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  • Title: Endometrial endothelial cell proliferation in long-term users of subdermal levonorgestrel.
    Author: Goodger AM, Rogers PA, Affandi B.
    Journal: Hum Reprod; 1994 Sep; 9(9):1647-51. PubMed ID: 7530724.
    Abstract:
    The aim of the present study was to quantify endothelial cell proliferation (a component of angiogenesis) using immunohistochemistry, in the endometrium of users of subdermal levonorgestrel (Norplant). It was postulated that the increased endometrial microvascular density seen in Norplant users, compared to normally cycling women, was associated with an increased rate of endothelial cell proliferation. The results, however, showed that the endometrial endothelial cell proliferative index of Norplant users (0.39 +/- 0.16%; mean +/- SEM) was significantly reduced compared to that seen in normally cycling women (8.99 +/- 1.64). At the same time, total numbers of endometrial endothelial cells per mm2 in Norplant users (317.40 +/- 13.88) were significantly higher than in normally cycling women (223.35 +/- 10.31). It is possible that in the endometrium with levonorgestrel use, there is either a reduced rate of regression of the blood vessels relative to the rest of the tissue, or there is a reduced rate of endothelial cell death or turnover. Peripheral oestrogen and progesterone concentrations, bleeding pattern over the previous 90 days, and the histological appearance of the endometrium did not appear to be associated with the endothelial cell proliferative index. The results suggest that subdermal levonorgestrel use affects the mechanisms that dictate the normal relationship between endometrial blood vessel growth and regression, and the surrounding non-vascular tissue. Quantification of endothelial cell proliferation by use of immunohistochemical staining of routinely processed endometrium revealed minimal angiogenesis in Norplant implant acceptors. It was hypothesized that the increased microvascular density of the endometrium of Norplant users and their bleeding problems reflect a levonorgestrel-induced increase in endothelial cell proliferation. 34 endometrial biopsies from 32 women attending the Raden Saleh Clinic in Jakarta, Indonesia, were collected 3-12 months after Norplant insertion. The mean endothelial cell proliferation index for the 32 Norplant users was 0.39 +or- 0.16%; 24 of the 34 biopsies showed no evidence of cell proliferation. There was no significant variation in this index based on the histologic appearance of the biopsy, bleeding pattern, or peripheral blood estrogen and progesterone concentrations. This index is significantly lower than that recorded in another study (8.99 +or- 1.64) during a normal menstrual cycle. Also observed was a significantly increased number of endothelial cells per sq. mm in Norplant users (317.40 +or- 13.88) compared to normally cycling women (223.25 +or- 10.31). Although the study hypothesis was rejected, the factors behind the increased density of blood vessels and endothelial cells in the endometrium of Norplant users remain unclear. It is possible that levonorgestrel induces a reduced rate of regression of the blood vessels compared to the rest of the tissue, or that there is a reduced rate of endothelial cell death or turnover.
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