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MANAGEMENT OF SPECIFIC CONDITIONS

This section addresses the following: management of sperm autoimmunity, male genital tract obstructions, gonadotropin deficiency, coital disorders, genital tract inflammation, and varicocele. Androgen replacement therapy is covered in another chapter.

Sperm Autoimmunity

Clinical Characteristics
Sperm autoimmunity is present in 6 to 10 per cent of men seen for treatment of infertility.[22, 116, 117] About half have spontaneously occurring sperm autoimmunity and the remainder have associated genital tract obstruction.[118] Autoimmune orchitis with inflammatory cell infiltrates in the testis may follow an episode of epididymo-orchitis, or occur spontaneously, but is very rare.[117] Men with spontaneously occurring autoimmunity have slightly higher frequencies of family histories of other autoimmune diseases and thyroid and gastric autoantibodies in their serum suggesting a familial predisposition to develop sperm autoantibodies.[22, 23] The types of genital tract obstruction associated with sperm autoimmunity appear to be those that have occurred after puberty, such as postgonococcal epididymitis, vasectomy, or traumatic obstructions. The obstruction may be one-sided.[117] Sperm autoimmunity is common in men with persisting infertility after vasectomy reversal.[118] About 70 per cent of men develop sperm antibodies in their serum within 12 months of vasectomy.[118] The presence of these antibodies is an relative adverse factor for success of vasovasostomy. Sperm autoimmunity is less common with congenital epididymal obstructions, Young syndrome, and congenital absence of the vasa.

Differential Diagnosis
Men with severe sperm autoimmunity must be distinguished from those with low-level sperm autoantibodies that are not relevant to the infertility. The latter have mucus penetration tests that are normal or only marginally impaired.[22, 117] Treatment for the antibodies is not warranted, and other causes of the couple's infertility should be sought. Many patients with low-level sperm antibodies have immunobead binding only to the tail tips, or IBT results with less than 70 per cent binding to the sperm heads.[73, 119] It is possible the antibody levels may vary over time either spontaneously or as a result of relief of obstruction. If there are few or no sperm present in the semen, the main problem is to determine whether the sperm antibodies are the only cause of the problem or whether there is also an obstruction or a spermatogenic disorder.

Pathophysiology
Despite intense study much remains unknown about sperm antibodies. Most of the epitopes for the autoantibodies are unknown. The antibodies may be naturally occurring and to sperm coating proteins from the epididymis and nonpeptide antigens.[120-123] The different patterns of immunobead binding to the sperm surface may result from antibodies binding to different sites, or from variations in the total amount of antibodies on the sperm. [73, 119] The autoantibodies could enter the genital tract because of defects in the blood-testis barrier or impairment of other mechanisms that make the testis an immunologically privileged organ.[116, 124] The antibodies may also be produced by lymphocytes resident in the epithelium of the epididymis.
Sperm antibodies interfere with fertility at several levels: interference with spermatogenesis, sperm agglutination in the male genital tract, reduced sperm motility and mucus penetration, interference with sperm binding to the zona pellucida, the acrosome reaction on the zona pellucida and penetration of the zona pellucida.[125-127] Sperm antibodies of different immunoglobulin classes can be found in serum, seminal plasma and on sperm. IgG and IgA sperm antibodies, particularly secretory IgA, locally produced in the male genital tract, cause the greatest interference with sperm function.[117, 119, 128]

Natural History
In most patients sperm autoimmunity causes persistent severe infertility. The pregnancy rate for untreated patients is less than 0.5 per cent per month.[22, 129] Glucocorticoid treatment usually only produces a transient benefit. Occasionally sperm autoimmunity may fluctuate in severity. The rare patients who produce pregnancies without treatment appear to have spontaneous improvements with a fall in antibody levels and increased sperm-mucus penetration. Sperm antibodies may decrease after relief of genital tract obstruction but this may take many months or years to occur.[117]

Treatment
Although there is a range of opinion, the effectiveness of glucocorticoid treatment for sperm autoimmunity has an evidence base in controlled clinical trials.[116, 117, 130] Although most clinicians and patients would choose ICSI as the preferred management initially, glucocorticoid treatment is reasonable when sperm autoimmunity is the only obvious cause for infertility in an otherwise healthy couple who wish to do everything possible to achieve a natural pregnancy and prepared to accept the risks of the treatment. Long-term glucocorticoid treatment is contraindicated if the woman is infertile or the man has other illnesses that increase the risks of serious adverse effects - particularly peptic ulcer disease, hypertension, obesity, or diabetes mellitus. ICSI has replaced the need for short-term glucocorticoid treatment before standard IVF.[131, 132] The couple may choose either ICSI or glucocorticoid treatment initially and try the other if the first treatment is unsuccessful. The couple may also pursue donor insemination or accept the infertility.

Various regimens of prednisolone or other glucocorticoid therapy have been used.[116, 117, 130] Because a number of cases of aseptic necrosis of the femoral head have been associated with high-dose methylprednisolone, it not used.

PREDNISOLONE THERAPY. Both continuous and intermittent prednisolone therapy regimens have been shown to be effective in placebo controlled trials although some small trials have produced negative results.[22, 116, 117, 130, 133] Continuous therapy is 0.75 mg/kg or 50 mg/d given as a single dose each morning with breakfast until a pregnancy occurs or for a maximum of four to six months. The intermittent regimen is to give 20 to 25 mg of prednisolone each day from day 1 through 10, or day 4 through 14, of the woman's cycle. If the semen quality and mucus penetration have not improved by three months, then the dosage is doubled and again after six months for a maximum of a further three months. If it is uncertain whether sperm autoimmunity alone or an associated primary spermatogenic defect or genital tract obstruction is causing severe oligospermia or azoospermia, prednisolone 50 mg/d may be given for four to eight weeks as a therapeutic trial.

MONITORING. Patients are carefully monitored for improvement in semen quality and for adverse effects. Semen tests are performed monthly about the time of the woman's menses. Semen analysis, IBT and sperm mucus penetration tests are performed to assess progress. Promising signs are: increased sperm concentration, motility, and mucus penetration and decreased IBT binding, particularly IgA levels falling to less than 70 per cent binding to the heads of motile sperm.

ADVERSE EFFECTS. Adverse effects of prednisolone treatment are common. Insomnia and dyspepsia are frequent early problems. After two to three months of treatment, Cushingoid appearance, muscle weakness, and joint aches are common. Transient decreases in muscle and bone mass and increased fat mass occur. Occasional adverse effects resulting from depressed immunity are herpes zoster or severe folliculitis. Serious adverse effects, such as depression, cataracts, Addisonian crisis after cessation of treatment, and aggravation of peptic ulcer disease, are rare. The main serious adverse effect is aseptic necrosis of bone, most commonly the femoral head.[22, 116, 117, 130, 134] This side effect has been described in a number of men being treated for sperm autoimmunity. Heavy alcohol drinking may predispose to it. Patients need to be advised carefully of this adverse effect because it has led to a number of litigation actions. It is also important to remember that other common illnesses, such as asthma and psoriasis, although improved during glucocorticoid treatment, may flare up after withdrawal. Rarely, semen quality deteriorates during glucocorticoid treatment.

GENERAL MANAGEMENT. The couple is advised to have intercourse frequently at the fertile time of the cycle, preferably daily. Semen is cryopreserved if the quality improves, as this may be used for artificial insemination or ICSI after cessation of the prednisolone therapy.

OTHER TREATMENTS. ICSI is the main alternative treatment. Testosterone suppression of spermatogenesis, AIH, washing sperm to remove sperm antibodies, antibiotic therapy, and standard IVF or GIFT without prior prednisolone therapy are ineffective.[22, 116, 117, 130] Surgery to relieve obstructions, such as repeat vasovasostomy and vasoepididymostomy, or removal of an orchitic testis could be considered. [117]

RESULTS. About 50 per cent of men treated with glucocorticoids for sperm autoimmunity have a reduction in sperm antibody levels and an increase in sperm concentration, motility, and mucus penetration.[22, 116, 130] Pregnancies occur in about 25 per cent of couples during a four- to six-month course of prednisolone or after a longer period of intermittent prednisolone therapy. Ovulatory disorders, endometriosis, and tubal abnormalities are negative prognostic factors, and in these couples it may be preferable to perform ICSI. ICSI produces live birth pregnancy rates of about 20% per attempt.[132] The presence of antibodies has no adverse effect on the outcome of ICSI the results being determined mainly by age and other female factors. Artificial insemination may be successful with stored semen from a previous course of prednisolone therapy.[22]

Genital Tract Obstruction

Clinical Characteristics
Most men with genital tract obstruction have azoospermia, normal testicular size, normal virilization, and normal serum FSH levels. However, some have combined obstruction and spermatogenic disorders, or partial obstructions and severe oligospermia. There may be a history of an event that caused the obstruction, such as epididymitis with gonorrhea or associated respiratory disease.[7, 16-18, 30-32] Because a few men with normal spermatogenesis have elevated FSH levels and some spermatogenesis may occur in association with a severe spermatogenic disorder, all patients should be offered further investigation.[91, 92, 110, 112] Sperm antibodies may be present and are an adverse prognostic factor for surgery.[117] In men with congenital absence of the vas or ejaculatory duct obstruction, semen volume, pH and fructose levels are low. The semen also does not have its characteristic smell and does not form a gel after ejaculation because it contains only prostatic and urethral fluid. The semen characteristics of complete ejaculatory duct obstruction are the same as for BCAV but the vasa are palpable. Rectal ultrasound may show the cause of the obstruction such as a cyst of the prostatic utricle.[115] Some men may have partial or intermittent ejaculatory duct obstruction and may notice the low ejaculate volume. Testicular biopsy is normal or there may be some reduction in spermatogenesis either as a coincidence or as a result of the obstruction particularly after vasectomy.[135]

Pathophysiology
Degeneration or failure of development of the Wolffian duct structures with cystic fibrosis gene mutations or other factors is covered above.[16-18] Some men with Young syndrome had children and must have developed the block in adulthood.[30-32] The pathology shows inspissated material in the head of the epididymis, and there are lipid inclusions in the epithelial cells. Young syndrome is not related to cystic fibrosis gene mutations.[17]

Postinflammatory obstructions after gonorrhea typically occur in the tail of the epididymis, whereas nonspecific bacterial inflammation produces more widespread destruction, and tuberculosis usually causes multiple obstructions in the epididymides and vasa. Back pressure blowout obstructions in the epididymis are frequent after vasectomy.[136] Iatrogenic causes of genital tract obstruction include inadvertent epididymectomy during testicular biopsy, vasal damage during hernia repair or pelvic or lower abdominal surgery such as renal transplantation, and ejaculatory duct obstruction from prostatectomy or complicated bladder catheterization.

Differential Diagnosis
Men with persistent azoospermia, normal testicular size, normal virilization, and normal FSH levels can be assumed to have obstruction until proved otherwise. Up to one third of men with this clinical picture are found to have a serious spermatogenic disorder on testicular biopsy despite the normal serum FSH level.[7] There are rare instances of normal men who show azoospermia on single occasions or over a short period.[5, 137] This "spurious azoospermia" must be excluded before surgery is contemplated. Once diagnosis of obstruction is confirmed, it is necessary to determine the feasibility of surgery. Intratesticular and caput-epididymal obstructions have a poor prognosis but cauda-epididymal and vasal obstructions can often be treated successfully with surgery.[136, 138] Distal obstructions are important to diagnose because they may be reversed at transurethral endoscopy.[139]
Sperm retrieval for ICSI, either from the testis or other part of the genital tract, is an alternative to surgery.[110, 112] ICSI is also used when reconstructive surgery is not possible, the female partner has an infertility problem or the couple can not wait six to twelve months to have a reasonable attempt at conceiving naturally after surgery.

General Management
Genetic abnormalities associated with the cystic fibrosis gene need to be considered if a pregnancy is to be attempted using the man's sperm. The woman should be screened for cystic fibrosis gene abnormalities and the couple counseled accordingly. Preimplantation or prenatal genetic diagnosis may be performed if mutations are found in both partners.[17] The woman should be investigated in detail to ensure her potential fertility before surgery is contemplated in the man. The prognosis of the procedure and the availability of other forms of treatment, including donor insemination, should be discussed realistically with the couple. For ICSI, sperm may be obtained by testicular biopsy or percutaneous sperm aspiration from the epididymis under local anesthesia. If a natural spermatocele is present, usable sperm may be obtained by direct puncture through the scrotal skin. It may be possible to combine vasoepididymostomy with sperm aspiration for cryopreservation or ICSI.[110, 112]

Epididymal and Vasal Surgery
Treatment of male genital tract obstructions is best undertaken by specialist microsurgeons.[136, 138, 139] The testis is exposed and the most proximal (to the testis) level of obstruction determined. A testicular biopsy is obtained and the patency of the vas is determined by syringing with saline or by vasography. The vas or epididymal tubule is opened proximal to the obstruction, and if possible, the presence of motile sperm is demonstrated by microscopy. Then microsurgical anastomosis between the ends of the vas or between the vas and the epididymal tubule is undertaken.

RESULTS. Vasovasostomy and vasoepididymostomy for caudal blocks produce relatively good results - 50 to 80 per cent of patients having sperm present in the semen; however, less than half of these produce a pregnancy within the first year.[136, 138] The poor results may be related to continuing obstruction, sperm autoimmunity, or coexisting spermatogenic disorders. The results of vasoepididymostomy for proximal blocks are poor.[136, 138] Although sperm may appear in the semen, pregnancies are extremely uncommon following vasoepididymostomy for caput epididymal blocks.[136] The results of ICSI with testicular or epididymal sperm, fresh or after cryopreservation, are similar to those obtained with sperm from semen.[110, 112]

Gonadotropin deficiency and suppression

Clinical Characteristics
Most men seeking treatment for infertility associated with gonadotropin deficiency have been treated with androgens, following presentation in adolescence with delayed puberty. The main diagnoses are Kallmann syndrome, other isolated gonadotropin deficiencies, combined gonadotropin and growth hormone deficiency and rarely pituitary tumours, trauma or craniopharyngiomas treated in childhood.[137] Occasionally men with previously undiagnosed prepubertal gonadotropin deficiency present with infertility. The clinical features are usually very small testes (<4mL) and severe androgen deficiency. There may be a child like appearance with lack of secondary sex hair development, failure of male pattern scalp hair recession and balding and eunuchoidal proportions. Gonadotropin deficiency may develop after puberty because of tumours, surgery or trauma of the pituitary or hemochromatosis. These men usually note loss of libido and may note reduced beard and body hair growth, low ejaculate volume and decreased testicular size. General lethargy, muscular weakness and hot flushes are also common but non-specific symptoms. Physical examination may show testicular atrophy, reduced secondary sex hair and dry finely wrinkled skin on the face. Gynaecomastia may be present. Features of underlying or associated conditions may be present for example: headache, visual disturbance and hormone excess or deficiency with pituitary tumours, or pigmentation, liver disease or diabetes with haemochromatosis.

Hyperprolactinemia is uncommon in men. It usually presents with loss of libido and impotence, low testosterone levels and variable semen analysis results from azoospermia to relatively normal. Galactorrhea may occur, sometimes with only minimal gynaecomastia. There is usually a pituitary tumour. Hyperprolactinemia associated with a pituitary macroadenoma is rare but important: as well as loss of libido there is usually progressively severe headache and visual field impairment. A number of paediatric syndromes include mental deficiency and gonadotropin deficiency but the patients rarely seek treatment for infertility as adults. Mutations of DAX1 cause adrenal hypoplasia and gonadotropin deficiency.[10, 108]

Gonadotropin suppression may occur in a variety of circumstances. The most common now appears to be the illicit use of anabolic and androgenic steroids or chorionic gonadotropin. Other hormones and drugs can cause gonadotropin suppression. Selective suppression of LH with intrathecal opioids for chronic pain has been discovered recently.[29] Rarely men are seen with hormone producing tumours for example adrenal adenomas, Leydig cell tumours or hCG producing teratomas which will suppress gonadotropins, usually there are features of marked hyperestrogenization with progressive gynecomastia. Very rarely men are seen with congenital adrenal hyperplasia with gonadotropin suppression and azoospermia who can be treated successfully by glucocorticoid suppression of ACTH.[25, 26]

Spermatogenesis may occur despite severe androgen deficiency - the so-called fertile eunuch syndrome. This is believed to be due to predominant LH deficiency or partial gonadotropin deficiency. There may be normal sperm concentrations but usually there is low ejaculate volume and sperm motility. The fertile eunuch syndrome commonly occurs with hyperprolactinemia, hemochromatosis, starvation, illness or in athletes in negative energy balance. It is also seen with partial or mild Kallmann syndrome.

Pathophysiology
Commonly gonadotropin deficiency is caused by genetic disorders of gonadotropin releasing hormone production or the GnRH receptor, loss of function of gonadotrophes, or suppression of gonadotropin secretion by extraneous steroids, other drugs or illness. There is usually a combined defect of androgen and gamete production. If the underlying cause cannot be corrected life long androgen replacement therapy is required. This is usually with a form of testosterone but when fertility is desired, treatment must be changed to gonadotropins. While experimental conditions may be found to indicate that either FSH or LH alone may be able to initiate spermatogenesis in humans, for practical clinical purposes treatment with LH alone (as hCG) is effective for fertile eunuch syndrome and may be effective where spermatogenesis has been stimulated before, either by natural puberty or previous gonadotropin therapy. In other situations both FSH and LH are required (see chapter by Hayes and Pitteloud).

Differential Diagnosis
In men with gonadotropin deficiency it is necessary to determine the cause of the disorder, or if this is not possible to exclude a serious underlying cause such as a pituitary tumour. With Kallmann syndrome there is hyposmia or anosmia from malformations of the rhinencephalon. Other abnormalities may also be present including colour blindness, cleft lip and cerebellar ataxia. Except where the diagnosis is obvious, detailed radiological examination of the pituitary and hypothalamic area is necessary, together with full pituitary function tests to determine if there are other hormone deficiencies.

Treatment
Gonadotropin suppression from administration of steroids or other agents is treated by withdrawal of the agents, and starvation induced gonadotropin suppression by refeeding. Hyperprolactinemia can be treated with bromocriptine or other dopamine agonist.[68] Gonadotropin deficiency caused by of gonadotrophe destruction or abnormalities of the GnRH receptor require treatment with gonadotropins. Some men with gonadotropin releasing hormone deficits can be treated successfully with pulsatile GnRH administration. For details of the gonadotropin and GnRH treatment, see chapter by Hayes and Pitteloud.

Coital Disorders

Male coital disorders important for infertility include impotence, failure of ejaculation, and retrograde ejaculation (see also chapter on erectile dysfunction by Lue and Gholami). Many men have problems with sexual performance after first learning about the infertility, but this usually ameliorates with time. Infrequent and poorly timed intercourse may result from incorrect advice, low libido or the psychological reaction to infertility.[5]

Impotence
Impotence may be associated with low libido from androgen deficiency with primary or secondary hypogonadism. Impotence related to vascular or neurological abnormalities (diabetic autonomic neuropathy or pelvic nerve damage) is uncommon in men presenting with infertility.[7] Selective impotence at the time of ovulation may indicate psychological problems and ambivalence about having children.

Failure of Ejaculation
Failure of ejaculation is usual with chronic spinal cord injury and may also be caused by antihypertensive and psychotropic drugs, but otherwise, is an infrequent cause of infertility in most societies.[140] Healthy men who cannot ejaculate with intercourse may be able to produce semen by masturbation, with a vibrator or other stimulation.

Retrograde Ejaculation
Retrograde ejaculation occurs when the bladder neck fails to contract at the time of ejaculation so that all or most of the semen passes into the bladder. Usually there is an obvious cause: prostatic surgery, diabetic neuropathy, pelvic nerve damage or spinal cord injury. Retrograde ejaculation is diagnosed by the finding of sperm in urine passed after ejaculation.

Differential Diagnosis
Recognition of a coital disorder is crucial; thus all infertile patients must discuss their sexual history in detail. Once recognized, the contribution of organic and psychological factors needs to be evaluated.

General Treatment
An optimistic prognosis can be given, provided that live sperm can be obtained. The couple are advised about the various techniques that might be used for collecting the sperm for AIH or other ART. The woman's potential fertility must be evaluated.

Specific Treatment
A drug, such as an antihypertensive or a tranquilizer, that may be contributing to the sexual disorder should be stopped temporarily or permanently.[27] Impotence may respond to sex behavior therapy, physical approaches with pumps and rubber occlusion devices to initiate and maintain erections, administration of sildanefil, intrapenile injections of vasodilators, and penile implants, but these seldom are needed in men with infertility. Some men with failure of ejaculation, or retrograde ejaculation may be able to ejaculate during intercourse with a full bladder, or after the administration of sildanefil or cholinergic antihistamines, such as brompheniramine or ephedrine.[141] Others require more powerful stimulation with vibrators or electroejaculation.[142, 143] If these are unsuccessful, sperm may be collected surgically from the vas, epididymis or testis.[112]

USE OF COLLECTED SEMEN. If semen can be obtained masturbation or by wearing nontoxic condoms to collect nocturnal emissions, the couple can be taught to inseminate samples at home. The timing of ovulation can be determined by calendar and either mucus symptoms or LH surge detected with a urinary LH dipstick kit. Cryopreservation of samples for AIH or ICSI may also be possible.

ASSISTED EJACULATION. Ejaculation may be stimulated by applying a vibrator to the underside of the penis near the frenulum of the glans. Vibrators with a 2mm pitch and frequency of 60 Hz or more are most effective. Men with complete spinal cord injuries below thoracic vertebra ten are unlikely to respond and will require electroejaculation. Modern electroejaculation equipment is safe: the probe includes a thermal sensor and proctoscopy is performed before and after the procedure to ensure there ate no burns or other damage to the rectum. A balloon catheter in the bladder is used to prevent retrograde ejaculation.[143, 144]

Semen obtained by assisted ejaculation from able-bodied men or in the acute stages of spinal cord injuries is often normal.[144] In contrast, with chronic spinal cord injury there is frequently low volume, high sperm concentration, and poor motility.[140, 143] As with necrospermia, repeated ejaculation over several days can improve sperm motility. If the semen quality is too poor for AIH, or the risks associated with electroejaculation are considered unacceptable, aspiration of sperm from the testis and ICSI produces good results. Assisted ejaculation may cause autonomic hyperreflexia with chronic spinal cord injuries above thoracic vertebra number 6.[140, 142] The resulting uncontrolled hypertension may cause cerebral hemorrhage. Careful monitoring of blood pressure and prophylactic nifedipine treatment usually prevents serious problems.[142] Men without complete sensory deprivation require general anesthesia for electroejaculation.

RETRIEVAL OF SPERM WITH RETROGRADE EJACULATION. Motile sperm may be obtained from the urine after retrograde ejaculation.[145] Urinary pH is adjusted to above 7 and osmolality to between 200 and 400 mOsm/kg by administration of 80 g of sodium bicarbonate and 2.0 to 2.5 L of water daily for 3 days before the expected time of ovulation. On the day of ovulation the man ejaculates and passes urine. Sperm are recovered from the urine by centrifugation, washed and resuspended in an IVF culture medium. The final pellet is resuspended in about 0.5 ml of culture medium for insemination. It is also possible to cryopreserve the sample obtained. If this method fails, electroejaculation and catheterization of the bladder could be considered.

Effects of Systemic Illness and Reversible Exposures to Toxins or Drugs

A very large number of exposures to agents in the environment, drugs and illnesses can adversely affect testicular function but it is rare to find patients in which such exposures can be confirmed as contributing to male infertility. However, this should always be considered during clinical evaluation. The most commonly encountered problems clinically are impairment of spermatogenesis by salazopyrin used for treatment of inflammatory bowel disease or arthritis, testosterone administration, anabolic steroid abuse and recent febrile illnesses causing transient reduction of spermatogenesis. Workplace exposures may be implicated in some patients but the association is rarely clear-cut enough to advise change of occupation.

Acute Illnesses

FEVER. The adverse effect of acute febrile illness on the semen quality is well known but only occasionally seen. Frequent hot baths or saunas may also have a similar effect. There is a temporary suppression of spermatogenesis which recovers over 3 to 6 months. Whether increased scrotal temperature because of clothing, varicocele, obesity or environmental temperature contributes to male infertility is controversial.

CRITICAL CONDITIONS. Suppression of gonadotropin secretion can occur with critical illness and such as hepatic failure, myocardial infarction, head injury, stroke, respiratory failure, congestive cardiac failure, sepsis, burns, starvation and severe stress, both psychological and physical. Transient decreases occur following drug or alcohol intoxication, anesthesia and surgery. The reduction in testosterone is proportional to the severity of some of the critical conditions and may predict the likelihood of recovery. There may also be direct effects on the testes and alterations in SHBG levels. The shutdown of testicular function may be a useful adaptation to illness or starvation. During recovery from the critical condition pulsatile secretion of gonadotropins increases in a manner reminiscent of the changes with puberty and gynecomastia may develop.

NUTRITIONAL ASPECTS. As mentioned above starvation is associated with gonadotropin suppression. Specific deficiencies of vitamins and minerals such as, B12, C, folate and zinc may affect testicular function, but these are rare in Western countries. Simple obesity may be associated with alterations in the hypothalamo-pituitary-testicular axis and impaired scrotal thermoregulation. The most common changes are increased conversion of androgens to estrogens in peripheral tissues and low sex hormone binding globulin levels related to insulin resistance. Total testosterone, SHBG levels and gonadotropin levels may be low and estrogen levels elevated. However, clinical androgen deficiency, estrogen excess and abnormal semen analysis are not regularly seen in morbidly obese men.

Chronic Illnesses
Impairment of testicular function is common in uncontrolled or poorly controlled chronic diseases. There is usually elevated gonadotropin levels indicating a primary testicular defect, but impaired gonadotropin secretion or hyperprolactinaemia may occur and changes in SHBG and aromatisation of androgens to estrogens are common. While this pattern of change in testicular function is a common nonspecific response to chronic illness, the mechanism is obscure. There may be symptoms and signs of androgen deficiency and estrogen excess. Hepatic cirrhosis is one of the classical conditions known to have a profound adverse effect on the male reproductive function. Testicular function may recover following liver transplantation. Similar primary hypogonadism may occur with non-cirrhotic liver disease, chronic alcoholism without liver disease and a variety of chronic diseases without alcoholism: chronic anemias, chronic renal failure, thyroid hyper or hypofunction, human immunodeficiency virus infection, lymphoma, leukemia, advanced metastatic cancers, rheumatoid arthritis, severe cardiac disease and chronic respiratory disease.

Effects of Drugs
Drugs may contribute to male infertility by affecting gonadotropin (eg steroids) or prolactin secretion (psychotropic agents), steroid hormone production or action (antiandrogens), spermatogenesis (salazopyrine, alkylating agents) or by reducing sexual performance (psychotropic and antihyprertensive drugs). Some drugs may also cause gynaecomastia (antiandrogens, estrogens).

There is currently no place for the use of testosterone treatment of infertile men either continuously for low testosterone levels resulting primary or secondary testicular failure or as 'testosterone rebound' therapy because testosterone suppresses gonadotropin secretion and reduces spermatogenesis. This inappropriate usage of testosterone persists in some quarters.

Abuse of androgens is widespread in people hoping to enhance athletic performance or body building. Some men are seen for infertility from azoospermia or oligozoospermia as a result. Others have sexual performance problems after stopping the drugs. The abuse may be concealed by the patient. Normal virilization but low testosterone, low SHBG and low, normal or transiently high gonadotropin levels may be seen. Recovery can take several months particularly after depot anabolic steroids.

Salazopyrin used for bowel disease and arthritis commonly causes spermatogenic defects. Usually there is poor sperm motility and morphology or oligospermia. The semen may be stained yellow. The antispermatogenic effect is caused by the sulphapyridine in the drug. Stopping the drug results in a recovery of sperm output within a few months provided the patient's health remains good and he does not have an underlying defect of spermatogenesis.

Other drugs and toxins are claimed to have adverse effects on spermatogenesis such as colchicine and anticonvulsants and some antihypertensive drugs, calcium channel blockers and antiparasitic chemotherapeutic drugs may impair sperm motility, capacitation or the acrosome reaction.

Genital Tract Inflammation

Specific inflammations of the genital tract such as mumps orchitis or gonorrheal epididymitis may cause sterility. Nonspecific inflammations in the accessory sex organs are more common in men with infertility than in fertile men.[5, 146, 147] Also, male accessory sex organ inflammation and infertility may be more important in some countries than in others.[5] Symptoms include chronic low back pain, intermittent dysuria, discharges from the penis on straining, and discomfort in the pelvic region or testes after ejaculation or prolonged sexual abstinence. The prostate may be enlarged and tender. The semen may show discoloration, variations of volume, increased viscosity, delayed liquefaction, high pH, sperm agglutination, bacteriospermia and pyospermia. The bacteria in semen are frequently not pathogens but the commensals of the urethra or skin.[146]

To have more than 1 million polymorphs per milliliter in semen determined by peroxidase reaction or monoclonal antibodies to leukocyte antigens is considered abnormal.[73] Although inflammatory cells could damage sperm by releasing free oxygen radicals or cytokines, bacteria could impair sperm motility, and inflammation could also cause partial genital tract obstruction, the actual contribution of nonspecific genital tract inflammation to male infertility is contentious. [146-148] Routine cultures of semen are not warranted except for sperm donors.

General Management
Men with clinical evidence of prostatitis require full urological assessment.[149] Specific infections with pathogenic agents are treated with appropriate agents. It remains unclear what should be done about asymptomatic pyospermia and non-specific male accessory gland inflammation. Therapeutic trials generally show no benefit from antibacterial therapy on semen quality.[150]

Antibiotics or other agents may be used if it is felt the pyospermia compromises semen quality or that bacteria might contaminate the IVF culture media. Because the organisms commonly implicated in nonspecific genital tract inflammation include Chlamydia, Mycoplasma and various bacteria, broad spectrum antimicrobial therapy is required if treatment it is to be given. Also, many of the standard drugs do not enter inflamed accessory sex organs. Trimethoprim, erythromycin, doxycycline, and norfloxacin are potentially effective.[151] Increased frequency of ejaculation to facilitate drainage of the accessory glands, and stress management may also help.

Varicocele

Varicoceles are found in about 25 per cent of men being examined for infertility. An additional 15 per cent of men may have a subclinical left varicocele indicated by a faint cough impulse in the spermatic cord or increase in diameter of the veins on ulreasound.[5, 7, 72, 138, 152] Varicoceles are also found in fertile men.[64] Varicoceles are more common in tall men and in men with larger testes.[7] They are less frequent in men with severe testicular atrophy, for example, with Kallmann and Klinefelter syndromes. When there is a moderate to large left varicocele the left testis is usually smaller than the right testis.

Pathophysiology
Men with varicoceles generally have poorer semen quality than those without varicoceles.[64, 72, 152] Thus varicoceles can have an adverse effect on testicular function. Various theories have been advanced for the effect, including vascular stasis, back pressure, interference with oxygenation, reflux of renal or adrenal products into the pampiniform plexus, and interference with the heat exchange function of the pampiniform plexus, but the precise mechanisms are not clear.[152] Varicoceles are usually first noticed at puberty and thereafter may increase in size but remain relatively stable in size throughout the man's lifetime. Symptoms, including swelling and a dragging sensation in the scrotum, are infrequent, and many men with a large varicocele are unaware of its presence. The sudden appearance of a varicocele in an adult should be taken seriously because it may be a feature of a renal carcinoma with extension into the left renal vein. This well-known clinical association is uncommon.

Differential Diagnosis
The semen quality in men with varicoceles varies from azoospermic to normal. There is no specific pattern of abnormality with varicocele. Testicular histology is also variable, the only common feature being that the defect in spermatogenesis is more severe on the left side than on the right side. Varicocele may be more of an association rather than an absolute cause of a couple's infertility. Therefore, full evaluation of other aspects of male infertility and of the female partner is necessary.

Treatment
The value of treatment of varicocele for infertility is controversial. One view is that treating varicoceles may not improve fertility; therefore, the varicoceles should only be treated for other reasons, such as symptoms.[152, 153] The other extreme is the belief that varicocele is the most important treatable cause of male infertility, therefore all varicoceles should be treated even if small.[138, 154] In the middle are those who would select cases. When there is an absent, obstructed, or atrophic right testis and all sperm in the semen come from the left testis treatment of the varicocele may produce a reasonable result.[155] Some would treat all medium or large varicoceles in men in whom there was no other obvious cause for the infertility and in whom the semen abnormality was not too severe.

Treatment of the varicocele involves the venographic obstruction of the incompetent veins or surgery to prevent venous back flow from the abdomen to the pampiniform plexus. Radiographic techniques involve placement of a sclerosant, glue or coil that promotes clotting in the vein and carry a lower morbidity than surgery under general anesthesia but there are relatively high failure and recurrence rates.[138, 152, 154] A variety of operations can be performed for varicocele. In the past retroperitoneal ligation and division of the testicular veins with or without preservation of the testicular artery and lymphatics was performed. Inguinal and scrotal microsurgical approaches have lower failure, recurrence and hydrocele rates.[138]

Successful venous occlusion will relieve pain and reduce the size of large varicoceles. Whether semen quality and fertility are improved is not certain.

Results
Because varicoceles are so frequent, treatment of varicocele for infertility became a common and several large series were published with claims of high success rates for improving semen and fertility.[156] Floating numerator pregnancy rates averaging 35 per cent (range 20 to 60 per cent) were commonly reported. Regression toward the mean in semen variables, the nature of subfertility and the need to include time in the denominator of pregnancy rates were ignored.[137] While there are reports of successful treatment of azoospermic men by varicocelectomy, transient azoospermia may follow a minor illness or occur for unknown reasons and thus such examples do not prove the value of treatment.[157] Most exponents of varicocele treatment regard azoospermia as a bad prognostic sign, especially if the FSH level is elevated.

FOLLOW-UP STUDIES AND CONTROLLED TRIALS. Follow-up studies of groups of treated and untreated patients with varicoceles suggest pregnancies are as frequent without treatment as with treatment of the varicocele.[153, 158-160] Attempts have been made to conduct randomized controlled clinical trials of varicocele treatment. Such trials are difficult because the ideal design with sham operations and blinding, which is so important in controlling for outcomes affected by psychological factors, is not possible. Large trials are also needed: for example about 250 pregnancies are required to have a high chance of finding a 25% increase in pregnancy rate after treatment significant at the 5% level.[137] The trials have produced conflicting results. A small prospective controlled study of percutaneous embolisation of the left testicular vein in 17-20 year olds showed an increase in testicular volume and sperm concentration in the treated group.[161] Others have reported similar beneficial effects of treatment of varicoceles in adolescents in less well controlled studies. A prospective randomised controlled trail of occlusion of the spermatic vein by surgical or angiographic techniques versus follow-up counselling alone for one year in 125 couples without other causes of infertility showed no difference in pregnancy rate: 29% and 25% respectively at 12 months.[162]

WHO set up a multicenter controlled trial of Palomo ligation in men with infertility of greater than 1 year duration, abnormal semen analyses, a moderate to large left varicocele and a potentially fertile female partner. Volunteers were randomized to immediate operation or operation delayed for 12 months to provide an untreated control group. One of the participating centers reported their results separately.[163] There was a substantial effect on pregnancy rate. Two pregnancies occurred in 20 couples during the one year of observation without treatment compared with 15 pregnancies in 20 couples in the year after the operation. During the year after the operation in the remaining 18 control patients there were 8 pregnancies. Semen analysis results also improved after the operation. There were another 248 couples in 12 countries in the trial and there was a less marked but significant improvement, the life table pregnancy rates at one year being: 35% for the operated group and 17% for the unoperated group (relative pregnancy rate 2.7, 95% confidence limits 1.6-4.4). Semen analysis results also improved over the first year in the operated group. In the control patients having the delayed operation the life table pregnancy rate at one year after the operation was 21%. However, there were problems with the WHO trial particularly with possible irregularities of randomization in some centers early in the trial, drop out rates were high and the results have not yet been published in detail.[152] Also, the pregnancy rates in the control group are lower than expected for untreated subfertile men with varicoceles: approximately 30% produce a pregnancy in 12 months.[153, 162]

Several groups have now confirmed in uncontrolled studies, Hudson's finding that patients who respond to treatment of varicocele have significantly greater GnRH stimulated rises in FSH than do non-responders.[164, 165] The mechanism of this intriguing observation remains obscure. It may be that a beneficial effect of treatment is greater in younger than in older men. The possibility that responders can be predicted from hormone profiles and age deserve critical evaluation. Certainly further trials are necessary to meet the demands of evidence based medicine and should involve objective methods of semen analysis and varicocele detection, and simpler methods of treatment such as antegrade sclerotherapy.[152, 164-166]

Thus while some people remain convinced of the value of treating varicoceles for infertility it is not easy to demonstrate this unequivocally and the apparent improvements in semen quality and fertility may result from random fluctuations and regression toward the mean.[137, 138, 151] The Cochrane collaboration review of varicocelectomy for infertility concludes there is insufficient evidence to recommend treatment.[167] It is clear that normal fertility is not achieved in a high proportion of patients treated for varicocele. Assisted reproductive technology is a realistic alternative for most couples who have not conceived after a reasonable time.

GENERAL MANAGEMENT

This section covers aspects of the management of couples with male infertility not amenable to specific treatment. A number will conceive during investigation. Others will decide not to continue with medical intervention. Some patients with treatable conditions may choose ICSI instead of treatment or after a treatment has been unsuccessful. However, most couples with male infertility have conditions for which there is no clearly defined and certainly effective treatment.[5, 7] In these it is important to discuss the prognosis for a natural pregnancy occurring, the ineffectiveness of treatments, and the availability of IVF and ICSI, donor insemination, and adoption. The investigation of the female partner should be reviewed and abnormalities treated when possible. Patients should be acquainted with the physiology of the menstrual cycle and symptoms of ovulation to help time sexual intercourse over the fertile phase of the cycle.[168] Good health practices should be promoted, particularly cessation of smoking because it reduces fertility in women.[65, 66] The psychological upheaval experienced by the couple should be discussed and additional help offered if necessary. Specialist infertility counsellors and patient support groups are particularly valuable in this area.

Prognosis for natural pregnancy

A number of factors in addition to semen quality affect the likelihood of natural pregnancies occurring.[1-4, 153, 169-171] Some are obvious, such as female disorders and coital dysfunction. Female age is important as fertility declines after about age 35 years. Duration of infertility is a major factor in most studies: the longer the infertility, the worse the outlook. The prognostic factors found in a study to determine the effect of varicocele surgery were: duration of infertility (negative), mean sperm concentration (positive), untreated sperm autoimmunity (negative), ovulatory disorders (negative), occupational group (farmers doing better than other workers), female age (negative), and previous fertility in the couple (positive).[153] Interestingly, varicocele presence and size were positive prognostic factors even though varicocele surgery was not significant. The pregnancy rate curves for different sperm concentration groups are shown in Figure 6. These factors can be used to advise patients about their chances of producing a natural pregnancy over time. The accuracy of such predictions is poor because the statistically significant factors only explain a small part of the variance (in the study above, about 17 per cent). New studies using automated methods for semen analysis may reveal additional prognostic factors with better predictive value. However, other factors currently not assessable, such as gamete transport, may have an important bearing on conception and may explain the occurrence of pregnancies in some couples despite severely abnormal semen analysis results. Patients should not be told natural conception is impossible unless there is an absolute barrier to fertility.

Figure 6. Pregnancy rate curves grouped according to average pretreatment sperm concentration. The number (n)of patients followed each year is shown. The numbers of men and pregnancies in each sperm concentration group are shown in the inset table (From Baker, H.W.G., Male Infertility. Chapter 171 In Endocrinology, 4th edition, DeGroot L.J. and Jameson J. L. (Chief Eds.), W.B. Saunders Co. Philadelphia PA. pp 2308-2328, 2001.)

Psychological Aspects

Infertility causes major trauma to the ego of most patients.[172] Many undergo a grief reaction with initial denial of the problem followed by a tendency to blame others and a period of depression before final acceptance of the infertility. The reaction may take years to resolve, and it can threaten the stability of the partnership, interfere with investigation and management of infertility, and lead to futile involvement in expensive "cures" offered by the unscrupulous. Participation in unsuccessful treatments during this phase often is particularly difficult emotionally for the patients. Stress may influence some aspects of semen quality.[173] An empathetic approach and involvement of independent counselors or self-help infertility groups may assist some couples. In most, the unpleasantness of the psychological reaction subsides with time.

Timing of Coitus

A practical approach is to advise intercourse each day when ovulation might occur. Ovulation can be predicted to occur about 14 days before a period is due. Knowing the range of menstrual cycle lengths allows calculation of the days when ovulation is most likely to occur. Symptoms of ovulation including mittleschmertz and midcycle mucus changes also help identify the fertile time.[168] Temperature charts may be used to indicate the end of the fertile time as the basal body temperature rises after ovulation. Ovulation timing by measurement of estrogen and progesterone metabolites in urine, urine or serum LH levels or ovarian ultrasonography may also be used.

General Health Aspects

Although life-style factors are probably of little relevance to fertility in most Western societies, healthy living has positive long-term benefits and will not affect the semen adversely. The following are advised: weight reduction for the obese; alcohol intake reduction for the moderate to heavy drinker; avoidance of social drugs, including tobacco; reduction of stress in the workplace, marriage, and that engendered by the infertility; and avoidance of heat from frequent sauna and spa baths.

Empirical Treatments: Evidence based versus unconfirmed treatments

Treatments of some causes of male infertility are available as discussed above but for the majority of patients with abnormal semen analyses there are no methods of proved effectiveness. A medical or surgical treatment may become established because it is logical and obviously effective - for example, gonadotropin treatment for Kallmann syndrome or vasoepididymostomies for post inflammatory obstructions of the tails of the epididymides. But in other situations where semen quality is reduced and there is subfertility rather than absolute sterility, it is necessary to demonstrate the treatment increases semen analysis results and pregnancy rates by a clinically meaningful amount. This evidence based medicine approach generally requires controlled clinical trials of promising methods. These trials are usually designed to detect a certain magnitude of difference in the primary responses and thus a positive result supports the use of the method.

However if the trial is negative, it merely does not confirm the magnitude of benefit tested, but it does not prove the method is of no value. In time the results of several trials can be combined by meta-analysis to get better estimates of the overall effects of the method. In the past many treatments were used in uncontrolled fashion for defects of sperm production.[137] Androgens have been given to suppress spermatogenesis in the hope that there would be "rebound" improvement after the treatment is stopped. Low-dose testosterone or weak androgens, such as mesterolone, have been given in the hope of improving epididymal maturation of sperm. hCG has been given for similar reasons. Antiestrogens have been used to increase gonadotropin secretion or gonadotropins - FSH and hCG - given to "stimulate" spermatogenesis. Antibiotics and anti-inflammatory drugs have been given for subtle infections for inflammations in the accessory sex organs. Antioxidants, amino acids, vitamins, herbs, and minerals such as zinc, cold baths and testicular coolers have been used. There are difficulties with the interpretation of the results of these treatments.[137] Marked improvements in semen quality can occur spontaneously (Figure 7).

Figure 7. Sperm concentration and motility in a man with severe oligospermia and severe hypospermatogenesis included in a therapeutic trial of clomiphene. Semen quality improved and his wife conceived. He was given the placebo! (Baker HWG: Requirements for controlled therapeutic trials in male infertility. Clin Reprod Fertil 4:13-25, 1986.)

Semen analysis results also display the phenomenon of regression to the mean: on average repeated semen analyses improve in men with initially abnormal results.[174] A good example of this is shown in a trial of zinc and folic acid in both oligospermic and normospermic men. Mean sperm concentration increased slightly in all oligospermic groups and in one group the increase was statistically significant. In contrast there was no consistent change in the mean sperm concentration in the normospermic groups.[175] Pregnancy rate data were not analyzed effectively in many early studies. Floating numerator pregnancy rates, in which a percentage of patients pregnant is given without regard for time of exposure have caused confusion in the infertility literature. Statistical methods for life table analysis and regression analysis with censored data are especially useful for assessing the impact of groups of variables on pregnancy rates, for analysis of prognostic factors, and for testing results of therapeutic trials.[137]

The empirical treatments either have not been submitted to adequately controlled clinical trials, or when they have, the trials have not shown consistently positive results. Meta-analyses have also produced conflicting results probably because of variable quality of the trials included in the analyses.[176, 177] Until there is sound evidence of the value of a drug or procedure from controlled therapeutic trials, patients should be advised that none of the empirical methods meet the requirements of evidence based medicine.

AIH is widely practiced with dubious evidence of efficacy in patients who do not have coital difficulties. Ovulation induction with intrauterine artificial insemination probably does increase the pregnancy rates by increasing the number of oocytes exposed to the sperm.[178, 179] Results are lower with timed intercourse and multiple ovulation induction.[179] Generally the results are poor when the semen analysis is abnormal[178] While this may be acceptable in countries where ART is expensive, the risk of multiple pregnancy is substantial. IVF or ICSI would be preferable because the number of pre-embryos placed in the uterus can be controlled and high multiple pregnancies avoided.

IVF/ICSI FOR MALE INFERTILITY

ICSI has revolutionized the management of male infertility. It involves the injection of single sperm into the ooplasm (Figure 8).[180-182] ICSI can be used with almost any live sperm with an expectation of results close to those obtained with standard IVF using normal sperm. ICSI may not be needed with mild semen disorders. Provided that more than about 2 million motile sperm can be harvested from an ejaculate, IVF can be attempted with an expectation of success close to that of IVF for other indications. The outcome depends particularly on sperm morphology and the ability of the sperm to bind to and penetrate the zona pellucida. ICSI should be offered if there is a chance of failure of fertilization with IVF: less than 2 million motile sperm per ejaculate, less than 5 per cent of sperm with normal morphology, less than 5 per cent of sperm with progressive motility and sperm autoimmunity with positive immunobead tests and zero sperm mucus penetration.[79, 132]]

Figure 8. Intracytoplasmic sperm injection.

Preparation of the patients

The couple needs to be counseled carefully about the procedures, predicted chance of a live birth and the possible complications. Special preparation of the man may be required. Trial-run sperm preparations help to identify those patients who have difficulty collecting semen. These patients should practice collections before attending for the IVF procedure. Men with many inflammatory cells in the semen could be treated with antibiotics. Those with low motility or sperm autoimmunity may have better sperm motility with short, 1-2 day durations of abstinence. Cryopreserved semen can be used as backup if the fresh semen is particularly poor on the day of ICSI in patients with fluctuating semen abnormalities. This is particularly useful when sperm are present in the semen only intermittently. Those patients who produce an unexpectedly poor sample on the day of IVF should provide a second sample later to supplement the first sample. Electroejaculation or needle biopsy of the testes can be used if the man is unexpectedly unable to collect semen.

Patients with genital tract obstruction can have sperm retrieved from the testis or epididymis by needle aspiration.[112] With persistent azoospermia and severe spermatogenic disorders such as Sertoli cell only syndrome or germ cell arrest in diagnostic biopsies, it may be possible to obtain sufficient testicular sperm for ICSI by extensive open biopsies. Examination of exposed testicular tissue under the operating microscope may allow selection of the larger diameter tubules which are more likely to contain more advanced spermatogenesis.[183, 184] However with no elongated spermatids seen in diagnostic biopsies the success rate is low.[185] Therefore the use of donor sperm or oocyte freezing if elongated spermatids can not be obtained should be discussed during preparation of the couple.

Approaches

The standard approach is to stimulate multiple ovarian follicular development with FSH and collect the oocytes by ultrasound guided transvaginal needle puncture of the ovaries after administration of hCG. ICSI or IVF is performed and the resulting embryos transferred into the uterine cavity at the two- to eight-cell stage with cryopreservation of remaining embryos. The frozen and fresh embryos of the same stage and quality produce similar implantation and pregnancy rates.
Various alternatives are also available. For example, GIFT is possible with mild semen abnormalities.

Embryos may be transferred into the fallopian tubes. Growth of the embryos in vitro for five to six days to blastocysts before transfer might improve implantation rates but proof that blastocyst transfer improves the efficiency of IVF is lacking. Biopsy of blastomeres for detection of chromosomal and genetic abnormalities is possible and will increase in use as more conditions causing serious hereditary diseases or defective embryo development are able to be diagnosed.[17]

Sperm Preparation

Various procedures have been developed for sperm preparation for IVF. Most popular are the "swim-up" procedure and centrifugation on gradients of colloidal silica.[186] Cryopreserved samples require especially gentle handling, particularly with dilution of the semen cryoprotectant medium with culture medium. Motility, even just an occasional slight twitch of the tail, is preferred in selecting sperm for ICSI. The morphology of the sperm cannot be assessed in detail at the magnification used but obviously grossly abnormal sperm would be excluded. If no motile sperm can be found various motility stimulants or hypoosmotic swelling can be used to show that the sperm are alive.[73, 187]

Results

With IVF and ICSI 60 per cent of oocytes fertilize and cleave normally over the first 48 hours. Live birth pregnancy rates for each fresh or cryopreserved embryo transferred on day 2 or 3 are about10-15 per cent in most clinics. [180, 181, 188] If two embryos are transferred at each procedure the chance of a successful pregnancy is cumulative: about 18 per cent after the first transfer, 33 per cent after two transfers, 45 per cent after three transfers, and 70 per cent after six transfers. About 20 per cent of the pregnancies resulting from transfer of two embryos produce twins.[188] A number of factors are known influence the success of IVF including embryo quality, number transferred and female age.[189] Implantation and pregnancy rates fall and pregnancy losses increase after age 35 mostly due to increasing abnormalities in the oocytes.

In general, the outcome is the same for the embryos obtained with either normal semen or abnormal semen by either standard IVF or ICSI.[188] The implantation rate, pregnancy wastage, perinatal mortality, and risk of congenital abnormalities are no greater than with patients who have IVF for other indications (Table 4). Low birth weight is slightly increased in IVF and ICSI children for unknown reasons. Congenital malformation rates also seem higher but this may be the result of including those in pregnancies terminated or ending in stillbirth. Reporting of malformations may also be more complete than for the general community.[190]

Evaluation of Failed Fertilization

When most or all oocytes fail to fertilize in IVF, the cause is usually defective sperm. On rare occasions the oocytes do not fertilize because of immaturity or abnormality, but this appears to be an unusual cause of total failure of fertilization of all the oocytes retrieved from a woman.[79, 81, 82] Studies with computer image analysis show that particular defects of sperm shape impair sperm-zona pellucida binding.[191] The shape of the acrosome area of the sperm head appears to be particularly important. Although some workers have reported patients that appear to have isolated defects of the sperm zona receptors these appear to be very rare, as poor sperm-zona binding is very uncommon in the absence of an obvious defect of sperm morphology.[79, 192] Thus careful evaluation of the semen quality before IVF should reveal those cases with defective sperm morphology and allow the couples to be warned that failure of fertilization is a possibility.[79]

Patients with idiopathic infertility can also be screened for disordered zona pellucida induced acrosome reaction and in confirmed cases ICSI is recommended to avoid failure of fertilization with standard IVF.[82] Unexpected failures of fertilization should be evaluated carefully, including examination of the number of sperm on the ZP and penetrating into the zona. With severe sperm defects, failure of sperm to bind to the zona or reduced sperm binding to the zona is common.[79] Failure of fertilization may also result from undiagnosed sperm autoimmunity, the presence of sperm antibodies in maternal serum, infected semen, or technical defects in the IVF laboratory.[131]
ICSI of unfertilized oocytes with the man's sperm 12 to 24 hours after standard IVF insemination may result in fertilization and pregnancy, but overall, the results are poor and many units would not perform this "ICSI rescue" procedure. Reinsemination of failed fertilization oocytes with donor sperm is also possible for diagnostic or therapeutic purposes. This procedure is not permitted in some countries.

Individual oocytes may not fertilize with ICSI. In these, the sperm head is often only partially decondensed. Failure of fertilization of all oocytes with ICSI is rare. Globospermic and immotile sperm have been found to produce low fertilization rates with ICSI. These sperm may not decondense after ICSI. The couples may need to consider other alternatives, such as donor insemination or adoption.

Complications of IVF/ICSI

Risks for the woman.
The ovarian hyperstimulation syndrome is a major risk with gonadotropin stimulation of multiple follicular development. Careful monitoring of the patients is necessary. If many follicles develop, embryo freezing rather than transfer avoids pregnancy and allows the ovaries recover, reducing the risk of severe complications such as thromboembolism, renal failure and death. Surgical complications including bleeding and infection from the oocyte collection procedure are rare. There are also small risks of complications from anaesthesia and sedation. Concerns about the ovarian stimulation drugs predisposing to breast or gynecological cancers appear to be unfounded.[193]

Risks for the child.
The known genetic risks are covered above. The mechanisms involved in the causation of the common forms of male infertility associated with oligospermia, asthenospermia and teratospermia are not understood. The sperm in the semen have a multitude of abnormalities in addition to those tested with standard semen analysis.[73] There is a correlation between the production of abnormal sperm and abnormal sperm DNA measured by the variety of techniques including acridine orange fluorescence, sperm chromatin structure assay and other techniques for DNA breaks including chromomycin staining, TUNEL and rocket assays.[194-197] Sperm with redundant cytoplasm are common in abnormal semen samples and these can be detected by a variety of methods including measurement of cytoplasmic enzymes such as creatine kinase.190 These sperm produce reactive oxygen species which can be assayed. [73, 196, 197] It is postulated that abnormal reactive oxygen species production could damage not only the sperm plasma membrane but also sperm DNA. Aitken et al.[196, 197] has shown that at low concentrations the ROS may enhance sperm function, in particular the ability to fuse with the oocyte membrane and yet the sperm may carry the damaged chromatin which could manifest later after fertilization as defects of implantation or pregnancy loss. However, the results of ICSI to date do not do not reveal such problems. The fertilization, implantation and pregnancy failure rates and congenital malformation rates are no greater with ICSI than with standard IVF (Table 4).[188, 190] It is possible the abnormal sperm with redundant cytoplasm are excluded in natural or assisted fertilisation by sperm aggregation caused by heavy coating with clusterin.[198]

On the other hand, a two to three fold increase in sex chromosomal aneuploidy has been noted with ICSI related to increased rates of chromosomal non-disjunction as a general association with abnormal spermatogenesis.[199-202] The treatment of rare patients with Klinefelter syndrome who produce some sperm has suggested this. An extra X chromosome in a male germ cell results in its death. Spermatogenesis in Klinefelter testes results from non-disjunction with loss of one X chromosome so that a clone of XY spermatogonia results. Animal studies of spermatogenesis in XXY testes show XY spermatogonia.[202] Natural fertility, confirmed by genetic testing, has been reported with Klinefelter syndrome. Early experience with ICSI with sperm obtained from the testes or semen of men with Klinefelter syndrome produced embryos and babies with normal karyotypes.[100, 101] This has now been confirmed by a number of groups and XXY embryos are rare.[203, 204] However chromosome analysis of sperm from men with typical or mosaic Klinefelter syndrome has revealed an increased frequency of sex chromosome aneuploidy. [200-202] Work in the mouse suggests this results from segregation errors during cell division from XY stem spermatogonia and raises the possibility that this is an associated feature of severely compromised spermatogenesis and could account for the increased sex chromosomal aneuploidy rate seen with ICSI embryos.[202]

Detailed follow up of children born as a result of ART has not revealed any particular congenital malformation or increased rate of malformations. However, pregnancy wastage, prematurity, Caesarian section rates and neonatal mortality and morbidity are increased mainly because of the multiple pregnancies, female age and pre-existing infertility. The results are similar with ICSI (Table 4). Studies suggesting increased congenital malformations rates and reduced intelligence in male babies after ICSI are unconfirmed.

USE OF DONOR SPERM

Donor insemination is a common method of managing male sterility.[205-211] Sperm banks may be involved in about 1 in 200 births in countries where the use of donor sperm is permitted. The main indications for donor insemination are untreatable sterility in the male, or where treatments and ICSI for severe or chronic subfertility have failed. The couple may choose donor insemination as the primary method of managing their infertility. Rarely, donor insemination is used because of genetic abnormalities in the male. Donor sperm may also be used in IVF when there is a combination of female infertility and male sterility. Because of the higher pregnancy rates, IVF with donor sperm may be used if donor insemination fails.[208] Donor sperm may also be used in IVF procedures as a backup, for example, when testicular sperm aspiration is to be attempted for severe spermatogenic defects and there is doubt whether sperm will be obtained.

Cryopreservation of Semen

Donor insemination can be performed in the setting of a specialist infertility clinic with patient counseling, ovulation monitoring, and insemination procedure available.[Barratt, 1993 #11321;[McGowan, 1983 #6929] Alternatively, the sperm bank may only supply semen for the patient and be separate from the clinics or physicians performing the artificial insemination. Because of the risk of transmission of infectious diseases, particularly human immunodeficiency virus (HIV) and hepatitis B, and also for convenience, donor insemination services now use only cryopreserved semen.[205-208] Semen cryopreservation with glycerol-egg yolk cryoprotectant and either vapor freezing or controlled-rate freezing in plastic straws or vials produces pregnancy rates equal to those with fresh semen.[205] Importantly, cryopreservation allows the semen to be quarantined for six months for donors to be recalled and retested for infectious diseases, particularly HIV, before any is used.

Selection of Donors

Prospective donors have their medical and family history evaluated and a physical examination to exclude the possibility of transmitting serious genetic diseases such as hemoglobinopathies or sexually transmissible infections. Donors sign a life-style declaration to indicate that they are not involved in any practices that might expose them to serious infections, such as HIV. There usually is an upper age limit of 40 to 45 years because of the increasing frequency of genetic abnormalities in sperm with age. Semen quality is selected to be in the upper part of the normal range, particularly for concentration and motility.[205, 208] The semen is cultured for bacteria and blood tested for hepatitis and HIV antibodies. The freezing of semen does not appear to cause any increase in the frequency of congenital abnormalities.[205, 208]
It is usual to match the physical characteristics of the recipient's husband and the donor including race, complexion, build, height, hair color, and eye color. In addition, blood groups may be matched. In some programs the recipient couple may be able to choose the donor on other information such as occupation and education. Known donors may also be used; these may be friends or relatives of the infertile couple. In this situation special counseling of the donors and recipients is necessary. Also, there should be a full workup of the known donor as for an anonymous donor, including cryopreservation and quarantining of the semen.
Donor factors relevant to the success of donor insemination are mainly to do with the quality of the semen. Post-thaw motility has the strongest predictive value for high fertilization rates, but sperm morphology, motility, and concentration are also significant.[205, 206] Despite selection of high-quality semen, there remains considerable variability in the pregnancy rates between donors. A policy to discard semen from a donor who produces no pregnancy after a certain number (e.g. 20 to 40) of inseminations is necessary.[206]

Counseling

The special nature of the use of donor sperm needs to be discussed in detail with the couple so that they are fully aware of the implications of having a child by donor. Donor insemination is forbidden in some religions. There may be local legislation or regulations to control the use of donated gametes. In some countries special laws have been enacted that may either allow or prevent the child from obtaining identifying information about the donor. The legal status of the child may also be specified in various ways. The couple needs to decide how and when to disclose the child's donor sperm origin. What and how much they should tell their friends and relatives about their infertility treatment should also be discussed, as should their reaction to acquaintances questioning the paternity of the child. The possibility that in the future half-siblings may unwittingly find each other and attempt to have children is of concern to some prospective parents and donors. This needs to be discussed carefully and the risks explained in view of the number of pregnancies permitted per donor by the clinic. Studies of donor families where there has been expert pretreatment counseling, indicate no physical or emotional problems with the children and greater marital stability than average.[209-211] Some donor offspring resent being told late about their donor conception and not having access to identifying information about the donor.

Procedures and Results

The prospective recipients are screened for HIV, hepatitis B and C, rubella immunity, blood group, and genetic conditions if necessary. Tests of tubal patency are performed if the history suggests pelvic pathology. The inseminations are timed to coincide with natural ovulation. Pregnancy rates with donor insemination are about 10 to 25 per cent per month for the first five to six months and then 5 to 10 per cent thereafter, so that about 50 per cent of women are pregnant by six months.[205, 208] Female age affects the pregnancy rates. Women over 35 have lower pregnancy rates than those under 35; for example, 65 per cent pregnant by one year under 35, and 50 per cent pregnant by one year over 35.[169, 205] Women with subfertile male partners have on average lower pregnancy rates than those with sterile male partners, indicating the presence of female factors contributing to the infertility when the male partner is subfertile.[205] Cumulative pregnancy rates for women who have had more than one pregnancy by donor insemination indicate higher conception rates over the first few months for the second pregnancy, about 33 per cent pregnant in the first cycle and 55 per cent by the second cycle.[205]
Multiple ovulation induction and intrauterine insemination may increase the pregnancy rates but at the risk of multiple pregnancy.[207] IVF may be used if no pregnancy has occurred after a reasonable number of inseminations, for example, 6 to 12.[208] Live birth pregnancy rates with IVF in such patients are high (25 to 33 per cent pregnant per attempt) and couples can be advised that they have an 80 per cent chance of having a child within two years.

PREVENTION OF INFERTILITY

Prevention is difficult because of the lack of understanding of the causes of most types of male infertility.[7, 27, 212] Mumps orchitis is such a rare cause of infertility, immunization for this disease will have little impact. It is important to recognize that subfertility often is a couple problem, both partners contributing. Therefore, general factors that would change a society's attitude to child-bearing could have an important impact on the frequency of infertility, for example, a trend toward having children at earlier ages. On the other hand, toxins and environmental factors known to cause defects of sperm production, such as dibromochlorobenzine, lead, benzene, ionizing radiation, and microwaves, are probably well controlled by environmental health measures.[52-63]

Preventable Diseases and Conditions

Sexually transmissible infections.
Postgonococcal epididymal obstructions appear to be the most important cause of infertility from sexually transmitted diseases. In countries where gonorrhea is treated promptly, postgonococcal epididymal obstruction is rare. On the other hand, it remains a common preventable cause of infertility in other countries.[5]

Undescended testes.
Although undescended testes have been sought and treated aggressively over the past 50 years, previously undescended testes remain a common association of male infertility, affecting about 7 per cent of the men seen.[7, 35-39] It is, therefore, uncertain whether early surgery for undescended testes has any impact on subsequent fertility. It is possible that the failure of normal descent is a feature of testicular dystrophy and that the sperm production will be poor whether or not the testes are placed in the scrotum. Because men who have had one testis removed usually have semen quality within normal limits, men with a unilateral undescended testis would not be expected to have poor semen unless there was an additional disorder of spermatogenesis in the contralateral descended scrotal testis. Thus, although orchiopexy is important for cosmetic aspects and reducing the risk and improving the ease of checking the testis for malignant change, it is not certain whether early orchiopexy preserves or promotes fertility.[40-42]

Varicocele.
As discussed above, the effectiveness of varicocelectomy for sperm defects is controversial.[138, 152-166] Varicoceles are common and usually appear about the time of puberty. Although some groups believe that varicoceles should be sought actively and treated in adolescence to prevent infertility, this approach could pose a major burden on the health resources because at least 15 per cent of men have varicoceles. Long term prospective trials are needed.

Vasectomy.
Vasectomy reversal and treatment for continuing infertility after attempted vasectomy reversal are now common.[213] Better counseling about the limited effectiveness of vasectomy reversal is needed. Cryopreservation of semen before vasectomy in men who are uncertain about their need for future fertility should be promoted. Also, cryopreservation of semen after vasectomy reversal, if the quality is adequate, is worthwhile because restenosis of the vasovasostomy sites can occur.

Semen Cryopreservation before Loss of Fertility

Men about to have treatment for malignant conditions may have sperm cryopreserved before commencing chemotherapy or radiotherapy.[46-48, 214] While pretreatment semen quality may be too poor for AIH, ICSI now has improved the outlook for successful pregnancies.[215] While the risks of having a child with a serious malformation or defect are difficult to estimate in humans semen collected during chemotherapy or radiotherapy must not be used because of the likelihood of induced mutations. [216, 217] Other illnesses that require treatment that might cause sterility include nephritis, prostatic disease, and inflammatory bowel diseases. Infertile men with conditions such as orchitis or Young syndrome that might involve progressively declining semen quality should also store any live sperm that can be obtained as insurance for the future. A similar approach could be extended to adolescents with risk factors for infertility such as undescended testes in childhood, testicular torsion and also possibly, a family history of infertility or a father with a Yq microdeletion. While the frozen sperm are only used by a small proportion of men who store semen the service continues to provide insurance for future fertility.[218] Some groups are offering to cryopreserve prepubertal testicular tissue prior to potentially sterilizing treatments in the expectation that effective techniques for transplantation or in vitro production of sperm will be developed in the future.[219, 220]