management of male fertility and gonodotropin role
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Management of male infer.lity and role of
gonadotropin Sandro C. Esteves, MD., PhD. Medical Director, ANDROFERT
Andrology & Human Reproduc=on Clinic Campinas, BRAZIL
UAE Reproductive Symposium 2015 - Dubai
Learning Objec.ves 1. Understand the WHO reference values
for semen analysis and the role of sperm DNA fragmenta.on tes.ng
2. Appraise which interven.ons may benefit infer.le men candidates to ART
3. Learn how to manage infer.le males with azoospermia and the role of gonadotropin
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2015
ANDROFERT
Semen analysis is s.ll the most widely used biomarker to predict
male fer.lity
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 3 2015
ANDROFERT
1980 1987 1992 1999 Volume (mL) ND ≥2 ≥2 ≥2 Count (106/mL) 20-‐200 ≥20 ≥20 ≥20 Total count (106) ND ≥40 ≥40 ≥40 Mo.lity (%) ≥ 60 ≥50 ≥50 ≥50 Progressive (%) ≥ 2 ≥25% ≥25% (a) ≥25% (a) Vitality (%) ND ≥50 ≥75 ≥75
Morphology (%) 80.5 ≥50 ≥30 (14)* Leukocytes (106/mL) <4.7 <1.0 <1.0 <1.0
*Strict criteria (Tygerberg); Esteves et al. Urology 2012
WHO reference values have changed
2010 ≥1.5 ≥15 ≥39 ≥40 ≥32% ≥58 ≥4* 1.0
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 4 2015
ANDROFERT
~2,000 specimens; recent fathers
Percen.le 5% 50% 95%
Volume (mL) 1.5 3.7 6.8 Count (x106/mL) 15.0 73.0 213.0 Total count (x106) 39.0 255.0 802.0 % Mo.le 40 61 78 % Progressive mo.lity 32 55 72 % Normal (Kruger) 4 15 44 % Alive 58 79 91
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2015
ANDROFERT
Urology 2012; 79(1):16-22
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2015
ANDROFERT
Proposal for a new report template
Esteves, Int Braz J Urol 2014; 40:443-‐53
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2015
ANDROFERT
History taking, physical examina.on, endocrine profile and laboratory sperm func.on tes.ng are minimum standards
Esteves Int Braz J Urol 2014
Male infer.lity evalua.on must go beyond a simple semen analysis
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2015
ANDROFERT
Conven.onal semen analysis is not enough
single-strand break
mis-match
damaged base double-strand
break
inter-strand crosslink
intra-strand crosslink
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 9 2015
ANDROFERT
DNA Damage
Environmental factors Phtalate exposure, radiation, temperature Diseases Varicocele, GTI, fever Life-‐style Obesity, smoking, medication Aging
Factors associated with sperm DNA fragmenta.on
Rubes et al 2007; Esteves & Agarwal 2011
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2015
ANDROFERT
Frequency of elevated SDF in men with unexplained infer.lity
Elevated SDF (27%)
Androfert; N=987
Elevated SDF (27%)
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 11 2015
ANDROFERT
19%
1.5%
Normal Elevated
Live birth rates with IUI
N=387; OR = 0.07 [95% CI: 0.01-‐0.48]
Bungum et al. Hum Reprod 2007
IUI outcome is nega.vely affected by elevated SDF
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2015
ANDROFERT
26% 42%
IVF ICSI
Pregnancy in cases of elevated sperm DNA fragmentation
IVF outcome is nega.vely affected by elevated SDF
Robinson et al. Hum Reprod 2012
Meta-‐analysis of 16 studies; 2,969
couples:
Increased miscarriage in IVF/ICSI associated to high SDF; RR = 2.16 95% CI: 1.54-‐3.03; p<0.00001
Bungum et al. Hum Reprod 2007
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2015
ANDROFERT
Fer.lity and Sterility 2014; 101(1):58-‐63
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2015
ANDROFERT
Andrologia 2014; 46(6): 602–9
Pa.ents with varicocele have higher propor.on of sperm with massive DNA damage
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2015
ANDROFERT
SDF is part of rou.ne work-‐up of male infer.lity at Androfert
Does the patient have high SDF?
Semen analysis
including SDF testing (SCD
assay)
High SDF if results >30%
What does the doctor need
to know?
Determine test and internal
validation
Lab SOP with post-analytical info for clinical
decision
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2015
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 17 2015
ANDROFERT
Role of interven.ons to infer.le men candidates
to ART
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 2015
ANDROFERT
Outcome Effect size (OR; 95% CI)
Live birth 4.85 [1.92, 12.24]
DNA fragmenta.on -‐13.80 [-‐17.50, -‐10.10]
Oral an.oxidants decrease SDF and improve ART outcomes
Showell et al. Cochrane Database Syst Rev 2011
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 19 2015
ANDROFERT
Oral an.oxidants to infer.le males Prescrip.on:
Vitamin C 500mg; Vitamin E 400 mg Folic acid 2 mg, Zinc 25 mg Selenium 26 mcg
Dura.on: minimum 2 months
Old concept ~90 days New concept ~60 days
Misell et al. J Urol 2006; Esteves & Agarwal Int Braz J Urol 2011
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 20 2015
ANDROFERT
Sperm DNA damage in tes.cular and ejaculated samples using the SCD test*
40.7%
8.3%
Ejaculate Tes.s
P<0.001
Sánchez-‐Marqn, Esteves & Gosálvez, in prepara@on
*Dual fluorescent cocktail probe
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2015
ANDROFERT
Wang YJ et al. Reprod Biomed Online 2012;25:307-‐14
Meta-‐analysis of 7 studies including 336 pts. indicated that SDF is significantly decreased auer varicocele repair (MD=3.4%; 95% CI -‐4.1 to -‐2.6; p<0.0001)
Effect of varicocele surgery on SDF
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2015
ANDROFERT
• Varicocele treated prior to ICSI (N=80)
• ICSI with untreated varicocele (N=162)
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2015
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Microsurgical subinguinal varicocele repair with aid of intraopera.ve doppler
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 24 2015
ANDROFERT
Management of azoospermia and the role of gonadotropin
therapy
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 25 2015
ANDROFERT
Azoospermia: the complete lack of sperm in ejaculate auer centrifuga.on
10-15% infertile males
1-3% male population
Cooper et al. Hum Reprod Update 2009; Esteves & Agarwal, Clinics 2013
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2015
ANDROFERT
Obstruc.ve
Non-‐obstruc.ve
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 tes.s, poor viriliza.on
Disrupted
Normal
Spermatogenesis
Esteves et al, Clinics 2011
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2015
ANDROFERT
Prognosis and management differen.ally affected by type of azoospermia
• Low FSH and LH (<1.2 mIU/L) • Low total testosterone (<300 ng/dL) • Hypotrophic testes
Hypogonadotropic hypogonadism
Congenital: Kallman syndrome Prader-Willi
Acquired: Pituitary tumor Steroid abuse Testosterone replacement therapy Fraieva et al. Clinics 68; 2013
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 28 2015
ANDROFERT
Classic treatment for male hypogonadism and infer.lity
u-‐hCG 1,000-‐2,000 IU; IM injec.ons; twice or t.i.w; minimum 12 weeks
Rec-‐hCG: SC self-‐injec.on qw Pre-‐filled syringe
Pen device Fraieva et al. Clinics 2013; 68(Suppl.1):81-‐8
Specific therapy in adult onset hypo-‐ hypo
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 29 2015
ANDROFERT
Rec-‐hCG for male hypo-‐hypo
Esteves & Papanikolaou Fer@l Steril 2011;96:S230
Series of men with adult-‐onset HH; Recombinant hCG (250 mcg qw for 12 weeks)
Baseline Pos`reatment
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2015
ANDROFERT
Tes.cular torsion; trauma Post-‐inflammatory (eg. Mumps orchi=s) Exogenous factors (eg. Cytotoxic drugs, irradia=on) Tes.cular cancer Systemic diseases (eg. Liver cirrhosis, renal failure)
Congenital Tes.cular dysgenesis/cryptorchidism Gene.c abnormali.es (Klinefelter syndrome, Yq microdele=ons, etc.)
Acquired
Idiopathic (unknown e.ology) Esteves et al. Clinics 2011; 66:691-‐700
NOA due to spermatogenic failure: an irreversible condi.on
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2015
ANDROFERT
Esteves et al. Int Braz J Urol 2011;37:570-‐83
40-‐50% of men with SF have residual spermatogenesis within the tes.s
§ Not enough for sperm to appear in ejaculate
§ 600-‐800 seminiferous tubules
§ Goals are: i. Op=mize sperm produc=on (if possible) ii. Iden=fy site of sperm produc=on (if
present) and retrieve sperm for ICSI
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2015
ANDROFERT
Challenges faced by health professionals providing care for men with SF
§ Counseling about the chances of finding tes.cular sperm
§ Usefulness of any medical interven.on before sperm retrieval
§ Which sperm retrieval method to apply § Reproduc.ve poten.al of retrieved gametes in ICSI treatment
§ Health of offspring
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 33 2015
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2015
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Complete AZFa, AZFb or AZFa+b microdele.ons unfavorable prognosis
YCMD SR success
AZFa nil AZFb nil AZFc 50-‐70%
Krausz et al. 2014; Esteves et al. 2013; Esteves 2015
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2015
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 36 2015
ANDROFERT
Interven.ons to infer.le males men with SF prior to a sperm retrieval avempt
Matura.on 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 mo.le sperm in postop.
ejaculate
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2015
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 auer varicocele repair, SRR increased
§ Haydardedeoglu 2010
53 30
Treated (N=66) Untreated (N=30)
SR success (%)
61 38
Treated (N=31) Untreated (N=65)
p<0.01
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 38 2015
ANDROFERT
Medica.on Hypogonadism (TT<300 ng/dl) in up to 50% men with SF High ITT levels essen=al for regula=ng spermatogenesis in combina=on with Sertoli cell s=mula=on by FSH
Paradoxically weak s.mula.on 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
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 39 2015
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
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 40 2015
ANDROFERT
ITT levels increase auer hCG; s.mulatory 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 auer hCG-‐based therapy
Spermatogonial DNA synthesis increased
PCNA expression
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 41 2015
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
Microdissec.on TESE Rescue ~15% of pa.ents with previous failed SR avempts1
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 42 2015
ANDROFERT
Testosterone and estradiol levels
<300 ng/dL
(10.4 nmol/L)
Hypogonadism category
Pure
Medica.on algorithm at Androfert Tx aimed at boos.ng 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 ra.o <10
Aromatase hyperac.vity
T/E ra.o >10 (nl)
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 43 2015
ANDROFERT
Esteves Asian J Androl 2015;17:1-‐12
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 44 2015
ANDROFERT
Sperm retrieval methods in NOA due to spermatogenic failure
Technique Acronym Success Tes.cular sperm aspira.on TESA 15-‐50%
Tes.cular sperm extrac.on TESE 20-‐60%
Microdissec.on tes.cular sperm extrac.on
Micro-‐TESE 40-‐67%
Esteves et al Int Braz J Urol 2013;37:570-‐83; Deruyver et al Andrology 2014;2:20-‐4
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 45 2015
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
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 47 2015
ANDROFERT
Morphometric evalua.on 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. Fer@l 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
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 48 2015
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 49 2015
ANDROFERT
On average, one top-‐quality addi.onal embryo for transfer or cryopreserva.on
Clean Room Technology & ICSI Results 2,315 pa.ents; 14,660 embryos
Esteves & Bento. Reprod Biomed Online 2013;26:9-‐21
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 50 2015
ANDROFERT
3,412 cycles
Tailored COS strategy to increase LBR in ICSI cycles involving severe male factor
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 retrieved
Clinical pregnancy Live birth
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 51 2015
ANDROFERT
Conclusions 1. Conven.onal semen analysis limited as
surrogate for assessing fer.lity; SDF tes.ng valuable laboratory tool for clinical decision
2. An.oxidant therapy, microsurgical varicocele repair and TESA-‐ICSI may improve ART outcome in selected individuals
3. Best management of azoospermia includes proper diagnosis, interven.ons to op.mize sperm produc.on, microsurgical SR, state-‐of-‐art laboratory care and tailored COS to ART candidates
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 52 2015
ANDROFERT
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