Sexual Differentiation

Normal sexual differentiation depends on the successful completion of three consecutive events: establishment of chromosomal sex, gonadal sex, and phenotypic sex. Chromosomal sex (normally XX or XY) is established at fertilization and maintained by mitotic division after that. Sexual differentiation is completed by 46 days of gestation (Table 39-1), where gestation lengths are 65 days for dogs and 64 days for cats.

TABLE 39-1 Timeline of sexual differentiation in canine fetuses*

* Differentiation of fetal gonads and internal genitalia occurs between 32 and 46 days of gestation relative to the maternal preovulatory luteinizing hormone (LH) surge.

In the early embryo, the gonads are undifferentiated (Figure 39-1). Gonadectomy of XX or XY embryos before gonadal differentiation results in the development of a female phenotype, leading to the conclusion that the basic embryonic plan is female. A gene located on the Y-chromosome (Sry gene) encodes a testis-determining protein that results in testis formation and establishes the male gonadal sex. Sry acts as a master switch turning on several genes that are located on other chromosomes, thus inducing a cascade of gene products that are necessary for testicular development. In the absence of the Sry gene, the default pathway to female gonadal sex is initiated, and an ovary develops.

Figure 39-1 Differentiation of the internal and external genitalia after the gonad develops into a testicle or an ovary. MIF, Müllerian inhibiting factor; DHT, dihydrotestosterone.

(Redrawn from Meyers-Wallen VN, Patterson DF: Disorders of sexual development in the dog. In Morrow D (ed): Current therapy in theriogenology, ed 2, Philadelphia, 1986, Saunders, pp 567-574.)

Following gonadal differentiation, development of the internal and external genitalia occurs. In the early embryo, both sets of internal tubular structures (wolffian and müllerian) develop initially. Two testicular secretions (müllerian-inhibiting factor [MIF] and testosterone) are responsible for masculinizing the tubular reproductive tract (see Figure 39-1). MIF, a glycoprotein produced by Sertoli cells, causes the müllerian (female) duct system (uterine tubes, uterus, cervix, and cranial vagina) to regress. Testosterone, a steroid hormone produced by Leydig cells, promotes the formation of the vas deferens and epididymides from the wolffian ducts. Testosterone is metabolized to dihydrotestosterone (DHT) within the cells of the urogenital sinus, the genital tubercle, and the genital swellings to result in the formation of the prostate and urethra, the penis, and the scrotum, respectively. Androgen-dependent masculinization is mediated through the binding of testosterone or DHT to the androgen receptor protein, the product of a gene on the X-chromosome.

Canine and feline male external genitalia originate from an undifferentiated urogenital tubercle (which forms at the level of the embryonic cloacal membrane). As a direct result of the influence of DHT, the prepuce develops from a circular plate of ectoderm invaginating at the level of the distal tip of the penis, whereas the junction between the preputial and penile mucosa (balanopreputial fold) dissolves at a later stage, also as a direct result of the action of androgens. In the absence of DHT (as in the normal female), the caudal vagina, vestibule, and vulva develop. Determination of gender in newborn dogs and cats may be difficult because the difference at this age is a slightly longer anogenital distance in males (13 to 15 mm) versus females (7 to 8 mm) (Figure 39-2). A pseudohermaphrodite is an animal that has the gonads of one sex with the internal and/or external genitalia and/or the chromosomal complement of the opposite sex (Box 39-1).

Figure 39-2 Anogenital distance in male (A) and female (B) 4-day-old Labrador Retriever pups. Arrow points to prepuce; arrowhead points toward scrotum; asterisk adjacent to vulva.

Testicular Descent

During fetal development, each testis moves to a position caudoventral to the inguinal canal from its original location near the caudal pole of the kidney. Testicular descent is coordinated by growth and regression of the gubernaculum. The gubernaculum extends from the caudal pole of the testis into the inguinal canal (Figure 39-3). Testicular descent occurs in three phases: intraabdominal, intrainguinal, and extrainguinal. During the intraabdominal migration, each testis moves toward its respective internal inguinal ring, and the caudal part of the gubernaculum enlarges enormously. The enlarging gubernaculum dilates the inguinal canal and extends the length of the scrotum, which facilitates the migration of the testis through the inguinal canal during the intrainguinal phase. In fact, the enlarged gubernaculum is present at birth and is frequently mistaken for descended testes in neonates. The extrainguinal phase is completed after birth in dogs and cats and involves regression of the gubernaculum, which guides/pulls the testis into the scrotum. Gubernacular outgrowth and enlargement are mediated by MIF. Testosterone plays a role in the regression of the gubernaculum and the terminal differentiation into the proper ligament of the testis and the ligament of the tail of the epididymis.

Figure 39-3 The normal relationship between the vaginal process, epididymal ligament, and gubernaculum.

(Redrawn from Peter AT: The reproductive system. In Hoskins JD (ed): Veterinary pediatrics: dogs and cats from birth to 6 months, ed 3, Philadelphia, 2001, Saunders, pp 463-475.)

The testes are in an abdominal or inguinal location at birth in puppies and kittens. The testes pass through the inguinal canal 3 to 4 days after birth but may move up and down within the inguinal canal until 10 to 14 weeks after birth. Therefore diagnosis for failure of testicular descent should not be made until the animal is at least 4 months of age. When palpating for the testes in young puppies and kittens, the clinician should place the index finger and middle finger on either side of the penis so that the testes can be found by gentle traction in a front-to-back direction.

Puberty

Most puppies and kittens attain puberty between 8 and 19 months of age, with a range of 4 to 22 months for both males and females (Table 39-2). At 2 months after birth, the ovary measures 5 mm in diameter. Environmental factors can affect the onset of puberty. Most female cats born early in the season or exposed when young either to tomcats or cycling females or to increasing amounts of light show the first signs of estrus before similar individuals born later or not exposed to these factors.

TABLE 39-2 Onset of puberty in the normal bitch and queen of reported breeds

At birth, normal ovaries will have thousands of follicles. At the onset of puberty, a cohort of follicles is selected to begin development. Follicular development is promoted by the release of hypothalamic (gonadotropin-releasing hormone) and pituitary hormones (follicle-stimulating hormone and luteinizing hormone). As the follicles grow, they release estradiol, which causes the physical and behavioral signs of proestrus. Estradiol concentrations peak in mid proestrus and are near baseline during estrus in the bitch, whereas they remain elevated throughout estrus in the queen. Luteinizing hormone is released around the onset of estrus in dogs but only in response to external stimuli (e.g., mating) in cats. Puberty in both the female dog and cat is defined as the occurrence of the first estrus.

The testes contain spermatogonia, which divide to form spermatozoa near the time of puberty. Sperm development and testosterone secretion result from the release of the same hypothalamic and pituitary hormones as in the female. By 3.5 months after birth, there is sufficient testosterone to initiate the growth of penile spines in tomcats, which reach their full size when the cats are between 6 and 7 months of age. Growth or regression of the spines has been positively correlated with androgen-dependent mating activity. In male dogs, territorial marking behavior begins at the time of puberty.

Reproductive Disorders in Male Pediatric Patients

Testicular Abnormalities

Congenital testicular abnormalities in cats and dogs include the congenital absence of one (monorchidism) or both (anorchidism) testes, testicular hypoplasia, and cryptorchidism. Puppies and kittens with XXY (Klinefelter’s) syndrome are phenotypically male, have a normal penis and prepuce, and have reportedly normal sexual behavior. Epididymides and small testis are present within the scrotum. However, ejaculates do not contain spermatozoa, and histologic evaluation of testicular tissue reveals seminiferous tubular dysgenesis with no evidence of spermatogenesis. More than one X-chromosome is deleterious to normal spermatogenesis. The XXY syndrome can arise by meiotic nondisjunction of the sex chromosomes during male or female gametogenesis or by mitotic nondisjunction in the early zygote. Nondisjunctional events leading to abnormal sex chromosome constitutions occur randomly and are not the result of a heritable defect. This syndrome is particularly well known; domestic shorthaired tomcats with this condition often feature a calico or tortoiseshell coat. In cats, the genes for orange and black coat color are X-linked alleles. Males with this coat color may also be XX/XY chimeras or XY/XY chimeras. In these two karyotypes, normal testicular histology and spermatogenesis may be present. A sample karyotype form is shown in Figure 39-4.

Figure 39-4 Sample karyotype form.

(Reproduced with kind permission from Drs. B.P. Chowdhary (Director) and T. Raudsepp (Associate Director) of the Molecular Cytogenetics Laboratory at the College of Veterinary Medicine and Biomedical Sciences, Texas A&M University.)

Failure of the testis to descend into the scrotum (cryptorchidism) is a development defect. Unilateral cryptorchidism is 4 times more common than bilateral cryptorchidism. If only one scrotal testis is present, careful ultrasonographic or surgical exploration of the contralateral inguinal canal and abdomen may be necessary to determine whether the missing scrotal testis is retained, hypoplastic, or absent. Inguinal retention is 3 times more likely than abdominal retention. For abdominal retention, tracing the vas deferens retrograde from its insertion on the dorsal aspect of the prostate is a useful method to find the testis. Cases of bilateral cryptorchidism can be distinguished from anorchidism postpubertally using challenge testing (Box 39-2).

BOX 39-2 Two challenge tests used to differentiate between bilateral cryptorchidism and anorchidism

Gonadotropin-releasing hormone (GnRH): 2 µg/kg intramuscularly (IM) for dogs and 25 µg IM for cats with a blood sample drawn 1 hour later for measurement of serum testosterone.

Human chorionic gonadotropin (hCG): 20 IU/kg IM for dogs and 250 IU IM for cats with a blood sample drawn 4 hours later for measurement of serum testosterone.

Serum testosterone concentrations exceeding 1 ng/ml following challenge testing support the diagnosis of cryptorchidism, and serum testosterone concentrations less than 1 ng/ml support a diagnosis of anorchidism.

In puppies with undescended testes, the right testis is usually retained in the inguinal region. On the other hand, in kittens, abdominal retention is more common than inguinal retention. The presence of a strong cranial suspensory ligament that fails to break down and prevents gubernacular outgrowth and migration has been proposed in cryptorchid individuals. Although the production of testosterone by the interstitial (Leydig) cells continues in the cryptorchid testis, spermatogenesis does not occur because of the elevated intraabdominal temperature relative to the cooler temperature within the scrotum. As a result, the testicular germinal epithelium degenerates, and the cryptorchid testis becomes smaller and soft. In dogs, these changes may be responsible for the 5 times greater incidence of Sertoli cell tumors and 3 times greater incidence of seminomas in cryptorchid testes compared with scrotal testes.

The reported incidence of cryptorchidism ranges from less than 0.1% to 13% in dogs and 0.37% to 1.7% in cats. Occasionally this abnormality occurs in association with other congenital defects (e.g., hypospadias, inguinal and umbilical hernias). Dog breeds with a higher incidence of cryptorchidism include the toy, miniature, and standard Poodle, Pomeranian, Yorkshire Terrier, Miniature Dachshund, Cairn Terrier, Chihuahua, Maltese, Boxer, Pekingese, English Bulldog, Old English Sheepdog, Miniature Schnauzer, Siberian Husky, and Shetland Sheepdog. Dog breeds with a low incidence of cryptorchidism include the Beagle, Golden Retriever, Labrador Retriever, Saint Bernard, Great Dane, and English Setter. There are no data at present to support that cryptorchidism is a hereditable defect in cats. However, Persian cats are overrepresented in feline surveys of cryptorchidism. Breeding trials in Boxers and Cocker Spaniels have confirmed that cryptorchidism is a hereditable condition involving a sex-linked autosomal recessive trait. Homozygous females appear to be phenotypically normal carriers that will transmit the gene to 50% of their offspring. Heterozygous males and heterozygous females will also be phenotypically normal carriers. Because of the heritable nature of this condition, professional organizations (e.g., British Veterinary Medical Association) recommend not breeding cryptorchid animals, their littermates, and their parents. Attempts to induce descent of the cryptorchid testis by hormonal treatments are relatively ineffective and do not correct the genetic flaw.

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