Male Reproductive System

CHAPTER 19


Male Reproductive System



The reproductive system is arguably the most important in terms of survival of a species. In production animals, reproduction is essential for the continued supply of product, be it meat, fiber, milk, or many other products. Most production animals rely on a small number of males as breeding stock, so in addition to being 50% of the reproductive team, an infertile male or one carrying an undesirable trait has a major impact.


The male reproductive system usually receives little attention and time; with some exceptions, replacement of a breeding male is often more effective than diagnosis and treatment. Infertility in the male is difficult to reverse unless the cause can be readily found and corrected. This is where knowledge of the disease processes, responses to injury, and prognosis are so important.


Companion animals are not given the same amount of study as production animals, especially the bull and ram. The aim here is to emphasize the disorders of all species and highlight the mechanisms and reactions of the male reproductive tract by examining the disorders of each anatomic location.



Structure


The male reproductive tract can be divided into three major areas based not only on anatomic location but also on functional characteristics and important disease processes. These are the scrotum and its contents, the accessory genital glands, and the penis and prepuce.



The Scrotum and Contents


The purpose of the scrotum and its contents is to supply spermatozoa for transportation to the female. Although the general focus is on the testis and its germinal cells contained in the seminiferous tubules, other parts have important functional characteristics that allow this to happen. Testicular development is quiescent until puberty when spermatogenesis begins. The testes therefore are small until puberty, when they increase to their adult size. The testes are covered by a capsule (once called the tunica albuginea), which is relatively nonexpansile and usually maintains the testicular contents under slight pressure. Within the testis are the interstitial and intratubular regions. Within the interstitium are the interstitial endocrine (Leydig) cells, blood vessels, lymphatics, and macrophages, dendritic cells, mast cells, and T lymphocytes. Each seminiferous tubule has a lining of myoid cells and a limiting membrane. There is a basement membrane between these structures. The arrangement of the seminiferous tubules varies from species to species, but the end result is the formation of spermatozoa. After spermatogenesis, spermatozoa are transported through rete tubules into the efferent ductules and then into the epididymis, a single and extremely long duct. In doing so, the spermatozoa mature and are concentrated. The pathway out of the scrotal area is through the deferent duct.


The purpose of the scrotum, vaginal tunics, and spermatic cord (deferent duct, pampiniform plexus, and cremaster muscle) is to protect and maintain spermatogenesis at a temperature slightly lower than body temperature. The testes are raised or lowered, according to ambient temperature, by the cremaster muscle. There is a counter current vascular system that allows the testes to be at a lower temperature than body temperature; the pampiniform plexus assists this process. The pulsatile nature of arterial blood flow is altered to form a continuous and lower pressure system. In addition, the scrotal skin, which is thin, often hairless, and in most species has abundant apocrine sweat glands, helps to maintain a lower testicular and epididymal temperature. The vaginal tunic, which is an outpouching of the peritoneum, allows for free movement of the testes within the scrotal sac. The scrotum is composed of skin, dartos muscle, and scrotal fascia. It is fused with the parietal layer of the vaginal tunic.



Cell Types


The functions of the male reproductive system are the production of testosterone and the production and transportation of spermatozoa. Spermatozoa are formed from germ (stem) cells by a process of spermatogenesis. Spermatogenesis occurs in three stages: the proliferative, meiotic, and spermatogenic stages. The proliferative phase involves the mitotically active spermatogonia. They are present at the periphery of the seminiferous tubules on the basement membrane. The second phase is the meiotic phase, in which spermatocytes are formed. In the spermatogenic phase, spermatids and finally spermatozoa are formed. Spermatozoa have a head, body, and tail. The head contains the nucleus and an acrosome, which contains enzymes required for the penetration of the zona pellucida. The body or midpiece contains mitochondria, and the tail is a flagellum.


Sertoli cells provide support, nutrients, hormones, and cytokines to permit spermatogenesis. During spermatogenesis, the cells pass into a region that is separated from and external to the immune system of the body. The barrier is called the blood-testis barrier, and it is maintained by the Sertoli cells (Fig. 19-1). Control of spermatogenesis is achieved through a combination of both central (luteinizing hormone [LH] on the interstitial endocrine cells and follicle-stimulating hormone [FSH] on Sertoli cells) and local (paracrine and autocrine molecules, including testosterone) factors, and there is considerable crosstalk between germ cells, Sertoli cells, and interstitial endocrine cells. Local modification of spermatogenesis is achieved through increased or decreased apoptosis at any stage of development. Many of the disorders and conditions that affect spermatogenesis increase or decrease the apoptotic rate.



The cells lining the various ducts, including the rete tubules, efferent ductules, and epididymides, are epithelial cells that have a variety of functions, in addition to being a barrier. Absorption, phagocytosis, and secretion are all part of their physiologic role. Movement of spermatozoa along these ducts and tubules is achieved through smooth muscle contraction and the cilia.


In the accessory genital glands, storage of spermatozoa (particularly in the ampulla, where present) and secretion of various substances are the major roles for the epithelium of these glands. From the pelvic urethra and through the penile urethra, the lining cells are urothelial in type.




The Penis and Prepuce


There is considerable structural difference between the penis and prepuce of the various species. In prepubertal animals, the prepuce is attached to the penis, but they become separated at sexual maturity. The penis of the horse is erectile and is located within a prepuce that produces a thick, waxy material called smegma. Ruminants and pigs have a long fibrous penis that has some erectile tissue. To accommodate a penis of sufficient length, there is a series of bends called the sigmoid flexure, and there is a retractor muscle to hold the penis in the prepuce. There is an extension of the urethra in small ruminants that is called the vermiform appendage or the urethral process. During ejaculation, this appendage spins and sprays semen onto the cervix. The glans of the penis of the boar has a corkscrew shape that allows it to insert into the cervix. The penis of dogs and to a lesser extent cats is erectile and has an os penis. The cat has projections of penile epithelium called spines or barbs on its penis, and they are testosterone dependent.



Function


The overall function of the male reproductive system is to provide genetic material to the female for combination with female genetic material to produce an offspring with a combined and hopefully better genetic makeup. This is achieved by several separate areas—the scrotum and contents, accessory genital glands, and the penis and prepuce.



The Scrotum and Contents


The testes are the location of preparation of genetic material for transfer to the female. One-half of the chromosomes are produced by the process of meiosis in the seminiferous tubules in the process of spermatogenesis (see the section on cells of the male reproductive system). The testes also produce the hormone testosterone to ensure development of male phenotypic and behavioral characteristics. It also provides the signals that stimulate females to come into heat and become receptive. The testis also produces other substances for the regulation of spermatogenesis. Spermatozoa leave the testis in a high volume of fluid—the rete testis fluid—and enter the epididymis. The epididymis has the function of supporting and directing spermatozoal maturation and concentrating the spermatozoa for ejaculation. The function of the testis and epididymis depends on unique requirements, including maintenance of a temperature below body temperature, and a continuous nonpulsatile blood flow. The scrotum provides support and with the cremaster muscle in concert with the dartos muscle of the scrotal wall, thermoregulation by raising the testis and epididymis closer to the body wall. The pampiniform plexus is a countercurrent system that assists in maintaining a lower temperature, and the long and tortuous testicular artery removes the pulses of the arterial supply. The deferent duct is the conduit for taking the concentrated spermatozoa to the accessory genital glands.



The Accessory Genital Glands


The function of the accessory glands is to produce ejaculatory fluid to support, nourish, and protect spermatozoa as they are transferred to the female. The energy source of spermatozoa includes fructose produced by the accessory glands, usually the vesicular glands. Accessory genital glands also provide the fluid for territorial scent marking. The domestic species have a differing size and arrangement of accessory glands to do this. The amount and type of fluid varies according to the unique arrangements and mating behavior of the species. Coitus in ruminants is a rapid event, and they produce a small and highly concentrated ejaculate that is deposited around the external os of the cervix. On the other end of the scale are pigs, where coitus takes about 20 minutes, insemination is intrauterine, and the ejaculate is high volume (up to 500 mL). Pigs have large vesicular glands that produce a watery fluid and large bulbourethral glands that produce a viscous mucoid product. The prostate of the dog is the only gland, and it provides all the seminal fluid. All species except the dog and pig have ampullae of the deferent ducts; these provide secretion and a storage site for spermatozoa.




Responses to Injury


Injury to the male reproductive system comes in many different forms, and there are many potential targets, including the pituitary and endocrine control, interstitial endocrine cells, Sertoli cells, spermatogenic germ cells, and the various ducts. Apart from the obvious redundancy of having bilateral systems, the male reproductive tract has very little functional reserve and cannot undergo compensatory change to any significant degree. Some testicular compensatory hypertrophy is possible and is discussed later in this chapter.


The formation of spermatic granulomas (Fig. 19-2) is one of the most dramatic and important responses of the male reproductive system to injury. Spermatic granulomas occur with rupture of a duct; spermiostasis and spermatocele are the usual preliminary stages. Spermatozoa are “foreign” to the body. Immunity to spermatozoa with the formation of antisperm antibody is a well-recognized phenomenon. The cell wall constituents and the high chromatin content make them resistant to degradation. Any injury that exposes spermatozoa to the tissue of the body results in severe inflammation, mostly of a granulomatous type. This can be a foreign body type response, an immunologic response, or both. The inflammation produced is usually chronic and results in severe scarring, which further obstructs tubules and ducts, leading to even more inflammation so that it becomes self-perpetuating. It is therefore critical to prevent such injury.



Injury to the testis can be the result of a primary attack on a target cell or may be secondary to interruption of hormonal regulation, whether systemic or local. The endpoint of an injury can therefore be far reaching. Regardless of the primary target, most injurious events result in germ cell degeneration and depletion. Germ cells are sensitive, but Sertoli cells are relatively resistant to injury. As a result, severe injury often results in seminiferous tubules containing only spermatogonia and Sertoli cells. As Sertoli cells degenerate, they become vacuolated and swollen. Exfoliation of normal germ cells can also occur. The spermatogenic epithelium responds to injury by increasing or decreasing apoptosis, resulting in spermatogenic arrest or a complete failure of spermatogenesis. As long as spermatogonia remain, spermatogenesis can restart. Failure of release of spermatozoa is an early indication of degeneration. The formation of multinucleated spermatid giant cells and phagocytosis of spermatozoa by Sertoli cells occur.


A major effect of injury to interstitial endocrine cells is the failure of the release of testosterone. This can effectively stop spermatogenesis by increasing apoptosis and by inhibiting maturation of spermatids. Direct damage to spermatozoa can affect motility and fertilizing capability. Recovery from injury, while taking time, is achieved by restarting spermatogenesis from the relatively resistant spermatogonia.


The testis is a specialized immunologic environment and has a reduced immune responsiveness, no doubt because of the importance of not developing an immunologic response to germ cells. Unfortunately, if an inflammatory response does occur within the testis, it is likely to be sustained.


Injury to the epididymis can have permanent and devastating effects. Injury affects not only the functions of the epididymides—including maturation and storage of spermatozoa, resorption of fluid, and secretion of materials—but severe injury also results in inflammation. Any constriction of the epididymal duct results in spermiostasis, potential rupture, and the formation of spermatic granulomas. Because the epididymis is very limited in its responses, alteration to the structure and function of the epididymis is often permanent and affects fertility in a dramatic fashion.


Injury to the accessory genital glands is not common, and they can recover, often with a reduced function. Functional reserve is often sufficient to maintain fertility.


The peritesticular tissues, in particular the vaginal tunics, are also prone to injury from peritoneal reactions secondary to epididymal disease or from a direct penetrating injury. The reaction of these tissues is identical to that of the peritoneum, and as such, fibrosis and adhesion are a common response. Adhesion can limit the movement of the testes and alter its ability to thermoregulate.



Portals of Entry


There are four main portals of entry of infectious and injurious agents to the male reproductive tract (Box 19-1). They include direct penetration and injury, ascending infection, hematogenous localization, and peritoneal spread.



The external location of the penis, prepuce, and scrotum makes them prone to direct penetrating injury and to blunt force trauma. Surprisingly, this is a relatively rare occurrence.


Ascending infection is relatively common. It occurs sporadically in adults but curiously is particularly a problem in pubertal animals when hormonal changes make the system more prone to infection from bacteria. This pubertal change was shown for Actinobacillus seminis and Histophilus somni, which are resident flora of the prepuce of sheep. The accessory genital glands in particular are targets, but there can be further ascension to the epididymis. It is exceedingly rare, because of the long length of the epididymis, for the testis to be involved in ascending infection. The male reproductive tract is also a target of pathogens that are spread by sexual activity. Spread from females or in some circumstances from other males is well recognized.


Hematogenous localization is a recognized portal of entry by specific pathogens, such as the various Brucella. The epididymis and the accessory genital glands are the main targets.


The vaginal tunic is an outpouching of the peritoneal cavity and any process affecting the peritoneum, whether infectious or neoplastic, affects the peritesticular tissues.



Defense Mechanisms


The male reproductive tract, and in particular the internal genitalia, is so exquisitely sensitive to injury that it is extremely important to prevent rather than respond to injury. The combined effect of the high antigenicity of spermatozoa and the exceedingly long and very narrow duct system means that there is little tolerance for inflammation, necrosis, or other injurious situations. Much of the reproductive system relies on isolation for protection and the prevention of infection or injury.



Innate Immunity


There are multiple factors that prevent infection and injury to the vulnerable tissues. The testes and epididymides are hidden from the external environment by their intrascrotal location and by the extremely long and narrow tube that connects them to the outside world. The thin luminal diameter and extreme length of the deferent duct makes ascending infection unlikely. There is almost continuous flow of fluid along the deferent duct and the epididymis, thus the flushing action is protective. Even the accessory genital glands are protected by the flushing action of urine and by the long length of the urethra in species, such as ruminants, and the pig.


Testicular and epididymal fluid has antibacterial properties. The high chlorine content may be partially responsible. Antimicrobial proteins in seminal plasma are numerous and include bovine seminal plasmin, lactoferrin, β-defensins, and the antibacterial CXC chemokine granulocyte chemotactic protein-2/CXCL6. Some of these are acquired in the epididymis, where they are bound to spermatozoa. There are also numerous cytokines normally produced in the tract. Epithelial cells of the reproductive tract have physical barrier proteins, including mucin, that prevent infection, and Toll-like receptors to stimulate inflammation.


Nonspecific cellular defenses are relatively few. Neutrophils are not normally present in seminal plasma but can infiltrate rapidly if required. Macrophages are present within tissue and particularly within the testes, where they are recruited and maintained by the interstitial endocrine cells. Their presence inhibits the immune response; the cell-mediated responses, such as natural killer cells, lymphocyte-activated killer cells, and cytotoxic T lymphocytes, are inhibited as part of immune privilege and tolerance.



Adaptive Immunity


Much of the reproductive tract can produce an adaptive immune response if called on to do so. Where it is important is in the more distal portions of the tract, particularly the accessory genital glands and the prepuce. Unfortunately, development of an adaptive response in the testis and the epididymis is often “too little, too late.” Also, development of adaptive responses in the testis is inhibited by local immunosuppressive factors. This does not, however, prevent adaptive immunity from developing in the testis. The epididymis and deferent duct do not have a developed mucosal immune system, but there is evidence that such a system exists in the accessory genital glands, particularly the ampulla and bulbourethral glands. When infection occurs, local immunity and transfer of serum immunoglobulin is present. Preputial immunity is also mediated by local humoral and cellular mechanisms. Immunoglobulin G (IgG)- and IgA-based systems are present. Much less is known of cell-mediated immune mechanisms in the male reproductive tract.


Using local immunity to protect against infectious disease, particularly those important sexually transmitted diseases, has had little success. Response to vaccination has been variable with some individuals having protective immunity, particularly with Campylobacter fetus infection in bulls. Systemic immunity to reproductive disease has also been of variable effectiveness. Although protecting against systemic infection, challenge to the reproductive tract has in some instances increased the response to the infection and caused more damage than would normally occur.



Inflammation


In general terms, inflammation of the male reproductive tract is similar to that of other systems. What is unique about the male genital tract is inflammation to spermatozoa. Spermatozoa and germ cells outside the blood-testis barrier are antigenic. There are also antigenic components within seminal fluid. Spermatozoa have antigens that attract immune cells and also nonspecifically bind immunoglobulin. These reactions can have a minimal effect on the tissues directly and act by agglutinating spermatozoa or by opsonization. In some instances, the effect is much more dramatic and immunization against spermatozoa can result in a severe inflammatory response. This inflammation can be local or spermatozoa can be “attacked” in those areas in which the tissue-spermatozoal barrier is the weakest. In many species, this is the region of the efferent ductules and the epididymis. This so-called autoimmune reaction to spermatozoa can be experimentally created, but a clinical correlate is infrequent. Local effects, however, are much more recognized. Direct damage to testicular parenchyma can result in granulomatous inflammation centered on the seminiferous tubules, the so-called intratubular orchitis. Where spermatozoa are exposed to the tissues of the body, the reaction is that of granulomatous inflammation. Macrophages and multinucleate giant cells are found adjacent to spermatozoa (see Fig. 19-2, C). Initially at least, CD4+ T lymphocytes are abundant. Immunoglobulin-producing cells, particularly IgG-containing cells, are found. Granulomas are formed with the characteristic appearance of layers of epithelioid macrophages with multinucleate giant cells and then lymphocytes and plasma cells with a surrounding of fibrous tissue. In advanced cases, inspissated spermatozoa are found within a fibrous capsule. The production of a fibrous capsule and resultant contraction leads to further obstruction to the various adjacent ducts and tubules, with the result that additional spermiostasis, spermatocele, and spermatic granuloma formation continues. This inflammation therefore has devastating effects on fertility. Further complications occur if spermatozoa are released into the cavity of the vaginal tunics because a severe periorchitis develops and results in fibrosis and the lack of ability to adequately thermoregulate the testes.



Disorders of Domestic Animals (Horses, Ruminants [Cattle, Sheep, and Goats], Pigs, Dogs, and Cats)


There are many different ways to approach disorders of the male reproductive system (see Appendix 19-1). Each approach has its own advantages and disadvantages. Some of the disorders affect more than one region, yet there are many disorders that have a primary manifestation in one anatomic location. Approaching disorders from a pathogenetic viewpoint is logical; however, it does not always account for clinical relevance or assist in the correlation between clinical signs and prognosis. Disorders are approached based on their anatomic location: scrotal contents, accessory genital glands, and the penis and prepuce—this approach is more clinically relevant. Before doing so, it is prudent to examine disorders of sexual development (DSD) because they fall in a distinct category.



Disorders of Sexual Development


There are a large number of anomalies of the male reproductive system (Box 19-2). Some have clinical relevance and others do not. Differentiating between these is very important. Some of the anomalies represent the most common disease of a particular species. Where this is the case, the disease is discussed under disorders of a particular anatomic location because this is the most clinically relevant place. We have attempted to divide the various anomalies into those that are major and minor based on effects on fertility and on the future breeding potential of the animal. Some anomalies have a genetic basis and such individuals should not be used as a stud animal, even though the animal may still be fertile.




Male Embryology


Normal males have an XY chromosomal sex. The differentiation of the bipotential fetal gonad to a testis depends on the presence of a gene—the sex-determining region of the Y chromosome (SRY) that codes for the testis-determining factor and on other genes that cause the germ cells to go into mitotic arrest. Supporting cells become the Sertoli cells, the steroid-producing cells become the interstitial endocrine cells (Leydig cells), and the mesenchyme develops the appearance of a testis. Further development requires the activation of many other genes that are not on the Y chromosome. The expression of SRY occurs briefly in the somatic cells of the indifferent gonads (or genital ridges). Because expression ceases shortly before Sertoli cells can be recognized, it is proposed that the functional gene product of SRY influences other genes, such as SOX9, that ensure the differentiation and maintenance of Sertoli cells. SOX9 is upregulated in XY individuals just before gonadal differentiation. Sertoli cells signal the other supporting cell precursor lines to differentiate along the male pathway. Early in sex differentiation, the embryo has a double set of ducts. The paramesonephric (Müllerian) ducts are female precursors, arising by invagination of the celomic cavity. The mesonephric (Wolffian) tubules and ducts are male precursors, arising from the primitive kidney, the mesonephros. The rete testis and efferent ductules are derived from mesonephric tubules. There are about 20 efferent ductules, although the number varies with species. The epididymis is derived from the part of the mesonephric duct within the mesonephros. The deferent duct, ampulla, and vesicular gland are derived from the distal part of the mesonephric duct, outside the mesonephros (Fig. 19-3).



After germ cells migrate from the yolk sac and the testes develop in the tissue of the genital ridge, the testes produce two hormones. Sertoli cells secrete the polypeptide hormone anti-Müllerian hormone (AMH, previously called Müllerian inhibitory substance) during embryonic development and at lower concentrations postnatally. AMH causes regression of the ipsilateral paramesonephric duct, indirectly through action on mesenchymal tissue. Sertoli cells stimulate differentiation of interstitial endocrine cells from the cells of the interstitium. Interstitial endocrine cells secrete the steroid hormone testosterone, which causes persistence and differentiation of the mesonephric ducts. Testosterone is likely transported down the mesonephric ducts rather than moving by simple diffusion. A third hormone, dihydrotestosterone, which is a metabolite of testosterone, is required for formation of the prostate gland, the closing of the urethral folds, and the formation of the penis and scrotum. The enzyme steroid 5α-reductase is produced by cells in the urogenital sinus, genital tubercle, and genital swellings and reduces testosterone to dihydrotestosterone. Functional androgen receptors on target tissues are necessary for androgen-dependent differentiation and growth. Species differences exist in whether the production of testosterone by interstitial endocrine cells is under the control of gonadotropin produced by the fetal pituitary gland or the placenta. Fetal interstitial endocrine cells are replaced by postnatal interstitial endocrine cells, which are relatively quiescent until puberty. The production of testosterone is regulated by luteinizing hormone (LH), which is under the control of gonadotropin-releasing hormone (GnRH) from the hypothalamus. Also, follicle-stimulating hormone (FSH) is controlled by GnRH; FSH is produced by the anterior pituitary gland. FSH regulates the activity of Sertoli cells and can thus influence AMH production. Sertoli cells stimulated by FSH produce a glycoprotein, androgen-binding protein, which fosters high testosterone concentration around the germ cells for the progression of spermatogenesis.


The external genitalia form when the genital tubercle is masculinized by the presence of androgens. Elongation of the tubercle forms the phallus; opposing urethral folds form the penile urethra; and the genital swellings fuse to form the scrotum.



Testicular Descent


The testes and epididymides undergo descent from their original location to the scrotum. There are three main phases in testicular descent: the abdominal translocation, the transinguinal migration and the inguinoscrotal migration. The developing gonads are held in place by cranial and caudal suspensory ligaments. The caudal ligament, the primitive gubernaculum testis, attaches the developing testis to the site of the inguinal canal. It develops into an intraabdominal and extraabdominal part that protrudes into the scrotum. Evagination of the peritoneum forms the inguinal canal and the vaginal tunic.


With the abdominal translocation phase particularly, stimulation of gubernaculum mesenchymal cells is controlled in rodents by the insulin-like peptide (INSL) hormone, INSL3. The receptor for INSL appears to be GREAT/LGR8. Other molecules are likely involved. The subsequent enlargement of the gubernaculum and progressive weakening of the cranial suspensory ligament anchors the testis so that with fetal growth, the testis retains its position near the inguinal canal.


Little is known of the transinguinal phase, apart from the lack of involvement of testosterone or INSL3. Dilation of the inguinal canal by the gubernaculum and then intraabdominal pressure is involved with movement of the testis through the inguinal canal to bring the testis and epididymis into a subcutaneous location. The third and inguinoscrotal phase of testicular descent is mediated by the hypothalamopituitary-induced production of gonadal androgens. Having said this, domestic animals with failure of testicular descent into the scrotum seldom have a deficiency of testosterone or a lack of the androgen receptor. The genitofemoral nerve and calcitonin gene–related proteins or binding sites are involved in rodents.



Major Anomalies


The most common and important major anomaly of the male reproductive system is failure of testicular descent or cryptorchidism. Testicular hypoplasia and segmental aplasia of the epididymis are a close second. These disorders and conditions are discussed further in the section on Disorders of the Scrotum and Contents. Much less common, but nevertheless important, are other DSD.



Disorders of Sexual Development: Errors of chromosomal, gonadal, or phenotypic sex are usually manifested by abnormalities in sexual dimorphism. Many of the abnormalities result in a female phenotype and are mentioned in more detail in Chapter 18. The concentration here is on those disorders that involve animals that have male gonads or are predominantly phenotypic males. One cannot always tell the underlying cause of sexual ambiguity by examining phenotype or even identifying the gonadal type. Complete definition of a DSD requires knowledge of all three components: chromosomal, gonadal, and phenotypic types.



Chromosomal Disorders of Sexual Development: Sex chromosomes can be abnormal in structure or number. Two examples of abnormal structure of the Y chromosome are deletion of the short arm and isochromosome formation (duplication of one arm and loss of the other). Affected individuals have a female phenotype and extremely hypoplastic gonads. A few cattle have been identified with an isochromosome Y. With duplication of one of the sex chromosomes in an individual with a Y chromosome (XYY or XXY), or a mosaic (as occurs with the calico or tricolor male cats), the external genitalia are male in character. Klinefelter syndrome (XXY) is discussed in the section on Testicular Hypoplasia. Chimeras, such as XX/XY, are phenotypically sexually ambiguous, and the degree depends on the relative amounts of each chromosome. Freemartins are chimeras and are discussed in Chapter 18.



XX Disorders of Sexual Development: Animals with an XX genotype, testicular tissue, and a male phenotype are called XX sex reversal individuals. They may be SRY positive or SRY negative. XX SRY-negative DSD is reported in many breeds of dogs, in goats, and in horses. Affected individuals have an ovotestis or testis. Those with ovotestes or a testis and an ovary are called hermaphrodites. Some ovotestes have an end-to-end arrangement of ovarian and testicular tissue, with clear demarcation between the two. Others have central testicular tissue with a periphery of ovarian structures. Bilateral hermaphrodites have an ovotestis on each side; unilateral hermaphrodites have an ovotestis on one side; and lateral hermaphrodites have a testis on one side and an ovary on the other. The genital tract in hermaphrodites is ambiguous and can be phenotypic male, female, or various combinations of the two, depending on the amount of hormones, including testosterone and AMH. It is assumed that XX SRY-negative individuals have a testis-determining region on another chromosome. XX SRY-positive DSD is not reported in domestic mammals.



XY Disorders of Sexual Development: There are three classifications of XY disorders of sexual development; those with disorders of gonadal development (gonadal dysgenesis, ovotestes, or aplasia), disorders of androgen synthesis or action, and miscellaneous types. They can be either XY SRY-positive or XY SRY-negative. XY DSD are identified in many species, including dogs and horses.


XY SRY-negative individuals usually have primitive and undifferentiated gonads, called gonadal dysgenesis, and a female phenotype. Their classification is therefore XY SRY-negative, gonadal dysgenesis DSD. XY SRY-positive individuals with a female phenotype usually have testes and are called male pseudohermaphrodites (Figs. 19-4 and 19-5). The differentiation of the genital tract can be slightly or greatly abnormal. In many cases, the mechanism for the abnormal differentiation is unknown, but there are well-recognized syndromes in which the underlying pathogenesis is known. Three such syndromes are persistent Müllerian duct syndrome (PMDS), androgen insensitivity, and steroid 5α-reductase deficiency.




PMDS is a rare disorder of AMH production or function. AMH can be absent or present in affected humans; the syndrome can be a result of either a mutation in the AMH gene or the AMH receptor. In animals, the syndrome is described in miniature schnauzer dogs and basset hounds with an autosomal recessive mode of inheritance and in a goat with an unknown mode of inheritance. Affected dogs have XY (or XXY) chromosomes and externally are normal males, with the common exception of unilateral or bilateral cryptorchidism. The testes, however, are attached to the cranial ends of uterine horns. When a testis has descended into the scrotum, the uterine horn passes through the inguinal ring. The deferent duct can be found microscopically within the myometrium. The cranial vagina and the prostate gland are often present. AMH is present in the testes of normal male dogs up to 143 days of age. AMH is present in the testes of young affected dogs also and is bioactive. A mutation in the structural gene for the AMH receptor results in AMH resistance in PMDS-affected dogs. Dogs with unilateral or bilateral scrotal testes can be fertile. Affected dogs may develop Sertoli cell tumor, hydrometra, and pyometra. Testicular abnormalities in PMDS, such as reduced spermatogenesis and tubular sclerosis, could be attributable to cryptorchidism. Cryptorchidism could be the result of interference with the MIS-controlled first phase of the function of the gubernaculums, the phase in which the testis migrates to the inguinal area.


Deficiency of 5α-reductase type 2, inherited as an autosomal recessive trait in humans, has not yet been documented in animals, but in all likelihood, it does exist. The enzyme converts testosterone to dihydrotestosterone, which is required for the masculinization of the urogenital sinus, tubercle, and genital swellings. Without dihydrotestosterone, these structures become caudal vagina, vestibule, clitoris, and vulva. Internally, mesonephric structures (deferent duct, epididymis) develop. The testes are likely to be retained.


Androgen receptor disorders are becoming increasingly recognized. Most cases are caused by a mutation in the androgen receptor gene, which is located on the X chromosome and thus in a single copy. Hundreds of mutations have been identified in other species, and the effects range from complete androgen insensitivity with female external genitalia (testicular feminization) (see Fig. 19-5) to mild male pseudohermaphroditism. The testes produce testosterone, but the stimulation of the mesonephric system is not normal because of defective androgen receptors. The normal androgen receptor has a hormone-binding and a DNA-binding domain; once activated by androgen, the domain changes shape and is able to bind to specific DNA sequences and regulate the transcription of other specific genes, leading to normal male differentiation. In humans with androgen insensitivity, the gene is rarely deleted, but numerous point mutations in the receptor gene have been identified, mostly in the hormone-binding and DNA-binding domains. Whether the result is partial or complete androgen insensitivity depends on the location of the mutation and the change in function of the receptor. Dihydrotestosterone binds to the androgen receptor with greater affinity than that of testosterone, and the receptor, when it acts as a transcriptional factor, might interact with different genes other than the testosterone-bound receptor. In domestic animals, complete androgen insensitivity is described in the equine, bovine, and feline species. The testes are often cryptorchid and are in the inguinal area. The first and second phases of testicular migration is normal. The inguinoscrotal third phase, which is under the control of androgens, does not occur. AMH produced by the testes causes regression of the paramesonephric ducts. External genitalia are female in complete androgen insensitivity, with a cranial blind end to the vagina, and neither the paramesonephric nor mesonephric ductal system is present.


Cryptorchidism is an XY SRY-positive DSD but is examined in detail as a separate entity in the discussion of the testis in the section on Disorders of the Scrotum and Contents.



Segmental Aplasia of Mesonephric Duct Derivatives: Segmental aplasia of the structures of mesonephric ductal origin (epididymis, deferent duct, ampulla, or vesicular gland) can involve any of the structures, but it most commonly involves the epididymis alone (Fig. 19-6) and less commonly other structures. Segmental aplasia is reported mainly in the bull and most commonly involves the body and tail of the epididymis and is unilateral. Its inheritance is thought to be autosomal recessive. Spermatozoa become impacted because the epididymal duct is blind ending; local dilation or rupture occurs secondarily, allowing escape of spermatozoa and formation of spermatic granulomas.




Ciliary Dyskinesia (Immotile Cilia Syndrome): One or more of several defects in the axoneme of cilia throughout the body and of the flagellum of spermatozoa causes ciliary dyskinesia, a rare disease identified in humans, dogs, pigs, mice, and rats. An autosomal recessive mode of inheritance is proposed. In dogs, heterogeneity of ultrastructural abnormalities of microtubule doublets and their dynein arms or central microtubules is reported. The effect on the reproductive system is immotile or hypomotile spermatozoa caused by flagellar lesions or to oligospermia (a subnormal concentration of spermatozoa) or azoospermia (no spermatozoa), presumably because of defective cilia in the epididymis and deferent duct. Because of defective cilia in the nasal mucosa, bronchial and bronchiolar mucosa, and ependyma, commonly associated lesions are rhinitis, bronchopneumonia, bronchiectasis, and hydrocephalus. Also associated is situs inversus, but the pathogenesis of the reversal of the normal left and right orientation of organs is unclear. Female infertility is related to defective function of cilia of the uterine tube.



Minor Anomalies


There are myriad minor anomalies that are of little consequence except when they are confused with other conditions that do affect fertility. Foremost of the minor anomalies are the various cysts that occur as a result of duplication or failure of regression of embryonic ducts and tubules.



Cysts of the Male Tract: It is often difficult to identify the origin of an individual cyst or group of cysts. In many instances, anatomic location is the determining factor. Many of the cysts are simply called inclusion cysts (Fig. 19-7). These have a wall of compressed collagen, a thin inner lining of flattened cells, and a clear fluid content. They are found where mesothelial cells are trapped adjacent to a serosal surface. Inclusion cysts attached to the head of the epididymis are good examples.


Sep 17, 2016 | Posted by in GENERAL | Comments Off on Male Reproductive System
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