Therapeutic Advances in Cardiovascular Disease

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Hyperaldosteronism in pregnancy
Genevive Escher Ther Adv Cardiovasc Dis 2009; 3; 123 originally published online Jan 26, 2009; DOI: 10.1177/1753944708100180 The online version of this article can be found at: http://tak.sagepub.com/cgi/content/abstract/3/2/123

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Therapeutic Advances in Cardiovascular Disease

Review

Hyperaldosteronism in pregnancy
` Genevieve Escher

Ther Adv Cardiovasc Dis (2009) 3(2) 123132 DOI: 10.1177/ 1753944708100180 The Author(s), 2009. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav

Abstract: Aldosterone is a key regulator of electrolyte and water homeostasis and plays a central role in blood pressure regulation. Hormonal changes during pregnancy, among them increased progesterone and aldosterone production, lead to the required plasma volume expansion of the maternal body as an accommodation mechanism for fetus growth. This review discusses the regulation of aldosterone production by aldosterone synthase (CYP11B2); the impact on aldosterone secretion due to the presence of a chimeric gene originating from a crossover between CYP11B1 and CYP11B2 in glucocorticoid remediable aldosteronism (GRA) the inherited form of hypertension; enhanced aldosterone production in aldosteroneproducing adenoma (APA); and idiopathic hyperaldosteronism (IHA). Features of hyperaldosteronism are also found in patients with apparent mineralocorticoid excess (AME), in which glucocorticoids exacerbate activation of the mineralocorticoid receptor (MR) because of a defect in the 11-hydroxysteroid dehydrogenase type 2 enzyme. Regulation of aldosterone production and tissue-specific activation of the mineralocorticoid receptor are prerequisites for optimal control of body fluids and blood pressure during pregnancy and contribute largely to the wellbeing of the mother-to-be. Keywords: aldosterone, pregnancy, CYP11B2, GRA, mineralocorticoid receptor

Introduction Pregnancy is a physiologic process tightly interconnecting changes in cardiovascular, endocrine and renal systems [Weissgerber and Wolfe, 2006]. At an early stage of pregnancy, ovarian steroid hormones set the basic general vasodilatation that, in turn, initiates a series of regulations in which the reninangiotensinaldosterone system (RAS) is activated and the control of antidiuretic hormone secretion relative to plasma osmolality is reset. Thus, a gradual increase in plasma volume combined with an increase in cardiac 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 consequence, 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 hypertension, 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 transporting tissues, and later in a range of nonepithelial 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 regulation of aldosterone production on salt and

Correspondence to: ` Genevieve Escher, PhD University Hospital of Berne, Division of Nephrology and Hypertension, Berne, Switzerland genevieve.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 potassium wasting, suppressed renin activity (PRA), and increased aldosterone levels [Conn, 1955]. Since the initial description of the syndrome, various forms of primary aldosteronism have been described [Rossi et al. 2006]. Aldosterone-producing 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 hyperplasia, 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 hyperaldosteronism 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 dexamethasone-like GRA. Excessive secretion of aldosterone is associated with an increased risk of cardiovascular events. The rate of stroke, myocardial infection and atrial fibrillation is increased in patients with primary aldosteronism [Rossi et al. 2006]. Treatment consists of an adrenalectomy, if necessary, or the use of the MR antagonist spironolactone combined with supplementation of oral potassium. Spironolactone was developed in the 1950s and shares structural elements with progesterone and androgens so that it is associated with progestogenic and antiandrogenic side effects. It is therefore not the drug of choice during pregnancy [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 represents a good candidate to antagonize the MR during pregnancy. This adaptative mechanism is associated with hemodynamic changes and correlates with an increased concentration of circulating aldosterone. The composition and dynamics of body fluids are also changed during pregnancy. Enlargement of the fluids compartment and increase 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 maintain the effective plasma osmolarity during pregnancy. 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 balance with significant weight loss and very little change in plasma volume, indicating an interstitial fluid loss. The sodium intake challenge is well tolerated, and little change in either weight or plasma volume occurs. The response to an acute administration 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 reninangiotensin 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 circulating 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
Plasma volume (ml) 4000

3000

Body fluids changes and the reninangiotensin system in pregnancy During 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).

10

20

30

40

68 weeks post-partum

Weeks of pregnancy

Figure 1. Changes in plasma volume during gestation. The dashed line represents plasma volume changes in nonpregnant women, the black line in pregnant women.

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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 vasomotor 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 the human placenta [Kalenga et al. 1996], and second to progesterone that can decrease angiotensin II sensitivity [Gallery and Brown, 1987]. (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 the cytochrome P450 family. The latter require adrenodoxin 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 aldosterone synthase (CYP11B2) that take place exclusively in the zona glomerulosa. First, hydroxylation of 11-deoxycorticosterone to corticosterone by the 11-hydroxylase CYP11B1 takes place; second, hydroxylation of corticosterone to 18-hydroxycorticosterone by 18-hydroxylase; and third, methylation of 18-hydroxycorticosterone by 18-methyloxydase to produce aldosterone. Since CYP11B1 also catalyses the biosynthesis of corticosterone from DOC,

Aldosterone biosynthesis Aldosterone is synthesized from cholesterol in the adrenal zona glomerulosa by a series of reactions

Cholesterol CYP11A1 Pregnenolone 3b-HSD2 Progesterone CYP21A 11-deoxycorticosterone CYP11B1 Aldosterone synthase (CYP11B2) Corticosterone CYP11B1 18-Hydroxylase 18-OH-corticosterone 18-Oxydase Aldosterone Corticosterone Cortisol CYP17 17-OH-pregnenolone 3b-HSD2 17-OH-progesterone CYP21A 11-deoxycortisol

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

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the late stages of cortisol and aldosterone synthesis 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 of aldosterone 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 components 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 hyperaldosteronism The CYP11B2 gene, expressed in the zona glomerulosa 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, expression of CYP11B2 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 linkage disequilibrium, are, first, a (344C/T) involving a C/T substitution in a putative binding site for the steroidogenic transcription factor SF-1 in the promoter region and, second, intron 2 conversion, in which most of the intron of CYP11B2 is replaced by that of CYP11B1. Although the
CYP11B2 Promoter 1 344C/T Intron Exon 2 3 4 5 Intron 2 conversion 6 78 9 3-UTR

Figure 4. Structure of the CYP11B2 gene and location of the most frequent polymorphisms.

CYP11B2 pathway

Urinary steroid metabolites

Hyperaldsoteronism

GRA

Deoxycorticosterone CYP11B1 Corticosterone 18-Hydroxylase 18-OH corticosterone 18-Oxydase Aldosterone

DOC, THDOC

THB, THA

18-OH-THA

THAldo

THAldo THAldo THE + THF + 5a-THF

THAldo

18-OH-F

18-oxo-F

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: tetrahydrocortisol; 18-OH-F: 18-hydroxy-cortisol; 18-oxo-F: 18-oxo-cortisol.

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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 lacking this 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 populations and/or sampling differences. The significance of the intron 2 conversion is unclear. It has been suggested that intron 2 might contain regulatory elements of the CYP11B genes. The frequency of the T allele 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-oxocortisol (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 diastolic function [Stowasser et al. 2005]. In GRA, aldosterone secretion is mainly regulated by ACTH rather than angiotensin II, so that administration of ACTH exacerbates the symptoms but glucocorticoids 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 synthase activity. As a consequence, aldosterone, 18-hydroxy-cortisol (18-OHF), and 18-oxocortisol (18-oxoF) are produced. Clinical diagnosis is based on the detection of increased tetrahydroaldosterone (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 dexamethasone treatment switches the mechanism of negative feedback regulation on, so that high aldosterone levels are suppressed and 18-OHF

5 CYP11B1 Promotor Coding region

5 CYP11B2 Promotor

Unequal cross-over 3 Coding region

5 GRA

3 Common recombination

5 ACTH responsive promoter Aldosterone production

3 Australian population

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 of GRA patients, Miyahara et al. [1992] found a second recombination between CYP11B1 and CYP11B2. In this case, the fusion protein is composed of exons 14 of CYP11B1 with the carboxy-terminal part (exon 59) of CYP11B2 (Figure 5, second recombination). As recombinations 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 production is solely under the control of ACTH in GRA, one might anticipate hyperaldosteronism exacerbation 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 developing pre-eclampsia. However, GRA women with chronic hypertension were at risk of exacerbated hypertension during pregnancy. Blood pressure followed the same pattern in GRA and normal 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 measured 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 genomic DNA of these patients, so that overexpression 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 in blood 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 expression was increased in RNA isolated from adrenal tumor resection of patients with APA. If an adrenal tumor is diagnosed during pregnancy, surgical intervention in the second trimester has the best outcome. Kreze et al. [1999] described the fatal outcome of a 28-year-old woman who refused to undergo surgery. She developed a gestosis 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 normalized. Solomon et al. [1996] described another case that underwent adrenalectomy in week 15 of gestation. Following the intervention, antihypertensive treatment and potassium supplementation could be withdrawn and a healthy child was born after 36 weeks of gestation. These two examples 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-suppressible. 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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Cortisol 11b-OHSD2 Cortisone

Progesterone 20a-OHSD 20a-OH-Progesterone

MR

11-DOC CYP11B2

Glomerular filtration rate Na+ retention

Aldosterone

Cardiac output

Plasma volume

RAS

Blood pressure

Vasodilatation

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

Apparent aldosterone excess Under normal conditions, aldosterone binds with high affinity to the mineralocorticoid receptor (MR) to stimulate renal sodium reabsorption and potassium excretion (Figure 6). Upon entering the cell, aldosterone binds to MR to form the aldosteroneMR complex that moves into the nucleus. There it binds to specific DNAhormone response elements sequences, thereby altering the transcription of messenger RNA and protein synthesis, ultimately leading to sodium retention. In a screening of 75 hypertensive 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 exacerbation of hypertension during pregnancy. Later, it was shown that MRL810 could be activated by cortisone [Rafestin-Oblin et al. 2003] and progesterone, explaining why the hypertensive phenotype 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 carbenoxolone 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 placental 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 differentiation of cytotrophoblasts to syncytiotrophoblast [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].

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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 concentration 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 implies that 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 substitution to maintain blood pressure and serum potassium in normal range [Wieacker et al. 1989]. Moreover, in women with primary aldosteronism, serum potassium and blood pressure often normalize during pregnancy, with recurrence of hypokalemia and hypertension after delivery, when progesterone concentrations go back to normal [Murakami et al. 2000]. The ultimate 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 continuous aldosterone infusion followed by a progesterone 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 circulating 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 balance within the body. Therefore, regulation of these two enzymes plays a central role for plasma volume regulation during pregnancy, when the maternal body is challenged with increasing progesterone concentrations.

Conclusion The 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 biology techniques have largely contributed to the understanding of the different subclasses of hyperaldosteronism and their underlying mechanisms. The development of new classes of antimineralocorticoid agents and laparoscopic interventions improved the wellbeing of pregnant women and the survival rate of the fetus. Body fluids are regulated 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 20OHSD enzyme activity, respectively, are responsible for sodium retention and K excretion in the absence of increased aldosterone plasma concentrations. 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 hyperaldosteronism in pregnancy is a demonstration of a successful collaborative effort of fundamental laboratory research and clinical application.

Acknowledgments This work was supported by a grant Nr 310000109774 from the Swiss National Science Foundation to GE. Conflict of interest statement None declared. References
Albiston, A.L., Smith, R.E., Obeyesekere, V.R. and Krozowski, Z.S. (1995) Cloning of the 11-HSD

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