Successful laparoscopic resection of virilizing ovarian steroid cell tumor, not otherwise specified, in a 22-year-old woman: a case report and evaluation of the steroidogenic pathway.

OBJECTIVE: Ovarian steroid cell tumor (SCT) is a rare tumor with steroid-producing ability. We report a 22-year-old woman with secondary amenorrhea and hirsutism caused by an ovarian SCT-not otherwise specified (NOS), who underwent successfully laparoscopic resection of the tumor. CASE REPORT: A 22-year-old null gravida woman presented to a hospital, having amenorrhea for 18 months and increasing facial hair. Physical examination revealed obesity (body mass index, 37.3 kg/m2) with evident facial and trunk hair. Total and free serum testosterone, and dehydroepiandrosterone sulfate levels were found to be elevated. Levels of serum adrenocorticotropic hormone, gonadotropins, cortisol, aldosterone, and ovarian steroids were observed to be within reference intervals. Although polycystic ovaries were not found, a hyperechogenic solid tumor (3 cm) was detected on transvaginal ultrasonography. Laparoscopic resection of the tumor was performed. One month post-surgery, total and free testosterone levels were observed to have decreased, and menstruation resumed two months thereafter. The patient was histologically diagnosed with ovarian SCT-NOS. Expression of ovarian steroidogenic enzymes, which are related to hyperandrogenism, was observed. No disease recurrence has been reported for more than 5 years post-surgery.

[Feminizing genitoplasty in virilization of the external genitalia].

The review focuses on the feminizing genitoplasty of the external genitalia in patients with disorders of sex development. The opinions of various surgeons and surgical schools on the timing, stages and methods of performing feminizing genitoplasty in girls with the virilization of the genitalia are presented. The development and improvement of surgical techniques for performing clitoroloplasty in patients with virilization of genitalia are described, as well as different types of labioplasty. The main methods of reconstruction of the urogenital sinus are given.

The Role of Patient Advocacy and the Declining Rate of Clitoroplasty in 46,XX Patients With Congenital Adrenal Hyperplasia.

Prior to the 1990s, most 46,XX infants with clitoromegaly secondary to congenital adrenal hyperplasia were treated with feminizing genitoplasty to make their cosmetic appearance congruent with their genotypic sex. A 2006 consensus statement for the management of intersex disorders accepted input from patient advocates and did not support purely cosmetic surgery for clitoromegaly. This study examined the extent to which the desired change was implemented in practice. Retrospective chart review was performed at a single Midwestern tertiary care medical center for patients born between 1979 and 2013. Of 45 virilized patients, 40 had clitoromegaly and 39 had urogenital sinus or posterior labial fusion. Twenty-seven (67.5%) patients underwent clitoroplasty and 33 (84.6%) underwent perineoplasty, including vaginoplasty, urethroplasty, imperforate vagina repair, and/or posterior labial fusion repair. There was a linear decline in the rate of clitoroplasty over time for the patient cohort. This study demonstrates the power of patient advocacy to improve medical practice.

Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

PURPOSE OF REVIEW: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a relatively common inherited disorder of cortisol biosynthesis that can be fatal if untreated. RECENT FINDINGS: The basic biochemistry and genetics of CAH have been known for decades but continue to be refined by the discoveries of an alternative 'backdoor' metabolic pathway for adrenal androgen synthesis and the secretion of 11-hydroxy and 11-keto analogs of known androgens, by the elucidation of hundreds of new mutations, and by the application of high-throughput sequencing techniques to noninvasive prenatal diagnosis. Although hydrocortisone is a mainstay of treatment, overtreatment may have adverse effects on growth, risk of obesity, and cardiovascular disease; conversely, undertreatment may increase risk of testicular adrenal rest tumors in affected men. SUMMARY: Refinements to screening techniques may improve the positive predictive value of newborn screening programs. Alternative dosing forms of hydrocortisone and additional therapeutic modalities are under study. Although surgical treatment of virilized female genitalia is widely accepted by families and patients, it is not without complications or controversy, and some families choose to defer it.

Surgical outcomes and complications of reconstructive surgery in the female congenital adrenal hyperplasia patient: What every endocrinologist should know.

Surgical management of classical congenital adrenal hyperplasia (CAH) in 46, XX females has evolved significantly. Virilization of the genitalia of 46, XX females with CAH begins prenatally as a result of excess fetal androgen production. Improved understanding of anatomy and surgical outcomes has driven changes in surgical techniques as well as the timing of surgery. For endocrinologists treating these patients, it is important to understand the outcome of genitoplasty, identify patients who need further treatment and direct these patients to experienced surgeons. We performed a literature search on PubMed of publications addressing CAH and genital reconstruction published in the English language from 1990 to the present. In accordance with our institutional review board, we performed a retrospective analysis of clitoroplasty and/or vaginoplasty procedures performed by a single surgeon at our institution from 1996 to 2015. We found that genital reconstruction in 46, XX CAH patients is associated with few immediate post-operative, infectious, and urinary complications. Vaginal stenosis is a common complication of vaginal reconstruction and requires evaluation by an experienced surgeon. Clitoral pain or decreased sensation can be associated with clitoral recession and clitorectomy. Outcomes in sexual satisfaction and gender identity can also be impacted by surgical technique and success. Long term follow up and patient reported feedback are crucial to our understanding and management of this special group of patients. Improved awareness and understanding of the complications of genital surgery will allow endocrinologists to know what to ask patients and be ready to provide them with a resource with the understanding and experience to help them improve their quality of life.

Postmenopausal hyperandrogenism: the under-recognized value of inhibins.

We report a 70-year-old female presenting with increased libido and mild but rapid onset virilism. Investigations showed markedly elevated androstenedione and 17 hydroxyprogesterone misdirecting to possible late-onset congenital adrenal hyperplasia. High serum testosterone and oestrogens with suppressed gonadotrophins, however, indicated an androgen-secreting tumour. A normal dehydroepiandrosterone sulphate and elevated inhibins A and B indicated the tumour was ovarian in origin, which was confirmed on pelvic examination and imaging. At laparotomy, a right ovarian sertoliform endometrioid carcinoma was removed, following which the patient developed menopausal vasomotor symptoms and improvement of her virilism. Serum testosterone, oestradiol, inhibins A and B became undetectable, gonadotrophins appropriately increased and 17 hydroxyprogesterone and androstenedione normalized. We propose that inhibins may be of diagnostic value and should be included in investigative algorithms of females with virilization and hyperandrogenaemia, especially if postmenopausal. Androgen-secreting tumours must be excluded before raised 17 hydroxyprogesterone concentrations are used to diagnose late-onset congenital adrenal hyperplasia in females with new-onset virilization.

Virilizing oncocytic adrenocortical carcinoma: clinical and immunohistochemical studies.

CONTEXT: Oncocytic tumors of the adrenal cortex are rare, mostly nonfunctioning and benign. SETTING: Report virilizing oncocytic adrenocortical carcinoma in a 50-year-old woman. PATIENT: She presented a recent and progressive virilization syndrome, associated with high blood pressure. Hormonal evaluation showed elevated serum testosterone and delta-4-androstenedione levels, normal urinary free cortisol level and incomplete suppression of cortisol at the 1 mg dexamethasone suppression test. CT scan of the abdomen revealed a 35 mm left adrenal mass. INTERVENTION: The patient underwent a left adrenalectomy, and the histological study showed a 3 cm oncocytic adrenocortical carcinoma with signs of malignancy. RESULTS: Immunohistochemical study revealed that tumor cells expressed the steroidogenic enzymes involved into androgen synthesis (3ßHSD and P450c17α), P450 aromatase and luteinizing hormone (LH) receptors. Post-operatively, signs of virilization improved rapidly, serum testosterone and delta-4-androstenedione levels returned to normal, as did the dexamethasone suppression test. During follow-up CT-scan and 18-FDG PET/CT showed a right ovary mass, corresponding to a follicular cyst associated with hyperthecosis. The patient is alive with no recurrence 48 months after adrenal surgery. CONCLUSION: Oncocytic adrenocortical carcinomas, although extremely rare, should be considered in women with a virilization syndrome. In this woman immunohistochimical studies revealed the presence of steroidogenic enzymes involved into androgen synthesis and aromatization, and LH receptors could be implicated in this pathology.

Pubertal outcome in a female with virilizing adrenocortical carcinoma.

Adrenocortical tumors are neoplasms that rarely occur in pediatric patients. Adrenocortical carcinoma (ACC) is even more uncommon, and is an aggressive malignancy with 5-year survival of 55% in a registry series. There is a lack of information on long-term endocrine outcome in survivors. We describe a 10-year follow-up in a patient who presented at 3 years 5 months with a 1-year history of axillary odor and 6 months' history of pubic hair development with an increased clitoral size. Androgen levels were increased and a pelvic sonogram revealed a suprarenal mass of the left kidney. The tumor was successfully removed. At 6 years 11 months, androgen levels increased again. Workup for tumor recurrence was negative and the findings likely represented early adrenarche. The patient had menarche at an appropriate time and attained a height appropriate for her family.

[CLITOROPLASTY FOR GENITAL VIRILIZATION IN GIRLS WITH CONGENITAL ADRENAL HYPERPLASIA].

OBJECTIVE: To investigate the effectiveness of clitoroplasty of reserving the clitoris dorsal neurovascular bundle and the ventral complete urethral plate for genital virilization in girls with congenital adrenal hyperplasia (CAH). METHODS: Between June 2000 and October 2015, 27 girls with genital virilization were treated with clitoroplasty of reserving the clitoris dorsal neurovascular bundle and the ventral complete urethral plate. The chromosomal karyotype was 46, XX in all patients, whose age ranged from 3 to 11 years (mean, 3.9 years). According to Parder's virilization scale, 5 cases were classified as stage Ⅱ, 18 cases as stage Ⅲ, and 4 cases as stage Ⅳ. The hormone tests showed decreased cortisol level and increased testosterone and 17-hydroxyprogesterone levels. They were diagnosed with non-salt-wasting CAH. RESULTS: All of the patients underwent clitoroplasty successfully. The mean operation time was 74 minutes (range, 58-95 minutes). Incision healed primarily. The patients were followed up 6 months to 10 years (median, 19 months). The external genitalia had good appearance, without necrosis of flap and the glans clitoris, abnormal sensation of the glans clitoris, or clitorism recurrence. Five girls had breast development and normal menstrual cycle during adolescence, and 1 patient who was followed up for 10 years gave birth to a son. CONCLUSIONS: Clitoroplasty of reserving the clitoris dorsal neurovascular bundle and the ventral complete urethral plate is a relatively ideal method for treating genital virilization in girls. It has less complications, good aesthetic and functional results. There are satisfactory outcomes when combining with the endocrine treatment.

Timing and Outcome Concerns regarding Feminizing Genitoplasty from the Perspective of Egyptian Families of Girls with Virilized External Genitalia.

BACKGROUND: Congenital adrenal hyperplasia in females leads to virilization of external genitalia and persistent urogenital sinus. There are controversies regarding the timing and outcomes of surgery. Deferring surgeries beyond childhood is difficult to implement in conservative societies, and may result in stigmatization and distress to individuals with disorders of sexual differentiation and their families. METHODS: Thirty girls with virilization due to congenital adrenal hyperplasia were admitted for single-stage feminizing genitoplasty, between 2011 and 2014. We prospectively studied the concerns and input of the families represented by the mothers. After comprehensive counselling, the mothers completed a questionnaire to clarify their priorities and concerns related to surgery. RESULTS: Surgeries were performed at a mean age of 22 months. Most cases ranged between Prader's degrees III and IV. Egyptian families believe that early surgical reconstruction is in the best interest of their girls. They are marginally more concerned about functional outcomes and future child bearing than external appearance and cosmetic outcomes. CONCLUSIONS: Social difficulties noticeably add challenges to the management plan within conservative societies. Early genital reconstructive surgery, when reasonably indicated, needs to remain a viable option. Comprehensive psychosocial support within a multidisciplinary approach is needed to defer feminizing genitoplasty in selected cases to adolescence.

Late prenatal dexamethasone and phenotype variations in 46,XX CAH: concerns about current protocols and benefits for surgical procedures.

OBJECTIVE: To describe the action of prenatal dexamethasone (PreDex) on the anatomy of female congenital adrenal hyperplasia (CAH) genitalia when started at later stages of gestation. MATERIALS AND METHODS: Our group follows a large cohort of French CAH patients who underwent PreDex therapy, of whom 258 were recently reported. Four 46,XX patients with a delayed PreDex treatment presented with a virilized genitalia and required surgical reconstruction. This is a retrospective report on genital phenotyping at the time of surgery of these four patients who began PreDex therapy at 8, 12, 20, and 28 weeks of gestation. RESULTS: Although this series is limited in number, the anatomical description of the length of the genital tubercle, the height of the urethra-vaginal confluence, and the degree of fusion of the genital folds seems to be dependent upon the starting date of PreDex. Most PreDex treatments prescribed up to now have covered the full duration of gestation. CONCLUSIONS: Our findings suggest that PreDex therapy could be limited to the period of the partitioning window. It is hoped that further prospective multicentric clinical studies will obtain ethical approval in order to elucidate the place and protocols of PreDex therapy in the management of CAH.

[Congenital adrenal hyperplasia in girls/young women]. / Das adrenogenitale Syndrom beim Mädchen/junger Frau.

BACKGROUND: With a mean global incidence of 1:14500, congenital adrenal hyperplasia (CAH) is the most common disorder of sexual differentiation (DSD). In case of female karyotype, the prenatal surplus of androgens causes virilization of the external genitalia. This includes clitoral hypertrophy and an increasing higher confluence of the urethra and normal developed proximal vagina, creating the urogenital sinus. Internal genitalia are female. METHOD: Until recently feminizing surgery was performed within the first 18 months of life, at least concerning clitoroplasty. Though the cosmetic result of this kind of surgery is quite good, functional shortcomings like clitoral hyposensibility were often reported. RESULTS: The latest discussion about treatment of intersex patients resulted in recommendations to prevent early surgery and observe the development of the child, until the child can decide for itself, if and in what direction it wants to undergo surgery. Though CAH patients are seen as a special group within intersex disorders, these recommendations should also be considered for them. The appropriateness of this change in treatment strategy is supported by publications concerning the long-term follow-up of patients, who finally chose a gender that was different from what physicians and parents had expected.

Virilized external genitalia in young girls: clinical characteristics and management challenges in a low-resource setting.

OBJECTIVE: Virilization of the external genitalia in young girls (VEG) manifests mostly as ambiguity of the genitalia and elicits concerns and uncertainties especially in settings with poor awareness. This study evaluates the profile and challenges of VEG in southeast Nigeria. METHODS: We analyzed 23 children with VEG managed in 2 referral centers in southeast Nigeria from June 2005 to January 2013. RESULTS: They presented at median age of 13.3 months (interquartile range [IQR] 3 months-3 years). The cases included 3 (13%) of Prader type 1, 6 (26%) of type 2, 11 (48%) of type 3, and 3 (13%) of type 4. Five of the Prader type 3 and all 3 cases of Prader type 4 were reared as male prior to presentation. Following evaluation, all the cases were assigned female gender at a mean age of 2.7 years (range 2 months-10.5 years). Appropriate feminizing genitoplasty was undertaken in all the cases and after a follow-up period of 3 months to 5 years (mean 2 years), 2 patients developed vaginal stenosis, and 3 cases had surgical wound infection. Poor awareness, delayed presentation, inadequate facilities, and lack of trained manpower were the challenges in the management of the cases. CONCLUSION: VEG in our setting is associated with delayed management. Focused health education and public awareness programs, and improved healthcare funding may improve outcome and minimize the need for gender reassignment.

Virilization of a young girl caused by concomitant ectopic and intra-adrenal adenomas of the adrenal cortex.

BACKGROUND: Adenomas of the adrenal gland are rare causes of virilization in childhood. CASE REPORT: A girl aged 2 years and 4 months presented with pubarche, distinct clitoral hypertrophy, tall stature, and increased height velocity. Plasma testosterone and dehydroepiandrosterone were elevated. Androgens remained unchanged after adrenocorticotropic hormone, and dexamethasone administrations. Ultrasound examination and magnetic resonance imaging indicated an extra-adrenal mass adjacent to the left adrenal gland, which was removed by endoscopic surgery. However, plasma androgens remained elevated and (131)I-iodomethyl-norcholesterol scintigraphy revealed tracer enhancement in the right adrenal gland, which was consecutively removed. Virilization regressed after extirpation of the adenomas and height velocity normalized. RESULTS: Histology revealed a circumscribed adenoma in the right adrenal gland and an epithelial mass with adrenal cortical cells in the left-sided ectopic tumor. In the ectopic tumor, melanocortin 2 receptor expression was augmented threefold compared to the control, indicating adrenal origin. CONCLUSIONS: In this young girl, virilization is due to concomitant ectopic and intra-adrenal adenomas of the adrenal cortex. By melanocortin 2 receptor expression, it was confirmed that the ectopic adenoma derived from the adrenal cortex. Specific scintigraphy, if available, assists in allocating the source of androgen hypersecretion.

Surgical aspects in the treatment of adrenocortical carcinomas in children: data of the GPOH-MET 97 trial.

Adrenocortical carcinomas (ACCs) are a rare entity, with an incidence of 1.5 per million population per year. The prognosis of ACC is poor. Complete surgical resection is essential for a curative approach and significantly determines overall prognosis. Tumor resection is sophisticated and complicated by the vulnerability of the tumor and its invasive growth. Chemotherapy and Mitotane are additional therapeutic approaches that are combined with surgery in an interdisciplinary strategy. In this study, 59 patients between 2 months and 18 years of age with histologically verified ACC were analyzed retrospectively with respect to oncosurgical aspects. Patients were registered in the GPOH-MET 97 trial of the Society of Pediatric Oncology and Haematology. Preoperative management, factors influencing surgical severity, and operative complications were assessed.The gender ratio was 1:2 (m:f). A total of 58 patients showed increased hormonal activity and associated clinical signs of hormonal excess. Tumor volume was ≥ 300 mL in 25 patients. These patients showed an increased rate of operative complications and a poorer overall survival (OS) rate (p<0.01). A total of 14 patients showed metastatic spread, particularly to the lungs and lymph nodes. Biopsy of the tumor was performed in 12 patients. Tumor rupture occurred in 11 patients. Preoperative biopsy and/or experienced tumor rupture were associated with poorer OS rate. R2 resection only was achievable in 5 patients, and surgery was not feasible in 3 patients.In conclusion, since most of the pediatric ACC are hormone active and can be diagnosed clinically, the need of a tumor biopsy has to be discussed critically. Thorough pre- and perioperative management is essential for oncosurgical success.

Virilizing ovarian Krukenberg tumor in a 27-year-old pregnant woman. A case report and literature review.

A case is reported of a 27-year-old pregnant woman with ovarian tumors, measuring 12 cm and 11.5 cm in the greatest diameter, discovered during investigation for virilization symptoms. Termination of the pregnancy at the 22nd week of gestation and tumorectomy with both adnexa were performed, with the provisional diagnosis of arrhenoblastoma. Pathological examination of the tumors showed typical Krukenberg neoplasms and subsequent upper GI tract endoscopy revealed a gastric cancer that was excised. The pathological examination revealed a diffuse type gastric adenocarcinoma with signet ring morphology, similar to ovarian tumors. In any case of ovarian tumor with unusual hormonal manifestations, in addition to hormonally active sex cord-stromal neoplasms, metastatic ovarian tumors must be considered as well, especially in cases of bilateral tumors.