asoprisnil and Uterine-Hemorrhage

Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands that exert clinically relevant tissue-selective progesterone agonist, antagonist, partial, or mixed agonist/antagonist effects on various progesterone target tissues in an in vivo situation depending on the biological action studied. The SPRM asoprisnil is being studied in women with symptomatic uterine leiomyomata and endometriosis. Asoprisnil shows a high degree of uterine selectivity as compared to effects on ovulation or ovarian hormone secretion in humans. It induces amenorrhea and decreases leiomyoma volume in a dose-dependent manner in the presence of follicular phase estrogen concentrations. It also has endometrial antiproliferative effects. In pregnant animals, the myometrial, i.e. labor-inducing, effects of asoprisnil are blunted or absent. Studies in non-human primates played a key role during the preclinical development of selective progesterone receptor modulators. These studies provided the first evidence of uterus-selective effects of asoprisnil and structurally related compounds, and the rationale for clinical development of asoprisnil.

Topics: Animals; Drug Evaluation, Preclinical; Endometrium; Estrenes; Female; Humans; Leiomyoma; Mammary Glands, Animal; Models, Animal; Models, Biological; Models, Molecular; Organ Specificity; Oximes; Primates; Progesterone Congeners; Receptors, Progesterone; Uterine Hemorrhage; Uterine Neoplasms; Uterus

Asoprisnil is a novel selective progesterone receptor modulator that exhibits partial agonist and antagonist activities in animals and humans. It demonstrates a high degree of progesterone receptor specificity and tissue selectivity. Although asoprisnil at high doses exhibited some antiglucocorticoid activity in animal models, no antiglucocorticoid effects were observed at therapeutic doses in humans. In male rats, asoprisnil showed mixed androgenic and antiandrogenic properties. Unlike antiprogestins, asoprisnil at high doses exhibited only marginal labor-inducing activity in guinea pigs during midpregnancy and was completely ineffective in inducing preterm parturition. In nonhuman primates, asoprisnil completely eliminated menstrual cyclicity and induced endometrial atrophy. Early clinical studies of asoprisnil in healthy volunteers demonstrated a dose-dependent suppression of menstruation, irrespective of the effects on ovulation, with no change in basal estrogen concentrations and no breakthrough bleeding. Phase 2 studies in subjects with uterine fibroids demonstrated that asoprisnil induced amenorrhea and reduced the volume of the dominant leiomyoma in a dose-dependent manner without altered basal estrogen and with virtually no clinical symptoms of estrogen deprivation. Asoprisnil seems to exhibit a direct inhibitory effect on both the endometrium and leiomyoma. In all studies to date, asoprisnil has maintained a favorable safety and tolerability profile. Thus, asoprisnil has the potential to target the major clinical symptoms of leiomyomata related to both menorrhagia and the size of the tumors and may, therefore, reduce or eliminate the need for surgery.

Topics: Animals; Endometrium; Estrenes; Female; Humans; Leiomyoma; Oximes; Oxytocics; Progesterone; Receptors, Progesterone; Uterine Hemorrhage; Uterine Neoplasms

Asoprisnil, a novel orally active selective progesterone receptor modulator, is being studied for the management of symptomatic uterine leiomyomata. The exact mechanism of action is not yet discerned. The primary objectives of this double-blind, randomized, placebo-controlled study included evaluation of the effect of asoprisnil on uterine artery blood flow. Furthermore, we assessed effects of asoprisnil on leiomyoma symptoms.. Thirty-three premenopausal patients scheduled for hysterectomy due to symptomatic uterine leiomyomata were recruited in four centers and treated with 10 or 25 mg asoprisnil or placebo for 12 wk before surgery. At baseline and before hysterectomy, all patients underwent sonographic assessment to measure impedance to uterine artery blood flow, determined by resistance index and pulsatility index, as well as volumes of largest leiomyoma and uterus. In addition, patients recorded intensity and frequency of menstrual bleeding on a menstrual pictogram. Each asoprisnil treatment was compared with placebo.. The increased pulsatility index in both asoprisnil groups and the statistically significantly increased resistance index within the 25-mg asoprisnil group suggest a moderately decreased uterine artery blood flow. Analysis of menstrual pictogram scores showed a statistically significant larger decrease in frequency and intensity of bleeding for both asoprisnil groups compared with placebo. Bleeding was suppressed by asoprisnil 25mg in 91% of patients. Asoprisnil treatment was well tolerated when administered daily for a 12-wk period, and no serious adverse events occurred.. Asoprisnil moderately reduced uterine artery blood flow. This effect may contribute in part to the clinical effects of asoprisnil.

Topics: Adult; Arteries; Data Interpretation, Statistical; Double-Blind Method; Endometrium; Estrenes; Female; Humans; Hysterectomy; Leiomyoma; Menstruation; Middle Aged; Myometrium; Ovary; Oximes; Pregnanediol; Quality of Life; Receptors, Progesterone; Regional Blood Flow; Ultrasonography, Doppler, Color; Uterine Hemorrhage; Uterine Neoplasms; Uterus; Vascular Resistance

To determine efficacy and safety of asoprisnil in patients with leiomyomata.. Phase 2, multicenter, prospective, randomized, double-blind, placebo-controlled, parallel-group study.. Twenty-eight sites in the United States and 1 in Canada.. One hundred twenty-nine women with leiomyomata.. Asoprisnil (5, 10, or 25 mg) or placebo orally daily for 12 weeks.. Uterine bleeding changes by using daily bleeding diaries, hemoglobin concentrations, dominant leiomyoma and uterus volume measured sonographically, patient-reported symptoms related to bloating and pelvic pressure, endometrial thickness and morphology, hormonal parameters, and standard safety measures.. Asoprisnil suppressed uterine bleeding in 28%, 64%, and 83% of subjects at 5, 10, and 25 mg, respectively, and reduced leiomyoma and uterine volumes. Median percentage decrease from baseline in leiomyoma volume was statistically significant at 25 mg compared with placebo after 4 and 8 weeks of treatment; by week 12, leiomyoma volume was reduced by 36%. There was a significant reduction in bloating with the two highest doses and in pelvic pressure with 25 mg by week 12. Asoprisnil was associated with follicular-phase estrogen concentration and minimal hypoestrogenic symptoms.. After 12-week treatment, asoprisnil controlled uterine bleeding while reducing leiomyoma volume and the associated pressure symptoms. Asoprisnil was well tolerated.

Topics: Adolescent; Adult; Double-Blind Method; Estrenes; Female; Humans; Leiomyoma; Middle Aged; Oximes; Oxytocics; Patient Selection; Placebos; Receptors, Progesterone; Uterine Hemorrhage; Uterine Neoplasms