If the penis is injured while erect, it may swell rapidly and massively from vascular rupture and hemorrhage. Hemorrhage usually originates from the superficial penile vessels in the plexus external to the tunica albuginea.357 The stallion may be kicked during mating, or hematomas may follow breeding a mare with a tightly sutured vulva or may be induced if the mare moves suddenly during mating.358,359 Injuries can also occur during semen collection if proper techniques are not employed.
Cutaneous abrasions, lacerations, and visible hemorrhage may be present. Paraphimosis occurs when enlargement is sufficient to prevent retraction of the penis through the preputial ring.357 Edema may extend to the scrotum and interfere with thermoregulation of the testes.360 Venous thrombosis, lymphatic occlusion, excoriation, and swelling accompany chronic inflammation.357 Hemorrhage from the corpus cavernosum penis (CCP) is uncommon. Rupture of the surrounding tunica albuginea, when healed, may develop fibrous adhesions that lead to penile deviation during erection.
Immediate treatment is directed toward reducing edema and inflammation and controlling infection. Treatment is similar to that described for paraphimosis in a later section. Sexual rest is indicated until the lesions have healed.361 If treatment is initiated early and paraphimosis does not occur, the prognosis for recovery is good.357,359
The penis of bulls is susceptible to injury during mating. The vigorous thrust that accompanies copulation predisposes the penis and prepuce to excoriations, lacerations, and bruising. Rupture of the tunica albuginea (penile hematoma or “broken penis”) occurs if the penis is misdirected during copulation.362 Penile hematomas most commonly occur in young, sexually aggressive bulls. Injuries occur when these bulls attempt to breed heifers or cows that are not receptive, when females falter or collapse under the weight of the bull, or when the bull slips because of poor footing.358 During copulatory thrusting in which the penis is bent, the tunica albuginea ruptures on the dorsal or dorsolateral surface of the penis opposite the attachment of the retractor penis muscle. Presumably, CCP pressure rapidly increases as the functionally closed system is compressed during bending to rupture the tunica albuginea. Experiments with fresh postmortem specimens indicated that a CCP pressure of 1180 to 1720 psi was required to rupture the tunica albuginea. Tearing virtually always occurred at the site described in naturally occurring cases. Mean peak CCP pressure recorded during normal coitus (275 psi) occurs when cavernous spaces fill with a relatively small volume of blood, perhaps as little as 110 mL.360 Blood escapes from the CCP into the surrounding tissue.357 The size of penile hematomas may be related to the number of repeated trials made by the bull before cessation of attempts at mating. Larger hematomas restrict full retraction of the penis and result in prolapse of the prepuce from the sheath. Secondary preputial injury is common.357
Diagnosis of penile hematoma is made based on the presence of a swelling immediately cranial to the scrotum. Initially it is soft, fluctuant, and painful, and becomes firm as clot organization and fibrin formation progress.358 The main differential diagnosis is extensive preputial laceration. If a distance of more than two handbreadths is present between the scrotum and the enlargement, the swelling is more likely to be a preputial laceration. Other differential diagnoses include rupture of the urethra, abdominal hernia, and chronic, fibrous adhesions. Dysuria usually does not occur in conjunction with penile hematoma. Other signs of urethral rupture or blockage, such as extensive preputial cellulitis and “water belly,” elevated blood levels of urea nitrogen and creatinine, and tissue necrosis do not occur. Abscess formation of penile hematomas sometimes occurs. A soft, fluxuant center is characteristic of an abscess. Occasionally, differentiation between blood clot and abscess may be difficult. An aseptic tap can be done to determine the character of the fluid, but the risk of inducing an abscess in a sterile hematoma is great and a tap should be used only as a last diagnostic resort or just before surgery.
If penile hematoma has been present for longer than 2 weeks, fibrous adhesions may form that prevent penile extension. Adhesions are frequent sequelae of abscesses, and have also been reported to occur secondary to infiltration of local anesthetics to block the dorsal nerves of the penis.358 Another sequela is the development of venous shunts that communicate between the CCP and either the peripenile vasculature or the corpus spongiosum penis (CSP).357,363 Such vascular shunts result in rapid drainage of blood from the CCP and impotence caused by failure to achieve or maintain full erection. If the dorsal nerves of the penis are damaged, sensation of the distal penis is lost or deficient and results in failure of the bull to successfully seek out the female’s vagina and/or ejaculate. Organization of the portion of the blood clot (thrombosis) within the body of the CCP may result in functional blockage of engorgement of the more distal cavernous spaces, preventing full erection.
Treatment of penile hematomas should be aimed not only at restoring the bull to usefulness, but also at preventing recurrence. Approximately 50% of bulls with hematomas that are treated conservatively (i.e., nonsurgically) are reported to return successfully to breeding.357 Some theriogenologists feel that small hematomas (less than football size) do not require surgery.364 However, Auburn University faculty report that surgical intervention is required to optimize chances of full recovery. Surgical correction has the advantages of (1) removing the blood clot before extensive fibrous adhesions develop, (2) permitting removal of blood clot from within the body of the CCP itself, thereby reducing the chance of blockage of cavernous filling, and (3) suturing the tunica albuginea, which should reduce the chance of recurrence of the condition after return to service and the likelihood of development of vascular shunts that will prevent complete filling of the CCP. Surgical intervention is not recommended before coagulation of the extravasated blood. Once significant fibrin formation is present, the prognosis for successful correction is greatly reduced and should be attempted only in valuable bulls.357
Additional recommendations before electing surgical intervention include extending the penis manually. Cases in which the penis can be extended from 6 to 8 inches or more beyond the sheath orifice, and in which penile sensation remains, carry a better prognosis.365 If engorgement of the distal penis does not occur after careful stimulation with the electroejaculator, blockage of the CCP should be suspected and reduces the prognosis. Finally, cases with abscesses are poor risks because severe restrictive adhesions usually develop.357
Regardless of whether surgical or conservative intervention is selected for a penile hematoma, the bull should be treated with high levels of systemic antibiotics in an attempt to prevent abscess formation. Penicillin is a good choice because abscesses are usually caused by A. pyogenes., Postsurgical complications are much the same as those that may occur without surgery, but these adverse consequences are reported to occur less frequently after surgery. Bulls should not be returned to service for 2 to 3 months after treatment.357,358
Adhesions of the penis and prepuce caused by trauma are uncommon in adult small ruminants. The penis does not separate from the prepuce until puberty and cannot be extended before this time (4 to 5 months of age in bucks).366 Most traumatic lesions of the penis or prepuce in sheep and Angora goats are from shearing injuries.264 Blockage of the urethral process by calculi can cause necrosis and sloughing of tissue that may extend into the glans penis.367 Fighting among horned animals may result in injury to the external genitalia, including the penis. In dairy goats the intersex condition can result in congenital malformation of the penis and prepuce (hypospadias).368
Stenosis of the preputial orifice prevents extension of the penis. The defect is likely to be a sequela to an injury that results in cicatrix formation, but may rarely be congenital.357,358 Tumors (such as melanoma or SCC) or Habronema, granulomas may encroach on the preputial cavity, thereby preventing penile extension.369
Acute posthitis often accompanies injuries to the prepuce or infections such as equine coital exanthema and dourine.357,358 Edema is common with acute posthitis, particularly after trauma. Gravitational effects typically worsen the preputial edema, which may induce prolapse of the external prepuce, trapping the penis in the swollen internal prepuce with a constricting preputial ring.357 Cicatricial scar formation may follow, narrowing the diameter of the preputial orifice. Transpreputial ultrasound examination may be of benefit in differentiating tumors or abscesses from inflammatory edema or hemorrhage. Containment of the penis within the prepuce causes preputial urine accumulation, worsening balanoposthitis and secondary bacterial infection. The extended chronic inflammation leads to cicatrix formation with phimosis.370
Preputial edema can be relieved by administration of diuretics and exercise. Application of crushed ice in plastic bags or preputial immersion in cold water may reduce inflammatory edema if performed soon after injury. Subsequently, emollient antibiotic preparations and hydrotherapy can be used to massage injured tissues and reduce edema. Systemic antibiotics and nonsteroidal antiinflammatory drugs are indicated to control secondary infection and inflammation. Sexual rest is indicated until the lesions have healed.361
A biopsy can be procured from encroaching tumors to identify cell types and improve prognostic capability.361 Cicatricial scars can sometimes be successfully removed surgically. Once inflammation and infection are resolved with local or systemic antibiotic and antiinflammatory drug treatment, incision of the ventral aspect of the preputial orifice (preputiotomy) may be necessary to enlarge the opening sufficiently to permit penile extension.371 Large tumors or granulomas of the prepuce can sometimes be successfully removed surgically if sufficient elastic and membranous tissue remain to permit normal penile extension and retraction.361 The prognosis for return to breeding soundness, however, is guarded when surgery must be performed. Postsurgical adhesions may develop that result in continued phimosis or penile deviation. In cases of habronemiasis, treatment with systemic insecticides or ivermectin may be indicated to kill remaining parasitic larvae.369 Congenital abnormalities can seldom be corrected surgically.
Trauma to the prepuce involving the elastic lamellar layers may prevent the required flexibility of the prepuce to permit penile extension. Breed predisposition to preputial injuries corresponds to genetic differences in pendulousness of the sheath and development of the muscles responsible for retraction of the prepuce. The polled gene is linked to weak or failed development of the preputial muscles, leading to habitual preputial eversion, which predisposes to injury. Brahman-blooded cattle have the added predisposition of a loose, pendulant sheath. With their tendency to partially evert the preputial membrane through the sheath orifice, they are at greater risk for damaging the prepuce accidentally than those breeds of cattle in which the sheath is held in close apposition to the abdominal wall.357,358,372
Inability of the bull to extend the penis most commonly follows injury to the penis and prepuce that culminates in strictures or adhesions that restrict normal penile movement.357,358,373-376 Other causes of phimosis include congenital anomalies such as a short penis, a short retractor penis muscle, and developmental abnormalities of the reproductive tract such as occur in pseudohermaphrodites.358,374
The more common preputial injuries are contusions, abrasions, lacerations, and frostbite. When the injured prepuce can be retracted, the injury may not be suspected unless hemorrhage is noted from the sheath or the bull is observed having difficulty during breeding. Although minor injuries may spontaneously resolve, more extensive injuries commonly progress to abscess formation and fibrous stricture formation.357,364,375,376 Extension and examination of the penis may result in further injury if the case is complicated by phimosis. In such cases an attempt to extend the penis to facilitate examination is contraindicated because forcibly stretching the prepuce will extend the laceration and spread infection to uncontaminated areas.357
Treatment of preputial injuries in the bull may be either medical or surgical. With few exceptions, such as fresh avulsive lacerations in the fornix area, surgical intervention carries a better prognosis when medical treatment is first carried out to control inflammation and infection.375 The healing leaves more normal tissue to be identified and salvaged during surgery. In cases in which the injured prepuce is retracted into the preputial cavity, digital or speculum examination can be done in an attempt to locate lesions and determine the extent and depth of tissue involvement. Systemic administration of antibiotic is necessary to reduce the incidence of abscess formation preoperatively, and antibiotic should be administered through the surgical and postsurgical periods if surgery is elected. When the injured prepuce remains prolapsed in presented bulls, the first consideration is to attempt to return the prepuce to the preputial cavity.357,375 The exposed epithelial covering of the prepuce is easily injured and becomes quite edematous and friable because of its pendent location. Hydrotherapy for 20 to 30 minutes may be helpful in cleansing the exposed prepuce and reducing edema. After the prepuce is gently cleansed and the degree of patency of the lumen is determined, a protective emollient preparation is used to massage edematous swelling upward out of the prolapse.375 Massage for 15 to 30 minutes may be required to reduce swelling sufficiently to permit the prepuce to be returned to the preputial cavity. If the prolapsed prepuce can be returned to the sheath, a retention technique should be used to prevent reprolapse. With the prepuce in place, a tube can be inserted just beyond the swollen internal portion of the prepuce to avoid urine retention. The tube is taped in place at the external preputial orifice. Tape should not extend past the proximal end of the tube, or urine retention and migration into peripreputial tissue will occur. If this technique will not retain the prepuce, a purse-string suture in the skin of the sheath orifice can be used.357 It should be tight enough to retain the prepuce but leave sufficient space for urine to pass freely. To avoid suture abscesses and stricture formation, the sheath should be clipped and prepared aseptically for suture placement, and sutures should be removed as soon as swelling and inflammation subside. If the prolapsed prepuce cannot be returned to the preputial cavity, the prognosis for correction without surgery is guarded. After cleansing as described previously, a portion of stockinette is coated in ointment and is applied over the prepuce. A diaper constructed from heavy canvas or burlap with straps and centrally located perforations for urine drainage is applied under the prepuce and tied up over the back to hold the prepuce gently next to the abdominal wall to decrease gravitational edema. It is changed daily until infection and swelling are controlled and the prepuce is either returned to the sheath or surgery is performed. Alternatively, the prolapsed portion of the prepuce can be wrapped in medicated gauze followed by application of a gentle but firm pressure wrap around a section of tubing. The pressure wrap is left in place temporarily to reduce edema, at which time the wrap is removed and the prepuce replaced into the sheath.375
Once sufficient healing has occurred the necessity for surgery is determined by extending the penis.357 Adhesions most commonly take the form of encircling cicatricial strictures that must be removed surgically. Guidelines suggested for predicting successful outcome of surgery include the following:
A minimum of 5 cm of normal prepuce should be present on either side of the surgical site, or proper unfolding may not be possible after surgery
Free prepuce remaining after surgery should be at least twice the length of the free portion of the penis, or the prepuce may be too short to permit full penile extension.Presurgical and postsurgical considerations, and surgical techniques used to correct phimosis, are described by Walker and Vaughan.357
Congenital anomalies contributing to phimosis are diagnosed based on physical examination of the entire reproductive tract. Abnormal karyotypes may be helpful in determining causes. If the penis cannot be extended with the techniques described and if evidence of injury or adhesions is not present, congenitally short penis or retractor penis muscles should be suspected.358 Accompanying history may provide information that the bull could copulate when young, but as he aged his abdomen progressively enlarged, causing the penis to be relatively of insufficient length to effect copulation.358
Phimosis is uncommon in small ruminants. It may be congenital, or acquired as a result of adhesions or preputial scarring associated with trauma or balanoposthitis. This condition is diagnosed during the physical examination and/or by observing the animal during the breeding process. If phimosis results from acute inflammation of the prepuce (posthitis), it may resolve when the preputial swelling reduces. However, the prognosis is guarded until scarring can be evaluated. Phimosis may also be congenital in small ruminants.367
When injury of the penis and the laminae of the prepuce is attended by hemorrhage and edema, paraphimosis (the inability to retract the penis into the prepuce) is likely to occur.357 Prolonged penile prolapse, caused by debility or paralysis after the use of some tranquilizers, usually culminates in extensive penile trauma.377,378 Protracted priapism (persistent erection) can lead to penile trauma and complications similar to those of penile prolapse.379 Penile paralysis and priapism are distinctly different conditions. Penile paralysis develops secondary to insufficient tone of the retractor penis muscles.380 Motor innervation of the retractor penis muscles in stallions is believed to be solely supplied by α-adrenergic fibers. When α-adrenergic blocking drugs such as phenothiazine-derivative tranquilizers are administered, paralysis of these muscles can cause penile prolapse.381 The prolapsed penis is flaccid and cannot be maintained in the retracted position.357,380 Priapism is a persistent erection without sexual arousal and is initially unassociated with penile paralysis. It develops from engorgement of the CCP with blood, and although the horse may not achieve a full erection, its penis is not flaccid.382,383 When the penis fails to detumesce, CO2 tension in the CCP increases, resulting in increased blood viscosity and subsequent venous occlusion where collecting veins join the cavernous spaces. Edematous swelling of corporeal trabeculae further reduces venous outflow, thus increasing the likelihood of irreversible venous occlusion, fibrosis of the cavernous trabeculae, and arteriolar occlusion. Disruption of the arteriovenous supply and fibrosis of the CCP prevent subsequent erections.361,384
Penile paralysis has been reported in exhausted or debilitated horses, in horses with myelitis or spinal injury, and in horses with severe injury to the penis.357,377 Traumatic inflammatory edema often results in severe swelling of preputial membranes that prevents retraction of the penis into the prepuce. The inability to retract the penis results in further gravitationally induced edema, and as the problem worsens, edematous fluid eventually oozes through the increasingly fragile penile and preputial integument. Cellulitis develops and the integument becomes thickened, inelastic, desiccated, necrotic, and irreversibly damaged.357,361 In cases of long-standing priapism, the distal end of the penis becomes cool to the touch, and the clot may become palpable in the body of the CCP as fibrin organization occurs. The organized clot may be visible on ultrasound examination.379
Prognosis for recovery becomes guarded to grave the more chronic the paraphimosis becomes. Principles of treatment are similar to those described for the bull. To maintain the penis within the prepuce, a temporary purse-string suture of heavy Vetafil can be placed near the preputial orifice. Alternatively, a padded plastic bottle from which the bottom has been removed can be used to support penile hematomas.385 After the injured penis is dressed, the bottle is placed over it and pushed back into the sheath. The bottle is held in place with straps running over the lumbar area and on either side of the scrotum up over the tail head. Voiding of urine occurs through the bottle. The apparatus should be cleaned and replaced twice daily until the penis can be retained in the retracted position. If the penis cannot be returned into the prepuce, an external support for the prolapse should be applied. Prolonged penile prolapse may result in excess gravitational pull that damages smooth muscle cells, the retractor penis muscle, and the pudendal nerves357,380; such sequelae decrease the prognosis for recovery and return to a successful breeding career. Chronic, refractory penile prolapse results in severe balanoposthitis that may require circumcision or penile amputation. Surgical penile retraction (the Bolz technique) is described by Walker and Vaughan.357
Medical treatment of horses with priapism has generally been unsuccessful.361,382 In cases of drug-induced priapism seen within 2 to 4 hours of occurrence, slow intravenous injection of 8 mg of benzotropine mesylate may cause detumescence and penile retraction to occur.386 If the animal is not seen immediately, treatment is the same as for traumatic paraphimosis. Rapid detumescence can be induced by injecting 10 mg of phenylephrine into the CCP, even in long-standing cases. However, the detumescence may be only transient. Flushing the CCP with heparinized lactated Ringer’s solution through 12-gauge needles to remove sludged blood has been recommended for horses with priapism of 12 to 24 hours’ duration that have not responded to medical treatment.361 If a blood clot forms in the CCP, the prognosis is poor and amputation may be necessary. Some stallions, if severe nerve damage does not occur, may regain the ability to breed and ejaculate when assisted with placement of the penis into either the vagina of the mare or an artificial vagina. When the stallion does not regain the ability to completely retract the penis into the sheath, continued penile trauma is likely to result in damage to the sensory nerves to the glans penis. Such horses may achieve an erection but may have difficulty both in seeking the mare’s vulva for intromission and in ejaculating. Ultrasonography of the CCP to detect cavernosal fibrosis may be useful in assessing prognosis for recovery from priapism. Prognosis for recovery is good once penile retraction occurs, but breeding should not be permitted until healing is complete.
Paraphimosis is less common than phimosis in the bull. The conditions have some common causes, but for paraphimosis the causes also include penile tumors, parasitic invasion, traumatic or spinal disease affecting innervation of structures responsible for penile retraction, inadvertently severed retractor penis muscles, and physical trapping of the penis by a constricted prepuce after injury. Penile paralysis and paraphimosis sometimes occur as a result of spinal injury or disease, and in rabies cases as well.357,358,373-376,387
Persistent exposure of the penis results in congestion, inflammation, and necrosis of the penile integument.358,373,374
Management of the prepuce has been discussed. Exposed portions of the penis should be frequently cleansed and protected by a bandage soaked in oily antibiotic preparations. The prolapsed penis should be supported close to the abdomen to reduce edema. The penis should be returned to the sheath as soon as possible and mechanically restrained if necessary. If the ability to retract the penis does not return in a few days, prognosis for recovery is poor.357
Traumatic injuries to the urethral process are usually obvious and are characterized by hemorrhage. Habronema, granulomas are firm and friable. Ulcers of the urethral process often become secondarily invaded with bacteria such as Pseudomonas, species. Parasitic lesions tend to regress during winter, but if untreated they may mineralize and result in recurrence of hemospermia during the following breeding season.388
Bacterial urethritis may be associated with hemospermia.389 Lesions can occur throughout the urethra, including the pelvic urethra in the area of the ejaculatory ducts. Diagnosis is based on demonstration of the lesions by fiberoptic examination.361 Ultrasonography and fractionation of the ejaculate may be helpful in eliminating involvement of the accessory sex glands.390
Urethral inflammation and lacerations may result in fibrous strictures.389 Strictures are often painful and may separate and bleed during urination and ejaculation. Bacteriologic culture of the urethra, urine, and semen; fiberoptic examination; and histologic examination of biopsies of lesions are helpful in making a diagnosis.5 Strictures in the distal urethra may be identified by contrast radiography of the extended penile urethra.357,389
Clinical signs of uroliths include dribbling of urine with chronic cystitis, dysuria and stranguria, occasional hematuria, recurrent colic, and a stilted, painful gait in the hindquarters. Penile protrusion is frequent or constant in cases of chronic, involuntary escape of urine.357 Diagnosis is by urinalysis, revealing the characteristic crystals, red and white blood cells, and bacteria. Urethral calculi typically restrict the passage of urethral catheters. Bladder calculi may be palpated per rectum or visualized by ultrasonography.357,388
Treatment of urethral injuries involves first removing inciting factors such as a tight stallion ring. Sexual rest is indicated while palliative therapy is given. The ability to void urine should also be established. Systemic treatment with antibiotics that are eliminated in the urine may be useful as a prophylactic measure or in cases in which secondary bacterial invasion has occurred. More severe cases of urethritis may be treated locally either by infusion of oily antibiotic preparations through sterile, rubber urethral catheters passed to the area of the seminal colliculus of the pelvic urethra, or alternatively by insertion of soluble suppositories through a perineal urethrostomy. After resolution of the urethritis, the urethrostomy is allowed to heal by granulation.389 Lacerations of the proximal urethra that result in hemospermia can be treated by perineal incision into the corpus spongiosum urethra (CSU) or by perineal corpus spongiotomy in which the CSP is incised but the incision is not extended into the urethra. These surgeries are believed to prevent stretching of the urethra when engorgement of the corpus spongiosum occurs during urination or erection. Repeated stretching is thought to prevent urethral lacerations from healing.391
Inflammation of the urethral process may respond to local antibiotic salves. Treatment of parasitic granulomas with ivermectin speeds resolution of these cases.369,392,393 Larger, nonresolving granulomas with mineralization may require surgical removal.394 The skin of the urethral process should be rolled inward when sutured to the mucous membrane to prevent eversion that predisposes it to reinjury after healing. Remaining hemorrhagic or ulcerative lesions are lightly cauterized with silver nitrate.388 More proximally located nonresolving urethral strictures, prolapsed subepithelial vessels, or ulcers can be removed surgically. Leave as much normal urethral mucosa as possible to avoid postsurgical stricture formation.389
Calculi lodged within the lumen of the pelvic urethra can be removed via perineal urethrostomy. Treatment for urethral calculi is described in the discussion of diseases of the urinary system, Chapter 34.
Urolithiasis is the primary problem affecting the urinary system that may interfere with normal function of the reproductive tract of the bull.395 It is of less importance in bulls than in steers but occasionally occurs and may result in hematuria or urethral obstruction.357,358 Urolithiasis is thoroughly discussed in Chapter 34.
In the stallion, inflammation of the glans penis (balanitis) and prepuce (posthitis) often occur together (balanoposthitis). Traumatic injury resulting in inflammation of the penis and prepuce has been discussed. Balanoposthitis may also be caused by dourine, EHV-3 infection (see Equine Coital Exanthema), miscellaneous bacteria, and parasites.359,373,374,396,397
Equine coital exanthema is caused by EHV-3.398 The occurrence of neutralizing antibodies to EHV-3 primarily in horses of breeding age suggests that spread of this infection may be primarily by genital contact.399 Typically an inapparently infected mare transmits the virus to a stallion at the time of breeding. The stallion then transmits the infection to other susceptible mares before developing clinical signs of the disease. Clinical signs in the stallion are sometimes more severe than those observed in the mare and may include systemic manifestations such as dullness, anorexia, and fever.399 Vesicles up to 1.5 cm in diameter develop first on the penis and then on the prepuce 2 to 5 days later. The vesicles progress to circumscribed pustules with raised borders and depressed centers, which slough and ulcerate.393,400 Scabs are seldom noted on penile lesions because they are rubbed off by extension and retraction of the penis during breeding.400 Some affected stallions may refuse to breed mares, whereas others breed willingly, even while extensive penile lesions are present. Healing occurs in a few weeks, often leaving depigmented spots.400
Some immunity to the virus is acquired after infection, because reinfection without recurrence of clinically apparent disease is common. It is probable that the virus remains in the genitalia in a latent form.373 Recurrent coital exanthema usually occurs in aged broodmares but may also occur in stallions.400 In stallions, recurrence within the same breeding season is uncommon. The relationship between viral recrudescence and recurrent coital exanthema in the equine is unknown but may mimic that in human genital herpes infections.
Diagnosis usually can be made on the basis of the characteristic clinical signs. During the acute stage the virus can be isolated from swabs or scrapings taken from the edge of erosions. Inclusions in lesion specimens can be confirmed by using an electron microscope to visualize typical herpesvirus particles in fluid or tissue samples. Probably the most sensitive, specific, and accurate tool for the detection of EHV-3 is the PCR assay. Demonstration of antibody titers in serum may be useful in establishing time of exposure to the virus.401
Infection with EHV-3 is self-limiting.373 Local treatment with antibiotic ointments will not speed healing but may minimize secondary bacterial infection and soreness.400 Care should be taken to avoid iatrogenic transmission of the infection (e.g., through contamination of sleeves, water, and examination or insemination equipment) to susceptible animals. Attending veterinarians may choose to refrain from breeding affected stallions until the lesions heal. One method that may be helpful in circumventing transmission of the infection while still breeding the stallion is to collect semen in an open-ended artificial vagina as soon as lesions are no longer painful. Collecting the semen as it directly exits the urethra reduces the chance of viral contamination from the penile and preputial lesions. It is imperative, however, to adhere to any breed registry restriction regarding artificial breeding.361
The external genitals of stallions harbor potentially pathogenic bacteria, fungi, and yeasts, yet balanoposthitis caused by bacterial agents is uncommon.402-404 These organisms are usually considered to be surface contaminants, and the stallion is a lesionless carrier in most instances in which venereal transmission occurs.378 Sperm motility, however, may sometimes be adversely affected by bacteria and their products in semen.403 Offensive odors may occasionally be associated with heavy colonization of the penis and sheath with Pseudomonas, species or Proteus, species.358 Documentation of a bacterial infection is dependent on serial isolation of a pathogen, preferably in large numbers and relatively pure culture.404 A single isolation of T. equigenitalis, is considered diagnostic for CEM.378 Samples for bacteriologic culture should be retrieved from the fossa glandis, free portion of the penile body, and folds of the external prepuce before washing of the genitals of a stallion presented to an estrual mare.404
If there is evidence of horizontal transmission of Pseudomonas, or Klebsiella, to mares, or if longevity of sperm is reduced in association with these organisms, the preferred method of management is to breed mares artificially with semen mixed with an antibiotic-containing semen extender.405 Antibiotic selection is based on trials comparing extended semen with and without antibiotic. Extenders containing antibiotics that control the offending bacteria and permit maintenance of sperm motility are then used to breed mares.406 Bacteria are usually not recovered after 5 to 30 minutes of incubation at room temperature.403,405,406 Penicillin G (1000 to 1500 U/mL), streptomycin sulfate (1000 to 1500 mcg/mL), polymyxin B (100 to 1000 U/mL), reagent grade gentamicin sulfate (100 to 1000 mcg/mL), amikacin sulfate (100 to 1000 mcg/mL), or ticarcillin (100 to 1000 mcg/mL) is usually the most suitable antibiotic.361 Gentamicin sulfate and amikacin sulfate should be buffered with 8.4% sodium bicarbonate solution to adjust pH to approximately neutral before they are mixed with semen extender. A suitable volume of extender can be infused into a mare’s uterus immediately before cover when natural service is necessary.405
Colonization of the external genitals with P. aeruginosa, and K. pneumoniae, can be treated by thoroughly washing the penis and prepuce, including the fossa glandis and diverticulum, daily with an iodine-based surgical scrub. The genitals are then rinsed with copious quantities of tap water with dilute disinfectants added (10 mL of concentrated HCl per gallon of water for Pseudomonas, colonization, or 40 mL of 5.25% sodium hypochlorite bleach per gallon of water for Klebsiella, colonization).407 Drying of the penis can be followed by generous application of 1% silver sulfadiazine cream. The procedure is repeated daily for 1 to 2 weeks and followed by serial cultures to determine if treatment was successful.408 The clinician should be cognizant that recolonization with these organisms may occur and that routine scrubbing and disinfection may predispose to infection of the genitals with potential pathogens by displacing commensal organisms.402
Balanoposthitis in the bull is caused by traumatic injury and infections. Whereas injury of the prepuce is more common, penile inflammation often accompanies the traumatic posthitis. A multitude of potentially pathogenic organisms inhabit the prepuce, and injuries predispose to infection particularly when deeper tissues are exposed. Pain and preputial discharge may be evident. Because of the presence of the many organisms in the preputial cavity, culture to identify a specific offending organism is likely to be misleading. When injury results in infection of the penis and prepuce, sexual rest in conjunction with local antibiotic treatment is indicated. Treatment should be performed as previously outlined for the penis and prepuce until inflammation is corrected.
Balanoposthitis unassociated with trauma has been associated with infections resulting from IBR-IPV, by tuberculosis, and by screwworm infestation.358,373,374,409 Acute lesions associated with IBR-IPV infections are numerous small pustules that progress to ulcers and erosions in a few days. Purulent preputial discharge is present, and lesions may become confluent. The prepuce and penis may become quite inflamed and swollen. Healing is commonly spontaneous and rapid, beginning in 1 week and usually complete in 2 weeks. Severe cases may take longer to resolve.409 Virus is shed from the prepuce for 2 weeks or longer, during which time venereal spread is possible. Sexual rest for 6 to 8 weeks has been recommended to prevent spread and to avoid abrasions that may aggravate inflammation.358 Enlargement of the lymphoid follicles may be present, along with a seromucoid exudate for several weeks. Histologic changes include the transient appearance of eosinophilic intranuclear inclusions in degenerating epithelial cells.373 Infusion of the preputial cavity daily may be of benefit in treatment, particularly in more severe cases. Vaccination with attenuated intranasal products has been reported as a method to prevent viral shedding into semen in bulls from AI studs.358,410 The vaccine has been infused into the prepuce experimentally and did not result in viral shedding in the semen. Because persistence of herpesvirus in body tissues is a common occurrence, recurrence of viral shedding in semen after apparent recovery may be possible. Tuberculosis of the penis and sheath apparently has not been reported in the United States for some time. It is characterized by enlarged, granulomatous lesions on the glans penis, prepuce, and sigmoid flexure that are prone to hemorrhage. Penile lymph glands may abscess.358
Balanoposthitis (also called pizzle rot, sheath rot, and ulcerative posthitis), commonly affects the penis and prepuce of intact and castrated male small ruminants.367,368,411,412 The disease is discussed in Chapter 34.
Phallocampsis, or deviation of the erect penis, is a relatively common condition in the bull. The most common cause of penile deviation is persistent penile frenulum.358 Other types of penile deviations include spiral, ventral, and S-curved deviations.357 Less commonly, preputial or penile injury may result in scar tissue formation that subsequently leads to deviation of the erect penis.357
When the penile frenulum persists, it remains connected to the ventral surface of the tip of the penis and the prepuce and causes the penis to bend ventrally during erection by preventing complete extension.413 Copulatory ability is interfered with except in some of the Zebu-influenced breeds that are endowed with a plentiful prepuce.357 Diagnosis is based on physical examination of the extended penis.
Because spiraling of the penis is thought to be a normal physiologic event that occurs in the vagina during ejaculation,414 care should be taken in making this diagnosis. Bulls affected with penile deviations often have a history of no problems in mating cows for some time, occasionally for several breeding seasons. If such bulls have been closely observed, it may have been noted that the condition did not occur on every mating attempt, but the frequency of occurrence gradually increased until bulls might require numerous mounts to successfully intromit and breed a cow in estrus.358 Penile deviations occur at full erection when the CCP is maximally distended with blood. Caution should be exercised in diagnosing this condition during erection stimulated by electroejaculation. Such erections are not considered to be entirely physiologic and frequently result in penile deviations in bulls that have no deviations under natural mating conditions. The spiral deviations that occur with use of the electroejaculator may be a result of tension exerted by the retractor penis muscles.357 Diagnosis is best based on observing occurrence of the deviation frequently in natural mating situations.
The ventral or rainbow deviation of the penis is less common than the spiral deviation and is a result of the apical ligament being too thin to support the engorged, stretched distal end of the erect penis.357 The ventral curvature may be quite pronounced, preventing affected bulls from directing and inserting the penis into the vagina of the female.
The least common of the spontaneous penile deviations is the S-shaped curvature. It primarily occurs in older bulls with an apical ligament that is short in relation to an excessively long penis.254 Penile deviations that result from adhesions that developed from penile or preputial injury are diagnosed based on physical examination.
Persistent penile frenulum is easily corrected by severing the persistent band. Owners of affected bulls should be advised of the probable genetic basis and therefore the undesirability of retaining such bulls for breeding.357 Treatment of spiral and ventral deviations is surgical.357
The most common neoplasm of stallion genitalia is SCC. Generally, it is of low malignancy.357,415 The tumor usually involves the glans penis but may also involve the shaft of the penis and prepuce and produce a fetid discharge.373,374 Large tumors may ulcerate and bleed, resulting in hemospermia. Carcinomas may resemble Habronema, granulomas, which are more common and are diagnosed by histologic examination of affected tissue.358,361 Carcinomas are usually well differentiated and surrounded by eosinophils. Necrosis and calcification may occur, but parasite larvae are usually not present373 unless secondary habronemiasis has occurred from flies feeding on the ulcerated tissue. Carcinomas may extend into the CCP or may metastasize to the inguinal lymph nodes or other abdominal or thoracic organs.373 The superficial inguinal lymph nodes lie midway between the prepuce and external inguinal ring; secondary tumors in this region often grow rapidly and develop necrotic centers with purulent sinuses that must be differentiated from bastard strangles.357
Tumors encountered much less frequently include melanoma, papilloma, angioma, lymphosarcoma, and sarcoid. Melanoma is a common equine tumor, especially of grey horses,369 and occasionally involves the penis and prepuce357,359,416 (see Chapter 40). Genital papillomas are rare in stallions but may occur on the glans or shaft of the penis. The lesions appear as multiple proliferative cutaneous growths and may become friable and result in hemorrhage during erection and ejaculation.361 The lesions are generally thought to be caused by a papilloma virus,417,418 and papilloma virus antigens have been found in cutaneous and genital papillomas.418 Angiomas and lymphosarcomas have occasionally been reported on the genitals of stallions.359 Sarcoids may involve the skin of the prepuce or scrotum357,416 (see Chapter 40).
When SCCs are relatively small and noninvasively attached to the skin, neoplasms may be successfully treated by cryosurgery or hyperthermia.419 Hyperthermic treatment (50° C for 1 to 2 minutes) appears to be most successful for SCC when lesions are small (less than approximately 2 cm). If the tumor is extensive but superficial, cryosurgery may be attempted after the tumor is debulked and hemorrhage controlled. The remaining base of the tumor is then frozen and thawed twice; healing occurs as necrotic tissue is sloughed. Successful treatment of small lesions has been reported with topical application of 5-fluorouracil.420 If removal of tumors is unsuccessful or if neoplasia is extensive, penile amputation may be necessary.357,421 If superficial inguinal lymph nodes are involved, euthanasia may be required.357
In contrast to nongenital squamous papillomas, genital forms generally are quite refractory to treatment.361 Surgical removal and autogenous vaccine administration have been tried to treat fibropapilloma of the penis of two stallions but did not effect a cure.388
Fibropapilloma is the only tumor that frequently invades the bovine penis or prepuce.373,374 The tumor may be single or multiple and usually affects young bulls. The cause is thought to be a papilloma virus antigenically similar to the virus that causes cutaneous papillomatosis in cattle.422 Frequent mounting among young bulls is thought to result in damage to epithelial surfaces of the penis and prepuce that serves as a route of entry for the virus.357,358
Small papillomas may be discovered during routine breeding soundness evaluations, but many become larger before they are discovered. Large fibropapillomas may prevent withdrawal of the penis into the preputial cavity. Fibropapillomas are pedunculated and attached at a narrow base in early cases. The surface becomes cauliflower-like and friable; hemorrhage is easily induced.
Many fibropapillomas regress spontaneously within a few months. Regression may be more likely in bulls approaching 2 years of age and usually occurs within 4 months of the appearance on the penis.422,423 Several vaccines, including autogenous preparations, have been used for treatment, but vaccines may be more successful for prophylaxis.358 Frequently, surgical removal is indicated, but the fibropapillomas may recur. If only superficial attachment is present, surgical removal is easily accomplished. Catheterization of the distal urethra before surgery is helpful in identifying its location to avoid injury. If attachment has become extensive and sessile, amputation of a portion of the distal penis may be necessary.357 Housing of young replacement bulls in individual pens, if possible, is recommended as a method to reduce the incidence of penile fibropapillomas.
Habronema muscae, Habronema microstoma, and Draschia megastoma, larvae commonly invade the urethral process, glans penis, and preputial ring of stallions.357,369 Other terms for this condition are genital bursatti, and summer sores.,373
Shallow irritations progress to irregular 1- to 3-cm granulomatous growths that may involve the entire circumference of the urethral process.358 Lesions are friable and bleed when manipulated. Stretching of the infected urethral process during penile engorgement and ejaculation may result in hemospermia.361 Pruritus associated with the lesions may be intense. Frequent micturition and dysuria may resemble urine spraying that accompanies accumulation of smegma in the urethral diverticulum (“bean”). Lesions subside during the colder months in northern areas but usually reappear and increase in size during subsequent warm weather.358 Diagnosis is made by seeing yellowish granules (calcified larvae) in the lesion and by microscopic identification of larvae.369
Hemospermia, refers to contamination of ejaculates with blood. Stallions with overt hemorrhage into ejaculates are subfertile. Erythrocytes rather than serum have been implicated for the marked depression of fertility, although the precise factor(s) involved are not known.389 A small amount of sanguineous contamination is compatible with fertility, especially if the semen is quickly diluted with a suitable extender before insemination. A disproportionate number of leukocytes to erythrocytes suggests infection of the internal genital organs. Specific causes of hemospermia include lacerations of the penis, cutaneous habronemiasis, urethritis, urethral lacerations, and infection or inflammation of the accessory genital glands,361 which are discussed elsewhere in this chapter.
Urospermia is an uncommon but perplexing disorder of breeding stallions. Affected stallions generally exhibit normal libido and mating ability, but semen becomes contaminated with urine during the ejaculatory process. The problem may be incessant or unpredictably intermittent; urination can occur at any time or continuously during ejaculation. The amount of urine ranges up to 250 mL or more.361
The underlying cause(s) of urospermia is speculative. Closure of the bladder sphincter and seminal emission are controlled by the α-adrenergic sympathetic nervous system, and a disturbance in this pathway might contribute to urospermia.424 Similarly, neuropathies that result in bladder paralysis (e.g., cauda equina neuritis or nerve damage secondary to EHV-3 infection or sorghum or Sudan grass poisoning) can create urinary incontinence that permits voiding during ejaculation. Most stallions with urospermia do not exhibit signs of a neurologic deficit.361
Gross contamination of ejaculated semen with urine is easily detected by its color and odor. Contamination with significant quantities of urine adversely affects sperm motility and fertilizing capacity. Elevated concentrations (relative to serum levels) of urea nitrogen or creatinine in semen document presence of urine in the ejaculate.361,425
Treatment options for urospermia vary, can be arduous, and are often unrewarding. Delay of semen collection (or breeding) until immediately after the stallion has voided urine may be a helpful management policy. Urination can be stimulated by administration of a diuretic drug (e.g., furosemide). Stallions may also void urine when provided access to feces of another stallion. Some stallions can be trained to urinate on command. Alternatively, the bladder can be catheterized to aid evacuation of urine before breeding, but urethritis or cystitis may result from routine use of this procedure. Fractionation of ejaculates using an open-ended artificial vagina can be used alone or in combination with any of the above measures. When an open-ended artificial vagina is used, only the first three jets of the ejaculate are collected. These jets contain a majority of the spermatozoa in the ejaculate, and urination may not occur until the end of the ejaculatory process.426 Dilution of urine-contaminated semen in extender can restore sperm motility. Semen may be centrifuged after initial dilution, and the sperm pellet resuspended in extender before insemination361; however, centrifugation to remove urine may not provide a significant advantage over dilution in extender.426
Pharmacologic agents such as bethanechol chloride or flavoxate hydrochloride have been used in an attempt to correct urospermia but usually without success.361 α-Sympathomimetic drugs have sometimes been used successfully to prevent retrograde ejaculation in men, but their use has not been critically studied in stallions.427 Oral administration of imipramine (100 to 500 mg twice daily) has reportedly been useful for controlling urospermia in stallions, presumably by enhancing contractility of the bladder neck during emission.424
Trauma to the scrotum can result in excoriation, lacerations, hemorrhage, and edema.358,373 Systemic diseases such as hepatic disease and EIA may result in scrotal edema.358,378 Suppurative inflammation may develop as an extension of scrotal injury.358 Adhesions often develop between the visceral and parietal tunics when inflammation, infection, or hemorrhage occurs.374 Adhesions are usually thin fibrous strands that become thickened over time. In such cases the testis and its tunics are not freely movable within the scrotum.373
Hydrocele is an accumulation of serous fluid within the vaginal tunic.374 Ascites, anasarca, or local lymphedema may contribute to hydrocele because the vaginal tunic communicates with the peritoneal cavity.373 Accumulation of a significant volume of fluid around the testis may cause thermal degeneration and a decline in seminal quality.428
Hematocele occurs when trauma to the scrotum results in accumulation of blood within the testicular tunics.374 Scrotal damage initially accompanies hematocele. Thermal degeneration of the testes follows, and a thick fibrous capsule encompasses the testis after the blood clot organizes.429
Diagnosis of scrotal injury, hydrocele, and hematocele is made by physical and ultrasonic examination of the scrotum. Testes remain freely movable within the scrotum if hydrocele is present. Ultrasonographic examination reveals variable amounts of anechoic fluid surrounding the testes and epididymides, which are easy to visualize because of their echoic nature against the fluid background. With hematocele, evidence of trauma is often present, with thickening of the scrotal skin. Blood surrounding the testis and epididymides becomes progressively more echogenic over time as the clot organizes.361,430 Extensive edema of the scrotal fascia next to the tunica dartos may be difficult to differentiate ultrasonographically from hematocele. Abdominal paracentesis is helpful in eliminating ascites or peritonitis as a cause of hydrocele. Palpation per rectum of stallions and bulls may occasionally reveal that the internal inguinal rings are enlarged, readily permitting fluid transfer into the vaginal cavity.
An aseptic tap is useful to identify the character of this fluid and must be performed with care not to contaminate or penetrate the testis or its visceral vaginal tunic.429 A modified transudate of low cellularity is typical of fluid drained from a hydrocele.431 Fluid usually returns after drainage unless the initiating cause is corrected.361
Acute scrotal injury is treated with cold water or ice application to reduce edema (see earlier discussion on penile and preputial injuries). Lacerations and abrasions should be treated with topical antibiotic ointments. Systemic antiinflammatory drugs and antibiotics may reduce swelling, control infection, and prevent abscess formation.361,429
Scrotal thickening usually results in elevation of testicular temperature, causing degeneration and atrophy similar to that seen with experimental scrotal insulation.432,433 Semen quality quickly deteriorates, and a rapid reduction in numbers and motility of spermatozoa occurs with a concurrent increase in morphologic abnormalities of spermatozoa.358,373,434 If swelling and edema resolve and adhesions do not develop among the testes, tunics, and scrotum, spermatozoa may gradually reappear in the ejaculate by 1 to 2 months after injury, but 4 to 5 months may be required for testes to return to normal size and sperm production.360 One or both testes may remain atrophic and become firm because of fibrosis and loss of tubules. If only one testis is atrophied, the normal testis may eventually hypertrophy.
If hemorrhage occurs within the scrotum or testicular tunics, the prognosis for return of testicular function is poor. In unilateral cases, surgical removal of the clot and affected testis may minimize damage and speed recovery of the remaining testis.435,436 Hydrocele is managed by correcting the underlying cause of fluid accumulation such as peritonitis or ascites.429 Exercise may aid in control of fluid accumulation in some horses. Some stallions and bulls with persistent minor fluid accumulations within the tunics may continue to produce sufficient normal spermatozoa.358 Permanent testicular degeneration may result in cases with extensive fluid accumulation that are unresponsive to therapy. If the condition is unilateral, removal of the affected testis may permit the animal to remain in service.431 Because hydrocele and associated impairment of spermatogenesis may be transient (2 to 6 months),428 caution should be exercised in recommending castration or culling of affected animals until demonstration that the disorder is long-standing.
The scrotal skin is delicate and vulnerable to dermatitis. Causes include nonspecific environmental contaminants, bacteria, fungi, parasites, and frostbite.* Scrotal abscesses are not uncommon in small ruminants and are due to shearing injuries and penetrating wounds.367 Treatment is directed toward removing the affected testis. Bulls affected by frostbite should be provided a warm and dry environment.437 Systemic and local antibiotics may be indicated. Abscesses should be drained. Thermal degeneration of the testes may follow dermatitis and may be temporary or permanent.358 Semen quality should be evaluated at periodic intervals after skin lesions have resolved to gauge prognosis for improvement and return to fertility.
Complete absence (aplasia) of one or both testes is rare and usually occurs in conjunction with anomalous development of other organs.358,438 Testicular hypoplasia may be unilateral or bilateral and affects both scrotal and abdominal testes.374 Testicular hypoplasia is thought to result from failure of germ cells to multiply in the gonad.258 Causes of testicular hypoplasia may include transplacental infections and intoxications, zinc deficiency, hormonal insufficiency, impaired testicular descent, abnormal karyotype, and vascular disturbances.† Exogenous administration of hormones to prepubertal males can result in testicular hypoplasia. Testicular size of adult stallions is reduced after prolonged administration of exogenous steroids.440-442 Scrotal circumference is diminished in bulls implanted with zeranol.443
Hypoplastic testes are usually smaller than normal, but they occasionally are normal in size.373 The scrotal circumference of beef bulls should be at least 32 cm at 12 months of age.444-446 Stallions 3 years of age should have a scrotal width greater than 8 cm.378,447 Yearling rams with a scrotal circumference of less than 30 cm and mature rams with a scrotal circumference of less than 32 cm are not recommended for breeding.448 The texture of affected testes varies from normal to soft in mild or moderate hypoplasia. Severely affected small testes are firm because of the relatively increased amount of stromal connective tissue.374
Depending on the number of seminiferous tubules affected, ejaculates from males with testicular hypoplasia may be azoospermic or may contain a low concentration of spermatozoa with numerous morphologic defects.358 Round spermatogenic cells may also appear in ejaculates, along with giant and medusa cells.374
No successful treatment is available for severe hypoplasia. The useful breeding life of males with testicular hypoplasia may be shortened because affected bulls are thought to be predisposed to early testicular degeneration.444 Because of the value of some individuals, particularly stallions, owners may elect to breed males with small testes. Effective management of such stallions is based on breeding a book of mares limited by the number of normal, motile spermatozoa present in ejaculates.
Incomplete or abnormal testicular descent is thought to be a genetic abnormality.358,368,374 The inheritance pattern in horses is thought to be dominant,449 although studies of offspring of some cryptorchid stallions suggest that inheritance of the condition may be multifactorial.450 The relative risk for equine cryptorchism also appears to be influenced by breed.451 Other modes of inheritance have been suggested from studies of offspring of cryptorchid rams, bucks, and bulls. These include a recessive gene with incomplete penetrance in Angora goats,452 a dominant gene with variable expressivity in Hereford cattle,453 and either an autosomal recessive gene or a dominant gene with incomplete penetrance in inbred sheep.454
Testes originate near the kidney and migrate to the superficial inguinal rings before descending into the scrotum; the epididymis precedes the testis in descent. Retained testes are located at some point along the path of migration.373 Ectopic testes not associated with cryptorchidism may be found under the skin of the ventral caudal abdomen or elsewhere in bulls.357,374
The majority of cases of cryptorchidism in stallions are unilateral.455 Although testicular descent can occur in horses up to 2 years of age, the testes are normally descended at birth in large animals.456 Testes are readily palpated in the scrotum of colts at 30 days of age.358,359 Spermatogenesis is inhibited in the abdominal testis because of the elevated temperature within the abdomen. The interstitial cells remain active and secrete testosterone,359,373,374 enabling even bilateral cryptorchids to maintain libido and copulatory activity. The descended testis may be hypertrophic373; unilateral cryptorchids are fertile but are not considered sound breeders.358,457
Deep palpation of the superficial inguinal rings may reveal the testis in the canal (“high flankers”). If the testis is not located in the inguinal canal, transrectal palpation or ultrasonography can be performed in stallions and bulls in an attempt to locate a testis or to detect the vas or epididymis entering the superficial inguinal ring, thereby providing evidence of descent into the inguinal canal.458
Equine cryptorchids have high basal concentrations of testosterone (usually >100 pg/mL) and respond to hCG administration (10,000 to 12,000 IU IV) with a significant elevation of circulating testosterone within 30 to 60 minutes if testicular tissue is present. Geldings and “false rigs” (geldings with malelike behavior) have low basal concentrations of testosterone (<40 pg/mL) and do not respond to hCG stimulation. Stallion testes contain a high concentration of conjugated estrogens, and a single measurement of high plasma conjugated estrogens (>400 ng/mL) is reported to be almost as reliable in diagnosing cryptorchidism as hCG stimulation.459,460 In some ruminants, measurement of testosterone concentrations before and after administration of hCG has also proved helpful in identifying cryptorchidism.461
Stimulation of testicular descent with repeated injections of GnRH, sometimes combined with hCG or acupuncture, has been attempted, but the success has not been critically evaluated. Surgical removal of the abdominal and scrotal testes is indicated.357 Surgical placement of the retained testis into the scrotum is not considered an ethical procedure.
Testicular degeneration is an acquired condition with multiple causes.462 Infections or traumatic orchitis may progress to permanent degeneration. Degeneration may be associated with thermal factors after elevation of body temperature by systemic infections; prolonged increase or decrease in ambient temperature; scrotal insulation from edema, dermatitis, scrotal hernias, or hemorrhage; or abnormal conformation resulting in an incompetent heat exchange system.* Degeneration results when testicular vasculature becomes occluded in torsion of the spermatic cord.466 Obstruction of the proximal epididymis and malformation of the efferent tubules results in degeneration caused by pressure within the seminiferous tubules.434 Various chemicals and ionizing radiation are capable of inducing testicular degeneration.373 Administration of steroid hormones may induce testicular degeneration by inhibiting secretion of gonadotropins.428,467,468 Gradual degeneration also occurs with increasing age.469
Diagnosis of testicular degeneration is based on physical examination and semen evaluation. Testes are typically thought to be small, but they may be normal size. Semen examination reveals a low concentration of spermatozoa, a decreased number of spermatozoa in the ejaculate, and a high percentage of spermatozoa with morphologic defects, sometimes with premature (round) germ cells.357 Without a history of normal testis size and function before atrophy, differentiation from testicular hypoplasia is usually not possible.374,378 Discrepancies between testicular size (measured by scrotal width in stallions and scrotal circumference in ruminants) and daily sperm output may indicate testicular degeneration.443,446,470,471
The measurement of plasma hormone concentrations may be helpful in establishing a diagnosis of testicular degeneration in large animals. However, the relationship between the concentrations of various hormones and the parameters of testicular function appears to be quite variable. Measurements of hormone concentrations in subfertile stallions have demonstrated that serum gonadotropins can be abnormally low or high.472 Hormonal criteria for confirming testicular degeneration in stallions typically include low concentrations of testosterone, with concurrent low LH concentrations in early cases of degeneration, or with high FSH and low estradiol concentrations in cases of chronic (or irreversible) testicular degeneration.360 Less is known concerning hormone concentrations in other large animal species with testicular dysfunction. In one study, plasma testosterone concentrations were lower in young beef bulls with testicular degeneration than in a similar group of normospermic bulls; however, patterns of secretion and plasma concentrations of LH and FSH were not significantly different between the two groups.446 Scrotal insulation of rams resulted in an increase in plasma FSH concentrations and a decrease in plasma testosterone concentrations within 1 to 4 weeks.473
Testicular biopsy can confirm degeneration.474 Excision of an amount of tissue sufficient for evaluation often results in hemorrhage, pressure degeneration, and necrosis.358 Therefore testicular biopsy is usually undertaken only as a final recourse. However, testicular biopsy in the stallion appears to be a relatively safe procedure.475
Once testicular degeneration has occurred, treatment is usually of no benefit.358 However, any factors that might contribute to testicular degeneration (such as febrile conditions or systemic illness) should be corrected. Treatment of injuries of the scrotum and its contents was described earlier in this chapter.
Recent findings regarding variations in serum hormone concentrations in subfertile stallions have stimulated an interest in gonadotropin replacement therapy, including the use of GnRH. Although the hypothalamic-pituitary-testicular (HPT) axis of the stallion is remarkably refractory to GnRH-induced downregulation compared with other domestic species,476 few controlled studies have evaluated the effectiveness of GnRH therapy. In one study, pulsatile or constant administration of GnRH for 20 weeks did not promote testicular growth or alter spermatozoa output in reproductively sound or unsound stallions.477
In some cases, degeneration is temporary, and improved semen quality is evident after 2 to 5 months. The prognosis for an animal recovering its fertility and the economic losses the client will sustain from treatment and decreased production must be considered when deciding whether treatment of testicular degeneration is warranted.
Orchitis is most commonly caused by infection or trauma. Bacterial infections may develop hematogenously, or occasionally by retrograde movement from infected accessory sex glands.374 Extension of infection to the testes from periorchitis or epididymitis also occurs.434 Testicular enlargement is due to edema that accompanies the inflammatory reaction. Contusion and inflammation of the testes occur in racing stallions, particularly standardbreds.359S. zooepidemicus, is commonly isolated from infectious orchitis in stallions.360 In bulls, infectious orchitis is caused by B. abortus, M. tuberculosis, A. pyogenes, Nocardia farcinica, bovine herpesvirus 3 (IBR-IPV), and other miscellaneous organisms.358,373,374,434 Epididymoorchitis in rams may be associated with B. ovis, or Actinobacillus seminis, and Actinobacillus,-like organisms.368
Acutely orchitic testes are hot, swollen, and painful. The swollen testis is turgid because of restriction by the tunica albuginea. Edema of the testicular parenchyma, and concurrent presence of periorchitis or epididymitis, may be detectable by ultrasound examination. Increased testicular temperature, congestion, and interference with circulation lead to ischemia and infarction. Abscesses sometimes develop, occasionally culminating in purulent liquefaction of testicular parenchyma. Testicular atrophy and fibrosis follow as the condition becomes chronic.373,374
Acutely affected animals may refuse to mate. Ejaculates may contain numerous white blood cells. Variable mineralization of seminiferous tubules can occur as a chronic change. Decreased sperm motility and increased sperm morphologic abnormalities are evident. Standardbreds affected by acute orchitis may switch from a trot to a pace, whereas thoroughbreds may suddenly develop a hopping gait.358
Treatment consists of scrotal cryotherapy and systemic administration of antiinflammatory drugs. Bacterial orchitis is treated with antibiotics chosen by semen culture and in vitro sensitivity. Antibiotic therapy should continue for 1 to 2 weeks beyond resolution of testicular swelling and pain.361 Testicular atrophy and sterility are common sequelae to orchitis.359 Changes in the testes, including precise measurements of in situ testis size, are followed by sequential ultrasound examinations or caliper measurements. Serial semen analyses over a period of several months allow the clinician to monitor response to treatment and return of testes to normal production of spermatozoa.
Support devices may aid in preventing recurrence of traumatic orchitis in racehorses. With Brucella, or Actinobacillus, orchitis in sheep, the presence of subclinical carriers in the flock must be considered.411
Primary testicular tumors are uncommon in large animals but may be slightly more frequent in older bulls than in stallions or rams. Testicular tumors originate from the interstitial (Leydig) cells, Sertoli cells, and the germinal epithelium. Testicular teratomas and lipomas of the testicular surface and lymphosarcoma also occur.* Although the incidence of testicular tumors is relatively greater in retained than in scrotal testes in dogs, this predisposition has not been confirmed in large animals, perhaps because most are castrated at an early age before the time of usual onset of testicular neoplasia. Retained testes in the horse, however, are thought to be more prone to neoplasia. Teratomas in particular are found more commonly in cryptorchid than in scrotal testes, probably because they are embryonal in origin and their size prevents migration of the testis into the scrotum.373,374
Seminomas are the most common primary testicular tumor in the descended testes of adult stallions, with the majority occurring in stallions over 10 years of age.373,374,481 Seminomas are not hormonally active and are usually benign but may be malignant and invade inguinal and abdominal tissues.361,482 Seminomas are rare and benign in bulls and are rarely seen in aged rams, where they are occasionally highly malignant.373 The tumor arises from the germinal epithelium and occurs in retained and scrotal testes; these tumors grow very rapidly.358,373
Interstitial (Leydig) cell tumors have been reported in stallions and bulls434 and can have a negative impact on semen quality and fertility.483,484 Most do not produce androgenic hormones.373 They may be single or multiple in one or both testes and are commonly 1 to 2 cm in diameter.373
Sertoli cell tumors are reported in horses, cattle, and sheep, but they are rare. Although metastasis is uncommon, extension of neoplastic tissue into the testicular vein and lymphatics can result in hydrocele.373 Because of the importance of Sertoli cells in spermatogenesis, these tumors are likely to exert an adverse effect on semen quality and fertility. Tumors in newborn or young calves may be a result of impaired embryogenesis.373,380
Teratomas are usually benign tumors commonly found in cryptorchid testes of horses.478,485 They are rare in other large domestic species. The tumors are often cystic and vary in diameter from 10 to 25 cm or more. Structures present in teratomas arise from all three embryonic layers and include hair, nervous tissue, salivary glands, adipose tissue, cartilage, and bone.373,374
Neoplastic testes are often larger than normal, with an affected scrotal testis often twice the size of the unaffected testis, especially in cases of seminoma. Abdominally located testicular tumors can be quite large. Neoplastic testes, particularly seminomas, are typically irregular and firm. Swelling may extend into the spermatic cord, and pain may be present that interferes with breeding or is evident on palpation. Ultrasonographically, testicular tumors tend to appear as discrete, well-circumscribed hypoechoic areas within the usually homogenous testicular parenchyma.361,430 However, seminomas may involve so much of the testis at the time of diagnosis that differentiation between neoplastic and normal tissue can be difficult.
Swelling of the affected testis may interfere with thermoregulation of the contralateral testis, resulting in decreased sperm production. Semen examination, however, may reveal seminal parameters to be within normal limits, and fertility may be acceptable. A significant amount of normal testicular parenchyma may remain covering the tumor, and living spermatozoa may or may not be present in the epididymis on the same side.358,373,374,486
Testicular tumors should be surgically removed. Although metastasis is uncommon, early identification and removal of unilateral tumors prevents spread to other tissues. If semen quality is satisfactory in seasonal breeders, removal may be delayed until the breeding season is completed to avoid the transient decrease in semen quality associated with postsurgical swelling. If neoplasia is bilateral, surgical removal may be delayed until semen quality deteriorates sufficiently to negate the use of the animal for breeding.361
Torsion of the spermatic cord occurs more commonly in stallions than in other large animals because of the horizontal position of the testes within the scrotum. Torsions may be transient or permanent and typically are of 180 to 360 degrees, but rotations may be greater.381 Abnormal elongation of the caudal ligament of the epididymis (scrotal ligament), the proper ligament of the testis, or an excessively long mesorchium may encourage spermatic cord torsion.466,487
Torsion of the spermatic cord occurs in degrees that vary from those producing no pain or abnormality of semen to those involving vascular obstruction and acute colic.359 Torsion is often a transient condition that does not interfere with testicular function or cause pain.457 In those cases the testis is usually rotated 180 degrees or less. If torsion is of sufficient degree to result in vascular compromise, acute pain results.358,359,487,488 Diagnosis of torsion of the spermatic cord is aided when displacement of the tail of the epididymis and scrotal ligament is evident on palpation. The head of the epididymis is normally located craniodorsal to the testis and the tail lies caudally, where it is attached to the testis by the proper ligament. The tail of the epididymis is most readily palpable, and its location is helpful in determining the degree of rotation. Torsions of 360 degrees or greater generally cause clinical signs that must be differentiated from strangulation of herniated contents into the scrotum. The primary method used to differentiate between the two conditions is palpation per rectum of the superficial inguinal ring to identify if herniation is present.361
Clinical signs of vascular impairment with spermatic cord torsion include abdominal discomfort, elevated heart and respiratory rates, unilateral swelling and edema of the scrotum, and increased testicular temperature.361 Affected testes are painful and quickly become soft and friable.358,359,487,488
Manual correction of spermatic cord torsion is sometimes possible, but recurrence is likely. To attempt manual correction, the horse is sedated and the testis is rotated in the direction opposite the torsion. Both hands are used to reposition the scrotum as the testis and its tunics are rotated.359 Surgical correction is indicated if manual correction is not possible.361 Nonsteroidal antiinflammatory drugs and analgesics may be administered to control pain.
The rapidity with which correction must occur is unknown; human testes may be salvageable if torsion is corrected within 6 hours. If hemorrhage or necrosis of the testis is evident, removal is indicated because the contralateral testis may become permanently damaged. The mechanism of the damage is probably immunologic, resulting from antibodies to spermatozoa liberated as a result of ischemia.489
Varicoceles are abnormally distended and tortuous veins of the pampiniform plexus.411,465 Varicoceles are most often recognized in rams, in which dilations in vessels may reach 15 cm and discourage movement and libido.454 The incidence of varicoceles increases significantly with age, reaching approximately 2% in rams 3 years of age and older.438 Varicoceles have been reported infrequently in stallions.361
Varicoceles may result from insufficiency of veins draining the testis or a deficiency of the fascia and connective tissue surrounding those veins that allows backflow and stasis of blood in the vessels.373 Infertility associated with varicocele is thought to result from disturbance of the local thermoregulatory mechanism, causing increased testicular temperature and subsequent disturbance in spermatogenesis.361 Concomitant atrophy of the testis is common in rams.438 Bilateral varicoceles and atrophied testes have been reported in the ram.490
Diagnosis of varicocele is made by palpating the dilated tortuous veins (“bag of worms”) within the spermatic cord.358,411 Confirmation of the varicocele has been accomplished by ultrasonographic examination in stallions. Large echolucent areas in the venous plexus of the spermatic cord, sometimes with concurrent distention of the central vein of the testis, are described as the identifying features.430 The ultrasonographic appearance of a suspected varicocele can be compared with the structures of an uninvolved contralateral testis and spermatic cord or those of an unaffected animal.
Thombosis of the varicocele can occur.358,373 The large, organizing laminated thrombi can be mistaken as Corynebacterium pseudotuberculosis, abscesses in the scrotal fascia of rams.373 Varicoceles might also be mistaken for sperm granulomas of the caput epididymis. Unless thrombosis has occurred, varicoceles are typically fluxuant and soft and fail to elicit pain when palpated.
Surgical removal of varicocele has improved semen quality and fertility of some human patients but has not been reported in large animals. Thrombosis of a varicocele necessitates unilateral castration, with transection of the spermatic cord proximal to the thrombus.357 Castration is also recommended for rams because of potential heritability risks.454
Epididymitis is caused by infection or trauma and may occur separately but is commonly secondary to orchitis or infection of the accessory sex glands.373,374,491 The tail of the epididymis is commonly involved, but the head and body may be affected. S. zooepidemicus, is commonly isolated from equine epididymitis, although a number of other miscellaneous organisms, including Proteus mirabilis, have been incriminated.358,492 In bulls, B. abortus, A. seminis, A. pyogenes, and other miscellaneous organisms cause epididymitis.373,374,491 In mature rams the disease is commonly associated with B. ovis, whereas in ram lambs organisms from the Actinobacillus, Haemophilus, Histophilus, and Corynebacterium, groups are prevalent.411,493 Routes of infection have been postulated to be hematogenous, venereal, or ascending from genitourinary passages, similar to routes of infection proposed for orchitis.358,373 All routes of infection are likely to occur to some degree, depending on the pathogen and species involved. In an interesting study performed in yearling rams, conjunctival inoculation of B. ovis, culminated primarily in localized infections of the reproductive tract, which tended to first result in lesions of the distal tail of the epididymis.494 Injuries, such as penetrating wounds, may also result in epididymitis.
Diagnosis of epididymitis is based on detection of clinical signs that include pain when irregular swellings of the epididymis are palpated, changes in shape and texture of the organ, adhesions between the epididymis and scrotal tunics, and enlargement of the tail of the epididymis.358,361,411 The course of epididymitis varies from acute swelling and edema to chronic abscesses, periorchitis, and fibrosis.373,374 Granulomas may develop if sperm escape into surrounding tissue.438,491,495 In rams, epididymal lesions may be palpable along the entire length. Abnormal sperm morphology (especially detached heads) and leukocytes in the ejaculate may be seen before lesions are palpable.496
Animals affected with the Actinobacillus, Histophilus, and Haemophilus, groups of organisms may acquire an epididymoorchitis syndrome.411,497 Affected rams are usually less than 1 year of age. They may be subclinical carriers or acutely ill with pyrexia, depression, pain as evidenced by an arched back, and unilateral or bilateral swelling and tenderness of the scrotal contents. If these animals recover from the acute phase, the disease may become chronic and is characterized by an enlarged, firm, and often irregular epididymis; palpable adhesions of portions of the epididymis to the testis and vaginal tunics; atrophic testes; abscess formation; and draining fistulas to the scrotal surface. Ultrasonographic examination of the epididymis may reveal dilated ducts, fluid accumulation around the tail of the epididymis, and cystic areas within the epididymis that contain purulent material.361,430
Inflammatory cells may be present along with abnormal sperm in the ejaculate of affected animals. Seminal leukocytes correlate positively with epididymitis lesions and correlate negatively with seminal quality.496 Bacteriologic culture of the semen may aid in identifying infectious causes. Serologic tests for B. ovis, and H. ovis, are available and are helpful in determining exposure to the organisms.411,497
Infectious causes of epididymitis are treated with systemic antibiotics selected by in vitro sensitivity. The ability of the antibiotic to gain access to the epididymis must also be considered. Treatment should continue for 1 to 2 weeks after inflammatory cells disappear from the semen. In unilateral cases, removal of the testis, epididymis, and spermatic cord on the affected side may salvage some valuable animals for breeding. If unilateral castration is elected, sequential postcastration examinations are indicated to ensure infection has not spread to remaining reproductive organs.361
Treatment of ram epididymitis is usually not recommended but might be attempted in valuable animals with minimal clinical signs. Oxytetracycline 10 mg/kg and dihydrostreptomycin 25 mg/kg IM twice daily for 7 days has been reported to resolve shedding of B. ovis.,498
In cases of moderate or severe bilateral epididymitis, the prognosis for recovery is poor. Obstructions and granulomas usually develop, resulting in sterility.438 Testicular atrophy is a common sequela to epididymitis.
Inflammation of the vesicular glands is uncommon in stallions but more likely in bulls.373,374,499-501 Bacterial infections including B. abortus, and P. aeruginosa, are incriminated in stallions.359,390,502-504 Various organisms have been isolated from cases of seminal vesiculitis in bulls including A. pyogenes, B. abortus, M. tuberculosis, mycoplasmas, ureaplasmas, C. psittaci, and H. somnus.,358,373,374,499,505
Vesiculitis may affect bulls of all ages but is most common in young growing bulls fed high-energy rations and housed together.499 The prevalence may reach 20% to 30% in small groups of yearling bulls in close confinement.501 The role of viral pathogens in outbreaks of the disease is not defined. Infections may arise by either ascending or descending routes from other areas of the urogenital tract, or hematogenously. Frequent homosexual activity among young bulls, high nutrition, and fast growth rates may be involved in spread of the infection.358
The seminal vesicles of affected stallions may be of normal size or enlarged and painful when palpated per rectum.502,503 Stallions may refuse to cover or may be unable to ejaculate.359 Semen contains numerous neutrophils and blood, and fertility of infected semen is reduced.390 Bacterial pathogens are readily recovered from semen of affected stallions.361 However, special culturing techniques are necessary to pinpoint the seminal vesicles as the site of internal genital infection (see under Clinical Pathology).404
Bulls affected with vesiculitis may exhibit few clinical signs other than deterioration of semen quality. In severe cases pelvic inflammation and peritonitis result in pain reflected by reluctance to move, stiff gait, tense abdomen, and refusal to mate.358 Other reproductive organs, particularly the ampullae, testes, and epididymides, may be inflamed.499 The vesicular glands may not be significantly increased in size during the acute phase. If inflammation becomes chronic, the glands usually enlarge, eventually losing their lobularity and becoming fibrotic.358,373 Abscesses are often associated with A. pyogenes, and may rupture into the rectum or urinary bladder.358,374 Tubercular vesicular adenitis results in marked enlargement of the glands with caseous nodule formation. B. abortus, causes suppuration, necrosis, and calcification of the glands.373 Purulent exudate is present in the ejaculate, sometimes as thick clots. Neutrophils may become less evident in semen as the condition becomes chronic. Poor sperm motility, increased morphologic defects, and an elevated pH are characteristics of semen from bulls with vesiculitis.358
Fertility of mildly affected bulls may remain satisfactory. More extensive involvement in which semen quality is markedly affected results in subfertility or infertility.501 Semen from bulls with vesiculitis freezes poorly, and antibiotics used in extenders usually do not control the high numbers of bacteria present.501
Bacterial pathogens can be recovered from the semen of affected stallions. However, without other evidence of infection of the accessory sex glands, recovery of pathogens from the semen should be interpreted with caution because the bacteria could originate from another location. Repeated samples for culture should be obtained from the sheath, penis, fossa glandis, preejaculatory fluid, urethra (before and after ejaculation), and seminal vesicle effluent manually expressed through a sterile urethral catheter positioned at the colliculus seminalis. Prostatic fluids can be collected through a catheter by massage per rectum. The first jet of a fractionated ejaculate includes the secretions of the ampullae.404 Alternatively, a suitable fiberoptic endoscope can be passed in the urethra to the level of the seminal colliculus and into the seminal vesicles. Purulent material may then be aspirated for culture.361
Vesicular secretions from bulls can be collected by extension and disinfection of the penis followed by irrigation of the distal urethra with sterile saline. A sterile catheter is then passed 30 cm into the urethra, and the accessory sex glands are massaged to stimulate their secretion. Fluid is collected into sterile containers.506
Accessory sex gland infections are treated with antibiotics selected by culture and in vitro sensitivity. Antibiotics are administered for 2 to 4 weeks, but treatment failures may occur.390 Negligible amounts of certain antibiotics may diffuse across mucosal cell borders into the seminal plasma.507 Properties of antimicrobials suitable for parenteral treatment of accessory sex gland infections include high lipid solubility, a favorable pKa, and low protein binding. The antimicrobial should have a pH that is basic relative to the accessory gland fluid into which penetration is desired.508 Vesicular and prostatic fluid have a pH of 7.3 to 7.5, whereas bulbourethral gland secretion has a pH of 8 to 8.2.404,447 Antimicrobials that may prove suitable for treatment include the basic macrolides such as erythromycin, which is fat soluble and has a high pKa, and trimethoprim, which also has a high pKa and a high percentage of nonionized molecules in plasma, favoring diffusion across the lipid membrane of epithelial cells.508 Because of its antimicrobial spectrum and tissue diffusion characteristics, enrofloxacin has been found to be very effective for systemic treatment of seminal vesiculitis in stallions. Treatment of stallions by lavage and instillation of antimicrobials directly into the seminal vesicles via a flexible videoendoscope can be accomplished by skilled operators. Removal of the affected gland has been performed in stallions and bulls.502,509,510 A technique used with fair success in stallions with localized vesicular adenitis is repeated irrigation through a catheter guided into the vesicles by endoscopy. Antibiotics are instilled into the vesicular gland lumen after each irrigation.361
The prognosis for correction of seminal vesiculitis is only fair to poor. Animals with mild cases may recover spontaneously in 2 to 3 months. In chronic cases glands that do not abscess become fibrotic and destroyed even though purulent material does not persist in the ejaculate.358 In stallions with vesicular adenitis, immediate filtration of the ejaculate in order to remove cellular debris and mixing of semen in an appropriate antibiotic-containing extender to control bacterial growth may maintain sperm motility and fertility.406
Blockage of the efferent ducts between the testes and penile urethra sometimes occurs in stallions. If the condition is bilateral, azospermia results in spite of apparent ejaculation. The ampullae are frequently tense, and enlargement may be demonstrated by ultrasonography.511-513 Massage of the ampullae per rectum followed by prolonged sexual stimulation and semen collection may result in ejaculation of a semen sample with a high concentration of spermatozoa, often present as “strings” or “plugs.”511 Large numbers of detached sperm heads, often in clumps, are commonly observed. Collection of semen on a regular schedule may aid in preventing recurrence once the blockage is relieved. Empirical treatment by blockade of β-receptors and stimulation of α-receptors has been successful in some stallions that fail to ejaculate.514
Sperm granulomas caused by accumulation of spermatozoa in blind efferent ducts are a common cause of infertility in the buck.368 Granulomas have also been identified in the stallion,515 and particularly in rams with sperm extravasation as a result of chronic epididymitis.373,374
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* Lutalyse, Pfizer Animal Health.
† Estrumate, Mobay Corporation, Animal Health Division, Shawnee, KS.
* Vibrin, SmithKline Beecham Animal Health, Exton, PA.
† Trivib-5L, Fort Dodge Labs, Fort Dodge, IA.
* Animal Health Division, Shawnee, KS.
* References 358, 367, 369, 373, 374, 434, 437.
† References 367, 368, 373, 374, 434, 439.