MALE INFERTILITY

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DR. Muhammad Ishfaq Postgraduate resident in urology & transplant, Institute of kidney diseases, hmc, Peshawar Pakistan July 2010

CONTENTS

DEFINITION ANATOMY AND PHYSIOLGY ETIOLOGIES EVALUATION TREATMENT

Definition of Infertility
The couple has not conceived after 12 months of contraceptive-free intercourse if the female is under the age of 34. 12 months is the lower reference limit for Time to Pregnancy (TTP) by the World Health Organization.1 Or

The couple has not conceived after 6 months of contraceptive-free intercourse if the female is over the age of 35 (declining egg quality of females over the age of 35 account for the age-based discrepancy as when to seek medical intervention

References
1.

Makar RS, Toth TL (2002). "The evaluation of infertility". Am J Clin Pathol. 117 Suppl: S95103. PMID 14569805.

Male factor 20% May extend from 30-40%, as contributory factor

TESTIS: THE MALE GONAD

VAS DEFERENS EPIDIDYMIS SEMENIFEROUS TUBULE RETE TESTIS

EFFERENT DUCTULE S

PHYSIOLOGY

REGULATION OF H-P-T AXIS

MALE REPRODUCTION: HORMONAL REGULATION

HYPOTHALAMUS GONADOTROPIN RELEASING HORMONE ANTERIOR PITUITARY
ve fe ed ba ck ve fe ed ba ck

FSH TESTES S E R T O L I CELL

LH

LEYDIG CELL

TESTOSTERONE
SPERMATOGENESIS REP.TRACT & OTHER ORGANS

INHIBIN

SPERMATOGENESIS
SPERMATOGONIA (DIPLOID)

MITOSIS

PRIMARY SPERMATOCYTES (DIPLOID)

SPERMATOGENESIS Contd.
PRIMARY SPERMATOCYTES MEIOSIS I

SECONDARY SPERMATOCYTES (HAPLOID) MEIOSIS II SPERMATIDS (HAPLOID)

SPERMATOZOA (HAPLOID)

SPERMIOGENES IS

SEMINIFEROUS TUBULE

Testis:
-Seminiferous tubules Germ cells Sertoli cells

-Interstitium Leydig cells macrophages, endothelial cells

Sertoli cells
Form blood-testes barrier:

Prevents autoimmune destruction of sperm. Produce FAS ligand which binds to the FAS receptor on surface to T lymphocytes, triggering apoptosis of T lymphocytes. Prevents immune attack.

Secrete inhibin. Phagocytize residual bodies:

May transmit information molecules from germ cells to Sertoli cells.

Secrete androgen-binding protein (ABP):

Binds to testosterone and concentrates testosterone in the tubules.

Blood testes barrier

Spermiogenesis

Sperm

sperm

55-65 m in length Three parts head, neck and tail. On the outside of the anterior two thirds of the head is a thick cap called the acrosome that is formed mainly from the Golgi apparatus. It contains enzymes similar to those found in lysosomes hyaluronidase and powerful proteolytic enzymes. These play important roles in allowing the sperm to enter the ovum and fertilize it.

Sperm
The tail of the sperm, called the flagellum, has three major components: (1) A central skeleton constructed of 11 microtubules, collectively called the axoneme (2) A thin cell membrane covering the Axoneme (3) A collection of mitochondria surrounding the axoneme in the proximal portion of the tail (called the body of the tail) Normal sperm move in a fluid medium at a velocity of 1 to 4 mm/min.

SPERM TRANSPORTATION

Sperm motility

Grading is as follows: Grade 0 is no movement, Grade 1 is sluggish movement, Grade 2 is slow movement but not straight, Grade 3 is movement in a straight line, and Grade 4 is terrific speed. Patients with abnormal motility should be evaluated for pyospermia, antisperm antibodies, varicocele, sperm ultrastructural abnormalities, or partial

Contribution in semen formation

Testes sperms (3 to 5%) Epidydimismaturation of sperms,phosphorylcholine,carnitine,sialic acid. Vas deference.. conduit,absorptive and secretive properties . Seminal vesicle.( 40 to 80%of ejaculate) fructose for sperm nutrition, prostaglandins and other coagulating substances, and bicarbonate to buffer the acidic vaginal vault. Prostate ..(10----30% of ejaculate ) enzymes and proteases to liquefy the seminal coagulum. This usually occurs within 20-25 minutes. The prostate also secretes zinc, phospholipids, phosphatase, and spermine Bulbourethral &periurethral gland, (2 to 5 %

ETIOLOGY

Etiology of male infertility

PRETESTICULAR TESTICULAR POST TESTICULAR

PRE-TESTICULAR

HYPOTHALAMIC DISEASES
GONADOTROPIN DEFICIENCY ISOLATED LH DEFECIENCY ISOLATED FSH DEFECIENCY CONGENITAL HYPOGONADOTROPIC SYNDROME

PITUATORY DISEASES

INSUFFICIENCY HYPERPROLACTINEMIA EXOGENOUS HORMONES GH DEFECIENCY

Coital disorders
Erectile dysfunction Ejaculatory failure

TESTICULAR

1. 2. . . 1. 2. . .

Bad semen quality GENETIC Klienfelter syndrome, Y chromosome deletion, Immotile cilia syndrome CONGENITAL Cryptorchidism ORCHITIS Infective Traumatic ANTISPERMATOGENIC AGENTS VASCULAR Torsion Varicocele IMMUNOLOGIC IDIOPATHIC

POST TESTICULAR
1. 2. . . 1. 2. . 1. 2.

OBSTRUCTIVE Epididymal Vasal EPIDIDYMAL HOSTILITY ACCESSORY GLAND INFECTION Prostitis Seminal vesiculitis IMMUNOLOGIC Post vasectomy Idiopathic

Infertility is also thought to be passed on to the son from the father.

FREQUENCY OF ETIOLOGIES
Varicocele Idiopathic Testicular failure Obstruction Cryptorchidism Low semen volume Semen agglutination Semen viscosity Others 37.4% 25.4% 9.4% 6.1% 6.1% 4.7% 3.1% 1.9% 5.9%

HOW TO APPROACH ?

EVALUATION OF INFERTILITY (MALE)

HISTORY PHYSICAL EXAMINATION SEMEN ANALYSIS HORMONE ASSESMENT

70% cases are detected with these

GENERAL EXAMINATION

Height Weight Thyroid Breast Secondary sexual character

LOCAL EXAMINATION

Scrotal volume (N=15-35ml) Testicular volume (N=15-25ml) Epididymis palpation Presence of varicocele P/R examination

Semen analysis

Gland Approximate%Description
Testes 2-5%Approximately 200- to 500-million spermatozoa produced in the testes, are released per ejaculation. seminal vesicle 65-75%amino acids, citrate, enzymes, flavins, fructose (the main energy source of sperm cells, which rely entirely on sugars from the seminal plasma for energy), phosphorylcholine, prostaglandins (involved in suppressing an immune response by the female against the foreign semen), proteins, vitamin C Prostate 25-30%acid phosphatase, citric acid, fibrinolysin, prostate specific antigen, proteolytic enzymes, zinc (serves to help to stabilize the DNA-containing chromatin in the sperm cells. A zinc deficiency may result in lowered fertility because of increased sperm fragility. Zinc deficiency can also adversely affect spermatogenesis.) bulbourethral glands < 1%galactose, mucus (serve to increase the mobility of sperm cells in the vagina and cervix by creating a less viscous channel for the sperm cells to swim through, and preventing their diffusion out of the semen. Contributes to the cohesive jelly-like texture of semen.), pre-ejaculate, sialic acid

WHY PERFORM SEMEN ANALYSIS?

n n n n

Diagnosis of sterility Diagnosis of infertility Prognosis for fertility Identify treatment options:

surgical treatment medical treatment assisted conception treatment

Therefore = a screening test to help direct management.

Oozoa Biomedical Inc, April 2005

Semen analysis

It is not measure of fertility. One source states that 30% of men with a normal semen analysis actually have abnormal sperm function 1 An abnormal test suggest likelihood of decreased fertility. There are certain limits below which it is not statistically possible to initiate pregnancy. Of these sperm count and motility correlate best with fertility.
"Understanding Semen Analysis". Stonybrook, State University of New York. 1999. http://www.uhmc.sunysb.edu/urology/male_infertility/SEMEN_ANALYSIS.html. Retrieved 2007-0805

1.

Semen collection

Period of exual abstinence 48-72 hours. why ? Sperm motility tends to fall when abstinence period is more then 5 days. 2 semen analysis Self stimulation,coitus interuptus(less ideal), special condoms. Analysis within one hour. During transit body temperature.

SEMEN ANALYSIS
Semen Parameters Volume Sperm density Sperm motility Forward progression Sperm morphology forms) normal (<1 million/mL) pH Viscosity Immunobead/MAR Normal range (WHO) (1.5-5.5 ml) (>20 million/mL) (>50%) 2(scale 1-4) (>30% normal >4% Kruger Leukocyte density >7.2 <3(scale 0-4) <10% coated

Sperm parameter reminder

Azoospermia= absent sperm Oligospermia= < 20 mio/cc Asthenospermia= < 50% motility Teratospermia= < 30% normal sperm (WHO) = < 6% normal sperm (Kruger morphology) Main Causes of Decreased Parameters Chromosomal abnormality 15 % (azoo), 5 % (oligo) De novo del of azoosp factor region (AZF) 13% (a/oligo) Cong. Bilat. Abs. of vas deferens (CBAVD) 1-2% (azoo)

ABNORMALITIES

Low ejaculate volume Oligozoospermia Asthenozoospermia Teratozoospermia Olgoasthenoteratozoospermia Azoospermia Aspermia Leucocytospermia Necrozoospermia

Classification of Male Infertility Status by Criteria of Semen Analysis

I. Low Ejaculate Volume

A. Drugs B. Retroperitoneal or bladder neck surgery C. Ejaculatory duct obstruction D. Diabetes mellitus E. Spinal cord injury F. Psychologic disturbances G. Idiopathic H. Incomplete collection

II. Azoospermia

A. Hypogonadotropic hypogonadism 1. Kallmann syndrome 2. Pituitary tumor B. Spermatogenic abnormalities 1. Chromosomal abnormalities 2. Y-chromosome microdeletions 3. Gonadotoxins 4. Varicocele 5. Viral orchitis 6. Torsion 7. Idiopathic

III. Oligoasthenoteratospermia (OAT)

A. Varicocele B. Cryptorchidism C. Idiopathic D. Drugs, heat, toxins E. Systemic infection F. Endocrinopathy

IV. Normal But Infertile

A. Gynecologic abnormality B. Abnormal coital habits C. Acrosomal defects

D.

Antisperm antibodies

E. Unexplained

V. Asthenospermia
A. Spermatozoal structural defects B. Prolonged abstinence C. Idiopathic D. Genital tract infection E. Antisperm antibodies F. Varicocele

Computer-aided semen analysis (CASA)

Apart from previous mentioned,CASA can detect: curvilinear velocity, defined as the average distance per unit time between successive sperm positions. The straight-line velocity, which is the speed of forward direction. linearity, which is the straight-line velocity divided by the curvilinear velocity for research purposes.

Absent or low ejaculate

ABSENT OR LOW EJACULATE VOLUME

RULE OUT INCOMPLETE COLLECTION AND SHORT ABSTINENCE PERIOD

POST EJACULATRY URINALYSIS

+ V E
RETROGRADE EJACULATION

-VE

SYMPATHOMIMETICS/BLADDER WASH/AIH

TRANSRECTAL ULTRASOUND

TRANSRECTAL ULTRASOUND

ABN ORM AL SEMINAL VESICAL ASPIRATION

NOR MAL FAILURE OF EMISSION

+ V E
EJACULATORY DUCT OBSTRUCTION

V E
EJACULATORY DUCT &EPIDYDIMAL OBSTRUCTION

SYMPATHOMIMETIC/ELE CTROEJACULATION

TURED & EPIDYDIDEMOVASOSTOMY

TURED ABSENT OR LOW

Azoospermia

AZOSPERMIA

Testis size Bilateral atrophy FSH low

Hypogonadotrop hic hypo gonadism

Vasa presen t
Normal/unilateral atrophy

Vasa absent

Bilateral vasal agenesis

CFTR testing FSH

MESA/IVF/AID adoption

high
Testicular failure

LH/Prolactin/CT MRI,gonadotropins

TESE/IVF/AI D adoption

Next

CONTD

FSH
Norma l

Abnor mal
Testicular failure

Testicular biopsy

Obstruction

TESE/IVF/AID adoption

Epidyidomovasostom y vasovasostomy

azoospermia

4848

Asthenospermia

ASTHENOSPERMIA

ANTISPERM ANTIBODIES

+V E
IMMUNOSUPRESION/A RT

-VE

< 5 %

MOTILIT Y

Viability assay high Electron microscopy Ultrastructural defects/IVF/ICSI

> 5 %

R/O HEAT,VARRICOCEL Systemic illness,pyospermia

low TRUS NEXT SLIDE

CONTD:

TRUS NORMA L
R/O HEAT,VARRICOCEL Systemic illness,pyospermia

ABNOR MAL
SEMINAL VESICAL ASPIRATION

+ V E EJACULATORY DUCT OBSTRUCTION

TURED ASTHENOSPERMIA

Hormonal study
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HORMONAL STUDY

1. 2.

Indications :
Sperm densities <10millions/ml Evidence of impaired sexual function(impotence,libido). Examination finding suggestive of endocrinopathy(eg thyroid).
On initial testing 10% of infertile male will have an abnormal hormone level with clinically significant endocrinopathy in 2 % of men

3.

Hormonal study

Serum FSH Serum Testosterones.

The combination of tests will detect 99% endocrine abnormalities. Testesterone reflects overall endocrine balance.FSH reflects more on sperm production. Serum LH & Prolactine if teststerone & FSH are abnormal.

Hormonal study

Plasma estradiole for underandronized male. LFTs &TFTs ,RBS etc if there is any evidence of disease.

Hormonal status in clinical Dx Clinical status Germ cell aplasia Testicualr failure HH FSH LH Normal T Normal Normal or

The WHO and Structured Management

(2000)

Oozoa Biomedical Inc, April 2005

RESEARCH & NEW TECHNIQUES

Sperm kinematics

The way sperm swim affects their fertility To get through the cervix, they have to swim in a straight path To get through the outer layer of the egg, they have to generate a lot of power this is seen as hyperactivated motility

Oozoa Biomedical Inc, April 2005

Genetic Evaluation
1.

Karyotype analysis
1. 2.

Abnormal karyotype in ~3-5% of infertile men Klinefelters (47 XXY); 1-2% of infertile men 7-10% of infertile men vs. ~2% of fertile men

2.

Y- chromosome micro-deletions
1.

3.

Cystic Fibrosis (CF) gene mutations

Carrier frequency; ~80% in CBAVD vs. ~30% of infertile vs. ~4% fertile men Pryor et al, 1997, Oates et al, 1992, Mak & Jarvi, 1997 Genetic evaluation is recommended in all infertile men with severe semen parameters in order to assess and prevent possible iatrogenic transmission of genetic mutations
1.

OTHER INVESTIGATIONS

Fructose content of seminal fluid (If absent-Congenital absence of seminal vesicle, Partial duct obstruction, Both) Urologic evaluation Scrotal thermography Post coital test Acrosome reaction assay Capicitation assay Urine for sperm

2nd line investigations

Semen leukocyte analysis Anti sperm antibodies test Hypoosmotic swelling test Sperm penetration assay Sperm chromatin structure Chromosomal studies CFTR Y-chromosome microdeletion analysis

Radiological testing

Scrotal ultrasound Venography TRUS CT scan,MRI Testes biopsy & vasography FNA mapping of testes Semen culture

Testicular biopsy

Azoospermic men with a normal-sized testis and normal fTindings on hormonal studies ; To evaluate for ductal obstruction, To further evaluate idiopathic infertility, and To retrieve sperm. Relative indications For testicular biopsy include ruling out partial obstruction in patients with severe oligospermia. Evaluating patients with hypogonadotropism to select those likely to respond to gonadotropin replacement, and Retrieving spermatozoa in azoospermic patients undergoing IVF or ICSI

Treatment

Assess Expectations for Male Infertility Treatment

What treatments were previously recommended?

Were they followed correctly? What results were obtained?

GENERAL TREATMENT

Education- coital frequency and timing Avoidance of substance/drug abuse Weight reduction Avoidance of hot bath/tight underwear Avoidance of horse riding, cycling

GENERAL TREATMENT
Diet

A diet high in antioxidants such as vitamin C and vitamin E has been proposed to improve the quality of sperm by decreasing the number of free radicals that may cause membrane damage. Additionally, the use of zinc, fish oil, and selenium has been shown to be of benefit in some studies.

Activity

Patients should limit the use of potentially spermatotoxic substances such as cigarettes, marijuana, and anabolic steroids. Environmental exposures to harmful substances and/or conditions should be minimized. The optimal timing to perform intercourse for conception is every 2 days at mid cycle. The use of spermatotoxic lubricants should be

Medications

Testosterone (Andro-LA, Androderm, Delatestryl, Depo-Testosterone) Clomiphene (Clomid, Serophene) Bromocriptine (Parlodel)

Menotropins (Pergonal, Repronex) Stimulate spermatogenesis. Contain 75 IU of FSH and 75 IU of LH per vial.

Human chorionic gonadotropin (Novarel, Profasi, Pregnyl)

PRETESTICULAR(ENDOCRINE)..
Hypogonadotropic hypogonadismPulsatile GnRh, hCG, hMG, Testosteron, Clomiphen citrate, Tamoxifen

Eugonadotropic hypogonadismAromatase inhibitor(Anastrazole) Hypergonadotropic hypogonadismIVF/ICSE, Donor sperm, Adaptation IdiopathicAndrogen, FSH, Clomiphen HyperprolactinemiaDopamine agonists Strict control of DM, Hypothyroid

PRETESTICULAR

COITAL DISORDERS

Erectile dysfunctionPDE5 Inhibitor (Sildenafil)

Retrograde ejaculation, Neurogenic impotence, Severa Hypospadius-

Intrauterine insemination (IUI) For ejaculatory problems phenylephrin or imipramine may be tried

POST TESTICULAR..

Prior vasectomy (most common cause) microsurgical vasovasostomy (better if less than 5 years) Epididymal or vasal obstruction -MESA -PESA -TESE -TESA/FNA -ICSI

TESTICULAR..

CryptorchidismOrchidopexy at 2-3 year of age VaricoceleHigh ligation of internal spermatic vein Gonadal failureSurgical retrieval of spermatozoa, followed by ICSI

Obstructive Azoospermia (OA): Management Options

Reconstructive surgery (vasal, epididymal) Resection of ejaculatory duct (cyst) Sperm retrieval from site proximal to obstruction Genetic counseling for CF patients

Management of NOA (I)

Hypogonadotropic hypogonadism Treatment Initial 1,000-2,500 IU HCG (x2/wk) followed by 75-150 IU HMG (x3/wk) (Finkel,1987) Combination of HCG and HMG (Yong , 1997) GnRH sc or pulsatile infusion (Kliesch,1994) LHRH pulsatile treatment (Shargil,1987) Outcome IHH after puberty showed better results. Sperm count increase in 3-6mos.

Management of NOA (II)

Varicocelectomy Mehan DJ (1976, Fertil Steril) Of 10 azoo men, 2 with varicocele results in pregnency

Matthews G, et al (1998, Fertil Steril) Of 22 with azoo, sperm recovery rate is 55%

Kim ED, et al (1999, J Urol) Of 28 men, 12(43%): mean post-op sperm count 1.2x106 /ml

Indication: severe hypospermatogenesis, MA spermatid stage

Management of NOA(III)

ICSI Ejaculatoy sperm: less invasive,cost effective HH, varicocele, mosaic Klinfelters synd. TESE Presence of spermatozoa in SCO, MA Nonmosaic Klinfelters syndrome (Bourne,1997 , Hum Reprod) ROSI MA spermatid stage

Assisted Reproduction Technology

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What is ART?

Group of high tech treatment methods to improve infertility. Techniques include

In Vitro Fertilization Artificial Insemination Gamete Intra-Fallopian Transfer And many more

ART Treatments for Infertility

A R T

IVF with embryo transfer Gamete intrafallopian transfer (GIFT) Zygote intrafallopian transfer (ZIFT) Cryopreservation Intracytoplasmic sperm injection (ICSI)

American Society for Reproductive Medicine. 2003. American Society for Reproductive Medicine. 2001.

Louise Brown

On July 25, 1978, Louise Joy Brown, the world's first successful "test-tube" baby was born in Great Britain.

History of ART

1978- first successful birth using In Vitro Fertilization 1984- first successful birth using Gamete Intra Fallopian Transfer 1986-first successful birth using Zygote Intra Fallopian Transfer

Methods of sperm retrieval

MESA PESA TESE TESA

IVF with Embryo Transfer

1 2 3

Egg and sperm are retrieved from couple, donor(s), or both Combined in a petri dish, incubated for 25 days If fertilization and cleavage occurs, embryo is transferred through a catheter to uterus

Gamete Intrafallopian Transfer (GIFT)

Oocytes retrieved via laparoscopy

Oocytes and sperm placed in same catheter Injected directly into the fallopian tube via laparoscopy Embryo travels through the fallopian tube to the uterus for implantation

Gamete Intra-Fallopian Transfer (GIFT)

A mixture of a womans eggs and sperm are placed into the fallopian tube during a laparoscopy. Once inserted, fertilization is allowed to occur.

Zygote Intrafallopian Transfer (ZIFT)

Combines techniques used in IVF and GIFT

1 2

Ova are placed in a petri dish with sperm If fertilization occurs, the zygote: Is injected into fallopian tube Travels through tube to uterus Implants in uterus

Zygote Intra-Fallopian Transfer (ZIFT)

Mixture of In Vitro Fertilization and Gamete Intra Fallopian Transfer. Fertilization takes place outside the uterus and placed into the fallopian tubes.

Cryopreservation
Sperm or embryos are preserved by freezing for replacement in subsequent cycles

Photo source: http://www.dcmsonline.org

Intracytoplasmic Sperm Injection (ICSI)

A single sperm is injected directly into the cytoplasm of the oocyte Increases probability of fertilization

Genetic risk of ICSI

Congenital anomaly : Autosomal abberation: <2% Y chromosomal abberation: 13% not results in major anomaly other than infertility Sex chromosomal abnormality Higher in ICSI than natural pregnancy 1%: 47XXY, XXX, 45X, etc (Liebaers,1995) Major malformation in Turner Infertility obligate in Klinfelters synd No major congenital handicaps No increased rate of mental retardation

IUI----intrauterine insemination

First choice for male immunological infertility

IUI----intrauterine insemination

Screening criteria for ICSI or IVF option

Density> 20 millions Motility>20%
SA sperm density

<20 million? ml

HBA screening

HBA > 60%

HBA <60% If not

ICSI

Sperm survival test >10 million/ml Motility>80%

IVF

Hyaluronan Acid Binding by Human Sperm: Assessment of sperm function and sperm selection for ICSI Only live and mature motile sperm will bind to Hyaluronan The sperm plasma membrane need to be incorporated with Hyaluronan and Zona binding receptors

Selecting an ART Program

Qualifications and experience of the clinic and its personnel. Support services available Cost Success rates of that specific program

Conclusion

Male infertility is multifactorial Hormones, physiology, environment, anatomy and DNA all play a role It is the delicate balance of all of these factors that must be weighed in order to optimize male fertility Every evaluation is different and every treatment strategy is geared toward the individual patient and circumstance and must always take into account the female partner

Lets go for a cup of tea, apne kharchey par

THANKS
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