Best Practice Policies for Male Infertility

0022-5347/02/1675-2138/0 THE JOURNAL OF UROLOGY® Copyright © 2002 by AMERICAN UROLOGICAL ASSOCIATION, INC.®

Vol. 167, 2138 –2144, May 2002 Printed in U.S.A.

BEST PRACTICE POLICIES FOR MALE INFERTILITY JONATHAN P. JAROW,* IRA D. SHARLIP,† ARNOLD M. BELKER,‡ LARRY I. LIPSHULTZ,§ MARK SIGMAN,㛳 ANTHONY J. THOMAS, PETER N. SCHLEGEL,¶ STUART S. HOWARDS, AJAY NEHRA,** MARIAN D. DAMEWOOD,†† JAMES W. OVERSTREET AND RICHARD SADOVSKY FOR THE MALE INFERTILITY BEST PRACTICE POLICY COMMITTEE OF THE AMERICAN UROLOGICAL ASSOCIATION, INC. KEY WORDS: infertility, male; testis; oligospermia; varicocele; practice guidelines

The Practice Guidelines Committee of the American Urological Association, Inc. (AUA) commissioned a Male Infertility Best Practice Policy Committee (MIBPPC) in 1998 to bridge the gap in male infertility between leading edge science and clinical practice, and provide urologists, gynecologists, reproductive endocrinologists, primary care practitioners, reproductive researchers and other health care providers with guidance for excellence of care in this rapidly changing field. The MIBPPC chose not to create a comprehensive treatise on male infertility, but rather to focus on areas that are new, poorly understood, poorly standardized, controversial and/or rapidly changing. The MIBPPC divided its efforts into 4 interrelated sections: 1) optimal evaluation of the infertile male, 2) evaluation of the azoospermic male, 3) management of obstructive azoospermia, and 4) varicocele and infertility. A separate report was created for each topic. The reports were submitted to peer review by 125 physicians and researchers from the disciplines of urology, gynecology, reproductive endocrinology, primary care and family medicine, andrology and reproductive laboratory medicine. The reports were then reviewed and approved by the Practice Guidelines Committee of the AUA, the Practice Committee of the American Society for Reproductive Medicine (ASRM) and the boards of the 2 organizations. The reports were printed and distributed jointly by the AUA and ASRM in 2001. We reviewed each report of the MIBPPC. I. OPTIMAL EVALUATION OF THE INFERTILE MALE

Approximately 15% of couples are unable to conceive a child after 1 year of regular unprotected intercourse. A male factor is solely responsible in about 20% of infertile couples and contributory in another 30% to 40%.1 If a male infertility factor is present, it is usually defined by abnormal semen analysis. When semen analysis is normal, other male factors may still be present. It cannot be overemphasized that each partner of an infertile couple should be evaluated simultaneously. Purpose of the male evaluation. The purpose of the male evaluation is to identify potentially correctable conditions, irreversible conditions that are amenable to assisted reproductive techniques using the sperm of the male partner,

irreversible conditions that are not amenable to the aforementioned techniques and for which donor insemination or adoption is a possible option, life or health threatening conditions that may underlie infertility and require medical attention and genetic abnormalities that may affect the health of the offspring if assisted reproductive techniques are to be used. Identification and treatment of reversible conditions may improve male fertility and allow conception to occur with intercourse. Detecting conditions for which there is no treatment spares couples the distress of attempting ineffective therapies. Detecting certain genetic causes of male infertility allows couples to be informed about the potential to transmit genetic abnormalities to their offspring. Finally male infertility may occasionally be the presenting manifestation of an underlying life threatening condition. Failure to identify diseases such as testicular cancer or pituitary tumors may have serious consequences, including death in rare cases. When to do an initial screening evaluation for infertility. An initial screening evaluation of the male partner of an infertile couple should be performed if pregnancy has not occurred within 1 year of unprotected intercourse. Evaluation may be done before 1 year if a known male infertility risk factor exists, such as bilateral cryptorchidism, or if a female infertility risk factor exists, such as age greater than 35 years or if a man questions his fertility potential. Components of an initial screening evaluation. The initial screening evaluation for male factor infertility should include a reproductive history and 2 properly performed semen analyses. If possible, the 2 semen analyses should be separated by a period of at least 1 month. Reproductive history should include questions about coital frequency and timing, duration of infertility and previous fertility, childhood illnesses and developmental history, systemic medical illnesses and previous surgeries, sexual history, including sexually transmitted infections, and gonadal toxin exposure, including heat. While a man may have a history of fertility, it does not exclude the possibility that he has acquired a new male infertility factor. Such men should be evaluated in the same way as men who have never initiated pregnancy. When to do a full evaluation for male infertility. A full evaluation by a urologist or other specialist in male reproduction should be done if the initial screening evaluation demonstrates an abnormal male reproductive history or semen analysis. Further evaluation of the male partner should also be considered in couples with unexplained infertility and in couples in whom there is a treated female factor and persistent infertility. Components of a full evaluation. The minimum full evaluation for male infertility should include a complete medical and reproductive history, physical examination by a urologist or other specialist in male reproduction and at least 2 semen analyses. Additional tests may then be performed to evaluate specific problems or questions identified by the history, physical examination and/or semen analyses. Medical History: The medical history should include the reproductive history, as described in the initial screening

Accepted for publication December 14, 2001. * Financial interest and/or other relationship with Bayer and Pfizer. † Financial interest and/or other relationship with Pfizer, Bayer, Lilly-ICOS and NaxMad. ‡ Financial interest and/or other relationship with AstraZeneca, Merck, Pfizer, Johnson and Johnson, Ryan International, Agagen, Chiron and Cardinal Health. § Financial interest and/or other relationship with Bayer, Pfizer, Lilly-ICOS, Unimed-Solvay and Humagen. 㛳 Financial interest and/or other relationship with Mentor and SDF Consultants. ¶ Financial interest and/or other relationship with Pharmacia, AstraZeneca and Hydromed. ** Financial interest and/or other relationship with American Medical Systems, TAP Pharmaceuticals, Neotonus and Alza. †† Financial interest and/or other relationship with WellSpan Health and Apple Hill Surgical Center. 2138

BEST PRACTICE POLICIES FOR MALE INFERTILITY

evaluation, plus a complete medical and surgical history, including medications and allergies, review of systems, family reproductive history and a survey of past infections, such as sexually transmitted diseases and respiratory infections. Physical Examination: In addition to the general physical examination, particular focus should be given to the genitalia, including examination of the penis, noting the location of the urethral meatus, palpation of the testes and measurement of their size, presence and consistency of the vasa and epididymides, presence of a varicocele, secondary sex characteristics, including body habitus, hair distribution and breast development, and digital rectal examination. Semen Analysis: Semen analysis is the cornerstone of the laboratory evaluation of the infertile male. Standard instructions to patients for semen collection should include a 2 to 3-day period of previous sexual abstinence. The specimen may be collected at home or in the laboratory. It may be collected by masturbation or by intercourse using special semen collection condoms that do not contain substances such as latex rubber that are detrimental to sperm. The semen specimen should be maintained at room or body temperature and examined within 1 hour of collection. To our knowledge precise normal values have not been established for semen parameters. The table lists reference values based on the clinical literature. Values that lie outside of these ranges suggest a male infertility factor and indicate the need for additional clinical and/or laboratory evaluation of the patient. It must be emphasized that reference values for semen parameters are not the same as the minimum values needed for conception and men with semen variables outside of the reference ranges may be fertile. Conversely patients with values within the reference range may still be infertile. Other procedures and tests for assessing male infertility. Other tests used to elucidate the etiology of patient infertility include additional semen analyses, endocrine evaluation, post-ejaculatory urinalysis, ultrasonography, specialized tests of semen and sperm, and genetic screening. Endocrine Evaluation: The minimum initial endocrine evaluation should consist of measurements of serum folliclestimulating hormone (FSH) and serum testosterone levels. This evaluation should be performed if there is an abnormally low sperm concentration, especially less than 10 million per ml., impaired sexual function or other clinical findings suggestive of a specific endocrinopathy. If the initial endocrine studies are abnormal, further endocrine evaluation should be considered. Endocrine disorders are extremely uncommon in men with normal semen parameters. Post-Ejaculatory Urinalysis: Post-ejaculatory urinalysis should be performed in patients with an ejaculate volume of less than 1 ml., except those with bilateral vasal agenesis or clinical signs of hypogonadism. The presence of any sperm on post-ejaculatory urinalysis in a patient with azoospermia or aspermia is suggestive of retrograde ejaculation. Azoospermia is the complete absence of sperm in the ejaculate and

Semen analysis reference values On at least 2 occasions: Ejaculate vol. (ml.) pH Sperm concentration (⫻106/ml.) Total sperm No. (⫻106/ml. ejaculate) % Motility Forward progression (scale 0–4) % Normal morphology

Plus: Sperm agglutination (scale 0–3) Viscosity (scale 0–4)

1.5–5.0 Greater than 7.2 Greater than 20 Greater than 40 Greater than 50 Greater than 2 Greater than 50, WHO 1987 Greater than 30, WHO 1992 Greater than 14, Kruger (Tygerberg) Strict Criteria, WHO 1999 Less than 2 Less than 3

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aspermia is the complete absence of semen during or immediately after ejaculation. In addition to retrograde ejaculation, low volume or absent ejaculate may be due to a complete lack of emission, ejaculatory duct obstruction, hypogonadism or congenital bilateral absence of the vasa deferentia. Transrectal Ultrasonography: Transrectal ultrasound is indicated in azoospermic patients with palpable vasa and low ejaculate volume to determine whether ejaculatory duct obstruction exists. Normal seminal vesicles are less than 1.5 cm. in anteroposterior diameter. Dilated seminal vesicles, dilated ejaculatory ducts and/or midline prostatic cysts on transrectal ultrasound are suggestive but not diagnostic of complete or partial ejaculatory duct obstruction. Some experts also recommend transrectal ultrasound for oligospermic patients with low volume ejaculates, palpable vasa and normal testicular size. Scrotal Ultrasound: Scrotal ultrasonography is indicated in patients with inconclusive findings on examination (which may occur in patients with testes that are in the upper scrotum), small scrotal sacs or other anatomical features that make physical examination of the scrotum and spermatic cord difficult. Scrotal ultrasonography is also indicated in patients in whom a testicular mass is suspected. Most scrotal pathology, including varicoceles, spermatoceles, absent vasa, epididymal induration and testicular masses, is palpable on physical examination. Although scrotal ultrasound may identify nonpalpable varicoceles, they have not been shown to be clinically significant. Specialized Clinical Tests of Semen and Sperm: Specialized tests of semen are not required for the standard diagnosis of male infertility. They may be useful in a small number of patients for identifying a male factor contributing to unexplained infertility or for selecting therapy, such as assisted reproductive technology. Less common specialized tests of semen are important investigative tools but they are not necessary for the routine evaluation of men with infertility. Such tests include quantitation of leukocytes in the semen, tests for antisperm antibodies, sperm viability tests, tests of sperm-cervical mucus interaction, the zona-free hamster oocyte test, computer aided semen analysis and several even less common, specialized tests of sperm function. Generally these specialized clinical tests should be reserved only for cases in which identification of the cause of male infertility would direct treatment. Genetic Screening: Azoospermia and severe oligospermia may be associated with genetic abnormalities. Genetic abnormalities may cause infertility by affecting sperm production or sperm transport. The 3 most common genetic factors known to be related to male infertility are 1) cystic fibrosis gene mutations associated with congenital absence of the vas deferens, 2) chromosomal abnormalities resulting in impaired testicular function and 3) Y chromosome microdeletions associated with isolated spermatogenic impairment. There is a strong association of congenital bilateral absence of the vasa deferentia with mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.2, 3 Almost all males with clinical cystic fibrosis have congenital bilateral absence of the vasa deferentia and about two-thirds with that condition but no other clinical signs of cystic fibrosis have mutations of the CFTR gene that are detectable by current laboratory tests. Therefore, it should be assumed that a man with congenital bilateral absence of the vasa deferentia harbors a genetic abnormality in the CFTR gene. For this reason it is important to test his partner for CFTR gene abnormalities before performing a treatment that uses his sperm. Genetic testing for CFTR abnormalities in the female should be offered before proceeding with treatments that use the sperm of men with congenital bilateral absence of the vasa deferentia. Chromosomal abnormalities have been found in the karyotypes of 10% to 15% of men with azoospermia and 5% with

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oligospermia but in less than 1% of normal men.4 Microdeletions of the Y chromosomes have been found in 10% to 15% of men with azoospermia or severe oligospermia.5 Men with nonobstructive azoospermia and severe oligospermia should be informed that they may have chromosomal abnormalities or Y chromosome microdeletions. Karyotyping and Y chromosome analysis should be offered to a male who has nonobstructive azoospermia or severe oligospermia before using his sperm for intracytoplasmic sperm injection (ICSI). Genetic counseling may be offered when a genetic abnormality is suspected in the male or female partner and should be provided when a genetic abnormality is detected. II. EVALUATION OF THE AZOOSPERMIC MALE

Azoospermia, defined as the complete absence of sperm in the ejaculate, is present in about 1% of all men6 and in about 10% to 15% of infertile men.7 Azoospermia is different from aspermia, which is the complete absence of seminal fluid emission at ejaculation. Initial diagnosis of azoospermia. The initial diagnosis of azoospermia requires absent sperm in at least 2 separate centrifuged semen samples. The WHO Laboratory Manual for the Examination of Human Semen and Semen-Cervical Mucus Interaction recommends that semen should be centrifuged for 15 minutes at 3,000 ⫻ gravity or greater.8 Differential diagnosis of the azoospermic patient. The numerous etiologies of azoospermia fall into 3 categories: 3) pre-testicular, 2) testicular and 3) post-testicular. Pretesticular causes of azoospermia are endocrine abnormalities that adversely affect spermatogenesis and are relatively rare. Testicular etiologies involve disorders of spermatogenesis intrinsic to the testes. Post-testicular etiologies of azoospermia are due to ejaculatory dysfunction or obstruction of sperm delivery to the urethral meatus and are found in approximately 40% of azoospermic patients.7 Pretesticular and post-testicular abnormalities that cause azoospermia are often correctable. Testicular disorders are generally irreversible with the possible exception of impaired spermatogenesis associated with varicoceles. Initial evaluation of the azoospermic patient. After establishing that there are no sperm in either of 2 centrifuged semen analyses the minimum initial evaluation of an azoospermic patient should include a complete medical history, physical examination and serum hormone tests. Relevant history includes previous fertility, childhood illnesses such as viral orchitis or cryptorchidism, genital trauma, or pelvic, vasal or inguinal surgery, infections such as epididymitis or urethritis, gonadal toxin exposures, such as radiation therapy and/or chemotherapy, recent fever or heat exposure and current medications, and family history of birth defects, mental retardation, reproductive failure or cystic fibrosis. Physical examination should note testis size (normal testis volume 20 ml. or greater) and consistency, secondary sex characteristics, including body habitus, hair distribution and gynecomastia, presence and consistency of the vasa deferentia, consistency of the epididymides, presence of a varicocele and masses on digital rectal examination. The initial hormonal evaluation should include measurement of serum testosterone and FSH levels. Evaluation of specific conditions associated with azoospermia. The results of the initial evaluation direct the strategy that must be used to determine the cause of azoospermia. The following sections discuss the evaluation of several specific conditions associated with azoospermia. Absent Vasa Deferentia (Vasal Agenesis): Since normal vasa are easily palpable within the scrotum, the diagnosis of bilateral or unilateral vasal agenesis is made by physical examination. Imaging studies and surgical exploration are not necessary to confirm the diagnosis but imaging studies may be useful for diagnosing abnormalities associated with vasal agenesis. As

mentioned, there is a strong association of congenital bilateral absence of the vasa deferentia with mutations of the CFTR gene.2, 3 Since it can be assumed that a man with congenital bilateral absence of the vasa deferentia harbors a genetic abnormality in the CFTR gene, genetic testing for CFTR abnormalities in the female should be offered before performing a treatment that uses his sperm because of an approximate 4% risk that she may be a carrier. If the female partner tests positive for a CFTR abnormality, the male should also be tested. If the female partner has a negative test for CFTR abnormality, testing the male partner is optional. Ideally genetic counseling should be offered before and after genetic testing of the 2 partners. Bilateral Testicular Atrophy: Bilateral testicular atrophy may be caused by primary or secondary testicular failure. The results of the initial endocrine tests are used to distinguish these 2 possibilities. Elevated serum FSH associated with normal or low serum testosterone is consistent with primary testicular failure. All patients with azoospermia due to testicular failure should be offered testing for abnormalities of chromosome karyotypes and for Y chromosome microdeletions. Patients with acquired hypogonadotropic hypogonadism should be evaluated for functioning and nonfunctioning pituitary tumors by measuring serum prolactin and imaging the pituitary gland. Ductal Obstruction: When vasal agenesis and testicular atrophy are not present, semen volume and serum FSH are key factors for determining the etiology of azoospermia. Azoospermic patients with normal ejaculate volume may have obstruction of the reproductive system or abnormalities of spermatogenesis. Azoospermic patients with low semen volume and normal sized testes may have ejaculatory dysfunction or ejaculatory duct obstruction. Patients With Normal Ejaculate Volume: To distinguish obstructive and nonobstructive causes of azoospermia in patients with normal ejaculate volume diagnostic testicular biopsy is indicated in those with normal testicular size, at least 1 palpable vas deferens and normal serum FSH. The MIBPPC did not reach a consensus on whether diagnostic testicular biopsy in these patients should be done on 1 or 2 sides and concluded that unilateral or bilateral biopsy is acceptable. When unilateral biopsy is done, it should be performed on the larger testis if there is asymmetry of testicular size. Normal serum FSH does not ensure normal spermatogenesis. Marked elevation of serum FSH to greater than 2 times the upper limit of normal is diagnostic of abnormal spermatogenesis. Therefore, a diagnostic testicular biopsy is not necessary in patients with markedly elevated FSH. However, if sperm retrieval with ICSI is being considered, testicular biopsy may be performed for prognostic purposes to determine whether spermatozoa are likely to be retrievable in the future by needle aspiration or open biopsy. However, the presence or absence of sperm in a biopsy specimen does not absolutely predict whether sperm are present elsewhere within that testicle. The MIBPPC did not reach a consensus regarding the value of prognostic biopsy in a patient with markedly elevated serum FSH. When testicular biopsy is normal, obstruction at some level in the reproductive system must be present and the location of obstruction may then be determined. Most men with obstructive azoospermia and no history suggesting iatrogenic vasal injury have bilateral epididymal obstruction. Epididymal obstruction can be identified only by surgical exploration. Vasography may be done to determine whether there is obstruction of the vas deferens or ejaculatory ducts. Because of the risk of vasal scarring and obstruction, vasography should not be performed at diagnostic testicular biopsy unless reconstructive surgery is done at the same time. Patients With Low Ejaculate Volume Less Than 1 Ml.: Testicular biopsy may be performed to confirm that spermatogenesis is normal and, therefore, reproductive tract obstruction must be present in patients with low ejaculate volume

BEST PRACTICE POLICIES FOR MALE INFERTILITY

azoospermia and palpable vasa. Transrectal ultrasonography with or without seminal vesicle aspiration and seminal vesiculography may be done to identify obstruction in the distal male reproductive tract. Alternatively vasography may be done to identify the site of reproductive tract obstruction in patients with low ejaculate volume azoospermia and palpable vasa but it should not be done unless reconstructive surgery is also done during the same surgical procedure. Low ejaculate volume less than 1 ml. that is not caused by hypogonadism or congenital bilateral absence of the vasa deferentia can be caused by ejaculatory dysfunction, such as retrograde ejaculation or absent seminal fluid emission, but it is most likely caused by ejaculatory duct obstruction. Ejaculatory dysfunction rarely if ever causes low ejaculate volume in azoospermia cases, although it is a well-known cause of aspermia or low ejaculate volume in oligospermia cases. Additional seminal parameters that can be helpful for determining ejaculatory duct obstruction are seminal pH and fructose since seminal vesicle secretions are alkaline and contain fructose. However, the results of semen pH and fructose testing may be misleading when these tests are not properly performed. Therefore, many experts tend to give less importance to these parameters than to other clinical findings. Genetic testing in patients with azoospermia. In addition to mutations in the CFTR gene that give rise to congenital bilateral absence of the vasa deferentia, genetic factors may have a role in nonobstructive forms of azoospermia. The 2 most common categories of genetic factors associated with nonobstructive azoospermia are 1) chromosomal abnormalities resulting in impaired testicular function and 2) Y chromosome microdeletions leading to isolated spermatogenic impairment. Karyotypic Chromosomal Abnormalities: The incidence of karyotypic abnormalities in azoospermic men is 10% to 15%.4 The Klinefelter syndrome, which is the most common form of sex chromosomal aneuploidy, accounts for approximately two-thirds of chromosomal abnormalities in infertile men. Structural abnormalities of the autosomal chromosomes, such as inversions and translocations, are also observed at a higher frequency in infertile men than in the general population. When the male has gross karyotypic abnormalities, the couple is at increased risk for miscarriage and for having children with chromosomal and congenital defects. Karyotyping should be offered to men who have nonobstructive azoospermia or severe oligospermia before performing ICSI with their sperm. Y Chromosome Microdeletions: Microdeletions of the Y chromosome may be found in 10% to 15% of men with azoospermia or severe oligospermia.5 These microdeletions are too small to be detected by karyotyping but can be found by using polymerase chain reaction to the analyze sequence tagged sites that have been mapped along the whole length of the Y chromosome. Most deletions causing azoospermia or oligospermia occur in nonoverlapping regions of the long arm of the Y chromosome (Yq11). The specific location of the deletion along the Y chromosome may significantly affect spermatogenesis. If the deleted region of the Y chromosome is in the AZFc region, sperm may be present in the ejaculate in many patients, although in severely reduced numbers. Other patients with AZFc region deletions may have azoospermia but may still have sperm production that is sufficient to allow sperm extraction by testis biopsy. However, a deletion involving the whole AZFb region may predict a poor prognosis for sperm retrieval despite extensive testicular biopsies.9 Poor sperm retrieval results may also exist in men with deletions involving the AZFa region.10 Sons of individuals with a Y chromosome microdeletion inherit the microdeletion and may consequently be infertile.11 Although a microdeletion of the Y chromosome is not thought to be associated with other health problems, sparse data exist on the phenotypes of the sons of fathers with such genetic abnormalities. It is important to note that a negative

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Y chromosome microdeletion assay does not necessarily rule out a genetic abnormality because other, currently unknown gene sequences on the Y or other chromosomes may also be necessary for spermatogenesis. Conversely it has been shown that some Y chromosome microdeletions may be found in fertile or subfertile males who have fathered children.5, 12 Y chromosome analysis should be offered to men who have nonobstructive azoospermia or severe oligospermia before performing ICSI with their sperm. Men with nonobstructive azoospermia and severe oligospermia should be informed of the potential genetic abnormalities associated with azoospermia or severe oligospermia. Karyotyping, Y chromosome analysis and genetic counseling should be offered to men with nonobstructive azoospermia before performing ICSI with their sperm. Genetic counseling may be offered when a genetic abnormality is suspected in the male or female partner and should be provided when a genetic abnormality is detected. III. MANAGEMENT OF OBSTRUCTIVE AZOOSPERMIA

Obstruction of the ductal system is responsible for approximately 40% of cases of azoospermia.7 Obstructive azoospermia may result from epididymal, vasal or ejaculatory duct pathology. Vasectomy is the most common cause of vasal obstruction. Severe genitourinary infections, iatrogenic injury during scrotal or inguinal surgical procedures and congenital anomalies are other common causes of obstructive azoospermia. Limited evaluation of the 2 partners is important before reaching a final decision on treating a couple with infertility due to obstructive azoospermia. Other factors unrelated or indirectly related to the obstruction may have a role in the management decision. For example, congenital bilateral absence of the vasa deferentia is associated with mutations in the CFTR gene. Genetic testing and counseling should be considered when treating these couples before therapy to allow the couple to make an informed decision on whether to use male partner sperm. Since female factors may also have a role, the female partner should be offered at least a limited evaluation before treatment of the infertile couple with obstructive azoospermia. Treatment methods for obstructive azoospermia. Men with obstructive azoospermia may father children by surgical correction of obstruction, which may produce pregnancy by intercourse and obviate the need for assisted reproductive technology, or by retrieval of sperm from the male reproductive system for in vitro fertilization (IVF)-ICSI. Surgical Treatment: Surgical correction may be accomplished by microsurgical reconstruction of the vas and/or epididymis, or in cases of ejaculatory duct obstruction by transurethral resection of the ejaculatory ducts. Before performing microsurgery in the male, the female partner should be evaluated to determine whether female infertility factors are present. Microsurgical reconstruction of the reproductive tract is often successful in patients with obstructive azoospermia. For example, after vasectomy reversal sperm returns to the ejaculate in 70% to 95% of patients and pregnancy is achieved without the need for assisted reproduction in 30% to 75% of couples. An important factor influencing the likelihood of sperm returning to the semen and pregnancy after vasectomy reversal is the number of years between vasectomy and attempted reconstruction. The obstructive interval and the chance for a successful vasectomy reversal outcome are inversely related.13 A common misunderstanding of the public and some health care professionals is it is futile to attempt to reverse vasectomy that was done more than 10 years previously. In contrast to this misunderstanding, there is no obstructive interval beyond which consideration of microsurgical reconstruction must be abandoned. Other factors influencing the success of vasectomy reversal

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include the presence or absence of sperm in intraoperative vasal fluid, gross appearance of the vasal fluid, the quality of sperm in the vasal fluid, the length of the vas segment between the epididymis and vasectomy site, and the presence or absence of sperm granuloma at the vasectomy site. The likelihood of pregnancy after vasectomy reversal is also heavily influenced by the age of the female partner. The accuracy and delicacy of microsurgical technique affect the outcome of reconstructive procedures on the male reproductive system. The best results are achieved by surgeons with training and ongoing experience in microsurgery. Vasoepididymostomy is performed for congenital, infectious, post-vasectomy or idiopathic epididymal obstruction. After this type of microsurgery 20% to 40% of couples achieve pregnancy through intercourse and without assisted reproductive techniques. To maximize successful outcomes surgeons performing vasectomy reversal should be comfortable with anastomosis involving extremely small luminal diameters and must be competent and comfortable with vasovasostomy and vasoepididymostomy because the latter may be unexpectedly necessary in many cases. Sperm retrieval and cryopreservation may be performed at microsurgical reconstruction to avoid a second procedure in the event that microsurgical reconstruction does not reverse patient azoospermia. The possibility of ejaculatory duct obstruction should not be overlooked in the differential diagnosis of obstructive azoospermia. This condition is uncommon but it can be treated with transurethral resection of the ejaculatory duct at the point where the duct enters the distal prostatic urethra near the verumontanum. Transurethral resection of the ejaculatory duct results in the appearance of sperm in the ejaculate in about half to three-fourths of cases and pregnancy in about a fourth of couples. Sperm retrieval techniques and IVF-ICSI. IVF-ICSI: ICSI is an adjunct to standard IVF. ICSI should be performed in almost all cases in which sperm are retrieved from the testes or epididymis of a man with obstructive azoospermia. The reason is that these sperm retrieval techniques rarely produce enough motile sperm for intrauterine insemination or for optimal results with standard IVF. ICSI provides a fertilization rate of 45% to 75% per injected oocyte when surgically retrieved epididymal or testicular spermatozoa are used.14 –20 The recently reported clinical pregnancy rate is 26% to 57% and the birth rate is 18% to 54%.16 –20 At most reproductive centers it is reasonable to expect a clinical pregnancy rate of 30% to 40% per cycle and a birth rate of 25% to 30% per cycle when surgically retrieved epididymal or testicular sperm is used for ICSI. Sperm Retrieval: The choice of sperm retrieval method in men with obstructive azoospermia depends primarily on the experience and preference of the physician who performs retrieval and the IVF laboratory embryologist. The opinion of the MIBPPC is that there are not enough data to conclude that the technique of sperm retrieval (open or percutaneous) or the source of sperm (testicular, epididymal, vasal or seminal vesicular) significantly affects the pregnancy rate. Each technique and sperm source usually provides a sufficient number of sperm for ICSI and may provide enough viable sperm for cryopreservation. Sperm retrieval may be performed before or simultaneously with female partner egg retrieval. The MIBPPC opinion is that there is insufficient evidence to prove that for successful ICSI fresh sperm harvested from the testis or epididymis are superior to cryopreserved sperm. At many laboratories fresh sperm are preferred. However, for numerous scheduling and financial reasons it is often appropriate to harvest sperm before oocyte retrieval and cryopreserve them for future use with the expectation of reasonable results. Risks Associated With IVF-ICSI: Any couple considering IVF-ICSI should be apprised of the risks involved in this type of treatment. These risks include the possibility of ovarian hyperstimulation, and the risks and consequences of multi-

ple gestations. IVF carries an incidence of mild ovarian hyperstimulation in up to 20%, moderate ovarian hyperstimulation in up to 5% and severe ovarian hyperstimulation in less than 1% of women who undergo IVF with or without ICSI.21 Severe ovarian hyperstimulation may require hospitalization and may be life threatening. The risk of multiple gestations in the United States is 30% to 35% for twins and 5% to 10% for triplets or higher gestations.22 Multiple gestation births are associated with increased infant morbidity and mortality.23, 24 Choosing microsurgical reconstruction or sperm retrieval with IVF-ICSI. In addition to the chance of a successful outcome and the risks of treatment, other factors may have important roles when choosing between microsurgical reconstruction and sperm retrieval with IVF-ICSI. Other Factors Favoring Microsurgical Reconstruction: Microsurgical vasovasostomy and vasoepididymostomy have been shown to be more cost-effective than sperm retrieval with IVF-ICSI.25, 26 When successful, reconstructive microsurgery allows couples to have subsequent children without additional medical treatment. Other Factors Favoring Sperm Retrieval With IVF-ICSI: If the interval from vasectomy to vasectomy reversal is lengthy, sperm retrieval with ICSI may be preferable because pregnancy occurs in only 30% to 40% of the female partners of men with an obstructive interval of greater than 15 years.13 Female infertility factors also favor the selection of IVF-ICSI, including female partner age because female fertility decreases progressively after age 35 years and is limited after age 40 years.27 The average interval from successful vasectomy reversal to pregnancy is 12 months. Thus, couples may prefer sperm retrieval with ICSI when the female partner is older than 37 years old. However, the success of IVF with or without ICSI decreases dramatically in women older than 40 years,22 decreasing the chance of pregnancy by vasectomy reversal or sperm retrieval with IVF-ICSI. Consensus of the MIBPPC. The consensus of the MIBPPC is that microsurgical reconstruction of the reproductive tract is preferable to sperm retrieval with IVF-ICSI in men with previous vasectomy if the obstructive interval is less than 15 years and no female fertility risk factors are present. Some individual MIBPPC members believe that microsurgical reconstruction is the preferable option at any obstructive interval, even after 15 years, when there are no female infertility risk factors. If epididymal obstruction is present, the decision to perform microsurgical reconstruction or sperm retrieval with IVF-ICSI should be individualized. Vasoepididymostomy should be performed by an expert in reproductive microsurgery. The consensus of the MIBPPC is that sperm retrieval with IVF-ICSI is preferred to surgical treatment when advanced female age is present, female factors requiring IVF are present, the chance of success with sperm retrieval with IVF-ICSI exceeds the chance for success with surgical treatment or sperm retrieval with IVF-ICSI is preferred by the couple for financial reasons. IV. VARICOCELE AND INFERTILITY

Varicoceles are present in 15% of the normal male population and in approximately 40% of those presenting with infertility.28 The preponderance of experimental data on clinical and animal models demonstrates a deleterious effect of varicoceles on spermatogenesis. Testicular temperature elevation and venous reflux appear to have an important role in varicocele induced testicular dysfunction, although to our knowledge the exact pathophysiology of varicocele induced damage is not yet completely understood. Detection of varicoceles. Routine evaluation of infertile men with varicoceles should include a careful medical and reproductive history, physical examination and at least 2 semen analyses. Physical examination should be performed with the

BEST PRACTICE POLICIES FOR MALE INFERTILITY

patient recumbent and upright. When a suspected varicocele is not clearly palpable, the scrotum should be examined while the patient performs the Valsalva maneuver in the standing position. Only palpable varicoceles have been documented to be associated with infertility. Scrotal ultrasonography and other diagnostic procedures are not indicated for detecting varicoceles in the standard evaluation of the infertile male. However, scrotal ultrasound may occasionally be helpful for clarifying an inconclusive physical examination of the scrotum. Spermatic venography may be useful for showing the anatomical position of refluxing spermatic veins that recur or persist after varicocele repair. Indications for treatment of a varicocele. Varicocele treatment should be offered to the male partner of a couple attempting to conceive when all of certain features are present, namely a varicocele is palpable, the couple has documented infertility, the female partner has normal fertility or potentially correctable infertility and the male partner has 1 or more abnormal semen parameters, or abnormal results on sperm function tests. Varicocele treatment is not indicated in patients with normal semen analyses or subclinical nonpalpable varicoceles. Male adults who have a palpable varicocele and abnormal semen analyses but are not attempting to conceive may also be offered varicocele repair. Young men who have a varicocele and normal semen analyses should be followed with semen analyses every 1 to 2 years. Adolescents who have a varicocele and objective evidence of decreased ipsilateral testicular size should be offered varicocele repair. Adolescents with a varicocele but normal ipsilateral testicular size should be offered followup monitoring with yearly objective measurements of testicular size and/or semen analyses. Varicocele treatment, intrauterine insemination and assisted reproduction. Varicocele repair may be considered the primary treatment option when a man with a varicocele has suboptimal semen quality and a normal female partner. Varicocele repair has the potential to reverse a pathological condition and effect a permanent cure for infertility, in contrast to intrauterine insemination or assisted reproductive techniques (ART), which would be required for each attempt at pregnancy. Other factors to be considered when choosing varicocele repair, intrauterine insemination or ART are the age and reproductive health of the female partner, unknown long-term health effects of IVF and ICSI on offspring resulting from these techniques and the possibly greater costeffectiveness of varicocele treatment compared with IVF with or without ICSI.29 Finally, failure to treat a varicocele may result in a progressive decrease in semen parameters, further compromising the male chance of future fertility.30 –32 IVF with or without ICSI may be considered the primary treatment option when there is an independent need for such techniques to treat a female factor regardless of a varicocele and suboptimal semen quality. Nevertheless, there are certain circumstances in which treatment of a varicocele should be considered before initiating ART even when a female factor is present. Specifically varicocele repair has been shown to restore at least low numbers of sperm to the ejaculate in some men with nonobstructive azoospermia due to hypospermatogenesis or late maturation arrest.33, 34 In these cases varicocele repair may restore sperm to the ejaculate, thus, making it possible to perform IVF-ICSI without testicular sperm aspiration or extraction. Therefore, testicular biopsy and varicocele repair may be offered to these men. Treatment of varicoceles. Treating physician expertise with the options available should determine the choice of varicocele treatment. The 2 approaches to varicocele treatment are 1) surgery and 2) percutaneous embolization. Surgical repair of a varicocele may be accomplished by various open surgical methods, including the retroperitoneal, inguinal and subinguinal approach, or by laparoscopy. Percutaneous embolization of a varicocele is accomplished by percutaneous emboli-

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zation of the refluxing internal spermatic vein(s). None of these methods has been proved superior to the others in its ability to improve fertility. Surgical Repair: Most experts perform inguinal or subinguinal surgical repair using loupes or an operating microscope for optical magnification. Techniques using optical magnification maximize preservation of the arterial and lymphatic vessels, while decreasing the risk of persistent or recurrent varicocele. Laparoscopy has been used for varicocele repair but this approach carries the risk of major intraperitoneal complications, such as injury to bowel, bladder and major blood vessels. Although it is uncommon, intraperitoneal complications may be serious and require laparotomy for correction. Percutaneous Embolization Treatment: Percutaneous embolization to repair varicoceles may be associated with less pain than after the standard inguinal surgical approach but the availability of physicians with experience in interventional radiological techniques is required. Moreover, in some patients interventional access to the internal spermatic veins cannot be achieved because of technical problems. Complications: The potential complications of varicocele repair are uncommon and usually mild. All approaches to varicocele surgery are associated with a slight risk of wound infection, hydrocele, persistent or recurrent varicocele, bleeding, and rarely testicular atrophy. The potential complications of an inguinal incision made for varicocele repair include scrotal numbness and a more prolonged period of postoperative pain. Results of varicocele treatment. Surgical treatment successfully eliminates more than 90% of varicoceles. The results of percutaneous embolization vary and depend on the experience and skill of the interventional radiologist performing the procedure. Most groups report that semen quality improves in the majority of patients after varicocele repair.35 The fertility outcome of varicocele treatment is less clearly defined. Of hundreds of studies of varicocele there are only 2 well designed, randomized prospective controlled studies of men with palpable varicoceles, abnormal semen parameters and normal spouses.36, 37 In 1 study there was no greater likelihood of pregnancy after varicocele repair, although significant improvement was detected in testis volume and semen parameters.36 The other study showed a conception rate of 60% in couples of whom the male underwent varicocele repair compared to only 10% in the untreated control group.37 Most of the many other studies of the fertility outcome of varicocele repair show improved fertility with only a few showing little or no effect on fertility. In 1 review of the literature the pregnancy rate was 33% in couples after varicocele repair compared with 16% in untreated couples in 1 year.29 Despite the scarcity of definitive studies of the fertility outcome of varicocele repair varicocele treatment should be considered a choice for appropriate infertile couples because varicocele repair has proved to improve semen parameters in most men, varicocele treatment may possibly improve fertility and the risks of varicocele treatment are slight. Followup. Patients should be evaluated after varicocele treatment for persistent or recurrent varicocele. If the varicocele persists or recurs, internal spermatic venography may be performed to identify the site of persistent venous reflux. Surgical ligation or percutaneous embolization of the refluxing veins may be done. Semen analyses should be performed after varicocele treatment at about 3-month intervals for at least 1 year or until pregnancy is achieved. Intrauterine insemination and ART should be considered in couples in whom infertility persists after anatomically successful varicocele repair.

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BEST PRACTICE POLICIES FOR MALE INFERTILITY COMMENT

The full reports of the MIBPPC of the AUA and Practice Committee of the ASRM for Reproductive Medicine are available on the AUA website at http://shop.auanet.org/timssnet/ products/best_practice/index.cfm and on the ASRM website at http://www.asrm.org/Media/Practice/practice.html#Joint. These reports are intended to provide medical practitioners with a peer reviewed consensus of principles and strategies for the health care of couples with male infertility problems. These reports are based on current professional literature, clinical experience and expert opinion. They do not establish a fixed set of rules or define the legal standard of care and they do not preempt physician judgment in individual cases. Physician judgment must consider variations in resources, patient needs and patient preferences. REFERENCES

1. Thonneau, P., Marchand, S., Tallec, A. et al: Incidence and main causes of infertility in a resident population (1,850,000) of three French regions (1988 –1989). Hum Reprod, 6: 811, 1991 2. Anguiano, A., Oates, R. D., Amos, J. A. et al: Congenital bilateral absence of the vas deferens. A primarily genital form of cystic fibrosis. JAMA, 267: 1794, 1992 3. Chillon, M., Casals, T., Mercier, B. et al: Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med, 332: 1475, 1995 4. De Braekeleer, M. and Dao, T. N.: Cytogenetic studies in male infertility: a review. Hum Reprod, 6: 245, 1991 5. Pryor, J. L., Kent-First, M., Muallem, A. et al: Microdeletions in the Y chromosome of infertile men. N Engl J Med, 336: 534, 1997 6. Willott, G. M.: Frequency of azoospermia. Forensic Sci Int, 20: 9, 1982 7. Jarow, J. P., Espeland, M. A. and Lipshultz, L. I.: Evaluation of the azoospermic patient. J Urol, 142: 62, 1989 8. WHO Laboratory Manual for the Examination of Human Semen and Semen-Cervical Mucus Interaction. New York: Cambridge University Press, 1999 9. Brandell, R. A., Mielnik, A., Liotta, D. et al: AZFb deletions predict the absence of spermatozoa with testicular sperm extraction: preliminary report of a prognostic genetic test. Hum Reprod 13: 2812, 1998 10. Krausz, C., Quintana-Murci, L. and McElreavey, K.: Prognostic value of Y deletion analysis. What is the clinical prognostic value of Y chromosome microdeletion analysis? Hum Reprod, 15: 1431, 2000 11. Kent-First, M. G., Kol, S., Muallem, A. et al: The incidence and possible relevance of Y-linked microdeletions in babies born after intracytoplasmic sperm injection and their infertile fathers. Mol Hum Reprod, 2: 943, 1996 12. Kent-First, M., Muallem, A., Shultz, J. et al: Defining regions of the Y-chromosome responsible for male infertility and identification of a fourth AZF region (AZFd) by Y-chromosome microdeletion detection. Mol Reprod Devel, 53: 27, 1999 13. Belker, A. M., Thomas, A. J., Jr., Fuchs, E. F. et al: Results of 1,469 microsurgical vasectomy reversals by the vasovasostomy study group. J Urol, 145: 505, 1991 14. Nagy, Z., Liu, J., Cecile, J. et al: Using ejaculated, fresh and frozen-thawed epididymal spermatozoa gives rise to comparable results after ICSI. Fertil Steril, 63: 808, 1995 15. Gil-Salom, M., Minguez, Y., Rubio, C. et al: Efficacy of intracytoplasmic sperm injection using testicular spermatozoa. Hum Reprod, 10: 3166, 1995 16. Tournaye, H., Merdad, T., Silber, S. et al: No difference in outcome after intracytoplasmic sperm injection with fresh or with frozen-thawed epididymal spermatozoa. Hum Reprod, 14: 90, 1999

17. Palermo, G. D., Schlegel, P. N., Hariprashad, J. J. et al: Fertilization and pregnancy outcome with intracytoplasmic sperm injection for azoospermic men. Hum Reprod, 14: 741, 1999 18. Kupker, W., Schlegel, P. N., Al-Hasani, S. et al: Use of frozenthawed testicular sperm for intracytoplasmic sperm injection. Fertil Steril, 73: 453, 2000 19. Habermann, H., Seo, R., Cieslak, J. et al: In vitro fertilization outcomes after intracytoplasmic sperm injection with fresh or frozen-thawed testicular spermatozoa. Fertil Steril, 73: 955, 2000 20. Mercan, R., Urman, B., Alatas, C. et al: Outcome of testicular sperm retrieval procedures in non-obstructive azoospermia: percutaneous aspiration versus open biopsy. Hum Reprod, 15: 1548, 2000 21. Bassil, S., Godin, P. A., Stallaert, S. et al: Ovarian hyperstimulation syndrome. A review. Assist Reprod Rev, 5: 90, 1995 22. Assisted reproductive technology in the United States: 1996 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry. Society for Assisted Reproductive Technology and American Society for Reproductive Medicine. Fertil Steril, 71: 798, 1999 23. Wilcox, L. S., Keily, J. L., Melvin, C. L. et al: Assisted reproductive technologies: estimates of their contribution to multiple births and newborn hospital days in the United States. Fertil Steril, 65: 361, 1996 24. Callahan, T. L., Hall, J. E., Ettner, S. L. et al: The economic impact of multiple gestation pregnancies and the contribution of assisted reproduction techniques to their incidence. New Engl J Med, 331: 244, 1994 25. Pavlovich, C. P. and Schlegel, P. N.: Fertility options after vasectomy: a cost-effectiveness analysis. Fertil Steril, 67: 133, 1997 26. Kolettis, P. N. and Thomas, A. J.: Vasoepididymostomy for vasectomy reversal: a critical assessment in the era of intracytoplasmic sperm injection. J Urol, 158: 467, 1997 27. Hull, M. G. R., Fleming, C. F., Hughes, A. O. et al: The agerelated decline in female fecundity: a quantitative controlled study of implanting capacity and survival of individual embryos after in vitro fertilization. Fertil Steril, 65: 783, 1996 28. Nagler, H. M., Luntz, R. K. and Martinis, F. G.: Varicocele. In: Infertility In The Male. Edited by L. I. Lipshultz and S. S. Howards. St. Louis: Mosby Year Book, pp. 336 –359, 1997 29. Schlegel, P. N.: Is assisted reproduction the optimal treatment for varicocele-associated infertility? A cost-effective analysis. Urology, 49: 83, 1997 30. Chehval, M. J. and Purcell, M. H.: Deterioration of semen parameters over time in men with untreated varicocele: evidence of progressive testicular damage. Fertil Steril, 57: 174, 1992 31. Gorelick, J. and Goldstein, M.: Loss of fertility in men with varicocele. Fertil Steril, 59: 613, 1993 32. Witt, M. A. and Lipshultz, L. I.: Varicocele: a progressive or static lesion? Urology, 42: 541, 1993 33. Matthews, G. J., Matthews, E. D. and Goldstein, M.: Induction of spermatogenesis and achievement of pregnancy after microsurgical varicocelectomy in men with azoospermia and severe oligoasthenospermia. Fertil Steril, 70: 71, 1998 34. Kim, E. D., Leibman, B. B., Grinblat, D. M. et al: Varicocele repair improves semen parameters in azoospermic men with spermatogenic failure. J Urol, 162: 737, 1999 35. Schlesinger, M. M., Wilets, I. F. and Nagler, H. M.: Treatment outcomes after varicocelectomy. A critical analysis. Urol Clin North Am, 21: 517, 1994 36. Nieschlag, E., Hertle, L., Fischedick, A. et al: Update on treatment of varicocele: counseling as effective as occlusion of the vena spermatica. Hum Reprod, 13: 2147, 1998 37. Madgar, I., Weissenberg, R., Lunenfeld, B. et al: Controlled trial of high spermatic vein ligation for varicocele in infertile men. Fertil Steril, 63: 120, 1995