Transcript of "Advancements in the medical management of male infertility"
EOFF 2012, Dubai, Nov 24th Sandro Esteves, MD, PhD Director, ANDROFERTCenter for Male Reproduction and Infertility Campinas, BRAZIL
Learning Objectives How to revert male hypogonadism and infertility by specific medical therapy Oral antioxidant therapy is a hot topic: what you need to know in 2012 Obesity is a risk factor for male infertility: how to use aromatase inhibitors to increase sperm production 2Esteves
Esteves, SC; EOFF 2012 Review this lecture at:http://www.androfert.com.br/review
Medical Therapy for Male Infertility Overview Specific Non-specific Therapy Therapy Empirical Genital tract treatment for infection idiopathic male infertility Endocrine disorders Antioxidants Aromatase inhibitors Ejaculatory disorders 4Esteves
Medical Therapy for Male Infertility Non-specific Androgens Therapy hCG/HMG FSH Empirical Anti-estrogens treatment for idiopathic male Bromocriptine infertility Alpha-blockers Systemic corticosteroids No demonstrable cause for abnormal semen parameters; ~44% infertile men 5Esteves
Empirical Medical Treatment for Idiopathic Male Infertility In general, NOT EFFECTIVE. Selected cases may benefit of FSH and anti-estrogens Guidelines on Male Infertility. 6 European Association of Urology 2012Esteves
Adult onset hypo-hypo: Medical therapy aimed to restore spermatogenesis and androgenic status Classic Treatment: Urinary hCG 1,000-2,000 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 8Esteves
Adult onset Hypo-hypo: hCG Preparations LH activity Ampoule/ % Protein Source Technology Route of (IU/ampule vial filling contamination administration or vial) method Urinary hCG 1,000- Filled-by- <5% Urine Chemical IM 10,000 bioassay extraction Recombinant 250µg Filled-by- Negligible Transfected Recombinant SC hCG mass CHO cells DNA (FbM) 9Esteves
Clinical Efficacy, Safety and Tolerability of Recombinant hCG to Restore Spermatogenesis and Androgenic Status of Hypogonadotropic Hypogonadism Males Series of 11 azoospermic males with adult onset hypo-hypo Pituitary tumor, Steroid abuse, Testosterone replacement therapy, Encephalic trauma Once a week SC self-administration of 250µg rec-hCG (ready-to-use prefilled 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 Evaluation Restoration of spermatogenesis and androgen production: 10/11 men; No side-effects Baseline Posttreatment 10 Esteves SC, Papanikolaou V; Fertil Steril 2011; Vol 96: S230Esteves
Specific and Non-Specific Medical Treatment of Male Infertility 1. There is little scientific evidence for an empirical medical treatment in idiopathic male infertility. 2. Medical treatment is recommended in cases of Hypogonadotropic Hypogonadism (GR-A) . 11Esteves
Oxidative Stress An emerging explanation 30%-80% of infertile men have for several elevated markers of OS Agarwal et al., Urology 2006 cases of male infertility Seminal Reactive Oxygen Species (ROS) (Log ROS + 1; cpm) 2,5 2 1,5 1 0,5 0 Fertile Infertile Pasqualotto et al., Fertil Steril 2000 12Esteves
Reactive Oxygen Species (ROS) 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 in mitochondria. Sources: Leukocytes (extrinsic) Spermatozoa (intrinsic) Sperm and Seminal Plasma Antioxidants: Enzymatic (SOD, catalase, GPX): inactivate ROS (conversion into other substances) Non-enzymatic (ascorbic acid, alpha-tocopherol, carnitine, etc.): neutralize ROS 13 Lampiao et al., Oxidative stress. In: Male Infertility. Parekattil & Agarwal (eds) 2012, pp.225-35Esteves
Rationale for Oral Antioxidants in Male Infertility AO classified according to their mechanism of action: Catalytic: enhances the already present antioxidant enzymes (Glutathione, NAC). Scavenging: Water soluble: react with oxidants in the cytosol (Vitamin C) Lipid soluble: protect cell membrane from lipid peroxidation (Vitamin E) 14Esteves
Oral Antioxidants 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 effect count, sperm motility Adverse effects 6 426 No effect Improve the outcomes of live birth and pregnancy rate for subfertile couples undergoing ART cycles 15 Showell MG et al. Antioxidants for male subfertility.Esteves Cochrane Database Syst Rev 2011 Jan 19;(1):CD007411.
Sperm DNA Fragmentation and Assisted Conception Live Birth Rates by Pregnancy by Method in Cases Intrauterine Insemination of Elevated Sperm DNA Fragmentation 42% 19% P <0.05 26% OR = 0.07 [95% CI: 0.01-0.48] 1.5% Normal Elevated IVF ICSI 16 Adapted from Bungum et al., Hum Reprod 2007Esteves
Sperm DNA Fragmentation and Miscarriage • Population: Meta-analysis of 16 cohort studies (2,969 couples), 14 prospective. • Techniques for DNA integrity: Acridine orange-based assays, TUNEL and COMET. • Findings: Significant increase in miscarriage rates in patients undergoing IVF/ICSI with high sperm DNA damage compared with those with low DNA damage. Risk ratio (RR) = 2.16 (1.54, 3.03), P < 0.00001). Miscarriage rates are positively correlated with sperm DNA damage levels 17 Robinson L et al. Hum Reprod. 2012; 27(10): 2908-17Esteves
Oral Antioxidant Therapy Controversies Methodological weakness of antioxidants trials make it difficult to determine “who”, “how” and “for how long” • Patient selection and controls • Associated pathology • Single or combination antioxidants • Dosage & formulation • Outcome measures • Varying duration of treatment • Lack of diagnostic markers for oxidative stress • Presence of molecular and genetic differences 18Esteves
Oral Antioxidants in Male Infertility Beneficial No effect Kodama 1997 Giovenco, 1987 Dawson, 1992 Moilanen, 1993 Kessopoulou, 1995 Iwanier, 1995 No consensus yet. Vezina, 1996 Rolf, 1999 Vicari, 2001; 2002 Sigman, 2006 Short-term use Lenzi, 2003; 2004 appear to be safe. Cavallini, 2004 Comhaire, 2005 Detrimental Caution against Grecco 2005 long-term use and indiscriminate use Menezo 2007 high doses; Tremellen 2007 of high dosages for increased mortality in long periods. Piomboni 2008 cancer population- Gil Villa 2009 based studies. Heinonen, 1994 Lonn, 2005 Bjelakovic, 2007 19Esteves
Who are the candidates for Oral Antioxidant Therapy? Infertile men with OS Diagnosis Indirect Assessment • Lipid Peroxidation (Malondialdehyde) • Protein oxidation products (eg. 8-OHdG) • Sperm DNA integrity Direct Assessment • Total Antioxidant Capacity • Seminal ROS Levels • Detection of Superoxide Anion 20 Esteves et al. What the gynecologist should know about male infertility:Esteves an update. Arch Gynecol Obstet 2012; 286(1): 217-29
Quick and Easy Tests for OS Sperm DNA Fragmentation Reactive Oxygen Species Sperm Chromatin Detection of Superoxide Dispersion Test: Anion: ● Sperm with absent “halos” ● Reduction of Nitroblue Tetrazolium have DNA strand breaks in Formazan (coloured intermediate) ● Semen/Spermatozoa ● Semen ● Quantitative ● Qualitative 21Esteves
How to use Antioxidant Therapy Treatment Strategy Once OS is diagnosed, Differentiate between focus on identifying Select antioxidant sperm and leukocyte and controlling source formulation and dosage source of ROS of increased ROS Varicocele Ascorbic acid (Vit. C) Testing for - tocopherol (Vit. E) Genital Infection Glutathione Leukocytes in Semen N-acetyl-cysteine Smoking Carnitine Medication Coenzyme Q10 Drug abuse Lycopene Picnogenol Systemic diseases Pentoxifylline Pollution Selenium Shao-Fu-Zhu-Yu-Tang Radiation Astaxanthin Lepidium meyenii -linolenic acid and lignans Folic acid 22 ZincEsteves
Oral Antioxidants in Male Our formula Infertility Vitamin C 500mg Vitamin E 400 mg Folic acid 2 mg Zinc 25 mg Selenium 26 mcg How long: minimum 2 months From initiation of sperm production to ejaculation Old concept ~80 days New concept Misell LM et al. J Urol. 2006 ~60 days 23 Esteves & Agarwal. Novel concepts in male infertility. Int Braz J Urol 2011; 37 (1): 5-15Esteves
Oral Antioxidant Therapy for Male Infertility 1. Oxidative stress impairs sperm function and is a risk factor for male infertility and miscarriage (GR-A) . 2. Current evidence suggest that OA supplementation for subfertile males improve the chances for pregnancy and live birth for couples undergoing ART (GR-A). 3. Well-designed studies are needed to determine the best candidates for AO therapy and which formulation and dosages yield better results. 24Esteves
Aromatase Inhibitors for Infertile Obese Men Serum Levels of Total Testosterone and Estradiol Normal > 10 T/E2 Ratio 𝟑𝟓𝟎 𝒏𝒈/𝒅𝑳 e.g.: 4.9 = 𝟔𝟐 𝒑𝒈/𝒎𝑳 T/E2 <10 Aromatase Hyperactivity Anastrozole 1 mg q1d 60-90 days Zumoff et al. Reversal of the hypogonadotropic hypogonadism of obese men by administration of 29 the aromatase inhibitor testolactone. Metabolism 2003; 52: 1126. Raman & Schlegel Aromatase inhibitors for male infertility. J Urol 2002; 167: 624.Esteves
Aromatase Inhibitors for Obesity-related Male Infertility Anastrazole (1mg q1d for 3-6 months) 18 15.6 15.6 16 14 P <0.05 12 10 8 5.9 5.5 6 4 2.9 3.5 2 0 T/E ratio Ejaculate volume Sperm Count (mL) (million/mL) Pre-treatment Post-treatment 30 Raman JD, Schlegel PN. Aromatase inhibitors for male infertility. J Urol. 2002;167:624-9Esteves
Aromatase Inhibitors for Obesity- related Male Infertility 1. Obesity is a risk factor for male infertility (GR-B). 2. Peripheral androgen aromatization is enhanced in men with elevated BMI. Obese men show increased plasma estradiol and low testosterone levels (GR-B). 3. Lowering estradiol levels, by administration of AI, increases LH and FSH levels by pituitary modulation, and increase testosterone levels (GR-A). 4. AI may stimulate sperm production (GR-C); effects upon 31 fertility are still to be determined.Esteves
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