New who standards for semen analysis - highlights and implications
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Transcript of New who standards for semen analysis - highlights and implications
Sandro Esteves, MD, PhD
DirectorANDROFERTCenter for Male Reproduction and InfertilityCampinas, BRAZIL
New WHO Standards for Semen Analysis:
Highlights and Implications
Training Program in Assisted Reproductive Technology 2011 Cleveland Clinic Reproductive Research Center
Esteves, 2
Learning Objectives
Highlight the New WHO Reference Values for Semen Analysis
Understand How the New Standards Were Obtained
Implications of the New WHO Standards for Clinical Practice
Debate is open: • Should the new WHO standards be adopted ?
Esteves, 3
Semen Analysis
Paramount importance
on initial male infertility
evaluation
surrogate measure of
fertility status
Functional status male reproductive
system
volume, count,
motility, morphology
influenced by several factors
do not account subcellular
dysfunctions
Semen characteristics
WHO 1980
WHO 1987
WHO 1992
WHO1999
WHO 2010
Volume (mL) ND ≥ 2 ≥ 2 ≥ 2 ≥ 1.5
Sperm count (106/mL) 20-200 ≥ 20 ≥ 20 ≥ 20 ≥ 15
Total sperm count (106) ND ≥ 40 ≥ 40 ≥ 40 ≥ 39
Total motility (%) ≥ 60 ≥ 50 ≥ 50 ≥ 50 ≥ 40
Progressive motility ≥ 2 ≥ 25% ≥ 25% (a) ≥ 25% (a) ≥ 32% (a+b)
Vitality (%) ND ≥ 50 ≥ 75 ≥ 75 ≥ 58
Morphology (%) 80.5 ≥ 50 ≥ 30 (14)* ≥ 4*
Leukocyte count (106/mL) < 4.7 < 1.0 < 1.0 < 1.0 < 1.0 *Strict (Tygerberg) criterion
Cut-off reference values for semen characteristics as published in consecutive
WHO manuals
New WHO StandardsHow they were obtained
1,953 semen samples of recent fathers Time to pregnancy (TTP) ≤ 12 mo 5 studies in 7 countries on 3 continents Laboratories with QC only Morphology by strict criterion (Kruger) Progressive and non-progressive motility Lower reference limits (5th centile)
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Centiles
5% 50%* 95%
Volume (mL) 1.5 3.7 6.8
Sperm count per mL (x106) 15.0 73.0 213.0
Sperm count per ejaculate (x106) 39.0 255.0 802.0
% Motility (total) 40 61 78
% Motility (progressive) 32 55 72
% Normal (strict criteria) 4 15 44
% Alive (eosin-nigrosin staining) 58 79 91
Cooper et al: World Health Organization reference values for human semen characteristics. Hum Reprod Update 16: 231-245, 2010
Percentile distribution of semen characteristics values of recent fathers whose partners had a TTP ≤ 12
months, used to establish the reference limits in the 2010 WHO manual
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New WHO StandardsHow they were obtained
“Studies were conducted in different regions of the world with some areas over-represented, such as Northern Europe, and others, such as Africa, parts of Europe and Central and South America, under-represented”
“The values presented are considered to represent global semen characteristics of fertile men”
Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker H, Behre H, Haugen T, Kruger T, Wang C, Mibzvo MT, Vogelsong K
World Health Organization reference values for human semen characteristics.
Hum Reprod Update 16: 231-245, 2010.
Esteves, 7
New WHO Standards
Critical Appraisal of the WHO New Reference Values for Human Semen and Impact on Diagnosis and Treatment of Subfertile Men
Urology 2011, in press• Sandro Esteves, BRAZIL• Armand Zini, CANADA
• Nabil Aziz, UNITED KINGDOM• Juan Alvarez, SPAIN
• Edmund Sabanegh, USA• Ashok Agarwal, USA
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New WHO references valuesCritical Appraisal
USA(Columbia, NYC, Minneapolis, LA)
AUSTRALIA (Melbourne)
NORWAY(Oslo)
FINLAND(Turku)
DENMARK (Copenhagen)
FRANCE(Paris)
UK(Edinburgh)
??
??? ?
Study Year Country TTP <12
months stated
Sperm morphology evaluation criterion
Overlapping authorship or collaboration
Bonde et al. 1998 Denmark Yes David Yes
Slama et al. 2002 France, Denmark,
UK, Finland
Yes David, Tygerberg
Yes
Swan et al. 2003 USA No Tygerberg Yes
Haugen et al. 2006 Norway Yes Tygerberg No
Stewart et al. 2009 Australia Yes Tygerberg Yes
Studies used to establish the new standards for human semen characteristics
in the 5th ed. WHO Manual
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Reasons for lower cutt-off
Merits Demerits
Different way of generating data:
• Method for semen analysis (higher QC standards; strict morphology)
• Population studied
Controlled studies No systematic review of fertile populations:
• Not representative of global fertile male population
Recent fathers with known TTP
Standardized semen analysis
Morphology using different criteria
Single semen specimen of each individual
Female age and fertility status neglected
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New WHO StandardsCritical Appraisal - Summary
Female Partner Influence on the Potential Fertility of a Man
Opportunity of Pregnancy
Very Low Low Moderate
Female 1/12 12/12 12/12
Male 1/12 1/12 3/12
Combined 1/144 12/144 = 1/12 36/144 = 1/4
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Indications for assisted reproductive techniques
Varicocele treatment
Referrals for male partner evaluation
New WHO Standards• Implications for Clinical Practice
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Implications for Practice• Referrals for male partner evaluation
Semen characteristics
Patient Specimen
Reference limits
WHO1999
WHO 2010
Volume (mL) 2.3 ≥ 2 ≥ 1.5
Sperm count (106/mL) 16.5 ≥ 20 ≥ 15
Progressive motility 40 ≥ 50% (a+b)
≥ 32% (a+b)
Vitality (%) 65 ≥ 75 ≥ 58
Morphology (%) 9 (14) ≥ 4
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Implications for Practice• Reclassification of semen analysis reports
Reclassified as “Normal” WHO 2010
(38.7%)
Couples (N=987) with infertility duration > 12 months
Source: ANDROFERT, Brazil
Morphology results accounted for 53% of reclassification
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Esteves, 16
Male Infertility Evaluation – much more than a simple semen analysis -
Implications for Practice• Varicocele treatment
Varicocele
• 35% of male infertility cases
Surgical
Treat
ment
•Effect•Decrease seminal oxidative stress•Improve sperm DNA integrity•Improve semen parameters•Increase the likelihood of spontaneous and assisted pregnancy
•Treatment Recommendation:• Clinical (palpable) varicocele and• Abnormal semen analysis results
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Implications for Practice• Varicocele treatment
• Health insurance• Authorization not granted• Reimbursement refused
Previous candidates for treatment now ineligible if semen
parameters are above the WHO 5th
centile
•Higher spontaneous pregnancy rates after varicocelectomy in men with clinical varicocele and mild oligozoospermia or normozoospermia than with moderate to severe oligozoospermia
Facts
Kamal KM, Jarvi K, Zini A: Microsurgical varicocelectomy in the era of assisted reproductive technology: influence of initial semen quality on pregnancy rates. Fertil Steril 75: 1013-1016, 2001.
Richardson I, Grotas AB, Nagler HM: Outcomes of varicocelectomy treatment: an updated critical analysis. Urol Clin North Am 35:191-209, 2008.
Normal Varicocele grade 2 Varicocele grade 3
87.8
49.937.4
62.956 55.6
8.4 7.3 6.1
Adolescents with and without Varicocele
Sperm count (million/mL) Progressive motility (% a+b)Morphology (%)
Mori et al. Does varicocele grade determine extent of alteration to spermatogenesis in adolescents? Fertil Steril 90: 1769-1773, 2008.
P=0.003 P<0.001
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Implications for Practice• Indications for ART
• Severe male factor infertilitySemen analysis results fall below
new reference limits
ICSI
• < 5% strict morphology thresholds currently used
• Indications unlike to change due to new WHO reference values
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Implications for Practice• Indications for ART
IUI• Mild male factor infertility• Unexplained male infertility
• Impact of new WHO reference values likely to be minimal
Esteves, 21
Implications for Practice• Indications for ART- Summary
WHO reference semen values not suitable to indicate treatment modality
Merely represent the distribution of semen profile of a group of recent fathers
Choice of ART should be based on: Clinical features of each case Center’s experience and reported results with different ART modalities
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Debate is open • Should the new WHO reference
values be adopted ?
Expanding the interpretation of the new WHO reference values: focus on the 50th percentile
Laboratories seeking to adopt the new standard should determine the strategy that would aid the clear communication of the clinical significance of the results
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Esteves, 24
Practical Points (1)
In 2010, WHO reported evidence-based standards for semen characteristics of fertile men that are much lower than those in previous editions.
New standards are not representative of global semen characteristics of fertile men and cannot be misinterpreted as a sign of sperm quality decline.
Standards do not accurately discriminate fertile and infertile men. A comprehensive infertility workup, including sperm function testing, is crucial to assess the male fertility potential.
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Practical Points (2)
Adoption of the new limits will have a profound impact on diagnosis of male infertility and treatment of conditions such as varicocele.
However, its impact on ART indication is likely to be minimal.
WHO should have allowed for an extensive debate within the scientific community before publishing these values.