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Hyperinsulinemia and Decreased Insulin-Like Growth Factor-Binding Protein-1 Are Common Features in Prepubertal and Pubertal Girls with a History of Premature Pubarche¹

Adolescent and Endocrine Unit (L.I., A.C.) and Hormonal Laboratory (N.P., S.R.), Hospital Universitario Materno-Infantil Vall d’Hebron, Barcelona, Spain; Clinica Pediatrica, University of Parma (M.Z.), Parma, Italy; and the Department of Pediatrics, Albert Einstein College of Medicine/Montefiore Medical Center (P.S.), Bronx, New York 10467

Address all correspondence and requests for reprints to: Lourdes Ibáñez, M.D., Adolescent and Endocrine Unit. Hospital Universitario Materno-Infantil Vall d’Hebron, P° Vall d’Hebron 119–129, 08035 Barcelona, Spain.

	Abstract

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The fasting insulin resistance index, mean blood glucose, mean serum insulin (MSI), early insulin response to glucose, glucose uptake rate in peripheral tissues, and insulin sensitivity indexes in response to a standard oral glucose tolerance test; serum insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), IGFBP-3, and sex hormone binding-globulin (SHBG) levels; and the free androgen indexes were evaluated in 98 girls with premature pubarche [PP; prepubertal (B1; n = 32), early pubertal (B2; n = 27), midpubertal (B3; n = 23), and postmenarcheal (B5; n = 16)] and in 86 Tanner stage- and bone age-matched controls. We ascertained whether hyperinsulinemia is already present in PP girls before or during pubertal development and whether these patients show a similar pattern of growth factor secretion as normal girls. Body mass indexes did not differ significantly between patients and controls within the same pubertal stage.

MSI levels showed a significant increase with pubertal onset in all subjects, as expected. Patients showed significantly higher MSI values than controls at all Tanner stages (P < 0.03, P = 0.03, P = 0.03, and P < 0.05 for B1, B2, B3, and B5, respectively); higher insulin response to glucose at B1, B2, and B3 (P < 0.03, P = 0.03, and P < 0.05, respectively); higher glucose uptake rate in peripheral tissues at B1 and B2 (P < 0.04 and P = 0.02, respectively); and a later rise in insulin sensitivity compared to controls. PP girls also showed lower IGFBP-1 levels at B1 and B5 (P < 0.01 and P = 0.02, respectively), lower SHBG concentrations at B5 (P < 0.0005), and higher free androgen indexes at B1, B3, and B5 (P < 0.01, P < 0.05, and P < 0.001, respectively) compared to controls. Among others, significant correlations between SHBG and MSI levels (r = -0.49; P < 0.0001) and between SHBG and IGFBP-1 levels (r = 0.41; P < 0.0001) were found in all subjects.

Hyperinsulinemia, increased early insulin responses to glucose, increased glucose uptake rate in peripheral tissues, elevated free androgen indexes, and decreased SHBG and IGFBP-1 levels are present in most girls with PP from childhood. These findings lend strong support to the concept that PP is not a benign condition, and long term follow-up of these patients into adulthood is recommended. The possible causal role of hyperinsulinemia in adrenal and/or ovarian androgen hypersecretion remains to be established.

	Introduction

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PREMATURE pubarche (PP) is defined as the early appearance of pubic hair before 8 yr in girls and 9 yr in boys (1). It is, in general, secondary to an early isolated maturation of the adrenal gland (premature adrenarche) with increased adrenal androgen secretion for chronological age (2, 3). In other cases, enzymatic defects of steroidogenesis account for the clinical picture (4).

Postpubertal follow-up of PP girls has revealed an increased incidence of functional ovarian hyperandrogenism at adolescence (5). This entity, which is closely related to the polycystic ovary syndrome (PCOS) (6), is characterized by an exaggerated ovarian 17-hydroxyprogesterone (17-OHP) response to testing with a GnRH agonist, often without other criteria for PCOS diagnosis, such as elevated LH levels (5, 6, 7). Dysregulation of ovarian cytochrome P450c17, which has both 17-hydroxylase and 17,20-lyase activities, seems to mostly account for the overactivity of thecal steroidogenesis (6).

Hyperinsulinemia, insulin resistance and adrenal hyperandrogenism are common features in adult women and in adolescents with PCOS and functional ovarian hyperandrogenism (8, 9, 10, 11, 12, 13), although no clear relationship between adrenal androgens and insulin resistance has been documented (14). Recent studies suggest that the lowering of insulin levels acts in a selective and sex-specific fashion to reduce circulating dehydroepiandrosterone sulfate (DHEAS) concentrations in men only (15, 16). Insulin also modulates insulin-like growth factor I (IGF-I) action and that of its binding protein (IGFBP-1) (17, 18) and inhibits sex hormone-binding globulin (SHBG) production in human hepatoma cell lines (19). The finding of an inverse relationship between SHBG and fasting serum insulin levels in healthy women suggests that insulin is a modulator of human SHBG metabolism (20, 21).

Puberty is characterized by a state of insulin resistance associated with concomitant increases in GH, IGF-I, and IGFBP-3 levels and a decrease in IGFBP-1 and SHBG concentrations (22, 23, 24). The hyperinsulinemia and increased IGF-I activity during puberty have been proposed as inducing factors in the development of PCOS (25).

The present study was performed to ascertain whether the hyperinsulinism found by us in some subsets of postpubertal PP girls (12) is present before or during puberty and whether these patients show a similar pattern of serum IGF-I, IGFBP-1, IGFBP-3, and SHBG secretion as normal girls.

	Subjects and Methods

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Subjects

Ninety-eight PP girls (age range, 5.9–17 yr) and 86 Tanner stage- and bone age-matched controls (26, 27) (age range, 6–16.9 yr) were studied. Controls were selected among short normal children (heights between the 10th and 25th percentile) and other children being seen by other unrelated pediatric subspecialties. Subjects were divided into 4 groups according to Tanner stage of breast development (26): prepubertal (B1), early pubertal (B2), midpubertal (B3), and postmenarcheal (B5). All girls in groups B1–B3 were premenarcheal. In all patients, PP was secondary to premature adrenarche; namely, they presented with elevated androstenedione (⁴-A) and/or DHEAS levels at PP diagnosis (28).

None of the subjects had acanthosis nigricans, thyroid dysfunction, Cushing’s syndrome, hyperprolactinemia, a family or personal history of diabetes mellitus, or late-onset congenital adrenal hyperplasia (29, 30).

Postmenarcheal girls were studied in the follicular phase (days 3–8) of the menstrual cycle. None of them was hirsute according to the Ferriman and Gallwey score (31), and none had menstrual irregularities. The protocol was approved by the institutional review committee at Barcelona Hospital. Informed consent from patients or their parents was obtained, as well as assent from minors. The baseline clinical characteristics of all groups are described in Table 1.

After 3 days of a high carbohydrate diet (300 g/day) and an overnight fast, a standard 75-g 2-h oral glucose tolerance test (OGTT) was performed in all subjects, starting at 0800 h. Blood was sampled 0, 30, 60, and 120 min after oral glucose administration for glucose and immunoreactive insulin measurements. Serum IGF-I, IGFBP-1, IGFBP-3, SHBG, and total testosterone (T) levels were measured from baseline blood samples, and the free androgen index (FAI) [T (nmol/L) x 100/SHBG (nmol/L)] was calculated. All samples were immediately centrifuged, and serum was separated and frozen at -20 C until assayed.

The fasting insulin resistance index (FIRI) was calculated as the product of the fasting serum insulin (microunits per mL) by the fasting serum glucose (nanomoles per L) divided by 25, as previously described (32). FIRI has been shown to have a better correlation with insulin sensitivity values than the fasting glucose/insulin ratio (32). All subjects had normal glucose tolerance according to WHO criteria (33).

The areas under the curve for glucose [mean serum glucose (MSG)], and insulin [mean serum insulin (MSI)] were calculated according to the trapezoidal rule. The initial insulin response to glucose (IRG), the glucose uptake rate in peripheral tissues (M value), and the degree of peripheral sensitivity to insulin (SI) were estimated simultaneously during the OGTT according to the method of Cederholm and Wibell, as previously described (11, 12, 34). Individual values within 2 SD of the control group values for each parameter tested were considered within the normal range.

Hormone assays

Serum glucose was measured by the glucose oxidase method. Immunoreactive insulin was assayed by a RIA kit (Pharmacia, Uppsala, Sweden). The mean intra- and interassay coefficients of variation were 4.7% and 7.2%, respectively. Serum IGF-I was determined by RIA with a previous acid extraction in a Sep-Pak column (Incstar Corp., Gif-Sur-Yvette, France). IGFBP-1 was measured by a quantitative immunometric assay (Medix-Biochemica, Oulu, Finland), and IGFBP-3 was determined using a commercially available kit (Mediagnost, Tubingen, Germany). All methods had intra- and interassay coefficients of variation between 4–8% in the relevant concentration ranges (11). Serum steroid concentrations (T, 17-OHP, DHEAS, and ⁴-A) were determined using commercially available RIA kits (12), and serum SHBG was determined by RIA using monoclonal anti-SHBG antibodies, as previously described (11).

Statistical analysis

Anthropometric data and hormonal results are expressed as the mean \ SEM unless otherwise stated. Hormone levels among independent groups were compared by one-way ANOVA corrected by Scheffe’s test for multiple comparisons. Analysis of covariance was performed to assess the contribution of body mass index (BMI) to the differences in the parameters tested between patients and controls. P < 0.05 was considered significant. Correlations were examined by linear regression analysis.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
IGFs and SHBG levels (Table 2)

Developmental changes. Serum IGF-I levels showed a significant increase throughout puberty in all subjects (P < 0.02 for patients and P < 0.0001 for controls vs. prepubertal values), whereas IGFBP-1 levels showed a progressive decline (P < 0.005, for both patients and controls). Serum IGFBP-3 levels did not vary significantly with pubertal progression.

Comparison between patients and controls. Patients showed higher serum IGF-I levels than controls at B1 (P < 0.005) and lower IGFBP-1 levels at B1 and B5 (P < 0.01 and P = 0.02, respectively), whereas IGFBP-3 values were similar in patients and controls within the same Tanner stage. PP girls had lower SHBG at B5 (P < 0.0005), and higher FAI indexes at B1, B3, and B5 (P < 0.01, P < 0.05, and P < 0.001, respectively). These differences persisted after adjusting for BMI.

Patterns of insulin secretion (Table 3 and Fig. 1)

Developmental changes. The FIRI increased during puberty in all subjects (P = 0.02 for both patients and controls) concomitantly with the expected increase in fasting serum insulin levels.

View larger version (33K): [in this window] [in a new window]   Figure 1. MSI levels and IGFBP-1 concentrations in patients and controls. *, Significantly different from controls. MSI: P < 0.03, P = 0.03, P = 0.03, and P < 0.05 for B1, B2, B3, and B5, respectively. IGFBP-1: P < 0.01 and P = 0.02 for B1 and B5, respectively.

Comparison between patients and controls. The FIRI was similar in patients and controls within the same Tanner stage, except at B1, where patients showed higher values (P = 0.02). The differences were no longer significant after controlling for BMI.

MSG levels were similar in patients and controls within the same Tanner stage, whereas MSI concentrations were significantly higher in patients at all Tanner stages (P < 0.03, P = 0.03, P = 0.03, and P < 0.05 for B1, B2, B3, and B5, respectively).

Patients showed higher IRG at B1, B2, and B3 (P < 0.03, P = 0.03, and P < 0.05 vs. controls, respectively) and higher M values at B1 and B2 (P < 0.04 and P = 0.02 vs. controls, respectively). SI indexes were similar between patients and controls within the same stage of pubertal development. The differences observed in MSI, IRG, and M values between patients and controls persisted after adjusting for BMI.

Correlations

Serum SHBG levels correlated inversely with BMI and MSI levels and positively with serum IGFBP-1 levels in all subjects (r = -0.52, P < 0.0001; r = -0.49, P < 0.0001; and r = 0.41, P < 0.0001, respectively).

MSI levels showed a positive correlation with BMI and FIRI in all subjects and correlated negatively with serum IGFBP-1 levels (r = 0.47, P < 0.0001; r = 0.44, P < 0.0001; and r = -0.32, P < 0.0001, respectively). The glucose uptake rate in peripheral tissues (M) showed a negative correlation with IGFBP-1 levels in all subjects (r = -0.4; P < 0.0001). An inverse correlation between SHBG and FAI was found only in patients (r = 0.37; P = 0.0002).

No significant correlations between serum ⁴-A, DHEAS, or 17-OHP at diagnosis of PP and the various parameters assessed during the OGTT were found.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The present study was conducted to assess whether the hyperinsulinemia present in some subsets of postmenarcheal PP girls was also present in these patients before or during pubertal development and whether they showed a distinct pattern of IGF-I, IGFBP-1, IGFBP-3, and SHBG secretion compared to normal girls.

Our results indicate that girls with a history of PP demonstrate more hyperinsulinism than normal girls before the onset of puberty and throughout all stages of pubertal development. The hyperinsulinemia is associated with an increased initial IRG and an increased glucose uptake rate in peripheral tissues (M value), both prepubertally and early in puberty, and with a later rise in insulin sensitivity during puberty. Patients also showed increased FAI and lower serum SHBG and IGFBP-1 levels at most pubertal stages tested.

The hyperinsulinemia in PP patients cannot be explained by differences in BMI compared to control values. Although postmenarcheal PP girls were slightly heavier than normal girls, all had normal IGF-I levels and BMI values (35).

Although the OGTT may have limitations when extrapolations to mechanisms of disease pathogenesis are attempted, the possibility of estimating simultaneously both insulin release and peripheral sensitivity to insulin with a physiological test with previously established good correlation with more invasive and complicated techniques (12, 34) appears to be suitable as an initial screening test. We recognize that in some subsets of young patients, more sophisticated investigations may be necessary. The OGTT does not create ethical problems when normal individuals are included for comparisons. The method used in our study to estimate insulin sensitivity might account in part for the failure to detect significantly decreased values in PP patients, although the young age at which these girls were evaluated may also explain the absence of significant abnormalities in this parameter. In this setting, a recent study in prepubertal PP girls using a well validated method such as the frequently sampled iv glucose tolerance test (36) detected decreased SI indexes only in patients with acanthosis nigricans and increased mean weight for length indexes. Lean prepubertal nonacanthotic patients had normal SI.

Serum IGF-I, SHBG, and IGFBP-1 levels followed a similar pattern in patients and controls throughout development. IGF-I levels increased and SHBG and IGFBP-1 levels decreased significantly with the onset of puberty, as expected (22, 23, 24). The finding of a better correlation between MSI and SHBG levels and between MSI and IGFBP-1 concentrations than between SHBG levels and FAI is in agreement with previous studies that suggested that insulin is the main physiological regulator of SHBG and IGFBP-1 production before and during puberty, with sex steroids playing a secondary role (37, 38). Low SHBG and IGFBP-1 levels have been shown to be useful markers for hyperinsulinemia and/or insulin resistance in subjects with intact endogenous insulin secretion (21, 39), whereas decreased SHBG concentrations are independent predictors for the development of type II diabetes in women (40). Thus, the decreased values of both parameters in PP girls might be an additional risk factor together with hyperinsulinemia for the eventual development of insulin resistance.

The possible pathogenetic role of hyperinsulinemia in premature adrenarche was not resolved by this study, although the finding of increased insulin levels in PP girls in the prepubertal period suggests that both events might be related in time. Recent reports suggest that in hyperandrogenic women, hyperinsulinemia, within the high physiological range, potentiates ACTH-stimulated steroidogenesis, causing an increase in 17-hydroxylase activity and a relative impairment of 17,20-lyase activity (41). The report of Nestler et al. (42) that hyperinsulinemia stimulates P450c17 activity in another steroidogenic tissue, namely the ovary, in obese PCOS women, further supports the above findings and suggests that at least in some subsets of hyperandrogenic patients, hyperinsulinemia and dysregulation of ovarian androgen secretion are pathogenetically related (42).

Insulin has been well documented to enhance the androgenic response of ovarian thecal cells to LH (43) and the FSH-mediated induction of LH responsiveness in granulosa cells (44), but has also been shown, together with IGF-I and IGF-I, to augment the steroidogenesis and ACTH responsiveness of human adrenocortical cells in culture (45). Thus, the hyperinsulinemia present in our PP patients could favor hyperandrogenemia by increasing adrenal steroidogenesis or act as a second hit to unmask latent abnormalities in the regulation of adrenal and ovarian steroidogenesis (46).

In summary, hyperinsulinemia, increased early IRG and glucose uptake rate in peripheral tissues, elevated FAI, and decreased SHBG and IGFBP-1 levels are common features during childhood in girls with PP, emphasizing the idea that PP is not a benign condition and that follow-up of these patients into adulthood is required. The possible causal role of hyperinsulinemia on adrenal and/or ovarian androgen hypersecretion in adult PP patients remains to be established.

	Footnotes

 
¹ This work was supported in part by Grant 95/5357 from the Fondo de Investigaciones de la Seguridad Social, National Health Service (Madrid, Spain).

Received October 16, 1996.

Revised March 19, 1997.

Accepted March 31, 1997.

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