Obesity
Original Article PEDIATRIC OBESITY
Impact of BMI on Gonadorelin-Stimulated LH Peak in Premenarcheal Girls with Idiopathic Central Precocious Puberty Jun-Fen Fu1, Jian-Feng Liang1, Xue-Lian Zhou1, Heranmaye C. Prasad1, Ju-Hua Jin1, Guan-Ping Dong1, and Susan Rogers Rose2
Objective: To clarify the impact of body mass index (BMI) on luteinizing hormone (LH) secretion in response to gonadorelin (GnRH) stimulation testing in girls diagnosed with idiopathic central precocious puberty (ICPP). Methods: Retrospective single-center cohort study was carried out in 865 confirmed ICPP girls who underwent GnRH stimulation tests. Pubertal development according to Tanner, sex hormone parameters, and LH secretion in response to GnRH-stimulation was compared. Results: Around 609 girls were of normal weight (70.4%), while 168 children (19.4%) were overweight, and 88 (10.2%) were obese. Peak LH levels after GnRH were much higher in the normal-weight group, with a median of 9.1 mIU ml21 (interquartile 5.2-13.1), compared with the median peak LH in the overweight and obese groups (8.5 mIU ml21, interquartile 5.3-11.6, and 6.2 mIU ml21, interquartile 5.3-11.0, respectively P < 0.001 for all comparisons). Peak LH/FSH ratio was also lower in the obese group (median 0.6, interquartile 0.68-0.90) compared with the normal-weight (median 0.8, interquartile 0.611.11) and overweight (median 0.8, interquartile 0.64-0.92) groups. Conclusions: Higher BMI is associated with lower LH response to GnRH-stimulation testing in girls with ICPP. It is recommended that BMI should be considered when interpreting GnRH-stimulation tests. Obesity (2015) 23, 637–643. doi:10.1002/oby.21010
Introduction Childhood obesity has become one of the biggest global public health problems in recent years. Increase in childhood obesity has a functional relationship with the increase in diseases related to obesity. Excess adiposity is also a risk factor for pubertal disorders. Evidence is mounting that excess adiposity advances the age of onset of puberty, making obesity a risk factor for precocious puberty (1,2).
Many recent studies have showed that obesity appears to influence gonadotropin secretion. Sleep-related SH rise was blunted in healthy premenarcheal pubertal girls with elevated body mass index (BMI) (5). In girls studied via overnight sampling, obesity was associated with reduced LH pulse frequency during prepuberty and early puberty but increased frequency during later puberty (6). Prepubertal and early pubertal obese girls also had relatively low morning LH values and reduced LH pulse amplitude throughout puberty (7).
Girls with central precocious puberty have high luteinizing hormone (LH) levels and a high LH-to-FSH ratio for age, with gonadal function being driven by increased secretion of gonadotropin-releasing hormone (GnRH). Though the mechanism of puberty onset is unclear, the hallmark of early puberty is sleep-entrained increase in LH pulse frequency and amplitude with subsequent reduction of LH release during waking hours (3,4).
Weight reduction in obese children was associated with FSH increase in boys and girls, while LH increased in boys and was unchanged in girls after a 10-week stay at a weight loss camp (8). Obese boys entered puberty at an earlier age than children of normal weight, and increased BMI was a major negative determinant of LH levels evoked by GnRH stimulation in boys with precocious puberty (9).
1 Division of Endocrinology, Children’s Hospital of Zhejiang University School of Medicine, Hangzhou, China. Correspondence: Jun-Fen Fu ([email protected] or [email protected]) 2 Division of Endocrinology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati School of Medicine, Cincinnati, Ohio, USA.
Funding agencies: The National Key Technology R&D Program of China (2012BAI02B03, 2009BAI80B01), National Natural Science Foundation of China (Grant No. 81270938), Zhejiang Provincial Key Medical Disciplines (Innovation Discipline, 11-CX24), and Zhejiang Province key scientific and technological innovation team (2010R50050) and Sea-related international exchanges and cooperation (S20120001534). Disclosure: The authors declared no conflict of interest. Author contributions: J.F was responsible for study design, literature review, and interpretation and the writing of the manuscript. J.L was responsible for data collection and analysis and editing of the manuscript. X.Z, J.J, X.W, G.D, Y.J were responsible for data collection and editing of the manuscript. H.C.P, S.R.R were responsible for interpretation and editing of the manuscript. Received: 26 September 2014; Accepted: 3 December 2014; Published online 3 February 2015. doi:10.1002/oby.21010
www.obesityjournal.org
Obesity | VOLUME 23 | NUMBER 3 | MARCH 2015
637
Obesity
Impact of BMI on LH Peak in Premenarcheal Girls with ICPP Fu et al.
However, there are very few reports about how BMI would affect the sex hormones and stimulated gonadotropins in obese girls with precocious puberty. Recently, in one study in 493 girls with idiopathic central precocious puberty(ICPP), BMI did not correlate with LH or LH/FSH peak ratio (10). To understand whether BMI would influence sex hormones and stimulated gonadotropin secretion in obese girls with precocious puberty, we retrospectively analyzed a cohort of 865 girls diagnosed with ICPP in our center. We expect this analysis to facilitate diagnostic and treatment decisions concerning these girls, and to improve interpretation of gonadorelin stimulation tests for the diagnosis of precocious puberty in girls with different degrees of adiposity.
Methods Subjects Retrospective review of a single-center cohort study was carried out in 865 girls (age >6 years when they were confirmed to have ICPP) who were hospitalized in our center for one night to determine their diagnosis between January 2009 and June 2014. We excluded those girls younger than 6 years because there are not national BMI standard reference ranges for them. Girls who were diagnosed with central precocious puberty due to organic pathologic changes were excluded. We also excluded the ICPP subjects who had experienced menarche. In total, 865 girls were in the final analysis. Subjects were classified according to their BMI: normal weight (BMI for age 5th to 0.6. In our study, ultrasound examinations were performed with the conventional full bladder technique. A 3–5 MHz mechanical sector scanner (SRT, General Electric) with electronic calipers calibrated to a velocity of 1540 n s21 was used. Images were obtained and interpreted by the same sonographer. The best images of the sagittal and axial views were recorded and used to obtain the measurements included in the study. Longitudinal (L), anteroposterior (AP), and transverse (T) diameters of the uterus as a whole, the corpus and cervix separately, and of the ovaries were measured. The formula for a prolate ellipsoid (V 5 L 3 AP 3 T 3 0.5233) was used to calculate the volume (V) of both the uterus and ovaries. The ratio AP corpus/AP cervix was also determined. Baseline blood samples were taken before intravenous (IV) administration of gonadorelin (2.5-3 lg kg21, maximum 100 lg). The samples of LH and FSH were taken at 30, 45, 60, and 90 min after the IV GnRH. LH, FSH, and E2 were measured by chemiluminescence (Siemens Healthcare Diagnostics Incorporation, Tarrytown, NY; sensitivities 0.05 IU l21, 0.1 IU l21, and 15 pg ml21, respectively; intraassay coefficients of variation (CVs) 2.0–3.7%; interassay CVs 4.8-7.0%). Among the 865 girls with ICPP, 253 girls admitted between March 2013 and June 2014 had the following additional evaluation: fasting glucose and insulin, leptin, and sex hormone binding globulin (SHBG) (Table 3). Blood glucose was determined using a glucose oxidase (hexokinase) method (Roche Diagnostics GmbH, Sandhofer Strasse, Mannheim, Germany; sensitivity 2.0 mg dl21; intraassay CV 1.7%; interassay CV 1.0%). Insulin was determined by chemiluminescence (Abbott Laboratories Diagnostics Division, Abbott Park, IL; sensitivity 1.0 mU ml21; intraassay CV 2.3–4.6%; interassay CV 1.7-4.0%). Leptin was measured by radioimmunoassay (Beijing North Biotechnology Company, Beijing, China; sensitivities 0.45 ng ml21; intraassay CV
Original Article PEDIATRIC OBESITY
Impact of BMI on Gonadorelin-Stimulated LH Peak in Premenarcheal Girls with Idiopathic Central Precocious Puberty Jun-Fen Fu1, Jian-Feng Liang1, Xue-Lian Zhou1, Heranmaye C. Prasad1, Ju-Hua Jin1, Guan-Ping Dong1, and Susan Rogers Rose2
Objective: To clarify the impact of body mass index (BMI) on luteinizing hormone (LH) secretion in response to gonadorelin (GnRH) stimulation testing in girls diagnosed with idiopathic central precocious puberty (ICPP). Methods: Retrospective single-center cohort study was carried out in 865 confirmed ICPP girls who underwent GnRH stimulation tests. Pubertal development according to Tanner, sex hormone parameters, and LH secretion in response to GnRH-stimulation was compared. Results: Around 609 girls were of normal weight (70.4%), while 168 children (19.4%) were overweight, and 88 (10.2%) were obese. Peak LH levels after GnRH were much higher in the normal-weight group, with a median of 9.1 mIU ml21 (interquartile 5.2-13.1), compared with the median peak LH in the overweight and obese groups (8.5 mIU ml21, interquartile 5.3-11.6, and 6.2 mIU ml21, interquartile 5.3-11.0, respectively P < 0.001 for all comparisons). Peak LH/FSH ratio was also lower in the obese group (median 0.6, interquartile 0.68-0.90) compared with the normal-weight (median 0.8, interquartile 0.611.11) and overweight (median 0.8, interquartile 0.64-0.92) groups. Conclusions: Higher BMI is associated with lower LH response to GnRH-stimulation testing in girls with ICPP. It is recommended that BMI should be considered when interpreting GnRH-stimulation tests. Obesity (2015) 23, 637–643. doi:10.1002/oby.21010
Introduction Childhood obesity has become one of the biggest global public health problems in recent years. Increase in childhood obesity has a functional relationship with the increase in diseases related to obesity. Excess adiposity is also a risk factor for pubertal disorders. Evidence is mounting that excess adiposity advances the age of onset of puberty, making obesity a risk factor for precocious puberty (1,2).
Many recent studies have showed that obesity appears to influence gonadotropin secretion. Sleep-related SH rise was blunted in healthy premenarcheal pubertal girls with elevated body mass index (BMI) (5). In girls studied via overnight sampling, obesity was associated with reduced LH pulse frequency during prepuberty and early puberty but increased frequency during later puberty (6). Prepubertal and early pubertal obese girls also had relatively low morning LH values and reduced LH pulse amplitude throughout puberty (7).
Girls with central precocious puberty have high luteinizing hormone (LH) levels and a high LH-to-FSH ratio for age, with gonadal function being driven by increased secretion of gonadotropin-releasing hormone (GnRH). Though the mechanism of puberty onset is unclear, the hallmark of early puberty is sleep-entrained increase in LH pulse frequency and amplitude with subsequent reduction of LH release during waking hours (3,4).
Weight reduction in obese children was associated with FSH increase in boys and girls, while LH increased in boys and was unchanged in girls after a 10-week stay at a weight loss camp (8). Obese boys entered puberty at an earlier age than children of normal weight, and increased BMI was a major negative determinant of LH levels evoked by GnRH stimulation in boys with precocious puberty (9).
1 Division of Endocrinology, Children’s Hospital of Zhejiang University School of Medicine, Hangzhou, China. Correspondence: Jun-Fen Fu ([email protected] or [email protected]) 2 Division of Endocrinology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati School of Medicine, Cincinnati, Ohio, USA.
Funding agencies: The National Key Technology R&D Program of China (2012BAI02B03, 2009BAI80B01), National Natural Science Foundation of China (Grant No. 81270938), Zhejiang Provincial Key Medical Disciplines (Innovation Discipline, 11-CX24), and Zhejiang Province key scientific and technological innovation team (2010R50050) and Sea-related international exchanges and cooperation (S20120001534). Disclosure: The authors declared no conflict of interest. Author contributions: J.F was responsible for study design, literature review, and interpretation and the writing of the manuscript. J.L was responsible for data collection and analysis and editing of the manuscript. X.Z, J.J, X.W, G.D, Y.J were responsible for data collection and editing of the manuscript. H.C.P, S.R.R were responsible for interpretation and editing of the manuscript. Received: 26 September 2014; Accepted: 3 December 2014; Published online 3 February 2015. doi:10.1002/oby.21010
www.obesityjournal.org
Obesity | VOLUME 23 | NUMBER 3 | MARCH 2015
637
Obesity
Impact of BMI on LH Peak in Premenarcheal Girls with ICPP Fu et al.
However, there are very few reports about how BMI would affect the sex hormones and stimulated gonadotropins in obese girls with precocious puberty. Recently, in one study in 493 girls with idiopathic central precocious puberty(ICPP), BMI did not correlate with LH or LH/FSH peak ratio (10). To understand whether BMI would influence sex hormones and stimulated gonadotropin secretion in obese girls with precocious puberty, we retrospectively analyzed a cohort of 865 girls diagnosed with ICPP in our center. We expect this analysis to facilitate diagnostic and treatment decisions concerning these girls, and to improve interpretation of gonadorelin stimulation tests for the diagnosis of precocious puberty in girls with different degrees of adiposity.
Methods Subjects Retrospective review of a single-center cohort study was carried out in 865 girls (age >6 years when they were confirmed to have ICPP) who were hospitalized in our center for one night to determine their diagnosis between January 2009 and June 2014. We excluded those girls younger than 6 years because there are not national BMI standard reference ranges for them. Girls who were diagnosed with central precocious puberty due to organic pathologic changes were excluded. We also excluded the ICPP subjects who had experienced menarche. In total, 865 girls were in the final analysis. Subjects were classified according to their BMI: normal weight (BMI for age 5th to 0.6. In our study, ultrasound examinations were performed with the conventional full bladder technique. A 3–5 MHz mechanical sector scanner (SRT, General Electric) with electronic calipers calibrated to a velocity of 1540 n s21 was used. Images were obtained and interpreted by the same sonographer. The best images of the sagittal and axial views were recorded and used to obtain the measurements included in the study. Longitudinal (L), anteroposterior (AP), and transverse (T) diameters of the uterus as a whole, the corpus and cervix separately, and of the ovaries were measured. The formula for a prolate ellipsoid (V 5 L 3 AP 3 T 3 0.5233) was used to calculate the volume (V) of both the uterus and ovaries. The ratio AP corpus/AP cervix was also determined. Baseline blood samples were taken before intravenous (IV) administration of gonadorelin (2.5-3 lg kg21, maximum 100 lg). The samples of LH and FSH were taken at 30, 45, 60, and 90 min after the IV GnRH. LH, FSH, and E2 were measured by chemiluminescence (Siemens Healthcare Diagnostics Incorporation, Tarrytown, NY; sensitivities 0.05 IU l21, 0.1 IU l21, and 15 pg ml21, respectively; intraassay coefficients of variation (CVs) 2.0–3.7%; interassay CVs 4.8-7.0%). Among the 865 girls with ICPP, 253 girls admitted between March 2013 and June 2014 had the following additional evaluation: fasting glucose and insulin, leptin, and sex hormone binding globulin (SHBG) (Table 3). Blood glucose was determined using a glucose oxidase (hexokinase) method (Roche Diagnostics GmbH, Sandhofer Strasse, Mannheim, Germany; sensitivity 2.0 mg dl21; intraassay CV 1.7%; interassay CV 1.0%). Insulin was determined by chemiluminescence (Abbott Laboratories Diagnostics Division, Abbott Park, IL; sensitivity 1.0 mU ml21; intraassay CV 2.3–4.6%; interassay CV 1.7-4.0%). Leptin was measured by radioimmunoassay (Beijing North Biotechnology Company, Beijing, China; sensitivities 0.45 ng ml21; intraassay CV
