Presentation on theme: "Why is Infertility Growing in Europe?"— Presentation transcript:
1 Why is Infertility Growing in Europe? Is there a link between different disorders ofmale reproductive organs and exposure tochemical compounds?Henrik Leffers University Department of Growth & Reproduction, Rigshospitalet, Copenhagen
2 Declining conception rates among cohorts of younger women Jensen et al Declining conception rates among cohorts of younger women Jensen et al. IJA, 2008
3 Declining conception rates among cohorts of younger women Jensen et al Declining conception rates among cohorts of younger women Jensen et al. IJA, 2008
4 Reproductive health problems Human reproductive health problems are very common, some are increasingThe man sitting next to you has probably more than 80% morphologically abnormal sperms (>90 %, if he is a young Dane)High demand for ART: almost 8 % of all Danish children were in 2007 born after IVF, ICSI, homolog or donor inseminationIn most cases the etiology is really not known, although we use terms as ”oligozoospermia” and ”ovarian failure”Do endocrine disrupters play a role?
6 Oct-4 expression in CIS cells (adult, subfertile male)
7 Gene expression in CIS cells in relation to germ cell differentiation PGCESCGonocyteInfantilesp-goniumBirthPubertySp-goniumCIS:SpermatocytesSpermatidsNANOG:OCT-4:AP-2TRA-1-60:PLAP:KIT:p53:Cyclin D2:CHK-2 :TSPY:MAGE A4:NY-ESO-1:DAZL 1:Hiwi:VASA:IMP-1:Pluripotency, self-renewal, survival in undifferentiated stageRegulation of cell cycle,DNA repair (mitotic division)Germ cell specifice.g. RNA processing
8 Rates in testis cancerDuring the many decades there have been a steadly increase in testicular cancer incidence in all the Nordic countries, with Denmark having the highest incidence followed by Norway, then Sweden and Finland.However, recently there have been a change as the incidence have decreased for denmark in the periodIn the search for causal factors irregularities from the general tendencies can often provide new clues as have been seen forexample with the war time effect, with men being born during the second world war had a lower risk of TC in many western countries.
9 Lessons from recent biological and epidemiological research on testis cancer Testis cancer is a sensor for poor reproductive health (incl. cryptorchidism, poor semen quality)Testis cancer is of fetal origin. Therefore, a search for causal factors should be directed towards adverse effects on the fetal testisIncreasing incidence of testis cancer. Other male reproductive problems are also becomming more common!
10 Perinatal exposure of Rats to Phthalates (DEHP, DBP) May cause a ”phthalate syndrome” in male offspring, includingLeydig cell abnormalitiesDysgenesis of Leydig cells and seminiferous tubulesHypospadiasUndescended testisSpermatogenic failure and infertility(Several papers from Paul Foster’s, Earl Gray’s, Rao Veeramachaneni’s and Richard Sharpe’s groups)
11 Phthalate Effects on Testis Dysgenetic areas in the testes on d4 postnatal after in utero exposure to DBP (500 mg/kg/day) Fisher et al. Hum Reprod, 2003)ControlDBPBrown = smooth muscle actin
12 The Rat Phthalate Syndrome Resembles Human Problems
13 Does Chemical Exposure Affect the Human Fetus? Association between excretion of phthalates in pregnant women’s urine and ano-genital distance in newborn boys, Swan et al. 2005
14 Does Chemical Exposure Affect the Fetus? Association between excretion of phthalates in pregnant women’s urine and ano-genital distance in newborn boys, Swan et al. 2005Association between Phthalate levels in breats milk and subtle changes in hormone levels in 3 month old boys, Main et al. 2006
15 Collection of breast milk Breast milk: post nataly month 1, n=130Serum samples from the children at 3 months, n= 96Btreats milk samples wree collected from 1 month after birth as additive aliquots over consecutive feedings, to obtain an everage exposure level during the first months of life. They were frozen at home and delivered to us at the 3 months exam of the child. In the 130 we selecetd for chemical analyseis, we were successful in obtaining a serum sample form 96 children at three months of age as well.
16 mEP, mBP: mBP: mMP, mEP, mBP: miNP: Changes in boys hormone levels associated with 10 fold higher phthalate levels in the milkmEP, mBP:mBP:mMP, mEP, mBP:miNP:+ 15,+8 % SHBG- 15% free testosterone+ 26, +19, +18 % LH /free testosterone ratioThese effects were seen also with some of the other metabolites, and I want to draw your attention especially to miNP, the phthalate foudn in highest concentration in milk, which was associaed with LH. Together, the effects seen fit with an anti-androgenic effect which triggers a higher LH drive.+ 97% LHMain KM et al. EHP 2006
17 Does Chemical Exposure Affect the Fetus? Association between excretion of phthalates in pregnant women’s urine and ano-genital distance in newborn boys, Swan et al. 2005Association between Phthalate levels in breats milk and subtle changes in hormone levels in 3 month old boys, Main et al. 2006Persistent pesticides in breast milk and cryptorchidism in the sons, Damgaard et al. 2006Flameretardants in breast milk and chryptorchidism in the sons, Main et al. 2007
18 Ongoing project: Uptake of phthalates and parabens through skin Comparisons between applications of ”basis lotion” with and without 2% phthalates and 2% parabensBloodsampling during 24 hours
19 Mono-butyl-phthalate in serum during 24 hours Janjua NR, Mortensen GK, Skakkebæk NE, Wulf HC, Andersson AM, 2008.
20 It seems safe to conclude…. The phthalates DEP, DBP, and BuP are rapidly taken up through the skin after topical application.Although these compounds have a high clearance rate some accumulation by every day use can occur.Normal use of cosmetics and skin care products containing these compounds is likely to result in recurrent serum spikes of the parent compounds and their metabolites.Janjua NR, Mortensen GK, Skakkebæk NE, Wulf HC, Andersson AM, 2008.
21 Effects of Mixtures of Endocrine Disrupting Substances Ulla Hass Dept. of Toxicology and Risk Assessment, National Food Institute, Danish Technical University, Denmark
22 Design of EDEN studies Anti-androgen alone or in mix Young adults: Malformations, semen quality, behaviourVia placentaVia milkBirthPups: AGD, nipple retention, reproductive organs, gene expression
23 Malformations of external reproductive organs in adult male offspring 1) Completely split penis and visible os penis, i.e. marked hypospadia 2) Blind vaginal opening
24 Something from Nothing 0% + 0% + 0% ~ 60%Christiansen et al 2008, Int. J. Androl. 31
26 Differences in prevalence of genital abnormalities between Denmark and Finland (From Boisen et al. Lancet 2004;Boisen et al. JCEM 205)DenmarkFinland
27 Geographic association between abnormalities in male reproductive health DenmarkHigh incidence of testicular cancerHigh prevalence of cryptorchidismHigh prevalence of hypospadiasLow sperm countsSmaller testes as newborns and lower inhibin-B levelsFinlandLow incidence of testicular cancerLow prevalence of cryptorchidismLow prevalence of hypospadiasHigh sperm countsBigger testes as newborns and higher inhibin-B levels
28 Can Different Environmental Exposures between Denmark and Finland explain the Different Reproductive Health Patterns?More Danish women smoke and drink during pregnancy (Jensen et al. Am J Epidemiol. 2004)Associations to different exposures to EDs?
29 Chemicals in breast milk from mothers of newborn boys DanishFinnish*: p<0.05
30 Conclusions We are all exposed to a mixture of endocrine disrupters ”Antiandrogenic” agents may be as important as chemicals with estrogenic actionsEvidence that testicular cancer, cryptorchidism, hypospadias and poor semen quality can be linked through a fetal mechanism causing testicular dysgenesis (TDS syndrome)We are beginning to see associations between fetal exposures of humans to some endocrine disrupters and symptoms of TDSCausal relationships between EDs and reproductive symptoms have been established in experimental animals, but not in humansCurrent ED research is focussed on the issue of possible additive effects of mixtures of different chemicals with different actions
31 Thanks toNiels E. Skakkebæk, Niels Jørgensen, Katharina Main, Anna-Maria Andersson, Ewa Rajpert-De Meyts, Anders Juul and several of their Ph.D. studentsJorma Toppari, FinlandOther European collaboratorsAnd many others