Elevation of Inducible Nitric Oxide Synthase Activity in Human Endometrium during Menstruation

Nitric oxide (NO) is a known agonist of programmed cell death (apoptosis). In order to discover its potential role during menstrual shedding, a process associated with extensive apoptosis, we evaluated activity and mRNA levels of the inducible and constitutive isoforms of NO synthase (NOS) in endometrial specimens of the proliferative (n = 11), late-secretory (n = 7), and menstrual (n = 17) phase of the cycle. These levels were compared with the proportion of apoptotic cells by detection of histochemically labeled DNA fragments. Inducible NOS (iNOS) activity during menstruation was six times that of the proliferative or late-secretory phase ( p < 0.05), whereas constitutive NOS activity remained unchanged. Competitive reverse transcription-polymerase chain reaction revealed 146% and 77% increases of iNOS mRNA expression in the late-secretory and menstrual phases, respectively, compared to the proliferative phase ( p < 0.05), whereas constitutive NOS mRNA expression remained constant. Inducible NOS immunostaining was restricted to epithelial cells, whereas constitutive NOS immunostainig was confined to vascular endothelia. In addition, the proportion of apoptotic cells within the glands of late-secretory or menstrual endometrium was twice that of the proliferative phase ( p < 0.05). We conclude that local production of NO is involved in the signal transduction mechanisms leading to endometrial breakdown during menstruation.