Hypoxia-associated genetic signature in ovarian steroid cell tumor NOS.

Steroid cell tumors, not otherwise specified (SCT-NOS), are uncommon ovarian neoplasms accompanied by virilization symptoms due to hyperandrogenism, which are malignant in approximately one-third of the cases. Given the rarity of SCT-NOS, their molecular underpinnings have not yet been studied in depth. In this case series, we performed the first comprehensive analysis of the genetic landscape of this rare ovarian tumor. A detailed clinicopathological description of an index case is also provided. Over a 20-year period, a total of eight patients were seen at our institution. Total nucleic acids (RNA and DNA) were extracted from evaluable formalin-fixed, paraffin-embedded tumor specimens (n = 7) and subjected to TruSight Oncology 500 testing and/or exome sequencing. The results identified pathogenic variants in several hypoxia-related genes - including HIF1A, VHL, SDHB, SRC, IDH2, and FOXO4. As the first comprehensive genetic analysis of SCT-NOS, this study shows that dysregulation in the hypoxia signaling pathway is a key molecular feature of this rare tumor. Clinically, long-term follow-up with periodic measurements of androgen levels should be pursued in all cases since recurrences may occur several years after the initial diagnosis.

Human chorionic gonadotrophin secreting adrenocortical neoplasm presenting with peripheral precocious puberty in an infant.

Adrenocortical tumor (ACT) is a rare malignant tumor which usually present with Cushing syndrome and virilization. Paraneoplastic syndromes (PNS) due to neoplasms can occur with peptides or cytokines secreted by the tumor. Here, we report a 13-month-old-male presented with severe masculinization. He had signs of precocious puberty with enlarged testicles, very high testosterone levels but low levels of gonadotrophins, and elevated ß-hCG. He underwent a left nephrectomy. The histopathological evaluation revealed a diagnosis of adrenocortical neoplasm. The levels of androgens and ß-hCG normalized after the resection of tumor, and the clinical findings improved within few months. We report the first pediatric patient with peripheral precocious puberty due to an ACT that secretes ß-hCG as PNS. A ß-hCG secreting ACT can cause severe virilization due to increased gonadal androgens stimulated by ß-hCG as well as due to increased adrenal androgens from the tumor.

Sertoli-Leydig cell ovarian tumour: a rare cause of virilisation and androgenic alopecia.

Sertoli-Leydig cell tumours (SLCTs) represent a rare cause of hyperandrogenic state. SLCTs are sex cord ovarian neoplasms, accounting for <0.2% of all ovarian tumours. Most of the sex cord-stromal tumours have a benign clinical course, with 10%-20% of them at risk of aggressive course. We report a case of a woman in her 30s who presented with androgenic alopecia, virilisation and secondary amenorrhoea. The evaluation revealed an extremely high testosterone level. Imaging for the localisation of source of excess testosterone with contrast-enhanced CT of the abdomen revealed a right ovarian mass. Hence, a diagnosis of testosterone-secreting ovarian tumour was considered. The patient underwent right salphingo-oophorectomy, and histopathology was reported as Sertoli cell tumour. Postoperatively, there was normalisation of serum testosterone levels with decrease in virilisation and resumption of spontaneous menstrual cycles. The patient conceived spontaneously after 2 months of surgery.

Ovarian steroid cell tumour inducing virilisation in a postmenopausal woman.

Hyperandrogenism with virilisation de novo in postmenopausal women is exceedingly rare, with aetiology oscillating between ovarian tumours, adrenal tumours, ovarian hyperthecosis and, less frequently, Cushing's syndrome. We report a case of a postmenopausal woman in her late 60s, referred from her primary healthcare physician to a gynaecology appointment due to hirsutism and vasomotor symptoms. At physical examination, clitoromegaly was also identified. Blood tests revealed severe hyperandrogenemia, with total testosterone above 200 ng/dL, but transvaginal ultrasound and abdominal CT were unremarkable. Three months later, abdominal CT was repeated, revealing a moderate heterogeneous enhancement with 18 mm on the left ovary, which was confirmed by transvaginal ultrasound. Total laparoscopic hysterectomy with bilateral adnexectomy was performed. Histopathological examination reported an ovarian steroid cell tumour not otherwise specified on the left ovary and bilateral ovarian hyperthecosis. Two months later, the patient had normal total testosterone and the hirsutism complaints were completely absent.

Postmenopausal hyperandrogenism.

Postmenopausal hyperandrogenism is a state of relative or absolute androgen excess originating from the adrenal glands and/or ovaries clinically manifested by the presence of terminal hair in androgen-dependent areas of the body, and other manifestations of hyperandrogenism such as acne and alopecia or the development of virilization. In such circumstances, physicians must exclude the possibility of rare but serious androgen-producing tumors of the adrenal glands or ovaries. Worsening of undiagnosed hyperandrogenic disorders such as polycystic ovary syndrome, congenital adrenal hyperplasia, ovarian hyperthecosis, Cushing syndrome and iatrogenic hyperandrogenism should be considered for differential diagnosis. Elevated serum testosterone not only causes virilizing effects, but also will lead to hypercholesterolemia, insulin resistance, hypertension and cardiac disease. An ovarian androgen-secreting tumor, which is diagnosed in 1-3 of 1000 patients presenting with hirsutism, comprises less than 0.5% of all ovarian tumors. Adrenal tumors, including non-malignant adenomas and malignant carcinomas, are less common than ovarian tumors but cause postmenopausal virilization. Measurement of serum testosterone, sex hormone-binding globulin, dehydroepiandrosterone sulfate, androstenedione and inhibin B is necessary in postmenopausal women with the complaints and signs of hyperandrogenism. Some tests to discard Cushing syndrome should also be done. After an etiological source of androgen hypersecretion has been suspected, we recommend performing magnetic resonance imaging of the adrenal glands or ovaries. Medical management with gonadotropin-releasing hormone agonist/analogues or antagonists has been reported for women who are either unfit for surgery or in whom the source of elevated testosterone is unidentified.

Prenatal Androgenization Induces Anxiety-Like Behavior in Female Rats, Associated with Reduction of Inhibitory Interneurons and Increased BDNF in Hippocampus and Cortex.

Anxiety is one of the most frequent psychiatric disorders. Despite the fact that most studies describe an anxiolytic effect of testosterone, hyperandrogenemia in mothers is assumed to be related to an increased risk of mood disorders in their offspring. An increasing body of scientific evidence suggests that an altered expression of interneuronal markers of the hippocampus may be the cause of anxiety. The aim of this study was to examine the influence of maternal hyperandrogenemia on behavioral parameters of anxiety-like behavior, neuropeptide Y (NPY) and parvalbumin (PV) expression in the hippocampus, and the level of the brain-derived neurotrophic factor (BDNF) in the hippocampus and cerebral cortex. Pregnant female Wistar albino rats were treated with testosterone undecanoate on the 20th day of gestation. Anxiety-like behavior in adult female offspring was evaluated by the elevated plus maze test and the open field. The number of PV and NPY immunoreactive cells in the hippocampus was determined immunohistochemically. The level of BDNF expression in the hippocampus and cerebral cortex was analyzed with the Western blot test. Prenatal hyperandrogenization increased anxiety-like behavior in female offspring and decreased expression of NPY+ and PV+ in the CA1 region of the hippocampus as compared to the control group. BDNF expression in the hippocampus and cerebral cortex of prenatally androgenized female offspring was significantly increased in comparison with the controls. Prenatal hyperandrogenization may be the cause of anxiety-like behavior in female offspring. Decrease in NPY and PV expression in the hippocampus may explain the possible mechanism of hyperandrogenization induced anxiety.

Bilateral Adrenocortical Adenomas along with Virilization and Cushing's Syndrome.

We herein present the case of a 27-year-old woman with clinical and biochemical features of virilism. Imaging studies revealed the presence of a bilateral adrenal tumor. Although the secretion of androgens was remarkable, the autonomous production of cortisol was also evident because of a loss of circadian rhythm and the absence of cortisol suppression by dexamethasone. The surgical excision of both adrenal tumors was performed, and the histological examination showed no malignancy. We also report the successful pregnancy and delivery of the patient who showed evolving adrenocortical insufficiency along with virilization and Cushing's syndrome and who continued to receive glucocorticoid replacement therapy during pregnancy.

Recurrent maternal virilization during pregnancy in patients with PCOS: two clinical cases.

BACKGROUND: Maternal virilization during pregnancy is a rare phenomenon. Polycystic ovary syndrome (PCOS), luteoma and luteinic cysts are the most frequent and benign etiologies. This article presents two cases of recurrent maternal virilization during pregnancy. CLINICAL CASES: Our reported cases were young women with Afro-Caribbean and Nigerian origins. Data were collected by history-taking, clinical examination, laboratory investigations, transabdominal ultrasonographic examination and Magnetic Resonance Imaging. Both patients were diagnosed with PCOS according to the Rotterdam criteria. During each of their pregnancies they both developed an explosive hirsutism, a deepening in the voice, a clitoromegaly. Gestational diabetes occurred during pregnancies. There was no fetal virilization, despite raising androgen levels, more than tenfold to normal. Improvement of hirsutism and normalization of androgens were described in postpartum. CONCLUSION: Only few cases of maternal virilization during pregnancy were reported in literature and even fewer concern recurrent and bilateral ovarian etiology. Hyperplasia of ovarian theca cells seems to be the most likely explanation, which would suggest that PCOS belongs to a spectrum of abnormal reactivity of the ovary to human Chorionic Gonadotrophin (hCG) stimulation along with luteoma and luteinic cyst of pregnancy.  Insulin resistance could worsen hyperandrogenism but is not enough to explain virilization. Treatment should focus on protecting the fetus of possible virilization as well as its mother, but also on preserving the subsequent fertility in both.

Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS.

Androgen excess is a hallmark of polycystic ovary syndrome (PCOS), a prevalent yet poorly understood endocrine disorder. Evidence from women and preclinical animal models suggests that elevated perinatal androgens can elicit PCOS onset in adulthood, implying androgen actions in both PCOS ontogeny and adult pathophysiology. Prenatally androgenized (PNA) mice exhibit a robust increase of progesterone-sensitive GABAergic inputs to gonadotropin-releasing hormone (GnRH) neurons implicated in the pathogenesis of PCOS. It is unclear when altered GABAergic wiring develops in the brain, and whether these central abnormalities are dependent upon adult androgen excess. Using GnRH-GFP-transgenic mice, we determined that increased GABA input to GnRH neurons occurs prior to androgen excess and the manifestation of reproductive impairments in PNA mice. These data suggest that brain circuit abnormalities precede the postpubertal development of PCOS traits. Despite the apparent developmental programming of circuit abnormalities, long-term blockade of androgen receptor signaling from early adulthood rescued normal GABAergic wiring onto GnRH neurons, improved ovarian morphology, and restored reproductive cycles in PNA mice. Therefore, androgen excess maintains changes in female brain wiring linked to PCOS features and the blockade of androgen receptor signaling reverses both the central and peripheral PNA-induced PCOS phenotype.

Delayed presentation of a virilising, pure testosterone-secreting adrenocortical carcinoma with coexistent composite myelolipoma and a venous thrombus extending to the heart.

A 40-year-old normotensive woman presented with abnormal facial hair for 4 years and amenorrhoea for 13 years. Hormonal, biochemical and haematological evaluation showed isolated elevation of serum testosterone and free testosterone. Her follicle-stimulating hormone and luteinising hormone were in the premenopausal range. Until recently she had reconciled to early 'menopause' and visited beauty clinics but never sought medical evaluation. Imaging revealed an enhancing left adrenal mass with fat densities and venous thrombus extending through the inferior vena cava to a 7 cm mass in the right atrium. She underwent left kidney-preserving surgery utilising hypothermic cardiopulmonary bypass with early clamping of the pulmonary artery without circulatory arrest. Histology showed adrenocortical carcinoma with composite incidental myelolipoma and neoplastic thrombus. At 2 months, testosterone has normalised and she is doing well. Isolated testosterone-secreting adrenocortical carcinoma with massive venous thrombus is rare as is coincidental composite macroscopic myelolipoma.

Virilism and Ectopic Expression of HSD17B5 in Mature Cystic Teratoma.

Mature cystic teratoma (MCT) is rarely involved in the overproduction of steroid hormones in contrast to sex cord stromal tumors. A 31-year-old woman visited our hospital with hirsutism, hoarseness, and hair loss from the scalp. Serum testosterone and free-testosterone levels were 7.3 ng/ml and 2.3 pg/ml, respectively, which were markedly in excess of the age adjusted female standard levels. Basal blood levels of steroid hormones and serum levels of 17-hydroxyprogesterone at 1 h after intravenous injection of adrenocorticotropic hormone demonstrated that 21-hydroxylase deficiency was not the underlying cause of her virilization. A subsequent chromosomal test with G-banding revealed a karyotype of 46XX. Magnetic resonance imaging revealed a mass in the left ovary, which was subsequently diagnosed as MCT. Detailed pathological analysis of the tumor indicated that it was comprised of skin components, sweat glands, with hair and fat texture, glandular epithelium and fibrous connective tissue, consistent with the characteristic composition of MCT. Immunohistochemical analysis demonstrated marked immunoreactivity of 17beta-hydroxysteroid dehydrogenase (HSD17B5), an enzyme that can convert androstenedione to testosterone. Following surgical removal of the tumor, testosterone and free testosterone levels were markedly decreased (0.3 ng/ml and 0.4 pg/ml, respectively) and other symptoms abated. In conclusion, this is the first report of an ovarian MCT associated with clinical virilization caused by the ectopic production of testosterone possibly because of an overexpression of intratumoral HSD17B5.

Androgenetic alopecia.

Androgenetic alopecia (AGA) is the most common form of alopecia, affecting up to 80% of men and 50% of women in the course of their life. AGA is caused by a progressive reduction in the diameter, length and pigmentation of the hair. Hair thinning results from the effects of the testosterone metabolite dehydrotestosterone (DHT) on androgen-sensitive hair follicles. In women, AGA produces diffuse thinning of the crown region with maintenance of the frontal hairline (Ludwig pattern AGA). In premenopausal women, AGA can be a sign of hyperandrogenism, together with hirsutism and acnes. Male pattern is characterized by bitemporal recession of the frontal hairline, followed by diffuse thinning at the vertex. Today, scalp dermoscopy is used routinely in patients with androgenetic alopecia, as it facilitates the diagnosis and differential diagnosis with other diseases, allows staging of severity, and allows you to monitor the progress of the disease in time and response to treatment. AGA is a progressive disease that tends to worsen with time. Medical treatment of AGA includes topical minoxidil, antiandrogen agents, 5-alpha reductase inhibitors.

A novel heterozygous mutation in steroidogenic factor-1 in pubertal virilization of a 46,XY female adolescent.

BACKGROUND: Steroidogenic factor-1 (SF-1) gene (NR5A1) mutations cause disorders of sexual development due to gonadal dysgenesis, particularly in 46,XY individuals. In cases exhibiting this mutation, the phenotype is heterogeneous, and it may vary within a spectrum ranging from complete female appearance to an infertile male. Virilization observed in some cases in the pubertal age group may lead to diagnostic difficulties. CASE: The present case report describes the clinical, histopathologic, and genetic characteristics of a 46,XY case, who was born with a female phenotype and raised as a girl, presented with findings of virilization in the pubertal period. She had no germ cells and very few Leydig cells with atrophic testis on biopsy and in whom a novel heterozygous mutation in the SF-1 gene (a heterozygous 7-bp deletion mutation in exon 7 [c.1308-1314del7bp] causing frameshift) was identified. SUMMARY AND CONCLUSION: Although the gonads are very dysgentic in patient with SF-1 mutations, sufficient androgen synthesis can cause severe virilization during puberty.

Evidence for masculinization of adipokine gene expression in visceral and subcutaneous adipose tissue of obese women with polycystic ovary syndrome (PCOS).

CONTEXT: Sex hormones, particularly androgens, may influence not only adipose tissue distribution but also its functions. OBJECTIVE: We explored the possibility of sexual dimorphism in adipose tissue and skeletal muscle function. DESIGN: This was a case-control study. SETTING: The setting was an academic hospital. PARTICIPANTS: Participants were severely obese men (n = 7), control women (n = 7), and hyperandrogenic women presenting with polycystic ovary syndrome (PCOS) (n = 7) submitting to bariatric surgery and an independent series of 40 patients with PCOS and 40 control women matched for age and body mass index. INTERVENTIONS: Samples of subcutaneous (SAT) and visceral adipose tissue (VAT) and skeletal muscle were obtained during bariatric surgery in severely obese subjects. MAIN OUTCOME MEASURES: Gene expression of chemerin, lipocalin-2, and omentin-1 in tissue samples was measured. We analyzed the effects of PCOS and obesity on serum concentrations of these adipokines in the larger series of women with PCOS and in control women. RESULTS: Expression of chemerin and lipocalin-2 was higher in VAT than in SAT in men and women with PCOS; the opposite was observed in control women. Omentin-1 expression was higher in VAT than in SAT in the three groups. No differences were observed in the skeletal muscle expression of these adipokines. Obesity increased serum chemerin and lipocalin-2 levels and tended to decrease omentin-1, irrespective of PCOS. CONCLUSIONS: The present results suggest that there is sexual dimorphism in some adipose tissue functions and that this dimorphism may be related to differences in androgen concentrations because women with PCOS show a masculinized pattern of expression of some adipokines.

Female pseudohermaphroditism associated with maternal steroid cell tumor, not otherwise specified of the ovary: a case report and literature review.

Maternal virilization in pregnancy with or without fetal female pseudohermaphroditism has several etiologies. Of these, pregnancy luteoma is the most common cause of maternal virilization during pregnancy, and approximately 20 cases have been reported in recent years. Moreover, four cases of pregnancy luteomas with female pseudohermaphroditism have been reported. However, the extremely rare steroid cell tumor, not otherwise specified (NOS), has been reported only once as a cause for maternal virilization. Herein, the authors report the first case of maternal virilization with female pseudohermaphroditism associated with steroid cell tumor-NOS along with the clinical course, pathological features, and a review of the literature.

Classic congenital adrenal hyperplasia with virilisation and salt-wasting: from birth to the adult life.

AIM: Our objective was to show the way the classic CAH presents after birth as a severe condition and develops to the adult life, effecting growth, height and weight, appearance, fertility, relationships and quality of life. CASE: We report the case of a 23-years-old female with the classic Congenital Adrenal Hyperplasia (CAH) from birth, diagnosed due to genital pigmentation, clitoromegaly and salt-wasting crisis, treated with glucocorticoid replacement (hydrocortisone, fludrocortisone and NaCI), followed by genital surgery, until the adult life when she continues treatment with fludrocortisone and prednisolone. CONCLUSION: A treatment challenge is to effectively control the excess androgen symptoms by using the lowest possible glucocorticoid dose. Patients well-being can be accomplished by team work, adapted therapy, continues follow-up and patient's compliance (Ref. 15).

Virilizing para-adrenocortical adenoma associated with idiopathic-acquired generalized anhidrosis in an adolescent girl.

Adrenocortical tumors are rare in childhood and adolescence. Virilization, alone or in combination with signs of overproduction of other adrenal hormones, is the most common clinical presentation. Here we report an unusual case of an African-American female adolescent presenting with idiopathic acquired generalized anhidrosis, dysregulation of body temperature, absence of adult body odor and dry skin in the face of a virilizing para-adrenocortical adenoma. Virilization signs regressed soon after removal of the tumor, but normalization of the 3alpha-androstenediol glucuronide (3alpha-AG) took longer compared to other measurable androgens; accompanied by anhidrosis. The association of remitting anhidrosis with normalized levels of 3alpha-AG suggests it might be a possible mechanism for anhidrosis. High 3alpha-AG levels might implicate the increased peripheral conversion of weak pro-androgens with different biochemical structure. We recommend obtaining 3alpha-AG beside other androgens in virilized patients with atypical dermatological symptoms in the face of hyperandrogenism.

Clinical, ultrasonographic, computed tomography and histopathological manifestations of ovarian steroid cell tumour, not otherwise specified: our experience of a rare case with female virilisation and review of the literature.

INTRODUCTION: Ovarian steroid cell tumours, not otherwise specified (NOS) are rare sex cord-stromal tumours of the ovary. These tumours should be considered a cause of isosexual precocious puberty in children and virilisation in adults. CASE: We report a case of 40-year-old woman with mental handicap who presented with 3 years of amenorrhea and progressive virilisation. Pelvic ultrasonography identified a 6.19 × 6.15 cm well-defined echogenic-multilobular mass arising from the left ovary. Fluid in the cul-de-sac was noted. Colour Doppler examination with endovaginal ultrasonography showed high vascularity of the tumour with low resistance to flow. A computed tomography (CT) scan of the upper and lower abdomen showed a lobular mass with diaphragms in the left adnexal structure and fluid in the cul-de-sac; no adrenal gland enlargement or additional tumour was detected. Laboratory analysis revealed increased levels of serum total testosterone. Total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed. Histological examination showed a benign steroid cell tumour, NOS without evidence of necrosis, haemorrhage or invasion. The immunohistochemical study showed that the tumour cells were positive for inhibin, CD 99, Melan A and vimentin and negative to CK AE1, CK AE3, progesterone and estrogen receptors. CONCLUSION: Careful medical history, physical examination, laboratory serum values and imaging studies are helpful in making the pre-operative diagnosis. Steroid cell tumours, NOS are usually benign, unilateral and characterised by the composition of two similar-appearing polygonal cell types. They differ from Leydig cell tumours in the lack of crystals of Reinke in their cytoplasm.

Laparoscopic surgery in 46,XX disorder of sex development: hysterosalpingectomy with gonadectomy.

PURPOSE: We present the outcomes of one of the largest series specifically of laparoscopic hysterosalpingectomy with bilateral gonadectomy in 46,XX patients with congenital adrenal hyperplasia raised as a male. PATIENTS AND METHODS: From June 2005 to March 2008, five patients raised as male were treated at our institution using laparoscopic surgery. 46,XX disorder of sex development was diagnosed in all the patients because of congenital adrenal hyperplasia. Hysterosalpingectomy with bilateral gonadectomy was performed completely laparoscopically in all five patients. RESULTS: All procedures were completed with minimal blood loss. The duration of the surgeries was 70-125 minutes. There were no complications during surgery or conversion to open surgery. The hospital stay ranged from 1 to 2 days, except in one patient who presented urinary retention and was discharged from the hospital a week after the surgery. CONCLUSIONS: Laparoscopic surgery can be safely used as part of the diagnosis and treatment of 46,XX disorder of sex development. Laparoscopy can be useful in the diagnosis as well as surgical management of Müllerian structures as well as intraabdominal gonads contrary to social sex.

Immune-mediated encephalitis and virilization in association with a mature cystic ovarian teratoma in an adolescent girl.

BACKGROUND: Mature cystic teratomas are the most common form of ovarian tumor in children and adolescents. These tumors are mostly benign and non-secreting. Virilization from an ovarian teratoma is exceptionally rare in pediatrics. Equally rare is the association of ovarian teratomas with auto-immune encephalitis. METHODS: We describe the case of a 15-year-old girl with menstrual abnormalities and virilization, who had a past medical history of encephalitis of an unknown etiology 16 months prior to presentation. RESULTS: Endocrine evaluation revealed an elevated serum testosterone and 17-hydroxy progesterone. A large left ovarian tumor was seen on a CT scan. Surgical excision revealed a mature cystic teratoma containing 6 liters of clear fluid with high androgen levels. Antibodies to the N-methyl-D-aspartate receptor of the hippocampus were detected in pre-operatively archived serum, but undetectable 6 months postoperatively. Immunohistochemistry studies on the tumor sections revealed that the antibodies in the patient's serum reacted with areas of the tumor expressing the N-methyl-D-aspartate receptor. Postoperatively, the patient's menstrual cycles became regular and her behavioral problems resolved. Her testosterone levels fell precipitously as well. CONCLUSION: Both virilizing mature cystic teratomas and teratoma-associated encephalitis are extremely rare in the pediatric population. We report on the first instance of these 2 rare entities occurring in the same patient.