DR. RABI NARAYAN SATAPATHYASST.PROFESSORDEPT. OF OBST.& GYNAECOLOGYSCB MEDICAL COLLEGE, CUTTACKMOB-09861281510EMAIL-drrabisatpathy@gmail.com

Relative Prevalence Of The Etiologies Of Infertility

10% 10%

40-50%

25-40%

Both male & femalefactor

Female factor

Male factor

Unexplainedinfertility

Incidence of Male Infertility is increasing ! !Incidence of Male Infertility is increasing ! !

PRESENTATION OF MALE INFERTILITYPRESENTATION OF MALE INFERTILITY

ABNORMAL SEMEN PROFILEABNORMAL SEMEN PROFILE MALE SEXUAL DYSFUNCTION MALE SEXUAL DYSFUNCTION

AZOOSPERMIA AZOOSPERMIA ERECTILE DYSFUNCTION ERECTILE DYSFUNCTION

OLIGOSPERMIA OLIGOSPERMIA EJACUALATORY DYSFUNCTION EJACUALATORY DYSFUNCTION

ASTHENOSPERMIA ASTHENOSPERMIA RETROGRADE EJACULATION RETROGRADE EJACULATION

TERATOZOOSPERMIA TERATOZOOSPERMIA PREMATURE EJACULATION PREMATURE EJACULATION

HIGH LEUCOCYTE COUNT HIGH LEUCOCYTE COUNT LOCAL ANATOMICAL DEFECTLOCAL ANATOMICAL DEFECT

COMBINATIONCOMBINATION

PretesticularPretesticular TesticularTesticular PosttesticularPosttesticular

EndocrineEndocrine Hypogonadotropic hypogonadismHypogonadotropic hypogonadism

Hypothyroidism, Hypothyroidism,

Hyperprolatinaemia Hyperprolatinaemia

DiabetesDiabetes

Coital disordersCoital disorders Erectile dysfunctionErectile dysfunction

Ejaculatory failureEjaculatory failure

GeneticGenetic Klinefelter’s Syndrome Klinefelter’s Syndrome

Y chromosome deletionY chromosome deletion

Immotile cilia syndromeImmotile cilia syndrome

Congenital Congenital CryptorchidismCryptorchidism

Infective (orchitis)Infective (orchitis)

Antispermatogenic agentsAntispermatogenic agents Heat, Chemotherapy, Drugs, Heat, Chemotherapy, Drugs,

IrradiationIrradiation

Vascular Vascular TorsionTorsion

VaricoceleVaricocele

Immunological Immunological

IdiopathicIdiopathic

ObstructiveObstructive EpididymalEpididymal

CongenitalCongenital

InfectiveInfective

VasalVasal

Genetic: Cystic fibrosisGenetic: Cystic fibrosis

Aquired: VasectomyAquired: Vasectomy

Ejaculatory duct obstructionEjaculatory duct obstruction

Epididymal hostilityEpididymal hostility Epididymal asthenospermiaEpididymal asthenospermia

Accessory gland Accessory gland

infectioninfection

ImmunologicalImmunological IdiopathicIdiopathic

Post vasectomyPost vasectomy

ETIOLOGICAL FACTORS IN MALE INFERTILITYETIOLOGICAL FACTORS IN MALE INFERTILITY

CAUSECAUSE PERCENTAGEPERCENTAGE

No demonstrable causeNo demonstrable cause

Idiopathic abnormal semenIdiopathic abnormal semen

VaricoceleVaricocele

Infectious factorsInfectious factors

Immunologic factorImmunologic factor

Other acquired factorsOther acquired factors

Congenital factorsCongenital factors

Sexual factorsSexual factors

Endocrine disturbances Endocrine disturbances

48.5%48.5%

26.4%26.4%

12.3%12.3%

6.6%6.6%

3.1%3.1%

2.6%2.6%

2.1%2.1%

1.7%1.7%

0.6%0.6%

Frequency of Etiologies in Male Factor InfertilityFrequency of Etiologies in Male Factor Infertility

WHO Study 1994, Eshre Capri Workshop Group (7057 men)WHO Study 1994, Eshre Capri Workshop Group (7057 men)

EVALUATION OF MALE EVALUATION OF MALE INFERTILITYINFERTILITY HistoryHistory

Physical examination Physical examination

Semen analysis Semen analysis

Additional proceduresAdditional procedures

- Sperm function tests- Sperm function tests - Immunological tests- Immunological tests - Semen culture- Semen culture - Hormone assays - Hormone assays - Testicular biopsy- Testicular biopsy - Chromosomal analysis - Chromosomal analysis - Vasography- Vasography - Scrotal ultrasound- Scrotal ultrasound - Transrectal ultrasound (TRU)- Transrectal ultrasound (TRU) - DNA integrity tests - DNA integrity tests

HISTORYHISTORY

Age and duration of marriage Age and duration of marriage Occupation –hyperthermia, pesticides, bicycling, stressOccupation –hyperthermia, pesticides, bicycling, stress H/O childhood problems – Cryptorchidism – surgery H/O childhood problems – Cryptorchidism – surgery

Delayed pubertyDelayed puberty Medical History – Mumps, syphilis, leprosy, tuberculosis Medical History – Mumps, syphilis, leprosy, tuberculosis

Chronic respiratory diseases –Chronic respiratory diseases –

Young’s syndrome – epididymal obstruction Young’s syndrome – epididymal obstruction

Immotile cilia syndrome – Sperms are immotile Immotile cilia syndrome – Sperms are immotile

Cystic fibrosis – Congenital absence of VASCystic fibrosis – Congenital absence of VAS

Endocrine disorder, diabetes, hypothyroidism, Endocrine disorder, diabetes, hypothyroidism,

Renal failure, Liver disease, hypertension, multiple sclerosisRenal failure, Liver disease, hypertension, multiple sclerosis

HISTORY (Contd…)HISTORY (Contd…)

Surgical & Traumatic History – Damage of VAS – Surgical & Traumatic History – Damage of VAS – Hernia, Hernia,

Orchidopexy, Vasectomy, Trauma, Torsion, Spinal cord Orchidopexy, Vasectomy, Trauma, Torsion, Spinal cord injuryinjury

Sexual history – Timing, frequency ,conception windowSexual history – Timing, frequency ,conception window H/O–Erectile & Ejaculatory problem - H/O–Erectile & Ejaculatory problem -

Nocturnal penile trumescence (NPT)Nocturnal penile trumescence (NPT) Family history – Family history – History of smoking, alcohol, radiation, heavy metals, History of smoking, alcohol, radiation, heavy metals,

estrogen exposureestrogen exposure Drugs – Antipsychotic, Antihypertensives, Cimetidine Drugs – Antipsychotic, Antihypertensives, Cimetidine

Anticonvulsants, Sex steroids, Environmental Anticonvulsants, Sex steroids, Environmental exposures exposures

PHYSICAL EXAMINATION PHYSICAL EXAMINATION

General – Obesity, Secondary sexual character , gynaecomastia, Body General – Obesity, Secondary sexual character , gynaecomastia, Body habitus, Thyroid gland, Galactorrhoea, Visual field defect, Features of habitus, Thyroid gland, Galactorrhoea, Visual field defect, Features of endocrinopathyendocrinopathy

Per abdomen – Scar of hernia, lymph node Per abdomen – Scar of hernia, lymph node Local examination Local examination * Scrotum- hernia, hydrocele, varicocele * Scrotum- hernia, hydrocele, varicocele * Testes – Present or absent * Testes – Present or absent Size (18-20ml)Size (18-20ml) Sensation Sensation * Penis – Hypospadius, phimosis * Penis – Hypospadius, phimosis * Epididymis & VAS – Presence, feel, presence of cyst * Epididymis & VAS – Presence, feel, presence of cyst

* Rectal examination* Rectal examination

Varicocele

SEMEN ANALYSIS (WHO 1999) SEMEN ANALYSIS (WHO 1999)

Volume Volume > 2ml > 2ml

pH pH 7.2-7.8 7.2-7.8

Sperm concentration Sperm concentration ≥≥ 20milion/ml20milion/ml

Total sperm count Total sperm count ≥≥ 40milion40milion

Motility Motility ≥≥ 50% with normal 50% with normal

morphology morphology

MorphologyMorphology ≥≥ 30% normal forms 30% normal forms

WBCWBC < 1 X 10 < 1 X 1066 / ml / ml

MAR test MAR test < 10% spermatozoa with < 10% spermatozoa with

adherent particle adherent particle

SEMEN ANALYSISSEMEN ANALYSIS

ENDTZ test can distinguish between leukocytes & ENDTZ test can distinguish between leukocytes &

immature germ cells (both round cells) immature germ cells (both round cells)

Sperm vitality test: Sperm vitality test:

* Eosin Nigration test* Eosin Nigration test

* * Hypoosmotic swelling testHypoosmotic swelling test

* H33258 Flurochrome test* H33258 Flurochrome testFructose estimation-Absent in Ejaculatory duct obstructionFructose estimation-Absent in Ejaculatory duct obstruction

Split Ejaculate-Split Ejaculate-

Limitations of WHO criteria

Significant overlapping of sperm characteristics between fertile and infertile men

Sperm motility and concentration are more important than sperm morphology

Change of cut off values and introduction of new parameters are needed to differentiate between fertile and infertile men

Kiran P et al;Fertil Steril, vol 85,No 3,March 2006:629-34

MATURE SPERMATOZOA

SPERM FUNCTION TEST SPERM FUNCTION TEST

Sperm cervical mucus interactionsSperm cervical mucus interactions a. In Vivo – a. In Vivo – Post Coital TestPost Coital Test (Sim’s Hunner test) (Sim’s Hunner test) b. In Vitro – b. In Vitro – I. Sperm cervical mucus contact test (SCMC test)I. Sperm cervical mucus contact test (SCMC test) II. Tube test (Kremar test)II. Tube test (Kremar test) Hemizona test (Human zona binding assay) Hemizona test (Human zona binding assay) Hypoosmotic swelling testHypoosmotic swelling test Swim up testSwim up test Computerised assisted seminal analysis (CASA)Computerised assisted seminal analysis (CASA) Evidence of acrosomal reactionEvidence of acrosomal reaction

IMMUNOLOGICAL TESTS IMMUNOLOGICAL TESTS

Indications –

• Abnormal semen profile

• Abnormal cervical mucus sperm interaction

• Failed Vasectomy reversal

• Marked Agglutination (more than 10%)

Two Tests –

a. Immunobead testa. Immunobead test

b. MAR testb. MAR test

c. Others – TAT test, Kibrick’s test, Frankling Duke test, Isojama’s

test (Not done now a days)

MIXED AGGLUTINATION REACTION (MAR) TEST

Screening test for detection of antisperm antibodies on the surface of sperm head or tail.

Washed sperms from the patient are mixed with antibody coated RBC, (Sheep RBC + rabbit antibody)

These antibody will form mixed agglutinates with motile sperms carrying immunoglobulins

MAR test is positive when particulate binding is found in over 10% spermatozoa.

HORMONE ASSAYS HORMONE ASSAYS Indication-Indication- when Sperm count is less than 10 when Sperm count is less than 10

million/mlmillion/ml

FSHFSH LHLH TestosteroneTestosterone Estradiol Estradiol Prolactin Prolactin TSHTSH

HORMONAL CONTROL OF SPERMATOGENESISHORMONAL CONTROL OF SPERMATOGENESIS

HypothalamusHypothalamus

GGnnRHRH

Anterior PituitaryAnterior Pituitary

FSHFSH LHLH

Sertoli cellSertoli cell Leydig cellLeydig cell

InhibinInhibin ABGABG TT

ABG+TABG+T

- Ve- Ve - Ve- Ve

- Ve- Ve

SpermatogenesisSpermatogenesis and and spermsperm maturationmaturation

Hormones in different clinical Hormones in different clinical conditionsconditions

FINDINGS FINDINGS DIAGNOSISDIAGNOSIS

1.1. Azoospermia or OligospermiaAzoospermia or Oligospermia

Small testes Small testes

FSH - HighFSH - High

Primary testicular failure Primary testicular failure

(Severe tubular damage) (Severe tubular damage)

2. Azoospermia2. Azoospermia

Normal testicular volume Normal testicular volume

FSH – Normal level FSH – Normal level

i. Bilateral genital tract obstruction i. Bilateral genital tract obstruction

ii.Sertoli cell only syndrome ii.Sertoli cell only syndrome

3. FSH – Lower or undetectable 3. FSH – Lower or undetectable

LH – LowLH – Low

Testosterone – Low Testosterone – Low

Other evidences of androgen def. Other evidences of androgen def.

Hypogonadism Hypogonadism

4. LH – High4. LH – High

Testosterone – High Testosterone – High Androgen receptor defect Androgen receptor defect

TESTICULAR BIOPSYTESTICULAR BIOPSY

Obstructive AzoospermiaObstructive Azoospermia Non Obstructive Azoospermia – To detect isolated Non Obstructive Azoospermia – To detect isolated

areas containing sperm cells for TESE – ICSIareas containing sperm cells for TESE – ICSI

Grading – Johonson’s Scoring System ( 1 – 10)Grading – Johonson’s Scoring System ( 1 – 10)

2 – Sertoli cell only2 – Sertoli cell only

3 – Spermatogonia3 – Spermatogonia

4,5 – Spermatocytes 4,5 – Spermatocytes

6,7 – Spermatids 6,7 – Spermatids

8,9,10 – Spermatozoa 8,9,10 – Spermatozoa

Histology Of Normal Testis

Histology of seminiferous tubule

GENETIC ANALYSIS GENETIC ANALYSIS

IndicationsIndications Azoospermia, Severe Oligozoospermia, Azoospermia, Severe Oligozoospermia,

VarietiesVarieties Klinefelter’s Syndrome (47XXY), Sex Reversal Klinefelter’s Syndrome (47XXY), Sex Reversal

Syndrome (46 – XX male) Syndrome (46 – XX male) Deletion of a part of Long arm of Y containing Deletion of a part of Long arm of Y containing

azoospermic factor (AZF) means Azoospermia azoospermic factor (AZF) means Azoospermia Mutation of specific gene like mutation of CFTR geneMutation of specific gene like mutation of CFTR gene

in cystic fibrosisin cystic fibrosis

Y Chromosome in Azoospermic men

Solid bars indicate presence of genetic material

Dashed regions indicate missing of genetic material in NOA men

Y-chromosome deletion in AZFb region indicates absence of sperms in sperm retrieval procedure

Sex Chromosome Abnormalities Leading Sex Chromosome Abnormalities Leading to Male Infertility to Male Infertility

Syndrome Karyotpe abnormalities Phenotype

Klinefelter’s syndrome 46, XY/47, XXY mosaic, 47, XXY – 49, XXXY

Male with increased height, small firm testes possibly female hair distribution

Mixed gonadal dysgensis 45, X/ 46, XY mosaic, possibly normal 46, XY

Male, female, or ambiguous genitalia, testis are streak

XX male syndrome 46, XX SRY translocation to the short arm of X

Male with Sertoli-cell-only on testis biopsy

XYY male 47, XYY Male, possibly increased height

TREATMENT MODALITIES OF MALE TREATMENT MODALITIES OF MALE INFERTILITYINFERTILITY

• General Measures General Measures

• Medical ManagementMedical Management

• Surgical Management:- Surgical Management:- Vasovasostomy, Epididymovasostomy, Vasovasostomy, Epididymovasostomy,

Repair of varicocele, Orchidopexy, Surgery forRepair of varicocele, Orchidopexy, Surgery for Hypospadius Hypospadius

• Artificial Insemination:-Artificial Insemination:- Intrauterine insemination (IUI)Intrauterine insemination (IUI)

• Assisted Reproductive Technology:-Assisted Reproductive Technology:- IVF & ET, IVF & ET,

Intracytoplasmic sperm injection (ICSI),Intracytoplasmic sperm injection (ICSI), PESA, MESA & PESA, MESA & TESE – TESE – ICSI, GIFT, ZIFTICSI, GIFT, ZIFT

• Management of Male Sexual DysfunctionManagement of Male Sexual Dysfunction

Medical ManagementMedical Management

• Hormonal – Hormonal – HCG, HMG, GHCG, HMG, GnnRH, Testosterone, CC, RH, Testosterone, CC,

Thyroxine, BromocryptineThyroxine, Bromocryptine

• Antibiotics, Corticosteroids, Aromatase inhibitorAntibiotics, Corticosteroids, Aromatase inhibitor

• Sperm Vitalising Agents – Sperm Vitalising Agents – Pentoxifylline, KallikreinPentoxifylline, Kallikrein

• Emperical TherapyEmperical Therapy

• AntioxidantsAntioxidants – In increased ROS – In increased ROS

Oxidative stress status in an ejaculate. Oxidative stress status in an ejaculate.

Pro-and anti-oxidative molecules have antagonistic Pro-and anti-oxidative molecules have antagonistic functions in semenfunctions in semen

Vasectomy Reversal

Vasovasostomy

Repair of Vericocele

Verecocelectomy-Testis is delivered to ligate internal spermatic veins

INTRAUTERINE INSEMINATION

(I U I)

Washed sperms are injected inside the

uterine cavity in stimulated cycle with proper monitoring of ovulation

Both fresh or frozen sperm can be used

Male: SEMINOPATHIES – OLIGOSPERMIA,

ASTHENOTERATOSPERMIA, LOW VOLUME SEMEN, HIGH VISCOUS SEMEN

ERECTILE FAILURE, EJACULATORY FAILURE, PREMATURE EJACULATION, RETROGRADE EJACULATION

Female: CERVICAL FACTOR ,OVULATORY

DYSFUNCTION,ENDOMETRIOSIS,VAGINISMUS UNEXPLAINED INFERTILITY IMMUNOLOGICAL INFFERTILITY

INDICATIONS OF I U I

STEPS OF INTRA-UTERINE INSEMINATION

Ensure tubal patency Semen analysis & culture

Ovarian stimulation Sperm Collection

Monitoring of ovarian Response & fixation of Sperm processingOvulation time

Insemination & Luteal support

SWIM – UP TECHNIQUESWIM – UP TECHNIQUE

Semen processing media(Ham’s F-10)Semen processing media(Ham’s F-10)

&&

SEMEN SAMPLESEMEN SAMPLE

INCUBATE AT 370C

30 MINUTE

Liquefied semen sample

Equal Quantity of MEDIA

Aspirate upper & middle part

In another centrifuge tube

Centrifuge at 2000 RPM

FOR 1 MINUTEDiscard supermatant & Leave pellet

Centrifugation

at 2000 RPM

15 minute

Mix

wellDiscard supernatant

& leave pellet

MEDIAPellet

Keep the tube inclined at 300

In incubator at 370c

For 45 minute

Layer 2 ml Media

Over Pellet

Add 0.5 ml. Semen processing media

& mix well

Sample ready for IUI

SINGLE LAYER DENSITY GRADIENT CENTRIFUGATION TECHNIQUE

* DENSITY GRADIENT MEDIA

* SPERM WASHING * SEMEN SAMPLE

MEDIA (Han’s F10)

INCUBATE AT 370C

30 MINUTE

Centrifugation

At 2000 RPM

LIQUEFIED SEMEN

D.G. Media

15 minute

Disard Supermatant Centrifugation at 2000 RPM Pellet with 2ml Add 2ml. Spermwashing

& Leave pellet 5 minute Spermwashing medium

Medium mix well with pellet Discard supermatant & leave pellet

Add 0.5 ml. Of sperm washing medium

Mix well with pellet

Pellet with

0.5 ml. Sperm washing medium

Keep at 370c

10-15 minute Sample ready for IUI

SWIM UP TECHNIQUE Vs LAYER TECHNIOUE Simple Less expensive Not suitable for

abnormal semen sample

Time consuming

Not so simple More expensive For seminopathy it is

better Less time is needed

RESULTS OF IUI

CLINICAL PREGNANCY – 10-25% IN AIH 20-40% IN AID

20-25% END IN MISCARRIAGE

Gamete Micromanipulation

P Z D-Partial Zona dissection

S U Z I-Subzonal dissection of sperm

I C SI-Intracytoplasmic sperm injection

Intracytoplasmic sperm Intracytoplasmic sperm injection (ICSI)injection (ICSI)

It involves the direct insertion of a single sperm cell into It involves the direct insertion of a single sperm cell into the cytoplasm of a single oocyte by micropuncturethe cytoplasm of a single oocyte by micropuncture

Indications – Indications –

Severe OATSevere OAT

ObstructiveObstructive azoospermiaazoospermia by MESA, PESA,TESA by MESA, PESA,TESA ````Nonobstructive azoospermiaNonobstructive azoospermia (NOA)(NOA) by TESE by TESE

Unexplained infertilityUnexplained infertility

Source of Sperms for ICSI

EJACULATED SPERMS

MESA: Microsurgical Epididymal sperm aspiration

PESA: Percutaneous Epididymal sperm aspiration

TESE: Testicular sperm extraction

TESA: Testicular sperm aspiration

Distribution of sperms in tubules of epididymis in obst. azoospermia Proximal part contains

maximum good sperms Distal part (identified by

yellow colour) contains less and damaged sperms

P E S A

M E S A

Testicular Fine Needle Aspiration (TESA--TFNA)

PercBiopsy

MULTIPLE LARGE TEST. BIOPSY

T E S E Microsurgical

Conventional

ICSI Laboratory

ICSI IS GOING ON (IRM, Kolkata)

RESULTS OF ICSIRESULTS OF ICSI

Fertilization rate - Fertilization rate - 60-70%60-70%

Pregnancy rate – Pregnancy rate – 20-40%20-40% /Embryo transfer /Embryo transfer

Male partner having abnormal karyotype in Male partner having abnormal karyotype in

Y-Chromosome micro deletion should undergo Y-Chromosome micro deletion should undergo genetic counselling before ICSIgenetic counselling before ICSI

TREATMENT OF OLIGOASTHENOTERATOZOOSPERMIA TREATMENT OF OLIGOASTHENOTERATOZOOSPERMIA (OAT)(OAT)

Infective

* Antibodies

Immunological

* Corticosteroid

* Condom

Endocrinal

* GnRH

* hCG

* hMG

* Testosterone

* CC

* Bromocryptine

* Thyroxin

Idiopathic

* CC

* Empirical

*Antioxidants

If FailsIf Fails

* IUI

*ART

TREATMENT OF AZOOSPERMIA

Azoospermia

Obstructive

* Surgery

* Epididymal sperm

Aspiration (MESA, PESA)

IVF-ET

GIFT

ZIFT

ICSI

* TESE – ICSI

* TDI

Non obstructive

* TESE – ICSI

* TDI

Endocrinal (Rare)

* GNRH

* HCG

* HMG

* CC

Treatment of Erectile and Ejaculatory Dysfunction Erectile Dysfunction

* Withdrawal of drugs

* Treatment of underlying cause * Psychosexual therapy * Local injection ,Vacuum pump * Transurethral pellet ,Penile implant * Sildenafil(Viagra),Tadalafil,Vardenafil

Ejaculatory Dysfunction * Psychosexual therapy * Vibrator * Electro-Ejaculation

Retrograde Ejaculation * Coitus in full bladder * Alphaadrenergic or cholinergic drugs * Insemination with post-voided urine after processing

Premature Ejaculation * Use of condom

* Pelvic Floor exercise * Squeeze techniques * IUI with ejaculated sperm

CONCLUSION

Male factor is involved up to half of infertile couples

Thorough evaluation is needed to detect the abnormality.

There are only few cases in practice where specific drug therapy is indicated

Though IUI is an effective procedure it has little role in severe OAT.

ICSI has revolutionized the management of male

infertility. But it is a very expensive procedure

CONCLUSION (Contd…)

Sexual dysfunction should always be enquired and be dealt with sympathy

Vibrator and Viagra are two effective tools available in ejaculatory and erectile failure

More research is needed to know paracrine regulation of spermatogenesis and to develop newer treatment to improve sperm parameters in VIVO

Irrespective of problems adoption of general measure is important in achieving pregnancy