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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.

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.

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.

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]

Virilization of the 46,XX infant may be attributed to maternal or fetoplacental origin. Maternal sources may be endogenous, as with an androgen-producing tumor, or drug-related. Iatrogenic virilization by maternal drug exposure is rarely reported, with individual case reports and case series demonstrating the effects of progesterone and other medications affecting the pituitary-ovarian axis.1-3 The class of medications known as aromatase inhibitors are recognized as effective in treating hormone receptor-positive breast cancer by preventing the conversion of androgens into estrogens by aromatase. In fetal development, placental aromatase plays a critical role in preventing virilization of the XX fetus by maternal and fetal androgens during development. In the setting of placental aromatase deficiency, the XX fetus may be virilized. It is conceivable, therefore, that maternal exposure to aromatase inhibitors early in gestation may lead to in utero virilization, though there have been no known reports of this phenomenon to date. We present a case of virilization of a 46,XX infant attributed to pharmacologic aromatase inhibition. The infant's parents provided informed consent for the reporting of this case. [ABSTRACT FROM AUTHOR]

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. 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. 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. [ABSTRACT FROM AUTHOR]

Competing Interests: Competing interests: Oriana Hoi Yun Yu reports participating in a consultancy meeting for Rybelsus (outside the submitted work). No other competing interests were declared.

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. 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. 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. [ABSTRACT FROM AUTHOR]

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.

Theca lutein cysts are rare, benign lesions responsible for gross cystic enlargement of both ovaries during pregnancy. This condition is also termed hyperreactio luteinalis. Elevated human chorionic gonadotropin (hCG) levels or states of hCG hypersensitivity seem to promote these changes, which in up to 30% of patients produce clinical signs of hyperandrogenism. Given the self-limiting course of theca lutein cysts, which are subject to spontaneous postpartum resolution, conservative treatment is the mainstay of patient management. Described herein is a rare case of theca lutein cysts with maternal virilization that failed to regress by 9 months after childbirth. Surgical intervention was eventually undertaken, necessitated by adnexal torsion. [ABSTRACT FROM AUTHOR]

Abstract NR2F2 encodes COUP-TFII, an orphan nuclear receptor required for the development of the steroidogenic lineages of the murine fetal testes and ovaries. Pathogenic variants in human NR2F2 are associated with testis formation in 46,XX individuals, however, the function of COUP-TFII in the human testis is unknown. We report a de novo heterozygous variant in NR2F2 (c.737G > A, p.Arg246His) in a 46,XY under-masculinized boy with primary hypogonadism. The variant, located within the ligand-binding domain, is predicted to be highly damaging. In vitro studies indicated that the mutation does not impact the stability or subcellular localization of the protein. NR5A1, a related nuclear receptor that is a key factor in gonad formation and function, is known to physically interact with COUP-TFII to regulate gene expression. The mutant protein did not affect the physical interaction with NR5A1. However, in-vitro assays demonstrated that the mutant protein significantly loses the inhibitory effect on NR5A1-mediated activation of both the LHB and INSL3 promoters. The data support a role for COUP-TFII in human testis formation. Although mutually antagonistic sets of genes are known to regulate testis and ovarian pathways, we extend the list of genes, that together with NR5A1 and WT1, are associated with both 46,XX and 46,XY DSD.

IntroductionCongenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) or 11-hydroxylase deficiency (11OHD) is characterized by underproduction of cortisol and overproduction of adrenal androgens. These androgens lead to a variable degree of virilization of the female external genitalia in 46,XX individuals. Especially in developing countries, diagnosis is often delayed and 46,XX patients might be assigned as males. This study aims to describe the clinical and biochemical characteristics of a unique cohort of untreated male-reared 46,XX classic CAH patients from Indonesia and discusses treatment challenges.MethodsNine untreated classic CAH patients with 46,XX genotype and 21OHD (n=6) or 11OHD (n=3), aged 3-46 years old, were included. Biometrical parameters, clinical characteristics, and biochemical measurements including glucocorticoids, renin, androgens, and the pituitary-gonadal axis were evaluated.ResultsAll patients had low early morning serum cortisol concentrations (median 89 nmol/L) without significant increase after ACTH stimulation. Three patients with salt wasting 21OHD reported one or more periods with seizures and/or vomiting in their past until the age of 6, but not thereafter. The remaining patients reported no severe illness or hospitalization episodes, despite their decreased capacity to produce cortisol. In the 21OHD patients, plasma renin levels were elevated compared to the reference range, and in 11OHD patients renin levels were in the low-normal range. All adult patients had serum testosterone concentrations within the normal male reference range. In 21OHD patients, serum 11-oxygenated androgens comprised 41-60% of the total serum androgen concentrations. Glucocorticoid treatment was offered to all patients, but they refused after counseling as this would reduce their endogenous androgen production and they did not report complaints of their low cortisol levels.DiscussionWe describe a unique cohort of untreated classic 46,XX male CAH patients without overt clinical signs of cortisol deficiency despite their cortisol underproduction and incapacity to increase cortisol levels after ACTH stimulation. The described adolescent and adult patients produce androgen levels within or above the normal male reference range. Glucocorticoid treatment will lower these adrenal androgen concentrations. Therefore, in 46,XX CAH patients reared as males an individual treatment approach with careful counseling and clear instructions is needed.

Introduction: Adrenocortical carcinoma (ACC) is rare, aggressive, and metastasizes mainly to the lungs, liver, and regional lymph nodes. This is the first reported case of a pediatric patient with adrenohepatic fusion (AHF) and functional ACC that solely invaded the liver. Case presentation: The patient was a 2 year and 9 month old female, with a 3-month history of weight gain, signs of virilization, Cushing's syndrome, hypertension, and a palpable mass in the right hypochondrium and epigastrium. Blood tests revealed the following: hemoglobin, 16.3 g/dL; cortisol, 25.3 μg/dL; and total serum testosterone, 1489.01 ng/mL. Ultrasonography and computed tomography initially revealed a hepatic tumor measuring 100 × 111 × 106 mm, with a volume of 615 mL. The patient was diagnosed with functional ACC. Curative resection (R0 resection) was performed, involving partial resection of the right hepatic lobe. The resected tumor was 12 × 10 × 7 cm and 650 g, with evidence of invasion into the liver capsule, which was consistent with ACC stage III (T4N0M0). Management included mitotane, cisplatin, etoposide, and doxorubicin, and favorable progress was noted at the 2-year and 3-month follow-up. Conclusion: In cases with AHF, a sufficient portion of the right hepatic lobe must be resected to ensure complete removal of the tumor.

ObjectiveTo provide a reference for the diagnosis and treatment of ovarian steroid cell tumors, not otherwise specified (SCTs-NOS).MethodsWe retrospectively analyzed the clinicopathological data of three patients with SCTs-NOS admitted to the Tianjin Medical University General Hospital from 2012 to 2022 and reviewed literature reports related to this disease.ResultsA total of 3 cases in our center and 70 cases searched in literature reports were included. The age at diagnosis ranged from 3 to 93 years (median, 34 years). The common clinical manifestations were hirsutism, acne, deepened voice, clitoromegaly, amenorrhea, and excessive weight gain. Tumor sizes ranged from 1.2 to 45 cm, with an average diameter of 6.5cm. Most of SCTs-NOS were benign, but some of them exhibited malignant behavior. Surgery was the main treatment and close follow-up was required. The follow up time of 73 cases ranged from 3 to 132 months (median, 21.3 months). Disease recurrence or progression occurred in 14 cases (19.2%). Three of the 73 patients had a successful pregnancy.ConclusionSCTs-NOS usually occur in women of reproductive age, which are mainly manifested as androgen excess symptoms. Surgery is an appropriate treatment for SCTs-NOS and should be individualized. Final diagnosis depends on pathology. SCTs-NOS have malignant potential, and the treatments for patients with malignant tumors and disease recurrence or progression were cytoreductive surgery, adjuvant chemotherapy, and gonadotrophin-releasing hormone agonists (GnRHa) therapy.

Background/Objective: Leydig cell tumors are a rare androgen-secreting ovarian tumor. We present a patient with virilization symptoms secondary to a Leydig cell tumor, with nonrevealing imaging studies, that was localized using ovarian vein sampling (OVS). Case Report: A 56-year-old postmenopausal woman was referred by her gynecologist to the endocrinology clinic for voice-deepening, clitoral enlargement, scalp hair loss, and excessive body hair growth. Her total testosterone was 11.5 (0.3-1.3 nmol/L), bioavailable testosterone was 7.19 (0.1-0.6 nmol/L), and dehydroepiandrosterone sulfate was 4.0 (0.8-4.9 μmol/L). Transvaginal ultrasound and abdominal magnetic resonance imaging showed no adrenal or ovarian masses bilaterally. On adrenal vein sampling (AVS) and OVS, total testosterone from the left gonadal vein was 780.0 (0.3-1.3 nmol/L) and right gonadal vein was 18.6 (0.3-1.3 nmol/L), with a left-to-right ovarian testosterone ratio of 41.94. A bilateral salpingo-oophorectomy was performed, and a 1.0 cm Leydig cell tumor in the left ovary was noted on histopathology. One month after surgery, her total and bioavailable testosterone were

Hormone-producing ovarian tumors in girls are an actual problem in modern gynecology, which is associated with certain difficulties in managing patients. Firstly, it is worth taking into account the higher anatomical mobility of tumors in girls than in adults, due to the high location of the ovaries, weakness of the ligamentous apparatus and the active lifestyle of the child, which causes a higher incidence of torsion of the volumetric mass in children. Secondly, surgical treatment of hormone-producing ovarian tumors leads to a decrease in ovarian reserve and irreversible consequences in the reproductive health of patients in the future, which is an extremely undesirable complication in childhood. Therefore, methods of fertility preservation should be discussed with girls and their parents. It is also important to note that hormone-producing ovarian tumors have a certain degree of malignancy and a tendency to recur. Thus, the relevance of this topic lies in the complexity of management of pediatric patients with this pathology due to the clinical features of the course and a higher probability of complications. Hormone-producing ovarian masses should also include follicular cysts and corpus luteum cysts, but the above structures are excluded from the discussion in this article.

Steroid cell tumors (SCT) of the ovary are rare, which has limited advances in the understanding of this enigmatic neoplasm. In this review, we summarize currently known clinicopathologic information on SCT. SCT are frequently hormonally active, leading to elevated serum and/or urine levels of androgenic hormones or their metabolites, and associated symptomatology, including virilization. The reported age at diagnosis is broad and has ranged from as young as 1 year old to 93 years old, although most patients were between ages 20 and 40 years. Most tumors are stage I and unilateral. The tumors are usually well circumscribed with a solid or solid to cystic cut surface. The tumors in one series reportedly ranged in size from 1.2 to 45 cm (average 8.4 cm). MRI is a useful imaging modality, typically showing a well delineated mass with contrast enhancement and lipid content on T2 and T1 weighted images, respectively. Microscopically, SCT display polygonal to epithelioid cells with abundant eosinophilic to vacuolated/clear cytoplasm and display an immunoprofile that is consistent with sex cord-stromal differentiation. Most cases are benign, without any recurrences after primary resection, but a subset – probably less than 20% of cases –are clinically malignant. Pathologic criteria that can specifically predict patient outcomes remain elusive, although features that correlate with adverse outcomes have been proposed based on retrospective studies. The molecular characteristics of SCTs are similarly under characterized, although there is some evidence of an enrichment for hypoxia-signaling gene mutations in SCT. In malignant SCT, the tumors generally show greater global genomic instability, copy number gains in oncogenes, and occasional BAP1 mutation. Future studies involving multi-institutional cohort and unbiased molecular profiling using whole exome/transcriptome sequencing are needed to help advance our molecular understanding of SCTs.

The diagnosis is made by peripheral blood tests for ovarian and adrenal hormones and imaging and, if possible, with adrenal and ovarian vein blood sampling. Although rare, an adrenal tumour was a remote possibility, but there was no adrenal abnormality on MRI (Table 1). In perimenopausal and especially postmenopausal women, rapidly progressing hirsutism and virilization could be a result of ovarian hyperthecosis or androgen-secreting ovarian tumour. [Extracted from the article]

Adrenal tumors are very rare causes of hyperandrogenism. Androgensecreting adrenal tumors are usually malignant; however, benign tumors have also been described in women. Adrenocortical carcinoma is very rare with incidence of 1 2 million per year. The androgen secreting type of adrenocortical carcinoma can be presented with hirsutism, acne, alopecia and virilization symptoms such as cliteromegaly. This case was presented with hyperandrogenism and virilization symptoms and it was diagnosed as having a very rare cause, namely androgen secreting adrenal tumor. Because the symptoms are related to gynecological complaints such as menstrual irregularities and cliteromegaly, these patients would first need to apply to their gynecologists, who may play an important role in the early diagnoses of these rare diseases.

The literature review is dedicated to the topical subject in current endocrinology and gynecology – clitoromegaly. At present, clitoromegaly is considered as a symptom of an endocrinological disease associated with impaired testosterone or androgen production. However, in most cases, the cause of the disease cannot be determined. A condition described in the clitoromegaly classification as an "idiopathic clitoromegaly" holds a leading place. Despite an opportunity to perform a successful clitoroplasty in childhood, adult patients with clitoromegaly quite often seek specialists` help. Such girls and women often suffer from anxietydepressive disorders related to social maladjustment associated due to sexological and psychological problems, which requires a sexologist or psychotherapist` supervision and treatment. Here, we provide the data on genetic syndromes accompanied by clitoromegaly. Differential diagnostics algorithms for neonates, young and adult women are proposed.

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 [ABSTRACT FROM AUTHOR]

Key Clinical Message Jacobs syndrome and congenital adrenal hyperplasia are separate entities but share common clinical features such as ambiguous genitalia. Further studies are needed to conclude the relationship between Jacobs syndrome and congenital adrenal hyperplasia. Abstract A 5‐month‐old male infant was evaluated for ambiguous genitalia. Examination revealed cryptorchidism, inguinal hernia, long phallus, and Grade 3 scrotal hypospadias. Serum 17‐OH progesterone was high and chromosomal analysis showed 47XYY/45XO. A diagnosis of Jacobs and CAH was made. The parents were counseled about the patient's condition. He was given hydrocortisone and referred to the pediatric surgeon for further management.

BackgroundCongenital Adrenal Hyperplasia (CAH) is a chronic disease that requires lifelong treatment. Patients may face stigmatization, which may affect their quality of life (QoL). Therefore, we assessed the clinical characteristics and QoL of patients with CAH in the Middle East.MethodsThis case-control study included patients with CAH aged >5 years from two tertiary centers (2020–2021). The patients were matched to a healthy control group and were then divided into pediatric and adult groups. Data were collected from their electronic medical records. Additionally, the EQ-5D-5L QoL questionnaire was completed by both the patients and control group to assess five domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression).ResultsThe study included 248 patients with CAH (females: 58.8%), with a family history of the condition (57.3%) and/or parental consanguinity (68.1%). The most frequently reported gene defect was CYP21A2, while the most commonly reported symptoms/signs were ambiguous genitalia and obesity. Almost all female patients had received corrective surgery. The questionnaire response rate was 86.3% (n=214/248). The CAH patient group’s mean total QoL score was 85.2 compared with 99.8 in the control. Further, CAH patients had lower QoL scores in all domains compared to those in the control group (p ≤ 0.0001–0.0023). The pain/discomfort and anxiety/depression domains were affected significantly more than the other domains were, with 47.7% and 44.4% participants, respectively, p

Background: We presented the clinical and genetic features of a male ambiguity due to 17-beta-hydroxysteroid dehydrogenase 3 (17B-HSD3) deficiency. Methods: The proposita was an 11-year-old girl and the first child of a consanguineous family. The external genitalia were completely female and had a short vaginal pouch. She had palpable gonads in her inguinal area and underwent bilateral gonadectomy at the age of two. At the age of 10, she was referred to our clinic for more evaluation. In pelvic sonography, uterine and ovarian were not seen. Her karyotype was 46, XY, and her LH and FSH levels were elevated, and three of the patient’s aunts and one of the mother’s aunts had similar signs. Conclusions: We identified a novel homozygous missense variation (c.731T>A, p. Ile244Lys) in the HSD17B3 gene. This alteration changes Isoleucine to Lysine in exon 10.

Pediatric adrenocortical tumors (ACTs) are rare entities with an incidence of 0.2% of all pediatric tumors. Only two cases of antenatally detected ACT have been reported in the literature. Our case is the first report of an antenatally detected suprarenal mass which manifested with postnatal virilizing features and was proven to be adrenocortical adenoma on histology.

Introduction: This study aimed to investigate the imaging features, clinical characteristics and neonatal outcomes of pregnancy luteoma. Material and methods: We retrospectively analyzed patients with pregnancy luteoma admitted to the First Affiliated Hospital of Sun Yat‐sen University between January 2003 and December 2022. We recorded their imaging features, clinical characteristics and neonatal outcomes. Additionally, we reviewed relevant studies in the field. Results: In total, 127 cases were identified, including eight from our hospital and 119 from the literature. Most patients (93/127, 73.23%) were of reproductive age, 20–40 years old, and 66% were parous. Maternal hirsutism or virilization (such as deepening voice, acne, facial hair growth and clitoromegaly) was observed in 29.92% (38/127), whereas 59.06% of patients (75/127) were asymptomatic. Abdominal pain was reported in 13 patients due to compression, torsion or combined ectopic pregnancy. The pregnancy luteomas, primarily discovered during the third trimester (79/106, 74.53%), varied in size ranging from 10 mm to 20 cm in diameter. Seventy‐five cases were incidentally detected during cesarean section or postpartum tubal ligation, and 39 were identified through imaging or physical examination during pregnancy. Approximately 26.61% of patients had bilateral lesions. The majority of pregnancy luteomas were solid and well‐defined (94/107, 87.85%), with 43.06% (31/72) displaying multiple solid and well‐circumscribed nodules. Elevated serum androgen levels (reaching values between 1.24 and 1529 times greater than normal values for term gestation) were observed in patients with hirsutism or virilization, with a larger lesion diameter (P < 0.001) and a higher prevalence of bilateral lesions (P < 0.001). Among the female infants born to masculinized mothers, 68.18% (15/22) were virilized. Information of imaging features was complete in 22 cases. Ultrasonography revealed well‐demarcated hypoechoic solid masses with rich blood supply in 12 of 19 cases (63.16%). Nine patients underwent magnetic resonance imaging (MRI) or computed tomography (CT), and six exhibited solid masses, including three with multi‐nodular solid masses. Conclusions: Pregnancy luteomas mainly manifest as well‐defined, hypoechoic and hypervascular solid masses. MRI and CT are superior to ultrasonography in displaying the imaging features of multiple nodules. Maternal masculinization and solid masses with multiple nodules on imaging may help diagnose this rare disease. [ABSTRACT FROM AUTHOR]