Endometrial breakdown in women using Norplant is associated with migratory cells expressing matrix metalloproteinase-9 (gelatinase B)

Abstract

Norplant, subdermally implanted slow-release levonorgestrel, is an effective and widely used contraceptive agent but has a high rate of discontinuation due to unacceptable abnormal uterine bleeding. Matrix metalloproteinases (MMPs) are expressed in normal cycling endometrium and are postulated to be responsible for the tissue breakdown at menstruation. We have compared the immunolocalization of MMP-9 and migratory cells in endometrium from Indonesian women using Norplant with normal controls. Positive MMP-9 immunostaining was observed intracellularly within stromal and intravascular leukocytes and extracellularly in areas of tissue lysis adjacent to these migratory cells. The MMP-9 positive cells were identified as neutrophils, eosinophils, CD3+ T-cells and macrophages. Quantitative assessment revealed that the number of MMP-9 positive cells, neutrophils and eosinophils were significantly increased in those endometrial biopsies from Norplant users displaying a shedding morphology and in normal controls at menstruation. There was no correlation between the number of MMP-9 positive cells and the number of bleeding days reported. Endometrial immunostaining for tissue inhibitor of metalloproteinases was similar in Norplant users and normal controls. These results suggest that MMP-9, an enzyme capable of degrading basement membrane components, may be involved in endometrial breakdown in women using Norplant.

A dynamic shift of VEGF isoforms with a transient and selective progesterone-induced expression of VEGF189regulates angiogenesis and vascular permeability in human uterus

“…In contrast, V 189 could be cleaved by uPA during steroid hormone removal resulting in menstruation. Also, the increase in CP induced by V 189 provides an explanation for the episodes of endometrial capillary rupture and irregular bleeding associated with progestin-based contraceptives and hormonal substitutive treatments (43).…”

Regulation of MMP‐9 expression and activity in the mouse uterus by estrogen

“…MMP-9 is expressed in the uterus during the reproductive cycle as well as during early pregnancy and oilinduced decidualization (Bany et al, 2000). Its expression is localized to epithelial, stromal, immune, and vascular cells (Rawdanowicz et al, 1994;Jeziorska et al, 1996;Freitas et al, 1999;Vincent and Salamonsen, 1999). MMP-9 protein has been detected in endometrial glandular epithelial cells with highest levels during the late proliferative phase and just after ovulation as well as in glandular secretions and uterine fluid during the peri-implantation phase.…”

Oxidative stress, vitamin E and progestin breakthrough bleeding

“…Oxidative stress causes an oxidation of lipids, proteins, and carbohydrates and is implicated in many important pathological events (Halliwell et al, 1992). Progestin-induced endometrial bleeding is characterized by endometrial stromal infiltration of leukocytes (Clark et al, 1996;Vincent et al, 1999) and these cells can release superoxide ions. In support of this finding, the production of epoxides in the endometrium of levonorgestrel (LNG) users with BTB were increased (White et al, 1991).…”