Hormone therapy initiation after the Women's Health Initiative

OBJECTIVES: To describe hormone therapy (HT) initiation after the 2002 publication of the Women's Health Initiative. DESIGN: Observational cohort (1999-2003) of women ages 40 to 79 years, five health plans, used HT in July 2002 and subsequently discontinued or never used before August 2002. RESULTS: Of discontinuers, 15.8% (3,203 of 20,205) reinitiated HT. Reinitiation was higher among estrogen users (23.8%) versus estrogen with progestin users (11.3%), and lower among those with diabetes (relative risk [RR]=0.68, 95% CI: 0.61-0.76), cardiovascular disease (RR=0.87, 95% CI: 0.83-0.92), and hyperlipidemia (RR=0.83, 95% CI: 0.79-0.88). Only 2.3% (2,072 of 90,261) of never users initiated (August 2002 to December 2003). First-time initiation was associated with cardiovascular disease (RR=1.17, 95% CI: 1.10-1.25) and hyperlipidemia (RR=1.24, 95% CI: 1.17-1.33) and was less common among those with diabetes (RR=0.70, 95% CI: 0.63-0.79). CONCLUSIONS: After the Women's Health Initiative, a minority of women reinitiated or became first-time initiators of HT. Women with cardiovascular disease, diabetes, and hyperlipidemia were less likely to reinitiate; women with cardiovascular disease and hyperlipidemia were more likely to be first-time initiators.     

Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women - results of the Danish Osteoporosis Prevention Study

Objectives: To study the fracture reducing potential of hormonal replacement therapy (HRT) in recent postmenopausal women in a primary preventive scenario. Methods: Prospective controlled comprehensive cohort trial: 2016 healthy women aged 45–58 years, from three to 24 months past last menstrual bleeding were recruited from a random sample of the background population. Mean age was 50.8±2.8 years, and the number of person years followed was 9335.3. There were two main study arms: a randomised arm (randomised to HRT; n=502, or not; n=504) and a non-randomised arm (on HRT; n=221, or not; n=789 by own choice). First line HRT was oral sequential oestradiol/norethisterone in women with intact uterus and oral continuous oestradiol in hysterectomised women. Results: After five years, a total of 156 fractures were sustained by 140 women. There were 51 forearm fractures in 51 women. By intention-to-treat analysis (n=2016), overall fracture risk was borderline statistically significantly reduced (RR=0.73, 95% CI: 0.50–1.05), and forearm fracture risk was significantly reduced (RR=0.45, 95% CI: 0.22–0.90) with HRT. Restricting the analysis to women who had adhered to their initial allocation of either HRT (n=395) or no HRT (n=977) showed a significant reduction in both the overall fracture risk (RR=0.61, 95% CI: 0.39–0.97) and the risk of forearm fractures (RR=0.24, 95% CI: 0.09–0.69). Compliance with HRT was 65% after five years. Conclusions: It is possible to reduce the number of forearm fractures and possibly the total number of fractures in recent postmenopausal women by use of HRT as primary prevention.     

Increased longevity in older users of postmenopausal estrogen therapy: the Leisure World Cohort Study

OBJECTIVE: To examine the effect of postmenopausal estrogen therapy (ET), including duration and recency of use, on all-cause mortality in older women. DESIGN: As part of a prospective cohort study of residents of a California retirement community begun in the early 1980s, Leisure World Cohort women (median age, 73 y) completed a postal health survey including details on ET use and were followed up for 22 years (1981-2003). Age- and multivariate-adjusted risk ratios (RR) and 95% CIs were calculated using proportional hazard regression. RESULTS: Of the 8,801 women, 6,626 died during follow-up (median age, 88 y). ET users had an age-adjusted mortality rate of 52.9 per 1,000 person-years compared with 56.5 among lifetime nonusers (RR = 0.91; 95% CI, 0.87-0.96). Risk of death decreased with both increasing duration of ET and decreasing years since last use (P for trend <0.001). The risk was lowest among long-term (> or =15 y) users (RR = 0.83; 95% CI, 0.74-0.93 for 15-19 y and RR = 0.87; 95% CI, 0.80-0.94 for 20+ y). For long-term users, the age-adjusted mortality rate was 50.4 per 1,000 person-years. Lower-dose users (< or =0.625 mg) had a slightly better survival rate than higher-dose users (RR = 0.84; 95% CI, 0.78-0.91 vs RR = 0.91; 95% CI, 0.83-0.97). Risk did not differ by route of administration (P = 0.56). Further adjustment for potential confounders had little effect on the observed RRs for ET. CONCLUSION: Long-term ET is associated with lower all-cause mortality in older women.     

Gynecologic consequences of long-term, unopposed estrogen replacement therapy

We evaluated the gynecologic risks of unopposed, long-term estrogen use in postmenopausal women. Our medical record review showed that unopposed estrogen users (mean dose, 0.9 mg of conjugated estrogens) had a significantly higher (P < 0.001) incidence of abnormal vaginal bleeding, curettage, hysterectomy, and endometrial cancer. The ratios of occurrence of these events among users compared with non-users were 7.8, 4.9, 6.6 and 7.7. The prevalence of hysterectomy reached 28.2% of users compared with 5.3% of non-users, and endometrial carcinoma developed in 9.9% of users compared with 1.4% of non-users.     

Prevention of osteoporosis and uterine effects in postmenopausal women taking raloxifene for 5 years

OBJECTIVE: Raloxifene hydrochloride (60 mg/day) is a selective estrogen receptor modulator indicated for the prevention and treatment of postmenopausal osteoporosis. Raloxifene treatment for 3 years increases bone mineral density (BMD) and, unlike tamoxifen (a triphenylethylene selective estrogen receptor modulator), does not stimulate the endometrium in healthy postmenopausal women. The effect of longer duration of treatment with raloxifene is not known. Therefore, the main objectives of these analyses are (1) to compare the effect of 5 years of treatment with raloxifene (60 mg/day) with placebo in terms of the likelihood of developing osteoporosis and (2) to evaluate the effect of 5 years of raloxifene treatment on the endometrium and incidence of vaginal bleeding. DESIGN: The current analyses include integrated data from two identically designed, prospective, double-blinded trials including postmenopausal women (mean age, 55 years) randomly assigned to either placebo (n = 143) or raloxifene (60 mg/day; n = 185). Osteoporosis and osteopenia were diagnosed according to World Health Organization criteria, using the manufacturer's database for the lumbar spine and the National Health and Nutrition Examination Survey's 1998 reference base for the hip. Endometrial thickness was determined using transvaginal ultrasonography. Clinical diagnoses of endometrial hyperplasia or endometrial cancer were confirmed by blinded review of histopathology reports. RESULTS: Compared with the case of placebo, raloxifene treatment for 5 years reduced bone turnover markers (osteocalcin: -10.9%, P < 0.001; bone-specific alkaline phosphatase: -7.2%, P = 0.042; urinary C-telopeptide: -11.1%, P = 0.034) and was associated with increased BMD in the lumbar spine (2.8%; P < 0.001) and total hip BMD (2.6%; P < 0.001). Women taking raloxifene were less likely to develop osteoporosis (relative risk [RR] for raloxifene v placebo: 0.13; 95% CI: 0.00, 0.37; P = 0.001) or osteopenia (RR: 0.23; 95% CI: 0.00, 0.81; P = 0.038) at the lumbar spine and were more likely to convert to normal BMD status at the lumbar spine (RR: 4.01; 95% CI: 1.34, 11.23; P = 0.043) and total hip (RR: 3.92; 95% CI: 1.12,14.27; P = 0.011) at 5 years, compared with the case of placebo. Raloxifene also significantly reduced total cholesterol (-5.5%; P < 0.001) and low-density lipoprotein cholesterol (-8.7%; P < 0.001), compared with the case of placebo. No significant changes in high-density lipoprotein cholesterol (P = 0.257) or triglycerides (P = 0.620) were detected. Incidence of hot flashes was higher among women taking raloxifene compared with those taking placebo [raloxifene, 47 (28.8%); placebo, 21 (16.8%); P = 0.017]. Women taking placebo or raloxifene reported a similar incidence of vaginal bleeding (P = 0.999) or of mean endometrial thickness of more than 5 mm at baseline and at each visit, up to the 5-year endpoint (P >/= 0.349). No diagnoses of endometrial hyperplasia or endometrial cancer were made in either treatment group. CONCLUSIONS: Five years of raloxifene treatment in healthy postmenopausal women preserves BMD, significantly reduces the likelihood of development of osteoporosis, and was not associated with an increased rate of vaginal bleeding, endometrial hyperplasia, or endometrial carcinoma, compared with the case of placebo.     

Controversy about uterine effects and safety of SERMs: the saga continues

From the perspective of endometrial safety, there has been great controversy about what special management, if any, tamoxifen-treated patients should undergo. Periodic blind endometrial sampling or transvaginal ultrasound has been advocated by some. Because of the problems associated with either of these techniques alone, we recommended an approach that used transvaginal ultrasound and then proceeded to sonohysterography when the endometrial echo on transvaginal ultrasound was not reliably thin and distinct. The American College of Obstetricians and Gynecologists (ACOG), in its committee opinion, stated that patients receiving tamoxifen therapy should only have an annual pelvic exam with pap smear if they remain asymptomatic. Newer data suggest, however, that there are high- and low-risk groups that can be identified by pretreatment screening. Before tamoxifen therapy, 17% of patients have polyps. These patients have 17 times the incidence of atypical hyperplasia than those whose uterus was negative before tamoxifen therapy. Such findings call into question the validity of the only study of raloxifene where uterine safety was the primary endpoint. In that study, any woman with baseline endometrial findings other than pristinely negative (i.e., low risk) was excluded. However, other raloxifene studies without pretreatment screening show relative risk (RR) = 0.8 (95% CI = 0.2, 2.7) for endometrial carcinoma. This compares with the women over 50 years of age in the Breast Cancer Prevention Trial (National Surgical Adjuvant Breast and Bowel Project P-1) with tamoxifen when the RR = 4.01 (95% CI= 1.70, 10.90). The existence of potentially high- and low-risk groups should be taken into account in any future clinical trials looking at the endometrial safety of selective estrogen receptor modulators (SERMs).     

The role of metformin in polycystic ovary syndrome: a systematic review

This meta-analysis evaluated the effectiveness of metforminin subfertile women with polycystic ovary syndrome (PCOS). Onlyrandomized trials investigating the effectiveness of metforminand PCOS definition consistent with the Rotterdam consensuscriteria, were eligible. Primary outcome was live birth rate.A literature search identified 27 trials. In therapy naïvewomen, we found no evidence of a difference in live birth ratewhen comparing metformin with clomifene citrate (CC) [relativerisks (RR) 0.73; 95% confidence interval (CI) 0.51–1.1]or comparing metformin plus CC with CC (RR 1.0; 95% CI 0.82–1.3).In CC-resistant women, metformin plus CC led to higher livebirth rates than CC alone (RR 6.4; 95% CI 1.2–35); metforminalso led to higher live birth rates than laparoscopic ovariandrilling (LOD) (RR 1.6; 95% CI 1.1–2.5). We found no evidencefor a positive effect of metformin on live birth when addedto LOD (RR 1.3; 95% CI 0.39–4.0) or FSH (RR 1.6; 95% CI0.95–2.9), or when co-administered in IVF (RR 1.5; 95%CI 0.92–2.5). In IVF, metformin led to fewer cases ofovarian hyperstimulation syndrome (OHSS) (RR 0.33; 95% CI 0.13–0.80).This meta-analysis demonstrates that CC is still first choicetherapy for women with therapy naïve PCOS. In CC-resistantwomen, the combination of CC plus metformin is the preferredtreatment option before starting with LOD or FSH. At present,there is no evidence of an improvement in live birth when addingmetformin to LOD or FSH. In IVF, metformin leads to a reducedrisk of OHSS.     

Association of exogenous estrogen and endometrial carcinoma.

To determine the association between the incidence of endometrial cancer and the use of estrogen in menopausal and post-menopausal women, we retrospectively compared 317 patients with adenocarcinoma of the endometrium with an equal number of matched controls having other gynecologic neoplasms; 152 patients used estrogen, as compared to 54 of 317 controls. Thus, the risk of endometrial cancer was 4.5 times greater among women exposed to estrogen therapy. When estrogen use was adjusted for concomitant variables such as obesity, hypertension, diabetes, parity, referral pattern, age at diagnosis, year of diagnosis and other gynecologic neoplasms, the magnitude of the increased relative risk was associated with several of these variables, and was highest in patients without obesity and hypertension. Exogenous estrogen therapy is associated with an increased risk of endometrial carcinoma, but this increased relative risk is less apparent in patients with physiologic characteristics previously associated with an increased risk.     

Hormone replacement in postmenopausal women: impact of progestogens on autonomic tone and blood pressure regulation

OBJECTIVE: Depressed heart rate variability (HRV) reflects an imbalance of autonomic tone and independently predicts increased cardiovascular risk in patients with congestive heart failure or after acute myocardial infarction. While hormone replacement therapy (HRT) with estrogens beneficially modulates autonomic tone and blood pressure (BP) regulation in postmenopausal women, the impact of concomitant treatment with progestogens remains unclear. DESIGN: In this cross-sectional study, HRV and BP were examined in 62 healthy women (ages 48-71 years) using digital beat-to-beat interval recordings of heart rate and 24-hour ambulatory BP measurements. RESULTS: Demographic parameters did not differ among women without HRT (n = 23), on estrogen (n = 17; ERT), or on progestogen-estrogen containing HRT (n = 22; PERT). Total power of HRV was significantly lower, whereas mean heart rate (HR) was significantly higher among women on PERT group versus controls and ERT (total power: 1611 +/- 146 vs. 2497 +/- 308 and 2472 +/- 348 ms(2); heart rate: 80.7 +/- 1.2 vs. 75.0 +/- 1.4 and 74.0 +/- 2.2 bpm; p < 0.05). In addition, low-frequency power and time-dependent parameters of HRV were lower among women on PERT group versus controls and ERT (p < 0.05). ERT use was associated with reduced systolic and diastolic daytime BP, whereas no significant differences were evident PERT users compared with controls. CONCLUSIONS: Progestogen-containing replacement therapy was associated with increased HR and an attenuation of HRV in postmenopausal women. BP was lower in women on ERT, whereas this effect was offset in the PERT group. These observations could at least partially explain the ambiguous results of progestogen-containing HRT on cardiovascular risk in the Heart and Estrogen/Progestin Replacement Study (HERS).     

Endometrial safety and tolerability of AERODIOL(R) (intranasal estradiol) for 1 year

Objective: the purpose of this study was to assess the endometrial safety and patient acceptability of a pulsed estrogen therapy provided by S21400 (intranasal 17 β-estradiol) in the treatment of postmenopausal symptoms. Design: postmenopausal women (n=408) entered an open-label, community based, multicentre trial. Patients received S21400 plus sequential (>90% of patients) or continuous progestogen. Treatment was initiated with a standard daily dose of 300 μg but dose adaptation was possible every 3 months from 150 to 600 μg daily. Endometrial biopsies were performed at entry and at 12 months, and bleeding patterns were recorded at 3-monthly intervals throughout the trial. Results: 71% of patients received 300 μg per day S21400 throughout the study, 3% had their dose decreased, 19% had their dose increased and 7% had their dose both decreased and increased. Three hundred and eleven biopsies were obtained after 12 months of treatment, there were no cases of endometrial hyperplasia. The 95% confidence interval [CI] for the rate of incidence was 0–1.2%. Cyclical bleeding occurred in 82% of sequential treatment cycles. Unexpected bleeding occurred in 5% of the treatment cycles. Presence of unexpected bleeding varied according to the treatment regimen, 15 and 4% of the cycles with combined continuous and sequential regimen, respectively. Unexpected bleeding was mostly spotting. Nasal treatment was well accepted. Nasal symptoms (itching sensation, rhinorrhea and sneezing) were mostly mild in intensity and they led to treatment withdrawal in approximately 3% of patients. The rate of treatment continuation was 85% at 1 year. Conclusions: S21400, in combination with continuous or sequential progestogen, exhibits good endometrial safety and patient acceptability in postmenopausal women.     

Coffee consumption and risk of fractures: a meta-analysis

Introduction

Recent studies have indicated higher risk of fractures among coffee drinkers. To quantitatively assess the association between coffee consumption and the risk of fractures, we conducted this meta-analysis.

Material and methods

We searched MEDLINE and EMBASE for prospective studies reporting the risk of fractures with coffee consumption. Quality of included studies was assessed with the Newcastle Ottawa scale. We conducted a meta-analysis and a cumulative meta-analysis of relative risk (RR) for an increment of one cup of coffee per day, and explored the potential dose-response relationship. Sensitivity analysis was performed where statistical heterogeneity existed.

Results

We included 10 prospective studies covering 214,059 participants and 9,597 cases. There was overall 3.5% higher fracture risk for an increment of one cup of coffee per day (RR = 1.035, 95% CI: 1.019-1.052). Pooled RRs were 1.049 (95% CI: 1.022-1.077) for women and 0.910 (95% CI: 0.873-0.949) for men. Among women, RR was 1.055 (95% CI: 0.999-1.114) for younger participants, and 1.047 (95% CI: 1.016-1.080) for older ones. Cumulative meta-analysis indicated that risk estimates reached a stabilization level (RR = 1.035, 95% CI: 1.019-1.052), and it revealed a positive dose-response relationship between coffee consumption and risk of fractures either for men and women combined or women specifically.

Conclusions

This meta-analysis suggests an overall harm of coffee intake in increasing the risk of fractures, especially for women. But current data are insufficient to reach a convincing conclusion and further research needs to be conducted.     

ADRB2 Gln27Glu基因多态性对经皮冠状动脉介入术后β受体阻滞剂临床疗效的影响

目的: 探讨β₂ 肾上腺素能受体( ADRB2 )Gln27Glu基因多态性对经皮冠状动脉介入术(PCI)后β受体阻滞剂临床疗效的影响。方法: 收集广东省人民医院PCI术后接受β受体阻滞剂治疗的冠心病患者384例,采用TaqMan基因分型技术检测 ADRB2 Gln27Glu基因型,分析Gln27Glu基因多态性对主要不良心脏事件(MACE)的影响。结果: 基因型分布频率符合Hardy-Weinberg平衡(P>0.05),各基因型患者间的一般临床特征没有显著差异(P>0.05);各基因型患者使用β受体阻滞剂种类的构成无显著差异(χ²=9.196,P>0.05);Cox单因素分析显示,左主干病变、糖尿病和高血压是发生MACE的相关因素,相对危险度分别为2.661(95%CI: 1.122~6.307)、2.431(95%CI: 1.127~5.242)和2.980(95%CI: 1.128~7.871),均P<0.05。 ADRB2 Gln27Glu基因多态性对MACE没有显著影响,相对危险度为1.408(95%CI: 0.650~3.053),P>0.05。结论: ADRB2 Gln27Glu基因多态性与PCI术后接受β受体阻滞剂治疗患者的临床疗效无明显相关性。     

Clinical evaluation, dose-finding and acceptability of AERODIOL, the pulsed estrogen therapy for treatment of climacteric symptoms

S21400 (AERODIOL^®) is a new intranasal formulation of 17β-estradiol. It provides a pulsed estrogen therapy that ensures sufficient estrogenisation of tissues to treat estrogen deficiency symptoms, particularly those of the menopause. This multicentric study was designed to determine dose-range, efficacy and acceptability of S21400. One hundred and thirty four women were allocated a daily dose of 100–900 μg for 12 weeks. The doses of 100, 600 and 900 μg were given in two daily administrations, the doses of 200, 300 and 450 μg were given in one and two daily administrations. Oral progestogen was added the last 10–14 days of each cycle of estrogen therapy in all non-hysterectornized women. S21400 showed a dose-effect relationship and provided adequate estrogenisation in more than 80% of patients receiving a dose ranging from 200 to 600 μg daily. Hormonal impregnation was judged sufficient in 23% of women receiving the lowest dose (100 μg). It was often considered excessive for daily doses of 900 μg (36%). After 12 weeks of treatment, efficacy was similar whether the total daily dose was given in one or two administrations. Treatment was well tolerated and accepted, with only minor nasal events (prickling, sneezing). It was perceived by 92% of patients as good or excellent and 81% chose to continue the nasal treatment when it was offered to them. An initial dose of 300 μg per day provides an optimal efficacy/tolerability ratio.

In summary, the pulsed estrogen therapy with AERODIOL^® in one daily administration offers a safe, well accepted and highly effective treatment to alleviate climacteric symptoms. It can be adapted easily to ensure optimal clinical efficacy.     

Efficacy and safety of umifenovir for coronavirus disease 2019 (COVID‐19): A systematic review and meta‐analysis

We conducted this systemic review and meta‐analysis in an attempt to evaluate the efficacy and safety of umifenovir in coronavirus disease 2019 (COVID‐19). We searched PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure, and medRxiv database. We included both retrospective and prospective studies. The mean difference (MD) and risk ratio (RR) with 95% confidence intervals (CI) were applied to assess the effectiveness of umifenovir for COVID‐19. A total of 12 studies with 1052 patients were included in our final studies. Compared with control group, umifenovir was associated with higher negative rate of PCR on day 14 (RR:1.27; 95% CI: 1.04 to 1.55). However, umifenovir is not related to nucleus acid negative conversion time (MD: 0.09; 95% CI: ?1.48 to 1.65), negative rate on day 7 (RR:1.09; 95% CI: 0.91 to 1.31), incidence of composite endpoint (RR:1.20; 95% CI: 0.61 to 2.37), rate of fever alleviation on day 7 (RR:1.00; 95% CI: 0.91 to 1.10), rate of cough alleviation on day 7 (RR:1.00; 95% CI: 0.85 to 1.18), or hospital length of stay (MD: 1.34; 95% CI: ‐2.08 to 4.76). Additionally, umifenovir was safe in COVID‐19 patients (RR for incidence of adverse events: 1.29; 95% CI: 0.57 to 2.92). The results of sensitivity analysis and subgroup analysis were similar to pooled results. There is no evidence to support the use of umifenovir for improving patient‐important outcomes in patients with COVID‐19.     

Fracture risk and bone density of peri- and early postmenopausal women with uterine leiomyomas

OBJECTIVES: Fracture risk and bone mineral density (BMD) among peri- and early postmenopausal women with leiomyomas requiring hysterectomy was evaluated. METHODS: We counted fractures among women with or without leiomyomas using data from the Kuopio Osteoporosis Study. The study population consisted of 6086 women aged 47-56 years with never-use of hormone replacement therapy (HRT) responding to the baseline and 5-year follow-up inquiries. Part of the sample (n=1271) underwent bone densitometry. RESULTS: Hysterectomy was carried out in 927 women, and 59% reported that this was attributable to leiomyomas. The hazard ratio (HR) was 0.68 (95% CI 0.49-0.94) for any and 0.73 (95% CI 0.43-1.26) for distal forearm fracture among women with leiomyomas compared to those without any. Among women postmenopausal at baseline, the corresponding HRs were 0.62 (95% CI 0.44-0.87) and 0.54 (95% CI 0.31-0.96); after adjusting for age, time since menopause weight, height and previous fracture 0.69 (95% CI 0.49-0.97) and 0.63 (95% CI 0.35-1.11). The baseline BMDs were 1.15 g/cm2 among hysterectomized leiomyoma and 1.12 g/cm2 (ns) among non-hysterectomized women at lumbar (L2-L4), and 0.94 and 0.93 g/cm2 (ns) at femoral sites. The follow-up lumbar BMDs were 1.13 and 1.09 g/cm2 (p<0.001) and the corresponding femoral values were 0.90 and 0.89 g/cm2 (ns), respectively. Among postmenopausal women, the corresponding baseline lumbar BMDs were 1.15 and 1.08 g/cm2 (p<0.001), femoral 0.93 and 0.90 g/cm2 (p=0.003); the follow-up lumbar BMDs 1.13 g/cm2 versus 1.07 g/cm2 (p<0.001); femoral BMDs 0.89 versus 0.87 (ns). CONCLUSIONS: Peri- and early postmenopausal women with a history of leiomyomas seem to have better BMD and less fractures compared with those without leiomyomas. This may be mediated through higher estrogen levels leading to higher BMD and the growth of leiomyomas.