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![Anti-sperm antibodies
(persist even if causes are addressed or reversed)
Ductal obstruction
acquired or congenital
unilateral or bilateral
Vasectomy
Epididymitis, Orchitis
Trauma, torsion
Cryptorchidism
Varicoceles
“Screening for antisperm antibodies should not be offered
because there is no evidence of effective treatment to
improve fertility. [NICE Guidelines 2013]](https://image.slidesharecdn.com/rhgcongress2018-renewoderich-181023082648/75/RHG-Congress-2018-Rene-Woderich-20-2048.jpg)
Uploaded byReproductive Health Group
RHG Congress 2018 - Rene Woderich
The document discusses the comparative effectiveness of testicular versus ejaculated sperm in cases of male infertility, particularly focusing on failed fertilization during ICSI. It highlights various classifications of male factor infertility and outlines guidelines and evidence showing the benefits of using testicular sperm in severe cases, while advocating for thorough analysis and treatment options for underlying causes. The conclusion emphasizes the importance of individual couple preferences, the role of female factors, and ongoing debates within the reproductive community regarding treatment approaches.
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RHG Congress 2018 - Rene Woderich
- 1. Testicular versus ejaculatedsperm should be used for ICSI in cases of failed fertilisation René Woderich Consultant Urologist Warrington
- 2. “Insanity Is Doingthe Same Thing Over and Over Again and Expecting Different Results” Misappropriated to A. Einstein
- 3. “in cases offailed fertilisation” 1) Failed natural fertilisation Analyse/ address/ treat underlying causes and persevere with natural conception? 2) Failed AFT with ejaculated sperm What about poor quality of ejaculated sperm? How many attempts? Is testicular (epididymal) sperm superior?
- 4. Overview • Infertility withpoor sperm quality • Reversible obstructive azoospermia • Medical treatment of ‘mild’ male factor infertility • Meta-analysis ejaculated vs. testicular sperm
- 5. 23.8 28.2 23.4 25.3 0 10 20 30 40 50 60 70 80 90 100 Ejaculate (2160)Epididymal (43) Testicular fresh (122) Testicular frozen (106) Transfers Deliveries per transfer ICSI RESULTS AND ORIGIN OF SPERM A. Van Steirteghem, 2004
- 7. Infertility Definition Failure to conceiveafter 1 year 10% couples 5% men 30% cause not identified - ideopathic
- 8. Relative incidence ofcauses of Infertility 25% female factor alone 25% male factor alone 25% male and female factor 25% unexplained
- 10. % Chance Conceptionwithin 1 year Trying time (months) Motile sperm (million/ ml) <12 24 48 96 0 0 0 0 0 0.5 16 12 9 6 1 25 19 14 9 2 34 26 19 13 5 36 28 21 14 >10 37 28 21 14
- 11. % Ovarian Reserveby Age Average ♀ age at ICSI
- 12. Normal Fertility Depends on: ♂Spermatogenesis ♂ Maturation in epididymis ♂♀ Coitus ♀ Transport through female genital tract ♀ Fertilisation ♀ Implantation
- 13. Semen Analysis WHO minimumstandard Volume 1-5 ml Density 20 million/ ml Motility > 50% Forward progression > 2% Morphology > 15% normal
- 14. Severe Male FactorInfertility Number < 1 million/ ejaculate Motility < 20% Progression < 2% (4%) Abnormal forms > 85%
- 15. Mild Male FactorInfertility Two or more semen analyses that have one or more variables which fall below the 5th centile as defined by the World Health Organization. (NICE 2013)
- 16. Definitions Aspermia – patientproduces no semen Azoospermia – semen contains no sperm Oligo(zoo)spermia – sperm concentration <20 mill/ ml Astheno(zoo)spermia – <50% sperm are active Terato(zoo)spermia - >85% sperm abnormally shaped OATS (Oligo-Astheno-Terato-Spermia) – all of the above Crypto(zoo)spermia – isolated sperm in ejaculate, detected only after extensive microscopic search (+/- centrifugation) Necro(zoo)spermia – all sperm are dead Pyospermia / Leucospermia – large numbers of WBC
- 17. Causes of Oligospermia Idiopathic Cryptorchidism Varicoceles Drugs/gonadotoxins Chemotherapy Radiotherapy Genito-urinary infections Endocrinopathy Partial ejaculatory duct obstruction Unilateral vasal obstruction Hypospermatogenesis Genetic
- 18. NICE Guidelines 2013 “Unlessthere is azoospermia, the predictive value of subnormal semen variables is limited. No functional test has yet been established that can unequivocally predict the fertilising capacity of spermatozoa. Sperm function tests such as computer-assisted semen analysis have not been found to be more predictive. Reliable sperm function tests are urgently required.”
- 19. NICE guidelines 2013 “Primarytesticular failure is the most common cause of male infertility due to oligozoospermia… ; however, in the majority of cases (66%) the cause is unknown. ... There is no effective treatment to restore fertility in primary testicular failure.”
- 20. Anti-sperm antibodies (persist evenif causes are addressed or reversed) Ductal obstruction acquired or congenital unilateral or bilateral Vasectomy Epididymitis, Orchitis Trauma, torsion Cryptorchidism Varicoceles “Screening for antisperm antibodies should not be offered because there is no evidence of effective treatment to improve fertility. [NICE Guidelines 2013]
- 21. Seminal fluid analysis Motility %sperm moving in 10 hpf Forward progression 0 non-motile 1 sluggish 2 slow 3 moderate 4 excellent Agglutination
- 22. Contribution of accessorysex glands to semen volume Volume (ml) Seminal vesicles 2.0 Prostate 0.5 Cowper’s glands 0.1
- 23. Main biochemical constituents ofseminal plasma Acid phosphatase L-carnitine Citric acid Fructose Glucosidase Glycerophosphocholine Magnesium Prostaglandins Zinc
- 24.
- 26. Spermcell with release ofcytoplasm round spermatid Sertoli-cell B spermatogonium cytoplasmic bridge spermatocyt tight-junction Spermatogenesis
- 30. Johnsen score count 10Complete spermatogenesis organised epithelium 9 many spermatozoa disorganised epithelium 8 < 10 spermatozoa 7 many spermatids 6 < 10 spermatids 5 many spermatocytes 4 < 10 spermatocytes 3 Spermatogonia 2 Sertoli cells only 1 No cells, tubular fibrosis
- 31. Relationship Between JohnsenScore and Testicular Size in 388 Testicular Biopsies from Azoospermic Men 2 cm 3 cm 4 cm 5 cm < 2 2.1-7.9 > 8.0
- 33. Essential Genetic Investigations Karyotypeall ICSI patients X-linked genetic defects Kallman’s Syndome Androgen insensitivity Sex chromosome aneuploidy Klinefelters (XXY) Autosomal defects CFTR gene Vasal aplasia Y chromosome microdelitions Hypospermatogenesis (DNA fragmentation ? Role)
- 34. Vincent et al.J. of Andrology, 2002 azoospermia oligozoospermia Obstructive Non-obstructive <5x106/ml 5-10 >10-20 total N° of subjects 144 648 648 628 583 % Anomalies 3 9.7 4.316.7 2651 9.7 4.3 7.70.5 % in the General population 0.4-0.6 INCIDENCE OF CHROMOSOMAL ANOMALIES
- 35. GENETIC CAUSES OF SPERMATO/SPERMIOGENESISFAILURE Gene Anomalies Chromosomal Anomalies >1000 genes involved in human spermatogenesiS (Hochstenbach and Hackstein 2000)
- 36. Yp Yq 1 2 3 4 5 6 Centromere 7 USP9Y -DBY -UTYAZFa AZFb CDY2 XKRY HSF2-L SMCY eIF-1AY RBMY1 AZFc PRY TTY2 DAZ BPY2 PRY CDY1 >1200 PATIENTS tested: ONEISOLATED GENE DELETION FOUND SEARCH FOR ISOLATED GENE DELETIONS
- 37. Type of deletionsFrequency AZFa complete 2,5% partial 2,5% AZFb complete 2,5% AZFb partial 14% AZFc 63% AZFb complete +AZFc 10,5% AZFb partial +AZFc 2,5% AZFa+b+c 2,5% 39 PATIENTS WITH DELETIONS / TOTAL 449 PATIENTS ANALYSED 1 2 3 4 5 6 7 AZFa AZFc AZFb Krausz et al. 1999 Hum. Reprod ; 1999 JCEM;2001 JCEM
- 38. Azoospermia <1x106 <5x106 >5x106 Indicationsfor routine screening 8-10x106 Phenotype number of deleted pat. / frequency totale pat. AZOOSPERMIA 26/175 14,8% <5 millions/ml 12/184 6,5% 5-20 millions/ml 1/59 1,6% Krausz et al. 1999 Hum. Reprod ; 1999 JCEM;2001 JCEM
- 39. Y chromosome microdeletions •7% unselected infertile men • 16% men with severe oligospermia • 25% with azoospermia • Y chromosome 11q position • AZF a – b – c (order of severity) • Genes RBW, DAZ, DBY, XXX • Commonest AZFc (Daz gene) • No phenotype abnormality • All male offspring have Y deletions • Obstructive azoospermia – no deletions
- 40. AZFa, AZFb, AZFc Micro-deletionAZFa – Sertoli cell only Micro-deletion AZFb – Maturation arrest Micro-deletion AZFc – Severe olgospermia Vogt et al 1996
- 41. Human Studies • 200fertile vs. 200 infertile men • Y deletion on PCR 2% vs. 7% • Most infertile men with deletion were azoospermic Pryor JL N Engl J Med 1997 • 20% azoospermic and 13% oligospermic men undergoing TESE for ICSI had AZFc deletions • Y deletion had no effect on fertilisation and implantations rates Silber SJ, Hum Rep
- 42. Surgery for infertility Ethicalconsiderations Natural pregnancy: Cheaper Less stressful Age of partner ICSI: Both require surgery Cost Safety
- 43.
- 45. Altered spermatogenesis Reflux of toxic metabolites Disturbed hormonal status Abnormal temperature regulation Varicocele Sperm DNA damage Increased ROS Elevated temperature Saleh RA et al Evaluation of nuclear DNA damage in spermatozoa from infertile men with varicocele. Fertil Steril 2003;80(6):1431-6
- 46. pre-operative post-operative 0 10 20 30 40 meanDFI(%) 38 33 .079 DNA FragmentationIndex pre – post Varicocelectomy
- 47. Randomised Controlled Trialsof Varicocele Treatment Study Treated Untreated Semen Quality Number Pregnant Number Pregnant Nilsson 1979 57 4 (8%) 45 8 (18%) No change Breznik 1993 38 13 (34%) 41 22 (54%) No sig. change Madgar 1995 25 8 (32%) 20 2 (10%) Improvement Yamamoto 1996 45 3 (7%) 47 4 (8.5%) Improvement Nieschlag 1998 62 18 (29%) 63 16(25%) Improvement WHO 1998 135 47(35%) 113 19(17%) Improvement ALL 27% 22% OR 1.32(0.9 1.96)
- 48. Randomised Controlled Trialsof Varicocele Treatment In Oligozoospermia Study Treated Untreated Semen Quality Number Pregnant Number Pregnant Madgar 1995 25 8 (32%) 20 2 (10%) Improvement Nieschlag 1998 62 18 (29%) 63 16(25%) Improvement WHO 1998 135 47(35%) 113 19(17%) Improvement ALL 29% 19% OR 2.26(1.4 –3.6)
- 49. NICE Guidelines 2013 Recommendation88 “Men should not be offered surgery for varicoceles as a form of fertility treatment because it does not improve pregnancy rates.” Research recommendation 15 “Randomised controlled trials are needed to compare the effectiveness of surgery for varicocele and in vitro fertilisation treatment in men with abnormal semen quality.”
- 50.
- 51. Reconstructive options: obstruction Vaso-vasostomy(vasectomy reversal) Vaso-epididymostomy Transurethral incision of ejaculatory ducts
- 52. Cause of Obstructive Azoospermiain 321 Men Site of obstruction n % Intra-testicular 47 16 Epididymal 163 51 Bilateral vasal aplasia 58 18 Unilateral vasal aplasia 39 12 Ejaculatory duct 3 1
- 58. Vaso-epididymostomy Patency rate 39-100% Pregnancyrate 18-30% Depending on: Cause of obstruction Microsurgical skills Age of spouse
- 60. NICE Guidelines 2013 Recommendation87 “Where appropriate expertise is available, men with obstructive azoospermia should be offered surgical correction of epididymal blockage because it is likely to restore patency of the duct and improve fertility. Surgical correction should be considered as an alternative to surgical sperm recovery and IVF.”
- 61.
- 62.
- 69. Microtese Schlegel P. Hum.Rep. 14, 131, 1999
- 70. 0 10 20 30 40 50 60 70 80 90 100 Ejaculate (2160) Epididymal(43) Testicular fresh (122) Testicular frozen (106) Transfers Deliveries per transfer ICSI RESULTS AND ORIGIN OF SPERM A. Van Steirteghem, 2004
- 71. In favour ofejaculated sperm Crucial role of epididymis in final steps of spermatogenesis: • Epigenetic gene modification • Changes in spermatozoas’ surface proteins • Sperm maturation • DNA stability/ resistance (“survival of the fittest”) • Acrosomal protein for zona pellucida penetration present in epididymal but not testicular sperm • Higher sperm motility the further distal in epididymis • ?Better results with epididymal vs. testicular sperm • Beneficial in conventional fertilisation
- 72. In favour ofextracted sperm • Needs thorough examination and prolonged preparation • Repeat centriguagation may increase reactive oxidative species/ further quality reduction • Technical challenges with cryopreservation • Mis-timing of oocyte extraction • Oxidative stress/ DNA damage during transit through male genital tract • Higher DNA fragmentation with lowest sperm count • Better ICSI outcomes with extracted sperm in obstructive azoospermia • ICSI bypasses complex mechanisms of oocyte investment and penetration • ICSI technician select sperm with highest motility and best morphology
- 73. Mild male factorinfertility: NICE 2013 The term ‘mild’ male factor infertility is used extensively in practice and in the literature. However, there is no formally recognised definition of what this means. Therefore, where the term ‘mild’ male factor infertility is applied in this guideline, it is defined as meaning: two or more semen analyses that have one or more variables which fall below the 5th centile as defined by the World Health Organization (WHO, 2010), and where the effect on the chance of pregnancy occurring naturally through vaginal intercourse within a period of 24 months would then be similar to people with unexplained infertility or mild endometriosis. Assisted reproductive treatments: IVF and ICSI are the preferred approaches with increasing degrees of sperm defects.
- 74. 83 Men withhypogonadotrophic hypogonadism should be offered gonadotrophin drugs because these are effective in improving fertility. 84 Men with idiopathic semen abnormalities should not be offered antio-estrogens, gonadotrophins, androgens, bromocriptine or kinin-enhancing drugs because they have not been shown to be effective. 85 Men should be informed that the significance of antisperm antibodies is unclear and the effectiveness of systemic corticosteroids is uncertain. 86 Men with leucocytes in their semen should not be offered antibiotic treatment unless there is an identified infection because there is no evidence that this improves pregnancy rates.
- 78. Included Evidence 2 furtherstudies with 340 pat / 277 ICSI cycles 6 cohort studies: 578 male pat, 761 ICSI cycles 1993-2014: 541 ejaculated sperm 153 fresh testicular sperm 67 frozen-thawed testicular sperm (all mTESE, TESE or TESE + TESA) Ovarian hyperstimulation: 4x long protocol of GnHR agonist + HMG or FSH 1x super-long protocol 1x not specified
- 79. Primary Outcomes 1. Fertilisationrate: number of normally fertilised ova 2. Embryo quality: Size and symmetry of blastomere, fragmentation rate Grade A embryo: 6-8 regular symmetrical blastomeres, no frag Good-quality embryo rate: n Grade A embryos / n fertilasations 3. Implantation rate: n gestational sacs / n of embryo transfers 4. Pregnancy rate n pregnancies / n ICSI cycles
- 80. Kang et al,Nature 2018
- 81.
- 82.
- 83.
- 84.
- 85. Strengths Best systematic reviewwith high statistical power Inclusion of 2 further studies with high numbers Exclusion of case reports Correction of error in use of Bendickson data
- 86. Limitations and Biases 1.Unable to separate intention-to-treat from per-protocol 2. Insufficient information re: risks from testicular biopsy 3. Heterogeneity of fresh/ frozen/ mixed sperm data No stat significance (but trends) in sub-group analyses (How does cryopreservation affect ICSI outcomes?) 4. Difference in ovarian hyperstimulation protocols 5. Maturity and morphology of oocytes 6. No reflection on complications of TESE RCTs ?unethical (random allocation or “sham” procedures) Did info on complications affect couples’ choice? 7. Maternal age 8. Severity of cryptozoospermia? 9. No data on other types of ‘poor quality sperm’ or idiopathic male/ mixed infertility
- 87. Summary • Guidelines andevidence in favour of testicular sperm/ ICSI in severe male-factor infertility • Evidence in favour of testicular sperm/ ICSI in cryptozoospermia • Not (yet) universally supported in reproductive community • Medical and surgical treatment are reasonable and recommended for reversible male infertility (and perseverance with natural conception, or use of ejaculated sperm) • Female factors incl. age important • Couple preferences and ethical considerations important