management of nonobstructive azoospermia

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

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


ANDROFERT

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


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

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


ANDROFERT

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


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Prognosis and management differen4ally affected by type of azoospermia

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

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


ANDROFERT

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


ANDROFERT

•  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


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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


ANDROFERT

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


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


ANDROFERT

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


ANDROFERT

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


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ANDROFERT

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

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


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 (micro-TESE; N=357)

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

Testicular histopathology


ANDROFERT

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


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Interven4ons to infer4le males men with SF prior to a sperm retrieval aZempt

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

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


ANDROFERT

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

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

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


ANDROFERT

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


ANDROFERT

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)


ANDROFERT Esteves Asian J Androl 2015: 17:1-‐12

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


ANDROFERT

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


ANDROFERT

Esteves Asian J Androl 2015;17:1-‐12


ANDROFERT


ANDROFERT

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


ANDROFERT

http://androfert.com.br/videos Esteves SC Int Braz J Urol 2013; 39(3):440


ANDROFERT

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


ANDROFERT

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

. Tub

ule

Dia

met

er

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


ANDROFERT

• Optimize sperm retrieval • Mechanical mincing • Enzymatic tissue digestion • Avoid iatrogenic damage


ANDROFERT


ANDROFERT

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


ANDROFERT

Sperm Vitrifica4on in “Cell Sleeper”


ANDROFERT

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


ANDROFERT

3,412 cycles

Oocyte number and LBR at Androfert (ICSI cycles involving severe male factor)


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

COS in ART involving NOA


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

COS in poor responders involving NOA


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

What about the health of resulting offspring

Esteves et al Asian J Androl 2014; 16: 602-6


ANDROFERT

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


ANDROFERT


ANDROFERT

What the future holds for men with spermatogenic failure…

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


ANDROFERT

Thank you धन्यवाद Obrigado

This presenta4on is available at hZp://www.slideshare.net/

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