Effects Of Low-dose Levonorgestrel Contraceptive Intrauterine Systems (LCS) On Endometrium

Background The levonorgestrel-releasing intrauterine systems(LNG-IUS, Minera) is a highly effective contraceptive method, which releases levonorgestrel (LNG) into uterine cavity at the rate of 20μg per day. The change of the uterine environment brings an efficient contraception. For one thing, an altered cervical mucus from LNG that act as a barrier to sperm migration, plus the endometrial atrophy prevent sperm-egg binding were the main mechanism of contraception. For another, the down-regulation of estrogen receptors (ER)and progesterone receptors (PR) in glands and stroma of the endometrium can inhibit cellular proliferation, embryo implantation thus be interrupted. As members of the family of steroid, ER and PR have a wide distribution in uterus, fallopian tubes, vaginal epithelium, bone, cardiovascular and many other tissues. Especially in the endometrial glandular epithelial and stromal cells. The presence of ER and PR in human endometrial epithelium, suggested that these cells respond to estrogen and progesterone and take charge of paracrine and autocrine regulation processes, which play a dominant position in endometrial physiology. The endometrium is the target of estrogen and progesterone. The specific combination of the ER and estrogen influence the change of target genes, that promoting the endometrium proliferation; After combining progesterone, PR lead the hyperplasia of endometrium to secretory phase, which produce the decidualization of stroma and cell apoptosis. We have suggested that the contraceptive mechanism of LNG-IUS is endometrium inhibition of proliferation through the down-regulation of ER and PR. However, the LNG-IUS develops systemic levels of LNG and results in hormonal adverse effects, such as spotting, amenorrhea, hirsutism and headache. However, LNG-IUS did not affect our living quality. LCS is a new intrauterine contraceptive system for up to 3 years use with an average in vitro release rate of 12μg of LNG per day. We aimed to study the effect of morphology and ultrastructure on endometrium and the expression of ER and PR after insertion of the LCS, which laid a foundation for it in the clinical application and experimental study of gynecological field.Objectives To study the changes of low-dose levonorgestrel-releasing intrauterine systems (LCS) on endometrial morphology, ultrastructure and the expression of ER and PR.Methods Twenty-seven healthy women who desired contraception were inserted LCS, and twenty-two women without installation of intrauterine devices (IUD) were used as controls. The changes of morphology and ultrastructure of endometrium tissue were observed by light microscope and transmission electron microscope (TEM). The expression of ER and PR were evaluated by immunohistochemical method using a semiquantitative analysis.Results Twenty-seven participants fitted with the LCS during the three years. Four cases fall off after insertion. No biopsy could be obtained in three cases because of endometrial atrophy. The results of twenty biopsies and control group are as follows.1. Under the light microscope, normal endometrial proliferative phase is presented, the increasing and expansive glands, the high columnar epithelial cells in control group; In LCS group, the endometrial gland reduced in number and some were atrophic under the light microscope. A decidual change following few inflammatory cells of stroma was presented.2. Electronic microscopy suggested that, the epithelial cell of glands presented high columnar, completed structure, no secretion in the gland cavity, abundant cellular organs and no edema in stroma of control group. In LCS group, the epithelial cell of glands presented low columnar, karyopyknosis and chromatin margination, decreasing cell organs. Edge lacked in partial mitochondria followed by vacuolar degeneration and rough endoplasmic reticulum presented. Changes could be concluded as cell inhibition of proliferation. TEM showed no necrosis and atypia in the endometrial cells after insertion of LCS.3. In control group, the expression of ER and PR in glands and stroma is high and hyperchromatic in the nucleus; compared with control group, staining nucleus decreased significantly in LCS group. Through a semiquantitative analysis, the expression of ER in glands and stroma decreased 76% and79%, respectively; the expression of ER in glands and stroma decreased 85% and79%, respectively. A statistically significant between two groups (P<0.05).Conclusion1. The endometrial glands atrophic and the stroma became decidualized is the main of morphological changes after insertion of LCS.2. Low active status and inhibition of proliferation in endometrial cells after insertion of LCS under TEM, no necrosis and atypia in the endometrial cells.3. LCS can inhibit the expression of ER and PR, then suppress proliferation in endometrium.