Department of Urology
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Illnesses We Treat Male - Factor Infertility It is estimated that one of five couples will have difficulty establishing a pregnancy and that a male factor will be identified as the sole or contributing cause in 40 percent of these cases. As the number of couples seeking assistance rises, male reproductive disorders have become an increasingly important part of the infertility examination. Current diagnostic and advanced treatment modalities have significantly improved prognosis and created a new era in the treatment of male-factor infertility. History and Physical Examination Childhood and developmental conditions that may have an impact on fertility include a history of undescended testicles, testicular torsion, trauma, and precocious or delayed puberty. Systemic illnesses such as diabetes mellitus, multiple sclerosis, and spinal-cord injury may impair normal ejaculation. Any previous retroperitoneal, pelvic, inguinal, or scrotal surgery should be noted. Prior exposure to sexually transmitted diseases may lead to reproductive-tract scarring. Because intratesticular sperm maturation requires 74 days, exposure during the past several months to systemic illness, fevers, excessive heat, or various medications should be elicited. Prior exposure to gonadotixins such as chemotherapy, radiation, exogenous androgenic steroids, as well as excessive alcohol use, cigarette smoking, and use of marijuana and other recreational drugs have all been associated with decreased fertility. Finally, it is important to inquire about the couple's sexual history including the frequency and timing of intercourse. To achieve conception, sexual intercourse should be initiated prior to ovulation and continued at a frequency of every other day during the ovulatory period. A thorough physical examination should ascertain overall body habitus, taking note of stigmata associated with endocrine disorders, and should assess neurologic status and inspect for prior surgical scars. The urologic examination focuses on accurately determining testicular size and evaluating for the presence of vas deferens and variococeles. Any epididymal, penile, or urethral abnormalities should be identified. A rectal examination is performed to evaluate the prostate and seminal vesicles. Semen Analysis A properly performed semen analysis evaluates several parameters including:
Initially, semen is a coagulum that under normal conditions liquefies within 1 hour after ejaculation. The seminal constituents responsible for coagulation originate in the seminal vesicles while the proteolytic enzymes that initiate liquefaction are found in the prostate. Following liquefaction, the quality of the seminal fluid can be evaluated. Viscosity is considered normal when the specimen can be gently passed through a 21 G needle. Impaired liquefaction and hyperviscosity in the presence of normal sperm motility and a normal postcoital test is probably of no clinical significance; however, when impaired motility is noted, trials of sperm processing followed by intrauterine insemination are worthwhile. Ejaculate volume Sperm count In the evaluation of the azoospermic male, a testicular biopsy provides critical information. Recently, it has been realized that even if a man shows azoospermia and a markedly elevated level of follicle-stimulating hormone (FSH), the testicular biopsy may identify occasional mature sperm that can be potentially utilized in conjunction with assisted reproductive technology. On the other hand, when obvious obstructive causes of azoospermia such as bilateral vasal agenesis or prior sterilization are present, a testicular biopsy is not indicated. Sperm motility Grade 0 = no movement Grade 1 = movement, but no forward progression Grade 2 = movement with slow forward progression Grade 3 = movement in an almost straight line with good speed Grade 4 = movement in a straight line with high speed In a normal semen analysis, >50 percent of the sperm should demonstrate grade 3 or 4 forward progression. Abnormalities of motility can arise from infection, the presence of antisperm antibodies, partial ejaculatory-duct obstruction, gonadotoxin exposure, and varicoceles. Necrospermia (when none of the sperm are moving) is a misnomer, because in some cases the sperm are alive yet immotile secondary to structural defects in the tail. With the currently available assisted reproductive technology techniques, men showing this defect should not necessarily be considered sterile. Sperm morphology A normal sperm has an oval configuration with a smooth contour, an acrosome comprising 40 percent to 70 percent of the distal part of the head, no abnormalities of the neck, midpiece, or tail, and cytoplasmic droplets filling no more than half the sperm head. All borderline forms are considered abnormal (Figure 1). Using these strict criteria, a normal semen analysis will contain more than 14 percent normal-appearing sperm. In some studies, classification of sperm according to the Kruger criteria has correlated well with in vitro fertilization (IVF) outcomes and various sperm-function assays. Some infertile men show numerous round cells in their semen. These round cells may be either immature sperm or white blood cells, and special staining techniques are needed to accurately differentiate between the two. Increased numbers of seminal leukocytes (leukospermia) may indicate a potentially treatable subclinical genital-tract infection, and appropriate cultures of both semen and prostate secretions should be performed. Seminal white blood cells may adversely affect sperm function either directly, through the release of soluble modulators (cytokines), or by production of harmful free oxygen radicals. pH Sperm Function Assays Currently, a comprehensive male-factor infertility evaluation includes a test of sperm function aimed at identifying abnormalities not apparent on the routine semen analysis. Such isolated defects may allow the clinician to recommend a more appropriate and informed treatment plan. As specific defects of fertilization are identified and more appropriate therapeutic plans can be recommended, it is hoped that improved success rates for many male-factor patients will be achieved. Cervical-Mucus Assay Assays of Sperm Function
Acrosome reaction The acrosome reaction is induced in vitro by exposure to the sperm to such agents as human follicular fluid, calcium ionophore A23187, or lysophosphatidylcholine. A normal semen sample is one that demonstrates few spontaneously reacting sperm and a good response to such acrosome-reaction-inducing agents. Calvo and colleagues reported that, in a group of 232 couples undergoing IVF, spermatozoa with a failed acrosome reaction (<5 percent) fertilized only 12 percent of the ova, whereas spermatozoa with acrosome reaction values >9 percent fertilized 50 percent of the ova. Acrosome-reaction-positive couples 2.9 times more likely to achieve fertilization than couples with a failed acrosome reaction assay. Certain couples with unexplained infertility and apparently normal semen analysis may be unable to achieve fertilization as a result of an inadequate acrosome reaction. Hemizona assay. The hemizona assay (HZA) evaluates the ability of human sperm to bind to the zone pellucida of the human oocyte (ovum). In this assay,intact oocytes are cut in half by micromanipulation techniques. Donor sperm are incubated with one zona half and the patient's sperm with the other half. The hemizona index (HZI) is calculated by counting the number of sperm bound to each zona half and dividing the number of patient sperm bound by the number of donor sperm bound. This HZI has been correlated with fertilization rates in vitro. The assay provides valuable insight into the ability of sperm to bind to the surface of human ova and may help identify those patients who would benefit from micromanipulation, by-passing sperm-occyte binding. However, clinical use of the hemizona assay has not been widespread, in part because of the limited availability of human ova. Sperm-penetration assay. In 1976, Yanagimachi and colleagues demonstrated with hamsters that cross-species fertilization can occur once the zona pellucida of the ovum is removed. This observation led to the development of the sperm-penetration assay (SPA) in which zona-free hamster ova are incubated with human sperm. For sperm-ovum fusion to occur, sperm must undergo multiple and complex events including capacitation, the acrosome reaction, penetration of the ooplasm, and chromatin decondensation. Pregnancy rates for couples with a normal SPA are higher whether the pregnancies are achieved through intercourse, intra-uterine insemination, or IVF. It has been shown that 95 percent of men with a normal SPA will fertilize human ova in vitro compared to only 50 percent of men with an abnormal SPA. Men whose sperm cannot penetrate any hamster ova are rarely able to fertilize any human ova in vitro. Accordingly, the SPA has become a significant diagnostic tool for gaining information about sperm function. Nevertheless, because there has been no accepted standardization of the assay, protocols vary widely among laboratories and have resulted in conflicting reports about its accuracy. Medical Therapy Ejaculatory dysfunction Hormonal abnormalities Treatment with exogenous gonadotropins or GnRH has restored spermatogenesis in men with hypogonadotropic hypogonadism. Although the semen parameters obtained are often severely ogligospermic, a large proportion of these men have successfully initiated pregnancies. Empiric Therapy As a result of numerous conflicting studies, there is significant controversy about the efficacy of clomipherene citrate for the treatment of male-factor infertility. It is difficult to predict which patients will respond to clomiphene, but those not likely to benefit include men with elevated baseline FSH levels, severely abnormal semen parameters, azoospermia, and those with extremely abnormal testis-biopsy results. Other empiric medical regimens have included tamoxifen, testolactone, androgens, exogenous gonadotropins, kallikreins, and antioxidants. Although a subset of patients may respond to these nonspecific medical therapist, conclusive data confirming their efficacy are lacking. The generally poor results often obtained with empiric medical therapy emphasize the importance of performing a thorough evaluation to identify specific treatable causes for male-factor infertility. Surgical Therapy
Variococeles, which are dilated spermatic veins located within the pampiniform plexus, are an important treatable cause of male-factor infertility. They are present in approximately 15 percent of all men but are observed in up to 40 percent of infertile men with primary infertility. It appears that, in the infertile male population, variococeles are a significant contributing cause, especially as men advance in age. Suggested mechanisms for varicocele formation have included impaired steroidogenesis, testicular hypoxia, reflux of metabolites, and -- the most widely accepted theory - testicular hyperthermia. Treatment options for varicocele include surgical repair, percutaneous venographic occlusion, and laparoscopy. A subinguinal microscopic surgical repair is advocated by many urologists as the current treatment of choice because of the thoroughness of the ligation, minimal recurrence and complication rate, and short post-operative recovery period. Despite an occasional study suggesting that varicocelectomy does not improve fertility, the preponderance of literature reports support varicocele correction. Seminal parameters improve in approximately 60 percent to 70 percent of the treated men, and pregnancy rates of approximately 35 percent to 50 percent are obtained within 1 year. A 1992 WHO project on human reproduction reported a deterioration in sperm concentration and motility over time in men with varicocele and noted a direct relation between the size of the varicocele and depression of semen parameters. The first prospective, randomized crossover study evaluating the efficacy of surgical varicocele repair has been reported by Madgar and colleagues. The group of men who underwent ligation of the varix achieved a 60 percent pregnancy rate during the first year, compared to a 10 percent pregnancy rate for the untreated cohort observed for the same period of time. Significantly, following surgical repair during the second year, the control group achieved a 44 percent pregnancy rate. This study thus supports the concept that varicoceles play a significant role in male-factor infertility. Microsurgical reconstructive surgery of the male reproductive tract continues to be an important treatment option for male-factor infertility. Of the approximately 500,000 men who undergo vasectomy annually in the United States, an increasing number present later for vasectomy reversal. Reconstruction of vasal patency is also indicated following obstruction of infectious, congenital or iatrogenic origin. Initial macrosurgical approaches have been replaced by the more-precise microsurgical techniques. Expected patency rates using these microsurgical techniques are around 90 percent, with pregnancy rates ranging from 50 percent to 80 percent. Belker and colleagues reported findings of the vasovasostomy study group, which evaluated 1247 men who underwent microsurgical vasectomy reversal and found that the interval since the vasectomy as well as the intraoperative vasal-fluid quality influenced patency and pregnancy rates. No appreciable difference was observed whether the microsurgical modified one-layer or the more technical two-layer vasovasostomy technique was used. However, delayed scarring following a successful vasovasostomy occurs in approximately 5 percent to 10 percent of cases, so cryopreservation of the sperm once patency has been restored should be considered. If, during vasal reconstruction, no sperm are identified by the proximal vasal segment because of an epididymal tubule rupture, or if an obstruction of inflammatory, iatrogenic, or congenital origin is at the level of the epididymis, a vasoepididymostomy is performed. Historically, following macrosurgical, fistula-forming vasoepididymostomy techniques, patency and pregnancy rates were extremely poor. With current microsurgical techniques, patency rates are about 50 percent to 70 percent, and pregnancy rates of 15 percent to 30 percent are expected. Two microsurgical techniques have been described: an end-to-end anastomosis and an end-to-side anastomosis. It is important to inform patients that, following a vasoepididymostomy, it may take up to 1 year before sperm appear in the ejaculate, and as up to 25 percent of initially patent vasoepididymal anastomoses may subsequently become obstructed by scarring, cryopreservation should be considered once patency has been restored. Fortunately, today, for those men who have failed microsurgical reconstructive surgery, retrieval of sperm in conjunction with oocyte micromanipulation offers a realistic hope of initiating a pregnancy. Assisted Reproductive Technology The Assisted Reproductive Technologies Program at Mount Sinai Intrauterine Insemination (IUI) In Vitro Fertilization Intracytoplasmic Sperm Injection (ICSI) Gamete micromanipulation implies actively assisting sperm penetration of the human ovum in vitro. Over the last decade, micromanipulation has evolved from the drilling of a hole in the zone pellucida, as originally described by Gordon and colleagues at the Mount Sinai Medical Center (partial zona dissection), to the subzonal insertion of sperm into the perivitelline space, to its current standard form, termed "intracytoplasmic sperm injection." By this technique, a single sperm is microinjected directly into the cytoplasm of the ovum. (Figure 2). ICSI was originally described by Van Steirteghan's group in Brussels. In a 1993 review of 150 consecutive ICSI cases, they reported a 64.2 percent fertilization rate and a 39.2 percent clinical pregnancy rate. An astonishingly 90 percent of the IVF/ICSI cycles resulted in an embryo transfer. Success with ICSI has subsequently been duplicated at numerous fertility centers worldwide. Today, couples with male-factor infertility who have failed prior IVF cycles, as well as men with extremely poor semen parameters (eg, low total motile-sperm count, poor strict-criteria morphology, abnormal sperm-function assays) routinely utilize ICSI when undergoing IVF treatment. ICSI has also become the standard when dealing with epididymal and testicular sperm. Men with congenital absence of the vas deferens as well as men with irreconstructable obstruction have demonstrated significantly improved fertilization and pregnancy rates with ICSI. Methods for sperm retrieval have included open microsurgical epididymal aspiration (MESA), percutaneous epididymal aspiration, and percutaneous testicular aspiration and biopsy. Regardless of the sperm retrieval technique used, live pregnancies have been reported, suggesting that all that is required for ICSI is an individual, genetically intact sperm. It has been recently appreciated that in approximately 50 percent of men with azoospermia on routine semen analysis, isolated intratesticular sperm can be identified and potentially used for ICSI. However, in this population of severely oligospermic men, various genetic defects located on the Y chromosome are being identified. Although more than 1000 pregnancies have been achieved worldwide following micromanipulation techniques, and the preliminary data from major ICSI centers indicate no significant increase in congenital anomalities, more-thorough research is required. It is important to appreciate that IVF/ICSI is still very costly, and the live-birth rate in most programs is only 20 percent to 30 percent. It is therefore prudent to perform a thorough evaluation, identify a correctable cause of male infertility, and determine if a more natural and cost-effective method of initiating a pregnancy can be used. Nevertheless, ICSI is a true modern-day "miracle" that, when indicated, achieves unprecedented pregnancy rates independent of sperm quality and source. Conclusion For further information or to schedule an appointment please
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