Evaluation of the Infertile Male

VOLUME 29 • NUMBER 12 POSTGRADUATE OBSTETRICS & GYNECOLOGY June 30, 2009 A BIWEEKLY PUBLICATION FOR CONTINUING MEDICAL EDUCATION IN OBSTETRICS AND GYNECOLOGY Evaluation of the Infertile Male: Part I Hossein Sadeghi-Nejad, MD Learning Objectives: After reading this issue, the participant should be able to: 1. Summarize the basic steps in the evaluation of male infertility. 2. Explain how to interpret a semen analysis report. 3. List the common genetic causes of male infertility. This article is the first in a two-part series. The chance that a “normal” couple will be unable to conceive after 1 year is approximately 10% to 15%. Infertility is the inability to achieve a pregnancy resulting in live birth after 1 year of unprotected intercourse, but a baseline evaluation should be undertaken at the time of presentation even if the 1-year definition has not been met. A male factor accounts for 20% of infertility as a sole factor and approximately 30% to 40% of infertility in combination with female causes. A “couple’s approach” in collaboration with female reproductive specialists and with attention to both the physical and psychological aspects of reproductive dysfunction is prudent to achieve optimal outcomes. The evaluation process should be undertaken in parallel with evaluation of the female partner and includes identification of surgically and medically reversible causes, genetic assessment when indicated for conditions that may affect the offspring, and counseling for potentially irreversible conditions. intercourse in relation to the female ovulatory cycle are assessed to establish the diagnosis of infertility. Information is sought regarding childhood medical-surgical history and pubertal sexual development; this includes questions related to undescended testicles, mumps, hypospadias, gynecomastia, herniorrhaphy or scrotal surgery, and the onset of pubertal changes. Delayed sexual development may indicate endocrine pathology. Cryptorchidism, even if unilateral, will result in reduced fertility.1 A history of anosmia in combination with azoospermia or severe oligospermia and low gonadotropins suggests Kallmann syndrome. Information about previous pregnancies (with the same or a different partner) can help shed light on the present condition. A history of chronic upper respiratory infections coexisting with male infertility may indicate immotile cilia syndrome or epididymal obstruction due to Young syndrome. Patients with cystic fibrosis (CF) or its milder genetic variant, congenital bilateral absence of the vas deferens (CBAVD) will also have obstructive azoospermia due to bilateral absence of the vasa and absent or atretic seminal vesicles. This can occur in possible combination with respiratory symptoms, although the diagnosis of CF is likely to have been made prior to presentation for an infertility work-up. Obstructive causes for male infertility may also be suggested by a history of urinary tract infection or bilateral epididymitis, whereas ejaculatory dysfunction (retrograde or anejaculation) may be due to retroperitoneal surgery, diabetic neuropathy, or medications such as alphablockers and sympatholytics. Other important details related to surgical history include pediatric or adult hernia repair with potential vasal occlusion and/or devascularization, scrotal surgery with potential epididymal injury secondary to electrocautery, and any prostate or pediatric bladder neck operation with retrograde ejaculation as a consequence. History The duration of unprotected intercourse and the couples’ basic knowledge about the timing and frequency of Dr. Sadeghi-Nejad is Associate Professor of Surgery/Urology, Division of Urology, University of Medicine and Dentistry of New Jersey, Newark, NJ, VA New Jersey Health Care System, East Orange, NJ, and Hackensack University Medical Center, Center for Reproductive Medicine, 20 Prospect Avenue #711, Hackensack, NJ 07601; E-mail: [email protected]. Dr. Sadeghi-Nejad disclosed that he is/was the recipient of grant/research support from Sanofi-aventis, Plethora Solutions, and Timm Medical Technologies; is/was a consultant/advisor to American Medical Systems and Coloplast; and is/was a member of the speakers bureau of American Medical Systems, Coloplast, Sanofi-aventis, and Pfizer. All staff in a position to control the content of this CME activity have disclosed that they have no financial relationships with, or financial interests in, any commercial companies pertaining to this educational activity. Lippincott CME Institute, Inc., has identified and resolved all faculty and staff conflicts of interest in any commercial organizations pertaining to this educational activity. The continuing education activity in Postgraduate Obstetrics & Gynecology is intended for obstetricians, gynecologists, and other health care professionals with an interest in the diagnosis and treatment of obstetric and gynecological conditions. 1 Postgraduate Obstetrics & Gynecology EDITORS William Schlaff, MD* Professor and Vice Chairman, Chief of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado Lorraine Dugoff, MD* Associate Professor, Section of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado FOUNDING EDITORS Edward E. Wallach, MD Roger D. Kempers, MD ASSOCIATE EDITORS J. Christopher Carey, MD Denver Health Medical Center Denver, Colorado Susan A. Davidson, MD University of Colorado Aurora, Colorado Marc A. Fritz, MD University of North Carolina Chapel Hill, North Carolina Alice R. Goepfert, MD University of Alabama, Birmingham, Alabama Veronica Gomez-Lobo, MD Washington Hospital Center Washington, District of Columbia Hope K. Haefner, MD University of Michigan Ann Arbor, Michigan Nancy Hueppchen, MD Johns Hopkins University Baltimore, Maryland Bradley S. Hurst, MD Carolinas Medical Center Charlotte, North Carolina Julia V. Johnson, MD University of Vermont Burlington, Vermont Peter G. McGovern, MD University of Medicine and Dentistry of New Jersey Newark, New Jersey William D. Petok, PhD Clinical Psychologist Baltimore, Maryland Lynn L. Simpson, MD Columbia University Medical Center New York, NY *Dr. Schlaff has disclosed that he is/was the recipient of grant/research funding from Organon and Wyeth. Dr. Dugoff has disclosed that she is the recipient of grant/research funding from Diagnostic Technologies Ltd. June 30, 2009 History of cancer and related chemotherapy or radiation must be sought, not only for the potential effects on spermatogenesis, but also for determination of a time interval until retrieved sperm can be safely used after such therapies. Spermatogenesis may be gravely affected even with small amounts of radiation. Patients should be questioned about recent fevers and systemic illness, because spermatogenesis may be adversely affected for 2 to 3 months, and semen analysis must be repeated in timely intervals up to 6 months after such episodes. Table 1 lists some of the drugs and prescription medications that have been shown to have spermatotoxic properties. If possible, these medications should be discontinued and/or the man should be switched to an alternative medication. Social habits such as excessive alcohol consumption and marijuana or cigarette smoking can have a very deleterious effect on fertility and must be included in the history, although a definitive link between the latter and sperm parameters has not been established.2 Anabolic steroid use among body builders and professional athletes will shut down the normal hypothalamicpituitary-testicular axis and, although at times reversible with removal of the offending agent and possible gonadotropin therapy, may lead to irreversible azoospermia. Potency, libido, and ejaculatory function should be carefully assessed. color, temperature, and hair distribution are noted. Gynecomastia or galactorrhea are possible indicators of excess circulating estrogens and/or prolactin. The spermatic cords are evaluated for symmetry and possible presence of varicoceles. The latter may be clearly visible with the patient in a standing position (grade III), visible with the Valsalva maneuver (grade II), or palpable with increased fullness after Valsalva (grade I). The fullness sensation and “bag of worms” appearance of varicoceles is expected to disappear when the patient lies down. If the asymmetry persists in the supine position, diagnoses other than varicoceles (i.e., cord lipoma or a retroperitoneal mass compressing the vessels) are more likely. Testes are carefully examined and compared in size and consistency. Reduced or absent spermatogenesis in small testes is the rule, as approximately two-thirds of the testis mass is accounted for by the seminiferous tubules. Normal Physical Examination Manganese The patient should be examined in a warm room and asked to stand when the reproductive organs are examined. In addition to the basic general examination, physical examination focuses on detection of abnormalities related to the male reproductive system, including potential endocrine factors. The body habitus as well as skin Table 1. Select List of Spermatotoxic Agents Alcohol Anabolic steroids Calcium channel-blockers Cancer chemotherapeutic agents Cimetidine Colchicine Dilantin Lead Marijuana Nicotine Nitrofurantoin Pesticides Spironolactone Sulfasalazine Valproic acid Postgraduate Obstetrics & Gynecology (ISSN 0194-3898) is published biweekly by Lippincott Williams & Wilkins, Inc., 16522 Hunters Green Parkway, Hagerstown, MD 21740-2116. Customer Service Manager, Audrey Dyson: Phone (800) 787-8981 or call (410) 528-8572. 24-Hour Fax (410) 528-4105 or E-mail [email protected]. Visit our website at LWW.com. Publisher, Nancy Axelrod. Copyright 2009 Lippincott Williams & Wilkins. Priority Postage paid at Hagerstown, MD, and at additional mailing offices. 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Permission to reproduce in any way must be secured in writing from: Permissions Dept., Lippincott Williams & Wilkins, 351 West Camden Street, Baltimore, MD 21201; Fax: (410) 528-8550; E-mail: [email protected]. For commercial reprints, E-mail [email protected]. Opinions expressed do not necessarily reflect the views of the Publisher, Editor, or Editorial Board. A mention of products or services does not constitute endorsement. All comments are for general guidance only; professional counsel should be sought for specific situations. 2 June 30, 2009 Postgraduate Obstetrics & Gynecology of sperm should be motile. Varicoceles, chromosomal abnormalities, and hematospermia, as well as collection errors and morphological abnormalities, may contribute to asthenospermia (low motility). The World Health Organization (WHO) system for reporting sperm motility categorizes sperm as having one of four movement patterns: rapid and progressive; slow progressive, nonprogressive; or nonmotile.3 WHO reference values for normal seminal parameters are listed in Table 2. The multitude of steps required for ovum fertilization, including sperm maturation in the female genital tract (capacitation) renders sperm motility as only a crude index of fertilizing capacity. Normal sperm morphology consists of smooth and oval heads with an acrosome that is well-defined and comprises 40% to 70% of the total surface area of the sperm head, but there is little agreement on a universal assessment system. The tail, midpiece, and neck should not show any abnormalities, and there should not be any cytoplasmic droplets larger than half the size of the sperm head. Strict criteria as defined by Kruger et al. and included in the WHO reference values are commonly used and reject borderline shapes as abnormal. This group reported that in men with normal sperm density and motility greater than 30%, a significantly higher fertilization rate was achieved with in vitro fertilization (IVF) by men who had greater than 14% perfectly normal forms.4 Other authors have found significant differences in fertilization when comparing men with less than 4% normal Kruger forms with those having greater than 4% normal-appearing spermatozoa. Additional testing, including sperm culture in cases of documented pyospermia and other tests to analyze sperm function, may be performed in select cases. These tests are not routine and are beyond the scope of this review. Another cause of male factor infertility is antisperm antibodies (ASAs) that form as a result of any type of disruption (trauma, previous genital infection, or genital tract obstruction) in the blood-testis barrier and present in up to 10% of men with infertility. ASAs can affect various sperm functions including motility, capacitation, and the acrosome reaction, and they may be an important factor in cases of unexplained infertility and abnormal postcoital test results.5 The ASA direct assay is used to detect antibodies directed against sperm-surface antigens in the testis volume is usually greater than 20 mL (4.5 cm long, 2.5 cm wide), but even small testes may show normal testosterone production if the Leydig cells are intact. Fullness of the epididymis or areas of tenderness and induration along the vas deferens and epididymis may be indicative of obstruction. Abnormalities of the urethral meatus (i.e., hypospadias or epispadias), phimosis, Peyronie’s disease (penile curvature), or other penile anatomic features that may interfere with normal intercourse and ejaculate delivery to the vagina must be noted. Laboratory Evaluation Semen analysis is the single most critical component of the laboratory evaluation of the infertile male, although an “abnormal” semen analysis does not necessarily imply sterility. Three separate semen samples during a 4- to 6week period should be collected after 2 to 3 days of ejaculatory abstinence, kept at room temperature, and delivered to the laboratory within 1 hour. The combined secretions of the prostate, seminal vesicles, and bulbourethral glands constitute the ejaculate fluid. Most of the seminal fluid is contributed by the seminal vesicles (approximately 70%; alkaline pH), which constitutes the bulk of the final portion of the ejaculate. The prostatic secretions contribute 20% to 30% to the seminal fluid volume and, together with the spermatozoa as well as secretions from Cowper’s glands and the epididymides, constitute the initial portion of the ejaculate. In conditions such as CBAVD, wherein the seminal vesicles are absent, atrophic, nonfunctional; or when the ejaculatory ducts are obstructed; semen analysis will demonstrate low volume (<1 mL) and an acidic pH (<7.0) because most of the seminal volume is made up of prostatic fluid. Coagulation of the seminal fluid is dependent on seminal vesicle sections and does not occur in this group of patients. Conversely, liquefaction of the coagulum occurs 5 to 20 minutes after ejaculation and is caused by the proteolytic enzymes found in the secretions of Cowper’s glands and the prostate. In general, 20 million spermatozoa/mL is accepted as the lower limit of normal sperm concentration, but there is a wide range of sperm density even in fertile men. Furthermore, different laboratories may report widely varying results in the same patient due to differences in counting chambers or technique. It is difficult, therefore, to define a normal sperm density or correlate conception rates with sperm density except in cases of azoospermia. Because abnormal sperm density often occurs simultaneously with abnormal motility and/or morphology, it is difficult to assess the relative importance of each parameter as a contributor to male factor infertility. Severe abnormalities of sperm motility may indicate ultrastructural defects, and complete evaluation in these cases will require electron microscopy, although the latter is rarely performed in clinical practice. Sperm motility is defined based on demonstration of flagellar movement and will decrease with time, so the specimen should be evaluated within 2 hours of ejaculation. At least 50% Table 2. World Health Organization Reference Values for Normal Semen Parameters3 Volume: 2.0 mL or more pH: 7.2 or more Sperm concentration: 20 × 106 or more spermatozoa/mL Total sperm number: 40 × 106 or more spermatozoa per ejaculate Motility: 50% or more with grade “a + b” motility or 25% or more with grade “a” motility Morphology: 15% or more by strict criteria Viability: 75% or more of sperm viable White blood cells: <1 million/mL 3 Postgraduate Obstetrics & Gynecology June 30, 2009 semen, as those detected in the serum (indirect assay) are not as clinically significant. The immunobead test detects IgA or IgG binding to sperm and is considered clinically relevant if more than 20% to 50% of sperm demonstrate binding to the polyacrylamide beads. intrachromosomal recombination process and cannot be seen on routine karyotype analysis, hence the term “microdeletion,” as molecular biology techniques are needed for diagnosis. AZFa microdeletion may be seen in approximately 1% of men with NOA, whereas AZFb or AZFb/AZFc microdeletions are found in 1% to 2% of this group. Pure AZFc microdeletions are more common and may be detected in approximately 13% of patients with NOA and 6% of severe oligospermics. Genetic testing is critical in patients with NOA and severe oligospermia, as it will help the couple have realistic expectations regarding the chances of both successful sperm retrieval and that a genetic anomaly will be passed on to the offspring. For example, it is known that if AZFa, AZFb, or AZFb/AZFc microdeletions are found in an azoospermic patient, testicular sperm extraction (TESE) will be unsuccessful, and there is no need to undergo an unnecessary procedure.12 Conversely, a more variable pattern is seen in men who have AZFc microdeletions, as these men may manifest a phenotypic spectrum ranging from low levels of sperm in the ejaculate to sperm found in testicular tissue and finally to complete lack of spermatogenesis.12,13 Patients with AZFc deletions should be offered TESE, as successful sperm retrieval can be accomplished in approximately 65% of this group, and adverse effects on assisted reproduction (i.e., intracytoplasmic sperm injection) or embryo development have not been observed.7 The parents, however, should be carefully counseled that all male offspring will inherit the same genetic anomaly and potentially will be sterile without the possibility of sperm retrieval. Some couples may choose not to use the husband’s sperm or choose preimplantation genetic testing to transfer only female embryos and therefore eliminate the chance that AZFc microdeletion will be passed on. The same logic also applies to AZFc-deleted men with low levels of sperm in the ejaculate who may pass on the deletion to male offspring. Genetic defects that affect the androgen receptor, androgen synthesis, and intracellular androgen function may have indirect effects on spermatogenesis. Tests for these defects are rarely performed in clinical practice. The CF gene encodes a protein, the CF transmembrane conductance regulator (CFTR). Mutations in both alleles of the CFTR genes may result in CBAVD, a condition that accounts for approximately 6% of all causes of obstructive azoospermia and 1% of infertility.14 More than 600 mutations have been observed in the CF gene on chromosome 7, and the most common (60%–70%) is the ∆F508, a three-base-pair deletion in exon 10. If only one copy of a CF mutation is present, the patient will have a carrier state without any clinical manifestations. When the two most “severe” allelic abnormalities are present (i.e., two copies of ∆F508), full-blown CF will be the phenotypic manifestation of the genetic abnormality. When “milder” combinations of the alleles are present (i.e., R117H/5T allele), vasal aplasia without the typical CF pulmonary and/or pancreatic manifestations will be Hormonal Evaluation Abnormalities in the hypothalamic-pituitary-testicular axis account for a very small percentage of patients with infertility (less than 5%). Follicle-stimulating hormone (FSH) is regulated by a negative feedback control system through inhibin, a hormone produced by the Sertoli cells in the testis. Elevated FSH is frequently a telltale sign of compromised spermatogenesis as the feedback system fails. Conversely, many other male factors in infertility, including mild oligospermia or motility deficiencies, may not be associated with hormonal abnormalities. Hence, routine hormonal evaluation is often not helpful unless severe oligospermia (<10 million/mL) or azoospermia is observed. When testosterone is measured in these patients, it is important to obtain early morning levels because of the diurnal variation. If testosterone deficiency is noted, serum prolactin should be measured, as the latter may be elevated secondary to a pituitary microadenoma and will also result in suppression of FSH and luteinizing hormone (LH). Genetic Testing An underlying genetic abnormality may be responsible for azoospermia or severe oligospermia in 10% to 15% of such cases, and genetic testing is warranted. Karyotype analysis will be helpful in delineating aberrations in chromosome number such as Klinefelter syndrome (47,XXY) or chromosome structure abnormalities such as ring Y, isodicentric Y, truncated Y, and various other translocations. Klinefelter syndrome is the most common karyotypic abnormality found in azoospermic patients, occurring in more than 80% of all sex chromosome aberrations in this group. Incidence reports range from 1 in 500 to 1 in 1000 live births; these account for approximately 3% of cases of male infertility and 10% of nonobstructive azoospermia (NOA).6 The vast majority of the cases are of the pure (i.e., nonmosaic) type 47,XXY and occur due to meiotic chromosomal nondisjunction (either paternal or maternal). Normal pregnancies and live births through assisted reproductive technology have been reported for both the mosaic and nonmosaic groups, but there are still some concerns about genetic abnormalities of the offspring based on higher levels of chromosomal aneuploidy in the evaluated sperm cells, and some investigators recommend preimplantation genetic testing.7 Regulation of spermatogenesis is partly controlled by genes that are located on the long arm of the Y chromosome. This area of the chromosome is named the azoospermia factor (AZF) region, and it is now known that severe (or complete) spermatogenic failure ensues when there are genomic microdeletions, single or combined, of three areas along AZF (AZFa, AZFb, and AZFc).8–11 These genetic “hits” occur due to an unusual 4 June 30, 2009 Postgraduate Obstetrics & Gynecology observed. These patients are expected to have absent or fully atretic vasa and distal two-thirds of the epididymis. The caput epididymis has a different embryologic development path and will be present and feel “full” on careful palpation. Moreover, these patients typically do not have any pulmonary or pancreatic pathology. The phenotypic findings depend on the levels of normal CFTR. It is important to note that not all men with CBAVD will have CF mutations, and approximately 20% of patients with CBAVD are thought to have the pathology as a result of another cause.15 Genetic counseling and testing the patient’s siblings are highly recommended. It is absolutely critical that the female partner of a man with CBAVD be tested for CF mutations using an “extended panel” CF test, which evaluates as many known mutations as possible (not with the routine 32-mutation screening test). This should be done before IVF for two important reasons: 1) 80% of men with CBAVD are homozygous for CF mutations, even if they do not have a known mutation detectable with standard testing; and 2) there is a very high carrier rate in the population (approximately 1 in 20 to 1 in 25 among partners of Northern European descent), and therefore, a real chance of the female partner being a CF carrier, resulting in a significant chance of transmitting full-blown CF to 25% of their offspring. It is also important to note that most commercial laboratories do not test for all CF mutations, and a negative test result is not a guarantee that a genetic abnormality will not be passed on to offspring. is indicated in patients who are suspected of having vasal obstruction in the inguinal or pelvic area. If contrast is noted throughout the vasa, ejaculatory ducts, and bladder, patency of the system is established. Even the most careful vasography may injure the vasal lumen; therefore, the test should not be performed routinely. If a previous testis biopsy has documented spermatogenesis, vasography can help define the exact site of obstruction. However, it is not required in the patient with spermatogenic dysfunction at the time of testis biopsy, nor in the patient with suspected EDO in whom TRUS is the preferred imaging modality. Retrograde contrast injection toward the epididymis will injure the latter and should never be performed. Scrotal sonography (with color duplex Doppler) has no role in the routine evaluation of the infertile male and has been shown to have a lower accuracy rate in detecting varicoceles compared with physical examination or venography by experienced clinicians. It may be useful occasionally for assessment of varicoceles in patients who are difficult to examine or those with history and physical examinations consistent with testicular malignancy. Diagnostic Categories Commonly Encountered Clinical Scenarios Normal-Volume Azoospermia. Absence of spermatozoa in an otherwise normal-volume ejaculate suggests either an obstruction to sperm flow between the testis and vasal ampullae (implies normal spermatogenesis) or markedly deficient spermatogenesis in the presence of a patent ductal system. In both scenarios, ejaculate volume is normal as there are no barriers to the prostatic or seminal vesicular contributions. Both congenital and acquired etiologies may cause vasal or epididymal obstruction. There are a myriad of acquired obstructive causes, which can occur anywhere along the path of the vasa or the epididymides, but postvasectomy obstruction is the most common in this category. A history of pelvic fracture or hernia repair, particularly in childhood, suggests more distal vasal obstruction, although this is more likely to be a unilateral process and will go unnoticed unless presenting with azoospermia in bilateral cases. Congenital epididymal obstruction typically occurs at the vasal-epididymal junction. Occlusion of the epididymis, and in fewer cases the vasa, may follow inflammatory or infectious conditions of the vas and epididymis (epididymitis or less commonly tuberculosis). The combination of bronchiectasis and epididymal obstruction by inspissated secretions is suggestive of Young syndrome. Semen volume is unaffected in conditions that cause primary spermatogenic failure. Abnormal testicular consistency, which may present as firm or soft based on the level of interstitial fibrosis, and bilateral small testicles on physical examination are suggestive. The more commonly observed scenario, hypergonadotropic hypogonadism, is one in which FSH is elevated, indicating primary testicular dysfunction with elevated gonadotropins Radiologic Evaluation When obstructive azoospermia is present and ejaculatory duct obstruction (EDO) or CBAVD is suspected, transrectal ultrasonography (TRUS) is the initial imaging diagnostic modality of choice. In patients with CBAVD, the seminal vesicles and ampullae of the vasa are absent or severely atretic, and TRUS will help define the anatomic abnormalities of these structures and confirm the diagnosis. The intrarenal collecting system, ureters, seminal vesicles, vasa, and distal two-thirds of the epididymis share a common embryological precursor, and a renal ultrasound scan should be obtained in patients with vasal aplasia to rule out ipsilateral mesonephric duct-derived structural anomalies. In an azoospermic or severely oligospermic patient with palpable vasa, acidic pH semen, and low-volume ejaculate, EDO should be suspected. Those with partial EDO may not have a very low volume, and definitive diagnosis of this entity is extremely difficult. Contributing factors include, but are not limited to, a history of epididymal pain, prostatitis, and ejaculatory pain. Presence of a midline prostatic cyst on TRUS is confirmatory in some cases but is not pathognomonic for EDO. More often, seminal vesicles will be seen to be dilated beyond their normal 1.5 cm diameter behind the bladder. When resection of the ejaculatory duct is planned, TRUS imaging can help guide the depth of resection. Vasography, now infrequently performed, permits radiologic visualization of the entire vas deferens from the most proximal straight portion to the ejaculatory duct and 5 Postgraduate Obstetrics & Gynecology June 30, 2009 not palpable on physical examination and are only detected with use of ancillary measures such as ultrasonography are not thought to play an important role in spermatogenic dysfunction. Inappropriate inclusion in published studies of this group of patients with subclinical varicoceles has complicated the assessment of efficacy of varicocele repair in treatment of male infertility. Oligospermia or asthenospermia may also be seen secondary to various toxins, environmental factors, and ASAs, although many cases remain unresolved without a clear-cut etiology. The latter diagnosis is entertained in the presence of a history predisposing to the development of immunologic infertility (i.e., testis trauma); excessive sperm agglutination; reduced motility with relatively normal sperm concentration; or an abnormal postcoital test result. Low-Volume Azoospermia. As discussed in the radiologic evaluation section, low-volume azoospermia (i.e., semen volume <1 mL) is typically due to either EDO or one of the syndromes of vasal aplasia. EDO may be secondary to scarring of the ducts following inflammatory/infectious processes in the prostate and ductal area. This is a more subtle diagnosis, as there will not be any obvious prostatic cysts or intraprostatic ductal dilation, and the sonographer must carefully evaluate the seminal vesicles and the vasal ampullae for dilation. Other causes include mechanical obstruction from a midline prostatic cyst of Mullerian origin. When the latter diagnosis is suspected, TRUS will yield confirmatory pathognomonic images. Partial EDO may be suspected when there is a combination of severe oligospermia, normal gonadotropins, and a normal testis examination. CBAVD has been covered in the genetic testing section of this review. The diagnosis is confirmed when the constellation of findings includes low-volume azoospermia with an acidic pH, normal testicular size and consistency, nonpalpable vasa and a dilated caput epididymis on physical examination, seminal vesicle aplasia, hypoplasia or cystic dysplasia as well as absent vasal ampullae on TRUS images, and normal serum gonadotropin levels. Retrograde ejaculation is yet another condition in the “low-volume” category, although azoospermia may or may not be seen.19 The etiology may be neurologic or anatomic due to failure of bladder neck coaptation during emission. Diagnosis is typically made with examination of the postejaculate urine specimen. In the patient with a normal voiding pattern, bladder catheterization is not required as the patient is asked to void, ejaculate, and subsequently provide a second, postejaculate urine when ready. Combined retrograde ejaculation and azoospermia may be seen in patients after retroperitoneal lymph node dissection for testis cancer. These patients may not only have retrograde ejaculation secondary to their surgery, but also spermatogenetic dysfunction in the remaining gonad due to the original pathology. due to an appropriate pituitary compensatory mechanism. Testosterone may be normal in this scenario, as Leydig cell function will not necessarily be affected. Some of the genetic causes of infertility discussed earlier in this article, such as Klinefelter syndrome, the XX male syndrome, and Y chromosome microdeletions, are associated with hypergonadotropic hypogonadism. Other causes include chemotherapy or radiation therapy for cancer and a history of mumps orchitis after childhood. The phenotypic manifestation of Klinefelter syndrome ranges from severe cases, presenting with learning difficulties and a eunuchoid appearance in teenage/early adult years, to those who may have very little outward signs of androgenic compromise and only present with infertility and NOA. The testes are small and serum testosterone is low to low-normal (with elevated LH) in both groups. More than half of patients may not have gynecomastia. Conversely, undetectable LH and FSH with very low testosterone levels are found when the pathology is at the level of the hypothalamus or the pituitary (hypogonadotropic hypogonadism). Tumors of the pituitary gland or treatments for such tumors may cause panhypopituitarism and thus hypogonadotropic hypogonadism. Other causes include Kallmann syndrome, typically presenting with a combination of anosmia, incomplete virilization, undetectable gonadotropins, and infertility. The pathology develops secondary to the failed migration of GnRH neurons from the olfactory area to the hypothalamus during fetal brain development. Prader-Willi syndrome is another form of hypothalamic dysfunction with more severe clinical findings including obesity, diabetes, mental retardation, cryptorchidism, and diabetes in addition to the findings noted for Kallmann syndrome. Anabolic, androgenic steroid abuse may also present with hypogonadotropic hypogonadism as pituitary LH release is suppressed and intratesticular testosterone production comes to a halt. Patients usually have the “bodybuilder” musculature and body habitus but suffer from severe oligospermia or even azoospermia. The condition may be reversible with discontinuation of the steroids and treatment with gonadotropins, but some cases are irreversible.16,17 Oligoasthenospermia. Normal-volume ejaculate with abnormal sperm concentration, motility, or morphology is very commonly encountered in the infertile male population. Varicoceles, abnormally dilated veins of the pampiniform plexus in the spermatic cord and the scrotum, are present in up to 40% of men presenting with infertility and are the most commonly observed associated finding in oligospermic men. Varicoceles are also found in approximately 15% of the fertile male population, and their presence does not necessarily imply infertility.18 A careful physical examination will detect unilateral left-sided varices in 80% of patients and bilateral varicoceles in 20%. The pathophysiology of testicular dysfunction secondary to varicoceles has not been definitively elucidated, but elevated testis temperatures, increased venous reflux, and elevated levels of superoxides have been noted in peer-reviewed publications as having an important role. Subclinical varicoceles that are Summary The critical role of the “male factor” in approximately 50% of all infertile couples should always prompt careful 6 June 30, 2009 Postgraduate Obstetrics & Gynecology evaluation of the male partner. This evaluation should include a careful history (including genitourinary history; medical problems; surgeries; reproductive and pubertal histories; and any medications, herbs or alternative medications used) and a physical examination. Routine scrotal ultrasonography to assess for subclinical varicoceles should not be performed. Laboratory evaluation comprises semen analysis, which includes assessment of semen volume, concentration, motility, and morphology. Blood tests are needed only when suggested by history, physical findings, or abnormal semen analysis parameters. Genetic testing (karyotype and Y microdeletion testing) is recommended for cases of severe oligospermia (concentration <10 million sperm/mL) or azoospermia (complete absence of sperm). Proper diagnosis will aid significantly in developing the best possible treatment options for the couple. Physicians caring for the infertile man should be intimately familiar with the genetic aspects of male infertility for effective patient counseling and informed decision making, with consideration of potential repercussions for subsequent generations when assisted reproductive technologies are used. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. REFERENCES 1. 2. 3. 4. Cendron M, Keating MA, Huff DS, Koop CE, Snyder HM, 3rd, Duckett JW. Cryptorchidism, orchiopexy and infertility: a critical long-term retrospective analysis. J Urol 1989;142(2 Pt 2):559-562; discussion 572. Vine MF, Margolin BH, Morrison HI, Hulka BS. Cigarette smoking and sperm density: a meta-analysis. Fertil Steril 1994;61(1):35-43. World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. New York: Cambridge University Press; 1999. Kruger TF, Menkveld R, Stander FS, et al. Sperm morphologic features as a prognostic factor in in vitro fertilization. Fertil Steril 1986;46(6):1118-1123. 16. 17. 18. 19. Bohring C, Krause W. Immune infertility: towards a better understanding of sperm (auto)-immunity—the value of proteomic analysis. Hum Reprod 2003;18(5):915-924. Sadeghi-Nejad H, Farrokhi F. Genetics of azoospermia: current knowledge, clinical implications, and future directions: part I. Urol J 2006;3(4): 193-203. Oates RD. The genetic basis of male reproductive failure. Urol Clin North Am 2008;35(2):257-270, ix. Oates RD, Silber S, Brown LG, Page DC. Clinical characterization of 42 oligospermic or azoospermic men with microdeletion of the AZFc region of the Y chromosome, and of 18 children conceived via ICSI. Hum Reprod 2002;17(11):2813-2824. Page DC, Silber S, Brown LG. Men with infertility caused by AZFc deletion can produce sons by intracytoplasmic sperm injection, but are likely to transmit the deletion and infertility. Hum Reprod 1999;14(7):1722-1726. Reijo R, Lee TY, Salo P, et al. Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat Genet 1995;10(4):383-393. Reijo RJ, Alagappan R, Patrizio P, Page DC. Severe oligospermia resulting from deletions of the azoospermia factor gene on Y chromosome. Lancet 1996;347:1290-1293. Sadeghi-Nejad H, Oates RD. The Y chromosome and male infertility. Curr Opin Urol 2008;18(6):628-632. Silber SJ, Repping S. Transmission of male infertility to future generations: lessons from the Y chromosome. Hum Reprod Update 2002;8(3):217-229. Anguiano A, Oates RD, Amos JA, et al. Congenital bilateral absence of the vas deferens: a primarily genital form of cystic fibrosis. JAMA 1992;267(13):17941797. McCallum T, Milunsky J, Munarriz R, Carson R, Sadeghi-Nejad H, Oates R. Unilateral renal agenesis associated with congenital bilateral absence of the vas deferens: phenotypic findings and genetic considerations. Hum Reprod 2001;16(2):282-288. Gazvani MR, Buckett W, Luckas MJ, Aird IA, Hipkin LJ, Lewis-Jones DI. Conservative management of azoospermia following steroid abuse. Hum Reprod 1997;12(8):1706-1708. Menon DK. Successful treatment of anabolic steroid-induced azoospermia with human chorionic gonadotropin and human menopausal gonadotropin. Fertil Steril 2003;79 Suppl 3:1659-1661. Report on varicocele and infertility. Fertil Steril 2008;90(5 Suppl):S247-249. Ohl DA, Quallich SA, Sonksen J, Brackett NL, Lynne CM. Anejaculation and retrograde ejaculation. Urol Clin North Am 2008;35(2):211-220, viii. View past*, current, and future issues of your paid subscription to Postgraduate Obstetrics & Gynecology online for free! Follow these instructions to log-on to your account. 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Lippincott Continuing Medical Education Institute, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Please do not use the answer forms and business reply envelopes that you may have on hand from previous issues of Postgraduate Obstetrics & Gynecology. Lippincott Continuing Medical Education Institute, Inc., designates this educational activity for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. 1. Male factor accounts for approximately 30% to 40% of infertility in combination with female causes, and as a sole factor, approximately A. 5% B. 10% C. 20% D. 30% E. 50% 6. There is no chance of sperm retrieval and hence no need for testicular sperm extraction (TESE) in all of the following scenarios, except A. AZFa microdeletion B. AZFb microdeletion C. AZFc microdeletion D. AZFb/AZFc microdeletion 7. The carrier rate for cystic fibrosis mutations in the United States population of Northern European descent is approximately A. 1 in 1000 B. 1 in 300 C. 1 in 20 D. 1 in 10 E. none of the above 2. A history of anosmia in combination with azoospermia or severe oligospermia and low gonadotropins suggests A. Kallmann syndrome B. Prader-Willi syndrome C. hypergonadotropic hypogonadism D. Y chromosome microdeletion E. idiopathic infertility 8. All of the following are suggestive of an “obstructive” cause for male infertility, except A. history of severe, recurrent urinary tract infections B. absent cauda epididymis on physical examination C. bilateral hydrocele repair D. diabetic neuropathy 3. Patients with congenital bilateral absence of the vas deferens (CBAVD) are likely to have A. low-volume ejaculate with an acidic pH B. normal-volume ejaculate with acidic pH C. abnormally copious ejaculate with unchanged pH D. increased risk of pyospermia E. none of the above 9. World Health Organization reference values for normal semen parameters include all of the following, except A. volume greater than 2 mL B. sperm concentration greater than 20 million per mL C. motility 50% or more D. pH of 6.0 or less 4. Elevated serum follicle-stimulating hormone levels are most commonly found in patients with A. CBAVD B. Klinefelter syndrome C. bilateral epididymal obstruction D. grade I varicoceles E. complete ejaculatory duct obstruction 10. Which of the following agents has been shown to have spermatotoxic effects? A. Dilantin B. Verapamil C. Marijuana D. A and C E. All of the above 5. Among azoospermic patients with nonobstructive pathology, Y chromosome AZFc microdeletions will be expected in A. 90% B. 75% C. 33% D. 25% E. 13% 8