Elevated inferior petrosal sinus levels of PTHrP in a patient with Cushing's disease.

PTHrP has been found in various tissues, including prolactinomas and growth hormone producing adenomas. The function and clinical importance of PTHrP are poorly understood. We report the case of a 25-year-old female patient with hirsutism. Autonomous ACTH-dependent hypercortisolism was documented by endocrine testing. Magnetic resonance imaging (MRI) revealed a 3-mm intrasellar hypointense lesion in the left side of the pituitary gland. The inferior petrosal sinus sampling disclosed a gradient of ACTH left central/peripheral of 30.5 and right central/peripheral of 2.0 and suggested the diagnosis of a left-sided pituitary ACTH secreting microadenoma. Interestingly, we found elevated PTHrP levels in the left inferior petrosal sinus with a gradient of 4.7 compared to peripheral venous blood and of 3.6 compared to the right sinus. Our results fit very well to the concept of a para-/autocrine secretion of PTHrP which has been proposed recently and suggest a role in the regulation of cell growth of pituitary adenomas.

Partial laparoscopic adrenalectomy for aldosterone-producing adenoma: short-and long-term results.

BACKGROUND AND PURPOSE: Laparoscopic surgery for adrenal gland tumors is the gold standard operative approach now. Adrenal-sparing surgery has special indications. We demonstrated the safety and feasibility of performing adrenal-sparing surgery by means of laparoscopy for aldosterone-producing adenoma (Conn's syndrome). PATIENTS AND METHODS: Between 1995 and 1999, seven patients with Conn's syndrome had laparoscopic adrenal-sparing resection of their tumors. These patients were followed up by means of radiology and biochemistry. RESULTS: All seven patients had successful laparoscopic surgery without complications. Most patients were discharged in 2 to 6 days (mean 3 days). At follow-up, the six patients investigated had normal blood pressure. No recurrences have been encountered with a median follow-up of 12 months in these six patients. CONCLUSIONS: Adrenal-sparing resection of tumors causing primary hyperaldosteronism is technically feasible by means of laparoscopy. This procedure has the advantage of keeping a greater reserve of normal adrenal tissue and of rapid postoperative recovery.

Levels and molecular properties of secretoneurin-immunoreactivity in the serum and urine of control and neuroendocrine tumor patients.

We have determined the levels of secretoneurin (SN), a novel 33-amino acid neuropeptide belonging to the class of chromogranins, in the serum and urine of healthy subjects and patients suffering from various tumors. SN serum levels averaged 22.1+/-1.1 fmol/mL. They were 5-fold higher in younger children and then declined continuously. SN levels were positively correlated with serum creatinine, suggesting an influence of renal function on the clearance of SN from the serum. In the urine 80.0 fmol/mL SN was present. In patients with endocrine tumors like gut carcinoids, endocrine pancreatic tumors, oat cell lung carcinomas, and pheochromocytomas, SN serum levels were elevated up to 45-fold. Patients suffering from neuroblastomas, insulinomas, pituitary adenomas including acromegaly, and solid nonendocrine tumors had concentrations in the normal range. In human serum, SN-immunoreactivity was confined to the free peptide SN; neither larger intermediate-sized forms nor the precursor secretogranin II were detected. An efficient removal of the small molecule SN from the serum by the kidney explains why SN serum levels are lower when compared to chromogranin A, which is present as large molecule in serum.

Changes in the volume of residual pituitary adenomas in patients with adult-onset growth hormone deficiency during replacement therapy with the recombinant human growth hormone.

In the course of a prospective study concerning recombinant human growth hormone replacement therapy in adult-onset growth hormone deficiency, we determined the volumes of residual tumors in six patients with pituitary macroadenomas who had formerly been treated with surgery alone or surgery and external radiotherapy. Pituitary CT scans in direct coronal views were obtained at baseline, and at 6, 12 and 18 months. The volumes of the residual tumors were calculated from the tumor diameters assuming that the tumors had an ellipsoid shape. Tumor volumes did not change in one patient and were reduced in two patients. In three patients, clinically non-significant tumor expansion by a median of 23.6 +/- 13.2% (range, 21.1-62.0%) was noted after 12 to 18 months. This tumor expansion did not cause signs or symptoms of a mass effect and did not influence further treatment. One of the six patients discontinued treatment and no further change in tumor size, as determined by MRT, was noted over a mean follow up of 34 months. Treatment was continued for up to 38 months in five patients. In four of these five patients no further change in tumor size was detected. However, treatment with the growth hormone was stopped in one patient since a 30% expansion in tumor volume, elevating the optic chiasm, was noted on MRT. None of the patients developed deterioration of visual fields. Interestingly, tumor invasion of the cavernous sinus had been present initially in all three who displayed tumor expansion while on rhGH. This first study in which diameters of residual pituitary adenomas in patients on growth hormone replacement therapy were prospectively and carefully measured, permits no conclusion regarding a causal relationship between growth hormone and tumor expansion, owing to the small number of patients. However, the observed incidence is not much different from that in former studies without growth hormone replacement therapy. Nevertheless, a close observation of the pituitary by imaging studies at regular intervals appears to be mandatory, particularly in patients with invasive residual adenomas.

Pheochromocytoma and sub-clinical Cushing's syndrome during pregnancy: diagnosis, medical pre-treatment and cure by laparoscopic unilateral adrenalectomy.

The coexistence of pheochromocytoma and primary adrenal Cushing's syndrome of the same adrenal gland has rarely been reported. We describe here the case of a female patient presenting with mild Cushing's stigmata, hypertension and diabetes mellitus in whom we diagnosed a pheochromocytoma of the left adrenal gland with coexisting non-ACTH-dependent cortisol hypersecretion. While hormonal work-up was still in progress, the patient became pregnant and wanted to carry her pregnancy to full-term. A laparoscopic adrenalectomy in the 17th week of gestation was decided upon and the patient accordingly prepared for surgery by pre-treatment with phenoxybenzamine. Successful surgery--the first ever reported laparoscopic resection of a pheochromocytoma in pregnancy--without perioperative complications was performed under general anesthesia, with the patient receiving peri- and post-operative hydrocortisone substitution. Pathohistological examination revealed a pheochromocytoma with positive immunostaining for interleukin-6 (IL-6) and negative immunostaining for ACTH, vasoactive intestinal polypeptide (VIP) and cytochrome P450, and with no signs of malignancy. A paracrine stimulation of the ipsilateral adrenal cortex by IL-6 produced by the pheochromocytoma, leading to cortical hyperplasia and subclinical Cushing's syndrome, is suggested by the positive immunostaining for IL-6 and the MRI findings. Post-operatively, secondary adrenal insufficiency ensued, necessitating continuing hydrocortisone replacement over 12 months. Hypertension resolved after surgery, and diabetes after the uncomplicated vaginal delivery at term.

[Systematic diagnostic workup: differential diagnosis of various forms of osteoporosis]. / Rationale Befunderhebung: Differentialdiagnose verschiedener Osteoporoseformen.

The objects of a rational approach to the diagnosis of osteoporosis are the identification of patients with osteopenia/osteoporosis by radiological methods, investigations concerning the etiology of the disease and an assessment of bone turnover by biochemical markers. Current classifications of osteoporosis are explained. The WHO classification of osteoporosis and a clinical classification according to severity are based on bone densitometry and fractures. In accordance with pathogenetic aspects a division in osteoporosis without or with known causes is possible (primary/secondary), moreover several regional forms of osteoporosis are mentioned. A classification in "low-" or "high-turnover" osteoporosis is possible by an assessment of the rate of bone loss. The diagnostic procedures in osteoporosis include the patients' history (pain, skeleton, risk factors for osteoporosis and for falls) and an exact physical examination. Essential radiological investigations are radiographs of thoracic and lumbar spine and a bone mass measurement (dual X-ray absorptiometry--DXA or quantitative computerized tomography--QCT, possibly also a quantitative ultrasonography). Basic laboratory tests, including markers of bone turnover are routinely performed, whereas additional specific tests are optional, according to the clinical situation. Scintigraphy and bone biopsy are seldom used in the diagnostic procedure. Practical guidelines for the diagnosis of osteoporosis in patients with or without pain are discussed. Diagnostic investigations should only be performed, if the patients gain benefit from it concerning prophylaxis or therapy.

Adrenocortical carcinoma evolving after diagnosis of preclinical Cushing's syndrome in an adrenal incidentaloma. A case report.

A 43-year-old female patient underwent abdominal ultrasonography and CT scan because of uncharacteristic abdominal pain. A 3-cm homogeneous adrenal tumor was diagnosed. The endocrine tests revealed an adrenal preclinical Cushing's syndrome (PCS). Due to the latent hormone excess we decided to operate on the adrenal tumor. Since the tumor was small, laparoscopic adrenalectomy was performed. Histological evaluation showed an adrenocortical tumor of undetermined nature. Four months later the patient presented with a metastasizing cortisol- and androgen-producing adrenocortical carcinoma (ACC). After pretreatment with ketoconazole to suppress the biosynthesis of adrenal steroids under substitution with hydrocortisone, we reduced the tumor load by surgery. Postoperatively we continued ketoconazole and started o, p'-dichlorodiphenyldichloroethane as well as chemotherapy with doxorubicin and suramin. However, the patient died from ACC 7 months after adrenalectomy. It is known from several reports that PCS may persist clinically silently or may progress to full-blown Cushing's syndrome. This is the first time a malignant course of PCS is described. Independent of the initial therapeutic strategy of PCS, i. e. surgery or regular follow-up visits, we must be aware that also relatively small adrenal tumors can harbor malignancy.

Surgery combined with dopamine agonists versus dopamine agonists alone in long-term treatment of macroprolactinoma: a retrospective study.

We retrospectively analysed the long-term treatment results (median 8 years) of 31 patients with macroprolactinoma. 17 patients were treated by pituitary surgery (group 1) followed by long-term dopamine agonist therapy whereas 14 patients received long-term dopamine agonist therapy alone (group 2). 2 patients of group 1 and 1 patient of group 2 had external pituitary irradiation because of progressive disease. The two groups were comparable with respect to age, gender and initial prolactin (PRL) levels. At the end of the observation period dopamine agonist dosage could be reduced by 50% in group 1 and by 39.3% in group 2. Pituitary function did not change substantially during therapy. Complete remissions (no visible tumour in CT or MRI, normal PRL levels under current dopamine agonist medication) were achieved in 23.5% of group 1 vs. 21.4% of group 2, partial remissions (reduction of PRL and tumour size) in 35.3% vs. 64.3%, stable disease in 23.5% vs. 7.1% and progressive disease in 17.7% vs. 7.1% (differences not significant). Visual field defects showed 28.4% remissions (complete and partial) in group 1 versus 50% in group 2. Dopamine agonist therapy could be stopped definitively in only 1 patient of group 2 with an invasive macroprolactinoma. Initial surgical reduction of tumour load followed by medical therapy does not seem to guarantee a better long-term outcome than dopamine agonist therapy alone if the patient responds to and tolerates dopamine agonist therapy. Surgery should be reserved for non-responders, drug-intolerant or non-compliant patients, and for those with acute severe neurological compromise.

Laparoscopic surgery for pheochromocytoma: adrenalectomy, partial resection, excision of paragangliomas.

PURPOSE: Surgical treatment of pheochromocytoma includes adrenalectomy, adrenal sparing surgery and excision of extraadrenal paragangliomas. We report our experience using laparoscopy for these procedures. MATERIALS AND METHODS: Between June 1992 and November 1997, 19 patients underwent laparoscopic surgery for pheochromocytoma. Of the patients 14 had solitary tumors, and 4 presented with bilateral pheochromocytomas and 1 or 2 additional paragangliomas. In 1 patient a recurrent pheochromocytoma was found in the contralateral adrenal following previous right adrenalectomy. One patient each had myocardiopathy, amaurosis and stroke secondary to severe hypertension. Two patients were pregnant. RESULTS: All solitary tumors were treated with laparoscopic adrenalectomy. Laparoscopic adrenal sparing surgery (4 cases, 2 bilateral) and bilateral adrenalectomy (1) were performed for multiple familial pheochromocytoma, and all paragangliomas were excised simultaneously. The pregnant patients underwent surgery at 16 and 20 weeks of gestation, respectively. All procedures were completed as planned. The rate of minor intraoperative and postoperative complications was 11% and 16%, respectively, and there were no major complications. In all patients the catecholamine levels returned to normal and no residual tumors were found at followup. None of the patients undergoing partial resection required steroid replacement therapy. CONCLUSIONS: In experienced hands, laparoscopic surgery for solitary and multiple pheochromocytoma and paraganglioma is feasible and safe, and does not increase the specific risks associated with pheochromocytoma surgery.

Adrenal-sparing laparoscopic surgery for aldosterone-producing adenoma.

We herein present the first case in the literature of enucleation of an aldosterone-producing adenoma by laparoscopy. The indication for adrenal-sparing surgery was bilateral adrenal adenoma. The operation turned out to be easier than laparoscopic adrenalectomy. The postoperative course was uneventful, and the patient was cured; split adrenal function tests showed normal function of both adrenal glands.

Effects of growth hormone (GH) replacement on bone metabolism and mineral density in adult onset of GH deficiency: results of a double-blind placebo-controlled study with open follow-up.

It is known that GH stimulates bone turnover and that GH-deficient adults have a lower bone mass than healthy controls. In order to evaluate the influences of GH replacement therapy on markers of bone turnover and on bone mineral density (BMD) in patients with adult onset GH deficiency, a double-blind placebo-controlled study of treatment with recombinant human GH (rhGH; mean dose 2.4 IU daily) in 20 patients for 6 months and an extended open study of 6 to 12 months were conducted. Eighteen patients, fourteen men and four women, with a mean age of 44 years with adult onset GH deficiency were evaluated in the study. Compared with placebo, after 6 months serum calcium (2.39 +/- 0.02 vs 2.32 +/- 0.02 mmol/l, P = 0.037) and phosphate (0.97 +/- 0.06 vs 0.75 +/- 0.05 mmol/l, P = 0.011) increased and the index of phosphate excretion (0.03 +/- 0.03 vs 0.19 +/- 0.02, P < 0.001) decreased significantly, and there was a significant increase in the markers of bone formation (osteocalcin, 64.8 +/- 11.8 vs 17.4 +/- 1.8 ng/ml, P < 0.001; procollagen type I carboxyterminal propeptide (PICP), 195.3 +/- 26.4 vs 124.0 +/- 15.5 ng/ml, P = 0.026) as well as those of bone resorption (type I collagen carboxyterminal telopeptide (ICTP), 8.9 +/- 1.2 vs 3.3 +/- 0.5 ng/ml, P < 0.001; urinary hydroxyproline, 0.035 +/- 0.006 vs 0.018 +/- 0.002 mg/100 ml glomerular filtration rate, P = 0.009). BMD did not change during this period of time. IGF-I was significantly higher in treated patients (306 +/- 45.3 vs 88.7 +/- 22.5 ng/ml, P < 0.001). An analysis of the data compiled from 18 patients treated with rhGH for 12 months revealed similar significant increases in serum calcium and phosphate, and the markers of bone turnover (osteocalcin, PICP, ICTP, urinary hydroxyproline). Dual energy x-ray absorptiometry (DXA)-measured BMD in the lumbar spine (1.194 +/- 0.058 vs 1.133 +/- 0.046 g/cm2, P = 0.015), femoral neck (1.009 +/- 0.051 vs 0.936 +/- 0.034 g/cm2, P = 0.004), Ward's triangle (0.881 +/- 0.055 vs 0.816 +/- 0.04 g/cm2, P = 0.019) and the trochanteric region (0.869 +/- 0.046 vs 0.801 +/- 0.033 g/cm2, P = 0.005) increased significantly linearly (compared with the individual baseline values). At 12 months, BMD in patients with low bone mass (T-score < -1.0 S.D.) increased more than in those with normal bone mass (lumbar spine 11.5 vs 2.1%, P = 0.030, and femoral neck 9.7 vs 4.2%, P = 0.055). IGF-I increased significantly in all treated patients. In conclusion, treatment of GH-deficient adults with rhGH increases bone turnover for at least 12 months. BMD in the lumbar spine and the proximal femur increases continuously in this time (open study) and the benefit is greater in patients with low bone mass. Therefore, GH-deficient patients exhibiting osteopenia or osteoporosis should be considered candidates for GH supplementation. However, long-term studies are needed to establish that the positive effects on BMD are persistent and are associated with a reduction in fracture risk.

Superoxide anion release from neutrophils in growth hormone deficient adults before and after replacement therapy with recombinant human growth hormone.

The observations that growth hormone primes neutrophils and stimulates various activities of monocytes suggested that it plays a role in the regulation of leukocyte biology. The in vivo reduction of growth hormone levels may be responsible for to the functional impairment of leukocytes observed in growth hormone deficient children. Whether leukocyte function is impaired in growth hormone deficient adults is not known as yet. We therefore studied superoxide anion release from neutrophils and chemotaxis of monocytes in 15 patients with adult-onset growth hormone deficiency before and after a period of 6 months of replacement therapy with recombinant human growth hormone. Analyses were performed by comparing functions of the leukocytes from these patients with those from age and sex-matched healthy control subjects. Before growth hormone treatment, patients received appropriate replacement therapy with thyroid, adrenal and gonadal hormones. The dose of recombinant human growth hormone was 0.25-0.5 U/kg/week (0.013-0.026 mg/kg/day) throughout the whole period of replacement therapy. In growth hormone deficient subjects, formylpeptide-triggered release of superoxide anions from neutrophils was significantly suppressed by about 40% before treatment as compared to healthy control subjects. After 6 months of replacement therapy, neutrophil superoxide anion release was similar in patients and healthy individuals. Neither before nor after replacement therapy, however, was there a difference in monocyte migration between control and growth hormone deficient subjects. These data indicate that neutrophil function is somehow altered in growth hormone deficient patients, even when receiving appropriate therapy with thyroid, adrenal and gonadal hormones, but that neutrophil function can be restored to near normalcy by growth hormone replacement therapy. This would suggest that suppressed neutrophil respiratory burst is due to the deficiency in growth hormone.

Technique and results of laparoscopic adrenalectomy.

OBJECTIVES: Our technique of laparoscopic adrenalectomy as well as the results of this method are presented. METHODS: Transperitoneal laparoscopic adrenalectomy was performed in 18 consecutive patients (10 right side, 8 left side) for Conn's disease (7 patients), pheochromocytoma (6 patients), Cushing's syndrome (1 patient), and large inactive adenoma (4 patients). The tumor size ranged between 1 and 8 cm (mean 4.2). One of the patients, who presented with Conn's disease and bilateral adenoma, underwent enucleation of the larger adenoma on the right side leaving the uninvolved portion of the adrenal gland intact. RESULTS: The mean operative time was below 3 h; blood loss was minimal in all cases except 2. Hypertensive crisis was not encountered in this series. The only postoperative complication seen was transient diabetes insipidus which occurred in 1 patient. Analgesics were required only on the first 2 postoperative days. Oral intake and ambulation were resumed within 24 h. Mean postoperative hospitalization was 4.6 days. CONCLUSIONS: In our hands, laparoscopic adrenalectomy proved to be associated with a low morbidity and few complications. In addition, it is one of the few procedures where laparoscopy can compete with open surgery in terms of operative time.

Endocrine ophthalmopathy in a patient under continuous immunosuppressive therapy after cardiac transplantation.

We present the case of a female patient who has been on immunosuppressive therapy consisting of cyclosporin A and prednisolone for 9 years because of heterotopic (auxiliary) heart transplantation in 1984. In 1992 the patient developed Graves' disease followed by endocrine ophthalmopathy class IV 1 year later. To our knowledge this is the first report on Graves' disease with subsequent severe endocrine ophthalmopathy in a patient under immunosuppressive treatment with cyclosporin A and prednisolone in doses that effectively prevent heart transplant rejection. Prednisolone, which is used as a first line treatment of endocrine ophthalmopathy, and cyclosporin A, both inhibit T cell function. However, in this patient they were not effective in preventing the development of Graves' disease with subsequent endocrine ophthalmopathy, both of which are autoimmune diseases.

MR volumetry for monitoring intramuscular bromocriptine treatment in macroprolactinomas.

OBJECTIVE: To assess volumetric changes of pituitary prolactinomas, we applied a threshold-based segmentation algorithm in two patients during intramuscular bromocriptine treatment. MATERIALS AND METHODS: Tumor volumes were calculated from contiguous slices of a 3D GE sequence and from conventional SE images. RESULTS: After a single 50 mg i.m. bromocriptine administration, the prolactinoma volumes decreased by 25 and 35% within 7 and 11 days, respectively. Volume calculations from 3D GE images were more accurate than calculations from 3 mm 2D SE images, especially for smaller tumors. A decrease of prolactinoma size was paralleled by a decrease of serum prolactin levels and correlated with an improvement of visual field and endocrine function in both patients. The end of the bromocriptine effect was indicated by a reincreasing tumor volume, which was observed after 30 days in the first patients and after 43 days in the second patient. CONCLUSION: Our results suggest that MR volumetry represents a useful tool to monitor changes of prolactinoma volume during bromocriptine treatment and may improve the clinical management of these patients.

Inhibition of superoxide anion release from circulating neutrophils by L-arginine in man.

In animal studies of myocardial ischemia/reperfusion L-arginine reduces necrotic injury by preservation of endothelial function and attenuation of neutrophil accumulation in ischemic cardiac tissue. Because release of oxygen radical species by circulating neutrophils is important in endothelial function and ischemia-reperfusion injury, this study investigated the effect of intravenous administration of L-arginine on the in vitro release of superoxide anion of neutrophils in healthy young adults. Neutrophils were obtained at various time points before, during, and after infusion of L-arginine (17 mg kg-1 min-1 for 30 min) and analyzed for superoxide dismutase inhibitable reduction of ferricytochrome c. The spontaneously occurring respiratory burst of polymorphonuclear leukocytes at basal conditions was compared with that after triggering by 1 mumol/l formylpeptide or 50 ng/ml phorbolester. Infusion of L-arginine inhibited both basal (P < 0.01) and formylpeptide-triggered (P < 0.05) release of superoxide anion did, but not affect release stimulated by phorbol 12-myristate 13-acetate. Pretreatment of neutrophils with 1 mmol/l L-arginine in vitro also significantly reduced formylpeptide-triggered (1 mumol/l) superoxide anion release, suggesting that the affects observed after in vivo pretreatment may be due to direct action of L-arginine on neutrophils. These findings demonstrate the ability of L-arginine to reduce release of oxygen radical species by circulating neutrophils in man.

[Trans-septo-sphenoidal operation for pituitary adenoma in 92 patients: results and follow-up endocrine studies]. / Transseptosphenoidale Operation von Hypophysenadenomen bei 92 Patienten: Ergebnisse und endokrine Verlaufskontrolle.

The short- and long-term therapeutic results of transseptosphenoidal adenomectomy were studied retrospectively in 92 patients with pituitary tumors (42 nonsecreting adenomas, 21 GH-, 15 PRL-, 10 ACTH-, 2 TSH-, and 2 FSH-secreting adenomas). Severe surgically related complications were not observed. The early remission rate was 53.7% in nonsecreting, 57.1% in GH-secreting, 60% in PRL-secreting, 88.9% in ACTH-secreting, and 75% in TSH- or FSH-secreting adenomas. The recurrence rate in patients with nonsecreting adenomas was 47.1%, with GH-secreting adenomas 10%, with ACTH-secreting adenomas 25%, and with TSH- or FSH-secreting adenomas 66.7%, respectively. A long-term cure rate of 69.2% was observed in prolactinomas in combination with a facultative dopamine agonist therapy. More patients had normal pituitary function concerning TSH, ACTH, and LH/FSH post-operatively (48.9% versus 46.6% preoperatively). These data confirm that transseptosphenoidal surgery is a safe and selective treatment for pituitary adenomas with efficient preservation of the normal pituitary gland.

Left-sided laparoscopic adrenalectomy.

Laparoscopic transperitoneal adrenalectomy was performed in a 42-year-old female with a left adrenocortical adenoma causing Conn's syndrome. No technical problems occurred during surgery and the patient recovered quickly.