Best practice policies for male infertility

Abstract

In 1998, the Practice Guidelines Committee of the American Urological Association, Inc. (AUA) commissioned a Male Infertility Best Practice Policy Committee (MIBPPC) to bridge the gap between leading edge science and clinical practice in male infertility and to provide urologists, gynecologists, reproductive endocrinologists, primary care practitioners, reproductive researchers, and other health care providers with guidelines for excellence of care in this rapidly changing field. The Male Infertility Best Practice Policy Committee chose not to create a comprehensive treatise on male infertility but rather to focus on areas that are new, poorly understood, poorly standardized, controversial, or rapidly changing. The MIBPPC created separate reports on four interrelated topics: [1] optimal evaluation of the infertile man, [2] evaluation of the azoospermic man, [3] management of obstructive azoospermia, and [4] varicocele and infertility. The reports were submitted to peer review by 125 physicians and researchers in urology, gynecology, reproductive endocrinology, primary care and family medicine, andrology, and reproductive laboratory medicine. The reports were then reviewed and approved by the Practice Committee of the American Society for Reproductive Medicine (ASRM). The reports were printed and distributed jointly by the AUA and the ASRM in 2001. This article reviews each report of the MIBPPC. Approximately 15% of couples cannot conceive a child after 1 year of regular, unprotected intercourse. Male factor infertility is solely responsible in about 20% of infertile couples and is contributory in another 30% to 40% (1Thonneau P Marchand S Tallec A Ferial M.L Ducot B Lansac J et al.Incidence and main causes of infertility in a resident population (1,850,000) of three French regions (1988–1989).Hum Reprod. 1991; 6: 811-816Crossref PubMed Scopus (580) Google Scholar). Male infertility factor is usually defined by abnormal results on semen analysis. However, even if results of semen analysis are normal, other male factors may be present. It cannot be overemphasized that both partners of an infertile couple should be evaluated simultaneously. The purpose of the male evaluation is to identify [1] potentially correctable conditions, [2] irreversible conditions that are amenable to assisted reproductive techniques using the sperm of the male partner, [3] irreversible conditions that are not amenable to the above techniques but for which donor insemination or adoption are possible options, [4] life- or health-threatening conditions that may underlie the infertility and require medical attention, and [5] 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 a male’s fertility and allow conception to occur through intercourse. Detection of untreatable conditions will spare couples the distress of attempting ineffective therapies. Detection of genetic causes of male infertility allows couples to be informed about the potential for transmitting genetic abnormalities to their offspring. Finally, male infertility may occasionally be the presenting manifestation of an underlying life-threatening condition. Failure to identify such diseases as testicular cancer or pituitary tumors may have serious consequences, including death. 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. An evaluation may be done before 1 year if the male partner has a known risk factor for male infertility, such as bilateral cryptorchidism; if the female partner has a risk factor for infertility, such as age older than 35 years; or if the male partner questions his fertility potential. The initial screening evaluation for male factor infertility should include a reproductive history and two properly performed semen analyses. If possible, the two semen analyses should be separated by at least 1 month. The reproductive history should include questions about [1] coital frequency and timing; [2] duration of infertility and previous fertility; [3] childhood illnesses and developmental history; [4] systemic medical illnesses and previous surgeries; [5] sexual history, including sexually transmitted infections; and [6] exposure to gonadal toxins, including heat. Although a man may have a history of previous fertility, he may have since acquired a new male infertility factor. Such men should be evaluated in the same way as men who have never initiated a pregnancy. 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 an abnormal semen analysis. Further evaluation of the male partner should also be considered in couples with unexplained infertility and in couples with a treated female factor and persistent infertility. The minimum full evaluation for male infertility should include a complete medical and reproductive history, a physical examination by a urologist or other specialist in male reproduction, and at least two semen analyses. Additional tests may then be used to evaluate specific problems or questions identified by these examinations. The medical history should include the reproductive history, as described in the initial screening 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. In addition to the general physical examination, particular attention should be given to the genitalia, including [1] examination of the penis, noting the location of the urethral meatus; [2] palpation of the testes and measurement of their size; [3] presence and consistency of both the vasa and epididymides; [4] presence of a varicocele; [5] secondary sex characteristics, including body habitus, hair distribution, and breast development; and [6] digital rectal examination. Semen analysis is the cornerstone of the laboratory evaluation of the infertile male. All patients should be instructed to abstain from sexual activity for 2 to 3 days before for semen collection. 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 kept at room or body temperature and examined within 1 hour of collection. Precise normal values have not been established for semen variables. The reference values in Table 1 are based on the clinical literature. Values that fall outside these ranges suggest a male infertility factor and indicate the need for additional clinical or laboratory evaluation of the patient. Of note, reference values for semen variables are not the same as the minimum values needed for conception, and men with semen variables outside the reference ranges may be fertile. Conversely, patients with values within the reference range may still be infertile.TABLE 1Semen analysis reference values.On at least two occasions:Ejaculate volume of 1.5–5.0 mLpH of >7.2Sperm concentration >20 million/mLTotal sperm count >40 million/ejaculateMotility >50%Forward progression >2 (scale of 0–4)Normal morphology >50% normalaWorld Health Organization, 1987., >30% normalbWorld Health Organization, 1992., or >14% normalcKruger (Tygerberg) Strict Criteria, World Health Organization, 1999.And:Sperm agglutination < 2 (scale of 0–3)Viscosity <3 (scale of 0–4)Sharlip. Male infertility practice guideline. Fertil Steril 2002.a World Health Organization, 1987.b World Health Organization, 1992.c Kruger (Tygerberg) Strict Criteria, World Health Organization, 1999. Open table in a new tab Sharlip. Male infertility practice guideline. Fertil Steril 2002. Other tests used to elucidate the etiology of a patient’s infertility include additional semen analyses, endocrine evaluation, postejaculatory urinalysis, ultrasonography, specialized tests on semen and sperm, and genetic screening. The minimum initial endocrine evaluation should consist of measurement of serum follicle-stimulating hormone (FSH) and serum testosterone levels. This evaluation should be performed if the patient has an abnormally low sperm concentration, especially less than 10 million cells/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 uncommon in men with normal semen variables. Postejaculatory urinalysis should be performed in patients with ejaculate volumes less than 1 mL, except if they have bilateral vasal agenesis or clinical signs of hypogonadism. The presence of sperm in a postejaculatory urinalysis specimen from a patient with azoospermia (absence of sperm in the ejaculate) or aspermia (complete absence of semen during or immediately after ejaculation) suggests retrograde ejaculation. In addition to retrograde ejaculation, ejaculate may be of low volume or absent owing to complete lack of emission, ejaculatory duct obstruction, hypogonadism, or congenital bilateral absence of the vasa deferentia (CBAVD). Transrectal ultrasonography (TRUS) is indicated in azoospermic patients with palpable vasa and low ejaculate volumes to determine whether ejaculatory duct obstruction is present. Normal seminal vesicles are less than 1.5 cm in anteroposterior diameter. Dilated seminal vesicles, dilated ejaculatory ducts, or midline prostatic cystic structures on TRUS suggest, but are not diagnostic of, complete or partial ejaculatory duct obstruction. Some experts recommend performing TRUS in oligospermic patients with low volume ejaculates, palpable vasa, and normal testicular size. Scrotal ultrasonography is indicated in patients with inconclusive findings on examination (as may occur in patients with testes that are in the upper scrotum), small scrotal sacs, or other anatomy that makes 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 abnormalities, including varicoceles, spermatoceles, absence of the vasa, epididymal induration, and testicular masses, are palpable on physical examination. Nonpalpable varicoceles on scrotal ultrasonography have not been shown to be clinically significant. Specialized tests of semen are not required for the standard diagnosis of male infertility but may be useful for identifying a male factor cause that contributes to unexplained infertility or for selecting therapy, such as assisted reproductive technology. 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 commonly used specialized tests of sperm function. Generally, these specialized clinical tests should be reserved for those cases in which identification of the cause of male infertility will direct treatment. Azoospermia and severe oligospermia may be associated with genetic abnormalities. Genetic abnormalities may cause infertility by affecting sperm production or sperm transport. The three 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. A strong association exists between CBAVD and mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene (2Anguiano A Oates R.D Amos J.A et al.Congenital bilateral absence of the vas deferens. A primarily genital form of cystic fibrosis.JAMA. 1992; 267: 1794-1797Crossref PubMed Scopus (474) Google Scholar, 3Chillon M Casals T Mercier B Bassas L Lissens W Silber S et al.Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens.N Engl J Med. 1995; 332: 1475-1480Crossref PubMed Scopus (802) Google Scholar). Almost all men with clinical cystic fibrosis have CBAVD, and about two thirds of men with CBAVD but no other clinical signs of cystic fibrosis have mutations of the CFTR gene that current laboratory tests can detect. Therefore, it should be assumed that a man with CBAVD harbors an abnormality in the CFTR gene. For this reason, it is important to test his partner for CFTR gene abnormalities before applying a treatment that uses his sperm. Genetic testing for CFTR mutations in the female partner should be offered before proceeding with treatments that use the sperm of men with CBAVD. Chromosomal abnormalities have been found in karyotypes of 10% to 15% of men with azoospermia and 5% of men with oligospermia but less than 1% of normal men (4De Braekeleer M Dao T.N Cytogenetic studies in male infertility a review.Hum Reprod. 1991; 6: 245-250PubMed Google Scholar). Microdeletions of the Y chromosome have been found in 10% to 15% of men with azoospermia or severe oligospermia (5Pryor J.L Kent-First M Muallem A Van Bergen A.H Nolten W.E Meisner L et al.Microdeletions in the Y chromosome of infertile men.N Engl J Med. 1997; 336: 534-539Crossref PubMed Scopus (462) Google Scholar). Men with nonobstructive azoospermia and severe oligospermia should be informed that they might have chromosomal abnormalities or Y-chromosome microdeletions. Karyotyping and Y-chromosome analysis should be offered to men with nonobstructive azoospermia or severe oligospermia before using their sperm for ICSI. Genetic counseling may be offered if a genetic abnormality is suspected in either the male or female partner and should be provided whenever a genetic abnormality is detected. Azoospermia, defined as the complete absence of sperm from the ejaculate, is present in about 1% of all men (6Willott G.M Frequency of azoospermia.For Sci Inter. 1982; 20: 9-10Scopus (109) Google Scholar) and in about 10% to 15% of infertile men (7Jarow J.P Espeland M.A Lipshultz L.I Evaluation of the azoospermic patient.J Urol. 1989; 142: 62-65PubMed Google Scholar). Azoospermia differs from aspermia, which is the complete absence of seminal fluid emission upon ejaculation. The initial diagnosis of azoospermia requires the absence of sperm from at least two separate centrifuged semen samples. The World Health Organization Laboratory Manual for the Examination of Human Semen and Semen-Cervical Mucus Interaction recommends that semen be centrifuged for 15 minutes at 3000 g or greater (8WHO Laboratory Manual for the Examination of Human Semen and Semen-Cervical Mucus Interaction. Cambridge University Press, New York1999Google Scholar). The numerous causes of azoospermia fall into three categories: pretesticular, testicular, and 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 either ejaculatory dysfunction or obstruction of sperm delivery to the urethral meatus; these are found in approximately 40% of azoospermic patients (7Jarow J.P Espeland M.A Lipshultz L.I Evaluation of the azoospermic patient.J Urol. 1989; 142: 62-65PubMed Google Scholar). The pretesticular and post-testicular abnormalities that cause azoospermia are frequently correctable. Testicular disorders are generally irreversible, with the possible exception of impaired spermatogenesis associated with varicoceles. After establishing that no sperm are present in two centrifuged semen analyses, the minimum initial evaluation of an azoospermic patient should include a complete medical history, a physical examination, and serum hormone tests. Relevant history includes [1] previous fertility; [2] childhood illnesses, such as viral orchitis or cryptorchidism; [3] genital trauma or previous pelvic, vasal, or inguinal surgery; [4] infections, such as epididymitis or urethritis; [5] exposure to gonadal toxins, such as radiation therapy or chemotherapy, recent fever, or heat and current medications; and [6] family history of birth defects, mental retardation, reproductive failure, or cystic fibrosis. Physical examination should note [1] size of the testes (normal volume ≥20 mL) and consistency; [2] secondary sex characteristics, including body habitus, hair distribution, and gynecomastia; [3] presence and consistency of the vasa deferentia; [4] consistency of the epididymides; [5] presence of a varicocele; and [6] masses on digital rectal examination. The initial hormonal evaluation should include measurement of serum testosterone and FSH levels. The results of the initial evaluation will direct the strategy that must be used to determine the cause of the azoospermia. The following sections discuss the evaluation of several specific conditions associated with azoospermia. Since normal vasa are easily palpable in 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. A strong association exists between CBAVD and mutations of the CFTR gene (2Anguiano A Oates R.D Amos J.A et al.Congenital bilateral absence of the vas deferens. A primarily genital form of cystic fibrosis.JAMA. 1992; 267: 1794-1797Crossref PubMed Scopus (474) Google Scholar, 3Chillon M Casals T Mercier B Bassas L Lissens W Silber S et al.Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens.N Engl J Med. 1995; 332: 1475-1480Crossref PubMed Scopus (802) Google Scholar). Since it can be assumed that a man with CBAVD harbors a genetic abnormality in the CFTR gene, genetic testing for CFTR mutations in the female partner should be offered before giving treatment that uses the male partner’s sperm, because there is an approximate 4% risk that the female partner may be a carrier. If the female partner tests positive for a CFTR mutation, the male partner should be tested as well. If the female partner tests negative for CFTR mutations, testing of the male partner is optional. Ideally, genetic counseling should be offered both before and after genetic testing of both partners. Bilateral testicular atrophy may be caused by primary or secondary testicular failure. The results of the initial endocrine tests are used to distinguish between these two conditions. An elevated serum FSH level associated with a normal or low serum testosterone level 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 measurement of serum prolactin and imaging of the pituitary gland. If vasal agenesis and testicular atrophy are not present, semen volume and serum FSH are key factors in determining the etiology of the 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. To distinguish between obstructive and nonobstructive causes of azoospermia in patients with normal ejaculate volume, diagnostic testicular biopsy is indicated for patients with normal testicular size, at least one palpable vas deferens, and a normal serum FSH level. The MIBPPC could not reach a consensus on whether diagnostic testicular biopsy in these patients should be done on one or both sides and concluded that either unilateral or bilateral biopsy is acceptable. If a unilateral biopsy is chosen, it should be performed on the larger testis in patients with asymmetrical testes. A normal serum FSH level does not guarantee normal spermatogenesis. Marked elevation of the serum FSH level to more than two 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 levels. However, if sperm retrieval with ICSI is being considered, a 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. The presence or absence of sperm in a biopsy specimen, however, does not absolutely predict whether sperm are present elsewhere within that testicle. The MIBPPC could not reach a consensus on the value of prognostic biopsy in a patient with a markedly elevated serum FSH level. If results of testicular biopsy are normal, obstruction at some level in the reproductive system must be present. The location of the 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 used to determine whether there is an obstruction in the vas deferens or ejaculatory ducts. Because of the risk for vasal scarring and obstruction, vasography should not be performed at the time of diagnostic testicular biopsy, unless reconstructive surgery is done at the same time. Testicular biopsy may be performed to confirm that spermatogenesis is normal and that reproductive tract obstruction must therefore be present in patients with low ejaculate volume azoospermia and palpable vasa. Transrectal ultrasonography, with or without seminal vesicle aspiration and seminal vesiculography, may be used to identify obstruction in the distal male reproductive tract. Alternatively, vasography may be used to identify the site of reproductive tract obstruction in patients with low ejaculate volume azoospermia and palpable vasa, but this test should not be done unless reconstructive surgery is done during the same surgical procedure. Low ejaculate volume that is not caused by hypogonadism or CBAVD may be caused by ejaculatory dysfunction (such as retrograde ejaculation or absence of seminal fluid emission) but is most likely caused by ejaculatory duct obstruction. Ejaculatory dysfunction rarely causes low ejaculate volume with azoospermia, although it is a well-known cause of aspermia or low ejaculate volume with oligospermia. Additional semen variables that can help in determining the presence of ejaculatory duct obstruction are seminal pH and fructose level, since the seminal vesicle secretions are alkaline and contain fructose. However, the results of semen pH and fructose testing may be misleading if these tests are not properly performed, therefore, many experts tend to give less importance to these variables than to other clinical findings. In addition to mutations in the CFTR gene that give rise to CBAVD, genetic factors may play a role in nonobstructive forms of azoospermia. The two most common categories of genetic factors associated with nonobstructive azoospermia are chromosomal abnormalities resulting in impaired testicular function and Y-chromosome microdeletions leading to isolated spermatogenic impairment. The frequency of karyotypic abnormalities in azoospermic men is 10% to 15% (4De Braekeleer M Dao T.N Cytogenetic studies in male infertility a review.Hum Reprod. 1991; 6: 245-250PubMed Google Scholar). The Klinefelter syndrome, the most common 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. If the male partner has gross karyotypic abnormalities, the couple is at increased risk for miscarriages and for having children with chromosomal and congenital defects. Karyotyping should be offered to men who have nonobstructive azoospermia or severe oligospermia before ICSI using their sperm is performed. Microdeletions of the Y chromosome may be found in 10% to 15% of men with azoospermia or severe oligospermia (5Pryor J.L Kent-First M Muallem A Van Bergen A.H Nolten W.E Meisner L et al.Microdeletions in the Y chromosome of infertile men.N Engl J Med. 1997; 336: 534-539Crossref PubMed Scopus (462) Google Scholar). These microdeletions are too small to be detected by karyotyping but can be found by using polymerase chain reaction to analyze sequence-tagged sites that have been mapped along the entire length of the Y chromosome. Most deletions that cause azoospermia or oligospermia occur in nonoverlapping regions of the long arm of the Y chromosome (Yq11). The 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 will be present in the ejaculate in many patients, albeit in severely reduced numbers. Other patients with AZFc region deletions will be azoospermic but may have sufficient sperm production to allow sperm extraction by testicular biopsy. A deletion involving the entire AZFb region, however, may predict a very poor prognosis for sperm retrieval despite extensive testicular biopsy (9Brandell R.A Mielnik A Liotta D Ye Z Veeck L.L Palermo G.D et al.AZFb deletions predict the absence of spermatozoa with testicular sperm extraction preliminary report of a prognostic genetic test.Hum Reprod. 1998; 13: 2812-2815Crossref PubMed Scopus (172) Google Scholar). Men with deletions involving the AZFa region may also have poor sperm retrieval (10Krausz C Quintana-Murci L McElreavey K Prognostic value of Y deletion analysis. What is the clinical prognostic value of Y chromosome microdeletion analysis?.Hum Reprod. 2000; 15: 1431-1434Crossref PubMed Scopus (230) Google Scholar). Sons of persons with a Y-chromosome microdeletion will inherit the microdeletion and may consequently be infertile (11Kent-First M.G Kol S Muallem A Ofir R Manor D Blazer S 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. 1996; 2: 943-950Crossref PubMed Scopus (233) Google Scholar). Although a microdeletion of the Y chromosome is not thought to be associated with other health problems, few data exist on the phenotypes of the sons of fathers with such genetic abnormalities. Of note, a negative result on Y-chromosome microdeletion assay does not rule out a genetic abnormality, because the patient may have a presently unknown gene sequences on the Y chromosome or on other chromosomes that might also be necessary for spermatogenesis. Conversely, some Y-chromosome microdeletions are found in fertile or subfertile men who have fathered children (5Pryor J.L Kent-First M Muallem A Van Bergen A.H Nolten W.E Meisner L et al.Microdeletions in the Y chromosome of infertile men.N Engl J Med. 1997; 336: 534-539Crossref PubMed Scopus (462) Google Scholar, 12Kent-First M Muallem A Shultz J Pryor J Roberts K Nolten W 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 Dev. 1999; 53: 27-41Crossref PubMed Scopus (237) Google Scholar). Analysis of the Y chromosome should be offered to men with nonobstructive azoospermia or severe oligospermia before ICSI with their sperm is performed. 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 ICSI using their sperm is performed. Genetic counseling may be offered when a genetic abnormality is suspected in the male or the female partner and should be done whenever a genetic abnormality is detected. Obstruction of the ductal system is responsible for approximately 40% of cases of azoospermia (7Jarow J.P Espeland M.A Lipshultz L.I Evaluation of the azoospermic patient.J Urol. 1989; 142: 62-65PubMed Google Scholar). Obstructive azoospermia may result from epididymal, vasal, or ejaculatory duct abnormalities. 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 both partners is important before reaching a final decision on the management of a couple with infertility due to obstructive azoospermia. Other factors that are unrelated or indirectly related to the obstruction may play a role in the decision about management. For instance, CBAVD is associated with mutations in the CFTR gene. Genetic testing and counseling should be considered in the management of these couples before treatment so that the couple can make an informed decision about whether to use the male partner’s sperm. Because female factors may also play a role, the female partner should be offered at least a limited evaluation before treatment of the infertile couple with obstructive azoospermia. Men with