Selective estrogen receptor modulator and selective progesterone receptor modulator: therapeutic efficacy in the treatment of uterine leiomyoma

Recent advances in endocrinology open a door for clinical application of selective estrogen receptor modulator (SERM) and selective progesterone receptor modulator (SPRM) in the treatment of uterine leiomyoma. With regard to SERM, treatment with raloxifene is shown to reduce leiomyoma size in postmenopausal women. Although raloxifene causes shrinkage of leiomyomas in combination with gonadotropin-releasing hormone agonist in premenopausal women, the effects of monotherapy with raloxifene on leiomyoma growth in premenopausal women remain controversial. By contrast, tamoxifen may not be suitable for long-term treatment of leiomyomas due to an agonistic action on the endometrium. Treatment with progesterone antagonist (RU486) or SPRM (J867) has been demonstrated to inhibit leiomyoma growth and improve clinical symptoms in premenopausal women. No serious adverse effects associated with SERM or SPRM have been reported. In light of therapeutic efficacy and few adverse effects, SERM and SPRM may hold promise as novel treatment modalities for leiomyoma. Further studies are warranted to determine the optimal strategy for the treatment of leiomyoma with SERM and SPRM.     

Therapeutic potential for the selective progesterone receptor modulator asoprisnil in the treatment of leiomyomata

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.     

Effects of the selective estrogen receptor modulator, raloxifene, on carotid artery pulsatility index in postmenopausal women

OBJECTIVE: Estrogen replacement therapy after menopause reduces the incidence of arterial disease and cerebrovascular events. The reduced incidence also seems to be due to a positive effect of estrogens on brain blood flow as shown by a decrease in the carotid artery pulsatility index. Raloxifene, a second-generation selective estrogen receptor modulator, has aroused considerable interest because of its tissue-specific agonist-antagonist effect on estrogen receptors. However, there have been no studies on the effect of raloxifene on carotid blood flow after menopause. METHODS: A total of 66 healthy women in postmenopause for more than a year were divided randomly into 2 groups: the first group (n = 33; mean age +/- SD, 53.3 +/- 5.2 years) was treated with raloxifene (one 60-mg capsule per day) for 6 months, and the other group (n = 33; mean age +/- SD, 51.9 +/- 4 years) was untreated. Doppler ultrasonography was used to measure carotid artery pulsatility index (PI) at the beginning of the study and at 2-month intervals. RESULTS: A reduction in carotid artery PI was observed in all patients receiving raloxifene. No significant changes were observed in the control group. The reduction with respect to baseline values was 6.1%(P <.05) after 2 months, 11.2% (P <.05) after 4 months, and 13.2% (P <.05) after 6 months of therapy.The higher the baseline PI, the greater was its reduction after therapy. CONCLUSIONS: After 6 months of therapy, raloxifene induced a reduction in PI similar to that reported after estrogen therapy. The present results further our understanding of the mechanisms by which raloxifene might reduce the incidence of cardiovascular disease in postmenopausal women.     

A phase II trial of arzoxifene,a selective estrogen response modulator,in patients with recurrent or advanced endometrial cancer

OBJECTIVES: The goal of this study was to determine response rate and evaluate toxicity of LY353381 (arzoxifene) in patients with recurrent or advanced endometrial cancer (EC). METHODS: A phase II, open-labeled study with arzoxifene was performed at 13 centers. Patients with measurable recurrent/advanced EC not amenable to curative therapies were eligible if either the primary tumor or recurrent tumor was ER+ and/or PR+. If receptor status could not be determined, patients with well or moderately well-differentiated EC were also permitted. Prior use of salvage chemotherapy was not allowed; however, prior use of progestagens was permitted and patients were stratified by prior exposure to progestagen. Patients received 20 mg/day PO, and were treated for at least 8 weeks in the absence of disease progression or unacceptable toxicity. Efficacy was based on the frequency of complete (CR) and partial (PR) responses, and a 95% confidence interval (CI) was calculated. The Kaplan-Meier method was used to analyze time to progression and duration of response. RESULTS: From February 1999 through April 2001, 37 patients were entered of whom 34 received treatment. Efficacy was evaluated for the 29 patients who received at least 4 weeks of therapy and at least one tumor response assessment. Safety was assessed in all 34 patients who received any drug. Thirty patients were defined as progestagen sensitive, and 4 patients were defined as progestagen failures. Twenty-six patients were ER+, and 22 were PR+. Nine (1 CR + 8 PR) of 29 patients responded (31%, CI 25-51%), with a median duration of response of 13.9 months. All 9 responses occurred in progestagen-sensitive patients. Two additional patients (one from each progestagen cohort) had stable disease for >or=6 months. The median progression-free interval was 3.7 months (CI 1.9-6.6 months) for all 29 patients. Toxicity was minimal with no grade 3-4 toxic effects, and 9 patients had only grade 1-2 toxic effects (7 grade 1, 2 grade 2). Hot flashes were the most common toxic effect and, in all 3 reported cases, were grade 1. CONCLUSIONS: Arzoxifene has demonstrated a high response rate with the longest median duration of response reported in a phase II trial of this patient population. The ease of administration and extremely favorable toxicity profile make this an agent warranting further evaluation.     

PvuII genetic polymorphism of estrogen receptor alpha in the group of postmenopausal women with osteopenia and osteoporosis

DESIGN: It was suggested that genetic factors play an important role in the regulation of bone mineral density and in the pathogenesis of bone fracture in osteoporosis. PvuII restriction polymorphism in the intron 1 of the gene coding estrogen receptor alpha (ER-alpha) is indicated to play a significant role in osteopenia and osteoporosis development. The goal of our study was to determine the frequency and the significance of PvuII polymorphism of the ER-alpha gene in the group of postmenopausal women with osteopenia and osteoporosis. MATERIALS AND METHODS: 93 postmenopausal women with osteopenia and osteoporosis (t-score lower than (-1), and 141 healthy postmenopausal women have been investigated for PvuII polymorphism of the ER-a gene using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) assays. RESULTS: We have observed higher frequency of homozygous genotype PP (25.8 vs. 19.8%) and P allele (50.6 vs. 46.1%) in the group of women with low level of t-score. In the osteopenic women (-2.5 < T-score < -1.0) the significant difference in the distribution of t-score index and genotypes has been found. t-score index correlated with body mass index (BMI), mean body weight, BMD aged matched (AM) and BMD young adults (YA) index. The AM and YA index correlated with the number of pregnancies. CONCLUSIONS: The presence of PP genotype and P allele could be connected with higher bone loss and with the development of osteopenia and osteoporosis in postmenopausal women.     

HMR 3339, a novel selective estrogen receptor modulator, reduces total cholesterol, low-density lipoprotein cholesterol, and homocysteine in healthy postmenopausal women

OBJECTIVE: To investigate the short-term effects of HMR 3339 in comparison with raloxifene and placebo on cardiovascular risk factors. DESIGN: A multicenter, randomized, placebo-controlled, double-blind, dose-ranging study. SETTING: Gynecologic outpatient department. PATIENT(S): One hundred eighteen healthy nonhysterectomized postmenopausal women. INTERVENTION(S): Participants received daily placebo (n = 22), 2.5 mg of HMR 3339 (n = 25), 10 mg of HMR 3339 (n = 24), 50 mg of HMR 3339 (n = 24), or 60 mg of raloxifene (n = 23) for 12 weeks followed by a 2-week washout period. MAIN OUTCOME MEASURE(S): Blood concentrations of lipids measured at baseline, and after 2, 4, 8, 12, and 14 weeks, and of lipoprotein(a), homocysteine, and endothelin-1 measured at baseline, and after 4 and 12 weeks. RESULT(S): After 12 weeks of treatment with HMR 3339, compared with placebo, serum total cholesterol was reduced (10 mg of HMR 3339: -9.7%; 50 mg of HMR 3339: -15.2%), low-density lipoprotein (LDL)-cholesterol (10 mg of HMR 3339: -10.8%; 50 mg of HMR 3339: -24.2%) and plasma homocysteine concentrations (2.5 mg of HMR 3339: -3.9%; 10 mg of HMR 3339: -10.8%; 50 mg of HMR 3339: -13.8%), suggesting a dose-dependent effect of HMR 3339. These effects were already apparent after 2 weeks of treatment for total cholesterol and LDL-cholesterol, and after 4 weeks of treatment for homocysteine. After 12 weeks, raloxifene, compared with placebo, significantly decreased total cholesterol (-10.5%), LDL-cholesterol (-15.0%), and triglycerides (-16.9%), but not homocysteine. High-density lipoprotein-cholesterol, lipoprotein(a), and endothelin-1 showed no significant changes in any of the active treatment groups. CONCLUSION(S): HMR 3339 reduces total cholesterol, LDL-cholesterol, and homocysteine concentrations in postmenopausal women.     

Selective estrogen receptor modulators: the future in menopausal treatment

The results of hormone therapy (HT) studies have changed the perception of HT benefits and risks. Selective estrogen receptor modulators (SERMs) represent drugs with a tissue-specific estrogen receptor agonist/antagonist activity and they are an alternative to HT. Each SERM stimulates and blocks different genes with different biological responses. Established SERMs or second generation are tamoxifen and raloxifene. Both SERMs have positive effects on breast, bone and lipids, but with an increased risk for venous thromboembolism and hot flushes. None of these SERMs has shown a preventive effect on non-vertebral fractures. At present, there is a new generation of SERMs (third generation: bazedoxifene, lasofoxifene and ospemifene) which has completed phase III clinical trials and has been submitted to the Health Regulatory Authorities for approval. A new concept, tissue selective estrogen complex (TSEC), has the potential to demonstrate the benefits of SERMs along with the additional benefits of estrogens. A long road to the ideal SERM still remains, but new SERMs represent an attractive new menopause treatment.     

Pain-free efficacy after treatment with sumatriptan in the mild pain phase of menstrually associated migraine

OBJECTIVE: To estimate the efficacy of sumatriptan 50-mg and 100-mg tablets in menstrually associated migraine when treatment is administered during the mild pain phase. METHODS: A randomized, double-blind, placebo-controlled, single-attack study was conducted. Menstrually associated migraine was defined as any migraine beginning on or between day -2 and day 4, with day 1 = first day of flow. Patients had at least a 1-year history of migraine as defined by International Headache Society criteria and reported regularly occurring menstrually associated migraines typically having a mild pain phase. Patients treated attacks within 1 hour of the onset of pain but only if the pain was mild at onset and while the pain was still mild. RESULTS: In the 349 women with menstrually associated migraine, sumatriptan was significantly more effective than placebo: 61% and 51% of patients who used sumatriptan 100 mg and 50 mg, respectively, were pain-free 2 hours after treatment compared with 29% of patients who used placebo (P <.001 for both comparisons). At 2 hours, 51% and 45% of patients who used sumatriptan 100 mg and 50 mg were free of pain and associated symptoms (photophobia, phonophobia, nausea, vomiting) compared with 25% of placebo patients (P <.001 for both comparisons). Adverse events were low for sumatriptan 100 and 50 mg, and both doses were generally well tolerated. CONCLUSION: Sumatriptan 50-mg and 100-mg tablets are generally well tolerated and effective in providing pain-free relief and relief of the associated symptoms of menstrually associated migraine when administered in the mild pain phase.     

Effects of the new generation selective estrogen receptor modulator EM-652 and oral administration of estradiol valerate on circulating,brain, and adrenal beta-endorphin and allopregnanolone levels in intact fertile and ovariectomized rats

OBJECTIVE: To investigate the effects of oral estradiol valerate (EV); EM-652, a new-generation selective estrogen receptor modulator; and both agents on central and peripheral beta-endorphin (beta-EP) and allopregnanolone levels in fertile and ovariectomized rats. DESIGN: Prospective study. SETTING: Animal laboratory in an academic research environment. ANIMALS: Thirteen groups of eight Wistar female rats received oral EV (0.01 or 0.05 mg/kg of body weight daily), EM-652 (0.1, 1, or 5 mg/kg daily), or EV (0.05 mg/kg daily) and EM-652 (0.1, 1, or 5 mg/kg/daily) for 14 days. INTERVENTION(S): beta-Endorphin levels content in the hypothalamus, hippocampus, anterior and neurointermediate pituitary, and plasma were measured. Allopregnanolone levels in the hypothalamus, hippocampus, anterior pituitary, adrenal glands, and serum were measured. MAIN OUTCOME MEASURE(S): beta-Endorphin and allopregnanolone levels. RESULT(S): In ovariectomized rats, administration of EV or EM-652 reverses changes in beta-EP and allopregnanolone levels induced by ovariectomy. Administration of EM-652 plus EV prevents the increase in beta-EP and allopregnanolone levels induced by EV in the hippocampus, hypothalamus, and pituitary but not in the adrenal glands and serum. CONCLUSIONS: In ovariectomized rats, EM-652 has an estrogen-like action that becomes antiestrogenic in the presence of EV administration. In fertile animals, EM-652 exerts estrogen-like or slight antiestrogenic effects.     

Defining forces that are associated with shoulder dystocia: the use of a mathematic dynamic computer model

OBJECTIVE: A computer model was modified to study the impact of maternal endogenous and clinician-applied exogenous delivery loads on the contact force between the anterior fetal shoulder and the maternal symphysis pubis. STUDY DESIGN: Varying endogenous and exogenous loads were applied, and the contact force was determined. Experiments also examined the effect of pelvic orientation and the direction of load application on contact force behind the symphysis pubis. RESULTS: Exogenous loading forces (50-100 N) resulted in anterior shoulder contact forces of 107 to 127 N, with delivery accomplished at 100 N of applied load. Higher contact forces (147-272 N) were noted for endogenously applied loads (100-400 N), with delivery occurring at 400 N of maternal force. Pelvic rotation from lithotomy to McRoberts' positioning resulted in reduced contact forces. Downward lateral flexion of the fetal head led to little difference in contact force but required 30% more exogenous load to achieve delivery. CONCLUSION: Compared with clinician-applied exogenous force, larger maternally derived endogenous forces are needed to clear the impacted anterior fetal shoulder. This is associated with >2 times more contact force by the obstructing symphysis pubis. McRoberts' positioning reduces shoulder-symphysis pubis contact force. Lateral flexion of the fetal head results in the larger forces that are needed for delivery but has little effect on contact force. Model refinements are needed to examine delivery forces and brachial plexus stretching more specifically.     

Lower vitamin D levels during the second trimester are associated with developing gestational diabetes mellitus: an observational cross-sectional study

Abstract

In this study, we aimed to compare serum 25(OH)D levels in women with and without gestational diabetes mellitus (GDM), and to identify the serum 25(OH)D levels associated with GDM. We recruited 40 women with GDM and 40 healthy pregnant women, aged 20–40?years and in the second trimester, at Gulhane Education and Research Hospital. We excluded women with chronic diseases, preeclampsia, pre-GDM, multiple pregnancies, and those taking medications related to calcium or vitamin D metabolism. We took anthropometric measurements and blood samples during the second trimester. Of the 80 pregnant women, pre-pregnancy body mass index was significantly higher among the GDM group than the healthy group (26.4?±?5.73?kg/m² vs. 22.6?±?3.56?kg/m², p?=?.001). Serum 25(OH)D levels in women with GDM were significantly lower than those in healthy women (16.8?±?9.90?ng/mL vs. 20.9?±?8.16?ng/mL, p?=?.016). The prevalence of severe vitamin D deficiency was as high as 72.5% among women in the GDM group, with a 1.74-fold increased risk of deficient status. Levels of 25(OH)D lower than a cutoff value of 14.0?ng/mL were determined to be related to GDM. These study results suggest that maternal vitamin D deficiency in mid-pregnancy is significantly associated with development of GDM.     

Morbidity that is associated with curettage for the management of spontaneous and induced abortion in women who are infected with HIV

OBJECTIVE: The purpose of this study was to determine the morbidity that is associated with curettage for the management of abortions in women who were infected with human immunodeficiency virus compared with women who were not infected with human immunodeficiency virus. STUDY DESIGN: Women who were infected with human immunodeficiency virus (cases) and who underwent curettage for the management of scheduled and unscheduled abortions in the first half of pregnancy between January 1, 1993, and December 31, 2002, were identified. Women who were not infected with human immunodeficiency virus (control subjects) were matched 3:1 to cases for gestational age, type of abortion, and year of procedure. Medical records were reviewed to obtain demographic characteristics, gestational age, abortion characteristics, and procedure-related complications. Chi-squared test, Student t test, and Wilcoxon rank-sum test were used to determine statistical significance. RESULTS: Seventy-one women who were infected with human immunodeficiency virus (cases) and 213 women who were not infected with human immunodeficiency virus (control subjects) who underwent curettage during the study period were evaluated. Forty-eight cases (68%) and 146 control subjects (69%) underwent a scheduled curettage. Twenty-three cases (32%) and 66 control subjects (31%) underwent an unscheduled curettage for spontaneous or incomplete abortion. No significant differences were seen in age, gravidity, or parity. There were significantly more black women in the HIV-infected cohort (P < .001), which was representative of our human immunodeficiency virus population. The mean gestational age in the cases was greater than in the control subjects (10.9 +/- 4.2 weeks of gestation vs 9.2 +/- 3.1 weeks of gestation; P = .004). Procedure-related complications occurred in 10 of the women (14%) who were infected with human immunodeficiency virus who underwent curettage, compared with 9 of the women (4%) who were not infected with human immunodeficiency virus (P = .004). With the use of logistic regression, complication rates were unaffected by the difference in gestational age. Infectious complications did not differ between the 2 groups (P = .435). CONCLUSION: There was a higher rate of procedure-related complications among women who were infected with human immunodeficiency virus and who underwent curettage for management of spontaneous and induced abortions. There was no increase in infectious morbidity in the women who were infected with human immunodeficiency virus.     

Tocolytic effect of a selective FP receptor antagonist in rodent models reveals an innovative approach to the treatment of preterm labor

Background

Management of preterm labor by tocolysis remains an unmet medical need. Prostaglandins play a major role in regulation of uterine activity and in molecular mechanisms of human labor and parturition. There is some circumstantial evidence that prostaglandin F2α by action through the prostaglandin receptor subtype FP is effective in key events during labor uterine contraction, rupture of membranes and cervical dilation. This role of FP is briefly reviewed. In this study, we tested the hypothesis that an orally active and selective FP antagonist may arrest labor and delay parturition in animal models.

Methods

We examined the effects of a small molecule selective antagonist of the FP receptor (AS604872) in inhibition of spontaneous uterine contraction in pregnant rat near term. We tested AS604872 for its ability to delay preterm birth in a mouse model in which the anti-progestin agent RU486 triggered parturition.

Results

By oral or intravenous dosing AS604872 reduced markedly and dose-dependently the spontaneous uterine contractions in late-term pregnant rats at gestational days 19–21. In pregnant mice, AS604872 delayed the preterm birth caused by RU486 administration. The effect was dose-dependent with a significant increase in the mean delivery time of 16 and 33 hours at oral doses of 30 mg/kg and 100 mg/kg, respectively, in the case of labor triggered at gestational day 14. In both models AS604872 appeared more effective than the β-agonist ritodrine.

Conclusion

The tocolytic activity displayed by a selective FP receptor antagonist supports a key role for the FP receptor in the pathophysiology of premature birth and demonstrates the therapeutic potential of an FP antagonist for the treatment of preterm labor cases in which uterine hyperactivity plays a dominant role.