Download - Medical Theraphy of Idiopathic OAT
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!