advancements in the medical management of male infertility

Sandro Esteves, MD, PhD

Director, ANDROFERT

Center for Male Reproduction

Campinas, BRAZIL

Esteves, 2

Learning Objectives

Overview of Male Infertility Conditions Subjected to Specific Medical Treatment

Conventional Specific Medical Treatment

Novel Specific Medical Treatment

Life-style and its Effect on Male Fertility

8% of men at

reproductive age

seek medical

assistance for

fertility-related

problems

Vital and Health Statistics, series 23, no. 26, CDC 2002; www.cdc.gov

Esteves, 4

US Census Bureau Estimates, 2004

2,383 subfertile

males

19% candidates for medical treatment

Male Infertility Etiology

Categories

Esteves et al.

An update on the initial assessment of the infertile male. CLINICS 2011; 66:1-10. Esteves, 6

Specific Medical Treatment

Overview

Conventional

Subclinical Male Genital

Tract Infection

Endocrine Disorders

Ejaculatory Disorders

Novel

Excessive Oxidative

Stress

Obesity-related Male

Infertility

Esteves, 7


Overview

Conventional


Tract Infection

Endocrine Disorders


Esteves, 8

Subclinical GTI

Hypogonadotropic Hypogonadism


Tract Infection

Prevalence: 10-20%

Primary target organs:

Epididymis

Prostate

Seminal Vesicles

Significant cause of idiopathic

male infertility

Bacteria E. Coli

N. Gonorrhoeae

C. Trachomatis

U. Urealyticum

M. hominis

Virus HPV

Herpes simplex 2

Epstein-Barr

CMV, HIV

hepatitis B

Protozoa T. vaginalis

T. gondii

Esteves, 9

Gram-negative

bacilli

Neisseria

gonorrhoeae

Chlamydia

trachomatis

Ureaplasma

urealyticum

Mycoplasma

hominis

Culture

Culture, nucleic

acid

amplification

tests (NAAT)

Culture, direct

fluorescent

antibodies,

immunoassay,

NAAT

Culture,

NAAT

Immunoassay,

NAAT,

Culture

fluorquinolones

penicillin,

fluorquinolones,

cefalosporins

azithromycin,

doxycycline,

ofloxacin

azithromycin,

doxycycline

azithromycin,

doxycycline

Anti-bacterial properties

Esteves, 10

Subclinical Male Genital Tract Infection

Endtz Test Simple diagnostic method

Peroxidase-negative

Peroxidase-positive

Granulocytes

substrate +

H2O2

+

semen

Yanushpolsky et al 1996, Erenpreiss et al 2002,

Sharma et al 2002, Saleh & Agarwal 2002, Aziz et al 2004

Leukocytospermia >1.0 x106 leukocytes per milliliter of semen

marker of reproductive

tract inflammation

Subclinical Male Genital Tract Infection

granulocyte macrophage lymphocyte

Henkel R et al, AJA 2007; Alvarez et al. Fertil Steril 2002

• 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

Esteves, 14

Treatment of Subclinical Male Genital

Tract Infection and Associated

Inflammatory Changes

Treatment of Subclinical Male Genital

Tract Infection and Associated

Inflammatory Changes

Max

Min

75th %

25th %

Median

-10

10

30

50

70

90

110

LEUCO_PR

LEUCO_PO

MOT_PRE

MOT_POS

MORF_PRE

MORF_POS

VIT_PRE

VIT_POS

P=0.001

P=0.04

P=0.50

P=0.58

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

N = 278

Androfert 1999-2009

42% leukocytospermia

resolution


Overview

Conventional


Tract Infection

Endocrine Disorders


Esteves, 16

Subclinical GTI


Features Low levels of FSH, LH,

testosterone

Absent/low virilization, hypotrophic testes, azoospermia

Main Causes:

● Congenital:

Kallmann syndrome

Prader-Willi

● Acquired:

Pituitary tumor

Pituitary radiation

Steroid abuse

Testosterone replacement therapy


MR

I

hCG 1000-2000 UI IM injections; twice or t.i.w;

minimum 12 weeks

Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 Week 10 Week 11 Week 12 Maintenance

Adult onset Hypo-hypo: Treatment to restore spermatogenesis and androgenic status

Standard Treatment:

Esteves, 18

hCG

preparations

Brand

names

Manufacturer LH activity

(IU/ampule

or vial)

Ampoule/

vial filling

method

% Protein

Contamination

Source Technology

used

Route of

administration

Urinary hCG Pregnyl Schering-

Plough;

Organon

10,000 Filled-by-

bioassay

<5% Urine Chemical

extraction

IM

Choragon Ferring 5,000

Filled-by-

bioassay

<5% Urine

Chemical

extraction

IM

Choriomon IBSA 5,000 Filled-by-

bioassay

<5% Urine

Chemical

extraction

IM

Corion,

Choriolife,

Pubergen,

LG IVF C,

Origen,

etc.

Win-Medicare,

Life-Medicare,

Sun Pharmac.,

Uni-Sankyo,

LG, etc

1,000;

2,000;

5,000

Filled-by-

bioassay

Unknown Urine

Chemical

extraction

IM

Recombinant

hCG

Ovidrel,

Ovitrelle

MerckSerono 250µg Filled-by-

mass

(FbM)

Negligible Transfected

CHO cells

Recombinant

DNA

SC

Adult onset Hypo-hypo: hCG Preparations

Esteves, 19

Evolution of hCG Preparations

Urine-derived

Recombinant technology

Esteves, 20

Clinical Efficacy, Safety and Tolerability of Recombinant hCG

to Restore Spermatogenesis and Androgenic Status of

Hypogonadotropic Hypogonadism Males

Esteves SC, Papanikolaou V; Fertil Steril 2011; Vol 96: S230

Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 Week 10 Week 11 Week 12 Evaluation

Case Series of 11 azoospermic males

Adult onset hypo-hypo

Causes:

Pituitary tumor; n=7

Steroid abuse; n=1

Testosterone replacement therapy; n=2

Cranioencephalic trauma; n=1

Mean ± SD hormone levels (mUI/mL) FSH: 0.46 ± 0.28; LH: 0.39 ± 0.32

Once a week SC self-administration of

250µg rec-hCG using a ready-to-use prefilled

syringe

Esteves, 21

Mean TotalTestosterone

(ng/dL)Mean CombinedTestis Volume

(cm3)Mean Sperm

Count (x106/mL)

41.3 24

0

647.5

33 36.0

Baseline Posttreatment

Recombinant hCG to Treat Men with Hypo-hypo Esteves SC, Papanikolaou V; Fertil Steril 2011; Vol 96: S230

Restoration of spermatogenesis and androgen production: 10/11 men

Side-effects not reported in men who responded to therapy

Pretreatment

Abnormal virilization

Posttreatment

Normal hair distribution

Pretreatment

Hypotrophic scrotum/reduced testes

Posttreatment

Normal scrotum and testes

Figure 2. Photographs illustrating a patient with gigantism associated with a pituitary tumor secreting growth hormone and prolactin cured by

transsphenoidal hypophysectomy. Secondary hypo-hypo was treated with rec-hCG leading to a marked improvement in virilization and testicular

volume (with patient permission).

Baseline Posttreatment

Esteves, 22


Overview

Conventional


Tract Infection

Endocrine Disorders


Novel

Excessive Oxidative Stress

Obesity-related Male Infertility

Esteves, 23

Esteves, 24


0

0,5

1

1,5

2

2,5

Fertile Infertile

Seminal Reactive Oxygen

Species (ROS) (Log ROS + 1; cpm)

Pasqualotto et al., Fertil Steril 2000

How Oxidative Stress Can be

Measured?

Indirect Assessment

• Lipid Peroxidation (Malondialdehyde)

• Protein oxidation products (eg. 8-OHdG)

• Sperm DNA integrity

Direct Assessment

• Total Antioxidant Capacity

• Seminal ROS levels

Esteves, 25

Esteves et al. What every GYN should know about male infertility.

Arch Gynecol Obstet 2012, Epub March 6

DNA Damage is the Main

Expression of ROS Production

and Oxidative Stress

• Quantification of sperm DNA strand breaks Principle

• Spermatozoa Specimen

• Nuclear dyes (Acridine orange, SCSA)

• Direct assessment (TUNEL, COMET)

• Sperm Chromatin Dispersion (SCD) Techniques

Esteves, 26

Sperm DNA Integrity and Assisted

Conception Results

19%

1.5%

Normal Elevated

Live Birth Rates by Intrauterine

Insemination

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

Adapted from Bungum et al., Hum Reprod 2007

26%

42%

IVF ICSI

Pregnancy by Method in Cases of Elevated Sperm DNA

Fragmentation

P <0.05

Esteves

27

Evidence-based Use of

Antioxidants in Male Infertility

Author Antioxidant Agent Results

Geva et al., 1996 Vit E 200 mg Increased fertilization in IVF

Suleiman et al, 1996 Vit E 100 mg Decreased ROS; increased

spontaneous PR

Wong et al., 2002 Folic acid 5 mg + Zinc

66 mg

Increased total sperm count

Greco et al., 2005 Vit C 1.0 g + E 1.0 g Improved sperm DNA integrity

Greco et al., 2005 Vit C 1.0 g + Vit E 1.0 g Increased CPR and IR in ICSI

cycles

Tremellen et al.,

2007

Menevit® (vit C + E;

zinc 25 mg; selenium 26

mcg; lycopene 6 mg)

Increased IR/PR in IVF/ICSI

cycles

Boxmeer et al., 2009 Decreased folate in

seminal plasma

Increased sperm DNA

fragmentation

Antioxidant Treatment Cochrane Review 2011

Outcome N

studies

N

participants

Effect size

(OR; 95% CI)

Live birth 3 214 4.85 [1.92, 12.24]

Pregnancy rate 15 964 4.18 [2.65, 6.59]

DNA fragmentation 1 64 -13.80 [-17.50, -10.10]

Miscarriage, sperm

count, sperm motility 6-16 242-700 No effect

Adverse effects 6 426 No effect

Improve the outcomes of live birth and pregnancy rate for

subfertile couples undergoing ART cycles

Showell MG et al. Antioxidants for male subfertility.

Cochrane Database Syst Rev 2011 Jan 19;(1):CD007411.

Antioxidants in Male

Infertility To whom?

Men at risk of eOS

How? q.d.

Vitamic C 500mg

Vitamin E 400 UI

Folic acid 2 mg

Zinc 25 mg

Selenium 26 mcg

How long?

Esteves, 30

Esteves et al. What the gynecologist should know about male infertility:

an update. Arch Gynecol Obstet 2012; Epub March 6

From Initiation of Sperm

Production to Ejaculation

Misell LM et al.: A stable isotope-mass spectrometric method for measuring

human spermatogenesis kinetics in vivo.

J Urol. 2006; 175: 242-6.

Old concept ~80 days

New concept ~60 days

Empirical Medical Treatment

for Idiopathic Male Infertility

Androgens

hCG/HMG

FSH

Anti-oestrogens

Bromocriptine

Alpha-blockers

Systemic corticosteroids

Magnesium supplementation

No demonstrable cause for altered semen parameters

Guidelines on Male Infertility.

European Association of Urology 2012


Overview

Novel


Esteves, 33

Obesity in Men at Reproductive Age

WHO: Global database on BMI, 2011 Esteves, 34

Esteves, 35

Jensen et al. Fertil Steril 2004; 82: 863; Hammoud et al. Fertil Steril 2008; 90: 2222;

Kriegel et al. RBM Online 2009; 19: 660;

Martini et al. Fertil Steril 2010; 94: 1739. Esteves, 36

Esteves, 37

Esteves, 38

Serum Levels of Total Testosterone and Estradiol

T/E2 Ratio Normal > 10

Eg.: 4.9 =350 𝑛𝑔/𝑑𝐿

62 𝑝𝑔/𝑚𝐿

T/E2 Ratio Normalization and Sperm Count Improvement

T/E2 <10

Aromatase Hyperactivity

Anastrozole 1 mg q1d 60 days

Zumoff et al. Reversal of the hypogonadotropic hypogonadism of obese men by administration of

the aromatase inhibitor testolactone. Metabolism 2003; 52: 1126. Raman & Schlegel Aromatase

inhibitors for male infertility. J Urol 2002; 167: 624. Esteves, 39

Medical Treatment for Klinefelter Syndrome Men Seeking Fertility

Esteves et al. Surgical treatment of male infertility in the era of ICSI – new insights.

CLINICS 2011; 66:1463-77.

Klin

efe

lter Karyotype:

47,XXY

47,XXY/46,XY

Features:

Azoospermia (>90%)

Small testes

Elevated FSH

Low Testosterone

Hypogonadism

Elevated testis expression

aromatase CYP19

Seekin

g F

ert

ility

Sperm Retrieval

and ICSI

Managem

ent Medical

Treatment prior

to Sperm

Retrieval

Foci of sperm

production (~40%) Sciurano et al., Hum

Reprod. 2009

Esteves, 40

Klinefelter Syndrome

Medical Treatment Prior to Sperm Retrieval

180

330

150

220

Baseline Testosterone Post-treatment TT

Positive Response to Therapy No response

Ramasamy et al., J Urol. 2009; 182: 1108-13.

72%

SRR: 72%

SRR: 55%

Series of 68 non-mosaic KS Men with Azoospermia

Medical Treatment: Aromatase inhibitor, hCG, CC

Positive Response: TT increase of >100ng/dL from baseline

P = 0.03

Esteves, 41

Life-style

Habits


Overview

Novel



Esteves, 42

Klonoff-Cohen H. Human Reproduction Update, Vol.11, No.2 pp. 180–204, 2005

Smoking

• Live birth delivery reduced by 3.7X

Alcohol

• Live birth delivery reduced by 5.5X

• Miscarriage increased by 2.7X

Stress

• Conflicting results

Caffeine

• No effect

Common Toxicants to Male

Reproductive Health

Environmental/Nutritional Endocrine disruptors (xenoestrogens

[Polychlorinated biphenyls, bisphenol

A, Phtalates]), Heavy Metals,

Pesticides

Ilicit Drugs Anabolic Steroids,

Marijuana, Cocaine, etc.

Cell Phone

Electromagnetic

Radiation

Medication Antidepressants (SSRI), Antipsychotics

(Lithium), Antihypertensives (calcium

channel blockers),

Cimetidine, Ketoconazole, Finasteride,

Antibiotics

Licit Drugs Cigarette smoking,

Alcohol

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Subclinical infections are treated with antibiotics

and leukocyte-induced inflammation can be

alleviated by oral antioxidants administration.

Medical treatment of adult onset hypo-hypo with

hCG is highly effective.

Antioxidant prescription to subfertile men is

recommended, especially in cases of eOS.

Sperm DNA damage marker of eOS.

Esteves, 46

Medical treatment (AI) is recommended for

obese/overweight subfertile men with aromatase

hyperactivity.

KS men with NOA are candidates to medical

treatment. AI, hCG and CC boost testosterone

production and may improve chances of SSR.

Re-evalualtion of life-style habits is of utmost

importance to optimize male reproductive health.

advancements in the medical management of male infertility

Health & Medicine