| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Article |
Department of Pediatrics (M.R.D., M.E.S., A.M.M., D.C., L.S.L., C.G., S.E.O.), Division of Pediatric Endocrinology, Columbia University, College of Physicians and Surgeons, New York, New York 10032; Department of Obstetrics and Gynecology (M.F.), Columbia University, New York, New York 10032; and Information Sciences Division (D.J.M.), Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962
Address all correspondence and requests for reprints to: Sharon E. Oberfield, M.D., Columbia University, College of Physicians and Surgeons, Division of Pediatric Endocrinology, 630 West 168th Street, PH 5 East-522, New York, New York 10032. E-mail: seo8{at}columbia.edu.
Abstract
Girls with premature adrenarche (PA), similar to women with polycystic ovarian syndrome, display alterations in the IGF system, may have impaired insulin sensitivity, and demonstrate unfavorable lipid profiles. Girls with PA are also at increased risk for functional ovarian hyperandrogenism. Metabolic studies in boys with PA, however, are limited. The objective of this study was to determine whether boys with PA show alterations in insulin sensitivity and the IGF system. We studied an ethnically heterogeneous group of 19 prepubertal boys: 11 with PA (age, 8.2 ± 0.7 yr; body mass index (BMI)-Z score, 1.8 ± 1.1) and 8 controls (age, 7.9 ± 0.8 yr; BMI-Z score, 1.2 ± 1.0). Fasting levels of glucose, insulin, proinsulin (P0), hemoglobin A1c, testosterone, SHBG, 
4-androstenedione, dehydroepiandrosterone sulfate, LH, FSH, IGF-I, IGF-binding protein-1, IGF-binding protein-3, free IGF-I, and lipids were measured. Ten of 11 boys with PA and six of eight controls underwent standard oral glucose tolerance testing. The insulin response to this test was measured by the insulin area under the curve. Measures of insulin sensitivity were calculated as the fasting glucose to insulin ratio, quantitative insulin sensitivity check index, and composite insulin sensitivity index. All values were adjusted for BMI-Z score. Total IGF-I, P0, ratio of P0 and fasting insulin level, and log insulin area under the curve were higher, and SHBG was lower in the boys with PA, compared with controls. Decreased insulin sensitivity was suggested by decreased composite insulin sensitivity index. A trend toward greater triglycerides was observed in the boys with PA, compared with the controls. Prepubertal boys with PA show differences in the IGF system and decreased insulin sensitivity, independent of obesity, as observed in girls with PA. These findings suggest that both boys and girls with PA should be monitored for the development of insulin resistance and associated complications, including diabetes mellitus and cardiovascular disease.
PREMATURE ADRENARCHE (PA) is defined as the appearance of pubic hair and/or axillary hair in the absence of thelarche or testicular development, associated with increased adrenal androgen production, before the age of 8 yr in girls and 9 yr in boys. This condition occurs more commonly in girls than boys with an unexplained sex ratio of nearly 10:1. Adrenal androgens are usually elevated for chronological age but within the range expected for the stage of pubic hair (1). Decreased levels of SHBG, hyperinsulinemia, insulin resistance, and unfavorable lipid profiles have been demonstrated in girls with PA (2, 3, 4, 5). PA does not significantly impact the onset and progression of puberty or final height (1). Postpubertally, girls with PA are at increased risk for the development of anovulation and functional ovarian hyperandrogenism, including polycystic ovarian syndrome (PCOS) (6, 7). Reduced fetal growth has been associated with additional risk for these endocrine/metabolic disturbances during or after puberty (8, 9). PCOS is characterized by hyperandrogenism and chronic anovulation, and its complications include hyperinsulinemia, insulin resistance, early onset of type 2 diabetes mellitus (DM), dyslipidemia, cardiovascular disease, and infertility (10, 11). Recently increased plasminogen activator-inhibitor type 1 activity, an early marker of cardiovascular risk in PCOS, was demonstrated in girls with PA (12). A significantly increased prevalence of impaired glucose tolerance and type 2 DM has also been found among first-degree relatives of girls with PA (13).
Both in vitro and in vivo studies have implicated a dysregulation of the IGF system in the pathophysiology of PA and PCOS. IGF-I and insulin have been shown to potentiate LH-stimulated androgen synthesis in theca-interstitial cells (14) and were also found to stimulate the proliferation of these ovarian cells (15). High concentrations of insulin alone induce androgen accumulation in cultures of ovarian stromal tissue obtained from hyperandrogenic women (16). Insulin and IGF-I have been shown to suppress production of SHBG in a human hepatoma cell line (17), and physiological levels of insulin and IGF-I also induce steroidogenic enzymes in cultured human adrenocortical cells (18, 19). Reduced concentrations of IGF-binding protein-1 (IGFBP-1) have been demonstrated in women with PCOS and girls with PA; IGFBP-1 levels are inversely correlated with fasting serum insulin levels (3, 20, 21, 22, 23, 24) and ACTH-stimulated adrenal hormone levels in girls with PA (20). Elevated total IGF-I has been reported in prepubertal girls with PA (3), and elevated free IGF-I levels have been noted in subjects with PCOS (23, 24). Our group has recently demonstrated elevated total and free IGF-I levels in prepubertal Hispanic girls with PA (25).
Studies in boys with PA are very limited. Potau et al. (26) found levels of IGF-I, IGFBP-1 and -3, and SHBG as well as measures of the glucose and insulin response to an oral glucose load to be comparable in boys with PA and controls. In a preliminary report, higher concentrations of IGF-I were demonstrated in boys with PA (27). The primary purpose of our study was to compare parameters of the insulin/IGF system in prepubertal boys with PA and matched controls. An additional aim of the study was to identify cardiovascular risk factors in prepubertal boys with PA through analysis of their lipid profiles and measures of insulin sensitivity. We hypothesized that PA in boys is associated with endocrine/metabolic disturbances similar to those demonstrated in girls with PA, which may have long-term sequelae in adulthood, including a predisposition to the complications of syndrome X, often considered the male counterpart of PCOS (28, 29).
Subjects and Methods
Subjects
We studied 19 prepubertal boys, 11 with PA and 8 controls. For the subjects with PA, the criteria for entry into the study were the appearance of pubic hair with or without axillary hair before 9 yr of age, testicular volume 3 cc or less, and a 4-androstenedione (4-A) and/or dehydroepiandrosterone sulfate (DHEAS) level(s) in Tanner II range with no evidence of an adrenal enzyme defect or other endocrinopathy (30). The criteria for entry into the control group included the absence of pubic hair on physical examination, testicular volume 3 cc or less, and no evidence of an adrenal enzyme defect or other endocrinopathy. None of the subjects was taking any medications at the time of the study. Eight of 11 boys with PA and 3 of 8 controls were obese, with obesity defined as a body mass index (BMI) greater than the 95th percentile for age and sex. BMI and BMI-Z scores based on 1 SD reference data from the National Health and Nutrition Examination Survey (31) were calculated, and all subjects were examined for the presence of acanthosis nigricans. Clinical characteristics of the subjects are presented in Table 1
. Informed consent from a legal guardian of each subject and assent from subjects over 7 yr of age were obtained before participation in the study. The study was approved by the Institutional Review Board of the Columbia-Presbyterian Medical Center.
|
Basal levels of glucose (G0), insulin (I0), proinsulin (P0), IGF-I, free IGF-I, IGFBP-1, IGFBP-3, DHEAS, 4-A, SHBG, testosterone, LH, FSH, hemoglobin A1c (HgA1c), and lipids were measured in all subjects after an overnight fast. Ten of 11 boys with PA and 6 of 8 controls underwent a standard 1.75 g/kg body weight (maximum 75 g) oral glucose tolerance test (OGTT). The subjects were instructed to maintain their usual diet until the overnight fast. Before and 30, 60, 90, and 120 min after the ingestion of oral glucose, blood was sampled for plasma glucose and serum insulin and proinsulin levels.
Measures of insulin sensitivity and insulin secretion
The fasting plasma glucose was divided by the fasting serum insulin to calculate the fasting glucose to insulin ratio (FGIR), a measure that has been validated in prepubertal girls with PA using the iv and OGTTs (5, 32, 33). The quantitative insulin sensitivity check index (QUICKI) and the composite whole-body insulin sensitivity index [ISI(composite)], both previously validated against the euglycemic insulin clamp, were also calculated (34, 35). QUICKI was calculated as 1/(log I0 + log G0), and ISI(composite) was calculated according to the following formula: 10,000/square root of [(G0)(I0)(mean serum insulin during OGTT)(mean blood glucose during OGTT)]. The area under the curve for insulin was calculated using the trapezoidal rule (36).
Assays
Insulin (by immunochemiluminometric assay), IGF-I, IGFBP-1, IGFBP-3, DHEAS, 4-A, testosterone, SHBG, FSH, LH, and HgA1c levels were measured by Esoterix Endocrinology (Calabasas Hills, CA). Plasma glucose levels were assayed by the glucose hexokinase method. Plasma total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured using the analyzer (Hitachi) in the Core Laboratory of the General Clinical Research Center at Columbia-Presbyterian Medical Center. Low-density lipoprotein (LDL) cholesterol was calculated according to the formula of Friedewald et al. (37). Free IGF-I levels were determined using a two-site immunoradiometric assay (Diagnostic Systems Laboratories, Inc., Webster, TX). The intra- and interassay coefficients of variation were 7.2% and 12.5%, respectively. A single assay was performed to include all of the samples in triplicate.
Data analysis
Analysis of covariance was used for comparisons between groups on continuous measures. Estimates of the effect of group were made, unadjusted, and adjusted for the contribution of BMI-Z scores by sequential and partial sums of squares methods, respectively. Insulin area under the curve in response to glucose challenge (IAUC120) was log transformed to normalize the distribution of the data. Pearson correlations were computed as measures of the strength of association between continuous measures. Results are reported as the mean ± SD unless otherwise noted. P values less than 0.05 were considered to represent statistical significance.
Results
The PA and control groups were comparable in terms of age, BMI, and BMI-Z score (Table 1
). As indicated by the range of BMI and BMI-Z scores, both groups were comprised of nonobese and obese individuals. Nine of 11 subjects with PA had bone age studies within 4 months of the visit, with a mean bone age of 9.6 ± 1.8 yr. In those subjects with PA who demonstrated significant bone age advancement, the bone age was associated with a correspondingly advanced height and/or weight age. Data for the control group were not available for comparison because only three of eight controls had bone age studies. In terms of ethnicity, 3 of 11 boys with PA were white, compared with none of the controls. Acanthosis nigricans was observed in both groups but was somewhat more common in the boys with PA. A family history of adult-onset diabetes and/or cardiovascular disease was elicited frequently in both groups. Two of 11 boys with PA and one of eight controls were products of pregnancies complicated by maternal DM. Birth weights were not different between the groups.
Mean DHEAS and 4-A levels were higher in the PA group, although the observed differences were not statistically significant (Table 2). The mean testosterone level was higher in the PA group, unadjusted for BMI-Z score. All 11 boys with PA had adrenarchal adrenal androgens (4-A and/or DHEAS). One subject with PA had a testosterone level of 15 ng/dl (prepubertal level, <10) with a prepubertal testicular volume (2.5 cc, Prader 2–3). One of eight control subjects had adrenarchal 4-A and DHEAS levels, whereas in the rest of the group, the 4-A and/or DHEAS levels were in the prepubertal range or overlapped with the earliest Tanner II range. The mean SHBG level was lower in the PA group, before and after adjustment for BMI-Z score. A trend toward greater triglyceride levels was noted for the PA vs. the control group. No other differences in the lipid levels were detected between the study groups (Table 3).
|
|
). The mean IGFBP-1 level in the boys with PA was approximately 2-fold lower than that in the controls, although this did not attain statistical significance. Nine of 11 boys with PA and 5 of 8 controls had IGFBP-1 levels below the normal fasting range (30–1000 ng/ml). The IGFBP-3 and free IGF-I levels did not differ between the PA and control groups, and the free fraction of IGF-I, expressed as the ratio of free to total IGF-I, was equivalent in both groups and similar to those of previous reports (38).
|
). ISI(composite) was significantly lower in the PA group, both unadjusted and adjusted for BMI-Z score, suggesting decreased insulin sensitivity in the boys with PA. The differences detected in fasting insulin, FGIR, and QUICKI did not persist after adjustment for BMI-Z score. Fasting proinsulin levels and the fasting proinsulin to insulin ratio were significantly increased in the boys with PA, compared with controls after adjustment for BMI-Z score.
|
Basal insulin was inversely correlated with IGFBP-1 in the boys with PA; a similar trend was observed in the control group. A trend toward an inverse correlation was noted for log IAUC120 with IGFBP-1 in both the PA and control groups (Table 6). Basal insulin correlated with free IGF-I levels in the controls (r = 0.86, P < 0.01), but not in the PA group, and did not correlate with total IGF-I levels in either group. As anticipated, IGFBP-3 correlated with the total IGF-I in the PA group (r = 0.85, P < 0.001), and a similar trend was seen in the control group (r = 0.63, P = 0.09). Although the mean free IGF-I represented approximately 1% of the total IGF-I in both groups, no relationships were noted among the total IGF-I, free IGF-I, or IGFBP-1 levels within either study group.
|
We found no statistically significant association between any component of the insulin/IGF system and androgen levels in the boys with PA. In the controls, IGF-I correlated with DHEAS (r = 0.83, P = 0.01), 4-A (r = 0.86, P < 0.01), and testosterone levels (r = 0.75, P < 0.05), although it should be noted that their testosterone levels were all very low and narrow in range (Table 2). IGFBP-3 also correlated with 4-A (r = 0.71, P < 0.05), and a trend was found in its relationship with DHEAS in the control group (r = 0.68, P < 0.07). Free IGF-I and IGFBP-1 did not correlate with androgen levels in either group.
Correlations between the IGF system and measures of insulin sensitivity
In the boys with PA, IGFBP-1 correlated with the FGIR and QUICKI, and a trend was observed in the relationship between IGFBP-1 and ISI(composite). Similarly, in the controls, IGFBP-1 correlated with the FGIR and ISI(composite), with a trend detected in its association with QUICKI (Table 6). We found no association between the measures of insulin sensitivity and total IGF-I in either study group. The free IGF-I also did not correlate with the measures of insulin sensitivity in the boys with PA, but in the controls, statistically significant inverse correlations were detected for FGIR (r = -0.75, P < 0.05) and QUICKI (r = -0.73, P < 0.05) as well as a trend for ISI(composite) (r = -0.77, P = 0.07).
Discussion
Hyperinsulinemia, unfavorable lipid profiles, reduced SHBG levels, and alterations in the IGF system have been demonstrated in prepubertal girls with PA and women with PCOS (2, 3, 4, 5, 20, 21, 22, 23, 24, 25). Furthermore, studies suggest that girls with PA are at risk for the development of PCOS and its complications (6, 7). Epidemiologic data indicate that a clustering of cardiovascular risk factors for syndrome X may be present in childhood (39, 40, 41, 42). The metabolic features and risk factors of boys with PA remain largely unexplored. Our preliminary results argue against a previously postulated sexual dimorphism in PA (26) and suggest that young boys with PA show differences in insulin sensitivity and the IGF system similar to those observed in their female counterparts.
IGF-I has been implicated in the pathogenesis of PA (3, 20, 25) and PCOS (21, 22, 23, 24). Elevated total IGF-I levels have been demonstrated in girls with PA (3, 25). We have found similarly increased levels of total IGF-I, independent of obesity, in boys with PA, compared with controls. In contrast to our previous finding of elevated free IGF-I levels in girls with PA, although the mean level was higher in the PA group, the difference in free IGF-I between boys with PA and controls was not statistically significant. The ratios of free to total IGF-I in each group were, however, identical. We suggest that we may have lacked sufficient power to detect a difference in the free IGF-I caused in part by our sample size. The nearly 2-fold lower level of IGFBP-1 in the PA group, compared with the controls, approached statistical significance (P < 0.06) before, but not after, adjustment for BMI-Z score and was therefore likely attributable to relative obesity in the PA group. Although adrenal androgens were somewhat higher in the PA group, compared with the controls, the lack of a statistically significant difference for 4-A and DHEAS may be attributed to the small study population as well as the overlapping ranges for Tanner I and II levels of these hormones (4-A: Tanner I—8-50 ng/dl, Tanner II—31-65 ng/dl; DHEAS: Tanner I—13-83 µg/dl, Tanner II—42-109 µg/dl; levels were measured by Esoterix, Inc.).
In addition, our observation of lower SHBG levels in the PA group is consistent with previous findings reported in girls with PA (4). Dyslipidemia has been demonstrated in girls with PA. Specifically, Ibanez et al. found that prepubertal girls with PA exhibit hypertriglyceridemia, but pubertal girls with a history of PA have higher very low-density lipoprotein cholesterol and triglycerides throughout puberty, higher LDL (Tanner breast stage 5) and total cholesterol (Tanner breast stages 3 and 5), and lower HDL cholesterol (Tanner breast stage 2) than controls (4). Similarly, we found a trend (P < 0.08, BMI-Z adjusted) toward higher triglycerides in our prepubertal boys with PA. Further studies are needed to determine whether dyslipidemia is a feature of boys with PA and those with a history of PA.
Although all of the subjects who underwent glucose tolerance testing had normal glucose tolerance, the boys with PA, similar to PA girls (3, 4), demonstrated comparative hyperinsulinemia. The boys with PA had a greater insulin response to glucose challenge as reflected by the insulin area under the curve data. The fasting proinsulin and P0/I0 ratio were elevated in the boys with PA, compared with controls, both of which have been associated with type 2 DM and impaired glucose tolerance in adults. Elevated P0 has also been shown to predict the development of type 2 DM (43, 44). These differences were independent of obesity. Decreased insulin sensitivity was suggested by decreased ISI(composite) both before and after BMI-Z adjustment. The differences in fasting insulin, FGIR, and QUICKI were statistically significant before, but not after, adjustment for BMI-Z score; this may be largely attributable to body habitus or related to the small sample size. The differences in insulin sensitivity in our population may be more evident using the ISI(composite), based on the response to glucose challenge, rather than the FGIR and QUICKI, which are calculated from the fasting insulin and glucose data. Abnormalities of stimulated hyperinsulinemia have been postulated to develop earlier than simple elevations of fasting insulin in children (45). Therefore, our findings in boys with PA are consistent with the proposed sequential development of insulin resistance.
The earlier study by Potau et al. (26), which found no difference in IGF-I levels or OGTT-derived parameters between boys with PA and controls, included 20 prepubertal subjects of ethnicity different from our subjects. Also in contrast to our study population, their subjects, both PA and control, represented a relatively lean cohort, and none had acanthosis nigricans or a family history of DM. Furthermore, a different measure of insulin sensitivity was used. Arslanian et al. (46) reported higher fasting insulin and IGF-I levels in black, compared with white, prepubertal children matched for age and BMI. Thus, although our groups were not matched for ethnicity, it is possible that the higher proportion of white subjects in the PA group would tend to minimize the observed group differences in insulin and IGF-I levels.
In a recent study of normal prepubertal and pubertal boys, Guercio et al. (47) concluded that the GH/IGF-I axis and insulin sensitivity are not involved in the mechanism of adrenarche because no correlation was found between DHEAS and FGIR or between DHEAS and IGF-I in their prepubertal subjects. We detected statistically significant correlations between IGF-I and androgen levels, including DHEAS and 4-A, and similar relationships between IGFBP-3 and these androgens in our prepubertal control subjects but found no association in the boys with PA. However, the correlations between 4-A and both IGF-I and IGFBP-3 in the control group may have been driven by a single subject. In a recent study of prepubertal girls with PA, we found significant positive correlations of total and free IGF-I with 4-A but not DHEAS (25). Given the limitations inherent to correlational analyses, particularly using small sample sizes, we could not conclude either from our results or those of Guercio et al. (47) that IGF-I does not contribute to adrenal androgen production in PA. Vuguin et al. (20) demonstrated a significant correlation of total IGF-I and a negative correlation of IGFBP-1 with ACTH-stimulated androgens in prepubertal girls with PA. Therefore, as has been previously suggested, ACTH-stimulated adrenal androgens, rather than basal levels, may be required to reveal a relationship between the IGF system and hyperandrogenism of PA.
Similar to previous findings in other populations (48), our results suggest that IGFBP-1 may serve as a marker of insulin sensitivity. In our study, IGFBP-1 correlated with two of three measures of insulin sensitivity [FGIR, QUICKI, or ISI(composite)] in both PA and control groups and tended to correlate with the remaining measure (P < 0.08). Furthermore, consistent with other studies showing suppression of IGFBP-1 in association with increased insulin levels (3, 20, 21, 22, 23, 24), IGFBP-1 was inversely correlated with fasting insulin in the subjects with PA, and a similar trend was observed in the controls.
Our results also corroborate prior evidence that SHBG may be a marker for hyperinsulinemia and/or insulin resistance (49, 50, 51). An inverse correlation of SHBG with fasting insulin was seen in the boys with PA, and SHBG was also negatively correlated with I0 in the controls. SHBG was inversely correlated with log IAUC120 in the boys with PA, with a comparable trend in the control group. Statistically significant correlations of SHBG with all measures of insulin sensitivity were noted in the boys with PA and controls, and we found significant correlations of SHBG with FGIR and ISI(composite) as well as a trend in its association with QUICKI. Of note is that the free IGF-I correlated positively with basal insulin and inversely with measures of insulin sensitivity in the controls but not in the subjects with PA. Further studies in other populations are needed to determine whether free IGF-I is also a marker of insulin sensitivity.
In conclusion, similar to girls with PA, prepubertal boys with PA show differences in the IGF system and decreased insulin sensitivity, independent of obesity. Expansion of this preliminary report is necessary to elucidate the role of IGF-I in PA and whether elevated levels of this growth factor are involved in its pathogenesis. Longitudinal follow-up of boys with PA is lacking, but these findings suggest that further studies should be undertaken to monitor boys as well as girls with PA long term for the development of insulin resistance and associated complications, including DM and cardiovascular disease.
Acknowledgments
Footnotes
This work was supported by NIH Grant RR-00645; and grants from Eli Lilly & Co.; Pharmacia & Upjohn, Inc.; and Genentech, Inc. These data were presented in part at the Annual Meeting of the Pediatric Academic Societies, May 2002, Baltimore, Maryland.
M.R.D. is a recipient of a Doris Duke Clinical Research Fellowship 2001–2002.
Present address for M.E.S.: Jacobi Medical Center and Albert Einstein College of Medicine, Bronx, New York 10461.
Abbreviations: BMI, Body mass index; 4-A, 4-androstenedione; DHEAS, dehydroepiandrosterone sulfate; DM, type 2 diabetes mellitus; FGIR, fasting glucose/insulin ratio; G0, basal level of glucose; HDL, high-density lipoprotein; HgA1c, hemoglobin A1c; IAUC120, insulin area under the curve in response to glucose challenge; IGFBP-1, IGF-binding protein-1; I0, basal level of insulin; ISI(composite), composite whole-body insulin sensitivity index; LDL, low-density lipoprotein; OGTT, oral glucose tolerance test; PA, premature adrenarche; PCOS, polycystic ovarian syndrome; P0, basal level of proinsulin; QUICKI, quantitative insulin sensitivity check index.
Received June 10, 2002.
Accepted September 2, 2002.
References
This article has been cited by other articles:
 |
|
 |
|
  P. Utriainen, R. Voutilainen, and J. Jaaskelainen Continuum of phenotypes and sympathoadrenal function in premature adrenarche Eur. J. Endocrinol., April 1, 2009; 160(4): 657 - 665. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. I. Hernandez, A. Martinez, T. Capurro, V. Pena, L. Trejo, A. Avila, T. Salazar, S. Asenjo, G. Iniguez, and V. Mericq Comparison of Clinical, Ultrasonographic, and Biochemical Differences at the Beginning of Puberty in Healthy Girls Born Either Small for Gestational Age or Appropriate for Gestational Age: Preliminary Results J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3377 - 3381. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Ong, N. Potau, C. J. Petry, R. Jones, A. R. Ness, J. W. Honour, F. de Zegher, L. Ibanez, and D. B. Dunger Opposing Influences of Prenatal and Postnatal Weight Gain on Adrenarche in Normal Boys and Girls J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2647 - 2651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P Korhonen, E Hyodynmaa, H-L Lenko, and O Tammela Growth and adrenal androgen status at 7 years in very low birth weight survivors with and without bronchopulmonary dysplasia Arch. Dis. Child., April 1, 2004; 89(4): 320 - 324. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
