Disorders of sexual development in the dog and cat

Abstract

Normal sexual differentiation occurs in three sequential steps—establishment of chromosomal (genetic) sex, development of gonadal sex, and development of phenotypic sex. Errors in the establishment of chromosomal, gonadal, or phenotypic sex cause abnormal sexual differentiation. Affected individuals are identified with a wide variety of patterns from ambiguous genitalia, to apparently normal genitalia with sterility or infertility. When a patient is suspected of having a disorder of sexual development, analysis of the chromosomal constitution and complete gross and histopathologic description of the gonads, internal and external genitalia are required to correctly categorize the type of disorder.

Introduction

Normal sexual differentiation occurs in three sequential steps—establishment of chromosomal (genetic) sex, development of gonadal sex and development of phenotypic sex. At fertilization, chromosomal sex is established (XX or XY); this composition is maintained in all cell lines throughout life. Despite their chromosomal sex, all early embryos are sexually indifferent; they possess bipotential genital ridges, wolffian and müllerian ducts, a urogenital sinus, a genital tubercle, and genital swellings. Sex chromosome constitution determines gonadal differentiation: the presence of a Y chromosome results in differentiation of the genital ridge into a testis. In the absence of a Y chromosome, the genital ridge differentiates into an ovary. The gene Sry, named for the sex-determining region on the Y chromosome, is necessary for either activation of genes inducing testis formation or suppression of genes encoding ovarian formation. The exact mechanisms of the pathways controlled by Sry are unknown. Genes identified as being involved in testis differentiation in humans, transgenic mice, or cell culture systems include Sox9 (Sry-like HMG box), Amh, Wt1, Sf1, and Drmt1 [1]. Normal XX individuals, which lack Sry, possess two X-linked Dax1 alleles which are involved with ovarian differentiation. Dax1 may play more of a role in turning off male-specific genes during gonadal differentiation, rather than turning on ovarian differentiation; it also likely plays a role in adrenal, pituitary, and hypothalamic development [2]. Determination of phenotypic sex (differentiation of the tubular reproductive tract and external genitalia) is dependent on gonadal sex. The default embryonic plan is female; if the genital ridges are removed from XX or XY embryos prior to gonadal differentiation, the female phenotype results. In normal XY individuals, Leydig cells within the testis secrete testosterone (T), which promotes differentiation of the wolffian duct into the epididymis and vas deferens. Sertoli cells in the testis secrete müllerian inhibiting substance (MIS), which causes regression of the müllerian ducts. Secretion of these two hormones must occur within a critical time window during embryonic development (different for each species) for normal masculinization to result. In the urogenital sinus, genital tubercle, and genital swellings, testosterone is converted by 5α-reductase to dihydrotestosterone (DHT), which causes the closure of the urethra, and development of the prostate, penis, and scrotum. Descent of the testes into the scrotum completes phenotypic development in the male. In normal XX individuals the absence of MIS, T, and DHT, allows the müllerian ducts, urogenital sinus, and genital tubercle and swellings to develop into female internal and external genitalia. The müllerian ducts develop into the oviducts, uterus, cervix, and cranial vagina; the urogenital sinus develops into the caudal vagina, and vestibule; the genital tubercle develops into the clitoris; and the genital swellings develop into the vulva. Errors in the establishment of chromosomal, gonadal, or phenotypic sex cause abnormal sexual differentiation. Affected individuals are identified with a wide variety of patterns from ambiguous genitalia, to apparently normal genitalia with sterility or infertility.

Section snippets

Disorders of chromosomal sex

Abnormal chromosomal sex results from defects in the number or structure of the sex chromosomes. These derangements result from random events during gamete formation or early embryonic development; therefore, they can be observed in dogs and cats of any breed and generally do not display a familial pattern. Abnormalities of chromosomal sex include XXY syndrome, XO syndrome, XXX syndrome, true hermaphrodite chimeras, XX/XY chimeras with testes, and XY/XY chimeras with testes.

The majority of

Disorders of gonadal sex

Individuals with disorders of gonadal sex have either an XX or XY sex chromosomal constitution, but the gonadal sex does not agree with the chromosomal sex (“sex-reversed”). Only XX sex reversal has been reported in the dog: affected dogs have a 78,XX karyotype with variable degrees of testicular differentiation of the gonad. No cases of XX sex reversal have been reported in the cat, and no cases of XY reversal have been reported in either the dog or cat. XX sex reversal includes XX true

Disorders of phenotypic sex

In individuals with disorders of phenotypic sex there is agreement of the chromosomal and gonadal sex, but the phenotypic sex (internal or external genitalia or both) disagrees with the gonadal sex. Syndromes that have been described in dogs and cats include: female pseudohermaphroditism, male pseudohermaphroditism, persistent müllerian duct syndrome, and defects in androgen-dependent masculinization. Descent of the testes into the scrotum completes the development of phenotypic sex. The

Agenesis and dysgenesis of the reproductive tract

Agenesis is the failure of a structure or organ system to develop due to non-appearance of its primordium during embryonic development. Dysgenesis is a defect in development of a structure or organ. In the reproductive tract of dogs and cats, agenesis or dysgenesis of the gonads, müllerian or wolffian ducts, urogenital sinus, genital tubercle, or genital swellings can be seen. Some examples would include monorchidism and testicular hypoplasia; ovarian agenesis and ovarian hypoplasia; segmental

Conclusion

Abnormalities in sexual differentiation arise when errors in the establishment of chromosomal, gonadal, or phenotypic sex occur. Since the external genitalia of many of these disorders can appear similar, and some disorders have a heritable basis, whereas others do not, it is important to correctly diagnose the type of disorder. Correct categorization of a patient suspected of having a disorder of sexual development requires cytogenetic evaluation, and gross and histopathologic description of…

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