Should Aldosterone Suppression Tests Be Conducted During a Particular Phase of the Menstrual Cycle, and, If So, Which Phase?

Results of a Preliminary Study

Ashraf H. Ahmed; Richard D. Gordon; Gregory Ward; Martin Wolley; Cynthia Kogovsek; Michael Stowasser

Disclosures

Clin Endocrinol. 2015;83(3):303-307. 

In This Article

Abstract and Introduction

Abstract

Background As renin and aldosterone levels vary during the menstrual cycle, and are critical criteria for interpretation of aldosterone suppression tests to confirm or exclude primary aldosteronism, outcome of testing may vary depending on the menstrual cycle phase. We assessed the effect of timing within the menstrual cycle on levels of renin, aldosterone and female sex steroids during fludrocortisone suppression testing (FST).

Methods In 22 women undergoing FST who experienced regular menstrual cycles, renin (measured as both plasma renin activity and direct renin concentration), aldosterone (mass spectrometry) and cortisol, progesterone, oestradiol, LH and FSH (immunoassay) levels were compared, relative to phase of cycle. Aldosterone levels were compared to those in age-matched males undergoing FST.

Results Progesterone (P < 0·0001) and aldosterone (P = 0·006) levels were higher in nine women (after one of 10 was excluded with anovulatory cycle) studied during the luteal phase than in the 12 studied during the follicular phase. All studied during the luteal phase had positive FST, and all three with negative FST were studied during the follicular phase. There were no significant differences in other parameters measured except FSH, which was higher (P = 0·02) during the follicular phase. Aldosterone was higher (P = 0·01) in women studied in the luteal (but not follicular) phase compared to men.

Conclusion The menstrual cycle may affect the outcome of FST and other suppression testing used to diagnose primary aldosteronism. Larger patient numbers and preferably restudy of the same patient in both phases should clarify this and determine the optimum time in the cycle for testing.

Introduction

Primary aldosteronism (PA) is a specifically treatable and potentially curable form of secondary hypertension, characterized by excessive, autonomous production of the salt-retaining hormone, aldosterone.[1] The use of the plasma aldosterone/renin ratio (ARR) to screen for PA in both hypokalaemic and normokalaemic hypertensives has shown PA to be the commonest specifically treatable and potentially curable form of secondary hypertension.[2–4] In patients who screen positive for PA by ARR testing, demonstration of aldosterone production which is relatively autonomous of its normal chronic regulator, angiotensin II, confirms the diagnosis. Practically, this is usually performed by demonstration of aldosterone production that cannot be suppressed when plasma levels of its principal regulator, renin, have been suppressed.[5] Four tests are commonly used to establish the diagnosis of PA, namely oral sodium loading, saline infusion, fludrocortisone administration with oral sodium loading, and captopril challenge testing.[1]

We previously reported that female sex hormones, aldosterone and renin concentrations [measured as direct renin concentration (DRC) and plasma renin activity (PRA)] fluctuate significantly during the menstrual cycle, and plasma aldosterone and renin are higher in the luteal phase.[6] Fommei and co-workers[7] observed a rise in plasma aldosterone in the luteal phase of the menstrual cycle and noted implications for screening criteria for PA. They also found that both progesterone and LH can stimulate aldosterone production by both normal adrenal cortex and APA in vitro,[8] and Szmuilowicz and colleagues described a relationship between aldosterone and progesterone in the normal menstrual cycle in 2006.[9] In screening for PA, Pizzolo et al.[10] reported that elevated ARR (using DRC) levels were more prevalent in hypertensive women than men (13·6% vs 2·3%). Importantly, these elevated ARR levels in women were associated in only a minority of cases with an eventual confirmatory diagnosis of PA.

Progesterone, secreted during the second half of an ovulatory menstrual cycle, has mineralocorticoid-antagonist activity.[11] Increases in circulating progesterone concentrations tend to be associated with natriuresis, lowering plasma volume and blood pressure, and followed by compensatory rises in plasma renin and aldosterone.[11] Fluctuations in oestrogen and progesterone concentrations which accompany the menstrual cycle thus have the potential to confound interpretation of aldosterone suppression tests.

If suppression tests could be misinterpreted because of prevailing female sex steroid levels (for example raising aldosterone levels above an arbitrary cut-off point for 'complete' suppression), then unnecessary invasive adrenal venous sampling might take place. This would be unfortunate, and a better understanding of the effects of female hormones on levels of aldosterone and renin during suppression testing is urgently required. We are not aware of any study reporting the effect of the phase of the menstrual cycle on fludrocortisone suppression testing (FST) results, and the current study was therefore designed to examine this important aspect.

Because FST requires 5 days for completion, we also hypothesized that transition from phase to phase of the menstrual cycle during FST may affect the accuracy of the results.

Plasma renin was for many years measured almost exclusively as PRA which incorporates the ability of all participating components of plasma, including substrate, to generate angiotensin I. Today, it is sometimes measured as PRA, but more often as DRC.[12] In this study, we employed both methods, to permit comparisons to be made.

Aldosterone has until recently been almost exclusively measured by immunoassay methods despite concerns over their accuracy.[13] For example, substantially different aldosterone concentrations were found using four different immunoassay methods.[14] Recently developed high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) methods present an opportunity to measure plasma aldosterone accurately and specifically.[15,16] We therefore employed such a method, developed and validated in our centre by Taylor et al.[16] in the present study.

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