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Ulipristal acetate, a progesterone receptor modulator for emergency contraception.

ABSTRACT: Unwanted pregnancy is a global reproductive health problem. Emergency contraception is defined as the use of drug or device after unprotected or underprotected intercourse to prevent an unwanted pregnancy. 1.5 mg of levonorgestrel as a single dose or in two doses with 12 h apart taken within 72 h of unprotected intercourse is the current gold standard emergency contraception regimen. This method is only effective if used as soon as possible after sexual intercourse and before ovulation. A single dose of 30 mg ulipristal acetate, a novel selective progesterone receptor modulator, has recently been proposed for the emergency contraception use up to 120 h of unprotected intercourse with similar side effect profiles as levonorgestrel. Ulipristal acetate could possibly prevent pregnancy when administered in the advanced follicular phase, even if luteinizing hormone levels have already begun to rise, a time when levonorgestrel is no longer effective in inhibiting ovulation.

SUBMITTER: Jadav SP

PROVIDER: S-EPMC3356949 | biostudies-other | 2012 Apr

REPOSITORIES: biostudies-other

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Ulipristal acetate, a progesterone receptor modulator for emergency contraception.

Jadav Shilpa P SP Parmar Dinesh M DM

Journal of pharmacology & pharmacotherapeutics 20120401 2

Unwanted pregnancy is a global reproductive health problem. Emergency contraception is defined as the use of drug or device after unprotected or underprotected intercourse to prevent an unwanted pregnancy. 1.5 mg of levonorgestrel as a single dose or in two doses with 12 h apart taken within 72 h of unprotected intercourse is the current gold standard emergency contraception regimen. This method is only effective if used as soon as possible after sexual intercourse and before ovulation. A single ...[more]

PMID: 22629083

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Progesterone receptor modulator for emergency contraception: a randomized controlled trial.

Project description:Compare the efficacy and adverse effects of CDB-2914, a new progesterone receptor modulator, to levonorgestrel for emergency contraception.We performed a randomized, double-blinded noninferiority trial, enrolling healthy women seeking emergency contraception within 72 hours of unprotected intercourse. Participants were randomly assigned to receive a single dose of 50 mg of CDB-2914, plus a placebo 12 hours later or two doses of 0.75 mg of levonorgestrel taken 12 hours apart. Follow-up was scheduled 5 to 7 days after the expected onset of the next menstrual period. Posttreatment pregnancy was established by a positive urine test at follow-up and confirmed by quantitative serum beta-hCG. Daily diaries were used from the time of emergency contraception use until next menses to record adverse effects and sexual activity.Product efficacy was evaluable in 775 of CDB-2914 users and 774 of levonorgestrel users. Pregnancies occurred in 7 (0.9%, 95% confidence interval 0.2-1.6%) and 13 (1.7%, 95% confidence interval 0.8-2.6%) women, respectively. Based on the estimated cycle day of unprotected intercourse, 85% and 69% of anticipated pregnancies, respectively, were averted. Nausea was reported by a somewhat greater percentage of CDB-2914 than levonorgestrel users (29% compared with 24%, P=.03), but the distribution of other adverse effects was similar in both groups. Women in both groups experienced considerable variation in menstrual cycle length as compared with their reported individual normal cycle lengths.CDB-2914 is at least as effective as levonorgestrel in preventing pregnancies after unprotected intercourse and has a similar side effect profile.I.

| S-EPMC2853373 | biostudies-literature

A randomized study on pharmacodynamic effects of vaginal rings delivering the progesterone receptor modulator ulipristal acetate: research for a novel estrogen-free, method of contraception.

Project description:ObjectiveTo determine whether a 3-month contraceptive vaginal ring (CVR) delivering ulipristal acetate (UPA) can inhibit ovulation in 90% of cycles.Study designThis was a randomized dose-finding parallel group clinical trial. Fifty-five healthy women with normal ovulation at baseline were randomized to receive a low-dose (1500 μg/day) or a high-dose (2500 μg/day) UPA-CVR for two consecutive 12-week treatment periods, followed by a recovery cycle. A subgroup of women received levonorgestrel (LNG) 1.5 mg orally twice (at the end of both 12-week ring periods) or once (at the end of the 24-week treatment). The primary outcome was ovulation suppression assessed by transvaginal ultrasound and hormone levels. Secondary outcomes included endometrial safety and bleeding patterns.ResultsAll subjects showed normal ovulation at baseline and recovery. Ovulation suppression was seen in 81.8% (95% CI: 73.3%, 88.5%) and 86.1% (95% CI: 78.1%, 92%) of treatment cycles with low and high-dose, respectively. Benign progesterone receptor modulator associated endometrial changes (PAEC) were seen during treatment; 78.8% at week 24, but resolved at recovery cycle. A few cases of heavy bleeding occurred near the end of the 24-week treatment, but a single dose of LNG every 12 weeks reduced the increase in endometrial thickness during the second treatment period and prevented excessive bleeding.ConclusionThe 3-month UPA-CVR may become an effective long-acting, user-controlled estrogen-free contraceptive. The greatest suppression of ovulation was seen with the 2500-μg/day ring.ImplicationsThe 3-month CVR delivering UPA 2500 μg/day can become an effective user-controlled estrogen-free contraceptive method. Benign PAEC during treatment returns to normal after discontinuation. The prevention of occasional excessive withdrawal bleeding, either by a progestin or by using higher UPA levels to increase follicle suppression may permit prolonged treatment.

| S-EPMC4253673 | biostudies-literature

Markers of Inflammation and Vascular Parameters in Selective Progesterone Receptor Modulator (Ulipristal Acetate)-Treated Uterine Fibroids.

Project description:The exact mechanism of selective progesterone receptor modulator action in leiomyoma still challenges researchers. The aim of the study was to assess the effects of ulipristal acetate (UPA) on immunoexpression of inflammatory markers and vascularization in fibroids. UPA-treated patients were divided into three groups: (1) good response (≥25% reduction in volume of fibroid), (2) weak response (insignificant volume reduction), (3) and no response to treatment (no decrease or increase in fibroid volume). The percentage of TGFβ, IL6, IL10, CD117, and CD68-positive cells were significantly lower in the group with a good response to treatment vs. the control group. Moreover, the percentage of IL10 and CD68-positive cells in the group with a good response to treatment were also significantly lower compared to the no response group. Additionally, a significant decrease in the percentage of IL10-positive cells was found in the good response group vs. the weak response group. There were no statistical differences in the percentage of TNFα-positive cells and vessel parameters between all compared groups. The results of the study indicate that a good response to UPA treatment may be associated with a decrease of inflammatory markers, but it does not influence myoma vascularization.

| S-EPMC8397116 | biostudies-literature

Characterisation of progestins used in hormonal contraception and progesterone via the progesterone receptor.

Project description:Different progestogens are widely used in hormonal therapy and mediate their therapeutic actions via the progesterone receptor (PR). Little published data exist on their relative efficacies and potencies via the PR, while those available may be confounded by off-target receptors, different methodologies and model systems. We performed dose-response analysis to investigate the efficacies and potencies for transcription of progesterone and several progestins widely used in contraception via the B isoform of human PR (PR-B). We compared responses using three different cell lines and two different transient transfection conditions. Results show that in vitro biological responses via PR-B for the select progestogens can vary significantly in biocharacter, rank order and absolute values for efficacies and potencies, depending on the cell line and transfection condition. Progestogen rank orders for published relative binding affinities are mostly different to those for relative efficacies and potencies. These in vitro differences suggest that rank orders and absolute values of the efficacies and potencies of the progestogens are likely to vary in vivo in a cell-specific and progestogen-specific manner, and cannot easily be extrapolated from in vitro data, as is usually the practice. While obtaining such data in vivo is not possible, these in vitro data show proof of concept for likely significant cell- and progestogen-specific PR-B effects.

| S-EPMC8129485 | biostudies-literature

The Cost-Effectiveness of Emergency Hormonal Contraception with Ulipristal Acetate versus Levonorgestrel for Minors in France.

Project description:ObjectiveTo evaluate the cost-effectiveness of ulipristal acetate and levonorgestrel in minors in France, and analyze whether it is worthwhile to provide ulipristal acetate to minors free of charge.MethodsThe cost-effectiveness of two emergency contraceptive methods was compared based on a decision-analytical model. Pregnancy rates, outcomes of unintended pregnancies, and resource utilization were derived from the literature. Resources and their costs were considered until termination or a few days after delivery. Deterministic and probabilistic sensitivity analyses were performed.ResultsThe cost of an unintended pregnancy in a French minor is estimated to be 1,630 € (range 1,330 € - 1,803 €). Almost 4 million € (3.1 € - 13.7 € million) in unintended pregnancy spending in 2010 could have been saved by the use of ulipristal acetate instead of levonorgestrel. The incremental cost of ulipristal acetate compared to levonorgestrel is 3.30 € per intake, or 418 € per pregnancy avoided (intake within 72 hours). In the intake within 24 hours subgroup, ulipristal acetate was found to be more efficacious at a lower cost compared to levonorgestrel.ConclusionsUlipristal acetate dominates levonorgestrel when taken within 24 hours after unprotected intercourse, i.e., it is more effective at a lower cost. When taken within 72 hours, ulipristal acetate is a cost- effective alternative to levonorgestrel, given that the cost of avoiding an additional pregnancy with ulipristal acetate is less than the average cost of these pregnancies. In the light of these findings, it is worthwhile to provide free access to minors.

| S-EPMC4589416 | biostudies-literature

Interventions for emergency contraception.

Project description: Not available

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Interventions for emergency contraception.

Project description: Not available

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Mechanism of Telapristone Acetate (CDB4124) on Progesterone Receptor Action in Breast Cancer Cells.

Project description:Progesterone is a steroid hormone that plays an important role in the breast. Progesterone exerts its action through binding to progesterone receptor (PR), a transcription factor. Deregulation of the progesterone signaling pathway is implicated in the formation, development, and progression of breast cancer. Next-generation selective progesterone receptor modulators (SPRMs) have potent antiprogestin activity and are selective for PR, reducing the off-target effects on other nuclear receptors. To date, there is limited information on how the newer generation of SPRMs, specifically telapristone acetate (TPA), affect PR function at the molecular level. In this study, T47D breast cancer cells were used to investigate the molecular mechanism by which TPA antagonizes PR action. Global profiling of the PR cistrome and interactome was done with chromatin immunoprecipitation sequencing (ChIP-seq) and rapid immunoprecipitation mass spectrometry. Validation studies were done on key genes and interactions. Our results demonstrate that treatment with the progestin (R5020) alone resulted in robust PR recruitment to the chromatin, and addition of TPA reduced PR recruitment globally. TPA significantly changed coregulator recruitment to PR compared with R5020. Upon conservative analysis, three proteins (TRPS1, LASP1, and AP1G1) were identified in the R5020+TPA-treated group. Silencing TRPS1 with small interfering RNA increased PR occupancy to the known PR regulatory regions and attenuated the inhibition of gene expression after TPA treatment. TRPS1 silencing alleviated the inhibition of proliferation by TPA. In conclusion, TPA decreases PR occupancy on chromatin and recruits coregulators such as TRPS1 to the PR complex, thereby regulating PR target gene expression and associated cellular responses.

| S-EPMC6157418 | biostudies-literature

Clinical Pharmacokinetics and Pharmacodynamics of the Selective Progesterone Receptor Modulator Vilaprisan: A Comprehensive Overview.

Project description:Vilaprisan is a highly potent selective progesterone receptor modulator in development for the treatment of symptomatic uterine fibroids and endometriosis. Its pharmacokinetics are characterized by rapid absorption, almost complete bioavailability, and dose-proportional exposure. The intrinsic factors of age, bodyweight, and race have no clinically relevant effect on the pharmacokinetics and pharmacodynamics of vilaprisan and do not warrant a dose adjustment. Similarly, vilaprisan can be used in patients with mild or moderate renal or hepatic impairment without dose adjustment, but its use is not recommended in patients with severe organ impairment. Vilaprisan has no perpetrator potential on cytochrome P450 (CYP) enzymes or transporters and therefore restrictions in the concomitant use of their substrates are not required. Nonetheless, because it is a sensitive CYP3A4 substrate itself, concomitant use of vilaprisan with strong CYP3A inhibitors or inducers is not recommended. However, there is no risk for QTc prolongation when vilaprisan and a strong CYP3A inhibitor are administered concomitantly, as indicated by a vilaprisan concentration-QTc response analysis across all studies with triplicate electrocardiogram measurements. Furthermore, due to its mode of action, vilaprisan is also not recommended to be used together with progestin-containing oral contraceptives. Vilaprisan shows a steep exposure-response relationship for inducing amenorrhea in patients with uterine fibroids experiencing heavy menstrual bleeding. Based on simulations, a dose of 2 mg/day is expected to induce a maximum bleeding reduction and was thus selected for phase III.

| S-EPMC8761719 | biostudies-literature

Effect of the Novel Selective Progesterone Receptor Modulator Vilaprisan on Ovarian Activity in Healthy Women.

Project description:This randomized, double-blind, parallel-group study in healthy young women investigated the effect of treatment with vilaprisan (0.5, 1, 2, or 4 mg/day for 12 weeks) on ovarian function by assessing the Hoogland score, which is based on the size of follicle-like structures as determined by transvaginal ultrasound and on estradiol and progesterone serum concentrations. Ovulation inhibition (ie, Hoogland score <6 in treatment weeks 1-4 and 8-12) was observed in >80% of the subjects receiving vilaprisan ?1 mg/day. The effect was dose dependent. With a Bayesian approach, the percentage of subjects with ovulation inhibition was estimated to increase from 37% in subjects receiving 0.5 mg/day vilaprisan to 76%, 86%, and 88% in subjects receiving 1, 2, and 4 mg/day, respectively. Follicle growth was not suppressed during treatment. The majority of subjects receiving ?1 mg/day had a Hoogland score of 4 (active follicle-like structures, ie, follicle diameter >13 mm, estradiol >27.2 pg/mL, no progesterone increase) both at beginning and end of treatment. Mean average estradiol as well as mean maximum progesterone concentrations were noticeably decreased during treatment with vilaprisan ?1 mg/day compared to pretreatment, but estradiol concentrations remained >80 pg/mL. Both hormones returned to pretreatment levels after the end of treatment, indicating a rapid resumption of normal ovarian activity. Amenorrhea occurred in the majority of subjects during treatment at dosages ?1 mg/day. The adverse events observed in this study confirm the known safety profile of vilaprisan. All in all, the results of this study support the development of vilaprisan for the long-term treatment of uterine fibroids.

| S-EPMC5813164 | biostudies-literature

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