medical management of male infertility

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


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


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


Who may benefit from medical Tx?


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


• 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


FraieMa & Esteves Clinics 2013

Adult onset hypo-‐ hypo Specific medical therapy

Rec-‐hCG for hypo-‐hypo males

Baseline PosMreatment Esteves & Papanikolaou FerDl Steril 2011


Series of men with adult-‐onset HH; Recombinant hCG (Ovitrelle 250 mcg)



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)


Hypo-‐hypo


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


Obesity in men at reproductive age


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


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




Estradiol levels

FSH & LH levels

Total Testosterone

levels

<300ng/dL

Normal/Elevated

T/E raDo <10

<1.2 mUI/mL


T/E raDo >10 (nl)

Hypo-‐hypo


Pure

Treatment

Pure hypogonadism

ART Candidates Severe oligozoospermia Non-‐obstrucDve azoospermia


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)


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


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


Medical Tx -‐ Key Messages (1)

Empirical medicaDon for idiopathic oligozoospermia not recommended

InferDle males with hypogonadism (TT<300) candidates for Tx


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


Minimum Tx duraDon 8 weeks; monitor TT levels regularly to dose DtraDon

medical management of male infertility

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