Prophylactic Laparoscopic Bilateral Gonadectomy for Complete Androgen Insensitivity Syndrome
1; 2; 3; 3; 2; 4
1Department of Urology, University of Arkansas for Medical Sciences
2Department of Pathology, University of Arkansas for Medical Sciences / Arkansas Children’s Hospital
3Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences
4Department of Pediatric Urology, Arkansas Children’s Hospital
Main Text
Table of Contents
Androgen insensitivity syndrome (AIS) is a rare condition caused by an X-linked mutation of the androgen receptor with an estimated incidence of 1–5 per 100,000 individuals. Varying degrees of presentation exist for complete, partial, or mild depending on the severity of androgen resistance. Patients with complete AIS (CAIS) are born phenotypically female but have male XY chromosomes and testes instead of ovaries. They exhibit normal secondary female sex characteristics such as breast development and external female genitalia but lack a uterus and other Müllerian duct structures due to testicular production of Müllerian-inhibiting factor (MIF). Due to androgen-resistance, androgen-dependent Wolffian duct products fail to develop such as the epididymis, vas deferens, and the seminal vesicles. These patients often present either during infancy with inguinal hernias or sublabial masses, or during adolescence with primary amenorrhea. On physical exam, they will typically have normal breast development, lack pubic or axillary hair, and will have a blind-ending vaginal pouch of varying vaginal lengths. Diagnostic work-up is often conducted using ultrasound or MRI, serum hormone levels, and karyotype analysis.
For patients with CAIS, their testes can be located within the inguinal canal, sublabially or intra-abdominally. Following puberty, patients with intra-abdominal testes are at a 15% increased risk (range 0–22%) of developing germ cell tumors (GCT). Management consists of prophylactic gonadectomy with subsequent hormone replacement therapy (HRT) to maintain normal pubertal development and promote adequate bone health. The debate regarding the timing of prophylactic gonadectomy is ongoing with some patient support groups arguing against gonadectomy citing concerns with long-term hormone therapy and the desire to preserve fertility. Current convention promotes delaying gonadectomy until after physiologic puberty has been achieved as the risk of developing prepubertal GCT is relatively low (0.8–2%). We outline the presentation, diagnosis, intraoperative techniques, and postoperative considerations for managing CAIS via bilateral laparoscopic gonadectomy.
Gonadectomy may be indicated in children with Differences of Sexual Development (DSD) who harbor Y-chromosome gonads due to the increased risk of gonadal malignancy.1 One such DSD is androgen insensitivity syndrome (AIS), which is caused by an X-linked mutation of the androgen receptor (AR).2 AIS is a rare diagnosis with an estimated incidence between 1–5 per 100,000 individuals.3 AIS can have varying degrees of presentation depending on the severity of androgen resistance, ranging from complete (CAIS), partial (PAIS), and mild (MAIS).4 Children with CAIS are phenotypically female in appearance with normal female external genitalia but have testes instead of ovaries and have a male karyotype (46, XY). In these patients, their testes are able to produce testosterone but, due to the defect in AR function, fail to produce Wolffian duct products such as the epididymis, vas deferens, and the seminal vesicles. Due to peripheral aromatization of this testosterone into estrogen, these patients have normal secondary female sex characteristics such as breast development. Nevertheless, the Sertoli cells of the testes continue to produce Müllerian-inhibiting factor (MIF), which inhibits the development of the Müllerian duct derivatives. This results in patients with a blind-ending vaginal pouch with an absence of other female sex organs such as the uterus, cervix, and fallopian tubes.5 In these patients, the testes can be located within the inguinal canal, be sublabial, or be intra-abdominal.6 Infants with androgen insensitivity may present with unilateral or bilateral inguinal hernias or labial masses. It is estimated that 1–2% of bilateral inguinal hernias among girls could represent a CAIS diagnosis, and it is important to maintain a strong clinical suspicion during your evaluation.7 Classically, CAIS presents during adolescence as primary amenorrhea in girls with normal breast development but little to no pubic or axillary hair on examination. CAIS is associated with abnormal testicular development as well as an increased risk of germ cell malignancy following puberty.8
This patient is a 15-year-old female of Asian descent with a past medical history of morbid obesity (BMI of 45), obstructive sleep apnea on CPAP, and prediabetes (HbA1c of 5.5) currently on metformin. She has a past surgical history of bilateral inguinal hernia repair as a young child. She has no history of previous pregnancies, is not sexually active, and was referred to our clinic for further evaluation of primary amenorrhea. She reports that she developed thelarche at age 11, but has sparse axillary and pubic hair and no signs of acne. In addition, she denies any pain, vaginal discharge, hirsutism, or galactorrhea. At an outside clinic, our patient denied bleeding following a progestin challenge, and no cervix was palpated during a previous pelvic exam.
Per the patient’s family history, she has three older sisters who are 19, 21, and 26 years of age. Her mother started menses at age 14. Her 26-year-old and 19-year-old sisters also report having regular menses that started around the age of 11, and the oldest sister has had four healthy children. Interestingly, her 21-year-old sister has also been seen by an out-of-state physician for evaluation of primary amenorrhea of unknown etiology. She was told that her vaginal hiatus was insufficient for childbirth and was referred to a specialist for further evaluation but was lost to follow-up.
On physical exam, the patient was obese, had Tanner stage 5 breast development with sparse axillary hair and no signs of acne present. On genitourinary exam, the patient had normal external female genitalia with sparse pubic hair. The vagina was normal in appearance, with no abnormal discharge, and a blind-ending vaginal pouch. We were unable to visualize or palpate the cervix or uterus on the exam. Exam findings were consistent for a potential congenital abnormality. Appropriate lab and imaging tests were then ordered.
Lab Results:
| Test | Result | Reference |
| B-hCG | Negative | Negative |
| FSH | 13.20 mIU/mL | 5–20 mIU/mL |
| LH | 22.20 mIU/mL | 5–20 mIU/mL |
| Prolactin | 8.1 ng/mL | 3.0–18.6 ng/mL |
| Estradiol | 38.33 pg/mL | 34–170 pg/mL (Female Tanner Stage 5) |
| Testosterone | 269 ng/dL | 20–38 ng/dL (Female Tanner Stage 5) |
| TSH | 1.94 mIU/L | 0.47–4.68 mIU/L |
| Chromosome Analysis | 46, XY | Female: 46, XX Male: 46, XY |
Initial labs were drawn to assess problems associated with the hypothalamic-pituitary-ovarian (HPO) axis, such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, and testosterone. In addition, a urine beta-hCG was conducted to rule out pregnancy. Labs for our patient revealed that she had an elevated testosterone level when compared to normal female patients. In addition, a karyotype analysis for our patient resulted in 46, XY chromosomes. Together, these findings are consistent with a diagnosis of CAIS, where elevated testosterone levels (abnormal female range, but normal male range) and high serum LH levels result due to impairment of androgen negative feedback on the anterior pituitary.
Imaging via pelvic ultrasound was ordered to assess for the presence or absence of the uterus and other female sex organs. Ultrasound imaging conducted at an outside hospital showed an absence of a uterus, fallopian tubes, and cervix. In addition, imaging revealed an absence of ovaries and was unable to accurately assess the location of potential intra-abdominal testes. Ultrasounds can be operator dependent, and MRI is widely considered to be the gold standard to diagnose and locate the gonads in surgical planning for laparoscopic gonadectomy and gonadal surveillance.5
One study by Wisniewski et al. examined long-term outcomes among 14 women with CAIS who were on long-term hormone replacement therapy (HRT) following gonadectomy.9 They found that overall these women can expect to have a normal active life span. A majority of these women exceeded the 90th percentile for height for normal adult females,9 making them taller than the average female while still being shorter than the normal male population.10 The most common medical condition that was diagnosed among these women was osteoporosis. The majority of women identified as having a heterosexual female gender identity and none of them desired gender reversal surgery. The majority reported being satisfied with their sexual functioning. The average vaginal length among this cohort was 8.8 cm, which is consistent with normal vaginal length ranging from 7–11 cm.9
Currently, there is no therapy available to reverse the underlying genetic mutation of the AR in patients with CAIS. Therefore, treatment is focused on prophylactic gonadectomy to prevent potential gonadal malignancy with subsequent HRT, treatment of the urogenital tract, if indicated, as well as psychological support. Gonadectomy is usually delayed until sexual maturation is complete during adolescence to allow for normal spontaneous pubertal development.3 If diagnosed early in infancy or childhood, early gonadectomy may be considered if the child presents with painful or uncomfortable inguinal or labial masses, but will require subsequent HRT to induce puberty at approximately 11–12 years of age.3 The timing of gonadectomy has become controversial with some patients and AIS support groups advocating for retaining their testes. A variety of reasons have been cited by these support groups for keeping the testes such as psychological factors, risks associated with the surgery, desire to potentially preserve fertility, and a reluctance to adhere to long-term HRT. Nevertheless, the reported risks for laparoscopic gonadectomy are very low, with an estimated risk of death of 0.1 per 1000 procedures, and the risk of injury to bowel or bleeding is reported at 2.4%.11 Furthermore, a study by Hannema et al. examined the testes of 44 patients with CAIS and found that germ cells rapidly declined in number after the first year of life and found no evidence of spermatogenesis in any of the testes, making fertility highly unlikely for CAIS patients.12 For CAIS patients who decide to retain their testes, it has been reported that the risk of developing germ cell tumors (GCT) increases with age.11 It is important to maintain close follow-up through active surveillance by utilizing regular imaging (ultrasound and/or MRI) and serum blood markers to screen for the potential development of GCT in these patients.13 While MRI can detect benign changes such as paratesticular cysts and adenomas, they cannot detect premalignant changes such as germ cell neoplasia in situ (GCNIS), which would require a biopsy of the gonads.14 In addition, the quality of ultrasound screening is usually operator dependent. One approach proposed by Wunsch et al. for patients who desire to retain their testes, would be to perform laparoscopic gonadal biopsy and surgically fix the intra-abdominal gonads near the abdominal wall to allow for better visualization via ultrasound.15
The primary goal of performing gonadectomy in the setting of CAIS is to lessen the risk of future malignancy. As in other forms of cryptorchidism, there is an increased risk of developing GCT. In CAIS, the risk of developing prepubertal GCT among these patients is considered to be very low ranging from 0.8–2.0%.16 Following puberty, this risk increases with age and is estimated to be roughly 15% (ranges from 0–22%).11 It is advocated that prophylactic gonadectomy occurs in the postpubertal period when feminization is completed in part by testicular estrogen that is partly derived from the conversion of androgens to estrogen.3, 8 Delaying gonadectomy until later in adolescence also allows care providers to obtain informed consent directly from their patients.
When evaluating children, whose HPO axis is still immature, an hCG stimulation test is necessary to properly evaluate Leydig cell testosterone secretion.17 Following gonadectomy, these patients will need long-term hormonal supplement therapy with estrogen replacement until the age of natural menopause (around 50–52 years of age) to maintain normal breast and bone development, psychosocial well-being, and sexual function.18 Because these patients do not have a uterus, progestins are not required to complement estrogen therapy.17 These patients will continue to retain normal secondary female sex characteristics and can attain normal sexual function but may require vaginal dilation therapy or vaginoplasty depending on the adequacy of their vaginal canal.17 Questions of infertility and gender identity can carry a heavy psychosocial impact for these patients, and it is strongly encouraged to offer counseling or support group therapy as part of a multi-disciplinary approach.9
CAIS (formerly known as Morris syndrome) represents one of the most common definable causes of 46, XY DSD. It results from a rare X-linked mutation of the AR that causes peripheral androgen resistance. These patients are born phenotypically female with normal female external genitalia. Commonly, these patients present in adolescence with primary amenorrhea, where the subsequent examination will reveal that these patients have a blind-ending vaginal pouch and an absence of internal female sex organs on imaging. Instead of ovaries, these patients have testes that may be found in the abdomen, inguinal canal, or labia. In children or infants, CAIS may present as an inguinal hernia or mass, where approximately 1–2% of female infants with inguinal hernias are found to have cryptorchidism with 46,XY karyotype.7 In this specific case, our patient had a past surgical history of bilateral inguinal hernia repair as a young child. This suggests a missed or delayed diagnosis and highlights the importance of maintaining a strong clinical suspicion of CAIS in pediatric female patients who present with bilateral inguinal hernias, which warrants further examination to rule out cryptorchidism.
The estimated risk for patients with AIS developing GCT is inversely related to the degree of androgen resistance. Patients with CAIS have more severe mutations of their AR that infer a complete loss of function. Without androgen stimulation, spermatogenesis is impaired and there is an associated rapid decline in germ cell numbers after the first year of life that theoretically confers a reduced risk of developing GCT later in life.14 This is in contrast to patients with PAIS, who still retain some degree of AR function and therefore are more likely to have surviving germ cells, which subsequently puts them at increased risk for developing GCT in adulthood.19 Historically, Manuel et al. reported a 3.6% cumulative risk of GCT in patients with Y-containing DSDs up to the age of 25 years that increased to 33% by 50 years of age.20 More recently, Deans et al. found in their review that CAIS patients were at a 15% increased risk of developing a gonadal malignancy in adulthood (range 0–22%).11 Cools et al. found that the estimated risk of developing GCT in CAIS patients before puberty was much lower at 0.8–2%.16
Due to the increased risk of gonadal malignancy among CAIS patients in adulthood, the current recommendation is to perform gonadectomy after sexual maturation is complete, typically around 15–16 years of age, as the risk of developing tumors before puberty is considered to be relatively low.21 This approach allows for spontaneous breast development and better bone mineralization during puberty due to physiologic hormone production by the testes and subsequent peripheral androgen conversion to estrogens.3, 8 Historically, laparotomy and bilateral gonadectomy were performed for patients with Y-chromosome containing DSD. Overtime, laparoscopic procedures became widely adopted for DSD patients due to the associated advantages of magnification and easy access to the pelvic cavity via a minimally invasive approach, which provides shorter postoperative recovery and length of hospitalization, and improved cosmesis.22, 23
Laparoscopic gonadectomy is performed while the patient is under general anesthetic via endotracheal intubation. The video monitor, insufflator, and light source are positioned at the foot of the patient. In this case, insufflation of the abdomen was performed using an open laparoscopy technique where a semilunar incision was made at the inferior aspect of the umbilicus and the fascia was elevated using hemostats. A Veress needle was then placed into the abdomen, and its correct position was confirmed using a saline drop test. A 10-mm Step trocar was then inserted through the umbilicus, and CO2 was used to obtain pneumoperitoneum. A 0o laparoscope was then introduced into the abdomen. Two additional 5-mm trocars for working instruments were placed at the level of the umbilicus on the right and left sides. The patient was then placed into Trendelenburg position, which allows for easier laparoscopic inspection of the pelvis to determine the location of the gonads and to inspect the pelvic organs. When the gonads are not readily apparent, identifying and following the gonadal vessels can help locate them.1
During laparoscopy, our patient’s gonads were noted above the closed internal rings bilaterally. Grossly, cysts were visualized on bilateral testes. The vas deferens traversed to the urethra, and there was no evidence of any Müllerian structures within the pelvis. A plane was dissected through the posterior peritoneum around the gonads away from the other retroperitoneal structures. It is important to determine the location and course of retroperitoneal structures such as the ureters and the iliac vessels to avoid iatrogenic injury. The internal spermatic vessels were then identified as they transverse to the gonad and fulgurated using the Ligasure device in four successive sections before transecting to reduce the likelihood of bleeding. The testes were then mobilized from the peritoneum, and the vas deferens were also fulgurated and divided in a similar fashion. The laparoscope was inserted through one of the working ports so that the gonads could be removed through the central 10-mm umbilical port. The abdominal CO2 pneumoperitoneum was then reversed, and the umbilical fascia was closed using 2-0 Vicryl suture. The skin at all of the port sites was closed using 5-0 Monocryl and covered with Dermabond.
Both of the gonads were excised without complication and sent to pathology for evaluation. The laparoscopic gonadectomy operating time, from incision to closure, was approximately 80 minutes. There was less than 5 mL of estimated blood loss. The patient was admitted overnight for observation due to social factors. She tolerated the procedure well, her pain was well controlled using multi-modal pain management, and she was discharged home the following morning. She was scheduled for follow-up in two weeks with her gynecologist to begin estrogen replacement therapy.
It is significant to note that under laparoscopy we were able to visualize bilateral vas deferens that traced down to the urethra. A case series of 44 CAIS patients by Hannema et al. found that 36% had epididymis or vas deferens present.12 Hannema et al. hypothesized that residual paracrine androgen activity may be able to induce the development of Wolffian duct products, even in patients with complete forms of AIS.12
Surgical pathology for our patient confirmed that both of her gonads were in fact atrophic testes. Interestingly, both testes demonstrated GCNIS and marked Leydig cell hyperplasia (Figures 1–2). The neoplastic cells stain with OCT3/4 and PLAP (Figures 3–4). Leydig cell hyperplasia, as seen in this patient, is a common finding in patients with CAIS.24 It has been proposed that high levels of LH, due to a lack of androgen negative feedback on the anterior pituitary, is responsible for increased Leydig cellularity.25 GCNIS is considered to be a premalignant tumor, where up to 50% will progress to GCT within 5 years.26 The risk of progression of GCNIS to invasive GCT is less certain in patients with CAIS. The “lack-of-androgen theory” proposed by Kaprova-Pleskacova et al., suggests that patients with CAIS are less likely to progress to GCT than patients with PAIS due to insufficient androgen response to promote survival of abnormal germ cells.27 Conversely, Kaprova-Pleskacova et al. also suggested that the same paracrine androgen activity potentially responsible for inducing Wolffian duct development as mentioned by Hannema et al.,12 could also promote GCNIS to develop into invasive GCT.27 The presence of vas deferens and histological evidence of GCNIS in our patient suggests potential residual paracrine androgen response. As such, we believe this case helps support the argument for the potential benefit of prophylactic gonadectomy among CAIS patients.
Our patient’s surgical pathology was also significant for bilateral paratesticular leiomyomas (Figure 5), a smooth muscle tumor that very rarely occurs within the urogenital tract. Their location may be intratesticular or paratesticular and are believed to be derived from the smooth muscle cells of the interstitial stroma, the muscular layer of the vessels of the tunica albuginea, the seminiferous tubules, as well as the paratesticular structures such as the spermatic cord, epididymis, vestigial remnants, and the tunica vaginalis.28 Leiomyomas are very rarely described in patients with AIS. In fact, there have only been four case reports within the literature describing leiomyomas being present on biopsy following gonadectomy in AIS patients.28-31 To our knowledge, this is the first documented case of bilateral paratesticular leiomyomas developing concurrently with GCNIS in a patient with CAIS.
Figure 1. Germ cell neoplasia in situ (GCNIS). Large atypical cells (black arrows) with abundant clear to faintly eosinophilic cytoplasm, a central nucleus with the prominent nucleolus, and evenly distributed chromatin are seen. H&E, 200x.
Figure 2. A) This image shows comparison of tubules involved by GCNIS (black arrows) with adjacent seminiferous tubules with normal spermatogenesis (yellow arrows); H&E, 200x. B) Low power image shows clusters of Leydig cells within the interstitium (dashed arrows); H&E, 100x.
Figure 3. Immunohistochemical stain for octamer-binding transcription factor (OCT) 3/4 shows strong nuclear immunoreactivity in GCNIS cells within the seminiferous tubules. Normal germ cells are negative; 200x.
Figure 4. Immunohistochemical stain with placental alkaline phosphatase (PLAP) highlights the tumor cells of GCNIS in a cytoplasmic membranous pattern; 200x.
Figure 5. A) Leiomyoma; H&E, 100x. Fascicles of spindled smooth muscle cells. B) Smooth muscle actin (SMA) cytoplasmic staining is diffuse and strong.
No specific equipment used.
Nothing to disclose.
The patient referred to in this video article has given their informed consent to be filmed and is aware that information and images will be published online.
Citations
- Calvo A, Escolino M, Settimi A, Roberti A, Caprio MG, Esposito C. Laparoscopic approach for gonadectomy in pediatric patients with intersex disorders. Transl Pediatr. 2016;5(4):295-304. https://doi.org/10.21037/tp.2016.09.06
- Kusumi M, Mitsunami M, Onoue H, et al. Complete androgen insensitivity syndrome and anti-Müllerian hormone levels before and after laparoscopic gonadectomy. Gynecol Minim Invasive Ther. 2017;6(3):126-128. https://doi.org/10.1016/j.gmit.2016.11.001
- Cheikhelard A, Thibaud E, Morel Y, et al. Complete androgen insensitivity syndrome: diagnosis and management. Expert Rev Endocrinol Metab. 2009;4(6):565-573. https://doi.org/10.1586/eem.09.31
- Lanciotti L, Cofini M, Leonardi A, Bertozzi M, Penta L, Esposito S. Different Clinical Presentations and Management in Complete Androgen Insensitivity Syndrome (CAIS). Int J Environ Res Public Health. 2019;16(7):1268. https://doi.org/10.3390/ijerph16071268
- Grasso D, Borreggine C, Campanale C, Longo A, Grilli G, Macarini L. Usefulness and role of magnetic resonance imaging in a case of complete androgen insensitivity syndrome. Radiol Case Rep. 2015;10(2):1119. https://doi.org/10.2484/rcr.v10i2.1119
- Nezzo M, De Visschere P, T'Sjoen G, Weyers S, Villeirs G. Role of imaging in the diagnosis and management of complete androgen insensitivity syndrome in adults. Case Rep Radiol. 2013;2013:158484. https://doi.org/10.1155/2013/158484
- Viner RM, Teoh Y, Williams DM, Patterson MN, Hughes IA. Androgen insensitivity syndrome: a survey of diagnostic procedures and management in the UK. Arch Dis Child. 1997;77(4):305-309. https://doi.org/10.1136/adc.77.4.305
- Galani A, Kitsiou-Tzeli S, Sofokleous C, Kanavakis E, Kalpini-Mavrou A. Androgen insensitivity syndrome: clinical features and molecular defects. Hormones (Athens). 2008;7(3):217-229. https://doi.org/10.14310/horm.2002.1201
- Wisniewski AB, Migeon CJ, Meyer-Bahlburg HF, et al. Complete androgen insensitivity syndrome: long-term medical, surgical, and psychosexual outcome. J Clin Endocrinol Metab. 2000;85(8):2664-2669. https://doi.org/10.1210/jcem.85.8.6742
- Hughes IA, Davies JD, Bunch TI, Pasterski V, Mastroyannopoulou K, MacDougall J. Androgen insensitivity syndrome. Lancet. 2012;380(9851):1419-1428. https://doi.org/10.1016/S0140-6736(12)60071-3
- Deans R, Creighton SM, Liao LM, Conway GS. Timing of gonadectomy in adult women with complete androgen insensitivity syndrome (CAIS): patient preferences and clinical evidence. Clin Endocrinol (Oxf). 2012;76(6):894-898. https://doi.org/10.1111/j.1365-2265.2012.04330.x
- Hannema SE, Scott IS, Rajpert-De Meyts E, Skakkebaek NE, Coleman N, Hughes IA. Testicular development in the complete androgen insensitivity syndrome. J Pathol. 2006;208(4):518-527. https://doi.org/10.1002/path.1890
- Döhnert U, Wünsch L, Hiort O. Gonadectomy in Complete Androgen Insensitivity Syndrome: Why and When? Sex Dev. 2017;11(4):171-174. https://doi.org/10.1159/000478082
- 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(5):498.e491-498.e496. https://doi.org/10.1016/j.jpurol.2017.02.013
- 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(11 Pt C):E958-965. https://doi.org/10.1111/j.1464-410X.2012.11181.x
- Cools M, Drop SL, Wolffenbuttel KP, Oosterhuis JW, Looijenga LH. Germ cell tumors in the intersex gonad: old paths, new directions, moving frontiers. Endocr Rev. 2006;27(5):468-484. https://doi.org/10.1210/er.2006-0005
- Batista RL, Costa EMF, Rodrigues AdS, et al. Androgen insensitivity syndrome: a review. Archives of Endocrinology and Metabolism. 2018;62:227-235. https://doi.org/10.20945/2359-3997000000031
- Bertelloni S, Meriggiola MC, Dati E, Balsamo A, Baroncelli GI. Bone Mineral Density in Women Living with Complete Androgen Insensitivity Syndrome and Intact Testes or Removed Gonads. Sex Dev. 2017;11(4):182-189. https://doi.org/10.1159/000477599
- Pyle LC, Nathanson KL. A practical guide for evaluating gonadal germ cell tumor predisposition in differences of sex development. Am J Med Genet C Semin Med Genet. 2017;175(2):304-314. https://doi.org/10.1002/ajmg.c.31562
- Manuel M, Katayama PK, Jones HW, Jr. The age of occurrence of gonadal tumors in intersex patients with a Y chromosome. Am J Obstet Gynecol. 1976;124(3):293-300.
https://doi.org/10.1016/0002-9378(76)90160-5 - Chertin B, Koulikov D, Alberton J, Hadas-Halpern I, Reissman P, Farkas A. The use of laparoscopy in intersex patients. Pediatr Surg Int. 2006;22(5):405-408. https://doi.org/10.1007/s00383-006-1662-3
- Esegbona G, Cutner A, Cuckow P, Creighton S. Laparoscopic gonadectomy in paediatric and adolescent girls with intersex disorders. BJOG: An International Journal of Obstetrics & Gynaecology. 2003;110(2):210-212. PMID: 12618168.
- Cools M, Looijenga L. Update on the Pathophysiology and Risk Factors for the Development of Malignant Testicular Germ Cell Tumors in Complete Androgen Insensitivity Syndrome. Sex Dev. 2017;11(4):175-181. https://doi.org/10.1159/000477921
- Jockenhövel, Rutgers JK, Mason JS, Griffin JE, Swerdloff RS. Leydig cell neoplasia in a patient with Reifenstein syndrome. Exp Clin Endocrinol. 1993;101(6):365-370.
- Akyüz M, Topaktaş R, Ürkmez A, Koca O, Öztürk M. Evaluation of germ-cell neoplasia in situ entity in testicular tumors. Turk J Urol. 2019;45(6):418-422. https://doi.org/10.5152/tud.2018.48855
- Kaprova-Pleskacova J, Stoop H, Brüggenwirth H, et al. Complete androgen insensitivity syndrome: factors influencing gonadal histology including germ cell pathology. Modern Pathology. 2014;27(5):721-730. https://doi.org/10.1038/modpathol.2013.193
- Siminas S, Kokai G, Kenny SE. Complete androgen insensitivity syndrome associated with bilateral Sertoli cell adenomas and paratesticular leiomyomas: case report and review of the literature. J Pediatr Urol. 2013;9(1):e31-34. https://doi.org/10.1016/j.jpurol.2012.06.013
- Goulis DG, Iliadou PK, Papanicolaou A, et al. R831X mutation of the androgen receptor gene in an adolescent with complete androgen insensitivity syndrome and bilateral testicular hamartomas. Hormones (Athens). 2006;5(3):200-204. https://doi.org/10.14310/horm.2002.11185
- Krichen Makni S, Mnif Hachicha L, Ellouze S, et al. Feminizing testicular syndrome with multiple hamartomas and bilateral paratesticular leiomyomas. Rev Med Interne. 2005;26(12):980-983. https://doi.org/10.1016/j.revmed.2005.08.003
- Savaş-Erdeve Ş, Aycan Z, Keskin M, et al. Complete androgen insensitivity syndrome associated with bilateral sertoli cell adenomas and unilateral paratesticular leiomyoma: A case report. The Turkish Journal of Pediatrics. 2016;58(6):654-657. https://doi.org/10.24953/turkjped.2016.06.012
Cite this article
John Doe, Stephen J. Canon, MD, Laura L. Hollenbach, MD, Georgia Gamble, MD, Laura A. Gonzalez-Krellwitz, MD, Amrit Singh, MD. Prophylactic laparoscopic bilateral gonadectomy for complete androgen insensitivity syndrome. J Med Insight. 2021;2021(313). https://doi.org/10.24296/jomi/313Procedure Outline
Table of Contents
- Dissection
- Transection of Vas Deferens
- Inspection and Hemostasis
- Dissection
- Transection of Vas Deferens
- Discussion of Pathology Findings
Transcription
CHAPTER 1
So our case today is a case of a 15-year-old young lady who presented with primary amenorrhea. Family and she reported that she's otherwise healthy, no significant urologic history, but she'd never had a menstrual cycle. So we evaluated her, first did a physical exam, and then did some labs. On exam, she was a normal 15-year-old young lady with the exception of her genital exam. We noted normal breast development for a 15-year-old young lady, but on her genital exam, she had a lack of any pubic hair present and also had normal labia noted. So we then proceed with obtaining labs and an ultrasound. Our initial findings in her labs included a low estradiol level for a 15-year-old female, and a markedly-elevated testosterone level. She also had elevated LH and FSH as well. And her karyotype type returned 46,XY. Her ultrasound was noted to have a lack of a uterus, but also intra-abdominal gonads consistent with that of testicles rather than ovaries. So our assessment is complete androgen insensitivity syndrome. So we met with the family and discussed this with the family and the patient at length. First, outlining the reasons for the diagnosis, and then ultimately her increased risk for intra-abdominal testicular malignancies in light of her complete androgen insensitivity syndrome. We also discussed the implications for future fertility and also sexual function and whatnot. Ultimately, these patients are at increased risk for intra-abdominal testicular malignancies. And since she's had adequate time for breast development and bone development, which is the standard of care for these patients, we then recommended bilateral gonadectomy. Our preference is to perform this with a laparoscopic approach. So the subsequent procedure, or video, will outline the steps of the procedure. Also, the intraoperative findings, and then subsequently the pathologic findings in this case.
CHAPTER 2
So first of all, we're going to inject the umbilicus here with local anesthetic. Just to minimize her pain post-op and during the procedure. All right.
CHAPTER 3
So you grab about like so. Okay. Like that. So we're incising at the umbilicus on the inferior aspect. Pick up right here, if you would. Now we're just going to take the incision down to the fascia. Okay, can I have a hemostat? We use a needle point Bovie. I don't know if you guys use that very much, but it's pretty sharp. Just so you know. Okay. Army-Navy. Now I'll hold this one just for a sec. Okay, just making a plane down to the fascia. Can I have another one of those? Hold like that. Now let me see the Army-Navy again. Come out with that. DeBakeys. I think we're down to the fascia there. Hemostat. Now we're just going to get control of the fascia with some hemostats - another one - in order to help facilitate - and switch out that one, just let that be, and then hold that right there. DeBakeys. Just so we've got good control on the fascia. Then we pass the Veress in. Now we're passing the Veress into the abdominal cavity. Okay, go ahead and go for it. Okay. Let's go ahead and insufflate there. Can we - what's that? You did the water drop test? We did the water drop test. Can we insufflate now? Can we turn the gas on? All right, so we're insufflating now. Wait until our pressure gets up to 15 mmHg before we put in the sheath. We're almost there, pressure's at 12, 13. In just a minute, we're going to… I think she's a little bit more full. In a minute, we're going to put in the port. Yeah, she's definitely tympanitic now. I think we're there. Okay. And you got the 12 mm? Yep. Can we get the Army-Navy again? Hold on a second. I got a little bit of return right there, let me… Hold right here. Let me see another hemostat. And let me see another Army-Navy. The other side. DeBakeys first. I think we were right there before. That should be it. Yep. All right, so just keep some back pressure for me. I'll tell you what, drop that one and hold the other one over here. Now we're putting in our port. All right, that's good. Now we're going to insufflate through our port. You can take those off. Now, we're going to look in with our camera.
CHAPTER 4
Here we go, white balancing. Okay, now we're good. Now we're looking inside the peritoneal cavity. Now… She has had a history of bilateral hernia repairs. And so now we're looking down in the pelvic area. We can see the bladder here, for the urachus, and the [medial] umbilical ligaments. First of all, let me look straight back, and… Her intestines look fine. Now we're going to need a Trendelenburg, please. We have a Foley catheter in the bladder currently to decompress the bladder. There's the testicle. So here we have a right testicle. That's kind of being hidden by the intestines. We're going to need to move those out of the way in just a minute. I'll tell you what, let's go ahead and put in our other working ports, so we can work around. And now we'll just use the 5 mm. Yep, with the Veress in it. All right, so now we're putting some local in, and identifying our port site. Look a little bit further south. We may just not be through, try that one more time. Okay. Back to you. Make an incision in the skin. Now I'm going to dilate down to the fascia, or at least close to it. Can you pull the camera back just a touch and see? No, okay. There it is. All right. Putting in a working port on the left side, along the midclavicular line or just lateral to it. All right. I need you to just - along the Langer's lines, just cut current. Placing the right working port now. I think you're getting close now. Going through the side. I think it might have popped back. Can we get another one of those? Sure. I think there's a testicle on the right, but on the left, I'm not really sure that there is one, but we're gonna look up underneath that omentum right there, to get to the bottom of it. But with her having a prior hernia repair, it is possible that we're going to, if we can't find a testicle, then we'll call and talk to the dad. Here you go. There you go, you got it now. All right, good deal. Here you go. Thank you. We're switching to a 0-degree lens. I think this will optimize our visualization. Okay. She's going to have to calibrate here. All right. Now… All right, you got it? So I have a LigaSure in my right hand and Marylands in my left. I may need a longer Maryland. Do you have a longer one? So, can you look down a little bit? I'm definitely going to need longer instruments on the left. Okay, so it looks kind of like a fallopian tube to me. That's really big. Clearly a gonadal structure, right there. It's not showing itself to us really readily yet. I'm going to have to dissect that around - from the surrounding structures. Let's look over on the left side, and see if we can identify anything over here. Okay, there we go. I think it's hiding down in the pelvis.
CHAPTER 5
All right. So this - is a gonadal structure of some sort right here with some cysts on it. Okay. I'm just going to develop a plane behind it, through the peritoneum. Bluntly. So, got to be careful, her ureter will be in that location, also, not far away from the iliacs as well, which should be right here. Can we get any more Trendelenburg? A little bit of scar tissue, I think from the prior surgery. Do you need me to move? Okay, this is good. Okay. Getting a little bit of plane behind the spermatic vessels to what appears to be a small testicle with a little bit of surrounding scar tissue, presumably from the history of inguinal hernia repair. All right. Let me see if I can sweep these anymore. All right. Without retracting it up like that, we really don't have much exposure at all. That seems a little bit better, don't you think? Can't see behind it super well. And so I want to be really cautious about doing anything underneath here that we can't see. Nothing else in the area that this could be other than gonad. We're right, just superficial to, or superior to, the internal ring. It looks like an epididymis there, on the lateral aspect. All right, so we have a plane behind there. All right, look up north, just a little bit right above it. Right above the testicle, right here. Okay, so I'm just going to spread it with my right hand a little bit. Do you have a hook? Can I have a hook? Okay, so we're going to use a hook to try to dissect off the peritoneum, just above where we're working in our - in this window in the peritoneum. I'm going to pull it up away from the other structures. All right, go ahead and try to incise the peritoneum a little more medial. So, all right, pretty good visualization right here. Kind of like to use the LigaSure on that though. Okay, so it looks like we have a little plane just anterior to the spermatic vessels on the peritoneum. I'd kind of like to see it a little bit better. And there we see the cystic structure on the gonad again, lateral, doing its best to get in our way. A little more peritoneum. All right, let's see if we can get a good picture of the internal spermatic vessels here, away from everything else. Okay, so what I'm going to do when we get through here, is I'm going to take this in about three different bunches right next to each other to make sure we get it ligated really well. Okay. May take it a little bit more broadly. And then before I cut, I'm just going to go a little more distal. And again. One more time. And then I'm going to go back to the middle or a little closer. And then cut that. Look down real quick. Before we lose that, I'd like to get another, I'd like to fulgurate it again. Now look just a little bit to your right. I want to make sure that I see that's intestine right there, maybe appendix. Away from where we are. Okay. Peritoneum on the backside here. I'm just going to go ahead and release that as well. Okay, so now I just want to demonstrate right here. Look down, first. All right, so we see - that looks like small intestine, and that is away from where we cauterized, and it looks fine. Okay. So now, that gives us a little more mobility in here to take down what we have here. I'm going to grab a little more north on the testicle. Again, pulling up and away from everything else in the pelvis, such as the ureter or the iliac vessels. Okay, I think we're about ready to switch the LigaSure to the other hand. So your ureter is more caudal from where we are, right? Yes, yeah. It'd be like right here. Right in there. But it'll - especially in a little kid, it can really sneak up on you. And so I think you have to be really cognizant of it. If you go a little bit further, like right in here, you'll get into the obturator foramen, and, you know, the obturator nerve potentially. Normally, these testicles are a little more mobile, but because of the prior surgery, it was stuck down near the intestines there, and on the posterior aspect of the peritoneum. So it wasn't as easy as a lot of times it is to dissect out. But now - and you can see also, we have a closed internal ring - this is where it would be, right here. Can you scoot in a little bit more? Why don't we clean off our camera too? I think it's a little bit… All right. So now, that's the peritoneum on the - just lateral to the testicle that we're taking down. Let me get a better purchase of the testicle here. Okay, now we're coming upon the vasal structure, which actually looks a little broader than I would imagine it to be. Of note, you can see it going toward - slide on down to the left. I'll tell you what, let me run it for just a second, you got that? Yeah, sure. So, bladder. If there was a uterus, we would see it right in this location. And there's no obvious uterine structure, although that is where the… You know, this also is where the prostate and the posterior urethra are. So, what appears to be a - kind of a broad vas deferens heading down toward the prostatic urethra, which is where the ejaculatory ducts would be. So, with that being said, let me give you this. And then I'm going to take back over, and then we're going to transect this vas deferens.
Clearly an abnormal looking testicle as well. Okay, so just to verify that we have proper orientation. So you can see we're outside the pelvis, we're away from the bladder. We're away from the rectum, we're anterior to the rectum. There is a, you know, gonadal structure that appears to be consistent with a testicle, with what appears to be a lateral sulcus. And so, what we need to do here is just transect this. I'm going to do it in a few - adjacent fulgurations - before transecting it. All right, again. And now we're going to transect it. Okay. So the right one is no longer attached, so we're going to leave it. Let's leave it right over here on the right side, in the right pericolic gutter.
Okay? Also, I don't see any bleeding there where we were working before. Let's look over on the right side, a little bit where the testicle originally was. Okay. It looks dry. You know, what might be easier is - for the other side, is let's switch sides. You think that looked like a fallopian tube, or are you thinking it looks like a...? I mean those - I don't know if you get gonadal cysts, but those look like paratubal cysts. Yeah.
CHAPTER 6
Some more of those cystic structures there. I'm going to switch that to my left hand. You know, being a laparoscopist, you get a little bit of practice with contorting your body, like you're playing twister. So, the added benefit is we get our ab workout in. Surgery is a full-contact sport. That's right. It feels like it after a day in. Okay. So I feel more confident now that we're in the right spot and that we see what looks like a gonadal structure. You know, I'm going to - I hate to do it - actually, we'll take this down first. You can see also, if you would look at the internal ring - left and up - also closed, no hernia. So they successfully fixed the hernias before. You can also see the iliacs. Look down just a little bit, right in there. So we want to stay away from those. So I'm going to incise the peritoneum distal to the testicle - since it's showing itself to us. So, if you looked real close, you can see the iliacs down there, through - and just medially, that would be where the ureter is. So, you know, it's important to - back up just a little bit - to always maintain your awareness because that could definitely change the feel of the case. I think traction, counter traction, exposure, and patience are key. I'm just going to get the peritoneum right in front of us. So this is gonad number two. You can see some cystic changes to it, but it appears to be a vas going up to it. If you would look over at the right side. And you can see where the other one was located. And there it is. We just took down the spermatics and the vas with the LigaSure in a couple different sections, right adjacent to each other. So, let's go ahead and get back to this. Okay, so I'm going to switch hands again. I just like the angle relative to the iliacs a little bit better from here. Especially with regard to the - internal spermatic vessels. So you can see, I can get above the iliacs here and spread without having to worry about past-pointing into the iliacs, which are right there. Okay. So just verifying our orientation again - to the gonadal structure here with the cysts, iliacs here, vas would be down here. There's no way that - sorry, the ureter would be down here. So there's no way that this can be ureter, it's too superficial, too anterior. Okay, so we're going to go ahead and come across this. I'll tell you what I am going to do, I'm going to just take a little bit of this down first - just so I can see it a little bit better. Almost making it bleed again. Taking the internal spermatics to the left gonad. Again, with the LigaSure. Just fulgurating adjacent - to the last fulguration to be able to ensure that we have good hemostasis before dividing it. And then, I'm going to go back to near the middle. Fulgurate and divide. No bleeding. Let's get that again. Just inspecting the posterior attachments here. I think I'm going to switch back again with the instruments in order to have a better angle with the LigaSure to take down what's left and also the vas. All right. Picking up on the vas. Making another little window on the distal attachments. I have it retracted up well. Okay, and now we're down to the vas on the left.
Just trying to dissect down to just - all we have left is the vas with one more fulguration. And now we're doing it. All right. And now the vas is transected on the left. I'm going to set this down over in the left also. You want to clear out the gas and then get a good view of the…
CHAPTER 7
All right, so here you see the fulgurated and ligated left vas deferens. Can we look on the right side? And there you see the fulgurated and ligated right vas difference. And then if you would show - okay. So there is the site where the testicle was previously - on the right, and then also on the left. All right, so I think we're ready to remove them. Since we have a 12-mm port, I think we probably can remove them through the port. We need a 5-mm camera. Do we have one? And then what I'm going to suggest we do is you look in through the left, and then I'll reach in and grab one at a time. While you have that out, I'm going to go ahead and take the gas down too, just to make sure that there's no bleeding. So just desufflate for a minute. Just taking the gas down, so that when we look back in, if there's any bleeding, then we should be able to see. It'll prevent tamponade of any small venous bleeders. Okay, so let's look back in again. Insufflating again. All right. Okay, so I'm going to try to grab it on an end and see if… Now importantly, we don't see any bleeding either. Okay. Little bit tight. Let me see if I can grab it right on the end. You have a Marylands? We'll give one more try with this, and then if I can't get it… It's not going to fit. I think we're going to have to reach back in, yeah. Well, let me just bring it out of the port. If we need to replace the port, we can. So we'll take them both out together. Are you ready? Watch your eyes. I'll tell you what, would you keep an eye on what it looks like in there? There we go. Got it. That is the right side. Here you go. Good. Thank you. All right. Oh no, it looks a little bigger, doesn't it? Let me grab it on its end and make sure that we have the skinniest part of it. Will it come through the port at all? Doesn't look like it. Do you have an endo bag, Endo Catch? I'll tell you what, just have it available, don't open it yet, I'm going to try to get it with - can I get a hemostat? I think I might be able to just... Oh, it's going up. Yeah. Army-Navy. Yeah, thank you. Almost there. Here we go. There's the left side, left gonad. All right, thank you. All right, let's look in and just make sure that we don't have any bleeding. Okay, so just to do a debrief. So we've done a cystoscopy, vaginoscopy, EUA. And then laparoscopic bilateral gonadectomy. We have two specimens. One's the right, one's the left gonad for gross and histology. I wonder if we need DNA extraction from that. We'll call and find out. Okay. Look right, down left, one more time. Good, and then on the right. And then down. All right, now let's look around at the intestines. Good. All right. And straight down. Okay, good. Well that looks - maybe over on your side. All right. So no intra-abdominal injuries, no bleeding. At this point we're going to close. We'll desufflate and close.
CHAPTER 8
I just want to make sure we have it all - all that gas out. I don't want it getting intestines coming up through there. Okay, do you want to go ahead and pull that? I'm just trying to close the fascia for the 12-mm port. I'm going to need a 2-0 Vicryl and a UR-6. Okay, if you can hold that. Sure. And then DeBakeys. There is the hole right there. I'll tell you what, I'll hold this one. Can you hold that for just a second? Another Kelly. I think this one I could actually reposition. Now, that's fascia. Could you hold this Constance? And then 2-0 Vicryl. Thank you. That's all right. Empty needle driver. She's not quite as deep as I thought she would be. Okay. And now I'm just going to put one right by it. Great. Okay. Needle driver, again. Okay. Now I'm going to tie this. All right, scissors. Let's see what this feels like before we let go of any of these. Needle down, I think I might put one more right over here. Just come off of this. All right, we almost have the fascia closed at the 12-mm port site. Since the others were step ports and they were small, we're going to leave them to close. You can let go of that now, and let's feel it. You know, I don't like the way to belly button is tethered down there. Another Adson. Would you hold this one right here? And Bovie. Can we get that Army-Navy. You're good. It's not a button hole. There's a little tissue that I think got incorporated in the closure. Go ahead and Bovie that. Yep. Mm hmm. Yeah. All right. I'm happy - hello. You happy? All right. Let's see, 5-0 monocryl. Can we get two of them? So, I usually just do subcuticular interrupteds. Okay. Pickups, Adsons. Okay, good, you got it. All right, so let me just show you how I like to do them. 5-0 Monocryl. And maybe you could do one over there on that side, and then if you finish up quicker than me, I'll let you do over here too. But just, can I get some other Adsons? I'm not sure those meet very well. Or I can use the, whatever the big facial closures are. Okay. We're going to use Dermabond here too. Okay, so we're just going to do some subcuticular interrupteds to close the - take two on that one. Okay, so you got that for there? Yes, sir. Can I have another one? Any reason why you like using interrupteds? Well on the umbilicus, with a kind of a semilunar incision, it's easier to close. It's hard to make a running suture straight. And I also like the fact that it doesn't dehisce. So we got the fascia closed. We got the specimen out. We checked to make sure that the fascia was closed well. And now we're closing the skin. The incision in the umbilicus will be really well hidden. It'll be hard to see. These others you'll see for about six months, and then they'll be hard to see as well. We're going to put Dermabond over each of the incisions, and that's it, as far as dressings go. All in all, I think that the case has gone well. I think the family will be very relieved, and the patient, that she won't be at risk for testicular malignancies anymore. It would be interesting to see what the final path shows because there were definitely some cystic changes on the gonad, which were - did not look completely normal. Well it didn't look normal at all actually. We did not see - importantly, we did not see any evidence of a uterus either. And again, we couldn't feel a cervix. And what would you guys estimate was her vaginal length? 7 cm. 7 cm for the vaginal length. Okay. So she's going to come back in about two to four weeks. We'll review the final path, we'll evaluate her incisions. We also have Dr. Hollenbach, our fantastic adolescent gynecologist, who's going to start hormone replacement therapy. So she'll need to be on hormone replacement therapy until the natural age of menopause in order to support bone and cardiac health. So we're going to give some Toradol for postoperative analgesia. So we are going to be admitting her, and that's because of social and language reasons more than anything. They live in northwest Arkansas and speak Hmong. But normally if you do this procedure, you would send them home the same day? Normally, we would send them home - yeah. Now we're just going to clean the incisions. In a second, we're going to put the Dermabond bond on. How much local did we inject? 7, sir. Okay, 7 ml of local. Could I have an Adsons, as well? Okay. I'm ready for the Dermabond. That side just got a little bit traumatized from the Bovie, I think. Here you go, you want to do that? I think you got enough.
CHAPTER 9
So our young lady had a stable, immediate postoperative recovery in the recovery room. And she was admitted for observation since the family lived a long ways away from the hospital where our tertiary referral center's located. She had good pain control, resumption of diet, and was ready for discharge to home the next day. We did initiate estrogen replacement hormone therapy with her gynecologist since patients who have had a prophylactic gonadectomy with complete androgen insensitivity syndrome require long-term hormone replacement. And she tolerated this well, and - which will also allow her to maintain normal bone development and also breast development.
So, she returned later for discussion of her pathology findings, which were very unusual and rare, even in this instance. She was found to have a bilateral germ cell carcinoma in situ in both specimens, as well as bilateral paratesticular leiomyomas. So we discussed these findings with the family, and ultimately also referred her to oncology, who will be following her for monitoring her tumor markers, as well as her general progress. So needless to say, we were very happy with the result, that we were able to intervene early in order to remove her gonads prior to conversion to formal germ cell tumors. And therefore, we're very optimistic about her long-term recovery. Thank you.