Evaluation of the Male for Infertility

Infertility is a major health concern for a large proportion of reproductive age patients. The purpose of this article is to give a concise but practical overview of the evaluation of the infertile man because approximately 40 % of infertility cases involve male factors. Significant medical pathology can now be uncovered by a comprehensive infertility evaluation of the man. Advances in the understandings and diagnoses of male factor infertility is advancing at a rapid pace. The man must not be ignored, and the following information is a guide to his evaluation.

Evaluation

The initial workup begins whenever the patient presents. This is predicted by the fact that the longer a couple remains infertile the less chance there is for cure. A rapid, noninvasive, cost-effective evaluation is essential.

History

The cornerstone of the evaluation of the infertile man is the history and physical examination. Table1 outlines the complete pertinent history. The sexual history is paramount. Some of the problems most commonly encountered in this patient population are related to the timing of intercourse, with it being too frequent or too infrequent. The history of an undescended testicle is significant. In a patient with a history of unilateral cryptorchidism, regardless of the time of orchidopexy, overall semen quality is considerably less than that found in normal men. Bilateral cyrptorchidism is extremely important. Progressive damage occurs to the germinal epithelium if the testicle is not in its proper position in the scrotum. It has been shown that orchidopexy should be performed prior to 2 years of age to maintain a significant level of spermatogenic function. Any previous surgery of the retroperitoneum, bladder neck (prostate), pelvis, inguinal region, or scrotum should be assessed. Any surgery on the bladder neck may cause retrograde ejaculation. Inguinal surgery such as herniorrhaphy, undertaken when an infant or an adult, may have caused vassal occlusion or vascular insufficiency to the testicule. Fever can cause impaired testicular function. The ejaculate may not be affected for more than 3 months after the event, as spermatogenesis takes about 74 days. Postpubertal mumps may cause mumps orchitis, which results in an atrophic testis. Fifty percent of patients with testicular cancer have subnormal sperm densities prior to therapy. A history of diabetes or multiple sclerosis should raise questions about potency and ejaculatory function. Exposure to drugs and toxins should be detailed. The routine use of hot tubs or saunas should be discontinued, as elevated temperatures impair spermatogenesis. A family history of cystic fibrosis is important owing to associated vassal agenesis and epididymal abnormalities. Finally, a history of anosmia (lack of smell) indicates the possibility of hypogonadotropic hypogonadism. Galactorrhea, head-aches, and impaired visual fields suggest the presence of a central nervous system tumor.

Table  No. 1

Infertility History

1) SEXUAL HISTORY 3) PAST SURGICAL HISTORY
  1. Duration of infertility
  2. Previous treatments
  3. Potency  surgery
  4. Timing and frequency of intercourse
  1. Orchietomy
  2. Orchidopexy
  3. Retroperitoneal surgery
  4. Pelvic, inguinal or scrotal surgery \
  5. Herniorrhaphy
2) PAST MEDICAL HISTORY 4) MEDICATIONS AND GONADOTOXINS
  1. Undescended testicles
  2. Testicular torsion / trauma
  3. Delayed puberty
  4. Pelvic injury
  5. Diabetes 
  6. Previous or current therapy 
  7. Viral and febrile illness history
  8. Postpubertal mumps orchitis
  9. Sexually transmitted diseases
  10. Urinary tract infections 
  11. Cystic fibrosis, or family history of it 
  1. Chemotherapeutic agents
  2. Therapeutic drugs
  3. Chemicals (pesticides)
  4. Recreational drugs :smoking, marijuana,cocaine
  5. Androgenic steroids
  6. Thermal exposure (hot tubs)
  7. Radiatio

 

Physical Examination

The physical examination must be thorough, with special attention to the genitalia. The penile curvature and location of the urethral meatus should be assessed, as abnormalities may result in improper delivery of the ejaculate. Testicular size and consistency must be recorded, with the length measured with calipers and the volume estimated with an orchidometer. Size is an important indicator of spermatogenic capability, as more than 80 % of the testis is involved in sperm production. When there is damage to the testicular tubules, loss of mass occurs. The normal length of the testis is about 4 cm and the volume more than 20 ml. Epididymal induration and irregularities should be noted. The presence of a vas must be documented, as 2 % of infertile men have congenital absence of the vas. Varicoceles, that is, dilated spermatic veins that present, as a “bag of worms” above the testicle in the scrotum must be identified. A varicocele can cause abnormalities in gonadal function. The scrotal contents should be palpated with the patient in both the supine and standing positions. Many varicoceles are not visible and may be discernible only when the patient stands or performs a Valsalva maneuver. Varicoceles often result in a smaller testis on that side. Ninety percent are left-sided, and any discrepancy in size between the two testes should arouse suspicion of a varicocele. A rectal examination is essential to assess prostate size, evidence of infection, and the presence of midline cysts. Look carefully for signs of hypogonadism, such as decreased body hair, gynecomastia, infantile genitalia, and decreased muscular development.

Laboratory Evaluation

The laboratory is an integral part of a full-service infertility center. If an on-site laboratory is not available, specimens must be analyzed by a dedicated infertility laboratory. Data from a reputable laboratory are critical . Unfortunately, the semen analysis must be done locally because the specimen must be evaluated shortly after production. Most other studies can be sent out to any reputable laboratory.

Semen Analysis

The primary laboratory test is the semen analysis. It must be emphasized that semen analysis is not a test for fertility. It does not separate patients into sterile and fertile groups; it does give diagnostic information and allows a directed evaluation and treatment. At least two semen analyses must be obtained to establish a baseline. The standard semen analysis allows evaluation of semen volume, pH, density (sperm per milliliter), motility, measurement of forward progression of sperm, and sperm morphology. The semen is examined also for evidence of sperm agglutination, hyperviscosity, and the presence of white blood cells. The World Health Organisation (WHO) range of values for normal semen analysis is given in

Table No. 2

WHO(1999) CRITERIA FOR NORMAL SEMEN ANALYSIS

SEMEN PARAMETER VALUE
Volume 2.0 –5.0 ml
Density >  20 million/ml
Motility >  50 %
Forward progression > 2 (scale 1 – 4)
Morphology > 30% normal forms
Leukocytes < 1 million / ml
Agglutination None
Hyperviscosity None

Some laboratories use computer-assisted semen analyses, which are of some value for measuring sperm motility, however, they should be used only as a source of supplemental information. Attention has been turned to a more accurate manual analysis of sperm morphology.

Leukocytes In The Semen

Leukocytes in semen have significant effects on sperm function. They modulate an autoimmune response, adversely affect motility and fertilizing capacity, and deter sperm transport in the female reproductive tract. The semen of most men contains some immature sperm forms (round cells), which ordinarily cannot be distinguished form white blood cells (WBCs). This often leads to an erroneous diagnosis of pyospermia or infection. Semen cultures are not indicated in asymptomatic patients, as they are essentially always negative. Routine cultures for a typical organisms are unwarranted because they are not always accurate, are labor- and cost-prohibitive, and have not been shown to have a clinical impact. For the few patients with symptoms of urinary or genital tract infections cultures should be prepared. The specific cultures obtained depend on the individuals ‘symptoms’ and examination but should include cultures of urine, expressed prostatic secretions, and a postprostatic massage urine sample. Common sexually transmitted organisms such as Chlamydia, Mycoplasma and Ureaplasma have been implicated in reproductive failure. Patients with active prostaititis or other urinary tract infections frequently have decreased sperm count and motility.

Fructose In The Semen

With low-volume oligospermia or low-volume azoospermia, one should be concerned about retrograde ejaculation and ejaculatory duct obstruction. The assessment for ejaculatory duct obstruction may incorporate a test for seminal fructose, a sugar produced in the seminal vesicles. Its absence may indicate the possible absence of the seminal vesicles or obstruction of the ejaculatory ducts.

Anti-Sperm Antibodies

The incidence of anti-sperm antibodies in the infertile man range from 8 % to 21 %. In men only antibodies present on the sperm surface are clinically important. Anti-sperm antibodies have implications at various stages in the fertilization process, that is, due to poor sperm penetration into cervical mucus; impaired acrosome reaction and zona binding. Risk factors for the development of sperm-bound antibodies include previous testicular surgery, trauma, or infection, as does a history of torsion, cryptorchidism and genitourinary infections. Additionally, obstructive azoospermia (possibly due to obstruction from a previous hernia repair, congenital absence of the vas deferens, or vasectomy) can induce sperm autoimmunity.

Sperm Function Tests

Hypo-Osmotic Swelling Test (Hos Test) : The integrity of sperm cell plasma membrane is essential for endowing fertilizing capability to the sperm. The assessment of plasma membrane function is therefore useful indicator of healthy sperm. The test is based on the principle of hypo-osmotic solutions being passively transferred across intact cell membranes.  Sperm with functionally intact cell membranes swell and their tails undergo coiling when exposed to hypo-osmotic conditions. There is a high degree of correlation between the results of swelling test and fertilizing capacity as measured by the sperm penetration assay.

Acrosome Intactness Test: The acrosome contains a number of enzymes which help human spermatozoa penetrate the outer investments of the ovum. Several functional and ultrastructural acrosomal defects that lead to male infertility have been reported. Acrosome Intactness Test evaluates the functional status of the acrosome and serves as a good indicator of sperm’s ability to penetrate the oocyte’s investments. The test is based on the ability of the proteolytic enzymes of the acrosome to dissolve gelatin when sperm are placed over a gelatin coated slide.

Sperm Nuclear Chromatin Decondensation Test: One of the early events of fertilization following the sperm penetration with the egg is the decondensation of the sperm nuclear chromatin. Sperm with defective heads don’t decondense and are dysfunctional. This test helps in determining the incidence of sperm with defective heads. The test is based on the principle of sodium dodecyl sulphate (SDS) and ethyl diamine tetra acetic acid’s (EDTA) ability to permeate the sperm head membrane and chelate the zinc protecting the disulfide linkages between the nuclear proteins. Exposure of sperm to these compounds facilitates the in vitro decondensation of nuclear chromatin and  thus aids in identifying sperm whose nuclei lack the ability to decondense.

Sperm Mitochondrial Activity Indices (Smai): Respiratory enzyme present in the mitochondria provide energy for sperm motility. The presence of these enzymes can be identified by the Nitroblue Tetrazolium (NBT) reaction. This dye when exposed to mitochondrial enzymes, gets reduced and precipitates to form a blue black compound called formazan. The intensity of the reaction and distribution of formazan are used to determine SMAI which is indicative of the functional status of the sperm mitochondria. Lack of mitochondrial enzymes impair sperm motility and may cause infertility.

Sperm-Cervical Mucus Interaction: The postcoital test assesses the sperm in the partner’s cervical mucus and the interaction between the two. The test is performed just prior to ovulation. A specimen of cervical mucus, obtained within a few hours of intercourse, is examined under a microscope. More than 10 sperm per high power field, most of which demonstrate progressive motility, constitutes  a normal study. Indications for postcoital testing include hyperviscous semen, unexplained infertility and low-volume semen with good sperm density. This test is contraindicated for patients with poor quality semen specimens. Inherent poor reproducibility and the fact that there are specimens from both parties make the study difficule to interpret. If an abnormal result is obtained, an in vitro cervical mucus penetration test may be performed. These tests have been developed to standardize and isolate semen factors.

Sperm Penetration Assay:  The sperm penetration assay is a sophisticated test that measures the physiologic ability of the human sperm to enter a zona-free hamster egg and begin the fertilization reaction. The zona pellucida is the barrier  to cross-species fertilization. When hamster eggs are rendered zona-free and penetrated by human spermatozoa in vitro, they serve as a substitute for human ova in a preliminary assessment of fertilizing capacity. For successful penetration, sperm must be able to undergo capacitation, the acrosome reaction, fusion with the oolema and incorporation into the ooplasm. Scoring is based on the percentage of ova penetrated, or number of penetrations per ovum. The lower limit of normal is 10 – 30 % of ova penetrated.

Hormonal Screening

A brief review of male reproductive endocrine physiology is essential. The testes are dual organs. There is an endocrine (hormonal) component consisting of Leydig cells, Sertoli cells, and germ (sperm) cells. This component is necessary for male sexual differentiation and maturation, normal potency and ejaculatory capability, and spermatogenic maturation. Endocrine and spermatogenic compartments are anatomically and functionally integrated. Proper hormone balance is initiated by a pulsatile hypothalamine release of gonadotropin releasing hormone (GnRH). This causes pituitary release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which have a direct action on the testis. FSH acts on Sertoli cells to provide a favorable milieu for spermatogenesis. LH stimulates the Leydig cell to secrete testosterone, providing the locally high concentration required for spermatogenesis. Serum testosterone reflects Leydig cell function and provides an indication for intratesticular testosterone. Table No.3 depicts the various hormonal patterns and their corresponding clinical entities.

Table  No. 3

Hormonal Patterns And Corresponding Clinical Status

CLINICAL STATUS
FSH LH
T
Normal Normal Normal Normal
Testicular failure Elevated Elevated Normal or Low
Germinal aplasia Elevated Normal  Normal 
Hypogonadotropic hypogonadism Low Low Low

Diagnostic Studies

Scrotal Ultra sonography

The use of ultrasonography to image organs and vessels and to measure blood flow is beneficial during evaluation of the infertile man. Its principal application regarding male factor infertility is for the diagnosis of varicoceles. The diagnosis is based on a venous diameter of 3.5 mm or more with the patient  at rest so he can be scanned  in the supine position. Subclinical varicoceles are approximately 3 mm  in diameter. Color flow Doppler allows determination of the direction and magnitude of blood flow. To detect the change in flow, or reflux, the patient must perform the Valsalva maneuver and may require examination in the standing position. This positioning allows adequate assessement of reflux in the testicular veins, although the accuracy and clinical significance are not absolute. Scrotal ultrasonography and color duplex Doppler are excellent adjuncts in patients with equivocal examinations.

Transrectal Ultrasonography

Transrectal ultrasonography (TRUS) is now being used to detect varying degrees of ejaculatory duct obstruction. It is essentially a noninvasive, inexpensive office procedure that is readily available. Ejaculatory duct obstruction is easily diagnosed, and the results are highly accurate when using TRUS in azoospermic patients with low ejaculate volume. Obstruction is documented by the presence of dilated seminal vesicles more than 1.5 cm in diameter seen on transverse imaging. Additional findings indicating obstruction include midline intraprostatic cystic structures and intraprostatic calcifications along the projected course of the ejaculatory ducts. The absence of seminal vesicles and ampulla of the vas is diagnostic of congenital abnormalities.

Postejaculate Urinalysis

A postejaculate urinalysis to detect retrograde ejaculation should be obtained in patients with anejaculation (no antegrade ejaculate), those with low-volume azoospermia, and all others with low-volume semen samples, including those with oligospermia and normal concentration. The patient voids to completion, produces anejaculate and then immediately voids into a specimen container. The unspun voided specimen is then evaluated. A diagnosis of retrograde ejaculation is confirmed when more than 10 sperm are noted per high power field

Testis Biopsy

Testis biopsy is reserved for patients who have azoospermia, essentially normal-size testes, palpable vas deferens and epididymis and a normal volume of semen. In these cases, testis biopsy allows the differentiation between patients with microtubular obstructive disease who are candidates for microsurgical repair and patients with disorders of sperm development. Testicular biopsy can be performed in the office under local anesthesia. Plain I % lidocaine is used to infiltrate the anterior scrotal skin and dartos layers. With the testicle firmly held in position and the anterior surface up against the scrotal wall, a 1 cm incision is made down to the tunica vaginalis. Holding stitches are placed in the tunica vaginalis and it is opened sharply the length of the incision. An eyelid retractor is placed and additional 1 % lidocaine is dripped on the the tunica  albuginia. A holding stitch is placed in the tunica albuginia, which is then incised approximately 0.5 – 1.0 cm in length. Testicular tubules extrude from the opening and are excised with tenotomy scissor. The tissue is placed in support medium, such as human tubular fluid or Ham’s F-10, for transport to the laboratory. The biopsy is best done where intravenous sedation can be administered. Testicular biopsy remains the gold standard in regard to diagnosis when one is searching for a small number of sperm. With the current use of the Johnson Scoring Technique when reading testicular biopsies, it has become a method of good prognostic value as it afforded a quantitative evaluation of germ cells and leydig cells over and above routine microscopic study. Additionally it permits evaluation of vassal patency, the status of the epididymis and surgical treatment of a varicocele if this was diagnosed per operatively.

Results Of Evaluation

Evaluation of the infertile male categorizes patients. Not only can diagnoses be made (see Table No.4) treatment plans can be discussed and initiated. Both partners should be present during the initial visit and any subsequent visit during which treatment decisions are made. Each case must be individualized with male partner issues, female partner issues, success rates for treatment options, costs, morbidities, and the couple’s expectations being addressed.                   

Table  No. 4

Diagnoses After Evaluation

Diagnosis Patients (%)
Varicocele 37 – 42
Idiopathic 20 - 25
Obstruction 6 - 14
Anti-sperm antibodies   3 - 9
Testicular failure 1 - 9
Pyospermia/infection 1 - 5
Ejaculatory dysfunction 1 – 3
Endocrinopathies 1