medical management of male factor infertility

Sandro C. Esteves, MD., PhD. Director, ANDROFERT

Andrology & Human Reproduction Clinic Campinas, BRAZIL

Medical Management of Male Infertility

Reproductive Andrology Surgery Workshop 2014 Al Jahra Hospital, KUWAIT

ISO 9001:2008

Available at:

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ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2014 APRIL

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Medical Management of Male Infertility

Lecture Outline Overview Empiric Tx of idiopathic oligozoospermia

Specific Tx for subclinical MAGI

Hormonal Tx for hypo-hypo

Aromatase inhibitors in obese-related male infertility

Antioxidants for oxidative-stress alleviation



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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 Anti-estrogens Bromocriptine Alpha-blockers Systemic corticosteroids



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Injectable testosteroned

GnRH

FSH/LH Azoospermia

Marked fall in ITT levels

Between the seminiferous tubules, Leydig cells produce

testosterone



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Who benefit from medical Tx?

Estradiol levels

FSH & LH levels

Total Testosterone

levels

<300 ng/dL

(10.4 nmol/L)

Normal/Elevated

T/E ratio <10

<1.2 mUI/mL

Hypogonadism category

T/E ratio >10 (nl)

Hypo-hypo

Aromatase hyperactivity

Pure

Treatment



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Deficient virilization; Hypotrophic testes Azoospermia Low FSH and LH (<1.2 mIU/L) Low total testosterone (<300 ng/dL)

Hypogonadotropic hypogonadism Specific medical therapy

• Congenital: Kallman syndrome Prader-Willi

• Acquired: Pituitary tumor Steroid abuse Testosterone replacement therapy



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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-injection w/pre-filled

syringe, qw Fraietta & Esteves Clinics 2013

Adult onset hypo- hypo Specific medical therapy



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Rec-hCG for male hypo-hypo

Baseline Posttreatment Esteves & Papanikolaou Fertil Steril 2011

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



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Total Testosterone

levels

<300ng/dL (10.4 nmol/L)

FSH & LH levels

Normal/Elevated

<1.2 mUI/mL

Estradiol levels

T/E ratio <10

T/E ratio >10 (nl)


Hypo-hypo


Pure

Treatment



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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



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Oligozoospermia in obese 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. Hum Reprod Update. 2013

Meta-analysis of 21 studies; 13,077 men



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Obesity in men at reproductive age



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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



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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



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Estradiol levels

FSH & LH levels

Total Testosterone

levels

<300ng/dL

Normal/Elevated

T/E ratio <10

<1.2 mUI/mL


T/E ratio >10 (nl)

Hypo-hypo


Pure

Treatment



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Pure hypogonadism ART Candidates Severe oligozoospermia Non-obstructive azoospermia

Options Anti-estrogens u-hCG/rec-hCG



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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)



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51 51

Sperm retrieval rate (%)

Positive response (n=252) No response (n=55)

Ø  Case series (n=307): unselected group of men with testicular failure and low testosterone levels (300 nd/dL)

Ø  Micro-TESE

Ø  Medication to boost testosterone production: Aromatase inhibitor, hCG, anti-estrogens (min. 2-3 months)

Ø  Positive response: posttreatment TT >250 ng/dL

Medication prior to SR in unselected men with NOA

Ramasamy et al., J Urol. 2011



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800

Before Clomiphene

After 90d; 25mg/d

Da Ros CT, Averbeck MA Int Braz J Urol 2012

Anti-estrogens in Hypogonadism

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



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Medical Tx - Key Messages (1)

Empirical medication for idiopathic oligozoospermia not recommended

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

hCG is the treatment of choice for adult-onset hypogonadotropic hyponadism



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Medical Tx - Key Messages (2) Aromatase inhibitors helpful for overweight/obese men with aromatase hyperactivity (T/E<10) and oligozoospermia

hCG/anti-estrogens helpful to boost testosterone production (sperm production?) in selected ART candidates

Minimum Tx duration 8 weeks; monitor TT levels regularly to dose titration



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Lecture Outline Overview Empiric Tx of idiopathic oligozoospermia

Specific Tx for subclinical MAGI

Hormonal Tx for hypo-hypo

Aromatase inhibitors in obese-related male infertility

Antioxidants for oxidative-stress alleviation



ANDROFERT

Subclinical Male Genital Tract Infection



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Urethritis, prostatitis

AnN-‐bacterial properNes (Zinc)

Yanushpolsky et al 1996, Saleh & Agarwal 2002, Aziz et al 2004

Leukocytospermia >1.0 x 106 leukocytes per mL of semen

marker of reproductive tract inflammation

Macrophage Neutrophils

Subclinical Male Genital Tract Infection (MAGI)



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25% 34% 39%

Normal Abnormal Abnl & Leukocytospermia

% DNA Damage (SCSA)

Seminal Leukocytes Endtz Test

Simple diagnostic method

Peroxidase-negative

Peroxidase-positive Granulocytes (Neutrophils)

substrate +

H2O2 +

semen

Esteves et al. CLINICS 2011; 66:1-10.



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•  Yanushpolsky et al, 1995; Erel et al., 1997 •  Branigan et al., 1995 Antibiotics

•  Lackner et al., 2006 •  Gambera et al., 2007

Cicloxigenase-2 Inhibitors

•  Oliva & Mutigner, 2006 Antihistamines

•  Tremellen et al., 2007 •  Piombini et al., 2008 Antioxidants

Treatment of Subclinical Male Genital Tract Infection and Associated

Inflammatory Changes



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Subclinical Male Genital Tract Infection

Azitromycin 1.0g single dose (couple)+ frequent ejaculation (every 2-3 days) + Antioxidants

42% leukocytospermia resolution (N=278; Androfert)



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OxidaNve Stress

30%-80% of infertile men have elevated markers of OS

Agarwal et al., Urology 2006

An emerging explanaNon for several cases of male inferNlity

Oral Antioxidants



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Chemical species with unpaired electron capable to oxidize lipids, proteins and nucleic acids:

Superoxide anion (•O-2) Hydroxyl radical (•OH) Hydrogen peroxide (H2O2) Peroxyl radical (ROO•) Hypochlorite ion (OCl-)

Generated from aerobic metabolism of sperm and leukocytes’ mitochondria

Lampiao et al., 2012

Reactive Oxygen Species (ROS)

Sperm and Seminal Plasma Antioxidants: Enzymatic (SOD, catalase, GPX): inactivate ROS by conversion into

other substances Non-enzymatic (ascorbic acid, alpha-tocopherol, carnitine, etc.):

neutralize ROS



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Rationale of Oral Antioxidants use OA classified according to their mechanism of action:

Catalytic: enhances the already present antioxidant enzymes (Glutathione, N-acetyl-cysteine). Scavenging: Water soluble: react with oxidants in the cytosol (Vitamin C) Lipid soluble: protect cell membrane from lipid peroxidation (Vitamin E)



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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

Showell MG et al. Cochrane Database Syst Rev 2011



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Oral Antioxidants

•  Short-term use appear to be safe

•  Caution against indiscriminate use of high dosages for long periods

Beneficial Kodama 1997 Dawson, 1992

Kessopoulou, 1995 Vezina, 1996

Vicari, 2001; 2002 Lenzi, 2003; 2004

Cavallini, 2004 Comhaire, 2005

Grecco 2005 Menezo 2007

Tremellen 2007 Piomboni 2008 Gil Villa 2009

No effect Giovenco, 1987 Moilanen, 1993 Iwanier, 1995

Rolf, 1999 Sigman, 2006

Detrimental long-term use and high doses; increased mortality in cancer population-based studies.

Heinonen, 1994 Lonn, 2005

Bjelakovic, 2007



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How to use Antioxidant Therapy

Ascorbic acid (Vit. C) α- tocopherol (Vit. E)

Glutathione N-acetyl-cysteine

Carnitine, Coenzyme Q10 Lycopene. Picnogenol

Pentoxifylline. Selenium Shao-Fu-Zhu-Yu-Tang

Astaxanthin Lepidium meyenii

α -linolenic acid and lignans Folic acid, Zinc

Select antioxidant formulation and dosage

Testing for

Leukocytes in Semen

Differentiate between sperm and leukocyte

source of ROS

Varicocele Genital Infection

Smoking Medication Drug abuse

Systemic diseases Pollution

Radiation

Focus on identifying and controlling source

of increased ROS



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Oral Antioxidants How I prescribe

Vitamin C 500mg; Vitamin E 400 mg Folic acid 2 mg, Zinc 25 mg Selenium 26 mcg

Minimum 2 months

Old concept ~80 days

New concept ~60 days

From initiation of sperm production to ejaculation

Misell LM et al. J Urol. 2006

Esteves & Agarwal. Novel concepts in male infertility. Int Braz J Urol 2011



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Asymptomatic leukocytospermia is mainly caused by urethritis

ROS production increase with an increase in leukocyte numbers

Antibiotic therapy is suggested, but effect on fertility is still unclear (GR-B)




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Oxidative stress impairs sperm function and is a risk factor for male infertility (GR-A) OA supplementation for subfertile males improve the chances of live birth for couples undergoing ART (GR-A)

Well-designed studies are needed to determine the best candidates for OA therapy and which formulation and dosages yield better results




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Thank you Obrigado شكرا

medical management of male factor infertility

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