Clinical management of infertile men with nonobstructive azoospermia: current practice and future perspectives
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This document summarizes a presentation on the clinical management of men with nonobstructive azoospermia (NOA). It discusses how NOA is one of the most challenging conditions in infertility care. For men diagnosed with NOA, tests are conducted to determine if the cause is hypogonadotropic hypogonadism or spermatogenic failure. For spermatogenic failure, sperm retrieval techniques may be used but success rates vary depending on the underlying cause. Interventions like varicocele repair before sperm retrieval may improve chances of finding sperm. The document emphasizes that biomarkers cannot definitively predict sperm retrieval outcomes for men with NOA due to spermatogenic failure.
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Clinical management of infertile men with nonobstructive azoospermia: current practice and future perspectives
- 1. Clinical Management of Men with Nonobstructive Azoospermia Sandro C. Esteves, MD., PhD. Medical & Scientific Director, ANDROFERT Andrology & Human Reproduction Clinic Campinas, BRAZIL Innovation in Male Infertility: Where Assisting Nature Meets Andrologists June 17, Tessaloniki GREECE
- 2. Learning objectives At the completion of this talk participants should be able to: • Understand why nonobstructive azoospermia is one of the most challenging conditions in infertility care • Learn how we manage infertile couples in whom the male partner has NOA at Androfert ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2015 ANDROFERT
- 3. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2015 ANDROFERT
- 4. Azoospermia: the complete lack of sperm in ejaculate after centrifugation 10-15% infertile males 1-3% male population Cooper et al. Hum Reprod Update 2009; Esteves & Agarwal, Clinics 2013 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2015 ANDROFERT
- 5. Esteves et al Int Braz J Urol 2014; 40: 443-53 Goals of semen analysis are to reduce analytical error and enhance precision Examination of pelleted semen Differentiation between ‘true’ azoospermia and cryptozoospermia Minimum 2 analyses Transient azoospermia due to medical conditions and biological variability Supernatant is discharged Pellet is meticulously examined Centrifugation at 3,000g for 15 minutes ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2015 ANDROFERT
- 6. Prognosis and management differentially affected by type of azoospermia Obstructive Non- obstructive Hypo-hypo Spermatogenic failure Clinical picture FSH/LH: or nl TT: low or nL Testes: small or nl Normal testes & endocrine profile; Mechanical blockage FSH/LH <1.2 mUI/mL, Low TT, small testis, poor virilization Disrupted Normal Spermatogenesis Esteves et al, Clinics 2011 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 9 2015 ANDROFERT
- 7. Cryptorchidism, testicular trauma, torsion, infection, radio- /chemotherapy, congenital abnormalities, systemic diseases Small testes (<15 cc; long axis <4.6 cm) Flat epididymis, palpable vas Elevated FSH levels (>7.6 mIU/ml in 90% men) Low testosterone levels (<300 ng/dl in up to 50% Diagnostic parameters provide >90% prediction of whether azoospermia is due to spermatogenic failure Medical history Physical examination Endocrine profile Esteves et al Clinics 2011 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2015 ANDROFERT
- 8. Verza Jr & Esteves, Atlas of Human Reproduction SBRH 2013 Isolated diagnostic biopsy rarely indicated provide no definitive proof of whether sperm will be found; may jeopardize future retrieval attempts Differential diagnosis with obstructive azoospermia Work-up in NOA associated to maturation arrest is unrevealing Wet examination and cryopreservation if sperm found Hypospermatogenesis Maturation arrest Sertoli cell-only ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 11 2015 ANDROFERT
- 9. Sperm retrieval highly successful regardless of cause of obstruction and method of retrieval Obstructive azoospermia is a favorable prognostic condition in male infertility 100% 96.6% 96.3% CBAVD Vasectomy Post-infection OBSTRUCTIVEAZOOSPERMIA Management options include reconstructive surgery and ART OA (N=146) Esteves et al. J Urol. 2013;189: 232-7 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2015 ANDROFERT
- 10. ICSI outcome in obstructive azoospermia comparable with fertile donors 64 61 47 34 61 66 50 38 2PN Fertilization (%) High quality embryos (%) Clinical pregnancy (%) Live birth (%) Obstructive azoospermia (N=146) Donor sperm (N=40) p=NS Esteves et al. Asian J Androl 2014; 16: 602-6 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2015 ANDROFERT
- 11. • Low FSH and LH levels (<1.2 mIU/L) • Low total testosterone levels (<300 ng/dL) • Hypotrophic testes NOA due to hypogonadotropic hypogonadism Congenital: Kallman syndrome Prader-Willi Acquired: Pituitary tumor Steroid abuse Testosterone replacement therapy Fraietta et al. Clinics 68; 2013 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2015 ANDROFERT
- 12. Rec-hCG for male hypo-hypo Esteves & Papanikolaou Fertil Steril 2011;96:S230 Series of men with adult-onset HH; Recombinant hCG (Ovitrelle 250 mcg qw for 12 weeks) Baseline Posttreatment ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2015 ANDROFERT
- 13. Frequency of azoospermia among 2,383 patients attending an Infertility Clinic Esteves et al. Clinics 2011; 66: 691-700. Azoospermia 35% 61% 36% 3% Hypo-hypo OA SF ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 17 2015 ANDROFERT
- 14. Testicular torsion; trauma Post-inflammatory (eg. Mumps orchitis) Exogenous factors (eg. Cytotoxic drugs, irradiation) Testicular cancer Systemic diseases (eg. Liver cirrhosis, renal failure) Congenital Testicular dysgenesis/cryptorchidism Genetic abnormalities (Klinefelter syndrome, Yq microdeletions, etc.) Acquired Idiopathic (unknown etiology) Esteves et al. Clinics 2011; 66:691-700 NOA due to spermatogenic failure: an irreversible condition ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 2015 ANDROFERT
- 15. Challenges faced by health professionals providing care for men with SF Counseling about the chances of finding testicular sperm Usefulness of any medical intervention before sperm retrieval Which sperm retrieval method to apply Reproductive potential of retrieved gametes in ICSI treatment Health of offspring ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 19 2015 ANDROFERT
- 16. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 20 2015 ANDROFERT
- 17. Esteves et al Fertil Steril 2010; Raman & Schlegel J Urol 2003; Hopps et al. Hum Reprod 2003; Damani et al JCO 2002 Etiology category Success in finding sperm Cryptorchidism 52-74% Post-infection 67% Torsion >50% Post-chemotherapy/RT 25-75% Genetic (KS, AZFc) 25-70% Idiopathic 50-60% Etiology cannot determine whether or not sperm will be found within the testis ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2015 ANDROFERT
- 18. FSH levels Testosterone levels Testicular volume electing candidates for SR Can biomarkers predict SR success? Diagnostic markers reflect global testicular function but not the presence of a site of active spermatogenesis Verza Jr & Esteves. Fertil Steril 2011; 96 (Suppl.): S53 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2015 ANDROFERT
- 19. Biopsy helpful for counseling but does not provide definitive proof of whether sperm will be found; may jeopardize future retrieval attempts 100% 40.3% 19.5% Presence of sperm within the testicle (N=357) Esteves & Agarwal. Asian J Androl 2014; 16: 642 Testicular histopathology ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2015 ANDROFERT
- 20. Complete AZFa, AZFb or AZFa+b microdeletions unfavorable prognosis YCMD SR success AZFa nil AZFb nil AZFc 50-70% Krausz et al. 2014; Esteves et al. 2013; Esteves 2015 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 24 2015 ANDROFERT
- 21. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 25 2015 ANDROFERT
- 22. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2015 ANDROFERT Interventions to infertile males men with SF prior to a sperm retrieval attempt
- 23. Rationale for varicocele repair Catch-up testicular growth among adolescents following varicocele repair Improvement in sperm parameters after varicocele repair Abnormally-low T restored to normal levels in some men after varicocele repair Wang et al Fertil Steril 1991; 55: 152-5; Su et al J Urol 1995; 154: 1752-5; Çayan et al J Urol 2002; 168: 929731-4; Hamada et al Nat Rev Urol 2013; 10: 26-37 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2015 ANDROFERT
- 24. Among 233 men with SF and clinical varicocele, about 1/3 had motile sperm in postoperative ejaculate Weedin et al J Urol 2010; 183: 2309-15 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 28 2015 ANDROFERT
- 25. Maturation arrest and hypospermatogenesis favorable prognosis Weedin et al J Urol 2010;183:2309-15 Among 233 men with SF and treated varicocele, 1/3 had motile sperm in postop. ejaculate ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 29 2015 ANDROFERT
- 26. Microsurgical subinguinal varicocele repair with aid of intraoperative doppler ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2015 ANDROFERT
- 27. Inci et al J Urol 2009;182:1500-5; Haydardedeoglu et al Urology 2010;75:83-6 Inci 2009 OR: 2.63 (95% CI: 1.05-6.60; p=0.03) Although 2/3 remain azoospermic after varicocele repair, SRR is increased Haydardedeoglu 2010 53 30 Treated (N=66) Untreated (N=30) SR success (%) 61 38 Treated (N=31) Untreated (N=65) p<0.01 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2015 ANDROFERT
- 28. Medication Hypogonadism (TT<300 ng/dl) in up to 50% men with SF High ITT levels essential for regulating spermatogenesis in combination with Sertoli cell stimulation by FSH Paradoxically weak stimulation of Leydig and Sertoli cells by endogenous gonadotropins Due to high baseline FSH and LH levels the relative amplitudes are low Shiraishi et al Hum Reprod 2012;27:331-9; Sussman et al Urol Clin N Am 2008;35:147-55 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2015 ANDROFERT
- 29. ITT levels increase after hCG; stimulatory effect on residual spermatogenic areas Shinjo E et al Andrology 2013;1:929-35; Shiraishi et al Hum Reprod 2012;27:331-9 273 1348 Before After ITT (ng/dl) ITT levels increased after hCG-based therapy Spermatogonial DNA synthesis increased ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2015 ANDROFERT
- 30. Testosterone and estradiol levels <300 ng/dL (10.4 nmol/L) Hypogonadism category Pure Medication algorithm at Androfert Tx aimed at boosting T Aromatase inhibitor (anastrozole 1mg orally qid) Rec-hCG (250 mcg SC qw); rec-FSH added (75 IU SC biw) if FSH levels <1.5 mIU/ml T/E ratio <10 Aromatase hyperactivity T/E ratio >10 (nl) ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2015 ANDROFERT Esteves Asian J Androl 2015;17:1-12
- 31. 1Shiraishi et al Hum Reprod 2012;27:331-9; Esteves Int Braz J Urol 2013;39:440 Medical therapy may increase SR success in men with SF Microdissection TESE Rescue ~15% of patients with previous failed SR attempts1 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 36 2015 ANDROFERT
- 32. Esteves Asian J Androl 2015;17:1-12 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2015 ANDROFERT
- 33. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 38 2015 ANDROFERT
- 34. Options for sperm retrieval in spermatogenic failure Technique Acronym Success Testicular sperm aspiration TESA 15-50% Testicular sperm extraction TESE 20-60% Microdissection testicular sperm extraction Micro- TESE 40-67% Esteves et al Int Braz J Urol 2013;37:570-83; Deruyver et al Andrology 2014;2:20-4 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 39 2015 ANDROFERT
- 35. http://androfert.com.br/videos Esteves SC Int Braz J Urol 2013; 39(3):440
- 36. Micro-TESE more effective than conventional TESE 45% 93% 64% 20% 25% 64% 9% 6% Overall Hypospermatogenesis Maturation Arrest Sertoli-cell Only Sperm Retrieval Success Rates Micro-TESE single-biopsy TESE Controlled series (N=60) Histology categories pairwise comparisons: p<0.0001 Method P=0.0005 Verza Jr & Esteves. Fertil Steril 2011; 96 (Suppl.): S53 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 41 2015 ANDROFERT
- 37. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 42 2015 ANDROFERT
- 38. Seminiferous tubule diameter associated with presence of sperm Verza Jr S, Esteves SC. Fertil Steril 2012; 98: S242; Esteves & Varghese J Reprod Sci 2012; 5(3):233-43 Median 25%-75% 5%-95% Raw Data yes No Presence of Sperm 160 180 200 220 240 260 280 300 320 340 360 380 400 420 Max.TubuleDiameter N=54; Tubule Diameter: KW-H (1;54) = 25.2; P<0.001 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 43 2015 ANDROFERT
- 39. Tissue removed (mg) Conventional TESE Micro-TESE P-value 65 ± 25 8.9 ± 2.5 <0.01 Conventional TESE Micro-TESE Verza Jr & Esteves Fertil Steril 2011; Esteves & Varghese J Reprod Sci 2013 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 44 2015 ANDROFERT Micro-TESE more efficient than conventional TESE
- 40. • Optimize sperm retrieval • Mechanical mincing • Enzymatic tissue digestion • Avoid iatrogenic damage ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 45 2015 ANDROFERT
- 41. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 46 2015 ANDROFERT
- 42. Clean Room IVF Lab
- 43. CPR Miscarriage rate 36,9% 23,0% 47,1% 15,0% Severe Male Factor (N=399) Conventional IVF lab Cleanroom IVF lab P=0.03 Esteves et al. Fertil Steril 2006 2,3 3,2 Average No. Top Quality Embryos ET Conventional lab Cleanroom lab N=2,315 Esteves & Bento. Reprod Biomed Online 2013;26:9-21 P=0.01 Cleanroom IVF lab positively impact cycle outcome in severe male factor infertility ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 49 2015 ANDROFERT
- 44. 41,4 47 43,3 20 100 64 61 34,2 Sperm retrieval (%) 2PN Fertilization (%) Top Quality Embryos (%) Live Birth (%) Non-obstructive (N=365) Obstructive (N=146) P<0.01 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 50 2015 ANDROFERT
- 45. Sperm Vitrification in “Cell Sleeper” ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 51 2015 ANDROFERT
- 46. 3,412 cycles; Androfert Individualized COS strategies to retrieve 10 to 15 oocytes per treatment cycle 0% 10% 20% 30% 40% 50% 60% 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 20 25 Number of oocytes retrieved Clinical pregnancy Live birth ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 52 2015 ANDROFERT
- 47. COS in cycles involving NOA ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 53 2015 ANDROFERT • Main goal: effectiveness • Clinical quality indicator: number oocytes • Protocol of choice: Antagonist + tailored recFSH dose according to patient subgroup cetrorelix (flexible); 150-300 IU/d pen injector >35yr and DOR: Antagonist + recFSH/recLH cetrorelix (flexible); follitropin alfa + lutropin alfa 2:1 ratio (1-2 vials/d); from stimulation D1
- 48. COS in poor responders involving NOA ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 54 2015 ANDROFERT • Goal: minimum of 8 MII oocytes • Strategy: Oocyte banking + fresh cycle and micro-TESE (day prior OPU) - Antagonist + recFSH/recLH (2:1 ratio; 2 vials/d from Sd1) - Minimal IVF stimulation
- 49. What about the health of resulting offspring Esteves et al Asian J Androl 2014; 16: 602-6 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 56 2015 ANDROFERT
- 50. Region N Outcome analyzed Main findings Palermo et al. 1999 USA 22 Congenital abnormalities No difference with obstructive azoospermia 4.5% vs 1.3% Vernaeve et al. 2005 Belgium 61 Perinatal data; Congenital abnormalities Lower gestational age (singletons); Increased frequency of premature twins; No difference with OA (4% vs 3%) Fedder et al 2007 Denmark 76 Congenital abnormalities No difference with other infertility categories (0% vs 4.0%) Belva et al.; 2011 Belgium 193 Perinatal data; Congenital abnormalities Similar perinatal outcomes; no difference 4.2% SF vs 5.2% OA (ns) Esteves & Agarwal. Clinics 2013; 68 (Suppl.1): 141-50 Neonatal Outcome of Babies BornHealth of offspring reassuring but a call for continuous monitoring needed due to limited data and lack of long-term follow-up ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 57 2015 ANDROFERT
- 51. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 58 2015 ANDROFERT What the future holds for men with spermatogenic failure…
- 52. Empirical treatments Reproductive Andrology Empowering clinical decisions & treatment efficiency Conventional semen analysis Conventional surgeries Sperm Function Testing Microsurgery Genetic diagnosis YCMD molecu lar diagno sis ANDROFERT Targeted therapy
- 53. Conclusions 1. Nonobstructive azoospermia worst prognostic condition in male infertility 2. Best management of NOA seeking fertility includes proper diagnosis, interventions to optimize sperm production, microsurgical SR, state-of- art laboratory care & individualized COS 3. Multidisciplinary team work is key goal achievement ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 60 2015 ANDROFERT
- 54. Thank you This presentation is available at http://www.slideshare.net/sand roesteves