Vaginal bleeding/spotting with conjugated estrogens/bazedoxifene,conjugated estrogens/medroxyprogesterone acetate,and placebo

ABSTRACT

Objective: In the 1-year phase 3 Selective estrogens, Menopause, And Response to Therapy-5 trial, cumulative amenorrhea rates with conjugated estrogens/bazedoxifene (CE/BZA) were similar to placebo and higher than with conjugated estrogens/medroxyprogesterone acetate (CE/MPA). This post hoc analysis reports bleeding/spotting rates in 4-week intervals (cycles) and 3-month intervals (quarters) with these therapies and the percentage of cases attributable to spotting only.

Methods: Generally healthy postmenopausal women with menopausal symptoms recorded vaginal bleeding/spotting in daily diaries while receiving CE 0.45 mg/BZA 20 mg, CE 0.625 mg/BZA 20 mg, CE 0.45 mg/MPA 1.5 mg, or placebo.

Results: A total of 1596 women in the modified intent-to-treat population contributed data. Incidence of bleeding/spotting was significantly (p < 0.001) lower with CE 0.45 mg/BZA 20 mg (0.54?4.44%), CE 0.625 mg/BZA 20 mg (1.26?5.02%), and placebo (1.55?4.82%) compared with CE 0.45 mg/MPA 1.5 mg (8.81?25.63%) in all 4-week cycles. Each quarter, <10% of women taking CE/BZA doses or placebo had bleeding/spotting, significantly (p < 0.001) less than the 21–36% with CE 0.45 mg/MPA 1.5 mg. Odds ratio for bleeding/spotting with CE 0.45 mg/BZA 20 mg vs CE 0.45 mg/MPA 1.5 mg was 0.1 in each quarter (95% CI, Q1–Q3: 0.1–0.2; Q4: 0.1–0.3). Across all treatments, most (88–100%) bleeding/spotting cases were spotting only. Mean days of bleeding/spotting were <1 per quarter with CE/BZA doses and placebo, which was significantly (p < 0.01) less than the 3–5 days per quarter with CE/MPA.

Conclusions: Bleeding/spotting with CE/BZA treatment was similar to placebo and significantly less frequent than with CE/MPA treatment. Most cases were spotting only across all treatments.     

The Danish osteoporosis prevention study (DOPS): project design and inclusion of 2000 normal perimenopausal women

Objective: In 1990 we initiated a 20 year, partly randomised study (Danish Osteoporosis Prevention Study, DOPS) in order to (a) evaluate clinical, biochemical and osteodensitometric variables as predictors of low bone mass and future osteoporotic fractures, and (b) test the hypothesis, that hormone replacement therapy (HRT) initiated shortly after menopause reduces the risk of later osteoporotic fractures. This report describes study design and baseline characteristics of the DOPS-cohort. Methods: The study design is pragmatic, attempting to mimic the normal clinical situation. Several HRT alternatives are available according to clinical need. It was considered futile, impractical and unethical to use placebo for 20 years. Instead the study focus on hard endpoints (fractures) confirmed by independent persons (peripheral fractures) or by methods which allow investigator blinding (spinal X-rays). Statistical evaluation will focus on intention to treat analyses evaluating the decision of HRT and it’s feasibility. With a compliance of 60% we will have sufficient statistical power (88%) to detect a fracture reduction of 40% in the treatments group. Clinical risk factors, current daily intakes of macronutrients, vitamins and minerals, anthropometric variables, biochemical variables (including bone markers and 25-hydroxyvitamin D), regional bone mineral density (BMD) and total body composition were assessed in all participants at entry and at various follow up intervals. Results: 2016 study participants were recruited by direct mailing to a random sample of 45–58 years old women. In the randomised arm 501 were allocated to HRT and 505 to no treatment. In the non-randomised arm 219 preferred HRT and 791 preferred no treatment. Post-randomisation analysis revealed a slight but significant difference in age (50.01 versus 50.44 years) but no difference in menopausal age, prevalence of hysterectomy, educational level, BMI, serum bone alkaline phosphatase, serum osteocalcin, urine hydroxyproline or serum 25-hydroxyvitamin D. In the non-randomised arm women preferring HRT were closer to menopause, had a higher prevalence of hysterectomy, were better educated, were leaner, and had lower bone turnover than the women, who refused HRT. Conclusion: It is possible to include a sufficient number of perimenopausal women in a randomised 20 year study on the antifracture effect of HRT.     

A randomized controlled trial of goserelin and medroxyprogesterone acetate in the treatment of pelvic congestion

Following identification of the proportion of pelvic congestion among symptomatic patients complaining of chronic pelvic pain, and in a totally asymptomatic group of patients requesting tubal ligation, the efficiency of goserelin acetate versus medroxyprogesterone acetate was compared objectively using pelvic venogram scores, and subjectively by symptom resolution, improvement of psychological status and sexual functioning in a prospective randomized trial in 47 patients with pure pelvic congestion syndrome. Patients received either goserelin acetate (3.6 mg/month for 6 months) or medroxyprogesterone acetate (MPA; 30 mg/day for 6 months). Among patients with chronic pelvic pain, those with pure pelvic congestion were mostly parous, had the most severe pelvic signs and symptom scores, lowest rates of sexual functioning, and higher states of anxiety and depression as compared with others. At 1 year after treatment, goserelin remained superior to MPA in terms of pelvic venographic improvement as an objective measure. In alleviation of signs and symptomatology, improvement of sexual functioning and reduction of anxiety and depressive states as subjective measures, goserelin acetate achieved a statistically significant advantage (P = 0.0001) compared with MPA.     

Clinicopathologic study of uterine endometrial carcinoma in young women aged 40 years and younger

To clarify what constitutes the adequate management of uterine endometrial carcinoma in young women, we reviewed clinicopathologically 31 patients aged 40 years and younger between January 1991 and June 2004. As a primary treatment, 12 cases chose hormonal treatment with medroxyprogesterone acetate (MPA; 600 mg/day) due to no findings of myometrial invasion and diagnosis of a grade 1, well-differentiated adenocarcinoma. In remaining 19 cases, surgery was performed. All the 19 patients who received surgery as a primary treatment are alive, with no evidence of a recurrence of the disease. In the 12 patients who received hormonal treatment, 8 patients eventually received a hysterectomy because of recurrence or no response to MPA. Of these eight patients, myometrial invasion was recognized in three patients. One of the eight patients died of the metastasized disease to the liver and brain after hysterectomy. After hormonal treatment, 4 of the 12 patients were exempted from surgery and showed no evidence of recurrence. Two patients had viable children. Progesterone receptor was negative in one case that died. Careful consideration should be given to hormonal treatment with MPA for the conservative management of endometrial carcinoma in young women. Moreover, MPA is not always a consistent management for every patient.     

哺乳妇女单次注射迪波盖司通~长效避孕针后血清和乳液中MPA浓度变化

目的:探讨中国妇女哺乳期使用迪波盖司通后血清和乳液醋酸甲羟孕酮(MPA)浓度变化。方法:10名产后哺乳妇女单次注射迪波盖司通(含MPA150mg),在注射后的第1、2、4、6、8、10和12周采集血样和乳液样本,用放射免疫方法测定MPA。结果:血清MPA浓度于注射后第1周最高,到第2、4周时下降明显,第4周后浓度下降趋势逐渐缓慢。乳液MPA浓度在第1周为最高,第2周比第1周降低了约1/2,之后10周平均浓度变化波动在5.09-8.15ng/ml之间。观察期间乳液/血清MPA浓度比值和曲线下浓度面积比值均为0.55。对象之间和同一对象不同时间点乳液/血清MPA浓度存在明显个体差异。结论:哺乳期使用迪波盖司通,将导致血液和乳液中含有一定量的MPA。     

Estrogen metabolism in menopausal hormone users in the women's health initiative observational study: Does it differ between estrogen plus progestin and estrogen alone?

The WHI found an unexpected reduced breast cancer risk in women using CEE alone. We hypothesized CEE alone induces estrogen hydroxylation along the 2-pathway rather than the competing 16-pathway, a pattern linked to reduced postmenopausal breast cancer risk. One thousand eight hundred and sixty-four women in a WHIOS case–control study of estrogen metabolism and ovarian and endometrial cancer were studied of whom 609 were current E + P users (351 used CEE + MPA), while 272 used E alone (162 used CEE). Fifteen EM were measured, and analyses were conducted for each metabolite, hydroxylation pathway (2-, 4-, or 16-pathway) and ratios of pathway concentrations using inverse probability weighted linear regression. Compared to E + P users, all EM were higher in E alone users (significant for unconjugated estrone, total/conjugated estradiol, total/unconjugated 2-methoxyestrone, 4-methoxyestrone and unconjugated estriol). The relative concentrations of 2- and 4-pathway EM did not differ between the MHT users (2-pathway EM comprised 15% and 4-pathway EM <2% of the total), but 16-pathway EM were lower in E alone users (p = 0.036). Ratios of 2- and 4-pathway EM compared to 16-pathway EM were significantly higher in E alone compared to E + P users. Similar but not significant patterns were observed in CEE-alone and CEE + MPA users. Our data suggest that compared to E + P users, women using E alone have more extensive metabolism via the 2- vs. the competing 16-pathway. This is consistent with epidemiologic evidence of reduced postmenopausal breast cancer risk associated with this metabolic profile and may provide a clue to the breast cancer risk reduction in CEE alone users during the WHI.     

醋酸甲羟孕酮的极谱行为及其分析应用

目的:研究醋酸甲羟孕酮(MPA)的电极反应机理,拟定了测定MPA的单扫描示波极谱法。方法:用单扫描示波极谱法、快速扫描循环伏安法、恒电位电解法、紫外分光光度法等多种技术进行研究。结果:在醋酸盐缓冲溶液中,MPA的C=C双键首先发生单电子单质子还原,产生了中间体自由基HMPA·。随后HMPA·可以单电子单质子方式进一步还原,形成产物H2MPA;同时也可以与中性MPA分子形成二聚体自由基HMPA·MPA·。在0.2mol·L^-1HAc—NaAc缓冲液中,MPA还原波的二阶导数峰电流iP″与其浓度C_MPA在2.0×10^-6～6.0×10^-5mol·L^-1范围内成线性关系,相关系数γ=0.998。结论:证实MPA的还原过程有中间体自由基参与。     

长效醋酸甲羟孕酮对子宫内膜癌组织中血管内皮生长因子的影响

目的 探讨长效醋酸甲羟孕酮对子宫内膜癌组织中血管内皮生长因子的影响.方法 选择原发性子宫内膜癌患者80例作为观察组,同时选取80例正常增生期子宫内膜组织做对照.比较观察组治疗前后与对照组VEGF的表达情况.结果 治疗前,观察组中VEGF阳性表达较对照组高,差异具有统计学意义(χ2=46.673,P<0.05);治疗后,2组VEGF阳性表达率比较,差异具有统计学意义(χ2=6.972,P<0.05).治疗后,观察组VEGF阳性表达较治疗前降低,差异具有统计学意义(χ2=14.171,P<0.05).治疗前和治疗后,子宫内膜癌患者病变组织中VEGF表达在不同年龄、组织分级、病理分期、病理类型、肌层浸润深度有不同,差异具有统计学意义(P均<0.05).结论 VEGF可通过促进血管形成参与到子宫内膜癌的发生发展过程,采用长效醋酸甲羟孕酮治疗子宫内膜癌可降低患者血管内皮生长因子的表达,从而抑制肿瘤的发生发展.