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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-2329
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 6 2068-2073
Copyright © 2006 by The Endocrine Society

Metformin Therapy during Puberty Delays Menarche, Prolongs Pubertal Growth, and Augments Adult Height: A Randomized Study in Low-Birth-Weight Girls with Early-Normal Onset of Puberty

Lourdes Ibáñez, Carme Valls, Ken Ong, 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 Pediatrics (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; 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
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context and Objective: Low-birth-weight (LBW) girls who enter puberty earlier (around 8–9 yr) tend to have earlier menarche, earlier growth arrest, and a shorter adult stature. At present, there is no therapy for most of these girls. In LBW girls with early puberty, hyperinsulinemic insulin resistance could underpin their rapid transit through puberty and their loss of adult stature. We explored the effects of insulin sensitization with metformin during puberty.

Setting, Design, and Patients: In an open-labeled, prospective study, 22 LBW girls (birth weight < –1.5 SD score for gestational age) with early-normal puberty (stage 2 breast development at age 8–9 yr) were randomized to remain untreated (n = 12) or to receive metformin (850 mg/d; n = 10) for 36 months (mean age at start, 9.0 yr). All girls remained untreated between 36 and 42 months.

Main Outcome Measures: Pubertal growth, body composition by absorptiometry, uterine-ovarian size by ultrasound, fasting insulin, glucose, lipids, leptin, IGF-I, and IGF-binding protein-1 were assessed.

Results: Metformin treatment resulted in a longer duration from stage 2 breast development to menarche (P < 0.01; median difference, +1.0 yr), taller near-adult height (P < 0.01), and leaner body composition (P < 0.001). Metformin was also associated with lower insulin resistance and leptin and IGF-I levels and higher SHBG and IGF-binding protein-1 levels and with a more favorable lipid profile. Bone mineral density and uterine-ovarian growth were unaffected.

Conclusion: Metformin treatment for 36 months in LBW girls with early-normal puberty normalized their pubertal progression to menarche and increased height gains up to adult stature. These data support the concept that insulin is a major codeterminant of the pubertal tempo and pubertal height gain in girls.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE PRIME SIGNAL that initiates puberty by disinhibiting pulsatile GnRH release in the hypothalamus remains to be elucidated. Multiple factors have been implicated in the timing of pubertal onset and in the rate of pubertal progression; the interrelated neuroregulations of the hypothalamo-gonadotropic and -leptinergic axes are thought to play a major role (1, 2, 3, 4, 5, 6, 7). For example, obese girls with insulin resistance and hyperleptinemia tend to experience an earlier onset and more rapid progression of puberty (8, 9, 10).

Menarche heralds the end of skeletal growth and the beginning of reproductive life. In girls, the normal age range for onset of puberty is 8–13 yr (11, 12, 13), and the age at onset of puberty is inversely related to the rate of progression through puberty (14), just as less prepubertal height gain is usually compensated by more pubertal growth. However, in girls who have experienced low birth weight (LBW) followed by rapid catch-up growth in infancy, these compensatory mechanisms may fail; consequently, such LBW girls with pubertal onset in the early-normal age range (8–9 yr) are at risk not only for an early menarche but also for an early growth arrest and thus for a short adult stature (15). At present, there is no conventional therapy for most of these girls, because their puberty starts too late to give a GnRH agonist (16) and because their stature in early puberty is too tall to give GH therapy.

In LBW girls with early puberty, hyperinsulinemic insulin resistance could underpin their rapid transit through puberty and the subsequent loss of adult stature. We therefore undertook an exploratory study to examine the effects of insulin sensitization on pubertal development, growth, and relevant endocrine changes.


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

The study population consisted of 22 girls (see Table 1Go). Inclusion criteria were 1) birth weight less than –1.5 SD score (SDS) for gestational age, which corresponds to a birth weight of less than 2.8 kg in term Catalan girls (this level of prenatal growth restraint being known to be associated with an early menarche and a reduced adult stature, if puberty starts at age 8–9 yr) (15); 2) history of onset of breast development [Tanner stage 2 or B2 (17)] at age 8–9 yr and less than 1 yr before study start; 3) height at enrollment at least 1 SD above the midparental height SD for chronological age (18); 4) bone age at least 1 yr above chronological age; and 5) central and progressive puberty, as judged by gonadotropin responses to GnRH agonist (19) and by pubertal dimensions of the internal genitalia on ultrasound examination (20).


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  		TABLE 1. Clinical, endocrine-metabolic, ultrasonography, and body composition indices in girls with low birth weight and early-normal puberty, who were randomized to remain untreated or to receive metformin (850 mg/d) for 36 months

 
The exclusion criteria were a family or personal history of diabetes mellitus, a history of precocious pubarche or the presence of other signs of androgen excess (21), evidence for thyroid dysfunction or glucose intolerance (22), and intake of medication known to affect gonadal function or carbohydrate metabolism.

This study was registered as ISRCTN06805028 and conducted in Barcelona, Spain, without support from the pharmaceutical industry, after approval by the Institutional Review Board of Sant Joan University Hospital and after informed consent from parents and assent from minors. None of the subjects or results from the present study have been reported previously.

Study design

In this open-labeled study (Fig. 1Go), girls were randomized to remain untreated (n = 12) or to receive metformin (850 mg) once daily at dinnertime (n = 10) for a total of 36 months. The randomization was performed according to the Gran Mos computer program (Institut Municipal d’Investigació Mèdica de Barcelona). Pubertal growth, body composition, uterine-ovarian size, and endocrine-metabolic markers were assessed 6-monthly from 0–36 months. Thereafter, all girls remained untreated, and 42 months after study start, one more auxological assessment was performed.


Figure 1
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  		FIG. 1. Summary of the study design.

 
Compliance with the medication was assessed by counting the number of pills remaining at each visit. Moreover, at each visit, all families/patients confirmed by interview their compliance.

Auxology

Birth-weight data were transformed into SDS for gestational age (21). Height was measured with a Harpenden stadiometer and transformed into SDS according to Tanner references (18) that are applicable to Catalan girls (23). Target height was defined as midparental height, adjusted for female gender. Body mass index (BMI) was calculated as the ratio of weight (in kilograms) to height squared (in meters) and was transformed into SDS for chronological age (24); bone age was assessed by a single observer (L.I.), according to the method of Greulich and Pyle (25).

Ultrasonography

The ultrasound examinations were performed in the full-bladder state. Scans were obtained by a single observer using an Acuson Sequoia 512 (Mountain View, CA) with a 4–6 MHz multifrequency sector probe. Uterine length was measured from the top of the fundus to the cervix. Longitudinal and transverse views of the ovaries were obtained for measurement of length, breadth, and depth of each ovary. Ovarian volume (right and left) was calculated using the formula for a modified prolate ellipsoid (depth x breadth x length/2) (20, 26).

Body composition

Body composition was assessed by dual-energy x-ray absorptiometry at study start and every 6 months with a Lunar Prodigy coupled to Lunar software (version 3.4/3.5; Lunar Corp, Madison, WI) (24). 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) (27). Total irradiation dose per assessment was 0.1 mS. Coefficients of variation (CVs) for scanning precision are 2.0 and 2.6% for fat and lean body mass (28), with an intraindividual CV for abdominal fat of 0.7%.

Endocrine-metabolic assessment, assays, and statistics

Fasting serum insulin, SHBG, IGF-I, high-density lipoprotein and low-density lipoprotein cholesterol, and triglycerides were assessed 6-monthly from 0–36 months, together with indices of hepatic and renal function, as additional safety variables. Serum leptin and IGF-binding protein-1 (IGFBP-1) were determined at 0 and 24 months. Fasting insulin resistance was estimated from fasting insulin and glucose levels using the homeostasis model assessment (HOMA) (29); the values in the study patients were compared with those of age- and pubertal-stage-matched controls from the same population (30).

Serum insulin, IGF-I, and SHBG were assayed as described (31, 32, 33); leptin was measured by RIA (Linco, St. Louis, MO), as described (32); and IGFBP-1 was measured by quantitative immunometric assay (Medix-Biochemma, Oulu, Finland) as described (33). Samples were kept frozen until assay.

For uniformity, results are expressed as mean ± SEM, unless mentioned otherwise. Differences in time trends for multiply repeated measures (Fig. 2Go: IGF-I, SHBG, percent body fat, and height gain) between the two groups were tested by repeated-measures ANOVA. Two-sided t tests (paired or unpaired, as appropriate) were used for statistical comparisons between groups; significance level was set at P < 0.05.


Figure 2
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  		FIG. 2. Longitudinal display of IGF-I and SHBG levels, percent body fat, and gains in height above baseline, in metformin-treated vs. untreated girls. Means ± 95% confidence interval are displayed. *, P < 0.05 for difference in time trends between the two groups by repeated-measures ANOVA; #, P < 0.05 at each time point by unpaired t test.

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go shows the endocrine-metabolic, body composition, and ultrasound results (0–36 months); Table 2Go summarizes the auxological findings after 42 months. Baseline characteristics were similar in untreated and metformin-treated girls; without being frankly obese (mean BMI < +2 SD), both subgroups were adipose (high fat fraction for a given BMI) and had high serum leptin concentrations (on average, >2-fold higher than the reference mean).


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  		TABLE 2. Height and bone age in girls with low birth weight and early-normal puberty, who were randomized to remain untreated or to receive metformin (850 mg/d) for 36 months

 
Metformin treatment was associated with relatively lower insulin, leptin, and IGF-I levels, higher SHBG and IGFBP-1 levels, a less atherogenic lipid profile, and a leaner body composition (Table 1Go and Fig. 2Go). Neither gain in bone mineral density nor growth of the internal genitalia was detectably altered.

Figure 3Go (left) depicts the effect of metformin on the duration of puberty, as judged by the time span from B2 to menarche. Untreated and metformin-treated girls had a similar mean age at start of B2 (8.7 vs. 8.6 yr) and at start of study (9.1 vs. 9.0 yr) but diverged in time to menarche: a median 2.0 vs. 3.0 yr (P < 0.01). Accordingly, metformin treatment was accompanied by a prolonged pubertal height gain (Table 2Go and Fig. 2Go).


Figure 3
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  		FIG. 3. Left, Time from onset of breast development (B2) to menarche in low-birth-weight girls with early-normal puberty. Untreated girls and metformin-treated girls had a similar age at B2. Metformin treatment was accompanied by a slower progress to menarche. Right, At 42 months after study start, metformin-treated girls are taller than the untreated controls, and their postmenarcheal growth velocity is still faster (Table 2Go). The horizontal bars display the medians for each group.

 
Figure 3Go (right) shows that metformin treatment increases (P < 0.01) near-adult height (relative to target height), as inferred from the last available height at 42 months. The ultimate effect of pubertal metformin treatment on adult height is expected to be slightly more pronounced, because all untreated girls have virtually stopped growing (height velocity < 2 cm/yr), whereas four of the 10 metformin-treated girls were still growing at a velocity greater than 2 cm/yr at 42 months (Table 2Go) (P < 0.01).

Metformin treatment was well tolerated; indices of hepatic and renal function remained stable throughout the study.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results of the untreated girls in this prospective study confirm the retrospective observation (15) that LBW girls with an early-normal onset of breast development tend to transit rapidly through puberty and to end up with a stature below target height. After comparison with the findings in untreated girls, the results from the treated girls indicate that insulin-sensitizing therapy with metformin (for 36 months) normalizes the timing of menarche (14, 34) and prolongs and augments pubertal growth up to adult height. Metformin treatment also results in a leaner body composition and less adverse lipid profile.

The mechanisms whereby metformin exerts its normalizing effects on pubertal progression and growth in this study population are likely to be multiple and interlinked. In girls, the rise in serum leptin concentrations during puberty is strongly related to fat mass and is inversely related to age at menarche (5, 6, 9, 35, 36, 37, 38). By reducing body adiposity (including abdominal fat mass) and thus leptinemia, metformin may attenuate the activity of the hypothalamic GnRH pulse generator (3, 7), enhance the gonadal feedback suppression on LH secretion (35), and decrease aromatase activity in ovarian granulosa cells (39). Alternatively, by reducing hyperinsulinemia and by concomitantly raising serum SHBG and IGFBP-1, metformin may alter the unbound estrogen and IGF-I fractions that act upon receptive tissues, such as the endometrium and the growth plate. Metformin-induced decreases of both circulating insulin and IGF-I may also reduce aromatase activity and estrogen biosynthesis within the ovary (40, 41). It remains to be determined whether metformin is also capable of normalizing the endocrine-metabolic state, the pubertal growth, and the menarcheal timing in other conditions of hyperinsulinemia and hyperleptinemia, such as simple obesity (6, 8, 10, 42, 43, 44).

In conclusion, metformin treatment in LBW girls with an early-normal pubertal onset was found to normalize the pubertal progression to menarche and to increase pubertal height gain and adult stature. These data support the concept that insulin is a major codeterminant of the pubertal tempo and pubertal height gain in girls. To what extent this modulation is directly or indirectly exerted through the interplay of insulin resistance, SHBG, estrogen, IGF-I, IGFBP-1, leptin, lipids, and body adiposity, among other factors, remains to be further elucidated.


   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).

L.I., C.V., K.O., D.B.D., and F.d.Z. have nothing to declare.

First Published Online February 21, 2006

Abbreviations: B2, Tanner stage 2; BMI, body mass index; HOMA, homeostasis model assessment; IGFBP-1, IGF-binding protein 1; LBW, low birth weight; SDS, SD score.

Received October 24, 2005.

Accepted February 13, 2006.


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 Introduction
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 Discussion
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