained.

The mechanisms whereby metformin is capable of delaying pubertal onset and progression in girls remain to be fully elucidated. In LBW girls with early-normal onset of puberty (age 8 yr), metformin recently proved to delay the progression to menarche and to augment pubertal height gain; these effects were accompanied by (relative) falls in body adiposity, leptinemia, and IGF-I and by increments in serum SHBG and IGFBP-1 (11). The endocrine-metabolic profile of PP girls resembles that of LBW girls with early-normal puberty; both include hyperinsulinemia, body adiposity, and high serum levels of IGF-I and leptin. This profile is even more striking in LBW-PP girls and is therefore thought to contribute to trigger adrenal and gonadal steroidogenesis, either directly or indirectly (1, 3, 4, 5, 28, 29, 30). The mechanisms accounting for the metformin-associated delay in pubertal onset in LBW-PP girls may thus be similar to those delaying the menarche of LBW girls with early-normal onset of puberty. For example, hyperinsulinemia is known to augment pituitary LH secretion and to raise leptin production by adipocytes (30, 31); concomitant decreases in hyperinsulinemia, hyperleptinemia, and body adiposity may have attenuated LH secretion, thereby contributing to a delay in the onset of puberty.

In conclusion, the efficacy of metformin treatment in PP girls is extended to include not only a less adipose body composition after 2 yr but also a less advanced onset of puberty and menses, while height gain is maintained. These findings open the perspective that, ultimately, metformin treatment may also prove to heighten the short adult stature of LBW-PP girls.


   Acknowledgments
 
We thank Montserrat Gallart for hormone measurements.


   Footnotes
 
F.d.Z. is a Senior Clinical Investigator of the Fund for Scientific Research (Flanders, Belgium).

First Published Online May 9, 2006

Abbreviations: BMI, Body mass index; DHEAS, dehydroepiandrosterone sulfate; IGFBP-1, IGF-I-binding protein 1; LBW, low birth weight; PP, precocious pubarche.

Received February 14, 2006.

Accepted May 3, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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