Adrenal adaptation in potassium-depleted men: role of progesterone?

Abstract

Background In rodents, the stimulation of adrenal progesterone is necessary for renal adaptation under potassium depletion. Here, we sought to determine the role of progesterone in adrenal adaptation in potassium-depleted healthy human volunteers and compared our findings with data collected in patients with Gitelman syndrome (GS), a salt-losing tubulopathy. Methods Twelve healthy young men were given a potassium-depleted diet for 7 days at a tertiary referral medical centre (NCT02297048). We measured by liquid chromatography coupled to tandem mass spectroscopy plasma steroid concentrations at Days 0 and 7 before and 30 min after treatment with tetracosactide. We compared these data with data collected in 10 GS patients submitted to tetracosactide test. Results The potassium-depleted diet decreased plasma potassium in healthy subjects by 0.3 ± 0.1 mmol/L, decreased plasma aldosterone concentration by 50% (P = 0.0332) and increased plasma 17-hydroxypregnenolone concentration by 45% (P = 0.0232) without affecting other steroids. CYP17 activity, as assessed by 17-hydroxypregnenolone/pregnenolone ratio, increased by 60% (P = 0.0389). As compared with healthy subjects, GS patients had 3-fold higher plasma concentrations of aldosterone, 11-deoxycortisol (+30%) and delta 4-androstenedione (+14%). Their post-tetracosactide progesterone concentration was 2-fold higher than that of healthy subjects and better correlated to plasma potassium than to plasma renin. Conclusion The increase in 17-hydroxypregnenolone concentration after mild potassium depletion in otherwise healthy human subjects suggests that 17 hydroxylation of pregnenolone prevents the increase in progesterone observed in potassium-depleted mice. The unexpected over-response of non-mineralocorticoid steroids to tetracosactide in GS subjects suggests that the adrenal system not only adapts to sodium depletion but may also respond to hypokalaemia.

Molecular Basis, Diagnostic Challenges and Therapeutic Approaches of Bartter and Gitelman Syndromes: A Primer for Clinicians

“…Another study has the intervetion of progesterone to alleviate the hypokalemia (NCT02297048). In line with this hypothesis, Blanchard et al [ 197 ] have reported that adrenal glands adapt their response to levels of hypokalemia and hyponatremia. This could be the first step towards a better understanding of the pathophysiology and, perhaps, towards a new therapeutic group.…”

GDF15 mediates renal cell plasticity in response to potassium depletion

“…In parallel, the consumption of salt (NaCl) and potassium (K + ) have been completely modified, switching from a rich-K + /low NaCl diet in the hunter-gatherer population to the opposite in the modern, westernized population (2). In a recent study, we showed that the median daily Na + and K + intakes in young Parisian males are 136 mmol and 57 mmol/day, respectively (3) which are far from the recommended values by the dietary reference intakes (maximal Na + intake 65 mmol/day and minimal K + intake 120 mmol/day). Fortunately, we have the ability to cope with these changes that occurred very recently in our eating habits thanks to our kidneys.…”

“…The samples used to measure urine GDF15 were described previously in (3). Briefly, The healthy volunteers were Caucasian males 18 to 35 years of age.…”

A mathematical model of potassium homeostasis: Effect of feedforward and feedback controls

“…One such mechanism is circadian rhythms which are known to impact secretion of hormones (such as ALD) as well as impact renal function [42][43][44][45]. To incorporate circadian rhythms, some model parameters, e.g., F GFR , would need to be made time dependent Progesterone has also shown to play a role in K + regulation in both males and females [46,47]. Future work may study the impact of other regulatory mechanisms, as these mechanisms become better characterized by new experimental data.…”