Menopause (New York, N.Y.)

Published by Lippincott, Williams & Wilkins
Print ISSN: 1072-3714,1530-0374
Objective: The aim of this study was to evaluate the efficacy and safety of a new low-concentration estriol formulation (0.005% estriol vaginal gel), providing an ultra low dose of estriol per application (50 μg), for the local treatment of postmenopausal vaginal atrophy. Methods: Postmenopausal women with symptoms and signs of vaginal atrophy were enrolled in a prospective, double-blind, placebo-controlled study. Women received either 1 g of vaginal gel containing 50 μg of estriol or placebo gel, daily for 3 weeks and then twice weekly up to 12 weeks. A cytological vaginal study, evaluation of vaginal pH, and assessment of symptoms and signs of vaginal atrophy were performed, and changes between baseline and weeks 3 and 12 were assessed. Adverse events were recorded. Results: A total of 167 women were included (114 received estriol and 53 received placebo). After 12 weeks of therapy, a superiority of estriol compared with placebo gel was shown in the change in maturation value and vaginal pH (P < 0.001 and P < 0.001, respectively). The superiority of estriol was well demonstrated in improvement of vaginal dryness (P = 0.001) and the Global Symptom Score (P = 0.018). Estriol gel proved also superior in the improvement of several of the most outstanding vaginal signs of vaginal atrophy evaluated. After 3 weeks, estriol gel also showed a superiority over the placebo gel in most symptoms and signs evaluated. Treatment-related adverse events were similar among groups. Conclusions: 0.005% Estriol vaginal gel, a new formulation providing an ultra low dose of estriol per application, was shown to be safe and effective in the treatment of postmenopausal vaginal atrophy.
Data from a pivotal efficacy trial have been reanalyzed to explore the impact of age, uterine status, and ovarian status on the efficacy of estradiol gel 0.1% (Divigel) for the treatment of moderate to severe vasomotor symptoms associated with menopause. Post hoc analyses were performed on data from a phase III clinical trial of estradiol gel 0.1%. These analyses explored the effects of age (<50, 50-59, ≥60 y) and uterine and ovarian status (intact or absent) on the change from baseline to week 12 in the frequency and severity of moderate to severe vasomotor symptoms. The effects of age, uterine status, and ovarian status were investigated for each individual dose (1.0, 0.5, and 0.25 g) of estradiol gel 0.1% (separately and pooled) compared with those of placebo. Treatment with any dose of estradiol gel 0.1% reduced both the frequency and severity of moderate to severe vasomotor symptoms from baseline regardless of age, uterine status, or ovarian status. Women 50 years or older, regardless of uterine or ovarian status, treated with estradiol gel 0.1% showed improvement in vasomotor symptoms compared with women given matched placebo. No interactions were detected between estradiol gel 0.1% treatment and age, uterine status, or ovarian status on vasomotor symptom frequency or severity. Estradiol gel 0.1% treatment numerically decreased the frequency and severity of vasomotor symptoms in healthy, postmenopausal women independent of age, uterine status, or ovarian status. To our knowledge, these data are the first to directly explore the effects of age, hysterectomy, and oophorectomy on the efficacy of transdermal estrogen therapy.
The objective of this study was to evaluate the efficacy and safety of three doses of estradiol gel 0.1% (Divigel, a novel formulation consisting of 1 mg estradiol per 1 g transdermal gel) to reduce the frequency and severity of vasomotor symptoms and signs of vulvar and vaginal atrophy associated with menopause. A total of 488 postmenopausal women were evaluated in a 12-week study comparing placebo with estradiol gel 0.1% at doses of 1.0, 0.5, and 0.25 mg/day, with estimated daily deliveries of 0.027, 0.009, and 0.003 mg of estradiol, respectively. Primary endpoints were the change from baseline in daily frequency and severity of moderate to severe vasomotor symptoms. Change from baseline in the signs of vulvar and vaginal atrophy (vaginal pH and percentage of superficial cells) was also assessed. Treatment with estradiol gel 0.1% showed statistically significant reductions in frequency and severity of vasomotor symptoms from baseline compared with placebo as early as Week 2 that were maintained throughout treatment. Signs of vulvar and vaginal atrophy were also significantly improved from baseline with all three doses of estradiol gel 0.1% compared with placebo. Low-dose transdermal estradiol gel 0.1% is an effective treatment for relief of vasomotor symptoms, as well as signs of vulvar and vaginal atrophy, associated with menopause. Estradiol gel 0.1% offers multiple dosing options to individualize patient therapy, including the lowest available effective dose (0.25 mg estradiol, delivering 0.003 mg/d estradiol) to treat the vasomotor symptoms of menopause.
The aim of this study was to assess the efficacy of TU-025, keishibukuryogan, a Japanese prescription herbal medicine used for hot flash management, in American women. This randomized, double-blind, placebo-controlled, phase II trial enrolled 178 postmenopausal women aged 45 to 58 years with a Mayo hot flash score greater than 28 per week who met other inclusion criteria. After a 1-week placebo run-in period, participants were randomly assigned placebo, or 7.5 g/day, or 12.5 g/day groups, for 12 weeks. Primary and secondary outcomes were measured using the Mayo Clinic Hot Flash Diary, the Greene Climacteric Index, and the Pittsburgh Sleep Quality Index. At 3 months, hot flash scores, climacteric symptoms, and sleep quality improved by 34% in the placebo group, 40% in the 7.5 g/day group, and 38% in the 12.5 g/day group. (P < 0.001). However, the differences in changes between groups were not statistically significant (P = 0.990). Diarrhea unexpectedly developed in 20% of participants receiving active medication. For American women, unlike the clinical experience for Japanese women, TU-025 did not significantly reduce the frequency and severity of hot flash symptoms, improve climacteric symptoms, or benefit sleep quality. This study identified several potentially significant methodological factors to be considered in future scientific assessments of traditional Asian medicines.
The present study was designed to determine whether Fructus Ligustri Lucidi (FLL) ethanol extract can directly regulate vitamin D metabolism both in vivo and in vitro. Eleven-month-old, aged Sprague-Dawley sham-operated and ovariectomized (OVX) female rats were fed a normal-calcium (Ca) diet (0.6% Ca, 0.65% phosphorus) and received either FLL (700 mg/kg) or vehicle daily for 12 weeks. The in vitro effects of FLL on vitamin D metabolism were studied using primary cultures of the rat renal proximal tubules. mRNA and protein expressions of 25-hydroxyvitamin D-1α hydroxylase (1-OHase) and vitamin D receptor (VDR) in the kidney and proximal tubule were measured using real-time polymerase chain reaction and Western blotting, respectively. The concentrations of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) synthesized by renal 1-OHase were measured by a competitive enzyme immunoassay. FLL treatment significantly increased serum 1,25(OH)2D3 levels in both sham (P < 0.01) and OVX (P < 0.05) rats. FLL increased renal 1-OHase and VDR protein and mRNA expressions in sham rats. Protein expression of renal 1-OHase, but not VDR, was also up-regulated in OVX rats during FLL treatment. 1-OHase mRNA and 1-OHase activity were increased by FLL treatment in primary cultures of renal proximal tubule cells. FLL could increase the circulating levels of 1,25(OH)2D3 in vivo in aged female rats by directly stimulating 1-OHase activity. Thus, it might be an ideal oral agent that can help to improve the ability to induce 1,25(OH)2D3 synthesis and Ca balance in postmenopausal women who are of high risk of developing osteoporosis.
More than 50% of all fractures occur in people without osteoporosis. Hormone therapy increases bone density, improves postural balance, and reduces fracture risk in postmenopausal women. It is unclear whether tibolone, a synthetic steroid hormone drug, can improve muscle strength. Thus, the aim of this study was to study the effects of low-dose tibolone therapy on muscle strength in older women. Eighty healthy women (69 completed the study) 60 years or older were recruited through advertising in the local media. They were randomly allocated to receive either tibolone 1.25 mg/day or placebo for 6 months. The stand-up test was used to assess leg muscle strength and balance. Handgrip and leg muscle strength were measured using JAMAR and modified Cybex dynamometers. Baseline characteristics, including serum estradiol values and muscle strength, were similar in the two groups. Compliance with the therapy regimen was very high, averaging more than 97% in both groups. After 6 months, mean values for handgrip strength, knee extensor strength, and average time to perform 10 stands were improved numerically in both groups compared with values during baseline. However, there were no significant differences in these parameters within or between groups, and differences remained nonsignificant after adjustment for age, serum estradiol, and baseline value. Short-term treatment with low-dose tibolone (1.25 mg/d) seems not to affect muscle strength in older women.
To investigate endometrial safety by assessment of endometrial biopsy samples and the tolerability and efficacy of the special Actaea or Cimicifuga racemosa extract (CR BNO 1055). Four hundred postmenopausal women with symptoms related to estrogen deficiency were enrolled into a prospective, open-label, multinational, multicenter study. Treatment duration (daily dose corresponds to 40 mg of herbal drug) was 52 weeks. To determine the probability of endometrial hyperplasia and more serious adverse endometrial outcome, the point estimator and upper limit of 95% CI were calculated. Descriptive statistics was used to assess the secondary endpoints. Endometrial safety has been proven because no case of hyperplasia or more serious adverse endometrial outcome occurred (point estimate: 0.0; upper limit of 95% CI: 0.011). Endometrial thickness, which was measured by endovaginal ultrasonography, did not show an increase. The number and intensity of hot flushes were markedly decreased. The dropout rate was less than 10%. The overall tolerability was good. The lack of endometrial proliferation and improvement of climacteric complaints as well as only few gynecologic organ-related adverse events are reported for the first time after a treatment period of 1 year. Due to the improved benefit:risk ratio, it must be assumed that the Cimicifuga racemosa special extract BNO 1055 is a safe alternative for treatment of climacteric complaints.
Baseline characteristics of the participants of the TRACE study
Exercise and exercise/BNO 1055 effects on primary study endpoints
Exercise and exercise/BNO 1055 effects on menopausal symptoms
Exercise and exercise/BNO 1055 effects on body composition
Exercise and exercise/BNO 1055 effects on maximum aerobic capacity
The aim of this study was to determine the effect of periodized exercise training with and without Cimicifuga racemosa (CR) on bone mineral density (BMD) and 10-year coronary heart disease (CHD) risk in early postmenopausal women. A total of 128 women were randomly assigned to three subgroups: exercise (EG, n = 43), exercise and CR supplementation (EGCR, n = 43), and wellness control (control group [CG], n = 42). Both exercise groups performed a periodized exercise program with high-intensity-resistance/high-impact exercise dedicated to bone parameters interspersed by blocks of 10 weeks of training focusing on CHD parameters. In addition to the exercise program, the EGCR was supplemented with 40 mg/day of CR according to the specification of the manufacturer. A low-intensity exercise program of 60 minutes per week for a period of 10 weeks interspersed with 10-week blocks without exercise was performed in the CG. Primary endpoints were BMD and 10-year CHD risk proposed by Wilson. Secondary endpoints were body composition and menopausal symptoms. BMD at the lumbar spine was maintained in both exercise groups (EG, -0.1% +/- 2.2%, P = 0.74; EGCR, -0.4% +/- 2.4%, P = 0.40) and significantly decreased (P < 0.001) in the CG (2.0% +/- 2.0%). Both exercise groups significantly differed from the CG (P = 0.001 and 0.005 for the EG and EGCR, respectively); however, no differences between the exercise groups with and without CR was determined. Although slight increases in femoral neck BMD were determined in both exercise groups (EG, 0.5% +/- 3.0%, P = 0.36; EGCR, 0.4% +/- 3.1%, P = 0.52), a reduction was assessed in the CG (-0.6% +/- 2.7%, P = 0.29). No significant differences were determined between the groups. The 10-year CHD risk significantly increased in the EGCR (12.9% +/- 25.1%, P = 0.018) and in the CG (16.5% +/- 27.8%, P = 0.007). The EG did not show corresponding changes (-2.7% +/- 21.9%, P = 0.60). However, no significant between-group differences were observed. In conclusion our exercise program favorably affected bone, menopausal symptoms, lean body mass, and, to a smaller extent, 10-year CHD risk in early postmenopausal women. Adjuvant supplementation of CR did not enhance these positive effects.
The aim of this study was to critically assess whether acupuncture therapy reduces vasomotor menopausal symptoms and to evaluate the adverse effects of acupuncture therapy on the basis of the results of randomized controlled trials (RCTs). Nineteen electronic databases, including English, Korean, Japanese, and Chinese databases, were systematically searched for RCTs in which acupuncture was used to reduce vasomotor menopausal symptoms before July 2008. There were no language restrictions. The methodological quality of the eligible studies was assessed using the categories provided by the Menstrual Disorders and Subfertility Review Group. Eleven studies, which included a total of 764 individual cases, were systematically reviewed. The methodological quality of the trials varied substantially. Six trials compared acupuncture treatment to sham or placebo acupuncture. Only one study using a nonpenetrating placebo needle found a significant difference in the severity outcomes of hot flashes between groups (mean difference, 0.48; 95% CI, 0.05-0.91). Five studies reported a reduced frequency of hot flashes within groups; however, none found a significant difference between groups. An analysis of the outcomes of the trials that compared acupuncture with hormone therapy or oryzanol for reducing vasomotor symptoms showed that acupuncture was superior. Three RCTs reported minimal acupuncture-related adverse events. There is no evidence from RCTs that acupuncture is an effective treatment in comparison to sham acupuncture for reducing menopausal hot flashes. Some studies have shown that acupuncture therapies are better than hormone therapy for reducing vasomotor symptoms. However, the number of RCTs compared with a nonpenetrating placebo control needle or hormone therapy was too small, and the methodological quality of some of the RCTs was poor. Further evaluation of the effects of acupuncture on vasomotor menopausal symptoms based on a well-controlled placebo trial is therefore warranted.
This study aims to investigate the effects of early growth response 1 (Egr1) on miR-106a/signal transducer and activator of transcription 3 (STAT3) regulating cognitive impairment in an ovariectomy model. Using the Morris water maze test, we assessed escape latency and time spent in a quadrant among mice at 6, 8, and 12 weeks after ovariectomy and their age-matched controls (n = 15 each group). Egr1, miR-106a, and STAT3 messenger RNA expression (n = 7) in the hippocampus and cortex of mice at 6, 8, and 12 weeks after ovariectomy was detected by quantitative real-time polymerase chain reaction, whereas Egr1, phospho-STAT3 (p-STAT3), and STAT3 protein expression (n = 8) was evaluated by Western blot analysis. Moreover, alterations in miR-106a and STAT3 expression were investigated in neuroblastoma (SH-SY5Y) cells transfected with a human Egr1 interference fragment (si-Egr1) or an Egr1-overexpressing plasmid (GV141-Egr1), respectively. Escape latency was significantly increased and time spent in a platform quadrant was reduced in mice at 12 weeks after ovariectomy compared with age-matched controls. Egr1 and miR-106a expression was obviously increased in the hippocampus and cortex at 12 weeks after ovariectomy, whereas STAT3 levels were decreased compared with 12-week controls. After SH-SY5Y cell transfection with the si-Egr1 fragment, miR-106a levels decreased and STAT3/p-STAT3 levels increased, whereas cotransfection of the miR-106a mimic caused a significant decrease in STAT3 levels. MiR-106a messenger RNA expression was significantly increased and STAT3/p-STAT3 protein levels were decreased by Egr1 overexpression, whereas simultaneous transfection with the miR-106a inhibitor inhibited alterations in STAT3 levels. This study suggests that Egr1 decreases STAT3 expression via miR-106a in ovariectomized mice with cognitive impairment, indicating that Egr1 represents a potential target for therapeutic intervention in postmenopausal cognitive decline.
To investigate the effect of estrogen therapy on the structural and functional properties of the middle cerebral artery during ischemia and reperfusion. Ovariectomized (OVX; n = 8) and ovariectomized with estrogen therapy (OVX+EST; n = 8) female Sprague-Dawley rats were exposed to 1 hour of ischemia using a model of temporary focal ischemia of the middle cerebral artery with 24 hours of reperfusion and compared to sham controls (CTL; n = 8). After occlusion and reperfusion, right middle cerebral arteries were removed from the brain and mounted on glass cannulas in a chamber that allowed for control over transmural pressure and measurement of lumen diameter. Lumen diameter was measured in response to increased transmural pressure (myogenic tone) as well as response to nitro-L-arginine, serotonin, and nifedipine. Cerebrovascular reactivity was compared to other stroke outcome measures, including infarct volume (%) and neurologic deficit. Serum estrogen was increased in OVX+EST rats (60.5 +/- 18.2 pg/mL) compared to OVX (0.2 +/- 0.2 pg/mL P < 0.05 vs OVX+EST) and CTL animals (1.3 +/- 1.0 pg/mL P > 0.05 vs OVX). OVX showed significantly less myogenic tone at 75 mm Hg (13.8 +/- 3.6%, P < 0.05 vs CTL) than CTL (29.8 +/- 4.7%) that was partially restored by estrogen therapy (21.2 +/- 4.5; P > 0.05). At serotonin concentrations of 10(-7) M, 3 x 10(-7) M, and 10(-6) M, the vessels from ischemic OVX rats showed significantly greater constriction (20.9 +/- 2.1%, 35.0 +/- 3.9%, and 39.4 +/- 3.4%, respectively) compared to nonischemic CTL rats (6.3 +/- 1.1%, 11.3 +/- 1.8%, and 16.8 +/- 2.5%, respectively P < 0.05). Estrogen therapy resulted in intermediate responses (18.2 +/- 5.3%, 25.2 +/- 6.6%, and 28.2 +/- 6.5%, respectively) that were not significantly different from the other groups. In addition, ischemia resulted in significantly greater dilation in response to 0.01 microM nifedipine in vessels from OVX animals (51.1 +/- 8.0%) compared to nonischemic CTL (18.0 +/- 3.8%; P < 0.05) and estrogen therapy resulted in an intermediate response (38.0 +/- 10.6; P > 0.05). Both reactivity to nitro-L-arginine and passive distensibility were not different among groups. There were no differences in percent infarct or neurologic deficit between ischemic groups. The influence of ischemia and reperfusion on vessel function was more dominant than that of estrogen therapy. However, estrogen therapy seemed to partially restore vessel function to similar levels as nonischemic vessels.
To study the relationship between current menopause status, occurrence of menopause transition during cancer treatment, and prevalence and severity of possible menopause-related symptoms. Data from the Cancer and Menopause Study (CAMS), a tumor-registry-based cohort of breast cancer survivors (BCS) diagnosed before age 50, were used. Using a standardized symptom checklist, women reported whether they were not at all, slightly, moderately, quite, or extremely bothered in the past 4 weeks by hot flashes, night sweats, vaginal dryness, pain with intercourse, breast sensitivity, joint pains, frequent mood changes, restless sleep, weight gain, forgetfulness, and difficulty concentrating. Current menopause status (by standard categories based on menstruation) and whether a persistent menopause transition occurred during cancer treatment were the main exposures. Linear (symptom severity as continuous outcome) and logistic (symptom present vs absent) regression models were adjusted for age, ethnicity, current smoking, alcohol use, chemotherapy, tamoxifen, body mass index, and depression scores. Mean age of the participants was 50 years. The prevalence of symptoms was high. Hot flashes occurred in 17%, 51%, and 71% of pre-, peri-, and postmenopausal BCS, respectively. Hot flashes, vaginal dryness, and pain with intercourse were more severe in postmenopausal compared with perimenopausal BCS. Having had a transition during breast cancer treatment was associated with worse hot flash severity, independent of current menopause status. Menopause-related symptoms are common in BCS. Effective treatment options are needed. Having a treatment-related transition confers a persistent effect on hot flash severity. Clinicians should include this information when counseling women on potential outcomes of their cancer therapy.
To evaluate factors associated with the sexuality of middle-aged women. Cross-sectional, population-based survey using an anonymous self-response questionnaire. A total of 276 Brazilian-born women, 40 to 65 years old with at least 11 years of formal education, participated in the study. The evaluation instrument was based on the Short Personal Experiences Questionnaire. Seven components were analyzed: satisfaction in sexual activities, orgasm, intensity of desire, self-classification of sexual life, frequency of arousal, sexual activity, and sexual fantasies. Sociodemographic, clinical, behavioral, and reproductive factors were evaluated. Data were analyzed using the chi and Fisher exact tests and Poisson multiple regression analysis. Prevalence ratios (PRs) and their 95% CIs were calculated. The median sexuality score was 9 (range, 2.45-13.77). Bivariate analysis indicated that being 50 years of age or older; in the menopausal transition or postmenopause; not having a sexual partner; reporting hot flushes, insomnia, depression, nervousness, sedentary lifestyle, arterial hypertension, or urinary incontinence; and poor self-perception of health were significantly associated with a below median sexuality score. Multiple regression analysis showed that the prevalence of below median scores was higher in older women (prevalence ratio [PR] = 1.03, 95% CI: 1.01-1.05) and in those with insomnia (PR = 1.46, 95% CI: 1.08-1.96). Having a sexual partner (PR = 0.68, 95% CI: 0.50-0.92) and feeling well (PR = 0.73, 95% CI: 0.57-0.94) was associated with a protective effect against a below median sexuality score. Older women and those with insomnia were more likely to have a low sexuality score, whereas those with a sexual partner and who felt well were less likely to have a low sexuality score.
Double-blind randomized controlled trials of estrogen and/or testosterone on sexual function among natural or surgical menopause in women are reviewed. Power, validity, hormone levels, and methodological issues were examined. Certain types of estrogen therapy were associated with increased frequency of sexual activity, enjoyment, desire, arousal, fantasies, satisfaction, vaginal lubrication, and feeling physically attractive, and reduced dyspareunia, vaginal dryness, and sexual problems. Certain types of testosterone therapy (combined with estrogen) were associated with higher frequency of sexual activity, satisfaction with that frequency of sexual activity, interest, enjoyment, desire, thoughts and fantasies, arousal, responsiveness, and pleasure. Whether specific serum hormone levels are related to sexual functioning and how these group effects apply to individual women are unclear. Other unknowns include long-term safety, optimal types, doses and routes of therapy, which women will be more likely to benefit from (or be put at risk), and the precise interplay between the two sex hormones.
Menopause is associated with physiological and psychological changes that influence sexuality. During menopause, the primary biological change is a decrease in circulating estrogen levels. Estrogen deficiency initially accounts for altered bleeding and diminished vaginal lubrication. Continual estrogen loss often leads to numerous signs and symptoms, including changes in the vascular and urogenital systems. Alterations in mood, sleep, and cognitive functioning are common as well. These changes may contribute to lower self-esteem, poorer self-image, and diminished sexual responsiveness and sexual desire. Other important nonhormonal factors that affect sexuality are health status and current medications, changes in or dissatisfaction with the partner relationship, social status, and cultural attitudes toward older women. The problems in sexual functioning related to estrogen deficiency can be treated with hormone therapy that includes estrogens alone and estrogens combined with androgens. Vaginal lubricants and moisturizers also may be useful in ameliorating postmenopausal sexual complaints. This article reviews the literature on the impact of menopausal estrogen loss on sexuality and on the effect of hormone therapy on sexual function during menopause.
The aim of the study was to investigate whether the -604T>C, 1192G>A, and 1719A>T polymorphisms in the kinase insert domain-containing receptor (KDR) gene confer risk for premature ovarian failure (POF) in Korean women. DNA samples from 133 POF patients and 230 controls were genotyped for the three KDR single nucleotide polymorphisms by polymerase chain reaction-restriction fragment length polymorphism analysis. The POF patients had significantly increased frequencies of the KDR -604TC and -604TC + CC genotypes (odds ratio [OR], 1.975; 95% CI, 1.219-3.201 and OR, 1.948; 95% CI, 1.221-3.109, respectively) and of the -604TC + CC/1192GG combined genotype (OR, 2.271; 95% CI, 1.359-3.795) and a decreased frequency of the 1192GA genotype (OR, 0.457; 95% CI, 0.231-0.905) compared with the controls. The genotype frequency of the 1719A>T polymorphism was not significantly different between the two groups. The frequencies of the KDR -604C/1192G/1719T, -604C/1192G, and -604C/1719T haplotypes (OR, 3.319; 95% CI, 1.564-7.041; OR, 2.083; 95% CI, 1.351-3.212; and OR, 1.979; 95% CI, 1.073-3.649, respectively) were significantly higher among POF patients than controls, whereas the -604T/1719T haplotype frequency (OR, 0.657; 95% CI, 0.472-0.915) was lower among POF patients. Carriers of the KDR -604C variant allele (-604TC and -604TC + CC genotypes; -604TC + CC/1192GG combined genotype; -604C/1192G/1719T haplotype, -604C/1192G haplotype, -604C/1719T haplotype) are consistently more prevalent among POF patients than among controls, suggesting that the KDR -604C allele may increase the risk of POF development in Korean women.
11β-Hydroxysteroid dehydrogenase type I (11βHSD1) regenerates active cortisol from inert cortisone in adipose tissue. Elevated adipose tissue 11βHSD1 activity is observed in obese humans and rodents, where it is linked to obesity and its metabolic consequences. Menopause is also associated with increased abdominal fat accumulation, suggesting that estrogen is also important in adipose tissue metabolism. The purpose of this current study was to establish whether estrogen signaling through estrogen receptor α (ER-α) and estrogen receptor β (ER-β) could influence 11βHSD1 in premenopausal and postmenopausal adipose tissues. Nineteen premenopausal (aged 26 ± 5 y; body mass index, 23.6 ± 1.6 kg/m) and 23 postmenopausal (aged 63 ± 4 y; body mass index, 23.4 ± 1.9 kg/m) healthy women were studied. Subcutaneous adipose tissue biopsies and fasting venous blood samples were taken. Body composition was measured by bioelectrical impedance analysis. Human Simpson-Golabi-Behmel syndrome adipocyte cells were treated with ER-α- and ER-β-specific agonists for 24 hours. Basic anthropometric data, serum 17β-estradiol and progesterone concentrations, ER-α and ER-β messenger RNA (mRNA) levels, and 11βHSD1 mRNA, protein, and activity levels were assessed. ER-β and 11βHSD1, but not ER-α, mRNAs were significantly increased in adipose tissue from postmenopausal women compared with premenopausal women. ER-β had a significant positive correlation with the mRNA level of 11βHSD1 in adipose tissue from premenopausal and postmenopausal women. This association between ER-β and 11βHSD1 was greatest in adipose tissue from postmenopausal women. In human Simpson-Golabi-Behmel syndrome adipocytes, diarylpropiolnitrile, a selective ER-β agonist, increased 11βHSD1 mRNA, protein, and activity levels. We conclude that, in adipose tissue, ER-β-mediated estrogen signaling can up-regulate 11βHSD1 and that this may be of particular importance in postmenopausal women.
To compare the mRNA expression of vascular endothelial growth factor (VEGF) 121 and 165 isoforms and thrombospondin-1 (TSP-1) after incubation with tibolone and tibolone metabolites 3alpha-hydroxytibolone, 3beta-hydroxytibolone, Delta4-tibolone, and 17beta-estradiol (E2) in cultured Ishikawa cells. Ishikawa cells (immortalized from a well-differentiated human adenocarcinoma cell line) were cultured in vitro to confluence. Tibolone, 3alpha-hydroxytibolone, 3beta-hydroxytibolone, Delta4-tibolone and E2 at concentrations of 1.0, 0.1 and 0.01 micromol/L were added to confluent cells and further cultured for an additional 24 h. Control cells were treated with medium in absence of hormone. Total RNA was extracted from control and treated Ishikawa cells. After reverse transcription, VEGF, TSP-1 and the housekeeping gene, beta-actin cDNAs, were amplified in a polymerase chain reaction spiked with 33p-dCTP. Relative abundance of VEGF 121 and 165 isoforms and TSP-1 mRNA was measured by scintillation spectroscopy. E2, tibolone, 3alpha-hydroxytibolone, and 3beta-hydroxytibolone increased both VEGF 121 and 165 mRNA compared with the control. However, Delta4-tibolone had no effect on either VEGF 121 or 165 mRNA compared with the control. Delta4-Tibolone increased TSP-1 mRNA expression compared with control levels. E2, tibolone, 3alpha-hydroxytibolone, and 3beta-hydroxytibolone did not increase TSP-1 mRNA expression at any concentration. Tibolone and the 3alpha- and 3beta-tibolone metabolites with E2 increased VEGF 121 and 165 isoforms. Conversely, Delta4-tibolone, which is reported to have progestational-like activity, did not stimulate VEGF 121 and VEGF 165 but increased TSP-1 mRNA synthesis in cultured Ishikawa cells. We hypothesize, based on these data, that the clinical finding of no endometrial growth in women using tibolone may be partly related to alterations in these angiogenic factors.
The aim of this study was to evaluate the verbal learning and memory performance of postmenopausal women who received tualang honey (Agro Mas) in comparison with women receiving estrogen plus progestin therapy and untreated controls. A total of 102 postmenopausal women were recruited and randomly assigned to three groups: tualang honey (20 g/d)[corrected], estrogen plus progestin therapy (Femoston 1/5), and untreated control. Their verbal learning and memory performances were assessed using the Malay version of the Auditory Verbal Learning Test before and after 16 weeks of intervention. Data were analyzed using the repeated-measures analysis of variance, and a P value of less than 0.05 was considered significant. There were significant differences in the mean scores of total learning as well as the mean scores of trials A1, A5, A6, and A7 between the three groups. There were also significant differences in the overall mean scores of total learning and trials A1 and A5 between both estrogen plus progestin therapy and tualang honey groups when compared with the untreated control group. However, significant differences in the mean score for trials A6 and A7 were only observed between the estrogen plus progestin therapy and untreated control groups. Postmenopausal women who received tualang honey showed improvement in their immediate memory but not in immediate memory after the interference and delayed recall. This is comparable with the improvement seen in women receiving estrogen plus progestin therapy.
Serum cancer antigen (CA) 125 is the only biomarker used frequently in women with or at risk for ovarian cancer. However, the same reference level is used before and after (prophylactic) bilateral salpingo-oophorectomy (BSO). We evaluated the effect of BSO on CA125 level in BRCA mutation carriers and tested which factors interact with the change in CA125 level. All women who participated in the Nijmegen gynecological screening program and underwent prophylactic BSO were included. Information was obtained on age, smoking, menopausal state, previous hysterectomy and breast cancer, histopathological examination of the adnexa, hormone therapy use, and CA125 level before and after surgical operation. Ovarian volume was calculated. The logarithmic-transformed CA125 levels were used in a linear mixed model to study the relative change in CA125 level and possible interaction. In 60 women, a relative decrease of 18% in CA125 level after BSO was found (P < 0.01). The median serum CA125 level was 10.15 U/mL before and 8.36 U/mL after BSO. Menopausal state interacted with CA125 before and after the surgical operation (P < 0.01). In addition, ovarian volume did not explain the difference in CA125 level (P = 0.94). BRCA mutation carriers show a relative decrease in CA125 level after BSO. Menopausal state interacts with CA125. Ovarian volume was excluded as a confounder. Possibly, the hormonal effect of ovaries plays a role in the CA125 level. Our study suggests that not the reference level of 35 U/mL but a lower level, as already suggested for postmenopausal women, should be applied to women after a salpingo-oophorectomy.
Osteoprotegerin (OPG), an inhibitor of osteoclastogenesis and osteoclast activation, has been reported to be linked to vascular biology. The aim of this study was to clarify the relationships between circulating OPG and the risk factors for vascular disorders in postmenopausal women. Eighty Japanese postmenopausal women were enrolled in this cross-sectional study. Clinical parameters (age, number of years since menopause, body mass index, systolic and diastolic blood pressure); serum concentrations of OPG, creatinine, calcium, and phosphorus; serum lipid profile; plasma glucose; and bone mineral density of the L2-4 vertebral bodies were determined for each woman. In rank-order correlation analysis, serum OPG concentrations had significant positive correlations with age (r = 0.29, P = 0.03), systolic blood pressure (r = 0.45, P < 0.01), diastolic blood pressure (r = 0.34, P < 0.01), and serum creatinine (r = 0.29, P = 0.04). Serum OPG concentration also had a marginally significant negative correlation with bone mineral density of the L2-4 vertebral bodies (r = -0.25, P = 0.06). However, serum OPG did not correlate with body mass index, serum lipid profile, or plasma glucose. The correlation of serum OPG with systolic blood pressure persisted after adjustment for both age and serum creatinine. These results suggest that increased circulating OPG in postmenopausal women is closely related to higher systolic blood pressure, which could cause atherosclerosis.
Objective and design: To review the relevant literature on the effect of surgical menopause on cardiovascular disease (CVD). Results and conclusions: Early menopause (before age 50) is associated with an increased risk of CVD. Bilateral oophorectomy around the time of menopause may impart either a small influence or no effect on increasing the risk of CVD; however, bilateral oophorectomy before menopause significantly increases the risk. Some data suggest a protective effect of estrogen therapy in this setting exist. The CVD risk is principally that of coronary heart disease and not cerebrovascular disease. Mortality rates may be increased in women with early menopause, either spontaneous or surgically induced. Hysterectomy per se, without bilateral oophorectomy, does not seem to increase CVD risk.
Flow diagram of progress through the phases of the randomized trial based on Consolidated Standards of Reporting Trials (CONSORT) recommendations. TCM, traditional Chinese medicine.
Group and baseline characteristics of the four study groups
A: Mean weekly hot flush severity scores as percentage of baseline. B: Mean weekly hot flush frequency scores as percentage of baseline. aWithin-group changes from baseline to postintervention. bWithin-group changes from baseline to follow-up. cBetween-group changes within the same intervention method from baseline to postintervention. dBetween-group changes within the same intervention method from baseline to follow-up. *P < 0.05. **P < 0.01. TCM, traditional Chinese medicine; AP, acupuncture; CHM, Chinese herbal medicine; ns, not significant.
Changes in hot flushes and MRS II scores in the AP groups
Changes in hot flushes and MRS II scores in the CHM groups
Objective: The aim of this study was to evaluate the feasibility of a clinical trial investigating the effects of acupuncture (AP) and Chinese herbal medicine (CHM) on hot flushes and quality of life in postmenopausal women. Methods: Forty postmenopausal women reporting at least 20 hot flushes per week were enrolled in a randomized controlled trial. They were randomly allocated to receive traditional Chinese medicine (TCM) AP, sham AP, verum CHM, or placebo CHM for 12 weeks. Follow-up assessment was conducted 12 weeks after intervention. Primary outcome measures included hot flush frequency and severity. As a secondary outcome measure, the severity of menopausal symptoms was assessed using the Menopause Rating Scale (MRS) II. Results: TCM AP induced a significant decline in all outcome measures from pretreatment to posttreatment compared with sham AP (hot flush frequency, P = 0.016; hot flush severity, P = 0.013; MRS, P < 0.001). In the TCM AP group, a larger decrease in MRS scores persisted from pretreatment to follow-up (P = 0.048). No significant differences were noted between the verum CHM group and the placebo CHM group. Compared with the verum CHM group, there was a significant decrease in MRS scores (P = 0.002) and a trend toward a stronger decrease in hot flush severity (P = 0.06) in the TCM AP group from pretreatment to posttreatment. Conclusions: TCM AP is superior to sham AP and verum CHM in reducing menopausal symptoms, whereas verum CHM shows no significant improvements when compared with placebo CHM.
To evaluate the relationship between the FMR1 premutation and premature ovarian failure (POF) in the Spanish population and the possible incorporation of this test in gynecological procedures for women with POF or early menopause (EM). Clinical and molecular genetic study. Ninety-eight premutated and six full-mutated carriers of fragile X syndrome and 43 women with POF were studied by polymerase chain reaction and Southern blot analysis for the CGG repeat expansion in the FMR1 gene. Among premutated carriers, 12.2% (12 of 98) presented with POF, and 15.3% (15 of 98) presented with EM. Neither POF nor EM was observed in any of the six full-mutated women. Two women of 43 from the POF population (4.65%) were carriers for the CGG premutation in the FMR1 gene. No correlation between CGG expansion size and age at menopause was found. A biased paternal origin of the premutation and a high twinning incidence was found in all premutated women, whether they had POF or not. Our data support the hypothesis that the FMR1 gene is one of the genes associated with POF and EM. Analysis of the CGG expansion in the FMR1 gene may be justified in women with POF and EM until the real role of the FMR1 premutation is determined.
Objective: The aim of our study was to investigate whether methylenetetrahydrofolate reductase (MTHFR) gene variant (MTHFR 677C>T) and thymidylate synthase (TS) gene variants (TS enhancer region [TSER] and TS 1494del6) confer a risk for premature ovarian failure (POF). Methods: We genotyped 136 POF patients and 236 controls among Korean women for the three single nucleotide polymorphism sites using polymerase chain reaction restriction fragment length polymorphism analysis. Differences in the MTHFR 677C>T, TSER, and TS 1494del6 genotype frequencies between POF patients and controls were compared, and odds ratios (ORs) and 95% CIs were determined as a measure of the strength of the association between genotypes and POF. Results: The MTHFR 677CT and CT + TT variant genotypes were more frequent in POF patients than in controls (OR, 2.249; 95% CI, 1.317-3.843; and OR, 2.132; 95% CI, 1.268-3.585, respectively). The combined genotype frequencies of MTHFR 677CT + TT/TSER 3R3R and 677CT + TT/TS 1494del6 del6/del6 were higher in patients than in controls (OR, 2.300; 95% CI, 1.219-4.337; and OR, 3.314; 95% CI, 1.623-6.767, respectively). The T-3R-del6 and T-2R-del6 (MTHFR 677C>T/TSER/TS 1494del6) haplotypes were more frequent in patients (OR, 1.450; 95% CI, 1.050-2.002; and OR, 2.911; 95% CI, 1.191-7.117, respectively), whereas the C-2R-del6 haplotype was less frequent in patients (OR, 0.372; 95% CI, 0.152-0.912). The T-del6 (MTHFR 677/TS 1494del6) haplotype frequency was higher among patients (OR, 1.653; 95% CI, 1.206-2.266), whereas the C-del6 haplotype frequency was lower among patients (OR, 0.700; 95% CI, 0.516-0.950). We did not find an association between TSER or TS 1494del6 polymorphisms and POF. Conclusions: Our data suggest that the MTHFR 677T allele may increase the risk for POF, which could lead to the development of novel genetic markers for predicting the risk of POF in patients.
To describe the prevalence and treatment of hot flushes in premenopausal and postmenopausal women from the 1960s to the 1990s. This prospective study, based on a random sample of the total female population of 430,000 in Gothenburg, Sweden, was started in 1968, with follow-ups in 1974, 1980, and 1992. The participants were 1,462 women born in 1930, 1922, 1918, 1914, and 1908 (participation rate 90.1%) who were representative of women of the same age in the general population. For the purpose of analyzing secular trends, we included 122 participants who were 38 years old and 47 who were 50 years old in 1980-1981. The prevalence of hot flushes increased from approximately 11% at 38 years to a maximal prevalence of approximately 60% at 52 to 54 years of age, then declined successively from approximately 30% at 60 years of age to approximately 15% at 66 years of age, and then to approximately 9% at 72 years of age. The predominant type of medication being prescribed changed during the observation period from sedatives/anticholinergic drugs in the 1960s to hormone replacement therapy in the 1980s. Hormone replacement therapy was considered to be an effective form of treatment for hot flushes by 70% to 87% of the women. Hot flushes were a common symptom, with a maximal prevalence of 64% at 54 years of age. Medical consultation and treatment did not increase in 50-year-old women from 1968-1969 to 1980-1981. Treatment changed and became more effective during the observation period.
The present study examined the association between body composition measurements, using dual-energy x-ray absorptiometry and anthropometry, with serum 25-hydroxyvitamin D levels in nonosteoporotic, postmenopausal women. Serum 25-hydroxyvitamin D, intact parathyroid hormone, insulin-like growth factor I levels, dual-energy x-ray absorptiometry measurements of fat and fat-free mass, anthropometric and handgrip strength measurements, dietary intake estimations, ultraviolet B radiation exposure, and physical activity levels were collected from 112 nonosteoporotic, postmenopausal women (age, 60.3 +/- 5.0 y; body mass index, 29.5 +/- 4.8 kg/m). At a bivariate level, serum 25-hydroxyvitamin D levels were inversely associated with regional and total body fat mass (P < 0.05), whereas positive associations were observed with regional and total body fat-free mass (P < 0.05). After controlling for age, serum intact parathyroid hormone, insulin-like growth factor I levels, ultraviolet B radiation exposure, and physical activity levels, most of the associations observed at a bivariate level between serum 25-hydroxyvitamin D levels and body composition indices (as obtained by dual-energy x-ray absorptiometry) remained significant. No significant associations were observed between anthropometric indices of body mass and serum 25-hydroxyvitamin D levels. An independent inverse association between serum 25-hydroxyvitamin D levels and dual-energy x-ray absorptiometry measurements of total body and regional fat mass was observed in nonosteoporotic, overweight, postmenopausal women. Further clinical trials are required to come to safe conclusions on whether it is the fat mass that affects serum 25-hydroxyvitamin D levels or vice versa and whether there is a need to also take into account body composition when providing recommendations for vitamin D intake in postmenopausal women.
To examine the role of estrogen replacement therapy on the development of gallbladder disease in postmenopausal women. Systematic review of the English literature was conducted. All studies that addressed the association between hormone replacement therapy and gallbladder disease published from 1970 to the present were reviewed. Seven observational studies, two clinical trials, two case series, and one nonrandomized and three randomized investigations were reviewed. The results of each study were reported and analyzed. Estrogen replacement therapy in postmenopausal women increased the chances for gallstone formation.
Soy phytoestrogens (SPEs) seem to have beneficial effects on the cardiovascular system with no adverse effects on the breast and uterus. Our objective was to examine the effects of oral estradiol alone, soy protein with phytoestrogens alone, and combinations of estradiol and SPEs on working memory of ovariectomized retired breeder female rats using the radial arm maze test. Eighty-four bilaterally ovariectomized retired breeder female rats were randomized into 12 groups to examine the effects of chronic treatment (10 months) with oral micronized estradiol (0, 0.5, 1, and 2 mg/1,800 Cal), SPEs (0, 72, and 144 mg/1,800 Cal), and all combinations of these doses of estradiol and SPEs on working memory. Oral administration of estradiol or SPEs resulted in a dose-dependent improvement in the performance of the radial arm maze tests. In addition, at each of the three doses of oral micronized estradiol tested, the performance of the radial arm tests was not significantly different in the presence or absence of SPEs. Our data suggest that SPEs may function as estrogen agonists in improving working memory in the ovariectomized retired breeder female rats and that SPEs do not antagonize the beneficial effects of estradiol on the working memory of these rats. No additional benefits on the radial arm maze test performance were observed with the tested combinations of estradiol and SPEs.
The androgenic effect of progestogen, necessary in early postmenopausal hormone replacement therapy (HRT), may adversely affect insulin sensitivity as well as body fat distribution and thereby increase the cardiovascular risk profile. The impact of HRT with sequential combined oral 17beta-estradiol and norethisterone acetate on insulin sensitivity and body composition in early menopause has not been studied. A randomized single blind placebo-controlled 6-month study of sequential combined 17beta-estradiol norethisterone acetate on insulin sensitivity and body composition was carried out. Thirty fit healthy postmenopausal women were enrolled and completed this 6-month study. Body composition was measured by dual-energy x-ray absorptiometry scanning, and insulin sensitivity was measured using the euglycemic hyperinsulinemic clamp. Studies were undertaken at baseline and after 6 months of therapy. The studies were performed during the estrogen-only phase of therapy. All women demonstrated a degree of decreased insulin sensitivity that was not modified by 6 months of hormone replacement therapy. Body composition remained unchanged over 6 months. There was no alteration in total body fat or the distribution of body fat. The percentage of central abdominal fat (android) was not altered. Six months of HRT with sequential combined oral 17beta-estradiol norethisterone acetate does not have an adverse effect on insulin sensitivity and does not promote an increase in weight or the more android distribution of body fat, which could contribute to the increased cardiovascular risk profile that is evident in postmenopausal women.
To determine the efficacy and tolerability of two strengths of percutaneous 17beta-estradiol in a hydroalcoholic gel and placebo in controlling vasomotor symptoms of menopause. A total of 221 postmenopausal women were assigned randomly to treatment with percutaneous 17beta-estradiol gel 1.25 g (containing 0.75 mg of estradiol) or 2.5 g (containing 1.5 mg of estradiol) or placebo gel applied once daily for 12 weeks. The primary efficacy variable was the mean change from baseline in the frequency of moderate/severe hot flushes. In addition, the mean changes from baseline in the frequency and severity of all hot flushes were assessed. Safety and tolerability were evaluated from endometrial biopsy, adverse events, and laboratory tests. A significant reduction (P < 0.05) in the mean frequency of moderate-to-severe hot flushes and mean frequency and severity of all hot flushes was observed with both 17beta-estradiol gel groups compared with placebo. The mean number of moderate-to-severe hot flushes at the end of the study with 17beta-estradiol gel 2.5 g, 17beta-estradiol gel 1.25 g, and placebo gel was 2.0, 2.8 and 5.2, respectively. The overall incidence of adverse events was not significantly different among groups, though a higher incidence of estrogen-related adverse events was reported with the 17beta-estradiol gel 2.5-g dose. 17beta-estradiol gel was effective and well tolerated for alleviating moderate-to-severe hot flushes in postmenopausal women. Therapy may be initiated with the 1.25-g dose with an increase to the 2.5-g dose if needed.
To investigate the effects of 1 mg 17beta-estradiol continuously combined with 2.5, 5, 10, or 20 mg dydrogesterone on the serum lipid profile of postmenopausal women. Serum lipid profile was measured in two 1-year studies performed in healthy, nonhysterectomized, postmenopausal women. One study (n = 182) had an open design and investigated oral 17beta-estradiol 1 mg daily continuously combined with dydrogesterone 2.5 mg daily; the other study (n = 326) had a double-blind, randomized design and investigated oral 17beta-estradiol 1 mg daily continuously combined with dydrogesterone at doses of 5, 10, or 20 mg daily. With all four dosages of dydrogesterone, serum total and low-density lipoprotein cholesterol were significantly reduced (-4.6% to -7.6% and -6.3% to -11.6%, respectively), whereas high-density lipoprotein cholesterol was significantly increased (+4.3% to +7.4%). Serum apolipoprotein A1 and B also improved significantly, reflecting the favorable changes in high-density lipoprotein and low-density lipoprotein cholesterol, as did lipoprotein(a). Oral 17beta-estradiol 1 mg daily continuously combined with dydrogesterone 2.5 to 20 mg daily has beneficial effects on serum lipid profile in postmenopausal women.
To evaluate the modification of lipid and lipoprotein by use of low doses of continuous-combined formulations of 17beta-estradiol (E ) and norethisterone acetate (NETA) in healthy postmenopausal women. The study was designed as a double-blind, randomized, placebo-controlled trial. A total of 120 healthy postmenopausal women were randomized to one of three treatment arms: (1) placebo group ( = 40); (2) E /NETA 0.25-mg group-subjects receiving oral continuous-combined E 1 mg and NETA 0.25 mg ( = 40); (3) E /NETA 0.5-mg group-women who were treated with E 1 mg and NETA 0.5 mg ( = 40). The duration of study was 12 months. Plasma levels of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and very low-density lipoprotein (VLDL) cholesterol, triglycerides, lipoprotein(a), apolipoprotein A and apolipoprotein B were determined on four occasions (i.e., baseline, 3-, 6-, and 12-month visits). There were no differences in the baseline characteristics among the three groups. A total of 102 women completed the study, resulting in a compliance rate of 85%. There was a significant reduction of total cholesterol, LDL cholesterol, and lipoprotein(a) in both combined groups when compared with placebo. The level of apolipoprotein B declined significantly only in the E /NETA 0.25-mg group. Decrements were observed within 3 months of treatment and maintained thereafter. No significant changes were found in triglycerides, VLDL cholesterol, HDL cholesterol, apolipoprotein A, and LDL/HDL ratio. Between the two active combined groups, no statistically significant differences were noted. Favorable changes in lipids and lipoproteins were associated with the low dose of E /NETA combinations. These effects may contribute to the reduction or prevention of atherogenesis in postmenopausal women.
Estrogens may induce cardioprotective effects and prevent neointima formation in response to vascular injury in vivo. The present study evaluated the effect of 17beta-estradiol on myocardial arterial remodeling and on vascular mitogen-activated protein kinase expression in experimental hypertension. The experiments were performed in intact female spontaneously hypertensive rats (SHR), in SHR that were ovariectomized at 10 or 25 weeks of age, and in ovariectomized SHR that were supplemented with 17 beta-estradiol (OVX + E2, 1.5 mg every 8 weeks, subcutaneous pellets). At 18 weeks of age, in all myocardial arterioles and small arteries studied, we found significant increases in wall-to-lumen ratio in ovariectomized rats as compared with intact animals. 17beta-estradiol significantly reduced the wall-to-lumen ratio in OVX + E2 rats. Perivascular fibrosis of small coronary arteries was significantly increased by ovariectomy, and this effect was prevented by long-term treatment with 17beta-estradiol. Phosphorylated extracellular signal-regulated kinase 1/2 significantly increased in mesenteric arteries from ovariectomized animals and this effect was prevented by 17beta-estradiol. Wall-to lumen ratio and perivascular fibrosis were significantly higher in older intact animals at 33 weeks of age. However, neither ovariectomy nor estradiol replacement had any effect on long-term hypertension-induced vascular remodeling. These data suggest that estradiol may exert a beneficial effect by protecting the vasculature from hypertension-induced myocardial arterial remodeling in the early stages of hypertension, but not when chronic alterations are established after a long-term period of hypertension.
The effect of site of application on 17-beta estradiol bioavailability was assessed in an open-label, randomized, crossover study of a once-weekly transdermal estradiol patch (Climara). After placement of a transdermal patch delivering 0.1 mg/day of estradiol on either the buttocks or abdomen, serial plasma samples were obtained over 7 days and for the immediate 24 h after patch removal. Plasma estradiol concentrations were used to estimate pharmacokinetic parameters for the rate and extent of absorption between the two sites. Plasma estradiol concentrations were sustained at premenopausal levels over the week in most subjects. After application on the buttock, mean peak plasma concentration (Cmax) was 125.1% and mean relative bioavailability (AUC(0-168)) was 117.2% of that from the abdomen site. In summary, the buttocks seem to be an acceptable site for the application for this once-weekly 17-beta estradiol transdermal delivery system. Because the extent of absorption was significantly more for buttock than for abdomen application, this application site may provide an advantage in women who experience menopausal symptoms at the end of the week.
Postmenopausal estrogen deficiency is associated with chronic inflammatory events that cause cardiovascular and osteoporosis diseases. The aim of this study was to investigate the relationship between interleukin (IL)-17 and serum estradiol levels, age, and postmenopausal duration, as well as bone loss. The relationship between serum IL-17A and estradiol levels was studied in 72 postmenopausal women and 22 premenopausal women. Enzyme-linked immunosorbent assay and chemiluminescence were used to detect IL-17A and estradiol, respectively. Estradiol levels were significantly higher and IL-17A levels were significantly lower in premenopausal women compared with postmenopausal women (estradiol: 239.44 [226.17] vs 74.21 [4.44] pmol/L, P < 0.0001; IL-17A: 2.88 [0.08] vs 3.5 [0.56] ng/mL, P < 0.0001). Seventy-eight of 94 women had lower estradiol levels (<83 pmol/L) with elevated IL-17A levels, in comparison with 16 women who had normal estrogen levels (3.43 [0.56] vs 3.01 [0.38] ng/mL, P < 0.0001). IL-17A levels inversely correlated with the total lumbar T-scores calculated in all women (P < 0.0001). IL-17A levels showed age-related dependency and a remarkable association with the postmenopausal period (P < 0.03). The results demonstrate a high prevalence of increased serum IL-17A levels in postmenopausal estrogen deficiency, which can play an inducing role in chronic inflammatory events such as bone loss.
Glucosamine (GlcN) is a popular supplement for osteoarthritis in postmenopausal women. Although GlcN possibly induces insulin resistance, the effects of GlcN on β-cell dysfunction are still obscure. In the present study, we investigated changes in insulin production and β-cell apoptosis in pancreatic islets after GlcN treatment in rats with or without ovariectomy and used MIN-6 cells to investigate the protective effects and molecular mechanisms of 17β-estradiol (E2) in GlcN-induced β-cell dysfunction. The rats were divided into four groups: (1) sham operation (SHAM; n = 8); (2) SHAM with 750 mg/kg/day GlcN injected intraperitoneally for 14 days (SHAM + GlcN; n = 10); (3) ovariectomy (OVX; n = 9); and (4) OVX with 750 mg/kg/day GlcN injected intraperitoneally for 14 days (OVX + GlcN; n = 9). Both GlcN and ovariectomy reduced the expression of insulin, determined by the staining intensity of insulin and reverse polymerase chain reaction. GlcN alone also induced β-cell apoptosis, and this adverse effect was aggravated after ovariectomy. In addition, we found that GlcN decreased calcium influx and insulin secretion by decreasing the protein levels of inwardly rectifying potassium in the ATP-sensitive potassium channel. GlcN decreased the protein levels of endoplasmic reticulum (ER) stress-associated proteins, including C/EBP homologous protein, phospho-protein kinase-like endoplasmic reticulum kinase, phospho-eukaryotic initiation factor 2α, and phospho-c-Jun N-terminal kinase. Finally, GlcN decreased cell viability. E2 counteracted GlcN-mediated attenuation in intracellular calcium concentration, extracellular insulin secretion, protein levels of inwardly rectifying potassium, cell viability, and protein levels of ER stress-associated proteins. ICI182.780 inhibited these beneficial effects of E2. GlcN impairs insulin secretion of β-cells by inhibiting Ca influx and enhancing β-cell apoptosis with increases in ER stress-related proteins, whereas E2 counters these adverse effects of GlcN.
Lysophosphatidylcholine (lysoPC), an active component of oxidized low-density lipoprotein, stimulates proliferation of vascular smooth muscle cells (VSMC). We investigated the direct impact of 17beta-estradiol (E2) on the proliferation of VSMC from rat aorta. VSMC derived from both female and male rats expressed estrogen receptors alpha and beta. Treatments with 1% fetal bovine serum or 5 microM lysoPC increased the incorporation of [3H]-thymidine in VSMC obtained from female rats. 17Beta-E2 did not alter the response to fetal bovine serum, but significantly suppressed the enhanced deoxyribonucleic acid synthesis which had been induced by lysoPC in a dose-dependent manner (10(-4)-10(-6) M). Estrogen also inhibited the proliferation of VSMC from male animals. ICI 182,780, a specific estrogen receptor antagonist, and 17alpha-E2, an inactive form of estradiol, also decreased the mitogenic response to lysoPC in VSMC. In addition, N-acetyl-L-cysteine, a potent antioxidant, inhibited the lysoPC effect. Flow cytometric analysis using the oxidation-sensitive probe 2',7'-dichlorofluorescin diacetate revealed that elevated intracellular formation of reactive oxygen species elicited with lysoPC was depressed significantly by 17beta-E2, ICI 182,780, or 17alpha-E2 as well as by N-acetyl-L-cysteine. 17Beta-E2 inhibits in vitro VSMC proliferation induced by lysoPC via a nongenomic antioxidant mechanism.
20-hydroxyecdysone has numerous favorable effects on a variety of organs, including the skin, where it improves wound healing. It is devoid of estrogenic and androgenic effects. Therefore, application of 20-hydroxyecdysone might be a new approach to improve skin conditions in postmenopausal women, and this was investigated in ovariectomized (OVX) rats. After ovariectomy, rats received Ecd (18, 57, or 116 mg/animal/day) or 17β-estradiol (E₂)-3-benzoate (60 μg/kg body weight) in food for 12 weeks, and skin samples were evaluated histologically to quantify two dermal layers, the subcutaneous fat and muscle layers. Epidermal thickness was lowest in the OVX animals, slightly higher in the E₂-treated animals, and significantly higher in the Ecd-treated animals. Dermal thickness was lowest in the intact and E₂-treated animals and highest in the Ecd-treated animals. The subcutaneous fat layer was thickest in the OVX animals, thinner in the intact animals, and intermediate in the Ecd-treated animals. The muscle layer was smallest in the OVX and intact animals and significantly larger in the E₂- and Ecd-treated animals. The number of proliferating cell nuclear antigen antibody-positive cells was lowest in OVX controls and significantly higher in all other groups. The Ecd-induced increases in epidermal and dermal thickness are suggestive of functional changes of the skin. The decreased amounts of subcutaneous fat in the E₂- and Ecd-treated animals point to either a fat catabolic or an antianabolic effect. The ovariectomy-induced decrease in subcutaneous musculature was prevented by Ecd but not by E₂. The stimulatory effects of Ecd on epidermal and dermal thickness and the muscle-increasing effects in the skin of OVX rats may indicate functional changes of the skin.
This study was designed to compare the effects of 17beta-estradiol (17beta-E2) and a phytoestrogen-containing soy extract on the immune system in an ovariectomized rat model of menopause. Specifically, T- and B-lymphocyte subsets, the balance of type 1 and 2 immune responses in the mesenteric lymph nodes, and serum levels of different classes of immunoglobulin were examined as study endpoints. Ovariectomized rats were treated with either the phytoestrogen-containing soy extract (50 or 100 mg/kg/day PO), 17beta-E2 (0.5 mg/kg/day PO), or vehicle; a sham control was included in the study. After the rats were killed, mesenteric lymph nodes and blood samples were collected. B- and T (CD4 and CD8)-lymphocyte subsets in mesenteric lymph nodes were evaluated by flow cytometry analysis. Cytokine-producing T lymphocytes were identified within each T-lymphocyte subset as TH1 (interferon-gamma CD4), TH2 (interleukin-4 CD4), TC1 (interferon-gamma CD8), and TC2 (interferon-4 CD8) lymphocytes. Serum levels of immunoglobulin classes were determined by enzyme-linked immunosorbent assay. There were no differences in the proportions of B lymphocytes and CD4 and CD8 T lymphocytes among groups. Treatment with 17beta-E2 and phytoestrogen-containing soy extract induced a reduction in TH1 and TC1 lymphocytes paralleled by a slight, nonsignificant, increase in the frequency of TH2. Data expressed as TH1/TH2 and TC1/TC2 ratios depicted a significant polarization of local immunity toward a humoral response. Evaluation of immunoglobulin serum levels did not show any significant difference among groups. Here we show that estrogens and soy phytochemicals similarly polarize the immune system toward a type 2 immune response in a preclinical model of menopause; our data draw attention to the crucial need to evaluate in clinical studies the potential side effects on the immune system of the complex soy products that are actually consumed in the postmenopausal setting.
A 2-year multicenter, double-blind, randomized, placebo-controlled study examined the efficacy and safety of different doses of 17beta-estradiol (E(2)) alone and continuous-combined oral formulations of E(2) and norethindrone acetate (NETA) versus placebo in the prevention of bone loss in newly menopausal women. Patients were randomized to one of seven groups: placebo, E(2) 0.25 mg, E2 0.5 mg, E(2) 1 mg, E(2) 1 mg/NETA 0.25 mg, E(2) 1 mg/NETA 0.5 mg, or E(2) 2 mg/NETA 1 mg. Treatment was a once-daily tablet taken for 26 months. The primary efficacy endpoint was the change in bone mineral density (BMD) at the lumbar spine, measured by dual-energy x-ray absorptiometry, at screening and at 13, 19, and 26 months. BMD changes at the femoral neck and trochanter were also assessed. Biochemical markers of bone metabolism were measured at baseline, and at 3, 6, 13, 19, and 26 months. Histological diagnoses of endometrial samples were tabulated for each treatment group. A total of 327 women were randomized and 189 women completed the 2-year trial. BMD at the lumbar spine decreased 2.3% in the placebo group. The lowest dose of unopposed E(2) prevented bone loss at the spine and hip. Significant increases in spine BMD compared with placebo occurred in all groups of treatment with E(2) and were more pronounced in the combination groups. Compared with placebo, women receiving active treatment experienced greater reductions in bone resorption markers. The effects were evident by 6 months and generally remained stable thereafter. Adverse events, primarily associated with the endometrium, were the most common reasons for discontinuation. There is a dose-dependent effect of E(2) on BMD. The addition of NETA seems to enhance the response in BMD observed with E(2). Low doses of E(2) (1 mg and lower) can be considered for the prevention of osteoporosis, while titrating the hormone dose to individual patient's needs.
Declining estrogen levels after menopause result in bone loss and increased fracture risk. This study investigated whether transdermal microdose 17beta-estradiol (E2) has efficacy and safety comparable to those of raloxifene, a selective estrogen-receptor modulator approved for the prevention and treatment of postmenopausal osteoporosis. This study involved a multicenter, randomized, double-blind, active-controlled, noninferiority trial in 500 osteopenic postmenopausal women comparing transdermal microdose E2 (0.014 mg/d) versus oral raloxifene (60 mg/d), administered for 2 years. Percent change from baseline in bone mineral density at the lumbar spine was measured after 2 years of treatment. Secondary endpoints included proportion of women with no loss of bone mineral density in lumbar spine, change in bone mineral density at hip, biochemical markers of bone turnover, and safety parameters. In the per protocol set, lumbar spine bone mineral density increased by 2.4% (95% CI, 1.9-2.9) with microdose E2 versus 3.0% (95% CI, 2.5-3.5) with raloxifene after 2 years; 77.3% of E2 recipients and 80.5% of those taking raloxifene had no bone loss in the lumbar spine. Both treatments were well tolerated. Most women (99% in the E2 group and 100% in the raloxifene group) showed no histological evidence of endometrial stimulation after 2 years. Mean dense area in breast mammograms was 19.8% in the E2 group versus 19.0% in the raloxifene group after 2 years. Transdermal microdose E2 was similarly effective as raloxifene in preventing bone loss at the lumbar spine. Both treatments were well tolerated, with no clinically significant effect on endometrium or breast density.
This study aims to characterize the pharmacokinetics/pharmacodynamics of drospirenone and estradiol in the treatment of postmenopausal women with moderate to severe vasomotor symptoms and to explore the relationship between the serum exposures of estradiol and drospirenone and efficacy, measured by reductions in moderate to severe hot flushes. Participants in a 12-week, double-blind, randomized, placebo-controlled study of daily drospirenone/estradiol in two low-dose combinations (0.25 mg/0.5 mg and 0.5 mg/0.5 mg), estradiol (0.3 mg), or placebo provided infrequent serum samples for pharmacokinetic analysis of estradiol and drospirenone, with additional frequent sampling during 24 hours in a study subset. Estradiol steady-state serum concentrations were described by a one-compartmental model with first-order elimination and zero-order absorption. The pharmacokinetics of drospirenone was described by a linear open two-compartment model with first-order elimination kinetics from the central compartment and delayed first-order absorption kinetics. A total of 1,516 serum estradiol concentrations and 736 serum drospirenone concentrations (n = 251) from 383 women were evaluated. Baseline estradiol concentrations increased with rising body mass index, and apparent clearance of estradiol at steady state was 39% higher in smokers versus nonsmokers. The serum exposures of both estradiol and drospirenone affected efficacy, as analyzed by a generalized linear model. Smoking had a negative effect on the efficacy of hormone therapy. The efficacy of low-dose drospirenone/estradiol for reducing vasomotor symptoms correlates with the serum exposure of estradiol and, for the first time, the serum exposure of drospirenone. Smoking adversely affects the clearance of estradiol and the efficacy of treatment.
Two prospective multicenter, double-blind, randomized, controlled trials were conducted to examine the safety and efficacy of three once-a-week continuous combined 17beta-estradiol/levonorgestrel (E2/LNG) transdermal systems (E2 0.045 mg/day with 0.015, 0.030, and 0.040 mg/day LNG) for the treatment of vasomotor symptoms and prevention of estrogen-induced endometrial hyperplasia in healthy, postmenopausal women. In study 1, performed in 293 hysterectomized and nonhysterectomized women with moderate to severe hot flushes, transdermal E2/LNG (E2 0.045 mg/day with 0.030 and 0.040 mg/day LNG) was compared with placebo for three 28-day treatment cycles. The frequency and severity of hot flushes were recorded daily. In study 2, performed in 845 women with intact uteri, transdermal E2/LNG (E2 0.045 mg/day with 0.015, 0.030, and 0.040 mg/day LNG) was compared with transdermal E2 0.045 mg/day monotherapy for thirteen 28-day treatment cycles. Women with endometrial tissue sufficient for evaluation underwent endometrial biopsy assessment at the end of cycle 13. Bleeding patterns were assessed throughout the study, and the Women's Health Questionnaire was used to assess well-being. In study 1, transdermal E2/LNG (E2 0.045 mg/day with 0.030 and 0.040 mg/day LNG) significantly decreased the number and severity of hot flushes when compared with placebo. Symptom relief was seen as early as 2 weeks posttreatment. Similarly, in study 2, all three doses of transdermal E2/LNG and E2 controlled hot flushes with no differences between groups. In study 2, no women receiving transdermal E2/LNG developed endometrial hyperplasia compared with 19 (12.8%) who received transdermal E2 0.045 mg/day (p < 0.001 for each dose). Significant improvements from baseline in scores on the Women's Health Questionnaire for vasomotor symptoms, sleep problems, sexual function, cognitive difficulties, and total score were noted at all or most time points with both transdermal E2/LNG and E2. Application-site reactions, vaginal hemorrhage, and breast pain were the most common adverse events reported with transdermal E2/LNG. The proportion of women with amenorrhea increased over time in all treatment groups in study 2. All three doses of this once-a-week combined E2/LNG transdermal system rapidly and effectively control vasomotor symptoms in postmenopausal women while protecting against endometrial hyperplasia. Amelioration of vasomotor symptoms also is accompanied by improvements in aspects of subjective well-being. Once-a-week transdermal E2/LNG, therefore, offers an effective and convenient formulation, the dosing of which can be individualized according to the needs of each patient.
To evaluate the efficacy and safety of different doses of 173-estradiol for the treatment of vasomotor and vulvovaginal symptoms. This was a randomized, double-blind, multicenter, parallel-group study. One hundred forty-five subjects, including naturally postmenopausal women aged 40-60 (who had not experienced menses for at least 12 months), women who had undergone hysterectomy, and women aged 25-60 who had undergone bilateral oophorectomy with or without hysterectomy were studied. Either placebo or 17beta-estradiol (1 mg or 0.5 mg) was given orally every day for 12 weeks, and vasomotor symptoms and vaginal epithelial cytology were evaluated. There were significant differences between placebo and the active treatments in the percentage change from baseline in the number of hot flushes (all hot flushes, 1 mg vs. placebo, p < 0.00 1; 0.5 mg vs. placebo, p = 0.007), with a more substantial proportion of subjects responding in the 1-mg group (mean change in mean number of hot flushes of 83.2%). Both doses were also more effective than placebo in increasing the proportion of mature vaginal cells (end-of-treatment mean values of 0%, 78.5%, and 21.5% for parabasal, intermediate, and superficial cells, respectively, in the 1-mg group; mean values of 0.3%, 80.8%, and 18.9% in the 0.5-mg group; and mean values of 15.2%, 74.7%, and 10.2% in the placebo group). The proportion of subjects reporting no vaginal dryness was greatest in the 1-mg group (mean percentage of days without dryness of 86.1% at weeks 9-12). For the relief of vasomotor and vulvovaginal symptoms, 17beta-estradiol I mg is effective and has an excellent safety profile.
Superficial and intermediate cells of the nasal respiratory epithelium at baseline (A) and during the sixth cycle of hormone therapy (B) from postmenopausal women using 1 mg 17A-estradiol and 2 mg drospirenone.  
To investigate the effects of drospirenone on nasal respiratory epithelium in postmenopausal women who are treated with hormone therapy (HT). Thirty-five naturally postmenopausal women participated in the prospective study. Women received continuous-combined HT containing 1 mg 17beta-estradiol and 2 mg drospirenone. Cytological changes of nasal middle and inferior turbinate respiratory epithelium were evaluated by using the maturation index, performed at baseline and on the sixth cycle of HT. Hematoxylin-eosin staining for the maturation index of the epithelial nasal cells of women reached better trophic aspects during 17beta-estradiol/drospirenone intake with respect to those observed at baseline (P < 0.001). The smears during HT emphasized the superficial and the intermediate types of cells, with a ratio index greater than 2. The parabasal cell content was less than 20%, and the karyopyknotic index showed degenerative changes in superficial and intermediate cells. Our study confirmed that the nasal respiratory epithelium is an ovarian steroid target. Drospirenone acts on nasal cells similarly to other progestogens.
To evaluate the effects of oral conjugated equine estrogens (CEE) and micronized 17beta-estradiol (E2) on breast proliferation in a postmenopausal primate model. Data from nine studies were analyzed retrospectively. The primary outcome measure was breast epithelial proliferation determined by immunolabeling for the Ki67 antigen. Other measures included progesterone receptor expression and endometrial thickness (as surrogate markers of systemic estrogen exposure) and urinary estrogen metabolite profile. All CEE doses were given at the human equivalent of 0.625 mg/day (n = 281), whereas E2 was given at the human equivalent of 1.0 mg/day or less (n = 131). Oral CEE resulted in a modest overall increase in breast epithelial proliferation of 75% that reached significance at P < 0.05 compared with placebo in one of four parallel-arm studies. In contrast, oral E2 resulted in a more substantial increase in breast epithelial proliferation of 259% (all studies) to 330% (parallel-arm studies only) that reached significance at P < 0.05 in all five E2 studies evaluated. Breast epithelial expression of progesterone receptor, a widely used marker of estrogen receptor activity, and endometrial thickness showed similar increases after treatment with CEE and E2 (P < 0.05 in all available studies). Relative amounts of urinary methoxyestrogens and the 2-hydroxyestrogen-to-16alpha-hydroxyestrone ratio were higher after CEE compared with E2 treatment (P < 0.05 for all). This retrospective analysis of oral estrogen effects in postmenopausal macaques suggests that standard doses of CEE may result in less estrogen-induced epithelial proliferation in the breast compared with E2.
The efficacy and safety of 25-microg 17beta-estradiol vaginal tablets (Vagifem) were assessed and compared with 1.25-mg conjugated equine estrogen vaginal cream (Premarin Vaginal Cream) for the relief of menopausal-derived atrophic vaginitis, resulting from estrogen deficiency. In a multicenter, open-label, randomized, parallel-group study, 159 menopausal women were treated for 24 weeks with either vaginal tablets or vaginal cream. Efficacy was evaluated by relief of vaginal symptoms and concentrations of serum estradiol and follicle-stimulating hormone. Safety was monitored by the incidence of adverse events, evaluation of endometrial biopsies, and clinical laboratory results. Patients also assessed the acceptability of the study medications. Composite scores of vaginal symptoms (dryness, soreness, and irritation) demonstrated that both treatments provided equivalent relief of the symptoms of atrophic vaginitis. At weeks 2, 12, and 24, increases in serum estradiol concentrations and suppression of follicle-stimulating hormone were observed in significantly more patients who were using the vaginal cream than in those who were using the vaginal tablets (p < 0.001). Fewer patients who were using the vaginal tablets experienced endometrial proliferation or hyperplasia compared with patients who were using the vaginal cream. Significantly more patients who were using the vaginal tablets rated their medication favorably than did patients who were using the vaginal cream (p < or = 0.001). Patients who were receiving the vaginal tablets also had a lower incidence of patient withdrawal (10% versus 32%). Treatment regimens with 25-microg 17beta-estradiol vaginal tablets and with 1.25-mg conjugated equine estrogen vaginal cream were equivalent in relieving symptoms of atrophic vaginitis. The vaginal tablets demonstrated a localized effect without appreciable systemic estradiol increases or estrogenic side effects. Vaginal tablet therapy resulted in greater patient acceptance and lower withdrawal rates compared with vaginal cream therapy.
The aim of this study was to evaluate the effect of 17beta-estradiol, raloxifene, and 1-alpha,25-dihydroxycholecalciferol or calcitriol on bone and lipid metabolism in chronic kidney disease and estrogen insufficiency. Six-month-old female Sprague-Dawley rats (n = 48) were ovariectomized and nephrectomized (seven eighths). One week after surgery, the rats were divided into six groups and treated with (1) placebo, (2) 17beta-estradiol 10 microg kg day, (3) raloxifene 1 mg kg day, (4) calcitriol 10 ng kg day, (5) 17beta-estradiol + calcitriol, and (6) raloxifene + calcitriol. A group of untreated animals with chronic kidney disease and normal ovarian function was used as a control group (n = 5). The rats were killed after 8 weeks of treatment. Blood samples were drawn for serum analyses; the right tibia was removed to perform histomorphometric analyses, uteri were used as tissue markers of estrogen replacement, and paraffin-embedded sections of the uterus and the fourth breast were used for histopathologic evaluation. Raloxifene, alone or combined with calcitriol, and 17beta-estradiol combined with calcitriol significantly diminished total cholesterol level compared with placebo. Qualitative histological and histomorphometric analyses showed that both the single treatments and their combinations were able to increase the trabecular connectivity compared with placebo. The less beneficial results were obtained with 17beta-estradiol alone, whereas the more beneficial results were obtained with the combined treatments, particularly with raloxifene and calcitriol. In summary, this experimental study demonstrates the advantages of replacing both hormonal deficiencies together. The combination of calcitriol and raloxifene, a selective estrogen receptor modulator, showed a better lipid, uterus, and bone profile.
This study aims to investigate the efficacy and safety of daily drospirenone/17β-estradiol in two low-dose combinations (0.25 mg/0.5 mg and 0.5 mg/0.5 mg, respectively) versus 17β-estradiol (0.3 mg) or placebo in postmenopausal women with moderate to severe vasomotor symptoms. Seven hundred thirty-five postmenopausal women aged 40 years or older who experienced a minimum of 7 to 8 moderate to severe hot flushes per day, or 50 to 60 moderate to severe hot flushes per week, participated in a 12-week, double-blind, randomized, placebo-controlled study. The primary efficacy variables were mean changes from baseline to weeks 4 and 12 in the weekly frequency and weekly mean daily severity of moderate to severe hot flushes recorded daily by the participants on diary cards. All active treatments were significantly more effective than placebo for the primary efficacy variables for drospirenone/17β-estradiol (P < 0.0001), and for 17β-estradiol (P < 0.01) at 4 and 12 weeks. Efficacy was greater for both low-dose drospirenone/17β-estradiol combinations versus the lower-dose 17β-estradiol. Change in vaginal pH and vaginal maturation index showed significant improvements (with P values versus placebo of <0.0001 and P ≤ 0.0028, respectively), and exploratory analysis of the Clinical Global Impressions scale score indicated an overall satisfaction of women with active treatments. All active treatments were generally well tolerated with low rates of adverse event-related dropouts, and the safety profile of drospirenone/17β-estradiol in both low-dose combinations was consistent with previous studies. Drospirenone 0.25 mg/17β-estradiol 0.5 mg is concluded to be the lowest dose with demonstrated efficacy in the treatment of postmenopausal women with moderate to severe vasomotor symptoms.
Top-cited authors
Susan R Davis
  • Monash University (Australia)
Pauline M Maki
  • University of Illinois at Chicago
Wulf H Utian
  • Case Western Reserve University
Nancy F Woods
  • University of Washington Seattle
Janet E Hall
  • National Institutes of Health