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Renal Inactivation, Mineralocorticoid Generation, and 11ß-Hydroxysteroid Dehydrogenase Inhibition Ameliorate the Antimineralocorticoid Effect of Progesterone in Vivo

Department of Endocrinology, Klinikum Benjamin Franklin, Freie Universität, 12200 Berlin, Germany

Address all correspondence and requests for reprints to: Dr. Marcus Quinkler, Division of Medical Sciences, Queen Elizabeth Hospital, University of Birmingham, Edgbaston, Birmingham, United Kingdom B15 2TH. E-mail: m.o.quinkler{at}bham.ac.uk.

	Abstract

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Progesterone (P) is a strong mineralocorticoid receptor (MR) antagonist in vitro. The high P concentrations seen in normal pregnancy only moderately increase renin and aldosterone concentrations. In previous in vitro studies we hypothesized that this may be explained by intrarenal conversion of P to less potent metabolites. To investigate the in vivo anti-MR potency of P, we performed an infusion study in patients with adrenal insufficiency (n = 8). They omitted 9-fluorocortisol for 4 d and hydrocortisone for 0.5 d before a continuous iv infusion of aldosterone for 8.5 h, with an additional iv P infusion commenced at 4 h. During aldosterone infusions the initially elevated urinary sodium to potassium ratio decreased significantly. Despite the 1000-fold excess of P over aldosterone, the urinary sodium to potassium ratio and urinary sodium excretion increased only slightly after 3 h of P infusion. We detected inhibition of renal 11ß-hydroxysteroid dehydrogenase type 2 by P, thus giving cortisol/prednisolone access to the MR. Urinary and plasma concentrations of 17-hydroxyprogesterone, a major metabolite of renal P metabolism, and those of serum androstenedione and deoxycorticosterone, a mineralocorticoid itself, increased significantly during P infusion. This supports the hypothesis of an effective protection of the MR from P by efficient extraadrenal downstream conversion of P.

	Introduction

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PROGESTERONE (P) BINDS in vitro with higher affinity to the human mineralocorticoid receptor (MR) than aldosterone, but confers only low agonistic MR activity. Therefore, P is a MR antagonist in vitro (1, 2, 3). During pregnancy, P concentrations reach high levels [400–700 nmol/liter (125–220 ng/ml)] and by far exceed those of aldosterone [1–6 nmol/liter (0.36–2.16 ng/ml)]. The reason why aldosterone can still act as a potent mineralocorticoid in these situations is not fully understood. The 10-fold higher plasma protein binding of P compared with aldosterone (4) and the higher stability of the aldosterone-MR complex (5) may be contributing factors. However, we have previously shown that renal P metabolism could be an effective protective mechanism for the MR, similar to the protection by 11ß-HSD type 2 (6, 7). This protective mechanism implies that during high P concentrations little anti-MR effect should be seen. This is in accordance with the progressive plasma volume expansion in normal pregnant women that is required for optimal pregnancy outcome. The anti-MR effect of P in vivo is demonstrated by activation of the renin-aldosterone system in normal pregnancy. Two additional observations indicate the anti-MR potency of progesterone. Firstly, pregnant women with Addison’s disease have an increasing requirement for 9-fluorocortisol substitution as pregnancy advances to maintain blood pressure and serum potassium in the normal range (8). Secondly, in patients with primary hyperaldosteronism, serum potassium and blood pressure often normalize during pregnancy, with recurrence of hypokalemia and hypertension after delivery (8, 9).

Until now the exact in vivo anti-MR potency of P was not known. Therefore, we sought to investigate its anti-MR potency in vivo, studying patients without functioning adrenal glands and thus devoid of endogenous aldosterone production. By choosing only males and postmenopausal females we ruled out the ovaries as a major source of endogenous P production. We challenged the patients with a continuous aldosterone infusion and then sought to antagonize the MR effect by P infusion.

	Subjects and Methods

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Subjects

Eight patients, aged 38–62 yr, without functioning adrenals (three postmenopausal women and five men) were recruited for the study (Table 1). Their renal function parameters and serum albumin levels were normal. They received detailed information on all aspects of the protocol and gave written informed consent before inclusion. The study protocol was reviewed and approved by the ethics committee of the Universitätsklinikum Benjamin Franklin (Berlin, Germany).

The patients stopped taking 9-fluorocortisol 4 d before the study and hydrocortisone 0.5 d before the study. To prevent hypocortisolemic crisis the patients received 1 mg prednisolone at 0800 h on the study day, followed by 0.5 mg prednisolone every 2 h as requested by the ethics committee. We chose prednisolone as the glucocorticoid substitute because it possesses a weaker mineralocorticoid activity than cortisol. Dehydroepiandrosterone (DHEA) and estrogen/progestin replacement was stopped at least 1 wk before the study, whereas all other medication was continued. During the study patients were encouraged to drink 250 ml water/h to produce sufficient amounts of urine. The patients received an indwelling cannula into the antecubital vein of each arm. One cannula was used for aldosterone and P infusions, the other for blood sampling. The patients received a continuous infusion (Infusomat, Braun Ag, Melsungen, Germany) with aldosterone iv over 8.5 h (12.5 µg/h) starting at 0800 h. After 4 h a continuous P infusion was started (0.15 mg/kg·h for 90 min, followed by 0.65 mg/kg·h for 180 min). Blood sampling and assessment of urinary volume were performed every 30 min for 8.5 h. Heart rate and blood pressure were recorded every 2 h.

Preparation of infusion solutions

For aldosterone infusions, 150 µg lyophilized aldosterone (Clinalfa AG, Läufelfingen, Switzerland) were diluted in 500 ml 5% glucose Ringer’s solution (containing 147.2 mmol/liter sodium, 4.02 mmol/liter potassium, 2.24 mmol/liter calcium, and 155.7 mmol/liter chloride). The P (Merck KgaA, Darmstadt, Germany) infusions were prepared as described previously (10, 11) with minor modifications. P (4.4 g) was dissolved in 220 ml ethanol solution (90%) and filtered under sterile conditions. Five milliliters of the P ethanol solution were injected slowly under constant shacking into the infusion solution containing 107.5 ml 5% glucose solution (Glucosteril Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany), 107.5 ml physiological electrolyte solution (Sterofundin 1/1E, Braun Melsungen AG, Melsungen, Germany), and 35 ml human 20% albumin solution (DRK Blutspendedienst Niedersachsen GmbH, Springe, Germany).

Analytical measurements

Serum hormone measurements were performed by RIA using commercially available assays: aldosterone (Diagnostic Products, Los Angeles, CA), P, 17-hydroxyprogesterone (17-hydroxy-P), estrone, testosterone, DHEA, and androstenedione (4-dione; all from DSL, Sinsheim, Germany). Cross-reactivity was less than 6% for all relevant steroids. Urinary excretion of 17-hydroxy-P in urine was also measured by RIA after extraction as described previously (12). Plasma renin concentrations were measured using a Renin-IRMA kit (Nichols Institute Diagnostics, San Juan Capistrano, CA) (13). Plasma deoxycorticosterone (DOC) concentrations were determined at the Pharmacological Institute (Ruprechts Karl Universität, Heidelberg, Germany) using an extraction method with slit column chromatography, followed by RIA. Urinary measurements of prednisolone and prednisone were performed by HPLC analysis at Krankenhaus Spandau (Berlin, Germany). Serum measurements of sodium, potassium, albumin, creatinine, and urinary creatinine were measured using a Hitachi 917 analyzing machine (Hitachi Medical Systems GmbH, Wiesbaden, Germany) in the central laboratory of University Hospital UKBF. Urinary measurements of sodium and potassium were performed with an IL 943 analyzing machine (Instrumentation Laboratory GmbH, Kirchheim bei München, Germany). Urinary chloride was measured with a dilution kit using a CRT-10 analyzing machine (Nova Biomedical Corp., Waltham, MA). All samples from an individual were analyzed in a single assay.

Statistics

Results are expressed as the mean ± SEM. Statistical significance was taken as P < 0.05. Statistical analysis was performed with the Wilcoxon test. Due to the small number of patients (n = 8), the highest level of statistical significance that could be reached with this test was P = 0.012.

	Results

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We investigated the effect of aldosterone and P infusion on urinary electrolyte excretion as an expression of MR activation or inhibition. At the beginning of the study the patients presented with plasma aldosterone concentrations below 0.06 nmol/liter (0.0216 ng/ml; Fig. 1A) and were in a slightly hypomineralocorticoid status, indicated by the increased urinary sodium to potassium ratio (Fig. 2A). Under continuous aldosterone infusion the patients obtained normal, nonpregnant, plasma aldosterone concentrations [0.2–1 nmol/liter (0.072–0.360 ng/ml)] over the entire period of the study (Fig. 1A). Due to the aldosterone infusions, the urinary sodium to potassium ratio decreased significantly (P < 0.05; Fig. 2A), mainly because of significantly (P < 0.05) decreased sodium excretion (data not shown). Urinary chloride excretion (Fig. 2B) and plasma renin concentration did not change significantly during this period. Urinary volume increased significantly (P < 0.05) to approximately 140 ml/30 min during this period (Fig. 2C).

View larger version (17K): [in this window] [in a new window]   FIG. 1. Plasma aldosterone (A), P (B), and 17-hydroxy-P (C) concentrations (mean ± SEM) during the administration of continuous aldosterone infusion over 8.5 h in eight patients without functioning adrenal glands. After 4 h a continuous progesterone infusion was started with two concentration steps. *, P < 0.05 compared with the starting point of aldosterone infusion (0 h). , P < 0.05 compared with the starting point of progesterone infusion (4 h). (To convert P, aldosterone, and 17-hydroxy-P concentrations to nanograms per milliliter, divide nanomoles per liter by 3.18, 2.77, and 3.03, respectively.)

View larger version (23K): [in this window] [in a new window]   FIG. 2. Urinary sodium (Na+) to potassium (K+) ratio (A), urinary chloride (Cl-) excretion (B), urinary volume (C), and urinary 17-hydroxy-P excretion (D; mean ± SEM) during the administration of continuous aldosterone infusion over 8.5 h in eight patients without functioning adrenal glands. After 4 h a continuous progesterone infusion was started with two concentration steps. *, P < 0.05 compared with 0.5 h. , P < 0.05 compared with 4.5 h.

The urinary sodium to potassium ratio (Fig. 2A) and sodium excretion increased significantly (P < 0.05) during P infusion, but the urinary sodium to potassium ratio did not reach similar hypomineralocorticoid levels as at the beginning of the study. Urinary chloride excretion (Fig. 2B), urinary volume (Fig. 2C), and urinary excretion of 17-hydroxy-P (Fig. 2D) increased significantly (all P < 0.05) during P infusion. Urinary chloride excretion at 8.5 h did not reach a significant difference, because there were only five samples. No changes in systolic or diastolic blood pressure, serum sodium, serum potassium, or plasma renin concentrations were observed (data not shown).

At baseline, serum 4-dione concentrations were higher in males than in postmenopausal females (Fig. 3A) due to testicular androgen synthesis. However, serum 4-dione levels in both male and female patients increased significantly (P < 0.05; Fig. 3A).

View larger version (17K): [in this window] [in a new window]   FIG. 3. Serum 4-dione (A) and DOC (B) concentrations (mean ± SEM) during the administration of continuous aldosterone infusion over 8.5 h in eight patients without functioning adrenal glands. After 4 h a continuous progesterone infusion was started with two concentration steps. , P < 0.05 compared with starting point of progesterone infusion (4 h). , Male subjects; , female subjects. (To convert 4-dione and DOC concentrations to nanograms per milliliter, divide nanomoles per liter by 3.49 and 3.03, respectively.)

To prevent hypocortisolemic crisis the subjects received prednisolone substitution on the test day. To evaluate 11ß-HSD type 2 activity in the human kidney, we analyzed the urinary prednisolone to prednisone ratio. We were able to investigate only six of eight urinary samples due to interference with the HPLC measurements. The urinary prednisolone to prednisone ratio increased significantly during P infusion (Fig. 4), indicating inhibition of 11ß-HSD type 2 in the kidney by P infusions.

View larger version (22K): [in this window] [in a new window]   FIG. 4. Urinary prednisolone to prednisone ratio (mean ± SEM) during the administration of continuous aldosterone infusion over 8.5 h in six patients without functioning adrenal glands. After 4 h a continuous progesterone infusion was started with two concentration steps. , P < 0.05 compared with starting point of progesterone infusion (4 h).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

A natriuretic effect of P in humans was described over 40 yr ago (16, 17, 18, 19, 20, 21). In most of these studies experimental subjects received large amounts of P im over several days, and urinary sodium and aldosterone excretion was measured, but plasma concentrations of P were not determined. Therefore, the exact in vivo anti-MR potency of P is still not known.

The observed increase in urinary chloride excretion during P infusion in our patients is in accordance with earlier reports (18) and could be caused by an additional inhibition of proximal sodium and chloride reabsorption in the thick ascending limb of the loop of Henle (22).

Urinary volume increased during aldosterone infusions and even more so under P infusions. This may be due to the rather high amount of liquid the patients consumed to guarantee sufficient urine flow. The further increase in urine flow during P infusion may have partly been caused by the diuretic potency of P. A similar phenomenon was described after i.m. P application in earlier reports (17). It is possible that this is caused by an additional inhibition of proximal sodium retention by P (22) or an increased renal blood flow caused by smooth muscle relaxation by P, resulting in a washout effect of the medulla (20). In accordance with this, decreased peripheral vascular resistance and increased renal plasma flow and glomerular filtration rate are observed during luteal phase and pregnancy (23).

The increase in plasma and urinary 17-hydroxy-P in patients without functioning adrenals during P infusion indicates an extraadrenal conversion of P to 17-hydroxy-P, possibly in the gonads or even in the kidney. The increased urinary 17-hydroxy-P excretion may be based on glomerular filtration as well as on renal production, thus proposing a possible intrarenal conversion of P to 17-hydroxy-P. 17-Hydroxy-P is a major renal P metabolite in vitro and has weaker affinity and antagonistic properties than P to the MR (3, 6). In human kidney tissue, 17-hydroxy-P is further inactivated to 17-hydroxy-20-dihydroprogesterone, which has very little intrinsic activity for the human MR (3, 6, 7).

In humans the main pathway for androgen synthesis is from pregnenolone via 17-hydroxypregnenolone to DHEA (24). The pathway from P via 17-hydroxy-P to 4-dione is energetically not preferred (25). Nevertheless, we found a significant increase in plasma 4-dione concentrations during P infusion with no change in plasma DHEA concentrations. 4-Dione may originate from the gonads, where 3ß-HSD expression by far exceeds that of P450c17, resulting in the release of predominantly 4-dione rather than DHEA. Concordantly, adrenal suppression with dexamethasone leads to almost complete suppression of serum DHEA/DHEA sulfate, whereas 4-dione is only reduced to 30% (26).

We showed that plasma DOC concentrations rose significantly during P infusion and reached higher levels than during the luteal phase and pregnancy in normal women. This indicates an extraadrenal conversion of P by 21-hydroxylase to the MR agonist DOC and supports previous reports that local formation of DOC in renal tissue might be an important para- or autocrine mechanism to protect the MR (27, 28, 29, 30).

P is a very potent inhibitor of 11ß-HSD type 2 (6). Therefore, it is interesting to investigate the in vivo inhibition of renal 11ß-HSD type 2 under high P concentrations. The urinary prednisolone to prednisone ratio increased significantly during P infusions. This indicates an inhibition of renal 11ß-HSD type 2. Due to this inhibition, less cortisol is inactivated to cortisone, and therefore more endogenous cortisol can bind as agonist to the MR (6). This may be an additional mechanism for sufficient MR activation in states of high P concentrations. It is possible that the prednisolone used in the study to prevent hypocortisolemic crisis may have had some mineralocorticoid effect. We consider this unlikely, however, because of the low dose of prednisolone used and the strong inactivation to prednisone by 11ß-HSD type 2. Although inhibition of 11ß-HSD type 2 may have a role in the attenuated antimineralocorticoid effect of P in vivo, it seems more likely that the 10-fold increase in DOC concentrations is the major cause of this effect.

In conclusion, the increase in the urinary sodium to potassium ratio and urinary sodium excretion during P infusion indicated an anti-MR effect of P. However, this effect was much weaker than would be expected from the rise in circulating P concentration. This may be partly explained by an effective enzyme-mediated protection of the MR and the extraadrenal DOC synthesis, as indicated by increased serum DOC concentrations during P infusion. An additional protective mechanism could be an inhibition of 11ß-HSD type 2 by P, thus giving the MR agonist cortisol access to the MR. The increases in serum and urinary 17-hydroxy-P and serum 4-dione in these patients without functioning adrenal glands indicate extraadrenal conversion of P.

	Acknowledgments

 
We thank Petra Exner (Department of Endocrinology, Universitätsklinikum Benjamin Franklin, Berlin, Germany); Mrs. Latter and Prof. Lübbert (Department of Gynecology, Universitätsklinikum Benjamin Franklin); Dr. Perschel, Marina Rochel, and R. Göber (Clinical Laboratory, Universitätsklinikum Benjamin Franklin); and Susan Richter and A. Pfeiffer (German Institute for Nutrition, Potsdam-Rehbrücke, Germany) for hormonal and electrolyte measurements. We are indebted to Prof. Schöneshöfer and Mrs. Zolchow (Department of Laboratory Medicine, Krankenhaus Spandau, Berlin, Germany) for urinary measurements of prednisolone and prednisone. We thank Dr. C. Maser-Gluth (Pharmacological Institute, Ruprechts Karl Universität, Heidelberg, Germany) for determination of plasma deoxycorticosterone concentrations. We thank M. S. Cooper (Birmingham, UK), W. Arlt (Birmingham, UK), and J. Lepenies (Berlin, Germany) for help with the manuscript.

	Footnotes

 
This work was supported by Grant DI 741/1-3 (to S.D.) and Postdoctoral Research Fellowship Grant QU 142/1-1 (to M.Q.) from the Deutsche Forschungsgemeinschaft.

Abbreviations: DHEA, Dehydroepiandrosterone; 4-dione, androstenedione; DOC, deoxycorticosterone; MR, mineralocorticoid receptor; 17-hydroxy-P, 17-hydroxyprogesterone; P, progesterone.

Received January 17, 2003.

Accepted April 10, 2003.

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