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BACKGROUND Paraneoplastic hypercalcemia is a well-described complication associated with a variety of malignancies. However, its incidence in gynecological malignancies is low. CASE REPORT A 53-year-old woman presented with progressive abdominal distention and irregular vaginal bleeding of several weeks' duration. A contrast CT abdomen and pelvis was significant for a mass in the lower uterine/cervical region, multiple peritoneal and omental masses, enlarged pelvic and paraaortic lymph nodes, and large-volume ascites. A pelvic exam revealed a fungating vaginal mass, with biopsy showing a high-grade tumor with immunohistochemical staining positive for vimentin, CD10, and cyclin D1, consistent with endometrial stromal sarcoma. During her hospitalization, the patient became increasingly lethargic. Workup showed severe hypercalcemia and evidence of acute kidney injury. The patient did not have evidence of bony metastatic disease on imaging studies. Further laboratory evaluation revealed an elevated PTHrP of 301 pg/mL (nl 14-27), a depressed PTH level of 3 pg/mL (nl 15-65), and a depressed 25-OH vitamin D level of 16 ng/mL (nl 30-100), consistent with humoral hypercalcemia of malignancy. The patient was treated with pamidronate, calcitonin, and intravenous fluids. She eventually required temporary hemodialysis and denosumab for refractory hypercalcemia, which improved her electrolyte abnormalities and clinical status. CONCLUSIONS Uterine malignancies of various histologies are increasingly recognized as a cause of humoral hypercalcemia. They are an important differential diagnosis in a woman with hypercalcemia and abnormal vaginal bleeding or abdominal symptoms., Competing Interests: Conflicts of Interest: None declared

T-cell acute lymphoblastic leukemia (T-ALL) comprises 15% of childhood leukemia. Although multiagent pulse chemotherapy has improved event-free survival in recent decades, the lack of reliable prognosticators and high rate of relapse remain a challenge. Described is a novel discovery of tumor-derived hyperprolactinemia in childhood T-ALL through a case associated with paraneoplastic galactorrhea. Prolactin production by tumor cells, although a rare phenomenon, is previously demonstrated in several adult cancers and 2 pediatric malignancies with unknown implications. This is the first report demonstrating tumor-derived prolactin in pediatric T-ALL and offers potential as a disease marker and therapeutic drug target.

Objective: There are now a large number of requests for N-methyl-D-aspartate receptor autoantibody (NMDAR-Ab) tests, and it is important to assess the clinical relevance of all results, particularly when they are reported as 'Low Positive'., Methods: The clinical data of 56 patients found Positive or Low Positive by the Oxford live cell-based assay were reviewed. An autoimmune basis for the condition was assigned as 'Definite', 'Possible' or 'Unlikely'. The number of core features (encephalopathy, psychiatric, cognitive, epileptic, extrapyramidal and inflammatory cerebrospinal fluid (CSF)) was tabulated., Results: Twenty-five (44.6%) patients had a Definite NMDAR-Ab encephalitis (eight ovarian teratomas, one Hodgkin's lymphoma), 18 (32.1%) a Possible NMDAR-Ab encephalitis and 13 (23.2%) an Unlikely autoimmune syndrome. Serum NMDAR-Ab levels were higher in patients with tumours. Positive NMDAR-Abs were found not only in patients with three or more core features and a Definite syndrome, but also in five patients classified as Possible. Conversely, Low Positive NMDAR-Abs were present in 7 Definite cases as well as in 13 Possible cases. Unlikely patients had mainly Low Positive antibodies and fewer core features. CSF NMDAR-Abs, only available in 11 pairs and at varying time points, broadly related to serum levels and were Positive in 3/3 patients with tumours but in only 2/5 Definite patients, and none of the Possible or Unlikely cases., Interpretation: Using live cell-based assays, Positive and Low Positive antibodies can be of clinical significance. The number of core clinical features should help to select those patients in whom an immunotherapy intervention might be considered, irrespective of the antibody level., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Context: Tumors producing IGF-2 (IGF-2oma) are a major cause of spontaneous hypoglycemia. The treatment mainstay is surgical resection. Many case reports note resolution of hypoglycemia after IGF-2oma resection; however, outcomes are variable according to tumor type. We report a case of resolving hypoglycemia, observed on continuous glucose monitoring, after resection of an IGF-2-producing solitary fibrous tumor of pleura and review the current literature., Case Report: A 69-year-old woman presented with impaired consciousness because of hypoglycemia. An IGF-2oma was diagnosed as the cause for hypoglycemia because of decreased serum insulin and IGF-1, the presence of a pleural tumor, and a high-molecular-weight form of serum IGF-2 detected by Western immunoblot. Surgical resection was performed; pathological examination demonstrated a solitary fibrous tumor with low-grade malignancy. Continuous glucose monitoring showed reversal of hypoglycemia after tumor resection. Approximately 2 years after resection, the patient has no signs of tumor recurrence or hypoglycemia., Conclusions: An IGF-2-producing solitary fibrous tumor of pleura in this case caused hypoglycemia. From a search of the literature of 2004-2014, 32 cases of IGF-2oma with hypoglycemia that underwent radical surgery were identified; in 19 (59%) patients, hypoglycemia was reversed, and there was no subsequent recurrence. The remaining 13 (41%) patients experienced tumor recurrence or metastasis an average of 43 months after initial tumor resection. The tumor of the present case was a low-grade malignancy. Regular follow-up with biomarker monitoring of glucose metabolism and assessment of hypoglycemic symptomatology, in conjunction with imaging tests, is important for detecting possible tumor recurrence and metastasis.

Aim: To examine the impact of surgical normalization of testosterone on body weight and on glucose and lipid metabolism and insulin sensitivity in a group of hyperandrogenic women with ovarian androgen-secreting tumours (OAST)., Methods: Five consecutive postmenopausal hyperandrogenic patients (aged 63 ± 5 years) with a diagnosis of OAST were prospectively evaluated. Clinical signs, symptoms and metabolic and hormonal parameters were collected at the time of the diagnosis and at follow-up, 12 months after surgical oophorectomy. A group of 15 age-matched and body mass index-matched postmenopausal control women served as a reference group., Results: At baseline, patients with OAST had very high testosterone levels and inappropriately low gonadotrophin levels for their menopausal status. All the women were overweight or obese, and one had a history of polycystic ovary syndrome and Type 2 diabetes. Twelve months after surgical oophorectomy, testosterone and gonadotrophin levels returned to appropriate values for menopausal status in all patients; however, no change in body weight was found. Fasting glucose levels slightly increased (P < 0·05) without any significant change in other metabolic parameters. In the woman with diabetes, a moderate decrease in haemoglobin A1c occurred. Red blood cell count and haematocrit values were normalized (P < 0·05, respectively)., Conclusion: Normalization of androgen levels achieved after surgical oophorectomy did not cause any significant change in body weight and insulin sensitivity. These findings may offer a different perspective on the impact of hyperandrogenaemia on metabolism., (© 2012 Blackwell Publishing Ltd.)

A 6-year-old intact female Labrador Retriever had diabetes mellitus, which had been difficult to control with insulin. The dog also had a solid ductal mammary carcinoma with very rapid growth, which was temporally related to onset of hypoglycemia. Eight months after initial diagnosis of diabetes, the dog had a hypoglycemic crisis. Insulin administration was stopped and serum glucose concentration returned to normal. Three months after discontinuing insulin, another hypoglycemic crisis occurred. During subsequent months, serum glucose concentrations remained at life-threatening levels (1.64-2.12 mmol/L, reference interval 4.44-6.66 mmol/L) simultaneously with an increase in the size of the mammary tumor, which reached a diameter of about 16 cm. At the time of surgery for removal of the tumor serum glucose concentration was 2.20 mmol/L and was then monitored every 3 hours after excision of the tumor. The glucose concentration continued to rise and reached 9.99 mmol/L 12 hours after the removal of the mammary tumor. Immunohistochemical staining demonstrated expression of insulin growth factor-2 by tumor cells, which apparently had caused the hypoglycemia during tumor growth even in a diabetic dog. Hyperglycemia associated with diabetes was pronounced after excision of the tumor and had been masked by the paraneoplastic effect of the tumor., (©2010 American Society for Veterinary Clinical Pathology.)

Background: Cushing's Syndrome (CS) which is caused by isolated corticotropin-releasing hormone (CRH) production, rather than adrenocorticotropin (ACTH) production, is extremely rare., Methods: We describe the clinical presentation, course, laboratory values and pathologic findings of a patient with isolated ectopic CRH causing CS. We review the literature of the types of tumors associated with this unusual syndrome and the behavior of these tumors by endocrine testing., Results: A 56 year old woman presented with clinical and laboratory features consistent with ACTH-dependent CS. Pituitary imaging was normal and cortisol did not suppress with a high dose dexamethasone test, consistent with a diagnosis of ectopic ACTH. CT imaging did not reveal any discrete lung lesions but there were mediastinal and abdominal lymphadenopathy and multiple liver lesions suspicious for metastatic disease. Laboratory testing was positive for elevated serum carcinoembryonic antigen and the neuroendocrine marker chromogranin A. Serum markers of carcinoid, medullary thyroid carcinoma, and pheochromocytoma were in the normal range. Because the primary tumor could not be identified by imaging, biopsy of the presumed metastatic liver lesions was performed. Immunohistochemistry was consistent with a neuroendocrine tumor, specifically small cell carcinoma. Immunostaining for ACTH was negative but was strongly positive for CRH and laboratory testing revealed a plasma CRH of 10 pg/ml (normal 0 to 10 pg/ml) which should have been suppressed in the presence of high cortisol., Conclusions: This case illustrates the importance of considering the ectopic production of CRH in the differential diagnosis for presentations of ACTH-dependent Cushing's Syndrome.

We herein describe a patient we encountered in whom mediastinal lymph node metastasis of lung cancer with an unknown primary lesion was complicated by both an endocrine abnormality and acanthosis nigricans. A 66-year-old male visited a local hospital and was diagnosed as having acanthosis nigricans. The patient was referred to our hospital for further examination. Computed tomography scans of the chest and the abdomen showed no adverse findings except for an enlargement of the mediastinal lymph node. No malignant lesions were detected in examinations of the upper gastrointestinal tract. Based on the above findings, the lesion was thus considered to possibly be mediastinal lymph node metastasis of an unknown primary tumor or malignant lymphoma. A thoracoscopic biopsy of the mediastinal lymph node was performed. The patient was diagnosed to have mediastinal lymph node metastasis of lung cancer with an unknown primary lesion and endocrine abnormality resulting from paraneoplastic syndrome. Palliative radiation therapy was initiated to prevent superior vena cava syndrome and esophageal passage failure or dysphagia. The cutaneous lesions markedly improved thereafter. The serum levels of adrenocorticotropic hormone decreased.

Humoral hypercalcemia of malignancy (HHM) is a metabolic phenomenon that is mediated by the paraneoplastic secretion of parathyroid hormone-related peptide (PTHrP). Gynecologic malignant neoplasms complicated by HHM have been reported for organs such as the uterus, cervix, ovary, vulva and the vagina. The purpose of our study was to perform a review of the published cases in the literature and, further, to identify parameters with effect on outcome. Among 34 women with gynecologic neoplasms, 22 suffered from ovarian and 6 from uterine malignancies, while 3 had vulvar and another 3 cervical cancer. Furthermore, clear cell carcinoma was the predominant histology associated with PTH-rP expression. A significant correlation was found between serum calcium and PTH-rP levels. Treatment of hypercalcemia was successful in all cases; pamidronate was utilized in 8 patients. Ovarian cancer patients with severe hypercalcemia and high PTH-rP serum levels had shorter survival compared to their counterparts with mild hypercalcemia or moderately elevated PTH-rP serum levels, but the differences were not statistically significant.

We present an unusual case of a 52-year-old woman with severe, uncontrollable, refractory diarrhea attributable to pancreatic endocrine carcinoma (ECA) with markedly elevated serum vasoactive intestinal polypeptide (VIP) and calcitonin levels. After initial correction of fluid and electrolyte abnormalities, the patient was treated with high-dose octreotide. Shortly thereafter, due to the intractable nature of her diarrhea, she underwent cytoreductive hepatic surgery. The pancreatosplenectomy specimen showed a poorly differentiated ECA of the distal pancreas, immunoreactive for synaptophysin, CD56, and S100 protein, with morphologically similar hepatic and lymph node metastases. Postoperatively, her diarrhea improved, along with decline in serum VIP and calcitonin levels. Systemic chemotherapy with etoposide and cisplatin did not result in any radiographic and biochemical improvement. Having radiologically stable disease with depot-octreotide and short-acting octreotide (Sandostatin), she was subjected to peptide receptor radiotherapy with [177Lu-DOTA0,Tyr]octreotate (LuTate) that resulted in marked clinical and biochemical improvement, along with dramatic reduction in the number and size of hepatic metastases. In summary, this is a unique case of metastatic VIP- and calcitonin-secreting pancreatic ECA with dramatic sustained clinical, biochemical, and objective tumor response to peptide receptor radionuclide therapy.

Endocrine venous sampling plays a specific role in the diagnosis of endocrine disorders. In this article, we cover inferior petrosal sinus sampling, selective parathyroid venous sampling, hepatic venous sampling with arterial stimulation, adrenal venous sampling, and ovarian venous sampling. We review their indications and the scientific evidence justifying these indications in the diagnosis and management of Cushing's syndrome, hyperparathyroidism, pancreatic endocrine tumors, Conn's syndrome, primary hyperaldosteronism, pheochromocytomas, and androgen-secreting ovarian tumors. For each sampling technique, we compare its diagnostic accuracy with that of other imaging techniques and, where possible, look at how it impacts patient management. Finally, we incorporate venous sampling into diagnostic algorithms used at our institution.

Humoral hypercalcemia of malignancy is a common metabolic disturbance associated with solid tumors, but it also occurs in lymphoma patients. Among these, low grade B-cell lymphoma accounts for only few cases, in which secretion of parathyroid hormone-related protein (PTHrP) remains even exceptional. We report the very rare case of a patient with a CLL type low grade leukemic B-cell lymphoma showing PTHrP-related hypercalcemia without evidence of bone lesions. Using immunohistochemistry, we demonstrate the cytoplasmic expression of PTHrP by the lymphoma cells in the bone marrow obtained at the onset of hypercalcemia. We postulate a pathogenetic role of leukemic cell production and secretion of PTHrP in hypercalcemia in low grade leukemic B-cell lymphoma.

Hypothalamic GHRH is secreted into the portal system, binds to specific surface receptors of the somatotroph cell and elicits intracellular signals that modulate pituitary GH synthesis and/or secretion. Moreover, GHRH is synthesized and expressed in multiple extrapituitary tissues. Excessive peripheral production of GHRH by a tumor source would therefore be expected to cause somatotroph cell hyperstimulation, increased GH secretion and eventually pituitary acromegaly. Immunoreactive GHRH is present in several tumors, including carcinoid tumors, pancreatic cell tumors, small cell lung cancers, endometrial tumors, adrenal adenomas, and pheochromocytomas which have been reported to secrete GHRH. Acromegaly in these patients, however, is uncommon. The distinction of pituitary vs. extrapituitary acromegaly is extremely important in planning effective management. Regardless of the cause, GH and IGF-1 are invariably elevated and GH levels fail to suppress (<1 microg/l) after an oral glucose load in all forms of acromegaly. Dynamic pituitary tests are not helpful in distinguishing acromegalic patients with pituitary tumors from those harbouring extrapituitary tumors. Plasma GHRH levels are usually elevated in patients with peripheral GHRH-secreting tumors, and are normal or low in patients with pituitary acromegaly. Unique and unexpected clinical features in an acromegalic patient, including respiratory wheezing or dyspnea, facial flushing, peptic ulcers, or renal stones sometimes are helpful in alerting the physician to diagnosing non pituitary endocrine tumors. If no facility to measure plasma GHRH is available, and in the absence of MRI evidence of pituitary adenoma, a CT scan of the thorax and abdominal ultrasound could be performed to exclude with good approximation the possibility of an ectopic GHRH syndrome. Surgical resection of the tumor secreting ectopic GHRH should be the logical approach to a patient with ectopic GHRH syndrome. Standard chemotherapy directed at GHRH-producing carcinoid tumors is generally unsuccessful in controlling the activated GH axis. Somatostatin analogs provide an effective option for medical management of carcinoid patients, especially those with recurrent disease. In fact, long-acting somatostatin analogs may be able to control not only the ectopic hormonal secretion syndrome, but also, in some instances, tumor growth. Therefore, although cytotoxic chemotherapy, pituitary surgery, or irradiation still remain available therapeutic options, long-acting somatostatin analogs are now preferred as a second-line therapy in patients with carcinoid tumors and ectopic GHRH-syndrome.

A case of erythrocytosis caused by gastric cancer that produced erythropoietin is described. To the authors' knowledge, no case of erythropoietin-producing gastric cancer has been reported until now. A 73-year-old man with a 4-year history of maintenance hemodialysis for diabetic nephropathy required phlebotomy. Serum erythropoietin level was 181 mU/mL (181 IU/L). Gastroscopy results showed rough mucosa with hemorrhaging caused by gastric cancer. The patient underwent distal gastrectomy, and serum erythropoietin level decreased to 27.1 mU/mL (27.1 IU/L) by postoperative day 8. Existence of erythropoietin in the tumor tissue was confirmed immunohistochemically. The presence of severe acquired cystic disease of the kidney, renal cell carcinoma, and other malignant tumors should be investigated in hemodialysis patients displaying erythrocytosis.

Objective: Pituitary tumors causing gigantism are rare in childhood and adolescence. In a review of 2367 patients with pituitary adenomas who were treated between 1970 and 1997, we found 15 cases (0.63%, 9 male and 6 female patients) of growth hormone-secreting pituitary adenomas in patients who were less than 20 years of age at the time of surgery, and we compared their characteristics with those of adenomas in an adult group., Methods: Patients were grouped according to their ages at the first operation, with five patients (33.3%) in the prepubescent group (0-11 yr), eight (53.3%) in the pubescent group (12-17 yr), and two (13.3%) in the postpubescent group (18-19 yr). All 15 patients exhibited the typical symptoms of growth hormone oversecretion. The incidence of hyperprolactinemia among patients with prepubescent onset was 66.7%. Radiological examinations demonstrated microadenomas in 4 patients (26.7%) and macroadenomas in 11 patients (73.3%). The mean follow-up period was 73.5 months., Results: Direct transnasal explorations were performed for all patients. Tumor invasion into the cavernous sinus was observed in six patients (40%). Radical tumor resection was performed for four patients (80%) in the prepubescent group, for five patients (62.5%) in the pubescent group, and for neither patient in the postpubescent group. Surgical morbidity was caused by permanent diabetes insipidus in three patients (20%). Rapid growth was postoperatively improved in 80% of the prepubescent age group. The recurrence rate was 13.3% (2 of 15 patients)., Conclusion: Transnasal pituitary surgery was found to be as safe in pediatric patients with gigantism as in adults. Growth hormone-secreting pituitary adenomas in childhood and adolescence were more likely to be invasive or aggressive than were those in adulthood. The clinical biological characteristics for children were different from those for adults.

Background and Objective: Serum TSH assay is a very sensitive and specific index of thyroid hormone (TH) action. Nevertheless, in particular clinical situations, such as those of inappropriate TSH secretion, the measurement of additional parameters evaluating peripheral TH action may be required in order to achieve a correct diagnosis and to assess the impact that thyroid hormone have on a given tissue. The availability of a specific RIA for serum carboxy-terminal cross-linked telopeptide of type I collagen (ICTP) prompted us to study the usefulness of this specific marker of bone resorption in the differential diagnosis of thyroid disorders., Design: Serum ICTP levels were measured in: (a) 10 patients with TSH-secreting pituitary adenoma (TSH-oma), (b) 40 with thyroid hormone resistance (RTH), as well as in (c) 28 patients with Graves' disease or toxic nodular goitre, (d) 31 with autoimmune primary hypothyroidism (PH) and in 8 of them during L-T4 replacement therapy, (e) 23 with central hypothyroidism (CH) during L-T4 therapy and 2 months after its withdrawal, and (f) 26 during TSH-suppressive treatment for goitre or non-metastatic differentiated thyroid cancer. Results were compared with those obtained in 2 groups of normal controls (Group A, n = 61, age range: 23-68 years; Group B, n = 32, age range: 6-15 years)., Methods: Serum TSH, free T4 (FT4) and free T3 (FT3) were measured by immunofluorometric assays. Serum ICTP was measured by a specific RIA with a sensitivity of 0.5 +/- 0.1 microgram/l, and intra- and interassay coefficients of variation lower than 6%., Results: Mean values of serum ICTP levels in adult controls were 3.8 +/- 1.6 (+/-SD) microgram/l, while in pre- or peri-pubertal controls it was higher than in adults (14.4 +/- 3.1 micrograms/l). Patients with TSH-oma showed significantly increased ICTP levels (8.7 +/- 5.0 micrograms/l, P < 0.001 vs controls), in contrast to those with RTH (3.0 +/- 1.0 micrograms/l, P < 0.02 vs controls). In the differential diagnosis of inappropriate secretion of TSH, ICTP values above 5 micrograms/l strongly indicated the presence of a TSH-oma. Circulating ICTP concentrations were definitely high in thyrotoxic patients (9.4 +/- 4.7 micrograms/l, P < 0.001) and values overlapping the normal range were observed in 8 cases, thus giving to this test a sensitivity and specificity of 71% and 93%, respectively. In contrast, serum ICTP levels in both PH and CH untreated patients were in the normal range, although significantly lower than in controls (2.6 +/- 1.0 and 1.8 +/- 0.7 micrograms/l, P < 0.001). During replacement therapy, ICTP levels rose significantly in both hypothyroid groups (5.1 +/- 2.5 and 2.7 +/- 1.3 micrograms/l). In 2 CH patients, borderline high ICTP levels (7.0 and 7.1 micrograms/l), associated with FT3 concentrations in the upper limit of the normal range, suggested the presence of L-T4 overtreatment; L-T4 dose reduction was followed by the decrease of both indices in a more physiological range (ICTP: 4.2 and 4.7 micrograms/l; FT3: 8.5 and 6.0 pmol/l). In patients treated with TSH-suppressive therapy at the minimal effective dose, ICTP levels did not significantly differ from those observed in adult controls (4.3 +/- 2.0 micrograms/l). The overall correlations between serum ICTP and FT4 or FT3 levels were highly significant (P < 0.001)., Conclusions: The present data indicate that serum type I collagen (ICTP) concentrations are modulated by circulating thyroid hormone concentrations. ICTP measurement is particularly useful in the differential diagnosis of the syndromes of inappropriate TSH secretion, in estimating thyroid hormone impact on bone in primary hyperthyroid states, and its longitudinal evaluation may reveal L-T4 overtreatment in patients on substitutive or TSH-suppressive therapy.

Steroidogenic tumors are derived from cells of male and female reproductive tracts, adrenal glands, central nervous system, and, to a lesser degree, from the liver and pituitary gland. The symptoms caused by these tumors are related to their secretory products. Because enzymatic pathways are shared by both adrenal- and gonadal-derived tissues, and the conversion of some of these steroids occurs in the adipose tissue, positive identification of many lesions cannot be based on peripheral blood hormone levels alone, but require complex protocols to improve diagnostic accuracy. Furthermore, these tumors often are smaller than the size limit of conventional imaging modalities and thus demand more precise imaging techniques. Although diagnosis and localization may be challenging, the rewards of a positive prognosis, with complete reversal of symptoms, are more likely to occur with early detection and treatment. This article is a review of the clinical syndromes associated with pediatric steroidogenic tumors; suggested strategies to facilitate their diagnosis, localization, and treatment are provided.

Thyrotropin (TSH)-secreting pituitary tumors may be found in two opposite clinical situations: the hyperthyroidism secondary to thyrotroph adenomas, also called central hyperthyroidism, and the long-standing primary hypothyroidism which can be accompanied by a compensatory pituitary enlargement. TSH-secreting pituitary adenomas belong to the syndromes of "inappropriate secretion of TSH" (IST). The adjective "inappropriate" indicates the lack of the expected suppression of TSH secretion when free thyroid hormone levels are actually elevated, as in the other forms of thyrotoxicosis. Moreover, TSH-omas have to be differentiated from the non-neoplastic form of IST which is due to resistance to thyroid hormone. Differently, pituitary hyperplasia, which is reversible on thyroid hormone replacement, is the more frequent cause of a pituitary mass occurring in the context of untreated primary hypothyroidism. Failure or delay in the recognition of the above clinical situations may cause dramatic consequences, such as unnecessary pituitary surgery in hypothyroid patients or improper thyroid ablation in those with central hyperthyroidism. In contrast, early diagnosis and proper treatment of TSH-secreting pituitary tumors prevents the appearance of signs and symptoms of mechanical compression of the adjacent structures by the expanding tumor mass (visual field defects, headache and hypopituitarism).

We studied the gonadotropic function in a 25-year-old woman suffering from congenital GH deficiency, complaining of primary amenorrhea and wishing to become pregnant. She disclosed a hypoplasic anterior pituitary within a small sella turcica and an ectopic posterior pituitary lobe located below the median eminence. Immunoreactive LH and FSH plasma levels were normal, basal and in response to a GnRH iv bolus but estradiol was low. LH pulse frequency was elevated and FSH bioactivity was low in a granulosa cell aromatase bioassay. Pulsatile administration of iv GnRH at a slower, normal pace, failed to induce ovulation or to increase FSH bioactivity, with or without concomitant GH replacement. However treatment with exogenous im gonadotropins, when preceeded by GH replacement, succeeded in inducing mature oocytes and pregnancy. We concluded that the hypogonadism observed in this patient was due to rapid GnRH pulsatility and poor biological activity of endogenous FSH.

Prolactin (PRL) Levels are frequently elevated in patients with non-PRL-secreting adenomas or other intrasellar and parasellar diseases ("pseudoprolactinomas"). This phenomenon is believed to result from a loss of dopaminergic inhibition on pituitary lactotrophs and is known as the "stalk-section effect." Using magnetic resonance imaging scans and a high-magnification sella technique, we measured a number of parameters indicative of the disruption of normal sellar structures. The investigator was blind to the patient's diagnosis and PRL level while collecting the data. Parameters measured were the tumor size, the angular deviation of the pituitary stalk, and the degree of compression of the pituitary stalk. Measurements were obtained from 44 patients with pathologically confirmed tumors that had no immunohistochemical reactivity to PRL. PRL levels were often higher than expected. Four patients (9%) had a PRL level of more than 150 ng/ml, and three patients (7%) had a PRL level of 200 ng/ml or more. One patient with a plasmacytoma eroding the sella floor had a PRL level as high as 504 ng/ml. There was no significant correlation of PRL level and the degree of pituitary stalk compression, stalk deviation, or tumor size. PRL levels were found to be markedly elevated in some patients with a tumor causing little distortion of the pituitary stalk. Conversely, PRL levels were often normal despite evidence of massive distortion of the stalk. Therefore, magnetic resonance imaging evidence of pituitary stalk distortion cannot be used to determine the diagnosis of prolactinoma versus pseudoprolactinoma in most cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Craniopharyngioma is the most common childhood tumor to involve the hypothalamus and pituitary. Although endocrine disturbances can be found in 80-90% of patients at presentation, only a minority of subjects seek medical attention for an endocrine-related complaint. Hormonal studies, while limited, indicate GH deficiency in 75% of children; deficiencies of LH/FSH (40%), ACTH (25%) and TSH (25%) also are common. In contrast, diabetes insipidus has been noted in only 9-17% of subjects prior to surgery. When possible, full evaluation of pituitary function should be performed; the minimum preoperative evaluation must include testing for and treatment of ACTH-adrenal insufficiency and diabetes insipidus.

In a case of androgen-producing granulosa cell tumor in a 29-year-old woman with profound virilization, diagnosis by determination of serum hormone levels is described. The removal of the tumor is followed by a normal endocrine profile and pregnancy eight weeks later.

The long-term results of transsphenoidal surgery for hormonally active pituitary adenomas were assessed in 3 follow-up studies. Eight out of 50 patients with microprolactinomas developed a persisting postoperative re-increase of prolactin levels during an average follow-up period of 4.1 years. None of the 43 acromegalic patients who had achieved a suppression of growth hormone to below 2 ng/ml during an oral glucose load shortly after surgery relapsed. However, when the remission criterion was only based on basal growth hormone below 5 ng/ml 4 out of 61 patients showed a re-increase of growth hormone levels to persistently elevated values during an average follow-up period of 6.1 years. 14 out of 66 patients followed-up for an average of 8.2 years after successful primary microadenomectomy for Cushing's disease developed recurrent hypercortisolism as documented by an abnormal suppression of cortisol after oral low dose dexamethasone.

The differential diagnosis of the various forms of inappropriate secretion of TSH (IST), i.e. generalized thyroid hormone resistance (GRTH), selective pituitary resistance [non-neoplastic IST (nnIST)], and tumoral pituitary TSH hypersecretion [neoplastic IST (nIST)], mainly rests on clinical observation, skull imaging, and measurement of several parameters assessing peripheral thyroid hormone effects. Clinically, patients with GRTH usually display compensated hypothyroidism, while those with nnIST or nIST are hyperthyroid. Since sex hormone-binding globulin (SHBG) measurement has been shown to be a reliable parameter in distinguishing between euthyroid and hyperthyroid states, we evaluated serum SHBG levels in 39 patients with IST (7 with GRTH, 15 with nnIST, and 17 with nIST). The results were compared to those in 68 normal subjects, 76 hyperthyroid patients, and 31 hypothyroid patients. SHBG levels in patients with either GRTH or nnIST were similar to those in controls or hypothyroid patients [GRTH, 40.5 +/- 11.8 (+/- SD) nmol/L (range, 26.4-57.5); nnIST, 29.7 +/- 12.8 nmol/L (range, 6.8-46.8); controls, 36.7 +/- 21.7 nmol/L (range, 5.4-96.5); hypothyroid, 30.8 +/- 14.4 nmol/L (range, 10.4-63.3)]. On the contrary, SHBG levels in patients with either overt hyperthyroidism or nIST were significantly higher than those in the above groups [hyperthyroid, 149 +/- 111 nmol/L (range, 48-557); nIST, 99.5 +/- 54.7 nmol/L (range, 21.6-259)]. The apparent overlap of SHBG values between hyperthyroid patients and controls almost completely disappeared when comparisons were made with control groups matched for age and sex. Additional indices of peripheral thyroid hormone action (basal metabolic rate, cardiac systolic time intervals, and Achilles' reflex time) were normal in patients with GRTH, while they were in the hyperthyroid range in patients with nnIST and nIST. After successful treatment of hyperthyroidism, SHBG levels normalized in patients with nIST, but they did not change in patients with nnIST. In conclusion, the measurement of SHBG in patients with IST is useful in differentiating the neoplastic form from that due to thyroid hormone resistance, but it fails to distinguish between generalized and pituitary resistance to thyroid hormone action. Moreover, the present data suggest that the resistance to thyroid hormone action in patients with nnIST is not selective at the thyrotroph cell level, but also involves the hepatic SHBG-synthesizing cells, thus supporting the view that the various forms of thyroid hormone resistance could represent a continuum of the same defect with variable expression in different tissues.

The purpose of this study was to ascertain whether the pituitary-adrenal responses to human corticotropin-releasing hormone (hCRH) in "non-functioning" adrenocortical adenoma would uncover a functional activity in these adrenal nodules. Eleven patients with incidentally discovered "silent" adrenocortical adenoma and eleven controls were studied. The initial clinical and laboratory examination, including an overnight 1 mg dexamethasone suppression test, revealed no abnormalities in any of the subjects. IR-ACTH and serum steroids (F, S, P, 17OHP, 18OHB, and aldosterone) were normal in both controls and patients. After pulse IV injection of 100 micrograms hCRH, the cortisol response was significantly exaggerated (P = 0.01). Stimulated plasma ACTH levels were, however, significantly lower in patients than in controls (P = 0.01), indicating counter-feedback regulation of cortisol. The peak cortisol/peak ACTH ratio (Fmax/ACTHmax) in the patients was significantly elevated (26.8 +/- 4.37 nmol/ng vs. 14.6 +/- 2.16 nmol/ng, P = 0.02). Two further patients with incidentally discovered "pre-Cushing's" adrenocortical adenoma displayed an even higher ratio (43.5 and 45.5 nmol/ng). In established Cushing's syndrome due to an autonomous adrenocortical adenoma, suppression of ACTH and of the ACTH response to hCRH occurs with a very high basal cortisol/basal ACTH ratio. Our findings suggest some functional activity even in clinically "silent" adrenocortical adenoma. Response to hCRH uncovers a continuous spectrum between adrenocortical adenoma, "pre-Cushing's", and Cushing's syndrome.

A 15-yr-old, apparently male, patient presented with a 2-yr history of gynecomastia and poor genital development. A normally formed, but small, penis with a phallic urethra was present, and testes were impalpable. The karyotype was 46,XX, and at laparotomy a uterus, Fallopian tubes, and ovaries were found, but there was no testicular tissue. The mother had had regular periods ever since menarche at 14 yr. She had complained of hirsutism since the birth of the child, and on examination 15 yr later had marked clitoromegaly. Serum androgens were elevated: testosterone, 4.5 nmol/L (normal, 0.5-3); dehydroepiandrosterone sulfate, 18 mumol/L (normal, 3-12); and androstenedione, 35 nmol/L (normal, 3-8). All failed to suppress with dexamethasone. Abdominal computed tomographic scan revealed a 9 X 6-cm mass in the position of the left adrenal gland. This was removed at laparotomy and found to be an adrenocortical tumor. Postoperatively, the androgens returned to normal. Virilization of a female fetus due to androgens secreted by a maternal adrenal tumor has only been described three times previously, and the presentation has never been delayed so long.

Tumors from patients with humoral hypercalcemia of cancer produce a parathyroid hormone-related protein (PTHRP). We have developed two region-specific immunoassays capable of measuring PTHRP in plasma: an immunoradiometric assay directed toward PTHRP amino acid sequence 1 to 74 and a radioimmunoassay directed toward PTHRP amino acid sequence 109 to 138. Sixty normal subjects had low or undetectable plasma PTHRP (1 to 74) concentrations (mean, 1.9 pmol per liter) and undetectable PTHRP (109 to 138) concentrations (less than 2.0 pmol per liter). Patients with humoral hypercalcemia of cancer (n = 30) had elevated levels of both PTHRP (1 to 74) (mean, 20.9 pmol per liter) and PTHRP (109 to 138) (mean, 23.9 pmol per liter). The plasma concentrations of immunoreactive PTHRP correlated with the levels of urinary cyclic AMP excreted; in some patients, the concentrations decreased after the tumors were resected. Patients with chronic renal failure (n = 15) had plasma PTHRP (1 to 74) concentrations similar to those in the normal subjects, but their plasma PTHRP (109 to 138) concentrations were elevated (mean, 29.6 pmol per liter). The levels of both peptides were normal in patients with hyperparathyroidism and those with hypercalcemia due to various other causes. Breast milk contained high concentrations of PTHRP. An anti-PTHRP (1 to 36) immunoaffinity column failed to extract PTHRP (109 to 138) immunoactivity from plasma, suggesting that the C-terminal region circulates as a separate peptide. We conclude that plasma PTHRP concentrations are high in the majority of patients with cancer-associated hypercalcemia and that the circulating forms of PTHRP in such patients include both a large N-terminal (1 to 74) peptide and a C-terminal (109 to 138) peptide. Measuring the concentrations of PTHRPs may be useful in the differential diagnosis of hypercalcemia.

Human choriogonadotropin (hCG) and free hCG-beta values for 934 serum samples from patients with seminomatous or nonseminomatous testicular cancer were measured by highly specific immunoradiometric assays (IRMAS). In non-seminoma samples, hCG and hCG-beta were highly correlated (r = 0.82, P less than 0.001). Of 112 "marker-positive" seminoma samples, only 46 (41.1%) showed both increased hCG and hCG-beta. In 39 cases (34.8%) only hCG-beta and in 27 cases (24.1%) only dimer-hCG was increased. This makes the determination of hCG and hCG-beta, either by two assays or by a single hCG (+hCG-beta) assay, most reliable in these patients. For all samples, hCG (+hCG-beta) was measured by a polyclonal RIA and a monoclonal IRMA, which differed in their cross-reactivities with hCG-beta (234% and 720%, respectively). The hCG (+hCG-beta) IRMA, as a result of its higher hCG-beta cross-reactivity, was superior to the hCG (+hCG-beta) RIA in detecting slightly increased hCG-beta. Additionally, 11 widely used commercial hCG kits were tested for their hCG-beta cross-reactivities and showed values between less than 3% and 264%.

There is only one previous report of an estrogen-secreting adrenal tumor occurring in a woman during reproductive years. Our patient presented with mild hirsutism associated with menstrual bleeding every 3-6 weeks. The occurrence of apparently intermenstrual bleeding prompted an evaluation of estrogen levels. Markedly elevated plasma estrone levels were found (860-2305 pmol/L; normal, 50-340). Lesser relative elevations in 11-deoxycortisol and androstenedione were noted. Computed tomographic scanning of the adrenal glands identified a large tumor, which was subsequently resected. Estrone levels fell to 120 pmol/L, and all other abnormalities were corrected. Eighteen months after adrenalectomy, ovulation occurred regularly, and steroid levels were entirely normal. Steroid production in a cell suspension made from tissue obtained from the 190-g tumor was compared with that occurring in normal human adrenal cells. The production of estrone by the tumor cells was 40-fold greater than that by normal adrenal cells. There was also a mild excess of 11-deoxycortisol produced by tumor cells, but the tumor cells were less than 50% as efficient as normal cells in producing cortisol, dehydroepiandrosterone, androstenedione, testosterone, and dehydroepiandrosterone sulfate. Examination of the steroid profile in plasma occurring in three other patients with adrenal tumors reveals that while elevations in estrone occur frequently, this is usually due to the peripheral conversion of very high levels of androstenedione. Estrone, androstenedione, and 11-deoxycortisol plasma levels were elevated in all four patients; dehydroepiandrosterone sulfate was elevated in only two of four patients. After resection of one of these tumors, all steroid levels remained normal despite the occurrence of extensive metastases. These observations confirm the difficulty of making a diagnosis of estrogen excess in a woman during reproductive years because of the paucity of physical signs. The acquisition of aromatase activity was clearly demonstrated by tumor cells from our patient in vitro. Elevated plasma concentrations of estrone, androstenedione, and 11-deoxycortisol provide useful markers for adrenal tumors, but no one steroid can be relied upon in all tumors, and metastases may lack the steroidogenic capabilities of the primary tumor.

The role of radioimmunoassay (RIA) in the diagnosis and management of endocrine tumors, such as pituitary tumors, insulinomas, and gastrinomas, has long been well established. A variety of nonendocrine tumors are capable of elaborating one or more humoral substances that resemble immunologically well-known, well-characterized biologically active hormones or their prohormone precursors or metabolic products. The possible value of mass screening for carcinoma of the lung by the detection of precursor adrenocorticotropic hormone (ACTH) in plasma was tested. However, the usefulness was limited by the potential for false-positive, i.e., elevation of marker concentration in the plasma of heavy smokers even in the absence of invasive carcinoma. Although on occasion a dramatic decrease of plasma ACTH after surgical resection or on some chemotherapeutic schedules has been observed, this does not occur with sufficient regularity to serve definitely as an objective measure of efficacy of therapy. The limitations of nonhormonal tumor markers, such as carcinoembryonic antigen (CEA), are also considered.

Prospective screening was carried out in 12 members of three families with multiple endocrine adenopathies, type I (MEA,I) and in 14 patients with no multiple endocrine adenopathies with and without other endorcinopathies. Elevated basal and responsive (after a meal) plasma concentrations of a relatively new candidate-hormone, human pancreatic polypeptide (hPP), were associated with pancreatic apudoma tumors in three asymptomatic patients with multiple endocrine adenopathies, type I. Two of these patients had excision of the tumors that resulted in normal plasma hPP concentrations postoperatively. Both tumors contained hPP predominantly by immunocytochemistry; one, a pure pancreatic polypeptide apudoma, was studied extensively demonstrating also by radioimmunoassay a high content of hPP and negligible amounts of insulin, glucagon, somatostatin, vasoactive intestinal polypeptide and gastrin. In this patient plasma concentrations of other polypeptides including insulin, glucagon, somatostatin, vasoactive intestinal polypeptide, gastrin, parathyrin, thyrocalcitonin, prolactin, corticotropin, growth hormone, thyrtropin and amine, serotonin, were within normal limits. The other patient, after excision of an hPP-detected pancreatic mixed hPP-gastrinoma, also became eugastrinemic postoperatively. Normal basal plasma hPP concentrations, but with exaggerated hPP responses to a meal in 11 patients, were associated with various combinations of islet cell hyperplasia, antral G cell hyperplasia with moderate hypergastrinemia and parathyroid hyperplasia. The patients with multiple endocrine adenopathies who have demonstrated this type of increased hPP response to a meal have not been operated on but are at risk for islet hyperplasia. Four of the 12 patients with multiple endocrine adenopathies, type I, with both normal basal and normally responsive hPP concentrations have no evidence as yet of pancreatic involvement.

This report describes a virilizing granulosa cell tumor in a postmenopausal woman. The tumor metastasized to the liver, urinary bladder, and spinal column. Although the bladder metastases were diagnosed initially as paraganglioma, review of the slides and the demonstration of abundant lipid within the tumor cells led to the correct diagnosis. The plasma testosterone and 17-hydroxyprogesterone levels were elevated, while the plasma 17-hydroxypregnenolone and dehydroepiandrosterone levels were normal, suggesting that the delta 4-pathway of testosterone biosynthesis was predominant in this tumor. Gonadotropin levels were suppressed and did not respond to gonadotropin-releasing hormone. Presumably, this suppression was due to an increase in the plasma testosterone level.

To estimate the prevalence of prolactinoma in the Zollinger-Ellison syndrome (ZES), serum prolactin (PRL) levels were measured by radioimmunoassay in 36 patients with ZES. Eight patients had elevated PRL levels; however, in one patient the finding was attributed to primary hypothyroidism rather than a prolactinoma. The seven other patients were believed to have previously undiagnosed prolactinomas on the basis of elevated serum PRL levels; the presence of pituitary tumors were confirmed in four by demonstration of sella turcica erosions or enlargement. Serial determinations over three to six years showed a tendency for serum PRL levels to increase modestly in four of six patients. Thus far, two patients have undergone transsphenoidal tumor resections with good results. This study suggests that the prevalence of prolactinoma in patients with ZES is substantial (10% for those with isolated ZES and 54% for those with ZES with multiple endocrine neoplasia, type 1, syndrome), and that early diagnosis is possible with measurement of serum PRL levels. Since levels of PRL tend to increase and clinically significant pituitary tumors can develop, determinations of serial serum PRL levels are recommended for all patients with ZES.

Eight patients with mediastinal or retroperitoneal germ cell tumors who had undergone testicular biopsy or orchiectomy were retrospectively analyzed for primary testicular abnormalities, subfertility, and abnormal sex hormone levels. Testicular tissue was abnormal in all patients, revealing peritubular fibrosis (six), decreased spermatogenesis (eight), interstitial edema (five), Sertoli cells only (one), and Leydig cell hyperplasia (two). Detailed hormone analysis in five patients revealed elevations of luteinizing hormone in four, decreased serum testosterone in two, elevations of estradiol in two, and elevation of human chorionic gonadotropin in one patient. A history of infertility was documented 2 months to 13 years before presentation in four patients and suspected in another. Extragonadal germ cell tumors, like their testicular counterparts are associated with primary germ cell defects, some of which seem to be independent of gonadotropin production by the tumor. In addition, the rather high incidence of antecedent infertility suggests that either a congenital or acquired primary germ cell defect contributes to defective spermatogenesis and the development of cancer in incompletely migrated germ cells.

Three patients with intracranial atypical teratomas presented with symptoms of endocrine dysfunction (diabetes insipidus, hyperprolactinemia, and anterior hypopituitarism) suggestive of a hypothalamic disorder. Computer-assisted tomography done in two of the three cases enabled us to document the presence of a mass and institute radiotherapy, without prior neurosurgical exploration. Computer-assisted tomography also provided a safe and effective method of assessing the effects of radiotherapy.

Seven patients with gut and pancreatic endocrine tumours have been treated with a long acting somatostatin analogue (SMS 201-995), given as a twice daily subcutaneous injection. This produced dramatic improvement in their endocrine related symptoms, in association with a fall in circulating tumour peptides. One of these patients has now been treated for seven months with this analogue which has controlled his previously life threatening diarrhoea caused by a malignant VIP secreting tumour. He gives his own injections twice daily, and has returned to a full and active life. This is a promising agent both for acute treatment of peptide hypersecretion, and for the long term management of some patients who are unresponsive to other available therapy.

To provide further understanding of humoral hypercalcemia in Hodgkin's disease (HD) the authors describe the clinical features and laboratory investigation of three patients recently treated at Massachusetts General Hospital. All were middle-aged men who presented with symptomatic hypercalcemia which led to a diagnosis of bulky intraabdominal HD. None had evidence of bone involvement or hyperparathyroidism. In the two cases tested 1,25(OH)2D3 was elevated at the time of diagnosis. These characteristics are remarkably similar to those of ten patients with HD and probable humoral hypercalcemia described in the literature. The diagnosis of HD was supported in Cases 1 and 3 by genomic blot analysis which showed no evidence of T-cell or B-cell tumor origin. In an in vitro assay, primary tumor medium from Case 1 stimulated dose-dependent bone resorption which was not entirely ascribable to 1,25(OH)2D3. The authors conclude that humoral hypercalcemia in HD predominantly affects males of middle age, that intraabdominal bulky disease is common, and that hypercalcemia appears to be mediated by tumor related production of 1,25(OH)2D3 in concert with a second factor.

Study Objective: To measure the serum levels of a newly described parathyroid hormone-like protein (PLP) which was isolated from malignant tumors associated with hypercalcemia, and determine whether PLP is a humoral factor in malignancy-associated hypercalcemia., Design: A cross-sectional study of serum levels of PLP using a newly developed radioimmunoassay., Setting: A university-affiliated Veterans Administration hospital in San Francisco, California, a University hospital in Hong Kong, and a private hospital in Danville, Pennsylvania., Patients: Patients with hypercalcemia (calcium greater than 2.65 mmol/L) and a diagnosis of malignancy were studied. Control groups included normocalcemic patients with malignancy, patients with hyperparathyroidism, and normal subjects., Measurements and Main Results: Serum immunoreactive PLP (iPLP) levels in normal subjects were less than 2.5 pmol eq/L (10 pg/mL), and 68% of subjects had undetectable levels. The serum concentration of iPLP was normal in 15 of 16 hypercalcemic patients with hyperparathyroidism. Serum iPLP was increased (greater than 2.5 pmol eq/L) in 36 of 65 (55%) patients with malignancy-associated hypercalcemia, with a mean value of 6.1 +/- 0.9 pmol eq/L (24 pg/mL). In a subgroup of patients with solid tumors serum iPLP was increased in 30 (71%) of 42 hypercalcemic patients, with a mean value of 6.5 +/- 0.9 pmol eq/L. Serum iPLP was elevated in only 3 of 23 normocalcemic patients with cancer. In patients with solid malignancies (n = 59), levels of iPLP were positively correlated with the total serum calcium (r = 0.43, P less than 0.01)., Conclusion: The data indicate a relation between the serum concentration of iPLP and the presence of hypercalcemia in solid malignancies. The results support a role for PLP as a humoral mediator of hypercalcemia in most patients with solid tumors. Measurement of iPLP should be useful in the differential diagnosis of hypercalcemia.