Medical TheraphyMedical Theraphy of Idiopathic of Idiopathic OATOAT

Hyun-Joo Kim M.D.

Department of Urology

Pochon CHA University

Medical TheraphyMedical Theraphy of Idiopathic OAT of Idiopathic OAT

Current Treatment Modalities

Considerations

Mission

OAT as a Diagnosis? OAT as a Diagnosis?

Concept of OAT FEVER≒

OAT is a Phenomenon !

Criteria of OAT on Semen AnalysisCriteria of OAT on Semen Analysis

Oligospermia <20x106/ml (WHO)severe <5x106/mlcrypto <1x106/ml

a few motile or immotile

Astheno <50% (WHO) severe <10%

Terato <30% (WHO) <14% (Strict Criteria) severe < 4% (Strict Criteria)

Idiopathic v.s SpecificIdiopathic v.s Specific

Specific Causes• Secondary Hypogonadism

• Varicocele

• Retrograde Ejaculation

• Infections

• Immunologic Infertility

Idiopathic Causes• All unknown causes

Prevalence of Male InfertilityPrevalence of Male Infertility

Normal/OAT 84.3%

Azoospermia 15.7%a

Obstructive 6.3%b

Non-obstructive 9.4%c

a. 981/6242 semen analysis (95.9-97)b. 165/416 testis bx (95.9-97) c. 251/416 testis bx (95.9-97) from CHA

Normal/OAT 84.3%

Azoospermia 15.7%a

Obstructive 6.3%b

Non-obstructive 9.4%c

a. 981/6242 semen analysis (95.9-97)b. 165/416 testis bx (95.9-97) c. 251/416 testis bx (95.9-97) from CHA

Prevalence of Abnormal Semen ParametersPrevalence of Abnormal Semen Parameters

All parameter 43% Motility 39% Oligospermia 10% Morphology 8%

from Greenberg, 1987

Specific Causes v.s Idiopathic Specific Causes v.s Idiopathic

Varicocele 39% Obstructive 8% Mechanical 8% Endocrine 6% Developmental 5% Immunologic 1%

Idiopathic 33%

from Schlegel and Pavlovich, 1997

Current Management Modality of Current Management Modality of Idiopathic OATIdiopathic OAT

Pharmacological

Sperm processing

ART

Management Idiopathic OAT:Management Idiopathic OAT:

Pharmacological TreatmentPharmacological Treatment

Hormonal Treatment• GnRH• HCG/HMG• Purified or recombinant FSH• Androgens• Anti-Estrogens

Non-Hormonal Treatment• Kallikrein• Bromocriptine• Anti-Oxidant: Vit. C or E

Spermatogenesis ISpermatogenesis I

Meta-Analysis of Medical Treatment in OATMeta-Analysis of Medical Treatment in OAT

Antiestrogensn=459

FSHn=223

Androgensn=1025

Kinin enhancing agentsn=197

odds ratio

0.25 0.5 1 2 5

Role of FSH ( in Monkey)Role of FSH ( in Monkey) Normal Normal + FSH

Hypophysectomy + T Hypophysectomy + T + FSH

FSH on Spermatogenesis IFSH on Spermatogenesis I

Quantitative Influence• Increase A-pale spermatogonia Spermatocyte, Spermatid

Qualititative Influence• Restore defective spermatozoal maturation (esp. acrosomal cap)

For adequate concentration of intratubular Testosterone

• LH for T, FSH for ABP

FSH on Spermatogenesis IIFSH on Spermatogenesis II

Stimulate Sertoli cell to enhance FSH dependent functions

Support spermatogenesis without interfering

negatively with Leydig cell physiology and

without locally increasing Estrogen level

Modulate intra-testicular paracrine and autoc

rine mechanism

Variable Results of FSH TreatmentVariable Results of FSH Treatment

Dose: may not high enough Frequency : short half-life Duration : too short Reduction in FSH receptor activity Low proliferative activity of A-pale sper

matogonia Elevated endogenous level of FSH

Management Plan for Idiopathic OAT IManagement Plan for Idiopathic OAT I

Considerations: Female factor, Severity of OAT, Previous Treatment, P/E

Oligo: • T.Vol.(normal), FF(-): Empirical Tx > 3mos.• T.Vol.<10cc or FF(+): ART• Severe OAT: ART• A few motile/immotile: ICSI p.r.n) oocyte freezing

Astheno: • >10%, FF(-): Empirical Tx > 3mos. or IUI• <10%, FF(-): Empirical Tx > 3mos. or ICSI p.r.n) T-Bx• 0%: Vital >20-30% : ICSI

Vital <10% : TESE-culture

Management Plan for Idiopathic OAT IIManagement Plan for Idiopathic OAT II

Terato: • General condition control

• Empirical Tx > 3mos. + IUI

Severe Terato: • General condition control

• Empirical Tx > 3mos. p.r.n) IUI or ICSI

• FF(+): ICSI

Treatment of Male Infertility?Treatment of Male Infertility?

Relative Concept of FERTILITY

Consider Cumulative P.R

Natural Pregnancy or ART?

Cumulative Live Birth RateCumulative Live Birth Rate

52.5%/36mos.

25.2%/36mos.

From Kamischke, 1999

Male FecundityMale Fecundity

from Schrader, 1988

Intra-and inter-individual variation of semen parameters in human, coefficient of variation

Semen parameters

COA of Individual

Intra – individual

Inter-Individua

l

Concentration 44 79

Normal forms 14 19

Motile sperm 45 26

Linear progression

16 19

Drugs, Chemical, and Metabolites possible to exert Drugs, Chemical, and Metabolites possible to exert toxic actions on the male gonadtoxic actions on the male gonad

Parent compound Usage MetabolitesAmiodarone anti-arrhythmia DesethylamiodaroneCephalosporin analogues anti-microbial drug N-MethyltetrazolethiolValproic acid anti-epileptic drug Isomers of 2-ethyl hexanol(?)Diethylhexyl phthalate plasticizer Mono-ethylhexylphthalate (MEHP)

(DEHP) 2-ethyl hexanol(?)Dibromochloropropane fungicide Dichloropropene derivatives (?) (DBCP)Ethylene glycol industrial solvent 2-Methoxyacetaldehyde (MALD) monoethyl ethern-Hexane environmental toxicant 2,5-HexanedioneAcrylamide industrial use N-Methylacrylamide,

N-isopropylacrylamideVinclozolin fungicide Butenoic acid derivatives

enanilide metabolite

1. Only substituent is a testicular toxin, not cephalosporin2. Questionable testicular toxin but probably teratogenic from Thomas, 1996

Environmental/Lifestyle factors to affect Environmental/Lifestyle factors to affect male fertilitymale fertility

Cigarette smoke Ingestion of female sex hormones Exposure to heavy metals(i.e. lead, arsenic) Alcohol Marijuana, anabolic steroids, cocaine Cancer chemotherapeutics Radiation exposure Increased testicular temperature Stress Lack of exercise Caffeine

Medical Treatment of OAT : Medical Treatment of OAT : Anti-EstrogensAnti-Estrogens

Medical Treatment of OAT : Medical Treatment of OAT : FSHFSH

Causes of Male InfertilityCauses of Male Infertility

Pre-Testicular • Disorders of H-P-G axis

Testicular• Spermatogenic Defects

Post-Testicular• Epididymal Dysfunction

• Obstructive change of passage

• Infection of Accessary glands

Prevalence of Male InfertilityPrevalence of Male Infertility

Pre-Testicular 8%

Testicular 80% (Idiopathic > 25%)

Post-Testicular 12%

from Sigman, 1987

Spermatogenesis ISpermatogenesis I

Testicular Causes:Testicular Causes: Spermatogenic Defects Spermatogenic Defects

Germ cell Defects

Somatic cell Defects

Communications Defects

Testicular expression of cytokinesTesticular expression of cytokinesCytokines Production Receptor

Leydig cell Sertoli cell Germ cells

IL-1 L, S,G + + +IL-6 L, S, + + ?TNFa G ? + ?IFN P,S,G n n nc-kit ligand S + n +EGF/TGFa L,P,S,G + + +TGFb P,S + + +Activin L,P,S + + +Inhibin L, S + + +IGF-I L,P,S,G + + +FGF L,P,S,G + + +NGF G n + - PDGF L, S + + -

Function of TestisFunction of Testis

Dependent on Gonadotropins and Correct action of local growth factors

Major system• Endocrine System

Local factors• depend on Endocrine system• “act as an adjusted fine local relay for the endocrine system”

Spermatogenic DefectsSpermatogenic Defects

OAT from

Inadequate Gonadotropin activity Imbalance in the intratesticular paracrine

regulation Mystery

Possible Diagnostic Tools of SpermatogenPossible Diagnostic Tools of Spermatogenic Defects ic Defects

Sperm chromosomal study Gonadotropin assay Germ cell and Somatic cell activity study Receptors study

Medical Treatment of idiopathic Medical Treatment of idiopathic OATOAT

For the good results of treatment,

Pt. SELECTION by Correct Diagnosis is mandatory!