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CASE SERIES |
https://doi.org/10.5005/jp-journals-10006-2328
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Prophylactic Gonadectomy in an Unmarried Individual: A Moral Dilemma
1Department of Obstetrics and Gynecology, KJK Hospital, Trivandrum, Kerala, India
2,3Department of Reproductive Medicine, KJK Hospital, Trivandrum, Kerala, India
Corresponding Author: Kokila Bagavathy Thanappan, Department of Obstetrics and Gynecology, KJK Hospital, Trivandrum, Kerala, India, Phone: +91 9690199138, e-mail: drkokila17@gmail.com
How to cite this article: Thanappan KB, Krishnanpillai J, Jayakrishnan N. Prophylactic Gonadectomy in an Unmarried Individual: A Moral Dilemma. J South Asian Feder Obst Gynae 2023;15(6):730–733.
Source of support: Nil
Conflict of interest: None
Received on: 15 June 2023; Accepted on: 28 July 2023; Published on: 04 December 2023
ABSTRACT
Background: Prophylactic gonadectomy can only be proposed to patients at risk of gonadal germ cell tumors (GGCTs) in disorders of sex development (DSDs) patients. However, this does not justify prophylactic gonadectomy given that they are uncommon and nearly always benign. In these cases, the survival rate of a malignant GGCT is better (approximately 95% at 5 years), but, chemotherapy also has its own lifelong side effects such as metabolic syndrome and cardiovascular risk.
Case presentation: This paper highlights 2 cases of young individuals aged 16–22 years who presented to KJK Hospital, Thiruvananthapuram with amenorrhea. After initial clinical and routine hormonal and radiological investigation, they were diagnosed with Androgen insensitivity syndrome and Mosaic Turner syndrome respectively on karyotyping. After discussing the condition and options of treatment with the patients and family, laparoscopic prophylactic gonadectomy was planned and performed, with removal of bilateral undescended testes and streak ovary in respective cases followed by hormonal replacement therapy.
Conclusion: Usually, the external genitalia in DSD are normal which makes it difficult to diagnose before puberty without any significant clinical indication. In our cases, it demonstrates that mere physical or clinical examination will not be sufficient to identify such cases. Therefore, in females with amenorrhea, genetic testing should be performed along with a general examination. The procedure risks are very low, as laparoscopic gonadectomy can be done as a daycare procedure and can be performed in 30–60 minutes duration with no visible scar. Added benefits of Laparoscopy include a provision to take biopsies or do gonadopexy. It is always advised to postpone gonadectomy till puberty as it allows spontaneous puberty, and allows informed decision-making by the patient.
Keywords: Complete androgen insensitivity syndrome, Karyotyping, Laparoscopic gonadectomy, Mosaic Turners syndrome, Prophylactic gonadectomy.
INTRODUCTION
Prophylactic gonadectomy can only be proposed to patients at risk of gonadal germ cell tumors (GGCTs) in disorders of sex development (DSDs) patients. However, this does not justify prophylactic gonadectomy given that they are uncommon and nearly always benign.
In these cases, the survival rate of a malignant GGCT is better (approximately 95% at 5 years), but, chemotherapy also has its own lifelong side effects such as metabolic syndrome and cardiovascular risk.
Decision-making about gonadectomy should have the patient as an active part of it. The postponement of eventual gonadectomy into adult age is of major advantage. It allows spontaneous puberty to occur and permits informed and authoritative decision-making by the patient.1
Classically, in indication for performing gonadectomy in patients with true risk of GGCTs, three factors have to be taken into account: Underlying diagnosis, sex and age at presentation, and molecular histopathological and immunohistochemistry findings (the latter having been recently added).
Despite advances, the risks of malignant transformation in such cases are still unknown, in terms of both rates of malignant transformation and times to develop them.
CASE DESCRIPTION
Case 1
An adolescent patient, born as a second child in the year 2007 was reared as female and unmarried, and presented to us with primary amenorrhea. Her mother mentioned she had an uneventful normal vaginal delivery with her. Attained all her milestones.
In 2023, at the age of 16 years, she reported to our hospital as primary amenorrhea. Without any significant medical or family history. On physical examination, height was 160 cm, BMI 27 kg/m2 with development of breasts at tanner 4 and absent pubic and axillary hair growth. On local examination, revealed normal female external genitalia, and the urethral opening. Bilateral labia majora appeared normal. On external examination, the vagina was normal with a 3 inch blind-ending vaginal pouch. We were unable to palpate the cervix or uterus on the exam. An oval mass of 3 cm × 2 cm could be palpated, with movement, clear boundary, and slight tenderness in the right inguinal region.2
Her hormonal profile showed elevated testosterone (220 ng/dL), high LH – 25.20 mIU/ML, Normal FSH, Estradiol, TSH, and prolactin levels. Pelvic MRI showed the absence of prostate, uterus, or ovary, and there were testes with para testicular cysts anteriorly in the bilateral inguinal canal. Male pseudohermaphroditism was suspected. Karyotyping was done, showing 46 XY, Disorder of sexual development (Table 1).
| Characteristics | Case 1 | Case 2 |
|---|---|---|
| Age (in years) | 16 | 22 |
| Phenotype | Female | Female |
| Presentation | Amenorrhea | Amenorrhea |
| Type of amenorrhea | Primary | Secondary |
| Secondary sexual characters | ||
| External genitalia | Female | Female |
| Breast development | Tanner 4 | Tanner 3 |
| Pubic/axillary hair | Absent | Present |
| Radiology | Uterus and tubes-absent bilateral testes-in inguinal canal | Hypoplastic uterus (5.7 cm × 2.0 cm) with thin endometrium and low volume right ovary with no follicles. |
| Genotype | 46 XY | 14/30-XO, 16/30-Iso X |
| Syndrome | Androgen insensitivity syndrome | Mosaic Turners syndrome |
| Interventions | Prophylactic gonadectomy | Prophylactic gonadectomy |
| Hormone replacement therapy | Yes | Yes |
The patient and her parents were counseled regarding the condition and provided information regarding treatment options. They were involved in combined decision-making and for prophylactic gonadectomy, as the risk for malignancy is high in the undescended gonad.
On laparoscopy, there was no evidence of Mullerian structures like the uterus, or fallopian tubes within the pelvis. Left side testis is found inside the peritoneal cavity through a deep inguinal ring. The right side testis not seen in the peritoneal cavity and was noted above the closed internal ring in the inguinal canal. Paratesticular cysts were present on both testes. The vas deferens traversed through the canal. On the right side, a plane was dissected through the peritoneum near the gonads away from the ureters and the iliac vessels. Peritoneal flap over deep inguinal ring lowered on the right side. Structures passing through the deep inguinal rings followed and the testis was dissected out. The internal spermatic vessels, passing to the gonad were then identified and coagulated using a Harmonic Ace scalpel to reduce bleeding. The testes and the vas deferens were then divided. The peritoneum was closed with 2–0 Vicryl as a continuous suture. Left-side gonadectomy was done after dissecting and coagulating the gonadal vessels and vas deferens and gonads were retrieved in endobag (Fig. 1).
Figs 1A to D: Case 1 – Androgen insensitivity syndrome. (A) Left side testis seen at deep inguinal ring; (B) Right testis felt inside inguinal canal; (C) Peritoneum opened and structures passing through right inguinal canal followed; (D) Bilateral gonadectomy done, followed by peritoneum closure with 2-0 Vicryl
She was scheduled for follow-up after two weeks and started on estrogen replacement therapy. Histopathology for our patient confirmed that both of her gonads were atrophic testes.
Case 2
A 22-year-old, unmarried female, presented with secondary amenorrhea for the last 7 years in our hospital. Her milestones history was normal. She got her menarche spontaneously at the age of 15 years, accompanied by 2 more menstrual cycles, followed by amenorrhea. According to her parents, her academic performance was average with her pursuing post-graduation now.
In 2016, on investigating the same, she was diagnosed with left ovarian dysgerminoma (Germ cell tumor) and had a left salpingo-oophorectomy done the same year. Following this she took 4 cycles of chemotherapy with cisplatin, bleomycin, and etoposide.
Post-procedure, she remained amenorrhoeic and was started on cyclic conjugated estrogen and progesterone (Hormonal therapy), for 12 months to no avail.
On physical examination, she was 141 cm tall with a BMI of 26.4 kg/m2. There were obvious Turner features. Breast development was Tanner 3 and pubic hair was Tanner 2. On local examination, External genitalia appeared female. There was palpable gonads/mass in the inguinal region. Systemic check-up was normal. Her hormonal profile showed elevated FSH and LH levels and reduced Estradiol level. (FSH – 110.57 mIU/mL, LH – 32.3 mIU/mL, TSH – 2.47 mIU/L, Estradiol – 2.37 ng/dL. Ultimately her karyotyping revealed to be 14/30-XO, 16/30-Iso X (Mosaic Turners syndrome) (Table 1).
Ultrasonogram imaging showed a hypoplastic uterus with thin endometrium and a small right ovary with no follicles, suggestive of a streak ovary.
The case was morally challenging in terms of future prospects and risk associated with the remaining ovary. After discussing the options with the patient and considering the endocrinologist’s and surgery oncologist’s opinion regarding the same, in view of the dysgenetic streak ovary, she was planning for prophylactic salpingo-oophorectomy. After pre anesthetic and cardiologist evaluation, and combined decision-making with the patient and her parents, the conclusion of laparoscopic gonadectomy was taken.
Intraoperative findings revealed to be a small uterus, with absent left adnexa. The right ovary appeared streak, right tube was normal with flimsy adhesion between the omentum and right adnexa. Bluish nodules were seen over the mesenteric and omentum, all over the peritoneal cavity and a Biopsy was taken from the same (Fig. 2).
Figs 2A and B: Case 2 – (A) Right sided streak ovary; (B) Retrieved specimen post right salpingo-oophorectomy
Histopathological report of the ovary and peritoneal/omental biopsy was within normal limits with suture granuloma and no tumor deposits. She was started on hormonal therapy with estrogen and progesterone replacement.
DISCUSSION
The priority was to reduce the risk of malignancy, GCT, due to cryptorchidism. In Androgen insensitivity patients, DSD though the risk of developing GCT in preteen is considered to be very low (ranges from 0.8 to 2.0%), but after puberty, this risk increases to 10 times (ranges from 0 to 22%). It is always recommended to perform prophylactic gonadectomy after puberty when estrogen partly derived from androgen conversion helps in feminization. Adding to the pros, delaying gonadectomy also allows patients to be mature enough in decision-making process.
Patients who have undergone gonadectomy will require long-term hormonal supplement therapy with estrogen replacement in order to preserve normal bone and breast growth, and their psychosocial and sexual well-being, until natural menopause at 50–52 years of age. As these individuals don’t have uteruses, progestins are typically not needed to supplement estrogen therapy; rather, might need vaginal dilation therapy or vaginoplasty depending on the existing conditions.
Severe mosaicism, such as 45, X/46, XY mosaicism is very rare (1.7 per 10,000 newborns).3 Unless there are obvious signs of Turner syndrome, growth, pubertal delay, or sexual ambiguity, this may go unnoticed till puberty. Because there is a high risk of gonadal cancer in those who harbor Y chromosome material, gonadectomy has always been advised, as soon as the diagnosis is confirmed.4
The typical Turner characteristics were not present in our patient, who had Mosaic. All other features, with the exception of short stature, are inconsistent. The results of a hormonal analysis also showed increased gonadotropins and low estrogen levels.
Dysgenetic gonads on themself are risk factors for the development of germ cell tumors, and gonadoblastoma is one of their precursor lesions, which may lead to GCT.
Gonadoblastoma locus on the Y-chromosome (GBY), located in the Yp is known as the origin of these tumors. Located proximally is sex-determining region Y protein (SRY) while distal is GBY. Sex-determining region Y protein is required for spermatogenesis and for H-Yantigen (oncogene), which is associated with the development of GCTs. It is always advised to look for Y-chromosome fragments in Turners if there are signs of virilization and/or when conventional cytogenetics is inconclusive.
However given that GCT can occur in such instances up to 30–35% of the time, according to the majority of research, we felt it was appropriate to suggest preventive gonadectomy to our patient.
Sex-determining region Y protein is functional in spermatogenesis and is the structural gene for H-Yantigen which is an oncogene, that is associated with the development of GCTs.
Recommendation for the search for Y-chromosome fragments in TS in two circumstances: signs of virilization and/or when there is a marker chromosome not identified by classical cytogenetics.
As major studies mention 30–35 % GCT incidence in such cases, we recommend prophylactic gonadectomy for both patients.
Infertility, the need for prolonged hormone replacement therapy, poor secondary sex characteristics, and a loss of quality of life, risk of anesthesia and surgery, all are consequences of gonadectomy. A childhood inguinal hernia should not justify an early gonadectomy. The hernia should be corrected, and the gonadopexy can be done. The chemotherapy for these, however, has its own lifelong side effects, such as a danger of metabolic syndrome and cardiovascular risk, despite the high survival rate of a malignant GGCT (95% at 5 years).
The risks of laparoscopic gonadectomy are extremely low and can be done as a daycare procedure. Bilateral gonadectomy takes approximately 45–60 minutes. Laparoscopy also allows biopsies, annual diagnostic follow-ups or gonadopexy, and, moreover, gonadectomy leaves almost no visible scar.
It always advised to postpone gonadectomy till puberty as it allows spontaneous puberty, and allows informed decision-making by the patient.
REFERENCES
1. Lucas-Herald AK, Bryce J, Kyriakou A, et al. Gonadectomy in conditions affecting sex development - A registry-based cohort study. Eur J Endocrinol 2021;184(6):791–801. DOI: 10.1530/EJE-20-1058.
2. 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. DOI: 10.1002/ajmg.c.31562.
3. Wu Q, Wang C, Shi H, et al. The clinical manifestation and genetic evaluation in patients with 45, X/46, XY mosaicism. Sex Dev 2017; 11(2):64–69.DOI: 10.1159/000455260.
4. Gravholt CH, Andersen NH, Conway GS, et al. Clinical practice guidelines for the care of girls and women with Turner syndrome: Proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eu J Endocrinol 2017; 177(3):G1–G70. DOI: https://doi.org/10.1530/EJE-17-0430.
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