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Biomedical subjects

G M Besser

Publications and source records attributed to G M Besser.

At least 73 records · Page 4Linked to original sources
PubMed2000

Primary hyperaldosteronism (Conn syndrome): MR imaging findings.

PURPOSE: To describe the magnetic resonance (MR) imaging features of the adrenal glands in primary hyperaldosteronism and assess MR imaging in the detection and characterization of aldosterone-producing adenoma (APA). MATERIALS AND METHODS: The authors retrospectively reviewed the cases of 20 patients (13 female and seven male patients; age range, 14-67 years; median age, 46 years) with primary hyperaldosteronism who underwent 1.5-T MR imaging between 1995 and 1998. All patients underwent transverse T1- and T2-weighted imaging, and chemical shift imaging was performed in 17 patients. Imaging results were correlated with findings at biochemical testing, venous sampling, or surgery. RESULTS: Among the 20 patients, 10 (50%) had APA and 10 (50%) bilateral adrenal hyperplasia (BAH). In the detection of APA, MR imaging had a sensitivity of 70%, specificity of 100%, and accuracy of 85%. APAs (mean size, 20 x 16 mm) were iso- or hypointense relative to the liver on T1-weighted images and slightly hyperintense on T2-weighted images. With chemical shift imaging, the signal intensity decreased on the out-of-phase images in six of seven (86%) patients with APA and in eight of nine (89%) patients with BAH. CONCLUSION: MR imaging has a high specificity in the detection of APA. As with nonhyperfunctioning adenoma, APA and BAH show evidence of intracellular lipid at chemical shift imaging.

Adenoma↗
PubMed2000

Hypothalamo-pituitary abnormalities in adult patients with langerhans cell histiocytosis: clinical, endocrinological, and radiological features and response to treatment.

Langerhans cell histiocytosis (LCH) is a rare disorder in which granulomatous deposits occur at multiple sites within the body, but which often involves the hypothalamo-pituitary axis (HPA). Although diabetes insipidus (DI) is a well recognized complication, the frequency of anterior pituitary and other nonendocrine hypothalamic (NEH) involvement has not been well defined, particularly in adult patients with the disease. We have evaluated the frequency and progression of LCH-related anterior pituitary and other NEH dysfunction and their responses to treatment in 12 adult patients with histologically proven LCH and DI. They were followed up for a median of 11.5 yr (range, 3-28 yr) after the diagnosis of DI was made. Study evaluations comprised clinical (including formal psychometric assessment where appropriate), basal and dynamic pituitary function tests, and radiology with computed tomography and/or magnetic resonance imaging scanning. Eleven patients received systemic treatment, and 5 patients received external beam radiotherapy confined to the HPA. The median age at diagnosis of DI was 34 yr (range, 2-47 yr); DI was the presenting symptom in four patients, whereas the remaining eight each developed DI 1-20 yr (median, 2 yr) after the diagnosis of LCH. Eight patients developed one or more anterior pituitary hormonal deficiencies at a median of 4.5 yr (range, 2-22 yr) after the diagnosis of DI: GH deficiency developed in eight patients (median, 2 yr; range, 2-22 yr), FSH-LH deficiency in 7 patients (median, 7 yr; range, 2-22 yr), and TSH and ACTH deficiency in five patients (median, 10 yr; range, 3-16 and 3-19 yr), respectively; five patients developed panhypopituitarism. In addition, seven patients with anterior pituitary dysfunction also developed symptoms of other NEH dysfunctions at a median of 10 yr (range, 1-23 yr): five morbid obesity (body mass index, >35), five short term memory deficits, four sleeping disorders, two disorders of thermoregulation, and one adipsia. All patients developed disease outside of the hypothalamus during the course of the study, and no fluctuation of disease activity in the HPA region was noted. Radiological examination of the HPA was abnormal in each of the eight patients with anterior pituitary involvement and in the seven patients with NEH dysfunction (one or more abnormalities): seven had thickening of the infundibulum, and one had hypothalamic and thalamic signal changes. All patients who had a magnetic resonance imaging scan had absence of the bright spot of the posterior pituitary on the T1-weighted sequences, and in four patients with DI and normal anterior pituitary function this was the only abnormality. The five patients who received radiotherapy to the HPA achieved a partial or complete radiological response, and there was no evidence of tumor progression in this region. No form of therapy, including chemotherapy, improved any established hormonal deficiencies or symptoms of NEH. In summary, in our adult patients with hypothalamic LCH and DI, anterior pituitary hormonal deficiencies developed in 8 of 12 patients; these occurred over the course of 20 yr. They were frequently accompanied by structural changes of the HPA, although these were often subtle in nature. In addition, symptoms of NEH dysfunction developed in up to 90% of such patients and complicated management. Radiotherapy may be useful in achieving local control of tumor, but established anterior, posterior pituitary, and other NEH dysfunctions do not improve in response to current treatment protocols. Patients with LCH and DI, particularly those with multisystem disease and a structural lesion on radiology, should undergo regular and prolonged endocrine assessment to establish anterior pituitary deficiency and provide appropriate hormonal replacement.

Adolescent↗
PubMed2000

Expression of the pituitary transcription factor Ptx-1, but not that of the trans-activating factor prop-1, is reduced in human corticotroph adenomas and is associated with decreased alpha-subunit secretion.

We have studied the expression of the pituitary transcription factors Ptx-1 and Prop-1 in a series of 34 pituitary adenomas fully characterized for in vitro hormone secretion and histological staining. In studies involving mammalian cell lines, the pituitary transcription factor Ptx-1 has been shown to be a pituitary hormone panactivator, whereas more recent studies have shown that it plays an important role in alpha-subunit gene expression. Its expression has not been examined previously in human pituitary adenomas characterized by in vitro hormone secretory profiles. Of the 34 pituitary adenomas studied, Ptx-1 expression was reduced by more than 50% compared to that of the housekeeping gene human glyceraldehyde-3-phosphate dehydrogenase in the 6 corticotroph adenomas, which also had significantly reduced alpha-subunit production (all 6 tumors secreting < or =0.5 ng/24 h). Mutations of the pituitary transcription factor Prop-1, which is responsible for the syndrome of Ames dwarfism in mice, are being increasingly recognized as a cause of combined pituitary hormone deficiency in humans, although ACTH deficiency has been described only once. Prop-1 expression was detected in all 34 pituitary adenomas, including 6 corticotroph adenomas and 5 gonadotroph adenomas. The expression of Prop-1 has not been described previously in these cell phenotypes.

Acromegaly↗
PubMed2000

Insulin-like growth factor I and the development of colorectal neoplasia in acromegaly.

Patients with acromegaly are at increased risk of colorectal neoplasia and, by analogy with high-risk nonacromegalic patients, may require regular colonoscopic screening. However, it is unknown whether the risk is equal in all patients or whether some should be regarded as carrying a particularly high risk. The aims of this study were: 1) to establish the natural history of colorectal neoplasia in acromegaly; 2) to establish which patients are at increased risk of developing neoplasia; and 3) to elucidate the influence of insulin-like growth factor I (IGF-I) in adenoma formation. A prospective colonoscopic evaluation of the development of new premalignant adenomas in the colon was performed in 66 patients with biochemically proven acromegaly who had previously undergone colonoscopic screening and removal of all visible polyps. Twenty-five patients (38%) had a total of 37 polyps detected at the second colonoscopy: nine (14%) had at least one adenoma, and 18 (27%) had one or more hyperplastic polyps (2 patients had both). The development of new adenomas, but not hyperplastic polyps, was associated both with elevated serum IGF-I (P < 0.005) and, to a lesser extent, with a previous adenoma at the original colonoscopy (P < 0.07). In summary, patients with acromegaly and in whom serum IGF-I remains elevated and/or who have had a previous adenoma should be regarded as having an especially high risk for the development of subsequent colorectal neoplasia. Serum IGF-I seems to be implicated in the development of colorectal neoplasia in acromegaly, although the exact mechanisms remain uncertain.

Acromegaly↗
PubMed2000

Linear growth and final height after treatment for Cushing's disease in childhood.

Cushing's disease is associated with growth failure in childhood and adolescence. Growth and final height were analyzed in 10 patients who were cured or in remission after treatment of Cushing's disease. Seven males and 3 females, aged 6.8-17.6 yr (bone age, 3.3-15.4 yr), had transsphenoidal surgery, which was combined with pituitary irradiation (4,500 cGy in 25 fractions) in 5 patients. At presentation, 5 patients were prepubertal (males), and 5 were pubertal (2 males and 3 females). The mean height SD score was -2.15 +/-1.26 (range, -0.21 to -4.32) compared with mean target height SD score of -0.43 +/- 0.58. Height velocity in 6 patients was subnormal (0.9-3.8 cm/yr). After treatment, short-term height velocity, over a mean interval of 0.57 yr, in 8 patients not receiving human GH (hGH) therapy, was variable (range, 0.8-7.6 cm/yr). GH stimulation tests (insulin tolerance test/glucagon) in 9 subjects showed peak GH levels of 0.5-20.9 mU/L. Eight were treated with hGH (14 IU/m2 wk), combined in 2 girls and 1 boy with a GnRH analog. After 1 yr of hGH, the mean height SD score had increased from -2.45 +/- 1.0 at initiation of hGH to -2.07 +/- 1.2 (P = 0.01). GH therapy was continued until final height or latest assessment. The mean final height SD score (n = 6) was - 1.24 +/- 1.38, and at the latest assessment the mean height SD score (n = 4) was - 1.52 +/- 1.33. Combining these 2 groups, the mean height so score was -1.36 +/- 1.29. The difference between final or latest height SD score and target height SD score was 0.93 +/- 1.13, i.e. less (P = 0.005) than the difference between height and target height SD score of 1.72 +/- 1.26 at presentation. In conclusion, catch-up and favorable long-term growth was seen after treatment for Cushing's disease. Posttreatment GH deficiency was frequent, and early hGH replacement may have contributed to the encouraging outcome.

Adolescent↗
PubMed2000

Alterations in serum protein levels in patients with Cushing's syndrome before and after successful treatment.

Alteration in serum protein concentration is used commonly in clinical practice as a nonspecific indicator of underlying disease or to monitor disease activity. Although hypercortisolemia may affect protein metabolism directly or indirectly, data regarding alterations of levels of serum protein in a large series of patients with Cushing's syndrome (CS) have been lacking. We have now evaluated, retrospectively, the levels of circulating serum albumin, globulins, total proteins, and the albumin to globulin ratio in 99 patients with endogenous CS before, immediately after, and 3, 6, and 12 months following successful treatment. Subjects with concomitant infections or other chronic diseases were excluded from the analysis. Although mean serum albumin and total protein levels were within the normal reference ranges, in general, they gradually increased after treatment with maximal values being reached at 12 months after normalization of hypercortisolemia (P < 0.0001 for both); there were no significant changes in serum globulin levels or in the albumin to globulin ratio. Patients with CS as a whole showed a weak but significant negative correlation between serum albumin and 0900 h cortisol level (r = -0.303; P = 0.0035). In conclusion, our data suggest that CS is associated with a small but significant reduction in circulating serum protein levels, which are restored following treatment of hypercortisolemia, although these changes occur within the reference range. Thus, extreme alterations in serum total protein or albumin levels in patients with CS should alert physicians to the presence of concomitant pathology, and additional specific investigation should be undertaken to elucidate the cause.

Adrenergic Agents↗
PubMed1999

Adrenal enlargement and failure of suppression of circulating cortisol by dexamethasone in patients with malignancy.

The aim of this study was to further elucidate the activity of the hypothalamo-pituitary-adrenal (HPA) axis in patients with malignancy and to correlate this with the size of the adrenal glands. Fourteen patients with a variety of malignancies were studied prior to receiving cytotoxic chemotherapy. During routine staging computerized tomographic (CT) scans, the size of the body, medial and lateral limbs of the adrenal glands were measured and compared with those of a normal group of patients studied previously. Measurements of 09:00 h serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels were made before and after the administration of dexamethasone (0.5 mg 6-hourly for 48 h) in addition to the peak cortisol response to i.v corticotropin releasing hormone (CRH). Overall, patients with malignancy had significantly larger adrenal glands than patients without malignancy; those with non-haematological malignancies had larger glands than patients with haematological malignancies. Following dexamethasone to suppress circulating cortisol levels, nine patients (64%) demonstrated abnormal resistance with cortisol levels > 50 nmol l(-1): mean value 294 nmol l(-1) (range 67-1147). Those patients who failed to suppress after dexamethasone had significantly larger adrenal glands than those that did suppress and tended to have non-haematological malignancies. ACTH levels were undetectable or low in three patients in whom it was measured and who did not suppress with dexamethasone. Following CRH, the cortisol levels were highest (823 and 853 nmol l(-1)) in two of these patients. Malignancy is associated with diffuse enlargement of the adrenal glands and resistance to dexamethasone-induced suppression of the HPA axis, which is not due to ectopic ACTH secretion. This disturbance of the normal control of the HPA axis is unexplained and its functional significance remains uncertain.

Adrenal Glands↗
PubMed1999

Effects of growth hormone replacement on physical performance and body composition in GH deficient adults.

OBJECTIVES: Adults with GH deficiency complain frequently of low energy levels resulting in a low perceived quality of life. Body composition is altered, with increased fat mass and decreased lean body mass, and muscle strength is reduced. The aims of this study were to determine the effects of GH replacement on physical performance and body composition in GH deficient (GHD) adults. STUDY DESIGN: The study consisted of a 6-month randomised, double-blind, placebo controlled study of the administration of GH (0.25 IU/Kg/week (0.125 IU/kg/week for the first four weeks)) followed by a 6-month open phase of GH therapy. PATIENTS: Thirty-five GHD adults (17F), mean age 39.8 years (range 21.1-59.9), on conventional replacement therapy as required. METHODS: Maximum aerobic capacity was measured using an incremental walking test to volitional exhaustion on a motorized treadmill. Quadriceps muscle strength was assessed by measuring maximum voluntary contractions and body composition by dual energy X-ray absorptiometry (DEXA). RESULTS: There were no statistically significant changes in quadriceps muscle strength between the GH and placebo groups. In both groups, there was a significant increase in quadriceps muscle strength compared to baseline during the double-blind period (GH group: P = 0.016; placebo group: P = 0.048). Compared to baseline, muscle strength was further improved in the GH treatment group after 12 months of treatment (P = 0.007). No further improvement was noted in the placebo group after 6 months on open GH treatment. In the placebo group, maximum aerobic capacity decreased during the placebo period (P = 0.017). No significant change was observed in the GH group. During open GH treatment the previously placebo treated group had a significant increase of maximum aerobic capacity (P < 0.049) whereas no significant improvement could be seen in the GH group. In the GH group there was a significant increase in lean body mass (P = 0.001) and a significant decrease in fat mass (P < 0.001). No statistically significant changes were noted in the placebo group: the differences in these changes between treatment groups were statistically significant (lean body mass: P = 0.009; fat mass: P < 0.001). The changes in body composition in the GH group during the 6 month placebo-controlled period were maintained during continued open treatment. Similar changes in body composition to those observed in the GH group during the 6 month placebo-controlled period were also seen in the placebo group once the patients received GH treatment. CONCLUSIONS: Our data show that GH replacement in GH deficient adults is associated with favourable changes in body composition, which could be important in the long term health outcome and physical activity of GH deficient patients. Our data support the concept that GH therapy alone, in the absence of some form of exercise programme, may increase the amount of lean tissue but not the quality or functional capacity of this tissue and it may be that training, in addition to GH therapy, may be necessary to significantly increase physical performance in these patients. We suggest that future trials with GH therapy and general approaches to the treatment of GH deficiency should include a planned activity programme as an approach to health improvement in these patients.

Absorptiometry, Photon↗
PubMed1999

Hexarelin as a test of pituitary reserve in patients with pituitary disease.

BACKGROUND: The insulin tolerance test (ITT) is the reference standard for the diagnosis of cortisol and growth hormone (GH) deficiency, but problems have occurred in small children in inexperienced hands and it is contraindicated in patients with cardiac disease and epilepsy. Hexarelin is a growth hormone-releasing peptide with GH-, ACTH/cortisol- and prolactin-releasing effects which involve both hypothalamic and direct pituitary mechanisms. We therefore investigated whether it could be used to test GH and ACTH/cortisol reserve in patients with pituitary disease. METHODS AND SUBJECTS: The changes in GH and cortisol in response to insulin-induced hypoglycaemia (intravenous human Actrapid 0.15 IU/kg) and hexarelin (2 microg/kg) in 19 patients with possible pituitary disease (5 males, mean age 39 years, range 21-70) were compared. The patients' responses during the hexarelin test were also compared to normal ranges of GH and cortisol responses established in healthy volunteers following hexarelin administration. RESULTS AND DISCUSSION: GH peak levels were significantly higher after hexarelin than after hypoglycaemia (mean +/- SEM; 67.1 +/- 16 vs. 26.9 +/- 6.8 mU/l respectively; P < 0. 001), while cortisol levels were significantly lower (420 +/- 34 vs. 605 +/- 50 nmol/l; P < 0.001). The peak responses of both hormones correlated significantly between the hexarelin and insulin-induced hypoglycaemia tests (r = 0.80, P < 0.001 for cortisol). Peak GH levels after hexarelin and ITT showed a significant positive correlation with IGF-I levels (r = 0.84 and r = 0.77, P < 0.001 for both). All patients with a subnormal GH response to hexarelin (<41.4 mU/l) had a peak GH response to ITT of <9 mU/l, and only one patient had a normal (although borderline) response to hexarelin with a subnormal GH response to the ITT. Although 17 of the 19 patients had corresponding cortisol responses to hexarelin and the ITT test (either failing or passing both), two patients had normal cortisol responses to hexarelin but subnormal responses to the ITT. A peak serum cortisol level following hypoglycaemia of >580 nmol/l is indicative of normal cortisol reserve, as established in patients undergoing surgery; only five of the normal volunteers and one of the thirteen patients with a normal ACTH/cortisol reserve on ITT had a peak cortisol >580 nmol/l in response to hexarelin. CONCLUSION: Adult patients who have a subnormal peak GH response to hexarelin are likely to be GH deficient on an insulin tolerance test. However, our data suggest that the hexarelin test is not a useful test of ACTH/cortisol reserve. The hexarelin test could be a useful first/screening test to diagnose adult GH deficiency, particularly in patients in whom an insulin tolerance test is contraindicated or who are already ACTH deficient and in whom the GH reserve alone is of interest.

Adrenocorticotropic Hormone↗
PubMed1999

Quantitative growth hormone secretion and final adult height.

OBJECTIVE: The relationship of quantitative GH secretion to height, growth velocity and puberty is complex and has been the subject of extensive study in children. This study was designed to relate quantitative GH secretion to final height. SUBJECTS: Twenty tall (> 183 cm, 90th centile for adult height) and 20 short (< 166 cm, 10th centile) postpubertal men who had recently completed linear growth (age range 18-27 years). MEASUREMENTS: GH dynamics were studied on four occasions; insulin (0.15 units/kg, iv)-induced hypoglycaemia and GHRH (100 mg, iv) with and without the anticholinesterase, pyridostigmine (120 mg orally). Spontaneous nocturnal GH secretion was assessed by 20 minute sampling from 2100 h until 0600 h. GH was measured by IRMA. Analysis was by comparison of peak GH response and area under the curve (AUC). GH profiles were further analysed using the 'pulsar' programme. RESULTS: The mean height in the tall group was 187.7 cm (range 183-197) compared to 163.5 cm (range 160-166) for the short group. No difference existed between groups in the GH response to hypoglycaemia or GHRH with and without pyridostigmine. Area under the curve, pulse number, length and amplitude for spontaneous nocturnal GH secretion showed no significant difference between the tall and short subjects. Serum IGF-I (mean 230.5 +/- 15. 4 vs. 230.6 +/- 18.9 microg/l) did not differ between the groups. CONCLUSIONS: Quantitative GH secretion does not appear to be an important determinant of final height in healthy individuals.

Adult↗
PubMed1999

Prolonged large bowel transit increases serum deoxycholic acid: a risk factor for octreotide induced gallstones.

BACKGROUND: Treatment of acromegaly with octreotide increases the proportion of deoxycholic acid in, and the cholesterol saturation of, bile and induces the formation of gallstones. Prolongation of intestinal transit has been proposed as the mechanism for the increase in the proportion of deoxycholic acid in bile. AIMS: To study the effects of octreotide on intestinal transit in acromegalic patients during octreotide treatment, and to examine the relation between intestinal transit and bile acid composition in fasting serum. METHODS: Mouth to caecum and large bowel transit times, and the proportion of deoxycholic acid in fasting serum were measured in non-acromegalic controls, acromegalic patients untreated with octreotide, acromegalics on long term octreotide, and patients with simple constipation. Intestinal transit and the proportion of deoxycholic acid were compared in acromegalic patients before and during octreotide. RESULTS: Acromegalics untreated with octreotide had longer mouth to caecum and large bowel transit times than controls. Intestinal transit was further prolonged by chronic octreotide treatment. There were significant linear relations between large bowel transit time and the proportion of deoxycholic acid in the total, conjugated, and unconjugated fractions of fasting serum. CONCLUSIONS: These data support the hypothesis that, by prolonging large bowel transit, octreotide increases the proportion of deoxycholic acid in fasting serum (and, by implication, in bile) and thereby the risk of gallstone formation.

Acromegaly↗
PubMed1999

Respiratory muscle strength in Cushing's syndrome.

The effect of Cushing's syndrome on respiratory muscle strength is unknown. Therefore, we studied 10 consecutive patients with severe Cushing's syndrome. The respiratory muscles were assessed using maximal inspiratory and expiratory mouth pressures (MIP, MEP), maximal sniff transdiaphragmatic pressures (max sniff Pdi), and maximal sniff esophageal pressures (max sniff Pes). Maximal quadricep strength was also assessed. The patients demonstrated an overall mean MIP 92 cm H(2)O, SD 19 (mean 105% of predicted; SD, 23%), mean MEP 134 cm H(2)O, SD 35 (mean 99% of predicted; SD, 25%), mean max sniff Pdi 107 cm H(2)O, SD 12 (mean 78% of predicted; SD, 10%) and mean max sniff Pes of 92 cm H(2)O, SD 11 (mean 92% of predicted; SD, 11%). Quadriceps muscle strength was reduced in all 10 patients: mean 26 kg, SD 9 (mean 49% of predicted strength, SD 21%). Respiratory muscle weakness was not found, despite the presence of severe quadriceps impairment. We conclude that major weakness of the respiratory muscles is not usual in Cushing's syndrome.

Adult↗
PubMed1999

Low expression of the cell cycle inhibitor p27Kip1 in normal corticotroph cells, corticotroph tumors, and malignant pituitary tumors.

The cell cycle is regulated by a number of inhibitors, including p27Kip1 (p27), which belongs to the kip1 family. By binding to the cyclin/cyclin-dependent kinase complexes, it regulates progression of G1 to S phase in the cell cycle. It has been reported that p27 knockout mice develop multiorgan hyperplasia and intermediate lobe pituitary tumors secreting ACTH. Previously, we and others have been unable to show any consistent change in messenger RNA expression or genomic mutations for p27 in human corticotroph adenomas. However, dysregulation at the protein level has been reported in nonendocrine tumors, and we, therefore, investigated the expression of p27 in a range of benign and metastatic pituitary tumors. We studied a total of 107 pituitaries, including normal pituitary (n = 20), Cushing's disease (n = 21), acromegaly (n = 19), nonfunctioning adenomas (n = 18), prolactinomas (n = 7), TSH-omas (n = 2), FSH-omas (n = 6), aggressive tumors showing invasiveness and recurrence (n = 9), and metastatic pituitary carcinomas (n = 5). Using standard immunohistochemical techniques with a highly specific monoclonal antibody, p27 expression was determined quantitatively as the percentage of cells showing strongly positive, weak, or negative staining. In each sample, approximately 500 cells were analyzed. We also analyzed normal pituitaries using double-labeling for p27 and each of the pituitary hormones to characterize the expression of p27 in each cell type. p27 was expressed in normal pituitary cells; in tumors expressing GH, prolactin, TSH, and FSH; and in aggressive tumors, but markedly reduced expression of p27 was seen in corticotroph tumors and pituitary carcinomas. In the normal pituitary, somatotroph, lactotroph, and thyrotroph cells showed strong p27 staining, whereas normal corticotroph cells showed a much lower level of p27 staining (P < 0.001). Somatotroph, lactotroph, gonadotroph, and thyrotroph adenomas showed a lower level of p27 expression compared with normal somatotrophs (P = 0.02), lactotrophs (P = 0.03), gonadotrophs (P = 0.01), and thyrotrophs, respectively, whereas the lower level of p27 expression present in normal corticotrophs virtually disappeared in corticotroph adenomas (P = 0.001). We conclude that pituitary adenomas show a lower level of p27 protein expression than the normal cells from which they are derived, with malignant transformation leading to complete loss of p27 immunoreactivity. Corticotrophs are quite different to other pituitary cell types in terms of p27 immunoreactivity because both normal and tumorous corticotrophs have low p27 staining, and we speculate that this may relate to their inherent control mechanisms.

Adenoma↗
PubMed1999

Modulation of 11beta-hydroxysteroid dehydrogenase isozymes by growth hormone and insulin-like growth factor: in vivo and in vitro studies.

The interconversion of hormonally active cortisol (F) and inactive cortisone (E) is catalyzed by two isozymes of 11beta-hydroxysteroid dehydrogenase (11betaHSD), an oxo-reductase converting E to F (11betaHSD1) and a dehydrogenase (11betaHSD2) converting F to E. 11betaHSD1 is important in mediating glucocorticoid-regulated glucose homeostasis and regional adipocyte differentiation. Earlier studies conducted with GH-deficient subjects treated with replacement GH suggested that GH may modulate 11betaHSD1 activity. In 7 acromegalic subjects withdrawing from medical therapy (Sandostatin-LAR; 20-40 mg/month for at least 12 months), GH rose from 7.1 +/- 1.5 to 17.5 +/- 4.3 mU/L (mean +/- SE), and insulin-like growth factor I (IGF-I) rose from 43.0 +/- 8.8 to 82.1 +/- 13.7 nmol/L (both P < 0.05) 4 months after treatment. There was a significant alteration in the normal set-point of F to E interconversion toward E. The fall in the urinary tetrahydrocortisols/tetrahydocortisone ratio (THF+allo-THF/THE; 0.82 +/- 0.06 to 0.60 +/- 0.06; P < 0.02) but unaltered urinary free F/urinary free E ratio (a marker for 11betaHSD2 activity) suggested that this was due to inhibition of 11betaHSD1 activity. An inverse correlation between GH and the THF+allo-THF/THE ratio was observed (r = -0.422; P < 0.05). Conversely, in 12 acromegalic patients treated by transsphenoidal surgery (GH falling from 124 +/- 49.2 to 29.3 +/- 15.4 mU/L; P < 0.01), the THF+allo-THF/THE ratio rose from 0.53 +/- 0.06 to 0.63 +/- 0.07 (P < 0.05). Patients from either group who failed to demonstrate a change in GH levels showed no change in the THF+allo-THF/THE ratio. In vitro studies conducted on cells stably transfected with either the human 11betaHSD1 or 11betaHSD2 complementary DNA and primary cultures of human omental adipose stromal cells expressing only the 11betaHSD1 isozyme indicated a dose-dependent inhibition of 11betaHSD1 oxo-reductase activity with IGF-I, but not GH. Neither IGF-I nor GH had any effect on 11betaHSD2 activity. GH, through an IGF-I-mediated effect, inhibits 11betaHSD1 activity. This reduction in E to F conversion will increase the MCR of F, and care should be taken to monitor the adequacy of function of the hypothalamo-pituitary-adrenal axis in acromegalic subjects and in GH-deficient, hypopituitary patients commencing replacement GH therapy. Conversely, enhanced E to F conversion occurs with a reduction in GH levels; in liver and adipose tissue this would result in increased hepatic glucose output and visceral adiposity, suggesting that part of the phenotype currently attributable to adult GH deficiency may be an indirect consequence of its effect on tissue F metabolism via 11betaHSD1 expression.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1999

Serum cytokines in thyrotoxicosis.

Overproduction of thyroid hormones promotes bone resorption in vivo and in vitro, and we have evaluated whether mediators of such effects could include the osteotropic cytokines. Previous studies have demonstrated raised serum interleukin (IL)-6 in thyrotoxic patients, but differentiating the contribution of the elevated thyroid hormones from that of the autoimmune inflammation present in Graves' disease (GD) has been difficult. We undertook a longitudinal study of 34 patients (19-45 yr old) with GD, toxic nodular goiter (TNG), or a history of thyroid carcinoma but no evidence of disease recurrence, receiving sufficient T4 to suppress TSH. Controls were 12 euthyroid females. The following measurements were made basally and for 6 months after carbimazole treatment: serum free T4, T3, bone-specific alkaline phosphatase (b-ALP), IL-6, IL-8, IL-1beta, tumor necrosis factor-alpha, IL-11, and urinary deoxypyridinoline (Udpd). Compared with controls (IL-6, 1.1 +/- 0.3 ng/L; IL-8, 3.2 +/- 0.8 ng/L), untreated patients with GD and TNG had elevated IL-6 (GD, 7.11 +/- 0.88 ng/L; TNG, 7.30 +/- 0.77 ng/L; P < 0.001) and IL-8 (GD, 10.3 +/- 1.23 ng/L; TNG, 9.81 +/- 1.27 ng/L; P < 0.001). These levels fell after treatment and were then indistinguishable from those in control subjects. Thyroid carcinoma patients on TSH suppressive therapy also had significantly raised levels of IL-6 (2.5 +/- 0.42 ng/L) and IL-8 (4.4 +/- 0.63 ng/L). When data from all the patients were pooled, the levels of IL-6 and IL-8 correlated with serum T3 and free T4 but not with Udpd or b-ALP. IL-1beta, IL-11, and tumor necrosis factor-alpha were not raised in any patient. The elevations in serum IL-6 and -8 that occur in hyperthyroidism seem to result from the chronic effects of thyroid hormone excess rather than the accompanying autoimmune inflammatory condition produced by Graves' thyroid or eye disease. The site of the presumed increased production of IL-6 and -8 is most likely from bone osteoblasts, despite the inability of bone markers (such as Udpd and b-ALP) to correlate with acute changes in thyroid hormone status produced by antithyroid therapy.

Adult↗