management of non obstructive azoospermia

Sandro C. Esteves, MD., PhD. Director, ANDROFERT

Campinas, Brazil

Management of Non-‐obstrucFve

Azoospermia

ISAR 2014, Ahmedabad INDIA

Available at:

hMp://www.androfert.com.br/review

Management of NOA ISAR 2014, Ahmedabad INDIA

Esteves, 2 ANDROFERT, Referral Center for Male ReproducFon

CenFles

2.5% 50% 97.5%

4 64 237

Sperm Count in Humans General PopulaFon of Unscreened Men

Cooper et al. Hum Reprod Update 2009; Esteves et al, Clinics 2011

Azoospermia Complete lack of sperm in ejaculate 1-‐3% male populaFon 10-‐15% male inferFlity populaFon

Sperm count per mL (x106)


Diagnosis Select the candidates for sperm retrieval and ICSI

Select who could benefit

from intervenFons prior to SR

Select the best SR method

Proper lab handling of surgically-‐extracted gametes

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Management of Non-obstructive Azoospermia (NOA)

Diagnosis -‐ Semen Analysis (x2)

Centrifuga2on at 3,000g for 15

minutes

The supernatant is discharged and the pellet

is examined


Azoospermia – DifferenFal Diagnosis


Azoospermia

ObstrucFve

Non-‐obstrucFve

Subtypes

Hypo-‐hypo

TesFcular failure

Spermatogenesis

Disrupted

Normal

Clinical Picture

High FSH/LH (NL) Low TT (NL)

Small tesFs (NL)

NL tesFs NL FSH, LH, TT

Mechanical block

FSH/LH <1.2 mUI/mL Low TT

Small tesFs Poor virilizaFon

NOA & TesFcular Failure EFology

TesFcular torsion; Trauma Post-‐inflammatory (eg. Mumps orchiFs) Exogenous factors (steroids, cytotoxic drugs, irradiaFon) TesFcular Cancer; Systemic diseases (liver cirrhosis, renal failure) Varicocele

Congenital TesFcular dysgenesis/cryptorchidism GeneFc abnormaliFes (Klinefelter syndrome, Yq microdeleFons, etc.)

Acquired

Idiopathic (Unknown etiology)

Untreatable condiFon

Sperm Retrieval and ICSI

Esteves SC & Agarwal A. An update on the clinical assessment of the infer2le male. Clinics 66; 2011


Esteves et al., Fer%l Steril 94; 2010; Raman and Schlegel. J Urol.170; 2003; Hopps et al. Hum Reprod. 180, 2003; Damani et al. JCO. 15; 2002

Etiology category SR success rate Cryptorchidism 52-74% Varicocele 63-68% Post-infection 67% Torsion >50% Post-chemotherapy/RT 25-75% Genetic (Klinefelter, AZFc Yq microdeletions) 25-70% Idiopathic 50-60%

No Presence of a site of sperm producFon is not related to the eFology of NOA

Esteves, 8 ANDROFERT, Referral Center for Male Reproduction

SelecFng candidates for SR Does e2ology play a role?

FSH levels Testosterone levels

TesFcular Volume

TesFcular Histopathology

Esteves, Miyaoka & Agarwal. Clinics 2011; Verza Jr. & Esteves. Fertil Steril 2011; Carpi et al. Fertil Steril 2009.

No Markers reflect global spermatogenic funcFon but not the presence of a site of sperm producFon in a dysfuncFonal tesFs


SelecFng candidates for SR Can biomarkers predict SR success?

SelecFng candidates for SR YCMD screening by PCR

Hamada et al. 2012; Esteves & Agarwal Int Braz J Urol 2011; Foresta et al Endocr Rev 2001.


AZFb deleted

Matura2on Arrest (RBMY; PRY)

SRR = 0%

AZFa deleted

Sertoli Cell Only

SRR = 0%

AZFc deleted

Hypospermatogenesis, Matura2on arrest, SCO

SRR ~70%

Azoospermia is a descripFve term of ejaculates that lack spermatozoa without implying a specific underlying cause.

NOA due to tesFcular failure is the most severe male inferFlity condiFon. It represents a spectrum of congenital or acquired tesFcular disorders that cannot be treated.


All men with tesFcular failure are candidate for SR but those with YCMD in subregions AZFa and/or AZFb.

Management of NOA Key Messages (1)

NOA and hypogonadism (TT<300ng/dL)

NOA and clinical

varicocele

Who can benefit from intervenFons prior to sperm retrieval?


NOA and hypogonadism (TT<300ng/dl)

Who can benefit from intervenFons prior to sperm retrieval?


Principle Boost testosterone produc2on

OpFons AnF-‐estrogens Aromatase inhibitors u-‐hCG/rec-‐hCG

Medical therapy before SR Hypogonadism


72 55

Sperm Retrieval Rate (%)

Positive Tx response (increase in TT) No response

Klinefelter Syndrome with NOA and hypogonadism; N=91

Ramasamy et al., J Urol. 2009

P = 0.03

Anti-estrogen (CC 50mg) every other day; no controls 64% men had sperm in the ejaculates post-Tx (mean: 3.8 M/mL); Spermatozoa obtained by SR in all who remained azoospermic.

NOA and favorable tesFcular hystopathology; N=43

Hussein et al, J Androl 2005

hCG for men with NOA and hypogonadism

FraieMa & Esteves Clinics 2013; Esteves & Papanikolaou FerFl Steril 2011


Classic treatment Urinary hCG 1,000-2,000 UI IM

injections; twice or t.i.w; minimum 12 weeks

SC self-‐injec2on w/pre-‐filled syringe, qw

Retrospective study with SR in 96 men with treated and untreated varicocele

Sperm retrieval success increased by 2.6-fold (53% vs. 30%) in men with treated varicocele

Inci et al, J Urol. 2009 Miyaoka & Esteves. Adv Urol 2012


NOA and clinical varicocele

Microsurgical Varicocele Repair

Weedin JW et al, J Urol. 2010

Meta-analysis of 11 case series (N=233) 39% men had motile sperm in postop. ejaculates (mean: 1.6 M/mL)

Retrospective study with SR in 96 pts. with treated and untreated varicocele

Success: 53% vs 30% (increased by 2.6-fold in treated pts.)


30-‐50% cases: minimal producFon within the tesFs, but not enough for sperm to appear in ejaculate Goal is to iden2fy site of produc2on and retrieve sperm for ICSI

Geographic loca2on unpredictable

Esteves SC & Agarwal A. Sperm Retrieval Techniques; In: Gardner D et al (Eds.), Human Assisted Reproductive Technology. Cambridge University Press, pp. 41-53, 2011

Which is the best sperm retrieval technique in NOA ?

Schlegel 1999

Amer et al. 2000

Okada et al. 2002

Okubu et al. 2002

Tsujimura et al. 2002

Ramon et al. 2003

Esteves et al. 2011

43%-‐53%

25%-‐41% Controlled Serie

s Sperm retrieval in NOA

which is the best technique?


TESE

Esteves et al. Sperm retrieval Techniques. Int Braz J Urol 2011

hMp://androfert.com.br/videos

Esteves SC, Int Braz J Urol 2013


Men with hypogonadism (TT<300) and clinical varicocele may benefit from intervenFons prior to SR, but evidence is modest


Men with NOA are not sterile. Foci of sperm producFon is found in 30-‐50% of cases.

Micro-‐TESE best method to idenFfy areas of sperm producFon; minimal Fssue removal facilitaFng sperm search and processing


Laboratory handling of surgically-retrieved spermatozoa

Avoid iatrogenic damage Optimize sperm retrieval Optimize ICSI outcomes

Esteves et al. Asian J Androl. In press


ICSI Outcome in Azoospermia

41.4 47 43.3 20

100

64 61 34.2

Sperm retrieval (%) 2PN FerFlizaFon (%)

Top Quality Embryos (%)

Live Birth (%)

Non-‐obstrucFve (N=151) ObstrucFve (N=146)

OR=0.033 95% CI: 0.007-‐0.164; p<0.001

OR=0.38 95% CI: 0.23-‐0.61; p<0.001

P<0.01

Tissue removed (mg) Open Large

Single-Biopsy TESE

Micro-TESE P-value

65 ± 25 8.9 ± 2.5 <0.01

Microsurgical vs single-‐biopsy TESE

Conven2onal TESE Micro-‐TESE

Fragment weight Fragment weight

Verza Jr & Esteves. Fer5l Steril 2011; Esteves & Varghese, 2013


35.7

244.6

6.3 3.2 36.9

273.3

2.0 1.2 37.0

257.7

2.5 1.7

GestaFonal age (wks) Birth weight (gramsx10)

% Perinatal death % Birth defects

NOA (n=63) Ejaculated Sperm (n=247)

ObstrucFve Azoospermia (n=117)

P = NS

Esteves & Agarwal. Reproductive outcomes including neonatal data of sperm injection in men with obstructive and nonobstructive azoospermia: case series and

systematic review. CLINICS, 2013

Health of Babies Born in NOA


Region

N children TesFcular failure

vs OA

Outcomes

Main findings

Palermo et al. 1999

USA 22 vs 158 Congenital abnormali2es

4.5% TF vs 1.3% OA (ns)

Vernaeve et al. 2005

Belgium 61 vs 196 Perinatal data Congenital abnormali2es

Lower gesta2onal age (singletons); Increased frequency of premature twins

4% TF vs 3% OA (ns)

Fedder et al 2007

Denmark 76 vs 282 Congenital abnormali2es

0% TF vs 4.0% OA (ns)

Belva et al.; 2011

Belgium 193 vs 474 Perinatal data;

Congenital abnormali2es

Similar perinatal outcomes; 4.2% TF vs 5.2% OA (ns)

352 children No major

difference

Esteves & Agarwal. Reproductive outcomes including neonatal data of sperm injection in men with obstructive and nonobstructive azoospermia: case series

and systematic review. CLINICS, 2013

Neonatal Outcome of Babies Born

SR rates and reproducFve outcomes arer ICSI are differenFally affected by NOA


Health of neonates not differenFally affected by NOA; limited data


Controlled lab condiFons and techniques important to improve SR and ICSI outcomes

Semen analyses and differenFaFon between azoospermia subtype

1. Diagnosis YCMD

2. Select candidates

for SR

Medical Tx in hypogonadism

Microsurgical repair of clinical varicoceles

3. Check who benefit of

intervenFons prior to SR

Micro-‐TESE

4. Select the best

SR method

Improve SR Avoid iatrogenic damage

Not jeopardize ICSI outcomes

5. OpFmal lab condiFons

and techniques

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Management of NOA Summary

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management of non obstructive azoospermia

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