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Abnormal Semen Parameters: What doctors should know

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Abnormal Semen Parameters: What doctors should know

  1. 1. Sandro Esteves, MD., PhD. Director, ANDROFERT Andrology & Human Reproduction Clinic Campinas, BRAZIL Abnormal Semen Parameters What doctors should know Reproductive Andrology Surgery Workshop 2014 Al Jahra Hospital, KUWAIT ISO 9001:2008
  2. 2. Available at: h"p://www.androfert.com.br/review   ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2014 APRIL ANDROFERT Abnormal semen parameters: what doctors should know
  3. 3. Lecture  Outline   Learning objectives Epidemiological trends and sperm development Routine semen analysis: where we are today Importance of sperm chromatin integrity and its clinical implications ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 3 2014 APRIL ANDROFERT
  4. 4. Epidemiological Trends •  10-15% of couples are infertile and 1 in 8 men seeks medical assistance for male infertility. •  Male factor infertility is responsible for up to 50% of cases of infertility: 20% as the sole reason and 30% as contributory. •  Increased incidence of male infertility may be attributed to environmental factors and modern life habits such as obesity, ageing, exposure to gonadotoxins and certain endocrine disruptors. •  Noticeable epidemiological increase in the incidence of testicular cancer and urogenital anomalies Irvin S, et al 1996, Auger J et al, 1995, Irvine DS 1994, Jørgensen N et al 2001, Jørgensen N et al 2002, Swan SH 2003, Feki NC et al, 2009 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 4 2014 APRIL ANDROFERT
  5. 5. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2014 APRIL ANDROFERT
  6. 6. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2014 APRIL ANDROFERT
  7. 7. Abnormal Semen Multiple causes, not exclusive –  Hormonal problems –  Genetic causes –  Varicocele –  Genital infection –  Chemotherapy, radiotherapy –  Cryptorchidism –  Idiopathic –  Gonadotoxin exposure –  Life-style factors –  Endocrine disruptors –  Etc. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2014 APRIL ANDROFERT
  8. 8. Routine Semen Analysis Functional Status of Reproductive Tract Seminal Fluid and Sperm Central Laboratory Investigation ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2014 APRIL ANDROFERT
  9. 9. •  Standardization •  Quality control •  Quality assurance •  Certification Semen Analysis: Andrology Lab ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 9 2014 APRIL ANDROFERT
  10. 10. Standards ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2014 APRIL ANDROFERT
  11. 11. New WHO Reference Values WHO 20101 1.5 15 39 32 (a+b) 58 4 <1.0 Semen Parameter WHO 1999 Volume (mL) ≥ 2.0 Count (x106/mL) ≥ 20 Total sperm number/ejaculate ≥ 40 Motility (%) ≥ 50 (a + b) Vitality (%) ≥ 75 Morphology (%)2 (14) Leukocytes (x106/mL) < 1.0 1Lower Limit (5% percentile), Recent fathers; 2Strict criteria Grade a = rapid progressive motility; Grade b = slow/sluggish progressive motility ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 11 2014 APRIL ANDROFERT
  12. 12. New WHO Reference Values Caution to Interpret Results ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2014 APRIL ANDROFERT
  13. 13. New WHO standards
 Reasons for Lower Cut-off Values •  Method for semen analysis (QC standards) •  Adoption of strict criterion for morphology •  Single specimen of each individual Different way of generating data •  Recent fathers with known TTP (≤ 12months) •  Selection bias Population studied Esteves et al. Urology 2012 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2014 APRIL ANDROFERT
  14. 14. Critical Appraisal of the WHO New Reference Values for Human Semen and Impact on Diagnosis and Treatment of Subfertile Men Esteves, Zini, Aziz et al, Urology, in press Columbia USA Melbourne Australia Turku Finland Oslo Norway Edinburgh UK Paris France Copenhagen Denmark 2010 WHO Reference: 1,953 men ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2014 APRIL ANDROFERT
  15. 15.     Volume (mL) 1.5 Sperm count (x106/mL) 15.0 Total count (x106) 39.0 % Motile (total) 40 % Motile (progressive) 32 % Normal (strict criteria) 4 %Alive 58 Cooper et al. Hum Reprod Update 2010  WHO  2010:  Recent  fathers  TTP≤12   mo.   Percentiles 5% 50%* 95% 3.7 6.8 73.0 213.0 255.0 802.0 61 78 55 72 15 44 79 91 New WHO Standards
 Reasons for Lower Cut-off Values ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2014 APRIL ANDROFERT
  16. 16. New WHO Standards: Implications Do we need to recall previous semen analysis reports?   Abnormal results WHO 1999 Reclassified as “Normal” WHO 2010 (38.7%) Couples (N=987) with infertility duration >12 months Source: ANDROFERT, Brazil Morphology by strict criterion accounted for 53% of reclassification ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2014 APRIL ANDROFERT
  17. 17. Referral Deferment Semen Parameters Case study Volume (mL) 2.3 Count (106/mL) 16.5 Progressive motility (%) 40 Vitality (%) 65 Morphology (%) 9 Reference 1999 2010 ≥ 2 ≥ 1.5 ≥ 20 ≥ 15 ≥ 50 ≥ 32 ≥ 75 ≥ 58 (14) ≥ 4 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 17 2014 APRIL ANDROFERT
  18. 18. Laboratories adopting the new standards should determine the strategy to communicate clinical significance of the reported results WHO Standards Interpretation Esteves SC. Int Braz J Urol 2014 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 2014 APRIL ANDROFERT
  19. 19. Semen Analysis Results Not accurate to discriminate fertile from infertile men Male infertility workup goes far beyond a simple semen analysis. History, physical examination, laboratory and sperm function tests are minimum standards Esteves, et al 2011; 2012; 2014 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 19 2014 APRIL ANDROFERT
  20. 20. Practical Points •  Routine semen analysis still central in laboratory evaluation of male infertility •  WHO new reference limits are lowered compared with previous references •  Caution to interpret new references –  Comparison with 90% percentile distribution is advisable –  Results not accurate to discriminate infertile from fertile males unless if at extreme levels –  Complete male infertility evaluation should be undertaken ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 20 2014 APRIL ANDROFERT
  21. 21. Lecture  Outline   Learning objectives Epidemiological trends and sperm development Routine semen analysis: where we are today Importance of sperm chromatin integrity and its clinical implications ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2014 APRIL ANDROFERT
  22. 22. Why semen analysis is not enough ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2014 APRIL ANDROFERT
  23. 23. Defects in Sperm DNA Structure single-strand break mis-match damaged base double-strand break inter-strand crosslink intra-strand crosslink Single-strand DNA break (ss-DB) Double-strand DNA break (ds-DB) Base deletion or modification Inter or intra-strand cross linkage Esteves et al 2013; Alvarez and Gosálbez 2011; Ward 2011 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2014 APRIL ANDROFERT
  24. 24. Biological mechanisms of SDF Protamination Failure Replacement of histone to protamines during spermiogenesis Oxidative Stress Epididymis transit Post-ejaculation: leukocytes, immature sperm, abnormal levels seminal plasma antioxidants Apoptosis During sperm maturation (testis & epididymis) Fernández et al. 2009; Alvarez and Sakkas 2010; Agarwal et al. 2013 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 24 2014 APRIL ANDROFERT
  25. 25. DNA  Damage   Environmental factors Phtalate exposure, radiation, temperature Diseases Varicocele, GTI, fever Life-style Obesity, smoking Aging External factors leading to SDF Kort et al. 2006; Rubes et al 2007; Viloria et al 2007; Esteves & Agarwal 2011
  26. 26. SDF and Male Infertility Etiologies Gosálbez et al. 2013 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2014 APRIL ANDROFERT
  27. 27. SDF and Infertility: Why bother? ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2014 APRIL ANDROFERT
  28. 28. 19% 1.5% Normal Elevated Live Birth Rates with Intrauterine Insemination OR = 0.07 [95% CI: 0.01-0.48] Bungum et al. Hum Reprod 2007 IUI Outcome and SDF ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 28 2014 APRIL ANDROFERT
  29. 29. 26% 42% IVF ICSI Pregnancy by Method in Cases of Elevated Sperm DNA Fragmentation IVF Outcome and SDF Robinson et al. Hum Reprod 2012 Meta-analysis of 16 studies and 2,969 couples Increased miscarriage in couples undergoing IVF/ICSI with high sperm DNA damage Risk ratio (RR) = 2.16 95% CI: 1.54-3.03; p<0.00001 Bungum et al. Hum Reprod 2007 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 29 2014 APRIL ANDROFERT
  30. 30. Frequency of elevated SDF in men with normal semen analysis Normal semen analysis results (WHO) ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2014 APRIL ANDROFERT Androfert; N=987
  31. 31. Practical Implications •  Successful pregnancies in IVF/ICSI cycles can be obtained using semen samples with a high proportion of DNA damage •  Sperm DNA damage is promutagenic and can give rise to mutations after fertilization, as the oocyte attempts to repair DNA damage before the initiation of the first cleavage. •  Mutations occurring at this point will be fixed in the germline and may be responsible for the induction of infertility, childhood cancer in the offspring and for a higher risk of imprinting diseases PANG M. G. et al Hum Reprod, 20: 1688–1694, 2005. Burrello et al Cytogenet Genome Res, 111:363–365, 2005. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2014 APRIL ANDROFERT
  32. 32. Fertility and Sterility 2014; 101(1):58-63 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2014 APRIL ANDROFERT
  33. 33. Correlation between SCD and TUNEL SCD more sensitive than TUNEL. Important to distinguish between the methods as they differently evaluate SDF. 20.6 11.5 % SDF SCD TUNEL Feijo & Esteves Fertil Steril 2014; 101(1):58-63 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 33 2014 APRIL ANDROFERT
  34. 34. Management ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2014 APRIL ANDROFERT
  35. 35. Take-home Messages (1) •  Male infertility is a important health issue •  Despite being genetically-determined, male fertility is modulated by external factors •  Life-style modifications should be considered in males seeking fatherhood ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2014 APRIL ANDROFERT
  36. 36. Take-home Messages (2) •  Normal semen analysis is not a guarantee of fertility, and vice-versa •  Male infertility evaluation should go far beyond routine semen analysis •  Minimal standards include history taking, physical examination, semen analysis, sperm functional tests, and other tests as appropriate ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 36 2014 APRIL ANDROFERT
  37. 37. Take-home Messages (3) •  Sperm chromatin integrity critical for a viable pregnancy •  Sperm DNA fragmentation common in men with unexplained infertility •  SDF testing provides information that is different and of better prognostic value than semen analysis •  Grading SDF may help in designing a cost effective management ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2014 APRIL ANDROFERT
  38. 38. Thank you Obrigado ‫شكرا‬ ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 38 2014 APRIL ANDROFERT

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