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Original Article |
-Reductase and 11ß-Hydroxysteroid Dehydrogenase Activity in Prepubertal Hispanic Girls with Premature Adrenarche
Division of Pediatric Endocrinology (M.E.S., A.M.M., L.S.L., D.S., S.E.O), Columbia University, New York, New York 10032; Children’s Hospital (C.H.L.S.), Oakland Research Institute, Oakland, California 94609; and Information Sciences Division, Nathan Kline Institute for Psychiatric Research (D.J.M.), Orangeburg, New York 10962
Address all correspondence and requests for reprints to: Sharon E. Oberfield, M.D., 630 West 168th Street, PH-5E-522, New York, New York 10032. E-mail: seo8{at}columbia.edu.
Abstract
Girls with idiopathic premature adrenarche, characterized by the early appearance of pubic hair and adrenal hyperandrogenism, may be at an increased risk for polycystic ovarian syndrome and its associated complications. Alterations of peripheral metabolism of adrenal steroids, specifically increased 5
-reductase and 11ß-hydroxysteroid dehydrogenase activities, have been documented in patients with polycystic ovarian syndrome and proposed as an underlying mechanism for the adrenal hyperandrogenism in this syndrome. We sought to investigate whether alterations in 5-reductase and 11ß-hydroxysteroid dehydrogenase activities are present in girls with premature adrenarche, suggesting a possible role in the pathogenesis of the hyperandrogenism of this condition. We studied C19 and C21 urinary steroid metabolites, 5/5ß and 11 oxo/11 hydroxy metabolite pairs as well as the ratios of the total 5/total 5ß and total 11 oxo/total 11 hydroxy metabolites in 24-h urine samples from 17 prepubertal Hispanic girls with premature adrenarche and seven controls. We found no differences in the 5-reductase or 11ß-hydroxysteroid dehydrogenase activities in the prepubertal girls with premature adrenarche, compared with the controls. When age and body mass index Z-score were controlled for in the statistical analysis, the results did not change. Total cortisol metabolites were not different in the girls with premature adrenarche, compared with the controls. In conclusion, we did not demonstrate a difference in the peripheral steroid metabolism, specifically 5-reductase and 11ß-hydroxysteroid dehydrogenase activities, in prepubertal Hispanic girls with premature adrenarche, compared with controls. Therefore, in this group of young girls, alterations in 5-reductase or 11ß-hydroxysteroid dehydrogenase activities do not appear to contribute to their early pubic hair development.
IDIOPATHIC PREMATURE ADRENARCHE (PA) in girls is characterized by the onset of pubic hair before 8 yr of age and elevated levels of adrenal androgens without evidence of true puberty or adrenal disorders. Recent observations have suggested that PA may be pathological and may predispose some of these girls to the development of polycystic ovarian syndrome (PCOS) and its complications (1, 2, 3, 4). PCOS is characterized by elevated adrenal and/or ovarian androgen levels and anovulation and is associated with complications including insulin resistance, early age of onset of glucose intolerance and type 2 diabetes mellitus, unfavorable lipid profiles, cardiovascular disease, and infertility (5, 6). Similarly, girls with PA have been shown to have insulin resistance and unfavorable lipid profiles (elevated total cholesterol, low-density lipoprotein, and triglyceride levels; decreased high-density lipoprotein levels; and an increased low-density lipoprotein/high-density lipoprotein ratio) (2, 3, 7, 8). Furthermore, there is a much higher prevalence of type 2 diabetes mellitus and impaired glucose tolerance in first-degree relatives of girls with PA (4).
Dysregulation of the insulin/IGF system has been suggested in the pathogenesis of PCOS and PA (9, 10, 11). Both in vivo and in vitro studies support a role for the insulin/IGF system in the pathophysiology of PA and PCOS. Clinical studies have demonstrated hyperinsulinemia and decreased levels of IGF-binding protein-1 in girls with PA and women with PCOS (9, 10, 11, 12, 13). In girls with PA, a relationship between androstenedione and free IGF-I levels and an inverse relationship between IGF-binding protein-1 and ACTH-stimulated adrenal hormone levels has been reported by us and others (14, 15). In vitro studies have shown that insulin and IGF-I stimulate ovarian and adrenal steroidogenesis (16, 17, 18, 19, 20, 21).
Although idiopathic PA is the most common cause of the premature development of sexual hair in girls, the pathogenesis of the hyperandrogenism seen in PA has not yet been clearly defined. In 1990 Stewart et al. (22) first proposed elevated 5-reductase (5R) activity as the underlying cause of PCOS, whereby increased cortisol metabolism resulted in increased ACTH levels in an effort to normalize the serum cortisol levels and in a secondary increase in adrenal androgen levels. Furthermore, Horton et al. (23) have shown that 5R activity may be mediated by IGF-I; free IGF-I has been shown to be elevated in women with PCOS (10), and, as we have recently demonstrated (15), in prepubertal girls with PA. Alterations of peripheral metabolism of adrenal steroids, specifically increased 5R and 11ß-hydroxysteroid dehydrogenase (11ßHSD) activities, have been identified in women with PCOS (22, 24). Furthermore, increased 5R activity recently has been demonstrated in a young population of women with PCOS (25).
There are many data relating abnormalities of cortisol metabolism, particularly 11ßHSD activity to obesity (26). However, several clinical studies of PCOS suggest that obesity may not fully account for abnormalities of 11ßHSD and 5R activities in PCOS. Stewart et al. (22) found increased 5R activity in PCOS subjects, compared with controls of similar weights; the average PCOS subject weighed 64.5 kg and the heaviest weighed 73 kg. Similarly, the enhanced 11ßHSD activity in PCOS reported by Rodin et al. (24) could not be solely explained by obesity and was seen in lean women with PCOS as well.
In the present study, we sought to determine whether 5R and/or 11ßHSD activities are also increased in prepubertal girls with PA and, therefore, possibly play a role in the pathogenesis of the characteristic hyperandrogenism and subsequent development of PCOS.
Subjects and Methods
Subjects
Twenty-four Hispanic prepubertal girls were enrolled in the study: 17 with PA and 7 controls. These represent Hispanic prepubertal PA and control girls recruited consecutively for a larger study of PA. Informed consent from a legal guardian of each subject and assent from subjects over the age of 7 yr were obtained before participation in the study. The study was approved by the Institutional Review Board of Columbia-Presbyterian Medical Center.
The criteria for entry into the study in the PA group included the appearance of pubic hair before 8 yr of age, adrenal androgens in the Tanner stage II range, no breast development on physical examination, and no evidence of an adrenal enzyme defect or other endocrine disorder (27). The criteria for entry in the control group included the absence of breast development and pubic hair on physical examination and were otherwise the same as for the PA group. Body mass index (BMI) and BMI Z-scores, based on 1 SD reference data developed from National Health and Nutrition Examination Survey I, were calculated for all subjects (28). All subjects had basal morning levels of the adrenal androgens dehydroepiandrosterone sulfate and 
4-androstenedione measured. Clinical characteristics of the subjects are presented in Table 1
.
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Twenty-four-hour urine collections were stored at -20 C until analysis by gas chromatography and mass spectrometry was performed, according to published methods (29, 30). Twenty-four-hour total urinary cortisol excretion was measured. The sum of the concentrations of the principal cortisol metabolites [tetrahydrocortisone (THE), tetrahydrocortisol (THF), 5-THF, cortolones, and cortols] was used as an assessment of the total daily cortisol production. Analysis of 5R activity was performed by comparing the ratio of each 5/5ß product (i.e. androsterone/etiocholanolone, 11ß-hydroxy androsterone/11ß-hydroxy etiocholanolone, 5-tetrahydrocorticosterone (THB)/THB, and 5-THF/THF) as well as the ratio of total 5/total 5ß metabolites. Analysis of 11ßHSD activity was performed by comparing the ratio of each 11-oxo/11ß-hydroxy product [i.e. 11-oxo/11ß-hydroxy (etiocholanolone + androsterone), cortisone/cortisol, THE/(THF + 5-THF), cortolones/cortols, and tetrahydro-11-dehydrocorticosterone/(THB + 5-THB)] as well as the ratio of total 11-oxo/total 11ß-hydroxy metabolites.
Data analysis
Comparison between groups on continuous measures was made using independent t tests with Saitherwaite correction in the event of statistically unequal variances. Analysis of covariance with age and BMI Z-score entered as continuous covariates was used to adjust for age and adiposity. Estimation of the direction and strength of the relationships between variables was made with simple Pearson correlations. All data are reported as means ± SD.
Results (Tables 1
and 2)
The PA group was somewhat younger than the control group (Table 1). We believe the age difference, however, was not of biological significance. As expected, dehydroepiandrosterone sulfate levels were higher in PA girls than in controls. No difference in 24-h total urinary excretion of cortisol was observed between the PA girls and controls. There was also no significant difference between the groups in daily cortisol production as measured by total measured cortisol metabolites (THE, THF, 5-THF, cortolones, and cortols). We did not detect any differences between the groups in 5R activity as measured by ratios of 5/5ß metabolite pairs or the ratio of total 5/total 5ß metabolites. Similarly, we did not see a difference in 11ßHSD activity as measured by either ratios of 11-oxo/11ß-hydroxy product pairs or the ratio of the total 11-oxo/total 11ß-hydroxy metabolites. There were still no differences after analysis of covariance was used to adjust for age, BMI Z-score, or both. No significant correlations were noted in the PA group between any measure of 5R or 11ßHSD activity and age or BMI Z-score.
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Idiopathic PA is the most common cause of premature development of sexual hair in girls and may be a risk factor for the subsequent development of PCOS and its many complications; the pathogenesis of the hyperandrogenism in PA has not yet been clearly defined. To identify possible causes of the hyperandrogenism, we studied 24-h urinary excretion of adrenal steroid hormone metabolites.
Stewart et al. (22) first proposed that increased 5R activity in PCOS caused increased cortisol metabolism, leading to increased ACTH secretion to normalize serum cortisol levels, and resulted in elevated adrenal androgens. Figure 1 is a schematic representation of the hypothesis relating alterations in 5R and/or 11ß-HSD activity to the adrenal hyperandrogenism of PA. Evidence of increased 5R activity in PCOS, seen as well in a young PCOS population, has been reported (22, 25). We were particularly interested in examining whether 5R activity was increased in girls with premature adrenarche because Horton et al. (23) have shown that 5R activity may be mediated by IGF-I, and we (15) recently reported increased levels of free IGF-I in prepubertal girls with premature adrenarche. In the current study, however, we did not detect a difference in 5R activity between Hispanic prepubertal girls with premature adrenarche and controls. On the basis of our results, it is doubtful that the relationship between the insulin/IGF-I system and the hyperandrogenism of PA is dependent on 5R activity. Therefore, on the basis of this study, we were unable to demonstrate that alterations in 5R activity are involved in the pathogenesis of PA.
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) (24). Altered 11ß-HSD activity was demonstrated by Rodin et al. (24) by studying their 24-h urinary steroid metabolites of a large group of women with PCOS. We sought to determine whether altered 11ß-HSD regulation was also present in a group of young girls with premature adrenarche. We were unable to identify any such alterations in 11ß-HSD activity and, therefore, doubt its involvement in the etiology of the hyperandrogenism of PA. However, it is still possible that the slightly higher BMI values in the control group, although not statistically significant, may have masked differences between the groups, despite our attempt to statistically adjust for this factor.
Negative findings with such a small sample size and wide variability of values for many of the metabolite pair ratios raise the issue of low statistical power and the risk of falsely accepting the null hypothesis of no difference between groups. To determine the boundaries of the true group differences, a post hoc analysis was conducted and shows the 95% confidence interval of the difference between the PA and control girls’ total 5/total 5ß ratio to be ± 0.55 U and the 95% confidence interval for the difference between the PA and control girls’ total 11-oxo/total 11-OH ratio to be ± 0.53 U. These differences remain sufficiently small that we believe it is unlikely that a larger sample size would evidence a clinically meaningful difference between these two groups.
In summary, the pathological basis for PA remains unclear. Although many girls with PA subsequently develop a clinical picture consistent with PCOS, and increased 5R and 11ß-HSD activities has been documented in women with PCOS, in this small group of young girls with PA, we were unable to demonstrate a similar difference in peripheral steroid metabolism.
Acknowledgments
We thank members of the Pediatric Endocrine Division at Columbia Presbyterian Medical Center (New York, NY) for their kind referral of subjects as well as the subjects for agreeing to participate. We also thank Allison Murphy, R.N., and the nurses and staff of the Pediatric General Clinical Research Center (GCRC) for their outstanding help. We acknowledge and thank Genentech, Inc., Eli Lilly & Co., and Pharmacia & Upjohn, Inc. for grant support. We gratefully acknowledge Esoterix Endocrinology and the GCRC laboratory for performing laboratory measurements.
Footnotes
This work was supported in part by grants from the NIH (Grant RR00645); Genentech, Inc.; Eli Lilly Co.; and Pharmacia Upjohn. This work was presented in part at the Lawson Wilkins Pediatric Endocrine Society Meeting, Montreal, Canada, July 2001.
Present address for M.E.S.: Jacobi Medical Center and Albert Einstein College of Medicine, Bronx, New York.
Abbreviations: 5R, 5-Reductase; 11ßHSD, 11ß-hydroxysteroid dehydrogenase; BMI, body mass index; PA, premature adrenarche; PCOS, polycystic ovarian syndrome; THB, tetrahydrocorticosterone; THE, tetrahydrocortisone; THF, tetrahydrocortisol.
Received December 20, 2001.
Accepted June 23, 2002.
References
-reductase activity in polycystic ovary syndrome. Lancet 335:431–433[CrossRef][Medline]
-reductase may be mediated via insulin-like growth factor-1. Endocrinology 133:447–451[Abstract]
-reductase and normal 11ß-hydroxysteroid dehydrogenase metabolism of C19 and C21 steroids in a young population with polycystic ovarian syndrome. J Ped Endocrinol Metab 13:253–259[Medline]
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