Management of Nonobstructive Azoospermia Before Surgical Sperm Retrieval

Management of NOA before Sperm Retrieval

Sandro C. Esteves, MD., PhD. Medical & Scien,fic Director, ANDROFERT Andrology & Human Reproduc,on Clinic

Campinas, BRAZIL

4th International Congress - Academy of Clinical Embryologists 18-20 September 2015, Kochi INDIA

ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2015

ANDROFERT

Azoospermia: the complete lack of sperm in ejaculate aEer centrifugaFon

10-15% infertile males

1-3% male population

Cooper et al. Hum Reprod Update 2009; Esteves & Agarwal, Clinics 2013


ANDROFERT

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


ANDROFERT

Prognosis and management differenFally affected by type of azoospermia

ObstrucFve

Non-‐obstrucFve

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 tesFs, poor virilizaFon

Disrupted

Normal

Spermatogenesis

Esteves et al, Clinics 2011


ANDROFERT

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


ANDROFERT

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


ANDROFERT

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


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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


ANDROFERT

FSH levels Testosterone levels

Testicular volume

elecFng 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


ANDROFERT

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 (N=357)

Esteves & Agarwal. Asian J Androl 2014; 16: 642

Testicular histopathology


ANDROFERT

Complete AZFa, AZFb or AZFa+b microdeleFons unfavorable prognosis

YCMD SR success

AZFa nil AZFb nil AZFc 50-‐70%

Krausz et al. 2014; Esteves et al. 2013; Esteves 2015


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IntervenFons to inferFle males men with SF prior to a sperm retrieval acempt

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


ANDROFERT

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


ANDROFERT

MaturaFon 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 moFle sperm in postop.

ejaculate


ANDROFERT

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


ANDROFERT

MedicaFon Hypogonadism (TT<300 ng/dl) in up to 50% men with SF High ITT levels essen,al for regula,ng spermatogenesis in combina,on with Sertoli cell s,mula,on by FSH

Paradoxically weak sFmulaFon 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


ANDROFERT

ITT levels increase aEer hCG; sFmulatory 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


ANDROFERT

Testosterone and estradiol levels

<300 ng/dL

(10.4 nmol/L)

Hypogonadism category

Pure

MedicaFon algorithm at Androfert Tx aimed at boosFng 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 raFo <10

Aromatase hyperacFvity

T/E raFo >10 (nl)


ANDROFERTEsteves Asian J Androl 2015;17:1-‐12

Shiraishi 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

MicrodissecFon TESE Rescue ~15% of paFents with previous failed SR acempts


ANDROFERT

Esteves Asian J Androl 2015;17:1-‐12


ANDROFERT


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OpFons for sperm retrieval in spermatogenic failure

Technique Acronym Success TesFcular sperm aspiraFon TESA 15-‐50%

TesFcular sperm extracFon TESE 20-‐60%

MicrodissecFon tesFcular sperm extracFon

Micro-‐TESE 40-‐67%

Esteves et al Int Braz J Urol 2013;37:570-‐83; Deruyver et al Andrology 2014;2:20-‐4


ANDROFERT

• Minimal tissue excision • Mechanical mincing • Enzymatic tissue digestion • Avoid iatrogenic damage •  Lab air quality control


ANDROFERT

3,412 cycles involving severe male factor inferFlity

Individualized COS strategies to retrieve 10-‐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


ANDROFERT

Conclusions Best management of NOA prior to SR includes: 1.  Proper diagnosis (clinical & endocrine)

Ø  DeselecFng AZF (a/b) carriers

2.  IdenFficaFon of candidates to intervenFons

Ø  varicocele Rx & medical Tx

3.  Carry out SR ≥3 months aEer intervenFons 4.  Tailored COS to retrieve 10-‐15 oocytes


ANDROFERT

Thank you

This presentaFon is available at hcp://www.slideshare.net/

sandroesteves

4th International Congress - Academy of Clinical Embryologists 18-20 September 2015, Kochi INDIA

Management of Nonobstructive Azoospermia Before Surgical Sperm Retrieval

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