dominique de ziegler, md professor and head reprod endocr and infertility cochin medical center...
TRANSCRIPT
![Page 1: Dominique de Ziegler, MD Professor and Head Reprod Endocr and Infertility Cochin Medical Center Paris, France](https://reader035.vdocument.in/reader035/viewer/2022070309/551d9da5497959293b8d6e8c/html5/thumbnails/1.jpg)
Dominique de Ziegler, MDProfessor and Head
Reprod Endocr and Infertility Cochin Medical Center
Paris, France
![Page 2: Dominique de Ziegler, MD Professor and Head Reprod Endocr and Infertility Cochin Medical Center Paris, France](https://reader035.vdocument.in/reader035/viewer/2022070309/551d9da5497959293b8d6e8c/html5/thumbnails/2.jpg)
Dominique de Ziegler, MDProfessor and Head
Reprod Endocr and Infertility Cochin Medical Center
Paris, France
![Page 3: Dominique de Ziegler, MD Professor and Head Reprod Endocr and Infertility Cochin Medical Center Paris, France](https://reader035.vdocument.in/reader035/viewer/2022070309/551d9da5497959293b8d6e8c/html5/thumbnails/3.jpg)
Dominique de Ziegler, MDProfessor and Head
Reprod Endocr and Infertility Cochin Medical Center
Paris, France
![Page 4: Dominique de Ziegler, MD Professor and Head Reprod Endocr and Infertility Cochin Medical Center Paris, France](https://reader035.vdocument.in/reader035/viewer/2022070309/551d9da5497959293b8d6e8c/html5/thumbnails/4.jpg)
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recruitment
maturation
selection
FSH
LH
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Le gynécologue et les mathématiques
Maths and the gynecologist
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Le gynécologue et les mathématiques
1 = 28 no “0”
Maths and the gynecologist
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recruitment
maturation
selection
FSH
LH
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25 26 27 28Cycle 1
Cycle 2LHFSH
P4 / E2
Menses
Nor
mal
1 3 5 7 9 11 13 15
1 3 5 7 9 11 13 15
The dogma says:
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25 26 27 28Cycle 1
Cycle 2LHFSH
P4 / E2
Menses
Nor
mal
1 3 5 7 9 11 13 15
1 3 5 7 9 11 13 15
Foll. phaseThe dogma says:
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25 26 27 28Cycle 1
Cycle 2LHFSH
P4 / E2
Menses
Nor
mal
1 3 5 7 9 11 13 15
1 3 5 7 9 11 13 15
Foll. phaseThe dogma says:
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25 26 27 28Cycle 1
Cycle 2LHFSH
P4 / E2
Menses
Nor
mal
1 3 5 7 9 11 13 15
1 3 5 7 9 11 13 15
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25 26 27 28Cycle 1
Cycle 2
Lon
g
LHFSH
Progesterone
Menses
Nor
mal
1 3 5 7 9 11 13 15
Nor
mal
P4 / E2
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25 26 27 28Cycle 1
Cycle 2
Nor
mal
Sho
rtL
ong
LHFSH
Progesterone
Menses
1 3 5 7 9 11 13 15
P4 / E2
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25 26 27 28Cycle 1
Cycle 2LHFSH
P4/E2
Nor
mal
1 3 5 7 9 11 13 15
1 3 5 7 9 11 13 15
Menses
Inter-cycle
2 hormones: E2,& P42 events: menses, FSH
Time onset of cycle II
Follicular phase
Time end of cycle I
21
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6
4
2
0
Control cycle
FSH IU/LInhibin U/LInhibinFSH
-5 -4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11
1200
900
600
300
0
E2 pmol/L E2
Progesterone
-5 -4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11
Cycle days
1000
800
600
400
200
0
P nmol/L120
100
80
60
40
20
0
From: Le Nestour et al., JCEM, 1993; 77: 439-42
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6
4
2
0
From: Le Nestour et al., JCEM, 1993; 77: 439-42
Control cycle
6
4
2
0
FSH IU/LInhibin U/L
Inhibin
FSH
-5 -4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11
1800
1500
1200
900
600
300
0
P nmol/L120
100
80
60
40
20
0
E2 pmol/L600
500
400
300
200
0
E2
Progesterone
-5 -4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11
E 2 T r e a t m e n tC y c l e d a y s
E2 day 25 - day 3
FSH IU/LInhibin U/LInhibinFSH
-5 -4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11
1200
900
600
300
0
E2 pmol/L E2
Progesterone
-5 -4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11
Cycle days
1000
800
600
400
200
0
P nmol/L120
100
80
60
40
20
0
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25 26 27 28Cycle 1
Cycle 2LHFSH
Menses
The menstrual cycleDialogue and modules
1 3 5 7 9 11 13 15
Nor
mal
CLProgesterone
Prise en charge globale
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25 26 27 28Cycle 1
Cycle 2LHFSH
Menses
The menstrual cycleDialogue and modules
1 3 5 7 9 11 13 15
CLProgesterone
Inhibin BE2
FSH
Nor
mal
dialogue
Prise en charge globale
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25 26 27 28Cycle 1
Cycle 2LHFSH
Menses
The menstrual cycleDialogue and modules
1 3 5 7 9 11 13 15
CLProgesterone
Inhibin BE2
FSH
Nor
mal
Negative feedback
dialogue
Prise en charge globale
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25 26 27 28Cycle 1
Cycle 2LHFSH
Menses
The menstrual cycleDialogue and modules
1 3 5 7 9 11 13 15
CLProgesterone
FSH
812
16Predictivity of d3 FSH
low E2
Negative feedback
Inhibin B
dialogue
E2
Nor
mal
Prise en charge globale
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25 26 27 28Cycle 1
Cycle 2LHFSH
Menses
The menstrual cycleDialogue and modules
1 3 5 7 9 11 13 15
CLProgesterone
FSH
812
16Predictivity of d3 FSH
low E2
Inhibin B
dialogue
E2
Negative feedback
Nor
mal
Prise en charge globale
FSH dominance
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25 26 27 28Cycle 1
Cycle 2LHFSH
Menses
The menstrual cycleDialogue and modules
1 3 5 7 9 11 13 15
Positive feedback
CLProgesterone
FSH
812
16Predictivity of d3 FSH
low E2
Inhibin B
dialogue
E2
Negative feedback
Nor
mal
FSH dominance
LH dominance
Prise en charge globale
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25 26 27 28Cycle 1
Cycle 2LHFSH
Menses
The menstrual cycleDialogue and modules
1 3 5 7 9 11 13 15
Positive feedback
OvulationCLProgesterone
FSH
812
16Predictivity of d3 FSH
low E2
Inhibin B
dialogue
E2
Negative feedback
Nor
mal
FSH dominance
LH dominance
Prise en charge globale
![Page 32: Dominique de Ziegler, MD Professor and Head Reprod Endocr and Infertility Cochin Medical Center Paris, France](https://reader035.vdocument.in/reader035/viewer/2022070309/551d9da5497959293b8d6e8c/html5/thumbnails/32.jpg)
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25 26 27 28Cycle 1
Cycle 2LHFSH
Menses
The menstrual cycleDialogue and modules
1 3 5 7 9 11 13 15
Positive feedback
Ovulation CLProgesterone
CLProgesterone
FSH
812
16Predictivity of d3 FSH
low E2
Inhibin B
dialogue
E2
Negative feedback
Nor
mal
FSH dominance
LH dominance
Prise en charge globale
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E2
P4
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Estrogen and Progesterone treatment
The menstrual cycle
The oocyte donor
The recipient
E2Progesterone
Donor egg IVF: A model to study the endometrial effects of E2 and progesterone
Respective roles of E2 and P4 the
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01 2 3 4 weeks
E2
P4300
0.4
0.2
(mg)
(mg)
20 24-6
E2/progesterone effects on endometrial morphology
de Ziegler et al J Clin Endocrinol Metab, 1992:74:322-31.de Ziegler et al, Fertil Steril 1991;56:851-5.
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01 2 3 4 weeks
E2
P4300
0.4
0.2
(mg)
(mg)
20 24-6
E2/progesterone effects on endometrial morphology
de Ziegler et al J Clin Endocrinol Metab, 1992:74:322-31.de Ziegler et al, Fertil Steril 1991;56:851-5.
Day 20 Day 24
Endometrial glands Endometrial stroma
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01 2 3 4 weeks
E2
P4300
0.4
0.2
(mg)
(mg)
20 24-6
E2/progesterone effects on endometrial morphology
de Ziegler et al J Clin Endocrinol Metab, 1992:74:322-31.de Ziegler et al, Fertil Steril 1991;56:851-5.
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A
01 2 3 4 weeks
E2
P4300
0.4
0.2
(mg)
(mg)
20 24-6
1
2
E2/progesterone effects on endometrial morphology
de Ziegler et al J Clin Endocrinol Metab, 1992:74:322-31.de Ziegler et al, Fertil Steril 1991;56:851-5.
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A
01 2 3 4 weeks
E2
P4300
0.4
0.2
(mg)
(mg)
20 24-6
1
2
E2/progesterone effects on endometrial morphology
No effect on endometrial m
orphology
de Ziegler et al J Clin Endocrinol Metab, 1992:74:322-31.de Ziegler et al, Fertil Steril 1991;56:851-5.
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Morphometric analysis of
endometrium in case of high E2
levels
Basir GS et al. Human Reprod
2001;16:435-40.
Nat. cycle Moderate COH
High responders w/gland-stromal dyssinchrony:Delayed glandular developmentOedematous stroma
E2 < 20’000 pmol/L
E2 > 20’000 pmol/L E2 > 20’000 pmol/L
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The good
The bad
The ugly
COH: hMG/FSH* Necessary for multiple follicular development * But also stimulates the ovarian production of:
E2
Foll. phase Luteal phase
E2
P4
Peptides
Androgens
P4
I
II
III
The consequences of COH:The “third factor” hypothesis
Respective roles of FSH and LH in stimulating the 3rd factor
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Regulation of HOXA-10 in the endometrium
HS Taylor
No effects of A4 and DHEA
No effects of A4 and DHEA
Testosterone
DHT
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Homeobox genes encode evolutionary conserved factors that are essential for the development of the organs.
Homeobox genes are grouped in 4 clusters (HOX A, B, C, D). In the drosophila (fruit fly), mutations in homeobox genes cause one body segment to develop with characteristics of another segment.
In humans, HOXA 10 and 11 control the development of the uterus and that of the endometrium under the influence of E2 and P.
1011
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A10
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The endometrium is reborn every month.
E2 and progesterone combine for full endometrial expression of HOXA 10.
Progesterone antagonizes the proliferative effects of E2 on epithelial cells.
Female reproductive tract and hematopoietic system: Regenerating stem cells progressively achieve functionality by terminal differentiation.
E2 and progesterone: Dualistic relationshipDualistic relationship
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Regulation of HOXA-10 in the endometrium
HS Taylor
No effects of A4 and DHEA
No effects of A4 and DHEA
Testosterone
DHT
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Uterus
Ovaries
Pituitary
Hypothalamus
Classification fonctionnelle: par étages
1
3
2
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Uterus
Ovaries
Pituitary
Hypothalamus
Functional amen.PCOD
1
3
2
4
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Uterus
Ovaries
Pituitary
Hypothalamus
E2
P4
FSH LH
FSH/LH
GnRH
1
3
Functional amen.PCOD
2
4
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Uterus
Ovaries
Pituitary
E2
P4
FSH LH
FSH/LH
GnRH
Asherman
Hypothalamus
Functional amen.PCOD
1
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Uterus
Ovaries
Pituitary
E2
P4
FSH LH
FSH/LH
GnRH
Asherman
Hypothalamus
1
Functional amen.PCOD
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Uterus
Ovaries
Pituitary
Hypothalamus
E2
P4
FSH/LH
GnRH
FSH LH Functional amen.PCOD
2
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Ovaries
Hypothalamus
FSH/LH
GnRH
FSH LH
E2
P4
Pituitary
Functional amen.PCOD
FSH w/ FSH/LH >1
2
Uterus
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Ovaries
Hypothalamus
FSH/LH
GnRH
AMHAntral Follicle Count (AFC)
FSH LH
E2
P4
Pituitary
Functional amen.PCOD
FSH w/ FSH/LH >1
2
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From: E. A. McGee and A. J. W. Hsueh Endocr Reviews 2000;2: 200-14.
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From: E. A. McGee and A. J. W. Hsueh Endocr Reviews 2000;2: 200-14.
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From: E. A. McGee and A. J. W. Hsueh Endocr Reviews 2000;2: 200-14.
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From: E. A. McGee and A. J. W. Hsueh Endocr Reviews 2000;2: 200-14.
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From: E. A. McGee and A. J. W. Hsueh Endocr Reviews 2000;2: 200-14.
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From: E. A. McGee and A. J. W. Hsueh Endocr Reviews 2000;2: 200-14.
AMH reflects the pool of in growth follicles
Proportional to the number of primordial foll.
Predict ovarian response to COH in ART
PCOS: levels are higher than in cycling controls
Ovarian endometriosis: increased production?
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Streuli I et al. FS, 2008
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Streuli I et al. FS, 2008
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Streuli I et al. FS, 2008
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Streuli I et al. FS, 2009
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Streuli I et al. FS, 2009
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Streuli I et al. FS, 2009
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Uterus
Ovaries
Pituitary
Hypothalamus
E2
P4
FSH/LH
GnRH
FSH LH
PRL 3
Functional amen.PCOD
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Uterus
Ovaries
Pituitary
Hypothalamus
E2
P4
FSH/LH
GnRH
FSH LH
PRL 3
AMHAntral Follicle Count (AFC)
Functional amen.PCOD
FSH w/ FSH/LH >1
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Pituitary
Hypothalamus
FSH/LH
GnRH
PRL
Uterus
OvariesE2
P4
FSH LH
HA NeurogenicPRL
Pituitary Space occupying lesion
HA: exclusion Dx
No HF
3
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Pituitary
Hypothalamus
FSH/LH
GnRH
PRL
Uterus
OvariesE2
P4
FSH LH
HA NeurogenicPRL
Pituitary Space occupying lesion
HA: exclusion Dx
No HF
3
- -
PRLProd: pituitary
Action: GnRH{
98%
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Pituitary
Hypothalamus
FSH/LH
GnRH
Uterus
OvariesE2
P4
FSH LH
HA NeurogenicPRL
Pituitary Space occupying lesion
HA: exclusion Dx
No HF
3PRL
- -
PRLProd: pituitary
Action: GnRH{
98%
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Pituitary
Hypothalamus
FSH LH
FSH/LH
GnRH
PRL
Aménohrées II: Approche diagnostique
HA NeurogenicPRL
Pituitary Space occupying lesion
HA: exclusion Dx
Classification fonctionnelle
POF Vs.oPOF
2
HA Vs.oHA
Hi FSH, FSH/LH>1, Lo AMH
PCO Vs.mild PCOS
Occult forms of HA and POF
Hi FSH/LH, Hi AMHLo FSH, FS/LH>1 + PRL, Nor AMH
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Uterus
Ovaries
Pituitary
Functional amen.PCOD
Hypothalamus
4
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Uterus
Ovaries
Pituitary
Functional amen.PCOD
Hypothalamus
E2
P4
FSH LH
FSH/LH
GnRH
4
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Uterus
Ovaries
Pituitary
Functional amen.PCOD
Hypothalamus
E2
P4
FSH LH
FSH/LH
GnRH+
-
B
Hyper sensibilité
FSH
4
Androgènes (4, T)-
+
+
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Uterus
Ovaries
Pituitary
Functional amen.PCOD
Hypothalamus
E2
P4
FSH LH
FSH/LH
GnRH+
-
-
--
B
Hyper sensibilité
FSH
inhibin
E2
4
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Functional amen.PCOD
Hyper androgénisme: bloquer la production ovarienne (COC)
Induirre ovulation (CC, AI, FSH/hMG).
CC est le TT de 1er choix; AI a des chance de le devenir. .
Pour blocage ovarien max, utiliser COC en continu
Anti androgènes peuvent être utilisés.
Si ovulation >8x/an, apport cyclique en progestatif est nécessaire.
Pas de désir de grossesse
Désir de grossesse
Risque de d’OHSS élevé.
Metformin probablement pas indiqée .
Metformin peut réduire le risque d’OHSS.
4
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Aménorrhée II: Approche fonctionnelle?
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Aménorrhée II: Approche fonctionnelle?
Pas de désir de grossesse
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Aménorrhée II: Approche fonctionnelle?
Pas de désir de grossesse Apport E2/P4
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Aménorrhée II: Approche fonctionnelle?
Pas de désir de grossesse Apport E2/P4
Les quantités d’E2 du THM sont le minimum pour une femme de 50 ans. 1
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Aménorrhée II: Approche fonctionnelle?
Pas de désir de grossesse Apport E2/P4
Les quantités d’E2 du THM sont le minimum pour une femme de 50 ans. Une jeune femme a besoin de plus d’E2 pour son bien être.
1
2
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Aménorrhée II: Approche fonctionnelle?
Pas de désir de grossesse Apport E2/P4
Les quantités d’E2 du THM sont le minimum pour une femme de 50 ans. Une jeune femme a besoin de plus d’E2 pour son bien être. E2/dehydroprogestérone (Duphaston, Femoston) n’est pas terratogène.
1
2
3
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Aménorrhée II: Approche fonctionnelle?
Pas de désir de grossesse Apport E2/P4
Les quantités d’E2 du THM sont le minimum pour une femme de 50 ans. Une jeune femme a besoin de plus d’E2 pour son bien être. E2/dehydroprogestérone (Duphaston, Femoston) n’est pas terratogène. Nous prescrivons souvent la CO ou Femoston 2/10 + E2 2mg/jour.
1
2
3
4
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Aménorrhée II: Approche fonctionnelle?
Pas de désir de grossesse Apport E2/P4
Les quantités d’E2 du THM sont le minimum pour une femme de 50 ans. Une jeune femme a besoin de plus d’E2 pour son bien être. E2/dehydroprogestérone (Duphaston, Femoston) n’est pas terratogène. Nous prescrivons souvent la CO ou Femoston 2/10 + E2 2mg/jour. Mêmes contrindications au TT oral que dans le THM.
1
2
3
4
5
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Aménorrhée II: Approche fonctionnelle?
Pas de désir de grossesse Apport E2/P4
Les quantités d’E2 du THM sont le minimum pour une femme de 50 ans. Une jeune femme a besoin de plus d’E2 pour son bien être. E2/dehydroprogestérone (Duphaston, Femoston) n’est pas terratogène. Nous prescrivons souvent la CO ou Femoston 2/10 + E2 2mg/jour. Mêmes contrindications au TT oral que dans le THM. Association Serazette/E2 transdermique est possible. .
1
2
3
4
5
6
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Aménorrhée II: Approche fonctionnelle?
Désir de conception
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Aménorrhée II: Approche fonctionnelle?
Désir de conception Induction ovulation
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Aménorrhée II: Approche fonctionnelle?
Asherman Chirurgie endoscopique.
Désir de conception Induction ovulation
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Aménorrhée II: Approche fonctionnelle?
Asherman
oPOF
Chirurgie endoscopique. COH-IVF, Protocole mauvaise répondeuse (mini Lupron).
Désir de conception Induction ovulation
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Aménorrhée II: Approche fonctionnelle?
Asherman
oPOF
POF
Chirurgie endoscopique. COH-IVF, Protocole mauvaise répondeuse (mini Lupron). IVF avec don d’ovocytes
Désir de conception Induction ovulation
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Aménorrhée II: Approche fonctionnelle?
Asherman
oPOF
POF
HA
Chirurgie endoscopique. COH-IVF, Protocole mauvaise répondeuse (mini Lupron). IVF avec don d’ovocytes Induction ovulation GnRH pump ou gonadotrophines LH-FSH (hMG)
Désir de conception Induction ovulation
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Aménorrhée II: Approche fonctionnelle?
Asherman
oPOF
POF
HA
Hyper PRL
Chirurgie endoscopique. COH-IVF, Protocole mauvaise répondeuse (mini Lupron). IVF avec don d’ovocytes Induction ovulation GnRH pump ou gonadotrophines LH-FSH (hMG) Anti PRL pour grossesse spontanée, autrement O traitement.
Désir de conception Induction ovulation
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Aménorrhée II: Approche fonctionnelle?
Asherman
oPOF
POF
HA
Hyper PRL
Hypophyse
Chirurgie endoscopique. COH-IVF, Protocole mauvaise répondeuse (mini Lupron). IVF avec don d’ovocytes Induction ovulation GnRH pump ou gonadotrophines LH-FSH (hMG) Anti PRL pour grossesse spontanée, autrement O traitement. Chirurgie selon pathologie.
Désir de conception Induction ovulation
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Aménorrhée II: Approche fonctionnelle?
Pas de désir de grossesse
Désir de conception
Apport E2/P4
Induction ovulation
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Dominique de Ziegler, MDProfessor and HeadReprod Endocrine
and InfertilityCharles Chapron, MD
Professor and ChairObstet Gynecology II
Hôpital CochinParis, France
Dr François X. Aubriot Dr Céline DavyDr Bruno BorgheseDr Alessandra FubiniDr Victoria IbecheoleDr Jannis VassilopoulosDr Sylvie EpelboinDr Louis MarcellinDr Pietro SantulliDr Ann MarszalekDr Laura Prat