Management of Male Infertility
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Transcript of 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
Esteves, 3 ANDROFERT, Referral Center for Male Reproduction
Semen Analysis
Functional Status of
Reproductive Tract
Seminal Fluid and Sperm
Central Laboratory
Investigation
Esteves, 4 ANDROFERT, Referral Center for Male Reproduction
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
Esteves, 5 ANDROFERT, Referral Center for Male Reproduction
Esteves, 6 ANDROFERT, Referral Center for Male Reproduction
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, 7 ANDROFERT, Referral Center for Male Reproduction
Esteves & Agarwal Int Braz J Urol 2011
Quick and Easy Test Sperm Chromatin Integrity Test (SCD)
Esteves, 8 ANDROFERT, Referral Center for Male Reproduction
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
Esteves, 9 ANDROFERT, Referral Center for Male Reproduction
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
Esteves, 10 ANDROFERT, Referral Center for Male Reproduction
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
Esteves, 11 ANDROFERT, Referral Center for Male Reproduction
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
Esteves, 12 ANDROFERT, Referral Center for Male Reproduction
Empirical Medical Treatment for Idiopathic Male Infertility
Guidelines on Male Infertility. European Association of Urology 2012
In general, NOT
EFFECTIVE
Esteves, 13 ANDROFERT, Referral Center for Male Reproduction
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
Esteves, 14 ANDROFERT, Referral Center for Male Reproduction
Injectable Testosterone is Detrimental
GnRH
FSH/LH
Between the seminiferous tubules, Leydig cells produce testosterone
Azoospermia Marked fall in ITT levels
Esteves, 15 ANDROFERT, Referral Center for Male Reproduction
Deficient virilization Hypotrophic testes Azoospermia Low FSH, LH and testosterone
Male Hypogonadotropic Hypogonadism Specific Medical Therapy
Esteves, 16 ANDROFERT, Referral Center for Male Reproduction
• 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
Esteves, 17 ANDROFERT, Referral Center for Male Reproduction
Contents
DIAGNOSIS MEDICAL TREATMENT SURGICAL TREATMENT ASSISTED REPRODUCTION
Esteves, 18 ANDROFERT, Referral Center for Male 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
Esteves, 19 ANDROFERT, Referral Center for Male Reproduction
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
Esteves, 20 ANDROFERT, Referral Center for Male Reproduction
Marmar et al., Fertil Steril 2008
Esteves, 21 ANDROFERT, Referral Center for Male Reproduction
Varicocele Surgery and Spontaneous Pregnancy
Esteves, 22 ANDROFERT, Referral Center for Male Reproduction
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
Esteves, 23 ANDROFERT, Referral Center for Male Reproduction
Male Factor and ART
Varicocele Repair Sperm Retrieval
Esteves, 24 ANDROFERT, Referral Center for Male Reproduction
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
Esteves, 25 ANDROFERT, Referral Center for Male Reproduction
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
Esteves, 26 ANDROFERT, Referral Center for Male Reproduction
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
Esteves, 27 ANDROFERT, Referral Center for Male Reproduction
Obstructive Azoospermia
Esteves, 28 ANDROFERT, Referral Center for Male Reproduction
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
Esteves, 29 ANDROFERT, Referral Center for Male Reproduction
http://androfert.com.br/videos
Esteves, 30 ANDROFERT, Referral Center for Male Reproduction
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
Esteves, 31 ANDROFERT, Referral Center for Male Reproduction
Non-Obstructive Azoospermia
Esteves, 32 ANDROFERT, Referral Center for Male Reproduction
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
http://androfert.com.br/videos
Esteves SC, Int Braz J Urol 2013
Esteves et al. Asian J Androl. In press
Esteves, 34 ANDROFERT, Referral Center for Male Reproduction
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
Esteves, 35 ANDROFERT, Referral Center for Male Reproduction
Take-home Messages
Esteves, 36 ANDROFERT, Referral Center for Male Reproduction
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