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Biomedical subjects

M C Sheppard

Publications and source records attributed to M C Sheppard.

At least 109 records · Page 6Linked to original sources
PubMed1994

Expression of epidermal growth factor (EGF), its receptor, and related oncoprotein (erbB-2) in human pituitary tumors and response to EGF in vitro.

Recent data indicate that epidermal growth factor (EGF) is a potent mitogen to normal pituitary cells. Its receptor (EGFR or c-erbB-1), a cellular homologue of a viral oncoprotein erbB, is knonw to be overexpressed in many tumors, but little is known about the expression of EGF and EGFR in pituitary tumors. Immunocytochemical analyses of EGF, EGFR, and c-erbB-2 (an EGFR-related oncoprotein) were carried out on paraffin-embedded sections of 54 pituitary tumors. In sections from normal pituitary, EGF was localized mainly in the gonadotrophs and thyrotrophs. EGFR was detected in only 5-10% of the cells in all of the normal pituitary sections and was almost undetectable in all (34/34) of the hormone-secreting tumors (19 GH-, 9 ACTH-, 4 PRL- and 2 TSH-secreting tumors). However, in 16/20 of the samples from clinically nonfunctioning tumors, EGFR was markedly overexpressed. The EGFR found in these tumors and in the normal tissue was not the truncated form of the EGFR because all sections stained positively with monoclonal antisera to both the intra- and extracellular domains of the EGFR. EGF was coexpressed in the same NFT samples that stained positively for EGFR and was also found in 2/19 GH-, 2/4 PRL-, and 1/2 of TSH-secreting tumors. The expression of c-erbB-2 was detected in all normal tissue, all NFT, and about half of GH-secreting tumors. No correlation was found with clinical parameters other than tumor categories. Because the overexpression of structurally intact EGFR was confined to NFT, the response of the tumor cells to EGF in vitro was examined. The addition of 1 nM EGF to NFT-derived cells resulted in an increase in [3H]thymidine uptake to 237.5 +/- 19.8% (mean +/- SEM, n = 3) of the control value. EGF also stimulated EGFR messenger RNA levels, shown by Northern blot analysis. In contrast, the expression of glycoprotein hormone common alpha-subunit gene in the tumor cells was reduced by EGF, T3, and 17 beta-estradiol. The novel findings of overexpression of EGFR in most NFT combined with the in vitro response to EGF resulting in an increase in tumor cell growth, up-regulation of EGFR gene and suppression of hormone gene expression implicate a role for EGF and its receptor in the development and/or progression of NFT.

Adult↗
PubMed1994

Characterization of thyroid hormone (T3) receptors in three osteosarcoma cell lines of distinct osteoblast phenotype: interactions among T3, vitamin D3, and retinoid signaling.

T3 is required for normal skeletal development, but its cellular targets in bone are unknown. T3 regulates target gene transcription via a specific nuclear receptor (T3R), which can heterodimerize with 9-cis-retinoic acid, 1 alpha, 25-dihydroxyvitamin D3, or retinoic acid receptors to modify T3 responsiveness. Serum-free cultures were developed to investigate hormone interactions in three osteosarcoma cell lines, ROS25/1, UMR106, and ROS17/2.8, that express fibroblast-like, preosteoblast, and mature osteoblast phenotypes. ROS25/1 expressed T3R alpha 1, but only low levels of T3R beta 1, whereas UMR106 and ROS17/2.8 cells expressed both receptor proteins. All cells expressed c-erb-A alpha 2 protein and equal levels of 1 alpha,25-dihydroxyvitamin D3 receptor, 9-cis-retinoic acid receptor, and retinoic acid receptor messenger RNAs. Endogenous T3R activity and the effects of D3 and 9-cis-RA on T3 responsiveness were determined in transfections using reporter genes containing T3 response elements from rat malic enzyme or alpha-myosin heavy chain genes. Cell-specific T3 responses were associated with differing patterns of T3R gene expression and stages of osteoblast phenotype expression. A change in T3R beta 1 gene expression during osteoblast phenotype differentiation may modify T3 action in developing bone.

Animals↗
PubMed1994

Comparison of second and third generation methods for measurement of serum thyrotropin in patients with overt hyperthyroidism, patients receiving thyroxine therapy, and those with nonthyroidal illness.

We compared serum TSH results determined in second and third generation assays in patients with thyroid disease and nonthyroidal illnesses (NTIs) to evaluate the usefulness of the more sensitive assay. We studied 19 subjects with untreated hyperthyroidism, 12 hyperthyroid subjects sampled at 4-week intervals after beginning carbimazole, 153 subjects receiving T4 replacement, and 300 hospital in-patients with a variety of NTIs. Serum TSH was measured, using a second generation immunometric method, together with free T4 and free T3. Samples with subnormal TSH (< 0.5 mU/L) were reassayed, using a more sensitive chemiluminescent immunometric method. Both assays revealed undetectable serum TSH levels in 18 of 19 overtly hyperthyroid patients. Undetectable TSH values (in both assays) were found in 30 of 33 patients with low serum TSH levels who were receiving treatment for hyperthyroidism, in association with normal thyroid hormone levels in 11. Undetectable TSH was evident in both patients receiving T4 and those with NTI, but use of the more sensitive assay led to a reduction in the number of subjects with undetectable TSH compared with the second generation results (T4-treated, 55 vs. 77 cases; NTI, 13 vs. 19 cases). There was a significant correlation between serum TSH and free T4 in the whole group on T4 (P < 0.001) and in those receiving T4 with low TSH (r = -0.33; P < 0.05); no significant correlation was evident in subjects with low serum TSH levels associated with NTI. An improvement in assay sensitivity led to a reduction in the number of patients being treated with T4 or with NTI in whom serum TSH was undetectable and, hence, an increase in those in whom overt hyperthyroidism could be excluded. Undetectable TSH results, even in a third generation assay, are not diagnostic of overt hyperthyroidism, but are also found in subjects with treated thyroid disease and NTI.

Analysis of Variance↗
PubMed1994

Modulation of epidermal growth factor binding and receptor gene expression by hormones and growth factors in sheep pituitary cells.

Epidermal growth factor (EGF) is a potent mitogen for sheep pituitary cells but the factors controlling the binding and expression of EGF and its receptor (EGFR) in the pituitary are poorly understood. Regulation of EGF binding and EGFR gene expression may determine cellular responsiveness to EGF and could play a role in neoplastic development. Scatchard analysis of 125I-EGF binding in cultured sheep pituitary cells revealed two receptor binding sites (high affinity class of 2.5 +/- 0.5 x 10(3) receptors/cell with a dissociation affinity constant (Kd) of 3.2 +/- 0.7 x 10(-10) M and low affinity class of 3.3 +/- 1.0 x 10(4) receptors/cell with a Kd of 7.1 +/- 1.3 x 10(-9) M). Exposure of the cultured cells to some target gland hormones of the pituitary (oestrogen, tri-iodothyronine and hydrocortisone), pituitary growth factors (EGF, basic fibroblast growth factor, transforming growth factor-beta) and a tumour-promoting phorbol ester (TPA) resulted in an increase in the binding affinity of the high affinity receptors while reducing the receptor number and also a reduction of EGFR mRNA levels, shown by Northern blot analysis. In contrast, forskolin, an activator of adenylate cyclase, showed no significant effect on EGF binding and receptor gene expression. We conclude that the EGFR in normal pituitary cels can be modulated by several hormones and other growth factors at both receptor binding and mRNA levels. Transmodulation of EGFR by hormones and growth factors in the pituitary may be one of the regulatory mechanisms controlling the balance of normal pituitary growth and function.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

The structure of the human thyroxine binding globulin (TBG) gene.

A portion of the human X-chromosome (> 5 kb) encoding the translated portion of the thyroxine-binding globulin (TBG) gene was sequenced. The primary templates for sequencing were isolated from a human X-chromosome library (two positive plaques from 400,000 screened initially with a TBG cDNA probe) or were produced by PCR amplification using leucocyte genomic DNA as the amplification template. Potential hormone response elements (HREs) were identified at either end of the gene. These HREs have sequences based on the consensus half-site of thyroid hormone response elements, although it is unclear whether the structures are functional HREs. Other potential regulatory elements also were identified towards the 3' end of the gene.

Animals↗
PubMed1993

Estradiol modulates thyroid hormone regulation of the human glycoprotein hormone alpha subunit gene.

We have examined mechanisms of regulation of the human glycoprotein hormone alpha subunit gene by thyroid hormone (T3) and estradiol. Pituitary-derived GH3 cells were transiently transfected with chimeric constructs comprising between 1,500 and 98 base pairs of human alpha subunit gene 5'-flanking sequence fused to the bacterial gene encoding chloramphenicol acetyltransferase (h alpha CAT) and treated with T3 and estradiol, alone and in combination. In pituitary cells, 98 base pairs of alpha gene 5'-flanking sequence were sufficient to mediate both inhibition of alpha gene promoter activity by T3 and stimulation by estradiol; inhibition of the alpha promoter by T3 was antagonized by estradiol. Mutation of nucleotides essential for T3 receptor binding to the alpha gene thyroid hormone response element abolished the response of h alpha CAT expression to estradiol as well as T3. In contrast to pituitary GH3 cells, estradiol treatment alone had no effect on expression of either h alpha CAT or the endogenous alpha gene in JEG-3 choriocarcinoma cells cotransfected with a human thyroid hormone receptor expression vector, but estradiol antagonized suppression of both endogenous and transfected alpha promoter activity by T3. Gel mobility shift assays demonstrated specific binding of in vitro synthesized human estrogen receptor (ER) to the alpha gene thyroid hormone response element. These findings suggest that estradiol modulates expression of the human alpha subunit gene in pituitary and choriocarcinoma cells by direct binding of ER to the alpha gene promoter, and that interaction of ER with the alpha gene negative TRE accounts for the antagonistic effects of estradiol and T3.

Base Sequence↗
PubMed1993

Tissue specific effects of thyroid hormone on 11 beta-hydroxysteroid dehydrogenase gene expression.

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) by converting active glucocorticoid to an inactive metabolite confers specificity upon the mineralocorticoid receptor (MR) and regulates ligand access to the glucocorticoid receptor (GR). Factors which influence 11 beta-HSD activity seem likely to be of considerable importance in the modulation of both mineralocorticoid and glucocorticoid hormone action. The administration of tri-iodothyronine (T3) to rats has previously been shown to reduce 11 beta-HSD activity in liver but not in kidney. We have studied the effect of T3 on 11 beta-HSD gene expression in vivo in rat liver, kidney, distal colon and pituitary. In addition the effects of T3 on 11 beta-HSD gene expression in vitro in the rat pituitary GH3 cell line have been studied. T3 administration to normal adult rats (40 micrograms/day, s.c. for 1, 3 and 7 days) resulted in a marked decline in liver and pituitary 11 beta-HSD mRNA levels and activity following 3 and 7 days of treatment. These reduced levels were maintained for 3 days following withdrawal of T3 treatment, but returned to control levels after 7 days. In contrast 11 beta-HSD mRNA and activity in kidney and distal colon were unaffected by T3 treatment at each time point studied. In vitro, levels of 11 beta-HSD mRNA and activity in GH3 cells were unchanged following 8, 24 and 72 h treatment with T3 (10(-8) to 10(-6) M). T3 bio-activity was confirmed by a marked dose-dependent decline in the expression of the T3 and glucocorticoid responsive gene, prolactin. T3 inhibits 11 beta-HSD gene expression in both liver and pituitary at a pre-translational level. This effect is absent in the predominantly mineralocorticoid target tissues, kidney and distal colon, i.e. it is tissue specific and as such is consistent with the existence of multiple differentially regulated isoforms of 11 beta-HSD. The time course of the T3 effect in liver and pituitary in vivo and the lack of any effect in vitro suggests that this action is indirect, and not as a result of interaction between the T3 receptor and the putative thyroid hormone response element on the rat 11 beta-HSD gene.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

Regulation of beta myosin heavy chain, c-myc and c-fos proto-oncogenes in thyroid hormone-induced hypertrophy of the rat myocardium.

1. In order to investigate the molecular mechanisms determining the hypertrophic response of the ventricular myocardium to thyroid hormone administration, changes in left and right ventricular expression of the c-myc, c-fos and H-ras proto-oncogenes in response to treatment with 3,3',5-tri-iodothyronine were defined. 2. Adult female Wistar rats were treated with daily subcutaneous injections of 3,3',5-tri-iodothyronine (50 micrograms) for 1, 3, 7 or 14 days (n = 6 in each treatment group) and the results from 3,3',5-tri-iodothyronine-treated animals were compared with those obtained from untreated controls (n = 6). Changes in the weight of the left and right ventricles in response to 3,3',5-tri-iodothyronine treatment were measured; changes in expression of the c-myc, c-fos and H-ras proto-oncogenes were determined in parallel by measurement of specific messenger RNAs by Northern and dot hybridization, as well as changes in expression of beta myosin heavy chain messenger RNA. 3. Treatment with 3,3',5-tri-iodothyronine resulted in increases in both left and right ventricular weights after 3 days, an effect maintained up to 14 days. Despite an increase in left ventricular weight, levels of beta myosin heavy chain, c-myc, c-fos and H-ras mRNAs in the left ventricle were unchanged; in contrast, an increase in right ventricular weight was associated with increased expression of beta myosin heavy chain, c-myc and c-fos messenger RNAs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Radioiodine therapy for hyperthyroidism in young patients--perception of risk and use.

Although radioiodine is increasingly the treatment of choice in hyperthyroidism, there are regional differences in its use which reflect, in part, concerns regarding safety. We investigated attitudes amongst general practitioners and consultant physicians to the role of radioiodine therapy, and reviewed our own radioiodine prescribing in patients aged less than 40 to elucidate any influence of age and/or sex. We surveyed general practitioners in the former Central Birmingham Health District and consultant physicians in the West Midlands Region to investigate treatment preferences in hyperthyroidism and perceived risk from radioiodine of hypothyroidism, carcinogenesis and infertility. Of 230 general practitioner and 130 consultant physician respondents, less than 1% considered radioiodine the treatment of choice in a 25-year-old female presenting with hyperthyroidism. At relapse after antithyroid drug treatment in a 25-year-old female, only 16.5% of general practitioners and 23.9% of physicians advocated radioiodine, the greatest number preferring partial thyroidectomy. For a 65-year-old at presentation, 49.1% of general practitioners and 62.3% of physicians considered radioiodine the treatment of choice. More than 10% failed to note the risk of hypothyroidism following radioiodine, while 11-34% perceived increased risk of malignancy or infertility. Review of our own practice demonstrated that of 100 patients given radioiodine, 94% were cured of hyperthyroidism when reviewed at a mean of 2.4 years from latest treatment, 70% being hypothyroid. Females given radioiodine were treated less promptly following diagnosis of hyperthyroidism than males (2.2 +/- 0.26 years vs. 1.6 +/- 0.4) and were more likely to have received a preceding course of antithyroid drugs (78% vs. 57%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

11-beta-hydroxysteroid dehydrogenase activity and gene expression in the hypertensive Bianchi-Milan rat.

OBJECTIVE: 11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD), by converting the active steroids cortisol and corticosterone to their inactive metabolites, regulates steroid exposure to the mineralocorticoid and glucocorticoid receptors. We explored the hypothesis that a defect in 11 beta-HSD could result in overstimulation of either the mineralocorticoid or glucocorticoid receptors with subsequent hypertension in an established animal model of hypertension, the Bianchi-Milan hypertensive (BMH) rat. DESIGN AND METHODS: Groups of BMH rats with established hypertension (42-46 days old) and prehypertensive rats (22 days old) were compared with age-matched normotensive control rats. Kidney and liver 11 beta-HSD and glucocorticoid receptor messenger RNA (mRNA) levels were assessed by Northern and dot-blot analyses, and 11 beta-HSD activity as percentage conversion of [3H]-corticosterone to [3H]11-dehydrocorticosterone by tissue homogenate. RESULTS: Hepatic 11 beta-HSD activity and gene expression were significantly reduced in the hypertensive BMH rat compared with its normotensive genetic control. 11 beta-HSD activity was also reduced in the prehypertensive BMH rat (aged 25 days) from hypertensive parents, excluding hypertension per se as the cause of the abnormality. Plasma corticosterone was higher in the hypertensive rats. There was no difference in renal 11 beta-HSD activity or gene expression between hypertensive and normotensive BMH rats, or in glucocorticoid receptor gene expression in the liver or kidney. CONCLUSIONS: Normal levels of renal 11 beta-HSD mRNA and activity are found in the BMH rat. However, the hypertensive BMH rat does demonstrate impaired hepatic 11 beta-HSD activity which occurs at a pretranslational level, although it is not clear how this relates to the pathogenesis of hypertension in this model.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

Thyroxine replacement therapy and circulating lipid concentrations.

OBJECTIVE: Hypothyroidism is a common disorder and while the association of overt hypothyroidism with hypercholesterolaemia is clear, the effect upon lipids of the minor abnormalities of thyroid function often found in those receiving T4 replacement therapy is unclear. The aim of the present studies was to define in those with hypothyroidism the effect upon circulating lipids of subtle changes in thyroid status, indicated by serum TSH values below or above the normal range. DESIGN: (i) Prospective study of short-term T4 treatment of those with subclinical hypothyroidism. (ii) Cross-sectional study of long-term T4 treatment, comparing non-T4 treated controls and T4 treated patients with serum TSH values either below or within the normal range. PATIENTS: Short-term T4 therapy was examined in 11 post-menopausal females with subclinical hypothyroidism (high TSH, normal free T4) studied before therapy and 6 weeks after T4 at incremental doses (50, 100, 150 micrograms/day). Long-term T4 treatment for hypothyroidism was investigated in 105 females on therapy for at least 1 year compared with 105 controls matched for age and menopausal status. MEASUREMENTS: Fasting levels of total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and HDL subfractions were determined in patients and controls. RESULTS: (i) T4 treatment of subjects with subclinical hypothyroidism resulted in reductions in total and LDL cholesterol with increasing T4 dose (P < 0.001). Comparison of lipid results pretreatment with those when TSH was restored to normal revealed no significant difference in lipids; in contrast, comparison of lipids in those with normal TSH compared with the same subjects when TSH was suppressed revealed reductions in total and LDL cholesterol. (ii) Long-term T4 treatment was associated with a reduction in total and LDL cholesterol measurements in those over 55 years receiving suppressive doses of T4 but no significant difference in lipids in those with normal serum TSH compared with non-T4 treated controls. CONCLUSION: Effects of T4 upon lipid measurements suggest that patients with subclinical hypothyroidism should receive replacement therapy. Doses of T4 which suppress TSH to below normal may have a more significant influence upon lipids than doses of T4 which restore TSH to the normal range.

Aged↗
PubMed1993

Sex differences in the incidence of colorectal cancer: an exploration of oestrogen and progesterone receptors.

Sex differences exist in the site specific incidences of colorectal cancer. The increased incidence of colonic cancer in women with breast cancer and the protective effect of increasing parity suggest a role for sex hormones. To explore the molecular basis, the expression of messenger RNA for oestrogen and progesterone receptors in the large bowel has been studied. With northern and dot blot analyses mRNA coding for oestrogen receptor and progesterone receptor in large bowel cancers and corresponding normal mucosa and in adenomatous polyps has been identified. There were no significant differences in receptor mRNA concentrations between males and females or between cancers, normal mucosae, and polyps, except for rectal cancers, which had higher progesterone receptor concentrations than corresponding normal tissue. Oestrogen and progesterone receptor mRNA concentrations were strongly correlated in both cancers and normal tissues. Enzyme immunoassay for oestrogen receptor gave values of 1.2-7.4 fmol/mg total protein, an amount similar to that seen in normal breast tissue. Oestrogen receptor protein and mRNA for oestrogen receptor and progesterone receptor are present in the large bowel.

Adenocarcinoma↗
PubMed1993

11 beta-hydroxysteroid dehydrogenase and corticosteroid hormone receptors in the rat colon.

In the rat kidney 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) maintains normal in vivo specificity for mineralocorticoid receptor (MR) by converting the active steroid corticosterone to inactive 11-dehydrocorticosterone, leaving aldosterone to occupy the MR. Clinical observations support the hypothesis that 11 beta-HSD also protects the distal colonic MR from glucocorticoid excess. We have measured 11 beta-HSD mRNA and activity along the rat colon and have analyzed the distribution of 11 beta-HSD, MR, and glucocorticoid receptor (GR) mRNA within rat distal colon using in situ hybridization. Levels of 11 beta-HSD mRNA (1.7 and 3.4 kb) and activity were higher in distal vs. proximal colon, paralleling reported MR mRNA levels. Within the distal colon mucosa both 11 beta-HSD immunoreactivity and mRNA was observed in cells in the lamina propria but not in epithelial cells. MR mRNA was present in surface epithelial cells, but was also colocalized with the same 11 beta-HSD-expressing cells in the lamina propria. In contrast GR mRNA was more uniformly distributed. The localization of MR mRNA to nonepithelial cells in the lamina propria, possibly neuroendocrine cells, suggests that mineralocorticoid-regulated sodium transport across colonic epithelial cells may also involve a paracrine mechanism. As with the kidney, exposure of active mineralocorticoid to the MR in these cells in the lamina propria is dictated by 11 beta-HSD in an autocrine fashion.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

Licorice inhibits 11 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid levels and potentiates glucocorticoid hormone action.

11 beta-Hydroxysteroid dehydrogenase (11 beta HSD) is responsible for the interconversion of cortisol to cortisone [corticosterone (B) to 11-dehydrocorticosterone in rodents] and confers ligand specificity to the mineralocorticoid receptor. Inhibition of 11 beta HSD by licorice derivatives [glycyrrhizic and glycyrrhetinic (GE) acids] results in cortisol/B and not aldosterone acting as a potent mineralocorticoid. 11 beta HSD is ubiquitously expressed and, by converting active glucocorticoid to inactive metabolites, may be an important prereceptor regulator of ligand access to the glucocorticoid receptor (GR). To investigate this further, we have studied the effect of 11 beta HSD inhibition by licorice derivatives on PRL gene expression (a known glucocorticoid target gene) in rat pituitary GH3 cells. Glycyrrhizic acid administration to rats in vivo (75 mg/kg.day for 5 days) resulted in inhibition of 11 beta HSD activity, as previously reported, but also a significant reduction in steady state 11 beta HSD mRNA levels in both predominantly mineralocorticoid (kidney and distal colon) and glucocorticoid (liver and pituitary) target tissues. In vitro, 11 beta HSD mRNA and activity were present in rat pituitary GH3 cells (81% conversion of B to 11-dehydrocorticosterone/4 x 10(6) cells after 24-h incubation) and inhibited by GE in a dose-dependent fashion. While B or GE alone (10(-8)-10(-5) M) had little or no effect on PRL mRNA levels or immunoassayable PRL, combinations of GE plus B resulted in marked inhibition of PRL mRNA levels and secretion, to such an extent that a concentration of 10(-6) M B with 10(-6) M GE was more potent than equimolar concentration of the synthetic GR agonist RU 28362. This inhibitory effect on PRL mRNA levels was blocked by a 10-fold excess of the GR antagonist RU 38486, but not by a 10-fold excess of the mineralocorticoid receptor antagonist RU 26752, confirming that this potentiation of glucocorticoid hormone action was operating through the GR and not the mineralocorticoid receptor. In addition to its established role as a competitive inhibitor of 11 beta HSD, licorice results in pretranslational inhibition of 11 beta HSD both in vitro and in vivo. 11 beta HSD is clearly an important mechanism in regulating tissue levels of active glucocorticoid and, hence, ligand supply to the GR.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

11 beta-Hydroxysteroid dehydrogenase deficiency and glucocorticoid status in patients with alcoholic and non-alcoholic chronic liver disease.

11 beta-Hydroxysteroid dehydrogenase (11 beta HSD), found predominantly in liver and kidney, is responsible for the shuttling of active cortisol to cortisone. A defect in this shuttle mechanism, e.g. after liquorice ingestion, results in an increase in the ratio of urinary cortisol [tetrahydrocortisol (THF)] to cortisone [tetrahydrocortisone (THE)] metabolites. The plasma cortisol half-life is prolonged, but concentrations remain normal because of a concomitant fall in cortisol production. Alcohol-induced pseudo-Cushing's syndrome is an ill defined cause of Cushing's syndrome. Because many of the documented cases have abnormal liver function tests, we have investigated whether abnormal hepatic 11 beta HSD activity may play a role in the pathogenesis of the condition. Fourteen patients with alcoholic (ALD) and 14 patients with non-alcoholic (CLD) chronic liver disease had marked deficiency of 11 beta HSD [5 alpha-THF + THF/THE: ALD, 1.94 +/- 0.38 (+/- SEM); CLD, 1.82 +/- 0.20] compared to controls (0.94 +/- 0.04; P < 0.01 and 0.001, respectively). In the CLD group, the daily cortisol production rate (as assessed by summation of principal cortisol metabolites) was reduced appropriately [median, 3,510; range, 1,101-8,940 micrograms/24 h; controls, 5,492 (range, 3,818-14,996) micrograms/24 h; P < 0.001], and normal 0900 h plasma cortisol and urinary free cortisol levels were maintained. However, in the ALD group, there was no concomitant fall in the cortisol production rate (sum of cortisol metabolites, 5,043 micrograms/24 h; range, 520-27,344). As a consequence, 0900 h plasma cortisol in the ALD group was significantly elevated (633 +/- 52 nmol/L) compared to values in the CLD group (487 +/- 48 nmol/L; P < 0.05) and controls (432 +/- 27 nmol/L; P < 0.001). Our findings of glucocorticoid excess in patients with chronic ALD may indicate that alcohol-induced pseudo-Cushing's syndrome develops as a result of continuing normal cortisol secretion in the face of impaired cortisol metabolism. The latter is mediated by defective hepatic 11 beta HSD activity; the former by either abnormal glucocorticoid feedback or stimulation of cortisol secretion at the level of the hypothalamus/pituitary.

11-beta-Hydroxysteroid Dehydrogenases↗