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Background: The standard regimen of the levonorgestrel-only pill (1.5 mg either in a single dose or in a dose of 0.75 mg twice, 12 h apart) administered orally for emergency contraception (EC) has been shown to have no effect on endometrial development and markers of endometrial receptivity. We aimed to explore whether repeated oral and single vaginal administration of levonorgestrel affect the endometrium and thus potentially increase the EC efficacy, compared with the standard regimen., Methods: Endometrial biopsies were taken from non-smoking, healthy women with proven fertility on cycle days LH + 6 to LH + 8 in control and levonorgestrel treatment cycles (each woman serving as her own control). Levonorgestrel was administered either orally (0.75 mg x 4, at 24 h intervals on LH + 1 to LH + 4; n = 8) or vaginally (a single dose of 1.5 mg on LH + 2; n = 7). Immunohistochemistry and real-time RT-PCR was performed to compare the levels of protein and mRNA for sex steroid receptors, interleukin-1beta, leukaemia inhibitory factor (LIF), vascular endothelial growth factor, cyclooxygenase-2, tumour necrosis factor-alpha, integrin alpha(v)beta(3) and mucin 1 in endometrial cells., Results: Following the repeated oral treatment, the immunoreactivity of both progesterone receptor (PR)-A and PR-B declined in glandular epithelium (P = 0.03 and P = 0.02, respectively), whereas stromal immunoreactivity and mRNA expression of LIF increased compared with control (P < 0.001 and P = 0.03, respectively). However, vaginal levonorgestrel did not cause any significant endometrial changes., Conclusions: The two regimens of levonorgestrel caused either only minor or no alterations in markers of endometrial receptivity. New agents targeting the endometrial development should be explored in order to increase EC efficacy.

At the development of receptivity the endometrium undergoes specific changes. Several factors have been suggested as markers of endometrial receptivity. A common feature for most of these factors is that they are directly, or indirectly, regulated by progesterone. The effect of various doses and regimens of mifepristone on endometrial development and markers of receptivity has been studied. Timed endometrial biopsies were assessed by immunhistochemistry, reverse transcriptase polymerase chain reaction (RT-PCR) and electron microscopy. In addition the contraceptive efficacy of these regimens was investigated. Administration of 200 mg of mifepristone immediately post ovulation has a pronounced effect on endometrial development and on suggested markers of receptivity. This regimen has been shown to be an effective contraceptive method. When 10 mg is given pre or post ovulation, only minor effects on the endometrium are observed. Our studies show that mifepristone, when administered in low doses that do not affect ovulation, significantly affects some of the studied markers of endometrial receptivity and reduces pregnancy rates; however, these activities are more pronounced with the higher dose, which is more effective. Our findings provide insight into the regulation of progesterone receptors of various suggested markers of endometrial receptivity and the possibility of using mifepristone for endometrial contraception.

The distribution of progesterone receptor isoform B may have important clinical significance. The aim of this study was to compare the expression, localization and regulation of progesterone receptor isoform B in the human Fallopian tube and endometrium following mifepristone in a dose effective for contraception. Fertile women were treated with a single dose of 200 mg mifepristone on day luteinizing hormone (LH)+2. Biopsies were obtained from the Fallopian tube on day LH+4 to LH+6 and from the endometrium on day LH+6 to LH+8. Progesterone receptor isoform B expression was analyzed by immunohistochemistry and reverse transcriptase polymerase chain reaction. Treatment with mifepristone increased progesterone receptor isoform B concentration in epithelial and stromal cells in the Fallopian tube and also increased progesterone receptor isoform B concentration in the glandular cells of the endometrium. These results further support the hypothesis that the contraceptive effect of mifepristone when given postovulatory is primarily due to alteration of the peri-implantation milieu influencing endometrial receptivity.

Prostaglandins (PG) are known to be involved in the process of human implantation. In several animal species treatment with prostaglandin synthesis inhibitors will prevent implantation. Cyclo-oxygenase (COX) is the rate-limiting enzyme in the synthesis of PGs and exists in two isoforms, COX-1 and COX-2. Defective implantation in COX-2-deficient mice has been demonstrated recently. In the present study, the expression of COX-1 and COX-2 was studied during the implantation period in healthy fertile women before and after treatment with the antiprogesterone, mifepristone. The study consisted of one control cycle and one treatment cycle. The subjects served as their own control. During the treatment cycle the subjects received 200 mg of mifepristone 2 days after the luteinizing hormone (LH) surge. Endometrial biopsies were obtained in the mid-luteal phase (LH + 6 to LH + 8) in both cycles. Using polyclonal antibodies against COX-1 and COX-2, immunostaining for COX-1 was found mainly in the glandular and luminal epithelium and for COX-2 mainly in the luminal epithelium and the perivascular cells. After treatment with mifepristone, expression of COX-1 in glandular epithelium and COX-2 in luminal epithelium significantly decreased whilst the immunostaining for COX-2 in the perivascular cells remained strong. This study shows the expression of both COX-1 and COX-2 during the implantation period and also indicates that treatment with mifepristone in early luteal phase impairs glandular epithelial function and endometrial receptivity.

Objectives: To study the effect of antiprogestin on ovarian function and endometrial development during the menstrual cycle and the possibility of using these compounds for contraceptive purposes., Methods: Administration of different doses of the antiprogestin mifepristone during the menstrual cycle; intermittent measurements of luteinizing hormone, progestin and estrogen in blood and/or urine; endometrial morphology and concentration of markers for endometrial receptivity; efficacy trials of the contraceptive effect of mifepristone., Results: A high dose of mifepristone administered in the follicular phase will inhibit follicular development. If mifepristone is given immediately after ovulation, the secretory development of the endometrium and the expression of, for instance, leukemia inhibitory factor and integrins will be inhibited. Similar effects on the endometrium are obtained with small weekly doses (2.5 or 5.0 mg) or small daily doses (0.5 mg) of mifepristone, which do not inhibit ovulation. Once-monthly administration of 200 mg mifepristone on the day after ovulation, and emergency postcoital treatment, are highly effective methods for preventing pregnancy. Even 5 mg once weekly has a significant contraceptive effect., Conclusions: The antiprogestin mifepristone has a number of effects during the menstrual cycle which makes the compound suitable for contraceptive use. Treatment after a single act of unprotected intercourse, and once-a-month treatment immediately after ovulation, have shown high contraceptive efficacy. A low-dose regimen which does not influence ovulation also has a contraceptive effect, but the efficacy needs to be improved before routine clinical use.

Objective: To determine whether a 5-mg dose of mifepristone is sufficient to prevent pregnancy., Design: Clinical study., Setting: Academic research center., Subject(s): Healthy, fertile, sexually active female volunteers., Intervention: Volunteers received a 5-mg dose of mifepristone once weekly, starting on cycle day 2, for up to 6 months. This was their only contraceptive method., Main Outcome Measure(s): Number of pregnancies., Result(s): The treatment resulted in a significant decrease in pregnancy rate without affecting the menstrual cycle or causing disturbing side effects., Conclusion(s): A low dose of mifepristone, which does not inhibit ovulation, reduces fertility significantly by affecting the endometrium. However, the contraceptive effect needs to be improved for the drug to compete with other contraceptive methods.

Integrins are cell surface receptors for the extracellular matrix and connect extracellular cell adhesion proteins to cytoskeletal components. Several investigators have recently described the expression of different integrins in the human endometrium as markers of receptivity. In the present study we investigated the effect of various doses of the antiprogestin mifepristone on the endometrial expression of integrins during the implantation phase. Endometrial biopsies from healthy fertile women were obtained in the midluteal phase. The study included one control and one, two or three treatment cycles. In treatment cycles either 2.5 (n = 9) or 5 mg (n = 5) of mifepristone was administered once weekly, 0.5 mg daily (n = 5), or 200 mg as a single dose administered on day 2 after the luteinizing hormone surge (day LH + 2; n = 8). By using polyclonal antibodies against integrin alpha(v)beta3, subunit beta3 and subunit alpha4 we found reduced immunostaining for alpha4 and beta3 subunit in glandular epithelium after treatment with mifepristone while alpha(v)beta3, expression appeared to be unaffected. No differences between treatment groups were noted. This study demonstrates that treatment with mifepristone interferes with integrin distribution during the implantation window. This may imply that the contraceptive effect of mifepristone is primarily due to impaired endometrial receptivity. However, since no effect was shown on the distribution of the vitronectin receptor, this integrin might be regulated differently by other factors such as cytokines.