Ovarian hyperthecosis in adolescent females: two case reports and a review of the literature.

OBJECTIVES: Ovarian hyperthecosis (OHT) is a rare cause of severe hyperandrogenism in the adolescent age group. We describe two case reports, and present an approach to management in this age group based on a review of the literature. CASE PRESENTATION: Patient A presented at age 13 years with a 2 year history of androphonia and hirsuitism. Her testosterone level was elevated at 8.3 nmol/L, and there was marked enlargement of her ovaries bilaterally. There were no focal adrenal or ovarian lesions identified on imaging. She was treated with a gonadotropin releasing hormone (GnRH) agonist and spironolactone with biochemical and clinical improvement. Patient B presented at age 14 years with secondary amenorrhoea, and a 2 year history of androphonia, hirsutism and androgenetic alopecia. Her testosterone level was 12 nmol/L, and a pelvic ultrasound revealed numerous follicles in each ovary which were otherwise normal in size. She was managed with GnRH agonist initially, and now continues on a combined oral contraceptive pill. CONCLUSIONS: Ovarian hyperthecosis needs to be considered in pre-menopausal women presenting with severe hyperandrogenism, after exclusion of androgen-producing adrenal and ovarian tumours. The principles of management in this age group are gonadotropin suppression and hormone replacement.

Ovarian Hyperthecosis in a 12-year-old Chinese Girl Presenting With Virilization.

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.

A Case of Ovarian Hyperthecosis in a Postmenopausal Woman.

We report a case of a 55-year-old postmenopausal woman who presented with symptoms of fatigue, male pattern hair loss, and hirsutism over 3 years. Investigations showed elevated total testosterone levels of 5.0 nmol/L (1.44 ng/mL; range, 0.3-3.1 nmol/L) using Beckman-Unicel-DXI-800 immunoassay. Testosterone levels were repeated by liquid chromatography-tandem mass spectrometry and were found to be elevated at 7.3 nmol/L (2.10 ng/mL). Estradiol was detectable and free androgen index was elevated. Dehydroepiandrosterone sulfate levels and androstenedione were within normal range, suggesting a nonadrenal source. Computed tomography scan of the abdomen showed no evidence of adrenal or adnexal tumor. GnRH analog stimulation test led to reduction of gonadotrophins and normalization of testosterone within 4 weeks. She had a biopsy of a cranial hair follicle, which showed androgenic alopecia. These investigations confirmed an ovarian source of androgens. Subsequently, she underwent bilateral salpingo-oophorectomy. Histological study of gonadal tissue confirmed the diagnosis of ovarian hyperthecosis. Four weeks after oophorectomy, her testosterone levels normalized and clinical symptoms improved. Ovarian hyperthecosis is a rare cause of hyperandrogenism in postmenopausal women and can pose a diagnostic and therapeutic challenge. Careful history and physical examination along with critical analysis of biochemistry and imaging studies is crucial for correct diagnosis.

A Rare Case of Hyperandrogenism Due to Fibrothecoma and Leydig Cell Tumor in a Postmenopausal Woman With Adrenal Adenoma: A Case Report and Literature Review.

Hyperandrogenism is an endocrine disorder characterized by an elevated level of androgen in women, which can be due to several etiologies, including ovarian and adrenal causes. Hyperandrogenism can result in hirsutism and virilization in severe cases. Ovarian etiologies can include ovarian hyperthecosis, hilus cell tumors, arrhenoblastomas, and Leydig cell tumors. Diagnosing the specific cause requires comprehensive work, and management is then tailored to address the specific etiology. Treatment may include bilateral oophorectomy and gonadotropin-releasing hormone (GnRH) analogs in combination with antiandrogen therapy. Surgery, medical treatment, and radiation therapy are also options for patients with hypercortisolemia. We present the case of a 58-year-old female who presented with clinical features of hyperandrogenism, which were confirmed with biochemical testing. She was found to have a non-functioning adrenal adenoma with no significant abnormality on ovarian imaging and biochemical hyperandrogenemia due to fibrothecoma and Leydig cell tumor, which resolved after bilateral salpingo-oophorectomy.

Ovarian Leydig Cell Tumor and Ovarian Hyperthecosis in a Postmenopausal Woman: A Case Report and Literature Review.

Ovarian Leydig cell tumor is a rare type of ovarian steroid cell neoplasms, presenting in only 0.1% of all ovarian tumor cases, and is generally androgen-secreting and unilateral. Although they are often malignant non-spreading tumors, which have excellent prognosis, benign ovarian Leydig cell tumors with low-risk malignancy can be also detected. Ovarian hyperthecosis is a rare non-neoplastic disorder, in most cases bilateral. Ovarian tumors and ovarian hyperthecosis are one of the main causes of hyperandrogenism in postmenopausal women, a condition strongly associated with both hormonal and metabolic changes. Here, we report a 65-year-old patient with complaints of excessive body hairiness and alopecia. The laboratory investigation showed increased levels of serum testosterone and dehydroepiandrosterone sulfate (DHEA-S). Imaging, including transvaginal ultrasound and pelvic MRI revealed the presence of two masses in the ovaries. The patient underwent a laparoscopic bilateral salpingo-oophorectomy due to the ovarian tumors unknown etiology, and histopathological examination revealed a unilateral benign left ovarian Leydig cell tumor with bilateral ovarian stromal hyperplasia and ovarian hyperthecosis. Making differential diagnosis between ovarian tumors and ovarian hyperthecosis is difficult. Bilateral salpingo-oophorectomy is the treatment of choice in postmenopausal women with benign Leydig cell ovarian tumor, as well as ovarian hyperthecosis, as it offers both a cure and diagnostic confirmation.

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.

Approach to androgen excess in women: Clinical and biochemical insights.

Androgen excess in women typically presents clinically with hirsutism, acne or androgenic alopecia. In the vast majority of cases, the underlying aetiology is polycystic ovary syndrome (PCOS), a common chronic condition that affects up to 10% of all women. Identification of women with non-PCOS pathology within large cohorts of patients presenting with androgen excess represents a diagnostic challenge for the endocrinologist, and rare pathology including nonclassic congenital adrenal hyperplasia, severe insulin resistance syndromes, Cushing's disease or androgen-secreting tumours of the ovary or adrenal gland may be missed in the absence of a pragmatic screening approach. Detailed clinical history, physical examination and biochemical phenotyping are critical in risk-stratifying women who are at the highest risk of non-PCOS disorders. Red flag features such as rapid onset symptoms, overt virilization, postmenopausal onset or severe biochemical disturbances should prompt investigations for underlying neoplastic pathology, including dynamic testing and imaging where appropriate. This review will outline a proposed diagnostic approach to androgen excess in women, including an introduction to androgen metabolism and provision of a suggested algorithmic strategy to identify non-PCOS pathology according to clinical and biochemical phenotype.

A rare case of postmenopausal hyperandrogenism due to ovarian hyperthecosis and hilus cell hyperplasia.

Postmenopausal hyperandrogenism is rare, and without consensus on specific investigative indices, diagnosis is challenging. A 77-year-old woman had a three-year history of hirsutism, male-pattern baldness and increased libido alongside elevated androstenedione, total testosterone and free androgen index levels. A magnetic resonance imaging (MRI) scan showed bilateral ovarian lesions, suggesting ovarian hyperthecosis. Histopathology obtained after a laparoscopic bilateral salpingo-oophorectomy confirmed ovarian hyperthecosis and hilus cell hyperplasia. We believe it's the first time they have been reported to occur in combination. The symptoms resolved within a month of surgery. This case highlights the difficulties of diagnosis alongside demonstrating the importance of management by a multidisciplinary team.

Depot Pure GnRH Antagonist for Long-term Treatment of Ovarian Hyperthecosis Monitored by Multisteroid LCMS Profiling.

Ovarian hyperthecosis (OHT), severe hyperandrogenism after menopause in the absence of ovarian or adrenal tumors, is usually treated by surgical excision. We report a 58-year-old woman presenting with severe hyperandrogenism (serum testosterone 15.7-31.0 nmol/L, normal female <1.8 nmol/L) with menopausal gonadotropins and virilization but no adrenal or ovarian lesions. Multisteroid profiling by liquid chromatography mass spectrometry (LCMS) of adrenal and ovarian vein samples identified strong gradients in the left ovarian vein (10- to 30-fold vs peripheral blood in 17OHP4, 17 hydroxyprogesterone, 17 hydroxypregnenolone, androstenedione, testosterone, dehydroepiandrosterone) but the right ovarian vein could not be cannulated with the same findings in a second ovarian vein cannulation. OHT diagnosis was confirmed by an injection of a depot pure gonadotropin-releasing hormone (GnRH) antagonist (80 mg Degarelix, Ferring) producing a rapid (<24 hour) and complete suppression of ovarian steroidogenesis as well as serum luteinizing hormone and follicle-stimulating hormone lasting at least 8 weeks, with reduction in virilization but injection site reaction and flushing and vaginal spotting ameliorated by an estradiol patch. Serum testosterone remained suppressed at 313 days after the first dose despite recovery of menopausal gonadotropins by day 278 days. This illustrates use of multisteroid LCMS profiling for confirmation of the OHT diagnosis by ovarian and adrenal vein sampling and monitoring of treatment by peripheral blood sampling. Injection of a depot pure GnRH antagonist produced rapid and long-term complete suppression of ovarian steroidogenesis maintained over 10 months. Hence a depot pure GnRH antagonist can not only rapidly confirm the OHT diagnosis but also induce long-term remission of severe hyperandrogenism without surgery.

Persistent Poor Metabolic Profile in Postmenopausal Women With Ovarian Hyperandrogenism After Testosterone Level Normalization.

CONTEXT: Data on prevalence of metabolic risk factors in hyperandrogenic postmenopausal women are limited. Also, the correlation between metabolic disorders and androgen excess in this scenario is poorly understood. OBJECTIVES: We aimed to assess the prevalence of obesity, hypertension, type 2 diabetes (T2D), and dyslipidemia (DLP) in postmenopausal women with hyperandrogenism of ovarian origin before and after surgical normalization of testosterone (T) levels, as well as the impact of androgen normalization on body mass index (BMI), glucose, and lipid metabolism. DESIGN: Retrospective study. SETTING: Tertiary health center. PARTICIPANTS: Twenty-four Brazilian women with postmenopausal hyperandrogenism who underwent bilateral oophorectomy between 2004 and 2014 and had histologically confirmed virilizing ovarian tumor (VOT) or ovarian hyperthecosis (OH) and T-level normalization after surgery were selected. MAIN OUTCOME MEASURES: FSH, LH, total and calculated free T, BMI, fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) serum levels were accessed before (n = 24) and 24 months after (n = 19) bilateral oophorectomy. RESULTS: At baseline, the overall prevalence rates of obesity, T2D, DLP, and hypertension were 58.3%, 83.3%, 66.7%, and 87.5%, respectively. No significant difference in prevalence was found between patients with OH and VOTs. At follow-up, FSH, LH, and total and free T levels had returned to menopausal physiologic levels, but mean BMI and mean FPG, HbA1c, LDL-C, HDL-C, and TG levels did not differ from baseline. CONCLUSIONS: Postmenopausal hyperandrogenism is associated with adverse metabolic risk. Long-term normalization of testosterone levels did not improve BMI, glucose, or lipid metabolism.

Value of selective venous catheterization in the diagnosis of hyperandrogenism.

OBJECTIVE: To discuss the clinical utility of ovarian vessel sampling in the context of the evaluation and treatment of ovarian hyperthecosis. DESIGN: Patient presentation in video format, ovarian vessel sampling demonstration, surgical technique explanation, surgical histology discussion and ovarian hyperthecosis review. SETTING: Academic medical center. PATIENT(S): A 30-year-old nulligravid female presented with severe hyperandrogenic features, consistent with polycystic ovary syndrome. INTERVENTION(S): During the course of her diagnostic evaluation, she underwent selective ovarian and adrenal vein sampling. MAIN OUTCOME MEASURE(S): Assessment of ovarian vessel testosterone levels and review of final histologic findings. RESULT(S): Selective ovarian and adrenal vein sampling revealed right ovarian testosterone levels that were 200 times the upper limit of normal. As occult malignancy was a concern, laparoscopy was performed, with nearly complete removal of the right ovarian stroma. Pathology revealed ovarian stromal hyperthecosis without evidence of malignancy. CONCLUSION(S): Selective venous sampling is a technically challenging procedure, which may help localize an occult malignancy in limited circumstances. In utilizing selective venous sampling, one must consider the limitations of the test, potential for false positive results, and possibility of unnecessary surgical interventions.

Severe hyperandrogenemia in postmenopausal woman as a presentation of ovarian hyperthecosis. Case report and mini review of the literature.

Ovarian hyperthecosis (OH) is characterized by the presence of abundant luteinized theca cells in ovaries that secret androgen. It typically presents as severe hyperandrogenism and/or virilization in postmenopausal woman. Here we describe a 66-year old woman with presentation of severe hirsutism, alopecia, clitoromegaly and laboratory finding of significantly elevated serum total testosterone concentration and hyperinsulinemia. Performed imaging studies revealed normal sized, homogeneous ovaries, signs of endometrial hypertrophy and normal adrenal glands. Due to severe hyperandrogenemia and signs of endometrial hypertrophy, the total abdominal hysterectomy with bilateral salpingo-oophorectomy has been performed. Pathological examination revealed OH and endometrial hyperplasia. Androgenic activity of ovarian stromal cells has been confirmed using alpha-inhibin histochemical staining. Postmenopausal hyperandrogenemia is a diagnostic and therapeutic challenge and the imaging studies often may be misleading and require careful and critical consideration.

Association of ovarian hyperthecosis with endometrial polyp, endometrial hyperplasia, and endometrioid adenocarcinoma in postmenopausal women: a clinicopathological study of 238 cases.

Ovarian hyperthecosis, a source of estrogen, may occur in postmenopausal women. In this study, we evaluated the possible association of ovarian hyperthecosis with endometrial polyp, endometrial hyperplasia, and endometrioid adenocarcinoma in postmenopausal women. Our study consisted of 238 postmenopausal women: 108 with endometrioid adenocarcinoma and 130 without endometrial carcinoma. The International Federation of Gynecology and Obstetrics system was used to grade endometrioid adenocarcinoma. Within the endometrioid adenocarcinoma cases, 48 (44.4%) were grade 1, 46 (42.6%) were grade 2, and 14 (13.0%) were grade 3. Among the noncancer cases, 71 (54.6%) had atrophic endometrium, 32 (24.6%) had endometrial polyp, and 27 (20.8%) had endometrial hyperplasia. The frequency of ovarian hyperthecosis in patients with endometrial polyp (46.9%), endometrial hyperplasia (55.6%), and grade 1 (43.8%), grade 2 (54.3%), and grade 3 (57.1%) endometrioid adenocarcinoma was each significantly higher than that in patients with atrophic endometrium (23.9%), supporting an association of these lesions with ovarian hyperthecosis in postmenopausal women. There was no statistically significant difference in the rate of ovarian hyperthecosis among patients with endometrial polyp, endometrial hyperplasia, and grade 1, grade 2, and grade 3 endometrioid adenocarcinoma. Our study indicates that ovarian hyperthecosis with its resultant risk factor of hyperestrinism may contribute to the pathogenesis of endometrial polyp, endometrial hyperplasia, and endometrioid adenocarcinoma in postmenopausal women. Although some studies show that grade 3 endometrioid adenocarcinoma has different genetic/molecular changes from its lower-grade counterparts, our study suggests that endometrioid adenocarcinoma of all grades may share the common risk factor of hyperestrinism.

Hirsutismo pós-menopausa: caso clínico raro de hipertecose ovárica / Post-menopausal hirsutism: a rare case of ovarian hyperthecosis

Durante o climatério podem ocorrer sinais clínicos de hiperandroginismo. Contudo quadros de virilização exigem investigação para exclusão de uma fonte produtora de androgênios. Doente de 66 anos, com menopausa espontânea aos 50, referenciada à consulta de ginecologia por hirsutismo após a menopausa, com agravamento no último ano e episódios demetrorragia que não valorizava. Ao exame objetivo tinha masculinização da voz, alopécia androgênica, aumento da pilosidade na face, tronco e membros e hipertrofia do clitóris.Feita ecografia endovaginal que revelou espessamento endometrial e ovários aumentados de volume para a idade; estudo analítico que demonstrou um valor de testosterona total elevado (225ng/dL); tomografia computadorizada da suprarrenal e ressonância magnética crânio-encefálica que não revelaram alterações; e histeroscopia com remoção de pólipo endometrial, associado a hiperplasia endometrial simples sem atipia. Submetida a histerectomia total com anexectomia bilateral. O estudo histológico concluiu tratar-se de hipertecose ovárica. Seis meses após a cirurgia apresentava normalização da testosterona sérica, acentuada redução do hirsutismo e melhoria da alopécia.O diagnóstico de hiperandrogenismo em mulheres na pós-menopausa constitui um desafio. Os meios complementares de diagnóstico nem sempre permitem detectar a origem da hiperandrogenemia. O tratamento da hipertecose ovárica melhora o hirsutismo e pode reduzir o risco de patologia maligna hormonodependente.

tMild clinical signs of hyperandrogenism such as hirsutism may arise during the menopausal transition as part of the aging process. However, development of virilization may be interpreted as the presence a specific source of androgen excess. 66 year-old menopausal woman, with a record of progressive hirsutism since menopausal age (50 years-old) exacerbated over the past year. Episodes of metrorrhagia were not valued by the patient. Physical examination showed deepening of voice, frontotemporal alopecia, hirsutism in face, trunk and limbs and hypertrophy of the clitoris. A transvaginal ultrasound revealed a thickened endometrium and enlarged ovaries considering her age and analytical study showed an increase of total testosterone (225ng/dL). No changes were detected at computerized tomography of adrenals and cerebral magnetic resonance. Performed an hysteroscopy with removal of endometrial polyp, associated to simple endometrial hyperplasia without atypia. The histological diagnosis after hysterectomy and bilateral salpingo-oophorectomy, revealed a ovarian hyperthecosis. Six months after surgery it was observed a testosterone within the normal range, marked hirsutism reduction and alopecia improvement.Diagnosis of hyperandrogenism in postmenopausal is a challenging task. Imaging techniques do not always reveal the source of excess androgens. The ovarian hyperthecosis treatment effectively improves hirsutism and reduces the risk of hormone-dependent tumors.

Ovarian hyperthecosis in the context of an adrenal incidentaloma in a postmenopausal woman / Coexistência de incidentaloma adrenal e hipertecose de ovário em mulher menopausada

Adrenal incidentaloma is not infrequent and can be found in hirsute women. We report a case of a 54-year-old woman with amenorrhea and hirsutism of abrupt onset and mild signs of virilization that had an adrenal incidentaloma coexisting with ovarian hyperthecosis. Basal total and free testosterone were 191 ng/dL and 179 pmol/L. Pelvic ultrasonography disclosed a right ovary with 10.3 cc and a left ovary with 9.8 cc without nodules or cysts, and computerized tomography of the abdomen disclosed a normal right adrenal gland. On the left adrenal gland a solid nodule with 0.8 cm was seen. After GnRHa administration, total testosterone was 23 ng/dL and free testosterone was 17 pmol/L. In view of a suppression of testosterone by GnRHa, the patient was submitted to a hystero-oophorectomy by laparoscopy. Symmetrically enlarged ovaries were seen. No tumor was apparent. Histology showed hyperthecosis, with foci of luteinized stromal cells. Only atretic follicles were detected. No hilar cell hyperplasia was seen. In conclusion, the presence of an adrenal mass in a hirsute woman can lead to a wrong diagnosis. In this case the suppression GnRHa test was fundamental to determine the origin of hyperandrogenemia.

Os incidentalomas adrenais não são infreqüentes e podem ser encontrados em pacientes com hirsutismo. Nesse relato, apresentamos o caso de coexistência de um incidentaloma adrenal com hipertecose de ovário, em uma mulher com 54 anos de idade com amenorréia e hirsutismo de início abrupto e sinais leves de virilização. As testosteronas total e livre basal foram de 191 ng/dL e 179 pmol/L, respectivamente. O ultra-som pélvico demonstrou o ovário direito com 10,3 cc e ovário esquerdo com 9,8 cc, sem nódulos ou cistos e a tomografia computadorizada de abdome demonstrou adrenal direita adrenal e nódulo sólido de 0,8 cm na adrenal esquerda. Após a administração de análogo de GnRH, as testosteronas total e livre foram de 23 ng/dL e 17 pmol/L, respectivamente. Considerando a supressão da concentração de testosterona pelo análogo de GnRH, a paciente foi submetida a histeroooforectomia por via laparoscópica. O diagnóstico histológico foi de hipertecose, com focos de células estromais luteinizadas. Somente folículos atréticos foram visualizados. Não se detectou hiperplasia de células hilares. Em conclusão, a presença de massa adrenal em uma paciente com hirsutismo pode levar ao diagnóstico errado. Neste caso, o teste de supressão com análogo de GnRH foi fundamental para se determinar a origem da hiperandrogenemia.