Definitions

Infertility is an inability or reduced ability to produce a pregnancy within a reasonable period of trying, usually 12 months. Sterility is a total inability to produce a pregnancy, and this may be reversible or irreversible. Subfertility is infertility without an absolute barrier to reproduction that would cause sterility, such as azoospermia. Hypogonadism is a nonspecific term for decreased testicular or ovarian function that could include a disorder of gamete production or function, or a disorder of sex hormone production or action. Usually hypogonadism indicates testicular failure associated with androgen deficiency. Primary hypogonadism results from disorders that affect the gonads directly and secondary hypogonadism results from defective pituitary gonadotropin secretion.

Incidence and Distribution

The average pregnancy rates in most human communities range from 15 to 30 per cent in the first month and decline in each subsequent month of trying. About 50 per cent of couples conceive a first pregnancy by 3-5 months and 85 per cent by 12 months [1]. Couples trying for a subsequent pregnancy have higher rates: 33 per cent in the first month and 50 per cent within two months [2]. Recently, there appears to have been an increase in pregnancy rates in the first few months of trying, possibly because of a more general awareness in the community of the timing of ovulation and the fertile phase of the menstrual cycle [3]. The 12 month period used to define infertility means that it afflicts about 15% of couples [1, 2, 4]. Infertility is thus common, the male contribution is substantial, and medical intervention is increasing. It is estimated that 0.6% of the 1995 health budget of Canada was used for infertility [4].
Infertility results from female disorders (anovulation, tubal obstruction, or other pathology) in about 30 per cent, a male disorder in 30 per cent, and disorders in both partners in 30 per cent. No abnormalities are found in about 10 per cent. Because male and female factors frequently coexist, both partners of the infertile couple are investigated and managed together [5, 6].

Etiology and Classification of Male Infertility

At present the precise cause cannot be determined in most men investigated for infertility [4, 5, 7]. 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 [8]. A classification of causes of male infertility based on the effectiveness of treatment is shown in Table 1. In this classification the effectiveness of treatment means medical intervention known to or proved by clinical trial to improve the chances of the man producing a conception by coitus or artificial insemination and does not include the use of IVF or ICSI to bypass the impairment.

CLINICAL EVALUATION

Patients with irreversible sterility can be separated from those with potentially treatable conditions or subfertility usually with standard clinical evaluation and some simple investigations (Table 1).

History

It cannot be overemphasized that both members of the couple need to be involved in the assessment and discussion of the results. The emotional reaction of the couple to the diagnosis of infertility may interfere with clinical evaluation and management. Intimate information may not be disclosed while the couple is embarrassed, hostile, or confused. Previous sexually transmissible infections or pregnancy may be concealed from the partner.

Nature and Duration of Infertility
Previous pregnancies and time taken to conceive each pregnancy and duration of infertility are important prognostic factors. The couple may be aware of an infertility-related problem, such as past undescended testes or orchitis. Some who present with a short duration of infertility may be unaware of the normal human pregnancy rates. The plan for investigation depends on the possibility of finding remediable abnormalities and on the age of the female partner.

Family History
The family history should be considered but may not be known because infertility is often not discussed openly. Increasing numbers of chromosomal and genetic causes for male infertility are being discovered (Table 2) .[9] The most important genetic causes include Kallmann syndrome [8-10], myotonic dystrophy, androgen receptor defects [8, 11], gonadotropin and gonadotropin receptor defects,[10, 12-14] cystic fibrosis and bilateral congenital absence of the vasa (BCAV)[15-18] and Yq microdeletions [8, 19-21]. While some of these cause sterility and are recessive disorders or de novo mutations, others may only affect fertility slightly. There are many paediatric syndromes which involve hypogonadism or undescended testes in association with ambiguous genitalia, multiple malformations or mental retardation but patients with these generally do not present for management of infertility. Other genetic diseases may be associated with infertility for example haemoglobinopathy, Huntington disease, polycystic kidneys, and mitochondrial disorders.[9] Predispositions to certain conditions may also have a genetic basis such as the anatomical variant of the tunica vaginalis which predisposes to testicular torsion, the association of Young syndrome to mercury poisoning in infancy and the familial aspects of sperm autoimmunity. Men with sperm autoimmunity have increased frequencies of both family histories of organ-specific autoimmune diseases and autoantibodies to thyroid and gastric parietal cells in their serum.[22, 23] Furthermore, brothers of men with poor semen analysis results are more often infertile than expected.[24] Thus it is postulated that genetic causes or predispositions will be found for most male infertility. However, genetic factors are not clear for the common types or associations of male infertility: idiopathic oligospermia, asthenospermia, teratospermia or varicocele and past undescended testes.

Coital Adequacy and Timing
Information on impotence and ejaculatory disturbances is important because intravaginal deposition of semen near the time of ovulation is crucial for fertility. Infrequent coitus is common in couples seen for infertility. Low libido may result from androgen deficiency, general illness, or a psychological reaction to the infertility. Disorders of ejaculation have recently been reviewed by Jannini et al (Jannini, EA; Simonelli, C; Lenzi, A.  Disorders of ejaculation.   J Endocrinol Invest              25           1006-1019            2002.).

Childhood and Pubertal Development
Treatment in childhood for penile or scrotal disorders (e.g. hypospadias, epispadias, urethral valves, undescended testes, inguinal hernia, or hydroceles) could be relevant. Sexual maturation may be delayed and incomplete with primary or secondary hypogonadism. There may have been associated growth problems that required treatment. Early puberty and growth resulting in short stature suggest congenital adrenal hyperplasia.[25, 26]

General Health
Any illness, acute or chronic, can impair sperm production in a nonspecific manner.[27] Acute critical illness such as severe trauma, surgery, myocardial infarction, burns, liver failure, intoxication, or starvation, is often accompanied by suppression of gonadotropin secretion and secondary hypogonadism. In contrast, a primary testicular disorder with elevated gonadotropin levels may occur with chronic illnesses. Increased peripheral conversion of androgens to estrogens may produce some features of feminization such as gynecomastia. The association of hypogonadism and feminization with chronic liver disease is well known. Similar hypogonadism may occur with other chronic illnesses such as chronic anemia, chronic renal failure, rheumatoid arthritis, chronic spinal cord injury, thyroid diseases, Cushing's syndrome, obesity, HIV infection and neoplasia. Sex hormone binding globulin levels are increased with some conditions such as cirrhosis and thyrotoxicosis but suppressed with others such as obesity, hypercortisolism and hypothyroidism.[27] Numerous drugs have side effects on the reproductive system.[27] Heroin addiction and intrathecal narcotic infusions to control chronic pain suppress LH secretion.[28, 29] Fever can cause transient declines of a few months' duration.[30] Diabetes mellitus may be associated with impotence in early uncontrolled stages, ejaculatory disorders with autonomic neuropathy, and sperm autoimmunity. Men with renal disease may have infertility of multifactorial origin, including testicular failure from chronic illness, cytotoxic drug exposure, zinc deficiency, and damage to the vasa or penile blood supply during kidney transplantation. However, as with cirrhosis, provided that metabolic decompensation is not severe, semen quality often is adequate for fertility [27]. Epididymal obstruction associated with chronic sinopulmonary disease (Young syndrome) was diagnosed frequently in Australia and the United Kingdom in the past yet is rare elsewhere[31]. Some cases of Young syndrome may have been caused by mercury poisoning in childhood from calomel containing teething powders[32]. These were withdrawn from the market in the mid 1950s when it was found that they caused Pink disease and Young syndrome is seen less commonly. Bronchiectasis and sinusitis are common in men with immotile sperm from cilial defects [33]. Situs inversus may also be present [34].

Testicular Symptoms
Previously undescended testes are common in men being investigated for infertility.[7, 35-37] Undescended testes may be associated with other congenital malformations and disorders of testicular hormone production or action during fetal development, such as Kallmann syndrome, insulin-like factor 3 mutations, androgen receptor mutations or defects of androgen metabolism, and diethylstilbestrol exposure in utero (Table 2).[38, 39] In Western countries this condition is usually treated in early childhood but whether early surgery reduces the severity of the subsequent spermatogenic disorder is unclear.[36] A testicular dystrophy may cause both the failure of descent and defective sperm production in adult life despite early surgery. It is difficult to explain otherwise how men with unilateral undescended testes are so frequent in the infertile population. Bilateral undescended testes carry a worse outlook for fertility than unilateral undescended testes. Infertility after bilateral treatment was about six times more common than in the general population and occurred in about half the men whereas after unilateral treatment infertility was increased by a factor of two and affected about 10%.[36, 37] Rarely, the testes atrophy after surgery because of interference with the blood supply or coincidental torsion.

Episodes of severe testicular pain and swelling may result from torsion, orchitis, or epididymo-orchitis and may be followed by loss or atrophy of the testis. Postinflammatory atrophy is particularly frequent with mumps orchitis but rare with other illnesses such as glandular fever and brucellosis. Epididymo-orchitis of bacterial origin is commonly associated with urethritis or urinary tract infections and may follow straining with heavy lifting. Sexually transmitted diseases are important, particularly if there was associated epididymal pain or swelling. Some patients have postgonococcal obstructions in the tails of the epididymides without clear or admitted histories of epididymitis.

Failure of development and a decrease in size of one or both testes are important symptoms of spermatogenic defects. Torsion of the testes may cause atrophy. The vasa may be damaged during hernia repairs and kidney transplantation. Testicular biopsy may inadvertently damage the epididymis especially if retroversion of the testis is not recognised and the biopsy is performed without taking the testis out of the tunica. Similarly, surgery for torsion, hydroceles or epididymal cysts may result in the obstruction of the epididymis. Hematomas in the scrotum and infarction of the testes may follow interference with the vascular supply of the testes. Rarely, autoimmune orchitis results from testicular injury or inflammation. Testicular tumors and carcinoma in situ occur with increased frequency in infertile men even without a history of undescended testes.[40-42]

Iatrogenic Infertility
Vasectomy and Sertoli cell only syndrome caused by Cytotoxic chemotherapy and radiation therapy for malignant tumors of the testes, leukemia, lymphoma and serious autoimmune diseases, are the most common forms of medically induced infertility.[43-48] Although some treatment regimens only suppress spermatogenesis temporarily, recovery of fertility is unpredictable.[43, 45-48] Alkylating agents, such as cyclophosphamide and busulfan, destroy spermatogonia.[44, 46] Antimetabolites may be used to treat psoriasis, rheumatoid arthritis or xenograft rejection, and can have transient adverse effects on spermatogenesis.[27] Treatment with sulfasalazine for inflammatory bowel disease or arthritis causes a reversible impairment of semen quality.[27, 47-50] Cessation of sulfasalazine often results in a marked improvement in semen quality over several months. Many other drugs have real or potential adverse effects on spermatogenesis or sexual performance, including androgens, anabolic agents, estrogens, glucocorticoids, cimetidine, spironolactone, antibacterials (especially nitrofurantoin), antihypertensive drugs, and psychotropic agents. However, these are not common causes of infertility in practice [27, 49-51].

Antispermatogenic Factors
The association of occupational and environmental exposures and reproductive disorders is receiving increasing attention.[52-54] Exposure to heat from frequent sauna baths, vehicle driving, furnaces and perhaps working outdoors in summer may cause a decline in spermatogenesis.[55-58] Impaired testicular heat exchange from obesity and varicoceles may accentuate the effect. Exposure to chemicals in the workplace or elsewhere, particularly nematocides, organophosphates, estrogens, benzene, and welding, zinc, lead, cadmium, or mercury fumes, may have antispermatogenic effects.[59-62] It is theorized that endocrine disrupting chemicals in the environment have impaired testicular development in utero and caused increasing frequencies of genital tract disorders and declines in average sperm concentration in some populations over the last 50 years.[63] Various social drugs, including tobacco, alcohol, marijuana, and narcotics, are potentially antispermatogenic, but these usually require heavy usage for an adverse effect.[27, 53, 58, 64-66] Some addicts have other organ damage, such as cirrhosis, which may further impair testicular function.[27]

Physical ExaminationPhysical Examination

A general physical examination is performed and specific abnormalities sought in certain circumstances, for example: of 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 tumors, and hyposmia with Kallmann syndrome.

Virilization
Hair distribution varies markedly between men. The loss or reduced growth of facial, pubic, axillary, and body hair is an important feature of androgen deficiency but often is unrecognized by patients. Men may note a reduced frequency of the need to shave. The stages of genital and pubic hair development can be recorded according to the method of Tanner. Eunuchoidal proportions (arm span greater than 5 cm longer than height or pubis-to-floor measurement greater than 5 cm longer than one half the height) result from delayed fusion of the epiphyses and are a good sign of delayed or incomplete puberty in Caucasians or Asians.

Gynecomastia
Gynecomastia of mild degree is common in men with testicular failure of any cause.[27] Marked gynecomastia may be associated with Klinefelter syndrome, cirrhosis, androgen receptor defects, estrogen-producing tumors or with anabolic steroid abuse and particularly the illicit use of human chorionic gonadoptropin( hCG). Galactorrhea is rare in men and usually but not always associated with hyperprolactinemia.[67, 68]

External Genitalia
Examination of the penis for the position of the meatus, phimosis, urethral strictures, and Peyronie disease is important because these may influence the adequacy or completeness of ejaculation. Inadequate penile size appears to be an exceptionally rare cause of infertility.[69]
Examination of the scrotal contents is critical in the evaluation of male infertility. A general approach to the examination is outlined in Figure 1. The body of the testes, the head, body, and tail of the epididymis and vas are palpated as shown on both sides. Sometimes it is difficult to examine the scrotum thoroughly because of ticklishness or because the scrotum is very tight. Testes may retract into the superficial inguinal region, especially if small. Testes not present in the scrotum may be palpable in the subcutaneous tissue in the groin or, occasionally, in the inguinal canal. Palpable remnants of the vas and epididymis in the scrotum suggest the testis has atrophied completely - the vanishing testis.[70]

Figure 1. Clinical examination of the scrotum: note testicular atrophy (15mL) absence of pubic hair and bronze coloured skin in a Caucasian man with hemochromatosis.

ORCHIOMETRY. The volume of the testis is determined by comparison with an orchiometer (Normal 15 to 35 ml).[71] In the absence of varicoceles the right and left testes are about equal in size. Testicular volume is related to body size and number of sperm per ejaculate. As seminiferous tubules occupy more than 90 per cent of the volume of the testes, impairment of spermatogenesis is reflected by reduced testicular size. Testicular atrophy suggests severe impairment of spermatogenesis.

TESTICULAR ABNORMALITIES. Pain on palpation or excessive tenderness suggests inflammation. Loss of normal testicular sensation may occur with chronic inflammations, neuropathy, or neoplasia. Reduced consistency or softness of the testes is a feature of reduced spermatogenesis. Abnormalities of shape and hard lumps suggest tumors or scars.
EPIDIDYMAL ABNORMALITIES. Palpable abnormalities include: congenital absence of the vas or other failures of development; enlargements of the heads or nodules in the tails of the epididymides with obstruction, spermatoceles and other cysts and tumors. In men with very small testes (<5ml), small epididymides suggest severe androgen deficiency, normal-sized epididymides suggest postpubertal testicular atrophy or a severe seminiferous epithelial disorder, such as Klinefelter syndrome.

VASAL ABNORMALITIES. Abnormalities of the vas include absence, nodules and gaps with vasectomy, and thickening or beading of the vas with severe postinflammatory scarring as from tuberculosis.

MISCELLANEOUS ABNORMALITIES. Incidental scrotal findings include: scars from surgery, scrotal dermatitis and pubic fat pads around the genitals in extreme obesity. Inguinal hernias and lipomas and encysted hydroceles of the cord are palpated above and behind the epididymis. Cysts "hydatids" of the appendix testis or epididymis are typically anterior to the head of the epididymis. Spermatoceles and cysts of the paradidymis are in the head or body of the epididymis. Retroversion of the testes is common: the vas and epididymis are anterior rather than posterior to the testes. Hydroceles of mild degree are common. A tense hydrocele may hide a testicular tumor. Unilateral absence of the vas may be associated with ipsilateral agenesis of the kidney and ureter on the same side. Many of these anomalies have little relationship with infertility.

CHECKING FOR VARICOCELE. With the man standing up, the scrotum can be inspected for swelling of the pampiniform plexus and a cough or Valsalva impulse seen or palpated by holding the spermatic cords between the thumb and index finger of each hand and elevating the testes toward the external inguinal ring (Figure 1)[72]. This manoeuvre reduces the risk of confusing contractions of the cremaster muscles with venous impulses. Varicocele size is graded: cough impulse without palpable enlargement of the spermatic cord (grade 1), palpable enlargement (grade 2), and visible enlargement (grade 3). Although predominantly a left-sided condition, varicoceles occasionally may be on the right side.
The accuracy and reproducibility of clinical examination even for structures as accessible as those in the scrotum may not be high. Varicoceles may vary in size from day to day. Even absence of the vasa may be overlooked. With practice, orchiometry can be repeated to within one to two orchiometer sizes.