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  • Title: Endometrial vasculature in Norplant users.
    Author: Rogers PA.
    Journal: Hum Reprod; 1996 Oct; 11 Suppl 2():45-50. PubMed ID: 8982745.
    Abstract:
    Disrupted, prolonged and irregular endometrial bleeding are major unwanted side-effects of progestin-only contraceptives. The aim of this paper is to review current information on steroid control of the microvasculature, microvascular heterogeneity and microvascular fragility, with emphasis on the relevance of these issues to the endometrial microvasculature in women receiving Norplant implant contraception. Subjects were either Indonesian women with between 3 and 12 months exposure to Norplant (n = 191) or Caucasian controls recruited in Melbourne, Australia. Norplant endometrium was always thinner than control endometrium, with a varied histology that usually included a basalis-type appearance, signs of haemorrhage and some dilated and congested subepithelial vessels. Thin-walled vessels were seen which could have been either blood vascular or lymphatics. Steroid control of the vasculature can operate through numerous direct and indirect mechanisms, with up to 30 genes relevant to vascular function having consensus oestrogen response elements in their promoter regions. The vasoactive effects of progesterone are less well documented. However, experimental data for direct effects on the endometrial vasculature are mounting. Progestin-induced endometrial breakthrough bleeding is often focal, suggesting that microvascular heterogeneity may be an important factor in understanding this phenomenon. Increased susceptibility to bleeding may result from increased microvascular fragility, possibly as a consequence of progestins altering the balance of angiogenic promoters and inhibitors in the endometrium, thus leaving the vessels in a permanently weakened state. Enhanced understanding of steroid control of the endometrial microvasculature, microvascular heterogeneity, and microvascular fragility is essential to controlling the disrupted, prolonged, and irregular vaginal bleeding associated with progestin-only contraceptives. A World Health Organization study involving 191 Indonesian women with 3-12 months of exposure to Norplant implants yielded important information on these aspects. The endometrium was consistently thinner (0.4 mm) in Norplant users compared with Australian controls (5.8 mm). Other histologic features characteristic of the endometrium in Norplant users included a basalis-type appearance and minimal functionalis, signs of hemorrhage, dilatation and congestion of subepithelial vessels, spindle-shaped periglandular cells, and breaks and signs of re-epithelialization in the surface epithelium. Steroid control of the vasculature can operate through numerous direct and indirect mechanisms, with up to 30 genes relevant to vascular function having consensus estrogen response elements in their promoter regions. The vasoactive effects of progestins are less well documented, but appear to be independent of their effects on the other tissue compartments. The vasculature varies considerably from vessel to vessel, and localized rupture of vessels appears responsible for breakthrough bleeding. It is hypothesized that exogenous progestin administration perturbs one or more steps of the normal angiogenic process, producing a situation in which parameters such as basement membrane breakdown or endothelial cell adhesion molecule expression are altered, leaving the vessels in a permanently weakened state.
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