Advancements in the Medical Management of Male Infertility
Sandro Esteves, MD, PhD Director, ANDROFERTCenter for Male Reproduction Campinas, BRAZIL
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 FertilityEsteves, 2
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.govEsteves, 4
Male Infertility Etiology Categories 2,383 subfertile males 19% candidates for medical treatment Esteves et al.Esteves, 6 An update on the initial assessment of the infertile male. CLINICS 2011; 66:1-10.
Specific Medical Treatment Overview Conventional Novel Subclinical Excessive Male Genital Oxidative Tract Infection Stress Obesity- Endocrine related Male Disorders Infertility Ejaculatory DisordersEsteves, 7
Specific Medical Treatment Overview Conventional Subclinical Male Genital Subclinical Tract Infection GTI Endocrine Hypogonadotropic Disorders Hypogonadism Ejaculatory DisordersEsteves, 8
Subclinical Male Genital Tract Infection Bacteria E. Coli N. Gonorrhoeae C. Trachomatis Prevalence: 10-20% U. Urealyticum M. hominis Primary target organs: Virus Epididymis HPV Herpes simplex 2 Prostate Epstein-Barr CMV, HIV Seminal Vesicles hepatitis B Significant cause of idiopathic Protozoa T. vaginalis male infertility T. gondiiEsteves, 9
Subclinical Male Genital Tract Infection Leukocytospermia >1.0 x106 leukocytes per milliliter of semen marker of reproductive granulocyte macrophage lymphocyte tract inflammationYanushpolsky et al 1996, Erenpreiss et al 2002,Sharma et al 2002, Saleh & Agarwal 2002, Aziz et al 2004
Henkel R et al, AJA 2007; Alvarez et al. Fertil Steril 2002
Treatment of Subclinical Male Genital Tract Infection and Associated Inflammatory Changes • Yanushpolsky et al, 1995; Erel et al., 1997 Antibiotics • Branigan et al., 1995 Cicloxigenase-2 • Lackner et al., 2006 Inhibitors • Gambera et al., 2007 Antihistamines • Oliva & Mutigner, 2006 • Tremellen et al., 2007 Antioxidants • Piombini et al., 2008Esteves, 14
Treatment of Subclinical Male Genital Tract Infection and Associated Inflammatory Changes Azitromycin 1.0g single dose (couple)+ frequent ejaculation (every 2-3 days) + Antioxidants110 90 P=0.04 P=0.58 N = 278 70 Androfert 1999-2009 50 42% leukocytospermia 30 P=0.001 P=0.50 resolution Max 10 Min 75th %-10 25th % LEUC O _PR MO T_PRE MO RF_PRE VIT_PRE LEUC O _PO MO T_PO S MO RF_PO S VIT_PO S Median
Specific Medical Treatment Overview Conventional Subclinical Male Genital Subclinical Tract Infection GTI Endocrine Hypogonadotropic Disorders Hypogonadism Ejaculatory DisordersEsteves, 16
HypogonadotropicHypogonadism Features Low levels of FSH, LH, testosterone MRI Absent/low virilization,hypotrophic testes, azoospermia Main Causes:● Congenital: Kallmann syndrome Prader-Willi● Acquired: Pituitary tumor Pituitary radiation Steroid abuse Testosterone replacement therapy
Adult onset Hypo-hypo: Treatment to restore spermatogenesis and androgenic status Standard Treatment: 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 MaintenanceEsteves, 18
Adult onset Hypo-hypo: hCG Preparations hCG Brand Manufacturer LH activity Ampoule/ % Protein Source Technology Route of preparations names (IU/ampule vial filling Contamination used administration or vial) method Urinary hCG Pregnyl Schering- 10,000 Filled-by- <5% Urine Chemical IM Plough; bioassay extraction Organon Choragon Ferring 5,000 Filled-by- <5% Urine Chemical IM bioassay extraction Choriomon IBSA 5,000 Filled-by- <5% Urine Chemical IM bioassay extraction Corion, Win-Medicare, 1,000; Filled-by- Unknown Urine Chemical IM Choriolife, Life-Medicare, 2,000; bioassay extraction Pubergen, Sun Pharmac., 5,000 LG IVF C, Uni-Sankyo, Origen, LG, etc etc. Recombinant Ovidrel, MerckSerono 250µg Filled-by- Negligible Transfected Recombinant SC hCG Ovitrelle mass CHO cells DNA (FbM)Esteves, 19
Evolution of hCG Preparations Urine-derived Recombinant technologyEsteves, 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 Case Series of 11 azoospermic males Adult onset hypo-hypo Causes: Pituitary tumor; n=7 Steroid abuse; n=1 Testosterone replacement therapy; n=2 Once a week SC self- Cranioencephalic trauma; n=1 administration of 250µg rec-hCG using Mean ± SD hormone levels (mUI/mL) a ready-to-use prefilled FSH: 0.46 ± 0.28; LH: 0.39 ± 0.32 syringe Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 Week 10 Week 11 Week 12 EvaluationEsteves, 21
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 Baseline Posttreatment 647.5 33 41.3 36.0 24 0 Mean Total Testosterone Mean Combined (ng/dL) Testis Volume Mean Sperm (cm3) Count (x106/mL) Baseline PosttreatmentEsteves, 22
Specific Medical Treatment Overview Conventional Novel Subclinical Male Genital Excessive Tract Infection Oxidative Stress Endocrine Disorders Obesity-related Male Infertility Ejaculatory DisordersEsteves, 23
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 et al. What every GYN should know about male infertility.Esteves, 25 Arch Gynecol Obstet 2012, Epub March 6
DNA Damage is the Main Expression of ROS Production and Oxidative Stress • Quantification of sperm Principle DNA strand breaks Specimen • Spermatozoa • Nuclear dyes (Acridine orange, SCSA) Techniques • Direct assessment (TUNEL, COMET) • Sperm Chromatin Dispersion (SCD)Esteves, 26
Sperm DNA Integrity and Assisted Conception Results Live Birth Rates by Pregnancy by Method in Cases Intrauterine of Elevated Sperm DNA Fragmentation Insemination 42% 19% P <0.05 26% OR = 0.07 [95% CI: 0.01-0.48] 1.5% Normal Elevated IVF ICSI 27 Adapted from Bungum et al., Hum Reprod 2007Esteves
Evidence-based Use of Antioxidants in Male Infertility Author Antioxidant Agent ResultsGeva et al., 1996 Vit E 200 mg Increased fertilization in IVFSuleiman et al, 1996 Vit E 100 mg Decreased ROS; increased spontaneous PRWong et al., 2002 Folic acid 5 mg + Zinc Increased total sperm count 66 mgGreco et al., 2005 Vit C 1.0 g + E 1.0 g Improved sperm DNA integrityGreco et al., 2005 Vit C 1.0 g + Vit E 1.0 g Increased CPR and IR in ICSI cyclesTremellen et al., Menevit® (vit C + E; Increased IR/PR in IVF/ICSI2007 zinc 25 mg; selenium 26 cycles mcg; lycopene 6 mg)Boxmeer et al., 2009 Decreased folate in Increased sperm DNA seminal plasma fragmentation
Antioxidant Treatment Cochrane Review 2011 Outcome N N Effect size studies participants (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 6-16 242-700 No effectcount, sperm motilityAdverse 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 et al. What the gynecologist should know about male infertility:Esteves, 30 an update. Arch Gynecol Obstet 2012; Epub March 6
From Initiation of Sperm Production to Ejaculation Old concept ~80 daysNew concept ~60 days Misell LM et al.: A stable isotope-mass spectrometric method for measuring human spermatogenesis kinetics in vivo. J Urol. 2006; 175: 242-6.
Empirical Medical Treatmentfor Idiopathic Male Infertility No demonstrable cause for altered semen parametersAndrogenshCG/HMGFSHAnti-oestrogensBromocriptineAlpha-blockersSystemic corticosteroidsMagnesium supplementation Guidelines on Male Infertility. European Association of Urology 2012
Specific Medical Treatment Overview Novel Obesity-related Male InfertilityEsteves, 33
Obesity in Men at Reproductive AgeEsteves, 34 WHO: Global database on BMI, 2011
Serum Levels of Total Testosterone and Estradiol Normal > 10 T/E2 Ratio 350 𝑛𝑔/𝑑𝐿 Eg.: 4.9 = 62 𝑝𝑔/𝑚𝐿 T/E2 <10 Aromatase Hyperactivity T/E2 Ratio Normalization and Anastrozole 1 mg Sperm Count Improvement 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 AromataseEsteves, 39 inhibitors for male infertility. J Urol 2002; 167: 624.
Medical Treatment for Klinefelter Syndrome Men Seeking Fertility Karyotype: Sperm Retrieval Medical Management Klinefelter Seeking Fertility 47,XXY and ICSI Treatment prior 47,XXY/46,XY to Sperm Retrieval Features: Azoospermia (>90%) Small testes Elevated FSH Low Testosterone Foci of sperm Hypogonadism production (~40%) Elevated testis Sciurano et al., Hum expression Reprod. 2009 aromatase CYP19 Esteves et al. Surgical treatment of male infertility in the era of ICSI – new insights.Esteves, 40 CLINICS 2011; 66:1463-77.
Klinefelter Syndrome Medical Treatment Prior to Sperm Retrieval Series of 68 non-mosaic KS Men with Azoospermia Medical Treatment: Aromatase inhibitor, hCG, CC Positive Response: TT increase of >100ng/dL from baseline 72% Positive Response to Therapy No response 330 P = 0.03 SRR: 72% 220 180 150 SRR: 55% Baseline Testosterone Post-treatment TT Ramasamy et al., J Urol. 2009; 182: 1108-13.Esteves, 41
Specific Medical Treatment Overview Novel Excessive Oxidative Stress Life- style Obesity-related Male Infertility HabitsEsteves, 42
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 effectKlonoff-Cohen H. Human Reproduction Update, Vol.11, No.2 pp. 180–204, 2005
Common Toxicants to Male Reproductive Health Ilicit Drugs Cell Phone Licit Drugs Anabolic Steroids,Cigarette smoking, Marijuana, Cocaine, etc. Electromagnetic Alcohol Radiation Environmental/Nutritional Medication Endocrine disruptors (xenoestrogens Antidepressants (SSRI), Antipsychotics[Polychlorinated biphenyls, bisphenol (Lithium), Antihypertensives (calcium A, Phtalates]), Heavy Metals, channel blockers), Pesticides Cimetidine, Ketoconazole, Finasteride, Antibiotics
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, 45
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.Esteves, 46