Changes in circulating levels and ratios of angiopoietins during pregnancy but not during the menstrual cycle and controlled ovarian stimulation.

OBJECTIVE: To determine whether angiopoietin (ANGPT)-1 and -2 are detectable in the circulation of nonhuman primates and women and whether these levels fluctuate in association with ovarian activity. DESIGN: Prospective. SETTING: National Primate Research Center, medical center, and infertility clinic. PATIENT(S): Adult female rhesus monkeys; 15 women donating oocytes for infertility treatment. INTERVENTION(S): Controlled ovarian stimulation with gonadotropins, removal of the corpus luteum and ovaries, oocyte retrieval, and ET. MAIN OUTCOME MEASURE(S): Circulating levels of ANGPT-1 and ANGPT-2. RESULT(S): Serum ANGPT-1 and ANGPT-2 levels were detectable and invariant in maintaining an ANGPT-1 to -2 ratio >1 in [1] macaques over the course of the natural menstrual cycle, during a controlled ovulation protocol, and after removal of the corpus luteum or ovaries and [2] women undergoing controlled ovarian simulation. In contrast, the ANGPT-1 to -2 ratio was markedly decreased (<<1) at mid-to-late gestation in macaques and in the follicular fluid of women undergoing controlled ovarian simulation because of increased levels of ANGPT-2. CONCLUSION(S): The ovary and its dominant structures are not major contributors to circulating levels of ANGPT-1 or ANGPT-2. The physiologic importance of the rising levels of ANGPT-2 after the luteal-placental shift in pregnancy is unknown.

Endometrial effects of a tissue selective estrogen complex containing bazedoxifene/conjugated estrogens as a menopausal therapy.

OBJECTIVE: To evaluate the endometrial safety of a tissue selective estrogen complex (TSEC; pairing of a selective estrogen receptor modulator [SERM] with estrogens) composed of bazedoxifene/conjugated estrogens (BZA/CE) in postmenopausal women. DESIGN: Randomized, double-blind, multicenter, placebo- and active-controlled, phase 3 study (Selective estrogen Menopause And Response to Therapy [SMART]-1). SETTING: Outpatient clinical. PATIENT(S): Healthy, postmenopausal women (n = 3,397) age 40-75 with an intact uterus. INTERVENTION(S): Single tablets of BZA (10, 20, or 40 mg) combined with CE (0.625 or 0.45 mg); raloxifene (60 mg); or placebo daily for 2 years. MAIN OUTCOME MEASURE(S): Incidence of endometrial hyperplasia at 12 months in the efficacy evaluable population. RESULT(S): Treatment with BZA (20 or 40 mg)/CE (0.625 or 0.45 mg) was associated with low rates (<1%) of endometrial hyperplasia that were not significantly different from those reported with placebo over 24 months. Endometrial thickness with BZA (20 or 40 mg)/CE (0.625 or 0.45 mg) was not significantly different from that with placebo. CONCLUSION(S): When combined with CE (0.625 mg or 0.45 mg), BZA (20 mg) was the lowest effective dose that prevented endometrial hyperplasia over 2 years of study, creating the possibility for a new, progestin-free menopausal therapy.

Subcutaneous DMPA vs. intramuscular DMPA: a 2-year randomized study of contraceptive efficacy and bone mineral density.

BACKGROUND: A formulation of depot medroxyprogesterone acetate (DMPA) has been developed that allows subcutaneous injection (104 mg/0.65 mL; DMPA-SC) and achieves highly effective contraception with a similar tolerability profile to intramuscular DMPA (150 mg/mL; DMPA-IM). STUDY DESIGN: This randomized, evaluator-blinded study was designed to compare efficacy, safety, and user satisfaction in women receiving DMPA-SC (n=266) or DMPA-IM (n=268) for 2 years with an option to continue for a third year. The primary objectives were to evaluate bone mineral density (BMD) changes and contraceptive efficacy after 2 years. RESULTS: A total of 225 women completed the first 2 years of this study (DMPA-SC, n=116; DMPA-IM, n=109). After 2 years of DMPA use, BMD loss was marginally smaller in the DMPA-SC group than in the DMPA-IM group at both the total hip (-3.3% and -3.6%, respectively) and lumbar spine (-4.3% and -5.0%, respectively). In those women who received DMPA during the third year, there were no statistically significant differences in BMD loss between DMPA-SC and DMPA-IM groups at the end of Year 3. Recovery of BMD was observed in the small subpopulation of women who had discontinued DMPA-SC or DMPA-IM after the second year. The 2-year treatment-failure cumulative pregnancy rate was 0% in the DMPA-SC group and 0.8% (95% confidence interval, 0.00-2.37%) in the DMPA-IM group (life-table method). Adverse events were similar in the two groups except that injection site reactions were more common in the DMPA-SC group. CONCLUSION: DMPA-SC is an effective and well-tolerated contraceptive option, providing comparable efficacy and BMD safety to DMPA-IM.

Efficacy and tolerability of desvenlafaxine succinate treatment for menopausal vasomotor symptoms: a randomized controlled trial.

OBJECTIVE: To compare efficacy and safety of desvenlafaxine succinate (desvenlafaxine) with placebo for the treatment of vasomotor symptoms. METHODS: This randomized, double-blind, placebo-controlled trial enrolled 707 healthy, postmenopausal women experiencing 50 or more moderate-to-severe hot flushes per week. Participants randomly received desvenlafaxine 50, 100, 150, or 200 mg or placebo daily. Trial duration was 52 weeks. Primary outcomes were change from baseline in average daily number of moderate-to-severe hot flushes and in daily hot flush severity score at weeks 4 and 12. RESULTS: Six hundred twenty women with an average of 11 moderate-to-severe hot flushes per day at baseline completed at least one on-therapy evaluation for primary efficacy end points; 519 participants completed 12 weeks of treatment, and 368 completed the study. Desvenlafaxine 100 mg/d achieved a significantly greater reduction compared with placebo in average daily number of hot flushes at weeks 4 (P=.013) and 12 (P=.005), reaching a 64% decrease from baseline at week 12, and the 75% responder rate was significantly higher for desvenlafaxine 100 mg (50%) compared with placebo (29%; P=.003; number needed to treat=4.7) at week 12. Average daily severity of hot flushes was significantly lower in the desvenlafaxine 100-mg group compared with placebo at week 12 (P=.020). Desvenlafaxine-treated women reported significantly more treatment-emergent adverse events than placebo-treated women during the first week of therapy only. CONCLUSION: Desvenlafaxine is an effective nonhormonal treatment for vasomotor symptoms in postmenopausal women. Its tolerability profile is consistent with that of other serotonin-norepinephrine reuptake inhibitors. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00421031 LEVEL OF EVIDENCE: I.

Postmenopausal hormone therapy and the risk of breast cancer: a contrary thought.

The most important unanswered question regarding postmenopausal hormone therapy and the risk of breast cancer is whether hormone therapy initiates the growth of new breast cancers or whether the epidemiologic data reflect a hormonal impact on preexisting tumors. In this perspective I review the evidence favoring hormonal effects on preexisting tumors and suggest that exposure to combined estrogen and progestin is beneficial, causing greater differentiation and earlier detection of breast cancers.

The future of postmenopausal hormone therapy: It's time to move forward.

There are good reasons why the use of postmenopausal hormone therapy is at a contemporary low level. But an analysis of these factors provides explanations that offer a basis for appropriate and renewed use. A more optimistic position is supported by an up-to-date appraisal of clinical studies.

Effects of low-dose norethindrone acetate plus ethinyl estradiol (0.5 mg/2.5 microg) in women with postmenopausal symptoms: updated analysis of three randomized, controlled trials.

BACKGROUND: Based on the potential risks of post-menopausal hormone therapy (HT) found by the Women's Health Initiative, guidelines for HT now recommend use of the lowest effective dose and shortest treatment duration consistent with individual treatment goals. Current (2003) guidance established by the US Food and Drug Administration (FDA) recommends that clinical assessments of HT include women with more frequent and more intense vasomotor symptoms than previously studied. Therefore, this analysis was conducted to further assess the efficacy of a low-dose combination of norethindrone acetate and ethinyl estradiol (NA/EE) previously assessed in dose-ranging studies, while meeting conservative FDA trial design and analysis criteria. OBJECTIVES: The aim of this post hoc analysis and overview was to present data on the efficacy and tolerability of a low-dose combination-NA/EE 0.5 mg/2.5 microg-in the treatment of postmenopausal symptoms, based on data from previously published studies of NA/EE. In addition, the effects of low-dose NA/EE on bone and endometrium are briefly reviewed. METHODS: Data from 3 previously published randomized, placebo-controlled trials were analyzed using current FDA guidance for the assessment of HT in postmenopausal women. Studies 1 and 2 assessed the efficacy of NA/EE at various doses, including 0.5 mg/2.5 microg, in vasomotor symptom (hot-flush [HF]) relief over 16 and 12 weeks, respectively, using self-reporting of symptom frequency and intensity (scores: 0=none; 1=mild; 2=moderate; and 3=severe) in daily diaries. Study 3 assessed the effects of NA/EE at various doses, including 0.5 mg/2.5 microg, on bone and endometrium, using quantitative computed tomography of the lumbar spine at 12 and 24 months and endometrial biopsy at 6, 12, 18, and 24 months of treatment. In all 3 studies, women were asked to record vaginal bleeding and spotting in diaries. Any adverse events were recorded in diaries and/or at clinic visits. Physical and gynecologic examinations and standard clinical laboratory testing were conducted at baseline and at appropriate follow-up visits in all 3 studies. RESULTS: Studies 1, 2, and 3 enrolled 219, 266, and 1265 women, respectively. Overall, in studies 1 and 2, 91% of women were white, the mean age was approximately 52 years, and mean time since last menstrual period was approximately 24 months. In study 1, NA/EE 0.5 mg/2.5 microg was associated with significant reductions from baseline in mean weekly total HF frequency from week 4 (63.6%) through week 16 (73.7%) (all, P<0.05). In study 2, the frequency of moderate or severe HFs was decreased by 61.1% at week 4 (P<0.05) and by 82.2% at week 12 (P<0.001) with NA/EE 0.5 mg/2.5 microg, and the mean intensity score was significantly lower than that with placebo at weeks 8 and 12 (both, P=0.001). In study 3, cumulative amenorrhea rates were approximately 90% in the NA/EE 0.5-mg/2.5-microg and placebo groups at 12 months. Lumbar spine bone mineral density (BMD) was maintained at 24 months with NA/EE 0.5 mg/2.5 microg but was significantly decreased from baseline, by 7.4%, in the placebo group (P<0.001). Endometrial hyperplasia was not observed in the group receiving NA/EE 0.5 mg/2.5 microg over 24 months. The tolerability of NA/EE was similar to that of placebo. The most common adverse events experienced with NA/EE were headache (15.2%), abdominal pain (10.2%), and breast pain (9.0%). CONCLUSIONS: The results from this post hoc analysis and overview of 3 previously published studies suggest that NA/EE 0.5 mg/2.5 microg was associated with decreased frequency and intensity of vasomotor symptoms. This dose of NA/EE was also associated with maintenance of BMD over 24 months, a significant positive effect on BMD compared with placebo. Low-dose NA/EE was also associated with cumulative amenorrhea rates comparable to those of placebo and was not associated with endometrial hyperplasia. This dose was well tolerated, with rates of adverse events generally similar to those of placebo.

Efficacy of a new, oral estradiol acetate formulation for relief of menopause symptoms.

OBJECTIVE: To determine the efficacy of three doses of a new, oral formulation of estradiol acetate (EA) for alleviation of vasomotor and urogenital symptoms in postmenopausal women. DESIGN: Two separate 12-week studies were undertaken in postmenopausal women with moderate to severe vasomotor symptoms. In the first study, women were randomly assigned to EA 0.9 mg/day, EA 1.8 mg/day, or placebo (study 1; N = 293), and in the second study to oral EA 0.45 mg/day or placebo (study 2; N = 259). Women recorded the frequency and severity of vasomotor symptoms daily and urogenital symptoms weekly on diary cards. Investigators assessed signs of vaginal atrophy. RESULTS: Frequency of moderate to severe vasomotor symptoms decreased significantly versus placebo, starting at week 2 in the EA 1.8-mg group (P = 0.005), week 3 in the EA 0.9-mg group (P = 0.003), and week 6 in the EA 0.45-mg group (P < 0.05). At week 12, mean percent reduction from baseline in vasomotor-symptom frequency was 91%, 78%, and 61%, respectively. Vasomotor-symptom severity decreased significantly versus placebo, starting at weeks 2 and 3 with EA 1.8 mg and 0.9 mg, respectively, and at week 5 with EA 0.45 mg. Vaginal pH and maturation index improved significantly in all EA groups versus placebo, and some signs and symptoms of vaginal atrophy improved at the EA 0.9- and 1.8-mg doses. Side effects were mild to moderate and consistent with estrogen therapy. CONCLUSIONS: Oral EA at all doses was well tolerated and significantly reduced the frequency and severity of postmenopause symptoms versus placebo.