Male Factor Infertility

Understanding Male Infertility

At least for half of all cases of childlessness, the male factor is a major contributing reason. This means that about 10% of all men in the world who are struggling to conceive are suffering from infertility.

Historically, infertility has been considered a women’s disease. It is only within the last fifty years that the importance of the male factor contribution to infertility has been recognized. The mistaken notion that infertility is associated with impotence or decreased masculinity may contribute to this fear.

The good news is that the rapid research advances in the area of male reproduction have brought about dramatic changes in the ability to both diagnose and treat male infertility. The majority of couples suffering from infertility can now be helped to conceive a child on their own.

Etiology and Classification of Male Infertility

At present, the accurate cause cannot be determined in most men investigated for infertility. Relationships between testicular damage, semen quality and fertility are not strong. Even genetic disorders may have marked phenotypic variation. For example with microdeletions in the long arm of the Y chromosome testicular histology may show Sertoli-cell only syndrome, germ cell arrest or hypospermatogenesis.

A classification of causes of male infertility based on the effectiveness of treatment is shown in below Table

What’s New in Male Infertility?

Introduction

Infertility is defined as a couple’s inability to achieve pregnancy following one year of appropriately timed and unprotected intercourse. By this measure, it has been estimated that approximately 15-20% of couples struggling to achieve pregnancy are unable to do so.

A female factor is the prime etiology in approximately 40% of these couples and another 30 – 40% is a pure male factor. A blend of male and female factors accounts for the remaining 20% to 30% of cases.

This suggests that in more than 50% of couples presenting for infertility evaluation, a male factor is contributory. Conservatively estimated, this means that 2.5 million American men would potentially benefit from fertility evaluation.

Historically, the approach to the infertile couple has started with an evaluation of the female, primarily because it is usually the female partner who has initiated a workup by consultation with her gynaecologist. It makes more sense, however, to start with the male partner, whose initial evaluation may be accomplished speedily and noninvasively.

Despite the obtainability of advanced reproductive technologies, detection of the problem causing male infertility and institution of directed treatment is possible in most cases. This specific treatment of the “male problem” is now successful, less expensive.

The most important part of the evaluation of the infertile male is the history and physical examination. Even in this era of “high-tech” medicine, it has been our experience that in 90 % of cases an accurate impression is obtained from an initial visit after a thorough history, physical examination, and light microscopic examination of a semen specimen. Further testing usually serves to confirm the diagnosis and help direct the course of therapy.

Fertility History

Prior to arrival at the office, the patient is asked to fill out, at home with the partner, a detailed fertility questionnaire The history begins with an assessment of the couple’s prior and current fertility status. The age of the partners and the duration of unprotected intercourse are established.

Fertility evaluation is appropriate sooner rather than later when the female partner is over age 35 or there has been a history of infertility in a prior relationship or risk factors leading the couple to suspect that a fertility problem exists (eg, cryptorchidism, testicular neoplasm, chemotherapy).

For idiopathic infertility, the chance of eventual achievement is inversely related to the duration of infertility. Female age is a vital factor. It should be recognized as to whether the infertility is primary or secondary for each partner and, if secondary, the nature and outcome of previous pregnancies with the same or any previous partner. Any previous infertility evaluation or treatment for either partner should be noted as well.

Sexual History

In almost 5% of couples donating for infertility evaluation, sexual dysfunction is causative. Is the semen ejaculated into the vagina? Does the couple use lubricants, jellies, oils, or saliva, most of which are known to be somewhat spermicidal? If lubrication is necessary, approximately 48-hr viability of sperm within the female reproductive tract, timing intercourse is essential.

Too regular intercourse or habitual masturbation depletes sperm reserves. The sexual history should also contain an assessment of libido, which roughly reflects serum testosterone levels.

Ejaculate History

The man should be interrogated regarding the nature and volume of a typical ejaculate. An obviously reduced semen volume and clear water like fluid suggest. The absence of the seminal vesicle component is related with either ejaculatory duct obstacle or congenital absence of the vas deferens (CAV).

Normal orgasm with low or absent semen volume should lead one to suspect retrograde ejaculation and warrant examination of a post ejaculatory urine specimen for the presence of sperm. Semen that fails to liquefy suggests prostatic dysfunction. Proteolysis enzymes present in prostatic secretions cause liquefaction of the protein coagulum derived from the seminal vesicles.

Medical History

Cryptorchidism means a hidden testis. It present in about 0.8% of newborn or 1-year-old males is an important risk factor for infertility. Fifty per cent of men with a history of unilateral cryptorchidism and 90% of men with a history of bilateral cryptorchidism are subfertile.

Hernia repair in infancy or childhood is associated with a 3-17% risk of injury to the inguinal or retroperitoneal vas deferens. Post pubescent mumps is associated with a 30% risk of unilateral orchitis and a 10% risk of bilateral orchitis. Which may result in severe abnormalities in spermatogenesis? The approximate age of onset of puberty is ascertained.

Men will usually remember pubertal landmarks only if they were very early or very late. Precocious puberty suggests an adrenal abnormality such as congenital adrenal hyperplasia. Very delayed or incomplete sexual maturation suggests hypogonadotropic hypogonadism (Kallmann’s syndrome when associated with anosmia) or pantesticular failure, such as Kleinfelter’s syndrome.

Any and all conditions or illnesses for which the patient has been or is currently being treated, including all medications currently or previously taken, are documented. Many prescription drugs interfere with spermatogenesis including painkillers and anabolic steroids.

Drugs of abuse such as alcohol, marijuana, and cocaine are directly gonadotoxic. A detailed occupational history is directed toward identifying exposure to gonadotoxic agents such as heat, ionizing radiation, heavy metals, and pesticides.

A family history directed at fertility problems in parents and siblings may be important. Intrauterine exposure to diethylstilbestrol (DES) is also associated with male genitourinary tract anomalies and dysfunction.

Physical Examination

Physical examination is performed in a warm room by an examiner with warm-gloved hands; Contraction of the dartos muscle induced by a cold room or cold examining hands makes the examination of the scrotum and its contents difficult. A proper fertility examination does not consist of casual observation of the scrotum and palpation of its contents. Have the patient completely disrobe and stand with his arms outstretched. Observe the general body habitus and hair distribution.

The respiratory system with suspected genital tract obstructions or immotile sperm, the prostate for ejaculatory duct obstruction or prostatitis, the endocrine system for hypopituitatism or other defects associated with testicular failure, the nervous system for autonomic neuropathy with coital disorders, optic field defects with pituitary tumours, and hyposmia with Kallmann syndrome.

Semen Analysis

Semen specimens are obtained by masturbation into a sterile wide-mouth container after 3 days of abstinence and analyzed within 2 hr. of the collection. Two to three analyses, separated by at least a month, are required for a meaningful evaluation. In the setting of recent febrile illness or exposure to gonadotoxic agents, we would repeat the semen analysis no sooner than 3 months later.

Semen is initially an opalescent coagulum that liquefies within 20-25 min. of ejaculation. The coagulation protein derives from the seminal vesicle. Liquefaction is secondary to the action of prostatic proteases. Failure of liquefaction is due to abnormalities of the prostate or its ducts.

Normal ejaculate volume is between 2 and 6 ml.

Seminal fructose derives from the seminal vesicles. Azoospermia coupled with low ejaculate volume of nonclotting watery fluids fructose-negative usually implies an obstruction of the ejaculatory duct. If the vasa are Palpable a Transrectal Ultrasound can be diagnostic.

Patients who are not azoospermic but oligo- or asthenospermic with a low semen volume may have partial ejaculatory duct obstruction or retrograde specimen is obtained by first having an ejaculation. A post-ejaculatory urine specimen is obtained by first having the patient empty his bladder prior to ejaculation and then voiding following ejaculation into a separate container.

Retrograde ejaculation is commonly seen in diabetics as well as in men who have had transurethral surgery at or near the bladder neck. Manual light microscopic evaluation of sperm concentration, motility, and morphology is still the gold standard.

Computer-assisted semen analysis (CASA) is most useful as a research tool and yet has not provided information that alters therapy. Azoospermic specimens are frequently misread by the computer as oligospermic and computerized morphology has not been perfected. CASA provides interesting information on sperm velocity and angularity that is useful in a research setting. Because pregnancy can be achieved with only one sperm, Specimens originally read as azoospermic should be centrifuged and the pellet examined for sperm.

Specimens with head-to-head or tail-to-tail agglutination are evaluated for anti-sperm antibodies or infection. Infection may be inferred from the presence of leukospermia (>1x 106 WBC/mL). Men with agglutination or leukospermia should have their semen cultured for aerobic and anaerobic organisms as well as Chlamydia and Mycoplasma.

The penis and scrotum should be washed with an antibacterial scrub Prior to culture to avoid inadvertent contamination with skin or faecal flora.

Proper interpretation of morphologic parameters requires an understanding of the scoring system and criteria employed by testing laboratory, broadly viewed; profound abnormalities in morphology are associated with poor fertilizing capacity when strict criteria (Kruger) are used. Men with fewer than 40% perfectly shaped sperm usually failed to fertilize without micromanipulation.

Large numbers of tapered sperm are seen in tests with elevated temperatures, such as varicocele, cryptorchid, or retractile testes, or in the testes of men who take saunas or hot baths.

Antisperrn antibodies bound to sperm are associated with lower pregnancy rates. Risk factors for antibodies include torsion, epididymitis, orchitis, unilateral or partial obstruction, and large varicoceles.

These are all conditions associated with impairment of the blood-testis barrier that usually prevents sperm antigens (which appear at puberty) from being exposed to the general circulation.

An immunobead assay detects antibodies on the sperm and in the serum.

• High levels of antibodies are most often seen with obstruction, in particular before (in serum) and after (in serum and on sperm) vasectomy reversal.
• Low levels of antibodies on sperm and moderate levels in serum are usually seen in men with large varicoceles.

A post-coital test is useful for evaluating sperm-cervical mucus interaction. A fair to good semen analysis associated with a poor post coital test is an indication for intrauterine insemination (IUI). Although IUI can overcome cervical mucus antibodies or decreased counts,

Therefore prior to instituting IUI, we obtain a sperm penetration assay (SPA) that assesses the sperm’s ability to bind and penetrate hamster oocytes, which have been rendered zona pellucida-free. Tests are interpreted as per cent oocytes penetrated or sperm penetrations per oocyte. These tests are not perfect but do correlate about 80% with the ability to penetrate human eggs in vitro.

Semen Analysis Normal Ranges (WHO Criteria, 1992) Semen Characteristics Units WHO (1992)

Endocrine Evaluation

The basic endocrine evaluation includes measurement of

• Serum testosterone (T)
• Follicle-stimulating hormone (FSH)

Testosterone is necessary for the development and maintenance of secondary sexual characteristics and libido as well as initiation and maintenance of sperrnatogenesis. Serum FSH crudely reflects the status of the serniniferous epithelium. Elevated serum FSH results from impaired secretion of inhibin, a Sertoli cell product that normally feeds back at the pituitary and hypothalamus to turn off FSH secretion and suggests abnormalities in the seminiferous epithelium and subsequently spermatogenesis. An FSH level greater than two to three times the upper limits of normal suggests severely impaired seminiferous tubule, but may still be treatable.

• Luteinizing hormone (LH)

LH is stimulatory to the Leydig cells and hence T production. Isolated LH abnormalities are very rare. LH levels need to be obtained only in men with abnormal T levels. Low levels of FSH, LH, and T are diagnostic of hypogonadotropic hypogonadism. These men have a delay or failure in the onset of puberty and therefore poorly developed secondary sexual characteristics and small firm testes. Testosterone replacement will masculinize these men but testicular growth and the initiation of spermatogenesis requires gonadotropin replacement.

Hypogonadotropic hypogonadism is usually due to a pituitary tumour, with the most common pituitary lesion being a benign prolactinoma. These are usually associated with a decreased libido, an elevated serum prolactin level, and decreased serum T and LH levels. Both macro and microadenomas are often best treated with bromocriptine. Serum estrogens, prolactin, and adrenal steroids are only measured if clinically indicated (low serum T, decreased libido, gynecomastia, or a history of precocious puberty).

Men who are partly masculinized have excessively long boundaries due to inattentive or lacking androgen stimulation required for epiphyseal closure at the time of puberty. This is seen in men with hypogonadotropic hypogonadism (Kallmann’s syndrome when related to the absent sense of smell or other midline defects) or Kleinfelter’s syndrome.

After estimation of body habitus, the thyroid is palpated and the heart and lungs auscultated. Chronic bronchitis associated with congenital epididymal dysplasia is seen in Young’s syndrome.

Situs Inversus with linked immotile sperm is seen in immotile cilia (Kartagener’s) syndrome.

The breasts are observed and palpated for gynecomastia, which can be linked with estrogen secreting testicular neoplasms, adrenal tumours, and liver disease. Nipple discharge or rawness may be seen with prolactin-secreting pituitary adenomas.

The abdomen is palpated and percussed. A large varicocele that does not collapse in the supine position warrants a search for an abdominal mass. An enlarged liver suggests hepatic dysfunction, which may be associated with infertility due to altered sex steroid metabolism.

The penis and urethral meatus are examined for condylomata. The urethra is milked for discharge. The location of the meatus is noted. Severe hypospadias may result in inadequate delivery of semen into the vagina.

The scrotal examination is first performed with the patient supine. This allows a varicocele, if present, to collapse; testis size and consistency can then be properly assessed. Use an orchidometer to measure testicular size. Normal testicular volume ranges from 15 to 30 cm. The testes should be firm in consistency. A change in testicular consistency is indicative of testicular pathology. Small soft testes specify poor spermatogenesis.

Small hard testes suggest post orchitis or post torsion atrophy or Kleinfelter’s syndrome. Focal anomalies in reliability raise the suspicion of malignancy. Smooth firm nodules palpated on the surface of the testes usually signify tunica albuginea cysts. Mobile small hard bodies, corpora amylacea, may be palpated floating within the tunica vaginalis. In general, testes that are normal in size and consistency usually have normal sperm production, whereas small-volume, soft testes are associated with impaired spermatogenesis.