Persistence of the Müllerian ducts
Keywords: Canine, persistent, Müllerian, uterus, ductus deferens, testis, histologyAt the outset. the author wishes to thank Dr Natalie Fraser of the University of Queensland for recognizing this case as being unique, performing the karyotype and bringing the case to the attention of the author. Furthermore, the author must thank both Drs Fraser and Xavier Schneider for making material available for histology. Please see their contact information below the references in this entry. Except for the histology, copyright for all images belong to Drs Fraser or Schneider.
A 2 year old Kelpie was presented for self-mutilation of ambiguous external genitalia. As shown below, a short penis protruded from between the vulva lips, a urethral opening being present at the end of that structure. Urine flowed from this opening.
Image size: 1630x 1174px
Image size: 800 x 590px
During gonadectomy, testicle-like structures were noted. These structures had adnexa resembling epididymides (see below). However, the tubular genital tract resembled a uterus, not the expected ductus deferentia. The tubular tract on either side approached fusion at the caudal extent of the operative field, even showing evidence of a structure resembling an intercornual ligament. However, it was impossible to identify fusion into a uterine body or cervix. Nevertheless, the structure was presumed to be a uterus. A prostate gland was not described. During the operation, other tubular structures adjacent to the uterine horns were not remarked upon. It was only during histological examination that it was evident that ductus deferentia had been present, lateral to the uterus. In retrospect, they could have been seen macroscopically (see below). Because only one section of the uterus was obtained for histology, it is not known if the ductus deferentia were complete on both sides.
Image size: 1141 x 1000px
The image below shows that two structures were present in the section of the tubular genital tract retained for histology. Clearly, a ductus deferens was present in this section and medial to it, a section of a uterine horn. Recall that the male or wolffian (mesonephric) system normally develops lateral to the müllerian or female (paramesonephric) system in embryos. Therefore this finding was consistent with normal early embryogenesis. Later in gestation of course, the uterus regresses in normal males. This is discussed later.
Image size: 800 x 590px
A cross section of the ductus deferens is shown below. It contained pseudostratified, ciliated epithelium and thick layers of inner circular and outer longitudinal smooth muscle; seemingly normal for a ductus deferens in every respect.
Image size: 1905 x 966px
Uterine histology revealed endometrial gland development that was simple and sparse but otherwise, surprisingly normal in appearance. Adrenal progesterone production may have stimulated gland development to some degree but hypoplasia of the lamina propria was no doubt due to the a relative absence of progesterone; otherwise augmented by corpora lutea.
Four tissue sections of one of the gonads were examined and no ovarian tissue was noted. This gonad contained only seminiferous tubules and was therefore, a testis. Spermatogenesis was completely absent; a situation that is to be expected in all cryptorchid testicles. Naturally, the epididymis was devoid of spermatozoa as well.
Image size: 1901 x 962px
Unfortunately only one gonad was examined histologically, leading one to assume that the contralateral gonad was also a testis. There is of course, the possibility that the unexamined gonad was an ovotestis. In such a case, the animal would be referred to as a "lateral, true hermaphrodite" but those individuals are rare. Therefore it may be safe to assume that both gonads were testes. That being the case, this dog would properly be referred to as a pseudohermaphrodite because the gonads were of one sex and the remainder of the reproductive tract was ambiguous. In addition, because the gonads were testes, this dog would most accurately described as a male pseudohermaphrodite (Female pseudohermaphrodites are extremely rare).
With persistent mullerian ducts, this male pseudohermaphrodite potentially belonged to one of two syndromes where mullerian ducts persist into adulthood in male animals. In the author's opinion, both can correctly be referred to as persistent mullerian duct syndromes (PMDS) i.e.
1. PMDS is found in males with testes and XY karyotypes. This is the form of PMDS commonly described in veterinary medicine; adopted from the description in humans.. It is inherited as a dominant autosomal trait. A male cat with PMDS is described in the Feline section of LORI. Mullerian ducts have been shown to persist in male animals even though anti mullerian hormone (AMH) is being produced, probably a result of a defective receptor site or its downstream intermediaries. Indeed, this appears to be the de facto case in dogs with PMSD. The mullerian system is presumed to be insensitive to AMH in such individuals.
2. PMDS may also be found in so called "sex reversed" XX males. The term "sex reversed" suggests that the reproductive tract is the complete opposite of what is expected according to the karyotype. However, this is seldom the case. Indeed, the phenotype of the XX reproductive tract varies greatly in XX animals. Some are obviously male-like, while others are so mildly androgenized (with small populations of seminiferous tubules in their ovaries) that pregnancy is possible. Therefore the author prefers the term "XX pseudohermaphrodite" because it covers the range of genital tract phenotypes that can occur in these individuals. In rare cases, XX animals with PMDS are true hermaphrodites i.e. their gonads have germinal tissue from both sexes; all the more reason not to refer to these animals as "sex reversed".
As mentioned earlier, the mullerian system develops by default in embryos i.e. if the the gonads (male or female) are removed from an embryo, the mullerian system will persist and form the cranial vagina, the cervix and the uterus. Alternatively, if an embryo has testes, sertoli cells are present, causing apoptosis and regression in the mullerian system.
In dogs with PMDS (of both types) AMH is produced by the Sertoli cells yet it does not suppress the mullerian system. In dogs, it has not been determined if insensitivity to AMH is due to aberrations in the molecular structure of AMH, abnormalities of AMH receptors sites or translation of AMH effects within target cells. In the image below, it is obvious that a substantial population of sertoli cells was present in the testis of this dog. Although serum concentrations of AMH were not measured, published data suggest that AMH was probably being produced.
Image size: 1905 x 1247px
A partially developed penis and os penis suggests that the leydig cells in the testes were indeed producing testosterone.
The presence of well developed wolffian ducts (ductus deferentia) lateral to the uterus was interesting but not unexpected because of the presence of testes. In fact, the wolffian system can be so well developed in some XY males with PMDS, that they can be fertile. Certainly, this has been described in humans.
The karyotype of dogs with classic PMDS is usually 78XY with the cause of PMDS located to an autosomal recessive gene. Initially, the author made a diagnosis of classic PMDS in this case. However, the karyotype in this male was later found to be 78XX. See below.
Image size: 1816 x 1128px.
This indicated that the persistence of mullerian ducts in this dog was not related to the autosomal gene abnormality described in the classic persistent mullerian duct syndrome. The cause of PMSD in dogs with XX karyotypes is unknown.
To describe this case as being one of "PMDS in a dog with XX sex reversal" would be incorrect. With testes and a mixture of both male and female tubular genital tracts, its phenotypic sex was certainly not reversed.
Selected references:
Belville, C. et al 1999. Persistence of mullerian derivatives in males. Am. J. Med. Genet.89:218–223.
Berkman, F. 1997. Persistent mullerian duct syndrome with or without transverse testicular ectopia and testis tumours. British J. Urology. 79:122-126
Hagjer, S et al. 2015 Intra-abdominal seminomas in bilateral undescended testes in a patient with persistent mullerian duct syndrome. Hellenic J. Surgery 87: 493-496
Haibel, G.K. and Rojko, J.L. 1990. Persistent Miillerian Duct Syndrome in a Goat. Vet Pathology. 27:135-137
Kaore A et al 2012. Persistent Mullerian Duct Syndrome NJIRM.3: 153-154
Knebelmann, B. et al 1991. Anti-Mullerian hormone Bruxelles: A nonsense mutation associated
with the persistent Mullerian duct syndrome. Proc. Natl. Acad. Sci. 88:3767-3771
Leocadio, D. E., et al. 2011. Anatomical and histological equivalence of the human, canine, and bull vas deferens. Can. J, Urology 18: 5699-5704
Meyers-Wallen, V.N. et al 1989. Müllerian inhibiting substance is present in testes of dogs with persistent mullerian duct syndrome. Biol. Reprod. 41:881-888
Meyers-Wallen, V.N. et al 1993. Mullerian inhibiting substance is present in embryonic testes of dogs with persistent mullerian duct syndrome. Biol. Reprod. 48:11410-1418
Nayak, V.J. et al 2014. Persistent mullerian duct syndrome: A case report and review of the literature. Int J Appl Basic Med Res. 4:125–127
Schulman, J. and Levine, S.H. 1989. Pyometra involving uterus masculinus in a cat
J Am Vet Med Assoc.194: 690–691
Weissbach, L. et al. 1999, Prognostic factors in seminomas with special respect to hCG: results of a preospective multicentric study. Eur Urol. 36:601-608
Meyers-Wallen, V.N. 2009. Review and Update: Genomic and Molecular Advances in Sex Determination and Differentiation in Small Animals. Reprod.Dom.Anim. 44:40–46
Verma, R.S. 1996 Genetics of Sex Determination. ISBN-10: 1559388366
Wu, X et al. 2009. A single base pair mutation encoding a premature stop codon in the MIS type II receptor is responsible for canine persistent Müllerian duct syndrome
J.Andrology, 30: 46-56
Contact information and acknowledgements:
Dr Natalie Fraser (natalie.fraser@uq.edu.au)
Dr Xavier Schneider (Xavier.Schneider@qldvetspecialists.com.au )
Thanks to Dr Herris Maxwell (maxwehs@auburn.edu) for raising the valid point that this dog could have been an XX male pseudohermaphrodite ("sex reversal"). The author had originally presumed it to be an XY male pseudohermaphrodite; a classic PMDS.
The author extends his thanks to L.Dobbin of the Diagnostic Quality Assurance Program at the AVC for allowing the use of their excellent Olympus BX6 1VS virtual microscopy equipment. For more information on the creation of virtual histology on the internet (soon to be featured on LORI) contact Ms Dobbin at 1-902-0831 or edobbin@upei.ca
