Non-hysterectomized Women Research Articles

Recent advances help understand and improve the safety of menopausal therapies.

Hormone therapy (HT) remains a mainstay of treatment of vasomotor symptoms, which are among the most common and most bothersome of menopausal symptoms. This review provides updates on HT and reviews newer menopausal therapies, focusing on recent safety data. An interpretative review of recent medical literature was conducted using computerized databases. The latest analyses from the Women's Health Initiative and other trials suggest that there is a window shortly after the onset of menopause in which HT provides optimal benefit with minimal risk. Risks of breast cancer, coronary heart disease, and probable dementia increase when a progestin is included in the HT regimen, which is necessary in nonhysterectomized women to counter the proliferative effects of estrogens on the endometrium. Attempts to further optimize the risk-benefit profile of menopausal therapies have led to the introduction of newer selective estrogen receptor modulators (bazedoxifene for osteoporosis, ospemifene for dyspareunia), tissue-selective estrogen complexes (conjugated estrogens/bazedoxifene for vasomotor symptoms and osteoporosis), and non-HT (low-dose paroxetine for vasomotor symptoms). Recent studies suggest that HT has a neutral or even beneficial effect on coronary heart disease and cognition when used in the early postmenopausal years. The risk-to-benefit ratio of estrogen therapy in hysterectomized women is more favorable than that of estrogen-progestin regimens in nonhysterectomized women. Conjugated estrogens/bazedoxifene now provides a progestin-free option for managing vasomotor symptoms in postmenopausal women with an intact uterus. Low-dose paroxetine may be an alternative for some women when hormonal treatments are contraindicated.

Pelvic organ prolapse (POP) surgery among Danish women hysterectomized for benign conditions: age at hysterectomy, age at subsequent POP operation, and risk of POP after hysterectomy.

The aim of this study was to describe the incidence of pelvic organ prolapse (POP) surgery after hysterectomy from 1977 to 2009, the time interval from hysterectomy to POP surgery, and age characteristics of women undergoing POP surgery after hysterectomy and to estimate the risk of undergoing POP surgery after hysterectomy. The study was a population-based registry study. Patient data from 154,882 women hysterectomized for benign conditions in the period from 1977 to 2009 were extracted from the Danish National Patient Registry. Patients were followed up from hysterectomy to POP surgery, death/emigration, or end of study period. An estimate of the hazard of undergoing POP surgery following hysterectomy was calculated. Survival analysis was performed using the Kaplan-Meier product limit method. The frequency of POP surgery on hysterectomized women was high the first 2 years of the follow-up period with almost 800 women operated yearly. More than one third (n = 2,872) of all women operated for POP were operated less than 5 years after the hysterectomy with a median of 8.6 years. The cumulated incidence of POP surgery after hysterectomy with follow-up of up to 32 years was 12 %; 50 % (n = 5,451) of all POP surgeries were in the posterior compartment. The mean age of women undergoing a first POP surgery after hysterectomy was 60 years. POP after hysterectomy occurs as a long-term complication of hysterectomy; 12 % of hysterectomized women were operated for POP. They were operated at younger age than non-hysterectomized women and half the POP operations were performed in the posterior compartment.

Breast-related effects of selective estrogen receptor modulators and tissue-selective estrogen complexes.

A number of available treatments provide relief of menopausal symptoms and prevention of postmenopausal osteoporosis. However, as breast safety is a major concern, new options are needed, particularly agents with an improved mammary safety profile. Results from several large randomized and observational studies have shown an association between hormone therapy, particularly combined estrogen-progestin therapy, and a small increased risk of breast cancer and breast pain or tenderness. In addition, progestin-containing hormone therapy has been shown to increase mammographic breast density, which is an important risk factor for breast cancer. Selective estrogen receptor modulators (SERMs) provide bone protection, are generally well tolerated, and have demonstrated reductions in breast cancer risk, but do not relieve menopausal symptoms (that is, vasomotor symptoms). Tissue-selective estrogen complexes (TSECs) pair a SERM with one or more estrogens and aim to blend the positive effects of the components to provide relief of menopausal symptoms and prevention of postmenopausal osteoporosis without stimulating the breast or endometrium. One TSEC combination pairing conjugated estrogens (CEs) with the SERM bazedoxifene (BZA) has completed clinical development and is now available as an alternative option for menopausal therapy. Preclinical evidence suggests that CE/BZA induces inhibitory effects on breast tissue, and phase 3 clinical studies suggest breast neutrality, with no increases seen in breast tenderness, breast density, or cancer. In non-hysterectomized postmenopausal women, CE/BZA was associated with increased bone mineral density and relief of menopausal symptoms, along with endometrial safety. Taken together, these results support the potential of CE/BZA for the relief of menopausal symptoms and prevention of postmenopausal osteoporosis combined with breast and endometrial safety.

Abnormal vaginal bleeding after epidural steroid injection: a paired observation cohort study

The use of epidural steroid injections has increased dramatically, but knowledge of potential adverse effects is lacking. An association between steroid injection and subsequent abnormal vaginal bleeding has been suspected clinically, but evidence has been limited to anecdotal reports. Paired observational retrospective cohort study using electronic medical records from a large integrated health care system. Participants were all nonhysterectomized women who underwent epidural steroid injections in 2011. For each steroid injection, encounters for abnormal vaginal bleeding during the 60 days preceding and 60 days after the injection were compared as paired observations. For women found to have bleeding, medical records review was performed to examine menopausal status and bleeding evaluation outcomes. Among 8166 epidural steroid injection procedures performed on 6926 nonhysterectomized women, 201 (2.5%) procedures were followed by at least 1 outpatient visit for abnormal vaginal bleeding. Women were 2.8 times more likely to present with abnormal vaginal bleeding during the postinjection period compared with the preinjection period (P < .0001). Of the 197 women with postinjection bleeding, 137 (70%) were premenopausal and 60 (30%) were postmenopausal. Postinjection bleeding prompted endometrial biopsy evaluation in 103 (52%) cases, with benign findings for 100% of premenopausal women (59/59) and 95% of postmenopausal women (42/44). Epidural steroid injections are associated with subsequent abnormal vaginal bleeding for both premenopausal and postmenopausal women. Women undergoing epidural steroid injection should be advised of abnormal bleeding as a potential adverse effect and providers should be aware of this association when evaluating abnormal bleeding.

One-year long-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus

The aim of this study was to assess the safety of ospemifene, a novel selective estrogen receptor modulator, for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. In this multicenter, randomized, double-blind, placebo-controlled, long-term safety extension study, nonhysterectomized women aged 40 to 80 years (n = 180) received daily oral doses of placebo, ospemifene 30 mg/day, or ospemifene 60 mg/day for 40 weeks (continued as blinded treatments from the initial 12-week pivotal efficacy study of ospemifene). The total treatment period was 52 weeks. Safety assessments included adverse events, cervical Papanicolaou tests, endometrial histology, endometrial thickness, gynecological examination, breast palpation, mammography, physical examination, and clinical safety laboratory assessments. No clinically significant adverse changes in safety assessments were observed in any treatment group. Most treatment-emergent adverse events were mild or moderate in severity. Hot flushes, the most frequently occurring treatment-emergent adverse event related to the study drug, had a low discontinuation rate (1.6%). No study participants discontinued because of endometrial or cervical pathology; no endometrial findings were clinically meaningful. On week 52, more than 95% of endometrial biopsy samples either were classified as atrophic or inactive or had insufficient tissue for diagnosis. There were no treatment-emergent adverse events of pelvic organ prolapse or venous thromboembolism. No cases of endometrial hyperplasia or carcinoma were observed. Only three participants (1.7%) taking ospemifene experienced vaginal bleeding or spotting, which was self-limiting. Daily doses of ospemifene 30 mg and ospemifene 60 mg yielded few treatment-emergent adverse events and demonstrated no significant endometrial changes during the 1-year treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus.

Primary fallopian tube carcinoma risk in users of postmenopausal hormone therapy in Finland

ObjectivePrimary fallopian tube carcinoma (PFTC) is a rare malignancy and only sparse data exist on its possible association with postmenopausal hormone therapy (HT). We therefore studied this association in a nationwide cohort of Finnish HT users. MethodsAll women>50years using systemic estradiol-only therapy (ET) (n=117,820 hysterectomized women) or estradiol–progestin therapy (EPT) (n=247,781 nonhysterectomized women) for ≥6months during 1994–2008 were identified from the national medical reimbursement register. The incidence of PFTC in HT users was compared to that in the comparable background population (standardized incidence ratio, SIR, with 95% confidence interval, CI). ResultsA total of 160 cases of PFTC were encountered in users of ET (n=34) or EPT (n=126). The use of EPT≥5years was accompanied by an increased risk for PFTC (SIR 2.15; 95% CI 1.66–2.72). The SIR increased further to 3.36 (95% CI 2.02–5.24) when EPT use lasted ≥10years. The EPT-related risk for PFTC was restricted to the sequential EPT and it was not seen for continuous EPT. Two leading progestins in EPT, norethisterone acetate and medroxyprogesterone acetate, associated with comparable risk elevations. ET use was not associated with the risk for PFTC. ConclusionsThe long-term, sequential use of EPT associates with an increased risk for PFTC. In absolute terms, 4 additional cases of PFTC would be detected in 10-year follow-up of 10,000 women who have used EPT for at least 5years.

Clustering of Multiple Human Papillomavirus Infections in Women From a Population-Based Study in Guanacaste, Costa Rica

To evaluate clustering patterns of prevalent infection with multiple human papillomavirus (HPV) types in 8365 nonhysterectomized women from the Guanacaste Study of HPV Natural History. HPV testing was performed on cervical cells by MY09/M11 L1 degenerate consensus primer polymerase chain reaction method, with dot-blot hybridization for genotyping. Logistic regression was used to model type-specific HPV positivity, adjusted for age, lifetime number of sexual partners, and specific HPV type prevalence. Woman-level random effects were added to represent unobservable risk factors common to all HPV types. The observed-to-expected ratio for infections with 2 types was 1.16 (95% credible interval: 1.11-1.21) and for ≥3 types was 1.04 (95% credible interval: .96-1.13). The tendency of HPV types to cluster increased significantly with the genetic similarity of L1 regions. P value < .01 was observed for 2 HPV pairs: HPV-62 and -81 were found together more, while HPV-51 and -71 were found together less often than expected. We found a small degree of aggregation between any HPV types and lack of clustering between specific carcinogenic types. Our data indirectly provide reassurance on lack of misclassification for the large majority of HPV types in multiple infections detected by the MY09/11 method and genotyped using dot-blot hybridization.

Preventing osteoporosis in symptomatic postmenopausal women

Osteoporosis is a common postmenopausal disease that has a substantial impact on the quality of life of older women and is associated with significant morbidity and mortality. There are various options for preventing osteoporosis in postmenopausal women, and all are associated with differing benefit-risk profiles. Estrogen therapy (in hysterectomized women) and estrogen/progestogen therapy (in nonhysterectomized women) are the most effective treatments available for the relief of vasomotor and urogenital symptoms in postmenopausal women and provide significant protection against osteoporotic fractures. Selective estrogen receptor modulators reduce bone loss and prevent vertebral fractures without endometrial or breast stimulation. Raloxifene, the only selective estrogen receptor modulator approved for osteoporosis prevention and treatment, significantly reduces vertebral but not nonvertebral or hip fractures. Bisphosphonates prevent bone loss and vertebral fractures; however, not all bisphosphonates have been shown to prevent nonvertebral fractures. Selective estrogen receptor modulators and bisphosphonates are not effective for menopausal symptoms. Hormone therapy should be considered as first-line therapy for preventing bone loss and fractures in early postmenopausal women who are symptomatic; other options include selective estrogen receptor modulators and bisphosphonates, especially in older, nonsymptomatic women. Future therapies are likely to include newer selective estrogen receptor modulators, combinations of estrogen with selective estrogen receptor modulators, and denosumab.

Risk of breast cancer during hormone replacement therapy: mechanisms.

Regarding estrogen replacement therapy, two main mechanisms have to be considered for it to be discussed as a potential carcinogen in the breast, and also considering the World Health Organization definition of estrogens and estrogen/progestogen combinations as "carcinogenic": (i) the proliferative/apoptotic effects on already pre-existing estrogen-sensitive cancer cells and (ii) the production of possible genotoxic estrogen metabolites. By addition of the progestogen component, as is usual in non-hysterectomized women, both mechanisms can lead to an increased risk compared to estrogenonly therapy. The detailed mechanisms underlying the development of the benign breast epithelial cell into clinically relevant breast cancer cells are very complicated. Based on these mechanisms, the following simplified summary of the main steps explains that: (i) an increased risk cannot be excluded, (ii) especially when estrogens are combined with progestogens, but (iii) there are differences between the preparations used in therapy; (iv) the risk seems to be very rare, needing very special cellular and extracellular conditions, (v) and could even be decreased in special situations of estrogen therapy. It is concluded that when critically reviewed, an increased risk of breast cancer during hormone replacement therapy cannot be excluded in very rare cases. Definitive mechanistic evidence for a possible causal relationship with carcinogenesis still remains open.

Endometrial safety of ultra-low-dose Vagifem 10 μg in postmenopausal women with vaginal atrophy

Objective The objective of the study was to evaluate the endometrial safety of a 10 μg estradiol vaginal tablet in the treatment of vaginal atrophy in postmenopausal women.Methods A total of 336 healthy, non-hysterectomized, postmenopausal women (age 59.5 ± 6.16 years, 9.4 ± 5.9 years from last menses) were treated with a 10 μg estradiol vaginal tablet for 12 months (once daily for 2 weeks and then twice weekly for 50 weeks). Endometrial histology was analyzed at baseline and at the end of the trial.Results Of the 336 enrolled subjects, 292 (86.9%) completed the 52-week study. All 336 subjects received an endometrial biopsy at baseline, and 283 had biopsy results at week 52, when 258 out of the 283 biopsy samples were classified as ‘atrophic’ or ‘inactive’ endometrium. There were 21 with ‘no tissue’ despite a repeat biopsy attempt to obtain endometrial tissue, one had insufficient tissue with endometrial thickness >4 mm, one was ‘weakly proliferative’ and two revealed polyps. No cases of endometrial hyperplasia or endometrial cancer were reported. The mean endometrial thickness decreased from 2.04 mm (n = 334) from study start to 1.94 mm (n = 293) after 52 weeks, and the estradiol levels remained at the low postmenopausal level.Conclusions After 12 months of treatment with the 10 μg estradiol vaginal tablet, there was no suggestion of endometrial stimulation and no cases of endometrial hyperplasia or cancer reported. This study provides reassuring data on the endometrial safety of treatment with the 10 μg estradiol vaginal tablet for 1 year in a large group of postmenopausal, non-hysterectomized women with vaginal atrophy.

Influence of hysterectomy on fistula formation in women with diverticulitis

: Diverticulitis is a risk factor for fistula formation but little is known about the influence of hysterectomy in this association. A population-based nationwide matched cohort study was performed to determine the risk of fistula formation in hysterectomized women with, and without, diverticulitis. : Women who had a hysterectomy between 1973 and 2003, and a matched control cohort, were identified from the Swedish Inpatient Register. Incidence of diverticulitis and fistula surgery was determined by cross-linkage to the Register, and risk was estimated using a Cox regression model. : In a cohort of 168 563 hysterectomized and 614 682 non-hysterectomized women (mean follow-up 11.0 and 11.5 years respectively), there were 14 051 cases of diverticulitis and 851 fistulas. Compared with women who had neither hysterectomy nor diverticulitis, the risk of fistula surgery increased fourfold in hysterectomized women without diverticulitis (hazard ratio (HR) 4.0 (95 per cent confidence interval (c.i.) 3.5 to 4.7)), sevenfold in non-hysterectomized women with diverticulitis (HR 7.6 (4.8 to 12.1)) and 25-fold in hysterectomized women with diverticulitis (HR 25.2 (15.5 to 41.2)). : Diverticulitis, and to a lesser extent hysterectomy, is strongly associated with the risk of fistula formation. Hysterectomized women with diverticulitis have the highest risk of developing surgically managed fistula.

Effects of menopausal hormone therapy on hemostatic parameters, blood pressure, and body weight: Open-label comparison of randomized treatment with estradiol plus drospirenone versus estradiol plus norethisterone acetate

Objectives Clinical studies have reported changes in hemostatic parameters in women taking menopausal hormone therapy (HT) and a small increased risk of venous thromboembolism. We compared the effects of two different HTs on hemostatic parameters in postmenopausal women. Study design An open-label, randomized study conducted at two centers in Germany compared continuous 28-week combined HT with 17β-estradiol 1 mg plus drospirenone 2 mg (E2/DRSP) daily versus E2 1 mg plus norethisterone acetate 0.5 mg (E2/NETA) daily in healthy postmenopausal women. Changes in D-dimer levels from baseline to the end of treatment, as well as effects on further parameters of coagulation, fibrinolysis, and global hemostasis, and effects on bleeding pattern, blood pressure, and body weight were evaluated. Results D-dimer levels increased by 9.1% (median change) with E2/DRSP ( n = 29) and by 15.1% with E2/NETA ( n = 30). Other hemostatic parameters showed <10% median change from baseline in both treatment groups, except for tissue plasminogen activator antigen (E2/DRSP, −1.9%; E2/NETA, −24.2%). Systolic blood pressure decreased from baseline by 6.4 mmHg in the E2/DRSP group compared with 0.1 mmHg in the E2/NETA group at final examination. Body weight remained stable in the E2/DRSP group (+0.18 kg) compared with a slight increase (+1.00 kg) in the E2/NETA group. In nonhysterectomized women, the mean number of bleeding/spotting days was 5.2 (2.0 bleeding/3.2 spotting) in the E2/DRSP and 8.2 (4.4 bleeding/3.8 spotting) in the E2/NETA group. Most nonhysterectomized women, however, remained amenorrheic during the study period (E2/DRSP, 68%; E2/NETA, 62%). Conclusion Both E2/DRSP and E2/NETA were associated with a minor increase in fibrinolytic activity and a slight change in the concentration of some coagulation factors. Both HTs were well tolerated. The decrease in systolic blood pressure and stable body weight in the E2/DRSP group are consistent with DRSP's anti-aldosterone properties.

Effects of bazedoxifene/conjugated estrogens on quality of life in postmenopausal women with symptoms of vulvar/vaginal atrophy

Objective To evaluate the effects of the tissue selective estrogen complex (TSEC) pairing bazedoxifene (BZA) with conjugated estrogens (CE) on sexual function and quality of life in postmenopausal women.Methods In this 12-week, double-blind, placebo-controlled study, postmenopausal, non-hysterectomized women (n = 652) with symptoms of moderate to severe vulvar/vaginal atrophy were randomized to once-daily treatment with BZA 20 mg/CE 0.45 or 0.625 mg, BZA 20 mg, or placebo. The Arizona Sexual Experiences (ASEX) Scale, Menopause-Specific Quality of Life (MENQOL) questionnaire, and Menopause Symptoms Treatment Satisfaction Questionnaire (MS-TSQ) were secondary measures used to assess the effects of BZA/CE on sexual function, menopausal symptoms, and satisfaction with treatment, respectively.Results At week 12, both BZA/CE doses were associated with significant improvement in ease of lubrication score from baseline compared with placebo (p < 0.05) on the ASEX scale, although there was no difference in the change in total score. The MENQOL questionnaire results at week 12 showed significant improvements in vasomotor function, sexual function and total scores with both BZA/CE doses vs. placebo or BZA 20 mg (p < 0.001). The MS-TSQ results showed that BZA/CE-treated subjects reported significantly greater overall satisfaction with treatment, as well as satisfaction with control of hot flushes during the day and night, effect on quality of sleep, and effect on mood or emotions, compared with subjects treated with placebo or BZA 20 mg (all p < 0.05).Conclusion Treatment with BZA/CE for 12 weeks was shown to significantly improve sexual function and quality-of-life measures in symptomatic postmenopausal women.

Bioidentical Hormones, Compounding, and Evidence-Based Medicine: What Women's Health Practitioners Need to Know

For many years, hormone therapy (HT), administered as estrogen alone (for hysterectomized women) or combined estrogen/progestin (for nonhysterectomized women), has been an effective treatment for menopausal symptoms and osteoporosis prevention. Questions regarding the benefit–risk profile of HT have prompted some women to seek alternative therapies. Compounded bioidentical HT has been promoted as a potentially safer option than conventional HT; however, there are a lack of sufficient data from well-designed comparative trials to support the safety or efficacy of this approach. Compounded bioidentical hormone formulations may be associated with additional risks for variability in quality, purity, and batch-to-batch consistency.

Progestin may modify the effect of low-dose hormone therapy on mammographic breast density

Objectives To evaluate the effect on breast density of two low-dose hormone therapy regimens identical in their estrogen component but different in the progestin.Methods A total of 81 non-hysterectomized postmenopausal women were allocated either to 17β-estradiol 1 mg and norethisterone acetate 0.5 mg (E2/NETA, n = 43) or to 17β-estradiol 1 mg and drospirenone 2 mg (E2/DRSP, n = 38). Treatment was continuous and lasted 12 months. The main outcomes were the changes in breast density according to the Wolfe classification between baseline and 12-month mammograms.Results Involution of the fibroglandular tissue was not seen in either of the treatment groups. Under E2/NETA, breast density increased in seven women (16.3%). In contrast, only three women (7.9%) exhibited a density increase under E2/DRSP.Conclusions Although hormone therapy appears to suspend breast involution, it does not increase breast density in the majority of treated women. Progestins differing in pharmacological properties may have a variable impact on breast density.

Transdermal hormone therapy in postmenopausal women: A review of metabolic effects and drug delivery technologies

Vasomotor symptoms (VMS) associated with menopause can cause significant discomfort and decrease the quality of life for women in the peri-menopausal and post-menopausal stages of life. Hormone therapy (HT) is the mainstay of treatment for menopausal symptoms and is currently the only therapy proven effective for VMS. Numerous HT options are available to treat VMS, including estrogen-only and estrogen-progestogen combination products to meet the needs of both hysterectomized and nonhysterectomized women. In addition to selecting an appropriate estrogen or estrogen-progestogen combination, consideration should be given to the route of administration to best suit the needs of the patient. Delivery systems for hormone therapy include oral tablets, transdermal patches, transdermal topical (nonpatch) products, and intravaginal preparations. Oral is currently the most commonly utilized route of administration in the United States. However, evidence suggests that oral delivery may lead to some undesirable physiologic effects caused by significant gut and hepatic metabolism. Transdermal drug delivery may mitigate some of these effects by avoiding gut and hepatic first-pass metabolism. Advantages of transdermal delivery include the ability to administer unmetabolized estradiol directly to the blood stream, administration of lower doses compared to oral products, and minimal stimulation of hepatic protein production. Several estradiol transdermal delivery technologies are available, including various types of patches, topical gels, and a transdermal spray.

Use of unopposed systemic estrogen therapy in non-hysterectomized women: A population-based study in the UK

A population study of 28 general practices in Oxfordshire, UK found that 0.028% of 17,712 non-hysterectomized women aged 45-60 years were using systemic unopposed estrogen. This is significantly lower than that reported in the Million Women Study.

A multicenter, prospective, randomized, double-blind, placebo-controlled study to investigate the efficacy of a continuous-combined hormone therapy preparation containing 1 mg estradiol valerate/2 mg dienogest on hot flushes in postmenopausal women

Objectives To evaluate the effects of an estrogen-reduced, continuous-combined hormone therapy preparation (HT) containing 1 mg estradiol valerate (1EV) and 2 mg dienogest (2DNG) on the number of moderate and severe hot flushes. Methods This study compared the effects of an oral continuous-combined HT containing 1 mg EV and 2 mg DNG (1EV/2DNG) with those of placebo. The planned treatment duration was 12 weeks. Data were obtained from 324 postmenopausal women. The primary efficacy variable was the individual relative change of the mean number of moderate and severe hot flushes per week. Weeks 5–12 of treatment were compared with the 2 weeks preceding the treatment phase. Results Moderate and severe hot flushes were reduced by 80.8 ± 30.9% in the 1EV/2DNG group and by 41.5 ± 39.4% in the placebo group. This difference was statistically significant ( p < 0.0001; Wilcoxon's rank sum test). The incidence of all types of hot flushes (mild + moderate + severe) was reduced by 75.2 ± 30.2% under 1EV/2DNG and by 35.3 ± 37.0% under placebo. In the subset of non-hysterectomized women, exposure to 1EV/2DNG led to 2.4 ± 6.2 days with bleeding in the reference period of 84 days of treatment, versus 0.3 ± 1.3 days in the placebo group. The safety profile of 1EV/2DNG was very similar to that of placebo. Conclusions Continuous-combined HT preparation with 1 mg EV and 2 mg DNG induced a significant reduction of moderate and severe hot flushes compared to placebo ( p < 0.0001). Thus, this low-estrogen preparation is an effective and safe option for HT.

Efficacy and tolerability of continuous combined hormone replacement therapy in early postmenopausal women

Continuous combined hormone replacement therapy (ccHRT) based on estradiol valerate (E2V) and medroxyprogesterone acetate (MPA) is effective for relief of menopausal symptoms three years or more after the menopause. This study was undertaken to examine the efficacy and tolerability of ccHRT in early postmenopausal women (last menstrual period 1.3 years before study entry). This was a 52-week, randomized, double-blind, multinational study of ccHRT comprising three different dose combinations of E2V/MPA in 459 early postmenopausal non-hysterectomized women experiencing 30 or more moderate to severe hot flushes a week and/or vasomotor symptoms requiring treatment. The primary endpoint was change in frequency and severity of moderate to severe hot flushes at 12 weeks. Secondary outcome measures included number of bleeding days and evaluation of tolerability. The frequency of hot flushes was reduced by >or=70% after one month (P<0.001 for all doses at week 2 onwards), with little evidence of statistically different dose effects. Severity of flushing was also attenuated by ccHRT. Mean number of bleeding days fell to <1 per 28-day cycle at 52 weeks. Rates of amenorrhoea approached 80-90% at the end of the study, but were significantly lower at several time points with the highest-dose regimen (2 mg E2V + 5 mg MPA) than with the lower-dose options (1 mg E2V + 2.5 mg MPA and 1 mg E2V + 5 mg MPA; P<0.05). Adverse events declined in frequency over time with all regimens but throughout the study were more numerous with the highest-dose regimen than with lower doses (P= 0.0002). Continuous combined HRT was effective for the relief of climacteric symptoms in early postmenopausal women and was well tolerated.

Levonorgestrel-releasing intrauterine system as an adjunct to estrogen for the treatment of menopausal symptoms-a review

Exogenous estrogen is an effective means of prevention for postmenopausal symptoms. Estrogen treatment should be combined with progesterone in non-hysterectomized women to prevent estrogen-induced malignant transformation of the endometrium. Progesterone supplementation using continuous combined estrogen + progesterone treatment may result in an increased incidence of breast cancer and cardiovascular disease. In addition, progesterone supplementation with sequential estrogen + progesterone treatment may cause immediate adverse effects, such as irregular bleeding and spotting, breast congestion, fluid retention, abdominal distention, and a change in lipid profile. All these effects are related, at least in part, to the progesterone component of the therapy.To avoid these complications, researchers are seeking safer progestational components and different modes of administration. In this article we review the findings on the use of the novel levonorgestrel-releasing intrauterine system as a therapeutic tool for localized, rather than systemic, progesterone administration in postmenopausal women.