1 / 34

Premature Ovarian Failure

Inserm Unit 845 , Research Center Growth & Signaling, Faculty of Medicine Necker, Paris. Dept Endocrinology & Reprod uctive Medicine, Hospital Pitié Salpetrière, Paris. Premature Ovarian Failure. Santiago, October 5th, 2007 Pr Philippe Touraine philippe.touraine@psl.aphp.fr.

bmains
Download Presentation

Premature Ovarian Failure

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Inserm Unit 845, Research Center Growth & Signaling, Faculty of Medicine Necker, Paris Dept Endocrinology & Reproductive Medicine, Hospital Pitié Salpetrière, Paris Premature Ovarian Failure Santiago, October 5th, 2007 Pr Philippe Touraine philippe.touraine@psl.aphp.fr

  2. 5 th Week of embryogenesis Endodermal stem cells Genital crest Ovogonia Oogonia Mitosis Meiosis Atresia Maximal at 20thWeek 28th Week Primary Oocytes 8th week : 600 000 oogonia

  3. 6-7 Million germ cells at 20th Week • 2/3 are oocytes in meiosis • 1/3 are oogonia Atresia • < 20 % germ cells at birth la naissance • 300 000 at puberty • 400-500 follicles during genital life

  4. Premature Ovarian Failure (POF) • WHO : Permanent Cessation of menstruations secondary to loss of follicular activity • Characterized by : • Women < 40 yrs • Amenorrhea > 4 months • Hypergonadotrophic Hypogonadism (FSH > 30 UI/L) Anasti JN, Fertil. Steril., 1998, 70 : 1-5. • Incidence : # 1% Coulam CB et al., Obstet. Gynecol., 1986, 67 : 604-6

  5. Autoimmunity FSHR anomalies Cx37, GDF9, BMP-15 Enzyme deficiencies Follicular Depletion Chemotherapy X chromosome anomalies Autoimmunity Follicular Dysfunction Accelerated atresia Premature Ovarian Failure 1% of 40-year-old-women Etiology most often remains unknown

  6. Follicular Depletion Chemotherapy X chromosome anomalies Autoimmunity Accelerated atresia Premature Ovarian Failure

  7. % cases with POF Total of cases with POF Primary amenoorhea Secondary amenorrhea Schlessinger et al., Am J Med Genet, 2002

  8. POF - FMR1 • 20% premutated and 14% grey zone develop POF (Bretherick, 2005) • 13-21% familial forms POF are premutated • 3-7% sporadic POF are premutated (Shermann, 2000) • Prevalence: 0.4% women with normal fertility

  9. Drugs Normal Cycles Normal cycles Oligomenorrhea Amenorrhea POF and chemotherapy Radiotherapy : 6 Gy on ovaries : non reversible POF

  10. Autoimmunity FSHR anomalies Cx37, GDF9, BMP-15 Enzyme deficiencies Follicular Dysfunction Premature Ovarian Failure

  11. Genetics of POF • Is there any argument for a genetic compound • Genes and physiological menopause • Correlation between age of menopause in mother and girls De Bruin, Hum Reprod 2001 • Cohort of twins: POF described in up to 63% Snieder, J Clin Endocrinol Metab 1998 Gosden R, Hum Reprod, 2007 • Familial cases in 15 to 20%

  12. Ovulation Blocade of follicular maturation Antral Secondary Primary Primordial Atresia Hsueh, Endocrine Review, 2000

  13. Ala189 Val NH2 COOH FSH receptor gene mutation in the Finnish population • 22 patients with primary amenorrhea • Pubertal development variable • Hypoplasic ovaries at histological examination • Presence of primordial and primary follicles

  14. Setting up a POF Network • Phenotyping of the patients (specificities of subgroups) • Constitution of a DNA Bank • Identification of new mutations of genes involved in folliculogenesis • Constitution of an ovarian tissue bank • Immunohistochemistry / steroidogenesis • Ovarian transcriptome • Prospective follow-up of population

  15. Clinical Phenotype Biological Phenotype Morphological Phenotype Questionnaire Karyotype Hormonal evaluation Ultrasonography Laparoscopy - Histology Current Evaluation

  16. 351 patients • 50 excluded • 40 yrs • FSH<30 mUI/l • Secondary POF • Karyotype “Turner-like” 74 patients < 18 yrs (25%) 301 patients 8 karyotypic anomalies 293 46,XX  idiopathic Bachelot et al., 2007, submitted

  17. 20 18 16 14 12 Number of Patients 10 8 6 4 2 0 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 Age at diagnosis (yrs) Mean age: 26.5 ± 7.8 Bachelot et al., 2007, submitted

  18. 250 200 150 Number of Patients Puberty 100 absence partial normal 50 0 Primary amenorrhea Secondary amenorrhea Bachelot et al., 2007, submitted

  19. Clinical Phenotype • 41 patients with a history of familial POF • 13.6% des POF • 59 patients with autoimmunity biomarkers • 19.6 % of POF • 37 with thyroid disorders • Diabetes, juvenile arthritis, vitiligo,…. • 6 patients with antiovarian antibodies (IFI) • 41 patients with fluctuating POF • 5 pregnancies; 3 births

  20. 134 woman have detectable E2 levels and 58 inhibin B • AMH detectable in 105 patients Bachelot et al., 2007, submitted

  21. Bone Mineral Density • Available for 151 patients • Mean age 28.7 yrs (15-42) • Definition WHO • 66 patients (42%) BMD normal • 63 patients osteopenia (42%), 14 at neck and 25 at lumbar • 22 patients osteoporosis (15%), 7 at neck and 20 at lumbar

  22. 100µm 100µm Two Different Patterns N = 75 N= 29 Bachelot et al., 2007, submitted

  23. Ovarian Histology 70 60 Follicular Histology 50 antrum Early antral 40 secondary primary primordial 30 Absence of foll 20 10 0 Primary 25% Secondary 70% Bachelot et al., 2007, submitted Amenorrhea

  24. Foll - Foll - 40 Foll + 35 Ultrasonogaphy 30 Foll + 25 20 15 10 5 Histo - Histo + Massin et al., 2004

  25. Pro272Leu Thr Asp224 Val Ile191 Leu Ile160 Thr Ala189 Val NH2 Leu601 Val Pro519 Thr Arg573 Cys Ala419 Thr COOH FSH Receptor gene mutations Patient 1 Patient 2 Patient 3 Beau et al. JCI, 1998Touraine et al., Mol Endocrinol, 1999Meduri et al., JCEM, 2003

  26. Phenotype-Genotype Correlation

  27. Rec FSH Stimulation

  28. Etiology actually possible in 30 patients (10%) • 8 with karyotype anomalies • 5 with FMR1 premutation • 16 anomalies of genes involved in POF • 2 APS type 2, 1 with multiple AI diseases

  29. What to do in our current practice? Clinical evaluation: Height Familial POF syndrome, Syndromic defects, Autoimmunity Karyotype Hormonal evaluation: FSH-E2; Androgens AMH, Inhibine B Ultrasonography: Surface, Presence of Follicles Evaluation of BMD DNA analysis: XFra FSHR analysis in patients with presence of follicles at ultrasonography Hormonal substitution Treatment of infertility Bachelot et al., 2007, submitted

  30. What to say? • Information +++ • Psychological help • HRT • Explanation about pregnancy plans (oocyte donation…) • Discussion about “ovaries to be frozen”

  31. Around POF Diagnosis Gross et al., Fertil Steril, 2005

  32. Radiology C Matuchansky C Balleyguier Hormonal Biochemistry K Laborde Cytogenetics Surgery F Lecuru B Paniel Pathology Cochin CHIC HEGP G Meduri Genetics M Misrahi, Bicêtre M Fellous, Cochin C Cotinot, INRA D Castrillon, Dallas, TX L.Messiaen, Gant, Belgium Department of Endocrinology and Reproductive Medicine Necker Hospital Pr F. Kuttenn Nathalie Massin Anne Bachelot Yvette Le Rouzic Philippe Touraine National and International Collaboration

  33. Team « Centre Maladies rares de la croissance » philippe.touraine@psl.aphp.fr Beau et al. J. Clin Invest, 1998;Touraine et al., Mol Endocrinol, 1999;Meduri et al., JCE&M, 2003; Massin et al., Hum Reprod, 2004; Bachelot et al., JCE&M, 2005; Massin et al., Horm Res, 2006 Meduri et al., Hum Reprod, 2006; Laissue et al., Eur J Endocrinol, 2006

More Related