Sex determination of the gonads is important for development of the sex phenotype (internal and external genitalia, secondary characteristics) and sexual behavior. A sex chromosome genotype of XY leads to the development of testes due to the sex-determining region of the Y chromosome (SRY) gene. The SRY gene induces downstream factors such as SRY-box containing gene 9 (SOX9), anti-Müllerian hormone, and glial cell line–derived neurotrophic factor in Sertoli cells.
Intersex conditions have been described in several domestic animal species.
True hermaphrodites are rare; they have both ovarian and testicular tissue and exhibit anomalies of the external genitalia. The karyotype is variable and can be a chimera, mosaic, or unknown.
Pseudohermaphroditism, often referred to as sex reversal syndrome, is more common. Animals have one or the other type of gonad and external genitalia of the opposite sex. Animals might be XY SRY negative or XX SRY negative. In horses, the most common type is 64XY SRY negative. Some cases of sex reversal are believed to be due to a recessive autosomal gene mutation.
In the most common intersex condition, male pseudohermaphroditism, testicular tissue is present in the abdominal cavity or beneath the skin in the scrotal region, and external genital organs resemble those of females. Persistent paramesonephric (Müllerian) duct syndrome is a rare form of pseudohermaphroditism that is inherited as an autosomal recessive condition in Miniature Schnauzers and occurs sporadically in other breeds (1).
Undescended testes are attached to the uterine horns, and the vasa deferentia are located in the wall of the uterus. Bilateral oviducts, a complete uterus with a cervix, and a cranial portion of the vagina are present. Bilateral scrotal testes or unilateral or bilateral cryptorchidism might also be present. Affected animals can present clinically with pyometra, urinary tract infection, prostate infection, or Sertoli cell tumor.
Diagnosis of pseudohermaphroditism is confirmed by the presence of a 78, XY chromosome constitution; bilateral testes; and the presence of all paramesonephric (Müllerian) duct derivatives (uterus, cervix, oviducts, and vagina). Androgen-dependent masculinization is that of a normal male.
Treatment is limited to castration and hysterectomy. The defect is inherited as an autosomal recessive trait in Miniature Schnauzers, and both females and males can be carriers. Homozygous affected dogs with a descended testis are generally fertile and capable of transmitting the trait to all offspring.
Polled intersex syndrome is well described in goats (2). Polled homozygotic males have decreased fertility due to segmental aplasia of the epididymides. They are often XX SRY negative. To prevent polled intersex syndrome, mating of polled does and bucks should be avoided.
Freemartinism Syndrome
Freemartinism syndrome is well known in cattle but has also been described in sheep, goats, and camelids (3). It causes varying degrees of female-to-male sex reversal of the internal and external genitalia as well as sterility in genetic females born co-twin to males. Vascular anastomosis of the chorionic placentas of the two fetuses results in transfer of anti-Müllerian hormone from the male to the female fetus, which inhibits development of the female tract.
Over 90% of all heifers born co-twin to bull calves are sterile (3).
Single-born freemartin females have been reported and are believed to result from the in utero death of a male co-twin (3).
The tubular genital organs in affected animals range from cordlike bands to near-normal uterine horns. Freemartins have a short vagina that ends blindly without communication with the uterus, and the cervix is absent. The ovaries usually fail to develop and remain small. (See images of freemartinism in a and a .)
External genitalia of a freemartin heifer. Note the increased anogenital distance and small vulva that are common in heifers with freemartinism.
Courtesy of Dr. Ahmed Tibary.
External genitalia of a freemartin ewe lamb. Note the increased anogenital distance that is a common clinical observation in freemartins. This lamb has a small vulvar opening and hypertrophic clitoris.
Courtesy of Dr. Ahmed Tibary.
Normal and freemartin cattle can be differentiated according to length of the vagina and presence or absence of a cervix. In calves 1–4 weeks old, the normal vaginal length is 13–15 cm, whereas in a freemartin, vaginal length is 5–8 cm (3). Vaginal length is easily measured by gently inserting a well-lubricated probe with a blunt end into the vagina.
Freemartins are XX/XY blood cell chimeras, and cytogenetic testing can demonstrate the presence of XX and XY chromosome patterns. The interchange of cells that occurs in the placental circulation between the fetuses can also be demonstrated by detecting two different blood types in a single animal.
Anti-Müllerian hormone (AMH) may be used as a marker to diagnose freemartinism in pubertal age animals. Mean AMH concentrations are lower in freemartin heifers compared to normal heifers; a cutoff value of ≤ 72 pg/mL and ≤ 68 pg/mL for AMH-1 and AMH-2, respectively, can be used to confirm diagnosis (4). AMH concentrations are most reliable for diagnosis in animals over 5 months old (5).
Other Chromosomal Abnormalities
Chromosomal abnormalities (XXY) have been described in males with azoospermia due to hypoplasia of the testes, epididymis, and vas deferens (1). Tortoiseshell or calico male cats possess two X chromosomes (XX/XXY, XY/XXY, or other chimeric or mosaic combination) and are sterile.
For More Information
Parkinson TJ. Infertility in the cow due to functional and management deficiencies. In: Noakes DE, Parkinson TJ, England GCW, eds. Veterinary Reproduction and Obstetrics. 10th ed. Saunders Ltd; 2019:361-407.
Griffin B, White S, Root Kustritz MVR. Disorders of sexual development and common reproductive pathologies. In: White S. ed. High‐Quality, High‐Volume Spay and Neuter and Other Shelter Surgeries. John Wiley & Sons, Inc; 2020:27-51.
Raudsepp T. Genetics of equine reproductive diseases. Vet Clin North Am Equine Pract. 2020;36(2):395-409.
References
Christensen BW. Disorders of sexual development in dogs and cats. Vet Clin Small Anim. 2012;42(3):515-526 doi:10.1016/j.cvsm.2012.01.008
Vaiman D, Pailhoux E, Schibler L, et al. Genetic mapping of the polled/intersex locus (PIS) in goats. Theriogenology. 1997;47(1):105-109, doi:10.1016/S0093-691X(96)00344-5
Padula AM. The freemartin syndrome: an update. Anim Reprod Sci. 2005;87(1-2):93-109. https://doi.org/10.1016/j.anireprosci.2004.09.008
Koca D. Nak Y, Sendag S, et al. Anti-Müllerian hormone: a novel biomarker for detecting bovine freemartinism. Reprod Domest Anim. 2024;59(2):e14542. doi:10.1111/rda.14542
Bozkurt G, Kaya F, Yildiz M, et al. Age-specific analysis of anti-Müllerian hormone and liver biochemical parameters in freemartin Holstein calves and heifers: a pilot study. Domest Anim Endocrinol. 2024;88:106855. doi:10.1016/j.domaniend.2024.106855
