Endometrial angiogenic response in Norplant users

Abstract

The levonorgestrel-releasing subdermal contraceptive implant Norplant is well accepted among Indonesian users, despite the problems with irregular and prolonged menstrual bleeding. Bleeding can be the major reason for women discontinuing their use of Norplant. The causes of endometrial bleeding may include disturbances in endometrial regeneration and angiogenesis. The aim of this study was to investigate endometrial angiogenic activity in Norplant users and to compare it to that in the normal menstrual cycle. The study also aimed to determine the correlation between endometrial angiogenic activity and plasma concentrations of oestradiol, progesterone, sex hormone binding globulin and levonorgestrel, as well as the free levonorgestrel index. The subjects for this study were selected from Norplant users with an exposure of between 3 and 12 months. Endometrial angiogenic response was assayed using an endothelial cell migration assay. Six blood samples to monitor oestradiol and progesterone concentrations were taken during the 2 weeks prior to endometrial biopsy. Samples for the analysis of sex hormone binding globulin and levonorgestrel were taken on the day of biopsy. The results showed that the median score of endometrial angiogenic activity in the 30 women used as controls were significantly higher than the 40 Norplant acceptors (z = -3.80, one tail, P < 0.001). There was no significant correlation between the endothelial migration score and peripheral hormonal concentrations or the free levonorgestrel index in Norplant users. There was no difference in the endometrial angiogenic activity in endometrium with and without bleeding problems. However, it is interesting to note that four Norplant acceptors who had an endothelial cell migration score > or = 1.0 had the lowest free levonorgestrel index.

Oxidative stress, vitamin E and progestin breakthrough bleeding

“…The local mechanisms that cause endometrial bleeding are still unclear. Following 3-12 months of Norplant use, the endometrium becomes very thin and the angiogenic response is decreased (Subakir et al, 1996). The spiral arteries are small and underdeveloped with increased dilatation of the veins and breaks in the endothelial lining (Hourihan et al, 1991).…”

“…Following exposure to progestin-only contraceptives, BTB tends to be prolonged or irregular, suggesting that normal endometrial repair mechanisms may be dysfunctional. In a previous study we have shown that decreased endometrial angiogenic response in Norplant users was not correlated with plasma concentrations of oestradiol, progesterone, sex hormone binding globulin (SHBG) or LNG (Subakir et al, 1996). Vitamin E is the major physiological lipidsoluble chain-breaking antioxidant, preventing peroxidation, and also modulates the metabolism of arachidonic acid (Packer and Lanvick, 1989).…”

Correlation of endothelial cell proliferation with vascular endothelial growth factor in endometrium of women with menorrhagia

“…Indeed, a previous study by Subakir et al, has shown that tissue from patients with menorrhagia may have elevated angiogenic potential. 19,21 Kooy et al in their study found that there was no significant difference in cellular proliferation in the stroma of endometrium from controls, patients with menorrhagia. 19 This indicated that the increase in endothelial cell proliferation in endometrium from patients with menorrhagia was specific and not the result of a general increase of cellular proliferation in the endometrium.…”

“…22 Rogers have shown repeatedly that levels of endothelial cells proliferation within human endometrium did not show any consistent pattern across the different stages of the menstrual cycle. 5,[19][20][21][22] Gargett et al found a highly significant correlation between the percentage of VEGF expressing vessels and vessels containing proliferating endothelial cells. 23 The percentage of proliferating vessels was higher in proliferative compared to secretory endometrium, but this was only statistically significant in the basalis layer.…”

Solving the Puzzle: What Is the Role of Progestogens in Neovascularization?

“…Rashidi et al demonstrated that P4 attenuates EC proliferation induced by gonadotropins, leading to an inhibitory effect on endometrial angiogenesis [ 121 ], and a consistent pattern has been found in ectopic endometrial lesions [ 68 ]. Synthetic progestins have a similar influence, and several studies have revealed that the levonorgestrel-releasing subdermal contraceptive has an anti-angiogenic effect, and that it significantly inhibits the proliferation rate of endometrial ECs, which results in reduced endometrial angiogenic activity [ 122 , 123 ]. Further, a sustained peak expression of cyclin E and A has been observed in this process, resulting in arresting of the EC cycle in G1 [ 124 ].…”