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Original Studies |
Department of Pediatrics, Division of Pediatric Endocrinology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York 10467; and the Department of Pediatrics, Oregon Health Sciences University (R.G.R.), Portland, Oregon 97201-3042
Address all correspondence and requests for reprints to: Joan DiMartino-Nardi, M.D., Division of Pediatric Endocrinology, Albert Einstein College of Medicine Montefiore Medical Center, 111 East 210th Street, Bronx, New York 10467. E-mail: jdpedendo{at}aol.com
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Abstract |
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The mean age of the patients was 6.8 yr, and bone age was 8.0 yr. Twenty-five patients had a family history of noninsulin-dependent diabetes mellitus and 19 patients had acanthosis nigricans. The mean SI for the entire group was 6.78 ± 5.21 x 10-4 min/µU·mL (normal prepubertal SI, 6.5 ± 0.54 x 10-4 min-1·µU-1·mL-1). However, 15 of the 35 girls had an SI that was more than 2 SD below the mean reported for normal prepubertal children. Of these 15 patients, 13 were obese, and 14 had acanthosis nigricans. For the entire group of girls, the mean ACTH-stimulated levels of 17-hydroxypregnenolone (17OHPreg), dehydroepiandrosterone (DHEA), androstenedione (AS), 17-hydroxyprogesterone (17OHP), and T and the ACTH-stimulated ratios of 17OHPreg/17OHP, 17OHPreg/DHEA, 17OHP/AS, and DHEA/AS did not differ from the levels reported for Tanner stage II–III pubertal girls.
The girls were divided into two groups based on their SI (group I, SI >2 SD below the mean for age; group II, normal SI). The group I girls with a reduced SI had significantly higher ACTH-stimulated levels of 17OHPreg (group I, 760 ± 87.84 ng/dL; group II, 428.9 ± 46.28 ng/dL; P = 0.002), 17OHPreg/17OHP ratio (group I, 3.95 ± 0.36; group II, 2.96 ± 0.35; P = 0.05), 17OHPreg/DHEA (group I, 2.06 ± 0.21; group II, 1.4 ± 0.13; P = 0.01), and free T (group I, 1 ± 0.23 ng/dL; group II, 0.49 ± 0.19 ng/dL; P = 0.014). Levels of sex hormone-binding globulin were lower in the group I girls. Furthermore, for the entire group of girls, the SI correlated inversely with ACTH-stimulated levels of 17OHPreg, DHEA, and AS and the ACTH-stimulated ratio of 17OHPreg/17OHP. IGF-I correlated inversely with SI (r = -0.94; P < 0.001) and correlated directly with the ACTH-stimulated levels of 17OHPreg (r = 0.8; P < 0.001) and AS (r = 0.63; P < 0.05). IGF-I also correlated with the ACTH-stimulated ratios of 17OHPreg/17OHP (r = 0.61; P < 0.05), 17OHPreg/DHEA (r = 0.9; P < 0.001), 17OHP/AS (r = 0.79; P < 0.001), and DHEA/AS (r = 0.96; P < 0.001). IGFBP-1 correlated inversely with the ACTH-stimulated levels of 17OHPreg (r = -0.38; P < 0.05) and DHEA (r = -0.36; P < 0.05).
To summarize, the ACTH-stimulated 
5-steroid levels were
higher in prepubertal girls with premature adrenarche and reduced
SI. There was a significant inverse correlation among
ACTH-stimulated hormone levels, SI, and IGFBP-1, whereas
IGF-I correlated directly with ACTH-stimulated androgens. These
findings support the hypothesis that insulin and IGFs may have a role
in the hyperandrogenism of premature adrenarche just as they do in
PCOS. Hence, in certain girls with premature adrenarche,
hyperandrogenism may be the first presentation of PCOS and/or insulin
resistance.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The specific etiology of the ovarian and adrenal hyperandrogenism in adolescent and adult woman with polycystic ovarian syndrome (PCOS) remains elusive. Several factors have been implicated, including hyperinsulinism, alterations of growth factors [insulin-like growth factor I (IGF-I) and IGF-binding proteins (IGFBPs)], dysregulation of the hypothalamic/pituitary/ovarian axis, and enzymatic defects of steroidogenesis (8, 9, 10, 11, 12, 13). We previously reported that 7 of 12 Black African-American and Hispanic girls with premature adrenarche had acanthosis nigricans and hyperinsulinism stemming from reduced insulin sensitivity, as do many women with PCOS (14). Furthermore, our group recently reported that many girls with premature adrenarche can have marked hyperandrogenism (15). As insulin and altered levels of growth factors have been implicated in the severe hyperandrogenism of PCOS, the purpose of this study was to determine whether insulin, IGF-I, IGFBP-1, and IGFBP-3 have a role in hyperandrogenism in prepubertal Black African-American and Caribbean Hispanic girls with premature adrenarche as well.
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Subjects and Methods |
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Thirty-five prepubertal girls (23 Caribbean Hispanics and 12 Black African-American) between 4–9 yr of age with premature adrenarche were recruited from the pediatric endocrine clinics at Montefiore Medical Center and Bronx Municipal Hospital Center. All studies were approved by the institutional review board of the Montefiore Medical Center, and written informed consent was obtained from one legal guardian of each patient before the study.
The criteria for entry included the appearance of Tanner stage II–III pubic hair in prepubertal girls before the age of 8 yr. Excluded were girls with breast development, malignancy, or an enzymatic defect of adrenal steroidogenesis (16). Twelve patients had been studied previously (14).
Bone age was assessed using the method of Greulich and Pyle (17). Body mass index (BMI) was calculated in all subjects using the formula: weight (kilograms)/height (meters)2 (18).
Twenty-five children had at least one first or second degree relative with Non Insulin Dependent Diabetes Mellitus. Ethnicity was determined by self reporting. Caribbean Hispanic girls had both parents from either Puerto Rico or the Dominican Republic, and Black African-American girls had both parents of non-Caribbean, non-Latin American descent.
Study protocol
All children underwent a standard ACTH stimulation test with the following steroids measured before and 60 min after an iv bolus of Cortrosyn (0.25 mg) (Organon Inc., East Orange, NJ): cortisol, 17-hydroxypregnenolone (17OHPreg), 17-hydroxyprogesterone (17OHP), 11-deoxycortisol, 11-deoxycorticosterone, dehydroepiandrosterone (DHEA), androstenedione (AS), and testosterone (T). All children underwent a LH-releasing hormone test to confirm their prepubertal status, with LH and FSH measured before and 20, 40, 60 min after an iv injection of Factrel (100 µg; gonadorelin hydrochloride, 100 µg) (Ayerst Laboratories, Inc., Philadelphia, PA). All children had a peak LH response of less than 5 mIU/mL.
The frequently sampled iv glucose tolerance test (FSIVGTT) was performed with tolbutamide on the morning after an overnight fast. A 21-gauge needle was placed into each arm, and the children were allowed to rest for 30 min. Baseline samples were drawn at -30, -15, and 0 min. At zero time 0.3 g/kg 25% dextrose was injected over 1 min. Samples were drawn from the contralateral arm at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 19, 22, 23, 24, 25, 27, 30, 35, 45, 50, 60, 70, 80, and 90 min. A tolbutamide bolus (5 mg/kg) diluted in 20 cc sterile water was infused at 20 min over a period of 30 s. Insulin and glucose levels were measured in samples mentioned above. In addition, blood sugar levels were checked with a bedside blood sugar-measuring device to monitor hypoglycemia, and a physician was present throughout each study to evaluate signs and symptoms of hypoglycemia. Subjects were supine throughout the study. No patient suffered any ill effects during the procedure.
The insulin sensitivity index (SI) was calculated using the MINIMOD computer program version NUDEMMI as reported by Bergman (19).
The girls were divided into two groups based on their SI: group I, reduced SI more than 2 SD below the mean for normal prepubertal girls; and group II, normal SI within 2 SD for normal prepubertal girls.
Baseline fasting serum samples were obtained for IGF-I, IGFBP-1, and IGFBP-3. Sex hormone-binding globulin (SHBG) and free T were also determined.
Laboratory findings
17OHPreg, 17OHP, AS, cortisol, T, DHEA, deoxycorticosterone, and insulin assays were performed by RIA (Endocrine Sciences, Inc., Calabasas, CA).
Serum concentrations of FSH and LH were measured by double antibody RIA, using reagents from Diagnostic Products (Los Angeles, CA) and Clinetics Corp. (Tustin, CA), respectively. The FSH assay is standardized against WHO International Reference Preparation 78/549, and the LH assay is calibrated against WHO First International Reference Preparation 68/40. In these procedures, the interassay coefficients of variations for FSH and LH were 3.6% at 15 IU/mL and 5.3% at 17 IU/mL, respectively. Glucose levels were measured using the glucose oxidase method (Hitachi Scientific Instruments, Tokyo, Japan).
IGF-I, IGFBP-1, and IGFBP-3 were measured using an active immunoradiometric assay (Diagnostic Systems Laboratories, Inc., Webster, TX). In these procedures, the intraassay coefficient of variation was 1.5% for IGF-I at 264 ng/mL, 4.6% for IGFBP-1 at 50 ng/mL, and 3.2% for IGFBP-3 at 28 ng/mL. The interassay coefficient of variation was 3.7% for IGF-I at 256 ng/mL, 6% for IGFBP-1 at 47 ng/mL, and 1.9% for IGFBP-3 at 22 ng/mL.
Statistics
Results were expressed as the mean ± SD or the
mean ± SE. Correlations between variables were
analyzed using the Spearman correlation coefficient (correlation of
ranks). The data were also fitted to the following nonlinear model (
= ß0 + ß1/x). A coefficient of determination,
r2, and the corresponding r were calculated for this model
along with the appropriate P value.
The hormonal data of the girls with reduced SI (group I) were compared to those of girls with normal SI (group II) using Student’s t test. P < 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The clinical characteristics of the study patients are summarized
in Table 1
. For the entire group, the
mean chronological age and bone age were 6.8 ± 1.06 and 8 ±
1.3 yr, respectively. All bone ages were within 2.5 SD of
the mean chronological age. Fifteen of the 35 girls (43%) had reduced
SI (group I). The group I subjects were heavier than those
in group II, although 2 girls with reduced SI had a normal
BMI. Fourteen of the 15 girls with reduced SI had
acanthosis nigricans. Subtle acanthosis nigricans was also detected in
5 of the 20 girls with normal SI. Acanthosis nigricans
occurred in both obese and lean patients. Twenty-five girls with
premature adrenarche had at least 1 family member with
noninsulin-dependent diabetes mellitus.
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All patients had a normal fasting blood sugar (<110 mg/dL) and a
mean fasting insulin level of 14.5 ± 11.5 µIU/mL (5–30
µIU/mL). The group I girls had fasting insulin levels significantly
higher than those in the group II girls. The hormonal profile of these
prepubertal girls with reduced SI is compared with that of
the girls with normal SI in Table 2. Fasting insulin levels correlated
inversely with SI (r = -0.77; P =
0.0001) and IGFBP-1 (r = -0.42; P < 0.05).
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The 60-min ACTH-stimulated hormonal profile of the prepubertal patients
with premature adrenarche was compared to the normative data for
healthy Tanner stage II–III pubertal children from Santo Domingo
previously reported by our group (Fig. 1)
(21). For the girls with premature adrenarche, the mean ACTH-stimulated
levels of 17OHPreg, DHEA, 17OHP, AS, and T, and the ratios
of 17OHPreg/17OHP, 17OHPreg/DHEA, 17OHP/AS, and
DHEA/AS were similar to the mean levels reported for
normal girls in early puberty.
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. Group I girls with reduced SI
had significantly higher ACTH-stimulated levels of 17OHPreg and
17OHPreg/17OHP and 17OHPreg/DHEA ratios. DHEA
levels were also higher in group I girls vs. group II girls,
but the mean levels were not statistically different. SHBG levels in
group I girls were significantly lower than those in group II girls,
and free T levels were significantly higher in group I girls.
For the entire group, SI correlated with the
ACTH-stimulated levels of 17OHPreg (r2 = 0.79;
P < 0.001), DHEA(r2 =
0.83; P < 0.001), AS (r2 = 0.87;
P < 0.001), and the ratio of 17OHPreg/17OHP
(r2 = 0.86; P = <0.001; Fig. 2).
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Fasting levels of insulin, IGF-I, IGFBP-1, and IGFBP-3 are also
listed in Table 2. In group I girls, IGFBP-1 levels were significantly
lower than those in group II (28 ± 5 vs. 79 ±
11.7 ng/mL; P = 0.001). Although IGF-I and IGFBP-3
levels were slightly higher in group I girls, there were no
significant differences in IGF-I and IGFBP-3 levels between the
two groups.
The correlations between IGF-I and IGFBP-1 with BMI, basal
insulin, and the ACTH-stimulated hormonal data are listed in Table 3. IGF-I correlated inversely with
SI (r = -0.94; P < 0.001) and
directly with the ACTH-stimulated levels of 17OHPreg and AS and the
ratios of 17OHPreg/DHEA, DHEA/AS, and
17OHP/AS. IGFBP-1 correlated with BMI, basal insulin, and the
ACTH-stimulated level of 17OHPreg and DHEA. IGFBP-3 did
not correlate with any of the above parameters.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Insulin and IGFs have a role in normal ovarian function and steroidogenesis. Derangements in the physiology of insulin and IGFs have been implicated in the pathogenesis of PCOS in adolescent and adult women. Insulin has been shown to directly and indirectly stimulate ovarian and adrenal steroidogenesis (22, 23, 24, 25). IGF-I has also been shown to stimulate adrenal steroidogenesis in vitro (26). IGF-I circulates bound to several proteins, and reduction of these (e.g. IGFBP-1 and IGFBP-3) increases the bioavailability of IGF-I. Hyperinsulinism further enhances IGF-I-induced steroidogenesis by increasing IGF-I production by the liver. Also, by reducing levels of IGFBP-1, insulin potentially increases the bioavailability of IGF-I (27, 28).
Our group reported that more than half of 12 prepubertal African-American and Hispanic girls with premature adrenarche had acanthosis nigricans and hyperinsulinism stemming from reduced insulin sensitivity, as do many adolescent and adult women with hyperandrogenism and PCOS. Our previous findings suggest that insulin may have a role in the hyperandrogenism of premature adrenarche (14). The purpose of this study was to investigate the roles of insulin and IGFs in the hyperandrogenism of Black African-American and Hispanic girls with premature adrenarche.
In this study, we report that the mean ACTH-stimulated androgen levels of girls with premature adrenarche were within 2 SD of those levels reported in normal Hispanic girls in early puberty (Tanner stages II–III). However, the patients with the lower insulin sensitivity and IGFBP-1 levels and the higher levels of IGF-I had significantly higher ACTH-stimulated levels of 17OHPreg and ratios of 17OHPreg/17OHP and 17 OHPreg/DHEA. The girls with reduced insulin sensitivity had higher basal free T and lower SHBG. This supports the hypothesis that insulin and IGFs may have a role in the modest hyperandrogenism of premature adrenarche, just as they do in the more severe hyperandrogenism of PCO. This is also consistent with in vitro findings that both insulin and IGF-I augment ACTH-dependent adrenal steroidogenesis in human adrenal cell culture (22). The concentrations of IGF-I, IGFBP-1, and IGFBP-3 reflect serum, not peripheral, tissue levels.
A recent report by Ibanez and colleagues supports the hypothesis that hyperinsulinism and alterations of growth factors may have a role in the hyperandrogenism of premature adrenarche. In that study, elevated mean serum insulin levels in response to an oral glucose tolerance test (OGTT) and reduced levels of fasting IGFBP-1 were found in a cohort of prepubertal and pubertal girls with a history of premature adrenarche (29). However, reduced insulin sensitivity using the OGTT was not detected. Ibanez et al. attributed their findings of normal SI (calculated from the OGTT) to the fact that the patients studied were young and might not yet have developed derangements in insulin sensitivity. In contrast, we noted that nearly 50% of the 35 prepubertal Black African-American and Caribbean Hispanic girls with premature adrenarche studied as young as 5 yr of age had a significant decrease in SI derived from the FSIVGTT. The FSIVGTT is a well validated method that reflects the effect of the endogenous secreted insulin on glucose levels. The SI using the FSIVGTT has been shown to correlate very closely with the SI determined by the more traditional insulin clamps studies (r = 0.84) (30, 31). We chose the FSIVGTT rather than the OGTT because it avoids the uncertainty of predicting the rate of absorption of glucose from the gastrointestinal tract, a rate that may be highly variable among individuals and between repeated procedures in single subjects (19, 20, 30).
Ethnic differences have been described in the pattern of insulin release and clearance. We chose to study Caribbean Hispanic and Black African-American girls, as Caribbean Hispanic women, in general, are at greater risk of developing PCOS, and Black African-American women are at increased risk of developing the complications of hyperinsulinism (hypertension, cardiovascular disease, and diabetes) (32, 33, 34). In a recent report, basal and first phase insulin levels obtained during a hyperglycemic clamp were higher in healthy Black African-American prepubertal children than in Caucasian American children (35). Similar findings of hyperinsulinemia and decreased insulin sensitivity have been described in African-American adolescents, and Caribbean-Hispanic women (32, 36, 37). We did not detect a difference in the insulin sensitivity between the African-American and Caribbean Hispanic patients, and we noted both normal and low SI in both groups of patients studied.
Insulin is a major regulator of SHBG and IGFBP-1 production by the liver (38, 39, 40). We noted our hyperinsulinemic patients to have lower levels of SHBG and IGFBP-1. Similar observations have been reported in women with PCOS (41).
Barnes et al. have hypothesized that there is an increase in
the activity of the ovarian cytochrome P450C17 enzyme in women with
PCOS, resulting in an exaggerated 17OHP response to a bolus dose of
LH-releasing hormone analog (42). Although the precise etiology of the
increased activity of this enzyme is not clear, increased cytochrome
P450 C17 activity is facilitated by insulin (43). Also, Miller and
colleagues reported that the serine phosphorylation of the adrenal
enzyme cytochrome P450C17 is required for the increased 17-hydroxylase
and 17–20-lyase activity of this enzyme in vitro (44). In
women with PCOS, Dunaif reported that their insulin resistance is
secondary to a defect in insulin signaling resulting from excessive
serine phosphorylation of the insulin receptor (44, 45). Hence, as the
process of serine phosphorylation causes both insulin resistance and
increased activity of a key enzyme in androgen biosynthesis, Miller has
hypothesized that this process may provide a common mechanism for the
etiology of the hyperandrogenism and the hyperinsulinism found in
premature adrenarche and PCOS (44). In our patients, the increased
17OHPreg is consistent with a relative increase in the 17 hydroxylase
activity of this enzyme in the 5-steroid pathway.
A recent article suggested that young girls of African-American origin develop pubertal changes at an earlier age than their Caucasian counterparts (46). Although this article implies that early sexual development in premature adrenarche is common and, hence, probably normal, our findings indicate that certain girls with premature adrenarche can have hyperinsulinism stemming from reduced insulin sensitivity and hyperandrogenism. Our findings suggest that careful follow-up of Black African-American and Caribbean Hispanic girls with premature adrenarche is indicated, as in some of these patients, the early hyperandrogenism may be the first presentation of PCOS and/or insulin resistance.
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Acknowledgments |
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Footnotes |
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Received February 5, 1998.
Revised December 22, 1998.
Accepted February 22, 1999.
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References |
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activity and serum free testosterone
after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med. 335:617–623.This article has been cited by other articles:
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