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(Hypertension. 1995;25:626-630.)
© 1995 American Heart Association, Inc.

Articles

11ß-Hydroxysteroid Dehydrogenase and Its Inhibitors in Hypertensive Pregnancy

Brian R. Walker; Paula M. Williamson; Mark A. Brown; John W. Honour; Christopher R. W. Edwards; Judith A. Whitworth

From the Department of Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland, UK (B.R.W., C.R.W.E.); the Department of Medicine, University of New South Wales, St George Hospital, Kogarah, NSW, Australia (P.M.W., M.A.B., J.A.W.); and the Department of Chemical Pathology, University College London Hospitals, London, UK (J.W.H.).

	Abstract

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Abstract Preeclampsia is accompanied by amplification of the sodium retention that is a feature of normal pregnancy. Recent evidence suggests that mineralocorticoid receptor activation is increased in preeclampsia, but classic mineralocorticoids (aldosterone, 11-deoxycorticosterone) are not present in excess. Cortisol can act as a mineralocorticoid receptor agonist only when its renal inactivation to cortisone by 11ß-hydroxysteroid dehydrogenase is impaired, for example, in congenital enzyme deficiency and after administration of exogenous inhibitors (eg, licorice). Endogenous inhibitors of this enzyme have been detected in human urine and are increased in pregnancy. To establish whether cortisol causes mineralocorticoid excess in hypertensive pregnancy and whether endogenous inhibitors of 11ß-hydroxysteroid dehydrogenase are responsible, we studied 25 hypertensive pregnant patients (13 with preeclampsia and 12 with gestational hypertension), 16 normotensive pregnant subjects, and 13 nonpregnant control subjects. Concentrations of plasma renin and aldosterone were increased in pregnancy, but less so in hypertensive pregnancy. Plasma potassium and urinary electrolytes were not different between the groups. Plasma cortisol was increased in pregnancy but not different in hypertensive pregnancy, and urinary cortisol, plasma and urinary cortisone, and urinary tetrahydrocortisol and tetrahydrocortisone were not different between the groups. Endogenous inhibitors of 11ß-hydroxysteroid dehydrogenase were more active in urine from pregnant women but were not increased further in hypertensive pregnancy. There were no differences in these parameters between patients with preeclampsia and gestational hypertension. We conclude that deficient inactivation of cortisol to cortisone does not contribute to the sodium retention of normotensive or hypertensive pregnancy and that endogenous inhibitors of 11ß-hydroxysteroid dehydrogenase have no evident pathophysiological significance in pregnancy.

Key Words: hydroxysteroid dehydrogenases • adrenal cortex hormones • blood pressure • hypertension, pregnancy-induced • pregnancy • preeclampsia • adrenal glands

	Introduction

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The reversible hypertension associated with pregnancy (either preeclampsia or gestational hypertension) remains unexplained. There is evidence that sodium retention, a feature of normotensive pregnancy, is exaggerated in these patients.^{1 2} Among several putative hemodynamic and neurohumoral mechanisms for this renal sodium retention is the possibility that patients with preeclampsia have increased activation of renal mineralocorticoid receptors. This is supported by decreased numbers of mineralocorticoid receptors on mononuclear leukocytes^{3 4} (similar to downregulation of these receptors, which occurs in primary hyperaldosteronism⁵ ) and by an increased colonic subtraction potential difference.⁴ These features of mineralocorticoid excess occur despite the observations that aldosterone and 11-deoxycorticosterone levels are, if anything, lower in preeclampsia than in normotensive pregnancy^{3 6 7} and that progesterone is a mineralocorticoid receptor antagonist.⁸ It may be that another potent mineralocorticoid receptor agonist is active in preeclampsia.

Recently, cortisol has emerged as a candidate for this role. Cortisol and aldosterone have an equal affinity for mineralocorticoid receptors,⁹ but these receptors are normally protected from exposure to cortisol by the enzyme 11ß-hydroxysteroid dehydrogenase (11ß-OHSD), which inactivates cortisol by conversion to cortisone.^{10 11} Defective 11ß-OHSD activity, such as occurs in the congenital syndromes of "apparent mineralocorticoid excess"^{12 13} and after administration of exogenous 11ß-OHSD inhibitors (including the principal active constituent of licorice, glycyrrhetinic acid¹⁴ ), is associated with cortisol-dependent hypokalemia, sodium retention, and hypertension. 11ß-OHSD deficiency has been documented in other hypertensive syndromes, including essential hypertension,¹⁵ ectopic corticotropin syndrome,¹⁶ and renal impairment,¹⁷ but the mechanism of all of these defects remains obscure. In 1992, Morris and colleagues¹⁸ reported the extraction from human urine of endogenous inhibitors of 11ß-OHSD, which they called glycyrrhetinic acid–like factors (GALFs). Several progesterone precursors and metabolites are competitive inhibitors of 11ß-OHSD in vitro,^{19 20} and, intriguingly, GALF activity was increased in pregnancy.

Previous investigators have measured cortisol and cortisone in plasma and saliva during pregnancy. Although circulating cortisol concentrations are elevated in pregnancy, there is controversy about whether this reflects increased cortisol secretion²¹ or can be accounted for by an estrogen-dependent increase in cortisol binding globulin.²² Plasma cortisol concentrations are unchanged in preeclampsia.²³ Cortisone levels have been reported to be elevated to a similar degree,^{24 25} but cortisone is not protein bound, so that total 11ß-OHSD activity may be increased in normotensive pregnancy. However, this increase may be attributable to abundant 11ß-OHSD activity expressed in the placenta.¹⁹ For measurement of the equilibrium between active cortisol and inactive cortisone in the kidney, which controls the access of cortisol to mineralocorticoid receptors, a study incorporating urinary measurements is required.

In the present study we examined the putative role of 11ß-OHSD deficiency, possibly caused by increased secretion of endogenous inhibitors, in the sodium retention of normotensive and hypertensive pregnancy.

	Methods

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Subjects
Subjects were recruited from the St George Hospital, Sydney, Australia. Local ethics committee approval and written informed consent were obtained for these studies.

Details of our subjects are shown in Table 1. Blood pressure was measured by nursing staff using a conventional mercury sphygmomanometer. Two control groups were studied: nonpregnant women recruited from the hospital staff, and normotensive pregnant women in their third trimester recruited from the outpatient clinic. Their records were checked after delivery to exclude those who subsequently developed hypertension or any other complication of pregnancy.

View this table: [in this window] [in a new window]   Table 1. Matching Criteria, Blood Pressure, and Mineralocorticoid Status

Women with hypertension in pregnancy were defined as having a third-trimester blood pressure greater than 140 mm Hg systolic and/or greater than 90 mm Hg diastolic (phase IV Korotkoff) after an overnight rest in the hospital. To exclude patients with preexisting essential hypertension, we only studied patients in whom first-trimester blood pressure was less than or equal to 140/90 mm Hg and blood pressure returned to less than 140/90 mm Hg after delivery.²⁶ Thirteen of these patients had preeclampsia (proteinuria >300 mg/d); the remainder were classified as having gestational hypertension.

Subjects from these groups were of similar age, and pregnant women were of similar gestation (Table 1). Systolic pressures were similar in nonpregnant and normotensive pregnant women and higher in those with gestational hypertension and preeclampsia. Diastolic pressures were slightly higher in normotensive pregnant than nonpregnant women and higher still in gestational hypertension and preeclampsia.

None of the nonpregnant or normotensive pregnant subjects were taking any regular medication, including oral contraceptives. In those with gestational hypertension, 2 were taking oxprenolol. In patients with preeclampsia, 5 were on no treatment, but the rest were taking combinations of oxprenolol (8), nifedipine (4), hydralazine (5), and methyldopa (1).

Subjects collected a single 24-hour urine specimen on an ad libitum diet and had blood withdrawn after 20 minutes of sitting.

Laboratory Assays
Plasma and urinary electrolytes and creatinine were measured by an autoanalyzer. Concentrations of plasma renin (measured by radioimmunoassay as the generation of angiotensin I), aldosterone (by direct radioimmunoassay), cortisol (by direct radioimmunoassay), and cortisone (by radioimmunoassay after high-performance liquid chromatographic [HPLC] separation) were measured as previously described.^{7 17} Urinary tetrahydrocortisol and tetrahydrocortisone were measured by gas chromatography and mass spectrometry.²⁷ Because 5-tetrahydrocortisol (allo-tetrahydrocortisol) peaks were obscured by other steroid metabolites in urine from pregnant women, only 5ß-tetrahydrocortisol was quantified. The ratio of urinary free cortisol to cortisone was also measured by gas chromatography and mass spectrometry.

The technique for measurement of GALF activity was adapted as previously described²⁸ from that of Morris et al.¹⁸ Chemicals were obtained from Sigma Chemical Co except where stated. Aliquots of urine were stored and transported at -20°C and thawed at room temperature. Sep-Pak C18 cartridges (Waters, Millipore) were primed with 2 mL methanol and 5 mL water before 20 mL urine was extracted under unit gravity. Sep-Pak cartridges were washed with 5 mL water and eluted with 2 mL methanol. Eluates were stored at -20°C. When higher concentrations of urinary extracts were required, eluates were dried under air at 20°C and reconstituted in a smaller volume of methanol.

Inhibition of 11ß-dehydrogenase activity in rat liver microsomes was measured in duplicate as previously described.^{28 29} Briefly, 40 µg/mL microsomal protein was incubated in Krebs' buffer at pH 7.4 for 10 minutes at 37°C with 1000 µmol/L NADP and 1.2x10^-7 mol/L 1,2,4,6,7-[³H]corticosterone. To each 240 µL of incubate, 10 µL of inhibitor (methanol, glycyrrhetinic acid in methanol, or urinary eluate in methanol) was added. After incubation, steroids were extracted with ethyl acetate and separated by reversed-phase HPLC with on-line scintillation counting. 11ß-Dehydrogenase activity was expressed as the percent conversion of [³H]corticosterone to [³H]11-dehydrocorticosterone after correction for apparent conversion in blank incubations.

For quantification of GALF activity in urinary eluates, the percent inhibition of 11ß-dehydrogenase activity in the presence of eluate was compared with a standard curve generated with increasing concentrations of glycyrrhetinic acid.²⁸ Urinary extracts were diluted or concentrated as necessary to obtain inhibitory values on the steepest section of the standard curve (between 20% and 60%). For most samples, this entailed concentration of 25 µL eluate to 10 µL for addition to the incubate. The interassay coefficient of variation for GALF quantification was 11%.

Statistics
Data for concentrations of plasma renin, aldosterone, cortisol, cortisone, and GALFs are expressed as median and interquartile range. All other data are expressed as mean and SD. Differences between groups were tested by ANOVA followed by the Mann-Whitney test or Student's t test as appropriate.

	Results

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Mineralocorticoid Receptor Activation
Plasma sodium was lower in both pregnant groups than in nonpregnant women and was not elevated in hypertensive pregnancy. Plasma potassium and urinary sodium and potassium excretions were not different between the groups. Concentrations of plasma renin and aldosterone were greatly increased in normotensive pregnancy but less so in both preeclampsia and gestational hypertension (see Table 1).

Cortisol and Its Metabolites
Cortisol and its metabolites were measured in plasma in 12 nonpregnant, 9 normotensive pregnant, and 18 hypertensive pregnant women (Fig 1 and Table 2). Plasma cortisol was increased to a similar degree in normotensive and hypertensive pregnancy. Plasma cortisone was no different between the groups so that the ratio of plasma cortisol to cortisone tended to rise in pregnancy, but this trend did not reach statistical significance.

View larger version (12K): [in this window] [in a new window]   Figure 1. Scatterplots show 11ß-hydroxysteroid dehydrogenase activity measured as the ratios of cortisol to cortisone in plasma (left) and in urine (middle) as well as the ratio of the principal metabolites of cortisol and cortisone in urine (right). No differences between groups reached statistical significance.

View this table: [in this window] [in a new window]   Table 2. Cortisol and Its Metabolites

Urinary steroids were measured in 12 nonpregnant, 13 normotensive pregnant, and 14 hypertensive pregnant women (Fig 2 and Table 2). Inadequate chromatographic separation of steroids prevented quantitation in samples from 3 nonpregnant and 2 hypertensive pregnant subjects for cortisol-cortisone ratio and from 1 normotensive pregnant woman for tetrahydrocortisol-tetrahydrocortisone ratio. These data were excluded from the analysis. No differences were apparent between groups for tetrahydrocortisol-tetrahydrocortisone ratio or for urinary free cortisol-cortisone ratio.

View larger version (19K): [in this window] [in a new window]   Figure 2. Scatterplot shows inhibitory activity for 11ß-hydroxysteroid dehydrogenase in urine. Glycyrrhetinic acid–like factor (GALF) excretion was significantly higher in both pregnant groups compared with the nonpregnant group (P<.01) but was not different between normotensive and hypertensive pregnant groups. GA indicates glycyrrhetinic acid.

Endogenous 11ß-OHSD Inhibitors
Urinary GALF activity was measured in 13 nonpregnant, 13 normotensive pregnant, and 15 hypertensive pregnant women (Fig 2). GALF activity was significantly increased in normotensive pregnancy (P<.01) but was not significantly different in hypertensive pregnancy. GALF activity did not correlate with plasma or urinary cortisol-cortisone ratios or with urinary tetrahydrocortisol-tetrahydrocortisone ratio.

Urinary GALFs were similar in women with gestational hypertension and preeclampsia, those receiving antihypertensive therapy compared with those on no therapy, and those who delivered small infants compared with infants that were appropriate for gestational age. Indeed, there was no correlation between birth weight and GALF activity, cortisol-cortisone ratios, or tetrahydrocortisol-tetrahydrocortisone ratios.

	Discussion

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Our results are consistent with previous reports^{1 3 7} and confirm that hypertensive pregnancy is associated with a relatively low plasma renin concentration compared with normotensive pregnancy, consistent with mineralocorticoid excess. There was no evidence of hypernatremia or hypokalemia in gestational hypertension or preeclampsia, but these features are commonly absent even in syndromes of primary hyperaldosteronism.³⁰ Plasma aldosterone was also lower in hypertensive pregnancy; hence, if there is excessive activation of mineralocorticoid receptors in preeclampsia or gestational hypertension, another mineralocorticoid receptor agonist must be responsible. Similar findings of "apparent" mineralocorticoid excess (ie, in the absence of raised aldosterone or 11-deoxycorticosterone) led to the original elucidation of the physiological role of 11ß-OHSD.¹² We have addressed the possibility that cortisol is the mineralocorticoid agonist in hypertensive pregnancy.

We have confirmed that plasma cortisol concentrations are elevated in pregnancy.^{21 25} We believe that most of this increase is accounted for by estrogen-dependent induction of cortisol binding globulin,²² because cortisol production rates (as judged by urinary excretion of its principal metabolites³¹ ) were not increased, and contrary to a previous report,²⁵ we found that cortisol metabolites that are not protein bound (eg, cortisone) were not elevated in pregnancy. Plasma cortisol levels were no higher in hypertensive than in normotensive pregnancy. We have considered whether, in the face of apparently normal cortisol secretion in hypertensive pregnancy, renal cortisol inactivation by 11ß-OHSD may be defective, allowing cortisol to have inappropriate access to mineralocorticoid receptors.

In the congenital syndrome of type 1 apparent mineralocorticoid excess¹² and after administration of glycyrrhetinic acid,¹⁴ impaired conversion of cortisol to cortisone in the kidney is manifest as increased ratios of cortisol to cortisone in plasma and of their principal metabolites (tetrahydrocortisol and tetrahydrocortisone) in urine. With the exception of a nonsignificant rise in plasma cortisol-cortisone ratio (which can be accounted for by increased cortisol binding globulin, as discussed above), we found no evidence for impaired renal 11ß-OHSD activity by these criteria in normotensive or hypertensive pregnancy.

In two other syndromes, that induced by carbenoxolone³² and the congenital syndrome of type 2 apparent mineralocorticoid excess,¹³ plasma cortisone and urinary tetrahydrocortisol-tetrahydrocortisone ratios are normal, but the half-life of [11-³H]cortisol is prolonged, indicating impaired renal conversion of cortisol to cortisone. This discrepancy is explained by associated impairment of the reverse conversion of cortisone to cortisol in the liver.^{13 33} In pregnancy, interconversion of cortisol and cortisone in the placenta may be an additional confounding factor for these measurements. Although we could not use radioisotopes in pregnancy to exclude this possibility, it appears that in all syndromes of defective 11ß-OHSD, the urinary free cortisol-cortisone ratio is increased (reflecting defective intrarenal cortisol inactivation that is independent of hepatic metabolism). We found no difference in urinary cortisol-cortisone ratio in either normotensive or hypertensive pregnancy and therefore no evidence that impaired renal 11ß-OHSD in pregnancy is obscured by impaired hepatic or placental cortisone metabolism.

One of the major stimuli for this study was the intriguing observation by Morris and colleagues¹⁸ that endogenous inhibitory activity for 11ß-OHSD was increased in urine from pregnant women. We have confirmed their observation but found no relationship between GALF activity and either blood pressure or 11ß-OHSD activity. The chemical identity of GALFs is not yet established, and it may be that they represent a paraphenomenon of pregnancy that has no physiological relevance, for example, as a result of increased progesterone metabolite excretion.^{19 20} Certainly, our data from this and other studies²⁸ suggest that their influence on renal 11ß-OHSD is negligible. However, before GALFs are discounted, it is worth considering that they may have important effects on 11ß-OHSD in extrarenal sites.

It is now well established that 11ß-OHSD is expressed as multiple tissue-specific isoforms. For example, in the distal nephron, there is a high-affinity, NAD-dependent isoform that avidly converts cortisol to cortisone,^{34 35 36} contrasting with the hepatic low-affinity, NADP-dependent isoform that converts cortisone to cortisol.³⁷ In separate studies, we have shown that GALFs have a greater effect in inhibiting extrarenal NADP-dependent activity than renal NAD-dependent activity (unpublished observations, 1994). We have not yet studied the effect of GALFs on the placental isoform,³⁸ where 11ß-OHSD may protect the fetus from excessive exposure to maternal glucocorticoids. Indeed, from animal studies we have proposed a relationship between reduced placental 11ß-OHSD activity, low birth weight, and high blood pressure in the offspring.³⁹ Thus, although the present study suggests that GALFs are not relevant in dictating blood pressure in the pregnant mother, it remains possible that they contribute to fetal outcome.

In summary, we have confirmed previous reports of features of apparent mineralocorticoid excess in hypertensive pregnancy and of increased endogenous inhibitors of 11ß-OHSD in pregnancy. However, we have not found any evidence that 11ß-OHSD is impaired in normotensive or hypertensive pregnancy nor any evidence that endogenous inhibitors of cortisol metabolism contribute to pregnancy-induced sodium retention or hypertension. It seems likely that other mechanisms are more important in the pathophysiology of gestational hypertension and preeclampsia.

	Acknowledgments

 
These studies were supported by a General Development Grant from the University of New South Wales and the Division of Medicine, St George Hospital, Sydney, and by a grant from the British Heart Foundation. B.R.W. received a fellowship from the Medical Research Council of Great Britain. Our thanks to the obstetricians of St George and Hurstville Community Co-operative Hospitals for allowing us to study their patients.

	Footnotes

 
Reprint requests to Dr Brian R. Walker, Department of Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, Scotland, UK. E-mail bw@srv0.med.ed.ac.uk.

Received October 17, 1994; first decision November 9, 1994; accepted December 5, 1994.

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