Cortisol, 11b-Hydroxysteroid

Dehydrogenases, and Hypertension

Stan H.M. van Uum, M.D., Ph.D.,1 Jacques W.M. Lenders, M.D., Ph.D.,2
and Ad R.M.M. Hermus, M.D., Ph.D.3

ABSTRACT

Hypersecretion of cortisol is associated with hypertension. In addition, an

abnormal cortisol metabolism may play a role in the pathogenesis of hypertension. The
11b-hydroxysteroid dehydrogenase (11b-HSD) isozymes catalyze interconversion of

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cortisol and cortisone and play an important role in the regulation of the effects of cortisol.
Activity of 11b-HSD type 2, converting active cortisol in inactive cortisone, is crucial in
preventing access of cortisol to the renal mineralocorticoid receptors (MRs). Decreased
activity of this isozyme in the kidney, either congenitally in Apparent Mineralocorticoid
Excess syndrome or acquired following licorice consumption, allows cortisol access to the
MRs, resulting in hypokalemic hypertension. In normotensive subjects, an association has
been demonstrated between blood pressure increase on a high-salt diet and a mild decrease
of renal 11b-HSD2 activity. In ectopic adrenocorticotropic hormone (ACTH), plasma
cortisol levels are very high, resulting in mineralocorticoid hypertension caused by
saturation of the available renal 11b-HSD2 capacity. Activity of the 11b-HSDs has also
been demonstrated in many extrarenal sites. Several studies have demonstrated extrarenal
effects of cortisol on blood pressure, as well as a possible role for altered extrarenal 11b-
HSD activities in the pathogenesis of hypertension. More studies are needed to clarify the
role of 11b-HSDs in the pathogenesis of hypertension.

KEYWORDS: Cortisol, 11b-hydroxysteroid dehydrogenases, hypertension, licorice

Educational Objectives: Upon completion of this article, the reader should be able to (1) describe the role of 11b-hydroxysteroid
dehydrogenases in regulating access of cortisol to mineralocorticoid and glucocorticoid receptors, (2) describe and clinically recognize
the role of renal 11b-hydroxysteroid dehydrogenases in various forms of hypertension, including the AME syndrome, licorice-induced
hypertension, and hypertension in Cushing’s syndrome, and (3) discuss the possible role for 11b-hydroxysteroid dehydrogenases in
primary hypertension.

C ortisol is a steroid hormone that is produced in
the adrenal cortex. It plays an important role in the
regulation of blood pressure. In Cushing’s syndrome,
overproduction of cortisol results in hypertension,
whereas in adrenal failure, insufficient cortisol secretion
results in serious, and sometimes life-threatening, hy-
potension.
In this article we first describe the relation be-
tween cortisol and hypertension. Next we describe the role
of the 11b-hydroxysteroid dehydrogenase (11b-HSD)

Cardiovascular Endocrinology; Editor in Chief, Jan Jacques Michiels, M.D., Ph.D.; Guest Editor, Marcel Th.B. Twickler, M.D., Ph.D. (U.U.),
Ph.D. (Paris VI). Seminars in Vascular Medicine, Volume 4, Number 2, 2004. Address for correspondence and reprint requests: Stan H.M. van Uum,
M.D., Ph.D., Assistant Professor, Endocrinology and Metabolism, Department of Medicine, University of Western Ontario, St. Joseph’s Health
Centre, Room G401, 268 Grosvenor St., London, Ontario N6A 4V2, Canada. 1Division of Endocrinology and Metabolism, Department of
Medicine, University of Western Ontario, London, Ontario, Canada, 2Division of General Internal Medicine, 3Division of Endocrinology,
Deptartment of Medicine, University Medical Center, Nijmegen, The Netherlands. Copyright # 2004 by Thieme Medical Publishers, Inc., 333
Seventh Avenue, New York, NY 10001 USA. Tel: +1(212)584-4662. 1528-9648,p;2004,04,02,121,128,ftx,en;svm00176x.
121
122 SEMINARS IN VASCULAR MEDICINE/VOLUME 4, NUMBER 2 2004
isozymes in regulating access of cortisol to glucocorticoid
and mineralocorticoid receptors. We then discuss some
of the mechanisms involved in cortisol-mediated hyper-
tension, including the effects of cortisol and 11b-HSDs
in the kidneys, blood vessels, and other organs.
CORTISOL AND HYPERTENSION
Hypertension is a common feature of Cushing’s syn-
drome. It is present in 75–90% of these patients.1
Treatment of high blood pressure with antihypertensive
drugs is mostly ineffective in these patients, and a
satisfactory decrease in blood pressure can only be
obtained after the restoration of normal cortisol levels.2
Cortisol also increases blood pressure in healthy subjects:
Oral administration of cortisol 50 mg every 6 hours for
5 days increased systolic blood pressure by 10 mm Hg.3
Next, studies were performed to investigate the
role of cortisol in the pathogenesis of primary hyperten-
sion. In the first study, in 1963, Vermeulen and collea-
gues did not find a difference in plasma cortisol levels
between hypertensive and normotensive subjects.4 In a
more recent study, the Paris Prospective Study I, the
morning plasma cortisol levels were mildly elevated in
hypertensive subjects compared with normotensive con-
trols; this difference was present at any body mass index
level, but particularly in lean subjects with high systolic
blood pressure.5
In other studies, the effect of dexamethasone,
which suppresses endogenous cortisol production, on
blood pressure was investigated. In an uncontrolled
study of hypertensive subjects, administration of dexa-
methasone 0.5 mg three times daily for 8 weeks resulted
in a decrease of diastolic blood pressure from 104
5 to
96
8 mm Hg (P < .0001), whereas systolic blood
pressure did not change. In another study of hyperten-
sive subjects, dexamethasone 0.5 mg ante nocte for 4
weeks resulted in a systolic blood pressure of 142
3 mm
Hg, which was significantly lower than during placebo
(149
5 mm Hg). Dexamethasone did not change
blood pressure in normotensive subjects,6 and in both
studies, normal baseline plasma cortisol levels were
found. These studies indicate that cortisol may play a
role in the pathogenesis of primary hypertension, even
when plasma cortisol levels are in the normal range.
11b-HYDROXYSTEROID
DEHYDROGENASES
Over the last decade, it has emerged that concentrations
of cortisol may vary within tissues and cells as a result of
local metabolism of cortisol by the 11b-HSD isozymes.
These isozymes catalyze interconversion of hormonally
active cortisol and inactive cortisone. Two distinct iso-
zymes have been described:7 first, in humans, 11b-
HSD1 is present in many tissues and is most abundantly
expressed in liver and adipose tissue.8,9 In vitro 11b-
HSD1 is nicotinamide adenine dinucleotide phosphate
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(reduced) [NADP(H)] dependent and catalyzes both
dehydrogenation and reduction.10,11 In the liver, 11b-
HSD1 predominantly acts as a reductase, converting
cortisone to active cortisol (see Fig. 1).
The second isozyme, 11b-HSD2, is a high-affi-
nity NAD-dependent enzyme that is highly expressed in
mineralocorticoid target tissues such as renal cortex,11,12
colon,11 salivary glands,13 and sweat glands.14 This
isozyme has mainly dehydrogenase activity and is already
active at very low cortisol concentrations. 11b-HSD2
plays a key role in regulating mineralocorticoid activity
of cortisol. In vitro experiments have shown that cortisol
and aldosterone have similar affinities for mineralocor-
ticoid receptors (MRs),15 so their functional aldosterone
selectivity in vivo is apparently not mediated by the
receptor structure. In vivo MRs are protected from
exposure to cortisol by the isozyme 11b-HSD2. This
isozyme rapidly metabolizes the active mineralocorticoid
cortisol to its inactive metabolite cortisone (see Fig. 2),
thus preventing stimulation of MRs by cortisol.
Figure 1 In the kidney, cortisol (F) is converted to
inactive cortisone (E) by 11b-hydroxysteroid dehy-
drogenase type 2 (11b-HSD2), and in the liver,
cortisone is converted back to cortisol by 11b-
HSD1 (interconversion of cortisol and cortisone is
indicated by dashed arrows). Activity of 11b-HSD1
had also been described in fat cells. 11b-HSD1 and
11b-HSD2 are both expressed in vascular tissue and
in many other tissues not shown in this figure.
VSM ¼ vascular smooth muscle.
 CORTISOL, 11b-HYDROXYSTEROID DEHYDROGENASES, AND HYPERTENSION/VAN UUM ET AL 123

Figure 2 Under physiological conditions, (a) cortisol is metabolized to cortisone by 11b-hydroxysteroid dehydrogenase type 2 (11b-
HSD2). As a consequence, the mineralocorticoid receptor (MR) will not be exposed to relevant cortisol concentrations. When 11b-HSD2
activity is reduced, either congenitally (Apparent Mineralocorticoid Syndrome) or by inhibition by glycyrrhetinic acid, cortisol is not
completely metabolized to cortisol, and IT therefore activates the MR (b). Urinary excretion of cortisol and its tetrahydrometabolites
(THF and allo-THF) is increased, whereas excretion of cortisol and its tetrahydrometabolite THE is decreased. This results in an increased

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ratio of (THF þ allo-THF) to THE, reflecting decreased activity of 11b-HSD2. 5ared ¼ 5a-reductase; 5bred ¼ 5b-reductase. (From van
Uum SH, Hermus AR, Smits P, Thien T, Lenders JW. The role of 11 beta-hydroxysteroid dehydrogenase in the pathogenesis of
hypertension. Cardiovasc Res 1998;38:16–24. Reprinted with permission of # European Society of Cardiology.)

Aldosterone is not metabolized by 11b-HSD2 and can
therefore bind to the MRs.
In studies on 11b-HSD activity in humans,
analysis of urinary corticosteroid excretion plays an
important role. In the kidney, cortisol is metabolized
to cortisone. In addition, cortisol is metabolized to its
tetrahydrometabolites tetrahydrocortisol (THF) and
allo-tetrahydrocortisol (allo-THF), and cortisone is meta-
bolized to tetrahydrocortisone (THE). Therefore, de-
creased 11b-HSD2 activity will result in an increased
urinary (THF þ allo-THF)/THE ratio and an increased
cortisol/cortisone ratio (see Fig. 2).
One concern regarding the urinary (THF þ allo-
THF)/THE ratio is that it probably reflects the total
11b-HSD activity within the body, which is a combina-
tion of 11b-HSD1 activity, mainly in the liver, and 11b-
HSD2 activity, mainly in the kidneys. Therefore, some
authors have suggested that the urinary ratio of free
cortisol over free cortisone may more accurately reflect
renal 11b-HSD2 activity.16
RENAL EFFECTS OF CORTISOL
AND 11b-HSDS IN HYPERTENSION
Renal activity of 11b-HSD2 is altered in several hyper-
tensive conditions and syndromes (Table 1). In the
following paragraphs, some of these conditions are
discussed in more detail.
Apparent Mineralocorticoid Excess Syndrome
The physiological relevance of 11b-HSD2 for the reg-
ulation of blood pressure and potassium balance was
demonstrated in studies in patients with the apparent
mineralocorticoid excess (AME) syndrome.17,18 These
patients were first described in the 1970s and present at a
young age with severe hypertension, hypokalemia, low
renin activity, and low aldosterone, and they suffer from
serious cardiovascular complications at a young age.
Overproduction of an adrenal mineralocorticoid hor-
mone was suspected but could not be demonstrated;
hence the term ‘‘apparent mineralocorticoid excess.’’ The
hypertension did respond to spironolactone, a MR
blocker, and the urinary (THF þ allo-THF)/THE ra-
tios ranged from 6 to greater than 70 in AME (a normal
ratio is around 1). Later it was established that AME is
caused by mutations in the gene coding for 11b-HSD2
that result in severely deficient isozyme activity, thus
enabling cortisol to access the MR.
At present, more than 30 mutations in the gene
coding for 11b-HSD2 have been described in  60
kindreds.19 AME is inherited as an autosomal recessive
Table 1 Renal 11b-HSD2 Activity in Several Forms
of Hypertension
11b-HSD2
Syndrome activity
Apparent Mineralocorticoid Excess ##
Glycyrrhetinic acid (licorice, chewing tobacco) #/# #
Chronic renal failure #
Salt-sensitive primary hypertension #
Primary hypertension ¼/ # ?
Cushing’s syndrome ¼/ "
Renal 11b-HSD2 activity in syndromes or conditions in which stimu-
lation of the renal mineralocorticoid receptors by cortisol seems to
play a role in the pathogenesis of hypertension.
124 SEMINARS IN VASCULAR MEDICINE/VOLUME 4, NUMBER 2 2004
disorder. Some heterozygous parents of patients with
AME were found to be normotensive,20 and others were
mildly hypertensive with some evidence for mineralo-
corticoid-based hypertension.21
Licorice
Licorice is consumed as a confectionary sweet, especially
in Europe and New Zealand, and is also used as a
sweetener in chewing gum, tobacco, and some herbal
teas. When the blood pressure–increasing effect of
licorice was first discovered, it was hypothesized that it
was the result of direct stimulation of the MR by licorice.
However, the affinity of glycyrrhetinic acid (GA), the
active constituent of licorice, for the MR is low.11 The
urinary ratio of (THF þ allo-THF)/THE is increased
after intake of licorice or GA.22,23 Later, it was demon-
strated that GA is a potent inhibitor of 11b-HSD2 activ-
ity, allowing cortisol to bind to the MRs and resulting in
hypokalemic hypertension. As little as 50 g licorice per
day (corresponding to  100 mg GA) may cause hyper-
tension and signs of mineralocorticoid excess.24
Cushing’s Syndrome
Hypertension is present in 80% of patients with Cush-
ing’s syndrome and in more than 95% of the patients
with ectopic ACTH production. This last subgroup
frequently presents with hypokalemic alkalosis. Plasma
cortisol/cortisone ratios are higher in patients with
ectopic ACTH production than in those with other
forms of Cushing’s syndrome,25 but in most forms the
mineralocorticoid excess is accompanied by increased
(THF þ allo-THF)/THE ratio in urine, indicating in-
sufficient renal 11b-HSD2 activity. This insufficient
11b-HSD2 activity is not caused by an absolute decrease
in renal 11b-HSD2 activity or by a direct inhibitory
effect of ACTH on isozyme activity.26 In severe hyper-
cortisolism, the arterial supply of cortisol to the kidneys
is so high that the available renal 11b-HSD2 activity
cannot maintain adequate conversion of cortisol to
cortisone. This is known as substrate saturation and
results in access of cortisol to renal MRs, and thus in
mineralocorticoid hypertension.25,27
Chronic Renal Failure
Chronic renal failure is accompanied by a decrease of
11b-HSD2 activity in the kidneys,28 and cortisol excre-
tion in the urine is decreased. The plasma cortisol/
cortisone ratio is increased because of a reduction of
the plasma cortisone concentration,28 whereas the
plasma cortisol concentration is not increased because
of negative feedback and a resultant reduction in cortisol
secretion. The decrease of renal 11b-HSD2 activity may
promote salt retention. Of interest, ACE-inhibitors and
Angiotensin-II receptor antagonists enhance renal 11b-
HSD2 activity, which may explain their natriuretic
effect.29,30 In patients with proteinuria, in the absence
of renal failure, the urinary ratio of free cortisol over free
cortisone is decreased compared with that of healthy
subjects. This indicates that renal 11b-HSD2 activity is
enhanced in these patients, and the altered 11b-HSD2
activity would therefore not contribute to sodium reten-
tion in patients with the nephrotic syndrome.31
Primary Hypertension
On the basis of the above findings, it was hypothesized
that activity of 11b-HSD2 might also be decreased in
patients with primary hypertension. The urinary ratio of
(THF þ allo-THF)/THE was increased in some stu-
dies,32,33 but other groups found normal ratios.34,35
Another study demonstrated an increase in the plasma
half-life of cortisol in a subgroup of patients with
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primary hypertension, which is compatible with de-
creased 11b-HSD2 activity, but the decrease in isozyme
activity could not be related to signs of mineralocorticoid
excess.36 A possible role for decreased 11b-HSD2 activ-
ity in familial predisposition to hypertension was also
suggested by the ‘‘four-corner study,’’ in which an im-
paired conversion of cortisol to inactive metabolites was
found in young men with mildly increased blood
pressure whose parents also had high blood pressure.37
This study indicated that the endogenous activity of
11b-HSD2 may be reduced in subgroups of patients
with primary hypertension.
Other studies focused on the effect of exogenous
11b-HSD2 inhibitors on blood pressure. In healthy
volunteers, oral intake of 50–200 g licorice per day for
2–4 weeks, corresponding to a daily intake of 75–540 mg
GA, resulted in a dose-dependent increase of blood
pressure up to 14 mm Hg at the highest dose.38 Admin-
istration of GA for 4 weeks resulted in a significantly
higher increase of blood pressure in patients with pri-
mary hypertension than in a control group of normo-
tensive volunteers. Systolic blood pressure increased with
12
5 and 6
8 mm Hg, respectively, and diastolic
blood pressure increased with 9
5 and 4
6 mm Hg,
respectively. Of note, in this study hypertensive patients
were included in whom the blood pressure was con-
trolled (SBP < 140 mm Hg and DBP < 90 mm Hg)
using a b-blocker or a calcium antagonist.39 We inves-
tigated the plasma cortisol/cortisone ratio, a parameter
reflecting 11b-HSD2 activity, in normotensive and
hypertensive subjects both before and after administra-
tion of GA. We did not find a difference in cortisol/
cortisone ratio at baseline, and there was also no differ-
ence in the increase of the cortisol/cortisone ratio
following GA.35 This indicates that the difference in
the increase of systolic blood pressure between normo-
tensive and hypertensive subjects may not be caused by a
 CORTISOL, 11b-HYDROXYSTEROID DEHYDROGENASES, AND HYPERTENSION/VAN UUM ET AL
difference in the inhibitory effect of GA on 11b-HSD2
activity but, more likely, by a postreceptor mechanism.
Next, the relation between 11b-HSD2 activity
and salt sensitivity was studied. Lovati et al40 recruited
149 normotensive young male subjects and measured
blood pressure during both a low-salt (20 mmol sodium
per day) and a high-salt (220 mmol sodium per day) diet.
Participants were characterized as salt sensitive if the
difference in mean arterial blood pressure between the
low- and high-salt diets was higher than 3 mm Hg;
otherwise, the subjects were determined to be salt
resistant. The urinary (THF þ allo-THF)/THE ratio
during low-salt diet was significantly higher in salt-
sensitive subjects (median ratio, 1.56) than in salt-
resistant subjects (median ratio, 1.10). In addition, there
was a positive correlation (r2 ¼ 0.51) between the salt-
induced increase in mean arterial pressure and the
urinary (THF þ allo-THF)/THE ratio. In another
study, the effect of GA on blood pressure and urinary
corticosteroids was assessed in salt-sensitive and salt-
resistant normotensive subjects.41 The urinary (THF þ
allo-THF)/THE ratio was higher in the salt-sensitive
subjects at baseline, and a more pronounced increase in
this ratio on GA was observed in the salt-sensitive
subjects than in salt-resistant subjects. There was also a
stronger increase in office mean blood pressure in salt-
sensitive subjects than in salt-resistant subjects. In con-
trast to the studies by Lovati et al40 and Ferrari et al,41
Kerstens et al42 found no difference in in vivo parameters
of 11b-HSD activity, that is, the ratios of (THF þ allo-
THE)/THE and of free cortisol/free cortisone in urine,
between salt-sensitive and salt-resistant normotensive
subjects, and there was no effect of sodium intake on
these parameters. Up until now, no data were available
on in vivo parameters of 11b-HSD2 activity and salt
sensitivity in patients with primary hypertension.
In summary, these studies indicate that renal 11b-
HSD2 activity may be decreased in some subgroups of
patients with primary hypertension, and in particular in
those with increased salt sensitivity. In these subjects, a
mild decrease in renal 11b-HSD2 activity may be caused
by polymorphisms in 11b-HSD2. In salt-resistant nor-
motensive subjects, in contrast, renal 11b-HSD2 activity
may be increased, possibly in an attempt to increase renal
sodium excretion.
EXTRARENAL EFFECTS OF CORTISOL
AND 11b-HSDS IN HYPERTENSION
Cortisol and Vascular Tone
Glucocorticoids and mineralocorticoids are important
for the maintenance of vascular tone,43 and both
glucocorticoid and mineralocorticoid receptors are pre-
sent in vascular tissue.44 In in vitro studies, administra-
tion of corticosteroids, including hydrocortisone and
125
corticosterone, resulted in increased noradrenalin-
induced vasoconstriction in aortic strips from rabbit,45
dog,46 and rat,47 and in strips from human umbilical
artery.48 Similar effects have been found in in vivo
studies. In pigs, administration of deoxycorticosterone
acetate for 50 days resulted in increased arterial vaso-
constriction to noradrenaline,49 whereas blocking of
glucocorticoid receptors blunted the pressor response
to noradrenalin in anesthetized rats.50
In humans, administration of hydrocortisone for
5–7 days increased forearm vascular resistance in re-
sponse to cold stimuli and intra-arterially administered
noradrenalin,51 and it resulted in impaired forearm
vasodilatation to acetylcholine.52 A follow-up study
demonstrated that this increase of noradrenalin-
mediated vasoconstriction was also found after admin-
istration of fludrocortisone, a mineralocorticoid receptor
agonist, but not after administration of dexamethasone,
a glucocorticoid receptor agonist.53 This indicates that
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the effect of hydrocortisone on noradrenalin-mediated
vasoconstriction may be mediated via vascular miner-
alocorticoid receptors.
Vascular 11b-HSD Activity and Vascular Tone
11b-HSDs are also present in the blood vessels. In 1991,
activity of 11b-HSD1 was described in rat smooth
muscle cells.54 Subsequent studies showed that admin-
istration of carbenoxolone, an inhibitor of 11b-HSD
activity, for 5 days resulted in enhanced vasoconstrictor
sensitivity to noradrenalin.55 Because increased sensitiv-
ity to noradrenalin is a known effect of cortisol adminis-
tration, it was hypothesized that 11b-HSD activity
protected vascular glucocorticoid receptors from cortisol.
Activity of 11b-HSD1 results in conversion of
cortisone to cortisol in vivo,56,57 and would, therefore, be
predicted to enhance glucocorticoid effects on blood
vessels. Activity of 11b-HSD2, which inactivates corti-
sol, has also been described in human vascular smooth
muscle cells.58 In 11b-HSD2 knockout mice, vascular
sensitivity to noradrenalin was increased while the sen-
sitivity to endothelium-derived nitric oxide was de-
creased,59 raising the possibilities that activity of 11b-
HSD2 might reduce glucocorticoid effects on blood
vessels and that decrease of vascular 11b-HSD2 activity
may enhance vascular effects of glucocorticoids. How-
ever, in a recent study in mouse aortas, exposure to
glucocorticoids in vitro altered neither endothelium-
dependent nor endothelium-independent relaxation of
mouse aortas.60 In addition, forearm vasoconstriction
on noradrenalin was not altered when carbenoxolone
was administered for 2 days (S.H. van Uum, R.J. Irving,
D.J. Webb, B.R. Walker, unpublished data, 2003).
Endothelial dysfunction in 11b-HSD2 knockout mice
can therefore not simply be explained by increased access
of corticosterone to endothelial glucocorticoid receptors.
126 SEMINARS IN VASCULAR MEDICINE/VOLUME 4, NUMBER 2 2004
Further studies are needed to elucidate the role of 11b-
HSD activities in blood vessels and to determine
whether the effect of glucocorticoids on endothelial
function may be caused by more indirect mechanisms.
Central Nervous System
In rat studies, the presence of mineralocorticoid recep-
tors has been described in the hippocampus.61 Expres-
sion of 11b-HSD type 2 has been demonstrated in the
commissural portion of the nucleus tractus solitarius, the
subcommissural organ, and the ventrolateral and ven-
tromedial hypothalamus62 —areas in the brain that are
known to be involved in cardiovascular regulation. In
rats, intracerebrovascular infusion of aldosterone for
14 days resulted in an increase of systolic blood pressure,
an effect that was not found when aldosterone was
administered subcutaneously. Furthermore, the blood
pressure–increasing effect of the 11b-HSD-inhibitor
carbenoxolone could completely be prevented by intra-
cerebrovascular infusion of a specific MR receptor
blocker.63 These studies indicate that MRs in the central
nervous system may play a role in the pathogenesis of
mineralocorticoid hypertension, but it remains to be
established whether this plays a role in the pathogenesis
of primary hypertension in humans.
Placental 11b-HSD2 Activity and Adult
Hypertension
Epidemiological studies have demonstrated a strong
association between low birth weight at term and in-
creased blood pressure in adult life.64 This original study
has been confirmed in many populations.65 Increased
fetal exposure to glucocorticoids inhibits fetal growth in
mice and humans,66 and 11b-HSD2 is present in the
placenta and regulates fetal exposure to maternal gluco-
corticoids. On the basis of these data, it was hypothe-
sized that decreased placental 11b-HSD2 activity might
increase fetal exposure to maternal glucocorticoids, re-
sulting in low birth weight and adult hypertension.67
Administration of dexamethasone (which is not meta-
bolized by 11b-HSD2 and passes the placenta) to
pregnant rats resulted in a 20% reduction of birth weight
and significantly increased systolic blood pressure in
offspring.67 Inhibition of 11b-HSD2 activity by carbe-
noxolone in pregnant rats has similar effects.68 However,
the relevance of this pathway in development of primary
hypertension in humans is not clear. A positive correla-
tion between birth weight and 11b-HSD2 activity has
been found in humans, but the correlation was weak and
the placenta seems to have a large reserve for clearance of
cortisol.69 Furthermore, in a study of a population in
which a large intake of licorice is common, no relation
between licorice intake during pregnancy and fetal birth
weight was found.70
CONCLUSION
The discovery of the AME syndrome has demonstrated
the crucial role of the 11b-HSD2 isozymes in regulating
access of cortisol to the renal mineralocorticoid recep-
tors. The importance of insufficient renal 11b-HSD2
activity has now extended beyond this rare syndrome. It
plays a role in licorice-induced hypertension and in
hypertension in the ectopic ACTH syndrome, but its
role in the pathogenesis of primary hypertension remains
to be demonstrated, in particular in salt-sensitive
subjects. Several extrarenal effects of cortisol and
11b-HSDs on blood pressure have been described.
The importance of these pathways in primary or other
forms of hypertension also needs further clarification.
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