Transcript Slide 1

How to diagnose and treat male
infertility in 2011
Roelof Menkveld, PhD
Andrology Laboratory, Department of Obstetrics and Gynaecology,
Tygerberg Academic Hospital and University of Stellenbosch.
III rd Congress of the Society of Reproductive Medicine
Cornelia Diamond Resort Belek, Antalya, Turkey
05 to 09 October 2011
Lecture objectives
• Give an overview of the evolution of the (normal) semen
parameter values of the different WHO manual editions
from 1980 to 2010 (WHO-5)
• Discuss the usefulness of the new semen parameter
values with special reference to normal sperm
morphology of WHO-5
• Discuss some treatment options in cases where men
present with poor semen analysis results
Old manuals
Old wording in previous manuals
– 1st edition
• No specific wording or definitions for semen
parameter values ( Used normal and fertile range)
– 2nd and 3rd editions
• Used term “normal” values
– 4th edition uses term “reference” values
Statement
– The (mean?) normal “reference” values quoted in
these manuals are for “normal” men and NOT the
MINIMUM requirements for fertilisation
New wording for definition of “normal” values in
5th WHO manual edition
New wording for “normal of reference” values
– Refer to
• Lower reference limits
• Reference ranges
Material and methods for WHO-5 edition (1)
• Reference population
– Fathers (Couples with time to pregnancies of ≤ 12
months)
– 1600+ couples
– Five centres from 3 continents
• Samples
– Only 1 sample per father
– Complete sample after 3-7 days of abstinence
WHO manual, 2010
Material and methods for WHO-5 edition (2)
• Methods
– Only laboratories following WHO manual guidelines
Sperm concentration by haemocytometer only
– Sperm morphology evaluation according to STRICT
CRITERIA only
• Statistics
– Reference values based on the lower 5th percentile
limits
WHO manual, 2010
Normal values for WHO manuals, editions 2- 4 and expected
lower reference limits and WHO- 5 manual
WHO edition and year
Semen parameter
2nd - 1987
3rd - 1992
4th - 1999
5th - 2010
Volume (ml)
2.0
2.0
2.0
1.5
Sperm concentration (106/ml)
20
20
20
15
Total sperm count (106)
40
40
40
39
Motility (% progressive)
50
50
50
28
Vitality (% live)
50
75
75
59
Morphology (% normal)
50
30
(15)
4
Recent studies proposing new “cut-off,
normal or reference” values
• Three types of literature studies
– Based on
• In vivo or in vitro pregnancies
• Fertile versus subfertile populations
• Lower interval values
Lower percentile intervals
• Ombelet et al., 1997 - Lower 10th percentile
• Menkveld et al., 2001 - Lower 10th percentile
• Haugen et al., 2006 - Lower 10th and 5th
percentile
Comparison of expected new WHO manual lower
reference values and recent published values
Publication
Semen parameter
Menkveld et
al., 2001*
Haugen et al., 2006
5th
10th
5th WHO
manual
Sperm concentration (106/ml)
N/A
10.6
16.9
15
Motility (% progressive)
20
33
43
28
Morphology (% normal)
3
3
4
4
*Adjusted ROC curve values
Comments on the lower reference values
of WHO-5 manual
• Has lead to more confusion especially with clinicians
• Need a more “precise or detailed” breakdown of
semen parameter values
• Need a new approach to interpretation of normal
sperm morphology values
Need for a more “precise or detailed”
breakdown of semen parameter values
Use of categories or intervals
Classification of male fertility potential according to semen
parameters as used at Tygerberg Hospital
Fertility potential classification
Semen parameter
Infertile
Subfertile
Fertile
Concentration (106/ml)
< 2.0
2.0 – 9.9
≥ 10.0
Motility (% progressive)
< 10
10 – 29
≥ 30
Morphology (% normal)
<5
5 - 14
≥ 15
< 1.0
> 6.0
1.0 – 6.0
Semen volume (ml)
Fertile or Normal = Optimal chance for pregnancy
Subfertile or Borderline = Reduced chance for pregnancy
Infertile or Pathological = Small change for pregnancy
Menkveld, 2007
Need for a new approach for the
interpretation of normal sperm morphology
values
Sperm morphology
• Values as determined by strict (Tygerberg)
criteria (Menkveld et al., 1990) and according
to the old editions of WHO manuals are not
applicable anymore due to decrease in
normal sperm morphology values over years
• New approach for interpretation of sperm
morphology parameters is needed
Menkveld et al., 1990
Overview of declining sperm morphology values over years
70
60
50
40
30
20
10
1968
1970
1972
1974
1976
1978
1980
1982
1984
1986
1988
1990
1992
1994
1996
1998
2000
2002
2004
2006
2008
0
Year of semen analyses
Menkveld etal., 1986; Menkveld, 2010
Prognostic sperm morphology groups
Currently used based on strict criteria (Menkveld et al., 1990)
• Normal
– ≥ 15% morphological normal spermatozoa
• Good prognosis group
– 5 to 14% morphological normal spermatozoa
• Poor prognosis group
– ≤ 4% morphological normal spermatozoa
WHO-5 lower (Normal) reference value
– ≥ 4% morphological normal spermatozoa
Menkveld et al., 1990; Kruger et al., 1986; Kruger et al., 1988; WHO, 2010
Declining normal sperm morphology values
Decline due to three possible reasons
– Stricter application of evaluation criteria
– Negative environmental influences
– Additional parameters for sperm morphology
abnormalities
Stricter application of sperm morphology
evaluation criteria
• Introduction of STRICT CRITERIA
– Strict versus liberal approach
• Chanced from borderline spermatozoa previous
regarded as normal to TOO BE REGARDED AS
ABNORMAL
– Over critical approach for interpretation of normal
– Inadequate training
Negative environmental influences
• Exposure to pseudo-estrogens of mother, unborn baby and male
– Higher incidences of decrease in male reproductive health
• Higher exposure to toxic environment and occupation hasards
– Decrease in spermatogenesis and lower/poorer semen
parameters
• Higher incidences of sexual transmitted diseases
– Lower semen parameters
– Increase of leukocytospermia
– Increased sperm DNA damage
Decline due to introduction of additional parameters
for sperm morphology abnormalities
• For example
– Differential classification of acrosome morphology
• Normal
• Staining defects
• Too large
• Too small
• Other/Amorphous
New approach for interpretation of sperm
morphology parameters is needed
• Better use of existing sperm morphology parameters
• Better quality control
• Use of additional sperm morphology parameter,
especially in patients with teratozoospermia
according new lower reference value of ≤ 3% (Poor
prognosis group)
Better use of existing sperm morphology
parameters
• Acrosome morphology (Acrosome index)
– TZI
– Cytoplasmic residues
– Semen cytology
• Identification, reporting and treatment of WBC on
semen smears
Better quality control for sperm morphology
evaluation
Problem
• Lack of intra- and inter-laboratory quality control
• Lack off standardisation between different international
QC schemes
Solutions
• Betters adherence to WHO guidelines (aim of new WHO
manual)
• Better co-operation between and standardisation of the
different international QC schemes
Use of additional sperm morphology
parameters
In WHO abnormal morphology group (≤ 3%)
• Identification of abnormal sperm morphology patterns
– Abnormal acrosome staining
– Large sperm/acrosome patterns
– Small sperm/acrosome patterns
– Elongated sperm morphology patterns
Large acrosomes – Spermac stain
• Spontaneous acrosome reaction
• No zona pellucida binding of spermatozoa
Small acrosomes
•Mostly non-viable
•Can not undergo acrosome reaction
•Can not bind to zona pellucida
Acrosome reacted – Papanicolaou staining
•Not able to bind to the zona pellucida
Acrosome reacted – Spermac stain
Acrosomes with staining defects
• Beginning of acrosome reaction ?
• Cysts and vacuoles ?
• Membrane damage ?
• Not able to bind to zona pellucida ?
• DNA status (MSOME) ?
arge headed spermatozoa
DNA status ?
Poor prognosis for normal in vitro fertilisation
Elongated spermatozoa pattern
• DNA damage
• Ultrastructural nuclear defects
• Stress
• Chromosome aneuploidy (Prisant et al., 2007)
Neck defects
• Absence of centriole – no spindle formation in oocyte
Midpiece abnormalities
• Mitochondrial defects (? Poor motility)
Cytoplasmic residues
• ROS production
• Immaturity of spermatozoa
Theoretical treatment option ( Male fertile)
Semen parameter
Fertility potential classification
Infertile
Subfertile
Fertile
Concentration (106/ml)
< 2.0
2.0 – 9.9
≥ 10.0
Motility (% progressive)
< 10
10 – 29
≥ 30
Morphology (% normal)
?? ≤ 3
?? ≤ 3
≥4
Semen volume (ml)
< 1.0
> 6.0
1.0 – 6.0
Treatment will depend on several factors
• Age of couple – ART for older women
• Years of infertility – If woman is “normal” give time
• If female factor treat with ART
Theoretical treatment option ( Male subfertile)
Semen parameter
Fertility potential classification
Infertile
Subfertile
Fertile
Concentration (106/ml)
< 2.0
2.0 – 9.9
≥ 10.0
Motility (% progressive)
< 10
10 – 29
≥ 30
Morphology (% normal)
≤ 3??
?? ≤ 3#
≥4
Semen volume (ml)
< 1.0
> 6.0
1.0 – 6.0
?? ≤ 3# - No apparent abnormal sperm morphology pattern
Treatment will depend on several factors
• Age of couple – ART for older women (IUI, IVF)
• Years of infertility – If woman is “normal” give limited time
• If female factor - treat with ART (IVF, ICSI)
Theoretical treatment option ( Male infertile)
Semen parameter
Fertility potential classification
Infertile
Subfertile
Fertile
Concentration (106/ml)
< 2.0
2.0 – 9.9
≥ 10.0
Motility (% progressive)
< 10
10 – 29
≥ 30
Morphology (% normal)
?? ≤ 3
?? ≤ 3
≥4
Semen volume (ml)
< 1.0
> 6.0
1.0 – 6.0
?? ≤ 3# - IF apparent abnormal sperm morphology pattern
Treatment = ICSI ??
Tygerberg Academic Hospital and University of
Stellenbosch Medical School, Tygerberg (Cape
Town), South Africa
Thank you for your attention
References
Haugen et al., Int J Androl 27:66-71,2006
Kruger et al., Fertil Steril 46:1118-23,1986
Kruger et al., Fertil Steril 49:112-7,1988
Menkveld R. In: Male infertility – Diagnosis and treatment.
Oehninger and Kruger (eds). Informa Healthcare, 2007
Menkveld et al., Human Reprod 5(5):586-92,1990
Menkveld R. Asian J Androl 12(1):47-58,2010
Menkveld et al., Arch Androl 17:143-4,1986
Menkveld et al., Hum Reprod 16:1165-71,2001
Ombelet et al., Hum Reprod 12:987-93,1997
World Health Organisation. WHO laboratory manual for
the examination and processing of human semen. WHO
Press, Geneva. 2010