Adrenomedullin and nitric oxide in menstrual and in vitro fertilization cycles. Relationship to estradiol

BACKGROUND Estradiol has marked systemic vasodilator effects which may be partially mediated by nitric oxide. Recently, a new vasodilator peptide, adrenomedullin, having potent vasodilatory action which is mediated at least in part by nitric oxide, has been isolated. This study investigated whether a relationship exists between circulating levels of estradiol, adrenomedullin, and nitrite/nitrate (the two stable oxidation products of NO metabolism) both in the spontaneous menstrual cycle and IVF cycles. METHODS Ten normal ovulatory infertile patients were included in this prospective longitudinal study. Circulating levels of estradiol, adrenomedullin, and nitrite/nitrate were investigated. Follicular fluid concentrations of adrenomedullin and nitrite/nitrate, as well as estradiol, were also determined in IVF cycles. RESULTS Serum nitrite/nitrate levels were significantly elevated in the late follicular phase compared to cycle day 3 of the spontaneous menstrual cycle thus paralleling plasma estradiol. However, no significant change in serum nitrite/nitrate concentration was found associated to multifollicular development and supraphysiological levels of estradiol in IVF cycles. Adrenomedullin plasma levels did not show significant variation either in menstrual or IVF cycles. No correlation was found between plasma estradiol levels and nitrite/nitrate serum concentrations or adrenomedullin plasma levels nor between circulating adrenomedullin and nitrite/nitrate both in menstrual and IVF cycles. Follicular fluid concentrations of estradiol and adrenomedullin but not nitrite/nitrate were significantly higher than those found in plasma or serum. Neither estradiol follicular fluid concentration correlated with those of adrenomedullin or nitrite/nitrate nor a relationship was observed between adrenomedullin and nitrite/nitrate. CONCLUSIONS Circulating levels of nitrite/nitrate show a significant increase during the late follicular phase in the normal menstrual cycle which is unrelated to adrenomedullin. In addition, this does not necessarily indicate a cause and effect relationship between nitrite/nitrate and estradiol levels given that no increase in nitrite/nitrate was observed from a hypoestrogenic to a hyperestrogenic state during IVF cycles. Further studies are necessary to clarify this subject. Also, the biological and clinical significance of the presence of adrenomedullin in the human follicular fluid remains to be elucidated.

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