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Fertiliteitsdiagnostiek anno 2011Fertiliteitsdiagnostiek anno 2011
Willem OmbeletGenk
Willem OmbeletGenk
Gent, 12-05-2011Gent, 12-05-2011
10-15 % van de koppels met kinderwens hebben 10-15 % van de koppels met kinderwens hebben fertiliteitsproblemenfertiliteitsproblemen
Oorzaken Oorzaken 30% man30% man 30% vrouw30% vrouw 30% man & vrouw30% man & vrouw 10% onbekend10% onbekend
Spermatogenesis
Female Male
Serum: infections, hormonal, thyroid, AMH Serum: infections, hormonalSemen sample
FSHPrl
HSGHysteroscopy
E2, Prog, LH
PCT
US uterus & ovaries
E2, Prog
0menses
2-3 14 28
Outpatient
LaparoscopyCT, MRI, ... Treatment
repeat semen sample US + Doppler scrotumGenetics
Oorzaken: vrouwOorzaken: vrouw
BaarmoederhalsfactorBaarmoederhalsfactor zz zz ImplantatiestoornisImplantatiestoornis
Syndr v AshermanSyndr v Asherman Poliepen, myomen, infectiesPoliepen, myomen, infecties
EileiderfactorenEileiderfactoren SterilisatieSterilisatie post-infectiepost-infectie erge endometrioseerge endometriose
EisprongstoornissenEisprongstoornissen PCOPCO hyperprolactinemiehyperprolactinemie
Andere afwijkingenAndere afwijkingen Post-heelkundePost-heelkunde
Meest frequente vrouwelijke factorAnovulatie
Meest frequente vrouwelijke factorAnovulatie
Oligomenorree (cyclus > 35 d)
Amenorree Primair (XO - syndr v Turner)Primair (XO - syndr v Turner) SecundairSecundair
normogonadotroop (hyperprolactinemie) hypogonadotroop hypergonadotroop (PCO – syndroom)
Hypogonadotrope amenorreeHypogonadotrope amenorree
stress, vermagering, sportstress, vermagering, sport
Simple weight loss amenorreeSimple weight loss amenorree
Exercise-associated amenorreeExercise-associated amenorree
Psychogene hypothalame amenorreePsychogene hypothalame amenorree
Lage E2, laag FSH en LH, hoog cortisolLage E2, laag FSH en LH, hoog cortisol
Hyperprolactinemie
Oligo- of anovulatie
Hyperandrogenisme
PCO-echografisch
PCO - Syndroom
Cyclus > 35 dagen
Hirsutisme, haaruitvalAcne
testosterone
12 follikels < 10mm – bilatOf
Ovarieel volume > 10 ml( 0.5233 x L x B x H )
Ovariële reserveOvariële reserve
Pro
po
rtio
n o
f p
oo
r q
ual
ity
oo
cyt
es(%
)102
103
104
105
106
Nu
mb
er o
f fo
llicl
es
107
0 10 20 30 40 50 60
50
75
100
25
Age (years)
Optimalfertility Declining
fertility End of fertility
Irregularcycles
Number of follicles
Proportion of poor quality oocytes
Menopause
100
Female Age (yrs)
0
50
25
75
41 51 6121
Cu
mu
lati
ve %
31
Men
opa
use
On
set
Irre
gu
lari
ty
Ste
rilit
y
Su
bfe
rtili
ty
46
Website: www.fvvo.beBroekmans, FV&V in ObGyn, 2009, 2, 79-89
Accuracy Non Pregnancy prediction
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
1 - Specificity
Se
ns
itiv
ity
sROC curve AFC sROC curve AMH sROC curve FSHAFC studiesAMH studiesFSH studies
Accuracy Poor Response prediction
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
1 - Specificity
Se
ns
itiv
ity
sROC curve AFC
sROC curve AMH
AFC studies
AMH studies
Broekmans, FV&V in ObGyn, 2009, 2, 79-89
Cavum- en tubapathologieCavum- en tubapathologie
Female Male
Serum: infections, hormonal, thyroid Serum: infections, hormonalSemen sample
FSHPrl
HSGHysteroscopy
E2, Prog, LH
PCT
US uterus & ovaries
E2, Prog
0menses
2-3 14 28
Outpatient
LaparoscopyCT, MRI, ... Treatment
repeat semen sample US + Doppler scrotumGenetics
HSG: unicornuate uterus, patent tube
MRI: unicornuate uterus
MRI: ectopic ovary anterior to the
external iliac vessels
Ombelet et al., N Engl J Med, 348, 667, 2003
Diagnostische Hysteroscopie Diagnostische Hysteroscopie
LaparoscopieLaparoscopie
Female Male
Serum: infections, hormonal, thyroid Serum: infections, hormonalSemen sample
FSHPrl
HSGHysteroscopy
E2, Prog, LH
PCT
US uterus & ovaries
E2, Prog
0menses
2-3 14 28
Outpatient
LaparoscopyCT, MRI, ... Treatment
repeat semen sample US + Doppler scrotumGenetics
WHO 1987: 3555 men with male factorWHO 1987: 3555 men with male factor
Normaal : ≥20 mill / ml
Oligozoospermie : < 20 mill / ml
Asthenozoospermie : < 25 % grade a< 50 % grade a + b
Teratozoospermie : < 30 % < 14 % (strict criteria)
WHO 1999 : “authority-based” // not “evidence-based”
Case-control studyCase-control study
143 fertile
Men from pregnant women < 20 weeks
144 subfertileExclusion: tubal factor & anovulation
ProspectiveProspectivestudystudy
Statistics: ROC analysis
W Ombelet et al, Hum Reprod, 12, 987-993, 1997
ResultsResultsResultsResults
Area (ROC)Area (ROC) Cut-off ROCCut-off ROCP10 (F)P10 (F)
Count 69.4 34 14.3
Motility (a+b) 60.9 45 28
Morphology 77.7 10 5
WHO 2010
4500 men / TTP< 12 months/ P4500 men / TTP< 12 months/ P55
VolumeVolume < 1.5 ml< 1.5 ml
Sperm concentrationSperm concentration < 15 million spermatozoa/ml< 15 million spermatozoa/ml
Total Sperm numberTotal Sperm number < 39 million spermatozoa< 39 million spermatozoa
MotilityMotility (grade A+B) (grade A+B) < 32 % progressive motile< 32 % progressive motile
MorphologyMorphology < 4 % normal< 4 % normal
VitalityVitality < 58 %< 58 %
Cooper et al., HRU, 16, 231-245, 2010
TUNEL assay. TUNEL-positive nuclei (with double-strand nuclear DNA fragmentation) of spermatozoa as represented by the intense (A) and dull (B) Texas red fluorescence in
the nuclear region. The healthy nuclei (without DNA fragmentation) are stained blue with DAPI (C) used as counterstain.
Angelopoulou et al., Reprod Biol Endocrinol, 5, 36, 2007
Sperm Chromatin Structure Assay – SCSA
100
1000
Gre
en
Flu
ore
scen
ce
Evenson et al., 1980
200 cells /minute5000 cells analysed/sample
Denatured ss DNA: red fluorescence
Tubal Factor No Tubal Factor
IMC< 1 million
Morphology < 4%
ICSI
IVF
IMC< 1 million
Morphology >= 4%
IMC>= 1 million
Washingprocedure
IMC< 1 million
Morphology < 4%
ICSI
IUI 4 x
IMC< 1 million
Morphology >= 4%
IMC>= 1 million
Washing procedure
Initial SemenSample
Algorithm for male subfertility treatment
< 30% or no fertilisation
< 30% or no fertilisation
ICSI
IVF
Semen profile in a general population Aim: to investigate sperm quality in a general populationAim: to investigate sperm quality in a general population
Semen profile in a general population Aim: to investigate sperm quality in a general populationAim: to investigate sperm quality in a general population
Website: www.fvvo.beOmbelet et al., FV&V in ObGyn, 2009, 1, 18-26
Azoospermia: etiologyAzoospermia: etiologyAzoospermia: etiologyAzoospermia: etiology
Non-obstructive
Maturation arrest Idiopathic, cryptorchidism, Idiopathic, cryptorchidism,
mumps, drugs …mumps, drugs …
Sertoli cell only Idiopathic, irridiation, Idiopathic, irridiation,
drugs …drugs …
Seminiferous tubular sclerosis
Genetic, Klinefelter, Genetic, Klinefelter, testicular torsion, …testicular torsion, …
Obstructive
Epididymal obstruction Post-infective, post-surgery,
…
Vas deferens obstruction CBAVD, post-vasectomy ..
Ejaculatory duct obstruction
Prostatic cysts, post-surgical, post-infective
Azoospermia: diagnosisAzoospermia: diagnosisAzoospermia: diagnosisAzoospermia: diagnosis
Non-obstructive
Genetic testingGenetic testing
FSH, FSH, inhibine Binhibine B
testicular volumetesticular volume
Obstructive
Genetic testingGenetic testing
FSH, inhibine B: nlFSH, inhibine B: nl
testicular volume: nltesticular volume: nl
KaryotypeKaryotype
Count < 5 millCount < 5 mill
Yq deletionsYq deletions13% if nonobstructive azoospermia13% if nonobstructive azoospermia3 - 7% with severe oligozoospermia3 - 7% with severe oligozoospermia““Transmitted to male offspring”Transmitted to male offspring”
AZFa, AZFb,AZFa, AZFb, AZFb +c,AZFb +c, YqYq deletionsdeletions
All azoospermicAll azoospermicNone with sperm onNone with sperm on
diagnostic biopsy or TESEdiagnostic biopsy or TESE
AZFc deletionsAZFc deletions27/42 severely oligospermic27/42 severely oligospermic
9/20 (45%) with sperm on biopsy9/20 (45%) with sperm on biopsy9/12 (75%) had sperm at TESE9/12 (75%) had sperm at TESE
Hopps et al, HR, 18, 1660, 2003
EVALUATION OF AZOOSPERMIAEVALUATION OF AZOOSPERMIAEVALUATION OF AZOOSPERMIAEVALUATION OF AZOOSPERMIA
AzoospermiaAzoospermia
VasectomyVasectomy EndocrineEndocrineevaluationevaluation
<< 15 years 15 years
Vas reversalVas reversal
HypogonadotropicHypogonadotropichypogonadismhypogonadism
Semen volumeSemen volume< 1 cc< 1 cc
GonadotropinsGonadotropins TRUSTRUS
Semen volumeSemen volume>> 1 cc 1 cc
Dilated SV’sDilated SV’s
Testis biopsy/Testis biopsy/sperm retrievalsperm retrieval
NormalNormalspermatogenesisspermatogenesis ICSIICSI
Vasogram/Vasogram/SV gramSV gram
EjaculatoryEjaculatoryductduct
obstructionobstruction
TUREDTUREDballoon dilationballoon dilation
FSHFSH< 2x normal< 2x normal
FSHFSH>> 2x normal 2x normal
GeneticGeneticevaluationevaluation
Testis biopsy/Testis biopsy/sperm retrievalsperm retrieval
No spermNo sperm Decreased spermDecreased spermproductionproduction
NormalNormalspermatogenesisspermatogenesis
TIDTIDadoptionadoption
TESE/ICSITESE/ICSI VasogramVasogramSpermSperm
retrieval/retrieval/ICSIICSI
EpididymalEpididymalexploration/VEexploration/VE
+/- sperm+/- spermretrievalretrieval
> 15 years> 15 years
Sperm retrieval/Sperm retrieval/ICSIICSI
CBAVDCBAVD
CF testingCF testing
Sperm retrieval/Sperm retrieval/ICSIICSI
Kolettis PN. J Androl 23:293-305, 2002.Kolettis PN. J Androl 23:293-305, 2002.
CF - 1/2500 births: carriers 1/25 CF - 1/2500 births: carriers 1/25
95% - “Wolffian duct abnormalities”95% - “Wolffian duct abnormalities”
CF - 1/2500 births: carriers 1/25 CF - 1/2500 births: carriers 1/25
95% - “Wolffian duct abnormalities”95% - “Wolffian duct abnormalities”
EVALUATION OF AZOOSPERMIAEVALUATION OF AZOOSPERMIAEVALUATION OF AZOOSPERMIAEVALUATION OF AZOOSPERMIA
AzoospermiaAzoospermia
VasectomyVasectomyEndocrineEndocrineevaluationevaluation
<< 15 years 15 years
Vas reversalVas reversal
HypogonadotropicHypogonadotropichypogonadismhypogonadism
Semen volumeSemen volume< 1 cc< 1 cc
GonadotropinsGonadotropins TRUSTRUS
Semen volumeSemen volume>> 1 cc 1 cc
Dilated SV’sDilated SV’s
Testis biopsy/Testis biopsy/sperm retrievalsperm retrieval
NormalNormalspermatogenesisspermatogenesis ICSIICSI
Vasogram/Vasogram/SV gramSV gram
EjaculatoryEjaculatoryductduct
obstructionobstruction
TUREDTUREDballoon dilationballoon dilation
FSHFSH< 2x normal< 2x normal
FSHFSH>> 2x normal 2x normal
GeneticGeneticevaluationevaluation
Testis biopsy/Testis biopsy/sperm retrievalsperm retrieval
No spermNo sperm Decreased spermDecreased spermproductionproduction
NormalNormalspermatogenesisspermatogenesis
TIDTIDadoptionadoption
TESE/ICSITESE/ICSI VasogramVasogramSpermSperm
retrieval/retrieval/ICSIICSI
EpididymalEpididymalexploration/VEexploration/VE
+/- sperm+/- spermretrievalretrieval
> 15 years> 15 years
Sperm retrieval/Sperm retrieval/ICSIICSI
CBAVDCBAVD
CF testingCF testing
Sperm retrieval/Sperm retrieval/ICSIICSI
Kolettis PN. J Androl 23:293-305, 2002.Kolettis PN. J Androl 23:293-305, 2002.
Grade I:
Grade II:
Grade III:
Testicular microlithiasisTesticular microlithiasis tumors tumors
varicocelevaricocele
Environmental factors
Male Fertility
Physicallighttemperatureradiationelectromagnetic fields
Socio-economicnutritionstarvationoccupationlife styleBehavioral
psychologic stressdrug addiction: coffee, smoking, alcoholextreme weight lossphysical stress: competitive sports
Biologicalinfections
viralbacterial....
Chemicalmedicationheavy metals
(Pb, Cd,...)pesticides
Occupational heat exposure and male fertility
Occupational heat exposure and male fertility
Cumulative conception rate according to the male partners
exposure to heat. Exposed = exposed to heat or
seated in a vehicle for more than 3 hours per day.
Thonneau et al, Lancet, 1996, 347, 204-5 and Bujan et al, 2000, Hum Reprod, 15, 1355 - 7.
Cell phones & oxidative stress
Agarwal, RBMOnline, 15, 266, 2007
ConclusieConclusie
Accurate diagnose blijft belangrijkAccurate diagnose blijft belangrijk AnamneseAnamnese Klinisch onderzoekKlinisch onderzoek Speciale onderzoekenSpeciale onderzoeken
Minimale onderzoeken // Maximaal rendementMinimale onderzoeken // Maximaal rendement
Infertiliteit Infertiliteit ≠ ≠ IVF & ICSIIVF & ICSI
Genk IVF team
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