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Cortisol Metabolism in Healthy Young Adults: Sexual Dimorphism in Activities of A-Ring Reductases, but not 11ß-Hydroxysteroid Dehydrogenases¹

University of Edinburgh, Endocrinology Unit, Department of Medical Sciences, Western General Hospital, Edinburgh, United Kingdom EH4 2XU

Address all correspondence and requests for reprints to: Dr. Brian R. Walker, University of Edinburgh, Endocrinology Unit, Department of Medical Sciences, Western General Hospital, Edinburgh, United Kingdom EH4 2XU. E-mail: b.walker{at}ed.ac.uk

	Abstract

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Cortisol is metabolized irreversibly by A-ring reductases (5- and 5ß-reductases) and reversibly (to cortisone) by 11ß-hydroxysteroid dehydrogenases (11ßHSDs). In rats, estradiol down-regulates 11ßHSD1 expression. In humans, ratios of urinary cortisol/cortisone metabolites differ in men and women. In this study, urinary cortisol metabolites and hepatic 11ßHSD1 activity were measured in healthy young men and women at different phases of the menstrual cycle.

Ten men and 10 women with regular menstrual cycles collected a 24-h urine sample, took 250 µg oral dexamethasone at 2300 h, took 25 mg oral cortisone at 0900 h (after fasting), and had blood sampled for plasma cortisol estimation over the subsequent 150 min. Women repeated the tests in random order in menstrual, follicular, and luteal phases.

Women excreted disproportionately less A-ring-reduced metabolites of cortisol [median 5-tetrahydrocortisol, 1811 (interquartile range, 1391–2300) µg/day in menstrual phase vs. 2723 (interquartile range, 2454–3154) in men (P = 0.01); 5ß-tetrahydrocortisol, 1600 (interquartile range, 1419–1968) vs. 2197 (interquartile range, 1748–2995; P = 0.03)] but similar amounts of cortisol, cortisone, and tetrahydrocortisone. Analogous differences were observed in urinary excretion of androgen metabolites. Conversion of cortisone to cortisol on hepatic first pass metabolism was not different (peak plasma cortisol, 733 ± 60 nmol/L in women vs. 684 ± 53 nmol/L in men; mean ± SEM; P = 0.55). There were no differences in cortisol or androgen metabolism between phases of the menstrual cycle.

We conclude that sexual dimorphism in cortisol metabolite excretion is attributable to less A-ring reduction of cortisol in women, rather than less reactivation of cortisone to cortisol by 11ßHSD1. This difference is not influenced acutely by gonadal steroids. 11ßHSD1 has been suggested to modulate insulin sensitivity and body fat distribution, but caution must be exercised in extrapolating inferences about its regulation from rodents to man. A-Ring reductases may have an equally important influence on metabolic clearance of cortisol and intracellular cortisol concentrations.

	Introduction

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CORTISOL IS metabolized by several enzymes (Fig. 1), including irreversible inactivation by A-ring reductases (5- and 5ß-reductases) and reversible interconversion to inactive cortisone. Interconversion with cortisone is catalyzed by 11ß-hydroxysteroid dehydrogenases (11ßHSDs), which are now recognized to play a crucial role in modulating activation of corticosteroid receptors. 11ßHSD type 2 (1, 2) inactivates cortisol in the distal nephron, thereby protecting mineralocorticoid receptors from inappropriate activation by cortisol. Congenital or acquired defects in 11ßHSD2 result in cortisol-dependent mineralocorticoid excess (3, 4, 5). More recently, the role of 11ßHSD type 1 (6) has been defined. This enzyme reactivates cortisone in many sites, including liver and adipose tissue (7, 8, 9), where it appears to maintain adequate exposure of glucocorticoid receptors to cortisol (10, 11, 12). Defects in 11ßHSD1 result in enhanced sensitivity to insulin. Increased activity of 11ßHSD1 has been postulated to be important in insulin resistance syndromes, particularly obesity (9, 13, 14).

View larger version (28K): [in this window] [in a new window]   Figure 1. Principal metabolites of cortisol (A) and androgens (B) measured in urine by gas chromatography and mass spectrometry. Dotted arrows indicate that more than one step is involved.

In rats, 11ßHSD1 expression and activity in liver are markedly lower in females than in males (21). Estradiol administration to gonadectomized rats potently represses 11ßHSD1 expression, an effect that depends at least in part on changes in the pattern of GH secretion (17). Evidence of whether estrogen regulates 11ßHSD1 in humans is surprisingly limited. In premenopausal healthy women, the ratio of urinary metabolites of cortisol to cortisone has been reported to be lower than that in men (22), but the characteristics of participants in that study were not described in detail. The same trend was observed in hypopituitary patients (23), but clearly there are potential confounding effects of hormonal replacement therapies in this group. In healthy postmenopausal women, the ratio of cortisol/cortisone metabolites was higher than that in men and was not influenced by estrogen replacement therapy (14).

In this study, we sought to clarify whether sex-specific difference in cortisol metabolism are observed in healthy young adults and to establish whether changes in urinary cortisol/cortisone metabolites could be attributed to differences in hepatic conversion of cortisone to cortisol by 11ßHSD1. In addition, we sought differences in these indexes of cortisol metabolism in different phases of the menstrual cycle.

	Experimental Subjects

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Lothian Research ethics committee approval and written informed consent were obtained. All participants were white Caucasians. Ten healthy men and 10 healthy women with regular endogenous menstrual cycles (between 24–34 days) were recruited by advertisement. Their characteristics are shown in Table 1. Groups were matched for age and body mass index. Inclusion criteria were: age, 20–45 yr; blood pressure, less than 160/90 mm Hg; no regular medication; no use of glucocorticoid therapy by any route during the previous 3 months; no psychiatric illness in the previous 3 months; and no abnormality of renal, thyroid, or liver function on biochemical screening.

	Materials and Methods

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Men were studied on one occasion. Women were studied on three occasions, in random order, during menstrual (2–5 days after starting menstruation), follicular (19–16 days before the next expected menstruation), or luteal (9–5 days before next menstruation) phases. All studies were completed in the winter months (December to March), and men and women were studied in parallel to avoid confounding effects of seasonal changes in steroid metabolite excretion (24).

On each occasion, subjects collected a 24-h urine sample, took 250 µg oral dexamethasone at 2300 h, and attended next day at 0830 h after an overnight fast. A venous cannula was inserted, and blood was withdrawn after 25 min for cortisol and, in women, estradiol and progesterone determinations. After 30 min, 25 mg oral cortisone acetate was administered, and blood was sampled during the next 150 min for plasma cortisol determination. The dose of dexamethasone was selected to lower baseline plasma cortisol so that a rise could be readily detected after cortisone administration without giving so much that dexamethasone metabolites might interfere with cortisone metabolism (25).

Laboratory measurements

Cortisol and its metabolites in urine were measured by gas chromatography and electron impact mass spectrometry after Sep-Pak C₁₈ extraction, hydrolysis with ß-glucuronidase, and formation of methoxime-trimethylsilyl derivatives as previously described (26). Epi-cortisol and epi-tetrahydrocortisol were used as internal standards, which were added to samples before extraction. Peaks of interest were quantified by the ratio of (area under the peak)/(area under neighboring internal standard peak), rather than the ratio of peak height against a line extrapolated from bracketed internal standards as used by many other groups. Ratios were compared against standard curves for each steroid included in every assay batch. The average intraassay precision for all steroids measured was less than 20% (n = 16 assays). In each assay batch, water samples were included containing standard steroids and average accuracy for all steroids varied from -4.4% to +5.5% (n = 16). Principal urinary androgen metabolites were measured using the same method, except that 5-androstan-3,17-diol was used as an internal standard. Pathways of cortisol and androgen metabolism leading to these metabolites are illustrated in Fig. 1. The ratio between 5ß-reduced and 5-reduced metabolites of cortisol and androgens was closely correlated (r = 0.80; P < 0.001).

Cortisol, estradiol, and progesterone were measured in plasma by commercial RIAs.

Statistics

Results are presented as the mean ± SEM for normally distributed variables; groups were compared using unpaired Student’s t tests or repeated measures ANOVA. Many of the urinary cortisol metabolites had skewed distributions, necessitating nonparametric analyses; these are presented as median (interquartile range). Data from men and women in the menstrual phase were compared by Mann-Whitney U tests; data from different phases of the menstrual cycle were compared by Friedman ANOVA. Data for men and women in luteal and follicular phases were not compared to avoid multiple statistical testing.

	Results

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Comparison between men and women

Men and women were well matched for age and body mass index, but men were taller and heavier, with android distribution of body fat (Table 1). Absolute excretion rates of urinary cortisol metabolites tended to be higher in men (Table 2). This was attributable principally to lower excretion of 5-reduced and 5ß-reduced metabolites of cortisol in women. Excretions of cortisol, cortisone, and tetrahydrocortisone were not different. Excretion of androgen metabolites also tended to be higher in men, accounted for by a trend toward lower excretion of 5-reduced metabolites in women.

Plasma cortisol after overnight dexamethasone suppression was not different between men and women (Table 3). The rise in plasma cortisol after oral cortisone administration is shown in Fig. 2. The rate of rise, maximum plasma cortisol, and area under the curves did not differ between men and women. However, the peak cortisol occurred earlier in men than women, apparently because cortisol was cleared from plasma more quickly in men.

View larger version (22K): [in this window] [in a new window]   Figure 2. Hepatic 11ßHSD1 activity. Plasma cortisol was measured after overnight dexamethasone suppression (250 µg, orally, at 2300 h) and oral administration of 25 mg cortisone acetate at 0900 h. Data are the mean ± SEM for males (n = 10), and females (n = 10) in menstrual, follicular, and luteal phases of the endogenous menstrual cycle. Comparisons are given in Table 3.

Accuracy of timing of phases of the menstrual cycle was confirmed by measurements of plasma estradiol and progesterone (data not shown). For all women, estradiol was higher in the follicular than in the menstrual phase, and progesterone was only detectable in the luteal phase.

There were no differences in urinary cortisol or androgen metabolite excretion (Table 2) or conversion of oral cortisone to plasma cortisol (Fig. 2) in different phases of the menstrual cycle.

	Discussion

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This study is consistent with previous observations that urinary excretion of the A-ring reduced metabolites of cortisol is lower in premenopausal women than in men (22), and that this is out of proportion to the excretion of other metabolites of cortisol in women. The disproportionality of these differences excludes technical confounders, such as incomplete urine collection. The absolute excretion rates for some cortisol metabolites, particularly 5-tetrahydrocortisol, are somewhat higher in this group than those reported by others in healthy volunteers (3, 27, 30, 31). This may reflect differences between groups of subjects or methodological differences, for example in the choice of internal standards. In addition, this study confirms previous reports that urinary androgen excretion is only marginally higher in men than in women (30), reflecting the fact that most urinary androgen metabolites are derived from adrenal androgens.

Previously, differences in cortisol metabolite excretion between men and women have been attributed to alterations in 11ß-hydroxysteroid dehydrogenases. Whether this reflects enhanced inactivation of cortisol to cortisone by 11ßHSD2 or impaired reactivation of cortisone to cortisol by 11ßHSD1 in women had not been tested. However, it was assumed that lesser 11ßHSD1 activity in women was responsible on the basis of studies in rats suggesting that only 11ßHSD1 is regulated by other hormones, including down-regulation by estrogen (17, 20, 21).

In the present study, ratios of urinary cortisol/cortisone (26, 27) suggest that conversion of cortisol to cortisone by renal 11ßHSD2 activity is lower, rather than higher, in women than men. Therefore, differences in 11ßHSD2 could not explain lower ratios of cortisol/cortisone metabolites; this is consistent with the hypothesis that these differences reflect sexual dimorphism in 11ßHSD1 activity. However, we also made a more specific assessment of hepatic 11ßHSD1 activity by measuring the conversion of cortisone administered orally into cortisol in the peripheral circulation. The rate of appearance of cortisol is lower when 11ßHSD1 is inhibited, e.g. by carbenoxolone (32), but is not influenced by 11ßHSD2 activity (33). The lack of sexual dimorphism in the rate of appearance of cortisol in the present study suggests that 11ßHSD1 activity is not different in men and women. Moreover, in marked contrast with dramatic changes over a similar time course in rats (17, 21), changes in estrogen levels in women during the menstrual cycle were not associated with alterations in any index of 11ßHSD1 activity.

The present data suggest an alternative explanation for the disproportionately low excretion of tetrahydrocortisols in women. As previously described in postmenopausal (14) and hypopituitary (23) women, the excretion of cortisol and cortisone is similar or even increased in women compared with that in men; the differences are observed only in the A-ring reduced metabolites. Thus, the ratios of urinary metabolites suggest that rates of A-ring reduction of cortisol are lower in women than in men. This is substantiated by examining A-ring reduction of androgen metabolites. Lower A-ring reduction could also explain why cortisol is cleared less rapidly from plasma in women than in men after an oral dose of cortisone. Unlike postmenopausal women (14), this difference does not affect the 5ß-reduction of cortisone and could therefore account both for the lower ratio of tetrahydrocortisols/tetrahydrocortisone observed in young women (22), but not postmenopausal women (14), and for the trend toward higher urinary cortisol/cortisone in women in this study.

It is not clear why A-ring reduction of cortisol should differ between men and women. The principal enzymes involved are 5ß-reductase (34) and 5-reductase types 1 and 2 (35). 5ß-Reductase is expressed in liver and is involved in the metabolism of bile acids. Although there is some evidence that affinities for cortisol and cortisone/androgens can be separated by semipurification and subcellular fractionation in vitro (36, 37), there is no evidence that there is more than one 5ß-reductase active in vivo in man (38). 5ß-Reductase activity is lower in female than in male rat livers (39), but it is up-regulated by estrogen (40). 5-Reductase type 1, the principal isozyme in human liver and fat (41), is usually thought to be constitutive and not regulated hormonally (42, 43), but there is some evidence that this isozyme is down-regulated by androgens (44, 45) more so than by estrogen (46), so that its activity is higher in female liver (47) and adrenal (48). 5-Reductase type 2 is expressed mainly in the prostate and is up-regulated by androgens (35). These observations from animals predict that activities of 5ß-reductase may be lower, and hepatic 5-reductase may be higher, rather than decreased, in women. Moreover, the lack of acute effect of changes in gonadal steroids on urinary cortisol metabolite excretion in the current study suggests that the explanation for sexual dimorphism in A-ring reductases does not relate to acute gonadal steroid regulation in humans. An alternative explanation relates to the relative mass of tissues expressing A-ring reductases in men and women. It is not clear whether the prostate contributes substantially to A-ring reduction of cortisol, but, interestingly, finasteride, a relatively specific inhibitor of 5-reductase type 2, does alter the relative excretion of cortisol metabolites in men (49). The quantity and distribution of body fat may also be important, as 5-reductase type 1 is expressed in adipocytes and is more active in peripheral sc than central visceral fat in culture (41), although the contribution of adipose 5-reductase activity to cortisol clearance may be small. Previous studies suggest that increased visceral fat in men may be associated with greater 5-reductase activity (14). However, the current study is too small, and subjects within it too similar, to explore whether differences in body fat distribution might explain sexual dimorphism in cortisol metabolite excretion.

We have previously reported cortisol metabolite profiles in older subjects, in whom we found relationships between greater central/visceral obesity and enhanced activity of 5-reductase, but not 5ß-reductase (14). The pattern of differences between older men and women contrasts with the results in young subjects studied here and previously (22). Older women had higher 5-reductase, but not 5ß-reductase, activity and higher ratios of metabolites of cortisol to those of cortisone in urine compared with men. Comparing values in Table 2 with values in the older population measured by the same method (14), it appears that there is little difference between postmenopausal and premenopausal women, but that the major differences are between younger and older men. Thus, aging in men may be associated with falling activities of 5-reductase and 11ßHSD1.

Whatever the reason for sexual dimorphism of A-ring reduction of cortisol and its change with age, this observation has important implications for physiological glucocorticoid action and for interpretation of apparent pathological disruption of cortisol metabolism. Lesser A-ring reduction of cortisol in women predicts a lower MCR of cortisol, which, in turn, predicts greater feedback suppression of the hypothalamic-pituitary-adrenal axis. If A-ring reduction is increased, as in obesity (14) and probably also in polycystic ovarian syndrome (50, 51), increased ACTH drive to the adrenal cortex may contribute to excessive androgen secretion. Conversely, a decline in A-ring reduction, as may occur with normal aging in men, may contribute to the fall in adrenal androgen excretion with age (52). In addition, the extent of A-ring reduction in specific organs, including adipose tissue and liver, will influence local concentrations of cortisol independently of circulating glucocorticoid concentrations. It remains to be established whether this has a potent influence on corticosteroid receptor activation, but it may contribute to the sexual dimorphism of body fat distribution.

Arguably the most important implications of this study are that care should be exercised in extrapolating to humans from studies of regulation of 11ßHSD1 in rodents, and that ratios of tetrahydrometabolites of cortisol and cortisone should be interpreted cautiously if they are not accompanied by measurements of cortisol and cortisone (26, 27). The latter has not been measured in some other studies comparing men and women (22) or in studies of polycystic ovarian syndrome (50, 51) or essential hypertension (53, 54). Arguably for this reason the inferences concerning 11ßHSD activities may have been overemphasized, and the potential importance of disturbances in A-ring reduction of cortisol may have been overlooked.

	Footnotes

 
¹ This work was supported by a Travelling Fellowship (to M.J.J.F.) from the Dutch Diabetes Federation and a Senior Research Fellowship (to B.R.W.) from the British Heart Foundation.

Received January 29, 1999.

Revised May 19, 1999.

Accepted June 8, 1999.

	References

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1. Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS. 1994 Cloning and tissue distribution of the human 11ß-hydroxysteroid dehydrogenase type 2 enzyme. Mol Cell Endocrinol. 105:R11–R17.
2. Agarwal AK, Mune T, Monder C, White PC. 1994 NAD⁺-dependent isoform of 11ß-hydroxysteroid dehydrogenase. Cloning and characterisation of cDNA from sheep kidney. J Biol Chem. 269:25959–25962.[Abstract/Free Full Text]
3. Stewart PM, Valentino R, Wallace AM, Burt D, Shackleton CHL, Edwards CRW. 1987 Mineralocorticoid activity of liquorice: 11ß-hydroxysteroid dehydrogenase deficiency comes of age. Lancet. 2:821–824.[Medline]
4. Mune T, Rogerson FM, Nikkila H, Agarwal AK, White PC. 1995 Human hypertension caused by mutations in the kidney isozyme of 11ß-hydroxysteroid dehydrogenase. Nat Genet. 10:394–399.[CrossRef][Medline]
5. Wilson RC, Harbison MD, Krozowski ZS, et al. 1995 Several homozygous mutations in the gene for 11ß-hydroxysteroid dehydrogenase type 2 in patients with apparent mineralocorticoid excess. J Clin Endocrinol Metab. 80:3145–3150.[Abstract]
6. Agarwal AK, Monder C, Eckstein B, White PC. 1989 Cloning and expression of rat cDNA encoding corticosteroid 11ß-dehydrogenase. J Biol Chem. 264:18939–18943.[Abstract/Free Full Text]
7. Walker BR, Campbell JC, Fraser R, Stewart PM, Edwards CRW. 1992 Mineralocorticoid excess and inhibition of 11ß-hydroxysteroid dehydrogenase in patients with ectopic ACTH syndrome. Clin Endocrinol (Oxf). 27:483–492.
8. Jamieson PM, Chapman KE, Edwards CRW, Seckl JR. 1995 11ß-Hydroxysteroid dehydrogenase is an exclusive 11ß-reductase in primary cultures of rat hepatocytes: effect of physicochemical and hormonal manipulations. Endocrinology. 136:4754–4761.[Abstract]
9. Bujalska IJ, Kumar S, Stewart PM. 1997 Does central obesity reflect ‘Cushing’s disease of the omentum’? Lancet. 349:1210–1213.[CrossRef][Medline]
10. Walker BR, Connacher AA, Lindsay RM, Webb DJ, Edwards CRW. 1995 Carbenoxolone increases hepatic insulin sensitivity in man: a novel role for 11-oxosteroid reductase in enhancing glucocorticoid receptor activation. J Clin Endocrinol Metab. 80:3155–3159.[Abstract]
11. Kotelevtsev YV, Holmes MC, Burchell A, et al.1997 11ß-Hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid inducible responses and resist hyperglycaemia on obesity and stress. Proc Natl Acad Sci USA. 94:14924–14929.
12. Jamieson PM, Nyirenda MJ, Walker BR, Chapman KE, Seckl JR. 1998 Interactions between oestradiol and glucocorticoid regulatory effects on liver-specific glucocorticoid-inducible genes: possible evidence for a role of hepatic 11ß-hydroxysteroid dehydrogenase type 1. J Endocrinol. 160:103–109.
13. Stewart PM, Boulton A, Kumar S, Clark PMS, Shackleton CHL. 1999 Cortisol metabolism in human obesity: impaired cortisone-cortisol conversion in subjects with central adiposity. J Clin Endocrinol Metab. 84:1022–1027.[Abstract/Free Full Text]
14. Andrew R, Phillips DIW, Walker BR. 1998 Obesity and gender influence cortisol secretion and metabolism in man. J Clin Endocrinol Metab. 83:1806–1809.[Abstract/Free Full Text]
15. Hammami MM, Siiteri PK. 1991 Regulation of 11ß-hydroxysteroid dehydrogenase activity in human skin fibroblasts: enzymatic modulation of glucocorticoid action. J Clin Endocrinol Metab. 73:326–334.[Abstract/Free Full Text]
16. Whorwood CB, Sheppard MC, Stewart PM. 1993 Tissue specific effects of thyroid hormone on 11ß-hydroxysteroid dehydrogenase gene expression. J Steroid Biochem Mol Biol. 46:539–547.[CrossRef][Medline]
17. Low SC, Chapman KE, Edwards CRW, Wells T, Robinson ICAF, Seckl JR. 1994 Sexual dimorphism of hepatic 11ß-hydroxysteroid dehydrogenase in the rat: the role of growth hormone patterns. J Endocrinol. 143:541–548.[Abstract/Free Full Text]
18. Escher G, Galli I, Vishwanath BS, Frey BM, Frey FJ. 1997 Tumor necrosis factor and interleukin 1ß enhance the cortisone/cortisol shuttle. J Exp Med. 186:189–198.[Abstract/Free Full Text]
19. Smith RE, Funder JW. 1991 Renal 11ß-hydroxysteroid dehydrogenase activity: effects of age, sex and altered hormonal status. J Steroid Biochem Mol Biol. 38:265–267.[CrossRef][Medline]
20. Albiston AL, Smith RE, Krozowski ZS. 1995 Sex- and tissue-specific regulation of 11ß-hydroxysteroid dehydrogenase mRNA. Mol Cell Endocrinol. 109:183–188.[CrossRef][Medline]
21. Low SC, Assaad SN, Rajan V, Chapman KE, Edwards CRW, Seckl JR. 1993 Regulation of 11ß-hydroxysteroid dehydrogenase by sex steroids in vivo: further evidence for the existence of a second dehydrogenase in rat kidney. J Endocrinol. 139:27–35.[Abstract/Free Full Text]
22. Raven PW, Taylor NF. 1996 Sex differences in the human metabolism of cortisol. Endocr Res. 22:751–755.[Medline]
23. Weaver JU, Taylor NF, Monson JP, Wood PJ, Kelly WF. 1998 Sexual dimorphism in 11ß hydroxysteroid dehydrogenase activity and its relation to fat distribution and insulin sensitivity; a study in hypopituitary subjects. Clin Endocrinol (Oxf). 49:13–20.[CrossRef][Medline]
24. Walker BR, Best R, Noon JP, Watt GCM, Webb DJ. 1997 Seasonal variation in glucocorticoid activity in healthy men. J Clin Endocrinol Metab. 82:4015–4019.[Abstract/Free Full Text]
25. Best R, Nelson SM, Walker BR. 1997 Dexamethasone and 11-dehydrodexamethasone as tools to investigate the isozymes of 11ß-hydroxysteroid dehydrogenase in vitro and in vivo. J Endocrinol. 153:41–48.[Abstract/Free Full Text]
26. Best R, Walker BR. 1997 Additional value of measurement of urinary cortisone and unconjugated cortisol metabolites in assessing the activity of 11ß-hydroxysteroid dehydrogenase in vivo. Clin Endocrinol (Oxf). 47:231–236.[CrossRef][Medline]
27. Palermo M, Shackleton CHL, Mantero F, Stewart PM. 1996 Urinary free cortisone and the assessment of 11ß-hydroxysteroid dehydrogenase activity in man. Clin Endocrinol (Oxf). 45:605–611.[CrossRef][Medline]
28. Edwards CRW, Walker BR. 1993 Cortisol and hypertension: what was not so apparent about ‘apparent mineralocorticoid excess.’ J Lab Clin Med. 122:632–635.[Medline]
29. Ulick S, Tedde R, Wang JZ. 1992 Defective ring A reduction of cortisol as the major metabolic error in the syndrome of apparent mineralocorticoid excess. J Clin Endocrinol Metab. 74:593–599.[Abstract]
30. Weykamp CW, Penders TJ, Schmidt NA, Borburgh AJ, van de Calseyde JF, Wolthers BJ. 1989 Steroid profile for urine: reference values. Clin Chem. 35:2281–2284.[Abstract/Free Full Text]
31. Rook GAW, Honour J, Kon OM, Wilkinson RJ, Davidson R, Shaw RJ. 1996 Urinary adrenal steroid metabolites in tuberculosis–a new clue to pathogenesis? Q J Med. 89:333–341.[Abstract/Free Full Text]
32. Stewart PM, Wallace AM, Atherden SM, Shearing CH, Edwards CRW. 1990 Mineralocorticoid activity of carbenoxolone: contrasting effects of carbenoxolone and liquorice on 11ß-hydroxysteroid dehydrogenase activity in man. Clin Sci. 78:49–54.[Medline]
33. Walker BR, Edwards CRW. 1994 Licorice-induced hypertension and syndromes of apparent mineralocorticoid excess. Endocrinol Metab Clin North Am. 23:359–377.[Medline]
34. Kondo K-H, Kai M-H, Setoguchi Y, et al. 1994 Cloning and expression of cDNA of human 4–3-oxosteroid 5ß-reductase and substrate specificity of the expressed enzyme. Eur J Biochem. 219:357–363.[Medline]
35. Jenkins EP, Andersson S, Imperato-McGinley J, Wilson JD, Russell DW. 1992 Genetic and pharmacological evidence for more than one human steroid 5-reductase. J Clin Invest. 89:293–300.
36. Furuebisu M, Deguchi S, Okuda K. 1987 Identification of cortisone 5ß-reductase as 4–3-ketosteroid 5ß-reductase. Biochim Biophys Acta. 912:110–114.[CrossRef][Medline]
37. Okuda A, Okuda K. 1984 Purification and characterisation of 4–3-ketosteroid 5ß-reductase. J Biol Chem. 259:7519–7524.[Abstract/Free Full Text]
38. Iyer RB, Binstock JM, Schwartz IS, Gordon GG, Weinstein BI, Southren, AL. 1990 Human hepatic cortisol reductase activities: Enzymatic properties and substrate specificities of cytosolic cortisol 4–5ß-reductase and dihydrocortisol-3-oxidoreductase. Steroids. 55:495–500.[CrossRef][Medline]
39. Mode A, Rafter I. 1985 The sexually differentiated 4–3-ketosteroid 5ß-reductase of rat liver. Purification, characterization, and quantitation. J Biol Chem. 260:7137–7141.[Abstract/Free Full Text]
40. Tsuji M, Terada N, Yabumoto H. 1983 Hormonal regulation of activities of 4-ene-5ß and 5-reductases and 17ß-ol-dehydrogenase in immature golden hamster ovary. J Steroid Biochem. 18:777–781.[CrossRef][Medline]
41. Killinger DW, Perel E, Daniilescu D, Kharlip L, Lindsay WN. 1990 Influence of adipose tissue distribution on the biological activity of androgens. Ann NY Acad Sci. 595:199–211.[Medline]
42. Melcangi RC, Poletti A, Cavarretta I, et al. 1998 The 5-reductase in the central nervous system: expression and modes of control. J Steroid Biochem Mol Biol. 65:295–299.[CrossRef][Medline]
43. Berman DM, Tian H, Russell DW. 1995 Expression and regulation of steroid 5-reductase in the urogenital tract of the fetal rat. Mol Endocrinol. 9:1561–1570.[Abstract/Free Full Text]
44. Yokoi H, Tsuruo Y, Miyamoto T, Ishimura K. 1998 Steroid 5-reductase type 1 immunolocalized in the adrenal gland of normal, gonadectomized, and sex hormone-supplemented rats. Histochemistry. 109:127–134.[CrossRef][Medline]
45. Eicheler W, Seitz J, Steinhoff M, Forssmann WG, Adermann K, Aumuller. 1995 Distribution of rat hepatic steroid 5-reductase 1 as shown by immunohistochemistry. Exp Clin Endocrinol Diabetes. 103:105–112.[Medline]
46. Zyirek M, Flood C, Longcope C. 1987 5-Reductase activity in rat adipose tissue. Proc Soc Exp Biol Med. 186:134–138.[CrossRef][Medline]
47. Bullock P, Gemzik B, Johnson D, Thomas P, Parkinson A. 1991 Evidence from dwarf rats that growth hormone may not regulate the sexual differentiation of liver cytochrome P450 enzymes and steroid 5-reductase. Proc Natl Acad Sci USA. 88:5227–5231.[Abstract/Free Full Text]
48. Lephart ED, Simpson ER, Trzeciak WH. 1991 Rat adrenal 5-reductase mRNA content and enzyme activity are sex hormone dependent. J Mol Endocrinol. 6:163–170.[Abstract/Free Full Text]
49. Imperato-McGinley J, Shackleton C, Orlic S, Stoner E. 1990 C19 and C21 5ß/5 metabolite ratios in subjects treated with the 5-reductase inhibitor finasteride: comparison of male pseudohermaphrodites with inherited 5-reductase deficiency. J Clin Endocrinol Metab. 70:777–782.[Abstract/Free Full Text]
50. Stewart PM, Shackleton CHL, Beastall GH, Edwards CRW. 1990 5-Reductase activity in polycystic ovarian syndrome. Lancet. 335:431–433.[CrossRef][Medline]
51. Rodin A, Thakkar H, Taylor N, Clayton R. 1994 Hyperandrogenism in polycystic ovary syndrome: evidence of dysregulation of 11ß-hydroxysteroid dehydrogenase. N Engl J Med. 330:460–465.[Abstract/Free Full Text]
52. Abraham D, Carpenter PC. 1997 Issues concerning androgen replacement therapy in postmenopausal women. Mayo Clinic Proc. 72:1051–1055.[Abstract]
53. Soro A, Ingram MC, Tonolo G, Glorioso N, Fraser R. 1995 Evidence of coexisting changes in 11ß-hydroxysteroid dehydrogenase and 5ß-reductase activity in patients with untreated essential hypertension. Hypertension. 25:67–70.[Abstract/Free Full Text]
54. Walker BR, Stewart PM, Shackleton CHL, Padfield PL, Edwards CRW. 1993 Deficient inactivation of cortisol by 11ß-hydroxysteroid dehydrogenase in essential hypertension. Clin Endocrinol (Oxf). 39:221–227.[Medline]

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