Inherited Disorders of Sexual Development in Dogs and Cats
Tufts' Canine and Feline Breeding and Genetics Conference, 2007
Vicki N. Meyers-Wallen, VMD, PhD, DACT
Baker Institute for Animal Health, Cornell University, Ithaca, NY, USA

Objectives of the Presentation

 The objective is to review the normal steps in sexual development and provide some examples of inherited types of abnormal sexual development in dogs and cats.

Overview of Normal Sexual Development

Development of the reproductive tract in mammals is controlled by genes, which are expressed in steps in specific pathways within the cells at specify times in embryonic life. Thus starting with the sex chromosomes and the autosomal chromosomes that carry these genes, there are three major steps in normal sexual development: Establishment of chromosomal sex, development of gonadal sex and development of phenotypic sex. Chromosomal sex is determined at the time of fertilization, with the zygote obtaining a normal number of autosomal chromosomes (autosomes) and either two X chromosomes or and X and a Y chromosome. Each cell normally maintains that sex chromosome constitution in further cell divisions as the embryo develops. Both XX and XY zygotes develop into embryos that are sexually indifferent, meaning that one can not tell which sex they are by eye. However, at this sexually indifferent stage, the embryos more closely resemble a female than a male phenotype. Near the end of this indifferent stage, the precursor of the gonad, the genital ridge, arises. If the genital ridge is removed at this indifferent stage, both XX and XY embryos will develop a female phenotype. This indicates that the basic embryonic plan is female, and that the ovary is not necessary at this embryonic stage for formation of the female phenotype. However, it also indicates that signals from a testis are necessary for male phenotypic development.

Gonadal sex development marks the end of the indifferent period of the embryo. This is a process under genetic control whereby the gonad becomes committed to either the ovary or testis pathway. For example in mammals, expression of the gene Sry on the Y chromosome signals the gonad to initiate testis development. Expression of genes such as Sox9, located on autosomes, is also necessary for testis development. No single genetic signal has yet been identified that is necessary to initiate ovarian development.

Phenotypic sex development is the development of the remainder of the sexual phenotype, and depends upon whether a testis is presence or absent. In the presence of secretions from a testis, major alterations occur in the embryo that masculinizes the phenotype. Specifically, Mullerian inhibiting substance (MIS), also called Anti mullerian hormone (Amh), is secreted by Sertoli cells in the testis. It binds to its receptor on the Mullerian ducts, causing their regression. Testosterone, secreted by Leydig cells of the testis, binds to the androgen receptor on the Wolffian ducts, stabilizing them so that they continue development into the vasa deferentia and the epididymides. In the tissues of the embryonic external genitalia, the urogenital sinus, the genital tubercle, and the genital swellings, testosterone is converted to dihydrotestosterone (DHT) by the enzyme 5 alpha reductase. DHT binds to the androgen receptor in those tissues, inducing them to form the male urethra and prostate, the penis, and the scrotum, respectively. Finally, testosterone and insulin like growth factor 3 (Insl3), also secreted by Leydig cells in the testis, induce changes in the ligaments holding the testis in place, such that the cranial ligament regresses and the caudal ligament develops into the gubernaculum. These ligamental changes are necessary for testis descent into the scrotum. In normal females, where testis secretions are absent, the basic embryonic plan continues to develop with minor alterations, resulting in a female phenotype. Specifically, since MIS is absent, the Mullerian duct system develops into the oviducts, uterus, and cranial vagina. In the absence of testosterone, the Wolffian ducts regress and DHT is not produced. Thus the external genitalia form the vestibule, caudal vagina, clitoris, and vulva, respectively. Finally, in the absence of testosterone and Insl3, the cranial and caudal ligaments holding the ovary are maintained, and the ovary remains in position near the kidney.

An abnormal sexual phenotype can result from failure at any step in these three major levels, but an error at one level usually affects all levels below it. However, disorders resulting from different causes can appear phenotypically similar externally, even though the cause is different. To correctly diagnose these disorders of sexual development, we currently classify them according to the first step at which development differs from the normal pattern. Eventually these disorders will probably be classified according to the specific genetic defect responsible. The diagnostic workup should include investigation at all three levels of sexual development to identify the first step that is abnormal (reviewed in Meyers-Wallen 1999, 2000, 2001). For example, chromosomal sex can be investigated by performing a karyotype, whereas gonadal sex and phenotypic sex should be initially investigated by gross and microscopic examination of the reproductive organs. Photographs of some of these disorders can be found on my website at :

Abnormalities of Chromosomal Sex

These disorders are caused by errors in the number or structure of the sex chromosomes, which is usually investigated by performing a karyotype to identify the number and structure of the chromosomes. For example, a normal cat has either a 38,XX or a 38, XY karyotype. A cat with a 39,XXY karyotype has an extra X chromosome in each cell. In humans, this disorder is known as Klinefelter's syndrome. Since these individuals and cats have a Y chromosome and Sry, they develop testes and consequently develop a male phenotype. However the additional X chromosome has an adverse effect on spermatogenesis that causes sterility. Thus the presence of additional sex chromosomes or the absence of a sex chromosome can have effects on the sexual phenotype. In addition, errors in the structure of the chromosomes such as insertions, deletions, or translocations can also cause an imbalance in chromosomes and disrupt the expression of genes that reside on the altered chromosomes. Such errors can result in a sexually ambiguous phenotype and their diagnosis usually requires genetic assays in addition to the karyotype.

Abnormalities of Gonadal Sex

Disorders in this category are called sex reversal disorders, as there is disagreement between the chromosomal and gonadal sex of the individual. For example in XX sex reversal, affected dogs have a normal female karyotype (78,XX), no Y chromosome, and yet develop testes (XX males) or ovotestes (XX true hermaphrodites). Canine XX sex reversal is of the Sry negative type, meaning that the Sry gene that is normally located on the Y chromosome is absent in affected dogs. Affected dogs are masculinized in proportion to the amount of testicular tissue within the individual. For example XX males have bilateral testes and usually have nearly normal male external genitalia, meaning that the prepuce is caudally displaced, with mild hypospadias and one or both testes are usually undescended (cryptorchid). However XX true hermaphrodites, which have ovotestes, have less testicular tissue present than XX males. Thus XX true hermaphrodites often have an enlarged clitoris containing a bone, but the remainder of the external phenotype appears female. The internal genitalia in XX males are masculinized with one exception. There are has male ducts such as epididymides and vasa deferentia. However a complete uterus is also present, due to failure of regression of the embryonic tissue from which the uterus arises (Mullerian duct system). The reason for this is unknown, but probably results from delayed secretion from the testis. In XX true hermaphrodites, both female and male internal genitalia can be present, such as epididymides as well as both oviducts and a uterus.

Sry-negative XX sex reversal has been reported in at least 8 breeds: the American cocker spaniel (Meyers-Wallen et al 1995a), German shorthaired pointer (Meyers-Wallen et al 1995b), beagle, Weimaraner, Kerry blue terrier, Chinese pug, Norwegian elkhound, and Basset hound (reviewed in Meyers-Wallen 1999, 2000, 2001). One or a few individuals have also been identified by our laboratory in these other breeds: Afghan hound, border collie, English cocker spaniel, soft coated wheaten terrier, American pit bull terrier, Doberman pinscher, Vizsla, Walkerhound, (Meyers-Wallen et al 1999), as well as in the Pomeranian, German pinscher, and Brussels griffon. Research continues to identify gene mutations responsible for this disorder.

Abnormalities of Phenotypic Sex

Individuals affected with these disorders have complete agreement between chromosomal and gonadal sex, being either XX females with ovaries or XY males with testes. Nevertheless they have a defect in the sexual phenotype. This category includes the pseudohermaphrodites. Other errors in male phenotypic development, such as hypospadias and cryptorchidism that do not result in phenotypic ambiguity and are also included in this category, but are not categorized as pseudohermaphroditism.

Female Pseudohermaphroditism

Female pseudohermaphrodites have a normal female karyotype and ovaries, but develop masculinized genitalia, ranging from an enlarged clitoris to nearly normal male external genitalia.

The majority of canine cases reported have resulted from administration of steroids (either androgens or progestagens) to the pregnant dam. These steroids cause masculinization of the external genitalia in female embryos because they can act like testosterone in the embryo. The affected 78,XX dogs have some masculinization of the external genitalia but do not have testes. At puberty they may exhibit signs of proestrus or estrus, such as blood in the urine. Fortunately such cases have become uncommon.

In cats, one case of inherited female pseudohermaphroditism has been reported, which was caused by an inherited enzyme defect in the adrenal gland: 11 beta hydroxylase deficiency (Knighton 2004).This resulted in overproduction of testosterone from the adrenals, not only in the embryo, but also after birth. This 38,XX cat had male external genitalia at birth (penis, prepuce, scrotum), although there were no testes in the scrotum. The cat was spayed and found to have a normal uterus and ovaries. By 14 months of age the cat was urine marking like a male and the veterinarian observed barbs, an androgen dependent characteristic, on the penis. Adrenal testosterone production in this cat resulted in serum testosterone concentrations as high as in normal males, and this continued into adulthood. Inherited congenital adrenal hyperplasias due to enzyme deficiencies are a common cause of human female pseudohermaphroditism, but are apparently rare in dogs and cats.

Male Pseudohermaphroditism

Male pseudohermaphrodites have a normal male karyotype and testes but have defects in either Mullerian duct regression or in androgen-dependent masculinization.

Persistent Mullerian Duct Syndrome

This is an inherited disorder that has been reported in the miniature Schnauzer in the USA and the basset hound in Europe, and may also occur in the Persian cat in the USA. In the miniature Schnauzer it is inherited as an autosomal recessive trait with expression limited to XY males. In spite of the presence of testes, there is failure of the embryonic Mullerian duct system to regress. Therefore, the Mullerian ducts continue to develop, forming the oviducts, uterus, and the cranial portion of the vagina. Internally, the epididymides, vasa deferentia and the prostate are also present, as these respond to testosterone production by the testes as in normal males. Approximately half the affected miniature Schnauzers are cryptorchid,, either bilaterally or unilaterally, probably because the uterus is attached to the testis and interferes with testis descent. The remaining affected dogs however, had normal testis descent and normal appearing external genitalia, such that the disorder would not be suspected by external examination alone. Thus such affected dogs can reproduce, passing the trait to their offspring. Affected dogs may develop signs of pyometra, urinary tract infection or prostate infection. The mutation responsible for this disorder has not been reported. However, it has been shown that affected miniature Schnauzers produce biologically active MIS (Meyers-Wallen et al 1993). Therefore, the defect is likely to lie at the target organ level, such as in the MIS receptor.

Disorders of Androgen-Dependent Masculinization

Affected animals in this category are XY males with bilateral testes and normal Mullerian duct regression, but complete or partial failure of androgen-dependent masculinization. For example, in humans these disorders result from defects in testosterone production, 5 alpha reductase deficiency, or defects in the androgen receptor. Defects that occur in spite of normal testosterone production are termed androgen insensitivity or androgen resistance syndromes. Defects known to occur in the androgen receptor are sometimes referred to as testicular feminization syndrome (Tfm). Absence of a functional androgen receptor has been reported in a cat and a dog. In the cat, failure of masculinization occurred in both the internal and external genitalia, as masculinization due to testosterone and DHT requires the androgen receptor (Meyers-Wallen et al 1989). Thus the affected cat had female external genitalia and only undescended testes internally. The Wolffian duct derivatives (epididymides and vasa deferentia) were absent as they could not respond to testosterone to develop further.


Failure of testis descent does occur with other disorders of sexual development discussed above. However in this category, isolated cryptorchidism, one or both testes fail to descend into the scrotum at the appropriate time, but the rest of the male phenotype is normal. In dogs, the transabdominal phase of testis descent occurs during gestation. The inguinoscrotal phase of descent occurs later, with the testes normally being located within the scrotum by day 10-14 after birth. This is a prevalent defect in dogs of many breeds, but apparently rare or unreported in cats. The genetic mechanisms responsible for normal and abnormal testis descent are incompletely understood. Surveys of cryptorchid pups report that approximately 25% of testes undescended at 6 weeks of age descended within 6 months without surgical or medical intervention. However, it is unknown whether such animals transmit genes responsible for cryptorchidism. Although at least four factors are known to be involved in normal testis descent in mice: testosterone, the androgen receptor, Insl3 and its receptor, it is unknown whether canine cryptorchidism results from defects in any of these. Although this disorder is inherited in dogs, the genetic mechanisms and mode of inheritance are incompletely understood. The present consensus is that several genes may be involved and that these can be inherited from both parents, with cryptorchid being expressed as a recessive trait only in males. As unilateral cryptorchid males are often fertile, it is not recommended that they be bred as they will pass the genes for this disorder to their offspring. Furthermore, dogs that exhibit late testicular descent, after 6 weeks of age, may also pass the genes for cryptorchidism to their offspring.


In this disorder of the urethral wall, the urinary orifice is located in an abnormal location, and the prepuce and penis are often adversely affected, but otherwise the individual has normal male development. The urethra and prepuce fail to fuse, either completely or partially, along the ventral border resulting in an open urethra and a urinary orifice that is displaced caudal to the tip of the penis. In the most severe form, the urinary orifice is located in the perineum and the prepuce and penis are open along their entire ventral aspect. This has been rarely observed in cats but has been reported in several dog breeds, most often in the Boston terrier. The etiology is unknown, but the prevalence in certain breeds suggests strongly that it is an inherited disorder.


 Since an abnormal sexual phenotype can result from failure at any of the three major levels during development, and disorders resulting from different causes can appear phenotypically similar externally, it is important to correctly diagnose disorders of sexual development, and determine whether they are inherited. Eventually such disorders are likely to be classified according to the responsible gene mutations.

References/Suggested Reading

1.  Knighton E. 2004. Congenital adrenal hyperplasia secondary to 11 beta-hydroxylase deficiency in a domestic cat. JAVMA 225:238-241.

2.  Meyers-Wallen VN. 2001. Inherited abnormalities of sexual development in dogs and cats. International Veterinary Information Service, New York.

3.  Meyers-Wallen VN. 2000. CVT Update: Inherited Disorders of the Reproductive Tract in Dogs and Cats. In: Bonagura J (ed), Current Veterinary Therapy XIII, W.B. Saunders Co., Phila., pp. 904-909.

4.  Meyers-Wallen VN. 1999. Inherited disorders in sexual development. J. Hered 90:93-95.

5.  Meyers-Wallen VN, Schlafer D, Barr I, Lovell-Badge R, Keyzner A.1999. Sry-negative XX sex reversal in purebred dogs. Molec Reprod Dev 53:266-273.

6.  Meyers-Wallen VN, Palmer VL, Acland GM, Hershfield B. 1995a. Sry-negative XX Sex Reversal in the American cocker spaniel dog. Mol Reprod Dev 41:300-305.

7.  Meyers-Wallen VN, Bowman L, Acland GM, Palmer VL, Schlafer D, Fajt V. 1995b. Sry-negative XX Sex Reversal in the German shorthaired pointer dog. J Hered 86:369-374.

8.  Meyers-Wallen VN, Lee MM, Manganaro TF, Kuroda T, McLaughlin D, Donahoe PK. 1993. Mullerian Inhibiting Substance is present in embryonic testes of dogs with Persistent Mullerian Duct Syndrome. Biol Reprod 48:1410-1418.

9.  Meyers-Wallen VN, Wilson JD, Griffin JE, Fisher S, Moorhead PH, Goldschmidt MH, Haskins ME, Patterson DF. 1989. Testicular feminization in a cat. JAVMA 195:631-634.

Speaker Information
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Vicki N. Meyers-Wallen, VMD, PhD, DACT
Baker Institute for Animal Health, Cornell University
Ithaca, NY

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