Sex steroid hormones exert biphasic effects on cytosolic magnesium ions in cerebral vascular smooth muscle cells: possible relationships to migraine frequency in premenstrual syndromes and stroke incidence

Abstract

Clinically, it is known that: (1) magnesium (Mg) supplementation relieves premenstrual problems (e.g., migraine, bloating and edema) occurring in the late luteal phase of the menstrual cycle; and (2) migraine syndromes, particularly in women, are associated with deficits in brain and serum ionized Mg levels. We investigated whether concentrations of sex steroid hormones, found in the serum during the menstrual cycle of women, are associated with changes in the levels of cytosolic free magnesium ions ([Mg 2+] i) in single cultured canine cerebral vascular smooth muscle cells. The resting level of [Mg 2+] i in these cells was 645 ± 89 μM before exposure to sex steroid hormones. Exposure of these vascular cells to a low concentration of estrogen (10 pg/ml) failed to interfere with the levels of [Mg 2+] i. However, exposure to estrogen, at concentrations ranging from 40 to 200 pg/ml, induced significant loss of [Mg 2+] i in a concentration-dependent manner. At a concentration of 200 pg/ml estrogen, the level of [Mg 2+] i decreased ∼30% in comparison with controls. Progesterone produced biphasic effects on the levels of [Mg 2+] i, depending on its concentration. Exposure of the cultured cells to a low concentration of progesterone (0.5 ng/ml) resulted in an increased level of [Mg 2+] i (from 690 ± 50 μM to 753 ± 56 μM, p < 0.05). However, when these cells were exposed to higher concentrations of progesterone (i.e., from 5.0 to 20 ng/ml), the cellular levels of [Mg 2+] i were decreased significantly. The higher the estrogen or progesterone concentration, the lower the levels of [Mg 2+] i. In contrast, testosterone, a male hormone, didn’t produce any significant alteration in [Mg 2+] i levels in these cerebral vascular smooth muscle cells. These data indicate that low, physiological concentrations of female sex hormones, estrogen and progesterone, help cerebral vascular smooth cells sustain normal concentrations of [Mg 2+] i, which are beneficial to vascular function, whereas high levels of estrogen and progesterone deplete, significantly, [Mg 2+] i in cerebral vascular smooth muscle cells, possibly resulting in cerebrovasospasms and reduced cerebral blood flows related to premenstrual syndromes, migraine and stroke risk. Our findings could provide new insight into the mechanism whereby migraine occurs frequently in the late luteal phase in the premenstrual syndrome. In addition, our results demonstrate that female sex steroids but not testosterone (in physiologic concentrations) can exert direct effects on [Mg 2+] i in cerebral vascular cells.