Transcript Diapositive 1

Premature Ovarian Failure
Santiago, October 5th, 2007
Pr Philippe Touraine
[email protected]
Inserm Unit 845,
Research Center Growth & Signaling,
Faculty of Medicine Necker, Paris
Dept Endocrinology &
Reproductive Medicine,
Hospital Pitié Salpetrière, Paris
5 th Week of embryogenesis
Endodermal stem cells
Genital crest
Ovogonia
8th week : 600 000 oogonia
Oogonia Mitosis
28th Week
Meiosis
Primary Oocytes
Atresia
Maximal at 20thWeek
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
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
Premature Ovarian Failure
1% of 40-year-old-women
Follicular Depletion
Chemotherapy
X chromosome anomalies
Autoimmunity
Follicular Dysfunction
Autoimmunity
FSHR anomalies
Cx37, GDF9, BMP-15
Enzyme deficiencies
Accelerated atresia
Etiology most often remains unknown
Premature Ovarian Failure
Follicular Depletion
Chemotherapy
X chromosome anomalies
Autoimmunity
Accelerated atresia
Total of cases with POF
% cases with POF
Primary amenoorhea
Secondary amenorrhea
Schlessinger et al., Am J Med Genet, 2002
POF - FMR1
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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
POF and chemotherapy
Drugs
Normal cycles
Normal Cycles
Oligomenorrhea
Amenorrhea
Radiotherapy : 6 Gy on ovaries : non reversible POF
Premature Ovarian Failure
Follicular Dysfunction
Autoimmunity
FSHR anomalies
Cx37, GDF9, BMP-15
Enzyme deficiencies
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%
Ovulation
Blocade of follicular maturation
Antral
Secondary
Primary
Primordial
Atresia
Hsueh, Endocrine Review, 2000
FSH receptor gene mutation in the
Finnish population
Ala189
Val
NH2
COOH

22 patients with primary amenorrhea

Pubertal development variable

Hypoplasic ovaries at histological examination

Presence of primordial and primary follicles
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
Current Evaluation
Biological
Phenotype
Clinical Phenotype
Morphological
Phenotype
Questionnaire
Karyotype
Hormonal
evaluation
Ultrasonography
Laparoscopy - Histology
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
Bachelot et al., 2007, submitted
293 46,XX
idiopathic
20
Number of Patients
18
16
14
12
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)
Bachelot et al., 2007, submitted
Mean age: 26.5 ± 7.8
Number of Patients
250
200
150
Puberty
100
absence
partial
normal
50
0
Primary amenorrhea
Bachelot et al., 2007, submitted
Secondary amenorrhea
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
Median (Range)
Normal range
FSH (IU/l)
82.6 (30.3–284)
3–9
LH (IU/l)
32.5 (5.9–109)
1–5
Estradiol (pg/ml)
25.8 (5–246)
20-350
Inhibin B (pg/ml)
10 (5–105)
60–200
• 134 woman have detectable E2 levels and 58 inhibin B
• AMH detectable in 105 patients
Bachelot et al., 2007, submitted
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
Two Different Patterns
100µm
100µm
N= 29
Bachelot et al., 2007, submitted
N = 75
Ovarian Histology
70
60
Follicular Histology
50
antrum
Early antral
secondary
40
primary
primordial
30
Absence of foll
20
10
0
Primary
25%
Bachelot et al., 2007, submitted
Secondary
70%
Amenorrhea
Foll 40
35
30
Foll 25
Foll +
20
15
Foll +
10
5
Histo -
Histo +
Massin et al., 2004
FSH Receptor gene mutations
Pro272Leu
Asp224
Ile191
Val
Leu
Ala189
Ile160
Thr
Val
NH2
Pro519
Thr
Leu601
Val
Arg573
Cys
Thr
Ala419
Patient 1
Beau et al. JCI, 1998
Thr
COOH
Patient 2
Touraine et al., Mol Endocrinol, 1999
Patient 3
Meduri et al., JCEM, 2003
Phenotype-Genotype Correlation
Patient 1
Patient 2
Patient 3
Finnish
population
Normal
Normal
Lack of
Delayed
Secondary
Primary
Primary
Primary
Antral Follicles
Early antral
follicles
Primordial
Follicles
Primary
Follicles
30% Arg573Cys
In vitro
R-FSH activity
15%
Leu601Val
0%
Undetectable
Puberty
Amenorrhea
Histology
Rec FSH Stimulation
Patient 1
Patient 2
Patient 3
E2 (pg/ml)
12
65
<20

<20
< 10
Inhibin B
(pg/ml)
Number of
follicules
Size
"
60
125
15

30
< 10
FSH/day (U/d)
Total dose
rec FSH
10-15/ovaire
(mm)
2-56-8,8
150750
10 275 U
6 - 8/ovary
2 – 42 - 4
100

10 300 U
3-4/ovary
2-3 mm
600
100 à 900
10 400
Etiology actually possible in 30 patients (10%)
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8 with karyotype anomalies
5 with FMR1 premutation
16 anomalies of genes involved in POF
2 APS type 2, 1 with multiple AI diseases
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
Bachelot et al., 2007, submitted
Hormonal substitution
Treatment of infertility
What to say?
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Information +++
Psychological help
HRT
Explanation about pregnancy plans (oocyte
donation…)
Discussion about “ovaries to be frozen”
Around POF Diagnosis
Gross et al., Fertil Steril, 2005
Hormonal Biochemistry
K Laborde
Cytogenetics
Nathalie Massin
Anne Bachelot
Yvette Le Rouzic
Radiology
C Matuchansky
C Balleyguier
Department of Endocrinology
and Reproductive Medicine
Necker Hospital
Surgery
F Lecuru
B Paniel
Pathology
Cochin
Philippe Touraine
Pr F. Kuttenn
CHIC
Genetics
HEGP
M Misrahi, Bicêtre G Meduri
National and International
M Fellous, Cochin
Collaboration
C Cotinot, INRA
D Castrillon, Dallas, TX
L.Messiaen, Gant, Belgium
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