Mullerian Ducts Remnants in the 46 XY Disorder of Sex DevelopmentCorrespondence Address :
Dr. Ashutosh Halder
Associate Professor,Department of Reproductive Biology All India Institute of Medical Sciences,New Delhi 110029(India)Tele:011-26594211,
Objective: The objective of this study was to find out the prevalence of mullerian duct remnants in the 46 XY disorder of sex development due to disorders in androgen synthesis/action.
Methods: Thirty eight cases of 46 XY disorder of sex development of disorders in androgen synthesis/action were evaluated for diagnosis and management, including mullerian duct remnants. Mullerian ducts remnants were found in nine of them (23.7%). The diagnostic evaluation consisted of pelvic ultrasonography, genitography, cystourethroscopy, genitoscopy and laparoscopy or laparotomy.
Results: The common types were an abnormally large prostatic utricle communicating with the urethra and a rudimentary uterus.
Conclusion: It is concluded that mullerian ducts remnants are common with the 46 XY disorder of sex development due to disorders in androgen synthesis/action. During evaluation of patients, this aspect should be kept in mind and during management, appropriate measures should be undertaken to prevent future complications like chronic urinary tract infections, stones and voiding troubles.
46 XY disorder of sex development; disorders in androgen synthesis/action; Mullerian duct remnants; Prostatic utricle
Normal male sexual differentiation is governed by two testicular hormones: testosterone (synthesized by the interstitial Leydig cells) and antimÃ¼llerian hormone (AMH; produced by Sertoli cells present in the seminiferous tubules) (1),(2). Androgen in the form of testosterone causes differentiation of the wolffian duct into the epididymis, vas deferens and seminal vesicles, whereas androgen in the form of dihydrotestosterone (DHT; testosterone is converted to dihydrotestosterone by the enzyme 5 α reductase) is needed for the virilization of the urogenital sinus and the external genitalia (3). The AMH produces regression of the mullerian duct i.e. uterus, tubes and upper vagina. At about 6 weeks of embryonic life, the mullerian ducts appear adjacent to the wolffian ducts. Mullerian ducts give rise to the uterus, the fallopian tubes and the upper vagina in females. In males, most portions of the mullerian duct regress, except for the cephalad end which persists as the appendix testis and the caudal end as the prostatic utricle (4). The prostatic utricle is a composite of the urogenital sinus and the mullerian duct. Regression of the mullerian duct in males is controlled by AMH, which is produced by the sertoli cells soon after testicular differentiation (5).
Incomplete embryonic regression of the mullerian ducts in otherwise normal males, has been attributed to an autosomal gene mutation that results in inappropriate synthesis and/or action of AMH (AMH deficiency syndrome) (6),(7). Mullerian ducts remnants (MDR) are seen frequently also in cases of the 46 XY disorder of sex differentiation (DSD) with (8),(9),(10) and without gonadal dysgenesis (11),(12).
Androgen insensitivity syndrome (AIS) is a heterogeneous group of defects in the androgen receptor, resulting in varying degrees of defective masculinization in 46 XY individuals. The AIS phenotype is complicated by the presence of somatic mosaicism for the AR gene mutation (13), (14). Cases of 46 XY DSD of AIS occasionally also exhibit mullerian ducts remnants (15),(16),(17),(18),(19). Mullerian ducts remnants in AIS may be associated in as many as 35% cases (20). This report presents nine cases with 46 XY DSD of disorders in androgen synthesis/action (probably AIS andunlikely to be a 5 α reductase deficiency syndrome) with MDR.
Patients and Methods
A total of 63 cases of DSD were evaluated in the department of Medical Genetics, SGPGIMS, Lucknow, India, as part of a specialized referral care. There were 41 cases of 46 XY DSD, 15 cases of 46 XX DSD (14 cases of congenital adrenal hyperplasia and one in utero androgen exposure), 04 cases of ovotestis DSD (formerly true hermaphrodite) and 03 cases of gonadal dysgenesis (including one with mixed gonadal dysgenesis). Among 41 cases of 46 XY DSD, there was 38 cases of disorders in androgen synthesis/action (AIS) and one each of AMH deficiency syndrome, testicular enzyme defect and testicular atrophy. Ambiguity of the external genitalia was the presenting complaint. There was no other abnormality. The cases were between one month and 24 years at the time of evaluation. All patients underwent cytogenetic study and hormonal evaluation (FSH, LH and testosterone; also estradiol to pubertal cases) including human chorionic gonadotropin (hCG) stimulation test in pre-pubertal cases. A minimum of 20 metaphases were examined in each case as per the routine cytogenetic practice of the laboratory. As part of the work-up to establish the diagnosis and to outline the plan of management, all cases were evaluated for internal sex organs. For this purpose, the patients were subjected to lower abdominal ultrasonography, genitogram, genitoscopy, urethro-cystoscopy and laparoscopy/laparotomy. An enlarged prostatic utricle was graded according to Ikoma (21) (Grade 0: opening located on the posterior urethra but the utricle does not extend over the verumontanum; Grade I: larger than Grade 0 but it does not reach the bladder neck; Grade II: more enlarged and its dome extends over the bladder neck. The prostatic utricle opens into the central area of the verumontanum in the prostatic urethra in Grades 0, I and II. In rare cases, the opening is situated in the bulbous urethra, just distal to the external sphincter and this is classified as Grade III).
Out of 38 cases of disorders in androgen synthesis/action (AIS), there were 9 cases with MDR. Nine cases with MDR were between 7 months to 18 years at the time of evaluation. (Table/Fig 1) shows the summary of major clinical findings of the 9 cases of disorders in androgen synthesis/action (AIS) with mullerian duct remnants and (Table/Fig 2) it also shows various genitogram findings of some of the cases.
The appearance of the genitalia of 9 cases with MDR ranged from near normal female to male with perineoscrotal hypospadias and micropenis. However, the genitalia were ambiguous in most of the patients. Among the three pubertal patients (reared as females), two sought attention because of virilization and suboptimal breast development,whereas the third one presented with virilization and asymmetric breast development.
All nine patients with MDR were found to have 46, XY chromosomes in peripheral blood lymphocytes.
Ultrasonography, Genitogram, Genitoscopy, Cystourethroscopy and Laparoscopy
Common urogenital sinus was seen in three cases; well-developed vagina although blunt, was seen in four cases and rudimentary uterus as fibrous nodule was demonstrated in three. An enlarged prostatic utricle was demonstrated in six cases. There were five cases of grade 2 and one case of grade 3 prostatic utricle in this series.
All patients underwent evaluation for FSH, LH and Testosterone (also Oestradiol to pubertal cases) initially. The hCG stimulation test was carried out in six pre-pubertal cases. Four were positive and two were equivocal for the hCG stimulation test. Basal testosterone of adult level was seen in three pubertal cases. One pre-pubertal case had near normal adult value of testosterone and thus had equivocal hCG stimulation.
Gonadal biopsy was carried out in four cases. Three were from the pre-pubertal age group. The findings were either normal testes, prepubertal testes or testes with Leydig cell hyperplasia without any evidence of spermatogenesis, as well as with no evidence of hyalinization and atrophy of the seminiferous tubules.
Sex assignment was carried out in all cases. It was according to the sex of rearing in all, except one, whose sex was changed from female to male following a request from the patient. Bilateral orchidectomy was carried out in two patients who presented with virilization and were reared as females. Genital reconstruction was carried out in seven patients.
These cases represent disorders in androgen synthesis/action likely to be AIS although the possibility of 5- ARDS was not excluded, as there was no facility of the DHT assay during the study period. These were cases with chromosomal sex as 46, XY; gonads as testes; normal/near normal function of testes; no in utero exposure of oestrogen/progesterone. There were three families with multiple affected sibs with variable presentation and sex of rearing (first family with three affected and reared all as males, second family with three affected and reared two as males and one as female and third family with two affected and reared as males). The post pubertal cases also had variable presentation, including asymmetric breast development, thus indicating AIS rather than 5 ARDS clinically.
The unexpected association of MDR in persons with disorders in androgen synthesis/action (AIS) raised the question as to whether this is a random coincidence or whether these were inherited abnormalities. This association appears in literature both as sporadic case reports (15),(16),(17), (22), as well as case series (20),(23). In one case series (20), this association was as high as 35%; in our series, this association was observed in 23.7% of the patients. The large number of patients with AIS in whom MDR has been noticed, suggests the role of androgens in the complete regression of the mullerian duct. Early testicular descent, leading to the removal of the mullerian structures from exposure to the effective range of AMH, has been suggested as an explanation for the persistence of mullerian duct remnants (16). Oestrogen also plays an important role in the modulation of the growth and development of the internal genital ducts (24). High oestrogen levels preserve the mullerian duct in males. The oestrogen induced inhibition of AMH action may be countered by androgen, indicating that the androgen/oestrogen ratio is essential for an adequate regression of the mullerian duct in males. This is also supported by an association between the prenatal administration of diethyl stillbesterol (DES) and the frequent occurrence of enlarged prostatic utricles (mullerian duct derivative) (25). Similarly, the injection of DES in pregnant mice with the AIS mutation gene inhibits the regression of the mullerian duct in normal as well as mutant male offspring (much less regression in mutant mice) (26). Human embryos with complete AIS is refractory to androgen action and thus, has an exaggerated oestrogenic response, which by interfering with AMH action, results in incomplete mullerian duct regression. Initially, it was thought that AMH does not require the action of androgen to exert its effect (27). However, since in postnatal testis, the sertoli cells are under androgenic control, it is possible that in the presence of abnormal or deficient androgen receptors, the secretion and/or action of AMH could be impaired, resulting in the incomplete regression of the mullerian duct (28). Probably maternal oestrogen and progesterone in the foetal circulation may also alter the ratio of androgens to antiandrogens (oestrogen), which may contribute to the incomplete regression of the mullerian duct in genetically susceptible AIS.
In this series, one sib pair (cases 8 and 9) showed some discordant phenotype which is commonly possible with AIS, as often (one third cases) associated with somatic mosaicism (29),(30),(31). Another case had high oestradiol level at puberty along with asymmetric breast development (indicates somatic mosaicism), which favours the diagnosis of AIS. The different phenotypes with similar mutation can also be explained through factors that modify AR action (32). Individual differences in androgen levels and the timing of its production during the critical period of genital organogenesis are among the factors which are likely to be involved. In another case (case 7), gonadotropins were like gonadal failure (primary) with normal testosterone (for age) and partially virilized. Testicular histology also did not co-relate with gonadal failure of that severity, although the possibility of gonadoblastoma, gonadal dysgenesis and Klinefelter syndrome (see Table 1) were excluded. The reason for high FSH despite normal testosterone was unexplainable.
These findings suggest that incomplete regression of the mullerian duct in the 46 XY DSD of disorders in androgen synthesis/action (AIS) is a reality and that it is not uncommon (as high as 23.7%). It is suggested that every case of 46 XY DSD with disorders in androgen synthesis/action (mainly AIS) should be evaluated for mullerian ducts and care should be taken during reconstructive surgery to prevent future complications associated with this derivative.
Mullerian ducts remnants are common with the 46 XY disorder of sex development due to disorders in androgen synthesis/action. During management, appropriate measures of mullerian ducts remnants should be undertaken to prevent future complications.
The author thanks the Departments of Medical Genetics, Medical Endocrinology, Surgical Endocrinology, Urology, Pathology and Radiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow for assisting in the workup and management of the cases with ambiguous genitalia.
Consent was taken as per routine practice before taking clinical photograph from cases/parents of cases.
Financial and non financial competing interests:None
AH carried out all evaluation workup including the initial clinical evaluation, formulated the activity plan, checked results, interpretated results and prepared the manuscript. AH will be the guarantor of the manuscript.
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