Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Journal of Pediatric Endocrinology and Metabolism

Editor-in-Chief: Kiess, Wieland

Ed. by Bereket, Abdullah / Darendeliler, Feyza / Dattani, Mehul / Gustafsson, Jan / Luo, Fei Hong / Mericq, Veronica / Toppari, Jorma

IMPACT FACTOR 2018: 1.239

CiteScore 2018: 1.22

SCImago Journal Rank (SJR) 2018: 0.507
Source Normalized Impact per Paper (SNIP) 2018: 0.562

See all formats and pricing
More options …
Volume 30, Issue 12


Higher phthalate concentrations are associated with precocious puberty in normal weight Thai girls

Khomsak Srilanchakon
  • Divison of Pediatric Endocrinology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Thawiphark Thadsri / Chutima Jantarat / Suriyan Thengyai
  • School of Pharmacy, Walailak University, Nakhon Si Thammarat, Thailand
  • Drug and Cosmetic Excellence Center, School of Pharmacy, Walailak University, Nakhon Si Thammarat, Thailand
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Wichit Nosoognoen / Vichit Supornsilchai
  • Corresponding author
  • Divison of Pediatric Endocrinology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2017-11-25 | DOI: https://doi.org/10.1515/jpem-2017-0281



The cause of precocious puberty may be associated with genetics and other conditions such as central nervous system (CNS) insults, or the exposure to endocrine disrupting chemicals (EDCs). Phthalates is known to be one of the EDCs and have estrogenic and antiandrogenic activities, and may be associated with advanced puberty. The objective of the study was to determine the association between urinary phthalate metabolites and advanced puberty.


A cross-sectional study was conducted in patients with precocious puberty (breast onset <8 years, n=42) and early puberty (breast onset 8–9 years, n=17), compared to age-matched controls (n=77). Anthropometric measurements, estradiol, basal and gonadotropin releasing hormone (GnRH)-stimulated follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels, uterine sizes, ovarian diameters and bone ages (BA) were obtained. Urine samples were collected and mono-methyl phthalate (MMP) and mono-ethyl phthalate (MEP) were analyzed by high performance liquid chromatography (HPLC) and adjusted with urine creatinine.


The median adjusted-MEP concentration in girls with precocious puberty, was greater than in normal girls (6105.09 vs. 4633.98 μg/g Cr: p<0.05), and had the same trend among early puberty and normal puberty (5141.41 vs. 4633.98 μg/g Cr: p=0.4), but was not statistically significant.


Precocious puberty girls had an association with increased MEP concentration. This is the first report of the association between urinary phthalate levels and precocious puberty in Thai girls.

Keywords: endocrine disruptor; phthalates; precocious puberty


  • 1.

    Neely EK, Crossen SS. Precocious puberty. Curr Opin Obstet Gynecol 2014;26:332–8.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 2.

    Cesario SK, Hughes LA. Precocious puberty: a comprehensive review of literature. J Obstet Gynecol Neonatal Nurs 2007;36:263–74.CrossrefPubMedGoogle Scholar

  • 3.

    Jaruratanasirikul S, Chanpong A, Tassanakijpanich N, Sriplung H. Declining age of puberty of school girls in southern Thailand. World J Pediatr 2014;10:256–61.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 4.

    Antoniazzi F, Zamboni G. Central precocious puberty: current treatment options. Paediatr Drugs 2004;6:211–31.CrossrefPubMedGoogle Scholar

  • 5.

    Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, et al. Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev 2009;30:293–342.Web of SciencePubMedCrossrefGoogle Scholar

  • 6.

    Frederiksen H, Skakkebaek NE, Andersson AM. Metabolism of phthalates in humans. Mol Nutr Food Res 2007;51:899–911.Web of SciencePubMedCrossrefGoogle Scholar

  • 7.

    Parveen M, Inoue A, Ise R, Tanji M, Kiyama R. Evaluation of estrogenic activity of phthalate esters by gene expression profiling using a focused microarray (EstrArray). Environ Toxicol Chem 2008;27:1416–25.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 8.

    Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect 2005;113:1056–61.CrossrefPubMedGoogle Scholar

  • 9.

    Chen CY, Chou YY, Wu YM, Lin CC, Lin SJ, et al. Phthalates may promote female puberty by increasing kisspeptin activity. Hum Reprod 2013;28:2765–73.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 10.

    Chou YY, Huang PC, Lee CC, Wu MH, Lin SJ. Phthalate exposure in girls during early puberty. J Pediatr Endocrinol Metab 2009;22:69–77.PubMedGoogle Scholar

  • 11.

    Yum T, Lee S, Kim Y. Association between precocious puberty and some endocrine disruptors in human plasma. J Environ Sci Health A Tox Hazard Subst Environ Eng 2013;48:912–7.CrossrefPubMedGoogle Scholar

  • 12.

    Colon I, Caro D, Bourdony CJ, Rosario O. Identification of phthalate esters in the serum of young Puerto Rican girls with premature breast development. Environ Health Perspect 2000;108:895–900.PubMedCrossrefGoogle Scholar

  • 13.

    Lomenick JP, Calafat AM, Melguizo Castro MS, Mier R, Stenger P, et al. Phthalate exposure and precocious puberty in females. J Pediatr 2010;156:221–5.CrossrefPubMedGoogle Scholar

  • 14.

    Lu JP, Zheng LX, Cai DP. Study on the level of environmental endocrine disruptors in serum of precocious puberty patients. Zhonghua Yu Fang Yi Xue Za Zhi 2006;40:88–92.PubMedGoogle Scholar

  • 15.

    Wen Y, Liu SD, Lei X, Ling YS, Luo Y, et al. Association of PAEs with precocious puberty in children: a systematic review and meta-analysis. Int J Environ Res Public Health 2015;12:15254–68.CrossrefWeb of SciencePubMedGoogle Scholar

  • 16.

    Poomthavorn P, Khlairit P, Mahachoklertwattana P. Subcutaneous gonadotropin-releasing hormone agonist (triptorelin) test for diagnosing precocious puberty. Horm Res 2009;72:114–9.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 17.

    Servaes K, Voorspoels S, Lievens J, Noten B, Allaerts K, et al. Direct analysis of phthalate ester biomarkers in urine without preconcentration: method validation and monitoring. J Chromatogr A 2013;1294:25–32.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 18.

    Wu J, Ye Z, Li X, Wang X, Luo F, et al. Optimization of a NH4PF6-enhanced, non-organic solvent, dual microextraction method for determination of phthalate metabolites in urine by high performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 2016;1014:1–9.CrossrefPubMedGoogle Scholar

  • 19.

    Sun J-N, Shi Y-P, Chen J. Simultaneous determination of plasticizer di(2-ethylhexyl)phthalate and its metabolite in human urine by temperature controlled ionic liquid dispersive liquid-liquid microextraction combined with high performance liquid chromatography. Anal Methods 2013;5:1427–34.Web of ScienceCrossrefGoogle Scholar

  • 20.

    Ogden CL, Kuczmarski RJ, Flegal KM, Mei Z, Guo S, et al. Centers for Disease Control and Prevention 2000 growth charts for the United States: improvements to the 1977 National Center for Health Statistics version. Pediatrics 2002;109:45–60.PubMedCrossrefGoogle Scholar

  • 21.

    Clark EJ, Norris DO, Jones RE. Interactions of gonadal steroids and pesticides (DDT, DDE) on gonaduct growth in larval tiger salamanders, Ambystoma tigrinum. Gen Comp Endocrinol 1998;109:94–105.CrossrefPubMedGoogle Scholar

  • 22.

    Toppari J. Environmental endocrine disrupters and disorders of sexual differentiation. Semin Reprod Med 2002;20:305–12.CrossrefPubMedGoogle Scholar

  • 23.

    Toppari J, Skakkebaek NE. Sexual differentiation and environmental endocrine disrupters. Baillieres Clin Endocrinol Metab 1998;12:143–56.CrossrefPubMedGoogle Scholar

  • 24.

    Takeyoshi M, Yamasaki K, Sawaki M, Nakai M, Noda S, et al. The efficacy of endocrine disruptor screening tests in detecting anti-estrogenic effects downstream of receptor-ligand interactions. Toxicol Lett 2002;126:91–8.CrossrefPubMedGoogle Scholar

  • 25.

    Harley KG, Berger K, Rauch S, Kogut K, Henn BC, et al. Association of prenatal urinary phthalate metabolite concentrations and childhood bmi and obesity. Pediatr Res 2017;82:405–15.Web of SciencePubMedCrossrefGoogle Scholar

  • 26.

    Ahmed ML, Ong KK, Dunger DB. Childhood obesity and the timing of puberty. Trends Endocrinol Metab 2009;20:237–42.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 27.

    Burt Solorzano CM, McCartney CR. Obesity and the pubertal transition in girls and boys. Reproduction 2010;140:399–410.Web of ScienceCrossrefPubMedGoogle Scholar

  • 28.

    Casazza K, Goran MI, Gower BA. Associations among insulin, estrogen, and fat mass gain over the pubertal transition in African-American and European-American girls. J Clin Endocrinol Metab 2008;93:2610–5.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 29.

    Dunger DB, Ahmed ML, Ong KK. Effects of obesity on growth and puberty. Best Pract Res Clin Endocrinol Metab 2005;19:375–90.CrossrefPubMedGoogle Scholar

  • 30.

    Jasik CB, Lustig RH. Adolescent obesity and puberty: the “perfect storm”. Ann N Y Acad Sci 2008;1135:265–79.PubMedCrossrefGoogle Scholar

  • 31.

    Kaplowitz PB. Link between body fat and the timing of puberty. Pediatrics 2008;121(Suppl 3):S208–17.CrossrefWeb of SciencePubMedGoogle Scholar

  • 32.

    Martos-Moreno GA, Chowen JA, Argente J. Metabolic signals in human puberty: effects of over and undernutrition. Mol Cell Endocrinol 2010;324:70–81.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 33.

    Roemmich JN, Clark PA, Lusk M, Friel A, Weltman A, et al. Pubertal alterations in growth and body composition. VI. Pubertal insulin resistance: relation to adiposity, body fat distribution and hormone release. Int J Obes Relat Metab Disord 2002;26:701–9.PubMedCrossrefGoogle Scholar

  • 34.

    Krstevska-Konstantinova M, Charlier C, Craen M, Du Caju M, Heinrichs C, et al. Sexual precocity after immigration from developing countries to Belgium: evidence of previous exposure to organochlorine pesticides. Hum Reprod 2001;16:1020–6.CrossrefPubMedGoogle Scholar

  • 35.

    Parent AS, Teilmann G, Juul A, Skakkebaek NE, Toppari J, et al. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr Rev 2003;24:668–93.CrossrefPubMedGoogle Scholar

  • 36.

    Rasier G, Toppari J, Parent AS, Bourguignon JP. Female sexual maturation and reproduction after prepubertal exposure to estrogens and endocrine disrupting chemicals: a review of rodent and human data. Mol Cell Endocrinol 2006;254–255:187–201.PubMedGoogle Scholar

  • 37.

    Dhillo WS, Chaudhri OB, Patterson M, Thompson EL, Murphy KG, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab 2005;90:6609–15.CrossrefPubMedGoogle Scholar

  • 38.

    Dhillo WS, Murphy KG, Bloom SR. The neuroendocrine physiology of kisspeptin in the human. Rev Endocr Metab Disord 2007;8:41–6.Web of ScienceCrossrefPubMedGoogle Scholar

  • 39.

    Popa SM, Clifton DK, Steiner RA. The role of kisspeptins and GPR54 in the neuroendocrine regulation of reproduction. Annu Rev Physiol 2008;70:213–38.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 40.

    Mueller JK, Heger S. Endocrine disrupting chemicals affect the gonadotropin releasing hormone neuronal network. Reprod Toxicol 2014;44:73–84.CrossrefWeb of SciencePubMedGoogle Scholar

  • 41.

    Navarro VM, Sanchez-Garrido MA, Castellano JM, Roa J, Garcia-Galiano D, et al. Persistent impairment of hypothalamic KiSS-1 system after exposures to estrogenic compounds at critical periods of brain sex differentiation. Endocrinology 2009;150:2359–67.Web of ScienceCrossrefPubMedGoogle Scholar

  • 42.

    Patisaul HB, Todd KL, Mickens JA, Adewale HB. Impact of neonatal exposure to the ERalpha agonist PPT, bisphenol-A or phytoestrogens on hypothalamic kisspeptin fiber density in male and female rats. Neurotoxicology 2009;30:350–7.PubMedCrossrefGoogle Scholar

About the article

*Corresponding author: Vichit Supornsilchai, MD, Associate Professor of Pediatrics, Division of Pediatric Endocrinology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand, Phone: +662-256-4996 (ext 115), Fax: +662-256-4911

Received: 2017-07-19

Accepted: 2017-10-04

Published Online: 2017-11-25

Published in Print: 2017-11-27

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: This study was funded by the Ratchadapiseksomphot Endowment Fund of Chulalongkorn University, Bangkok, Thailand (Grant no. RA58/090).

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Citation Information: Journal of Pediatric Endocrinology and Metabolism, Volume 30, Issue 12, Pages 1293–1298, ISSN (Online) 2191-0251, ISSN (Print) 0334-018X, DOI: https://doi.org/10.1515/jpem-2017-0281.

Export Citation

©2017 Walter de Gruyter GmbH, Berlin/Boston.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Maria Street, Sabrina Angelini, Sergio Bernasconi, Ernesto Burgio, Alessandra Cassio, Cecilia Catellani, Francesca Cirillo, Annalisa Deodati, Enrica Fabbrizi, Vassilios Fanos, Giancarlo Gargano, Enzo Grossi, Lorenzo Iughetti, Pietro Lazzeroni, Alberto Mantovani, Lucia Migliore, Paola Palanza, Giancarlo Panzica, Anna Papini, Stefano Parmigiani, Barbara Predieri, Chiara Sartori, Gabriele Tridenti, and Sergio Amarri
International Journal of Molecular Sciences, 2018, Volume 19, Number 6, Page 1647

Comments (0)

Please log in or register to comment.
Log in