Management of Male Infertility

XVIII Annual Ob-Gyn Conference, KUWAIT 2013

Management of Male Infertility
What the GYN need to know
Sandro C. Esteves, MD, PhD
Director, ANDROFERT
Campinas, Brazil

Contents
DIAGNOSIS
MEDICAL TREATMENT
SURGICAL TREATMENT
ASSISTED REPRODUCTION
Esteves, 2

ANDROFERT, Referral Center for Male Reproduction

Management of Male Infertility

Available at:

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

Esteves, 3


Semen Analysis

Central
Laboratory
Investigation

Esteves, 4

Functional
Status of
Reproductive
Tract

Seminal Fluid
and Sperm


WHO 2010: Recent fathers TTP≤12 mo.

Volume (mL)
Sperm count (x106/mL)
Total count (x106)
% Motile (total)
% Motile (progressive)
% Normal (strict criteria)
% Alive

5%
1.5
15.0
39.0
40
32
4
58

Percentiles
50%*
95%
3.7
6.8
73.0
213.0
255.0
802.0
61
78
55
72
15
44
79
91
Cooper et al. Hum Reprod Update 2010

Esteves, 5


Esteves, 6


Sperm DNA Integrity
Background

Normal sperm chromatin essential for
paternal genetic transmission

Increased Sperm
DNA Fragmentation

Unexplained infertility
Recurrent pregnancy loss
Poor outcomes in IUI and IVF

Principle

Quantification of sperm DNA strand breaks

Specimen

Semen, spermatozoa

Techniques

Nuclear dyes (Acridine orange, SCSA)
Direct assessment (TUNEL, COMET)
Nuclear matrix assays (SCD)
Esteves & Agarwal Int Braz J Urol 2011

Esteves, 7


Quick and Easy Test
Sperm Chromatin Integrity Test (SCD)
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
Feijo & Esteves Fertil Steril 2013
Esteves, 8


IUI Outcome in Men with
High Sperm DNA Damage
Live Birth Rates with
Intrauterine Insemination
19%

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

1.5%
Normal
Esteves, 9

Bungum et al. Hum Reprod 2007

Elevated

IVF Outcome in Men with
High Sperm DNA Damage
Pregnancy by Method in
Cases of Elevated Sperm DNA
Fragmentation
42%

Increased miscarriage in couples
undergoing IVF/ICSI with high
sperm DNA damage

26%

IVF

Meta-analysis of 16 studies and
2,969 couples

ICSI

Risk ratio (RR) = 2.16
95% CI: 1.54-3.03; p<0.00001
Robinson et al. Hum Reprod 2012

Bungum et al. Hum Reprod 2007

Esteves, 10


Sperm DNA Damage is Associated to
Elevated Oxidative Stress

DNA damage
DNA Damage

Evaluation of
Evaluation of
DNA damage
DNA Damage
Esteves & Agarwal Int Braz J Urol 2011
Esteves, 11


Oral Antioxidants for the Male
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

Showell MG et al. Cochrane Database Syst Rev 2011

Esteves, 12


Empirical Medical Treatment for
Idiopathic Male Infertility
Androgens
hCG/HMG
FSH
Anti-estrogens
Bromocriptine
Alpha-blockers
Systemic corticosteroids

In general,
NOT
EFFECTIVE
Guidelines on Male Infertility.
European Association of Urology 2012

Esteves, 13


Anti-estrogens for the Male
1400

ng/dL

ITT levels
ral
ent
fall
ative c ck
eg
N
feedba

1200
1000

Upper Limit

800
600

Normal Testosterone
Levels

400
200
0

Esteves, 14

Lower
Sperm
Counts

Lower Limit
Before
Clomiphene

After
90d; 25mg/d

Da Ros CT, Averbeck MA Int Braz J Urol 2012


Injectable Testosterone is Detrimental
GnRH

Azoospermia
FSH/LH

Marked fall in ITT levels

Between the seminiferous tubules,
Leydig cells produce testosterone
Esteves, 15


Male Hypogonadotropic Hypogonadism
Specific Medical Therapy
Deficient virilization
Hypotrophic testes
Azoospermia
Low FSH, LH and testosterone
•  Congenital:
Kallman syndrome
Prader-Willi
•  Acquired:
Pituitary tumor
Steroid abuse
Testosterone replacement therapy
Esteves, 16


Male Hypogonadotropic Hypogonadism
Specific Medical Therapy
Series of men with adult-onset HH
Recombinant hCG; 250 mcg per week; 12 weeks
SC self-injection
w/pre-filled
syringe, qw

Esteves & Papanikolaou Fertil Steril 2011
Fraietta et al, Clinics 2013
Esteves, 17


Contents
DIAGNOSIS
MEDICAL TREATMENT
SURGICAL TREATMENT
ASSISTED REPRODUCTION
Esteves, 18


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

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

Esteves, 19


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


Varicocele Surgery and Spontaneous
Pregnancy

Marmar et al., Fertil Steril 2008

Esteves, 21


Varicocele Treatment
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%

Miyaoka & Esteves. Adv Urol 2012

Esteves, 22


Fer&lity
Restora&on

Spontaneous

Pregnancy

Fer&lity

Improvement

ICSI

Outcomes

Fer&lity

Improvement

Sperm
Retrieval
in

Azoospermia

Esteves, 23


Male Factor and ART

Varicocele Repair
Sperm Retrieval

Esteves, 24


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

Varicocele Treated
prior to ICSI (N=80)
ICSI with Untreated
Varicocele (N=162)

Esteves, 25


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

Microsurgical
varicocele repair prior
to sperm retrieval ICSI
(N=66)
Sperm Retrieval in the
presence of varicocele
(N=30)

Successful Sperm Retrieval
OR: 2.63 (95% CI: 1.05-6.60; P=0.03)
53%
30%

Treated Varicocele
Untreated Varicocele

Esteves, 26


Sperm Retrieval in Azoospermia

Normal sperm production
Mechanical blockage
Vasectomy, Post-infectious,
Congenital

Esteves, 27

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

Esteves, 28


http://androfert.com.br/videos
Esteves, 29


Esteves, 30


Obstructive Azoospermia
PESA + rescue TESA

OBSTRUCTIVE
AZOOSPERMIA

PESA alone

97.3
%

100%

96.6%

96.3%

78.1
%

CBAVD
Successful Retrievals
Esteves, 31

Vasectomy

Post-‐infection

Esteves et al. J Urol 2013


Non-Obstructive Azoospermia
Sperm production minimal or
absent for sperm in ejaculate

Technique

Geographic location unpredictable
TESE

Testicular
Sperm
Aspiration
Testicular
Sperm
Extraction
Microsurgical
Testicular
Sperm
Extraction

Acronym

Success

TESA

15-50%

TESE

20-60%

Micro-TESE

40-67%

Esteves & Agarwal. Sperm Retrieval Techniques.
Cambridge University Press, 2011
Esteves, 32


Esteves SC, Int Braz J Urol 2013


Sperm Retrieval and ICSI in Azoospermia
Non-obstructive

Obstructive

100
41.4

P<0.01
47

64
43.3

61
20

Sperm retrieval (%)

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

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

34.2

Live Birth (%)

OR=0.38
95% CI: 0.23-0.61; p<0.001
Esteves et al. Asian J Androl. In press

Esteves, 34


TESA-ICSI and Sperm DNA Damage
Sperm

% TUNEL +

% CPR

Ejaculated (N=18)

23.6

6

Testicular (N=18)

4.8

44

<0.001

<0.05

P value

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


Take-home Messages
Routine semen analysis not a good male fertility discriminator.
Sperm DNA damage provides information of great prognostic
value.
Antioxidants helpful to decrease oxidative stress and DNA
damage. Specific medical therapy only valid for hypogonadism
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
Esteves, 36


Management of Male Infertility

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