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Biomedical subjects

C H Shackleton

Publications and source records attributed to C H Shackleton.

At least 55 records · Page 3Linked to original sources
PubMed1995

Corticosteroids in human blood: IX. Evidence for adrenal secretion of sulfate-conjugated cortisol, 11 beta,17 alpha-dihydroxy-4-pregnene-3,20-dione-21-yl-sulfate.

A method was developed for the estimation of levels of cortisol-21-sulfate (F KS), cortisone-21-sulfate (ES), and 20(alpha + beta)-reduced cortisol-21-sulfates in blood plasma. Levels of these conjugates were determined in peripheral vein plasma of 42 normal subjects, 21 men, and 21 women (age range 20-64 years) and in adrenal vein plasma of patients with various adrenocortical disorders, six patients with primary hyperaldosteronism, five patients with Cushing's syndrome, and in two obese patients, suspected to have Cushing's syndrome, but with inconclusive laboratory findings. Adrenal vein blood was obtained by percutaneous, trans-femoral adrenal vein catheterization. Levels of non-conjugated (free) cortisol were determined in all plasma samples along with those of the sulfated steroids. F kappa S was found in all plasma samples, both in men and women. The variation in F kappa S levels paralleled that in the free cortisol levels, thus the ratio of F kappa/F kappa S was the same in the blood samples drawn at 8 AM as in those drawn at 4 PM or 5 PM (ranges: 17.5-36.3 in men, 23.6-45.8 in women). The levels of F kappa S were relatively lower in women than in men (women 610-880 ng/100 mL at AM, 300-510 ng/100 mL at PM; men: 760-1,220 ng/100 mL at AM, 380-760 ng/100 mL at PM). Plasma levels of total sulfate-conjugated delta 4-3-keto-C-21 steroids (F kappa S + E kappa S + 20(alpha+beta)-dihydrocortisol-21-sulfates) were 30-40% higher than those of the levels of cortisol-21-sulfate alone (separated by thin-layer chromatography). In the adrenal vein plasma, levels of delta 4-3-keto-C-21-steroid-21-yl sulfates were 20 to 40 times higher than levels of these steroids in the peripheral blood. The bulk of the steroid sulfate measured in the adrenal vein plasma consisted of cortisol-21-sulfate. The ratio of F kappa/F kappa S in the adrenal vein plasma was markedly smaller than in the peripheral vein plasma; it was 6.9-12.3 in males and 4.9-6.7 in females, whereas in the peripheral vein of the same subjects it was 19.2-43.7 in males and 21.4-48.3 in females. Cortisol-21-sulfate isolated from adrenal vein plasma was identified by mass spectrometry. The data presented provide evidence for the secretion of this conjugate by the adrenal cortex. Its secretion appears to be markedly elevated in patients with Cushing's syndrome, both due to hyperplasia and due to adrenal adenoma, as compared with normal subjects and patients with primary aldosteronism, both males and females. However, the F kappa/F kappa S ratio was markedly lower in Cushing's patients due to adrenal adenoma than due to adrenal hyperplasia, this suggesting that ACTH is stimulating intra-adrenal hydrolysis of cortisol sulfate.

Adrenal Cortex Diseases↗
PubMed1995

Mineralocorticoid hypertension and congenital deficiency of 11 beta-hydroxysteroid dehydrogenase in a family with the syndrome of 'apparent' mineralocorticoid excess.

The so-called syndrome of 'apparent mineralocorticoid excess' (AME) is a rare cause of endocrine hypertension thought to result from a defect in the peripheral conversion of cortisol to cortisone. Less than 30 cases have been described. From a consanguineous marriage we present a family comprising 2 and probably 3 affected cases of AME. The index case is a 4-year-old boy with mineralocorticoid hypertension, short stature, failure to thrive, hypokalaemic nephropathy and osteopenia. The ratio of the urinary excretion of tetrahydrocortisone/tetrahydrocortisols was reduced at 0.05 (reference range 1.77-2.11), and the plasma half-life of 3H-11 alpha-cortisol elevated at 152 minutes (reference range 30-50) indicative of severe 11 beta-hydroxysteroid dehydrogenase deficiency. Plasma cortisol concentrations were normal and daily secretion rate reduced. Dexamethasone administration induced a natriuresis in keeping with the observation that cortisol itself is the implicated mineralocorticoid. Treatment with amiloride lowered blood pressure, increased potassium levels, and resulted in an increase in growth rate. The boy's twin brother died at the age of 3.5 years following a trivial diarrhoeal illness and was almost certainly affected. AME was also diagnosed in a younger brother (age 17 months), but both parents are normal. Congenital deficiency of 11 beta-hydroxysteroid dehydrogenase should be considered in any child with mineralocorticoid hypertension and failure to thrive. As cortisol is the 'offending' mineralocorticoid in this condition, the term 'apparent' mineralocorticoid excess is perhaps obsolete.(ABSTRACT TRUNCATED AT 250 WORDS)

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

Several homozygous mutations in the gene for 11 beta-hydroxysteroid dehydrogenase type 2 in patients with apparent mineralocorticoid excess.

Four deleterious mutations are described in the gene for HSD11B2, which encodes the type 2 isoenzyme of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD2). In seven families with one or more members affected by apparent mineralocorticoid excess, this disorder is shown to be the result of a deficiency in 11 beta HSD2. Surprisingly, the patients are all homozygous for their mutation. This results from consanguinity in two families and possibly from endogamy or a founder effect in four of the other five families. The absence of compound heterozygotes remains to be investigated.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

The biochemical and phenotypic characterization of females homozygous for 5 alpha-reductase-2 deficiency.

The biochemical and physiologic manifestations of decreased 5 alpha-dihydrotestosterone (DHT) in females are characterized. Three females from the large Dominican kindred with 5 alpha-reductase-2 deficiency were identified as homozygous for a point mutation (R246W, C-->T) on exon 5 of the 5 alpha-reductase-2 gene by single strand DNA conformational polymorphism analysis and DNA sequence analysis. Body hair was decreased; there was no history of acne. Despite delayed menarche, all were fertile, and two had twins. Urinary 5 beta/5 alpha C19 and C21 steroid metabolite ratios were elevated. Plasma testosterone was normal to elevated, with low DHT, resulting in an increased testosterone/DHT ratio. 3 alpha,5 alpha-Androstanediol glucuronide was low. Menstrual cycle profiling performed in two subjects showed ovulatory gonadotropin peaks. Sebum production was normal. 5 alpha-Reductase-2-deficient homozygotic females demonstrate the importance of DHT in the physiology and pathophysiology of body hair growth. Normal sebum implies regulation by the 5 alpha-reductase-1 isoenzyme. Delayed puberty suggests involvement of 5 alpha-reductase-2 in menarche at the hypothalamic/pituitary and/or ovarian level. As two had nonidentical twins, DHT and/or the DHT/estradiol ratio may regulate follicular development, with lower levels permitting more than one dominant follicle per cycle and higher levels impairing follicular development and ovulation. Thus, females with 5 alpha-reductase-2 deficiency highlight a role for DHT in hirsutism and/or menstrual disorders.

Adult↗
PubMed1995

11 beta-Hydroxysteroid dehydrogenase activity in Cushing's syndrome: explaining the mineralocorticoid excess state of the ectopic adrenocorticotropin syndrome.

A characteristic feature of the ectopic ACTH syndrome is a state of mineralocorticoid excess, although the etiology remains obscure. Some forms of endocrine hypertension, such as licorice ingestion, have been explained by cortisol acting as a mineralocorticoid in the setting of inhibition or deficiency of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). This enzyme is responsible for the conversion of cortisol (F) to hormonally inactive cortisone, and its activity in vivo can be inferred from the ratio of the urinary excretion of tetrahydrocortisol (THF) and its isomer (5 alpha THF) to tetrahydrocortisone. Twenty-two patients with Cushing's syndrome (11 pituitary dependent, 9 ectopic, and 2 adrenal adenomas) and 13 controls were studied. Compared to controls. Cushing's patients had a significant increase (P < 0.001) in the excretion of all principal metabolites of F, secondary to a 5- to 6-fold increase in the cortisol secretion rate [median, 34.0 (range, 13.3-327) mg/day in Cushing's vs. 6.1 (range, 2.5-10.3) mg/day in controls]. The THF plus 5 alpha THF/tetrahydrocortisone ratio was significantly increased in Cushing's syndrome regardless of etiology [mean, 1.81 (range, 1.09-9.99) in Cushing's vs. 0.81 (range, 0.51-1.47) in controls; P < 0.001), indicative of defective 11 beta HSD activity. Furthermore, compared to patients with pituitary-dependent Cushing's, this ratio was significantly higher in patients with the ectopic ACTH syndrome (4.12 vs. 1.49; P < 0.01) and was inversely correlated with serum potassium levels (r = -0.57; P = 0.01; n = 22). One explanation for the mineralocorticoid excess state of the ectopic ACTH syndrome appears to be that cortisol gains inappropriate access to the mineralocorticoid receptor through failure of its normal metabolism by 11 beta HSD. The reason for the defective 11 beta HSD activity is unclear, but it may be secondary to substrate saturation, inhibition by other adrenal steroids, or product inhibition.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

Intact protein electrospray ionization tandem mass spectrometry can be the sole technique used for confirming the structure of a variant hemoglobin.

A mutation within the human alpha-globin resulting in an 18 u mass increment was characterized by sequencing the intact M(r) 15000 protein in the gas phase by electrospray ionization tandem mass spectrometry. No separation of the variant protein from its normal counterpart and other components of the hemolysate was performed prior to mass spectrometric analysis. Collision-induced dissociation of the globin molecules carrying 18 protons was affected by their exposure to methane in the collision cell of a triple quadrupole mass spectrometer equipped with an electrospray ion source. Consideration of the major fragmentation ions (b758+, y"284+ and y"617+) narrowed down the mutation site to the last 28 amino acid residues within the protein sequence. Examination of low-abundance product ions allowed the unequivocal identification of the mutation as alpha 136 Leu --> Met, a hemoglobin previously named Hb Chicago.

Amino Acid Sequence↗
PubMed1994

Purification and enzymatic properties of a recombinant fusion protein expressed in Escherichia coli containing the domains of bovine P450 17A and rat NADPH-P450 reductase.

A fusion protein containing the heme domain of bovine cytochrome P450 17A and the flavin domains of rat NADPH-cytochrome P450 reductase has been genetically engineered by linking the modified cDNAs for each gene with the codons for serine and threonine. Transformation of Escherichia coli (DH5 alpha) and growth under defined conditions permits expression of 600-700 nmol of membrane-bound fusion protein per liter of growth medium (approximately 4% of cellular protein). A method has been developed for the solubilization, isolation, and purification to homogeneity of this protein. In the presence of NADPH the purified fusion protein catalyzes the 17 alpha-hydroxylation of progesterone and pregnenolone as well as the conversion of 17 alpha-hydroxypregnenolone to dehydroepiandrosterone. The 17,20-lyase activity is enhanced sixfold by the addition of purified rat liver cytochrome b5. Further, dehydroepiandrosterone is slowly metabolized to a number of additional more polar metabolites while 17 alpha-hydroxy-progesterone is slowly converted to dihydroxy-progesterone metabolites as well as a small amount of androstenedione in a reaction not influenced by cytochrome b5. Use of 5 alpha-pregnan steroids as substrates show the importance of the 3 beta-hydroxyl group for cytochrome b5 stimulated 17,20-lyase activity. Studies investigating the factors affecting electron transport between the flavin and heme domains suggest that the protein exists as a tight complex functioning as a self-contained biocatalytic unit.

Amino Acid Sequence↗
PubMed1993

The isolation and characterization of estradiol-fatty acid esters in human ovarian follicular fluid. Identification of an endogenous long-lived and potent family of estrogens.

The estradiol-fatty acid esters are highly potent and long-lived estrogens that were first isolated and identified from in vitro biosynthetic experiments (Mellon-Nussbaum S., Ponticorvo, L., Schatz, F., and Hochberg, R. B. (1982) J. Biol. Chem. 257, 5678-5684). Other studies have indicated that these esters exist endogenously, but the evidence is indirect, resting solely on the presence of a nonpolar saponifiable metabolite. Although there are similar reports of other naturally occurring fatty acid esters of biologically active steroid hormones, likewise, none has been isolated and characterized. In this study we have found that follicular fluid from the ovaries of women stimulated with gonadotrophins contains relatively large amounts of a nonpolar saponifiable derivative of estradiol (approximately 10(-7)M), which we presumed to be fatty acid esters. Using a combination of chromatographic techniques we isolated these estradiol metabolites and identified them by mass spectral analysis. They are a mixture of five different estradiol-17 fatty acid esters. The amount of each present was determined by separating the esters by reversed phase high performance liquid chromatography and then quantifying each peak by radioimmunoassay and UV absorption. The esters of estradiol are predominantly unsaturated, with linoleate the most abundant comprising 43% of the total. The other esters are: palmitate (20%), arachidonate (19%), oleate (14%), and stearate (4%). Thus these studies conclusively demonstrate the existence of these unusually powerful estrogens.

Arachidonic Acid↗
PubMed1993

Analysis of taxol and related diterpenoids from cell cultures by liquid chromatography-electrospray mass spectrometry.

Authentic taxanes (taxol, 10-deacetyltaxol, cephalomannine, 10-deacetylcephalomannine, baccatin III) and extracts from cell cultures derived from various yew tree species have been analyzed by microbore high-performance liquid chromatography (HPLC)-electrospray mass spectrometry (ESMS). All gave excellent positive-ion ES spectra with dominant protonated molecules at low nozzle-to-skimmer bias value (45 V). By increasing the voltage value to 85 V, fragmentation increased and structurally informative spectra were obtained. The fragments found were both of the C-13 side-chain and of the taxane ring, so their analysis gave important information about the taxane structure and any chemical modifications at different positions of the molecule. When tandem MS was used (argon gas, 25 eV collision energy), fragments similar to those obtained from collision-induced dissociation in the source were detected. The cell culture extracts were analyzed by microbore HPLC-ESMS and excellent spectra were obtained on 5-10 ng of separated compounds; even greater selectivity and sensitivity were obtained through use of selected-ion monitoring (SIM). With SIM, 100 pg of all taxanes could readily be detected. In the HPLC-ESMS mode, only 10% of the eluent was mass-analyzed, so 90% would be available for recovery through fraction collecting.

Cells, Cultured↗
PubMed1993

Corticosteroidogenesis in the toad Bufo arenarum H: evidence for a precursor role for an aldosterone 3 beta-hydroxy-5-ene analogue (3 beta, 11 beta, 21-trihydroxy-20-oxo-5-pregnen-18-al).

A material isolated following pregnenolone incubations with toad (Bufo arenarum) inter-renal tissue at 28 degrees C has been identified as a 3 beta-hydroxy-5-ene analogue of aldosterone (3 beta, 11 beta, 21-trihydroxy-20-oxo-5-pregnen-18-al). The initial identification was made by enzymic and m.s. methods, and structural confirmation was achieved through comparison with chemically synthesized authentic material. The relative efficacy of corticosterone, 18-hydroxycorticosterone and the 3 beta-hydroxy-5-ene aldosterone analogue as aldosterone precursors was evaluated. In the in vitro situation studied, the 3 beta-hydroxy-5-ene steroid was by far the best precursor.

3-Hydroxysteroid Dehydrogenases↗
PubMed1993

Collisionally activated dissociation and tandem mass spectrometry of intact hemoglobin beta-chain variant proteins with electrospray ionization.

Electrospray ionization collisionally activated dissociation (CAD) mass spectra of multiply charged human hemoglobin beta-chain variant proteins (146 amino acid residues, 15.9 kDa), generated in the atmospheric pressure/vacuum interface and in the collision quadrupole of a triple-quadrupole mass spectrometer, are shown and compared. Several series of structurally informative singly and multiply charged b- and y-mode product ions are observed, with cleavage of the Thr 50-Pro 51 CO-NH bond to produce the complementary y96 and b50 sequence ions as the most favored fragmentation pathway. The eight different beta-globin variants studied differ by a single amino acid substitution and can be differentiated from the observed m/z shifts of the assigned product ions. The overall fragmentation patterns for the variant polypeptides are very similar, with the exception of the Willamette form, in which Arg is substituted for Pro- 51, and multiply charged y96 product ions are not observed. Circular dichroism spectra of normal beta A and beta Willamette show very little difference under a variety of solvent conditions, indicating that fragmentation differences in their respective CAD mass spectra are substantially governed by primary rather than secondary structure.

Adult↗
PubMed1993

Taxoid side-chain structure determination by electrospray ionization tandem mass spectrometry.

A method to elucidate the side-chain structure of novel taxoids was developed through use of electrospray ionization tandem mass spectrometry. The intact side-chain fragments produced by source fragmentation in the atmosphere-to-vacuum interface were further dissociated in the collision cell of a triple quadrupole mass spectrometer. The distinctive collisionally induced dissociation mass spectra were remarkably informative and gave detailed information on the side-chain functionalities. This technique proved valuable in the characterization of new taxoids produced by yew-tree cell cultures.

Alkaloids↗
PubMed1993

Mass spectrometry in the diagnosis of steroid-related disorders and in hypertension research.

The use of GC/MS and microbore HPLC/electrospray mass spectrometry for clinical studies in hypertension and mineralocorticoid research is described. In particular, an automated GC/MS method allows nearly quantitative measurements of metabolites of major steroids of adrenal, placental and gonadal origin. This method is able to distinguish almost all steroid related disorders. Electrospray mass spectrometry in conjunction with microbore HPLC is the latest mass spectrometry technique applicable to biochemical investigations. It offers high sensitivity (15 pg) for measurement of intact steroid conjugates and related compounds.

Adolescent↗
PubMed1993

Deficient inactivation of cortisol by 11 beta-hydroxysteroid dehydrogenase in essential hypertension.

OBJECTIVE: 11 beta-Hydroxysteroid dehydrogenase protects renal mineralocorticoid receptors from cortisol by converting cortisol to inactive cortisone. 11 beta-Dehydrogenase deficiency, either congenital or after inhibition by liquorice and carbenoxolone, results in cortisol-dependent mineralocorticoid excess and hypertension. We tested the hypothesis that the same mechanism occurs in some patients with essential hypertension. DESIGN/PATIENTS: Twenty patients with essential hypertension were compared with 19 matched healthy controls. MEASUREMENTS: 11 beta-Hydroxysteroid dehydrogenase activity was assessed by the half-life of 11 alpha-3H-cortisol, and by the ratios of cortisol to cortisone in plasma and of their metabolites in urine. Renal mineralocorticoid receptor activation was assessed by plasma potassium, renin activity and aldosterone. RESULTS: Half-lives of 11 alpha-3H-cortisol were prolonged in a subgroup of hypertensives (mean +/- SE 53.2 +/- 3.6 min in hypertensives vs 42.3 +/- 2.3 in controls, P < 0.05; seven of the 20 hypertensives had half-lives exceeding 2 SD of controls). Ratios of cortisol to cortisone in plasma and of their metabolites in urine were not different. 11 alpha-3H-Cortisol half-lives correlated with blood pressure but not with indices of renal mineralocorticoid receptor activation. CONCLUSIONS: 11 beta-Dehydrogenase is defective in a proportion of patients with essential hypertension. The normal ratios of cortisol to cortisone in plasma and of their metabolites in urine, also seen after carbenoxolone administration, suggest that 11 beta-reductase conversion of cortisone to cortisol is also defective. Unlike other syndromes of 11 beta-dehydrogenase deficiency, the defect was not associated with mineralocorticoid excess. We suggest that it may cause hypertension by increasing exposure of vascular steroid receptors to cortisol.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

Measurement of endogenous synthesis of plasma cholesterol in rats and humans using MIDA.

We used the mass isotopomer distribution analysis (MIDA) technique to measure endogenous synthesis of plasma cholesterol in vivo in rats and normal human subjects. Sodium [1-13C]- or [2-13C]acetate was infused, and plasma free cholesterol was analyzed by gas chromatography-mass spectrometry. Frequencies of mass isotopomers M0-M4 (mass-to-charge ratio 368-372) were quantified. The enrichment of the true precursor for cholesterol synthesis (acetyl-coenzyme A in contributing tissues) was determined using the MIDA method. This technique remains mathematically valid even if more than one tissue contributes to circulating free cholesterol. The fractional contribution (f) from endogenous synthesis to free cholesterol in normal women (n = 5) was 2.48 +/- 0.39% after 7 h in the postabsorptive state and 1.27 +/- 0.41% after 8 h of refeeding. In ad libitum-fed rats (n = 12), f was 2.89 +/- 0.44% after 12 h, whereas administration of recombinant tumor necrosis factor increased this value fourfold. Next, the rate constant (k) for removal of labeled free cholesterol from plasma was calculated. Higher masses (M2-M4) were followed to avoid the problem of persistent label incorporation. During the 60 h after cessation of [13C]acetate infusions, k was 0.02490 +/- 0.00298/h in humans. Using these values of k and f, absolute cholesterogenesis was 568 +/- 55 mg/day in normal women (follicular menstrual phase), similar to prior estimates based on whole body sterol balances. Women also exhibited a diurnal variation for endogenous cholesterol synthesis (34.6 +/- 5.4 mg/h nighttime vs. 15.9 +/- 5.2 mg/h daytime) consistent with current knowledge about rhythms in cholesterogenesis. Checks on the model were internally consistent (e.g., comparisons among different isotopomers for calculating precursor enrichment). We conclude that fractional and absolute endogenous cholesterol synthesis can be measured using stable isotopes in vivo by the MIDA technique.

Adult↗
PubMed1993

Increased de novo hepatic lipogenesis in human immunodeficiency virus infection.

We measured de novo lipogenesis in human immunodeficiency virus (HIV) infected men using a newly developed stable isotope method. HIV-infected subjects with a history of weight loss (n = 17, mean weight loss 14.9 +/- 3.2 kg), asymptomatic HIV-seropositive subjects with normal CD4 T-cell counts (n = 7) and healthy HIV seronegative controls (n = 11) were studied. Hepatic lipogenesis was determined by infusion of [2-13C]-acetate, using the recently described xenobiotic probe technique with mass isotopomer analysis. Hepatic acetyl-coenzyme A enrichment was measured by high performance liquid chromatography/mass spectrometry of secreted sulfamethoxazole-acetate, with measurement of incorporation into very low density lipoprotein-fatty acids by gas chromatography-mass spectrometry. Circulating tumor necrosis factor (TNF), interleukin-1 (IL-1), interferon alpha (IFN alpha), insulin, and triglycerides were measured concurrently, and 7-day weighed food records were performed. De novo hepatic lipogenesis was increased 3- to 4-fold in HIV-infected subjects with weight loss compared to normal controls (P < 0.05 for palmitate and stearate in both overnight-fasted and fed states), and was also significantly increased in asymptomatic HIV seropositive subjects. Circulating TNF and IL-1 were not measurable in any subject (detection limit 2 pg/ml for IL-1 and 20 pg/ml for TNF). Serum IFN alpha was measurable in 11 out of 17 subjects with wasting and correlated significantly with de novo lipogenesis in overnight-fasted but not fed states. Serum IFN alpha was unmeasurable in asymptomatic HIV-infected subjects despite elevated lipogenic rates. Serum triglyceride concentrations were elevated in subjects with weight loss (2.09 +/- 0.28 mmol/L) and asymptomatic HIV-positives (1.34 +/- 0.34 mmol/L) in comparison to controls (0.67 +/- 0.08 mmol/L), and correlated with lipogenesis. Food intake correlated inversely with lipogenesis in the overnight-fasted state. We conclude that HIV infection is characterized by abnormal fat anabolism. This applies to subjects with reduced lean body mass and to asymptomatic HIV-positive subjects with normal T-cell counts. The former observation may have implications for the pathophysiology and treatment of the wasting syndrome. The latter observation is consistent with activation of the immune response and a state of viral nonlatency in early HIV disease.

Adult↗
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↗