Management of nonobstructive azoospermia
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This document provides an overview of the clinical management of nonobstructive azoospermia (NOA). It begins by defining NOA and explaining its challenges. It then discusses the diagnostic evaluation and differentiates between obstructive and nonobstructive causes. For NOA due to spermatogenic failure, the document outlines that the condition is irreversible and reviews sperm retrieval techniques and their success rates depending on the underlying etiology. It also notes that while biomarkers can reflect testicular function, they cannot definitively predict whether sperm will be found for retrieval.
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Management of nonobstructive azoospermia
- 1. Clinical Management of Nonobstruc4ve Azoospermia Sandro C. Esteves, MD., PhD. Medical Director, ANDROFERT Andrology & Human Reproduc=on Clinic Campinas, BRAZIL Andrology Workshop - ISAR 2015 - Chennai
- 2. Learning objec4ves At the comple4on of this talk par4cipants should be able to: • Understand why nonobstruc=ve azoospermia is one of the most challenging condi=ons in infer=lity care • Learn how we manage infer=le couples in whom the male partner has NOA at Androfert ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2015 ANDROFERT
- 3. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 3 2015 ANDROFERT
- 4. Azoospermia: the complete lack of sperm in ejaculate aEer centrifuga4on 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, 4 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, 5 2015 ANDROFERT
- 6. Diagnostic parameters provide >90% prediction of whether azoospermia is due to spermatogenic failure Medical history Cryptorchidism, testicular trauma, torsion, infection, radio-/ chemotherapy, congenital abnormalities, systemic diseases Physical examination Small testes (<15 cc; long axis <4.6 cm) Flat epididymis, palpable vas Endocrine profile Elevated FSH levels (>7.6 mIU/ml in 90% men) Low testosterone levels (<300 ng/dl in up to 50%) Esteves et al Clinics 2011 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2015 ANDROFERT
- 7. Obstruc4ve Non-‐ obstruc4ve Hypo-‐hypo Spermatogenic failure Clinical picture FSH/LH: ñ 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 tes4s, poor viriliza4on Disrupted Normal Spermatogenesis Esteves et al, Clinics 2011 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2015 ANDROFERT Prognosis and management differen4ally affected by type of azoospermia
- 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, 8 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 OBSTRUCTIVE AZOOSPERMIA 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, 9 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, 10 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 FraieZa et al. Clinics 68; 2013 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 11 2015 ANDROFERT
- 12. Classic treatment for male hypogonadism and infer4lity u-‐hCG 1,000-‐2,000 IU; IM injec4ons; twice or t.i.w; minimum 12 weeks Rec-‐hCG: SC self-‐ injec4on qw Pre-‐filled syringe Pen device FraieZa et al. Clinics 2013; 68(Suppl.1):81-‐8 Specific therapy in adult onset hypo-‐ hypo ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2015 ANDROFERT
- 13. Rec-‐hCG for male hypo-‐hypo Esteves & Papanikolaou Fer5l Steril 2011;96:S230 Series of men with adult-‐onset HH; Recombinant hCG (Ovitrelle 250 mcg qw for 12 weeks) Baseline PosTreatment ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2015 ANDROFERT
- 14. 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, 14 2015 ANDROFERT
- 15. Tes4cular torsion; trauma Post-‐inflammatory (eg. Mumps orchi=s) Exogenous factors (eg. Cytotoxic drugs, irradia=on) Tes4cular cancer Systemic diseases (eg. Liver cirrhosis, renal failure) Congenital Tes4cular dysgenesis/cryptorchidism Gene4c abnormali4es (Klinefelter syndrome, Yq microdele=ons, etc.) Acquired Idiopathic (unknown e4ology) Esteves et al. Clinics 2011; 66:691-‐700 NOA due to spermatogenic failure: an irreversible condi4on ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2015 ANDROFERT
- 16. Challenges faced by health professionals providing care for men with SF § Counseling about the chances of finding tes4cular sperm § Usefulness of any medical interven4on before sperm retrieval § Which sperm retrieval method to apply § Reproduc4ve poten4al of retrieved gametes in ICSI treatment § Health of offspring ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2015 ANDROFERT
- 17. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 17 2015 ANDROFERT
- 18. 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, 18 2015 ANDROFERT
- 19. FSH levels Testosterone levels Testicular volume elec4ng 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, 19 2015 ANDROFERT
- 20. 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% Hypospermatogenesis Maturation Arrest Sertoli-cell only Presence of sperm within the testicle (micro-TESE; N=357) Esteves & Agarwal. Asian J Androl 2014; 16: 642 Testicular histopathology ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 20 2015 ANDROFERT
- 21. Complete AZFa, AZFb or AZFa+b microdele4ons 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, 21 2015 ANDROFERT
- 22. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2015 ANDROFERT
- 23. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2015 ANDROFERT Interven4ons to infer4le males men with SF prior to a sperm retrieval aZempt
- 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, 24 2015 ANDROFERT
- 25. Matura4on 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 mo4le sperm in postop. ejaculate ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 25 2015 ANDROFERT
- 26. 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, 26 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 aEer 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, 27 2015 ANDROFERT
- 28. Medica4on Hypogonadism (TT<300 ng/dl) in up to 50% men with SF High ITT levels essen=al for spermatogenesis in combina=on with Sertoli cell s=mula=on by FSH Paradoxically weak s4mula4on of Leydig and Sertoli cells by endogenous gonadotropins Due to high baseline FSH and LH levels the rela=ve 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, 28 2015 ANDROFERT
- 29. Study Study design Study group Medication Findings Pavlovich et al. 2001 Case series 43 men with T/E ratio <10 Testolactone No effect Hussein et al. 2005 Prospective cohort 42 men with favorable hystology Clomiphene Sperm found in SA in 64.3%; All men who remained azoospermic had success at SR Selman et al. 2006 Prospective cohort 49 men with maturation arrest rec-hFSH and hCG No return of sperm in ejaculate; posttreatment SRR were 21.4% Ramasamy et al. 2009 Case series 56 men with nonmosaic Klinefelter Testolactone or anastrozole, alone or combined with hCG SRR increased by 1.4-fold Reifsnyder et al. 2012 Retrospective cohort 307 men with hypogonadis m Aromatase inhibitors, hCG or Clomiphene, alone or combined No effect Shiraishi et al. 2012 Prospective cohort 28 men with idiopathic SF hCG alone or combined with rec-hFSH SR success in 21% of the treated men vs. none in untreated men Hussein et al. 2013 Prospective cohort 612 unselected men Clomiphene alone or combined with hCG or hMG Sperm found in SA in 10.9% of treated males; SRR higher in men who remained azoospermic and treated (57.0 vs. 33.6%, p<0.001) ! Aromatase inhibitors and gonadotropins have been used with variable results Esteves Asian J Androl 2015;17:1-‐12 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 29 2015 ANDROFERT
- 30. Testosterone and estradiol levels <300 ng/dL (10.4 nmol/L) Hypogonadism category Pure Medica4on algorithm at Androfert Tx aimed at boos4ng 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 ra4o <10 Aromatase hyperac4vity T/E ra4o >10 (nl) ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2015 ANDROFERT Esteves Asian J Androl 2015: 17:1-‐12
- 31. ITT levels increase aEer hCG; s4mulatory 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 aEer hCG-‐based therapy Spermatogonial DNA synthesis increased PCNA expression ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2015 ANDROFERT
- 32. 1Shiraishi et al Hum Reprod 2012;27:331-‐9; Esteves Int Braz J Urol 2013;39:440 hCG-‐based therapy may increase SR success in men with SF Microdissec4on TESE Rescue ~15% of pa4ents with previous failed SR aZempts1 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2015 ANDROFERT
- 33. Esteves Asian J Androl 2015;17:1-‐12 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 33 2015 ANDROFERT
- 34. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2015 ANDROFERT
- 35. Sperm retrieval methods in NOA due to spermatogenic failure Technique Acronym Success Tes4cular sperm aspira4on TESA 15-‐50% Tes4cular sperm extrac4on TESE 20-‐60% Microdissec4on tes4cular sperm extrac4on 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, 35 2015 ANDROFERT
- 36. http://androfert.com.br/videos Esteves SC Int Braz J Urol 2013; 39(3):440
- 37. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2015 ANDROFERT
- 38. Tissue removed (mg) Large Single- Biopsy TESE Micro- TESE P- value 65 ± 25 8.9 ± 2.5 <0.01 Optimizing sperm retrieval Conven=onal TESE Micro-‐TESE Fragment weight Fragment weight Verza Jr & Esteves Fertil Steril 2011; Esteves & Varghese J Reprod Sci 2013 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 38 2015 ANDROFERT
- 39. Morphometric evalua4on of seminiferous tubules increases SR efficiency 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 Verza Jr S, Esteves SC. Fer5l Steril 2012; 98: S242; Esteves & Varghese J Reprod Sci 2012; 5(3):233-‐43 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, 39 2015 ANDROFERT
- 40. • Optimize sperm retrieval • Mechanical mincing • Enzymatic tissue digestion • Avoid iatrogenic damage ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 40 2015 ANDROFERT
- 41. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 41 2015 ANDROFERT
- 42. On average, one top-‐quality addi4onal embryo for transfer or cryopreserva4on Clean Room Technology & ICSI Results 2,315 pa4ents; 14,660 embryos Esteves & Bento. Reprod Biomed Online 2013;26:9-‐21 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 42 2015 ANDROFERT
- 43. Sperm Vitrifica4on in “Cell Sleeper” ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 43 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, 44 2015 ANDROFERT
- 45. 3,412 cycles Oocyte number and LBR at Androfert (ICSI cycles involving severe male factor) ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 45 2015 ANDROFERT 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 Clinical pregnancy Live birth Esteves et al., in prepara5on
- 46. COS in ART involving NOA ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 46 2015 ANDROFERT • Main goal: effec4veness • Clinical quality indicator: number oocytes • Protocol of choice: Antagonist + tailored recFSH dose according to pa4ent subgroup cetrorelix (flexible); 150-‐300 IU/d pen injector >35yr and DOR: Antagonist + recFSH/recLH cetrorelix (flexible); follitropin alfa + lutropin alfa 2:1 ra=o (1-‐2 vials/d); from s=mula=on D1
- 47. COS in poor responders involving NOA ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 47 2015 ANDROFERT • Goal: minimum of 8 MII oocytes • Strategy: Oocyte banking + fresh cycle and micro-‐TESE (day prior OPU) -‐ Antagonist + recFSH/recLH (2:1 ra4o; 2 vials/d from Sd1) -‐ Minimal IVF s4mula4on
- 48. 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, 48 2015 ANDROFERT
- 49. 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 Born Health 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, 49 2015 ANDROFERT
- 50. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 50 2015 ANDROFERT What the future holds for men with spermatogenic failure…
- 51. Conclusions 1. Nonobstruc4ve azoospermia worst prognos4c condi4on in male infer4lity 2. Best management of NOA seeking fer4lity includes proper diagnosis, interven4ons to op4mize sperm produc4on, microsurgical SR, state-‐of-‐ art laboratory care & individualized COS 3. Mul4disciplinary team work ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 51 2015 ANDROFERT
- 52. Thank you धन्यवाद Obrigado This presenta4on is available at hZp://www.slideshare.net/ sandroesteves