Early menarche is associated with insulin-resistance and non-alcoholic fatty liver disease in adolescents with obesity
-
Anna Di Sessa
, Anna Grandone
Abstract
Objectives
Recent evidence linked early menarche to a higher risk of insulin-resistance (IR) and nonalcoholic fatty liver disease (NAFLD) in adulthood. We aimed to evaluate the impact of early menarche on glucose derangements and NAFLD in a sample of Italian adolescents with obesity.
Methods
Anthropometric and biochemical evaluations were conducted in all the enrolled 318 obese patients (mean age 12.31 ± 2.95 years). NAFLD was defined by the presence of ultrasound detected liver steatosis and/or alanine transaminase (ALT) levels >40 IU/L.
Results
Patients with early menarche showed both higher homeostasis model assessment of insulin-resistance (HOMA-IR) (p=0.008) and ALT (p=0.02) values, an increased prevalence of NAFLD (p=0.001), and lower Matsuda and Insulinogenic Index (IGI) values than the other obese patients. The association between early menarche and both ALT and Matsuda Index remained significant in General Linear Models (GLMs) in which respectively body mass index standard deviation score (BMI-SDS) and Matsuda Index, and BMI-SDS were included as covariates. Patients with early menarche also showed a higher risk of both HOMA-IR>3 (OR 1.69, CI 1.05–2.70, p=0.02) and NAFLD (OR 1.10, CI 1.01–1.21, p=0.03).
Conclusions
Girls with obesity presenting early menarche showed higher HOMA-IR levels, lower Matsuda Index and IGI values, and higher risk of NAFLD compared to girls without early menarche.
-
Research funding: None declared.
-
Author contributions: ADS drafted the paper. EMDG, AG, and ADS participated in the conception and the design of the study. AG, ADS, and GC performed the statistical analyses. GRU, PM, and GC examined the patients and collected anthropometric data. EMDG supervised the design and execution of the study. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.
-
Competing interests: The authors declare that they have no conflict of interest.
-
Informed consent: Written informed consent was obtained from all the participants before any procedure.
-
Ethical approval: The ethical committee of the University of Campania “Luigi Vanvitelli” approved the study. Written informed consent was obtained from all the participants before any procedure.
References
1. Biro, FM, Greenspan, LC, Galvez, MP. Puberty in girls of the 21st century. J Pediatr Adolesc Gynecol 2012;25:289–94. https://doi.org/10.1016/j.jpag.2012.05.009.Search in Google Scholar
2. Reinehr, T, Roth, CL. Is there a causal relationship between obesity and puberty? Lancet Child Adolesc Health 2019;3:44–54. https://doi.org/10.1016/S2352-4642(18)30306-7.Search in Google Scholar
3. Ryu, S, Chang, Y, Choi, Y, Kwon, MJ, Kim, CW, Yun, KE, et al.. Age at menarche and non-alcoholic fatty liver disease. J Hepatol 2015;62:1164–70. https://doi.org/10.1016/j.jhep.2014.11.041.Search in Google Scholar
4. Yi, KH, Hwang, JS, Lim, SW, Lee, JA, Kim, DH, Lim, JS. Early menarche is associated with non-alcoholic fatty liver disease in adulthood. Pediatr Int 2017;59:1270–5. https://doi.org/10.1111/ped.13422.Search in Google Scholar
5. Zhang, Z, Hu, X, Yang, C, Chen, X. Early age at menarche is associated with insulin resistance: a systemic review and meta-analysis. Postgrad Med 2019;131:144–50. https://doi.org/10.1080/00325481.2019.1559429.Search in Google Scholar
6. Mueller, NT, Pereira, MA, Demerath, EW, Dreyfus, JG, MacLehose, RF, Carr, JJ, et al.. Earlier menarche is associated with fatty liver and abdominal ectopic fat in midlife, independent of young adult BMI: the CARDIA study. Obesity 2015;23:468–74. https://doi.org/10.1002/oby.20950.Search in Google Scholar
7. Le, S, Xu, L, Schumann, M, Wu, N, Törmäkangas, T, Alén, M, et al.. Does sex hormone-binding globulin cause insulin resistance during pubertal growth? Endocr Connect 2019;8:510–7. https://doi.org/10.1530/EC-19-0044.Search in Google Scholar
8. Ahmed, ML, Ong, KK, Dunger, DB. Childhood obesity and the timing of puberty. Trends Endocrinol Metabol 2009;20:237–42. https://doi.org/10.1016/j.tem.2009.02.004.Search in Google Scholar
9. Chen, X, Liu, Y, Sun, X, Yin, Z, Li, H, Liu, X, et al.. Age at menarche and risk of all-cause and cardiovascular mortality: a systematic review and dose-response meta-analysis. Menopause 2018;26:670–6. https://doi.org/10.1097/GME.0000000000001289.Search in Google Scholar
10. de Zegher, F, García Beltrán, C, López-Bermejo, A, Ibáñez, L. Metformin for rapidly maturing girls with central adiposity: less liver fat and slower bone maturation. Horm Res Paediatr 2018;89:136–40. https://doi.org/10.1159/000479369.Search in Google Scholar
11. Cacciari, E, Milani, S, Balsamo, A, Spada, E, Bona, G, Cavallo, L, et al.. Italian cross-sectional growth charts for height, weight and BMI (2 to 20 yr). J Endocrinol Invest 2006;29:581–93. https://doi.org/10.1007/bf03344156.Search in Google Scholar
12. Marzuillo, P, Grandone, A, Di Sessa, A, Guarino, S, Diplomatico, M, Umano, GR, et al.. Anthropometric and biochemical determinants of estimated glomerular filtration rate in a large cohort of obese children. J Ren Nutr 2018;28:359–62. https://doi.org/10.1053/j.jrn.2018.01.001.Search in Google Scholar
13. Cole, TJ. The LMS method for constructing normalized growth standards. Eur J Clin Nutr 1990;44:45–60.Search in Google Scholar
14. Marzuillo, P, Grandone, A, Conte, M, Capuano, F, Cirillo, G, Di Sessa, A, et al.. Novel association between a nonsynonymous variant (R270H) of the G-protein-coupled receptor 120 and liver injury in children and adolescents with obesity. J Pediatr Gastroenterol Nutr 2014;59:472–5. https://doi.org/10.1097/mpg.0000000000000463.Search in Google Scholar
15. Di Sessa, A, Umano, GR, Cirillo, G, Del Prete, A, Iacomino, R, Marzuillo, P, et al.. The membrane-bound O-Acyltransferase7 rs641738 variant in pediatric nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr 2018;67:69–74. https://doi.org/10.1097/mpg.0000000000001979.Search in Google Scholar
16. Marzuillo, P, Di Sessa, A, Umano, GR, Nunziata, L, Cirillo, G, Perrone, L, et al.. Novel association between the nonsynonymous A803G polymorphism of the N-acetyltransferase 2 gene and impaired glucose homeostasis in obese children and adolescents. Pediatr Diabetes 2017;18:478–84. https://doi.org/10.1111/pedi.12417.Search in Google Scholar
17. Shashaj, B, Luciano, R, Contoli, B, Morino, GS, Spreghini, MR, Rustico, C, et al.. Reference ranges of HOMA-IR in normal-weight and obese young Caucasians. Acta Diabetol 2016;53:251–60. https://doi.org/10.1007/s00592-015-0782-4.Search in Google Scholar
18. Abdul-Ghani, MA, Matsuda, M, Balas, B, DeFronzo, RA. Muscle and liver insulin resistance indexes derived from the oral glucose tolerance test. Diabetes Care 2007;30:89–94. https://doi.org/10.2337/dc06-1519.Search in Google Scholar
19. TODAY Study Group. Effects of metformin, metformin plus rosiglitazone, and metformin plus lifestyle on insulin sensitivity and β-cell function in TODAY. Diabetes Care 2013;36:1749–57. https://doi.org/10.2337/dc12-2393.Search in Google Scholar
20. Matsuda, M, DeFronzo, RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 1999;22:1462–70. https://doi.org/10.2337/diacare.22.9.1462.Search in Google Scholar
21. Di Sessa, A, Umano, GR, Miraglia Del Giudice, E. The association between non-alcoholic fatty liver disease and cardiovascular risk in children. Children 2017;4. https://doi.org/10.3390/children4070057.Search in Google Scholar
22. Facchini, FS, Hua, N, Abbasi, F, Reaven, GM. Insulin resistance as a predictor of age-related diseases. J Clin Endocrinol Metab 2001;86:3574–8. https://doi.org/10.1210/jcem.86.8.7763.Search in Google Scholar
23. Kivimaki, M, Lawlor, DA, Smith, GD, Elovainio, M, Jokela, M, Keltikangas-Jarvinen, L, et al.. Association of age at menarche with cardiovascular risk factors, vascular structure, and function in adulthood: the Cardiovascular Risk in Young Finns study. Am J Clin Nutr 2008;87:1876–82. https://doi.org/10.1093/ajcn/87.6.1876.Search in Google Scholar
24. Remsberg, KE, Demerath, EW, Schubert, CM, Chumlea, WC, Sun, SS, Siervogel, RM. Early menarche and the development of cardiovascular disease risk factors in adolescent girls: the Fels Longitudinal Study. J Clin Endocrinol Metab 2005;90:2718–24. https://doi.org/10.1210/jc.2004-1991.Search in Google Scholar
25. Li, W, Liu, Q, Deng, X, Chen, Y, Liu, S, Story, M. Association between obesity and puberty timing: a systematic review and meta-analysis. Int J Environ Res Publ Health 2017;14:1266. https://doi.org/10.3390/ijerph14101266.Search in Google Scholar
26. Sorensen, K, Aksglaede, L, Munch-Andersen, T, Aachmann-Andersen, NJ, Petersen, JH, Hilsted, L, et al.. Sex hormone-binding globulin levels predict insulin sensitivity, disposition index, and cardiovascular risk during puberty. Diabetes Care 2009;32:909–14. https://doi.org/10.2337/dc08-1618.Search in Google Scholar
27. Faienza, MF, Wang, DQ, Frühbeck, G, Garruti, G, Portincasa, P. The dangerous link between childhood and adulthood predictors of obesity and metabolic syndrome. Intern Emerg Med 2016;11:175–82. https://doi.org/10.1007/s11739-015-1382-6.Search in Google Scholar
28. Ibáñez, L, Lopez-Bermejo, A, Diaz, M, Marcos, MV, de Zegher, F. Early metformin therapy to delay menarche and augment height in girls with precocious pubarche. Fertil Steril 2011;95:727–30. https://doi.org/10.1016/j.fertnstert.2010.08.052.Search in Google Scholar
29. Ibáñez, L, Valls, C, Ong, K, Dunger, DB, de Zegher, F. Metformin therapy during puberty delays menarche, prolongs pubertal growth, and augments adult height: a randomized study in low-birth-weight girls with early-normal onset of puberty. J Clin Endocrinol Metab 2006;91:2068–73. https://doi.org/10.1210/jc.2005-2329.Search in Google Scholar
30. Elks, CE, Ong, KK, Scott, RA, van der Schouw, YT, Brand, JS, Wark, PA, et al.. Age at menarche and type 2 diabetes risk: the EPIC-InterAct study. Diabetes Care 2013;36:3526–34. https://doi.org/10.2337/dc13-0446.Search in Google Scholar
31. Targher, G, Day, CP, Bonora, E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010;363:1341–50. https://doi.org/10.1056/nejmra0912063.Search in Google Scholar
32. Mueller, NT, Liu, T, Mitchel, EB, Yates, KP, Suzuki, A, Behling, C, et al.. Sex hormone relations to histologic severity of pediatric nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2020;105:3496–504. https://doi.org/10.1210/clinem/dgaa574.Search in Google Scholar
33. Nokoff, N, Thurston, J, Hilkin, A, Pyle, L, Zeitler, PS, Nadeau, KJ, et al.. Sex differences in effects of obesity on reproductive hormones and glucose metabolism in early puberty. J Clin Endocrinol Metab 2019;104:4390–7. https://doi.org/10.1210/jc.2018-02747.Search in Google Scholar
© 2021 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Editorial
- Covid19 pandemic and pediatric endocrinology and metabolism—Are we through with it?
- Original Articles
- Invisible burden of COVID-19: enzyme replacement therapy disruptions
- Anthropometric, biochemical and hormonal profiles of the partially admixed pygmoid group in Rampasasa (Flores, Indonesia)
- Etiologies, profile patterns and characteristics of children with short stature in Jordan
- Sexual maturity assessment in Indian children—a study from western India
- Bone density and bone health alteration in boys with Duchenne Muscular Dystrophy: a prospective observational study
- Sensory, voluntary, and motor postural control in children and adolescents with mucopolysaccharidosis
- Prevalence and MRI findings of incidentally detected pituitary non-enhancing lesion on brain MRI in children
- Oral glucose tolerance response curve predicts disposition index but not other cardiometabolic risk factors in healthy adolescents
- Early menarche is associated with insulin-resistance and non-alcoholic fatty liver disease in adolescents with obesity
- Liraglutide combined with intense lifestyle modification in the management of obesity in adolescents
- Exploring the inter-subject variability in the relationship between glucose monitoring metrics and glycated hemoglobin for pediatric patients with type 1 diabetes
- Screening for asymptomatic diabetes and metabolic comorbidities in pediatric patients during therapy for acute lymphoblastic leukemia
- Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry
- Experience with the targeted next-generation sequencing in the diagnosis of hereditary hypophosphatemic rickets
- Newborn screening and molecular features of patients with multiple acyl-CoA dehydrogenase deficiency in Quanzhou, China
- Case Reports
- Dual diagnosis of Ochoa syndrome and Niemann-Pick disease type B in a consanguineous family
- Severe hypercalcemia in an infant with unbalanced translocation of chromosomes 2 and 8: a possible contribution of 2p duplication
- Epileptic phenotype in late-onset hyperinsulinemic hypoglycemia successfully treated by diazoxide
- Precocious sexual development in a male toddler caused by unrecognized transdermal exposure to testosterone: case report and review of the literature
Articles in the same Issue
- Frontmatter
- Editorial
- Covid19 pandemic and pediatric endocrinology and metabolism—Are we through with it?
- Original Articles
- Invisible burden of COVID-19: enzyme replacement therapy disruptions
- Anthropometric, biochemical and hormonal profiles of the partially admixed pygmoid group in Rampasasa (Flores, Indonesia)
- Etiologies, profile patterns and characteristics of children with short stature in Jordan
- Sexual maturity assessment in Indian children—a study from western India
- Bone density and bone health alteration in boys with Duchenne Muscular Dystrophy: a prospective observational study
- Sensory, voluntary, and motor postural control in children and adolescents with mucopolysaccharidosis
- Prevalence and MRI findings of incidentally detected pituitary non-enhancing lesion on brain MRI in children
- Oral glucose tolerance response curve predicts disposition index but not other cardiometabolic risk factors in healthy adolescents
- Early menarche is associated with insulin-resistance and non-alcoholic fatty liver disease in adolescents with obesity
- Liraglutide combined with intense lifestyle modification in the management of obesity in adolescents
- Exploring the inter-subject variability in the relationship between glucose monitoring metrics and glycated hemoglobin for pediatric patients with type 1 diabetes
- Screening for asymptomatic diabetes and metabolic comorbidities in pediatric patients during therapy for acute lymphoblastic leukemia
- Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry
- Experience with the targeted next-generation sequencing in the diagnosis of hereditary hypophosphatemic rickets
- Newborn screening and molecular features of patients with multiple acyl-CoA dehydrogenase deficiency in Quanzhou, China
- Case Reports
- Dual diagnosis of Ochoa syndrome and Niemann-Pick disease type B in a consanguineous family
- Severe hypercalcemia in an infant with unbalanced translocation of chromosomes 2 and 8: a possible contribution of 2p duplication
- Epileptic phenotype in late-onset hyperinsulinemic hypoglycemia successfully treated by diazoxide
- Precocious sexual development in a male toddler caused by unrecognized transdermal exposure to testosterone: case report and review of the literature