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Les lolitas : environnement et précocité sexuelle
Charles Sultan Françoise Paris Pascal Philibert Nicolas Kalfa Laura Gaspari Laurent Maimoun Jean Pierre Daurès 1 - Unité d’Endocrinologie et Gynécologie Pédiatriques, Service de Pédiatrie I, Hôpital Arnaud de Villeneuve, CHU Montpellier, France 2 - Service d’Hormonologie (Développement et Reproduction), Hôpital Lapeyronie, CHU Montpellier, France 3 - Institut de Génétique Humaine, CNRS UPR1142, Montpellier, France 4 - Département d'informatique Médicale du CHU de Nîmes et EA-2415 UM-1 GYN 2012, 2 Juin 2012, Monaco
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No potential conflict of interest
Ch.Sultan M.D. From : Le Monde (Dec. 2009) No potential conflict of interest
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Les lolitas : environnement et précocité sexuelle
Outline 1 – Secular trends in timing of puberty 2 – Environmental endocrine disruptors and early / precocious puberty - animal studies - in vitro data - studies in human 3 – Consequences of earlier maturation of girls 4 - Conclusion
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Les lolitas : environnement et précocité sexuelle
1 – Secular trends in timing of puberty 2 – Environmental endocrine disruptors and early / precocious puberty - animal studies - in vitro data - studies in human 3 – Consequences of earlier maturation of girls 4 - Conclusion
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The range of attainment of various stages of puberty in females
(PAG books) Breast Development Stages 2 3 4 5 Pubic Hair Stages 2 3 4 5 Regular Menses Menarche Axillary Hair Max. Growth Rate Age (Yrs) 8 10 12 14 16
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Les lolitas : environnement et précocité sexuelle
* the secular trend toward earlier pubertal development * earlier onset of puberty (Herman-Giddens, US) - cross-sectional - clinically based study prevalence of B2/P2 at age - 8 years - 15% white girls - 48% black significant increase in the percentage of girls entering puberty at an earlier age / than previously reported * the age of puberty onset has fallen substantially
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Les lolitas : environnement et précocité sexuelle
. Environmental signals Secondary sexual characteristics and menarche in young girls M. Herman-Giddens, Pediatrics 1997, 99, 4, 505 “increasing use of plastics, insecticides .… (environmental disrupting chemicals) should be investigated in relation to the earlier onset of puberty"
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Pediatrics, 2009
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Pediatrics, 2010
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Les lolitas : environnement et précocité sexuelle
* the secular trend toward earlier pubertal development theories and speculations 1 - overall improvement in socioeconomic conditions 2 - public health success (nutrition, infection) 3 - effect of different types of diet (soy-based formulas) 4 - greater BMI(dietary intake, physical activity) 5 - change in social structures (stress = a puberty accelerator) 6 - hypersexualization of culture 7 - genetic differency among racial / ethic groups 8 - adaptive mechanisms ? 9 – endocrine disrupting chemicals (« xenoestrogens ») ++
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Les lolitas : environnement et précocité sexuelle
1 – Secular trends in timing of puberty 2 – Environmental endocrine disruptors and early / precocious puberty - animal studies - in vitro data - studies in human 3 – Consequences of earlier maturation of girls 4 - Conclusion
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Best Practice & Research Clinical Endocrinology & Metabolism, 2006
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Les lolitas : environnement et précocité sexuelle
1 – Secular trends in timing of puberty 2 – Environmental endocrine disruptors and early / precocious puberty - animal studies - in vitro data - studies in human 3 – Consequences of earlier maturation of girls 4 - Conclusion
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Les lolitas : environnement et précocité sexuelle
* Animal studies 1. Exposure to bisphenol A advances puberty (K.L. Howdeshell) prenatal exposure to a dose of bisphenol A comparable to levels found in the environment postnatal growth rate ( weight) - accelerated the postpubertal ovulation ( puberty) Nature, 1999, 401, 763
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Les lolitas : environnement et précocité sexuelle
* Animal studies 2. Exposure of newborn female rats to environmental estrogens : sustained hyperprolactinemia and alterations in E2-Rc expression (S. Khurana, Endocrinology, 2000, 141, 4512) Bisphenol A: up-regulated ER expression MBH . uterus in prepubertal rats
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Kisspeptin neurons as central processors in the regulation of GnRH secretion / onset of puberty
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Les lolitas : environnement et précocité sexuelle
1 – Secular trends in timing of puberty 2 – Environmental endocrine disruptors and early / precocious puberty - animal studies - in vitro data - studies in human 3 – Consequences of earlier maturation of girls 4 - Conclusion
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Activité estrogèno-mimétique
Paris F., Mol.Cell.Endo., 2002, 160: 39-44
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ERa, ERb and AR activity of various phenyl-derived compounds
Chemical structure and name ERa ERb AR 100 100 100 75 75 75 50 50 50 25 25 25 bisphenol A 25 50 75 100 310-5 10-6 310-6 10-5 310-7 10-7 4-tert-octylphenol concentration (M) concentration (M) concentration (M) F. Paris, MCE, 2002
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Les lolitas : environnement et précocité sexuelle
. Environmental signals = chemical (EDCS) Mechanisms of action 1 - Activation of transcription of estrogen-dependent genes 2 - Reduction of transcriptional activity induced by androgens 3 - Transcriptional repression of downstream genes 4 – Impact on the Kiss-GPR-54 system 5 - Oncogenic effect 6 - Transgenerational impact 7 - Adipose tissue +
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Les lolitas : environnement et précocité sexuelle
1 – Secular trends in timing of puberty 2 – Environmental endocrine disruptors and early / precocious puberty - animal studies - in vitro data - studies in human 3 – Consequences of earlier maturation of girls 4 - Conclusion
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Med Sci Monit, 2009
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* Epidemiological studies in girls
Les lolitas : environnement et précocité sexuelle * Epidemiological studies in girls (1) Michigan cohort (4000 individuals) : PCB . Breast-fed daughters of mothers with a high serum PCB = earlier menarche years vs non-breastfed girls years (2) The great lakes cohort . DDE (DDT) = lowers age of menarche
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(H.W. Blank, Epidemiology, 2000, 11, 641)
Les lolitas : environnement et précocité sexuelle Breastfed girls born to women who had been accidentally exposed to polybrominated biphenyls have a earlier menarche (11. 6 y) , vs (12.7 years) According to PBB levels in utero High exposure y Moderate exposure 12.2 y Low exposure 12.6 y Not breasfted 12.7 y Post-natal (translactational) exposure to biphenyl accelerate onset of puberty (H.W. Blank, Epidemiology, 2000, 11, 641)
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* Epidemiological studies in girls
Les lolitas : environnement et précocité sexuelle * Epidemiological studies in girls (1) Michigan cohort (4000 individuals) : PCB . Breast-fed daughters of mothers with a high serum PCB = earlier menarche years vs non-breastfed girls years (2) The great lakes cohort . DDE (DDT) = lowers age of menarche
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* Epidemiological studies in girls
Les lolitas : environnement et précocité sexuelle * Epidemiological studies in girls (3) BOURGUIGNON (2001) = adopted girls with CPP = DDE levels : 5 to 10 tms higher / native belgium girls (4) WANG (2005) National Children's study = exposure to EDCS in utero can alter - the growth of mammary glands - the age of onset of puberty of the offsprings
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Environmental disruptors and precocious puberty in adopted girls
(M. Kristewska et al, 2001)
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* Epidemiological studies in girls
Les lolitas : environnement et précocité sexuelle * Epidemiological studies in girls (3) BOURGUIGNON (2001) = adopted girls with CPP = DDE levels : 5 to 10 tms higher / native belgium girls (4) WANG (2005) National Children's study = exposure to EDCS in utero can alter - the growth of mammary glands - the age of onset of puberty of the offsprings
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* Epidemiological studies in girls
Les lolitas : environnement et précocité sexuelle * Epidemiological studies in girls (5) COLON ( 2000) = premature thelarche in girls / phtalates = phtalate levels x 5 (adipose tissues) (6) MASSART (2005) = Precocious puberty in girls from Toscany = Prevalence of CPP 16/ / intensive agricultural area
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Gaspari et al. submitted
Premature thelarche: a consequence of environmental pollutants exposure? Mean: ± 7.05 Controls: 3.53 ± 2.23 (p <0.01) Gaspari et al. submitted
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4-month-old girl vaginal bleeding (3 times) B 3-4, marked pigmentation of mammary areola no pubic hair pelvic ultrasonography uterine lenght 69 mm !!! BA = CA GnRH test - Family living on a farm where 22 tons of several pesticides (p,p’-DDD, p,p’-DDT, lindane, endosulfan sulfate) Father reported a decreased libido
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Schoeters, 2008
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Les lolitas : environnement et précocité sexuelle
1 – Secular trends in timing of puberty 2 – Environmental endocrine disruptors and early / precocious puberty - animal studies - in vitro data - studies in human 3 – Consequences of earlier maturation of girls 4 - Conclusion
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the secular trend toward earlier pubertal development
implications As puberty has advanced biological maturation has come to precede psychological and social maturation significantly this developmental mismatch has considerable societal implications ++
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Consequences of early maturation of girls
Les lolitas : environnement et précocité sexuelle Consequences of early maturation of girls 1 - Greater weight and BMI 2 – Insulin resistance 3 – Metabolic syndrome 4 - PCOS 5– Cardio-vascular diseases 6 – Breast cancer risk ++
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Consequences of early maturation of girls
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International Journal of Obesity, 2005
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Consequences of early maturation of girls
Les lolitas : environnement et précocité sexuelle Consequences of early maturation of girls 1 – Lower self-esteem during adolescence 2 – Lower level of body satisfaction 3 – Greater likewood of depression 4 – Greater likewood of earling disorders 5 – Greater perceived stress 6 – Greater vulnerability to peer pressures 7 – Younger age of sexual initiation 8 – Younger age of smoking and drug use 9 – Lower life-long academic achievement
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Pubertal timing, and not pubertal status, increases the risk of
negative psychological outcome negative social outcome for the teenagers Child Psychiatry and Human Development, 2005
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Early maturing girls : at risk for
1 – psychosocial adaptation problems 2 – depression and anxiety 3 – problem behaviors / delinquency 4 – physical aggression, hostility, hyperactivity 5 – earlier sexual behaviors 6 – sex transmitted diseases 7 – pregnancy ( contraceptive methods) « Puberty acceleration hypothesis « Child Psychiatry and Human Development, 2005
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Consequences of early pubertal timing
1 – Depression / physical changes 2 – Other internalizing symptoms (psychomatic ++) 3 – Eating disorders 4 – Poor academic performance 5 – Substance abuse 6 – Earlier initiation of sexual intercourse 7 - Delinquency Dev Rev, 2007
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* the secular trend toward earlier pubertal development
a risk factor ? a sentinel ? simply an event to be anticipated sooner 1 - early hyperestrogenization can increase the risk of some reproductive cancers ! . earlier feminization can result in girls adopting "adult" roles and behaviours before they are emotionally "mature" 2 - earlier onset of puberty (premature thelarche ppp) could be an indicator of exposure to environmental endocrine disruptors +++ 3 - care has to be taken not to medicalize early puberty inappropriately !
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Les lolitas : environnement et précocité sexuelle
1 – Secular trends in timing of puberty 2 – Environmental endocrine disruptors and early / precocious puberty - animal studies - in vitro data - studies in human 3 – Consequences of earlier maturation of girls 4 - Conclusion
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Les lolitas : environnement et précocité sexuelle
Conclusion 1 1 – The GnRH pulse generator is modulated by peripheral environmental signals 2 – EDC may have a direct / peripheral effect on breast premature thelarche 3 – EDC may contribute to obesity development / insulin- resistance EDC may thus have a major impact : 1 – increased prevalence of premature thelarche 2 – earlier pubertal onset in girls 3 – increased prevalence of precocious puberty in girls
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Les lolitas : environnement et précocité sexuelle
Conclusion 2 Public health issues EDC = a new paradigm - endocrine balance : fetus, newborn, adolescent, adult - metabolism, obesity - CNS : behavior, sex identity - estrogen-dependent cancers
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Conclusion 3
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Les lolitas : environnement et précocité sexuelle
"Attendre d'en savoir assez pour agir en toute lumière, c'est se condamner à l'inaction" Jean Rostand
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