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

No potential conflict of interest Ch.Sultan M.D. From : Le Monde (Dec. 2009) No potential conflict of interest

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

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

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

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

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"

Pediatrics, 2009

Pediatrics, 2010

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 ») ++

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

Best Practice & Research Clinical Endocrinology & Metabolism, 2006

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

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

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

Kisspeptin neurons as central processors in the regulation of GnRH secretion / onset of puberty

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

Activité estrogèno-mimétique Paris F., Mol.Cell.Endo., 2002, 160: 39-44

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

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 +

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

Med Sci Monit, 2009

* 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 11.6 years vs non-breastfed girls 12.5 years (2) The great lakes cohort . DDE (DDT) = lowers age of menarche

(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 11. 6 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)

* 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 11.6 years vs non-breastfed girls 12.5 years (2) The great lakes cohort . DDE (DDT) = lowers age of menarche

* 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

Environmental disruptors and precocious puberty in adopted girls (M. Kristewska et al, 2001)

* 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

* 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 16/10 000 / intensive agricultural area

Gaspari et al. submitted Premature thelarche: a consequence of environmental pollutants exposure? Mean: 12.31 ± 7.05 Controls: 3.53 ± 2.23 (p <0.01) Gaspari et al. submitted

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

Schoeters, 2008

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

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 ++

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 ++

Consequences of early maturation of girls

International Journal of Obesity, 2005

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

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

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

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

* 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 !

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

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

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

Conclusion 3

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