Tehran University Medical Journal

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Breakthrough bleeding (BTB) is the cause of 50% of discontinuations of use by long-acting progestogen-only contraceptive users. BTB appears to be associated with capillaries of abnormal morphology and fragility. Disturbances in vessels integrity, intercellular junctions or alteration of the basement membrane (BM) composition has been proposed to contribute toward the fragility of these capillaries. In a clinical trial study, 34 healthy fertile volunteers were studied before and during use of levonorgestrel releasing subdermal contraceptive implant Norplant. Three endometrial biopsies were taken from each volunteer, one before insertion and 2 at different time intervals after exposure to Norplant. Then 3 major components of BM of endometrial vessels Collagen IV (CIV), laminin and heparan sulphate proteglycan (HSPG) were immunostained and studied. The density of immunostained vessels by each antibody were measured and compared with density of vessels stained by CD34. Double immunostain of CD34 and laminin was also used for demonstration of vessels without BM. Significant decrease in vascular density showing BM components were shown in the study. The density of laminin, CIV, and HSPG-positive vessels were decreased from 176±8, 166±6.6 and 61±6 vessels/mm² (Mean±SEM) in the endometrium of Norplant acceptors before use control samples to 156±6, 144±6.2 and 33±2.9 in the endometrium of Norplant acceptors after 2 to 13 weeks Norplant exposure, respectively (P<0.05). This was occurring at the same time as the overall density of small vessels in Norplant exposed endometrium was showing increase. Significant decrease was also demonstrated over 13 to 42 weeks of use in the densities of laminin and HSPG-positive vessels compared with control (P<0.05), although decrease in the density of CIV positive vessels was not significant. Percentages of vessels showing BM was also calculated in the study. Significant decrease in the percentage of vessels showing BM were demonstrated after 2 to 13 weeks of Norplant use. The percentages of CD34 positive vessels showing laminin, CIV and HSPG-positive BM in control samples were 97±3%, 88±32% and 31±2% (Mean±SEM) which significantly decreased to 79±3%, 75±4% and 20±2% in Norplant users, respectively (P<0.05). Decrease in the percentage of vessels showing BM was thought to be due to disturbances in the integrity of BM in endometrial vessels of women using Norplant, which could be a cause for the fragility of the vessels. The decrease could also be due to decrease in the density of arteriols and increase in the density of venules and appearance of solid cords of endothelial cells. Double immunostaining of the endometrial vessels with anti-CD34 and anti-laminin clearly demonstrated loss of BM or weak staining of BM in the endometrial vessels of Norplant users. Clarification of the local mechanisms which leads to capillary fragility and abnormal endometrial bleeding may lead to the development of better treatments or prevention and ultimately improve the acceptability of these contraceptives.

Keywords: Breakthrough bleeding, Levonorgestrel, Vessels, Laminin, Collagen IV, Heparan sulphate proteoglycan, Norplant

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