How to diagnose and treat male infertility in 2011 Roelof Menkveld, PhD

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How to diagnose and treat male infertility in
2011Roelof 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

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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

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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

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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

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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
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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
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Normal values for WHO manuals, editions 2- 4 and
expected lower reference limits and WHO- 5 manual
Semen parameter WHO edition and year WHO edition and year WHO edition and year 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
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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

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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

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Comparison of expected new WHO manual lower
reference values and recent published values
Semen parameter Publication Publication Publication Publication
Semen parameter Menkveld et al., 2001 Haugen et al., 2006 Haugen et al., 2006 5th WHO manual
Semen parameter Menkveld et al., 2001 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
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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

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Need for a more precise or detailed breakdown
of semen parameter valuesUse of categories or
intervals
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Classification of male fertility potential
according to semen parameters as used at
Tygerberg Hospital
Semen parameter Fertility potential classification Fertility potential classification Fertility potential classification
Semen parameter Infertile Subfertile Fertile
Concentration (106/ml) lt 2.0 2.0 9.9 10.0
Motility ( progressive) lt 10 10 29 30
Morphology ( normal) lt 5 5 - 14 15
Semen volume (ml) lt 1.0 gt 6.0 1.0 6.0
Fertile or Normal Optimal chance for
pregnancy Subfertile or Borderline Reduced
chance for pregnancy Infertile or Pathological
Small change for pregnancy Menkveld, 2007
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Need for a new approach for the interpretation of
normal sperm morphology values
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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
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Overview of declining sperm morphology values
over years
Menkveld etal., 1986 Menkveld, 2010
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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
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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

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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

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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

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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

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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)

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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

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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

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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

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• Large acrosomes Spermac stain
• Spontaneous acrosome reaction
• No zona pellucida binding of spermatozoa

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• Small acrosomes
• Mostly non-viable
• Can not undergo acrosome reaction
• Can not bind to zona pellucida

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• Acrosome reacted Papanicolaou staining
• Not able to bind to the zona pellucida

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Acrosome reacted Spermac stain
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• Acrosomes with staining defects
• Beginning of acrosome reaction ?
• Cysts and vacuoles ?
• Membrane damage ?
• Not able to bind to zona pellucida ?
• DNA status (MSOME) ?

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• Large headed spermatozoa
• DNA status ?
• Poor prognosis for normal in vitro fertilisation

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Elongated spermatozoa pattern

• DNA damage
• Ultrastructural nuclear defects
• Stress
• Chromosome aneuploidy (Prisant et al., 2007)

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• Neck defects
• Absence of centriole no spindle formation in
  oocyte
• Midpiece abnormalities
• Mitochondrial defects (? Poor motility)

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Cytoplasmic residues

• ROS production
• Immaturity of spermatozoa

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Theoretical treatment option ( Male fertile)
Semen parameter Fertility potential classification Fertility potential classification Fertility potential classification
Semen parameter Infertile Subfertile Fertile
Concentration (106/ml) lt 2.0 2.0 9.9 10.0
Motility ( progressive) lt 10 10 29 30
Morphology ( normal) ?? 3 ?? 3 4
Semen volume (ml) lt 1.0 gt 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

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Theoretical treatment option ( Male subfertile)
Semen parameter Fertility potential classification Fertility potential classification Fertility potential classification
Semen parameter Infertile Subfertile Fertile
Concentration (106/ml) lt 2.0 2.0 9.9 10.0
Motility ( progressive) lt 10 10 29 30
Morphology ( normal) 3?? ?? 3 4
Semen volume (ml) lt 1.0 gt 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)

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Theoretical treatment option ( Male infertile)
Semen parameter Fertility potential classification Fertility potential classification Fertility potential classification
Semen parameter Infertile Subfertile Fertile
Concentration (106/ml) lt 2.0 2.0 9.9 10.0
Motility ( progressive) lt 10 10 29 30
Morphology ( normal) ?? 3 ?? 3 4
Semen volume (ml) lt 1.0 gt 6.0 1.0 6.0
?? 3 - IF apparent abnormal sperm morphology
pattern Treatment ICSI ??
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Tygerberg Academic Hospital and University of
Stellenbosch Medical School, Tygerberg (Cape
Town), South Africa
Thank you for your attention
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References

• Haugen et al., Int J Androl 2766-71,2006
• Kruger et al., Fertil Steril 461118-23,1986
• Kruger et al., Fertil Steril 49112-7,1988
• 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 17143-4,1986
• Menkveld et al., Hum Reprod 161165-71,2001
• Ombelet et al., Hum Reprod 12987-93,1997
• World Health Organisation. WHO laboratory manual
  for the examination and processing of human
  semen. WHO Press, Geneva. 2010