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Sandro C. Esteves, MD., PhD. Director, ANDROFERT
Campinas, Brazil
Medical Management of Male
InferDlity
Delhi & Chennai, INDIA 2013
Available at:
hMp://www.androfert.com.br/review
Medical Management of Male Infer1lity Delhi & Chennai, INDIA 2013
Esteves, 2 ANDROFERT, Referral Center for Male ReproducDon
Lecture Outline
Esteves, 3 ANDROFERT, Referral Center for Male ReproducDon
Medical Management Overview
Empiric Tx of idiopathic oligozoospermia
Specific Tx for subclinical MAGI
Hormonal Tx for hypo-‐hypo
Aromatase inhibitors in obese-‐related male inferDlity
AnDoxidants for oxidaDve-‐stress alleviaDon
Empirical medical Tx of idiopathic oligozoospermia
Guidelines on Male Infertility. European Association of Urology 2012
In general, NOT
EFFECTIVE
Esteves, 4 ANDROFERT, Referral Center for Male ReproducDon
Androgens hCG/HMG/FSH Aromatase inhibitors AnD-‐estrogens BromocripDne Alpha-‐blockers Systemic corDcosteroids
Injectable testosterone is bad
GnRH
FSH/LH
Between the seminiferous tubules, Leydig cells produce testosterone
Azoospermia Marked fall in ITT levels
Esteves, 5 ANDROFERT, Referral Center for Male ReproducDon
Who may benefit from medical Tx?
Esteves, 6 ANDROFERT, Referral Center for Male ReproducDon
Estradiol levels
FSH & LH levels
Total Testosterone
levels
<300ng/dL (10.4 nmol/L)
Normal/Elevated
T/E raDo <10
<1.2 mUI/mL
Hypogonadism category
T/E raDo >10 (nl)
Hypo-‐hypo
Aromatase hyperacDvity
Pure
Treatment
Deficient viriliza1on; Hypotrophic testes Azoospermia Low FSH and LH (<1.2 mIU/L) Low total testosterone (<300 ng/dL)
Male hypogonadotropic hypogonadism Specific medical therapy
Esteves, 7 ANDROFERT, Referral Center for Male ReproducDon
• Congenital: Kallman syndrome Prader-‐Willi
• Acquired: Pituitary tumor Steroid abuse Testosterone replacement therapy
Classic treatment for male hypogonadism and infertility Urinary hCG 1,000-2,000 UI IM
injections; twice or t.i.w; minimum 12 weeks
Rec-‐hCG: SC self-‐injecDon w/pre-‐filled syringe, qw
Esteves, 8 ANDROFERT, Referral Center for Male ReproducDon
FraieMa & Esteves Clinics 2013
Adult onset hypo-‐ hypo Specific medical therapy
Rec-‐hCG for hypo-‐hypo males
Baseline PosMreatment Esteves & Papanikolaou FerDl Steril 2011
Esteves, 9 ANDROFERT, Referral Center for Male ReproducDon
Series of men with adult-‐onset HH; Recombinant hCG (Ovitrelle 250 mcg)
Who may benefit from medical Tx?
Esteves, 10 ANDROFERT, Referral Center for Male ReproducDon
Total Testosterone
levels
<300ng/dL (10.4 nmol/L)
FSH & LH levels
Normal/Elevated
<1.2 mUI/mL
Estradiol levels
T/E raDo <10
T/E raDo >10 (nl)
Hypogonadism category
Hypo-‐hypo
Aromatase hyperacDvity
Pure
Treatment
Estradiol levels in obese men is modulated by aromatase polymorphism
Aromatase is a product of the CYP19 gene
Most common polymorphism is tetranucleotide repeat (TTTAn)
Higher TTTAn (X-X) repeat associated with increased E2 levels
Esteves, 12 ANDROFERT, Referral Center for Male Reproduction
Oligozoospermia in obese men
Meta-analysis of 21 studies; 13,077 men
Risk of Oligozoospermia: Overweight*: OR=1.28 (95% CI 1.06-1.55)
(95% CI 1.59-2.62) *BMI greater than or equal to 25; **BMI greater than or equal to 30;
Sermondade et al. BMI in relation to sperm count: an updated systematic review and collaborative meta-analysis. Hum Reprod Update. 2013
Esteves, 13 ANDROFERT, Referral Center for Male Reproduction
Obesity in men at reproductive age
Esteves, 14 ANDROFERT, Referral Center for Male Reproduction
Total Testosterone (ng/dL) and Estradiol (pg/mL) Levels
T/E2 Ratio Normal > 10
Zumoff et al. Metabolism 2003; Raman & Schlegel J Urol 2002
T/E2 <10 Aromatase Hyperactivity
Aromatase inhibitors in obese-related oligozoospermia
Anastrozole 1 mg q1d 60 days
Esteves, 15 ANDROFERT, Referral Center for Male Reproduction
Raman & Schlegel. J Urol. 2002
5.9 2.9
5.5
15.6
3.5
15.6
0 5
10 15 20
T/E ratio Ejaculate volume (mL)
Sperm Count (million/mL)
Anastrazole (1mg q1d for 3-6 months) in Oligozoospermia
Pre-treatment Post-treatment
Aromatase Inhibitors for Obesity-related Male Infertility
Esteves, 16 ANDROFERT, Referral Center for Male Reproduction
Who may benefit from medical Tx?
Esteves, 17 ANDROFERT, Referral Center for Male ReproducDon
Estradiol levels
FSH & LH levels
Total Testosterone
levels
<300ng/dL
Normal/Elevated
T/E raDo <10
<1.2 mUI/mL
Hypogonadism category
T/E raDo >10 (nl)
Hypo-‐hypo
Aromatase hyperacDvity
Pure
Treatment
Pure hypogonadism
ART Candidates Severe oligozoospermia Non-‐obstrucDve azoospermia
Esteves, 18 ANDROFERT, Referral Center for Male ReproducDon
OpDons AnD-‐estrogens u-‐hCG/rec-‐hCG
Ramasamy et al., J Urol. 2009
Ø 68 men with non-mosaic KS Ø Non-obstructive azoospermia and
hypogonadism Ø ART candidates Ø Medication to boost testosterone
production: Aromatase inhibitor, hCG, anti-estrogens (2-3 months)
Ø Micro-TESE as SR method Ø Positive response: increase in TT
>100 ng/dL from baseline levels
72
55
Sperm Retrieval Rate (%)
Positive response
P = 0.03
Medication before sperm retrieval in Klinefelter syndrome men (47,XXY)
Esteves, 19 ANDROFERT, Referral Center for Male Reproduction
51 51
Sperm retrieval rate (%)
Posi1ve response (n=252)
No response (n=55)
Ø Case series (n=307): unselected group of men with tesDcular failure and low testosterone levels (300 nd/dL)
Ø Micro-‐TESE
Ø MedicaDon to boost testosterone producDon: Aromatase inhibitor, hCG, anD-‐estrogens (min. 2-‐3 months)
Ø PosiDve response: posMreatment TT >250 ng/dL
MedicaDon prior to SR in unselected men with NOA
Esteves, 20 ANDROFERT, Referral Center for Male Reproduction
Ramasamy et al., J Urol. 2011
800
Before Clomiphene
AZer 90d; 25mg/d
Da Ros CT, Averbeck MA Int Braz J Urol 2012
AnD-‐estrogens for hypogonadism
1000
1200
1400
600
400
200
0
ng/dL
Upper Limit
Lower Limit
Lower Sperm Counts
ITT levels fall
Normal Testosterone Levels
Nega1ve centr
al
feedback
Esteves, 21 ANDROFERT, Referral Center for Male ReproducDon
Medical Tx -‐ Key Messages (1)
Empirical medicaDon for idiopathic oligozoospermia not recommended
InferDle males with hypogonadism (TT<300) candidates for Tx
Esteves, 22 ANDROFERT, Referral Center for Male ReproducDon
hCG is the treatment of choice for adult-‐onset hypogonadotropic hyponadism
Medical Tx -‐ Key Messages (2)
Aromatase inhibitors helpful for overweight/obese men with aromatase hyperacDvity (T/E<10) and oligozoospermia
hCG/anD-‐estrogens helpful to boost testosterone producDon (sperm producDon?) in selected ART candidates
Esteves, 23 ANDROFERT, Referral Center for Male ReproducDon
Minimum Tx duraDon 8 weeks; monitor TT levels regularly to dose DtraDon