Premature Ovarian Failure
-
Upload
alexandra-brennan -
Category
Documents
-
view
215 -
download
1
description
Transcript of Premature Ovarian Failure
Premature Ovarian Premature Ovarian FailureFailure
Premature Ovarian Premature Ovarian FailureFailure
Santiago, October 5th, 2007 Santiago, October 5th, 2007
Pr Philippe Touraine Pr Philippe Touraine
[email protected]@psl.aphp.fr
Inserm Unit 845Inserm Unit 845, , Research Center Growth & Research Center Growth &
Signaling, Signaling, Faculty of Medicine Necker, ParisFaculty of Medicine Necker, Paris
Dept Endocrinology & Dept Endocrinology & ReprodReproductive Medicine,uctive Medicine,
Hospital Pitié Salpetrière, ParisHospital Pitié Salpetrière, Paris
8th week : 600 000 oogonia8th week : 600 000 oogonia
5 th Week of embryogenesis 5 th Week of embryogenesis
Endodermal stem cells Genital crestEndodermal stem cells Genital crest
OvogoniaOvogonia
Oogonia MitosisOogonia Mitosis
28th Week28th Week
MeiosisMeiosis
Primary OocytesPrimary Oocytes
AtresiaAtresia
Maximal at 20thWeekMaximal at 20thWeek
6-7 Million germ cells at 20th Week6-7 Million germ cells at 20th Week
2/3 are oocytes in meiosis2/3 are oocytes in meiosis
1/3 are oogonia 1/3 are oogonia
AtresiaAtresia
< 20 % germ cells at birth la naissance< 20 % germ cells at birth la naissance
300 000 at puberty300 000 at puberty
400-500 follicles during genital life400-500 follicles during genital life
Premature Ovarian Failure Premature Ovarian Failure (POF)(POF)
Premature Ovarian Failure Premature Ovarian Failure (POF)(POF)
WHO WHO : Permanent Cessation of menstruations : Permanent Cessation of menstruations secondary to loss of follicular activitysecondary to loss of follicular activity
Characterized by Characterized by : : Women < 40 yrsWomen < 40 yrsAmenorrhea > 4 monthsAmenorrhea > 4 monthsHypergonadotrophic Hypogonadism (FSH > 30 Hypergonadotrophic Hypogonadism (FSH > 30 UI/L)UI/L)
Anasti JN, Fertil. Steril., 1998, Anasti JN, Fertil. Steril., 1998, 70 : 1-5.70 : 1-5.
IncidenceIncidence : # 1% : # 1% Coulam CB et al., Obstet. Gynecol., 1986, 67 : 604-6Coulam CB et al., Obstet. Gynecol., 1986, 67 : 604-6
Premature Ovarian FailurePremature Ovarian FailurePremature Ovarian FailurePremature Ovarian Failure
1%1% of of 40 40--yearyear--oldold-women-women
Etiology most often remains unknownEtiology most often remains unknown
AutoimmunityAutoimmunityFSHR anomaliesFSHR anomalies
Cx37, GDF9, BMP-15Cx37, GDF9, BMP-15Enzyme deficienciesEnzyme deficiencies
Follicular DysfunctionFollicular Dysfunction
Accelerated atresiaAccelerated atresia
Follicular DepletionFollicular DepletionChemotherapyChemotherapy
X chromosome anomaliesX chromosome anomaliesAutoimmunityAutoimmunity
Premature Ovarian Premature Ovarian FailureFailure
Premature Ovarian Premature Ovarian FailureFailure
Accelerated atresiaAccelerated atresia
Follicular DepletionFollicular DepletionChemotherapyChemotherapy
X chromosome anomaliesX chromosome anomaliesAutoimmunityAutoimmunity
Schlessinger et al., Am J Med Genet, 2002Schlessinger et al., Am J Med Genet, 2002
Total of cases with POFTotal of cases with POF % cases with POF% cases with POF
Primary amenoorheaPrimary amenoorheaSecondary amenorrheaSecondary amenorrhea
POF - POF - FMR1FMR1POF - POF - FMR1FMR1
20% premutated and 14% grey zone develop POF (20% premutated and 14% grey zone develop POF (Bretherick, 2005Bretherick, 2005)) 13-21% familial forms POF are premutated13-21% familial forms POF are premutated 3-7% sporadic POF are premutated (3-7% sporadic POF are premutated (Shermann, 2000Shermann, 2000)) Prevalence: 0.4% women with normal fertilityPrevalence: 0.4% women with normal fertility
Radiotherapy : 6 Gy on ovaries : non reversible POFRadiotherapy : 6 Gy on ovaries : non reversible POF
POF and POF and chemotherapychemotherapy
POF and POF and chemotherapychemotherapy
OligomenorrheaOligomenorrheaNormal CyclesNormal Cycles
DrugsDrugs Normal cyclesNormal cycles
AmenorrheaAmenorrhea
Premature Ovarian Premature Ovarian FailureFailure
Premature Ovarian Premature Ovarian FailureFailure
AutoimmunityAutoimmunityFSHR anomaliesFSHR anomalies
Cx37, GDF9, BMP-15Cx37, GDF9, BMP-15Enzyme deficienciesEnzyme deficiencies
Follicular DysfunctionFollicular Dysfunction
Genetics of Genetics of POFPOF
Genetics of Genetics of POFPOF
Is there any argument for a genetic compoundIs there any argument for a genetic compound
Genes and physiological menopauseGenes and physiological menopause
– Correlation between age of menopause in mother and Correlation between age of menopause in mother and
girlsgirls
De Bruin, Hum Reprod 2001De Bruin, Hum Reprod 2001
– Cohort of twins: POF described in up to 63%Cohort of twins: POF described in up to 63%
Snieder, J Clin Endocrinol Metab 1998Snieder, J Clin Endocrinol Metab 1998
Gosden R, Hum Reprod, 2007Gosden R, Hum Reprod, 2007
– Familial cases in 15 to 20%Familial cases in 15 to 20%
Primordial
Primary
Ovulation
Hsueh, Endocrine Review, 2000Hsueh, Endocrine Review, 2000
Antral
Secondary
AtresiaAtresia
Blocade of follicular maturationBlocade of follicular maturation
22 patients with primary amenorrhea22 patients with primary amenorrhea Pubertal development variablePubertal development variable Hypoplasic ovaries at histological examinationHypoplasic ovaries at histological examination Presence of primordial and primary folliclesPresence of primordial and primary follicles
FSH receptor gene mutation in theFSH receptor gene mutation in theFinnish populationFinnish population
FSH receptor gene mutation in theFSH receptor gene mutation in theFinnish populationFinnish population
NH2NH2
COOHCOOH
AlaAla189 189 Val Val
Setting up a POF Setting up a POF NetworkNetwork
Setting up a POF Setting up a POF NetworkNetwork
Phenotyping of the patients (specificities of Phenotyping of the patients (specificities of
subgroups)subgroups)
Constitution of a DNA BankConstitution of a DNA Bank Identification of new mutations of genes involvedIdentification of new mutations of genes involved
in folliculogenesisin folliculogenesis
Constitution of an ovarian tissue bankConstitution of an ovarian tissue bank Immunohistochemistry / steroidogenesisImmunohistochemistry / steroidogenesis
Ovarian transcriptomeOvarian transcriptome
Prospective follow-up of populationProspective follow-up of population
Current EvaluationCurrent EvaluationCurrent EvaluationCurrent Evaluation
Clinical PhenotypeClinical Phenotype
QuestionnaireQuestionnaireKaryotypeKaryotype
BiologicalBiologicalPhenotypePhenotype
HormonalHormonalevaluationevaluation
MorphologicalMorphologicalPhenotypePhenotype
UltrasonographyUltrasonographyLaparoscopy - HistologyLaparoscopy - Histology
351 patients351 patients
50 excluded50 excluded40 yrs 40 yrs
FSH<30 mUI/lFSH<30 mUI/lSecondary POFSecondary POF
Karyotype “Turner-like”Karyotype “Turner-like”
301 patients301 patients8 karyotypic anomalies8 karyotypic anomalies
293293 46,XX idiopathic 46,XX idiopathic
74 patients74 patients< 18 yrs< 18 yrs(25%)(25%)
Bachelot et al., 2007, submittedBachelot et al., 2007, submitted
Age at diagnosis (yrs)
Mean age: 26.5 ± 7.8
Nu
mb
er
of
Pati
en
ts
0
2
4
6
8
10
12
14
16
18
20
1112131415161718192021222324252627282930313233343536373839
Bachelot et al., 2007, submittedBachelot et al., 2007, submitted
Primary amenorrheaSecondary amenorrhea
Nu
mb
er
of
Pati
en
ts
0
50
100
150
200
250
absencepartialnormal
Puberty
Bachelot et al., 2007, submittedBachelot et al., 2007, submitted
Clinical PhenotypeClinical PhenotypeClinical PhenotypeClinical Phenotype
41 patients with a history of familial POF41 patients with a history of familial POF13.6% des POF13.6% des POF
59 patients with autoimmunity biomarkers59 patients with autoimmunity biomarkers19.6 % of POF19.6 % of POF3737 with thyroid disorders with thyroid disordersDiabetes, juvenile arthritis, vitiligo,….Diabetes, juvenile arthritis, vitiligo,….6 patients with antiovarian antibodies (IFI)6 patients with antiovarian antibodies (IFI)
41 patients with fluctuating POF41 patients with fluctuating POF
5 pregnancies; 3 births5 pregnancies; 3 births
Median (Range)Median (Range) Normal Normal rangerange
FSH (IU/l)FSH (IU/l) 82.6 (30.3–284)82.6 (30.3–284) 3–93–9
LH (IU/l)LH (IU/l) 32.5 (5.9–109)32.5 (5.9–109) 1–51–5
Estradiol Estradiol (pg/ml)(pg/ml)
25.8 (5–246)25.8 (5–246) 20-35020-350
Inhibin B Inhibin B (pg/ml)(pg/ml)
10 (5–105)10 (5–105) 60–20060–200
• 134 woman have detectable E2 levels and 58 inhibin 134 woman have detectable E2 levels and 58 inhibin
BB
• AMH detectable in 105 patientsAMH detectable in 105 patientsBachelot et al., 2007, submittedBachelot et al., 2007, submitted
Available for 151 patients Available for 151 patients
Mean age 28.7 yrs (15-42)Mean age 28.7 yrs (15-42)
Definition WHO Definition WHO
• 66 patients (42%) BMD normal 66 patients (42%) BMD normal
• 63 patients osteopenia (42%), 14 at neck and 63 patients osteopenia (42%), 14 at neck and
25 at lumbar25 at lumbar
• 22 patients osteoporosis (15%), 7 at neck and 22 patients osteoporosis (15%), 7 at neck and
20 at lumbar 20 at lumbar
Bone Mineral DensityBone Mineral DensityBone Mineral DensityBone Mineral Density
100µm100µm 100µm100µm
N= 29N= 29 N = 75N = 75
Two Different PatternsTwo Different PatternsTwo Different PatternsTwo Different Patterns
Bachelot et al., 2007, submittedBachelot et al., 2007, submitted
Ovarian HistologyOvarian HistologyOvarian HistologyOvarian Histology
0
10
20
30
40
50
60
70
Secondary70%
secondary
primordialprimary
Early antral
Absence of foll
antrum
Follicular Histology
Primary25%
AmenorrheaBachelot et al., 2007, submittedBachelot et al., 2007, submitted
Histo -Histo - Histo +Histo +
5
10
15
20
25
30
35
40
Foll +Foll +
Foll +Foll +
Foll -Foll -
Foll -Foll -
Ult
raso
nog
ap
hy
Ult
raso
nog
ap
hy
Massin et al., 2004Massin et al., 2004
FSH Receptor gene FSH Receptor gene mutationsmutations
FSH Receptor gene FSH Receptor gene mutationsmutations
Patient 1Patient 1 Patient 2Patient 2 Patient 3
NH2NH2
COOHCOOH
IleIle160 160 Thr Thr
ArgArg573 573 Cys Cys
AspAsp224 224 Val Val
AlaAla189 189 Val Val
LeuLeu601 601 Val Val
Pro519 Thr
IleIle191191 Leu Leu
Ala419 Thr
ProPro272272Leu ThrLeu Thr
Beau et al. JCI, 1998Beau et al. JCI, 1998 Touraine et al., Mol Endocrinol, 1999Touraine et al., Mol Endocrinol, 1999 Meduri et al., JCEM, 2003Meduri et al., JCEM, 2003
Phenotype-Genotype Phenotype-Genotype Correlation Correlation
Phenotype-Genotype Phenotype-Genotype Correlation Correlation
Patient 1Patient 1 Patient 2Patient 2 Patient 3Patient 3 FinnishFinnish
populationpopulation
PubertyPuberty NormalNormal NormalNormal Lack ofLack of DelayedDelayed
AmenorrheAmenorrheaa
SecondarySecondary PrimaryPrimary PrimaryPrimary PrimaryPrimary
HistologyHistology Antral Antral FolliclesFollicles
Early Early antral antral
folliclesfollicles
PrimordiaPrimordial Folliclesl Follicles
Primary Primary FolliclesFollicles
In vitroIn vitro
R-FSH R-FSH activityactivity
30% 30% Arg573CysArg573Cys
15% 15% Leu601ValLeu601Val
0%0% UndetectablUndetectablee
Rec FSH StimulationRec FSH StimulationRec FSH StimulationRec FSH Stimulation
Patient 1 Patient 2 Patient 3
E2 (pg/ml)
12 65
<20 <20
< 10
Inhibin B (pg/ml)
60 125 15 30 < 10
Number of follicules
10-15/ovaire 6 - 8/ovary 3-4/ovary
Size " (mm) 2-56-8,8 2 – 42 - 4 2-3 mm
FSH/day (U/d) 150750 100 600 100 à 900
Total dose rec FSH
10 275 U 10 300 U 10 400
Etiology actually possible in Etiology actually possible in 30 patients 30 patients (10%)(10%)
8 with karyotype anomalies 8 with karyotype anomalies
5 with FMR1 premutation5 with FMR1 premutation
16 anomalies of genes involved in POF16 anomalies of genes involved in POF
2 APS type 2, 1 with multiple AI 2 APS type 2, 1 with multiple AI diseasesdiseases
Clinical evaluationClinical evaluation: : HeightHeightFamilial POF syndrome, Syndromic defects, AutoimmunityFamilial POF syndrome, Syndromic defects, Autoimmunity
KaryotypeKaryotypeHormonal evaluationHormonal evaluation: : FSH-E2FSH-E2; ; AndrogensAndrogens
AMH, Inhibine BAMH, Inhibine BUltrasonographyUltrasonography: : SurfaceSurface, , Presence of FolliclesPresence of Follicles
Evaluation of BMDEvaluation of BMDDNA analysisDNA analysis: : XFraXFra
FSHR analysis in patients with presence of follicles at ultrasonographyFSHR analysis in patients with presence of follicles at ultrasonography
Hormonal substitutionHormonal substitutionTreatment of infertilityTreatment of infertility
What to do in our current practice?
What to do in our current practice?
Bachelot et al., 2007, submittedBachelot et al., 2007, submitted
What to say?What to say?What to say?What to say?
Information +++Information +++ Psychological helpPsychological help HRTHRT Explanation about pregnancy plans Explanation about pregnancy plans
(oocyte donation…)(oocyte donation…) Discussion about “ovaries to be frozen”Discussion about “ovaries to be frozen”
Gross et al., Fertil Steril, 2005Gross et al., Fertil Steril, 2005
Around POF Around POF DiagnosisDiagnosisAround POF Around POF DiagnosisDiagnosis
Department of EndocrinologyDepartment of Endocrinology and Reproductive Medicineand Reproductive Medicine
Necker HospitalNecker HospitalPr F. KuttennPr F. Kuttenn
Pathology Pathology CochinCochinCHICCHICHEGPHEGP
G MeduriG MeduriGeneticsGenetics
M Misrahi, BicêtreM Misrahi, BicêtreM Fellous, CochinM Fellous, CochinC Cotinot, INRAC Cotinot, INRA
D Castrillon, Dallas, TXD Castrillon, Dallas, TXL.Messiaen, Gant, BelgiumL.Messiaen, Gant, Belgium
SurgerySurgery F LecuruF LecuruB PanielB Paniel
RadiologyRadiologyC MatuchanskyC MatuchanskyC BalleyguierC Balleyguier
Hormonal BiochemistryHormonal BiochemistryK LabordeK Laborde
CytogeneticsCytogenetics
Nathalie MassinNathalie MassinAnne BachelotAnne Bachelot
Yvette Le RouzicYvette Le Rouzic
Philippe TourainePhilippe Touraine
National and InternationalNational and InternationalCollaborationCollaboration
Team « Centre Maladies rares de la croissance »[email protected]
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