Persistent Müllerian duct syndrome
Keywords: feline, cat, cryptorchid, testes, Müllerian, inhibin, AMH
A feral tomcat was admitted for routine castration. The right testis was present in the scrotum and the cat had a penis with well developed barbs, suggesting the presence of androgens. The left testis was was not palpable in either the scrotum or inguinal canal. Therefore an exploratory laparotomy was performed to locate and remove it. A uterus, normal in appearance was present in the abdomen. At the cranial tip of the left uterine horn, a structure resembling a small testis (testicle) was present. The right uterine horn passed through the right inguinal canal. The scrotal testis on that side was removed and the tip of the right uterine horn drawn cranially into the abdominal cavity so that a hysterectomy could be performed. The uterus with both gonads is shown below.
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Dr Heather Hillier (hhillier@stjohns.ca) brought this case to the attention of the author and retains copyright for the image shown above.
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The image above shows the histology of the retained gonad (top) and the scrotal testicle (bottom). The retained gonad was a testis with poorly developed seminiferous tubules containing cells that were a mixture of spermatogonia and sertoli cells. Some tubules contained only sertoli cells. Areas between the tubules were populated by leydig cells and a cell type that the author was not able to identify with certainty. These were labeled "Unknown cell type". The nuclei of these cells bore a strong resemblance to those of the leydig cells but their vacuolated, and small amount of cytoplasm was not typical for normal leydig cells. Perhaps they were indeed leydig cells but a sub-population showing functional artifacts.
The lower part of the image shows the seminiferous epithelium of the descended testicle. It was normal in appearance; spermiation was even occurring in some areas.
The image below shows a complete absence of spermatozoa in a cross section of the epididymis from the retained testis (the top inset). In terms of the non-functional seminiferous tubules in that testis, this was expected. It was surprising however, to find no spermatozoa in the epididymis of the scrotal testis. This may indicate that there was non-union between that testicle and its epididymis.
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A cross section of the uterus revealed the expected tissue layers of a normal uterus. However, the endometrial glands were poorly developed. Nevertheless, many glands contained eosinophilic material, suggesting secretory activity.
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This cat showed an unusual form of intersex known as persistent Müllerian duct syndrome (PMDS). It would not be surprising to find PMDS in any mammal but it is well known in humans and has also been described in dogs, notably Miniature Schnauzers. A remarkable case with a completely dissected tract was described by Haibel, G.K. and Rojko (1990) in a goat. A presumptive diagnosis of PMDS has been made in a male cat with pyometra but to the author's knowledge, this is first case where the condition has been verified in a cat histologically.
Some basic endocrinology will help in understanding this unusual condition.
AMH and inhibin are closely related dimer proteins, part of a large family of growth factors that control protein secretion as well as cell growth and differentiation. Importantly and especially in the case of AMH, they also control programmed cell death (apoptosis). Both AMH and inhibin are produced by sertoli cells in males and the granulosa cells of follicles in females. The principal function of inhibin is to decrease FSH secretion in both males and females. That of AMH, is to prevent FSH binding to pre-antral follicles and (of great importance in this case) to cause apoptosis of the Müllerian system in males.
Recall that the Müllerian system persists by default in embryos i.e. if the the gonads (male or female) are removed from an embryo, the Müllerian system will persist and grow into a cranial vagina, cervix and uterus. However, if an embryo has testes, it is the presence of sertoli cells in those testes, producing AMH, that cause cell death and regression in the Müllerian system. Of course, the presence of testes also causes masculinization of the embryo. Returning to the case in hand, this animal had two testicles; one scrotal and the other retained; both were likely sources of AMH.
Strictly speaking, an animal with PMDS is a male pseudohermaphrodite because its genital tract does not match the sex of its gonads. But unlike other male pseudohermaphrodites, its external genitalia are normal in appearance. It is the internal genital tract that does do not match the sex of the gonads.
| Disentangling oneself from all definitions, it is perhaps easiest for the reader to picture a male with PMDS as being normal in every sense (masculine appearance, libido and even fertility in a few cases) but for the retention of a uterus that would otherwise have regressed under the influence of AMH. In a few cases, a normal Wolffian system exists, abaxial to the uterus, explaining how some men with PMDS are fertile. |
In dogs, it has been shown that AMH is actually present in many cases of PMDS but probably because of receptor site abnormalities, it is unable to exert its effect on the Müllerian system. In humans, that is also true in some cases but in others, the concentrations of AMH are low or undetectable. In a small proportion of cases reported in humans, both AMH concentrations and receptor sites were normal. In those cases, the cause of the condition was unclear. It is not yet known if all these situations occur in dogs as well.
Most cases of PMDS are associated with autosomal recessive abnormalities. The basic karyotype of affected males is usually normal i.e. 46XY in the case of men, 60XY in the goat mentioned earlier and 78XY in the case of dogs. Karyotyping was not performed on the cat described here.
PMDS is usually discovered at surgery and affected males are often cryptorchids; unilaterally or bilaterally (the goat was not cryptorchid). Scrotal hernias containing the testis and part of the uterus are also part of the PMDS syndrome. As expected, the cryptorchid testes in these cases occasionally become neoplastic as well.
| Important: As seen in the canine section of LORI, it is possible that this cat could have been an XX pseudohermaphrodite (a case of "sex reversal") because XX pseudohermaphrodites may also show persistence of the Mullerian system in the face of anti-Mullerian hormone production. However, to date, no cases of XX sex reversal have been described in cats. Therefore the cat in this entry was in all probability, an XY male pseudohermaphrodite and therefore, a case of PMDS. |
Selected references:
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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
Meyers-Wallen, V.N. et al 1989. Müllerian inhibiting substance is present in testes of dogs with persistent müllerian 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
