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Although hyperandrogenism is a frequent cause of consultation in adolescent girls, more severe forms with virilization must lead to suspicion of an adrenal or ovarian tumor. However, they may also reveal a 46,XY disorder of sexual development (DSD). Here, we describe four adolescent girls referred for pubertal virilization and in whom we diagnosed a 46,XY DSD. We performed gene mutation screening by Sanger sequencing (all patients) and by next-generation sequencing (NGS) in patient #4. We identified new heterozygous NR5A1 gene variants in patients #1 and #2 and a homozygous SRD5A2 gene deletion in patient #3. Patient #4 received a diagnosis of complete androgen insensitivity in childhood; however, due the unusual pubertal virilization, we completed the gene analysis by NGS that revealed two heterozygous HSD17B3 variants. This work underlines the importance of considering the hypothesis of 46,XY DSD in adolescent girls with unexplained virilization at puberty.

Total testosterone, which is peripherally converted to its biologically active form dihydrotestosterone (DHT), is the first-line hormone investigation in hyperandrogenic states and infertility in premenopausal women. Polycystic ovary syndrome (PCOS), the most common cause of hyperandrogenism and infertility in young women, is often associated with mild elevations of total testosterone. Whereas very high levels of total testosterone (>2–3 SD of normal reference), are most often associated with hyperandrogenic signs, menstrual irregularity, rapid onset of virilization, and demand a prompt investigation. Herein, we report a case of a 32-year-old woman who was referred to the endocrinology outpatient clinic due to secondary amenorrhea and extremely high testosterone levels without any virilization signs. We initially suspected pitfalls in the testosterone laboratory test. Total serum testosterone decreased after a diethyl-ether extraction procedure was done prior to the immunoassay, but testosterone levels were still elevated. An ovarian steroid-cell tumor (SCT) was then revealed, which was thereby resected. Twenty-four hours post surgery, the total testosterone level returned to normal, and a month later menstruation resumed. This case emphasizes that any discrepancy between laboratory tests and the clinical scenario deserves a rigorous evaluation to minimize misinterpretation and errors in diagnosis and therapeutic approach. Additionally, we describe a possible mechanism of disease: a selective peripheral target-tissue response to high testosterone levels that did not cause virilization but did suppress ovulation and menstruation.

Introduction: Children with 45X/46XY difference/disorder of sex development (DSD) have varying internal/external genitalia/gonads, Turner-like features, and increased risk of gonadal malignancy. We present a case of concomitant virilization and feminization as a unique feature of gonadoblastoma in a boy with 45X/46XY DSD. Case presentation: The patient was born with ambiguous genitalia (phallus of 2cm, perineal urethra) and a Turner-like phenotype. Ultrasound scan revealed horseshoe kidneys, intra-abdominal gonads, and Mullerian remnants. His karyotype was 45X/46XY with atypical Y chromosome. Initial gonadotrophin levels were very high. Biopsy of the bilateral gonads revealed testicular tissue. It was decided to raise the baby as a boy. Staged orchidopexy and hypospadias repair were done between 4 and 6 years of age. He remained under close clinical, biochemical and radiological follow-up for the potential development of gonadal malignancies. He developed penile enlargement at the age of11 years. Within a few months, he developed bilateral gynecomastia and rapid cystic enlargement of the gonads. Hormone quantification revealed elevated serum estrogen, a peri-pubertal testosterone level, and normal tumor marker levels. After a multidisciplinary team discussion, he underwent surgical exploration and removal of a bulky uterus and both gonads. Histology showed evidence of gonadoblastoma within the testicular and the ovarian stroma. Conclusion: Children with DSD are at high risk for developing gonadoblastomas, which can present as rapid concurrent isosexual and heterosexual pubertal development. It is critical that patients with DSD remain under close oncologic surveillance.

Virilization is a rare condition in postmenopausal women, usually attributed to androgen excess of ovarian or adrenal origin. A 62-year-old woman presented with excessive hair loss of 3 months' duration and was investigated for an endocrine cause of alopecia. The hormonal evaluation revealed increased testosterone but normal levels of androstenedione and dehydroepiandrosterone sulfate, while the results of transvaginal ultrasonography and abdominal computed tomography were unremarkable. Based on these findings, the possibility of an adrenal androgen-secreting tumor was ruled out and suspicion of Leydig cell hyperplasia was raised. A bilateral laparoscopic salpingo-oophorectomy was performed due to the age of the patient and the diagnosis of Leydig cell hyperplasia was confirmed by histopathological examination. The postoperative course of the patient was uneventful and a repeat hormonal evaluation after the operation showed a normalization of androgen levels. In conclusion, Leydig cell hyperplasia should be considered as a likely cause of hyperandrogenism of ovarian origin in women who develop virilization. In postmenopausal women, bilateral oophorectomy will treat the disorder and provide a conclusive diagnosis via histopathological examination.

Introduction In females, congenital adrenal hyperplasia (CAH), a spectrum of inherited genetic conditions related to the disruption of adrenal steroidogenesis, is among the most common conditions leading to inappropriate virilization. For adolescent and adult women, progression of hirsutism may have many psychological concerns. Objectives To explore the psychological distress of a young Tunisian woman who sought medical help and psychological support at a late stage, after suffering from genital ambiguity and severe virilization. Methods Harboring phenotypic male transformation at puberty, our patient attended genetic counselling for cytogenetics assessment. Clinical, biological, psychological and genetic explorations were thus carried out. Results A 17-year-old female was born from first-degree consanguineous parents, and had healthy siblings (a sister and three brothers). After a single menstrual episode at puberty, she developed amenorrhea and an unexpected progressive virilization, including hirsutism with an inappropriate beard that she had to shave every day and a male voice. Clinical examination revealed a male morphotype with an enlarged clitoris that resemble a penis, male-type pubic hair, underdeveloped of breasts, abnormal cutaneous hyperpigmentation, and a short stature. Pelvic ultrasound revealed a small uterus, but with no visualized gonads. Genetic exploration showed a female 46,XX karyotype and the absence of Y chromosome sequences. Diagnosis of a non-classic CAH was confirmed. Psychological assessment found that the psychological development of the sexual identity corresponded to the assignment of the female sex. A severe psychological suffering due to the non-acceptance of her virile appearance impaired the quality of her daily personal and social life. Stigmata of a depressive syndrome were also revealed. Conclusions Particular attention to the psychological assessment of patients with CAH is recommended, as changes in physical appearance have a detrimental impact on psychological and mental well-being. Disclosure of Interest None Declared

Background: Adrenocortical tumors are rare neoplasms of childhood; most of which are functional in childhood, producing excess hormones. Virilization, precocious puberty, and Cushing's syndrome are common presenting features. Clinical Description: A 6-year-8-month-old girl presented with features of virilization, which started appearing at 2 ½ years of age. The mother gave a history of progressive enlargement of the clitoris with the development of pubic, axillary, and facial hair over the years. There was no history of perinatal complications, features of adrenal insufficiency, atypical external genitalia at birth, or family history of malignancy. On examination, she had features of heterosexual peripheral precocious puberty. The hormonal investigation was suggestive of cortisol and androgen excess. Radiologically, she had an adrenal tumor appearing like adrenocortical carcinoma (ACC)-large size, high noncontrast Hounsfield units, and poor washout. Management and Outcome: As virilization was not present since birth and there was no evidence of adrenal insufficiency, therefore, the possibility of congenital adrenal hyperplasia was unlikely. Investigations revealed that the testosterone levels were much higher than other adrenal androgen precursors like dehydroepiandrosterone sulfate. This was a clinical clue to the well-differentiated and benign nature of the tumor although radiologically it appeared like ACC. The child underwent en bloc resection of the mass, and histopathology was suggestive of a benign adrenocortical adenoma. Seven days after surgery, the serum testosterone had dropped substantially. Conclusion: This case creates awareness about the possibility of an adrenocortical neoplasm in a child with early-onset virilization, which can be diagnosed correctly by following a step-wise, logical sequence of investigations.

Introduction: Adrenal oncocytic tumors are rare, especially among children. They are often nonfunctioning and benign but can express with Cushing syndrome, female virilization, precocious pseudo-puberty, or hirsutism when they are hormonally active. However, complex association of amenorrhea with Cushing syndrome and hirsutism in female children is unusual. Case presentation: We present the case of a 15-year-old girl with recent amenorrhea, Cushing syndrome, and hirsutism. Blood tests showed elevated cortisol and androgens levels. Imaging studies showed a large mass in the left adrenal gland. After laparoscopic adrenalectomy, the histopathological examination diagnosed an adrenocortical oncocytoma categorized as benign by the Lin-Weiss-Bisceglia classification. The patient was discharged from hospital on the 4th postoperative day. After 16 months, she remains recurrence-free clinically and on imagery. Conclusion: To our knowledge, this clinical endocrine picture due to unusual co-secretion of cortisol and androgens by an adrenal oncocytic tumor is exceptional, particularly in children. Only three similar cases have been reported in the pediatric literature yet. However, this condition is amenable to surgery with complete resolution of abnormal clinical manifestations.

Summary: Total testosterone, which is peripherally converted to its biologically active form dihydrotestosterone (DHT), is the first-line hormone investigation in hyperandrogenic states and infertility in premenopausal women. Polycystic ovary syndrome (PCOS), the most common cause of hyperandrogenism and infertility in young women, is often associated with mild elevations of total testosterone. Whereas very high levels of total testosterone (>2-3 SD of normal reference), are most often associated with hyperandrogenic signs, menstrual irregularity, rapid onset of virilization, and demand a prompt investigation. Herein, we report a case of a 32-year-old woman who was referred to the endocrinology outpatient clinic due to secondary amenorrhea and extremely high testosterone levels without any virilization signs. We initially suspected pitfalls in the testosterone laboratory test. Total serum testosterone decreased after a diethyl-ether extraction procedure was done prior to the immunoassay, but testosterone levels were still elevated. An ovarian steroid-cell tumor (SCT) was then revealed, which was thereby resected. Twenty-four hours post surgery, the total testosterone level returned to normal, and a month later menstruation resumed. This case emphasizes that any discrepancy between laboratory tests and the clinical scenario deserves a rigorous evaluation to minimize misinterpretation and errors in diagnosis and therapeutic approach. Additionally, we describe a possible mechanism of disease: a selective peripheral target-tissue response to high testosterone levels that did not cause virilization but did suppress ovulation and menstruation., Learning Points: Total testosterone is the most clinically relevant hormone in investigating hyperandrogenic states and infertility in premenopausal women. Very high total testosterone levels in women (>2-3 SD of normal reference) are most often associated with hyperandrogenic signs, menstrual irregularities, and a rapid onset of virilization. In women with very elevated testosterone levels and the absence of clinical manifestations, laboratory interference should be suspected, and diethyl ether extraction is a useful technique when other methods fail to detect it. Ovarian steroid cell tumors (SCT) encompass a rare subgroup of sex cord-stromal tumors and usually secrete androgen hormones. SCTs are clinically malignant in 25-43% of cases. A selective response of peripheral target tissues to testosterone levels, with clinical manifestations in some tissues and no expression in others, may reflect differences in the conformation of tumor-produced testosterone molecules.

Objective: To evaluate a rare case of a postmenopausal woman with hirsutism and virilization due to Leydig cell tumors (LCTs) of both ovaries. Methods: In this challenging case, the diagnostic studies included the detection of total/free testosterone, hemoglobin, and estradiol levels; adrenal computed tomography; and pelvic magnetic resonance imaging. Results: A 61-year-old woman presented for the evaluation of hirsutism. Physical examination revealed normal vital signs and evidence of virilization. The baseline laboratory findings were hemoglobin level of 16.2 g/dL (reference, 12.0-15.5 g/dL), total testosterone level of 803 ng/dL (reference, 3-41 ng/dL), and free testosterone level of 20.2 pg/mL (reference, 0.0-4.2 pg/mL). Pelvic magnetic resonance imaging showed bilateral homogeneous ovarian enhancement. Based on the magnetic resonance imaging findings and clinical presentation, the patient was diagnosed with ovarian hyperthecosis and underwent laparoscopic bilateral oophorectomy. Pathology confirmed LCTs in both ovaries. Six months later, testosterone levels normalized, with significant improvement in hirsutism and virilization. Conclusion: Clinicians should be aware of androgen-secreting tumors, including rare bilateral LCTs in postmenopausal women presenting with progressing hirsutism and virilization. Marked hyperandrogenemia with total testosterone level of >150 ng/dL (5.2 nmol/L) or serum dehydroepiandrosterone sulfate level of >700 μg/dL (21.7 mmol/L) is typically found. It should be recognized that diffuse stromal Leydig cell hyperplasia and small LCTs may be missed on imaging, and in some cases only pathology can confirm the result.

All girls presenting with virilization (which signifies severe hyperandrogenism) warrant thorough investigation. Ovarian hyperthecosis (OHT) is a rare cause of virilization in premenopausal women. Here, we report the case of a previously healthy 12-year-old Chinese girl with signs of virilization at puberty. Her serum total testosterone was elevated at 5.1 nmol/L (146.97 ng/dL) (normal: <1.4 nmol/L, <40.35 ng/dL). Workup for Cushing syndrome, sex development disorders, congenital adrenal hyperplasia, and adrenal and ovarian androgen-secreting tumors was unrevealing. Ovarian and adrenal venous sampling demonstrated ovarian hyperandrogenism without lateralization. Ovarian biopsy revealed nests of theca cells in the stroma of the right ovary, substantiating the diagnosis of OHT. A single dose of a GnRH analog resulted in the complete suppression of serum testosterone, supporting the diagnosis of OHT. Medical treatment with hormonal replacement therapy normalized serum testosterone levels. Our case report illustrates the diagnostic approach to virilization among girls at puberty and the diagnosis of OHT as the underlying pathology. [ABSTRACT FROM AUTHOR]

The Spanish artist, Jusepe de Ribera, painted a portrait of a virilized woman in 1631. He provided a brief clinical history on stone tablets, which indicates that the woman most likely harbored a benign, androgen-secreting ovarian tumor for 15 years.

Abstract Ovarian cystadenomas may present in a functional manner. Biochemical workup of seemingly benign ovarian lesions should be considered in the appropriate clinical context.

Abstract 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.

We present a case of a patient diagnosed in the 3rd trimester of pregnancy with a Krukenberg tumor being a metastasis of stomach cancer. Due to severe pre-eclampsia, the pregnancy was solved by Caesarean section, a female child was born with severe virilization.

Although hyperandrogenism is a frequent cause of consultation in adolescent girls, more severe forms with virilization must lead to suspicion of an adrenal or ovarian tumor. However, they may also reveal a 46,XY disorder of sexual development (DSD). Here, we describe four adolescent girls referred for pubertal virilization and in whom we diagnosed a 46,XY DSD. We performed gene mutation screening by Sanger sequencing (all patients) and by next-generation sequencing (NGS) in patient #4. We identified new heterozygous NR5A1 gene variants in patients #1 and #2 and a homozygous SRD5A2 gene deletion in patient #3. Patient #4 received a diagnosis of complete androgen insensitivity in childhood; however, due the unusual pubertal virilization, we completed the gene analysis by NGS that revealed two heterozygous HSD17B3 variants. This work underlines the importance of considering the hypothesis of 46,XY DSD in adolescent girls with unexplained virilization at puberty.

A 4-month-old girl presented us with genital ambiguity. The patient had a persistent urogenital sinus, posterior labial fusion with clitoromegaly. MRI reveals ovary-like mass in left inguinal region and right abdominal cavity. Uterus and vagina was also identified. Her mother was diagnosed with a right androgen-producing adrenocortical tumor 14 months after the birth of a virilized infant.

Androgen-producing steroid cell ovarian tumors are rare, comprising less than 1% of ovarian neoplasms, and can present with infertility and rapid virilization. Here we discuss the case of a 28-year-old woman who presented with an unusually insidious 2-year history of infertility, hirsutism, and clitoromegaly who was found to have an elevated serum testosterone and a left ovarian mass. She underwent oophorectomy and pathology revealed a steroid cell tumor, not otherwise specified (NOS), with no malignant features. Following surgery, the patient’s hyperandrogenic symptoms resolved with normalization of testosterone within 6 months, and she was able to conceive spontaneously. In reproductive-aged women with progressive hyperandrogenic symptoms, androgen-producing tumors, including those of ovarian origin, should be suspected. Thorough investigation, including plasma hormone levels and tumor histology, can lead to accurate diagnosis and management. Treatment should be guided by histology and surgical staging, with consideration for future fertility desires. Women who have not completed childbearing can undergo unilateral oophorectomy or tumor resection for benign tumors, with close monitoring of sex hormone levels postoperatively.

Background. NR5A1 [Steroidogenic factor 1 (SF1)] is a nuclear receptor that is essential for the development of gonads and adrenal glands as well as the establishment of steroidogenesis in these organs. The clinical findings of the mutations of NR5A1 gene in 46, XY individuals are variable. Virilization at puberty can be seen in some of the 46, XY children who have a female phenotype and are raised as female. A girl aged 13 years and 10 months old was brought by the family for deepening of her voice. On physical examination, her breast development was Tanner stage 2, axillary hair (+) and pubic hair was Tanner stage 4. She had labioscrotal fusion and 4.4 cm phallus (External Masculinisation Score was 6). Hypergonadotropic hypogonadism, low AMH and high testosterone levels were detected in laboratory tests. Uterus was not visualized in pelvic ultrasonography. Karyotype analysis was reported as 46, XY. Sequence analysis of the NR5A1 gene revealed a novel heterozygote c.1075_1089del (p.Leu359_Leu363del) variant. The patient was raised as a female and oestrogen replacement was started following gonadectomy. Conclusion. It should be kept in mind that virilization may develop at puberty in individuals with 46, XY disorder of sexual development due to NR5A1 mutation. [ABSTRACT FROM AUTHOR]

We report a case of a 4-year-old girl with an ovarian steroid cell tumor, not otherwise specified (SCT-NOS). She was admitted to the hospital with progressing virilization and Cushing’s syndrome, which included abnormality of the perineum, hirsutism, hypertrichosis, flushing of face, hoarseness, and weight gain. Blood testing showed a significantly increased testosterone level and slightly increased cortisol level. Computed tomography scan revealed an 8.0 × 5.0 × 5.0 cm tumor of the right ovary. The patient underwent right salpingo-oophorectomy, and pathological examination showed malignant potential. Three courses of bleomycin, etoposide, and cisplatin were administered as postoperative chemotherapy. After tumor resection, her testosterone decreased to undetectable levels. However, during the course of the treatment, the patient suffered from adrenal insufficiency resulting in the need for hydrocortisone replacement therapy. Although SCT-NOS in childhood are typically benign, pathological findings should be carefully observed for potential malignancy. In cases of cortisol-producing SCT-NOS, serum levels should be monitored, and hydrocortisone replacement therapy should be considered before resection.

We describe virilization in a newborn female secondary to bilateral congenital juvenile granulosa cell tumor (JGCT). The patient presented with abdominal mass and ambiguous genitalia at birth, and bilateral ovarian masses were discovered on further imaging. The patient underwent bilateral salpingo-oophorectomy in staged procedures, as it became apparent that we could not spare the ovaries. Diagnosis of JGCT was confirmed by surgical pathology. She required no adjuvant therapy and has no signs of recurrence at two-year follow-up.

Virilizing ovarian dermoid cysts are very rare. The source of androgen in these cysts may be tumors such as Sertoli–Leydig cell tumor or Leydig cell hyperplasia. A 52-year-old postmenopausal female with virilization was found to have an ovarian dermoid cyst on ultrasound. Her serum testosterone levels were elevated. Leydig cell hyperplasia within the dermoid cyst was found to be the source of androgen in this patient.