Practice Essentials
Infertility in men can result from deficiencies in sperm formation, concentration, or transportation. This general division allows an appropriate workup of potential underlying causes of infertility and helps define a course of action for treatment.
The image below depicts male ductal anatomy.
Signs and symptoms
The initial step in the evaluation of an infertile male is to obtain a thorough medical and urologic history. Such a history should include consideration of the following:
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Duration of infertility
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Previous fertility in the patient and the partner
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Timing of puberty (early, normal, or delayed)
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Childhood urologic disorders or surgical procedures
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Current or recent acute or chronic medical illnesses
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Sexual history
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Testicular cancer and its treatment
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Social history (eg, smoking and alcohol use)
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Medications
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Family history
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Respiratory disease
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Environmental or occupational exposure
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Spinal cord injury
The physical examination should include a thorough inspection of the following:
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Testicles (for bilateral presence, size, consistency, symmetry)
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Epididymis (for presence bilaterally, as well as any induration, cystic changes, enlargement, tenderness)
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Vas deferens (for presence bilaterally, defects, segmental dysplasia, induration, nodularity, swelling)
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Spermatic cord (for varicocele)
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Penis (for anatomic abnormalities, strictures, or plaques)
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Rectum (for abnormalities of the prostate or seminal vesicles)
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Body habitus
Depending on the findings from the history, detailed examination of other body functions may also be warranted.
See Presentation for more detail.
Diagnosis
The semen analysis is the cornerstone of the male infertility workup and includes assessment of the following:
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Semen volume (normal, 1.5-5 mL)
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Semen quality
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Sperm density (normal, >15 million sperm/mL)
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Total sperm motility (normal, >40% of sperm having normal movement)
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Sperm morphology (sample lower limit for percentage of normal sperm is 4%)
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Signs of infection – An increased number of white blood cells (WBCs) in the semen may be observed in patients with infectious or inflammatory processes
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Other variables (eg, levels of zinc, citric acid, acid phosphatase, or alpha-glucosidase)
Other laboratory tests that may be helpful include the following:
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Antisperm antibody test
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Hormonal analysis (FSH, LH, TSH, testosterone, prolactin)
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Genetic testing (karyotype, CFTR, AZF deletions if severe oligospermia (< 5 million sperm/mL)
Imaging studies employed in this setting may include the following:
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Transrectal ultrasonography
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Scrotal ultrasonography
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Vasography
An abnormal postcoital test result is observed in 10% of infertile couples. Indications for performing a postcoital test include semen hyperviscosity, increased or decreased semen volume with good sperm density, or unexplained infertility.
If the test result is normal, consider sperm function tests, such as the following:
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Capacitation assay
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Acrosome reaction assay
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Sperm penetration assay
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Hypoosmotic swelling test
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Inhibin B level
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Vitality stains
Testicular biopsy is indicated in azoospermic men with a normal-sized testis and normal findings on hormonal studies to evaluate for ductal obstruction, to further evaluate idiopathic infertility, and to retrieve sperm.
See Workup for more detail.
Management
The following causes of infertility, if identified, can often be treated by medical means:
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Endocrinopathies
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Antisperm antibodies
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Retrograde ejaculation
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Poor semen quality or number
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Lifestyle issues
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Infections
Surgical interventions to be considered include the following:
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Varicocelectomy
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Vasovasostomy or vasoepididymostomy
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Transurethral resection of the ejaculatory ducts
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Sperm retrieval techniques
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Electroejaculation
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Artificial insemination
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Assisted reproduction techniques
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In vitro fertilization
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Gamete intrafallopian transfer (GIFT) and zygote intrafallopian transfer (ZIFT)
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Intracytoplasmic sperm injection
See Treatment and Medication for more detail.
Background
Infertility is defined as the inability to achieve pregnancy after one year of unprotected intercourse. An estimated 15% of couples meet this criterion and are considered infertile, with approximately 35% due to female factors alone, 30% due to male factors alone, 20% due to a combination of female and male factors, and 15% unexplained. Conditions of the male that affect fertility are still generally underdiagnosed and undertreated.
Causes of infertility in men can be categorized as obstructive or nonobstructive. Infertile men may have deficiencies in sperm formation, concentration (eg, oligospermia [too few sperm], azoospermia [no sperm in the ejaculate]), or transportation. This general division allows an appropriate workup of potential underlying causes of infertility and helps define a course of action for treatment.
The initial evaluation of the male patient should be rapid, noninvasive, and cost-effective, as nearly 70% of conditions that cause infertility in men can be diagnosed with history, physical examination, and hormonal and semen analysis alone. More detailed, expensive, and invasive studies can then be ordered if necessary.
Treatment options are based on the underlying etiology and range from optimizing semen production and transportation with medical therapy or surgical procedures to complex assisted reproduction techniques. Technological advancements have made conceiving a child possible with as little as one viable sperm and one egg. [1] Although the workup was traditionally delayed until a couple was unable to conceive for 12 months, evaluation may be initiated at the first visit in slightly older couples.
Pathophysiology
Gonadal and sexual functions are mediated by the hypothalamic-pituitary-gonadal axis, a closed-loop system with feedback control from the testicles. The hypothalamus, the primary integration center, responds to various signals from the central nervous system (CNS), pituitary gland, and testicles to secrete gonadotropin-releasing hormone (GnRH) in a pulsatile pattern approximately every 70-90 minutes. The half-life of GnRH is 2-5 minutes.
Release of GnRH is stimulated by melatonin from the pineal gland and inhibited by testosterone, inhibin, corticotropin-releasing hormone, opiates, illness, and stress. GnRH travels down the portal system to the anterior pituitary, located on a stalk in the sella turcica, to stimulate the release of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). See the image below.
Male infertility. Hypothalamic-pituitary-gonadal axis stimulatory and inhibitory signals. Gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary. FSH stimulates the Sertoli cells to facilitate sperm production, while LH stimulates testosterone release from the Leydig cells. Feedback inhibition is from testosterone and inhibin.
FSH and LH, glycopeptides with a molecular weight of 10,000 Daltons, are each composed of an alpha chain that is identical to that of human chorionic gonadotropin (hCG) and thyroid-stimulating hormone (TSH), but with a beta chain that is unique for each. FSH has a lower plasma concentration and longer half-life than LH, and it has less obvious pulsatile changes. The pulsatile nature of GnRH is essential to normal gonadotropin release; a continuous stimulation inhibits their secretion.
The hypothalamus also produces thyrotropin-releasing hormone (TRH) and vasoactive intestinal peptide (VIP), both of which stimulate prolactin release from the anterior pituitary, and dopamine, which inhibits prolactin release. Men with elevated prolactin levels present with gynecomastia, diminished libido, erectile dysfunction, and occasionally galactorrhea. Prolactin inhibits the production of GnRH from the hypothalamus and LH and FSH from the pituitary. Gonadotropin release is modulated by various other signals, such as estradiol (a potent inhibitor of both LH and FSH release), and inhibin from the Sertoli cell, which causes a selective decrease in FSH release.
FSH and LH are released into the systemic circulation and exert their effect by binding to plasma membrane receptors of the target cells. LH mainly functions to stimulate testosterone secretion from the Leydig cells of the testicle, while FSH stimulates Sertoli cells to facilitate germ cell differentiation.
Testosterone is secreted in a diurnal pattern, peaking a few hours after the man awakens from sleep. In the body, testosterone circulates 2% in the free form, 44% bound to sex hormone–binding globulin (SHBG), and 54% bound to albumin. Testosterone is converted to dihydrotestosterone (DHT) by the action of 5-alpha reductase, both locally and in the periphery, and to estrogen in the periphery. Testosterone and estradiol function as feedback inhibitors of gonadotropin release.
The testicle contains the Leydig cells and the Sertoli cells and is covered by the tunica albuginea, which also provides septae that divide it into approximately 200-350 pyramids (see image below). These pyramids are filled with the seminiferous tubules. A normal testicle contains 600-1200 seminiferous tubules with a total length of approximately 250 meters. The interstitium between the seminiferous tubules contains the Leydig cells, fibroblasts, lymphatics, blood vessels, and macrophages. Histologically, Leydig cells are polygonal with eosinophilic cytoplasm. Occasionally, the cytoplasm contains crystalloids of Reinke after puberty.
Male infertility. Testicular histology magnified 500 times. Leydig cells reside in the interstitium. Spermatogonia and Sertoli cells lie on the basement membrane of the seminiferous tubules. Germ cells interdigitate with the Sertoli cells and undergo ordered maturation, migrating toward the lumen as they mature.
Seminiferous tubules are made up of Sertoli cells and germ cells and are surrounded by peritubular and myoid cells.
Sertoli cells are columnar, with irregular basal nuclei that have prominent nucleoli and fine chromatin. They rest on the basement membrane and serve mainly to support, nourish, and protect the developing germ cells and to provide a blood-testis barrier to provide a microenvironment that facilitates spermatogenesis and maintains the germ cells in an immunologically privileged location. Sertoli cells also secrete inhibin, which provides negative feedback on the hypothalamus, and androgen-binding protein, which helps modulate androgen activity in the seminiferous tubules. In addition to stimulation by FSH, Sertoli cell function is modulated by intratesticular testosterone and signals from peritubular myoid cells.
Germ cells (precursors to spermatozoa) are derived from the gonadal ridge and migrate to the testicle before testicular descent. In response to FSH stimulation at puberty, germ cells become spermatogonia and undergo an ordered maturation to become spermatozoa. The entire process of development from spermatogonium to spermatid takes 74 days and is described in 14 steps; as they mature, the developing spermatids progress closer to the lumen of the seminiferous tubule.
Spermatogonia rest on the basement membrane and contain dense nuclei and prominent nucleoli. Three types are described: A dark (Ad), A pale (Ap), and B cells. Ad cells (stem cells) divide to create more Ad cells (stem cell renewal) or differentiate into daughter Ap cells every 16 days. Ap cells mature into B spermatogonia, which then undergo mitotic division to become primary spermatocytes, which are recognized by their large centrally located nuclei and beaded chromatin. The mitotic division does not result in complete separation; rather, daughter cells maintain intracellular bridges, which have functional significance in cell signaling and maturation.
Primary spermatocytes undergo meiosis as the cells successively pass through the preleptotene, leptotene, zygotene, and pachytene stages to become secondary spermatocytes. During this time, the cells cross from the basal to the adluminal compartments. Secondary spermatocytes contain smaller nuclei with fine chromatin. The secondary spermatocytes undergo a second meiosis and become spermatids. This reduction division (ie, meiosis) results in a haploid chromosome number. Therefore, a total of 4 spermatids are made from each spermatocyte.
Next, the spermatids undergo the process of spermiogenesis (through stages named Sb1, Sb2, Sc, Sd1, and Sd2), which involves the casting of excess cytoplasm away as a residual body, the formation of the acrosome and flagella, and the migration of cytoplasmic organelles to their final cellular location. The acrosome, a derivative of the Golgi process, surrounds the nucleus anteriorly and contains enzymes necessary to penetrate the ovum. The mature spermatid is then located adjacent to the tubule lumen and contains dark chromatin with an oval-shaped nucleus.
After their release from the Sertoli cells into the lumen of the seminiferous tubules, the spermatids successively pass through the tubuli recti, rete testis, ductuli efferentes, and, finally, the epididymis (see image below). The epididymis is a 3- to 4-cm long structure with a tubular length of 4-5 m. As sperm move from the head to the tail, they mature and acquire fertilization capacity. Sperm from the head move with immature wide arcs and are generally unable to penetrate the egg, while those from the tail propel forward and have better penetration capacity. The transit time varies with age and sexual activity but is usually from 1-12 days. The epididymis additionally secretes substances for sperm nutrition and protection such as glycerophosphorylcholine, carnitine, and sialic acid.
Sperm next enter the vas deferens, a 30- to 35-cm muscular conduit of Wolffian duct origin. The vas is divided into the convoluted, scrotal, inguinal, retroperitoneal, and ampullary regions and receives its blood supply from the inferior vesical artery. In addition to functioning as a conduit, the vas also has absorptive and secretory properties.
During emission, sperm are propelled forward by peristalsis. After reaching its ampullary portion behind the bladder, the vas joins with the seminal vesicles, at the ejaculatory duct, which empties next to the verumontanum of the prostate.
During ejaculation, the ejaculate is propelled forward by the rhythmic contractions of the smooth muscle that surrounds the ducts and by the bulbourethral muscles and other pelvic muscles. Bladder neck closure during ejaculation is vital to ensure antegrade ejaculation.
Normal ejaculate volume ranges from 1.5 to 5 mL and has a pH level of 7.05-7.8. The seminal vesicles provide 40-80% of the semen volume, which includes fructose for sperm nutrition, prostaglandins and other coagulating substances, and bicarbonate to buffer the acidic vaginal vault. Normal seminal fructose concentration is 120-450 mg/dL, with lower levels suggesting ejaculatory duct obstruction or absence of the seminal vesicles.
The prostate gland contributes approximately 10-30% (0.5 mL) of the ejaculate. Products include enzymes and proteases to liquefy the seminal coagulum. This usually occurs within 20-25 minutes. The prostate also secretes zinc, phospholipids, phosphatase, and spermine. The testicular-epididymal component includes sperm and comprises about 5% of the ejaculate volume.
In addition to the components already listed, semen is also composed of secretions from the bulbourethral (Cowper) glands and the (periurethral) glands of Litre, each producing 2-5% of the ejaculate volume, serving mainly to lubricate the urethra and to buffer the acidity of the residual urine. The ordered sequence of release is important for appropriate functioning.
For conception, sperm must reach the cervix, penetrate the cervical mucus, migrate up the uterus to the fallopian tube, undergo capacitation and the acrosome reaction to digest the zona pellucida of the oocyte, attach to the inner membrane, and release its genetic contents within the egg. The cervical mucus changes consistency during the ovulatory cycle, being most hospitable and easily penetrated at mid cycle. After fertilization, implantation may then take place in the uterus. Problems with any of these steps may lead to infertility.
Frequency
United States
An estimated 10-15% of couples are considered infertile, defined by the World Health Organization (WHO) as the absence of conception after at least 12 months of unprotected intercourse. In US men, the risk correlates to approximately 1 in 25. Low sperm counts, poor semen quality, or both account for 90% of cases; however, studies of infertile couples without treatment reveal that 23% of these couples conceive within 2 years, and 10% more conceive within 4 years. Even patients with severe oligospermia (< 2 million sperm/mL) have a 7.6% chance of conception within 2 years. [2]
International
Patterns of male infertility vary greatly among regions and even within regions. The highest reported fertility rates are in Finland, while Great Britain has a low fertility rate. A combination of social habits, environmental conditions, and genetics is suspected to contribute to this variation.
Debate has occurred in the literature regarding a poorer semen quality, decreased sperm counts (113 million/mL in 1940 compared with 66 million/mL in the 1990s), and decreased fertility in men today compared with fertility 50 years ago. [3] Investigators hypothesize that environmental conditions and toxins have led to this decline; however, others argue that this is solely because of differences in counting methods, laboratory techniques, and geographic variation.
Mortality/Morbidity
Many patients who present with infertility as their primary complaint have a serious underlying medical disease, such as pituitary adenomas, hormonally active tumors, testicular cancer, liver and renal failure, and cystic fibrosis (CF). Evaluating patients for such life-threatening or life-altering conditions during the workup is important.
In addition, the risk of cancer appears to be increased in infertile men. In a study of 2238 infertile men, 451 with azoospermia and 1787 without, male infertility was associated with an increased risk of developing cancer in comparison with the general population. [4, 5] Median age at initial evaluation was 35.7 years, and median follow-up was 6.7 years.
Overall, 29 men developed some type of cancer, including 10 (2.2%) with azoospermia and 19 (1.1%) without azoospermia. [5] Compared with the general population of Texas, infertile men had a higher risk of overall cancer (standardized incidence ratio [SIR], 1.7; 95% confidence interval [CI], 1.2-2.5).
The risk was significantly higher in azoospermic men than in nonazoospermic men (SIR, 2.9; 95% CI, 1.4-5.4). [5] The risk of cancer in nonazoospermic infertile men was similar to that in the general population (SIR, 1.4; 95% CI, 0.9-2.2), although there was a trend toward an elevated risk.
The men who developed cancer in the study developed a variety of malignancies, including prostate cancer, testicular cancer, CNS cancer, melanoma, and stomach cancer. [5]
Sex
Isolated conditions of the female are responsible for infertility in 35% of cases, isolated conditions of the male in 30%, conditions of both the male and female in 20%, and unexplained causes in 15%. Even if one partner has an obvious cause for the infertility, a thorough evaluation of both partners for completeness is prudent. In addition, both partners may be aided by evaluation of their sexual practices.
Age
The effect of aging on fertility is unclear. As men age, their testosterone levels decrease, while estradiol and estrone levels increase. Studies have shown that, as men age, their sperm density decreases. Young men have spermatids present in 90% of seminiferous tubules, which decreases to 50% by age 50-70 years and to 10% by age 80 years. Additionally, 50% of Sertoli cells are lost by age 50 years, and 50% of Leydig cells are lost by age 60 years. Despite this, aging men may achieve fertility rates similar to those in younger men, although conception often takes longer.
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Male infertility. Hypothalamic-pituitary-gonadal axis stimulatory and inhibitory signals. Gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary. FSH stimulates the Sertoli cells to facilitate sperm production, while LH stimulates testosterone release from the Leydig cells. Feedback inhibition is from testosterone and inhibin.
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Male infertility. Testicular histology magnified 500 times. Leydig cells reside in the interstitium. Spermatogonia and Sertoli cells lie on the basement membrane of the seminiferous tubules. Germ cells interdigitate with the Sertoli cells and undergo ordered maturation, migrating toward the lumen as they mature.
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Male infertility. Normal male ductal anatomy.
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Male infertility. Varicocele. A - Physical examination revealing the characteristic "bag of worms." B - Anatomy of the dilated pampiniform plexus of veins.
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Male infertility. Technique of open vasography: The vas distal to the site of incision is determined to be patent if saline is injected without resistance. Alternatively, radiographic contrast dye is injected through the vas deferens and radiography is performed, or blue dye may be injected and visualized in the urine to confirm patency. A vasovasostomy or vasoepididymostomy may then be performed at this level.
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Male infertility. Technique of microscopic varicocelectomy. The individual veins of the pampiniform plexus are isolated (top) and ligated, taking care to preserve the testicular artery (bottom) isolated using the intraoperative Doppler.
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Male infertility. Technique of vasovasostomy: Upper left is confirmation of sperm from the proximal vas deferens, proving proximal patency. Upper right is the inner layer anastomosis using interrupted #10-0 Prolene. Lower left is the inner layer anastomosis completed. Lower right is the outer layer anastomosis using #9-0 Prolene completed.
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Male infertility. Technique of vasoepididymostomy. Left upper is confirmation of mature sperm in epididymis. Right upper is the inner layer anastomosis of the end of the vas to the side of the epididymal tubule using interrupted #10-0 Prolene. Left lower is the inner layer completed. Right lower is the outer layer anastomosis using interrupted #9-0 Prolene completed.
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Male infertility. Technique of intracytoplasmic sperm injection (ICSI). A micropipette is used to inject a single sperm directly into an egg.
Tables
Analysis |
Finding |
Conclusion/Further investigation |
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Ejaculate volume |
Low (< 1.5 mL) |
Postejaculation urine (retrograde ejaculation) TRUS (absence of vas deferens) Hormonal evaluation (hypogonadism) |
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High (>5 mL) |
Likely contaminant |
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Semen quality |
Does not coagulate |
TRUS (ejaculatory duct obstruction) |
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Does not liquefy |
Hormonal analysis |
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Sperm density |
Oligospermia (< 20 million per mL) Severe oligospermia (< 5 million per mL) |
TRUS (partial ejaculatory duct obstruction) Antisperm antibody evaluation Hormonal analysis Physical examination for varicocele |
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Azoospermia |
Sperm centrifuged to verify azoospermia Postejaculation urine (retrograde ejaculation) Hormonal evaluation Testicular biopsy (testicular failure) TRUS (ejaculatory duct obstruction) |
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Motility |
Decreased |
Antisperm antibodies Physical examination for varicocele |
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*All semen analyses with abnormal results should be repeated. |
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