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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 29  |  Issue : 5  |  Page : 243-251

Gonadectomy in patients with disorder of sexual development


Department of Urology, National Taiwan University Hospital, Taipei, Taiwan

Date of Web Publication3-Sep-2018

Correspondence Address:
Kuo-How Huang
Department of Urology, National Taiwan University Hospital, No.7 Chung-Shan South Road, Zhongzheng District, Taipei 100
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/UROS.UROS_35_18

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  Abstract 


Objective: The objective of this study is to investigate clinical characteristics and treatment outcomes of patients with disorder of sexual development (DSD) who underwent gonadectomy at a single tertiary center. Materials and Methods: We retrospectively enrolled patients with DSD who received gonadectomies in our hospital from 2000 to 2015. The clinical presentations, laboratory tests, image studies, operative findings, and pathology reports were collected by reviewing medical records. Results: A total of 18 patients with DSD were analyzed, including 17 46XY karyotype and one 45X/46XY karyotype. Among them, 17 patients were assigned female gender. The most common diagnoses were androgen insensitive syndrome (n = 5), 46XY gonad dysgenesis (n = 5), and 17α-hydroxylase deficiency (n = 3). Initial presentations included amenorrhea (n = 9), ambiguous genitalia (n = 5), and abnormal prenatal screening (n = 3). The peak age of gonadectomies was 5 at infantile (1–2 years) and 7 at adolescent period (11–15 years). A total of 19 gonadectomies were performed without complications; pure inguinal approach in 6, inguinal plus laparoscopy exploration in 13. There were no malignancies in all resected gonads; in addition, spermatogenesis was found in only one resected gonad. Conclusions: Female gender assignment was more frequently chosen in our series. The presentations and diagnoses in children with DSD were various; it is important to select individualized treatment strategy for these patients.

Keywords: Disorder of sexual development, gonadectomy, gonadoblastoma


How to cite this article:
Chen KT, Tai YS, Chiang IN, Chang HC, Huang KH. Gonadectomy in patients with disorder of sexual development. Urol Sci 2018;29:243-51

How to cite this URL:
Chen KT, Tai YS, Chiang IN, Chang HC, Huang KH. Gonadectomy in patients with disorder of sexual development. Urol Sci [serial online] 2018 [cited 2018 Sep 23];29:243-51. Available from: http://www.e-urol-sci.com/text.asp?2018/29/5/243/238433




  Introduction Top


The term disorders of sex development (DSD) is defined as congenital conditions with abnormal development of chromosomal, gonadal or anatomical sex.[1] The clinical characteristics among patients with DSD show a wide variety. The management of these patients highly depends on the specific diagnosis, which are mainly based on patients' clinical manifestations with genetic and laboratory study.

In DSD patients, gonadectomies were performed due to the concern of the malignant potential of gonads.[2] The malignant potential of gonads has been reported in previous literatures.[3],[4],[5] Germ cell malignancy mostly occurs in DSD patients with Y-chromosomal components. Therefore, gonad in patients with 46XY gonadal dysgenesis who are assigned as female should be removed to prevent malignancies in the future.

Growing evidence suggested the frequency of gonadoblastoma in DSD patients remains various and it is not necessary for all DSD patients to receive gonadectomies. Moreover, the optimal timing of gonadectomy remains controversial.

The rarity of the disorder makes the establishment of standard treatment guidelines difficult. The individualized treatment strategy is very important for each patient with DSD while achieving final diagnosis after a comprehensive genetic, endocrine, and psychological evaluations. Meanwhile, the preference of patients and parents should be put into consideration. Here, we investigate the clinical characteristics and treatment outcomes of gonadectomies in DSD patients in a 15-year period in our institute. It is also thefirst report of DSD on Taiwanese patients.


  Materials and Methods Top


From April 2000 to July 2015, a total of 18 patients with DSD underwent gonadectomies in our institution. A multidisciplinary team including pediatric endocrinologists, urologists, gynecologists, radiologist, and pathologists were involved in the diagnosis and treatment for these patients.

We retrospectively collected clinical data from medical chart review including clinical manifestations, laboratory, genetic, image studies, operative and histological findings in all patients.


  Results Top


Gender assignment

In our study with the 18 patients, 17 patients were found with 46XY karyotype. All of the 17 patients were assigned as female after a multidisciplinary discussion. One patient with 45X/46 XY karyotype was assigned as male gender.

Diagnosis

The DSD diagnoses were based on patient's clinical manifestations, endocrine profile [Supplement [Table 3], karyotyping, and pathologic result. Among these 18 patients, androgen insensitive syndrome was diagnosed in 5, 46XY gonadal dysgenesis in 5, 17-α hydroxylase deficiency in 3, ovotesticular disorder of sex development in 2, 17β-hydroxysteroid dehydrogenase 3 deficiency in 1, 45X/46XY gonadal dysgenesis in 1, and 46XY DSD, unspecified in 1 [Table 1].{Table 3}
Table 1: Patient characteristics

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The initial presentations of these patients included amenorrhea at adolescent age in 9, ambiguous genitalia at birth in 5, and mismatch of gender and phenotype of prenatal chromosomal screening at infantile age in three patients. Extraordinarily, one patient with female appearance presented due to inguinal nodules. This patient had female external genital organ and bilateral inguinal gonads; however, further magnetic resonance imaging (MRI) failed to demonstrate Mullerian remnant and vagina structure. One patient visited our hospital with the presentation of hypertensive crisis, hypokalemia, metabolic alkalosis and amenorrhea at the age of 21 years. Her final diagnosis was 17α-hydroxylase deficiency.

Evaluation for gonadal status

Physical examination, ultrasonography, MRI, and laparoscopy can help to evaluate the gonadal anatomical position and status. The function of gonads could be determined by blood biochemical and endocrine tests.

Through physical examination, 14 gonad-like masses were palpable in 8 patients, either located at inguinal or labia major area; 12 of 14 palpable masses were confirmed to be gonads pathologically after gonadectomies. Two gonad-like masses were proved to be lymph node by pathologic report.

Four patients with impalpable gonads received sonographic examination. The sonography helped to identify two inguinal gonads, whereas all of the 8 gonads were identified by surgical exploration during gonadectomies. MRI was performed in 11 patients (one of the patients received one-side gonadectomy already) and identified 19 gonads. The two “MRI-missing” gonads were eventually found by subsequent laparoscopic exploration.

Laparoscopy was performed in 13 patients and achieved successful gonadectomies in most patients. There were three gonads could not be identified by laparoscopy in childhood, and were found later by second-time laparoscopic exploration in adolescent age.

Surgical approach

In all 18 patients, gonadectomies started by inguinal exploration to identify gonads. If failed, we immediately converted to laparoscopic exploration. In these 18 patients, totally 19 surgical attempts were being performed, including six pure inguinal approaches and 13 laparoscopy-combined approaches [Supplement [Table 2].
Table 2: Histological findings in resected gonads of 18 patients with disorder of sexual development

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The peak age for DSD diagnoses was mainly at both infantile and adolescent age. Most of our patients (16 of 18 patients) received gonadectomies within 1 year after making the diagnosis of DSD [Figure 1].
Figure 1: Age at diagnosis of disorder of sexual development and age at receiving gonadectomy. The peak age of definite diagnosis of disorder of sexual development and gonadectomies were at infantile and at adolescent period

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A so-called “delayed gonadectomy” protocol was adopted in one patient with complete androgen insensitive syndrome (CAIS). This patient was diagnosed at 1-year-old, while we decided to keep the gonads that could have hormone secretion for achieving puberty at adolescent age. The gonads were resected at the age of 14 years; after her second sex, characteristics had been achieved.

Histology result

The detailed histological features are listed in [Table 2]. Among all the resected gonads, none demonstrated evidence of malignant change. Occasional spermatogenesis activity has been found in only one gonad. The remaining gonads without spermatogenesis, histology mostly showed aggregated and immature Sertoli cells and hyperplastic Leydig cells. Nevertheless, dysgenetic Sertoli cells were observed in one gonad.{Table 2}


  Discussion Top


In our series, all of the patients assigned as female were with 46, XY. The only DSD patient who was assigned as male was diagnosed at adolescent age with 45X/46 XY karyotype, whose micropenis with proximal hypospadias needed surgical correction during the subsequent follow-up.

Several factors should be considered to determine gender assignment, including the specific diagnosis, patient's preference, external genital appearance, practical surgical options, need for life-long replacement therapy, fertility potential, and family opinion.[1],[6] Hence, a multidisciplinary team includes pediatric endocrinologist, urologist, gynecologist, plastic surgeon, and psychiatrist is usually required for a comprehensive evaluation and treatment planning.[7]

Various approaches were used for evaluating the anatomical status before conducting gonadectomies. In our series, among patients with impalpable gonads by physical examination, four patients received sonography examination. These patients were all at adolescent age, while only two out of eight gonads were detected. Compared to sonography, MRI served as a better modality to detect impalpable gonads before surgery. Nineteen of twenty-one gonads were detected through MRI in the present study. In contrast, Alaniz et al. described 39 patients with DSD who underwent MRI and/or sonography before prophylactic gonadectomy and suggested comparable results of MRI and sonography.[8] In their series, 54% of gonads were identified through ultrasonography and 41% of gonads were identified through MRI. There were no reliable characteristics on image study to suggest premalignant change or malignant potential in their study. Mansour et al. also reported similar identification rate of gonads between sonography (90%) and MRI (86%) in 25 patients with DSD.[9] In addition, Steven et al. reported 27% detection rate by preoperative sonography in 15 DSD patients with intra-abdominal gonads.[10] The heterogeneous results for detective efficacy of MRI and sonography may be attributed to several factors, including various disease entities among DSD patients, different ages of DSD diagnosis, observer-dependent sonography evaluations, different MRI image quality, facilities and experience for radiologist to read MRI. Nevertheless, MRI serves as the image with highest sensitivity and specificity for gonad anatomical evaluation before conducting surgery, which also help to make surgical planning for gonadectomy.

Laparoscopy is the approach to make the definitive diagnosis of gonad position and the existence of Müllerian structures. During laparoscopic exploration, we could assure vanishing testis, do gonadectomies or biopsies at the same time.[11],[12] In our series, 3 out of 26 gonads were missed during thefirst-time laparoscopic exploration but were found during the second-look laparoscopy. The “second-look” laparoscopy is feasible when the subsequent hormone profile was inconsistent with previous laparoscopic diagnosis, as was shown in the two patients in the present study whose inconsistent hormone profile was found at adolescent age. Laparoscopy provides direct vision to the pelvic structures. By tracing the spermatic cords along the abdominal side wall, most gonads could be identified. In the present study, laparoscopy examination serves as the standard modality for impalpable gonads which could be identified during inguinal exploration. Till now, direct inspection through laparoscopy remains the diagnostic standard for impalpable testis in such patients, images including MRI and sonography alone are insufficient to make the final diagnoses due to the limited sensitivity and specificity.[13]

Gonadectomy has been performed in patients with DSD due to the concern of its potential malignant change, especially for DSD patients who contains Y chromosome materials.[14],[15] A specific diagnosis is essential for individualized management in DSD patients. Hughes et al. stratified the risk of malignancies for DSD patient as high, intermediate, low and no risk groups based on the specific diagnosis and recommended the adequate treatment modalities for each of the four disease group [Supplement Table 1]. Risk of progression later in life toward gonadoblastoma or testicular carcinoma in situ depends on its specific diagnosis and a changed endocrine environment in a susceptible individual.[1],[16] In our series, one patient with a diagnosis of CAIS received gonadectomy in adolescent age despite that the diagnosis of DSD was made. For the low risk of malignant change before early adulthood,[17] the functional gonad was preserved for achieving secondary sex characteristics for puberty.



In fact, histology results in our series indicated that there was no evidence of malignant or premalignant change among the resected gonads. In the present study, the peak age of gonadectomies was infancy (1–2 years) or adolescence (12–15 years); most gonadectomies were performed within 1 year after the diagnosis of DSD.

Jiang et al. reported a large series with 202 Y-chromosome-containing DSD patients who underwent prophylactic gonadectomies. The incidence of gonadal malignancy in patients with CAIS, pure 46, XY gonadal dysgenesis, 45 X/46 XY mixed gonadal dysgenesis, 17a-hydroxylase/17, 20-lyase deficiency and partial androgen insensitivity syndrome were 27.1% (13/48), 22.4% (15/67), 10.9% (5/46), 10% (2/20), and 9.5% (2/21), respectively.[18] The surprisingly high malignant rate for gonadectomies in Jiang's study may be attributed to late gonadectomies at older mean age (20.6 years old). Other studies on DSD patients receiving gonadectomy indicated malignant potential change actually existed even in patients with low-risk DSD. Since the risk of malignant change increased with age, several researchers suggested that gonadectomies should be considered in all adult Y-chromosome-contained DSD patients.[5] The necessity and efficacy of performing gonad biopsy in DSD remain a controversial issue.[19] Wünsch et al. reported 40 patients with DSD underwent laparoscopy assessment, while 19 patients received gonadectomy and 21 patients received gonadopexy.[13] For low-risk DSD patients, gonadopexy may also be feasible if the gonad shows relatively normal appearance and biopsy shows no evidence of malignancy.

This is thefirst case series reported from Taiwan; however, there are several limitations in the present study. First, this is a retrospective study with small patient number. Second, the diagnoses of DSD in the present study were based on karyotype, hormone profile, imaging and clinical manifestations, some newly developed molecular, or genetic diagnostic tool were not used for making the specific diagnosis of DSD.[20],[21] Currently, prospective registries (EuroDSD/I-DSD) have already been launched in the United States and in Europe to achieve a long-term follow-up.[22],[23] In the future, the stand guideline for optimal timing or modalities of surgical treatment may be available.


  Conclusions Top


Multidisciplinary team is required for the diagnosis and treatment in DSD patients. The optimal guideline for prophylactic gonadectomies in such patients is still lacking. Early gonadectomy should be considered in high-risk DSD patients after comprehensive evaluations.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Alaniz VI, Kobernik EK, Dillman J, Quint EH. Utility of ultrasound and magnetic resonance imaging in patients with disorders of sex development who undergo prophylactic gonadectomy. J Pediatr Adolesc Gynecol 2016;29:577-81.  Back to cited text no. 8
    
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Mansour SM, Hamed ST, Adel L, Kamal RM, Ahmed DM. Does MRI add to ultrasound in the assessment of disorders of sex development? Eur J Radiol 2012;81:2403-10.  Back to cited text no. 9
    
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Steven M, O'Toole S, Lam JP, MacKinlay GA, Cascio S. Laparoscopy versus ultrasonography for the evaluation of mullerian structures in children with complex disorders of sex development. Pediatr Surg Int 2012;28:1161-4.  Back to cited text no. 10
    
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Wünsch L, Holterhus PM, Wessel L, Hiort O. Patients with disorders of sex development (DSD) at risk of gonadal tumour development: Management based on laparoscopic biopsy and molecular diagnosis. BJU Int 2012;110:E958-65.  Back to cited text no. 13
    
14.
Looijenga LH, Hersmus R, Oosterhuis JW, Cools M, Drop SL, Wolffenbuttel KP, et al. Tumor risk in disorders of sex development (DSD). Best Pract Res Clin Endocrinol Metab 2007;21:480-95.  Back to cited text no. 14
    
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Pleskacova J, Hersmus R, Oosterhuis JW, Setyawati BA, Faradz SM, Cools M, et al. Tumor risk in disorders of sex development. Sex Dev 2010;4:259-69.  Back to cited text no. 15
    
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Hersmus R, van Bever Y, Wolffenbuttel KP, Biermann K, Cools M, Looijenga LH, et al. The biology of germ cell tumors in disorders of sex development. Clin Genet 2017;91:292-301.  Back to cited text no. 16
    
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Chaudhry S, Tadokoro-Cuccaro R, Hannema SE, Acerini CL, Hughes IA. Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis. J Pediatr Urol 2017;13:498.e1.  Back to cited text no. 17
    
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Jiang JF, Xue W, Deng Y, Tian QJ, Sun AJ. Gonadal malignancy in 202 female patients with disorders of sex development containing Y-chromosome material. Gynecol Endocrinol 2016;32:338-41.  Back to cited text no. 18
    
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Cools M, Looijenga LH, Wolffenbuttel KP, T'Sjoen G. Managing the risk of germ cell tumourigenesis in disorders of sex development patients. Endocr Dev 2014;27:185-96.  Back to cited text no. 19
    
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Kutney K, Konczal L, Kaminski B, Uli N. Challenges in the diagnosis and management of disorders of sex development. Birth Defects Res C Embryo Today 2016;108:293-308.  Back to cited text no. 20
    
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