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      Factors that predict a positive response on gonadotropin-releasing hormone stimulation test for diagnosing central precocious puberty in girls

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          Abstract

          Purpose

          The rapid increase in the incidence of precocious puberty in Korea has clinical and social significance. Gonadotropin-releasing hormone (GnRH) stimulation test is required to diagnose central precocious puberty (CPP), however this test is expensive and time-consuming. This study aimed to identify factors that can predict a positive response to the GnRH stimulation test.

          Methods

          Clinical and laboratory parameters, including basal serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2), were measured in 540 girls with clinical signs of CPP.

          Results

          Two hundred twenty-nine of 540 girls with suspected CPP had a peak serum LH level higher than 5 IU/L (the CPP group). The CPP group had advanced bone age ( P<0.001), accelerated yearly growth rate ( P<0.001), increased basal levels of LH ( P=0.02), FSH ( P<0.001), E2 ( P=0.001), and insulin-like growth factor-I levels ( P<0.001) compared to the non-CPP group. In contrast, body weight ( P<0.001) and body mass index ( P<0.001) were lower in the CPP group. Although basal LH was significantly elevated in the CPP group compared to the non-CPP group, there was considerable overlap between the 2 groups. Cutoff values of basal LH (0.22 IU/L) detected CPP with 87.8% sensitivity and 20.9% specificity.

          Conclusion

          No single parameter can predict a positive response on the GnRH stimulation test with both high sensitivity and specificity. Therefore, multiple factors should be considered in evaluation of sexual precocity when deciding the timing of the GnRH stimulation test.

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          Most cited references12

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          Adequacy of a single unstimulated luteinizing hormone level to diagnose central precocious puberty in girls.

          Using basal specimens from original gonadotropin radioimmunoassays, it was not possible to differentiate prepuberty from puberty hence gonadotropin-releasing hormone or gonadotropin-releasing hormone analog (GnRHa) testing was required to make this distinction. Third-generation gonadotropin assays have far greater specificity and sensitivity. Using a group of patients who had the diagnosis of central precocious puberty (CPP) verified or excluded by using GnRHa and traditional diagnostic criteria, the objective of this study was to determine if a single basal gonadotropin measurement was adequate to verify the diagnosis of CPP by using 2 third-generation gonadotropin assays. Girls referred for assessment of early puberty had previously been evaluated for central precocious puberty including gonadotropin-releasing hormone analog stimulation testing with gonadotropin measurements by 2 different chemiluminescent third-generation immunoassays. Diagnosis of central precocious puberty was made on the basis of the response to the gonadotropin-releasing hormone analog, and clinical criteria. Girls with central precocious puberty had luteinizing hormone responses ranging from 9.1 to 67.6 U/L, the prepubertal luteinizing hormone response range was 0.2 to 5.0 U/L. Basal serum luteinizing hormone and follicle-stimulating hormone concentrations from these girls have been assessed to determine the utility of using such a single sample to diagnose central precocious puberty. Basal luteinizing hormone levels using the 2 third-generation gonadotropin assays were sufficient to diagnose central precocious puberty in >90% of the girls. Luteinizing hormone values were undetectable in both assays with different lower limits of detection ( 0.83 U/L, except a single value of 0.46 U/L. The basal follicle-stimulating hormone failed to differentiate prepubertal girls from those with central precocious puberty, whereas luteinizing hormone/follicle-stimulating hormone ratios would seem to have limited discernment. A single basal luteinizing hormone measurement is adequate to document a pubertal hypothalamic-pituitary-ovarian axis in most but not all girls with central precocious puberty.
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            Pubertal maturation in girls and the relationship to anthropometric changes: pathways through puberty.

            Patterns of pubertal maturation may have an impact on several risk factors associated with adult morbidity and mortality, such as obesity. We examined the relationship of the initial manifestation of puberty in girls with anthropometric measures, as well as age at menarche. White females (n = 1166, ages 9 and 10 at intake) were followed with annual visits for 10 years. Physical examinations included height, weight, skinfold thicknesses, and pubertal maturation assessment. During the course of the study, 443 of 859 eligible females (51.6%) were observed to have asynchronous maturation in the development of puberty, that is, initial areolar/breast (thelarche pathway) or pubic hair (adrenarche pathway) development, without development of the other characteristic. Using a longitudinal regression model, significant interactions were noted between initial pubertal manifestation and years since onset of puberty on the following outcomes: sum of skinfolds thickness, percent body fat, waist-to-hip ratio, and body mass index (BMI). However, age of onset of pubertal maturation was the same in the 2 groups (10.7 years). Females in the thelarche pathway had earlier menarche (12.6 vs 13.1 years) as well as greater skinfolds, body fat, and BMI at the time of menarche. Females in the thelarche pathway also had greater body fat and BMI 1 year before puberty and throughout puberty compared with those in the adrenarche pathway. Females who enter puberty through the thelarche pathway, as compared with the adrenarche pathway, had greater sum of skinfold thicknesses, BMI, and percent body fat 1 year before the onset, as well as throughout, puberty. Because larger body composition and earlier age of menarche of females in the thelarche pathway parallel the epidemiologic profiles of women who are obese or at risk for obesity, these females may be at greater risk for adult obesity.
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              Adult height in girls with idiopathic true precocious puberty.

              GnRH analogs are used to suppress pituitary-gonadal activity in children with true precocious puberty. The indications for therapy in this situation are not established, as some girls have a slow evolutive form, and the capacity of GnRH analogs to preserve the adult height has not been evaluated. This study analyzes the growth and adult heights of 2 groups of girls with idiopathic true precocious puberty, 1 with a predicted height of 155 cm or less (group 1, 19 cases) and the other with a predicted height of more than 155 cm (group 2, 15 cases). Group 1 patients were treated with a long-acting GnRH analog (D-Trp6-GnRH), and group 2 patients were followed without therapy. Group 1 showed greater clinical signs of estrogenization, vaginal maturation index (P < 0.03), plasma estradiol (P < 0.0004), and ratio of LH/FSH peaks (P < 0.01) at the initial evaluation than did group 2. The mean target heights were similar (difference, 0.9 cm). In group 1, the adult height (159 +/- 1.1 cm) was greater than the predicted height before therapy (152 +/- 1.4 cm; P < 0.0001). The difference between the adult height and the predicted height before therapy (mean, 6.5 cm) correlated positively with the bone age advance (P < 0.01), negatively with the predicted height (P < 0.05), and positively with the difference between the target and predicted heights (P < 0.001) before therapy. In group 2, the adult height (162 +/- 1.4 cm) was similar to the predicted height at the initial evaluation (162.5 +/- 1.4 cm). Adult heights correlated with target height in group 1 and with predicted height at the initial evaluation in group 2. In conclusion, some girls with true precocious puberty and poor adult height prediction who are treated with GnRH analog achieve an adult height more comparable to their target height. However, the lack of effect on height in girls with predicted height at the onset of therapy similar to their target height and preservation of the growth potential in the slow evolutive forms suggest that these forms might not require immediate therapy. Careful follow-up before therapy may be a better way of evaluating their natural course.
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                Author and article information

                Journal
                Ann Pediatr Endocrinol Metab
                Ann Pediatr Endocrinol Metab
                APEM
                Annals of Pediatric Endocrinology & Metabolism
                The Korean Society of Pediatric Endocrinology
                2287-1012
                2287-1292
                December 2013
                31 December 2013
                : 18
                : 4
                : 202-207
                Affiliations
                [1 ]Department of Pediatrics, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea.
                [2 ]Sowha Children's Hospital, Seoul, Korea.
                Author notes
                Address for correspondence: Ho-Seong Kim, MD, PhD. Department of Pediatrics, Endocrine Research Institute, Severance Children's Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea. Tel: +82-2-2228-2069, Fax: +82-2-393-9118, kimho@ 123456yuhs.ac
                Article
                10.6065/apem.2013.18.4.202
                4027085
                24904878
                f43bbfca-6556-475b-98a6-499efb5e7c75
                © 2013 Annals of Pediatric Endocrinology & Metabolism

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 October 2013
                : 25 October 2013
                : 18 November 2013
                Funding
                Funded by: Inje University
                Categories
                Original Article

                precocious puberty,diagnosis,gonadotropin-releasing hormone,forecasting,female

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