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Doenças e Disfunções
.Infertilidade
.Disfunção erétil
.Infecção urinária
.DST
.Próstata
.Rim
.Bexiga
.Testículos
.Pênis
.Cálculos urinários
.Vasectomia
.Reversão de Vasectomia

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HPV na Prática Clínica

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Cornell University
Weill Medical College
Cornell Institute for Reproductive Medicine

Center for Male Reproductive Medicine and Microsurgery

Directors

Marc Goldstein, M.D. Marc Goldstein, M.D., F.A.C.S. is Professor of Reproductive Medicine and Urology at Weill Medical College of Cornell University, Co-Executive Director of the Cornell Institute for Reproductive Medicine and Co-Director of the Center for Male Reproductive Medicine and Microsurgery at the New York Presbyterian Hospital-Weill Medical College of Cornell University. He is Staff Scientist with the Population Council's Center for Biomedical Research, located on the campus of Rockefeller University.

Peter N. SchlePeter N. Schlegel, M.D., F.A.C.S. is an Associate Professor of Urology and Vice Chairman for Clinical Affairs in Urology at The Weill Medical College of Cornell University, a Staff Scientist at The Population Council, Center for Biomedical Research, a Visiting Associate Physician at The Rockefeller University Hospital, and an Associate Attending Surgeon at The New York Hospital.gel, M.D.

Anatomy and Physiology of Male Reproduction

1. HORMONAL CONSIDERATIONS
2. TESTICULAR ANATOMY
3. SEMINIFEROUS TUBULES
4. THE EPIDIDYMIS

Compared to other species, human males have relatively poor sperm producing capacity and human testicular function is very sensitive to a wide variety of environmental insults. This may be related to the human (upright) posture and hydrostatic pressure on venous testicular outflow, or other unknown factors, but it is necessary for clinicians to be aware of the high incidence of subfertility in men. Perhaps it is a reflection of the incredible ability of humans to adapt the environment to promote their own survival or the expectation that fertility should be nearly spontaneous, but many human couples seek evaluation for infertility. The human male reproductive system includes the hypothalamic-pituitary-testis axis as well as the epididymis, vas deferens, seminal vesicles, prostate and urethra. Production of spermatozoa requires approximately 3 months from the initial mitotic divisions through the myriad changes readying sperm for ejaculation and fertilization. Highlights of this transformation include (1) the unique environment created within the testis for spermatogenesis to occur; (2) preservation of a set of stem cells relatively resistant to external injury and able to produce rapidly proliferating germ cells destined to become spermatozoa; (3) meiosis, that results in formation of the haploid gamete; and (4) the dramatic differentiation of the prospective gamete in a form that is specialized to transport chromosomal material in a structure ideally suited for transit of the female reproductive tract. The spermatozoon resulting from this complex process assumes its final shape and size in the testis. In the normal state, it also acquires the ability to fertilize as well as a capacity for motility in the epididymis. Unfortunately, the mechanisms by which the epididymis exerts these changes on the traversing spermatozoon and the actions of the human reproductive tract after relief of chronic obstruction remain largely unknown.

1. HORMONAL CONSIDERATIONS
An appropriate hormonal milieu must exist for the reproductive organs to produce, mature and transport the highly specialized male gamete to the ejaculatory duct. The entire system of hormone balance is initiated by the pulsatile hypothalamic release of GnRH ( gonadotropin-releasing hormone). Pituitary LH ( luteinizing hormone) secretion is determined by GnRH pulses from the hypothalamus, that occur approximately every two hours and are carried via a venous portal network to the pituitary. This hypothalamohypophyseal portal connection allows an exact synchrony of GnRH and LH pulse secretion. FSH ( follicle-stimulating hormone) secretion is also stimulated by GnRH, but FSH and LH are differentially regulated by hormonal and other factors that are poorly understood. The factors influencing FSH secretion are produced by Sertoli cells and other components of the testis that probably includes peptides of the inhibin and activin families. Within the testis, LH stimulates Leydig cell synthesis of testosterone. Testosterone production by the Leydig cell provides locally high intratesticular concentrations of this hormone that stimulates spermatogenesis. Testosterone concentrations in peripheral blood of men change dramatically during the life cycle. Testosterone reaches a maximum concentration during the second or third decade of life, then reaches a plateau, and declines thereafter. Additionally, annual and daily rhythms in testosterone concentration occur, typically with a testosterone peak in the early morning. Other, irregular fluctuations in testosterone concentration may also be detectable in peripheral blood. Testosterone is normally aromatized in peripheral tissue to estrogens. Excessive testosterone levels, associated with gonadotropin, clomiphene citrate or flutamide treatment, may paradoxically result in increased feminization from conversion of androgens to estrogens by aromatase. Similarly, increased aromatase activity is associated with alcoholism and chronic liver disease, as well as testis tumors.Accurate clinical assessment of the pituitary gonadotropins LH and FSH must take into account their pulsatile release. During clinical research studies, three serum samples are obtained, one every 30 minutes, and the sera pooled for accurate determination of mean gonadotropin levels. This process is usually not necessary in clinical practice, but the clinician should be aware of the potential for LH and FSH peaks to be measured in a single gonadotropin determination, and perform repeat evaluation if LH and FSH hormone levels are both elevated. Testosterone levels may be decreased in the late afternoon or evening. Interpretation of serum testosterone levels should take the diurnal secretion of this hormone into account. Prolactin, another pituitary hormone, may affect fertility by decreasing LH production, resulting in a decrease in testosterone and subsequently, decreased libido. The release of prolactin is mediated by dopamine, and the dopamine antagonist bromocriptine will ameliorate the antifertility effects of hyperprolactinemia.Testosterone is converted intracellularly within most androgen-sensitive organs to dihydrotestosterone. Function of the prostate, seminal vesicles, vas deferens, and other sex accessory organs are all androgen-dependent. The degree to which partial androgen deprivation in the hypogonadal man affects the function of these organs is unknown. Furthermore, the effects of "low-normal" serum testosterone levels on these organs and a man's fertility potential are unknown. Abnormally elevated serum testosterone levels are peripherally converted by the aromatase enzyme to estrogens. In addition, chromosomal abnormalities such as Klinefelter's syndrome(xxy), and some testicular tumors have elevated aromatase levels. Some obese patients may also have increased aromatase activity, since aromatase levels are high in adipose tissue, as well as fat. Therefore, hormonal evaluation of the infertile man should include determination of serum LH, FSH, testosterone and prolactin. For men with clinical gynecomastia, serum estradiol should be measured.

2. TESTICULAR ANATOMY
The human testis is an ovoid mass that lies within the scrotum. The average testicular volume is 20 cc in healthy young men and decreases in elderly men. In Asian men, testes tend to be smaller. Normal longitudinal length of the testis is approximately 4.5 to 5.1 cm. The testicular parenchyma is surrounded by a capsule containing blood vessels, smooth muscle fibers and nerve fibers sensitive to pressure. The functional role of the testicular capsule is unknown, but may relate to movement of fluid out through the rete testis or control of blood flow to the testis. The testis contains seminiferous tubules and interstitial cells. The tubules are segregated into regions by connective tissue septa. The seminiferous tubules are long V-shaped tubules, both ends of which usually terminate in the rete testis. Measurement of testicular size is critical in the evaluation of the infertile man, since seminiferous tubules (the spermatogenetic region of the testis) occupy approximately 80% of testicular volume. So, a rough estimate of spermatogenic cell capacity is provided by assessment of testicular size. Testicular consistency is also of value in determining fertility capacity. A soft testis is likely to reflect degenerating or shrunken spermatogenic components within the seminiferous tubules. The seminiferous tubules drain toward the central superior and posterior regions of the testis, the rete testis, that has a flat cuboidal epithelium. The rete coalesces in the superior portion of the testis, just anterior to the testicular vessels, to form 5-10 efferent ductules. These efferent ducts leave the testis and travel a short distance to enter the head, or caput region of the epididymis. The efferent ducts coalesce in a somewhat variable pattern within the caput epididymis to form a single epididymal tubule.The artery to the testis is specialized in that it is highly coiled and intimately associated with a network of anastomotic veins that form the pampiniform plexus. The counterflowing vessels are separated only by the thickness of their vascular wall in some areas. This vascular arrangement facilitates the exchange of heat and small molecules, including testosterone. The transport of testosterone is a concentration-limited, passive diffusion process in men. The counter-current exchange of heat in the spermatic cord provides blood to the testis that is 2 to 4 °C lower than rectal temperature in the normal individual. A loss of the temperature differential is associated with testicular dysfunction in humans with idiopathic infertility, as well as men with varicocele or cryptorchidism. Whether elevated testicular temperature causes or is simply a reflection of testicular dysfunction is unknown. Only the association between elevated testicular temperature and seminiferous failure have been demonstrated. In the distal inguinal canal, 50% of men will have a single testicular artery identifiable under l0 x power magnification dissection of the cord, with 30% of men having two arteries and 20% with three arteries.The venous system is somewhat unique because the spermatic veins are thin-walled, poorly muscularized, and lack effective valves except at the inflow points into the inferior vena cava or the renal vein. The right spermatic vein usually drains into the vena cava. The left spermatic vein drains into the left renal vein. The renal vein on the left side is thought to have a higher intraluminal pressure because the vein is compressed as it passes between the superior mesenteric artery and the aorta. This "nutcracker effect" may impair flow through the left renal and spermatic veins, especially in young men with limited retroperitoneal fat. The differential anatomy of the left and right spermatic veins is thought to explain, at least in part, the higher prevalence of varicoceles on the left side. The exact mechanism by which varicoceles cause infertility is unknown. In animal models, varicoceles are associated with increased blood flow to the testis and increased interstitial fluid in the testis. These two findings may impair regulation of testicular temperature and decrease intratesticular concentrations of testosterone or other local factors important for spermatogenesis.

3. SEMINIFEROUS TUBULES
The seminiferous tubules provide a unique environment for the production of germ cells. The structures involved in this process include germinal elements and supporting cells. The supporting cells include the peritubular cells of the basement membrane and the Sertoli cells. The germinal elements comprise a population of epithelial cells, including a slowly dividing primitive stem cell population, the rapidly proliferating spermatogonia, spermatocytes undergoing meiosis, and the metamorphosing spermatids. The seminiferous tubule also produces an environment known as "the blood-testis barrier". The testis is unique in that the differentiating germ cells are potentially antigenic, and recognizable as foreign; however, little immunological reaction is usually detectable within the testis.Developmentally, the testis develops from the undifferentiated gonad. These primitive germ cells are referred to as gonocytes after the gonad differentiates into a testis by forming seminiferous cords. At this time, the gonocytes are located in a central position within the seminiferous cords. They are subsequently classified as spermatogonia after the gonocytes have migrated to the periphery of the tubule. From birth to approximately 7 years of life, there appears to be very little morphological change within the human testis. From 7 to 9 years of life, mitotic activity of gonocytes is detectable, with spermatogonia populating the base of the seminiferous tubule in numbers equal to those of the Sertoli cells. There appears to be little further morphological change in spermatogonia until spermatogenesis begins at the time of puberty. Further information regarding the maturation of gonocytes and their migration to the base of the seminiferous tubule, including the factors that may be responsible for these changes, may provide greater insight into the effects of cryptorchidism on fertility and impact on the appropriate timing of intervention for treatment of cryptorchidism.

4. THE EPIDIDYMIS
Spermatozoa in the unobstructed testis are not motile and are incapable of fertilizing ova. Spermatozoa become functional gametes only after they migrate through the epididymis and undergo an additional maturation process, thereby acquiring the capacities for both progressive motility and fertility. The function of the obstructed epididymis and its effects on maturation of spermatozoa may be very different from what is observed in the unobstructed state. Anatomically, the epididymis can be divided into three regions: the caput, the corpus, and the cauda epididymis. However, these anatomical divisions have been defined based on findings in animals, not in humans. The human epididymal epithelium is relatively homogeneous as viewed under the microscope, and grossly, the epididymis does not have the same distinct gross anatomical subdivisions that are easily seen in the rat, rabbit and other animals. Unfortunately, there is little information available regarding the functional diversity of these three regions of the human epididymis. The data that exist on human epididymal function are almost entirely derived from observations of men after relief of chronic epididymal obstruction.In humans, the epididymis receives its blood supply from two sources: branches of the testicular as well as the deferential vessels that travel along the vas deferens. Clinically, the blood supply becomes important after a vasectomy with interruption of the vasal vessels. At the time of vasectomy reversal, the testicular side of the vas deferens is then supplied by branches off the testicular vessels, which travel either through collaterals, or along the entire length of the epididymis. Similarly, if division of the vasal vessels occurs accidentally during vasography, and a secondary obstruction to the vas deferens (and vasal vessels) is found and addressed in the groin, then the intervening segment of vas deferens can be totally devascularized. The viability of the vas should be considered prior to vaso-vasostomy in this situation.Observations by Silber regarding the fertility of men who have undergone bilateral vasal anastomosis to the vasa efferentia, indicate that in the obstructed human male reproductive tract, some sperm may acquire motility and fertilizing ability without passing through the epididymis. Although not absolutely required for male fertility, the functional importance of the human epididymis is strongly supported by several other observations regarding men who have undergone intervention for the relief of chronic epididymal obstruction. In 1990, Silber reported fertility results for men who underwent vasoepididymostomy at the level of either the caput or corpus epididymis. For both groups of men, the patency rate was approximately 70%. For men who underwent anastomosis at the corpus level, 72% of men achieved pregnancy with their partners, whereas only 43% of men were able to impregnate their wives after vasoepididymostomy at the caput level. Therefore, the presence of a longer length of epididymis appears to promote fertility after relief of chronic obstruction. Our studies in men with congenital absence of the vas deferens or other surgically unreconstructable obstruction of the vas have indicated that the longer the segment of epididymis present, the greater the likelihood of pregnancy with sperm obtained from these men. Almost all of the information regarding human epididymal function are derived from observations of men who have undergone surgical reversal of long term reproductive tract obstruction. The results of several published observations of men with unobstructed reproductive tracts was compiled by Bedford. As indicated (in NY Acad Sci 541: 284-291, 1988), the fertility potential of sperm from the caput region of the obstructed human epididymis is minimal.The exact fate of unejaculated epididymal spermatozoa in humans is also unknown. Some sperm have been documented to be phagocytosed by macrophages in the epididymis, and sperm have been detected in urine. However, the mechanisms by which quantitative clearance of sperm occurs from men during periods of sexual abstinence is unknown.In normal, unobstructed systems, the majority of spermatozoa taken from the vasa efferentia and diluted in a physiologic solution are immotile or exhibit only weak tail movements. These observations in the unobstructed human epididymis are very different from what is seen after relief of chronic epididymal obstruction. Our observations confirm those of several investigators, that, although the motility of ejaculated spermatozoa is initially poor following vaso-epididymostomy at the level of the caput epididymis, sperm motility may improve greatly up to 1 1/2 years after vasoepididymostomy. These findings suggest that following vasoepididymostomy the caput epididymis or vas deferens may undergo compensatory adaption over time and support sperm motility maturation despite exposure of sperm to a shortened length of epididymis. In animal models, vasal obstruction causes changes in the intrinsic motility of fluid through the epididymal lumen. These changes are not completely reversed by technically successful vasovasostomy. It is not known what effect the apparent change in epididymal contractility may have on epididymal function.Studies on laboratory animals describe many changes that occur to sperm during epididymal transit. These include a change in net sperm surface charge, addition and alteration of membrane proteins, alterations in sperm lectin-binding properties, changes in immunoreactivity and iodination characteristics, acquisition of an increased capacity for glycolysis, modification of adenylate cyclase activity, alterations in cellular phospholipid and phospholipid-like fatty acid content and an increased ability to adhere to the zona pellucida of the egg. Whether similar modifications occur in human spermatozoa during epididymal migration is unknown. Biochemical changes observed in human spermatozoa during epididymal transit involve the formation of disulfide bonds within the sperm nucleus and tail and the oxidation of sperm membrane sulfhydryl groups. These changes are thought to provide improved structural integrity to the sperm membrane. The changes in structural integrity of sperm may be necessary for the development of progressive motility and successful penetration of eggs.Protein secretion and the storage capacity of the epididymis has been shown to be profoundly affected by changes in epididymal temperature in animals. Some have even postulated that the driving force for evolution of the scrotal location of testes is to have the epididymis maintained at a temperature below that of body core temperature, in the scrotum. Whether the functions of the human epididymis are similarly affected by body temperature is unknown. The potential influence of temperature on epididymal function in man may be an important consideration in explaining the relationship between varicocele and male infertility. If temperature significantly affects human epididymal function, then it could explain improvements in semen parameters that may occur less than three months (one full cycle of spermatogenesis) after varicoceletomy.The human spermatozoon is approximately 60 µm in length. Normal forms have an oval sperm head, 4.5 µm long and 3 µm wide, consisting principally of a nucleus, which contains the highly compacted chromatin material, and the acrosome, a membrane-bound organelle that covers 40-70% of the surface of the sperm head and contains the enzymes required for penetration of the outer vestments of the egg prior to fertilization. The middle piece of the spermatozoon is a highly organized segment consisting of helically arranged mitochondria surrounding a set of outer dense fibers and the characteristic 9 + 2 microtubular structure of the sperm axoneme. The mitochondria contain the enzymes required for oxidative metabolism and the production of adenosine triphosphate (ATP), the primary energy source for the cell. Absence of some components of the microtubules is associated with immotile cilia in the sinus and pulmonary tracts, with resultant pulmonary and sinus infections. The association of sperm immotility with upper respiratory infections (Young's syndrome) due to ciliary dysfunction or absent dynein cross-arms between the microtubules (Kartagener's syndrome) resulting in bronchiectasis and nonmotile sperm have been well documented. Other syndromes of ciliary dysfunction have recently been described in children with recurrent sinusitis (ciliary dyskinesia). It is yet to be demonstrated whether the boys affected with the childhood manifestations of ciliary dyskinesia will suffer from infertility problems after puberty. The highly specialized structure and physiology of the spermatozoon is marvelously suited for its single purpose: to carry genetic material to the egg during reproduction.The rate of transport of fluid through the vas deferens is not known in the human. Just prior to ejaculation, the testes are brought up close to the abdomen and fluid is rapidly transported through the vas deferens toward the region of the ejaculatory ducts and subsequently into the prostatic urethra. After ejaculation, intravasal fluid is transported back toward the epididymis and occasionally into the seminal vesicles as well. The retrograde transport of sperm to the seminal vesicles has been documented by videoradiography during ejaculation after vasography. The return of sperm to the seminal vesicles after ejaculation may help explain the prolonged presence of sperm in the ejaculate for some men after vasectomy.The ejaculatory ducts enter the prostatic urethra just lateral to the verumontanum. In the case of obstruction of the ejaculatory ducts, resection of the floor of the prostate should be performed just lateral to the midline and superior to the verumontanum. Vasography can be performed prior to transurethral resection (TUR) of the ejaculatory ducts with placement of methylene blue in the vasography fluid. This allows the surgeon to cystoscopically identify the lack of flow of dye and confirm relief of obstruction of the ejaculatory ducts during TUR.The ejaculate consists of components from different accessory organs. Each of these organs and the characteristics of the fluid that they produce is listed below. These characteristics can be used clinically to evaluate ejaculatory dysfunction.

Understanding Male Infertility

By Marc Goldstein, M.D., FACS

Infertility effects one in every six couples who are trying to conceive. In at least half of all cases of infertility a male factor is a major or contributing cause. This means that about 10% of all men in the United States who are attempting to conceive suffer from infertility.
Historically, infertility has been considered a women's disease. It is only within the last fifty years that the importance of the male factor contribution to infertility has been recognized. The mistaken notion that infertility is associated with impotence or decreased masculinity may contribute to this fear. The good news is that the rapid research advances in the area of male reproduction have brought about dramatic changes in the ability to both diagnose and treat male infertility. The majority of couples suffering from infertility can now be helped to conceive a child on their own.
The most common identifiable cause of infertility in men is varicocele. This is a condition of enlarged veins in the scrotum that causes abnormalities in the temperature regulation of the testis. Enzymes that are responsible for both sperm and hormone (testosterone) production have an optimal temperature at which they operate most effectively. If this temperature is elevated by even one degree, sperm and testosterone production are adversely effected.
The evidence for the negative effect of varicocele on testicular function in male fertility is now overwhelming. What is less certain, however, is the effect of repairing the varicocele on restoring testicular function. Dozens of reports have been published demonstrating the benefit of varicocele surgery. However in most of these reports, controlled studies were lacking. Microscopes were not used in older surgical procedures, which made it extremely difficult to locate the tiny artery that provides the major source of nourishment for the testis. Subsequently this artery was often tied off which clearly was unlikely to improve testicular function. Tiny lymph ducts were also inadvertently tied off, often causing a condition called "hydrocele," which is a bag of fluid that develops around the testicle.
These results led me and a colleague, Joel Marmar, to independently and simultaneously develop a microsurgical technique of varicocelectomy employing an operating microscope providing magnification between 6 and 30 power. This enabled positive identification and preservation of the main artery and the lymph ducts eliminating potential damage to the testicle as well as eliminating the complication of hydrocele. Using these techniques in several thousands of patients, the average healthy sperm count after repair of the large varicoceles has been shown to increase 128%. In addition, the first prospective randomized study comparing varicocelectomy to no surgery was sponsored by the World Health Organization (WHO) and reported in Fertility and Sterility. The results showed the pregnancy rate in couples where men with varicoceles underwent surgery was three times higher than when men did not undergo surgery.
The second major cause of infertility in men is blockages or obstructions of the male reproductive tract. This is particularly true for men with zero sperm count, a condition called "azoospermia." Men with zero sperm count can be divided into two broad groups:

1. men who have an obstruction problem or blockage, meaning they are making sperm, but the sperm can't get out, or
2. men who have a production problem, meaning they are not making sperm, a condition called "non-obstructive " azoospermia.

" We can easily determine which group an infertile male is in by doing a testicular biopsy, also using a microscope to minimize discomfort and complications.Blockage can also be caused by a urinary tract infection or by the sexually transmitted diseases chlamydia and gonorrhea. Bacteria can infect the tiny duct called the "epididymis," which is essentially a swimming school for sperm before they are able to swim to fertilize an egg. Infection of the epididymis can cause scarring and blockage, inhibiting the sperm from leaving the duct to fertilize an egg. With the use of microscopes employing 30-power magnification, blockage repair success rates are extremely high.One of the most common causes of blockage is vasectomy. Approximately 500,000 to a million men undergo vasectomy each year in this country for permanent birth control. With an increase in divorce rates coast-to-coast, the demand for reversal of vasectomy is also growing. Currently, using a new technique we developed here at The New York Presbyterian Hospital-Weill Medical College of Cornell University called the microdot technique, we have achieved return of sperm in 99% of men undergoing vasectomy reversal in whom we find sperm in at least one of their vas ducts.Approximately 1% of all infertile men are born with the congenital absence of the vas deferens, the "equivalent" of a vasectomy. Unfortunately, there are no artificial tubes strong enough to replace the vas deferens. However, we are now able to help such men conceive using an operating microscope to retrieve sperm from the tiny ducts of the epididymis, freeze them and use them later for in- vitro fertilization (IVF) with the injection of the single sperm directly into an egg.The most exciting new development in the field of male infertility is the ability to treat men with severe sperm production problems called non-obstructive azoospermia. Even though these men may have no sperm in their semen, we can now find sperm between the cells of the testicles in almost half of these cases. Using an operating microscope, the medical team at The New York Presbyterian Hospital-Weill Medical College of Cornell University, including Drs. Schlegel, Girardi, Rosenwaks, Davis, Palermo and other colleagues, has been able to achieve pregnancies in half of those men in whom sperm can be found within the testicle. Genetic testing of these men with non-obstructive azoospermia has revealed that 10% to 15% are missing a tiny piece of their Y chromosome. This condition is called micro Y deletion. Human beings have 46 chromosomes, males have one X chromosome and one Y chromosome and females have two X chromosomes. The Y chromosome carries the genes that are responsible for producing sperm. Men who have low to no sperm count might be missing a small piece of that Y chromosome. Unfortunately helping men with micro Y deletion have children almost guarantees their male children will have the same infertility problem. However, these children will be healthy in every other way.Artificial techniques of reproduction have advanced to the point where a single sperm can be physically injected into an egg. This procedure, called intracytoplasmic sperm injection (ICSI), was developed in Belgium by Gianpiero Palermo, a physician/scientist who now works with us at The New York-Cornell Hospital. ICSI has dramatically changed the treatment available for even the most severe male factor infertility. Because of this technique, 90% of all infertile men, including half of all men with non-obstructive azoospermia, have the potential to conceive their own genetic child.Our ability to combat male infertility has never been stronger. It is entirely possibly that, within 10 to 20 years, scientists will be able to take cells from any tissue in a man's body and induce these cells to fertilize an egg using some future version of ICSI. The steps in such a process are very complex and not understood at present. Once the process is mastered, however, male infertility will become a thing of the past.

What's New in Male Infertility Treatment at Cornell

The Fertility Evaluation:

1. Introduction
2. Fertility History
3. Sexual History
4. Ejaculate History
5. Medical History
6. Physical Examination
7. Semen Analysis
8. Endocrine Evaluation

Introduction
Infertility is defined as a couple's inability to achieve pregnancy following one year of appropriately timed and unprotected intercourse. By this criterion it has been estimated that approximately 15-20% of couples attempting to achieve pregnancy are unable to do so. A female factor is the primary etiology in approximately 40% of these couples and another 30 - 40% are pure male factor. A combination of male and female factors accounts for the remaining 20% to 30% of cases. This suggests that in more than 50% of couples presenting for infertility evaluation, a male factor is contributory. Conservatively estimated, this means that 2.5 million American men would potentially benefit from fertility evaluation. Historically, the approach to the infertile couple has started with an evaluation of the female, primarily because it is usually the female partner who has initiated a workup by consultation with her gynecologist. It makes more sense, however, to start with the male partner, whose initial evaluation may be performed rapidly and noninvasively. Despite the availability of advanced reproductive technologies, detection of the problem causing male infertility and institution of directed treatment is possible in most cases. This specific treatment of the "male problem" is often more successful, less expensive and possibly less invasive than ICSI or other assisted reproductive treatments. In addition, about 1% of men who present with the symptom of "infertility" will actually have a serious medical problem causing the infertility that, if left untreated, may jeopardize a man's health or life. The most important part of the evaluation of the infertile male is the history and physical examination. Even in this era of "high-tech" medicine it has been our experience that in 90 % of cases an accurate impression is obtained from an initial visit after a thorough history, physical examination, and light microscopic examination of a semen specimen. Further testing usually serves to confirm the diagnosis and help direct the course of therapy.

Fertility History
Prior to arrival at the office, the patient is asked to fill out, at home with the partner, a detailed fertility questionnaire The history begins with an assessment of the couple's prior and current fertility status. The age of the partners and the duration of unprotected intercourse is established. Fertility evaluation is appropriate sooner rather than later when the female partner is over age 35 or there has been a history of infertility in a prior relationship or risk factors leading the couple to suspect that a fertility problem exists (eg, cryptorchidism, testicular neoplasm, chemotherapy).For idiopathic infertility the chance of ultimate success is inversely related to the duration of infertility. Female age is an important factor. Our in vitro fertilization (IVF) program's results steadily and inexorably decline after age 34. It should be established as to whether the infertility is primary or secondary for each partner and, if secondary, the nature and outcome of prior pregnancies with the same or any previous partner. Any previous infertility evaluation or treatment for either partner should be noted as well.

Sexual History
In approximately 5% of couples presenting for infertility evaluation, sexual dysfunction is causative. Is the semen ejaculated into the vagina? Does the couple use lubricants, jellies, oils, or saliva, most of which are known to be somewhat spermicidal? If lubrication is necessary, we recommend Astroglode, Replens or Mineral oil. Given an approximate 48-hr viability of sperm within the female reproductive tract, timing intercourse is important. Too frequent intercourse or compulsive masturbation depletes sperm reserves. The sexual history should also include an assessment of libido, which crudely reflects serum testosterone levels.

Ejaculate History
The man should be questioned regarding the nature and volume of a typical ejaculate. A markedly diminished semen volume and clear.waterlike fluid suggests. absence of the seminal vesicle component associated with either ejaculatory duct obstruction or congenital absence of the vas deferens (CAV). Normal orgasm with low or absent semen volume should lead one to suspect retrograde ejaculation and warrant examination of a postejaculatory urine specimen for the presence of sperm. Semen that fails to liquefy suggests prostatic dysfunction. Proteolytic enzymes present in prostatic secretions cause liquefaction of the protein coagulum derived from the seminal vesicles.

Medical History
Cryptorchidism means a hidden testis. It present in about 0.8% of newborn or 1 year old males, is an important risk factor for infertility. Fifty percent of men with a history of unilateral cryptorchidism and 90% of men with a history of bilateral cryptorchidism are subfertile. Hernia repair in infancy or childhood is associated with a 3-17% risk of injury to the inguinal or retroperitoneal vas deferens. Postpubescent mumps is associated with a 30% risk of unilateral orchitis and a 10% risk of bilateral orchitis, which may result in severe ipsilateral abnormalities in spermatogenesis. The approximate age of onset of puberty is ascertained. Men will usually remember pubertal landmarks only if they were very early or very late. Precocious puberty suggests an adrenal abnormality such as congenital adrenal hyperplasia. Very delayed or incomplete sexual maturation suggests hypogonadotropic hypogonadism (Kallmann's syndrome when associated with anosmia) or pantesticular failure, such as Kleinfelter's syndrome.Any and all conditions or illnesses for which the patient has been or is currently being treated, including all medications currently or previously taken, are documented. Many prescription drugs interfere with spermatogenesis, including cimetidine, sulfasalazine, nitrofurantoin, and anabolic steroids. Drugs of abuse such as alcohol, marijuana, and cocaine are directly gonadotoxic. A detailed occupational history is directed toward identifying exposure to gonadotoxic agents such as heat, ionizing radiation, heavy metals, and pesticides. A family history directed at fertility problems in parents and siblings may be important. Intrauterine exposure to diethylstilbestrol (DES) is also associated with male genitourinary tract anomalies and dysfunction.

Physical Examination
Physical examination is performed in a warm room by an examiner with warm-gloved hands, Contraction of the dartos muscle induced by a cold room or cold examining hands makes examination of the scrotum and its contents difficult. A proper fertility examination does not consist of a casual observation of the scrotum and palpation of its contents. Have the patient completely disrobe and stand with his arms outstretched. Observe the general body habitus and hair distribution. Men who are incompletely masculinized have disproportionately long extremities due to absent or deficient androgen stimulation required for epiphyseal closure at the time of puberty. This is seen in men with hypogonadotropic hypogonadism (Kallmann's syndrome when associated with absent sense of smell or other midline defects) or Kleinfelter's syndrome.After evaluation of body habitus, the thyroid is palpated and the heart and lungs auscultated. Chronic bronchitis associated with congenital epididymal dysplasia is seen in Young's syndrome. Situs inversus with associated immotile sperm is seen in immotile cilia (Kartagener's) syndrome. The breasts are observed and palpated for gynecomastia, which can be associated with estrogen secreting testicular neoplasms, adrenal tumors, and liver disease. Nipple discharge or tenderness may be seen with prolactin-secreting pituitary adenomas. The abdomen is palpated and percussed. A large varicocele that does not collapse in the supine position warrants a search for an abdominal mass. An enlarged liver suggests hepatic dysfunction, which may be associated with infertility due to altered sex steroid metabolism. The penis and urethral meatus is examined for condylomata. The urethra is milked for discharge. The location of the meatus is noted. Severe hypospadias may result in inadequate delivery of semen into the vagina.Scrotal examination is first performed with the patient supine. This allows a varicocele, if present, to collapse; testis size and consistency can then be properly assessed. Use an orchidometer to measure testicular size. Normal testicular volume ranges from 15 to 30 cm . The testes should be firm in consistency. A change in testicular consistency is indicative of testicular pathology. Small soft testes indicate poor spermatogenesis. Small hard testes suggest postorchitis or posttorsion atrophy or Kleinfelter's syndrome. Focal irregularities in consistency raise the suspicion of malignancy. Smooth firm nodules palpated on the surface of the testis usually represent tunica albuginea cysts. Mobile small hard bodies,corpora amylacea, may be palpated floating within the tunica vaginalis. Transillumination of the scrotum in a darkened room differentiates solid from cystic masses. In general, testes that are normal in size and-consistency usually have normal sperm production, whereas small-volume, soft testes are associated with impaired spermatogenesis. The normal epididymis, posterolateral to the testes, is soft and barely palpable. Induration, modularity, or irregularities are suggestive of epididymal pathology. A full, firm, easily outlined epididymis that is nontendcr suggests epididymal obstruction. Epididymal cysts or spcruiutoccies are firm, smooth, transilluminate, and almost always located in the caput. The vas deferens should be palpated bilaterally. The vas is the diameter and consistency of a venetian blind cord, and is usually posteromedial and separate from the internal spermatic cord structures. We have observed bilateral congenital absence of the vas deferens (CAV) in 1.3% of of patients presenting for infertility evaluation. With a relaxed scrotum, the diagnosis of CAV can almost always be made by palpation. These men will have azoospermia associated with low seminal volumes and nonclotting clear ejaculate. Serum follicle-stimulating hormone (FSH) is usually normal, reflecting normal spermatogenesis. Testes biopsy and scrotal exploration are not necessary prior to therapy. Because the vas deferens derives from the ureteral bud, CAV is associated with. an 11% incidence of renal agenesis and abnormalities. A renal sonogram should be obtained in all men with CAV. Most men with CAV test positive for cystic fibrosis gene mutations, although they do not have any pulmonary manifestations of this disease.We test the patient and their wives for cystic fibrosis (CFTR) gene mutations and refer the couples for genetic counseling.Men with cystic fibrosis (CFTR mutations in association with digestive and/or pulmonary problems) will often have bilateral congenital absence of the vas deferens. CAV, whether associated with cystic fibrosis or not, may be treated using sperm retrieval and in vitro fertilization to effect pregnancies.Large varicoceles are readily seen through the relaxed scrotal skin in a warm room with the patient standing. Small varicoceles may be appreciated as a distinct impulse and palpable dilation of the internal spermatic veins during the Valsalva maneuver. The best method to elicit a strong and sustained Valsalva is to tell the patient to bear down as if having a bowel movement. If a varicocele is detected, the patient should be placed supine. A varicocele should completely collapse when the patient is supine. A large varicocele, which does not collapse in the supine position, leads to suspicion of a retroperitoneal mass and an abdominal sonogram is indicated. In the hands of an experienced sonographer scrotal ultrasound with color flow Doppler is useful in the evaluation of questionable varicoceles, especially in obese men or men with a small tight scrotum. Our monographic criteria for the diagnosis of a varicocele is the presence of any internal spermatic veins greater than 3 mm in diameter associated with retrograde flow on Valsalva. Subclinical or questionable varicoceles are of limited clinical interest. Our data has clearly shown that response to varicoceletomy is related to varicocele size. Men with large varicoceles sustain a greater improvement in semen quality following varicocele surgery than men with small or subclinical varicoceles. Digital rectal examination is always performed. The size and consistency of the prostate is noted. Masses, cysts, irregularities, tenderness, and whether or not the seminal vesicles are palpable are noted. Stool should be tested for occult blood.

Semen Analysis
Semen specimens are obtained by masturbation into a sterile wide-mouth container after 2-5 days of abstinence and analyzed within 2 hr of collection . Two to three analyses, separated by at least a month, are required for a meaningful evaluation. In the setting of a recent febrile illness or exposure to gonadotoxic agents we would repeat the semen analysis no sooner than 3 months later. Semen is initially an opalescent coagulum that liquefies within 20-25 min of ejaculation. The coagulation protein derives from the seminal vesicle. Liquefaction is secondary to the action of prostatic proteases. Failure of liquefaction is due to abnormalities of the prostate or its ducts. Normal ejaculate volume is between 2 and 6 mL. Sixty-five percent of the volume is from the seminal vesicles, 30-35% from the prostate, and 3-5% from the vasa. Seminal fructose derives from the seminal vesicles. Azoospermia coupled with low ejaculate volume of nonclotting watery fluids fructose-negative, Usually implies an obstruction of the ejaculatory duct. If the vasa are Palpable a transrectal Ultrasound can be diagnostic. Patients who are not azoospermic but oligo- or asthenospermic with a low semen volume may have partial ejaculatory duct obstruction or retrograde specimen is obtained by first having ejaculation. A postejaculatory urine specimen is obtained by first having the patient empty his bladder prior to ejaculation and then voiding following ejaculation into a separate container. Retrograde ejaculation is commonly seen in diabetics as well as in men who have had transurethral surgery at or near the bladder neck.Manual light microscopic evaluation of sperm concentration, motility, and morphology is still the gold standard. Computer-assisted semen analysis (CASA) is most useful as a research tool and yet has not provided information that alters therapy. Azoospermic specimens are frequently misread by the computer as oligospermic and computerized morphology has not been perfected. CASA provides interesting information on sperm velocity and angularity that is useful in a research setting. Because pregnancy can be achieved with only one sperm, specimens originally read as azoospermic should be centrifuged and the pellet examined for sperm. Specimens with head-to-head or tail-to-tail agglutination are evaluated for antisperm antibodies or infection. Infection may be inferred from the presence of leukospermia (>1x 106 WBC/mL). Men with agglutination or leukospermia should have their semen cultured for aerobic and anaerobic organisms as well as Chlamydia and Mycoplasma. The penis and scroturn should be washed with an antibacterial scrub Prior to culture to avoid inadvertent contamination with skin or fecal flora.Proper interpretation of morphologic parameters requires an understanding of the scoring system and criteria employed by testing laboratory, Broadly viewed, profound abnormalities in morphology are associated with poor fertilizing capacity when strict criteria (Kruger) are used. Men with fewer than 40% perfectly shaped sperm usually failed to fertilize without micromanipulation. Large numbers of tapered sperm are seen in testes with elevated temperatures, such as varicocele, cryptorchid, or retractile testes, or in the testes of men who take saunas or hot baths. Antisperrn antibodies bound to sperm are associated with lower pregnancy rates. Risk factors for antibodies include torsion, epididymitis, orchitis, unilateral or partial obstruction, and large varicoceles. These are all conditions associated with impairment of the blood-testis barrier that usually prevents sperm antigens (which appear at puberty) from being exposed to the general circulation. An immunobead assay detects antibodies on the sperm and in the serum. High levels of antibodies are most often seen with obstruction, in particular before (in serum) and after (in serum and on sperm) vasectomy reversal. Low levels of antibodies on sperm and moderate levels in serum are usually seen in men with large varicoceles. A postcoital test is useful for evaluating sperm-cervical mucus interaction. A fair to good semen analysis associated with a poor postcoital test is an indication for intrauterine insemination (IUI). Although IUI can overcome cervical mucus antibodies or decreased counts, the success of IUI is dependent on the sperm's ability to fertilize an egg, Therefore prior to instituting IUI, we obtain a sperm penetration assay (SPA) that assesses the sperm's ability to bind and penetrate hamster oocytes, which have been rendered zona pellucida-free. Tests are interpreted as percent oocytes penetrated or sperm penetrations per oocyte. These tests are not perfect but do correlate about 80% with the ability to penetrate human eggs in vitro.
Semen Analysis Normal Ranges (WHO Criteria, 1992)

Varicocele

Introduction
Etiology
Pathophysiology
Diagnosis
Surgical Treatment

1. Indications
2. Microsurgical technique

Complications of varicocele Repair
Results
Cost-effectiveness
Summary
Reference and Suggested Reading

Introduction

Varicoceles are abnormally dilated testicular veins (pampiniform plexus) of in the scrotum, which is normally secondary to internal spermatic vein reflux. Varicocele is found in approximately 15% of the general population, 35% of men with primary infertility and in 75-81% of men with secondary infertility. It is more common on the left side. In adolescents, the incidence of varicocele is approximately 15%; the abnormality is extremely rare in prepubertal boys

Although most men with varicoceles are able to father children, there is abundant evidence that varicoceles are detrimental to male fertility. A study by the World Health Organization (WHO) on over 9,000 men showed that varicoceles are commonly accompanied by decreased testicular volume, impaired sperm quality, and a decline in Leydig cell function.2 Another report by Johnson and colleagues showed that 70% of healthy, asymptomatic military recruits with palpable varicoceles had an abnormality on semen analysis.3 Furthermore, studies in animals4,5 and humans6-8 suggest that varicoceles cause progressive testicular damage over time. It appears that surgical repair of varicoceles not only halts this declines in testicular function but often reverses it. Whether the improvements in semen parameters, seen in 80% of men after varicocele ligation, translate into improved pregnancy and delivery rates has been a matter of ongoing controversy. Recent studies employing non-operated control groups clearly indicate that varicocelectomy does improve pregnancy rates.48

Etiology
Presumably due to anatomic differences, varicoceles are much more common on the left side. The incidence of bilaterality is anywhere from 15 to 50% but isolated right varicoceles are fairly rare. The left internal spermatic vein empties into the left renal vein. It is 8 to 10cm longer than the right internal spermatic vein, which drains into the inferior vena cava. This is believed to result in increased hydrostatic pressure that is transmitted down the vein to the scrotal pampiniform plexus, causing dilation and tortuosity of these vessels.9 Elevated pressure in the left internal spermatic vein may also result from compression of the left renal vein between the aorta and the superior mesenteric artery, a phenomenon known as the "nutcracker effect." Radiologic studies have documented relative distention of the proximal left renal vein suggesting partial distal obstruction.10

Varicoceles may also arise secondary to reflux of venous blood into the pampiniform plexus as a result of absent or incompetent valves within the internal spermatic vein. A report by Braedel et al. on over 650 consecutive men with varicoceles revealed that 73% had absent internal spermatic venous valves on venography.11

Varicoceles generally become clinically manifest at the time of puberty. Although there is no data to suggest a genetic basis for these lesions and hereditary patterns have not been identified, these issues have been poorly studied. Retroperitoneal masses such as sarcomas, lymphomas, and renal tumors have been known to cause varicoceles by obstructing venous outflow from the testicles but varicoceles are not known to be a component of any clinically recognized syndrome.

Pathophysiology
Despite a large number of animal and human studies, the exact mechanism whereby varicoceles cause impaired testicular function remains poorly understood. Theories include abnormally high scrotal temperature, hypoxia due to venous stasis, dilution of intratesticular substrates (e.g. testosterone), imbalances of the hypotalamic-pituitary-gonadal axis, and reflux of renal and adrenal metabolites down the spermatic vein. Data exist to both support and refute each of these possibilities. In addition, nitric oxide,12 reactive oxygen species,13 and regulators of apoptosis14 have all recently been implicated in the pathophysiology of varicoceles. It appears that cigarette smoking in the presence of varicocele has a greater adverse effect than either factor alone.15

The most vigorously studied pathophysiologic theory is that of increased testicular temperature. It has long been observed that even minor fluctuation in temperature can affect spermatogenesis and sperm function.16,17 It has been suggested that varicoceles impair testicular thermoregulation by disrupting the countercurrent heat exchange mechanism in the pampiniform venous plexus. Reversal of testicular blood flow abnormalities and a drop in testicular temperature have been seen in the rat after varicocele repair.18 Recently, Wright and colleagues showed in humans that scrotal skin surface temperatures were elevated in men with varicoceles compared to control patients. Following varicocele ligation, scrotal temperatures returned to a level nearly identical to those of controls.19 Previous studies have demonstrated that scrotal skin surface temperatures reliably reflect intratesticular temperatures.20 The pathophysiology of varicocele is probably multi-factorial.

Diagnosis

Varicoceles are defined as dilations of veins of the pampiniform plexus, which are believed to be caused by incompetent valves of the internal spermatic veins.

The diagnosis of a clinical significant varicocele is generally made on physical examination of the scrotum and its contents. The patient is examined in the supine and standing position in a warm room that promotes relaxation of the scrotal dartos muscle and facilitates accurate evaluation for varicocele. The scrotum should be inspected carefully for any easily visible dilated veins (Figure 1a, 1b). The spermatic cord should be palpated between thumb and forefingers for palpable vein. Both sides of spermatic cords should be palpated while the patient performs a Valsalva maneuver.

The severity of the varicoceles is graded I through III using the system outlined in following table 1. Grade I varicoceles can be thought of as small, Grade II, medium and Grade III, large. Varicoceles should significantly diminish in size when the patient assumes the supine position. If the varicocele remains prominent with the patient supine, this finding suggests a mechanical obstruction to testicular venous outflow such as a retroperitoneal mass (sarcoma, lymphoma or a renal tumor with venous thrombus). An abdominal ultrasound or CT scan should be obtained to evaluate the retroperitoneum in these patients.

Table1: Clinical Varicocele Classification

Scrotal ultrasonography with color flow Doppler imaging may prove useful in equivocal cases or in patients with a body habitus that makes accurate physical examination of the scrotum impossible. Using ultrasonography, the diameter of the internal spermatic vein can be measured and retrograde flow through the vein during Valsalva documented. Veins that are greater the 3.5mm can generally be detected on physical exam. Those that are 2.7mm or less are usually not palpable and have been termed "subclinical" varicoceles.21 The need for diagnosing and treating subclinical varicoceles is controversial.22 Recent studies have indicated that repair of subclinical varicoceles is of questionable value.23 However, other reports have indicated that repair of small palpable or subclinical right varicoceles may be beneficial if present in conjunction with a larger left sided varix.24-26

Venography is generally considered the most accurate method of varicocele diagnosis when performed by an experienced interventional radiologist.27 Due to its invasiveness, venography is usually only performed in the research setting to document recurrences or for a comparison to other, less invasive diagnostic techniques.

A multi-center WHO study on the influence of varicocele on fertility parameters demonstrated that the mean Testosterone (T) concentration of men older than 30 years of age with varicoceles was significantly lower than that of younger patients with varicoceles, whereas this trend was not seen in men without varicoceles.2,32 When exogenous hCG is administered to men with varicoceles, a blunted T response is observed compared to controls without varicoceles.28 Repairing varicoceles appears to improve serum Testosterone (T) levels. This observation was made over twenty years ago by Comhaire and Vermeulen29 and was confirmed recently in a larger series by Su, et al.30 Taken together, these findings indicate that varicoceles result in abnormal Leydig cell function in some men, but these patients may also be the ones to most benefit from surgical repair.

The abnormalities of semen parameters in infertile men with varicocele were first objectively described by Macleod in 1965 57. In that study, Macleod observed that the vast majority of semen samples, obtained from 200 infertile men with varicocele, were found to have an increased number of abnormal forms, decreased motility and lower mean sperm counts. This 'stress pattern', which is also characterized by an increased number of tapered forms and immature cells, was also reported in other studies. However, other investigators have shown that the characteristic stress pattern is not a sensitive marker for varicocele, and believe that it is not diagnostic of this pathology. A large number of studies have evaluated the effects of varicocelectomy on semen parameters. Most of these studies have demonstrated an improvement in sperm density with or without a concomitant increase in sperm motility and morphology after varicocelectomy, suggesting a cause and effect relationship between varicocele and abnormal semen parameters. However, because the bulk of the reported outcome data on varicocelectomy comes from uncontrolled or poorly designed controlled studies, the value of those results is limited. The impact of the grade of varicocele on the magnitude of improvement in semen quality after varicocelectomy is equivocal. Steckel et al., reported that men with larger varicoceles present with lower sperm densities, and show greater relative improvement in semen quality than men with smaller varicoceles who present with higher mean sperm densities59. On the other hand, Braedel et al., demonstrated less of an improvement in sperm density in men with grade 3 varicocele, than men with smaller varicoceles.60

Although the relationship between varicocele size and seminal improvement following varicocele repair was controversial for many years, the overall rates of seminal improvement following varicocele repair have been approximately 65%. Moreover, some recent studies indicated that the degree of improvement of semen parameters following varicocele repair is directly proportional to the size of the varicocele repaired surgically.

Surgical Treatment
1. Indications: The majority of men with varicoceles remain fertile and asymptomatic. Therefore, treatment of all varicoceles is clearly unnecessary. The authors advocate surgical correction of clinically detectable varicoceles associated with abnormal semen parameters in an infertile couple following appropriate evaluation of the female partner. This includes men with azoospermia and very severe oligospermia.

Palpable varicoceles should be corrected in adolescent boys when accompanied by ipsilateral testicular atrophy or if the varicocele is very large. It has been suggested that adolescents with varicocele and an abnormal gonadotropin response to LHRH may also benefit from repair.32 Finally, varicoceles associated with debilitating testicular pain may be considered for repair.

A variety of surgical approaches have been advocated for varicocele repair (varicocelectomy), including open surgical, laparoscopic, and percutaneous techniques. Ideally, the perfect procedure would be one that ligates both the veins contributing to the varix at the time of repair and those that could cause a recurrence in the future. However, some veins clearly must be preserved so as to allow drainage of blood from the testis and prevent vascular engorgement. Therefore, the ideal procedure should be one that leaves the testicular arteries, lymphatics, and vas deferens intact. A minimally invasive procedure which reduces morbidity, pain and recovery time is also desirable.

2. Microsurgical Technique: We believe that the technique most closely approaching this "ideal" is the mini-incision, inguinal, or subinguinal microsurgical varicocelectomy with delivery of the testicle.33 Although it is a technically demanding approach, the real advantages of the microsurgical approach to varicocele repairs are reliable identification and preservation of the testicular artery or arteries, cremasteric artery or arteries, and lymphatic channels and reliable identification of all internal spermatic veins and gubernacular veins. Delivery of the testis assures direct visual access to all possible routes of venous return, including external spermatic, cremasteric, and gubernacular veins. Postoperatively, venous return is via the vasal veins, which drain into the internal pudental system and usually have competent valves.

The introduction of microsurgical technique to varicocelectomy has resulted in a substantial reduction in the incidence of postoperative hydrocele formation and testicular atrophy or azoospermia, respectively. This is because the lymphatics can be more easily identified and preserved. Furthermore, the use of magnification enhances the ability to identify and preserves the 0.5 - 1.5-mm testicular artery, thus avoiding the complications of atrophy or azoospermia.

Microsurgical Approaches: After standard preparation and draping of the patient, the position of the external inguinal ring is marked as " X" on the skin. The incision extends about 2 cm from the mark following natural skin line (Figure 2). The size of the incision depends somewhat on the obesity of the patient and the size of the testicle being delivered.

The spermatic cord is exposed by hooking an index finger under the external inguinal ring while sliding a small Richardson retractor in the incision along the dorsum of the index finger and pulling in the opposite direction .The cord is encircled with a Babcock clamp (Figure 3). With gentle traction the cord is exposed, encircled with a Babcock clamp, and delivered. The ilioinguinal and genital branches of the genitofemoral nerve are excluded and preserved. The Babcock clamp is replaced with a Penrose drain and the testis is delivered.

The gubernaculum is carefully inspected and any veins encountered are either electrocoagulated or clipped and divided depending on their size. All perforating external spermatic veins and gubemacular veins are also divided (Figure 4). The gubernacular veins have been demonstrated radiographically to account for 10% of varicocele recurrences10.

Delivery of the testicle enables the surgeon to identify and ligate these vessels, which are responsible for some varicocele recurrences (Figure 5).

Once all external spermatic perforators and gubernacular veins have been divided, the testicle is returned to the scrotum and the spermatic cord remains elevated over a large Penrose drain for stabilization in preparation for microscopic examination (Figure 6)

The operating microscope is then brought into the operating field and the cord is examined under 8 to 15-power magnification. The internal and external spermatic fascias are opened longitudinally and the cord is examined. The magnification is increased to 15 power and 1 % papverine is dripped over the cord. The testicular artery is identified by its pulsation and is dissected free from all surrounding tissue, tiny veins, and lymphatics using a fine-tipped, non-locking micro-needle holder and Pierse tissue forceps. The pulsation of suspected by seeing a pulsating column of blood appears just over the needle holder. The artery is identified and then encircled with a zero silk suture to preserve it (Figure 7). Any additional artery encountered are also identified and preserved in this manner. All remaining internal spermatic veins with the exception of the vasal veins are clipped with hemoclips or ligated and divided. Care is taken to preserve a majority of lymphatics as these can contribute to hydrocele formation postoperatively when divided.

At the completion of varicocelectomy, the cord should contain only the testicular artery or arteries, vas deferens and associated vessels, cremasteric muscle (with its veins ligated and artery preserved), and spermatic cord lymphatics.

This meticulous approach to varicocelectomy requires extensive training and the use of a high-quality operating microscope. Even loupe magnification is inadequate for the reliable identification of the tiny vascular channels and lymphatics of the spermatic cord. An experienced surgeon can perform this procedure in less than 30 minutes per side, and the procedure is always performed on an ambulatory basis.

Using the microsurgical technique at Cornell, we have reviewed our results of over 1,500 men who underwent microsurgical varicocelectomy, the couples' pregnancy rate was 43 % after one year and 69% after 2 years compared to 16% in couples with men who declined surgery and had hormone treatment or used insemination. There have been only 14 recurrences (1%), no hydrocele, no testicular atrophy, and a 1% incidence of inadvertent unilateral (one side only) testicular artery ligation14.

Some authors have suggested that the technique employed should be governed by the clinical situation. In a recent report, Abdulmaaboud et al. advocated percutaneous embolization for isolated left-sided varicoceles and laparoscopy for bilateral varicoceles.35 Failure rate for Balloon occlusion is 25% and laparoscopic approach requires general anesthesia and is also with great potential morbidity.

Complications of Varicocele Repair
Hydrocele formation is the most common complication reported after non-microsurgical varicocelectomy, with an average incidence of about 7%36 Hydroceles form secondary to ligation of the testicular lymphatics. At least half of all post-

varicocelectomy hydroceles grow to a size that produces sufficient discomfort to warrant surgical hydrocelectomy. The effect of hydrocele function on spermatogenesis and fertility is unknown. Theoretically, large hydroceles may impair testicular function by insulating the testis and preventing normal thermoregulation. Use of the operating microscope has essentially eliminated the development of hydroceles following varicocelectomy.37, 38

Testicular artery ligation is also a common complication of non-microsurgical varicocelectomy although its true incidence is unknown.39 Injury or ligation of the testicular artery may cause testicular atrophy, impaired spermatogenesis, or both. Animal studies indicate that testicular atrophy occurs anywhere from 20% to 100% of the time following testicular artery ligation.40,41 In humans, Penn, et al. reported a 14% incidence of frank testicular atrophy, when the testicular artery was purposefully ligated during renal transplantation.42 Optical magnification and/or the use of a fine tipped Doppler probe facilitate identification and preservation of the testicular artery.

The incidence of varicocele recurrence following surgical repair varies from 1% to 45%. The incidence of recurrence depends upon the type of procedure performed and the use of magnification. Venographic studies have shown that recurrent varicoceles are caused by periarterial, parallel inguinal, midretroperitoneal, gubernacular and transcrotal collateral veins.36 The only approach equipped to deal with these vessels is the inguinal or subinguinal microscopic technique with delivery of the testis. A comparison of the various approaches to varicocelectomy is summarized in table 2.

Table 2: Techniques of Varicocelectomy

Our recurrence rate at Cornell is less than 1%. Unintentional testicular artery ligation occurs in less than 1% of cases and hydroceles have been essentially eliminated. We have seen clinically significant improvements in semen parameters for over 80% of patients and natural pregnancy rates of 43% and 69% at one and two years respectively, controlling for female factors.

Results
Increasing evidence suggests that varicocele ligation improves semen quality and pregnancy rates. Unfortunately, the bulk of this data comes from retrospective, poorly controlled studies. Only two randomized, prospective, controlled studies have been performed. Nieschlag and colleagues reported on 125 couples with varicoceles who underwent either angiographic embolization, surgical ligation, or counseling.43 They found that semen parameters improved significantly in the treatment groups but pregnancy rates were no different than those couples receiving only counseling. Most of the varicoceles in this study were small (Grade I) and a microsurgical, artery sparing technique was not applied. A second study by Madgar, et al. was especially convincing because it employed a cross over design.44 Forty-five couples were randomized to receive either immediate varicocelectomy or delayed varicocelectomy following one year of observation. Despite the fact that a retroperitoneal, high ligation technique was used, pregnancy rates were 6 times higher in the men undergoing immediate varicocelectomy compared to those in the observation group (60% vs. 10% respectively) over the first year. Furthermore, pregnancy rates rose 4-fold in the observation group during the first year after surgical correction.

Overall, varicocelectomy results in significantly improved semen parameters in 60% to 80% of men and pregnancy rates of 20% to 60%. 45 One should keep in mind, however, that most of the studies used to generate these figures employed what the authors believe to be suboptimal varicocelectomy techniques. Using the microscopic subinguinal approach, we have observed a 69% pregnancy rate at two years postoperatively when female infertility factors were excluded.46

As mentioned previously, varicocelectomy can even be effective in men with azoospermia or severe oligospermia. Matthews and Goldstein recently reported that 55% of azoospermic men and 69% of men with zero motile sperm before surgery had motile sperm observed in their ejaculate after varicocele repair.47 Thirty-one percent of these otherwise sterile men contributed to pregnancies leading to live births including 19% who did so without the help of assisted reproduction. Steckel and co-workers found that men with large varicoceles have poorer semen quality than men with small varicoceles.59 Fortunately, the men with larger (Grade III) varicoceles also showed a greater degree of improvement following varicocelectomy.

When discussing varicocelectomy as a treatment for male infertility, it is again important to remember that varicoceles cause a progressive decline in testicular function (both spermatogenesis and steroidogenesis) with time.2 Thus, for couples desiring more than one child, the ability of varicocelectomy to prevent further deterioration may be even more important than the procedure's early beneficial effects on semen quality.

Varicocelectomy is indicated in adolescents when accompanied by ipsilateral testicular atrophy. Studies on adult men with varicoceles have shown that the degree of testicular atrophy is proportional to the clinical grade of the varicocele.48 Varicocele patients with testicular atrophy have worse semen parameters than those without atrophy.49 Several studies have shown quite convincingly that correction of adolescent varicocele results in rapid catch-up growth of the affected testis.50,53 In addition, a recent study by Lenzi and colleagues showed that adults who had varicoceles corrected during adolescence had significantly better semen parameters than adults with varicoceles detected during adolescence who did not have them repaired.54

Many men with varicoceles often experience intermittent, mild discomfort in the testis and scrotum on the affected side. The pain is usually described as a dull, throbbing ache. On rare occasions, the pain caused by a varicocele can become debilitating. After exhausting more conservative measures and ruling out other etiologies, varicocele ligation may be the only treatment alternative remaining. Peterson and colleagues recently reported on 35 patients who underwent varicocelectomy purely for the relief of pain.55 Eighty-six percent of the men experienced complete resolution of the pain postoperatively. Unfortunately, 11% had either persistent or worsening symptoms.

Cost -effectiveness
In the last decade, assisted reproductive techniques such as intracytoplasmic sperm injection (ICSI) have revolutionized the treatment of male infertility. The rising success rates and widespread availability of ICSI has led some gynecologists and reproductive endocrinologists to "bypass" both the evaluation and treatment of the male while proceeding straight to assisted reproduction. This is unfortunate because many cases of male infertility are caused by correctable conditions such as varicocele.

The managed care era has ushered in a heightened awareness of cost effectiveness and outcomes research. Schlegel recently performed a comparison of ICSI and varicocelectomy for the treatment of varicocele-associated infertility using a "cost per delivery" analysis.56 Total hospital delivery costs, complication costs, and costs attributable to multiple gestations were taken into account along with the published pregnancy and delivery rates for the two procedures. The overall cost per delivery for varicocelectomy averaged $26,300 compared to a striking $89,000 per delivery for ICSI in 1994 U.S. dollars. The European experience is similar. Comhaire, et al. has estimated that varicocelectomy is seven times more cost effective than ICSI.57 Although ICSI can clearly facilitate pregnancies in couples with varicocele-associated infertility, it is a very expensive alternative.

Summary
Varicoceles are common. They may be detected in 15% of the male population, 35% of men with primary infertility and up to 80% of men with secondary infertility. Studies have shown that varicocele causes progressive duration-dependent injury to the seminiferous epithelium and testicular function over time. The most likely pathophysiologic mechanism is an elevation of testicular temperature due to impaired scrotal thermoregulation. Varicocele repair will halt this duration-dependent process.

The most common complications from varicocelectomy are hydrocele, varicocele recurrence, and testicular artery injury. Use of the operating microscope allows for reliable identification of spermatic cord lymphatics, internal spermatic veins and venous collateral, and the testicular artery or arteries so that the incidence of these complications can be reduced significantly. Delivery of the testis through a small subinguinal incision provides direct visual access to all possible avenues of testicular drainage. Although some controversy continues to surround varicocelectomy as a treatment of male factor infertility, a great deal of data does exist to support this form of therapy. Ultimately, a final answer will require a large, prospective, randomized and controlled study using a microsurgical, artery and lymphatic sparing technique.

Congenital Bilateral Absence of Vas Deferens
Congenital bilateral absence of vas deferens (CBAVD)is diagnosed in 1.3 % of the men referred for infertility evaluation. Moreover, CBAVD accounts for 27% of the men with primary obstructive azzospermia. An almost equal number of men with other causes of surgically unreconstrucatable obstructuctive azoospermia are referred for evaluation. In the past decade, the techniques of epididymal sperm retrieval and micromanipulation to assist fertilization have been two of the most exciting developments in the field of male infertility treatment. Men with congenital bilateral absence of the vas defences (CBAVD), or acquired reproductive tract obstruction are now able to achieve pregnancies with use of these advanced techniques. We have found that microsurgical epididymal sperm aspiration (MESA) using a glass micropipet technique simultaneous to intracytoplasmic sperm injection (ICSI) appears to maximize opportunities of pregnancy for these infertile couples with unreconstructable male reproductive tract obstruction. MESA from individual epididymal tubules with a micropuncture technique allows retrieval of high numbers of sperm with optimal quality for immediate use during ICSI as well as for cryopreservation. A unique micropuncture pipet holding apparatus, MESA- Holder has been developed at Cornell. Its unique 180° angle adjustable pipet holding system simplifies the procedure of micropuncture epididymal sperm retrieval. The micropuncture technique is an atraumatic technique that limits damage to the epididymal tubules and avoids potential blood cell contamination of the epididymal fluid, while yielding high quantities of motile spermatozoa. Experience with the last 59 couples with obstructive azoospermia who selected to undergo MESA-ICSI at Cornell from April, 1995 to June, 1996 is presented. Sperm was retrieved from the epididymis in 59/59 (100%) attempts, despite multiple aliquots of previous unsuccessful sperm retrieval attempts at other institutions. In all 59 cases motile sperm were cryopreserved as well. Clinical pregnancies were achieved in 80%( 47/59) cycles for these couples. Ongoing pregnancies or deliveries have occurred for in 68% (40/59) cycles of simultaneous MESA-ICSI. .Simultaneous MESA-ICSI appears to provide optimal pregnancy and delivery rates for couples where the man has unreconstructable reproductive tract obstruction.

Ejaculatory Duct Obstruction
Men with fructose-negative azoospermia, low semen volume, and at least one palpable vas deferens have either a congenital vasal anomaly or obstruction of the ejaculatory duct. Digital rectal examination may reveal a midline cystic structure. Transrectal sonography has revolutionized the diagnosis and treatment of ejaculatory duct obstruction. If a midline cystic lesion or dilated ejaculatory ducts and seminal vesicles are visualized sonographically, we may ask our sonographer to aspirate 2-3 cm of fluid and instill methylene blue. The aspirate is examined microscopically and if sperm are found, transurethral resection (TUR) of the ejaculatory duct is performed without need for prior vasography as the presence of sperm indicates that at least one side is not obstructed more proximally and that the cyst or dilated ejaculatory duct communicates with a nonobstructed vas. The instillation of methylene blue assists in localizing the opening of the ejaculatory duct and confirms that resection has entered the system. Transrectal aspiration should be performed immediately prior to anticipated surgery and should employ the same bowel prep and antibiotic prophylaxis used for transrectal prostate biopsy. If no sperm are found in the aspirate, vasography is necessary. This is performed as previously described. If no sperm are found in the vas, vasoepididymostomy is performed at the same sitting. If ejaculatory duct obstruction is confirmed by vasography employing a 50% water-soluble contrast media, the umbilical artery catheters used for vasography stents are left in place so that a dilute methylene blue solution can be injected by the assistant during resection. The resectoscope, with the 24-Fr cutting loop, is engaged with a finger placed in the rectum providing anterior displacement of the posterior lobe of the prostate. The ejaculatory ducts course between the bladder neck and the verumontanum and exit at the level of and along the lateral aspect of the verumontanum. Resection should be carried out in this region with great care taken to preserve the bladder neck proximally, the striated sphincter distally, and the rectal mucosa posteriorly, Efflux of methylene blue from dilated orifices confirms adequate resection, Avoid excessive coagulation. If formal vasography is performed, the hemivasotomies are closed employing microsurgical technique. A Foley catheter is left overnight and the patient should receive a 5- to 7-day course of antibiotics.

Electroejaculation
Men with neurologic impairments in their sympathetic outflow, as in traumatic spinal cord injury (SCI), demyelinating neuropathies (multiple sclerosis), diabetes, and following retroperitoneal lymph node dissection (often for testis tumor), frequently have abnormalities or absence of seminal emission. Electroejaculation (EEJ) has been proven to be a safe and effective means to obtain motile sperm suitable for assisted reproductive techniques (intrauterine insemination or in vitro fertilization).Electroejaculation (EEJ) is normally performed under general anesthesia, though for men with a complete spinal cord injury (SCI), anesthesia may not be necessary. To prevent autonomic dysreflexia, men with SCI, particularly above the level of T-5, are premeditated with 20mg of nifedipine, sublingually, 15 minutes prior to EEJ. The procedure begins by first catheterizing the patient in supine position and emptying the bladder completely. The use of Betadine and Surgilube is to be avoided because of their spermicidal effect. Instead, the urethra is lubricated with glycerin or, preferably, by instillation of 2 cc of 6% simulated human tubal fluid and plasmanate. The pH of the urine should be assessed to ensure its alkalinity (pH>6.5). Oral sodium bicarbonate may be used if necessary. Because retrograde ejaculation (backwards ejaculation into the bladder) occurs frequently in this procedure, an additional 10 cc of the simulated human tubal fluid and plasmanate is instilled into the bladder to help preserve any sperm inside the bladder. The catheter is then removed. Although it is possible to perform the procedure in lithotomy position, lateral decubitus position is preferred, as it allows easier access to both the penis and rectum.The patient is put on his side with his thighs and knees slightly flexed. All pressure points are appropriately padded. A blood pressure cuff is applied to the patient's left arm for continuous blood pressure monitoring every 2 minutes. Digital rectal examination and anoscopy should be performed before and after the procedure to inspect the rectal ampulla and mucosa for any injury. In patients with SCI, it is not uncommon to find rectal mucosal abrasion, especially if they are being managed with a chronic digital bowel program. If anoscopic inspection is not performed prior to the EEJ, one could mistakenly attribute the rectal abrasion to be caused by the procedure. After proper inspection, a well-lubricated large rectal probe with horizontal electrode plates is introduced gently into the rectal ampulla, and is stabilized against the anterior rectal wall at the level of the seminal vesicles and prostate. Electrostimulation via the rectal probe may then begin.The rectal probe is connected to an adjustable output power source and is capable of simultaneously recording the temperature of the probe through a thermistor. The amount of current and voltage needed depends on the patient's body habitus and the extent of his neurologic injury. In patients with incomplete SCI, the procedure may be limited by their tolerance to pain, as sensation may be present.Rhythmic delivery of current is performed by manually turning the dial to increase the voltage delivery progressively for a few seconds. After a few initial stimulation, the voltage is reduced to zero. Voltage is then gradually increased until erection/ejaculation has occurred. The voltage at which the first erection/ejaculation occurs is noted and is then increased to a level 30% to 50% higher, depending on patient's tolerance and the rectal temperature which is constantly monitored and displayed. Ejaculation may be entirely retrograde. In these cases, sweating, piloerection, " goose bumps" on the things and buttocks, and erection may be the only signs that the patient is adequately stimulated and that ejaculation has occurred. The number of stimulation, the current, and the voltage necessary to produce a maximum erection are noted, as this information will be useful for subsequent procedure if needed. The ejaculate is collected directly into a cup containing 3 cc of human tubal fluid (HTF) buffer.The probe temperatures as well as the number of stimulation required to achieve full erection and ejaculation are recorded. The ejaculate is then collected in a sterile wide-mouth plastic container. The numbers of stimulation and maximum voltage required may vary and ejaculation may be retrograde. If the probe temperature rises rapidly to above 40oC, we either change the rectal probe or suspend the stimulation until the temperature falls below 38oC.Following electroejaculation, anoscopy is performed again prior to returning the patient in the supine position. The bladder is catheterized to collect the post-ejaculate urine, which is sent along with the ejaculate to the IVF laboratory for processing.Currently, employing this technique, semen can be obtained in more than 90% of neurologically impaired men. More than 40% of the couples achieve pregnancy with IUI or IVF. Pregnancy rates are slightly better among couples in which the male partner had SCI (43%) or idiopathic anejaculation (33%) then those who had undergone retroperitoneal lymph node dissection (20%) or had diabetes (0%).

Specific Medical Treatments

1. Infection
2. Antisperm Antibodies
3. Hypogonadotropic Hypogonadism
4. Normogonadotropic Hypogonadism
5. Retrograde Ejeculation

Infection
Semen cultures, urine cultures, and cultures of expressed prostatic secretions are indicated in the presence of leukospermia. In patients who demonstrate symptoms referable to the genitourinary tract or sperm agglutination, cultures are obtained after the penis, scrotum, and perineum have been cleansed with an antibacterial scrub as previously described. If cultures are positive, treatment should employ an agent to which the cultured organism is sensitive and that has no effect on spermatogenesis but good genitourinary penetration. Antibiotics with such a profile include the fluoroquinolones and tetracyclines. In the absence of a positive culture but with a high clinical suspicion of infection we employ empiric fluoroquinolone or tetracycline therapy for 3-6 weeks, treating both partners.

Antisperm Antibodies
Our approach to the management of patients with antisperm antibodies is to identify and treat the underlying problem, ie, repair the obstruction or varicocele. If this is not successful, we initiate treatment with 20 mg of prednisone twice daily days 1-10 of the wives' cycle and 5 mg on days 11 and 12 for 3 months. Following this treatment course we reevaluate -for the presence of antibodies. Aseptic necrosis of the femoral head is the most devastating complication of steroid therapy (1 % incidence), although this is uncommon with short term (< 6 months), intermittent (12 days/month) therapy. We now recommend IVF with ICSI which is very successful for severe antibody problems.

Hypogonadotropic Hypogonadism
This condition is due to the lack of the hypothalamic decapeptide gonadotropin-releasing hormone (GnRH), When associated with midline defects such as anosmia, it is called Kallmann's syndrome. Very low or undetectable serum levels of LH, FSH and T in a prepubertal appearing adult confirms the diagnosis. Treatment for the development of secondary sexual characteristics and maintenance of libido is Depo-Testosterone. For induction of spermatogenesis, the Depo-Testosterone is discontinued. Human chorionic gonadotropin (hCG) 1500 IU 3 times weekly is begun. After 3-6 months of hCG therapy, when serum T,Ievels are in the normal range, human menopausal gonadotropin (hMG) 25-75 IU 3 times weekly is added. Sperm usually begin to appear in the ejaculate 6-18 months after initiation of therapy. Testis size and sperm counts remain lower than normal, but pregnancies occur regularly with sperm densities in the 2-6 million per mL range. Men who fail to respond to gonadotropin replacement may respond to pulsatile administration of GnRH by pump.

Normogonadotropic Hypogonadism
These patients have low sperm counts and normal levels of FSH and LH, but a low serum T. Before treatment, a prolaebou should be obtained to rule out a pituitary tumor. In these men clomiphene citrate 25 mg daily (1/2 tab) blocks the negative feedback inhibition of estrogen to the pituitary increasing LH and FSH release and subsequently increasing serum T and improving sperm densities. Semen parameters improve in 94% of men with 40% pregnancy rate achieved. Serum T, estradiol, and a semen analysis are obtained every 3 months. Failure to respond may be attributable to over- or understimulation. If posttreatment testosterone levels remain low, increase the dose to 50 mg daily. If levels exceed 1000 ng/dL and/or estradiol levels exceed 60 ng/L, reduce the dose by 50%. We have observed nonbacterial pyospermia develop in 17% of previously nonpyospermic clomiphene citrate-treated men. As no clomiphene-treated man who has developed pyospermia has contributed to a pregnancy, we serially monitor semen analyses for its development.

Retrograde Ejaculation
Retrograde ejaculation is associated with a diminished volume or complete lack of seminal emission, and is often the first symptom of diabetes mellitus. The diagnosis may be confirmed by microscopic examination of a posteiaculation urine specimen. Pseudoephedrine (Sudafed) 120 mg 3 times daily will convert approximately 25% of men to antegrade ejaculation. Ejaculation with a full bladder is sometimes helpful. A full bladder stimulates increased a-adrenergic activity at the bladder neck. If these measures fail, the urine may be alkalinzed and the sperm from the postejaculate urine retrieved, processed, and used for IUI or IVF with ICSI.