Cardio Advances--hyperaldosteronism in Pregnancy

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Therapeutic Advances in Cardiovascular Disease

DOI: 10.1177/17539447081001802009; 3; 123 originally published online Jan 26, 2009;Ther Adv Cardiovasc Dis Genevive Escher

Hyperaldosteronism in pregnancy

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Therapeutic Advances in Cardiovascular Disease Review

Hyperaldosteronism in pregnancy

Genevieve Escher

Abstract: Aldosterone is a key regulator of electrolyte and water homeostasis and plays acentral role in blood pressure regulation. Hormonal changes during pregnancy, among themincreased progesterone and aldosterone production, lead to the required plasma volumeexpansion of the maternal body as an accommodation mechanism for fetus growth. This reviewdiscusses the regulation of aldosterone production by aldosterone synthase (CYP11B2); theimpact on aldosterone secretion due to the presence of a chimeric gene originating froma crossover between CYP11B1 and CYP11B2 in glucocorticoid remediable aldosteronism(GRA) the inherited form of hypertension; enhanced aldosterone production in aldosterone-producing adenoma (APA); and idiopathic hyperaldosteronism (IHA). Features of hyperaldos-teronism are also found in patients with apparent mineralocorticoid excess (AME), in which

glucocorticoids exacerbate activation of the mineralocorticoid receptor (MR) because ofa defect in the 11-hydroxysteroid dehydrogenase type 2 enzyme. Regulation of aldosteroneproduction and tissue-specific activation of the mineralocorticoid receptor are prerequisitesfor optimal control of body fluids and blood pressure during pregnancy and contribute largelyto the wellbeing of the mother-to-be.

Keywords: aldosterone, pregnancy, CYP11B2, GRA, mineralocorticoid receptor

IntroductionPregnancy is a physiologic process tightly

interconnecting changes in cardiovascular, endo-

crine and renal systems [Weissgerber and Wolfe,

2006]. At an early stage of pregnancy, ovarian

steroid hormones set the basic general vasodilata-

tion that, in turn, initiates a series of regulations

in which the reninangiotensinaldosterone

system (RAS) is activated and the control of anti-

diuretic hormone secretion relative to plasma

osmolality is reset. Thus, a gradual increase in

plasma volume combined with an increase in car-

diac function allows the maintenance of blood

pressure to overcome systemic vasodilatation.

A functional arteriovenous shunt forms with the

development of the utero-placental circulation.

At the end of the first trimester, a decrease in

peripheral resistance occurs in parallel to

an increase in cardiac output, and, as a conse-

quence, blood pressure decreases and

remains low until the end of the pregnancy

[Chapman et al. 1998]. The absence of these

early events could be the cause of pre-eclampsia,

the most serious hypertensive complication of

pregnancy, characterized by the triad hyper-

tension, proteinuria and edema [Roberts and

Cooper, 2001].

Aldosterone is secreted by the adrenal gland in

response to Na

deficiency or K

loading, and

accounts for Na

retention and K

excretion in

the distal tubule and the colon. Aldosterone

binds to the mineralocorticoid receptor (MR).

This receptor was first described in Na

trans-

porting tissues, and later in a range of nonepithe-

lial tissues such as cardiomyocytes and blood

vessels [Connell and Davies, 2005]. In the renal

distal tubule, aldosterone increases Na transport

by inducing the Na

/K

ATPase via SGK-1

[Lee et al. 2008]. Na

retention leads to water

retention, and inappropriately high aldosterone

concentrations therefore result in increased

blood volume and cardiac output. Together

with a reflex vasoconstriction, there is consequent

onset of hypertension. In normal pregnancy,

plasma aldosterone concentration increases in

parallel to progesterone, and these changes are

considered normal physiological requirements

for the development of the placenta [Brown

et al. 1995]. Despite this, aldosterone remains

tightly regulated, allowing the maternal body to

overcome salt restriction or loading, and its role is

central in the maintenance of volume expansion

during pregnancy. The effect of an altered regu-

lation of aldosterone production on salt and

http://tac.sagepub.com 123

Ther Adv Cardiovasc Dis

(2009) 3(2) 123132

DOI: 10.1177/1753944708100180

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Correspondence to:Genevieve Escher, PhD

University Hospital ofBerne, Division ofNephrology and

Hypertension, Berne,Switzerlandgenevieve.escher@

dkf.unibe.ch

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water retention is enhanced when hormonal

changes such as those seen in pregnancy occur.

In 1955, Dr Jerome Conn described the classical

syndrome of primary aldosteronism characterized

by hypertension, hypokalemia due to renal potas-sium wasting, suppressed renin activity (PRA),

and increased aldosterone levels [Conn, 1955].

Since the initial description of the syndrome, var-

ious forms of primary aldosteronism have been

described [Rossi et al. 2006]. Aldosterone-produ-

cing adenoma (APA) is the most common cause

of primary aldosteronism and occurs in about

60% of cases. Idiopathic hyperaldosteronism

(IHA), which can be associated with bilateral

micronodular or macronodular adrenal hyper-

plasia, accounts for about 40% of cases.

Glucocorticoid-remediable aldosteronism (GRA)

is a very rare familial form of hyperaldosteronism[Dluhy and Lifton, 1999]. A second form of

familial aldosteronism, familial hyperaldosteron-

ism type 2 (FHII), has also been described

[Stowasser et al. 1992] and is defined by the

recurrence of aldosteronism of any form within

a kindred that is not suppressed by dexametha-

sone-like GRA. Excessive secretion of aldosterone

is associated with an increased risk of cardiovas-

cular events. The rate of stroke, myocardial infec-

tion and atrial fibrillation is increased in patients

with primary aldosteronism [Rossi et al. 2006].

Treatment consists of an adrenalectomy, if neces-

sary, or the use of the MR antagonist spironolac-tone combined with supplementation of oral

potassium. Spironolactone was developed in the

1950s and shares structural elements with proges-

terone and androgens so that it is associated with

progestogenic and antiandrogenic side effects.

It is therefore not the drug of choice during preg-

nancy [Jeunemaitre et al . 1987]. Eplerenone,

a spironolactone derivative, was designed to

enhance selective binding to the MR. Eplerenone

has only 0.1% of the binding affinity to the

androgen receptor (AR) and less than 1% to

the progesterone receptor (PR) and thus repre-

sents a good candidate to antagonize the MRduring pregnancy.

Body fluids changes and the reninangiotensinsystem in pregnancyDuring normal pregnancy, there is a marked

expansion in plasma volume starting in the first

trimester, accelerating in midgestation and

stabilizing after week 34 of gestation, as already

shown by Pirani et al . [1973] (Figure 1).

This adaptative mechanism is associated with

hemodynamic changes and correlates with

an increased concentration of circulating aldos-

terone. The composition and dynamics of body

fluids are also changed during pregnancy.

Enlargement of the fluids compartment andincrease in cardiac output occur [Longo, 1983].

Interestingly, the control mechanisms responsible

for maintaining the homeostasis accept this new

steady state in pregnancy as normal. Thus,

osmolarity thresholds for thirst sensation and

vasopressin release are reset downwards to main-

tain the effective plasma osmolarity during preg-

nancy. As a final result, there is a cumulative gain

in salt and water, enhancing placental perfusion

to protect the pregnant woman and her fetus.

Three to 5 days after administration of a low salt

diet, normal pregnant women come into balancewith significant weight loss and very little change

in plasma volume, indicating an interstitial fluid

loss. The sodium intake challenge is well toler-

ated, and little change in either weight or plasma

volume occurs. The response to an acute admin-

istration of sodium is handled appropriately and

depends on previous sodium balance. There is a

rapid sodium excretion in pregnant women

already sodium depleted, and a slower excretion

in those previously sodium depleted [Gallery and

Brown, 1987].

The appearance of an additional reninangioten-sin system (RAS) in the placenta next to the

usual one in the maternal kidney accounts for

the regulation of aldosterone production during

pregnancy. There is an early increase in circulat-

ing concentrations of renin [Pirani et al. 1973]

due to ovarian secretion and decidual

production. In the liver, an increased synthesis

of angiotensinogen is observed and attributed to

Plasmavolume(ml) 4000

3000

Weeks of pregnancy

10 20 30 40 68 weekspost-partum

Figure 1. Changes in plasma volume during gesta-tion. The dashed line represents plasma volumechanges in nonpregnant women, the black line inpregnant women.

Therapeutic Advances in Cardiovascular Disease 3 (2)

124 http://tac.sagepub.com



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the increased circulating estrogen produced by

the growing placenta. This leads to increased

serum angiotensin II and aldosterone levels that

contribute mostly to sodium retention and the

resultant water retention required for volume

expansion in pregnancy [Gallery et al. 1979].However, the effect of angiotensin II on the

systemic vasculature; that is, an increased vaso-

motor tone, is not observed in pregnant women.

In a historic study performed by Assali and

Westersen [1961], it was shown that a two

times higher infusion rate of angiotensin II was

required to obtain the same vascular response as

in nonpregnant women. More than 10 years

later, Gant et al. [1973] showed that angiotensin

II sensitivity was downregulated during

pregnancy. These changes in angiotensin II

responsiveness in pregnancy are attributed first

to a downregulation of the AT1 receptor in thehuman placenta [Kalenga et al . 1996], and

second to progesterone that can decrease angio-

tensin II sensitivity [Gallery and Brown, 1987].

Aldosterone biosynthesisAldosterone is synthesized from cholesterol in the

adrenal zona glomerulosa by a series of reactions

(Figure 2) [Connell and Davies, 2005]. Following

translocation of cholesterol to the mitochondria

by steroidogenic acute regulatory protein

(StAR), cholesterol is converted to aldosterone

by multiple reactions catalyzed by two families

of enzymes, dehydrogenases and members of thecytochrome P450 family. The latter require adre-

nodoxin and adrenodoxin reductase for electron

transfer from the cofactor to the enzyme. First,

cholesterol is converted to pregnenolone by the

P450 side-chain cleavage enzyme (CYP11A1)

that is released to the cytosol and where it is

converted to progesterone by 3-HSD2.

Progesterone undergoes 21-hydroxylation by

CYP21A to produce 11-deoxycorticosterone

(DOC). This, in turn, is converted to aldosterone

by three successive reactions catalyzed by aldos-

terone synthase (CYP11B2) that take place

exclusively in the zona glomerulosa. First, hydro-xylation of 11-deoxycorticosterone to corticoster-

one by the 11-hydroxylase CYP11B1 takes

place; second, hydroxylation of corticosterone to

18-hydroxycorticosterone by 18-hydroxylase;

and third, methylation of 18-hydroxy-

corticosterone by 18-methyloxydase to produce

aldosterone. Since CYP11B1 also catalyses

the biosynthesis of corticosterone from DOC,

Cholesterol

Pregnenolone

Aldosterone

Corticosterone

18-OH-corticosterone

11-deoxycorticosterone

Progesterone

CYP11A1

3b-HSD2

CYP21A

CYP11B1

18-Hydroxylase

18-OxydaseAldosteronesy

nthase

(CYP11B2)

Corticosterone

CYP11B1

17-OH-pregnenolone

17-OH-progesterone

11-deoxycortisol

Cortisol

CYP17

3b-HSD2

CYP21A

Figure 2. Aldosterone biosynthesis: the CYP11B2 pathway. Zona glomerulosa is represented in orange, zonafasciculata in green.

G Escher




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the late stages of cortisol and aldosterone synth-

esis are identical. CYP11B1 additionally catalyses

the formation of cortisol by hydroxylation of

11-deoxycortisol in the zona fasciculata. Thus, a

specific expression pattern of CYP11B2 and

CYP11B1 ensures the appropriate synthesis ofaldosterone and cortisol in the zona glomerulosa

and in the zona fasciculata of the adrenal gland.

The aldosterone synthase pathway can be

assessed in urine by quantifying single compo-

nents of the CYP11B2 pathway (Figure 3), and

quantification of each of these steroids as well as

detection of novel steroids are used for the clinical

diagnosis of hyperaldosteronism [Shojaati et al.

2004].

CYPB11B2 in primary hyperaldosteronismThe CYP11B2 gene, expressed in the zona glo-

merulosa of the adrenal glands, shares 90%

nucleotide sequence identity in the introns and

95% in the exons with the CYP11B1 gene

coding for the 11-hydroxylase that is essential

for cortisol synthesis. Both genes are located in

close proximity on chromosome 8q and might

have arisen from the duplication of an ancestral

gene. Despite their strong sequence homology,

they are under different regulatory mechanisms.

Whereas expression of CYP11B2 is regulated by

angiotensin II and potassium via protein kinase C

[LeHoux et al. 2000], CYP11B1 is under the

regulation of ACTH via cAMP and protein

kinase A, and this is attributed to the highly

divergent 50 upstream regions. CYP11B2

mRNA is also detected in extra-adrenal tissues

like blood vessels, heart tissue and mononuclear

leukocytes. In cardiovascular tissues, expressionofCYP11B2 is controlled by the RAS system and

potassium [Takeda et al. 1996].

The gene CYP11B2 is composed of nine exons,

and several polymorphisms have been described

in the literature so far (Figure 4). The two most

frequent polymorphisms, which are in close link-

age disequilibrium, are, first, a (344C/T) invol-

ving a C/T substitution in a putative binding site

for the steroidogenic transcription factor SF-1 in

the promoter region and, second, intron 2 con-

version, in which most of the intron of CYP11B2

is replaced by that of CYP11B1. Although the

DOC, THDOC

THB, THA

18-OH-THA

THAldo

Urinary steroid

metabolites

Hyperaldsoteronism GRA

THAldo

THAldo

THE + THF + 5a-THF18-OH-F

18-oxo-F

THAldo

Deoxycorticosterone

18-OH corticosterone

18-Oxydase

18-Hydroxylase

CYP11B2pathway

Aldosterone

Corticosterone

CYP11B1

Figure 3. CYP11B2 pathway and its corresponding urinary steroids in normal and disease state.DOC: deoxycorticosteron; THDOC: tetrahydrodeoxycorticosteron; THB: tetrahydrocorticosteron; THA:tetrahydrodehydrocorticosteron; THAldo: tetrahydroaldosteron; THE: tetrahydrocortison; THF: tetrahydro-cortisol; 18-OH-F: 18-hydroxy-cortisol; 18-oxo-F: 18-oxo-cortisol.

CYP11B2

1 2 3 4 5 6 7 8 9Promoter

3-UTR

Intron

Exon

344C/T Intron 2conversion

Figure 4. Structure of the CYP11B2 gene andlocation of the most frequent polymorphisms.





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(344C/T) polymorphism has been widely

studied, its clinical implications with respect to

hypertension and cardiovascular disease still

remain uncertain. Subjects with the T allele in

the SF-1 binding site have a higher urinary

aldosterone excretion rate than those lackingthis allele, raising the possibility of an increased

aldosterone synthase activity [Davies et al. 1999].

Moreover, the T allele was also reported to be

more common in hypertensive individuals in a

study performed by Brand and coworkers

[1998]. In contrast with these two studies,

Tamaki et al. [1999] reported an association

with SF-1 C allele and higher aldosterone to

renin ratios in a Japanese population. However,

SF-1 homozygote rate TT and the T allele

frequency were unusually high, suggesting

either a true genetic difference between the popu-

lations and/or sampling differences. The signifi-cance of the intron 2 conversion is unclear. It has

been suggested that intron 2 might contain reg-

ulatory elements of the CYP11B genes. The fre-

quency of the Tallele and the intron 2 conversion

allele is significantly increased in patients with

hypertension [Yu et al. 2008].

Glucocorticoid remediable aldosteronism (GRA)

is an autosomal dominant form of hypertension.

This disease is characterized by early onset of

moderate to severe hypertension with high

plasma aldosterone, suppressed plasma renin

activity and production of two rare steroids,

18-hydroxycortisol (18-OHF) and 18-oxocorti-

sol (18-oxoF) [Dluhy and Lifton, 1999]. The

incidence of premature cerebrovascular events is

high in these patients since enhanced circulating

aldosterone concentrations lead to increased left

ventricular wall thickness and reduced diastolicfunction [Stowasser et al. 2005]. In GRA, aldos-

terone secretion is mainly regulated by ACTH

rather than angiotensin II, so that administration

of ACTH exacerbates the symptoms but gluco-

corticoids normalize them. The cause of the

disease is attributed to the presence of a chimeric

gene originating from a crossover between

CYP11B1 and CYP11B2 (Figure 5). The hybrid

gene contains the promoter region of CYP11B1

at the 50 end and CYP11B2 at the 30 end, so that

this hybrid gene is ectopically expressed in the

zona fasciculata through CYP11B2 promotor,

thus exposing cortisol to aldosterone synthaseactivity. As a consequence, aldosterone,

18-hydroxy-cortisol (18-OHF), and 18-oxocorti-

sol (18-oxoF) are produced. Clinical diagnosis is

based on the detection of increased tetrahydroal-

dosterone (THAldo), 18-OHF and 18-oxoF in

urine (Figure 4). The latter two urinary steroids

are almost undetectable in urine of healthy

people. The dexamethasone suppression test is

the next step in GRA diagnosis. Since ACTH

drives abnormal steroidogenesis, 3 days of dexa-

methasone treatment switches the mechanism of

negative feedback regulation on, so that high

aldosterone levels are suppressed and 18-OHF

5 3

5 3

5 3

CYP11B1

CYP11B2

GRA

Unequal cross-over

5 3

ACTH

responsive promoter

Aldosterone production

Promotor

Australian population

Common recombination

Promotor Coding region

Coding region

Promotor Coding region

Coding region

Figure 5. Recombination of CYP11B1 and CYP11B2 in glucocorticoid remediable aldosteronism.

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and 18-oxoF concentrations in urine decrease.

However, the gold standard for GRA diagnosis

remains the detection of the chimeric gene by

long-amplification PCR [Mulatero et al. 1998].

The presence of the chimeric gene is the final

proof of GRA. In an Australian population ofGRA patients, Miyahara et al. [1992] found a

second recombination between CYP11B1 and

CYP11B2. In this case, the fusion protein is com-

posed of exons 14 of CYP11B1 with the car-

boxy-terminal part (exon 59) of CYP11B2

(Figure 5, second recombination). As recombi-

nations between CYP11B1 and CYP11B2 were

already found to occur at two different sites,

one might speculate that other recombinations

could take place and would explain the absence

of the chimeric gene when urinary steroid pattern

and dexamethasone suppression test mimic the

GRA ones.

Wyckoff et al. [2000] performed a retrospective

analysis of pregnancy outcome in 39 mothers

with GRA. Sufficient outcome information was

found for only 16. A higher risk of developing

pre-eclampsia was suspected for the following

reasons. First, since RAS is thought to play a

role in the development of pre-eclamspsia, the

dysregulation of volume homeostasis by RAS as

seen in GRA might also influence the risk of

developing pre-eclampsia. Second, the placenta

produces corticotropin-releasing hormone

[Goland et al. 1986]. As aldosterone productionis solely under the control of ACTH in GRA, one

might anticipate hyperaldosteronism exacerba-

tion during pregnancy in a GRA patient. Third,

hyperaldosteronism per se could affect the risk of

developing pre-eclampsia. Finally, GRA mothers

develop hypertension that is an additional risk for

eclampsia, regardless of the cause. Interestingly,

the conclusion of this study revealed that women

with GRA actually had no increased risk of devel-

oping pre-eclampsia. However, GRA women

with chronic hypertension were at risk of exacer-

bated hypertension during pregnancy. Blood

pressure followed the same pattern in GRA andnormal pregnant women, but the baseline was

higher in GRA. Study of pregnancy outcome of

GRA patients has provided essential information

for the clinicians caring for them.

Increased aldosterone synthase activity was mea-

sured in isolated mononuclear leukocytes (MNL)

of patients with IHA and was significantly

increased when compared with that of patients

with APA or to normal controls. This increase

correlated with increased CYP11B2 mRNA

expression in MNL [Miyamori et al . 2000].

However, no mutation was detected in the geno-

mic DNA of these patients, so that overexpres-

sion of CYP11B2 was attributed to the presence

of regulatory factors. A year later, Mulatero et al.[2001] reported that the presence of the C allele

was in excess in IHA patients when compared to

hypertensive groups with normal aldosterone

levels. In a Japanese study, however, the presence

of the T allele at (344) was considered as an

independent risk factor for hypertension

[Matsubara, 2000].

They are only few cases of IHA in pregnancy

reported in the literature. Neerhof et al. [1991]

described a severely hypertensive patient who was

treated with high doses of four antihypertensive

agents and experienced a drastic improvement inblood pressure with enalapril maleate. However,

emergency delivery at 26 weeks was performed

due to deterioration of the state of the fetus.

This example underlines the tremendous and

potentially life-threatening effect of hormonal

changes during pregnancy on blood pressure

regulation.

Oda et al. [2006] found that CYP11B2 expres-

sion was increased in RNA isolated from adrenal

tumor resection of patients with APA. If an adre-

nal tumor is diagnosed during pregnancy, surgi-

cal intervention in the second trimester has thebest outcome. Kreze et al. [1999] described the

fatal outcome of a 28-year-old woman who

refused to undergo surgery. She developed a ges-

tosis in week 27 of pregnancy and the infant died

9 days after emergency delivery. The patient later

underwent a laparoscopic adrenalectomy and

blood pressured and potassium levels normal-

ized. Solomon et al. [1996] described another

case that underwent adrenalectomy in week 15

of gestation. Following the intervention, antihy-

pertensive treatment and potassium supplemen-

tation could be withdrawn and a healthy child

was born after 36 weeks of gestation. These twoexamples emphasize the importance of fast action

upon diagnosis of APA during pregnancy.

Little is known about FHII, another familial

variety of primary aldosteronism that includes

tumors and that is not glucocorticoid-suppressi-

ble. Although the molecular basis remains

unclear, a recent linkage analysis study showed

an association with chromosomal region 7p22

[So et al. 2005].





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Apparent aldosterone excessUnder normal conditions, aldosterone binds with

high affinity to the mineralocorticoid receptor

(MR) to stimulate renal sodium reabsorption

and potassium excretion (Figure 6). Upon enter-

ing the cell, aldosterone binds to MR to form

the aldosteroneMR complex that moves into

the nucleus. There it binds to specific DNA-

hormone response elements sequences, thereby

altering the transcription of messenger RNA

and protein synthesis, ultimately leading to

sodium retention. In a screening of 75 hyperten-

sive patients, a mis-sense mutation resulting in

the substitution of a leucine for a serine

(S810L) in exon 6, codon 810 (MRL810) was

detected [Geller et al. 2000]. Women harboring

this mutation experienced a dramatic exacerba-

tion of hypertension during pregnancy. Later, it

was shown that MRL810 could be activated by

cortisone [Rafestin-Oblin et al. 2003] and proges-

terone, explaining why the hypertensive pheno-

type was enhanced during pregnancy.

Plasma cortisol levels are an order of magnitude

higher than those of aldosterone, and cortisol has

an equally high affinity for the MR [Funder,

2007]. Its ability to activate MR in aldosterone

target tissues is limited by 11-hydroxysteroid

dehydrogenase type 2 (11-OHSD2), the

enzyme that inactivates cortisol into cortisone

[Albiston et al. 1995]. Thus, MR is protected

from high exposure to glucocorticoids

(Figure 6). If this enzyme is blocked by carbenox-

olone or carries a loss-of-function mutation as in

the syndrome of apparent mineralocorticoid

excess, described for the first time in 1977 by

New in a three-year-old American Indian girl

[New et al. 1997], cortisol becomes an MR

agonist and mimics the effect of aldosterone.

During pregnancy, 11-OHSD2 is a major pla-

cental enzyme critically important for providing

the appropriate environment for the normal

development of the fetus. In the placenta, 11-

OHSD2 activity is upregulated during the differ-

entiation of cytotrophoblasts to syncytiotropho-

blast [Schoof et al . 2001]. Loss-of-function

mutation accounts for low birth weight, and

reduced 11-OHSD2 activity is associated with

intrauterine growth retardation [Dave-Sharma

et al. 1998]. Mutations in 11-OHSD2 could

also form part of the explanation of the high

rate of failed pregnancies found in a family with

AME [Krozowski et al. 1997].

Cardiac output

Blood pressure

MR

Progesterone

20a-OH-Progesterone

RAS

Glomerular filtration rate

Na+ retention

Plasma volume

Cortisol

Cortisone

11b-OHSD2

Aldosterone

Vasodilatation

CYP11B2

11-DOC

20a-OHSD

Figure 6. Blood pressure regulation during pregnancy. Beside aldosterone, MR occupancy is protected by11-OHSD2 and 20-OHSD enzymes to avoid excess binding and consequent sodium retention byglucocorticoids and progesterone. Progesterone also acts as an inhibitor of 11-OHSD2.

G Escher




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A third steroid showing affinity for the MR exists,

namely progesterone. Despite its high affinity for

the MR in vitro, progesterone confers only a low

agonistic mineralocorticoid activity in vivo

(Figure 6) [Myles and Funder, 1996]. During

pregnancy, progesterone increases to reach a con-centration more than 100-fold higher than that of

aldosterone. The reason why aldosterone still acts

as a potent mineralocorticoid in these situations

is not fully understood. Possible explanations are,

first, a ten-fold higher plasma protein binding of

progesterone compared with aldosterone;

second, a higher stability of the aldosterone-MR

complex than the progesterone-MR complex;

and, third, local metabolism of progesterone to

20-OH-progesterone by 20-OHSD in a

mechanism similar to the protection of cortisol

by 11-OHSD2 [Quinkler et al . 2003]

(Figure 6). This protective mechanism impliesthat little MR activation should be seen in the

presence of high progesterone concentrations, in

accordance with the progressive plasma volume

expansion occurring during pregnancy. Since

20-OH-progesterone has less affinity for the

MR, one might anticipate that mutations in

20-OHSD could indirectly affect blood pressure

regulation, especially during pregnancy. The

anti-MR effect of progesterone is best illustrated

by the fact that pregnant women with Addisons

disease require increased 9-fluorocortisol sub-

stitution to maintain blood pressure and serum

potassium in normal range [Wieacker et al .

1989]. Moreover, in women with primary aldos-

teronism, serum potassium and blood pressure

often normalize during pregnancy, with recur-

rence of hypokalemia and hypertension after

delivery, when progesterone concentrations go

back to normal [Murakami et al. 2000]. The ulti-

mate proof of the in vivo anti-MR potency of

progesterone was given by Quinkler et al .

[1999]. By challenging males or postmenoposal

females with adrenal insufficiency with a contin-

uous aldosterone infusion followed by a proges-

terone infusion, he observed an increase in

urinary sodium to potassium ratio and urinary

sodium excretion during progesterone infusion,

indicating an anti-MR effect of progesterone

in vivo. This effect, however, was much weaker

than would be expected from the rise in circulat-

ing progesterone concentrations, an observation

explained, on one hand, by the enzyme-mediated

protection of the MR, and, on the other hand,

by 11-OHSD2 inhibition by progesterone

[Quinkler et al. 2003] (Figure 6).

Although MR seems to be at first nonselective,

local regulation of its occupancy by 11-OHSD2

and 20-OHSD allows its appropriate activation,

leading to adequate sodium and potassium bal-

ance within the body. Therefore, regulation of

these two enzymes plays a central role forplasma volume regulation during pregnancy,

when the maternal body is challenged with

increasing progesterone concentrations.

ConclusionThe role of aldosterone in body fluid regulation

during pregnancy and its mechanism of action via

MR are of pivotal importance for a successful

pregnancy outcome. The medical profession has

come a long way since Conn described the first

patient with primary aldosteronism. Medical

imagery and improvement of molecular biologytechniques have largely contributed to the under-

standing of the different subclasses of hyperaldos-

teronism and their underlying mechanisms. The

development of new classes of antimineralocorti-

coid agents and laparoscopic interventions

improved the wellbeing of pregnant women and

the survival rate of the fetus. Body fluids are regu-

lated during pregnancy by aldosterone as well as

by an appropriate activation state of the MR. On

a molecular level, inappropriate local activation

of the MR by glucocorticoids or progesterone

excess due to decreased 11-OHSD2 or 20-

OHSD enzyme activity, respectively, are respon-sible for sodium retention and K

excretion in

the absence of increased aldosterone plasma con-

centrations. Thus, a tiny dysregulation at the

genetic or prereceptor level leads to an alteration

of appropriate volume expansion, causing

damage on both the maternal and fetal side.

The unveiling of the underlying causes of hyper-

aldosteronism in pregnancy is a demonstration of

a successful collaborative effort of fundamental

laboratory research and clinical application.

AcknowledgmentsThis work was supported by a grant Nr 310000-

109774 from the Swiss National Science

Foundation to GE.

Conflict of interest statementNone declared.

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