Ovarian Ageing: mechanisms and clinical consequences Reproductive Ageing: a basic and clinical update SSIF, Taormina, April 29 and 30, 2011

Transcription

1 Ovarian Ageing: mechanisms and clinical consequences Reproductive Ageing: a basic and clinical update SSIF, Taormina, April 29 and 30, 2011 Frank J Broekmans Professor Reproductive Medicine and Surgery University Medical Center Utrecht 35

2 Health risks associated with menopause Early menopause is related to: Cardiovascular disease Decreased bone density Colorectal cancer Infertility Hartge, 2009 Late menopause is related to: Breast, endometrial and ovarian cancer

3 Questions What do we know about mechanisms of Ovarian Ageing? How are quantity and quality decline in Ovarian Ageing related? Are reliable Markers available for estimating Ovarian Age? Can these Markers help us in Clinical Conditions? Conclusions

4 Reproductive Ageing = Ovarian Ageing Not CNS Ageing

5 Phases Ovarian ageing process Age in yrs Soules FS 2001

6 Follicle wastage at high speed Primordial follicle number weeks Fetal Life 18 weeks 40 weeks Pre puberty Regular cycles Irregular years Extra-Uterine life

7 Frequency of Occurrence Menopause.. and its variation 400 Distribution of Age at Menopause final cessation of cyclic ovarian function ,00 30,81 38,62 46,43 54,24 62,05 Age at Menopause

8 Is variation in AMP caused by difference in peak numbers of follicles?? Wallace, PLOSone2010

9 Number of follicles Proportion of poor quality oocytes (%) Ovarian Ageing = Quantity and Quality Decline of Follicles and Oocytes with age Number of follicles Proportion of poor quality oocytes Optimal fertility Declining fertility End of fertility Menopause Age (years) Irregular cycles Redrawn after de Bruijn, te Velde. In: Preservation of fertility. London, Taylor & Francis, 2004:3.

10 Fecundity declines with female age Evidence from Natural Populations

11 Resumed meiosis is increasingly defective with higher female age Rate of haploidy and the incidence of aneuploidy according to maternal age in a sample of 1,397 human oocyte II karyotypes. Pellestor, CCI 2005 young egg donors old egg donors First meiotic spindles in oocytes Volarcik, 1998

12 The issue is Variability

13 Age at last child in Natural Fertility population: variability Broekmans 2004, Bouchard 1994 Frequency of Occurrence Distribution of Age at Menopause ,00 30,81 38,62 46,43 54,24 62,05 Age at Menopause

14 Parallellity and Variation in Reproductive Events Distributions of age at: Age last child Onset Cycle Irregularity Natural Menopause Broekmans, 2009 Treloar, 1981 den Tonkelaar, 1998

15 Source of Variation Folliculogenesis Continuous Intermittent

16 Source of Variation Multiple environmental AND genetic factors COMPLEX TRAIT Environmental factors: Smoking Iatrogenic Rosen, MP 2010 Genetic factors: Multiple genes involved Heritability 65-80% Snieder, 1998; de Bruin, 2001; van Asselt 2004

17 What do we know about mechanisms of Ovarian Ageing? Follicle wastage largely Unnoticed Oocyte quality decline reducing Fertility Variability Genetic factors dictate Quantity

18 Questions What do we know about mechanisms of Ovarian Ageing? How are quantity and quality decline in Ovarian Ageing related? Are reliable Markers available for estimating Ovarian Age? Can these Markers help us in Clinical Conditions? Conclusions

19 Poor Responders to hyperstimulation have poorer oocyte and embryo quality OMEGA study Vd Gaast, RBM 2006

20 Artificial Reduction in Quantity Mice experiments Ovx Mice: Earlier onset of irregular cyclicity Earlier onset of aneuploidy Difference age independant Brook, HumGen 1989

21 The poor responder in IVF: is the prognosis always poor? Age matters!!! Female age and pregnancy rate per cycle started in Poor Responders (n=3200) Author Female age >46 Biljan et al % 4.2% Galey-Fontaine et al % 4.9% Hanoch et al % 6.0% 6.5% Inge et al % 12.7% Rooij, van et al % 4.0% Saldeen et al % 3.0% Sutter, de et al % 12.0% Ulug et al. 19.5% 7.2% 1.5% Yih et al % 21% 17% 11% Zhen et al % 2.8% A systematic literature review. Oudendijk and Yarde, Submitted 2011

22 Poor Response relates to Miscarriage Rate in ART pregnancies, effect is age related Haadsma, RBM 2010

23 Age matched relation between Ovarian Response or Surgery and Odds for Trisomy Odds Ratio Odds Ratio Odds For Trisomic Pregnancy 5 4,5 4 3,5 3 2,5 2 1,5 1 0,5 0 Haadsma, to 4 5 to 8 9 reference Response Categories (oocyte number) Odds for Trisomic Pregnancy 3,5 3 2,5 2 1,5 1 0,5 0 yes Previous Ovarian Surgery no

24 P Poor Responder and Cumulative OPRates Probability Ongoing Pregnancy in IVF cycle 2 or PR NR Exp PR Expected = abnormal ORT Unexp PR (FSH AMH AFC InhB) Female Age Hendriks, RBM 2008

25 The concept of Quantity and Quality Broer, Academic Thesis, 2011 Number of Follicles Poor Oocyte Quality Rate Optimal Fertility Declining fertility Menopausal Transition Post Menopause End of Fertility % % 60% % % % Age (years)

26 How are quantity and quality decline in Ovarian Ageing related? Variability may be dictated by different mechanisms Female age interferes with the effect of quantity

27 Questions What do we know about mechanisms of Ovarian Ageing? How are quantity and quality decline in Ovarian Ageing related? Are reliable Markers available for estimating Ovarian Age? Can these Markers help us in Clinical Conditions? Conclusions

28 Number of follicles Proportion of poor quality oocytes (%) A good marker should correctly predict oocyte quality and ongoing pregnancy prospects: Current Fertility Prediction A good marker describes the wastage pattern of the primordial follicle pool: Menopause Prediction Reproductive Lifespan Number of follicles Proportion of poor quality oocytes Optimal fertility Declining fertility End of fertility Menopause Age (years) Irregular cycles

29 Variation in age at menopause and preceding reproductive events Cumulative % Age

30 Menopause and Natural Sterility have fixed time relation: reproductive lifespan prediction Cumulative % Te Velde, HRU Age

31 Does the similarity imply interrelationship at the individual level?? Distributions of age at: Age last child Onset Cycle Irregularity Natural Menopause Broekmans, 2009 Treloar, 1981 den Tonkelaar, 1998

32 Poor Quantity = Early Menopause De Boer, HR 2002 Broekmans, End Rev 2009

33 Relation Age MP and onset Cycle irregularity Lisabeth, JCE 2004

34 Ovarian reserve tests Female age Basal Hormones FSH, Anti-Müllerian Hormone (AMH) Sonographic parameters Antral follicle count (AFC)

35 Circulating AMH 6-10 mm 2-5 mm? Pre-antral follicles Primary follicles 0,1-2 mm the AFC Primordial pool Broekmans, ER 2009, Broer, COOG 2010

36 Markers according to STRAW Broekmans, 2010

37 Are reliable Markers available for estimating Ovarian Age? Direct Quality markers are absent For the purpose of Current Fertility prediction Quantitative markers may fail.. Future Fertility Prediction Quantitative markers are promising..

38 Questions What do we know about mechanisms of Ovarian Ageing? How are quantity and quality decline in Ovarian Ageing related? Are reliable Markers available for estimating Ovarian Age? Can these Markers help us in Clinical Conditions? Conclusions

39 Response prediction IVF AMH Lab test Cycle stable Assay!!!!!!!! Accuracy Hyperresponse prediction AFC Clinical test Cycle stable Standardisation!!! Broer, 2009, 2010

40 Searching for the zero prognosis patient

41 Current Fertility Prediction Individual Patient Data Analysis: the IMPORT study Female age with or without any ORT fails to predict accurately zero prognosis cases N=5500 AUC Age 0.57 AFC 0.50 AMH 0.55 Age + AFC 0.58 Age + AMH 0.57

42 Female age and AMH in concert may indicate levels of prognosis for live birth

43 Future Fertility = Menopause Prediction FollowUp Data 255 women with proven fertility, years and regular cycles at T1 AMH measured Broer, JCEM, 2011 T1 12 years T2 1996/ /2009

44 Predicting age Menopause from age and AMH Broer JCEM, 2011 Low age specific AMH Shift towards younger age at menopause High age specific AMH Shift towards higher age at menopause

45 Family History MP age of mother affects the ovarian reserve conditions of the daugther (at average 40) Steiner, Menopause 2008

46 Messages The variability in timing of ovarian ageing is considerable and affects fertility and more Relation between quality and quantity is confusing, but likely age dependant Markers for ovarian ageing reflect quantity and poorly reflect fertility (better focus on Reproductive Life span prediction?)

47 Thank You Frank Broekmans Professor Reproductive Medicine and Surgery University Medical Centre Utrecht The Netherlands the IMPORT* studygroup Richard A. Anderson Mahnaz Ashrafi László Bancsi, Ettore Caroppo, Alan B. Copperman, Thomas Ebner, Talia Eldar-Geva, Mehmet Erdem, Ellen M. Greenblatt, Kannamannadiar. Jayaprakasan, Nick Raine-Fenning, Ellen Klinkert, Janet Kwee, Antonio La Marca, MyvanwyMcIlveen, Luis T. Merce, Shanthi Muttukrishna, Scott M. Nelson, Ernest H.Y. Ng, Biljana Popovic Todorovic, Jesper M.J. Smeenk, Candido Tomás Paul J.Q. Van der Linden, K.Vladimirov, Patrick Bossuyt Simone Broer Jeroen van Disseldorp Monique Sterrenburg Marieke Verberg Dave Hendriks Ellen Klinkert Ilse van Rooij Laszlo Bancsi Kim Broeze (AMC) Brent Opmeer (AMC) Madeleine Dolleman Bart Fauser Nick Macklon (Southampton) Ben W Mol (AMC) Nils Lambalk (VUMC)