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

Discussion

This study reports for the first time statistically significant differences in the results of aldosterone suppression tests conducted during the follicular and luteal phases of the menstrual cycle, raising the possibility that the time of the cycle during which the suppression test is undertaken may affect the accuracy of the conclusion drawn with respect to the presence or absence of PA.

Both aldosterone and renin have already been reported to be higher in the luteal than the follicular phase of the menstrual cycle of normal premenopausal women.[6,18,19] In the current study of hypertensive premenopausal women suspected of having PA, there were again higher levels of aldosterone in women who completed the FST during the luteal phase compared with those who completed the test during the follicular phase. There were, however, no significant differences in renin levels measured by both DRC and PRA. This is probably because renin levels were low in this cohort (who had been selected for FST on the basis of a high ARR) at baseline, and if anything would have been suppressed even further by FST, thereby eliminating any detectable difference that may have otherwise existed between the two groups. One possible explanation for the higher aldosterone levels (despite no difference in renin) is a direct stimulatory effect of progesterone (levels of which were markedly higher in the luteal group as expected) on aldosterone production by the zona glomerulosa (ZG), occurring independently of the renin angiotensin system, as has been proposed by Szmuilowicz and co-workers.[9] Results of in vitro studies examining this issue have been conflicting, however, with Nicolini et al.[8] observing a stimulatory effect, while Vecchiola et al.[20] reported an inhibitory effect of progesterone on adrenal aldosterone production.

Because FST requires 5 days for completion and aldosterone levels fluctuate during the menstrual cycle, this study raises the following questions:[1]could false-positive FSTs occur during the luteal phase?[2]could false-negative FSTs occur during the follicular phase? This is perhaps less likely as aldosterone levels in these premenopausal women were similar during the follicular phase to those in age-matched men; and[3] if ovulation occurs during FST (that is, FST is conducted during the transition from the follicular to the luteal phase), could the progesterone peak after ovulation affect the accuracy of FST results? Further studies seeking to answer these important questions are warranted and are proposed using saline suppression testing instead of FST and with each woman being tested during each phase of her cycle.

Obvious limitations of the present study include a relatively small number of participants and measurement of aldosterone, progesterone and renin in two independent groups of females. Consequently, we cannot conclude with any certainty that some of the FST results during the luteal phase represented false positives. However, the fact that aldosterone levels at the end of FST were higher during the luteal but not the follicular phase than those in males is certainly suggestive. As well, two of the 7 with unilateral aldosterone production completed FST during the luteal phase and 5 completed FST during the follicular phase. Of the 7 who were found to have bilateral aldosterone production, 4 completed FST during the luteal phase and 3 completed it during the follicular phase. A better approach would have been to perform FST twice (once during the follicular and once during the luteal phase) in the same group of subjects, but this was not practical due to the complex and relatively prolonged duration of the FST protocol and the need for inpatient admission. We recently reported in a pilot study that seated saline suppression testing (SSST), which is much simpler, quicker and less costly, may be a reliable alternative to FST.[21] If this proves to be the case with expansion of patient numbers, our intention is to perform SSST during different phases of the menstrual cycle in premenopausal subjects suspected of having PA in an attempt to confirm and expand our current findings. As SSST is completed within just a few hours (rather than days), this approach will also avoid the potential problem of conducting suppression testing during the transition from one phase of the menstrual cycle to the other.

In conclusion, the results of this study suggest that hormonal changes during the menstrual cycle may have the capacity to affect FST results and their interpretation. It would be premature to make a recommendation as to the optimal time in the cycle in which to perform aldosterone suppression tests based on such preliminary data. However, we will be examining with interest whether aldosterone suppression tests performed during the menses or early follicular phase, when oestradiol and progesterone are at their lowest concentrations, might have any advantages. This study should at least draw attention to the need for further studies on this question and the 'caution' it raises may lead to routine recording henceforth of the stage or stages of the cycle during which any aldosterone suppression tests are performed.

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