Type 2 diabetic patients with resistant hypertension should be screened for primary aldosteronism.

BP control in diabetic patients is often poor. The contribution of secondary hypertension due to undiagnosed PA in hypertensive type 2 diabetic patients is not well studied. We prospectively screened 100 consecutive Asian type 2 diabetic patients with difficult-to-control or resistant hypertension for PA. PAC (pmol/L) to PRA (ng/mL/h) ratio was measured; those with PAC-to-PRA ratio >550 (corresponding PAC >415) underwent intravenous 0.9% SLT. Patients with PAC >/=140 following SLT had CT adrenals and bilateral AVS. Thirteen patients (13%) were confirmed to have PA, and all had resistant hypertension. Eight had a surgically correctable form of PA. Patients with PA had higher mean (SD) systolic [159.0 (10.6) vs. 146.0 (10.7) mmHg, p=0.001] and diastolic BP [94.6 (6.0) vs. 87.6 (5.9) mmHg, p=0.001], lower serum potassium [3.5 (0.6) vs. 4.3 (0.5) mmol/L, p=0.001], and higher PAC [679.3 (291.0) vs. 239.5 (169.4) pmol/L, p=0.001]. Identification and institution of definitive treatment for PA resulted in better BP control and in a reduction in the use of antihypertensive medications. Our findings demonstrate a high prevalence of PA in type 2 diabetic patients with resistant hypertension. Systematic screening for PA in this select group is recommended, as targeted treatment improves BP control.

Unusual presentation of pheochromocytoma with ischemic sigmoid colitis and stenosis.

A 45-year-old woman with poorly controlled hypertension and diabetes mellitus presented with left iliac fossa pain, constipation alternating with diarrhea, and weight loss. She had been diagnosed with idiopathic cardiomyopathy five years previously. Echocardiogram had shown a left ventricular ejection fraction (LVEF) of 35%; coronary angiogram was normal. Colonoscopy revealed sigmoid colitis with stenosis. Abdominal computed tomography revealed a 5 cm right adrenal tumor. Twenty-four hour urinary free catecholamines and fractionated metanephrine excretion values were elevated, confirming pheochromocytoma. Her colitis resolved after one month of adrenergic blockade. Repeat echocardiogram showed improvement of LVEF to 65%. After laparoscopic right adrenalectomy, the patient's hypertension resolved, and diabetic control improved. Timely management avoided further morbidity and potential mortality in our patient.

A hyperthyroid patient with measurable thyroid-stimulating hormone concentration - a trap for the unwary.

INTRODUCTION: In a patient with hyperthyroidism, the detection of elevated thyroid hormone concentration with measurable thyroid-stimulating hormone (TSH) value poses considerable diagnostic difficulties. CLINICAL PICTURE: This 38-year-old lady presented with clinical features of thyrotoxicosis. Her serum free thyroxine concentrations were unequivocally elevated [45 to 82 pmol/L (reference interval, 10 to 20 pmol/L)] but the serum TSH values were persistently within the reference interval [0.49 to 2.48 mIU/L (reference interval, 0.45 to 4.5 mIU/L)]. TREATMENT: Investigations excluded a TSH-secreting pituitary adenoma and a thyroid hormone resistance state and confirmed false elevation in serum TSH concentration due to assay interference from heterophile antibodies. The patient was treated with carbimazole for 18 months. OUTCOME: The heterophile antibody-mediated assay interference disappeared 10 months following the initiation of treatment with carbimazole, but returned when the patient relapsed. It disappeared again 2 months after the initiation of treatment. CONCLUSIONS: Clinicians should be aware of the potential for interference in immunoassays, and suspect it whenever the test results seem inappropriate to the patient's clinical state. Misinterpretation of test values, arising as a result of assay interference, may lead to misdiagnosis, unnecessary and at times expensive investigations, delay in initiation of treatment and worst of all, the initiation of inappropriate treatment.

Development of ipsilateral adrenocortical carcinoma sixteen years after resection of an adrenal tumour causing Cushing's syndrome.

INTRODUCTION: At times, it may be difficult to differentiate early stage, low-grade adrenocortical carcinoma from benign adrenal adenoma. CLINICAL PICTURE: A 53-year-old lady underwent right adrenalectomy for a 4-cm adrenocortical tumour causing Cushing's syndrome. Histology revealed an adrenocortical adenoma. Sixteen years later, she presented with a 14-cm adrenal tumour, again on the right side. TREATMENT: She underwent surgical removal of the tumour. Histology confirmed adrenocortical carcinoma. OUTCOME: She died of metastatic disease 17 months later. CONCLUSIONS: This case highlights the importance of long-term, systematic follow-up of patients treated for benign adrenal adenomas, especially if the tumour size exceeds 4 cm.

Anaplastic thyroid carcinoma with destructive thyrotoxicosis in a patient with preexisting multinodular goiter.

Presentation of anaplastic thyroid carcinoma with thyrotoxicosis is extremely rare and its occurrence in a patient with Wegener's granulomatosis has not been reported previously. We describe an elderly lady with Wegener's granulomatosis who developed a rapidly growing anaplastic thyroid carcinoma in a preexisting multinodular goiter and discuss the mechanism of thyrotoxicosis in this patient.

Is ovarian and adrenal venous catheterization and sampling helpful in the investigation of hyperandrogenic women?

OBJECTIVE: To audit our practice of performing ovarian and adrenal venous catheterization and sampling in hyperandrogenic women who fail to suppress their elevated androgen levels following a 48-h low-dose dexamethasone suppression test (LDDST). We considered the technical success rate of catheterization, the extra information obtained in addition to the standard biochemical tests and imaging findings, and the impact of sampling on management decisions. DESIGN: A retrospective analysis of the results of all ovarian and adrenal venous catheterizations performed at St Bartholomew's Hospital, London, in the years 1980-1996. PATIENTS AND METHODS: Baseline ovarian and adrenal androgens were measured in all women presenting with symptoms and signs of hyperandrogenism. Those patients who failed to suppress their elevated testosterone (T), androstenedione (A4) and/or dehydroepiandrosterone-sulphate (DHEAS) levels following a LDDST to within the normal range or to less than 50% of the baseline value were investigated further with adrenal computed tomography (CT), ovarian ultrasound, and ovarian and adrenal venous catheterization and sampling. RESULTS: Results were available in 38 patients. The overall catheterization success rate was: all four veins in 27%, three veins in 65%, two veins in 87%. The success rate for each individual vein was: right adrenal vein (RAV) 50%, right ovarian vein (ROV) 42%, left adrenal vein (LAV) 87% and left ovarian vein (LOV) 73%. Eight patients were found to have tumours by means of imaging (adrenal CT and ovarian ultrasound), three adrenal and five ovarian, seven of which underwent operation. In six of these patients the clinical presentation was suggestive of the presence of a tumour; in addition, the combination of imaging findings allowed the detection of suspicious adrenal and ovarian masses in all eight cases. The five patients with ovarian tumours had serum testosterone levels > 4.5 nmol/l. In a further eight patients, laparotomy was performed based on a combination of diagnostic and therapeutic indications; in two of these patients the catheterization results were suggestive of an ovarian tumour. All these eight patients were shown histologically to have polycystic ovarian syndrome (PCOS), and no occult ovarian tumour was identified. None of the patients with nontumourous hyperandrogenism had a baseline testosterone level in excess of 7 nmol/l (median 4.4 nmol/l, range 2.5-7 nmol/l). CONCLUSIONS: Our results suggest that ovarian and adrenal venous catheterization and sampling should not be performed routinely in women presenting with symptoms and signs of hyperandrogenism, even if they fail to suppress their elevated androgen levels to a formal 48-h LDDST. All patients presenting with symptoms and signs of hyperandrogenism and elevated androgen levels, and where the suspicion of an androgen-secreting tumour is high, should have adrenal CT and ovarian ultrasound imaging to detect such a tumour. Venous catheterization and sampling should be reserved for patients in whom uncertainty remains, as the presence of a small ovarian tumour cannot be excluded on biochemical and imaging studies used in this series alone. Its use should be restricted to units with expertise in this area.

Treatment of advanced neuroendocrine tumours using combination chemotherapy with lomustine and 5-fluorouracil.

OBJECTIVE: Combination chemotherapy with the two agents streptozotocin (SZT), which is a nitrosurea, and 5-fluorouracil (5-FU), an alkylating agent, has a long-established role in the treatment of neuroendocrine tumours; however, it is often accompanied by considerable toxicity, and it has not been assessed in a comparative manner with other current chemotherapy regimens. In order to assess the therapeutic response and adverse effects using an alternative nitrosurea, lomustine (CCNU), which has a different side-effect profile, in combination with 5-FU, we have reviewed all patients with neuroendocrine tumours who received this form of treatment in our department. DESIGN: Retrospective analysis of the case notes of patients with metastatic neuroendocrine tumours who received treatment with the combination of CCNU and 5-FU, and who were followed up according to a defined protocol in a given time frame. PATIENTS: Thirty-one patients with metastatic neuroendocrine tumours (18 with carcinoid tumours, five islet-cell tumours, five chromaffin-cell tumours and three medullary carcinoma of the thyroid) treated with the combination of CCNU and 5-FU, and when necessary additional therapy, over a 22-year period, were included in this analysis. MEASUREMENTS: The symptomatic, hormonal and tumoural responses before and after chemotherapy with the combination of CCNU and 5-FU over a median follow-up duration of 25 months (range 9-348 months) were recorded. Of the 31 patients (16 males; median age 52 years, range 20-86 years), eight (four males; median age 61 years, range 30-74 years) were treated with the combination of CCNU and 5-FU alone (Group 1), whereas the other 23 patients (12 males; median age 47 years, range 20-86 years) received additional therapy with other chemotherapeutic regimens, somatostatin analogues, alpha-interferon or radiolabelled meta-iodobenzylguanidine (131I-MIBG) therapy (Group 2). RESULTS: A total of 121 therapeutic cycles was administered (mean 3.9, range 1-14 cycles). None of the patients obtained a complete tumour response. A partial tumour response (not a complete but a 50% or greater reduction of all measurable tumour) was seen in six out of the 29 patients (21%) (four out of eight in Group 1 and two out of 21 in Group 2, respectively). There was no tumour progression in eight out of the 29 patients (27.5%) (one out of eight in Group 1 and seven out of 21 in Group 2, respectively). The median survival over the period of the study was 48 months (95% confidence interval, CI, 22-74 months). The overall 5-year survival rate was 42% (95% CI, 17-67%) for all patients and 50% (95% CI, 18-83%) for the carcinoid group alone, according to Kaplan-Meier analysis. A complete or partial symptomatic response was obtained in 12 out of 27 (44%) patients who presented with symptoms (four out of eight in Group 1 and eight out 19 in Group 2, respectively) and a complete or partial hormonal response in eight out of 19 patients (42.1%) who presented with hormonally active disease (two out of four in Group 1 and six out of 15 in Group 2, respectively). Nine out of the 15 (60%) patients with carcinoid tumours who presented with symptoms obtained a symptomatic response, five out of 10 patients (50%) a hormonal response, and four out of 16 (25%) patients a partial tumoural response, respectively. The combination of CCNU and 5-FU was safe and well tolerated. Serious side-effects necessitating the termination of CCNU and 5-FU were seen only in two patients, and mainly consisted of reversible bone marrow suppression. No chemotherapy-related death was recorded. CONCLUSIONS: Chemotherapy with CCNU and 5-FU, either alone or in combination with other therapeutic modalities, produces considerable symptomatic and hormonal improvement and moderate tumour regression/stabilization according to currently accepted WHO criteria, particularly in patients with metastatic gastroenteropancreatic neuroendocrine tumours with minimal adverse effects. However, long-term survival was still relatively poor. It may therefore be a valuable additional therapl was still relatively poor. It may therefore be a valuable additional therapeutic option, particularly for well-differentiated carcinoid and islet-cell tumours, but mainly reserved for when there is no response or progression of the disease after currently available first-line treatment with somatostatin analogues or radiopharmaceuticals.

A rare cause of syncope in a patient with diabetes mellitus--a case report.

INTRODUCTION: Hypoglycaemic episodes in patients with diabetes mellitus are mostly due to excess doses of exogenous insulin or oral hypoglycaemic agents, coupled with poor caloric intake and excessive unplanned physical exertion. Hypoglycaemia as a result of endogenous hyperinsulinaemia due to an insulinoma is extremely rare in such patients. CLINICAL PICTURE: This patient with type 2 diabetes mellitus presented with episodes of syncope. Investigations confirmed recurrent hypoglycaemia from endogenous hyperinsulinaemia, with localisation of a tumour in the tail of the pancreas. TREATMENT: Distal pancreatectomy and splenectomy. Histology confirmed an insulinoma. OUTCOME: No further hypoglycaemic episodes were noted. The patient returned to his diabetic state with rather poor glycaemic control. CONCLUSIONS: Repeated hypoglycaemic episodes in a patient with diabetes mellitus despite complete withdrawal of hypoglycaemic agents should lead one to consider other causes of hypoglycaemia.

Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with (131)I-meta-iodobenzylguanidine [(131)I-mIBG].

OBJECTIVE: Meta-iodo-benzyl-guanidine labelled with 131-iodine [(131)I-mIBG] has been used extensively for imaging tumours originating from the neural crest but experience with its therapeutic use is limited, particularly for non-catecholamine secreting tumours. In order to assess the therapeutic response and potential adverse effects of the therapeutic administration of (131)I-mIBG, we have reviewed all patients who had received this form of treatment in our department. DESIGN: Retrospective analysis of the case notes of patients with neuroendocrine tumours who received treatment with (131)I-mIBG and were followed-up according to a defined protocol in a given time frame. PATIENTS: Thirty-seven patients (18 with metastatic carcinoid tumours, 8 metastatic phaeochromocytoma, 7 metastatic paraganglioma and 4 metastatic medullary carcinoma of the thyroid) treated with (131)I-mIBG over a 15-year period were included in this analysis. MEASUREMENTS: The symptomatic, hormonal and tumoural responses before and after (131)I-mIBG therapy over a median follow-up duration of 32 months (range 5-180 months) were recorded. Of the 37 patients (22 males; median age 51 years, range 18-81 years), 15 were treated with (131)I-mIBG alone whereas the other 22 received additional therapy. RESULTS: A total of 116 therapeutic (131)I-mIBG doses were administered [mean cumulative dose 592 mCi (21.9 GBq); range 200-1592 mCi (7.4-58.9 GBq)]. None of the patients showed a complete tumour response. However, 82% of patients treated with (131)I-mIBG alone and 84% who received additional therapy showed stable disease over the period of follow-up. Overall survival during the period of the study was 71%. The overall 5-year survival rate was 85% (95% confidence interval, 72-99%) for all patients and 78% (95% confidence interval, 55-100%) for the carcinoid group alone, according to Kaplan-Meier analysis. Symptomatic control was achieved in all the patients treated with (131)I-mIBG alone, and in 72% of those receiving additional therapy. Hormonal control was noted in 50% and 57% of patients, respectively. (131)I-mIBG therapy was safe and well tolerated. Serious side-effects necessitating the termination of (131)I-mIBG therapy were seen in only 2 of our patients. CONCLUSIONS: (131)I-mIBG therapy produces symptomatic and hormonal improvement and moderate tumour regression/stabilization in patients with metastatic neuroendocrine tumours with minimal adverse effects. It may be a valuable alternative or additional therapeutic option to the currently available conventional treatment modalities.

Comparison of somatostatin analog and meta-iodobenzylguanidine radionuclides in the diagnosis and localization of advanced neuroendocrine tumors.

A comparison has been made of [(123)I]meta-iodobenzylguanidine ([(123)I]MIBG) and [(111)In]pentetreotide scintigraphy in 54 patients with a variety of neuroendocrine tumors of whom 46 patients had metastatic disease. [(111)In]Pentetreotide scintigraphy was more sensitive in detecting metastatic lesions, as demonstrated on computed tomography and/or magnetic resonance scanning, than [(123)I]MIBG: 67% vs. 50% for carcinoid tumors (n = 24), 91% vs. 9% for pancreatic islet cell tumors (n = 12), 100% vs. 60% for medullary thyroid carcinomas (n = 5), and 75% vs. 100% for pheochromocytomas/paragangliomas (n = 4). In only 2 patients were lesions seen with [(123)I]MIBG scanning that were not apparent with [(111)In]pentetreotide. With the exception of pancreatic islet cell tumors, both radionuclides exhibited a similar sensitivity in detecting hepatic metastases, whereas in three patients the two radionuclides exerted a complementary role as different deposits exhibited uptake to only 1 or the other radionuclide. Hepatic metastases were the most important clinical predictor of a positive scan for both radionuclides. Neither elevated 5-hydroxyindoleacetic acid levels nor any other hormonal marker was predictive of a positive scan. In 8 patients with clinical and/or hormonal evidence of a neuroendocrine tumor but negative conventional radiology, [(111)In]pentetreotide scintigraphy was more sensitive than [(123)I]MIBG (37.5% vs. 12.5%) in detecting lesions. In conclusion, scintigraphy with [(111)In]pentetreotide detects more metastatic lesions than [(123)I]MIBG in patients with carcinoid and pancreatic islet cell tumors and medullary thyroid carcinomas; [(123)I]MIBG scintigraphy may be more sensitive for sympathoadrenomedullary tumors. The radionuclides may exert a complementary role in the detection and treatment of neuroendocrine tumors in occasional patients, as areas of different pattern of uptake were identified within the same patient. These data have implications not only for staging such tumors, but also for identifying patients who might benefit from treatment using either [(131)I]MIBG or radioactive somatostatin analogs.

Panhypopituitarism due to pituitary cyst of Rathke's cleft origin--two case reports.

INTRODUCTION: Rathke's cleft cysts are cystic sellar and suprasellar lesions, characteristically lined by a single layer of ciliated cuboidal or columnar epithelium. CLINICAL PICTURE: We report 2 patients who presented with gastrointestinal symptoms and were initially investigated for dyspepsia. However, attention was subsequently drawn to persistent hyponatraemia that led to the diagnosis of panhypopituitarism due to Rathke's cleft cyst. TREATMENT: Transsphenoidal surgery followed by drainage of the cyst and partial excision of the cyst wall in both patients. OUTCOME: No recurrence of the lesions over a mean follow-up of 16 months. There has been an improvement of the hypothalamo-pituitary-adrenal axis in 1 patient and the hypothalamo-pituitary-thyroid axis and visual fields in the other. CONCLUSION: Symptomatic Rathke's cleft cysts are rare and can occasionally cause panhypopituitarism. Ideal management of these cysts is unclear, but aspiration followed by partial excision of the cyst wall seems the best initial option.

The value of radiolabelled MIBG and octreotide in the diagnosis and management of neuroendocrine tumours.

Neuroendocrine tumours have a particular tendency to express functional receptors and/or uptake mechanisms. Radionuclides, such as 123I-MIBG, which is taken up by a specific uptake mechanism, and 111In-pentetreotide, which binds to somatostatin receptors, present an imaging modality based on these physiological characteristics rather on purely anatomical alterations. They have been successfully utilised for both the diagnosis and staging of neuroendocrine tumours, as they can identify lesions beyond the diagnostic sensitivity of conventional imaging modalities. Scintigraphy with 111In-pentetreotide is in general more sensitive but scintigraphy with 123I-MIBG may occasionally demonstrate lesions not evident with 111In-pentetreotide. Although both are effective in identifying hepatic metastases there may be quantitative and qualitative differences in the pattern of uptake. 131I-MIBG therapy, based on a positive 123I-MIBG scan, produces symptomatic and hormonal improvement and moderate tumour regression/stabilisation in many patients with metastatic neuroendocrine tumours with minimal adverse effects. It may be a valuable alternative or additional therapeutic option to the currently available conventional treatment modalities. Although experience with 90Y-DOTA-D-Phe1-Tyr3-octreotide therapy is still limited, preliminary studies have demonstrated useful activity in tumours with positive 111In-pentetreotide scans, and yet other radionuclide analogues may become available. However, treatment with the combination of both radionuclides is another therapeutic possibility.

Placental alkaline phosphatase, insulin, and adenine nucleotides or adenosine synergistically promote long-term survival of serum-starved mouse embryo and human fetus fibroblasts.

Earlier we showed that in serum-starved fibroblasts placental alkaline phosphatase (PALP) can exert growth factor-like effects. Here we report that in mouse embryo (NIH 3T3) and human fetus (HTB-157) fibroblasts, PALP (200 nM) alone provided full protection against serum starvation-induced cell death for 5 days. After 12 days, substantial effects of PALP on cell survival required the copresence of insulin (500 nM) and ATP or adenosine (100 microM). In serum-starved NIH 3T3 cells, PALP induced activating phosphorylation of p42/p44 mitogen-activated protein (MAP) kinases; insulin, but not ATP, had small additional effects. PALP also stimulated the expression of various cyclins; ATP both prolonged and enhanced PALP-induced expression of cyclins A and E. Finally, ATP/adenosine enhanced activation of Akt kinase by insulin. The results suggest that PALP may be a regulator of growth and remodeling of fetal tissues during the second and third trimester of pregnancy when it is expressed.

Expression of human choline kinase in NIH 3T3 fibroblasts increases the mitogenic potential of insulin and insulin-like growth factor I.

In mammalian cells, growth factors, oncogenes, and carcinogens stimulate phosphocholine (PCho) synthesis by choline kinase (CK), suggesting that PCho may regulate cell growth. To validate the role of PCho in mitogenesis, we determined the effects of insulin, insulin-like growth factor I (IGF-I), and other growth factors on DNA synthesis in NIH 3T3 fibroblast sublines highly expressing human choline kinase (CK) without increasing phosphatidylcholine synthesis. In serum-starved CK expressor cells, insulin and IGF-I stimulated DNA synthesis, p70 S6 kinase (p70 S6K) activity, phosphatidylinositol 3-kinase (PI3K) activity, and activating phosphorylation of p42/p44 mitogen-activated protein kinases (MAPK) to greater extents than in the corresponding vector control cells. Furthermore, the CK inhibitor hemicholinium-3 (HC-3) inhibited insulin- and IGF-I-induced DNA synthesis in the CK overexpressors, but not in the vector control cells. The results indicate that high cellular levels of PCho potentiate insulin- and IGF-I-induced DNA synthesis by MAPK- and p70 S6K-regulated mechanisms.

alpha(1)-antitrypsin can increase insulin-induced mitogenesis in various fibroblast and epithelial cell lines.

alpha(1)-Antitrypsin (AT), the archetypal member of the superfamily of serine proteinase inhibitors, inhibits leukocyte elastase activity and thereby can prevent lung damage. Here we show that in fibroblasts from human fetal lung and mouse embryo as well as in certain epithelial cells AT can also enhance the stimulatory effects of insulin on DNA synthesis and cell proliferation. Warming of AT at a moderate (41 degrees C) temperature for a longer time (21 h) or at a higher (65 degrees C) temperature for 30 min before treatment increased its stimulatory effects on both DNA synthesis and activating phosphorylation of p42/p44 mitogen-activated protein kinases. The results suggest that AT may promote regeneration of damaged tissues under pathophysiological conditions which are associated with fever.

Growth factor-like effects of placental alkaline phosphatase in human fetus and mouse embryo fibroblasts.

Human placental alkaline phosphatase (PALP) is synthesized in the placenta during pregnancy and is also expressed in many cancer patients; however, its physiological role is unknown. Here we show that in human fetus fibroblasts as well as normal and H-ras-transformed mouse embryo fibroblasts PALP stimulates DNA synthesis and cell proliferation in synergism with insulin, zinc and calcium. The mitogenic effects of PALP are associated with the activation of c-Raf-1, p42/p44 mitogen-activated protein kinases, p70 S6 kinase, Akt/PKB kinase and phosphatidylinositol 3'-kinase. The results suggest that in vivo PALP may promote fetus development as well as the growth of cancer cells which express oncogenic Ras.

Menstrual irregularity in women with acromegaly.

Menstrual irregularity is common in women with acromegaly, occurring in 40-84%. Although it has been attributed to gonadotropin deficiency and/or PRL excess, it has not been evaluated in detail, and its pathogenesis is not well understood. To explore the various possible pathogenic mechanisms, we have analyzed the clinical, endocrinological, and radiological characteristics of 47 women with active acromegaly within the reproductive age range (15-41 yr) with respect to their menstrual pattern; 9 patients (19%) had normal cycles, 7 (15%) had oligomenorrhea, 29 (62%) had amenorrhea, and 2 (4%) had polymenorrhea. Compared to patients with normal cycles (n = 9), patients with menstrual irregularity (oligo/polymenorrhea or amenorrhea; n = 38) were more hirsute, had lower serum estradiol (normal: median, 76.5 pmol/L; range, 20-570; menstrual irregularity: median, 283; range, 140-431; P < 0.01), and sex hormone-binding globulin (SHBG; normal: median, 19.6 nmol/L; range, 5-52; menstrual irregularity: median, 48; range, 18-60; P < 0.01), but similar testosterone levels; in addition, patients with amenorrhea had higher serum GH (normal: median, 100 mU/L; range, 8.8-400; amenorrhea: median, 30; range, 10.7-120; P < 0.05). PRL levels in excess of 1000 mU/L were found in 16 of the 38 patients with menstrual irregularity compared to only 1 of the 9 patients with normal cycles. Patients with menstrual irregularity had a greater impairment of anterior pituitary function than patients with normal cycles. Acromegalic patients who were defined as estrogen sufficient (estradiol, >140 pmol/L) had clinical baseline endocrine profiles and LH responses to GnRH stimulation similar to those in patients with polycystic ovarian disease. There was a positive correlation between GH levels and tumor size (r = 0.35; P < 0.05) and an independent inverse correlation between GH and SHBG levels (r = -0.6; P < 0.01), which persisted even in patients who were estrogen sufficient, but there was no correlation between GH and estradiol levels; in addition, there was a negative correlation between estradiol levels and tumor size (r = -0.42; P < 0.05). Thirty-five of the patients with menstrual irregularity had meso- or macroadenomas and 3 had microadenoma, whereas 6 of the 9 patients with normal cycles had microadenomas. In conclusion, menstrual irregularity is common in women with acromegaly (81% of our patients). Amenorrheic patients have higher GH levels, are mainly estrogen deficient, and tend to have larger tumors than patients with normal cycles. However, the independent negative correlation between GH and SHBG levels suggests that GH may, directly or indirectly, lead to a fall in SHBG, possibly determined by the hyperinsulinemia known to occur in acromegaly. Low SHBG levels may contribute to the menstrual disturbance seen in acromegaly in addition to any gonadotropin deficiency or hyperprolactinemia and may account for hirsutism in the presence of normal testosterone levels.

Bombesin promotes synergistic stimulation of DNA synthesis by ethanol and insulin in fibroblasts.

In NIH 3T3 fibroblasts and several other cellular systems, ethanol (50-80 mM) was previously shown to greatly enhance the mitogenic effects of insulin particularly in the presence of zinc. Here we report that in NIH 3T3 fibroblasts the combined stimulatory effects of ethanol and insulin on DNA synthesis can be further increased by bombesin both in the absence and presence of zinc. Bombesin also enhanced insulin-plus-ethanol-induced DNA synthesis in mouse Swiss 3T3 and Balb/c 3T3 fibroblasts, but in these cells bombesin was effective only in the presence of zinc. In NIH 3T3 fibroblasts, the potentiating effects of ethanol on insulin-induced DNA synthesis by the zinc-dependent and bombesin-dependent mechanisms were additive. Wortmannin, an inhibitor of phosphatidylinositol 3'-kinase (PI3K), prevented the comitogenic effect of ethanol in the presence of bombesin but not in the presence of zinc. Furthermore, bombesin, but not ethanol, was found to enhance the stimulatory effect of insulin on PI3K activity. Rapamycin, an indirect inhibitor of p70 S6 kinase actions, inhibited the comitogenic effects of ethanol in the presence of both zinc and bombesin. However, only ethanol, but not bombesin, enhanced the stimulatory effect of insulin on p70 S6 kinase activity; this effect of ethanol was zinc-dependent. Neither ethanol nor bombesin enhanced the stimulatory effects of insulin on the phosphorylation (activation) of p38/p42/p44 mitogen-activated protein kinases. The results suggest that in mouse fibroblasts maximal stimulation of DNA synthesis by physiologically relevant concentrations of ethanol occurs if both PI3K and p70 S6 kinase are activated. These data suggest a mechanism by which ethanol may affect growth in affected human tissues during its tumor promoting actions.

The role of cytotoxic chemotherapy in the management of aggressive and malignant pituitary tumors.

Pituitary tumors are mostly benign lesions, although 5-35% are locally invasive. A small number exhibit a more aggressive course, infiltrating dura, bone and sinuses, and are designated highly aggressive. However, the presence of metastases separate from the pituitary in the central nervous system or at a distance is necessary to designate pituitary tumors as carcinomas, i.e. truly malignant. When conventional therapeutic modalities fail, systemic chemotherapy remains the last option. We report seven such patients, three with highly aggressive and four with malignant pituitary tumors (n=4) four women; median age, 32 yr; range, 23-48 yr), who received one or more courses of chemotherapy with lomustine and 5-fluorouracil (median, two courses; range, one to six courses). Three patients with systemic metastatic disease had a shorter survival (median, 5 months; range, 1-14 months) than the one patient with central nervous system metastases alone (10 yr). A patient with an aggressive nonmetastatic prolactinoma who initially responded to chemotherapy died from another nondisease-associated cause. Two patients, one with an aggressive and one with a metastatic tumor, achieved symptomatic improvement with a median duration of 6 months. A hormonal reduction greater than 50% was observed in two of seven patients; only one patient who had an aggressive tumor obtained an objective tumor response. The median survival from the time of initiation of chemotherapy in patients with malignant tumors ranged from 3-65 months. Two patients with malignant tumors developed disease progression while receiving chemotherapy; no patient with extracranial metastases showed a response. Treatment was well tolerated, with minimal individual side-effects. Three patients with no response to initial treatment received different chemotherapeutic regimens with no additional response. All patients with metastatic malignant tumors eventually died. Treatment with cytotoxic chemotherapy is noncurative, and current experience is limited. Until another more specific form of treatment is available, chemotherapy may still be of some value in patients with highly aggressive and malignant pituitary tumors, at least in achieving a temporary remission or delay in progression. The combination of lomustine/5-fluorouracil proved easy to administer with minimal toxicity, although the response rate was only 14%. Until a more specific treatment is found, an optimal chemotherapeutic regimen needs to be established.