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| Chapter 7 - Clinical Management of Male Infertility | ||
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This section addresses the management of sperm autoimmunity, male genital tract obstructions, coital disorders, genital tract inflammation, and varicocele. Treatment of gonadotropin deficiency and androgen replacement therapy are covered in Chapters by Hayes and Pitteloud, and Handelsamn.
Sperm autoimmunity is present in 6% to 10% of infertile men.35 They have sperm coated with antibodies to the extent that sperm function is impaired, particularly sperm - mucus penetration and sperm zona-pellucida binding, resulting in severe infertility. Natural pregnancy rates without treatment are very low and fertilisation rates with standard IVF are low or zero. Other men have positive IBT, sometimes with only to tail tip binding and normal or only marginally impaired mucus penetration.65 These low-level sperm autoantibodies are probably irrelevant to the infertility and other causes of the couple’s infertility should be sought. Sperm autoimmunity can be treated by glucocorticoids in immunosuppressive doses. Antibody levels fall and semen quality improves in about 50% of patients and about 25% produce natural conceptions during a 4-6 month course of treatment.35 There are significant risks of severe side effects particularly aseptic necrosis of bone. The superior results of ICSI make this treatment obsolete and only useful in exceptional circumstances.
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. 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. The presence of sperm antibodies in blood serum by indirect IBT indicates sperm are being formed but is an adverse prognostic factor for successful surgery. With bilateral congenital absence of the vasa 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. Rectal ultrasound shows absent or atrophic seminal vesicles with bilateral congenital absence of the vasa but with ejaculatory duct obstruction the seminal vesicles and ejaculatory ducts are dilated and the cause of the obstruction may be obvious such as a cyst of the prostatic utricle.96 Testicular biopsy is usually normal but there may be some reduction in spermatogenesis either as a coincidence or as a result of the obstruction, particularly after vasectomy.97
Degeneration of the Wolffian duct structures occurs with cystic fibrosis gene mutations but can be of variable extent. Although most often only the heads of the epididymides are palpable, some men with bilateral congenital absence of the vasa have parts or all of the epididymides and scrotal vasa present with absent or atrophic pelvic vasa and seminal vesicles. Young’s syndrome which is now rare, is not related to cystic fibrosis gene mutations. The pathology shows inspissated material in the head of the epididymis, and there are lipid inclusions in the epithelial cells.41, 42 As some men with this syndrome have fathered children, the blockage may develop in adulthood.
Post-inflammatory 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 or destruction of the prostate and seminal vesicles. Back pressure blowout obstructions in the epididymis are frequent after vasectomy. 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.
Men with persistent azoospermia, normal testicular size, normal virilization, and normal FSH levels can be assumed to have obstruction until proved otherwise. As many as 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.6, 13 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.98 Distal obstructions are important to diagnose because they may be reversed at transurethral endoscopy.96 It is important to test for sperm in urine after ejaculation in patients with possible ejaculatory duct obstruction as partial retrograde ejaculation can produce the same the semen characteristics as ejaculatory duct obstruction (Table 5). Also large cysts causing ejaculatory duct obstruction can affect the bladder neck and cause retrograde ejaculation.
Female partners of men with bilateral congenital absence of the vasa should be screened for cystic fibrosis gene mutations and the couple counseled accordingly. Preimplantation or prenatal genetic diagnosis may be performed if mutations are found in both partners. 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 with the couple. Sperm retrieval for ICSI, either from the testis or other parts of the genital tract, is an alternative to surgery.91 ICSI is also used when reconstructive surgery is not possible, the female partner has an infertility problem, or the couple cannot wait 6 to 12 months to have a reasonable attempt at conceiving naturally after surgery. For ICSI, sperm may be obtained by testicular biopsy or percutaneous sperm aspiration from the epididymis under local anesthesia. If a 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.
Treatment of male genital tract obstructions is best undertaken by specialist microsurgeons.98 The testis is exposed and the most proximal (to the testis) level of obstruction determined. 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. Microsurgical anastomosis between the ends of the vas or between the vas and the epididymal tubule is then undertaken.
Vasovasostomy and vasoepididymostomy for caudal blocks produce relatively good results, with 50% to 80% of patients having sperm present in the semen. However, less than half of these produce a pregnancy within the first year.98 There may be continuing obstruction, sperm autoimmunity, or coexisting spermatogenic disorders. The results of vasoepididymostomy for proximal blocks are poor. Although sperm may appear in the semen, pregnancies are extremely uncommon after vasoepididymostomy for caput epididymal blocks. In contrast, the results of ICSI with testicular or epididymal sperm, fresh or after cryopreservation, are similar to those obtained with sperm from semen.91
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.7, 13, 23 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. 7 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. 82 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.
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 or opioid for chronic pain. 7, 105 Other hormones and drugs can cause gonadotropin suppression. 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. 31, 32
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. 7, 23 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. 13, 82 Gonadotropin deficiency caused by of gonadotrophe destruction or
abnormalities of the GnRH receptor require treatment with
gonadotropins. 125 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.
Male coital disorders impacting fertility include erectile dysfunction (impotence), failure of ejaculation, and retrograde ejaculation. Many men have problems with sexual performance after first learning about their 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.6
Erectile dysfunction may be associated with low libido from androgen deficiency with primary or secondary hypogonadism. (This topic is considered in detail in the Chapter of Bochinski et al.) Erectile dysfunction related to vascular or neurologic 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 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.74, 99 Healthy men who cannot ejaculate with intercourse may be able to produce semen by masturbation, with a vibrator, or other stimulation.
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.
Recognition of a coital disorder is crucial and thus all infertile patients must discuss their sexual history in detail. Once recognized, the contribution of organic and psychological factors needs to be evaluated.
An optimistic prognosis can be given provided that live sperm can be obtained. The couple is advised about the various techniques that might be used for collecting the sperm for artificial insemination or other ART. The woman’s potential fertility must be evaluated.
A drug, such as an antihypertensive or a tranquilizer, that may be contributing to the sexual disorder should be stopped temporarily or permanently.36 Erectile dysfunction may respond to sex behavior therapy, administration of phosphodiesterase 5 inhibitors, intrapenile injections of vasodilators and physical approaches with pumps and rubber occlusion devices to initiate and maintain erections or penile implants, but these are seldom 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 phosphodiesterase 5 inhibitors, imipramine, or cholinergic antihistamines, such as brompheniramine or ephedrine.99 Others require more powerful stimulation with vibrators or electroejaculation.74 If these are unsuccessful, sperm may be collected by needle biopsy of the testis.100
If semen can be obtained by 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 symptoms of ovulation or luteinizing hormone surge detected with a urinary luteinizing hormone dipstick kit. Cryopreservation of samples for AIH or ICSI may also be possible.
Ejaculation may be stimulated by applying a vibrator to the underside of the penis near the frenulum of the glans. Vibrators with a 2-mm pitch and frequency of 60 Hz or more are most effective. Men with complete spinal cord injuries below T10 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 are no burns or other damage to the rectum. A balloon catheter in the bladder is used to prevent retrograde ejaculation.74
Semen obtained by assisted ejaculation from able-bodied men or in the acute stages of spinal cord injuries is often normal.74 In contrast, with chronic spinal cord injury, there is frequently low volume, high sperm concentration, and poor motility.74 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 T6.74 The resulting uncontrolled hypertension may cause cerebral hemorrhage. Careful monitoring of blood pressure and prophylactic nifedipine treatment usually prevents serious problems. 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.101 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 approximately 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.
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 whom 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 salazopyrine used for treatment of inflammatory bowel disease or arthritis, testosterone administration, anabolic steroid abuse, long-term high-dose opiate use, and febrile illnesses causing transient reduction of spermatogenesis.36 Workplace exposures may be implicated in some patients, but the association is rarely clear-cut enough to advise change of occupation.52, 53
The adverse effect of acute febrile illness on the semen quality is well known but only occasionally seen.36, 38, 39 Frequent hot baths or saunas may also have a similar effect. There is a temporary suppression of spermatogenesis that recovers over 3 to 6 months. Whether increased scrotal temperature because of clothing, varicocele, obesity, or environmental temperature contributes to male infertility is controversial.
Suppression of gonadotropin secretion can occur with critical illness such as hepatic failure, myocardial infarction, head injury, stroke, respiratory failure, congestive cardiac failure, sepsis, burns, starvation, general anesthesia and severe stress, both psychological and physical.36 Transient decreases occur after 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 sex hormone–binding globulin 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.36
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.102 Simple obesity may be associated with alterations in the hypothalamic-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, sex hormone–binding globulin levels and gonadotropin levels may be low and estrogen levels elevated. There are reports of hypogonadotrophic hypogonadism associated with gross obesity and indications that it can be treated with aromatase inhibitors.103, 104 However, clinical androgen deficiency, estrogen excess, and abnormal semen analysis are not regularly seen in moderately obese men and the cause and effect relationship is not clear. It may be reduced testicular function predisposes to or aggravates obesity.
Impairment of testicular function is common in uncontrolled or poorly controlled chronic diseases.36 There are usually elevated gonadotropin levels, indicating a primary testicular defect, but impaired gonadotropin secretion, hyperprolactinemia, changes in sex hormone–binding globulin, and increased aromatization of androgens to estrogens may occur. Although this pattern of abnormal 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 classic conditions known to have a profound adverse effect on the male reproductive function. Testicular function may recover after 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, HIV infection, lymphoma, leukemia, advanced metastatic cancers, rheumatoid arthritis, severe cardiac disease, and chronic respiratory disease.
Drugs may contribute to male infertility by affecting gonadotropin (e.g., steroids, opiates) or prolactin secretion (psychotropic agents), or spermatogenesis (salazopyrine, alkylating agents) or by reducing sexual performance (psychotropic and antihypertensive drugs). Some drugs may also cause gynecomastia (antiandrogens, estrogens).36, 105
There is currently no place for testosterone treatment of infertile men, either continuously for low testosterone levels resulting from primary or secondary testicular failure, or as "testosterone rebound" therapy because testosterone suppresses gonadotropin secretion and reduces spermatogenesis. Abuse of androgens is widespread in people hoping to enhance athletic performance or bodybuilding. Some men are seen for infertility with azoospermia or oligospermia as a result. Others have sexual performance problems after stopping drug use. The patient may conceal the abuse. Normal virilization but low testosterone, low sex hormone–binding globulin, and low, normal, or transiently high gonadotropin levels may be seen. Recovery can take several months sometimes longer than 12 months , particularly after depot anabolic steroids.
Salazopyrine 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 sulfapyridine 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.36, 105
Specific inflammations of the genital tract such as mumps orchitis or gonococcal epididymitis may cause sterility. Nonspecific inflammations in the accessory sex organs are more common in men with infertility than in fertile men.6, 106-109 Also, male accessory sex organ inflammation and infertility may be more important in some countries than in others.6 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 in 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.106
To have more than 1 million polymorphs per milliliter in semen, as determined by peroxidase reaction or monoclonal antibodies to leukocyte antigens, is considered abnormal.60 Although inflammatory cells could damage sperm by releasing oxygen free 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.108, 109 Routine cultures of semen are not warranted except for sperm donors.
General Management
Men with clinical evidence of prostatitis require full urologic assessment.110 Specific infections with pathogenic agents are treated with appropriate agents. It remains unclear what should be done about asymptomatic pyospermia and nonspecific male accessory gland inflammation. Therapeutic trials generally show no benefit from antibacterial therapy on semen quality.111, 112 Antibiotics or other agents may be used if it is thought that 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.111, 112 Increased frequency of ejaculation to facilitate drainage of the accessory glands and stress management may also help.
The mechanism by which varicoceles cause infertility and the effectiveness of treatment in improving semen quality and natural fertility are controversial.6, 8, 113-115
Varicoceles are found in approximately 25% of men being examined for infertility. An additional 15% may have a subclinical left varicocele indicated by a faint cough impulse in the spermatic cord or increase in diameter of the veins on ultrasound.6, 8, 113 Varicoceles are also found in fertile men. 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, in Kallmann and Klinefelter syndromes. When there is a moderate to large left varicocele, the left testis is usually smaller than the right testis.
Men with varicoceles generally have poorer semen quality than those without varicoceles.113, 116 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, ROS generation and interference with the heat exchange function of the pampiniform plexus.113 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.
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. Varicocele may be an association rather than the cause of a couple’s infertility. Therefore, full evaluation of other aspects of male and of the female partner is necessary.
The value of treatment of varicocele for infertility is particularly contentious.113-115 One view is that treating varicoceles may not improve fertility; therefore, the varicoceles should only be treated for other reasons, such as symptoms.8, 114 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.115 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.117
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 coils that promotes clotting in the veins. They have lower morbidity than surgery under general anesthesia, but relatively high failure and recurrence rates. 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. Successful venous occlusion will relieve pain and reduce the size of large varicoceles. Whether semen quality and fertility are improved is not certain.
Because varicoceles are so frequent, treatment of varicocele for infertility became common and several large series were published with claims of high success rates for improving semen and fertility. Floating numerator pregnancy rates averaging 35% (range, 20%–60%) 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.118 Although 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. Most exponents of varicocele treatment regard azoospermia as a bad prognostic sign, especially if the FSH level is elevated.
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.8, 114 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, approximately 250 pregnancies are required to have a high chance of finding a 25% increase in pregnancy rate after treatment significant at the 5% level.13
So far, the trials have produced conflicting results and meta analysis does not support varicocelectomy improves fertility.114 But the trials are generally small and have problems. For example, the World Health Organization set up a multicenter controlled trial of Palomo ligation in men with infertility of more 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.119 There was a substantial effect on pregnancy rate. Two pregnancies occurred in 20 couples during the 1 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 1 year being 35% for the operated group and 17% for the un-operated group (relative pregnancy rate, 2.7; 95% confidence interval, 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 1 year after the operation was 21%. However, there were possible irregularities of randomization in some centers early in the trial and high dropout rates, and the results were not published in detail.113 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.8, 120
Thus, although 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. Although better trials are needed, meta-analyses do not support treatment of varicocele for infertility. It is clear that normal fertility is not achieved in a high proportion of patients treated for varicocele. ART is a realistic alternative for most couples who have not conceived after a reasonable time.
| Chapter 7 - Clinical Management of Male Infertility | ||
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