Androgen-secreting Tumors Research Articles

Virilización y enfermedad metabólica en mujer postmenopáusica relacionado a hiperplasia e hipertecosis ovárica

ResumenDurante la transición menopáusica pueden aparecer signos clínicos leves de hiperandrogenismo, como parte del proceso de envejecimiento normal, pero el desarrollo de virilización franca sugiere una fuente específica de exceso de andrógenos debiendo descartar la presencia de tumores secretores de andrógenos tanto a nivel adrenal como ovárico.Se presenta un caso de una mujer de 51 años postmenopáusica con signos de virilización de 12 meses de evolución, asociado a antecedente personal de diabetes tipo 2 e hipertensión arterial, de mal manejo en el último año. Las pruebas de laboratorio mostraron una franca elevación de los niveles de andrógeno sérico e hiperinsulinemia asociada. Las imágenes solicitadas evidenciaron ambos ovarios aumentados de tamaño de aspecto homogéneo y sólido, con glándulas adrenales de aspecto conservado, lo que hizo sospechar de una posible hiperplasia tecal del estroma ovárico. Se realizó una anexectomía bilateral por laparoscopia, cuya anatomía patológica confirmó la presunción diagnóstica. Los dosajes de testosterona sérica al mes de la cirugía retornaron a valores cercanos a la normalidad para una mujer postmenopáusica.El diagnóstico causal de virilización en mujeres posmenopáusicas es un desafío, y por lo general están asociadas con patologías poco frecuentes. Una historia clínica detallada es fundamental para diferenciar el desarrollo progresivo de virilización que caracteriza las causas benignas de la rápida progresión que caracteriza a los tumores malignos. La interpretación de pruebas correctas de laboratorio con imágenes complementarias, así como la búsqueda de antecedentes de riesgo cardiovascular como la diabetes y la hipertensión asociadas son fundamentales para establecer un correcto diagnóstico y tratamiento.

Post Menopausal Hyperandrogenism: A Case of a Steroid Cell Tumor of the Ovary

Introduction: Postmenopausal hyperandrogenism is a rare condition that causes hirsutism, virilization, and clitoromegaly that should be carefully evaluated in order to avoid overlooking an androgen secreting tumor (1). Case: A 48 year old African American female with a prior history of polycystic ovarian syndrome (PCOS) presented for evaluation of hirsutism. Of note, she also underwent menopause at age 41 after receiving chemotherapy for a history of multiple myeloma, and she has been on steroids since the time of her diagnosis. On exam, she had thick, dark hair growth on her chin, upper lip, and chest, as well as male-patterned baldness, acne, easy bruising, proximal muscle weakness, deep voice, and elevated blood pressure. Prior to endocrinology evaluation, she was started on spironolactone 25 mg BID. Lab work up included dehydroepiandrosterone sulfate (DHEAS) 73 mcg/dL (27-240 mcg/dL), 17-hydroxyprogesterone 74 ng/dL (31-455 ng/dL), androstenedione 271 ng/dL (30-200 ng/dL), total testosterone 763 ng/dL (8-60 ng/dL), bioavailable testosterone 244 ng/dL (0.8-10 ng/dL), hemoglobin A1c 4.3%, follicle stimulating hormone 30 IU/L, luteinizing hormone 23.9 IU/L, insulin 11 mcIU/mL (2.6-24.9 mcIU/mL), glucose 71, insulin-like growth factor 1 236 ng/mL (44-227 ng/mL) with subsequent normal glucose suppression test. While transvaginal ultrasound did not note any abnormal findings, a computed tomography of the abdomen/pelvis showed a new hyperdense focus in the left ovary as well as a tiny right adrenal nodule, most likely an adenoma. Follow up magnetic resonance imaging confirmed a 1.6 cm enhancing solid left ovarian mass; it also confirmed a right adrenal adenoma and left adrenal thickening versus a tiny adenoma. Urine metanephrines and catecholamines were normal. Patient had total hysterectomy and bilateral oophorectomy; pathology showed a steroid cell tumor. Conclusion: Postmenopausal hyperandrogenism has several causes: insulin resistance, PCOS, non-classic congenital adrenal hyperplasia, medications, and tumors of the ovaries or adrenals. Severe hyperandrogenemia should raise the suspicion of an ovarian or adrenal neoplasm, necessitating prompt imaging (1). Certain imaging may not reveal smaller masses, and additional imaging or ovarian/adrenal vein sampling may be needed. Typically, an elevated DHEAS with a high testosterone suggests an adrenal source, while androstenedione can be elevated in both glands. Once identified, the involved gland is surgically resected. This patient was found to have a steroid cell tumor, which has malignant potential. They make up less than 0.1% of all ovarian tumors (2). Initial treatment is surgical resection and may necessitate chemotherapy if malignant.1) Markopoulos MC, Kassi E, Alexandraki KI, Mastorakos G, Kaltsas G. Hyperandrogenism after menopause. Eur J Endocrinol. 2015 Feb;172(2):R79-91. doi: 10.1530/EJE-14-0468. Epub 2014 Sep 15. PMID: 25225480.2) Hayes, Mary C. M.D.; Scully, Robert E. M.D. Ovarian Steroid Cell Tumors (Not Otherwise Specified), The American Journal of Surgical Pathology: November 1987 - Volume 11 - Issue 11 - p 835-845

Elevated Testosterone Levels With Unclear Etiology- the Need for Longer Follow up and Role of Dexamethasone Suppression Test as a Useful Tool to Distinguish Tumorous vs Non Tumorous Etiology

Background: Severe hirsutism in women in conjunction with elevated testosterone level raises concern for androgen secreting tumors. When initial investigations and radiological imaging do not identify a tumorous pathology, clinicians are faced with a dilemma on whether to investigate further or to consider a benign cause such as PCOS or ovarian hyperthecosis. There is inadequate evidence on how long these patients need to be followed up before considering a benign cause for their symptoms. Clinical Case: 57 years-old female, with pertinent history including primary hypothyroidism and eczema, was referred to endocrine clinic in September-2011 for work-up of severe hirsutism and elevated testosterone levels of 4.1 nmol /L (n: 0 - 2.5). All other tests including androstenedione, DHEAS, baseline pituitary profile and 24-hours urinary free cortisol levels were unremarkable. MRI of adrenal glands and ovaries was also unremarkable. Patient was presumptively diagnosed with ovarian hyperthecosis and commenced on spironolactone. There was improvement in hirsutism and patient was discharged from clinic in Feb 2012. Patient was re-referred to endocrine clinic 7 years later in September-2019 for worsening of hirsutism, male pattern baldness. At this stage, patient had testosterone levels of 17– 23 nmol/L (n: 0 - 2.5). Free androgen index 76.6% (n:0–7), SHBG (35 nmol/L, n: 18 – 114). Androstenedione (4 nmol, n: 1 – 8.5) DHEAS (2.3 umol/L, n: 0.3 – 12), 24-hours urine free cortisol level (< 13 nmol, n: < 165 nmol), 17-hydroxyprogesterone, serum ACTH, TSH, LH and FSH and estradiol levels were all normal. On examination patient had signs of virilization which had developed over previous six months. Patient had a low dose dexamethasone suppression test (0.5 mg of dexamethasone 6 hourly for 48 hours). The androgen profile obtained pre and post test showed no suppression in testosterone but well suppressed cortisol. Patient had repeat MRI of the adrenals and ovaries which revealed focal enhancing mass in right ovary (3.3 x 2.5 x 2.6 cm). Patient had an urgent bilateral oophorectomy and histology confirmed a rare steroid cell tumour of the right ovary. Following surgery there has been a significant improvement in her symptoms. Conclusion: Patients with elevated testosterone level and unclear etiology need longer follow up and review of investigations when symptoms worsen as yet undiscovered sinister etiology could be the likely reason. Dexamethasone suppression can be considered as a useful tool to distinguish tumorous vs non tumorous etiology in early stage of investigations as poor suppression of androgens with dexamethasone increases the likelihood of tumorous etiology1

Diagnosis of Sertoli-Leydig Cell Tumor of the Ovary Complicated by the Pattern of Hyperandrogenemia and Results of Imaging

Introduction: Virilization in a postmenopausal woman requires evaluation for an androgen-secreting tumor. The differential diagnosis includes adrenal carcinomas and adenomas and Sertoli-Leydig cell tumors, granulosa-theca cell tumors, and hilus-cell tumors of the ovaries. We present a case of virilization in a postmenopausal woman caused by a Sertoli-Leydig cell tumor (SLCT) in which evaluation was complicated by the pattern of androgen elevation, bilateral adrenal nodules, and absence of an adnexal mass. Case: A 64-year-old female was referred for evaluation of hyperandrogenism. Hirsutism, temporal hairline regression, and unusually deep voice were noted on examination. Two total testosterone levels obtained one month apart were 146 ng/dL (2-45), and measurements of dehydroepiandrosterone sulfate (DHEAS) and androstenedione were 299 mcg/dL (12-133) and 1.84 ng/mL (0.130-0.820), respectively. Abdominal CT revealed bilateral adrenal nodules - 2 cm and - 5 Hounsfield units (HU) on the left, and 1.5 cm and 5 HU on the right - but no ovarian masses. Transvaginal ultrasonography also failed to identify a discrete ovarian mass but showed endometrial hyperplasia. Virilization, magnitude of testosterone elevation, and results of imaging were felt to be most strongly indicative of ovarian hyperthecosis, and the patient underwent laparoscopic bilateral salpingo-oophorectomy and hysterectomy. The right ovary was 2.3 cm in largest diameter and approximately 90% replaced by an orange-red mass that showed Sertoli and Leydig cells on microscopy, immunohistochemical staining for the sex cord proteins inhibin and calretinin, and presence of the Leydig cell marker melan A. It was classified as well differentiated. Additional CT imaging and robotic assisted laparoscopy confirmed a stage IA tumor. One month after surgery, hyperandrogenemia had completely resolved (total testosterone < 10 ng/dL, androstenedione 0.379 ng/mL, and DHEAS 99 mcg/dL), and changes of virilization had mostly regressed at an eight months appointment. Discussion: SLCTs are a type of sex-cord stromal ovarian tumor. They constitute < 0.5% of ovarian tumors but account for approximately 75% of testosterone-secreting ovarian masses. This patient’s case was unusual for multiple reasons: 1. Age - most SLCTs are diagnosed in the second or third decade, 2. Imaging - CT and ultrasonography usually show a solid or solid and cystic adnexal mass, and co-existing adrenal nodules are rare, likely due to typical young age of presentation, and 3. Pattern of androgen elevation - DHEAS was more than two-fold elevated, and usually < 10% of DHEA and DHEAS are produced by the ovaries. However, DHEAS fell significantly after oophorectomy. SLCTs are a potential etiology of virilization in postmenopausal women even in the absence of a detectable adnexal mass and when biochemistries and imaging raise the possibility of an adrenal source of androgen.

Neuroendorine paraneoplastic syndromes

Skin is commonly affected by neuroendorine paraneoplastic syndromes (PNS). This is due to the expression of receptors in the skin by which abnormally secreted neuroendocrine hormones and mediators elicit directly, and indirectly, cutaneous key signs and thus facilitate early diagnosis of these diseases. In acromegaly, induction of the growth hormone-insulin-like growth factor‑1 axis results in trophic changes of the acral portions of the skin and mucosal membranes including cutis verticis gyrata. The skin signs of non-iatrogenic Cushing syndrome are identical with those of exogenous prolonged intake of glucocorticoids: centripetal accumulation of adipose tissue, plethora and striae distensae. Episodic flushing of the face and trunk (together with explosive diarrhea) is akey feature of carcinoid tumors. Fibrotic remodeling of the heart and retroperitoneal space, and less commonly of the skin, are important complications mediated by abnormally secreted 5‑hydroxytryptamine (serotonin, 5‑HT), the latter eliciting profibrotic responses on HT2B-receptor-expressing fibroblasts. Androgen-secreting tumors lead to well-established receptor-mediated cutaneous signs of peripheral hyperandrogenisms: seborrhea, acne, hirsutism, and androgenetic alopecia. In contrast, the pathogenesis of necrolytic migratory erythema as akey feature of glucagonoma remains incompletely understood and is thought to be related to hypoaminoacidemia. This review summarizes the clinical features of neuroendocrine PNS with skin involvement, elucidates its underlying pathophysiology, lists differential diagnoses, and explains key diagnostic steps and principal therapeutic options. An interdisciplinary approach is essential to provide the best care of all patients with neuroendocrine PNS.

An adolescent girl with coexisting ovarian mature cystic teratoma and HAIR-AN syndrome, an extreme subtype of polycystic ovarian syndrome.

SummaryPolycystic ovarian syndrome (PCOS) is associated with menstrual irregularities, ovulatory dysfunction, hirsutism, insulin resistance, obesity and metabolic syndrome but is rarely associated with severe hyperandrogenaemia and virilisation resulting in male pattern baldness and clitoromegaly. Total serum testosterone greater than twice the upper limit of the reference range or free androgen index of over five-fold elevated suggests a diagnosis other than PCOS. We reported a case of a 15 years old obese girl presented with secondary amenorrhoea, virilising signs: frontal baldness, clitoromegaly and prominent signs of insulin resistance and marked acanthosis nigricans. Her total testosterone level was markedly elevated at 9.4 nmol/L (0.5–1.7 nmol/L) and MRI pelvis revealed a right ovarian mass with fat and cystic component and a left polycystic ovary. The patient underwent laparoscopic right ovarian cystectomy and histologically confirmed mature cystic teratoma. Post-operatively, her testosterone level declined but did not normalise, menses resumed but remained irregular. Her fasting insulin was elevated 85.2 mIU/L (3–25 mIU/L) and HOMA-IR was high at 13.1 (>2) with persistent acanthosis nigricans suggesting co-existing HAIR-AN syndrome, an extreme phenotype of polycystic ovarian syndrome.Learning pointsRapid onset of hyperandrogenic symptoms, especially if associated with signs of virilisation must raise the suspicion of an androgen-secreting tumour.Total serum testosterone greater than twofold the upper limit of the reference range or free androgen indices over fivefold suggest a diagnosis other than polycystic ovarian syndrome (PCOS).High levels of testosterone with normal levels of the DHEA-S suggest an ovarian source.Ovarian androgen-secreting tumour and HAIR-AN syndrome, an extreme spectrum of PCOS can co-exist.

Диагностика и тактика ведения пациенток с гиперандрогенией в раннем репродуктивном возрасте

Hyperandrogenism is characterized by the presence of clinical symptoms and / or biochemical parameters of high androgen levels. Dermopathy and particularly acne and hirsutism are regarded as the main clinical markers of hyperandrogenism. Cosmetic problems associated with hyperandrogenism are often the reason for young woman to seek medical attention. Body hair growth in atypical areas, acne and trophic skin changes have a significant effect on the emotional state, provoke a sense of imperfection and loss of attractiveness, and reduce the quality of life. Concomitant menstrual disorders (up to 50–75%) complicate the patient’s state and determine an increased risk of gynecological disorders in the future. The causes of hyperandrogenism in early reproductive age can be varied: from more common physiological hyperandrogenism in adolescence, idiopathic hyperandrogenism, polycystic ovary syndrome (PCOS) and the atypical form of congenital adrenal hyperplasia to less common hyperthecosis, acromegaly, hyperprolactinemia, hypothyroidism, Cushing’s disease, and androgen-secreting tumors. The diagnostic search should begin with assessing complaints and clinical symptoms, and a complete physical examination. To confirm biochemical hyperandrogenism, total and free testosterone, and free androgen index are evaluated. Additional methods of examination are used to clarify the diagnosis. Treatment is prescribed in accordance with the established diagnosis. Androgen-secreting tumors require surgical intervention. Other causes of hyperandrogenism are usually treated with medication. According to current recommendations, combined oral contraceptives are the first-line therapy for the most common conditions accompanied by hyperandrogenism (hirsutism, acne vulgaris, PCOS) in early reproductive age. A clinical solution may be a combined administration of microdoses of ethinylestradiol (20 μg) and drospirenone (3 mg), progestagen with antiandrogenic property in the mode 24 + 4 (for instance: Dimia). This article presents clinical cases of diagnosis and management tactics for patients of early reproductive age with hyperandrogenism. Conclusion. The differential diagnosis of physiological and pathological conditions accompanied by hyperandrogenism is one of the current challenges for obstetrician-gynecologist. A properly developed algorithm of examination, interpretation of its results, therapy and prevention of complications are of great importance. Key words: acne, alopecia acreata, congenital adrenal hyperplasia, hyperandrogenism, hirsutism, girls, drospirenone, combined oral contraceptives, contraception, adolescents, early reproductive age, polycystic ovary syndrome, ethinylestradiol

In vitro differentiation of theca cells from ovarian cells isolated from postmenopausal women.

Can human theca cells (TCs) be differentiated in vitro? It is possible to differentiate human TCs in vitro using a medium supplemented with growth factors and hormones. There are very few studies on the origin of TCs in mammalian ovaries. Precursor TCs have been described in neonatal mice ovaries, which can differentiate into TCs under the influence of factors from oocytes and granulosa cells (GCs). On the other hand, studies in large animal models have reported that stromal cells (SCs) isolated from the cortical ovarian layer can also differentiate into TCs. After obtaining informed consent, ovarian biopsies were taken from eight menopausal women (53-74 years of age) undergoing laparoscopic surgery for gynecologic disease not related to the ovaries. SCs were isolated from the ovarian cortex and in vitro cultured for 8 days in basic medium (BM) (G1), enriched with growth factors, FSH and LH in plastic (G2) or collagen substrate without (G3) or with (G4) a GC line. To confirm TC differentiation, relative mRNA levels for LH receptor (Lhr), steroidogenic acute regulatory protein (Star), cholesterol side-chain cleavage enzyme (Cyp11a1), cytochrome P450 17A1 (Cyp17a1), hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1 (Hsd3b1) and hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2 (Hsd3b2) were assessed. Immunohistochemistry was also performed for their protein detection and a specific marker was identified for TCs (aminopeptidase-N, CD13), as were markers for theca and small luteal cells (dipeptidyl peptidase IV (CD26) and Notch homolog 1, translocation-associated (NOTCH1)). Finally, we analyzed cell ultrastructure before (Day 0) and after in vitro culture (Day 8), and dehydroepiandrosterone (DHEA) and progesterone levels in the medium using transmission electron microscopy (TEM) and ELISA, respectively. Results obtained from qPCR showed a significant increase (P < 0.05) in mRNA levels of Lhr in F2 (floating cells in G2) and G4, Cyp17a1 in G1 and F1 (floating cells in G1) and Hsd3b2 in G1, G2, G3 and G4. Immunohistochemistry confirmed expression of each enzyme involved in the steroidogenic pathway at the protein stage. However, apart from G1, all other groups exhibited a significant (P < 0.05) rise in the number of CD13-positive cells. There was also a significant increase (P < 0.05) in NOTCH1-positive cells in G3 and G4. Ultrastructure analyses by TEM showed a distinct difference between groups and also versus Day 0. A linear trend with time revealed a significant gain (q < 0.001) in DHEA concentrations in the medium during the culture period in G1, G2, G3 and G4. It also demonstrated a statistical increase (q < 0.001) in G2, G3 and G4 groups, but G1 remained the same throughout culture in terms of progesterone levels. N/A. Shorter periods of in vitro culture (e.g. 2, 4 and 6 days) could have led to increased concentrations of differentiated TCs in G2, G3 and G4. In addition, a group of cells cultured in BM and accompanied by COV434 cells would be necessary to understand their role in the differentiation process. Finally, while our results demonstrate that TCs can be differentiated in vitro from cells isolated from the cortical layer of postmenopausal ovaries, we do not know if these cells are differentiated from a subpopulation of precursor TCs present in ovarian cortex or ovarian SCs in general. It is therefore necessary to identify specific markers for precursor TCs in human ovaries to understand the origin of these cells. This is a promising step toward understanding TC ontogenesis in the human ovary. Moreover, in vitro-generated human TCs can be used for studies on drug screening, as well as to understand TC-associated pathologies, such as androgen-secreting tumors and polycystic ovary syndrome. This study was supported by grants from the Fonds National de la Recherche Scientifique de Belgique (FNRS) (C.A.A. is an FRS-FNRS Research Associate; grant MIS #F4535 16 awarded to C.A.A.; grant 5/4/150/5 awarded to M.M.D.; grant ASP-RE314 awarded to P.A.) and Foundation Against Cancer (grant 2018-042 awarded to A.C.). The authors declare no competing interests.

Androgen-Secreting Tumor with Oncocytic Features and Myelolipoma Arising from Ectopic Adrenal Cortical Tissue Located in Broad Ligament of the Uterus: Too Rare a Disease!

Hirsutism or excess growth of androgen-dependent hairs in a male pattern distribution associated with menstrual irregularities is frequently encountered in clinical practice. Polycystic ovary syndrome and non-classic congenital adrenal hyperplasia are the common underlying causes; androgen-secreting ovarian or adrenal neoplasms also need to be ruled out in appropriate settings, particularly in presence of virilization and grossly elevated circulatory androgens. Elevated 17α-hydroxyprogesterone (17-OH-P), though highly suggestive of congenital adrenal hyperplasia, is not specific for the disease, and grossly elevated values are occasionally encountered in androgen-producing tumors. Ectopic adrenocortical tissue or adrenal rest at times may undergo tumor formation and become hormonally active. In this article, androgen-secreting tumor of adrenal rest located in broad ligament of the uterus is reported as the underlying cause of severe hyperandrogenism in a young lady who was initially diagnosed with simple virilizing form of congenital adrenal hyperplasia due to 21 hydroxylase deficiency following elevated circulatory 17-OH-P levels.

COMPARISONS OF GLUCOSE INTOLERANCE TESTING FOR THE DETECTION AND DIAGNOSIS OF PREDIABETES AND TYPE II DIABETES MELLITUS IN REPRODUCTIVE AGE WOMEN WITH POLYCYSTIC OVARY SYNDROME

Polycystic Ovary Syndrome (PCOS) is one of the most common metabolic conditions affecting reproductive-age women. Its etiology is not completely understood. PCOS is diagnosed using the 2003 Rotterdam Criteria (ROT), in which patients must meet at least two of the three following criteria: (1) clinical or biochemical evidence of hyperandrogenism, (2) anovulation/oligomenorrhea and (3) polycystic ovarian morphology on ultrasound with the exclusion of other etiologies (e.g., congenital adrenal hyperplasia, androgen-secreting tumors, Cushing's syndrome).

Tumor de células de Leydig puro de ovario en mujer premenopáusica

Los tumores de células de Leydig del ovario son un tipo raro de tumores del estroma del cordón sexual, con menos de 0,1% de todos los tumores de ovario. Representan un desafío diagnóstico, no solo por su incidencia esporádica sino también por presentar imágenes aparentemente normales. Aunque son más comunes en las mujeres menopaúsicas, también se ha descrito casos en mujeres premenopáusicas. La característica clínica más común es la aparición de virilización rápida y progresiva; más de 75% de las pacientes muestra signos de virilización debido a la sobreproducción de testosterona. La concentración sérica de testosterona representa el marcador más útil en el diagnóstico del tumor ovárico secretor de andrógenos. El tumor de células de Leydig ovárico siempre debe ser considerado en mujer en edad reproductiva con síntomas de virilización. Se presenta un caso de tumor de células de Leydig puro de ovario en mujer premenopáusica.

SUN-005 Hirsutism Due to Bilateral Leydig Cell Tumors

Severe hyperandrogenism in post-menopausal women is rare. It may be caused by either benign or malignant neoplasms of the adrenal or ovary. We report a rare case of a post-menopausal woman with hirsutism associated with virilization due to Leydig cell tumors (LCT) of both ovaries. Case report 61 yo female presented for evaluation of hirsutism. She had also been experiencing increased facial hair growth, deepening of voice, clitoromegaly, alopecia, and acne. Physical examination: normal vital signs. Patient had signs of virilization, including coarse hair along her upper lip, chin, lower abdomen and inner thigh with Ferriman-Gallwey score of 8, acne, and clitoromegaly. She had no signs of acanthosis nigricans or Cushing syndrome. Base line labs: Hemoglobin 16.2 gm/dL (ref 12.0 to 15.5), total testosterone 803 ng/dL (ref 3–41), free testosterone 20.2 pg/mL (ref 0.0–4.2), estradiol 77 pg/mL (<6.0−54.7), estrone 148 pg/mL (ref 7–40), FSH 11.5 mIU/mL (ref 25.8 - 134.8), LH 6.90 mIU/mL (ref 7.7 - 58.5), androstenedione 28 ng/dL (ref 17–99), DHEAS 99.9 mcg/dL (ref 19–205), dehydroepiandrosterone 512 ng/dL (ref 31–701), inhibin A 2.3 pg/mL (ref <5), inhibin B <7.0 pg/mL (ref 00-16.9), 17-alpha hydroxyprogesterone 187 ng/dl (ref <51). Her other serum markers such as anti -Mullerian hormone, alpha-fetoprotein, and hCG were normal. A CT scan of adrenals: normal. Similarly a transvaginal US did not show any ovarian pathology, however MRI of the pelvis showed homogeneous ovarian enhancement bilaterally and based on this information a diagnosis of ovarian hyperthecosis was considered and patient underwent laparoscopic bilateral oophorectomy. Pathology confirmed: LCT in both ovaries. Laboratory values performed 3 months later showed the following values: hemoglobin 14.2 gm/dL, total testosterone 13 ng/dL, free testosterone 1.4 pg/mL, LH 124 mIU/mL, FSH 99mIU/mL, estradiol <5.0 pg/mL. In 6 months she had significant improvement in hirsutism and virilization. Discussion Hyperandrogenism, especially serum testosterone in the male range with rapidly progressive hirsutism or virilization signs in a female indicates tumor etiology. Androgen-secreting ovarian tumors are usually small and often embedded in the ovary. Transvaginal US is useful in the diagnosis of ovarian tumors. However, in our case, transvaginal US failed while MRI scan showed bilaterally enlarged ovaries and with this information patient underwent bilateral oophorectomy. Although 5 cases of bilateral LCT are reported in the literature, LCT is unilateral 95% of the time, the pathogenesis of Leydig cell proliferation and LCT is unclear. In conclusion, androgen secreting tumors should be considered in women (especially in post-menopausal state) with hyperandrogenism and hirsutism. In fact, diffuse stromal Leydig cell hyperplasia and small Leydig cell tumors may be missed on imaging and in some cases only pathology can confirm the result.

A review of 300 consecutive cases of Polycystic ovarian syndrome: clinical presentation and management

Background: Polycystic ovary syndrome (PCOS) is a common heterogeneous endocrine disorder. The prevalence of PCOS varies depending on which criteria are used to make the diagnosis, but can be as high as 15%–20%. Aim and objectives: To review the demographic details, presenting symptoms, biochemical features and management in women with PCOS and differentiate patients who have polycystic ovarian morphology (PCOM) and have hypothalamic amenorrhoea. Method: Retrospective observational study of 300 consecutive new cases with suspected PCOS were referred to the reproductive endocrinology clinic in a tertiary referral hospital (Kings college hospital, London) from 2008-2015. Electronic medical records were reviewed and Microsoft Excel software was used for data collection and analysis. Inclusion and exclusion criteria’s: All patients with suspected PCOS fulfilling Rotterdam criteria were included in the study. Phenotypically similar androgen excess disorders like congenital adrenal hyperplasia (CAH), androgen secreting-tumor and Cushing’s syndrome were excluded. Results: The mean (+/-SD) age was 30 (+/-6.7) years [range 14-49]. A total of 213 (71%) had oligomenorrhoea, 61 (20.3%) had amenorrhoea, while 26 (8.6%) had regular cycles. 135 (45%) presented with subfertility, while 93 (31%) had hirsutism. Mean (+/-SD) FSH and LH were 5.5 IU/L (+/-2.8) and 17.8 IU/L (+/-7.9), respectively, while mean (+/-SD) estradiol level was 253.4 pmol/L (+/-267.1). 27/61 (44.2%) women with amenorrhoea, had low estradiol [mean (+/-SD) &lt;176 pmol/l (123.8+/-30.8 )]. Mean (+/-SD) anti-Mullerian hormone (AMH) was 44.6 pmol/L (+/-33.1). 39/45 (87%) had elevated AMH while 6/45 (13%) had normal AMH levels. Mean (+/-SD) testosterone level was 2.0nmol/L (+/-1.5) and 36 (16%) patients had elevated total testosterone levels. Mean (+/-SD) Sex Hormone Binding Globulin (SHBG) and Free Androgen Index (FAI) were 45.9 (+/- 29.4) and 5.8 (+/- 6.6). 20/43 (47% of women assessed) had elevated androstenedione levels with a Mean (+/-SD) of 13.06 (+/- 7.5). Elevated triglycerides and/or total cholesterol was noted in 13/44 (29.5% of women assessed). 13/28 (46.4% of women assessed) had raised HbA1C. In a total of six (2%) patients, the ovaries did not appear polycystic. Conclusion: A significant proportion of women with hypothalamic amenorrhea with PCOM were classed as PCOS.

Virilizing ovarian tumor: the challenges of differential diagnosis

SertoliLeydig cell tumor is a rather rare type of ovarian neoplasms belonging to the group of sex cordstromal tumors. This malignancy is characterized by androgen overproduction, which results in the so-called virilization and can be accompanied by various metabolic disorders such as abdominal obesity, disturbances of carbohydrate and protein metabolism, and high blood pressure. During differential diagnosis, it is important to identify the source of androgen overproduction. An androgen-secreting ovarian tumor needs to be differentiated from androgen-secreting adrenal tumor, ovarian stromal thecomatosis (hyperthecosis), and endogenous hypercorticism (the Cushings syndrome). In most cases, the SertoliLeydig cell tumor is associated with DICER1 mutation carriership. If a patient is found to carry the DICER1 mutation, patients relatives need to undergo genetic testing as the individuals with mutations in this gene have an elevated risk of developing a broad range of benign and malignant tumors (most of these tumors are relatively rare in the overall population). The awareness of this rare ovarian neoplasm among medical specialists (obstetriciansgynecologists, endocrinologists, and oncologists) is supposed to ensure timely diagnosis and adequate treatment of this disease.

A rare presentation of an androgen-secreting tumour without hyperandrogenic symptoms

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Immunodetection and quantification of enzymatic markers in theca cells: the early process of ovarian steroidogenesis†.

The association between theca cells (TCs) and granulosa cells is pivotal to steroid biosynthesis in the ovary. During the late secondary follicle stage, TCs form a layer around granulosa cells, after which their steroidogenic function falls under the control of luteinizing hormone (LH) that activates the cAMP signaling pathway via a G protein-coupled receptor. In addition to perilipin-2, a marker for lipid droplets containing esters as substrates for TCs to produce steroidogenic hormones, other essential proteins, like steroidogenic acute regulatory protein (StAR), cytochrome P450 11A1, cytochrome P450c17, 3 beta-hydroxysteroid dehydrogenase/delta 5 ->4-isomerase type 1, and 3 beta-hydroxysteroid dehydrogenase/delta 5 ->4-isomerase type 2, play a role in the cascade after luteinizing hormone-choriogonadotropic hormone receptor (LH/CG-R) occupation by LH. The aim of the present study was to assess expression levels and corresponding amounts of LH/CG-R, perilipin-2, and enzymes involved in the steroidogenic pathway of TCs based on follicle stage. Immunohistochemical analysis of each of these proteins was therefore performed on ovarian samples from nine adult women, most (n=8) with BRCA1 and/or BRCA2 mutations undergoing prophylactic bilateral oophorectomy. Pictures were taken of the theca layer of secondary, small (<3000μm), and large (>3000μm) antral follicles and corpora lutea at 100× magnification. ImageJ software was used to analyze the surface area and expression intensity of each protein at each stage, known as the staining index. Overall, our data showed that LH/CG-R, perilipin-2, and StAR expression increased in the course of folliculogenesis and luteinization. Similarly, cytochrome P450 11A1, cytochrome P450c17, 3 beta-hydroxysteroid dehydrogenase/delta 5 ->4-isomerase type 1, and 3 beta-hydroxysteroid dehydrogenase/delta 5 ->4-isomerase type 2 expression were substantially elevated in TCs during folliculogenesis, evidenced by their coordinated action in terms of area covered and expression intensity. This study, conducted for the first time on human ovarian tissue, contributes to localizing and quantifying expression of key steroidogenic proteins at both intracellular and tissue levels. These findings may shed new light on pathological conditions involving the human ovary, such as androgen-secreting tumors of the ovary and other disorders associated with ovarian TCs in patients with polycystic ovary syndrome.

Androgen-secreting adrenal tumor with hypertension and lack of virilization signs: A clinical case

Androgen-secreting adrenal tumor with hypertension and lack of virilization signs: A clinical case

SAT-289 An Unusual Virilizing Ovarian Tumor in Adolescence

Background: The etiology of hyperandrogenism in adolescent females includes polycystic ovarian syndrome, non-classical congenital adrenal hyperplasia (CAH), Cushing’s syndrome, androgen-secreting tumors (adrenal or ovarian) or exogenous use. Ovarian tumors producing androgens comprise <5% of all ovarian neoplasms and usually originate from sex cord stromal cells. There are sporadic case reports of mature cystic teratomas (MCTs), a type of germ cell tumor, causing hyperandrogenism in women but only two reported cases of virilizing MCTs in adolescent girls (1, 2). We present a third case of this nature. Case presentation: A 17-year old girl with no past medical history presented with worsening abdominal distension and discomfort. She was also noted to have excessive thick facial hair which she stated had been present throughout adolescence. She reported recent irregularity in her menstrual periods. She had no history genital abnormalities at birth or premature adrenarche, thelarche or menarche. She denied using anabolic steroids or other medications. Family history was negative for CAH or sudden infant death. On examination, there was significant abdominal distension, terminal hair over the chin, upper lip, side-burns and abdomen, as well as severe clitoromegaly with prominent glans measuring 3cm x 1.5cm, but no evidence of acanthosis nigricans. Chemistry showed testosterone of 178.3 ng/dL (3.75 - 49.57 ng/dL), DHEA-S of 550.4 mcg/dL (150.0 - 590.0 mcg/dL) and 17-hydroxyprogesterone of 224.7 ng/dL (26 - 325 ng/dL). Her abdomino-pelvic ultrasound and CT scan showed a 35.5 cm cystic mass with focal fatty components and dystrophic calcifications suggestive of MCT. Adrenal glands were normal. The patient underwent an exploratory laparotomy with left salpingo-oopherectomy and right cystectomy. Preliminary pathology results showed bilateral MCTs. Two weeks post-operatively, testosterone level decreased to 32.5 ng/dL. Conclusion: Given the normalization of testosterone after surgery, the bilateral MCTs are the suspected source of the patient’s androgen excess. MCTs are the most common ovarian neoplasm in adolescent females, but they are an exceedingly rare cause of hyperandrogenemia. They can be slow-growing and local manifestations may not present until years later. However, testosterone-secreting MCTs may be brought to a physician’s attention due to signs of virilization. A multidisciplinary approach with primary care physicians, endocrinologists, gynecologists and pathologists is needed to make an accurate diagnosis in a timely manner.

Gonadotropin-dependent pubertal disorders are common in patients with virilizing adrenocortical tumors in childhood.

ObjectiveTo investigate the impact of early exposure to androgen excess on gonadotropin-dependent puberty (GDP) and final height (FH) of patients with androgen-secreting adrenocortical tumors (ACT) in childhood.MethodsRetrospective cohort study. Occurrence of GDP and achievement of FH were evaluated. Central precocious puberty (CPP) and early fast puberty (EFP) were considered pubertal disorders. Patients with normal puberty and pubertal disorders were compared.ResultsThe study included 63 patients (44F), followed in a single institution from 1975 until 2017. At diagnosis of ACT, median age was 25.8 months; duration of signs, 6 months; stature SDS, 0.5 (−3.6 to 3.9) and bone age advancement, 14.7 months (−27.9 to 85.4). To date, 37 patients developed GDP: 26 had normal puberty; one, precocious thelarche; seven, CPP and three, EFP. GnRHa effectively treated CPP/EFP. Tall stature and older age at diagnosis of ACT were associated with risk of CPP alone (RR 4.17 (95% CI 1.17–14.80)) and CPP/EFP (RR 3.0 (95% CI 1.04–8.65)). Recurrence/metastasis during follow-up were associated with risk of CPP alone (RR 4.17 (95% CI 1.17–14.80)) and CPP/EFP (RR 3.0 (95% CI 1.12–8.02)). Among the 19 patients that reached FH, stature SDS dropped from 1.4 to −0.02 since diagnosis of ACT (P = 0.01). Seventeen achieved normal FH. There was no difference in FH SDS between patients with normal puberty and pubertal disorders (P = 0.75).ConclusionsGonadotropin-dependent pubertal disorders are common in patients with androgen-secreting ACT in childhood. FH is usually not impaired. The study reinforces the importance of close follow-up after surgery to identify and treat consequences of early exposure to androgen excess.

A rare case of pure testosterone-secreting adrenal adenoma in a postmenopausal elderly woman

BackgroundHyperandrogenemia is more common in puberty and reproductive age, but relatively rare in postmenopausal women. Postmenopausal virilization may result from androgen-producing tumors. Androgen-secreting adrenal tumors are rare in clinical practice and are diagnosed as adrenocortical carcinoma, most of which can co-secrete androgen and cortisol. Highly elevated serum testosterone level with normal adrenal androgens such as dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS) and androstenedione is usually regarded as ovary origin. Here we describe an unusual case of a postmenopausal woman with markedly elevated serum testosterone level, while DHEAS, androstenedione, 17-hydroxyprogesterone and cortisol were within the normal range.Case presentationA 67-year-old postmenopausal woman with hirsutism in the upper lip and armpit, accompanied by clitoromegaly for 5 months. Hormonal evaluation showed markedly elevated serum testosterone level (714.8 ng/ml), whereas DHEAS, androstenedione, 17-hydroxyprogesterone, and cortisol were within the normal range. Imaging examination showed a mass of 1.5 cm in diameter in the left adrenal gland and normal appearance of both ovaries. PET-CT indicated that it was a case of benign adrenal adenoma and excluded ovarian abnormalities and other ectopic tumors. Thus, a pure testosterone-secreting adrenal tumor was suspected and then adrenalectomy was performed. Histology and immunohistochemistry furtherly confirmed the benign adrenocortical adenoma with immunohistochemistry positive for inhibin α, melan A, β-captenin, SYN (focal), Ki-67(< 3%), and negative for chromogranin (CgA), cytokeratin (CK), S-100, P53. After surgery, the level of testosterone returned to normal range and the clinical symptoms also subsided.ConclusionsPure testosterone-secreting adrenal adenomas are extremely rare, but it can induce severe hyperandrogenism and virilization. The source identification of hyperandrogenemia only based on the levels of testosterone, DHEAS and androstenedione is limited. It is important to evaluate not only ovaries but also adrenals in all women with virilization particularly during menopause, even their androstenedione, DHEA and DHEAS level are normal.