OBJECTIVE To present a case of concomitant secretion of cortisol, androgens, and 11-deoxycorticosterone (DOC) by an adrenocortical carcinoma and review the literature in an attempt to identify similar cases. METHODS The patient's medical history, physical examination, laboratory data, computed tomographic scan, and histopathologic results were analyzed and summarized in a case report, and an extensive review of the literature was performed. RESULTS Endocrinologic data showed excess cortisol production, substantially elevated testosterone and androstenedione levels, and profoundly increased DOC in the setting of suppressed aldosterone. An abdominal computed tomographic scan showed a left adrenal tumor. A left adrenalectomy was performed, and the histopathologic diagnosis was stage II adrenocortical carcinoma. The review of the pertinent literature revealed the absence of any identical cases in the past. CONCLUSION Our patient presented with a rare case of cosecretion of cortisol, testosterone, androstenedione, and DOC by an adrenocortical carcinoma, resulting in a clinical picture consistent with Cushing's syndrome, hyperandrogenism, and primary hypermineralocorticoidism. We recommend the routine performance of a DOC assay in the setting of mineralocorticoid excess in association with low plasma aldosterone levels.

Objective To present a case of pulmonary metastases from adrenocortical carcinoma that were secreting fully functional cortisol resulting in clinical Cushing's syndrome and to compare the steroidogenic enzyme expression in primary and lung.Methods Our patient's medical history, physical examination, laboratory data, imaging studies and histopathologic results were analyzed and summarized in a case report. The original tumor and the pulmonary metastases were then immunohistochemically evaluated for steroidogenic enzymes.Results Initial endocrinological workup revealed hyperandrogenism and 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 MRI showed no adrenal masses. However, chest 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 immunoreactivity was detected in the original tumor but not in the lung metastases.Conclusion This case demonstrates some interesting features of ACC that pose challenges to its management, including the difficulties in establishing the pathological diagnosis, the potential for fully functional steroidogenesis even in late metastases, and the plasticity of steroidogenic potential in tumor cells.

Nandrolone, an anabolic steroid, slows denervation atrophy of rat muscle, prevents denervation-induced nuclear accumulation of intracellular domain of the Notch receptor (NICD) and elevates expression of Numb. Numb acts as an inhibitor of Notch signaling and promotes myogenic differentiation of satellite cells. Turnover of Numb is regulated by mdm2, an E3 ubiquitin ligase. With these considerations in mind, we investigated the effects of nandrolone on the expression of Numb and mdm2 proteins and determined the effect of mdm2 on nandrolone-induced alterations in Numb protein in C2C12 myoblasts. When C2C12 cells were cultured in a medium favoring differentiation [DMEM containing 2% horse serum (HS)], nandrolone upregulated Numb protein levels in a time-dependent manner and prolonged Numb protein half-life from 10h to 18h. In contrast, nandrolone reduced the expression of mdm2 protein. To determine whether the decreased mdm2 expression induced by nandrolone was responsible for the increased levels and prolonged half-life of Numb protein in this cell line, mdm2-siRNA was employed to inhibit mdm2 expression. Compared to cells transfected with scrambled siRNA (negative control), transfection with mdm2-siRNA increased basal Numb protein expression but abolished the further increase in Numb protein levels by nandrolone. In addition, transfection of mdm2-siRNA mimicked the effect of nandrolone to prolong the half-life of Numb protein. Moreover, when C2C12 cells were forced to over-express mdm2, there was a significant decline in the expression of both basal and inducible Numb protein. Our data suggest that nandrolone, by a novel mechanism for this agent in a muscle cell type, increases Numb protein levels in C2C12 myoblasts by stabilizing Numb protein against degradation, at least in part, via suppression of mdm2 expression.

CONTEXT Cushing's Disease (CD) alters fat distribution, muscle mass, adipokine profile, and cardiovascular risk factors. It is not known whether remission entirely reverses these changes. OBJECTIVES Our objective was to determine whether the adverse body composition and cardiovascular risk profile in CD change after remission. DESIGN, SETTING, AND PATIENTS Fourteen CD patients were studied prospectively: before surgery (active disease) and again postoperatively 6 months after discontinuing oral glucocorticoids (remission). Whole-body magnetic resonance imaging was used to examine lean and fat tissue distributions. OUTCOME MEASURES Body composition (skeletal muscle and fat in the visceral, bone marrow, sc, and inter-muscular compartments) and cardiovascular risk factors (serum insulin, glucose, leptin, high-molecular-weight adiponectin, C-reactive protein, and lipid profile) were measured in active CD and remission (mean 20 months after surgery). RESULTS Remission decreased visceral, pelvic bone marrow, sc (including trunk and limb sc), and total fat; waist circumference; and weight (P < 0.05). Remission altered fat distribution, resulting in decreased visceral/total fat (P = 0.04) and visceral fat/skeletal muscle ratios (P = 0.006). Remission decreased the absolute muscle mass (P = 0.015). Cardiovascular risk factors changed: insulin resistance, leptin, and total cholesterol decreased (P < 0.05), but adiponectin, C-reactive protein, and other lipid measures did not change. CONCLUSIONS CD remission reduced nearly all fat depots and reverted fat to a distribution more consistent with favorable cardiovascular risk but decreased skeletal muscle. Remission improved some but not all cardiovascular risk markers. Remission from CD dramatically improves body composition abnormalities but may still be associated with persistent cardiovascular risk.

CONTEXT Hormonal therapy has been the mainstay of treatment for advanced prostate cancer for over 70 yr. The timing and extent of androgen ablative therapy for earlier stage disease remains controversial. In addition, recent studies demonstrate that so-called "castration-resistant" tumors are still dependent on androgen receptor signaling. PATIENT AND METHODS A 66-yr-old man presented with clinical stage T1C N+ M0 prostate cancer and received primary androgen deprivation therapy. Over the course of the next 17 yr, he was treated with various forms of androgen deprivation therapy, including two newer agents, abiraterone acetate and MDV 3100. A review of the literature was conducted to identify indications, controversies, and new developments regarding hormonal therapy for prostate cancer. CONCLUSIONS Androgen deprivation therapy remains the treatment of choice for metastatic prostate cancer; however, it is not without its adverse effects, and most men with advanced disease eventually develop castration resistance. Newer compounds that more specifically and effectively target androgen and androgen receptor signaling in prostate cancer cells may provide more long-lasting remissions in advanced disease.

The pituitary gland undergoes much anatomic and physiologic variation during pregnancy. Pituitary disease may have a significant impact on a patient prior to conception as well as throughout her pregnancy. It is imperative to provide care to patients affected by pituitary disease with a multidisciplinary approach involving endocrinologists, obstetricians and, when appropriate, neurosurgical care, as this group of disorders can represent a substantial level of morbidity and mortality for both mother and fetus.

Prostate cancer (PCa) bone metastases are a major cause of morbidity and mortality. There are no effective therapies for PCa bone metastases that prolong survival. Prostatic acid phosphatase (PAP) is a secretory protein expressed by PCa cells. We demonstrate that PAP is strongly expressed in PCa bone metastases in 7/7 patients, while prostate-specific antigen (PSA) is only weakly expressed. The human PCa cell line VCaP secretes PAP and induces an osteoblastic reaction in bone similar to that seen in human PCa bone metastases. Coculture of MC3T3 mouse preosteoblast cells with VCaP cells induces MC3T3 cell growth and differentiation as measured by alkaline phosphatase secretion, and this effect is inhibited by addition of the PAP-inhibitor, l-tartrate. Taken together, these data indicate that PAP is expressed in PCa bone metastases and may play a causal role in the osteoblastic phase of the disease.

BACKGROUND Pituitary adenomas are a common cause of endocrinal dysfunction, which comprise 10-20% of all intracranial tumors. Although almost all of them arise within the sella turcica, there are some rare cases in which a pituitary adenoma is located outside the intrasellar region, so it is defined as an ectopic pituitary adenoma (EPA). CASE DESCRIPTION We described a case of a 31-year-old male with a serum prolactin (PRL) value of 240 ng/ml Magnetic resonance imaging (MRI) showed a space-occupying mass within the sphenoid sinus (SS) which partially enhanced by gadolinium. MRI did not reveal any sellar floor defect and an empty sella was detected. As dopamine agonist treatment had failed in lowering the serum PRL level, he underwent surgical treatment. A transsphenoidal approach without opening the sellar floor was performed using an operating microscope and the lesion within the SS was completely removed. CONCLUSION Although intrasphenoidal EPAs are rare findings, the presence of an endocrine disorder related to pituitary hormones, and a space-occupying mass within the SS associated with either a normal sellar pituitary gland or an empty sella must lead us to suspect this diagnosis.

CONTEXT: Unlike pituitary macroadenomas, microadenomas (micros) are not commonly associated with hypopituitarism. In clinical practice, we have observed that patients with ACTH-secreting micros have a higher than expected prevalence of central hypothyroidism (HT), and we speculated that this effect might be due to glucocorticoid-induced suppression of the hypothalamic-pituitary-thyroid axis. OBJECTIVE: To determine whether there is a difference in the prevalence of central HT among ACTH micros compared to other types of microadenoma, and if so, to investigate whether this is directly related to the degree of hypercortisolism. DESIGN, SETTING, AND PATIENTS: Retrospective study of 149 newly diagnosed patients with pituitary micros: 34 ACTH-secreting, 72 prolactin-secreting (PRLomas), and 43 clinically non-functioning adenomas (NFAs). MAIN OUTCOMES MEASURES: Prevalence of central HT, correlation between normalized free T4 or TSH vs. normalized urinary free cortisol or salivary cortisol. RESULTS: The prevalence of central HT was significantly higher in the ACTH- compared to the non-ACTH adenomas: 18%(ACTH), 1%(PRL) and 0%(NFAs). The mean normalized free T4 was lower in the ACTH micros compared to the non-ACTH micros,(1.29 ± 0.06 vs. 1.50 ± 0.23, p=0.0001). There was no correlation between the degree of hypercortisolism, as reflected by 24 hr urine free cortisol and salivary cortisol, and free T4 or TSH levels among the ACTH adenomas. Similarly, there were no differences in mean UFC or salivary cortisol between ACTH adenomas with and without central HT. Following transsphenoidal adenomectomy, central HT recovered in 3 of 6 patients with ACTH micros. CONCLUSIONS: These findings suggest that patients with ACTH-secreting microadenomas should always, at a minimum, undergo testing for central HT. However, given the potential for recovery of thyroid function following cure of Cushing disease, we recommend withholding thyroid hormone replacement until after pituitary surgery © 2012 Blackwell Publishing Ltd.

OBJECTIVE Extra-ventricular neurocytoma (EVN) is rare, mainly described within the cerebral hemispheres or spinal cord. We report a case of sellar neurocytoma presenting with chiasmal compression. CLINICAL PRESENTATION A 50-year-old woman presented with decreasing vision and a bitemporal field deficit. CT and MRI demonstrated an enhancing invasive sellar lesion extending into the sphenoid sinus and left cavernous sinus, with speckled calcification and compression of the optic chiasm. Pituitary function was normal apart from a mildly elevated prolactin level consistent with stalk effect. INTERVENTION Endoscopic trans-sphenoidal resection of the lesion was performed revealing a firm, vascular tumour. Some residual tumour was left within the left cavernous sinus. Histology revealed a neurocytic tumour with nests, islands and strands of neuropil. Diffuse synaptophysin, chromogranin, neurofilament protein and CD56 positivity was seen. A histological diagnosis of EVN, WHO grade II was made and adjuvant radiotherapy was given for the residual tumour. CONCLUSION This is only the second case of neurocytoma of the sella reported. It should be considered in the differential diagnoses of sellar lesions that appear radiologically atypical for pituitary adenomas.

Pituitary adenomas rarely originate outside the sella turcica. Ectopic locations include the suprasellar region, sphenoid sinus, cavernous sinus and clivus. We describe a 50-year-old female who presented with clinical signs and biochemical evidence of acromegaly. Pituitary MRI demonstrated a 2 mm hypointense lesion on the right side of the pituitary gland. However upon drilling of the upper clival bone to expose the sella during endoscopic transsphenoidal surgery, soft tumor-like tissue was encountered within the clivus. Exploration of the sella, including the area of hypointensity noted on preoperative imaging, did not identify any other abnormality. Immunohistochemical examination of the fully resected tumor demonstrated growth hormone immunoreactivity. Failed preoperative diagnosis of this rare ectopic GH-producing tumor was compounded by the presence of a misleading pituitary abnormality consistent with a microadenoma. The epidemiology and pertinent literature of this uncommon condition is discussed.

The objective of this study was to describe a familial screening for AIP mutations in the context of aggressive prolactinoma in childhood. A 12-year-old boy, presented headaches and bilateral hemianopsia. He had adequate height and weight for his age (50(th) percentile), Tanner stage G1 P1. His bone age was 10 years. Prolactin was 10.560 ng/mL (3-25), FSH and LH were undetectable, IGF-1, TSH, Free T4, ACTH, and cortisol were within normal ranges. MRI showed a pituitary macroadenoma, 5.3 X 4.0 X 3.5 cm with compression of the optic chiasm, bilateral cavernous sinus invasion, encasement of carotids, and extension to clivus. Surgical debulking was performed. Resistance to cabergoline was characterized and he was submitted to two surgeries and radiotherapy. Immunohistochemical evaluation included prolactin, ACTH, GH, FSH, LH,AIP, c-erb B2, Ki-67, and p53. Genomic DNA was isolated from the index case and 48 relatives, PCR and sequencing were performed.A germline A195V mutation in AIP was identified in the index case and in five asymptomatic relatives. Germline mutations in the AIP gene may be involved in the predisposition to pituitary adenoma formation, as cause or co-factor in pathogenesis of aggressive tumors in young patients.

In this article, the present status of neurosurgical operations for Cushing's disease is briefly reviewed. Transsphenoidal surgery is considered the treatment of choice in most patients with Cushing's disease once the diagnosis has been established. In a considerable proportion of patients, even sophisticated imaging does not directly depict the tiny microadenoma. The search for the tumor is technically difficult, particularly when the sella turcica is small, the dura vascularized and the sphenoid sinus poorly pneumatized. Thus, even in expert hands, microadenomas cannot always be identified intraoperatively. Usually, a selective adenomectomy is attempted, preserving pituitary functions. There is a huge variation of surgical outcomes reported. As an estimate, a remission rate of some 75% can be expected 5 years after surgery. Almost all data available to date derive from microsurgical operations. Unfortunately, even in patients who initially remit, recurrences may occur. Low postoperative serum cortisol levels and a long-lasting adrenocortical insufficiency seem to be factors associated with a favorable long-term outcome. When no distinct microadenoma can be identified intraoperatively, partial or even total hypophysectomy has been suggested. However, the outcome of these procedures is less favorable than with selective resections of distinct adenomas. Less than 10% of pituitary adenomas associated with Cushing's disease are macroadenomas. These also bear a less favorable outcome than microadenomas. Only for selected patients with mainly extrasellar tumor localizations are craniotomies recommended. A close cooperation with the endocrinologist is mandatory for a neurosurgeon operating on patients with Cushing's disease, namely for the pre- and perioperative care and for long-term follow-up.

Double pituitary adenomas are rare occurrences in autoptical, surgical and neuroradiological series and are mostly due to non-functioning pituitary adenomas, GH-secreting and prolactin-secreting adenomas. ACTH secreting tumours are more rare and, to our knowledge, two distinct ACTH-producing adenomas within the same pituitary have never been reported. We herewith describe a 56 year old woman with Cushing' s disease due to two clearly distinct ACTH-secreting pituitary adenomas. She presented with signs and symptoms of hypercortisolism and hormonal testing was indicative for pituitary-dependent Cushing' s syndrome. Sellar MRI visualized an asymmetric pituitary gland with suspect lesions in both the right and the left pituitary lobes. Both lesions were removed during transsphenoidal surgery and remission of hypercortisolism ensued. Pathology confirmed the existence of two distinct adenomas located in different sites in the gland. Both presented ACTH immunoreactivity but displayed distinct morphological features. Our case indicates that double ACTH-secreting pituitary adenomas may occur in patients with Cushing' s disease. Careful radiological, surgical and pathological examination is necessary to recognize this condition and avoid surgical failure.

A 77-year-old female presented with a rare cavernous sinus cavernous hemangioma with extension to the sella turcica, neuroradiologically mimicking nonfunctioning pituitary macroadenoma. The lesion was partially removed via transsphenoidal surgery, and the histological diagnosis was cavernous hemangioma. After stereotactic radiosurgery using a cyber knife, the lesion decreased in size. Stereotactic radiosurgery may be a good option for cavernous sinus cavernous hemangioma with high risk of surgical bleeding.

Ectopic pituitary adenomas (EPAs) are rare lesions. The purpose of this study was to describe the CT and MRI features of sphenoid sinus EPAs. Eight patients with histology-proven EPAs in the sphenoid sinus, all of whom underwent CT and MRI, were reviewed retrospectively. The following imaging features were analysed:(i) size,(ii) margin,(iii) CT attenuation characteristics and (iv) MRI signal intensity. In addition, the involvement of adjacent structures and the time-intensity curve (TIC) of dynamic contrast-enhanced (DCE) MRI were analysed. All EPAs had well-defined margins and showed no relationship to the intrasellar pituitary gland. The mean size was 28 mm (range, 20-46 mm). On non-enhanced CT, the lesions appeared isodense to grey matter in 7 (88%) patients and hypodense in 1 (12%) patient. Only two patients underwent post-contrast CT, and they showed moderate enhancement. On T1 weighted images, EPAs appeared isointense in 6 (75%) patients and hypointense in 2 (25%). On T2 weighted images, the lesions appeared hyperintense in 2 (25%) patients and isointense in 6 (75%). EPAs showed mild to moderate heterogeneous contrast enhancement and exhibited a cribriform-like appearance. Two patients underwent DCE MRI; the TIC showed a rapidly enhancing and slow washout pattern. The following features were also seen: an empty sella, bone changes and involvement of the cavernous sinus (5 patients; 62.5%). In conclusion, a high index of suspicion for EPA and a familiarity with the imaging findings may help to diagnose this rare entity accurately.

Adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas are sometimes difficult to visualize, even with high-quality magnetic resonance imaging, due to their small size and variable location. Sampling the cavernous or inferior petrosal sinus is helpful for confirming the central origin of a tumor, but ectopic corticotroph adenomas in the paraseller region also typically exhibit a high central/peripheral plasma ACTH ratio. We experienced an extremely rare case of Cushing's disease caused by an ACTH-secreting microadenoma located entirely inside the left cavernous sinus attached to the medial wall (ectopic pituitary adenoma) that was not visible by preoperative MRI. In this case, the microadenoma was completely removed and an endocrinologic cure was achieved. This case reveals that in addition to meticulous sectioning of the pituitary gland, bilateral periglandular inspection with visualization of the medial wall of the cavernous sinus and of the diaphragm should always be performed to detect ectopic parasellar microadenomas when no adenoma is visible by preoperative MRI.