Adaptation to potassium depletion in human : role of progesterone ?

In this study, we examined whether reduction in the intake of K + induce lasting changes in the plasma concentration of circulating steroids. We have previously shown that plasma progesterone (PG) levels specifically increases in response to chronic and sustained K + depletion in male and female mice. In this physiological context, progesterone regulates renal K + handling by stimulating the expression of H,K‐ATPase type 2 (HKA2) through a RU486 (PG receptor antagonist)‐sensitive pathway. The human adrenal steroidogenesis strongly differs from rodents because of the presence of a CYP17 activity that metabolizes PG into 17‐OH PG and may prevent its accumulation and release in the plasma. To address the role of PG in renal adaptation to K depletion in human, we designed a cross‐over protocol in which healthy subjects were submitted to a 7‐days K + depleted diet in the absence (placebo period) or presence of a PG antagonist (RU486 period). We studied their renal adaptation to K + depletion and the induced changes in plasma adrenal steroids concentrations before and 1h after stimulation by ACTH (SYNACTHENE®). Since this adaptation could be relevant in the case of severe and chronic renal hypokalemia, plasma adrenal steroids were measured in patients with chronic severe renal hypokalemia related to a congenital salt losing tubulopathy, the Gitelman syndrome. During the two periods, a week of reduction of dietary K + intake induced both daily urinary excretion of K + and fractional excretion of K + decreased by a factor 2, without affecting daily urinary excretion or fractional excretion of Na + . Under placebo condition, plasma K + concentration decreased by 0.3 ± 0.1 mmol/l (p= 0.0180) and subjects became slightly hypokalemic, without change in plasma concentrations of sodium, chloride, bicarbonate or creatinine. As expected, plasma aldosterone decreased by 55% and more surprisingly, DHEA decreased by 20% but the other steroids concentration (Cortisol, PG, 17‐OH PG, deoxycorticosterone, delat4‐androstenedione) are not modified neither under basal or after SYNACTHENE® treatment. Under RU486 treatment, the decrease of the plasma K + level is much faster than under placebo and the plasma aldosterone concentration is decreased even more than under the placebo period indicating that RU486 interferes with the regulation of the K + balance. The basal level of steroids is similar in Gitelman patients compared to healthy volunteers. However, the stimulation of adrenal steroidogenesis by SYNACTHENE® induces a stronger rise of PG, 17‐OH PG and delta4‐androstenedione indicating that in Gitelman patients the 3bHSD activity is stimulated but not activated. Altogether, these results indicate that, in men, a moderate reduction of the K + intake does not result in a visible rise of plasma PG but the effect of RU486 and the putative stimulation of the adrenal 3bHSD‐dependent steps in Gitelman patients may indicate that this hormonal system may be relevant in the regulation of K + balance. Support or Funding Information The DRIVING trial was supported by research grants from the French Ministry of Health (CRC 2012 grant # CRC12122)