Management of Male Infertility

Sandro C. Esteves, MD, PhD Director, ANDROFERT

Campinas, Brazil

Management of Male Infertility

What the GYN need to know

XVIII Annual Ob-Gyn Conference, KUWAIT 2013

Contents

DIAGNOSIS MEDICAL TREATMENT SURGICAL TREATMENT ASSISTED REPRODUCTION

Esteves, 2 ANDROFERT, Referral Center for Male Reproduction

Available at:

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

Management of Male Infertility


Semen Analysis

Functional Status of

Reproductive Tract

Seminal Fluid and Sperm

Central Laboratory

Investigation


Volume (mL) 1.5 Sperm count (x106/mL) 15.0 Total count (x106) 39.0 % Motile (total) 40 % Motile (progressive) 32 % Normal (strict criteria) 4 % Alive 58

Cooper et al. Hum Reprod Update 2010

WHO 2010: Recent fathers TTP≤12 mo. Percentiles

5% 50%* 95% 3.7 6.8

73.0 213.0 255.0 802.0

61 78 55 72 15 44 79 91


Sperm DNA Integrity

Normal sperm chromatin essential for paternal genetic transmission Background

Unexplained infertility Recurrent pregnancy loss Poor outcomes in IUI and IVF

Increased Sperm DNA Fragmentation

Quantification of sperm DNA strand breaks Principle

Semen, spermatozoa Specimen

Nuclear dyes (Acridine orange, SCSA) Direct assessment (TUNEL, COMET) Nuclear matrix assays (SCD)

Techniques


Esteves & Agarwal Int Braz J Urol 2011

Quick and Easy Test Sperm Chromatin Integrity Test (SCD)


Feijo & Esteves Fertil Steril 2013

Intact DNA: Sperm with “Halo” Represents dispersed chromatin

without breaks

Absent/small “Halo”: Damaged DNA Represents DNA strand breaks

Semen/Spermatozoa

Quantitative Test: Normal: <20% sperm with fragmented

DNA

19%

1.5%

Normal Elevated

Live Birth Rates with Intrauterine Insemination

OR = 0.07 [95% CI: 0.01-0.48]

Bungum et al. Hum Reprod 2007

IUI Outcome in Men with High Sperm DNA Damage


26%

42%

IVF ICSI

Pregnancy by Method in Cases of Elevated Sperm DNA

Fragmentation

IVF Outcome in Men with High Sperm DNA Damage

Robinson et al. Hum Reprod 2012

Meta-analysis of 16 studies and 2,969 couples Increased miscarriage in couples undergoing IVF/ICSI with high sperm DNA damage

Risk ratio (RR) = 2.16 95% CI: 1.54-3.03; p<0.00001

Bungum et al. Hum Reprod 2007


Sperm DNA Damage is Associated to Elevated Oxidative Stress

Esteves & Agarwal Int Braz J Urol 2011

Evaluation of DNA damage

DNA damage

Evaluation of DNA Damage

DNA Damage


Outcome No. studies Effect size (OR; 95% CI)

Live birth 3 4.85 [1.92, 12.24]

Pregnancy rate 15 4.18 [2.65, 6.59]

DNA fragmentation 1 -13.80 [-17.50, -10.10]

Miscarriage, sperm count, sperm motility

6-16 No effect

Oral Antioxidants for the Male

Showell MG et al. Cochrane Database Syst Rev 2011


Empirical Medical Treatment for Idiopathic Male Infertility

Guidelines on Male Infertility. European Association of Urology 2012

In general, NOT

EFFECTIVE


Androgens hCG/HMG FSH Anti-estrogens Bromocriptine Alpha-blockers Systemic corticosteroids

800

Before Clomiphene

After 90d; 25mg/d

Da Ros CT, Averbeck MA Int Braz J Urol 2012

Anti-estrogens for the Male

1000

1200

1400

600

400

200

0

ng/dL

Upper Limit

Lower Limit

Lower Sperm Counts

ITT levels fall

Normal Testosterone Levels

Negative central

feedback


Injectable Testosterone is Detrimental

GnRH

FSH/LH

Between the seminiferous tubules, Leydig cells produce testosterone

Azoospermia Marked fall in ITT levels


Deficient virilization Hypotrophic testes Azoospermia Low FSH, LH and testosterone

Male Hypogonadotropic Hypogonadism Specific Medical Therapy


• Congenital: Kallman syndrome Prader-Willi

• Acquired: Pituitary tumor Steroid abuse Testosterone replacement therapy

Esteves & Papanikolaou Fertil Steril 2011 Fraietta et al, Clinics 2013

SC self-injection w/pre-filled syringe, qw

Male Hypogonadotropic Hypogonadism Specific Medical Therapy

Series of men with adult-onset HH Recombinant hCG; 250 mcg per week; 12 weeks


Contents

DIAGNOSIS MEDICAL TREATMENT SURGICAL TREATMENT ASSISTED REPRODUCTION


Miyaoka & Esteves. Adv Urol 2012 Agarwal, Esteves, Hamada. Nature Urol Rev 2013

Varicocele

35% subfertile men Lower Sperm Count and Quality Lower Sperm Function Elevated Oxidative Stress Levels Elevated Sperm DNA Damage


Varicocele Treatment for Infertility

Indications (all criteria met): Infertile couples; Normal female or treatable female infertility; Abnormal semen analysis and/or sperm function test. ASRM Practice Committee, Fertil Steril 2008


Marmar et al., Fertil Steril 2008


Varicocele Surgery and Spontaneous Pregnancy


Varicocele Treatment

Miyaoka & Esteves. Adv Urol 2012

Technique Recurrence Postop Hydrocele

Retroperitoneal (Palomo) 7-35% 6-10%

Laparoscopy 2-7% 0-9%

Embolization 2-24% NR

Inguinal (Ivanissevich)

0-37%

7%

Microsurgical Subinguinal 0-1% 0-1.6%

Fer&lity Improvement

Sperm Retrieval in

Azoospermia

Fer&lity Improvement

ICSI

Outcomes Fer&lity Restora&on Spontaneous Pregnancy


Male Factor and ART

Varicocele Repair Sperm Retrieval


Varicocele Treated prior to ICSI (N=80)

ICSI with Untreated Varicocele (N=162)

SC Esteves, FV Oliveira, RP Bertolla ANDROFERT and Division of Urology, São Paulo Federal University, BRAZIL

The Journal of Urology; Vol. 184: 1442-6, 2010

Clinical Outcome of Intracytoplasmic Sperm Injection in Infertile Men With Treated and Untreated Clinical Varicocele


K Inci, M Hascicek, O Kara et al. Department of Urology, Hacettepe University, Ankara, Turkey

The Journal of Urology Vol. 182,1500-5, 2009

53% 30%

Successful Sperm Retrieval

Treated Varicocele Untreated Varicocele

OR: 2.63 (95% CI: 1.05-6.60; P=0.03)

Microsurgical varicocele repair prior to sperm retrieval ICSI (N=66)

Sperm Retrieval in the presence of varicocele (N=30)

Sperm Retrieval and Intracytoplasmic Sperm Injection in Men With Nonobstructive Azoospermia, and Treated and Untreated Varicocele


Sperm Retrieval in Azoospermia

Normal sperm production

Mechanical blockage

Vasectomy, Post-infectious, Congenital

Sperm production deficient or absent

Cryptorchidism, Radiation, Chemotherapy, Trauma, Genetic, Orchitis, Varicocele, Gonadotoxins, Unexplained


Obstructive Azoospermia


Technique Acronym

Percutaneous Epididymal Sperm Aspiration PESA

Microsurgical Epididymal Sperm Aspiration MESA

Testicular Sperm Aspiration TESA

Esteves & Agarwal. Sperm Retrieval Techniques. Cambridge University Press, 2011


http://androfert.com.br/videos

100% 96.6% 96.3%

CBAVD Vasectomy Post-‐infection

OBSTRUCTIVE AZOOSPERMIA

78.1%

97.3%

Successful Retrievals

PESA + rescue TESA PESA alone

Obstructive Azoospermia

Esteves et al. J Urol 2013


Non-Obstructive Azoospermia


Technique Acronym Success Testicular Sperm Aspiration

TESA 15-50%

Testicular Sperm Extraction

TESE 20-60%

Microsurgical Testicular Sperm Extraction

Micro-TESE 40-67%

Esteves & Agarwal. Sperm Retrieval Techniques. Cambridge University Press, 2011

TESE

Sperm production minimal or absent for sperm in ejaculate

Geographic location unpredictable


Esteves SC, Int Braz J Urol 2013

Esteves et al. Asian J Androl. In press


Sperm Retrieval and ICSI in Azoospermia

41.4 47 43.3 20

100

64 61 34.2

Sperm retrieval (%) 2PN Fertilization (%) Top Quality Embryos (%)

Live Birth (%)

Non-obstructive Obstructive

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

TESA-ICSI and Sperm DNA Damage

Sperm % TUNEL + % CPR

Ejaculated (N=18) 23.6 6 Testicular (N=18) 4.8 44 P value <0.001 <0.05

Greco et al. Hum Reprod 2005

DNA damage in Testicular Spermatozoa (13.3%) is three-fold lower compared with Ejaculated Spermatozoa (39.7%)*

*Absolute differences between two specimens ranging from -3.3% to -56.3%. Moskovtsev et al. Fertil Steril 2010


Take-home Messages


Antioxidants helpful to decrease oxidative stress and DNA damage. Specific medical therapy only valid for hypogonadism

Routine semen analysis not a good male fertility discriminator. Sperm DNA damage provides information of great prognostic

value.

Microsurgical varicocele repair increases chances of spontaneous and assisted conception

Sperm retrieval is routinely used in ART. Reproductive potential of surgically-retrieved sperm depends

on type of azoospermia

Thank You

Management of Male Infertility

Health & Medicine

Transcript of Management of Male Infertility