Fifteen-Year History of Virilization in a 17th-Century Woman.

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.

Ovarian Leydig Cell Tumor Associated with Recurrent Torsion and Virilization in an Adolescent Patient.

Ovarian tumors are rare in children; however, their incidence increases with age. Of these ovarian tumors, Leydig cell tumors are some of the rarest, accounting for less than 0.1% of all ovarian tumors across all ages. Leydig cell tumors predominantly occur in postmenopausal women and are characterized by nodular proliferation of Leydig cells in the ovarian hilum with intracytoplasmic Reinke crystals. These tumors secrete androgens, which can disrupt ovarian function, clinically presenting with abnormal uterine bleeding and virilization. Although they are generally benign, current recommendations are for treatment with a unilateral salpingo-oophorectomy. In adolescents, hyperandrogenism is most commonly caused by polycystic ovarian syndrome (PCOS); however, the differential for hyperandrogenism is broad. We present a case of a 15-year-old girl with a history of primary amenorrhea who presented with a Leydig cell tumor associated with recurrent ovarian torsion and virilization. This case reviews the challenges with diagnosis, management, and future implications of a rare androgen-secreting tumor in young patients.

Pure androgen-secreting adrenal tumor (PASAT): A rare case report of bilateral PASATs and a systematic review.

Background: Adult pure androgen-secreting adrenal tumors (PASATs) are extremely rare, and their characteristics are largely unknown. Methods: A rare case of adult bilateral PASATs was reported, and a systematic literature review of adult PASATs was conducted to summarize the characteristics of PASATs. Results: In total, 48 studies, including 40 case reports and 8 articles, were identified in this review. Analysis based on data of 42 patients (including current case and 41 patients from 40 case reports) showed that average age was 40.48 ± 15.80 years (range of 18-76). The incidence of adult PASAT peaked at 21-30 years old, while that of malignant PASAT peaked at 41-50 years old. Most PASAT patients were female (40/42, 95.23%), and hirsutism was the most common symptom (37/39, 94.87%). Testosterone (T) was the most commonly elevated androgen (36/42, 85.71%), and 26 of 32 tested patients presented increased dehydroepiandrosterone sulfate (DS) levels. In malignancy cases, disease duration was significantly decreased (1.96 vs. 4.51 years, P=0.025), and tumor diameter was significantly increased (8.9 vs. 4.9 cm, p=0.011). Moreover, the androgen levels, namely, T/upper normal range limit (UNRL) (11.94 vs. 4.943, P=0.770) and DS/UNRL (16.5 vs. 5.28, P=0.625), were higher in patients with malignancy. In total, 5 out of 7 patients showed an increase in DS or T in the human chorionic gonadotropin (HCG) stimulation test. Overall, 41 out of 42 patients (including current case) underwent adrenal surgery, and recurrence, metastasis, or death was reported in 5 out of 11 malignant patients even with adjuvant or rescue mitotane chemotherapy. Conclusion: Adult PASAT, which is predominant in women, is characterized by virilism and menstrual dysfunction, especially hirsutism. Elevated T and DS may contribute to the diagnosis of adult PASAT, and HCG stimulation test might also be of help in diagnosis. Patients with malignant PASAT have a shorter disease duration, larger tumor sizes and relatively higher androgen levels. Surgery is recommended for all local PASATs, and Malignancy of PASAT should be fully considered due to the high risk of malignancy, poor prognosis and limited effective approaches.

Approach to Investigation of Hyperandrogenism in a Postmenopausal Woman.

Postmenopausal hyperandrogenism is a condition caused by relative or absolute androgen excess originating from the ovaries and/or the adrenal glands. Hirsutism, in other words, increased terminal hair growth in androgen-dependent areas of the body, is considered the most effective measure of hyperandrogenism in women. Other symptoms can be acne and androgenic alopecia or the development of virilization, including clitoromegaly. Postmenopausal hyperandrogenism may also be associated with metabolic disorders such as abdominal obesity, insulin resistance, and type 2 diabetes. Mild hyperandrogenic symptoms can be due to relative androgen excess associated with menopausal transition or polycystic ovary syndrome, which is likely the most common cause of postmenopausal hyperandrogenism. Virilizing symptoms, on the other hand, can be caused by ovarian hyperthecosis or an androgen-producing ovarian or adrenal tumor that could be malignant. Determination of serum testosterone, preferably by tandem mass spectrometry, is the first step in the endocrine evaluation, providing important information on the degree of androgen excess. Testosterone >5 nmol/L is associated with virilization and requires prompt investigation to rule out an androgen-producing tumor in the first instance. To localize the source of androgen excess, imaging techniques are used, such as transvaginal ultrasound or magnetic resonance imaging (MRI) for the ovaries and computed tomography and MRI for the adrenals. Bilateral oophorectomy or surgical removal of an adrenal tumor is the main curative treatment and will ultimately lead to a histopathological diagnosis. Mild to moderate symptoms of androgen excess are treated with antiandrogen therapy or specific endocrine therapy depending on diagnosis. This review summarizes the most relevant causes of hyperandrogenism in postmenopausal women and suggests principles for clinical investigation and treatment.

Rare virilizing tumor: ovarian steroid cell tumor, not otherwise specified: a case report.

BACKGROUND: Ovarian steroid cell tumors, not otherwise specified is a rare sex cord-stromal tumor. Almost 60% of all steroid cell tumors are categorized as not otherwise specified and represent less than 0.1% of all ovarian neoplasm. Some of them are endocrinologically active, producing virilization signs in young women. The recommended treatment is primarily surgical. CASE PRESENTATION: We present the case of a 20-year-old Mexican woman with secondary amenorrhea and virilization signs. She was treated with combined oral contraceptives from 13 years old, due to a misdiagnosis of polycystic ovarian syndrome. However, 4 months after stopping medication, amenorrhea and virilization signs worsened. Biochemically, she had high serum total testosterone and free testosterone levels, and a pelvic and transvaginal ultrasound followed by a pelvic tomography scan demonstrated a right adnexal tumor. She underwent right salpingo-oophorectomy and the histopathological and immunochemistry exams confirmed the diagnosis. The patient was followed for a year after surgery and until then, her menses were regular and she had no recurrence of virilization signs. CONCLUSION: The purpose of this case report is to alert physicians to rule out ovarian steroid cell tumor, not otherwise specified diagnosis in young women with increased testosterone after discarding common causes such as polycystic ovarian syndrome. A multidisciplinary team including a gynecologist, endocrinologist, radiologist, and pathologist should be involved for correct diagnosis at the proper time.

Rare manifestation of hyperreactio luteinalis: when both the mother and baby girl are virilised.

Hyperreactio luteinalis is a benign, pregnancy-related condition with cystic enlargement of the ovaries and elevated androgen. However, only one-third of patients manifest as maternal virilisation and rarely does it cause fetal virilisation. Here, we report a virilised baby girl born to a virilised mother because of hyperreactio luteinalis. This case illustrates our management to maternal and fetal virilisation.

Virilization by an Ovarian Tumor: Presentation Is Not Always Acute.

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.

Carcinoma adrenal virilizante en una adolescente: reporte de caso / Virilizing adrenal carcinoma in an adolescent: case report

Los tumores suprarrenales virilizante son infrecuentes y representan 5-6% de los tumores de esas glándulas1. Pueden secretar diferentes andrógenos como dehidroepiandrosterona sulfato (DHEAS), androstenediona y testosterona. Las características clínicas dependen de la edad de presentación; en niños pueden determinar pubertad precoz y en mujeres en edad fértil ocasionar hirsutismo, amenorrea o ciclos oligomenorreicos y diversos grados de virilización2. Los carcinomas adrenocorticales son tumores raros y la incidencia es aproximadamente uno a dos por millón de habitantes/año3,4. Los exámenes de imagen como la tomografía o la resonancia confirman el origen suprarrenal, valoran la presencia de metástasis y definen la conducta terapéutica5. La presentación inicial en pacientes pediátricos mayoritariamente es con virilización6 y aproximadamente el 50% de los pacientes adultos con carcinoma adrenal tienen un estadio de la enfermedad relativamente avanzado7. El tratamiento de elección es la cirugía y sigue siendo la mejor esperanza para la supervivencia a largo plazo8. El pronóstico habitual para el carcinoma adrenocortical es generalmente malo con una supervivencia global a 5 años de 20 a 25%5 en adultos, pero en niños y adolescentes la supervivencia puede llegar al 100%9. Se presenta el caso de una paciente con fenotipo totalmente masculino con diagnóstico de carcinoma adrenal virilizante que comienza en la infancia y se diagnostica en la adolescencia.

Virilizing adrenal tumors are uncommon and represent 5-6% on tumors of these glands1. They can secrete different androgens such as dehydroepiandrosterone sulfate (DHEAS), androstenedione, and testosterone. Clinical features depend on the age of presentation; in children they can determine precocious puberty and in women of childbearing age cause hirsutism, amenorrhea or oligomenorrheic cycles and various degrees of virilization2. Diagnosis consists of clinical evidence of hyperandrogenism, accompanied by an increase in androgens in the blood, especially DHEAS, whose origin is mainly adrenal. Adrenocortical carcinomas are rare and the incidence is approximately one to two per million inhabitants/year3,4. Imaging tests such as tomography or resonance confirm the adrenal origin, assess the presence of metastases and define the therapeutic approach5. In initial presentation in most pediatric patients is with virilization6 and approximately 50% adult's patients with adrenal carcinoma have a relatively advanced stage of the disease7. The treatment of choice is surgery and is the best hope for long-term survival. The usual prognosis for adrenocortical carcinoma is generally poor with a 5-year overall survival of 20 to 25%5 in adults, but in children and adolescent's survival can reach 100%9. We present the case of a patient with a totally male phenotype diagnosed with virilizing adrenal carcinoma that begins in childhood and is diagnosed in adolescence.

Ovarian Leydig Cell Tumor: Cause of Virilization in a Postmenopausal Woman.

BACKGROUND Only 0.5% of all ovarian tumors are Leydig cell tumors and they are generally benign and unilateral. These androgen-secreting tumors lead to virilizing symptoms, most often in postmenopausal women. Because Leydig cell tumors are typically small, diagnosing them accurately can be challenging. CASE REPORT We report the case of a 77-year-old woman who was referred to our Endocrinology Clinic because of a 5-year history of hirsutism (Ferriman-Gallwey score of 11) with no discernible cause. The patient had high levels of serum testosterone and a normal level of dehydroepiandrosterone sulfate. Imaging, including transvaginal ultrasound and pelvic magnetic resonance, revealed a 16-mm uterine nodule, which was suspected to be a submucous leiomyoma, but no adrenal or ovarian lesions. Despite the lack of findings on imaging and because of the high suspicion for an androgen-secreting ovarian tumor, bilateral laparoscopic oophorectomy was performed. Histological examination of the specimen revealed a non-hilar Leydig cell tumor that measured 8 mm in its largest axis. After the surgery, the patient had significant clinical improvement and her laboratory test results normalized. Her sister had the same symptoms and laboratory findings at a similar age, which raised the suspicion of a possible familial genetic syndrome. No genetic testing was performed, however, because the patient's sister declined further diagnostic investigation. CONCLUSIONS Leydig cell tumors are rare, and even when they are small, they can cause symptoms related to androgen excess. As a result, diagnosing them often is challenging.

Virilising adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare malignancy, with an estimated annual incidence of 0.7-2 cases per million and a median overall survival of 3-4 years. Hormone-secreting ACCs represent most cases; of these, only a small minority presents with virilisation alone. Early diagnosis is key to increase the chances of a better outcome. Here, we report a case of a 41-year-old woman who presented with menstrual irregularities, hirsutism and virilising symptoms, associated with abdominal discomfort and constitutional symptoms. On physical examination, there was a palpable mass in the right upper quadrant. Laboratory workup revealed elevated serum androgens. The imaging study showed a 163×110×122 cm right adrenal mass with features consistent with ACC and suggested potential hepatic invasion. Our patient underwent surgical resection, and the histopathological findings confirmed the diagnosis. She was referred to a specialised centre for follow-up and adjuvant therapy.

Occult symptomatic bilateral pure Leydig cell tumors in a postmenopausal woman: a case report.

BACKGROUND: Pure Leydig cell tumors (LCTs) represent 0.1% of ovarian masses. Postmenopausal patients typically present with virilization. Although LCTs can be challenging to locate on conventional imaging, positron emission tomography (PET) has been demonstrated to be effective. CASE: A 64-year-old postmenopausal woman presented with alopecia, facial hirsutism, and clitoromegaly. Laboratory findings included elevated testosterone and androstenedione. Ultrasound, computed tomography, and magnetic resonance imaging showed no adnexal masses. PET did not demonstrate ovarian fludeoxyglucose-avidity. Histopathology after bilateral salpingo-oophorectomy revealed bilateral Leydig cell tumors. Her testosterone normalized 2 weeks postoperatively. CONCLUSION: We describe the occult, symptomatic, bilateral ovarian Leydig cell tumors, an occurrence that has not been described in the literature. Virilizing tumors must be considered in patients with evidence of hyperandrogenism, even without pelvic masses on imaging.

Delayed Identification of Adolescent Adrenal Cortical Carcinoma Initially Diagnosed as Polycystic Ovary Syndrome.

BACKGROUND: Adrenocortical carcinoma is a rare, isolated malignancy. CASE: A 13-year-old girl presented with secondary amenorrhea, hirsutism, and hypertension. Her clinical manifestations were interpreted as polycystic ovary syndrome and hyperinsulinemia. The rapid progression of this pubertal girl's virilization should have, but did not draw clinical attention to her malignancy. Because her condition worsened, she ultimately was transferred to our hospital because of an abdominal mass. She was diagnosed with a very large adrenal cortical carcinoma with pulmonary metastasis. The child was in the advanced stage and presented adrenal crisis after chemotherapy and mitotane treatment. SUMMARY AND CONCLUSION: Rapidly progressive masculinization, with a marked increase in adrenal-derived androgens, might indicate rare adrenal neoplasms.

Challenges of CYP21A2 genotyping in children with 21-hydroxylase deficiency: determination of genotype-phenotype correlation using next generation sequencing in Southeastern Anatolia.

BACKGROUND/PURPOSE: Although it is known that there is generally a good correlation between genotypes and phenotypes, the number of studies reporting discrepancies has recently increased, exclusively between milder genotypes and their phenotypes due to the complex nature of the CYP21A2 gene and methodological pitfalls. This study aimed to assess CYP21A2 genotyping in children with 21-hydroxylase deficiency (21-OHD) and establish their predictive genotype-phenotype correlation features using a large cohort in Southeastern Anatolia's ethnically diverse population. METHODS: The patients were classified into three groups: salt-wasting (SW), simple virilizing (SV) and non-classical (NC). The genotypes were categorized into six groups due to residual enzyme activity: null-A-B-C-D-E. CYP21A2 genotyping was performed by sequence-specific primer and sequenced with next generation sequencing (NGS), and the expected phenotypes were compared to the observed phenotypes. RESULTS: A total of 118 unrelated children with 21-OHD were included in this study (61% SW, 24.5% SV and 14.5% NC). The pathogenic variants were found in 79.5% of 171 mutated alleles (60.2%, 22.2%, and 17.6% in SW, SV and NC, respectively). Patient distribution based on genotype groups was as follows: null-16.1%, A-41.4%, B-6.0%, C-14.4%, E-22%). In2G was the most common pathogenic variant (33.9% of all alleles) and the most common variant in the three phenotype groups (SW-38.8%, SV-22.2% and NC-23.3%). The total genotype-phenotype correlation was 81.5%. The correlations of the null and A groups were 100% and 76.1%, respectively, while it was lower in group B and poor in group C (71.4% and 23.5%, respectively). CONCLUSION: This study revealed that the concordance rates of the severe genotypes with their phenotypes were good, while those of the milder genotypes were poor. The discrepancies could have resulted from the complex characteristics of 21-OHD genotyping and the limitations of using NGS alone without integrating with other comprehensive methods.

A rare cause of postmenopausal hyperandrogenism.

We present an unusual case of mucinous cystadenoma presenting with severe virilisation in a postmenopausal woman. A 71-year-old woman was referred to our outpatient endocrinology clinic because of rapidly progressive androgenic alopecia, clitoromegaly and male pattern pubic hair growth for 1 year. Her medical history was unremarkable. The serum testosterone level was 3.35 µg/L (normal range, <0.4 µg/L), and the dehydroepiandrosterone sulfate level was 267 µg/L (normal range, 100-800 µg/L). MRI of the abdomen revealed a 4×4 cm cystic ovarian mass. A bilateral salpingo-oophorectomy was performed, and histopathology showed a unilocular cystic structure with a yellowish content, compatible with mucinous cystadenoma. Postoperative testosterone levels quickly normalised (<0.4 µg/L).Rapidly developing postmenopausal hyperandrogenism easily turns into a diagnostic challenge for the clinician. Hormone-secreting neoplasms of the ovary are most commonly of sex cord stromal derivation, but atypical causes must be recognised as well. Cystadenomas are among the most common benign ovarian neoplasms and are classically considered 'non-functional' tumours. Most of these tumours are asymptomatic and found incidentally on pelvic examination or with ultrasound. To date and to the best of our knowledge, there are only five cases of mucinous adenoma causing virilisation in postmenopausal women identified in the literature. This sixth case adds strength to the link between ovarian mucinous cystadenoma and severe, rapidly progressive hyperandrogenism during menopause. In this case, surgical resection is the treatment of choice.

Ovarian Sex Cord Stromal Tumor, Steroid Cell, NOS in an Adolescent: A Case Report.

BACKGROUND: Ovarian steroid cell tumor, not otherwise specified (NOS), is a rare type of sex cord stromal tumor, which often presents with androgenic symptoms and has a high frequency of malignancy. CASE: This is a case of a 14-year-old Native American girl who presented with acne, amenorrhea, and virilization and was found to have a 2.9-cm solid ovarian mass. Initial pathology revealed steroid-appearing cells with round nuclei, clear/vacuolated cytoplasm, and a low mitotic index. Final diagnosis was ovarian steroid cell tumor, NOS Stage IA. A laparoscopic left salpingo-oophorectomy was subsequently performed. No tumor recurrence was noted 2 years after her initial diagnosis. SUMMARY AND CONCLUSION: Long-term data on these tumors are limited; however, malignancy, recurrence, and death have been reported. This suggests that close follow-up is essential for appropriate management.

Pediatric adrenocortical tumours.

Childhood adrenocortical tumors (ACTs) are rare, representing ∼0.2% of all pediatric malignancies and having an incidence of 0.2-0.3 new cases per million per year in the United States, but incidences are remarkably higher in Southern Brazil. At diagnosis, most children show signs and symptoms of virilization, Cushing syndrome, or both. Less than 10% of patients with ACT exhibit no endocrine syndrome at presentation, although some show abnormal concentrations of adrenal cortex hormones. Pediatric ACT is commonly associated with constitutional genetic and/or epigenetic alterations, represented by germline TP53 mutations or chromosome 11p abnormalities. Complete tumor resection is required to achieve cure. The role of chemotherapy is not established, although definitive responses to several anticancer drugs are documented. For patients undergoing complete tumor resection, favorable prognostic factors include young age, small tumor size, virilization, and adenoma histology. Prospective studies are necessary to further elucidate the pathogenesis of ACT and improve patient outcomes.

Case of ovarian steroid cell tumor diagnosed after presenting acute heart failure.

We report a rare case of an ovarian steroid cell tumor with a diagnosis prompted by heart failure symptoms. A 28-year-old Japanese nulligravida/nullipara with a chief complaint of respiratory discomfort during physical exertion and exhibiting heart failure symptoms was referred to our hospital. She also had signs of virilization, including secondary menorrhea since the age of 20, hirsutism and balding. Cushing's syndrome was suspected, and further examinations showed hypertestosteronemia and right ovarian tumor. Symptomatic treatment for heart failure with diuretics and antihypertensives was followed by abdominal right adnexectomy performed due to the androgen-producing ovarian tumor. The tumor was solid and larger than a fist, and confirmed as a steroid cell tumor through postoperative histopathology. Serum total testosterone levels normalized at day 3 postoperatively, and menstruation resumed 2 months later. Our case was diagnosed due to heart failure symptoms, and its treatment resulted in improvement in virilization signs.

Adolescent ovarian thecoma presenting as progressive hyperandrogenism: case report and review of the literature.

Hyperandrogenism is frequent and under investigated in adolescent girls. A 15-year-6-month-old French girl presented with oligomenorrhea and slowly progressing virilization 2 years post-menarche. Medical history revealed prenatal pesticide exposure through maternal professional activity and recurrent premature thelarche. Severe hirsutism, mild facial acne and clitoromegaly were noted. Serum androgens (testosterone: 94 ng/dL, 4-androstenedione: 8.23 ng/mL) were high and non-classic 21-hydroxylase deficiency was excluded. Pelvic ultrasonography showed a left ovarian mass, confirmed by computed tomography scan. Tumor markers were negative. Laparoscopic surgery was performed. The pathological diagnosis was benign luteinized thecoma. Postoperatively, the menstrual cycle and serum androgens became normal and hirsutism slowly improved. Hyperandrogenism 2 years after menarche should be systematically investigated, even if slowly progressive, since it may be a symptom of a rare virilizing ovarian tumor, like thecoma.