Luteoma of Pregnancy Associated with Nearly Complete Virilization of Genetically Female Twins

ObjectiveTo describe a pregnancy that was complicated by the virilization of the mother and two 46XX infants.MethodsWe outline the clinical presentation and diagnosis of the virilization of a mother and her twins, reviewing pertinent literature.ResultsWe report the case of a 40-year-old Caucasian female who conceived a trichorionic triplet pregnancy through in vitro fertilization (IVF) but underwent cytoreduction at 13 weeks of gestation, leaving a diamniotic dichorionic twin pregnancy. At 16 weeks of gestation the mother experienced increasing acne, facial hair, and deepening of her voice. Due to preeclampsia, the twins were delivered via caesarean section at 33 weeks of gestation. The infants had male-appearing external genitalia (Prader score IV-V) but no palpable gonads. Congenital adrenal hyperplasia was ruled out for both twins and they were both found to have a uterus and a 46XX karyotype. Maternal testosterone level was elevated at birth (1,981 ng/dL), but the infants had normal levels. Maternal testosterone levels returned to normal after delivery, consistent with a luteoma of pregnancy, although imaging was negative for a mass.ConclusionThis is the second reported case of complete virilization associated with a luteoma of pregnancy. Whether or not IVF and related procedures increase the risk for a luteoma and whether or not fetal reduction procedures disrupt placental aromatases and increase the risk of virilization in the face of elevated androgen levels are questions that require further research. (Endocr Pract. 2014;20:e18-e23)     

Divergent Gender Identity in Three Siblings With 46Xx Karyotype and Severely Virilizing Congenital Adrenal Hyperplasia Caused by A Novel Cyp11B1 Mutation

ObjectiveTo describe conflicting gender identities in three karyotypically female siblings with congenital adrenal hyperplasia (CAH) caused by a novel mutation in the CYP11B1 gene, who were assigned as males at birth and followed up to adulthood.MethodsWe present 3 siblings (16, 14 and 10 years old) who were born with severe genital virilization and raised as males. Clinical examination showed Prader IV to V external genitalia with a stretched penile length of 7 to 11 cm. Adrenocorticotrophic hormone (ACTH) stimulation test showed a stimulated 11 deoxycortisol (11DOC) level of 12,300-18,700 μg/L (normal 0-5 μg/L). Their karyotypes were 46 XX, and they had normal-sized uterus and ovaries on pelvic ultrasound. DNA was isolated from peripheral leukocytes, and polymerase chain reaction (PCR) and direct sequencing revealed a novel CYP11B1 mutation. This mutation leads to a c.53_54 T insertion (c.53_54insT) with frameshift and truncation at c.115 (codon 39) of CYP11B1.ResultsPsychological evaluation of the oldest sibling suggested a female gender identity, and she declared herself as female, and female sex was re-assigned after 1 year of psychosocial adjustment. Psychological assessment for the 2 younger siblings and a fourth 46XY sibling with the same condition revealed male gender identities, and they continued their lives as males without significant difficulties.ConclusionDivergent gender identity was observed in three severely masculinized 46XX siblings with CAH who carried the same CYP11B1 mutation and had comparable postnatal and probably prenatal androgen exposure and environmental circumstances. These cases suggest that the basis of gender identity is more complex than chromosomal, biochemical, and genetic constitution. (Endocr Pract. 2014;20:e191-e197)     

Adrenocorticotropic Hormone Independent Macronodular Adrenal Hyperplasia due to Aberrant Receptor Expression: Is Medical Treatment Always an Option?

ObjectiveTo investigate the efficacy of medical treatment as an alternative option to bilateral adrenalectomy in patients with cortisol excess due to adrenocorticotropic hormone (ACTH) independent macronodular adrenal hyperplasia (AIMAH).MethodsWe focused on the efficacy of somatostatin analogues in a patient with food-dependent AIMAH and of leuprolide acetate in a patient with AIMAH due to aberrant LH/hCG receptor expression.ResultsTwo female patients with bilateral macronodular adrenal hyperplasia and cortisol excess were evaluated for the presence of aberrant cortisol responses. One patient demonstrated an aberrant response to mixed meal and the other, a menopausal female, to luteinizing hormonereleasing hormone (LHRH) and human chorionic gonadotropin (hCG) administration. In the first patient, subcutaneous octreotide was administered prior to mixed meal and completely abolished food-induced cortisol secretion. Thus, the patient was treated with the long-acting somatostatin analogue octreotide long-acting release (LAR) for 3 months. There was no control of cortisol excess upon reevaluation and acute subcutaneous octreotide administration prior to meal was no longer effective in blocking food-induced cortisol secretion. The second patient successfully responded to leuprolide acetate and, for 40 months, her cortisol excess remains in long-term control.ConclusionA luteinizing hormone/human chorionic gonadotropin (LH/hCG) responsive patient with AIMAH sustained long-term control of cortisol excess on leuprolide acetate. In contrast, in a meal-responsive patient with apparent gastric inhibitory polypeptide (GIP) dependent AIMAH, did not achieve remission under somatostatin analogues. (Endocr Pract. 2013;19:e77-e82)     

Hyperandrogenism Due to a Testosterone-Secreting Sertoli-Leydig Cell Tumor Associated With a Dehydroepiandrosterone Sulfate-Secreting Adrenal Adenoma in a Postmenopausal Woman: Case Presentation and Review of Literature

ObjectiveTo report a case of hyperandrogenism attributable to the presence of an adrenal adenoma secreting dehydroepiandrosterone sulfate (DHEA-S) and an ovarian Sertoli-Leydig cell tumor secreting testosterone in a postmenopausal woman.MethodsThe laboratory, radiologic, and pathologic findings in our case are described. In addition, the pertinent literature is reviewed.ResultsA 56-year-old woman presented with a history of gradual increase in facial and body hair, scalp hair loss, male pattern baldness, and deepening of her voice, beginning a few years after spontaneous menopause at age 49 years. She had hypertension, obesity, and type 2 diabetes mellitus. Laboratory tests showed elevated levels of total testosterone (348 ng/dL) and DHEA-S (2,058 μg/dL), and a left adrenal tumor (3 by 4 cm) was detected on abdominal computed tomographic scan. Laparoscopic left adrenalectomy was performed, and the pathologic diagnosis was adrenal adenoma. The DHEA-S returned to normal levels, but the serum testosterone concentration remained elevated. Transvaginal ultrasonography disclosed an ovarian tumor. Bilateral oophorectomy was performed, and an ovarian Sertoli-Leydig cell tumor was diagnosed. The hormonal and clinical picture normalized after this surgical intervention.ConclusionAfter extensive review of the literature, we believe that this is the first reported case of a coincidental DHEA-S-secreting adrenal adenoma and a testosterone-secreting ovarian Leydig cell tumor causing signs of virilization. (Endocr Pract. 2009;15:149-152)     

Adrenal Cortical Carcinoma With Late Pulmonary Metastases Causing Clinicical Cushing’s Syndrome: Case Report With Immunohistochemical Analysis Of Steriodogenic Enzyme Production

ObjectiveTo present a case of pulmonary metastases from adrenocortical carcinomas (ACC) that were secreting fully-functional cortisol resulting in clinical Cushing’s syndrome and to compare the steroidogenic enzyme expression in the primary tumor and lung.MethodsWe analyzed and summarized the patient’s medical history, physical examination results, labora tory data, imaging studies, and histopathologic results. The original tumor and the pulmonary metastases were then immunohistochemically evaluated for steroidogenic enzymes.ResultsInitial endocrinological workup revealed hyperandrogenism and adrenocorticotropic hormone (ACTH) independent Cushing’s due to a 4 cm left adrenal mass. The patient was initially diagnosed with an adrenal adenoma. Four years later, the patient developed recurrent Cushing’s syndrome. Repeat magnetic resonance imaging (MRI) showed no adrenal masses; however, chest computed tomography (CT) showed multiple bilateral lung nodules and biopsy revealed metastases of adrenal origin. Upon immunohistochemical analysis, side chain cleavage, 17α hydroxylase, 3β hydroxysteroid dehydrogenase, and 21 hydroxylase immunoreactivity were detected in both the original and pulmonary metastatic lesions with patterns of disorganized steroidogenesis. Dehydroepiandrosterone sulfotransferase (DHEA-ST) immunoreactivity was detected in the original tumor but not in the lung metastases.ConclusionThis case demonstrates some inter esting features of ACC that pose challenges to its management, including the difficulties in establishing the pathologic diagnosis, the potential for fullyfunctional steroidogenesis even in late metastases, and the plasticity of steroidogenic potential in tumor cells. (Endocr Pract. 2012;18:e138-e143)     

Deoxycorticosterone-Producing Adenoma Concomitant with Aldosterone-Producing Microadenoma: A Challenging Combination

ObjectiveTo describe the challenging case of a 59-year-old male with a deoxycorticosterone (DOC)-producing adrenal adenoma concomitant with an aldosterone-producing microadenoma.MethodsWe measured the patient’s aldosterone and progesterone levels during adrenal venous sampling (AVS). The steroidogenic enzyme expression was studied with in situ hybridization (ISH). Steroids profiles were determined in the peripheral serum obtained before and after the operation, as well as in the main adrenal tumor.ResultsThe patient was diagnosed with primary aldosteronism (PA) based on typical clinical findings. He had an adrenal tumor located at the lower pole of the left adrenal gland. The aldosterone concentration in the adrenal vein proximal to the adrenal tumor was higher than that of the ipsilateral adrenal vein distal to the tumor during the AVS. Progesterone was only elevated in the adrenal vein proximal to the tumor, suggesting that the tumor produced steroids other than aldosterone. The postoperative findings revealed that the main tumor was accompanied by 2 microadenomas. The main adrenal tumor was diagnosed as a DOC-producing adenoma, and one of the microadenomas was diagnosed as aldosterone-producing based on the ISH and the determination of the steroid profiles.ConclusionsConcomitant PA masked the key findings of a DOC-producing tumor; the suppression of aldosterone in this patient. Multiple sampling in the adrenal vein considering the location of the adrenal tumor provided a clue to the diagnosis. Progesterone measurement during AVS is easy and may be useful in diagnosing rare adrenal tumors that produce intermediate products in adrenal steroid biosynthesis. (Endocr Pract. 2014;20:e171-e175)     

Proteome analysis of adrenal cortical tumors

Introduction: Adrenal tumor is a relatively common tumor. The discrimination between adrenal cortical adenoma (ACA) and adrenal cortical carcinoma (ACC) is crucial as these two diseases have distinct prognosis. ACA is a benign tumor curable by surgical excision, while the prognosis of ACC is extremely poor, with a 5-year mortality of 75–90%. Therefore, previous proteomic studies focused on markers allowing the differentiation between ACA and ACC.

Areas covered: Several proteomic approaches based on the analysis of various samples such as human tissues, urine, and cell lines. In this review, we focused on proteomic studies performed to improve adrenal tumor diagnosis and identify ACC therapeutic targets.

Expert commentary: The rapid development of cancer genomics provided a lot of information, which affects functional proteomics. In practice, differentially expressed proteins between ACA and ACC have been suggested in several proteomic studies and had a biologic implication in ACC.     

Transformation of a Pituitary Macroadenoma into to a Corticotropin-Secreting Carcinoma Over 16 Years

ObjectiveTo describe a case of a pituitary macroadenoma that differentiated into a corticotropin (ACTH)-secreting carcinoma with metastasis to the thigh.MethodsWe present a case report with a 16-year follow-up that includes anatomic and endocrine documentation of the history of an ACTH-secreting carcinoma.ResultsA 32-year-old woman presented for evaluation in 1989 because of visual feld defects. Magnetic resonance imaging revealed a locally invasive 3-cm macroadenoma. She had no clinical signs of cortisol excess. The patient underwent surgical debulking followed by a course of radiation directed to the pituitary. Results from retrospective immunohistochemical staining with antibodies against ACTH, prolactin, and MIB-1 were negative. Postoperatively, she could not be weaned from exogenous steroids without developing symptoms of adrenal insuffciency. In 1995, she developed left facial palsy and diplopia caused by tumor growth. In 1997, the patient developed progressive symptoms of cortisol excess, which continued after exogenous steroid replacement was discontinued. The patient’s clinical status continued to deteriorate because of local mass effect from tumor growth and uncontrolled hypercortisolism. She underwent bilateral adrenalectomy in 2003. The patient remained debilitated in a long-term care facility for 2 years when she was found to have a mass on her left hip. Biopsy results of the obturator muscle revealed metastatic tumor of neuroendocrine origin with strong reactivity to ACTH antibodies and MIB-1 labeling in 8% of tumor cell nuclei.ConclusionA pituitary tumor can transform into an ACTH-secreting carcinoma in an indolent manner. Patients with invasive pituitary adenomas require long-term surveillance to monitor for differentiation into pituitary carcinoma. (Endocr Pract. 2007;13:463-471)     

A child with a 21-ring chromosome, 45,XX,21-/46,XX,21r investigated with the banding technique

Summary Chromosomal analysis of lymphocytes and fibroblasts in a slightly retarded 7-month-old female infant with some minor malformations showed a mosaicism 45,XX,G-/46,XX,Gr. The ring chromosome was identified as No. 21 by banding technique.

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Zusammenfassung Chromosomenuntersuchungen an Lymphocyten und Fibroblasten bei einem 7 Monate alten Mädchen mit leichter statomotorischer Entwicklungsverzögerung und degenerativen Stigmata zeigten ein Mosaik 45,XX,G-/46,XX,Gr. Durch die Bandentechnik mit Trypsinbehandlung konnte das Ringchromosom als Nr.21 identifiziert werden.

     

Extraovarian steroid cell tumor 'not otherwise specified' as a rare cause of virilization in twelve-year-old girl.

BACKGROUND: We present a 12-year-old girl with a 5-year history of progressive virilization. RESULTS: Regarding elevated plasma levels of 17-hydroxyprogesterone (17-OHP) and androgens, normal ultrasound and CT scan of ovaries and adrenal glands, the nonclassic form of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency was presumed the cause of virilization. As the glucocorticoid therapy did not normalize high levels of 17-OHP and androgens, and the DNA analysis did not demonstrate a mutation causing CAH, a laparotomy was performed. Near the right ovary a tumor was found and extirpated. Pathohistological studies determined it to be a rare steroid cell tumor, 'not otherwise specified'. Within the next months the signs of virilization resolved and menarche occurred. CONCLUSIONS: Steroid cell tumor should be considered in differential diagnosis of virilization in childhood. Regarding the age of our patient and pathohistological findings of the tumor, her prognosis is favorable.     

Corticotropin-Independent Cushing Syndrome in a Child With an Ovarian Tumor Misdiagnosed as Nonclassic Congenital Adrenal Hyperplasia

ObjectiveTo describe a patient with corticotropinindependent Cushing syndrome previously diagnosed and treated as congenital adrenal hyperplasia (CAH).MethodsWe describe the initial manifestations, clinical investigations, and postoperative follow-up of the patient and review similar cases in the literature.ResultsA 5 and 9/12-year-old girl who was initially diagnosed and treated as having CAH and was noncompliant with glucocorticoid therapy presented with weight gain, hypertension, and a mass in the lower abdomen. On physical examination, she was a cushingoid-appearing girl with proximal muscle weakness and notable facial acne. Laboratory findings included elevated serum testosterone, 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, androstenedione, estradiol, and cortisol, as well as elevated urinary cortisol and cortisone. Serum corticotropin was undetectable. She had normal serum electrolytes and plasma renin activity. Computed tomography scan of the abdomen and pelvis showed a cystic mass with a focal enhancing solid component arising from the right ovary, which was subsequently determined to be a steroid cell tumor not otherwise specified.ConclusionAlthough ovarian steroid cell tumors typically secrete gonadal steroids, the rare steroid cell tumors not otherwise specified can secrete both glucocorticoids and gonadal steroids and are an unusual cause of Cushing syndrome. (Endocr Pract. 2008;14:875-879)     

Metformin-Responsive Classic Salt-Losing Congenita L Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency: a Case Report

ObjectiveTo study the effect of adding metformin to standard steroid replacement therapy in a patient with classic salt-losing congenital adrenal hyperplasia due to 21- hydroxylase deficiency with suboptimal biochemical and clinical control.MethodsWe present the clinical and laboratory findings before and after the addition of metformin to the therapeutic regimen of the study patient.ResultsA 17-year-old girl had been diagnosed as a neonate with classic salt-losing congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (CYP21A2 deficiency). She was treated with hydrocortisone, 20 mg in the morning and 10 mg at bedtime, and fludrocortisone, 50 mcg daily. While on steroid replacement, she maintained normal serum electrolytes, glucose, blood pressure, and external genitalia, but she continued to express clinical features of obesity, hirsutism, amenorrhea, and acanthosis nigricans. Elevated laboratory measurements included the following: fasting 17-hydroxyprogesterone, 3410 ng/dL; total testosterone, 326 ng/dL; and androstenedione, 390 ng/dL. She was initiated on metformin, 500 mg twice daily after meals. After 3 months, the patient lost 2 kg, amenorrhea resolved, 17-hydroxyprogesterone decreased to 1539 ng/dL, total testosterone decreased to 163 ng/dL, and androstenedione levels remained unchanged.ConclusionsMetformin, an agent known to reduce insulin resistance, further suppressed the 17-hydroxyprogesterone concentration in a patient with classic congenital adrenal hyperplasia on steroid replacement therapy. Metformin may improve clinical and biochemical outcomes in classic congenital adrenal hyperplasia without the risk of iatrogenic Cushing syndrome. (Endocr Pract. 2008;14:889-891)     

Bilateral Ovary Adrenal Rest Tumor in a Congenital Adrenal Hyperplasia Following Adrenalectomy

Objective:In contrast to the high incidence of testicular adrenal rest tumors in adult male patients with congenital adrenal hyperplasia (CAH), ovarian adrenal rest tumors (OARTs) in female CAH patients are rare. In this case report, we describe a case of bilateral OART in a female patient with CAH due to 21-hydroxylase deficiency.Methods:We present a detailed case report with the clinical, imaging, and laboratory findings of the patient. The pertinent literature is also reviewed.Results:A 17-year-old patient was known to have CAH due to 21-hydroxylase deficiency. Since the second month of her gestational age, her mother was treated with cortisone-replacement therapy. The patient was treated with hydrocortisone and fludrocortisone since the neonatal period. Her pertinent history included a bilateral adrenalectomy at the age of 13 years in 2006, and for 3 years she led a normal puberty life with no complaint with hormonal replacement therapy. Nevertheless, in 2009, she developed a virilizing syndrome. Subsequently, she underwent surgery in December 2009 for right adnexectomy. However, the regression of the masculinizing mass was not complete and worsened several months after the surgery. A new pelvic magnetic resonance image showed the activation of a contralateral ovarian mass, necessitating a left adnexectomy in August 2010.Conclusion:This case demonstrates some interesting features of OART that pose challenges to its management. If an OART is detected early enough and glucocorticoid therapy is received, it is possible that the OART will decrease in size following suppression of adrenocorticotropic hormone levels. (Endocr Pract. 2014;20:e69-e74)     

Insulinoma in a Young Female Patient With Systemic Lupus Erythematosus: A Case Report

ObjectiveFasting hypoglycemia may occur in subjects with systemic lupus erythematosus (SLE) when accompanied with insulin-binding antibodies or insulin-receptor antibodies. However, insulinoma has not been reported in SLE subjects with hypoglycemia.MethodsWe present a case report and review the relevant literature.ResultsA 26-year-old female with underlying SLE experienced several episodes of neuropsychiatric symptoms in a fasting state. The steroid dosage was titrated up, but in vain. Timely imaging studies showed a pancreatic tumor, and insulinoma was proven by pathology. Hypoglycemia did not recur after surgery.ConclusionPhysicians should distinguish insulinoma from autoimmunity-mediated hypoglycemia in SLE patients with fasting hypoglycemia. (Endocr Pract. 2014; 20:e256-e259)     

Ovarian Hilus-Cell Hyperplasia and High Serum Testosterone in a Patient With Postmenopausal Virilization

ObjectiveTo describe a woman with postmenopausal virilization and hirsutism caused by hilus-cell hyperplasia.MethodsWe present a case report including laboratory, radiographic, and pathologic findings in a patient with postmenopausal hirsutism and virilization caused by ovarian hilus-cell hyperplasia as well as a brief review of the literature.ResultsA 60-year-old postmenopausal woman presented with extensive hirsutism, male-pattern hair loss, and clitoromegaly. The patient’s plasma testosterone levels were very high, but computed tomography showed the adrenal glands to be normal in size. Pelvic ultrasonography revealed a cystic lesion in the left ovary. After bilateral salpingo-oophorectomy, histologic examination demonstrated a diffuse pattern of hilus-cell hyperplasia in the ovarian hilum.ConclusionIn the differential diagnosis of postmenopausal virilization, hilus-cell hyperplasia, although rare, should be considered.     

Role of the inhibin/activin system and luteinizing hormone in adrenocortical tumorigenesis.

Adrenal masses are one of the most common endocrine tumors diagnosed. Although most adrenal tumors are inactive adenomas, a considerable proportion is associated with hormonal hyperfunction and/or malignancy. The adrenocortical carcinoma (ACC) is a rare but highly malignant tumor. Most ACCs in adults are diagnosed in an advanced tumor stage limiting therapeutic options. Accordingly, despite some progress in diagnostic and therapeutic approaches, the overall survival rate of patients with ACC remains poor. However, the prerequisite for the development of new diagnostic tools and therapeutic options in the management of patients with ACC is the elucidation of the molecular pathogenesis of adrenal tumorigenesis. Although our understanding of adrenal tumor biology has increased substantially over the last decades, the regulation of many molecular pathways involved in adrenocortical growth and differentiation awaits further elucidation. Luteinizing hormone (LH) and activin have only recently emerged as hormones likely to play opposite roles in adrenocortical hormone secretion and cellular proliferation. Recent evidence from studies on human surgical tumor sample expression and detailed characterization of murine adrenal tumor models suggests stimulatory effects of LH on adrenocortical growth and function. On the contrary, activin, which plays a critical role as a paracrine and autocrine factor regulating cellular growth and differentiation, has been demonstrated to induce apoptosis and suppress proliferation in the human and murine adrenal cortex. In this review, we will summarize molecular and functional aspects of adrenal tumorigenesis and highlight some prospects for future clinical applications.     

Identification of luteinizing hormone-releasing factor and alpha-subunit of glycoprotein hormones in human pancreatic islets

Using an immunoperoxidase technique, staining of human pancreatic islets was observed with antisera to luteinizing hormone-releasing factor (LRF) and to the glycoprotein hormones hCG, LH and the alpha-subunit. Treatment of fixed tissue sections with protease inhibitors or heat did not affect the staining indicating that the positive results were not a non-specific effect of protease activity in vitro. No staining was observed in the islets with antisera against the beta-subunit of LH, FSH or hCG suggesting that the material which stained was free alpha-subunit rather than native hormone. The association of LRF and alpha-subunit in human pancreatic islets raises the possibility of a functional relationship between the two in this site.     

Sustained Remission with the Kinase Inhibitor Sorafenib in Stage IV Metastatic Adrenocortical Carcinoma

ObjectiveTo report our experience using kinase in- hibition therapy with sorafenib in a patient with advanced adrenocortical carcinoma.MethodsWe describe the clinical,laboratory, and ra- diologic findings of the study patient and discuss the clini- cal course with sorafenib therapy.ResultsA 56-year-old woman presented with rapid development of virilization, cushingoid features, hyper- tension, weight gain, and abdominal distension. An 8-cm left adrenal lesion was found on computed tomography, re- moved surgically, and confirmed as adrenal carcinoma on pathologic examination. Postoperative scanning revealed metastases to both lungs and the liver that were confirmed by fine-needle biopsy, thus establishing stage IV disease. Treatment with the adrenolytic agent mitotane failed to halt disease progression. A trial of sorafenib resulted in regres- sion and eventual resolution of bilateral metastatic lung lesions, reduction in size of the hepatic lesion, normaliza- tion of androgen hypersecretion, and marked clinical im- provement. The radiologic and biochemical remission on sorafenib has continued for 28 months.ConclusionMultiple kinase inhibitors such as sorafenib provide targeted oncologic treatment and may be effective in treating advanced adrenal cancer. (Endocr Pract. 2010;16:441-445)