Acromegaly.

Acromegaly is a rare, chronic, progressive disease characterized by an excess secretion of growth hormone (GH) and increased circulating insulin-like growth factor 1 (IGF-1) concentrations. It is caused by a pituitary adenoma in the vast majority of cases. The clinical diagnosis, based on symptoms related to GH excess, is often delayed due to the insidious nature of the disease. Consequently, patients often have established systemic complications at diagnosis with increased morbidity and premature mortality. Serum IGF-1 measurement is recommended as the initial screen for patients with suspected acromegaly. The gold standard diagnostic test remains the oral glucose tolerance test with concomitant GH measurement. Therapy for acromegaly is targeted at decreasing GH and IGF-1 levels, ameliorating patients' symptoms and decreasing any local compressive effects of the pituitary adenoma. The therapeutic options for acromegaly include surgery, medical therapies (such as dopamine agonists, somatostatin receptor agonists and the GH receptor antagonist pegvisomant) and radiotherapy. A multidisciplinary approach is recommended with often a requirement for combined treatment modalities. With disease control, associated morbidity and mortality can be reduced. The recently published evidence-based guidelines by the Endocrine society addressed important clinical issues regarding the evaluation and management of acromegaly. This review discusses advances in our understanding of the pathophysiology of acromegaly, diagnosis of various forms of the disease and focuses on current treatment modalities, and on future pharmacological therapies for patients with acromegaly.

Tissue specific regulation of glucocorticoids in severe obesity and the response to significant weight loss following bariatric surgery (BARICORT).

CONTEXT: Tissue cortisol exposure is under the control of the isozymes of 11ß-hydroxysteroid dehydrogenase (11ß-HSD). 11ß-HSD1 in vivo, acts as an oxoreductase converting inactive cortisone to active cortisol. We hypothesized that 11ß-HSD1 activity is dysregulated in obesity and alters following bariatric surgery induced weight loss in different tissues. METHODS: We recruited 21 patients prior to undergoing bariatric surgery and performed cortisol generation profiles (following oral cortisone administration), urinary corticosteroid metabolite analysis, adipose tissue microdialysis, and tissue gene expression before and after weight loss, following bariatric surgery. Archived tissue samples from 20 previous bariatric surgery patients were also used for tissue gene expression studies. RESULTS: Gene expression showed a positive correlation with 11ß-HSD1 and BMI in omental adipose tissue (OM) (r = +0.52, P = .0001) but not sc adipose tissue (r = +0.28, P = .17). 11ß-HSD1 expression in liver negatively correlated with body mass index (BMI) (r = -0.37, P = .04). 11ß-HSD1 expression in sc adipose tissue was significantly reduced after weight loss (0.41 ± 0.28 vs 0.17 ± 0.1 arbitrary units, P = .02). Following weight loss, serum cortisol generation increased during a cortisol generation profile (area under the curve 26 768 ± 16 880 vs 47 579 ± 16 086 nmol/L/minute, P ≤ .0001.) Urinary corticosteroid metabolites demonstrated a significant reduction in total cortisol metabolites after bariatric surgery (15 224 ± 6595 vs 8814 ± 4824 µg/24 h, P = .01). Microdialysis of sc adipose tissue showed a threefold reduction in cortisol/cortisone ratio after weight loss. CONCLUSIONS: This study highlights the differences in tissue specific regulation of cortisol metabolism in obesity and after weight loss. Following bariatric surgery hepatic 11ß-HSD1 activity increases, sc adipose tissue 11ß-HSD1 activity is reduced and total urinary cortisol metabolites are reduced indicating a possible reduction in hypothalamic pituitary adrenal axis drive. 11ß-HSD1 expression correlates positively with BMI in omental adipose tissue and negatively within hepatic tissue. 11ß-HSD1 expression is reduced in sc adipose tissue after weight loss.

Central hypoadrenalism.

CONTEXT: Central hypoadrenalism is a frequent complication of pituitary and hypothalamic pathology and is associated with increased morbidity and mortality. Optimal exogenous glucocorticoid use is dependent on the use of appropriate diagnostic tests and careful assessment of the clinical response to glucocorticoid replacement therapy. EVIDENCE ACQUISITION: A PubMed search for the terms central hypoadrenalism, ACTH deficiency, glucocorticoid suppression, and glucocorticoid replacement was conducted; the papers identified and the references listed were used to build a reference list. EVIDENCE SYNTHESIS: The published literature was assessed to present a summary of the available evidence with regard to etiology, diagnosis, and treatment of central hypoadrenalism. CONCLUSIONS: A functional hypothalamic pituitary adrenal axis is essential for normal health and life expectancy; its complexity presents challenges to the clinician in the identification of patients and in the maintenance of such patients in a glucocorticoid-sufficient state. The most common cause of central hypoadrenalism remains exogenous glucocorticoid use. Further research in this field should be directed toward disease prevention by minimizing glucocorticoid exposure and toward the identification of a biomarker for glucocorticoid sufficiency that will aid clinicians in optimizing treatment.

Synergistic induction of local glucocorticoid generation by inflammatory cytokines and glucocorticoids: implications for inflammation associated bone loss.

OBJECTIVES: Synovial fibroblasts and osteoblasts generate active glucocorticoids by means of the 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme. This activity increases in response to proinflammatory cytokines or glucocorticoids. During inflammatory arthritis synovium and bone are exposed to both these factors. This study hypothesised that glucocorticoids magnify the effects of inflammatory cytokines on local glucocorticoid production in both synovium and bone. METHODS: The effects of inflammatory cytokines (IL-1beta/tumour necrosis factor alpha; TNFalpha) and glucocorticoids, alone or combined, were assessed on the expression and activity of 11beta-HSD1 in primary synovial fibroblasts, primary human osteoblasts and MG-63 osteosarcoma cells. A range of other target genes and cell types were used to examine the specificity of effects. Functional consequences were assessed using IL-6 ELISA. RESULTS: In synovial fibroblasts and osteoblasts, treatment with cytokines or glucocorticoids in isolation induced 11beta-HSD1 expression and activity. However, in combination, 11beta-HSD1 expression, activity and functional consequences were induced synergistically to a level not seen with isolated treatments. This effect was seen in normal skin fibroblasts but not foreskin fibroblasts or adipocytes and was only seen for the 11beta-HSD1 gene. Synergistic induction had functional consequences on IL-6 production. CONCLUSIONS: Combined treatment with inflammatory cytokines and glucocorticoids synergistically induces 11beta-HSD1 expression and activity in synovial fibroblasts and osteoblasts, providing a mechanism by which synovium and bone can interact to enhance anti-inflammatory responses by increasing localised glucocorticoid levels. However, the synergistic induction of 11beta-HSD1 might also cause detrimental glucocorticoid accumulation in bone or surrounding tissues.

ACTH deficiency, higher doses of hydrocortisone replacement, and radiotherapy are independent predictors of mortality in patients with acromegaly.

CONTEXT: A number of retrospective studies report that patients with acromegaly have increased morbidity and premature mortality, with standardized mortality ratios (SMR) of 1.3-3. Many patients with acromegaly develop hypopituitarism as a result of the pituitary adenoma itself or therapies such as surgery and radiotherapy. Pituitary radiotherapy and hypopituitarism have also been associated with an increased SMR. METHODS: Using the West MIDLANDS: Acromegaly database (n = 501; 275 female), we assessed the influence of prior radiotherapy and hypopituitarism (and replacement therapy) on mortality in patients with acromegaly. Median duration of follow-up was 14.0 yr (interquartile range, 7.9-21 yr). RESULTS: All-cause mortality was elevated [SMR, 1.7 (1.4, 2.0); P < 0.001]. On external analysis, prior radiotherapy, ACTH, and gonadotropin deficiency were associated with an elevated SMR [radiotherapy SMR, 2.1 (1.7-2.6); P = 0.006; ACTH deficiency SMR, 2.5 (1.9-3.2); P < 0.0005; and gonadotropin deficiency SMR, 2.1 (1.6-2.7); P = 0.037]. On internal analysis, the relative risk (RR) of mortality was increased in the radiotherapy [RR, 1.8 (1.2-2.8); P = 0.008] and ACTH-deficiency groups [RR, 1.7 (1.2-2.5); P = 0.004], but not in the gonadotropin- or TSH-deficiency groups. In the ACTH-deficient group, increased replacement doses of hydrocortisone greater than 25 mg/d were associated with increased mortality compared to lower doses. CONCLUSIONS: Radiotherapy and ACTH deficiency are significantly associated with increased mortality in patients with acromegaly. In ACTH-deficient patients, a daily dose of more than 25 mg hydrocortisone is associated with increased mortality compared to lower doses. These results have important implications for the treatment of patients with acromegaly and also raise issues as to the optimum hydrocortisone treatment regimens for ACTH-deficient patients.

Medical therapy in patients with acromegaly: predictors of response and comparison of efficacy of dopamine agonists and somatostatin analogues.

CONTEXT: Acromegaly is associated with increased morbidity and mortality. Treatment options include surgery, radiotherapy, and medical therapy. AIMS: The objective of the study was to examine the role of prolactin status, prior surgery, and radiotherapy on the response to medical therapy in patients with acromegaly and assess the relative efficacy of dopamine agonist therapy compared with somatostatin analog therapy. MATERIALS AND METHODS: A total of 276 patients with acromegaly received either dopamine agonists (DA) and/or somatostatin analogs (SSA). One hundred seventy-two patients had received surgery and 73 radiotherapy prior to receiving medical therapy. One hundred ninety-eight of 276 received DA, and 143 of 276 received SSA. GH and IGF-I values at baseline and after 12 months on therapy were analyzed. RESULTS: In the DA group, basal prolactin concentration did not predict response to therapy, GH percent reduction: hyperprolactinemia, 26.7% (-10.4 to 48) vs. normoprolactinemia, 34.8% (0.2-53.2), P = 0.58; IGF-I percent reduction: hyperprolactinemia 30.0% (9.2-43.1) vs. normoprolactinemia 16.8% (4-37), P = 0.45. Prior surgery was not associated with any difference in response to DA: GH percent reduction (P = 0.1) and IGF-I percent reduction (P = 0.08). By contrast, prior radiotherapy was associated with an enhanced efficacy of GH response to DA, P = 0.02. In the SSA group, there was no effect of prior surgery or radiotherapy on response of GH, but radiotherapy was associated with less marked IGF-I percent reduction (P = 0.05). SSA were more potent than DA at decreasing both GH [62.8% (20.7-85%) vs. 42.4% (-6.5 to 68.6), P < 0.008] and IGF-I [SSA 40.4% (0-64.3) vs. 8% (0-40.8), P = 0.05]. CONCLUSIONS: The effects of DA are irrespective of baseline prolactin concentrations. Prior radiotherapy is associated with differences in GH and IGF-I response to DA and SSA therapy.

Monitoring disease activity using GH and IGF-I in the follow-up of 501 patients with acromegaly.

CONTEXT: The aims of treatment in patients with acromegaly are to achieve serum GH/IGF-I concentrations associated with cure or normalization of mortality and alleviation of symptoms. OBJECTIVE AND METHODS: Using the West Midlands Acromegaly database (n = 501) we investigated the reliability of basal fasting GH in predicting nadir or mean GH during oral glucose tolerance test (OGTT) or GH day curve (GHDC), respectively, the degree of discordance between disease activity measured by GH and IGF-I values and the effect of radiotherapy on the above relationships. In total 773 OGTT and 507 GHDC were performed. RESULTS: Basal fasting GH was strongly correlated with nadir/mean GH on OGTT/GHDC (r = +0.87, P < 0.0001, r = +0.93, P < 0.0001, respectively). A basal GH < 2.5 microg/l was associated with a nadir/mean GH during OGTT/GHDC < 2.5 microg/l in 98.6% and 88.2% of cases, respectively. Elevated IGF-I was seen in 32.4% and 46.4% of patients with GH nadir values during OGTT < 1 and < 2.5 microg/l, respectively, and in 21.2% and 45.9% of GHDC with mean GH < 1 and < 2.5 microg/l, respectively. Radiotherapy increased the discordance in GH and IGF-I as markers of disease activity at GH < 2.5 microg/l (elevated IGF-I-values when OGTT nadir GH < 2.5 microg/l: radiotherapy 55.5%vs. no radiotherapy 36.9%, P = 0.002). CONCLUSIONS: There is a close relationship between a basal fasting GH < 2.5 microg/l and nadir/mean GH < 2.5 microg/l during OGTT/GHDC. There is a large discordance between disease activity when assessed by GH and IGF-I which is further increased by radiotherapy. These observations illustrate the challenge of defining appropriate biochemical end-points to achieve control of disease and normalization of mortality in acromegaly.

Elevated cerebrospinal fluid (CSF) leptin in idiopathic intracranial hypertension (IIH): evidence for hypothalamic leptin resistance?

OBJECTIVE: The aetiology of idiopathic intracranial hypertension (IIH) is not known, but its association with obesity is well-recognized. Recent studies have linked obesity with abnormalities in circulating inflammatory and adiposity related cytokines. The aim of this study was to characterize adipokine and inflammatory cytokine profiles in IIH. DESIGN: Paired serum and cerebrospinal fluid (CSF) specimens were collected from 26 patients with IIH and compared to 62 control subjects. Samples were analysed for leptin, resistin, adiponectin, insulin, IL-1beta, IL-6, IL-8 (CXCL8), TNFalpha, MCP-1 (CCL2), hepatocyte growth factor, nerve growth factor and PAI-1 using multiplex bead immunoassays. RESULTS: CSF leptin was significantly higher in patients with IIH (P = 0.001) compared to controls after correction for age, gender and body mass index (BMI). In the control population, BMI correlated with serum leptin (r = 0.34; P = 0.007) and CSF leptin (r = 0.51; P < 0.0001), but this was not the case for the IIH population. Profiles of other inflammatory cytokines and adipokines did not differ between IIH patients and controls once anthropometric factors had been accounted for. CONCLUSIONS: IIH was characterized by significantly elevated CSF leptin levels which did not correlate with BMI. We suggest that CSF leptin may be important in the pathophysiology of IIH and that obesity in IIH may occur as a result of hypothalamic leptin resistance.

Progesterone is extensively metabolized in osteoblasts: implications for progesterone action on bone.

The effect of progestogens on bone is controversial with some studies suggesting an anabolic action while others show no effect. Prereceptor metabolism via localized expression of specific enzymes may have major impact on progesterone action in bone and may explain some of the discrepancies between studies. We therefore investigated the metabolism of progesterone in primary cultures of human osteoblasts and MG-63 osteoblastic cells. Osteoblasts and MG-63 cells were incubated with 4- (14)C-progesterone tracer and 50 nM unlabeled progesterone, and magnitude and pattern of progesterone metabolism were determined by two-dimensional thin-layer chromatography. Conventional and Taqman real-time PCR analysis were used to assess expression of progesterone metabolizing enzymes. In both types of cells the two major metabolic products of progesterone were 20 alpha-dihydroprogesterone and 5 alpha-dihydroprogesterone, but conversion to 3 alpha, 5 alpha- and 3 beta, 5 alpha-tetrahydroprogesterone was also detected. This activity was concomitant with expression of mRNAs for the enzymes AKR1C1, 5 alpha-reductase type 1 and AKR1C2, and 3 beta-HSD type 1 and 3-hydroxysteroid epimerase. In MG-63 cells progesterone metabolism was largely mediated via 5 alpha-reductase. In primary osteoblasts progesterone metabolism was unaffected by treatment with dexamethasone or estradiol, but in MG-63 cells dexamethasone pretreatment increased 5 alpha-reductase activity. Progesterone is subject to extensive intracellular inactivation in human osteoblasts, with potential attenuation of local progesterone receptor responses. Conversely, osteoblasts have the capacity to convert progestogens to metabolites reported to have anabolic actions through the estrogen receptor.

Adrenal suppression in bronchiectasis and the impact of inhaled corticosteroids.

The present study identified three patients with bronchiectasis receiving inhaled corticosteroids (ICSs) who had symptomatic adrenal suppression secondary to ICS. The prevalence of adrenal suppression is unknown in bronchiectasis. The frequency of adrenal suppression and the impact of ICS use in bronchiectasis patients were examined. In total, 50 outpatients (33 receiving ICSs) underwent a short Synacthen test and completed a St George's Respiratory Questionnaire (SGRQ). Symptoms of adrenal suppression, steroid use and lung function were compared between subjects who were suppressed and those who were not. Adrenal suppression was evident in 23.5% of subjects who did not receive ICSs and 48.5% of those who did. Basal cortisol and the increments by which cortisol increased 30 min after Synacthen were lower in suppressed than in nonsuppressed subjects. The incremental cortisol rise was negatively correlated with SGRQ impacts and total score, suggesting a worse quality of life in those who had an impaired adrenal response. The greatest frequency of generalised symptoms was seen in the suppressed group. A significant proportion of subjects with bronchiectasis have evidence of adrenal suppression, and this is increased when inhaled corticosteroids are also used. Impairment of the cortisol response to stimulation is associated with poorer health status.

Local and systemic glucocorticoid metabolism in inflammatory arthritis.

BACKGROUND: Isolated, primary synovial fibroblasts generate active glucocorticoids through expression of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). This enzyme produces cortisol from inactive cortisone (and prednisolone from prednisone). OBJECTIVE: To determine how intact synovial tissue metabolises glucocorticoids and to identify the local and systemic consequences of this activity by examination of glucocorticoid metabolism in patients with rheumatoid arthritis (RA). METHODS: Synovial tissue was taken from patients with RA during joint replacement surgery. Glucocorticoid metabolism in explants was assessed by thin-layer chromatography and specific enzyme inhibitors. RT-PCR and immunohistochemistry were used to determine expression and distribution of 11beta-HSD enzymes. Systemic glucocorticoid metabolism was examined in patients with RA using gas chromatography/mass spectrometry. RESULTS: Synovial tissue synthesised cortisol from cortisone, confirming functional 11beta-HSD1 expression. In patients with RA, enzyme activity correlated with donor erythrocyte sedimentation rate (ESR). Synovial tissues could also convert cortisol back to cortisone. Inhibitor studies and immunohistochemistry suggested this was owing to 11beta-HSD2 expression in synovial macrophages, whereas 11beta-HSD1 expression occurred primarily in fibroblasts. Synovial fluids exhibited lower cortisone levels than matched serum samples, indicating net local steroid activation. Urinary analyses indicated high 11beta-HSD1 activity in untreated patients with RA compared with controls and a significant correlation between total body 11beta-HSD1 activity and ESR. CONCLUSIONS: Synovial tissue metabolises glucocorticoids, the predominant effect being glucocorticoid activation, and this increases with inflammation. Endogenous glucocorticoid production in the joint is likely to have an impact on local inflammation and bone integrity.

Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement.

OBJECTIVE: Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushing's syndrome, because there is no recent consensus on the management of this rare disorder. PARTICIPANTS: Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushing's syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushing's disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushing's disease, and 5) management of ectopic ACTH syndrome, Nelson's syndrome, and special patient populations. EVIDENCE: Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking. CONSENSUS PROCESS: Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority. CONCLUSIONS: ACTH-dependent Cushing's syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushing's syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushing's disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushing's syndrome, early diagnosis and prompt therapy are warranted.

Expression profiling of 11beta-hydroxysteroid dehydrogenase type-1 and glucocorticoid-target genes in subcutaneous and omental human preadipocytes.

Obesity is associated with increased morbidity and mortality from cardiovascular disease, diabetes and cancer. Although obesity is a multi-factorial heterogeneous condition, fat accumulation in visceral depots is most highly associated with these risks. Pathological glucocorticoid excess (i.e. in Cushing's syndrome) is a recognised, reversible cause of visceral fat accumulation. The aim of this study was to identify depot-specific glucocorticoid-target genes in adipocyte precursor cells (preadipocytes) using Affymetrix microarray technique. Confluent preadipocytes from subcutaneous (SC) and omental (OM) adipose tissue collected from five female patients were treated for 24 h with 100 nM cortisol (F), RNA was pooled and hybridised to the Affymetrix U133 microarray set. We identified 72 upregulated and 30 downregulated genes by F in SC cells. In OM preadipocytes, 56 genes were increased and 19 were decreased. Among the most interesting were transcription factors, markers of adipocyte differentiation and glucose metabolism, cell adhesion and growth arrest protein factors involved in G-coupled and Wnt signalling. The Affymetrix data have been confirmed by quantitative real-time PCR for ten specific genes, including HSD11B1, GR, C/EBPalpha, C/EBPbeta, IL-6, FABP4, APOD, IRS2, AGTR1 and GHR. One of the most upregulated genes in OM but not in SC cells was HSD11B1. The GR was similarly expressed and not regulated by glucocorticoids in SC and OM human preadipocytes. C/EBPalpha was expressed in SC preadipocytes and upregulated by F, but was below the detection level in OM cells. C/EBPbeta was highly expressed both in SC and in OM preadipocytes, but was not regulated by F. Our results provide insight into the genes involved in the regulation of adipocyte differentiation by cortisol, highlighting the depot specifically in human adipose tissue.

Conventional pituitary irradiation is effective in lowering serum growth hormone and insulin-like growth factor-I in patients with acromegaly.

BACKGROUND: There has been recent controversy as to the effectiveness of conventional pituitary irradiation in reducing circulating GH levels to less than 2.5 ng/ml and/or normalization of serum IGF-I. OBJECTIVES: Our objectives were to determine the effects of conventional pituitary irradiation on 1) lowering of serum GH and IGF-I levels, 2) the proportion of patients who achieve a GH level less than 2.5 ng/ml and a normal age-corrected IGF-I and the time taken to achieve this, and 3) the incidence of hypopituitarism and other adverse effects. DESIGN: We conducted retrospective data collection from 14 centers throughout the United Kingdom. PATIENTS: We studied 1840 patients with acromegaly, of whom 884 had received conventional pituitary irradiation. MEASUREMENTS: We assessed circulating GH and IGF-I levels and pituitary function at intervals after irradiation. RESULTS: Mean GH levels declined from 13.5 to 5.3 ng/ml at 2 yr after irradiation, to 2.0 ng/ml by 10 yr, and to 1.1 ng/ml at 20 yr. Twenty-two percent of patients achieved a level less than 2.5 ng/ml by 2 yr, 60% by 10 yr, and 77% by 20 yr. The interval to achieve this depended on the preirradiation GH level. IGF-I levels fell in parallel to those of GH with 63% of patients having a normal level by 10 yr. The proportions of patients with new pituitary hormone deficiencies 10 yr after irradiation were 18% for LH/FSH, 15% for ACTH, and 27% for TSH. No other side effects were noted. CONCLUSIONS: In this, the largest series reported, conventional pituitary irradiation is shown to be an effective and safe means of reducing both serum GH and IGF-I concentrations in patients with acromegaly.

Growth hormone and pituitary radiotherapy, but not serum insulin-like growth factor-I concentrations, predict excess mortality in patients with acromegaly.

Increased mortality in patients with acromegaly has been confirmed in a number of retrospective studies, but causative factors and relationship to serum IGF-I remain uncertain. The West Midlands Pituitary database contains details of 419 patients (241 female) with acromegaly. Serum IGF-I data from the Regional Endocrine Laboratory were available for 360 patients (86%). At diagnosis, mean age was 47 yr (range, 12-84) and mean duration of follow-up was 13 yr (0.5-48). Sixty-one percent were treated by surgery and 39% by nonsurgical means. Radiotherapy was used alone or as adjuvant therapy in 50%. All patients were registered with the Office of National Statistics to obtain information on deaths. At the date of analysis (31 December 2001), 95 of the 419 patients had died (43 males), giving a standardized mortality ratio of 1.26 [confidence interval (CI), 1.03-1.54; P = 0.046]. After controlling for age and sex, data indicated that mortality was increased in subjects with posttreatment GH levels more than 2 micro g/liter, compared with those with levels less than 2 micro g/liter [ratio of mortality rates (RR), 1.55 (range, 0.97-2.50); P = 0.068]. By contrast, a much smaller increase was observed for subjects with elevated posttreatment IGF-I levels compared with those with normal levels [RR, 1.20 (range, 0.71-2.03); P = 0.50]. Treatment with radiotherapy was associated with increased mortality [RR, 1.67 (range, 1.09-2.56); P = 0.018], with cerebrovascular disease the predominant cause of death [standardized mortality ratio, 4.42 (range, 2.71-7.22); P = 0.005]. These results confirm the increased mortality in acromegaly and suggest that reduction of GH levels to less than 2 micro g/liter is beneficial in terms of improving long-term outcome. The sole use of IGF-I as a marker for effective treatment of acromegaly is not justified by this data. This study also highlights the potential deleterious effect of radiotherapy.

Characterization of human trophoblast as a mineralocorticoid target tissue.

In mineralocorticoid target tissues, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) confers mineralocorticoid receptor selectivity by metabolizing hormonally active cortisol to inactive cortisone, allowing aldosterone access to the receptor. This enzyme is also expressed in high abundance in fetal tissues, particularly in placental trophoblast, where a role has been proposed in regulating fetal growth and development by protecting the fetus from maternal hypercortisolaemia and modulating local glucocorticoid receptor (GR), rather than mineralocorticoid receptor-mediated responses. As such the placenta has not been considered a mineralocorticoid target tissue. We have used conventional RT-PCR and real-time quantitative RT-PCR to demonstrate that primary cultures of term human cytotrophoblast express the mineralocorticoid-responsive genes Na/K-ATPase (alpha1 and beta1 subunits), epithelial sodium channel (ENaC, alpha and gamma subunits) and the serum and glucocorticoid-inducible kinase (SGK). SGK expression was found to be rapidly and strongly induced by corticosteroids (24- and 38-fold by 10(-7) mol/l aldosterone and 10(-7) mol/l dexamethasone respectively after 1 h). Dexamethasone-, but not aldosterone-stimulated SGK induction was inhibited by GR antagonist (RU38486), confirming the presence of a functional mineralocorticoid receptor and suggesting that placental trophoblast expresses a functional mineralocorticoid receptor, which is in part responsible for the corticosteroid regulation of SGK expression. Placental 11beta-HSD2 may protect the MR in a fashion analogous to classical mineralocorticoid tissues to modulate trophoblast sodium transport.

11beta-hydroxysteroid dehydrogenases, cell proliferation and malignancy.

The enzymes 11beta-hydroxysteroid dehydrogenase type 1 and 2 (11beta-HSD1 and 2) have well-defined roles in the tissue-specific metabolism of glucocorticoids which underpin key endocrine mechanisms such as adipocyte differentiation (11beta-HSD1) and mineralocorticoid action (11beta-HSD2). However, in recent studies we have shown that the effects of 11beta-HSD1 and 2 are not restricted to distinct tissue-specific hormonal functions. Studies of normal fetal and adult tissues, as well as their tumor equivalents, have shown a further dichotomy in 11beta-HSD expression and activity. Specifically, most normal glucocorticoid receptor (GR)-rich tissues such as adipose tissue, bone, and pituitary cells express 11beta-HSD1, whereas their fetal equivalents and tumors express 11beta-HSD2. We have therefore postulated that the ability of 11beta-HSD1 to generate cortisol acts as an autocrine anti-proliferative, pro-differentiation stimulus in normal adult tissues. In contrast, the cortisol-inactivating properties of 11beta-HSD2 lead to pro-proliferative effects, particularly in tumors. This proposal is supported by experiments in vitro which have demonstrated divergent effects of 11beta-HSD1 and 2 on cell proliferation. Current studies are aimed at (1) characterizing the underlying mechanisms for a "switch" in 11beta-HSD isozyme expression in tumors; (2) defining the molecular targets for glucocorticoids as regulators of cell proliferation; (3) evaluating the potential for targeting glucocorticoid metabolism as therapy for some cancers. These and other issues are discussed in the present review.

Expression of 11beta-hydroxysteroid dehydrogenase (11betaHSD) proteins in luteinizing human granulosa-lutein cells.

In a range of tIssues, cortisol is inter-converted with cortisone by 11beta-hydroxysteroid dehydrogenase (11betaHSD). To date, two isoforms of 11betaHSD have been cloned. Previous studies have shown that human granulosa cells express type 2 11betaHSD mRNA during the follicular phase of the ovarian cycle, switching to type 1 11betaHSD mRNA expression as luteinization occurs. However, it is not known whether protein expression, and 11betaHSD enzyme activities reflect this reported pattern of mRNA expression. Hence, the aims of the current study were to investigate the expression and activities of 11betaHSD proteins in luteinizing human granulosa-lutein (hGL) cells. Luteinizing hGL cells were cultured for up to 3 days with enzyme activities (11beta-dehydrogenase (11betaDH) and 11-ketosteroid reductase (11 KSR)) and protein expression (type 1 and type 2 11betaHSD) assessed on each day of culture. In Western blots, an immunopurified type 1 11betaHSD antibody recognized a band of 38 kDa in hGL cells and in human embryonic kidney (HEK) cells stably transfected with human type 1 11betaHSD. The type 2 11betaHSD antibody recognized a band of 48 kDa in HEK cells transfected with human type 2 11betaHSD cDNA but the type 2 protein was not expressed in hGL cells throughout the 3 days of culture. While the expression of type 1 11betaHSD protein increased progressively by 2.7-fold over 3 days as hGL cells luteinized, both 11betaDH and reductase activities declined (by 52.9% and 34.2%; P<0.05) over this same period. Changes in enzyme expression and activity were unaffected by the suppression of ovarian steroid synthesis.

Abnormal expression of 11 beta-hydroxysteroid dehydrogenase type 2 in human pituitary adenomas: a prereceptor determinant of pituitary cell proliferation.

The physiological effects of glucocorticoids (GCs) are, at least in part, mediated by inhibition of cell proliferation. Two isozymes of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) interconvert cortisol (F) and inactive cortisone (E), and are thus able to modulate GC action at an autocrine level. Previously, we have demonstrated absent expression of 11 beta-HSD2 in normal pituitaries; however, in a small number of pituitary tumors analysed, 11 beta-HSD2 was readily demonstrable. Here we have used real-time RT-PCR to quantify expression of mRNA for 11 beta-HSD1 and 2 in 105 human pituitary tumors and have performed enzyme expression and activity studies in primary pituitary cultures. Overall, pituitary tumors expressed lower levels of 11 beta-HSDl mRNA compared with normals (0.2-fold, P<0.05). In contrast, expression of 11 beta-HSD2 mRNA was 9.8-fold greater in tumors than in normals (P<0.001). Enzyme assays showed significant 11 beta-HSD2 activity (71.9+/-22.3 pmol/h/mg protein (mean+/-s.d.)) but no detectable 11 beta-HSDl activity. Proliferation assays showed that addition of glycyrrhetinic acid (an 11 beta-HSD2 inhibitor) resulted in a 30.3+/-7.7% inhibition of cell proliferation. In summary, we describe a switch in expression from 11 beta-HSDl to 11 beta-HSD2 in neoplastic pituitary tissue. We propose that abnormal expression of 11 beta-HSD2 acts as a proproliferative prereceptor determinant of pituitary cell growth, and may provide a novel target for future tumor therapy.