DIAGNOSIS & MANAGEMENT OF MALE INFERTILITY

Dr. SHASHWAT K. JANI

Assistant Professor Sheth V.S. Gen. Hospital AHMEDABAD. Mob : 99099 44160 Email : drshashwatjani@gmail.com

INTRODUCTION
The number of couples affected by infertility
is currently estimated to be 15%

Of all couples attempting to have children.

The difficulties are attributable to a significant male factor alone in 30% of couples. additional 20%.

Combination of male and female factors in an

Therefore, in 50% of all infertile couples, an abnormal male factor contributes to reproductive failure.

INTRODUCTION
The primary care practitioner often is the
first health care professional the patient seeks
Absolute critical initial evaluation of the subfertile male.

Thorough history and physical examination Laboratory tests, including at least a semen
analysis Hormonal evaluation.
Appropriate to refer the couple to an infertility specialist.

Definition of "Infertility"
Infertility is a disease **. The duration of the failure
to conceive should be twelve or more months before an investigation is undertaken unless medical history and physical findings dictate earlier evaluation and treatment. ** Any deviation from or interruption of the normal structure or function of any part, organ, or system, or combination thereof, of the body that is manifested by a characteristic set of symptoms or signs, and whose etiology, pathology, and prognosis may be known or unknown: Dorland's Medical Dictionary 1988:481.

Approved by the Practice Committee of the American Society for Reproductive Medicine (Formerly The American Fertility Society), March 27, 1993. Approved by the Board of Directors of the American Society for Reproductive Medicine (Formerly The American Fertility Society), July 17, 1993.

PRE-TESTICULAR CAUSES OF INFERTILITY Hypothalamic disease

Isolated gonadotropin deficiency (Kallmann's syndrome) Isolated LH deficiency ("Fertile eunuch") Isolated FSH deficiency Congenital hypogonadrotropic syndromes

Pituitary disease
Pituitary insufficiency (tumors, infiltrative processes, operation, radiation) Hyperprolactinemia Hemochromatosis Exogenous hormones (estrogen-androgen excess, glucocorticoid excess, hyper and hypothyroidism).

TESTICULAR CAUSES OF INFERTILITY

Chromosomal abnormalities (Klinefelter's

syndrome, XX disorder (sex reversal syndrome), XYY syndrome)Noonan's syndrome (male Turner's syndrome)Myotonic dystrophyBilateral anorchia (vanishing testes syndrome) Sertoli-cell-only syndrome (germinal cell aplasia) Gonadotoxins (drugs, radiation) Orchitis Trauma Systemic disease (renal failure, hepatic disease, sickle cell disease) Defective androgen synthesis or actionCryptorchidism Varicocele

History of the Infertile Male

Male Reproductive

History Duration of unprotected intercourse Previous pregnancies Previous infertility evaluations

Female

Reproductive History Age Gravida/para Physician's name Ovulation with technique to assess Current status of female infertility evaluation

Personal History Developmental Puberty (normal/delayed/pre cocious) History of undescended testes History of gynecomastia

Surgical Pelvic surgery (Y-V plasty to bladder neck, transurethral surgery) Inguinal surgery (herniorrhaphy, orchidopexy)

History

Sexual History Potency/libido Coital technique Timing and frequency of intercourse Use of lubricants

Family History Cystic fibrosis Androgen receptor

deficiency Hypogonadism

Gonadotoxins Chemical exposure (work, therapeutic) Smoking (marijuana, cigarettes) Occupational Thermal exposure (saunas, hot tubs, briefs) Radiation exposure (work, diagnostic, therapeutic)

Medication Maternal (DES) Personal use Steroids Endocrine History Headaches, visual disturbances, anosmia Excessive growth of hands, feet, jaw Retardation of hair growth (facial, body) Breast changes

The duration of the couple's infertility and whether or not other treatment has been attempted
In the past, the fertility evaluations 1 year of unprotected intercourse. Current philosophy Evaluation of one's fertility may properly begin

at whatever time patients express concern, and both the male and female portions of a fertility workup can be undertaken simultaneously in an efficient, cost-effective, and timely fashion.

History of bladder, pelvic, or retroperitoneal surgery

Suggesting the possibility of.. Ejaculatory dysfunction with associated Incomplete or retrograde ejaculation.

Sexual habits
Timing: The optimal timing for intercourse is
every 48 hours & time when ovulation is most likely (usually at the female's midcycle). if necessary,only in limited amounts.

Coital habits:Cautione- to use lubricants only

Spermatotoxic lubricants (such as K-Y Jelly, Lubifax, Surgilube, Keri Lotion) and even saliva can impair sperm motility.

Other lubricants, such as raw egg white,

vegetable oil, safflower oil, peanut oil, and petroleum jelly, do not impair in vivo sperm motility.

Childhood illnesses and disorders

Cryptorchidism: both unilateral and bilateral,
frequently is associated with oligospermia. 30% with unilateral cryptorchidism and 50% of men with bilateral cryptorchidism

have sperm densities below 20 million/mL, 80% with unilateral Cryptorchidism are fertile. fertility rate is only 50% for couples in whom the
male has a history of bilateral cryptorchidism.

testes remaining undescended until after puberty do

not function well and that fertility rates are not improved with postpubertal orchidopexy.

Childhood illnesses and disorders

Testicular trauma or a history of unilateral testicular torsion also may adversely affect the testes. Approximately 30% to 40% of men with a history of unilateral testicular torsion have an abnormal semen analysis. ?? A breakdown in the blood-testis barrier may be the cause The testis susceptible to torsion may have had a preexisting spermatogenic defect (a high incidence of impaired spermatogenesis in the biopsied contralateral testis).

Childhood illnesses and disorders

Delayed or incomplete puberty may reveal an
endocrinologic etiology (such as Klinefelter's syndrome or idiopathic hypogonadism). endocrine problem.

gynecomastia may also suggest an underlying

Bilateral mumps orchitis experienced

prepubertally seems to have no effect, but mumps orchitis experienced postpubertally is associated with severe testicular damage in 10% of patients.

 Diabetes mellitus or multiple sclerosis

can impair potency as well as ejaculation.

Treatment for cancer affects fertility.

treated with radiation or chemotherapy for testis ,any other cancer is at risk of impaired spermatogenesis. Patients with testicular cancer are particularly affected.

Past history of a herniorrhaphy

suggests the possibility of an iatrogenic vasal injury.

Inflammatory process
Any inflammatory process that involves
the lower urinary tract may lead to adverse scarring of the ductal system, obstruction, that may affect fertility. transiently impair spermatogenesis.

e.g., ejaculatory duct stenosis or

Any generalized febrile episode may

 Immotile cilia syndrome (nonmotile

sperm secondary to an ultrastructural defect in the sperm tail) may be the cause of infertility in the male with recurrent respiratory infections (Kartagener's syndrome or Young's syndrome).
without their knowledge by a number of men who may also have congenital absence of the vasa and seminal vesicles and, consequently,

A gene for cystic fibrosis is carried

A low ejaculate volume and azoospermia.

Exposure to elements increasing the overall scrotal temperature

Cryptorchidism Scrotal varicoceles
impaired spermatogenesis associated with these disorders. To optimize their sperm production, men are encouraged to avoid the use of saunas and hot tubs.

Medications, Toxins, and Drugs Associated with Male Infertility

Medications Toxins

Androgenic steroids Antihypertensives Cancer chemotherapy H2 blockers Ketoconazole Spironolactone Cychlosporine Nitrofurantoin Sulfasalazine Colchicine Allopurinol Tetracycline Erythromycin Gentamicin

Agent Orange Anesthetic gasses Benzene Dibromochloropropane Lead Manganese Other Drugs Alcohol Heroin Marijuana Methadone Tobacco

Physical Examination
Body Habitus Decreased body hair
Gynecomastia Eunuchoid proportions

Phallus Scrotum

Peyronie's disease Congenital curvature Hypospadias Testicular volume Epididymal induration Presence/absence of vas deferens Varicocele
Prostate size Prostatic/seminal vesicularmass / induration/cysts

Digital Rectal Examination

Semen Analysis 48 to 72 hours of abstinence. Collection ideally, at the laboratory By masturbation Into a container furnished by the

laboratory that has been tested to ensure that it will not alter the sperm sample's quality. kept at body temperature before.

Should be analyzed within 1 hour and

Semen Analysis Characteristics analyzed are semen

volume, sperm density, sperm motility, forward progression, and sperm morphology. In addition, the sample is analyzed for the presence of leukocytes that might indicate infection or inflammation An aliquot of the sample is air-dried on a slide and stained for determination of sperm shape or morphology. Normal semen samples contain at least 50% morphologically normal sperm.

World Health Organization (WHO) Criteria For Normal Semen Values Volume pH Sperm concentration Viscosity Total sperm count Motility Forward progression Morphology Agglutination 1.5 5.0 ml 7.2-7.8 > 20 million/ml < 3 scale ( 0 4) > 40 million/ejac > 50% >2 scale ( 0 4 ) > 30% normal forms < 2 ( scale 0 3)

Normal biochemical Values

Acid Phosphatase 25,000-60,000 IU/ml Zinc
90-250 mg/100 ml

Fructose

150-600/100 ml

Nomenclature

Aspermia- Failure of formation or emission

of semen Oligospermia/ Oligozoospermia- The count <20 million /ml Poly zoospermia- Count >350 million /ml Azoospermia- No spermatozoa in the semen Asthenospermia- reduction in vitality / Motility of spermatozoa Necrospermia/Necrozooospermiaspermatozoa are dead or motionless Teratospermia/ TeratozoospermiaPresence of high number of malformed spermatozoa

Semen analysis
Color; Whitish grey to yellow tends to be more
yellowish with longer abstinence, genital tract infection-finally reddish in sever form. Odor: Chestnut flowers/amniotic fluid like From oxidation of spermine prostatic gland secretion Coagulation and Liquefaction: within 5-40 mins Coagulative enzyme in seminal vesical Liquefying enzyme Seminine prostate gland.

Agenesis of seminal vesical or occlusion of ejaculatory ducts. Failure to liquefy - Poor prostate lytic activity. Following liquefaction SF achieves viscous state.Hyperviscocity impairs sperm motility.

Complete lack of coagulation

Semen analysis Volume

Hypospermia: Volume <1.5 ml Hyperspermia:>5.5ml Plasma : Vehicle/ Diluent /Buffering medium/Source of energy. Semen volume mainly Seminal vesical secretions. S. Vol.- Androgen defi., proximal occlusion of ejaculatory duct or incomplete ejaculation.

PH

>8 Acute disease of seminal vesical or delayed measurement <7 occlusion of ejaculatory duct occlusion, contamination with urine

Microscopic Examination Motility

Grade 4 Rapid and Linearly progressive Grade 3 Slower sluggish linear or non linear Grade 2 Non progressive motility Grade1 immotile Freshly ejaculated sperm cell velocity 75/s Standardization of temperature

Motility loss of 10-20% with in 3 hr considered WNL.

Automated Semen Analysis

Closed circuit- Video tape-digital data display-1973 Doppler /turbidimetric method -1974-77 Light scattering determination of motility 1978 Multiple Exposure photographic technique Present scenario Cellsoft system: cell size and luminosity The Hamilton Thorn system:infrared beam Provide Data for
Concentration Motility Velocity Linearity Lateral head displacement, circular motio ,Morphology

Biochemical analysis
Epididymal fluidGlycerylphosphorycholine(GPC) & carnitine Inhibin by sertoly cell FSH control Prostate gland fluid ; [Enzymes(Acid Phosphatase etc.), citric acid, Zinc, spermine] Seminal Vesical ; Fructose, Prostaglandines Sperm Creatine phosphokinase

Usual Findings of Hormonal Status Correlated to Clinical Diagnosis

Clinical Status Normal men Germinal aplasia Testicular failure Hypogonadotropic hypogonadism Hypergonadotropic hypogonadism FSH (mIU/mL) Normal Elevated Elevated Decreased LH (mIU/mL) Normal Normal Elevated Decreased Testosterone (ng/100 mL) Normal Normal or decreased Normal or decreased Decreased

Elevated

Elevated

Low-normal or decreased

Additional Laboratory Tests

infertility.

Between 10% and 20% "unexplained"

In the female, this percentage is rapidly

decreasing as more sophisticated techniques have been developed to accurately identify the efficacy of evaluation.

In the male, additional tests to identify

other abnormalities of semen parameters. leukocyte and antisperm antibody identification, as well as tests of sperm function.

Cervical Mucus/Sperm Interaction Assays

The postcoital test (PCT), first performed by Sims,

This test evaluates sperm concentration and motility in an aspirate of cervical mucus at midcycle shortly after the couple has intercourse. a normal PCT- >20 spermatozoa/hpf. An abnormal PCT secondary to inappropriate timing of coitus,ASA, anovulation, an abnormal hormonal milieu, female or male genital tract infections, poor semen quality, and male sexual dysfunction. spermatozoa can survive in the cervical mucus, failure to find motile spermatozoa is more difficult to interpret.

presence of motile spermatozoa indicates that

Computer-Assisted Semen Analysis (CASA)

objective, and standardized evaluation of sperm concentration and movement.

introduced in the 1980s to provide an automated, The variables measured are sperm density, percent

motility, straight-line velocity, curvilinear velocity, linearity, average path velocity, amplitude of lateral head displacement, flagellar beat frequency, and hyperactivation This technology is based on digitalized sperm images that are visualized by a video camera and analyzed by a computer.

OTHER TESTS ARE :

Viability stain assays. Sperm Capacitation Assays, Mannose-Ligand Receptor Assays, Acrosome Reaction Assays Sperm Penetration Assay (SPA) Reactive Oxygen Species (ROS) Assay

Diagnostic studies
Transrectal ultrasound (TRUS) :

1. Standard criteria -

2.

low volume and acidic azoospermic semen specimens. These findings suggest absence of seminal vesicle fluid in the semen consistent with complete ejaculatory duct obstruction. Also, dilated seminal vesicles are suggestive of ejaculatory duct obstruction due to a midline cyst, which may respond to a transurethral resection of the ejaculatory ducts (TURED). Ultrasound guidance may be used during needle aspiration of the seminal vesicles, which may help determine if there is ejaculatory duct obstruction.

Vasography

Performed at the time of testicular biopsy if

normal spermatogenesis is demonstrated. A transverse micro-incision in the vas near the junction of the straight and convoluted portions will allow immediate examination of the effluxing fluid for the presence of sperm as well as localization of the level of obstruction. Saline, Indigo caramine or hypaque or renograffin should be injected in antegrade direction to check the level of obstruction . A microsurgical technique should be used to repair the vasotomy site, i.e., closure with 10-0 and 9-0 monofilament microsutures.

Testicular Biopsy
Performed in patients with azoospermia,severe unexplained
oligospermia,assymetrical testicular lesion,for mapping of the testes for later sperm aspiration for ICSI,for screening of germ cell neoplasia or CIS . Local anesthesia using a cord block and local infiltration often with mild sedation utilized or general anesthesia. A "window" techniqueis used.With a no-touch technique, the specimen is excised with sharp Iris scissors and promptly placed in Bouin's, Zenker's, or buffered glutaraldehyde solution.Prior to placing the specimen into the solution, a touch preparation slide can be made for immediate review, i.e., testicular cytology. Hemostasis is obtained with careful use of electrocautery, and the tunica albuginea is closed with fine, absorbable suture as are the layers of the scrotum.

 Testicular Needle Biopsy: office procedure, with

Testicular Biopsy

little pain and low morbidity, and yields adequate information. Techniques have been described using the Vim-Silvermann26 or Tru-Cut biopsy needle27 to obtain a core of tissue or using fine-needle aspiration with material smeared on the microscope slide.. Testicular Fine-Needle Aspiration (FNA) Cytology: described as a minimally traumatic procedure having high correction with histologic studies. Testicular FNA has not gained widespread acceptance in the evaluation of the infertile male for numerous reasons. Although cellular detail is excellent, information regarding peritubular fibrosis, the interstitial tissue, and cellular arrangement is lacking. Testicular Cytology: "touch imprint and cytospin techniques.These methods provide a rapid means of examining the cellular contents of the seminiferous tubules.

VARICOCELE
Dilatation of the pampiniform venous plexus. 15%of general population Left > right, bilateral (30-50%) Pathophysiology : Renal and adrenal reflux, hypoxia,hormonal dysfunction,hyperthermia. Impaired fertility,scrotal pain,etc. Surgical Rx : Scrotal, inguinal(modified ivanissevich),retroperitoneal(modified palomo)& laproscopic approch. Nonsurgical Rx : Percutaneous venous occlusion with use of detachable balloons,coils,and sclerotherapy 51-78% improvement in semen quality and 2453% pregnancy rate after varicocele Rx.

Pituitary tumors
Mainly prolactin-secreting tumors S/S:-impaired libido,visual field

changes,elevated prolactin,low testosterone,normal LH. Radiographic diagnosis Bromocryptine Surgical Rx: Transsphenoidal surgical ablation or removal

Procedures to Improve Sperm Production

Vasovasostomy:
#Indication: for congenital absence of the ductal system,stricture following infection,vasectomy,functional obstruction. #Technique:under GA,vertical scrotal incision,two layer anastomosis with 9-0 & 10-0 nylon

*Epididymovasotomy: For proximal obstruction If sperm are absent more proximal epididymal exploration is performed Anastomosis with nylon 10-0 in two layers A new technique triangulation end-to-side vasoepididymostomy with good results. *Incision of ejaculatory ducts: Patients with azoospermia or severe oligospermia,low semen volumes,palpably present vas deferens Transurethral incision over ejaculatory duct

*Microscopic epididymal sperm aspiration(MESA): Popularized in 1988 A man in whom sperm transport from the testicle to the the ejaculate in not possible b/o agenesis or obstructive problems. Through an operating microscope,sperms upto 1020million are directly aspirated from a single isolated epididymal tubule Success of pregnancy-25%-40% *Percutaneous epididymal sperm aspiration(PESA): Blind procedure increase the risk of damage Appropriate when pt.has obstruction and desires only one child Low success rate in copmare to MESA

TREATMENT :

A ) SPECIFIC THERAPY. B ) EMPIRIC THERAPY.

SPECIFIC THERAPY :
(A) Hypogonadotrophic hypogonadism :
CC + Gonadotrophins. CC = 25 75 mg on alt. day. For 3 -9 months. First to initiate spermatogenesis: hCG = 2000-3000 iu twice a wkfor 6 -8 wks till testosterone comes to normal. Then , HMG / uFSH / 75iu added thrice a wk and hCG once a wk.

 ( B ) Hyperprolactinemia:
For Pituitary Macroadenoma: Surgically removed. For Microadenoma : Cabergolin 0.5mg 2 mg. twice a wk. Maintain level : 10 15 microgm /ml.

( C ) Genital tract infection: Chlamydia Doxycycline. ( D ) Disorders of ejaculation ( E ) Immunological : no role of steroids. ( F ) Isolated testosterone deficiency: hCG 2000 iu twice a wk. ( G ) Congenital adrenal hyperplasia : dexamethasone 0.5mg HS.

EMPIRIC THERAPY :
1) CC :
25 50 mg for 25 days for 3- 6 months. 2) hCG : 2500 5000 iu twice a wk. 3 ) FSH + hCG: for idiopathic normogonadotrophic oligozoospermia 4 ) Tamoxifen + Testosterone : 20 mg/ day ( for idiopathic oligozoospermia)

5 ) Zinc : Very useful in low testosterone level with Zinc deficiency. 120 -220 mg twice a day for 3 months. 6 ) Ketotifen : histamine release inhibitor . 1 mg BD for 3 6 months. 7 ) Antiserotonin agents : Cyproheptadine HCL 4 mg TID for 3 mnths 8) Captopril : ACE inhibitor . Kinase II inhibitor . 50 mg / day for 3 months.

 9 ) Anti inflammatory drugs :

Doxycycline : 100 mg bd for 14 days. Tetracycline & Metronidazole also effective. Helps in Oligoathenoteratozoospermia. 10 ) Indomethacin : 25 mg tds . increases sperm count & motility. 11 ) Aanastrazole : Aromatase inhibitor 1 mg / day. 12 ) FSH + Nalotrexane : Improve spermatogenesis.

ROLE OF ANTIOXIDANTS:
Systematic treatment of an infertile man with antioxidants has received great interest in recent years and it seems to have some clinical benefit , though the story remains somewhat confused .!!!

 1 ) Vitamin E : ( Tocopherol )
improves motility. 300 600 mg/day for 6 -12 weeks. 2 ) Vitamin C : ( Ascorbic acid ) improves sperm quality & function. 1000 mg / day. 3 ) Vitamin B 12 : Useful for synthesis of DNA & RNA . For oligospermia & Asthenospermia. 1000 1500 microgm / day for 6 months.

 4 ) Folic Acid :
Additive to other drugs to improve function. 5 mg / day. 5 ) Pentoxyphylline : improves microcirculation. improves count & motility. 1.2 mg / day for 3 6 months. 6 ) Arginine : improves motility. 4 mg / day.

 7 ) Selenium :
Antioxidants as well as Anti inflammatory. Concentrated in Male reproductive tract. Highest concentration in prostate. 225 microgm / day. 8) Glutathione : Positive effect on sperm motility. 600 mg IM daily . Not very popular.

 9 ) L Carnitine & L Acetyl Carnitine :

Imp role in sperm cell metabolism. Highest conc. in epididymal fluid. Useful in OAT and low grade varicocle. 10 ) Co enzyme Q10 : Component of mitochondrial respiratory chain. Available as 50 100 mg soft gel capsules that has 100 % absorption.

 11) Lycopene :
Most potent lipophillic anti oxidants and Carotinoid anti oxidants. It protects sperm from damage by ROS .