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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
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 post-
natal 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 in-
sulin 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 adren-
arche [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,
C ATALAN GIRLS WITH precocious pubarche (PP; pubic
hair at ⬍ 8 yr of age) because of exaggerated adren-
arche 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 postmen-
arche 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 hyper-
leptinemic, 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 con-
tribute to drive their rapid transit to postmenarche (8 –11).
We postulated that hyperinsulinemic insulin resistance
First Published Online May 9, 2006
Abbreviations: BMI, Body mass index; DHEAS, dehydroepiandros-
terone sulfate; IGFBP-1, IGF-I-binding protein 1; LBW, low birth weight;
PP, precocious pubarche.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the en-
docrine community.
2888
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The Journal of Clinical Endocrinology & Metabolism 91(8):2888 –2891
Copyright © 2006 by The Endocrine Society
doi: 10.1210/jc.2006-0336
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, met-
formin treatment may also prove to heighten the short adult stature of
LBW-PP girls. (J Clin Endocrinol Metab 91: 2888 –2891, 2006)
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
Subjects and ethics
The study population consisted of 38 LBW-PP girls (Table 1). 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).
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 carbohy-
drate metabolism.
The study protocol was registered under number ISRCTN84749320
and was approved by the Institutional Review Board of Barcelona Uni-
versity, 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, Bar-
Ibáñez et al. • Metformin to Delay Precocious Puberty in Girls J Clin Endocrinol Metab, August 2006, 91(8):2888 –2891 2889

TABLE 1. Baseline characteristics of the study population

Total (n ⫽ 38) Untreated (n ⫽ 19) Treated (n ⫽ 19)

Birth weight (kg) 2.4 ⫾ 0.1 2.5 ⫾ 0.1 2.4 ⫾ 0.1
Gestational age (wk) 38.6 ⫾ 0.4 38.7 ⫾ 0.6 38.5 ⫾ 0.5
Age at diagnosis of PP (yr) 6.8 ⫾ 0.2 7.1 ⫾ 0.2 6.6 ⫾ 0.3
Age at study start (yr) 7.9 ⫾ 0.1 8.0 ⫾ 0.2 7.9 ⫾ 0.2
Bone age (yr) 9.0 ⫾ 0.1 9.1 ⫾ 0.2 8.8 ⫾ 0.2
Height (cm) 129.4 ⫾ 1.2 130.0 ⫾ 1.9 128.9 ⫾ 1.6
Weight (kg) 31.0 ⫾ 0.9 30.8 ⫾ 1.2 31.3 ⫾ 1.4
BMI (kg/m2) 18.4 ⫾ 0.3 18.1 ⫾ 0.4 18.7 ⫾ 0.6
Adrenal androgens at PP diagnosis
DHEAS (␮g/dl) 102 ⫾ 6 96 ⫾ 5 108 ⫾ 10
Post-ACTH 17-OHP (ng/dl) 274 ⫾ 16 281 ⫾ 24 268 ⫾ 20
Values are mean ⫾ SEM. To convert units to SI, multiply the concentrations of DHEAS by 0.02714 and those of 17-hydroxyprogesterone
(17-OHP) by 0.03026.

celona, 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, testoster-
one, 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 ab-
dominal fat mass of 0.7% (17). Indicative references for body composi-
tion 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 quanti-
tative 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

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

All at Untreated Metformin

Referencea
0 month 0 monthb 24 months ⌬ 0 –24 months 0 monthb 24 months ⌬ 0 –24 months
Tanner breast stage 1 1 3.1 ⫾ 0.2 i
2.1 ⫾ 0.2 1 2.4 ⫾ 0.2 i
1.4 ⫾ 0.2j
BMI (kg/m2) 17.7 ⫾ 0.4 18.4 ⫾ 0.3 18.1 ⫾ 0.4 20.3 ⫾ 0.7i 2.2 ⫾ 0.4 18.7 ⫾ 0.6 19.5 ⫾ 0.6h 0.8 ⫾ 0.2k
IGF-I (ng/ml) 171 ⫾ 15 206 ⫾ 8d 215 ⫾ 10 289 ⫾ 21g 74 ⫾ 23 197 ⫾ 11 258 ⫾ 22f 61 ⫾ 24
Fasting insulin (␮U/ml) 6.6 ⫾ 0.7 8.4 ⫾ 0.5c 8.2 ⫾ 0.6 13.9 ⫾ 1.1i 5.7 ⫾ 1.2 8.6 ⫾ 0.9 12.0 ⫾ 1.0i 3.4 ⫾ 0.6j
HOMA-IR 1.0 ⫾ 0.1 1.8 ⫾ 0.1e 1.8 ⫾ 0.1 3.2 ⫾ 0.3i 1.4 ⫾ 0.3 1.9 ⫾ 0.2 2.8 ⫾ 0.2i 0.9 ⫾ 0.2
IGFBP-1 (ng/ml) 83 ⫾ 6 67 ⫾ 5c 70 ⫾ 7 35 ⫾ 5i ⫺36 ⫾ 6 64 ⫾ 6 40 ⫾ 3i ⫺24 ⫾ 4
SHBG (␮g/dl) 3.6 ⫾ 0.1 1.6 ⫾ 0.1e 1.6 ⫾ 0.1 1.2 ⫾ 0.1h ⫺0.4 ⫾ 0.1 1.5 ⫾ 0.1 1.4 ⫾ 0.1 ⫺0.1 ⫾ 0.1j
Testosterone (ng/dl) 16 ⫾ 2 30 ⫾ 2e 28 ⫾ 3 37 ⫾ 2f 9⫾4 32 ⫾ 3 28 ⫾ 4 ⫺4 ⫾ 4j
DHEAS (␮g/dl) 42 ⫾ 5 99 ⫾ 7e 95 ⫾ 9 152 ⫾ 12i 57 ⫾ 11 104 ⫾ 10 125 ⫾ 13f 21 ⫾ 9j
LDL-cholesterol (mg/dl) 83 ⫾ 3 105 ⫾ 5d 102 ⫾ 6 106 ⫾ 5 4⫾5 107 ⫾ 7 98 ⫾ 5g ⫺9 ⫾ 3j
HDL-cholesterol (mg/dl) 65 ⫾ 2 60 ⫾ 2c 61 ⫾ 3 51 ⫾ 2i ⫺10 ⫾ 2 60 ⫾ 3 56 ⫾ 2 ⫺4 ⫾ 2j
Triglycerides (mg/dl) 55 ⫾ 4 69 ⫾ 6c 63 ⫾ 7 79 ⫾ 10 17 ⫾ 8 74 ⫾ 10 65 ⫾ 7 ⫺9 ⫾ 6j
Leptin (ng/ml) 8⫾1 20 ⫾ 1e 20 ⫾ 1 26 ⫾ 3f 6⫾2 21 ⫾ 2 20 ⫾ 2 ⫺1 ⫾ 2j
Fat mass (kg) 6.4 ⫾ 0.6 10.6 ⫾ 0.7e 10.3 ⫾ 0.9 16.1 ⫾ 1.4i 5.7 ⫾ 0.8 10.8 ⫾ 1.0 13.1 ⫾ 1.0i 2.2 ⫾ 0.5l
Abdominal fat mass (kg) 1.2 ⫾ 0.2 2.9 ⫾ 0.3e 2.8 ⫾ 0.3 4.8 ⫾ 0.4i 2.0 ⫾ 0.3 3.0 ⫾ 0.4 3.4 ⫾ 0.3 0.4 ⫾ 0.3l
Lean mass (kg) 20.2 ⫾ 1.0 19.6 ⫾ 0.4 19.6 ⫾ 0.5 24.8 ⫾ 0.8i 5.3 ⫾ 0.5 19.7 ⫾ 0.7 25.8 ⫾ 0.9i 6.1 ⫾ 0.4
BMD (g/cm2) 0.71 ⫾ 0.04 0.74 ⫾ 0.02 0.73 ⫾ 0.02 0.85 ⫾ 0.02i 0.12 ⫾ 0.01 0.75 ⫾ 0.02 0.86 ⫾ 0.03i 0.11 ⫾ 0.02
BMC (kg) 1.03 ⫾ 0.05 1.04 ⫾ 0.03 1.04 ⫾ 0.04 1.39 ⫾ 0.06i 0.35 ⫾ 0.03 1.05 ⫾ 0.04 1.39 ⫾ 0.06i 0.34 ⫾ 0.03
Girls were randomized to remain untreated (n ⫽ 19) or to receive treatment with metformin (425 mg/d; n ⫽ 19) for 24 months. Values are
mean ⫾ SEM. To convert units to SI, multiply the concentrations of testosterone by 0.03467, those of androstenedione by 0.0349, and those of
DHEAS by 0.02714, and divide the concentrations of SHBG by 0.0288, those of triglycerides by 88.5, and those of high-density lipoprotein
(HDL)-cholesterol and low-density lipoprotein (LDL)-cholesterol by 38.7. BMC, Bone mineral content; BMD, bone mineral density; HDL,
high-density lipoprotein; HOMA-IR, homeostasis model assessment for insulin resistance; LDL, low-density lipoprotein.
a
Nonsymptomatic prepubertal girls matched for body size; n ⫽ 24 for endocrine-metabolic variables, age 8.3 ⫾ 0.3 yr (18); n ⫽ 12 for IGFBP-1
and leptin, age 8.2 ⫾ 0.2 yr; n ⫽ 13 for body composition, age 8.4 ⫾ 0.4 yr.
b
No significant differences between randomized subgroups at 0 month.
c
P ⬍ 0.05; d P ⱕ 0.01; e P ⱕ 0.001 vs. reference.
f
P ⬍ 0.05; g P ⱕ 0.01; h P ⱕ 0.001; i P ⱕ 0.0001 vs. baseline (0 month).
j
P ⬍ 0.05; k P ⱕ 0.01; l P ⱕ 0.001 for 0- to 24-month change (⌬) vs. untreated.

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2890 J Clin Endocrinol Metab, August 2006, 91(8):2888 –2891 Ibáñez et al. • Metformin to Delay Precocious Puberty in Girls

estimated from fasting insulin and glucose levels using the homeostasis Preliminary results during the third study year indicate that
model assessment (HOMA-CIGMA Calculator program version 2.00) metformin treatment is also associated with a delay of men-
(19). Samples were kept frozen at ⫺20 C until assay, and markers in both
groups were assayed at the same time.
arche; five of 19 untreated girls already experienced men-
Data on birth weight and gestational age were obtained from hospital arche, whereas this was the case in none of the 19 metformin-
records and transformed into sd scores (12). treated girls (P ⫽ 0.016 by ␹2).
Two-sided t tests were performed to compare the total study pop- Metformin treatment was well tolerated; indices of hepatic
ulation with the indicative references, and t tests were also performed and renal function remained unchanged throughout treatment.
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-mea- Discussion
sures ANOVA. For uniformity, all results are expressed as mean ⫾ sem.
The level of statistical significance was set at P ⬍ 0.05. Prepubertal, Longitudinal and cross-sectional studies have shown that
short-term results (0 – 6 months) of part of this study population (n ⫽ 33) LBW-PP girls are at risk for early onset of puberty and men-
have been reported previously (18). ses and, thereafter, for a relatively short stature and for
further progression to anovulation and to hyperinsulinemic
Results
hyperandrogenism, which is a variant of polycystic ovary
Table 2 summarizes the main results at 0 and 24 months. syndrome (2, 12, 20 –23). These sequential outcomes are
Baseline values of the study population were suggestive of thought to be partly attributable to hyperinsulinemic insulin
insulin resistance, androgen excess, an atherogenic lipid pro- resistance and its correlates, such as an adipose body com-
file, and an adipose body composition. After 24 months, position (even in the absence of obesity), a proinflammatory
metformin-treated girls displayed less insulin resistance and state, high circulating leptin concentrations, adrenal hy-
less androgen excess and had a less atherogenic lipid profile perandrogenism, an atherogenic lipid profile, and low SHBG
and a less adipose body composition than the untreated girls. levels (1–5, 18, 23). Accordingly, insulin sensitization with
Figure 1 highlights a selection of longitudinal findings. metformin is under exploration as an approach not only to
Between the subgroups, there is a striking difference in pu- prevent postmenarcheal progression to polycystic ovary syn-
bertal development, which is reflected in the respective IGF-I drome (24 –26) but also to prevent earlier steps within this
patterns. Despite a slower course into and through puberty, sequence. In prepubertal LBW-PP girls, metformin treatment
the metformin-treated girls maintained their gains in height is known to induce within 6 months a less adipose body
and lean mass, whereas they attenuated their fat excess. composition, an attenuated adrenarche, a more favorable
Metformin-treated girls entered into B2 approximately 0.4 lipid profile, and a less proinflammatory state, as judged by
yr after the untreated girls (9.5 ⫾ 0.1 vs. 9.1 ⫾ 0.1 yr; P ⬍ 0.01). normalization of the adipocytokine pattern and by a decrease

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.

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Ibáñez et al. • Metformin to Delay Precocious Puberty in Girls J Clin Endocrinol Metab, August 2006, 91(8):2888 –2891 2891

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