High prolactin levels in patients with Cushing's disease without pathological evidence of pituitary adenoma

OBJECTIVE This study was designed to compare the clinical and biochemical features of patients with Cushing's disease without pathological evidence of pituitary adenoma (n= 11) to those in whom a pituitary ACTH adenoma was documented (n= 11). DESIGN The clinical and biochemical features of 11 patients with Cushing's disease without pathological evidence of pituitary adenomas were compared to 11 subjects with ACTH-secreting adenomas. The patients underwent transsphenoidal microsurgery between 1979 and 1989. During surgery, when an adenoma was not visualized, a partial hypophysectomy of the central mucoid wedge was performed. MEASUREMENTS Cushing's disease was established by the clinical features of hypercortisolism and the high levels of 24-hour free urinary Cortisol with no suppression in response to low, but with suppression in response to high, doses of dexamethasone. Basal and post TRH-GnRH plasma prolactin, FSH and LH levels were assessed in each patient before transsphenoidal microsurgery. RESULTS Similar results were observed in patients with and without ACTH-secreting adenomas regarding cure rate, and free urinary Cortisol levels both basal and after 2 days of dexamethasone, 8 mg daily. After surgery, plasma Cortisol levels in cured patients were lower in subjects with ACTH-secreting adenomas than in those without pituitary tumours (P < 0.05). Areas under the curve of PRL (P<0.002) and LH (P< 0.04) were significantly higher in patients without pituitary adenoma after TRH-GnRH administration. Compared to controls, the peak prolactin level after TRH-GnRH administration was higher in patients without pituitary adenoma (P < 0005) and lower in those with ACTH adenoma (P< 0.05). Furthermore, a peak prolactin level equal to or greater than 1410 mU/l during the TRH-GnRH test was found in 11/11 patients without ACTH adenoma and 3/11 patients in the other group (P < 0 001), while the CT-scan findings were suggestive of pituitary adenoma in six patients of each group. CONCLUSION This study suggests that patients with Cushing's disease without pituitary adenomas can be distinguished from those with ACTH-secreting adenomas by their high prolactin levels after TRH-GnRH administration.     

Prolactin receptors in human pituitary adenomas

OBJECTIVE In the rat, prolactin receptors (PRL-R) have been identified In normal pituitary cells and In anterior pituitary tumours induced by oestradiol. No published data are available concerning PRL-R in the human pituitary. The aim of our study was therefore to detect the presence of PRL-R in the normal human pituitary gland and human pituitary adenomas. DESIGN Evaluation of free and total PRL-R In the normal pituitary gland and different pituitary tumours characterized by Immunocytochemical analysis. PATIENTS Twenty-six unselected patients (14 M, 12 F) who underwent surgery for pituitary adenoma (3 prolactinomas, 4 GH-PRL adenomas, 5 GH adenomas, 1 ACTH adenoma, 9 glycoprotein and/or α-subunlt adenomas, 4 null ceils adenomas) were studied. Nine pltultaries from subjects whose death was unrelated to brain and endocrine diseases, were also studied as a control group in the PRL binding studies. MEASUREMENTS Free PRL-R in microsomal membranes were determined by in-vitro radioreceptor assay using ¹²⁵l-labelled human PRL as llgand. Total PRL-R were also measured In the same membrane fractions by removing endogenous PRL bound to its receptors using 4 m MgCl². Serum PRL levels were also evaluated in all patients before surgery using an IRMA method. RESULTS Specific binding values for PRL (free PRL-R) were 0.39±0.03% (range 0–1.96%) In the pituitary adenomas. These binding values were Identical to those observed in normal pltultaries (0.38±0.07%, range 0.1–0.78%). Elevated PRL binding (1.25% and 1.96%) was found in two patients with PRL secreting adenomas and very high serum PRL levels (5768 and 11240 mU/l. No PRL binding was shown In 4 patients. Treatment of membranes with 4 M MgCl² increased the specific binding (total PRL-R) In both pituitary tumours (0.5±0.11%; P<0.001) and normal pituHarles (0.47±0.07%; P<0.02). CONCLUSIONS Our data have demonstrated the presence of prolactin receptors in normal cadaveric pituitary and in most pituitary adenomas, Irrespective of histological classification. In particular, elevated prolactin receptor levels were shown In PRL-secreting tumours from patients with markedly increased serum PRL levels. Our study may support several lines of experimental evidence for a specific functional role for PRL in the growth of some pituitary adenomas.     

Expression of p16<Superscript>INK4A</Superscript> gene in human pituitary tumours

Pituitary adenomas comprise 10–15% of primary intracranial tumours but the mechanisms leading to tumour development are yet to be clearly established. The retinoblastoma pathway, which regulates the progression through the cell cycle, is often deregulated in different types of tumours. We studied the cyclin-dependent kinase inhibitor p16^INK4A gene expression at mRNA level in human pituitary adenomas. Forty-six tumour specimens of different subtypes, 21 clinically non-functioning, 12 growth hormone-secreting, 6 prolactin-secreting, 6 adrenocorticotropin-secreting, and 1 thyrotropin-secreting tumours were studied. All clinically non-functioning and most of the hormone-secreting tumours were macroadenomas (38/46). The RT–PCR assay and electrophoresis of the PCR-products showed that p16^INK4A mRNA was undetectable in: 62% of non-functioning, 8% of growth hormone-secreting, 17% of prolactin-secreting and 17% of adrenocorticotropin-secreting adenomas. Forty percent of all macroadenomas and 25% of microadenomas had negative p16^INK4A mRNA, the latter results suggest that the absence of p16^INK4A product might be an early event in tumours with no expression of this suppressor gene. Within the non-functioning adenomas 63% were “null cell” and 37% were positive for some hormone, both subgroups showed similar percentage of cases with absence of p16^INK4A mRNA. Our results show that clinically non-functioning macroadenomas have impaired p16^INK4A expression in a clearly higher proportion than any other pituitary tumour subtype investigated. Other regulatory pathways may be implicated in the development of tumours with positive p16^INK4A expression.     

Expression of the transferrin receptor in human anterior pituitary adenomas is confined to gonadotrophinomas

OBJECTIVE  The human pituitary gland is affected selectively by conditions associated with iron deposition, but the mechanisms for this are unknown. In this study we have determined whether the transferrin receptor, which mediates iron uptake by cells, could be detected immunocytochemically in human pituitary adenomas in vitro .
PATIENTS  Data were derived from 35 patients undergoing transsphenoidal surgery and included 13 with clinically non-functioning adenomas, 15 with acromegaly, 4 prolactinomas, 2 patients with Cushing's disease and one patient with Nelson's syndrome.
MEASUREMENTS  Transferrin receptor immunopositivity was determined for each adenoma in dispersed cell culture using a specific monoclonal antibody.
RESULTS  Eight of 13 clinically functionless adenomas showed immunopositive transferrin receptor expression, whilst adenomas from 15 patients with acromegaly, 4 prolactinomas, 2 Cushing's syndrome and one patient with Nelson's syndrome were negative. The eight transferrin receptor positive tumours were gonadotrophinomas and accounted for eight of the nine tumours which secreted and immunostained for FSH; all eight also secreted and immunostained for LH.
CONCLUSIONS  These findings may reflect a special requirement for iron by gonadotrophin secreting cells in comparison to other pituitary cell types and this could underlie the reasons why in the normal pituitary these cells are especially susceptible to malfunction in iron overload syndromes such as genetic haemochromatosis and β-thalassaemia.     

THE LEVELS AND SUBCELLULAR DISTRIBUTION OF HORMONES AND MARKER ENZYMES IN PITUITARIES FROM CONTROL SUBJECTS AND PATIENTS WITH PROLACTINOMAS, ACROMEGALY OR FUNCTIONLESS PITUITARY TUMOURS

Pituitary homogenates were prepared from patients undergoing pituitary ablation for breast or prostatic carcinoma (controls) and from patients with either PRL- and GH-secreting pituitary adenomas or from patients with 'functionless' pituitary tumours. The principal subcellular organelles, plasma membrane, lysosomes, mitochondria, endoplasmic reticulum, cytosol and hormone-containing granules were characterized by sucrose density gradient centrifugation. Tissue from patients with prolactinomas showed hormone granules, lysosomes and endoplasmic reticulum of lighter density than controls; cytosol, mitochondria and plasma membrane were similar. PRL-secreting tumours showed a 2-fold increase in PRL content with significant reduction of LH, FSH and GH. Activities of various lysosomal enzymes, except for PRL proteolytic activity, were significantly reduced. Similar conclusions were found for GH-secreting pituitary adenomas with a striking reduction in PRL proteolytic activity. Functionless tumours showed significant amounts, though reduced compared to control tissue, of all hormones. In contrast to the hormone-secreting adenomas, the activity of the lysosomal enzyme N-acetyl-beta-glucosaminidase was significantly increased compared to control tissue.     

The release of leptin and its effect on hormone release from human pituitary adenomas

BACKGROUND: Leptin is the protein product of the obese gene, known to play an important role in body energy balance. The leptin receptor exists in numerous isoforms, the long isoform being the major form involved in signal transduction. Leptin expression has recently been demonstrated in the human pituitary, both in normal tissue and in pituitary adenomas. The long isoform of the leptin receptor has also been shown to be present in pituitary adenomas; however, contrasting results have been obtained regarding its expression in the normal human pituitary. AIM: The aim of this study was (i) to investigate the presence and pattern of distribution of leptin mRNA and the long isoform of its receptor mRNA in the normal pituitary and in different types of pituitary adenomas with RT-PCR; (ii) to study leptin secretion from human pituitary tumours in culture and (iii) to assess in vitro pituitary hormone release following stimulation with human leptin. RESULTS: Leptin receptor long isoform expression was detected in 2/4 GH-secreting adenomas, 12/17 non-functioning adenomas, 5/9 ACTH-secreting adenomas, 1/2 prolactinomas, 2/2 FSH-secreting adenomas and 5/5 normal pituitaries. The receptor long isoform did not segregate with any particular tumour type, and varying levels of expression were detected between the tissues studied. Leptin mRNA was detected at a low level of expression in 2/7 GH-secreting adenomas, 9/14 non-functioning adenomas, 2/3 ACTH-secreting adenomas, 1/3 prolactinomas and 1/3 FSH-secreting adenomas. We were unable to detect leptin mRNA in any of the five normal pituitaries removed at autopsy; however, immunostaining of a non-tumorous pituitary adjacent to an adenoma removed at transsphenoidal surgery showed scattered leptin positive cells. Culture of pituitary adenomas showed that 16/47 released leptin into the incubation media. Leptin release did not correlate with tumour type or with any of the other pituitary hormones released. In vitro leptin stimulation of pituitary tumours caused stimulation of FSH and alpha-subunit secretion from a non-functioning adenoma and TSH secretion from a somatotroph adenoma. CONCLUSION: We conclude that not only is leptin stored within the pituitary, but it may also be released from pituitary cells and modulate other pituitary hormone secretion. Pituitary leptin may therefore be a novel paracrine regulator of pituitary function.     

Pure α-subunit producing tumor derived from a thyrotropic tumor: Impaired regulation of a-subunit and its mRNA by thyroid hormone

We have recently described a mouse pituitary tumor line which produces only the α-subunit of the glycoprotein hormones. This tumor line may be a useful animal model to study autonomous pituitary tumors which secrete only α-subunit. Our pure α-subunit producing tumor was derived from a thyrotropic tumor which secreted intact TSH as well as free α-subunit. Our current studies compare the regulation of α-subunit biosynthesis in a conventional thyrotropic tumor and the α-subunit producing tumor. Thyroxine or triiodothyronine administration to mice bearing the a-subunit producing tumor resulted in no change in plasma α-subunit concentration, and a 10–19% reduction in tumor α-subunit mRNA concentration that was not statistically significant. In contrast, thyroxine administration to mice bearing the thyrotropic tumor resulted in an 81% reduction in plasma α-subunit concentration, and a 75% reduction in tumor α-subunit mRNA concentration (P < 0.01). Other studies using a cDNA specific for thyrotropin-β (TSHβ) failed to detect TSHβ mRNA in the α-subunit producing tumor, while TSHβ mRNA was easily detected in the conventional thyrotropic tumor. We conclude that during the development of the a-subunit producing tumor from a thyrotropic tumor, loss of TSHβ mRNA was also associated with an impaired capacity for thyroid hormone to decrease concentrations of α-subunit mRNA.     

Age-related and gender-related occurrence of pituitary adenomas

OBJECTIVE To evaluate the various types of pituitary adenomas according to sex and age group. Few studies have attempted such an analysis, and most have focused on specific age groups, especially children. Recent data suggest that the frequency of different types of pituitary adenomas varies according to age and sex. DESIGN A retrospective review of the records of 2230 patients who underwent surgery for a pituitary adenoma at the University of California, San Francisco (UCSF), between January 1969 and June 1993. METHODS The distribution of tumours was analysed according to age at surgery, sex, and the clinical pheno-type of the tumour. Age groups were defined as the decades of life. RESULTS Prolactinomas were the most common tumours (39%), followed by endocrlne-inactive adenomas, growth-hormone-releasing adenomas, and adrenocorficotrophic hormone-releasing adenomas causing Cushing's disease; ACTH-releasing adenomas causing Nelson's syndrome and thyrotrophin (TSH)-releasing adenomas were rare. The female-to-male ratio differed considerably between the various adenoma types and between age groups. Prolactinomas, ACTH-releasing adenomas, and TSH-releasing adenomas occurred mostly in females; endocrine-inactive and GH-releasing adenomas occurred mostly in males. In older age groups, all adenoma types, except for endocrine-inactive adenomas, tended to assume a more balanced gender distribution. Among patients with prolactinomas, endocrine-inactive, ACTH-releasing, and to a lesser extent GH-releasing adenomas, the greatest discrepancy in gender distribution seemed to coincide with the peak Occurrence of each tumour type. The peak Occurrence was from the second to the fifth decade of life for prolactinomas and from the fourth to the eighth decade for endocrine-inactlve adenomas. GH-releasing, ACTH-releasing, and TSH-releaslng adenomas were more evenly distributed throughout the adult life span. CONCLUSIONS The frequency of pitultary adenomas varies greatly according to age and sex. The various adenoma types have thelr peak occurrence in distinctly dlfferent age groups and differ greatly in their female-to-male ratios. The female-to-male ratio for a given adenoma type varies greatly with age.     

Reduced serum levels of dehydroepiandrosterone sulphate in adrenal incidentalomas: a marker of adrenocortical tumour

BACKGROUND AND OBJECTIVE Reduced serum levels of dehydroeplandrosterone sulphate (DHEAS) have been shown In patients with Cushing's syndrome resulting from adrenocortical adenoma, In contrast with normal DHEAS levels In patients with Cushing's disease. The elm of this study was to verify whether patients with incidentally discovered adrenocortical adenomas also have reduced levels of DHEAS. DESIGN Evaluation of serum DHEAS, serum and urinary cortisol, plasma ACTH and low dose dexamethasone suppression test In patients with adrenal Incidentaloma and Cushing's syndrome. PATIENTS Thirty-two patients with adrenal Incidentaloma and, as controls, 17 patients with overt Cushing's syndrome, were studied. RESULTS Serum DHEAS levels lower than normal were found In 21/24 (81.5 %) patients with adrenocortical Incidentaloma, but In only 1/8 patients with a mass of non-adrenocortical origin. This patient had massive bilateral metastatic infiltration of both adrenal glands and primary adrenal failure. The prevalence of low DHEAS levels in the two groups was significantly different (P= 00001). In patients with adrenocortical Incidentaloma, the prevalence of low DHEAS levels was significantly higher (P= 00001) than that found for some hormonal alterations Indicating pre-clinical hypercortlsoilsm (high urinary cortisol, unsuppressed serum cortisol after low dose dexamethasone administration and low plasma ACTH). Low DHEAS levels were found in all patients with Cushing's syndrome due to adrenocortical adenoma but in none of those with Cushing's disease. CONCLUSIONS Our results Indicate that the finding of low DHEAS levels can be considered a marker of the adrenocortical origin of an adrenal Incidentaloma, provided adrenal failure has been excluded.     

Vasopressin levels in Cushing's disease: inferior petrosal sinus assay, response to corticotrophin-releasing hormone and comparison with patients without Cushing's disease

BACKGROUND Higher vasopressin (AVP) levels have been found in the inferior petrosal sinus ipsilateral to the ACTH-secreting adenoma than in the contralateral one, suggesting a potential pathogenetic role of AVP in Cushing's disease. DESIGN In order to investigate AVP release, plasma ACTH and AVP concentrations were assayed in the inferior petrosal sinuses and in the peripheral blood before and after CRH stimulation. PATIENTS Twenty patients with Cushing's disease and 12 with other pituitary diseases were subjected to simultaneous and bilateral inferior petrosal sinus sampling for diagnostic purposes. Ten healthy sex and age-matched subjects served as control for peripheral AVP values. MEASUREMENTS Plasma ACTH concentrations were measured by RIA using commercial kits. Plasma AVP concentrations were assayed by RIA in acetone extracts of 1–2 ml plasma. RESULTS Plasma AVP levels in the inferior petrosal sinuses were significantly higher in Cushing's disease than in patients with other pituitary diseases (P<0.05) and in both groups AVP levels were higher in the inferior petrosal sinuses than in the peripheral blood (P<0.01). In Cushing's disease, ACTH, but not AVP levels, were higher in the inferior petrosal sinus ipsilateral to the adenoma than in the contralateral one (P<0.01). Seven patients showed a significant ACTH and AVP increase (greater than 50% of baseline) after CRH stimulation in the inferior petrosal sinus ipsilateral to the adenoma. Conversely, no change was found in AVP levels in the remaining 13 patients. When AVP values were analysed in relation to surgical cure, higher inferior petrosal sinus levels (P<0.05) were found in 6 patients with poor outcome: 4 of these patients had significantly decreased plasma AVP concentrations (by 32–43% of baseline) after CRH bolus. Peripheral AVP levels were similar in healthy subjects and patients with Cushing's disease whereas they were significantly reduced in patients with other pituitary diseases (P<0.002). CONCLUSIONS The results of this study show that patients with Cushing's disease and poor surgical outcome had the highest AVP levels in our series. CRH administration caused different effects on AVP levels: it increased them in 35% of patients whereas there was no response in the remaining patients. On the basis of these findings, it is hypothesized that AVP might be involved in the persistence of ACTH hypersecretion in a subset of patients poorly responsive to surgery.     

Effects of insulin-like growth factor-I on growth hormone and prolactin secretion and cell proliferation of human somatotrophinomas and prolactinomas in vitro

OBJECTIVE IGF-I inhibits GH secretion from normal and some tumorous pituitary tissue, and has been shown to be mitogenic for gonadotrophinoma cells in vitro. It is not known whether IGF-l affects somatotrophinoma cellular proliferation or the secretion of other hormones, such as PRL and α-subunit, which are often co-secreted by these tumours. We have therefore examined the effects of IGF-l on proliferation and hormonal secretion of human somatotrophinomas and prolactinomas in vitro. DESIGN Pituitary adenoma tissue was dispersed to single cells in monolayer culture. The effects of 100 nw IGF-I on GH, PRL and α-subunit secretion were determined over 4-hour and over 4-day periods, and a 4-day dose-response study using 1–100 nM IGF-I was performed on two tumours. Adenoma cell S-phase proliferation was determined after bromodeoxyuridine Incorporation for 1 hour after 4 days, using a double immunostaining method. RESULTS Over 4 hours, 100 nw IGF-I had no effect on GH, PRL or α-subunit secretion in 7 tumours. Over 4 days, 100 nw IGF-I reduced GH secretion In 518 somatotrophinomas (range 17–84%, P < 0·05) compared to controls, with tumours responding to IGF-I having lower basal serum and in-vitro GH levels than tumours unaffected by IGF-I (P < 0·05). There was no effect on α-subunit secretion in any of the three tumours studied. PRL co-secretion was increased In 315 somatotrophinomas compared to control (20, 30 and 37%, P < 0·05), with tumours responding to IGF-I being associated with lower basal serum and in-vitro PRL levels than those tumours unaffected by IGF-I. IGF-I also increased PRL secretion in 2/2 prolactinomas (27 and 32%, P < 0·05) compared with control. GH was inhibited and PRL secretion was stimulated by 1 and 10 nw IGF-I in the two dose-response studies. The proliferative labelling index did not exceed 1·9% in any tumour and no proliferative effect was found with 100 nw IGF-I in any somatotrophinoma. CONCLUSION IGF-I inhibited tumorous GH in 62% and stimulated PRL secretion in 71 % of tumours over 4 days, without affecting α-subunit secretion or being mitogenic for somatotrophinoma cells in vitro. No hormonal effects were observed over short (4-hour) incubations. IGF-I may be a newly recognized factor directly stimulating tumorous PRL secretion.     

In-vitro evidence for the regulation of 17,20-lyase activity by cytochrome b5 in adrenocortical adenomas from patients with Cushing's syndrome

OBJECTIVE The electron transfer system molecules, NADPH-cytochrome P450 reductase (Red) and cytochrome b5 (bS) are known to increase the relative activity of 17,20-lyase to 17α-hydroxylase in vitro. Consistent with this hypothesis, we have reported recently that adrenocortical adenomas from patients with Cushing's syndrome that produced exceptionally high concentrations of androgens also contained more b5 mRNA as well as greater 17,20-lyase activity than adenomas that produced low concentrations of androgens. This finding was suggestive but inconclusive in linking b5 functionally to this difference in adenoma 17,20-lyase activity. In the present study, we have extended this finding by examining the effect of bS on microsomal 17,20-lyase activity using an antibody against cytochrome b5. DESIGN Biochemical quantitation of the content of b5 and Red activity in the microsomal fraction of the tumours and determination of 17,20-lyase activity In the microsomes in the presence or absence of an antibody against b5. PATIENTS Seven patients with a clinical diagnosis of Cushing's syndrome secondary to benign adrenocortical adenoma were studied. MEASUREMENTS The microsomal activities of 17α-hydroxylase, 17,20-lyase and 3β-hydroxysterold dehydrogenase were measured by in-vitro enzyme assay with thin layer chromatography. Microsomal Red activity was assayed by measuring NADPH-dependent cytochrome c reduction reaction. Cytochrome b5 concentration was determined by spectrophotometric analysis. RESULTS An in-vitro enzyme assay of microsomal fractions from the adenoma showed that the 17,20-lyase activities of two adenomas that produced high concentrations of adrenal androgen were threefold greater than those of five other adenomas that produced low concentrations of androgens. Cytochrome b5 concentrations were greater in the two adenomas with high 17,20-lyase activity than in the other adenomas, while no significant difference in Red activity was observed among all the adenomas. The increased 17,20-lyase activity in the two adenomas was partially but significantly antagonized by an antibody against b5. CONCLUSIONS These results suggest that differences in tissue b5 are functionally associated with differences in 17,20-lyase activity in adrenocortical adenomas In Cushing's syndrome, resulting in a dissociated secretion of Cortisol and androgens in some patients.     

Quantitative in-situ hybridization histochemistry of anterior pituitary hormone mRNA species in human pituitary adenomas

We have examined the anterior pituitary hormone messenger (m) RNA species contained in biopsies of 41 pituitary tumours obtained at hypophysectomy using in-situ hybridization histochemistry. The adenoma were grouped clinically into 12 prolactinomas, 8 somatotrope adenomas, 16 non-functioning, 4 Nelson's syndrome, and 1 thyrotrope adenoma. Of these, 10 contained no detectable anterior pituitary hormone mRNA species and 11 appeared to be expressing the gene responsible for the patients' clinical state in isolation. In a number of cases the accumulation of specific mRNA species was not accompanied by an increase in the circulating levels of the corresponding hormone or subunit. Evidence of activation of more than 1 anterior pituitary hormone gene was present in 16 adenomas of which only 7 showed a pattern of activation or amplification of gene expression which would suggest deregulation of either the inositol phospholipid or cAMP second messenger pathway. It was therefore not possible from these data to postulate that isolated deregulation of a single second messenger transduction pathway is a common etiological factor in pituitary tumour formation.     

The improvement of insulin resistance in patients with adrenal incidentaloma by surgical resection

OBJECTIVE: Several recent studies have indicated that patients with adrenal incidentaloma often have disturbed glucose tolerance or/and hypertension. It is unclear whether these metabolic conditions could be caused by adrenal incidentaloma. We investigated the prevalence of disturbed glucose tolerance, hypertension and insulin resistance in the patients with non-functioning adrenal incidentaloma and evaluated the changes of the parameters such as glucose tolerance, blood pressure and insulin sensitivity after adrenalectomy. PATIENTS AND METHODS: Among 15 patients with incidentally discovered adrenal tumours in our department from 1996 to 1999, 4 patients were diagnosed as having pre-clinical Cushing's syndrome and the other 11 as having non-functioning tumours based on detailed endocrinological examinations including dexamethasone suppression testing. Four tumours with pre-clinical Cushing's syndrome and 8 tumours out of 11 patients with non-functioning tumours were diagnosed histopathologically as adrenocortical adenomas and the other 3 as of non-adrenal origin including a myelolipoma, an adrenal vascular cyst and an endothelioma. The prevalence of disturbed glucose tolerance was determined with an oral glucose tolerance test, and insulin sensitivity was evaluated by the method of steady state of plasma glucose (SSPG). RESULTS: All 12 patients with adrenocortical adenoma exhibited insulin resistance based on the SSPG (6.9-13.2 mmol/l). Before surgical removal of the tumours, the SSPG titre was relatively higher in the patients with pre-clinical Cushing's syndrome than in those with non-functioning with adrenocortical adenoma (mean value 11.65 vs. 8.99 mmol/l), whereas 2 of the 3 patients with non-adrenocortical tumours did not have insulin resistance. Among the 12 patients with adrenocortical adenoma, 7 (58%) and 9 (75%) patients exhibited hypertension and disturbed glucose tolerance, respectively. After removal of the tumours, SSPG of the patients with adrenocortical adenoma, but not that of the other 3 patients with non-cortical tumours, was significantly decreased compared to pre-adrenalectomy values. There are no significant differences in the changes of SSPG titres between in pre-clinical Cushing's syndrome and in non-functioning adrenocortical adenoma. Systolic blood pressure, but not diastolic blood pressure, was also significantly decreased in the patients with adrenocortical adenoma. CONCLUSION: High prevalences of disturbed glucose tolerance, insulin resistance and hypertension were found among the patients with non-functioning adrenocortical tumours. Adrenocortical adenoma may be one of the risk factors for insulin resistance that is believed to induce disturbed glucose tolerance and/or hypertension. Therefore, it is useful to evaluate insulin resistance for the patients with adrenal incidentalomas since results are likely to be helpful in deciding whether to remove the tumour by surgery.     

Prevalence of Gs alpha mutations in Korean patients with pituitary adenomas

The reported frequencies of Gs alpha mutations (gsp mutations) in growth hormone (GH)-secreting pituitary adenomas are variable (ranging from 4.4 to 43%), and the presence of these mutations in the other pituitary adenomas is still a matter of controversy. Previous clinical and biochemical analyses of patients with GH-secreting pituitary adenomas and gsp mutations produced conflicting results and did not demonstrate obvious characteristics. Therefore, we investigated the prevalence of gsp mutations in Korean patients with pituitary adenomas and elucidated the characteristics of these patients. Forty-four GH-secreting adenomas, 7 prolactin (PRL)-secreting adenomas and 32 clinically non-functioning adenomas were examined for the presence of point mutations in codon 201 and 227 of the Gs alpha gene using a nested PCR and direct sequencing of DNA extracted from fresh tissue or paraffin-embedded pituitary adenoma samples. Seven of the 44 GH-secreting pituitary adenomas had point mutations at codon 201 or 227; of these, five mutations were in codon 201 and two were in codon 227. In patients with gsp mutations, mean tumor size was significantly smaller than in patients without gsp mutations (15.9+/-8.7 mm vs. 24.9+/-14.9 mm, P<0.05). Age, sex, basal GH levels, GH response to oral glucose loading, GH response to octreotide and surgical outcome were not different in the two groups. One of the 32 clinically non-functioning pituitary adenomas had a point mutation at codon 201; none of the seven prolactinomas had these mutations. These results show that gsp mutations are not rare in Korean acromegalic patients and mean tumor size is significantly smaller in acromegalic patients with gsp mutations. Our results also confirm the low frequency of gsp mutations in clinically non-functioning pituitary adenomas and the absence of gsp mutations in prolactinoma.     

Pituitary adenomas in childhood and adolescence. Clinical analysis of 10 cases

Pituitary adenomas in childhood and adolescence constitute 2-6% of all operated pituitary adenomas. We report the clinical features, treatment and follow-up of 10 pediatric patients affected by pituitary adenomas. All patients underwent clinical evaluation, endocrine tests, magnetic resonance imaging and visual field assessment. Follow-up ranged from 8 to 132 months (median 52.6). All patients were older than 10 years of age; 60% were males. In 50% the initial complaints were headache and/or visual impairment, all except one had clear evidence of endocrine dysfunction. Ninety percent were macroadenomas. According to hormone measurements and immunostaining 50% were prolactinomas, 20% were pure GH-secreting and 30% were non-functioning adenomas. Prolactinomas in two females were successfully treated with cabergoline. The other patients underwent surgery: three prolactinomas are still being treated with dopamine agonists and a GH-secreting adenoma is being treated with octreotide LAR and cabergoline. Two patients were also treated with conventional radiotherapy. Treatments were completely successful in 50% of patients: these have normal hormone secretion, full pubertal development, no significant tumor mass and normal visual field. Hypersecretion of prolactin persists in two cases; partial or complete hypopituitarism is present in four, relevant tumor remnant in another four and impairment of visual field is present in two cases. In conclusion, pediatric adenomas occur mostly in pubertal age, are prevalently macroadenomas and clinically functioning. Medical therapy should be preferred for secreting adenomas, but in some cases, notably prolactinomas in males, surgery and eventual radiotherapy may be needed.