“POF” Premature Ovarian Failure “New Fronteries”

1. “POF”Premature Ovarian Failure“New Fronteries” N.Cem FIÇICIOĞLU, M.D., Ph.D. Professor and Director Department of Gynecology & Obstetrics and IVF Center Yeditepe University, School of Medicine Istanbul

2. Ovarian failure is a natural consequence of the aging process

3. The life history of ovarian follicles ovulation Atresia cyclic recruitment After puberty initial recruitment Depletion of follicles maturation Atretic Antral Seconder primer (depletion) (initial recruitment) Primordial

4. Recruitment InitialRecruitment CyclicRecruitment Growth of significantnumber of smallfollicles Long time Slowdevelopement Beginswithpuberty FSH A limitedcount of follicles Everymounth Hirshfield 1989

5. Before menopause • The last 10-15 years before menopause • The rapid depletion of follicle when the total count reduced to 25.000

6. Unfortunately, many women experience premature ovarian failure while still in reproductive age Clinical Criteria for Diagnosing Premature Ovarian Failure •  4 months of amenorrhea • Two serum FSH values  40 mIU/mL • 1 month apart in a woman aged  40 7 Anasti JN. FertilSteril 1998;70:1-15

7. POFIncidence • By age 30’s%0.1 • By age 40’s%1

8. FSH≥40 IU/lthere is no follicle in theovaries Goldenberg RL Am J ObstetGynecol 1973;116:1003-9 • Therearesome intermittent ovarian functions in karyotypically normalovarian failure Rebar RW J ReprodMed 1982;27:179-186

10. FunctionalClassification of Premature ovarian failure Ovarian follicle depletion Ovarian follicle dysfunction Decreased reserve - Pure gonadal dysgenesis - Thymic hypo/aplasia - Idiopathic Accelerated atresia - X-related (Turner synd) - FMR-1 gene mutation - Galactosemia - Toxins - Iatrogenic - Viral oophoritis - Ataxia telangiectasia - Idiopathic Steroidogenic enzyme defects - 17  hydroxylase deficiency - 17-20 desmolase deficiency - Aromatase deficiency Autoimmunity - Lymphocytic oophoritis - Gonadotropin receptor antibodies? Signal defects - Abnormal gonadotropin receptor - Abnormal G protein signaling Specific genetic defects - Blepharophimosis-epicantus-ptosis syndrome Idiopathic - Resistant ovary syndrome Nelson et al. Endocrinol Metab Clin North Am. 2003;32(3):613-37

11. Increasing Number of POF-Related Genes are Identified on X-Chromosome Zfx (X-linked zinc finger protein) - located on Xp 22.1 and 21.3 - Zfx knock out mouse is infertile and has dimished number of germ cells DIA gene(Diaphanous gene) -located on Xq21 -contain 7 different regions for ovarian development in drosophilia USP9X gene (ubiquitin-specific protease 9 gene) - located on Xp11.4 - required for eye and gonad development in drosophila - function unknown in mammals XIST locus (X inactivation site) - located on Xq13 - required for the reactivation of the silenced X chromosome during oocyte maturation - 2 X chromosomes with 2 intact XIST loci are necessary for a normal meiosis to occur in the oocyte - mutation causes meiotic arrest and oocyte depletion • FMR1 gene (Fragile X) “ %6” • -located on Xq27.3 • -extreme expansion of CGG • repeats is associated with mental • retardation without POF • modest repeats cause POF • without mental retardation 8 Nelson et al. Endocrinol Metab Clin North Am. 2003;32(3):613-37

12. Fragil X mental retardation 1“FMR1” %6 • Triple CGG repeats 41-55 intermediate… increase risk of POF? 55-200 premutations… FXTAS…FXPOF >200 Full mutation… Fragile X syndrome Fertil Steril March 2007, Wittenberger, et all

13. Autoimmune Lymphocytic Oophoritis “%4” • Markedly enlarged ovaries with luteinized cysts (like PCOS but androgen deficiency) • Intense lymphocytic infiltration of theca • Primordial follicles spared • Typically with subsequent Addison’s, rarely isolated • Adrenal cortex autoantibodies • Part of autoimmune polyendocrinopathy (MIM) • FSH, LH, Androgens, Inhibin b Fertil Steril 2005 Bakolov et all

14. Laboratory Evaluation of POF • Karyotype for all (incidence not affected by age if not primary amenorrhea) • thyroid& adrenal antibodies • Ovarian antibodies of no proven benefit • Fragile X testing if family history of POF, MMR, Ataxia, Tremor etc.

15. Antimüllerian Hormon “AMH”, ‘MIF’ • This marker shows Primordial follicles pool • Ovarian aging / oocyte morfology • The relations with Antral follicles and age Fıçıcıoğlu C., Fertil.Steril. 2006 Silberstein T., Human Reproduction, 2005 De Vet A et al., Human Reproduction, 2002, NL

16. Early foll. AMH as an indicator of ovarian reserve. Fıçıcıoğlu C., et all. Fertil.Steril. 2006AMH >0.25 ng/ml %96, <0.25ng/ml only %23 good responders

19. A fertility profile,consistent of autoimmune testing and assessment of tripleCGG repeats on the FMR1 gene, could thus become a universalscreening test for the fertility potential of young women.

20. The prediction of ovarian function • FSH • Inhibin b • AMH • E2 • Antral follicle count • Over 30 triple count CGG repats on the FMR1 gene denote incresed risk toward premature ovarian senescence • Autoimmune testing Fertil Steril 2008, Gleicher N et all HumReprod 2008,Rohr J et all J Clin endocrino Metob 2008,Tsigkou A et all

21. Treatment and Follow Up • Prednisone for auotimmune ovarian failure unproven • Gonadotropin treatment is unproven and can exacerbate unrecognized autoimmune ovarian failure • ERT does not prevent pregnancies • Annual follow up for thyroid/diabetes screening; others if clinically indicated • Addison screening if antibody- positive

22. POF & Fertility Restoration • CC • Mehta AE, 1992 • Oestrogens • Chen FP, Chang SY, 1997 • OCP • Check JH, 1990 • Danazol • Anasti JN, 1994 • Gonadotrophins • Johnson TR, 1979 • GnRH Analogs • Ishizuka B, 1992 • Corticosteriods • Cowchock FS, 1988 • Van Kasteren YM, 1999

23. Effects of pretreatment with estrogens on ovarian stimulation with gonadotropins in women withpremature ovarian failure: a randomized, placebo - controlled trial Tartagni, M. Fertil Steril 2007;87:858 – 61.

24. The combination of corticosteroids with pituitary suppression followed by ovarian stimulation with gonadotrophin appeared to be beneficial in restoring ovarian function in patients with idiopathic POF and normal karyotype.

25. Corticosteroids do not influence ovarian responsiveness to gonadotropins in patients with premature ovarian failure: a randomized, placebo-controlled trial

28. Facts about cancer Radiotherapy Chemotherapy Not all cancer drugs havethe same gonadotoxic potential Gonadotoxicity. Abdominal irradiation Pelvic irradiation Craniospinal irradiation Total body irradiation

29. Different Classes of Agents Affect Different Stages of Follicular Growth Size of human follicles Small oocyte Primordial follicle Follicle initiation Alkylating Agents 50 mm Preantral Phase Platinum >3 Months 200 mm Anti- metabolites Developingantral cavity 500 mm FSH-dependent Expanding antrum 1000-6000 mm Antral Phase Preovulatory orGraafian follicle >6000 mm

30. High Risk Cyclophosphamide Chlorambucil Melphalan Busulfan Nitrogen Mustard Procarbazine Intermediate Risk Cisplatin Adriamycin Low Risk Methotraxate 5-Fluorouracil Vincristine Bleomycin Actinomycin D Indeterminate Risk Taxanes Cytotoxic Agents According to the Risk of Amenorrhea Modified from Sonmezer & Oktay, Hum Reprod Update, 2004

31. Radiotherapy and the ovary Ovarian damage depends on Patient’s age Radiation field Radiation dose

32. Ovarian Tissue Freezing Ovarian cryopreservation maybe the only option for fertility preservation, especially in prepubertal children and those who do not have time to undergo ovarian stimulation for oocyte or embryo cryopreservation.

33. Conclusions • 46XX POF is reversible in up to 10% of patients • Cancer treatment: most common cause of POF? • Recent research shows that OSE stem cell may produce new egg in vitro…… • Donation • There is currently no efficient treatment for POF but fertility preservation may be considered • The prediction of ovarian function is the most important part of preservation of female infertility • Management to symptom resolution and bone protection and psychosocial support

34. Thank you for your attention!

35. Reserve • PRENATAL 6-7 MİLYON OOSİT • YENİDOĞANDA 2 MİLYON OOSİT • PUBERTEDE 300-400 BİN OOSİT VARDIR. • 400 TANESİ SEKONDER OOSİT OLUR OVULASYONLA ATILIR.

36. “Antral folikül sayısı, over rezervini değerlendirmede ilk seçenek olarak önerilmektedir(Hendriks ve ark. 2005a). FSH/LH, GH,IGF1, EGF,IL1, NO preovulatuar antral Gonadotropine bağımlı FSH pre antral sekonder FSH,GDF-9 Aktivin, primer Gonadotropine-cevap cGMP ? primordial FOLLICLE MOUNTAIN

37. Yale University Fertility Center, Yale University, New Haven, CT; Weill Medical College of Cornell University, Center for Reproductive Medicine and Infertility, New York, NY.

38. Foliküllerin dinlenme havuzundan recruitment’ı • Reprodüktif hayatta primordial ve primer foliküller sekonder ve daha büyük foliküller orijinal folikül havuzunda sürekli azalma • Recruitment terimi,folikül gelişimi sırasındaki iki önemli fakat farklı noktayı açıklamak için kullanılmıştır. (Meijs 1990, Gosden 1983, Rombauts 1998) • İnisiyal recruitment, önemli sayıda küçük folikülün , uzun bir zaman içinde yavaşca büyümesini ifade eder.(Hirshfield 1989 )

39. Siklik recruitment • Puberteden sonra başlar • Birçok antral folikülü, atreziden koruyan dolaşımdaki FSH artışı sonucu meydana gelir. • Siklik recruitment sırasında sınırlı sayıda folikül gonado-tropinler sayesinde kurtularak büyümeye devam eder • Bu foliküllerde oositler büyümelerini tamamlamıştır, zona pellucida ile mayoza devam etmeye hazırdırlar. • Her ay bir Graf folikülü ovulasyon için hazırlanır.

40. Gonadotropin Receptor Defects Involved in POF • LHCGR gene • located on 2p21 • inactivating mutation causes • follicle dysfunction: • Low E2, low/nl FSH, high LH • Multicystic Ovaries • FSHR gene • located on 2p21-16 • mutation in the ligand binding domain of FSHR causes dramatic reduction in FSHR binding capacity and signal transduction • -Finnish type: auto-recessive inheritance • -spontaneous 46XX POF