Uterine bleeding with hormone therapies in menopausal women: a systematic review.

Uterine bleeding is a common reason why women discontinue menopausal hormone therapy (HT). This systematic review compared bleeding profiles reported in studies for continuous-combined HT approved in North America and Europe for moderate to severe vasomotor symptoms in postmenopausal women with a uterus. Non-head-to-head studies showed that uterine bleeding varies by formulation and administration route, with oral having a better bleeding profile than transdermal formulations. Cumulative amenorrhea over a year ranged from 18 to 61% with oral HT and from 9 to 27% with transdermal HT, as reported for continuous-combined HT containing 17ß-estradiol (E2)/progesterone (P4) (56%), E2/norethisterone acetate (NETA) (49%), E2/drospirenone (45%), conjugated equine estrogens/medroxyprogesterone acetate (18-54%), ethinyl estradiol/NETA (31-61%), E2/levonorgestrel patch (16%), and E2/NETA patch (9-27%). Amenorrhea rates and the mean number of bleeding/spotting days improved over time. The oral E2/P4 combination was amongst those with lower bleeding rates and may be an appropriate alternative for millions of women seeking bioidentical HT and/or those who have bleeding concerns with other HT.

Menopausal hormone therapy for primary prevention: why the USPSTF is wrong.

The US Preventive Services Task Force (USPSTF) Draft Recommendation statement on Menopausal Hormone Therapy: Primary Prevention for Chronic Diseases, released in May 2017, perpetuates a major disconnect between the primary population affected, women within roughly 10 years of menopause, and the data cited. Furthermore, major elements of the evidence relied upon have been misinterpreted or misstated, particularly in regard to coronary heart disease and breast cancer, for which there is no statistically significant evidence of harm. As currently drafted, the recommendations reiterate the USPSTF statements of 2012, 2005 and 2002, and will perpetuate egregious harm to the public health. In an attempt to avoid that outcome and to facilitate a return to rational discourse regarding menopausal hormone therapy, an ad hoc group of experts in menopausal health submitted this comprehensive response to the USPSTF.

Pharmacokinetic studies of solubilized estradiol given vaginally in a novel softgel capsule.

OBJECTIVE: To evaluate the bioavailability and safety of a novel vaginal capsule containing solubilized bioidentical 17ß-estradiol for vulvar and vaginal atrophy and compare its pharmacokinetics with that of an approved vaginal estradiol tablet in healthy postmenopausal women. METHODS: Two randomized, single-dose, two-way cross-over, relative bioavailability trials compared the pharmacokinetics of a solubilized vaginal estradiol softgel capsule (TX-004HR, test) with that of a vaginal estradiol tablet (Vagifem®, reference) in postmenopausal women (aged 40-65 years) at 10-µg and 25-µg doses. In each study, women were randomly assigned to receive a single dose of the test capsule or reference tablet, followed by a single dose of the alternate drug after a 14-day washout. RESULTS: Thirty-five women completed the 10-µg study and 36 completed the 25-µg study. Significantly lower systemic levels of estradiol, estrone, and estrone sulfate at both doses of the test product were observed compared with equivalent doses of the reference product, with lower AUC0-24 and Cmax and earlier tmax. No adverse events were reported in either trial. CONCLUSION: TX-004HR, a novel estradiol vaginal softgel capsule, exhibited significantly lower systemic exposure than equivalent doses of an approved vaginal estradiol tablet at both 10-µg and 25-µg doses. Both doses of each product were safe and well-tolerated.

Conflicts of interest in government-funded studies.

Conflict of interest in scientific publications has become a topic of critical importance. A primary focus has been the relationship between authors, journals and the pharmaceutical industry. That focus must be expanded to include government funding organizations. There are significant benefits to authors and investigators in participating in government-funded research, and to journals in publishing it. There are substantial risks to patients in not considering the potential for conflict of interest.

Effect of desvenlafaxine on mood and climacteric symptoms in menopausal women with moderate to severe vasomotor symptoms.

OBJECTIVE: To assess effects of desvenlafaxine (administered as desvenlafaxine succinate) on secondary outcomes of mood, climacteric symptoms, and treatment satisfaction in postmenopausal women with moderate to severe menopausal vasomotor symptoms (VMS). METHODS: A 12-week, multicenter, double-blind, placebo-controlled trial was conducted in postmenopausal women with ≥ 50 moderate to severe hot flushes per week. Participants were randomly assigned to desvenlafaxine 100 mg/day, desvenlafaxine 150 mg/day, or placebo. Secondary outcome efficacy variables included Profile of Mood States (POMS), Greene Climacteric Scale (GCS), and Menopausal Symptoms Treatment Satisfaction Questionnaire (MS-TSQ) scores. Change from baseline in POMS total mood disturbance (TMD) score and subdomain scores were evaluated using analysis of covariance, adjusting for treatment and study site as factors and baseline score. GCS total and subdomain scores were analyzed similarly. Treatment satisfaction was analyzed using the row mean score test. RESULTS: A total of 458 women were enrolled. At week 12, desvenlafaxine 100 mg/day significantly improved POMS TMD scores (p <0.001) and four of six POMS subdomains compared with placebo (all p ≤ 0.005). Women taking desvenlafaxine 100 mg/day experienced significantly greater improvement in GCS total scores (p <0.001) and five of six subdomains (all p ≤ 0.029) compared with placebo. Treatment with desvenlafaxine 100 mg/day resulted in significantly greater treatment satisfaction overall and in six of seven additional MS-TSQ items (all p ≤0.042). Desvenlafaxine 150-mg/day results were similar. CONCLUSIONS: Desvenlafaxine treatment improved mood and climacteric symptoms in postmenopausal women with moderate to severe VMS compared with placebo, and more women were satisfied with desvenlafaxine treatment than with placebo.

Bazedoxifene/conjugated estrogens for menopausal symptom treatment and osteoporosis prevention.

Postmenopausal women with vasomotor and vaginal symptoms are commonly treated with estrogens or combined estrogen/progestin therapy (hormone therapy). However, hormone therapy is associated with some safety and tolerability concerns and its benefit/risk profile may vary for women based on their time since menopause. The tissue selective estrogen complex (TSEC) pairs a selective estrogen receptor modulator with one or more estrogens, with the goal of relieving menopausal symptoms and preserving bone mineral density without stimulating the breast or endometrium. Bazedoxifene/conjugated estrogens (BZA/CE) is the first TSEC in clinical development. BZA 20 mg/CE 0.45 and 0.625 mg have been shown in phase-3 clinical trials to significantly improve hot flushes and vulvar/vaginal atrophy measures in symptomatic postmenopausal women and to prevent bone loss in postmenopausal women at risk for osteoporosis while ensuring endometrial safety. These doses of BZA/CE have also demonstrated significant improvements in quality-of-life scores, sleep parameters, and treatment satisfaction compared with placebo. BZA 20 mg/CE 0.45 and 0.625 mg showed high cumulative rates of amenorrhea and low rates of breast pain, similar to those with placebo. The favorable treatment effects seen with BZA/CE were generally consistent in women < 5 or ≥ 5 years since menopause. Based on its demonstrated efficacy and safety in women both closer to or further from menopause, BZA/CE may be an appropriate alternative to hormone therapy for the treatment of menopausal symptoms and the prevention of osteoporosis.

HRT and breast cancer risk: a realistic perspective.

A new analysis from the Women's Health Initiative included data on breast cancer incidence over a 11-year period from the randomized trial of conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) and a subsequent observational follow-up. The conclusions were that CEE/MPA use was associated with an increase in both breast cancer incidence and mortality. We have concerns over the validity of their statistical analyses, as adjustments for baseline characteristics or for multiple comparisons demonstrate no significant differences in incidence between those allocated to CEE/MPA or placebo. We suspect that the apparent increase in mortality is the result of surveillance and detection bias rather than a true cause and effect. Even if such an effect were true, mortality from breast cancer would still be a very rare event. We also question the clinical relevance and applicability of their findings. The data over the 11 years show no increased risk of breast cancer with CEE/MPA in women who had not previously used hormone replacement therapy (HRT), and the vast majority of women on HRT would not be prior users at initiation. It should be remembered that women using CEE alone showed a significant decrease in breast cancer risk in the WHI trial and follow-up. Even if combined estrogen?progestogen HRT did cause an increase in breast cancer risk, and this is not proven, the magnitude of that risk is small, and less than that risk seen with many lifestyle factors. HRT is a benefit, not a risk, for those women requiring it.

The endometrium--from estrogens alone to TSECs.

This article reviews publications dating back more than a century describing investigations of the endometrium, including those examining the relationship between endometrial hyperplasia and carcinoma, the influence of estrogens on the endometrium, and strategies for protecting the endometrium from unopposed estrogen stimulation. Endometrial hyperplasia and carcinoma studies date from before 1900. The influence of endogenous estrogens on the endometrium became evident with observations of endometrial hyperplasia and/or carcinoma in women with estrogen-secreting tumors or polycystic ovarian disease. Later, observational studies and randomized, controlled trials suggested a relationship between unopposed estrogens and endometrial cancer and hyperplasia. The first, and to date only, effective clinical strategy for protecting the endometrium from unopposed estrogen stimulation has been the use of progestins. A new approach for endometrial protection in menopausal therapy is the pairing of a selective estrogen receptor modulator (SERM) with estrogen(s), also known as a tissue selective estrogen complex (TSEC). Effective protection of the endometrium as well as treatment of menopausal symptoms and prevention of osteoporosis would be key elements for a clinically useful TSEC.

The assessment of bleeding patterns in postmenopausal women during continuous combined hormone replacement therapy: a review of methodology and recommendations for reporting of the data.

OBJECTIVES: To systematically review methods used to report data on bleeding patterns among postmenopausal women enrolled in clinical trials of continuous combined hormone replacement therapy (HRT); and to propose the use of standardized terms, definitions, and methods for collecting and reporting bleeding data in such trials. METHODS: A MEDLINE search identified 18 published reports of bleeding patterns among postmenopausal women enrolled in prospective clinical trials that included a continuous combined HRT treatment arm. Only two of these trials were not randomized. Methods for collecting and analyzing bleeding pattern data were collated from these published reports and examined for consistency. RESULTS: Comparisons across studies revealed little consistency in definitions and indices utilized to report bleeding patterns among postmenopausal women administered continuous combined HRT regimens in clinical trials. While a majority of the trials incorporated definitions established by the World Health Organization for the evaluation of bleeding with hormonal contraception, a number of the studies expanded on these definitions to reflect additional dimensions of bleeding such as volume. Indices calculated from daily bleeding data to describe bleeding patterns in treatment groups were highly variable among studies. CONCLUSION: Inconsistencies among clinical trials in bleeding pattern definitions and indices limit understanding and comparison of typical bleeding patterns with continuous combined HRT regimens. Standardized definitions, data collection procedures, and indices are proposed to enhance understanding of bleeding patterns with hormone therapy and enrich the quality of patient counselling on HRT.

Effect of estrogen plus progestin on risk for biliary tract surgery in postmenopausal women with coronary artery disease. The Heart and Estrogen/progestin Replacement Study.

BACKGROUND: Animal and observational epidemiologic studies have reported that estrogens may increase the risk for gallstones. No major clinical trials have examined the effect of estrogen plus progestin therapy in postmenopausal women on the risk for biliary tract surgery. OBJECTIVE: To determine the effect of estrogen plus progestin on the risk for biliary tract surgery in postmenopausal women with known coronary artery disease. DESIGN: Randomized, double-blind placebo-controlled trial of postmenopausal hormone therapy for coronary heart disease. SETTING: 20 U.S. clinical centers. PARTICIPANTS: 2253 postmenopausal women with a gallbladder, 44 to 79 years of age at baseline, in the Heart and Estrogen/progestin Replacement Study (HERS). INTERVENTION: Conjugated equine estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg, daily in one tablet or identical placebo. MEASUREMENTS: Documented biliary tract surgery. RESULTS: A total of 147 women (7%) were hospitalized for biliary tract surgery in HERS. Treatment with estrogen plus progestin resulted in a marginally significant 38% increase in the relative risk for biliary tract surgery (P = 0.05). A small absolute difference in risk suggested that for every 185 women treated with estrogen plus progestin, one additional woman had biliary tract surgery per year. After adjustment for baseline and in-study statin use, the association was attenuated further (P = 0.09). After adjustment for treatment assignment and other variables, increased body mass index, fibric acid use, and a history of nonsurgical gallbladder disease were associated with an increased risk for biliary tract surgery, whereas statin use was associated with a decreased risk (for each comparison, P < 0.05). CONCLUSION: Estrogen plus progestin therapy among postmenopausal women with known coronary disease resulted in a marginally significant increase in the risk for biliary tract surgery.

Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism.

OBJECTIVE: To determine the effects of lower doses of conjugated equine estrogens (CEE) alone or CEE and medroxyprogesterone acetate (MPA) on lipoproteins, carbohydrate metabolism, and coagulation/fibrinolytic factors. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Multicenter substudy of the Women's HOPE trial. PATIENT(S): Seven hundred and forty-nine healthy, postmenopausal women. INTERVENTION(S): Women were randomized to receive the following doses in milligrams per day: 0.625 CEE; 0.625 CEE/2.5 MPA; 0.45 CEE; 0.45 CEE/2.5 MPA; 0.45 CEE/1.5 MPA; 0.3 CEE; 0.3 CEE/1.5 MPA; or placebo. MAIN OUTCOME MEASURE(S): Assessment of lipids, lipoproteins, glucose tolerance, and coagulation/fibrinolytic factors at baseline, cycle 6, and year 1. RESULT(S): One year of treatment with any of the CEE or CEE/MPA regimens studied increased high-density lipoprotein cholesterol (HDL-C); the 10% increase in HDL-C for the CEE 0.45/MPA 1.5 group was similar to the CEE 0.625/MPA 2.5 group. Low-density lipoprotein cholesterol was significantly reduced in all of the active treatment groups except the CEE 0.3/MPA 1.5 group at cycle 13. Apolipoprotein A-I and triglyceride levels increased and apolipoprotein B levels decreased in all groups. The lipoprotein (a) level was reduced in the CEE 0.45/MPA 2.5, CEE 0.45/MPA 1.5, and CEE 0.625/MPA 2.5 groups. Minimal changes were observed in carbohydrate metabolism for all groups. Fibrinogen and PAI-1 activity decreased and plasminogen activity increased in all groups. Decreases in antithrombin III and protein S activities were significant for all active treatment groups except the CEE 0.3/MPA 1.5 group. CONCLUSION(S): Lower doses of CEE and CEE/MPA induce favorable changes in lipids, lipoproteins, and hemostatic factors with minimal changes in carbohydrate metabolism.

Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate.

OBJECTIVE: To determine the endometrial safety of lower doses of continuous combined conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA). DESIGN: Randomized, double-blind, placebo-controlled study (the Women's Health, Osteoporosis, Progestin, Estrogen study). SETTING: Study centers across the United States. PATIENT(S): Healthy, postmenopausal women (n = 2,673) with an intact uterus. INTERVENTION(S): Patients received CEE 0.625 mg/day, CEE 0.625/MPA 2.5 mg/day, CEE 0.45 mg/day, CEE 0.45/MPA 2.5 mg/day, CEE 0.45/MPA 1.5 mg/day, CEE 0.3 mg/day, CEE 0.3/MPA 1.5 mg/day, or placebo for 1 year. Endometrial biopsies were evaluated at baseline, cycle 6, and year 1 using a centralized protocol. MAIN OUTCOME MEASURE(S): Efficacy of lower doses of CEE/MPA in reducing the incidence of endometrial hyperplasia rates associated with unopposed CEE. RESULT(S): Endometrial hyperplasia rates ranged from 0 to 0.37% for all CEE/MPA doses. Twenty-nine of the 32 cases of endometrial hyperplasia developed in women who were administered CEE 0.625 mg or CEE 0.45 mg. The incidence of endometrial hyperplasia increased with age for patients administered CEE alone. As expected, there were some inconsistencies among pathologists' ratings in the numbers of hyperplasias and incidence rates for the CEE-alone regimens. There were too few cases of hyperplasia in the combination groups to evaluate consistency among pathologists. CONCLUSION(S): One year of treatment with lower doses of CEE/MPA provides endometrial protection comparable to commonly prescribed doses. These regimens may be used by clinicians to individualize hormone replacement therapy in postmenopausal women.

Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate.

OBJECTIVE: To evaluate the efficacy of lower doses of conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for relieving vasomotor symptoms and vaginal atrophy. DESIGN: A randomized, double-blind, placebo-controlled trial (the Women's Health, Osteoporosis, Progestin, Estrogen study). SETTING: Study centers across the United States. PATIENT(S): Two thousand, six hundred, seventy-three healthy, postmenopausal women with an intact uterus, including an efficacy-evaluable population (n = 241 at baseline). INTERVENTION(S): Patients received for 1 year (13 cycles; in milligrams per day) CEE, 0.625; CEE, 0.625 and MPA, 2.5; CEE, 0.45; CEE, 0.45 and MPA, 2.5; CEE, 0.45 and MPA, 1.5; CEE, 0.3; CEE, 0.3 and MPA, 1.5; or placebo. MAIN OUTCOME MEASURE(S): Number and severity of hot flushes and Papanicolaou smear with vaginal maturation index (VMI) to assess vaginal atrophy. RESULT(S): In the efficacy-evaluable population, reduction in vasomotor symptoms was similar with CEE of 0.625 mg/d and MPA of 2.5 mg/d (the most commonly prescribed doses) and all lower combination doses. CEE of 0.625 mg/d alleviated hot flushes more effectively than the lower doses of CEE alone. VMI improved in all active treatment groups. CONCLUSION(S): Lower doses of CEE plus MPA relieve vasomotor symptoms and vaginal atrophy as effectively as commonly prescribed doses.

Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding.

OBJECTIVE: To evaluate vaginal bleeding profiles with lower doses of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) as continuous combined therapy. DESIGN: The Women's Health, Osteoporosis, Progestin, Estrogen (Women's HOPE) study, a randomized, double-blind, placebo-controlled trial. SETTING: Study centers across the United States. PATIENT(S): Two thousand six hundred seventy-three healthy, postmenopausal women. INTERVENTION(S): Women received CEE, 0.625 mg/d; CEE, 0.625 mg/d, plus MPA 2.5 mg/d; CEE, 0.45 mg/d; CEE, 0.45 mg/d, plus MPA, 2.5 mg/d; CEE 0.45 mg/d, plus MPA, 1.5 mg/d; CEE, 0.3 mg/d; CEE, 0.3 mg/d, plus MPA, 1.5 mg/d; or placebo for 1 year. MAIN OUTCOME MEASURE(S): Bleeding data were analyzed in efficacy-evaluable and intention-to-treat populations. RESULT(S): Cumulative amenorrhea and no bleeding rates were higher with lower doses of CEE/MPA than with CEE 0.625/MPA 2.5. A linear trend between time since menopause and cumulative amenorrhea was observed (P<.05) in all CEE/MPA groups except the CEE 0.45/MPA 1.5 group. The proportion of patients who experienced no bleeding in cycle 1 was 89%, 82%, and 80% in the CEE 0.3/MPA 1.5, CEE 0.45/MPA 1.5, and CEE 0.45/MPA 2.5 groups, respectively. These values were significantly greater than the incidence of no bleeding in the CEE 0.625/MPA 2.5 group (P<.05). CONCLUSION(S): Lower-dose regimens of CEE and MPA produce higher rates of amenorrhea and no bleeding compared with CEE 0.625/MPA 2.5 and may be appropriate for newly menopausal patients.

The positive predictive value of cervical smears in previously screened postmenopausal women: the Heart and Estrogen/progestin Replacement Study (HERS).

BACKGROUND: The benefits and risks of performing annual cervical smears on postmenopausal women are not well defined. The independent effect of hormone replacement therapy on development of cytologic abnormalities is unknown. OBJECTIVE: To determine the positive predictive value of cervical smears in previously screened postmenopausal women and to determine the effect of oral estrogen plus progestin on incident cervical cytologic abnormalities. DESIGN: Prospective cohort study (incidence) and randomized, double-blind, placebo-controlled trial (hormone therapy). SETTING: 20 U.S. outpatient and community clinical centers. PARTICIPANTS: 2561 women with a uterus and normal cytologic characteristics at baseline. INTERVENTIONS: Annual smears; oral conjugated equine estrogens, 0. 625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or identical placebo. MEASUREMENTS: Incident cytologic abnormalities (atypical squamous cells of undetermined significance, atypical glandular cells of undetermined significance, low-grade squamous epithelial lesion, and high-grade squamous epithelial lesion) and final histologic diagnoses. RESULTS: The incidence of new cytologic abnormalities in the 2 years following a normal smear was 110 per 4895 person-years (23 per 1000 person-years [95% CI, 18 to 27 per 1000 person-years]). Among the 103 women with known histologic diagnoses, one had mild to moderate dysplasia. The positive predictive value of any smear abnormality identified 1 year after a normal smear, therefore, was 0% (CI, 0% to 5.0%) (0 of 78 women); the positive predictive value of abnormalities found within 2 years was 0.9% (CI, 0.0% to 3.0%) (1 of 110 women). In hormone-treated compared with non-hormone-treated women, the incidence of cytologic abnormalities was nonsignificantly higher (relative hazard, 1.36 [CI, 0.93 to 1.99]), largely because of a nonsignificant 58% greater incidence of atypical squamous cells of undetermined significance (relative hazard, 1.58 [CI, 0.99 to 2.52]). CONCLUSIONS: Because of a poor positive predictive value, cervical smears should not be performed within 2 years of normal cytologic results in postmenopausal women. Therapy with oral estrogen plus progestin does not significantly affect the incidence of cytologic abnormalities.

Hormone replacement therapy: effect of progestin dose and time since menopause on endometrial bleeding.

OBJECTIVE: To analyze the effects of two continuous combined hormone replacement regimens on bleeding profiles in postmenopausal women, based on progestin dose and time since the patient's last spontaneous menstrual period. METHODS: A randomized, double-masked, multicenter trial was conducted in 1724 women recruited from 99 sites. Six hundred seventy-eight women received a continuous regimen of oral conjugated equine estrogens (CEE), 0.625 mg/day, combined with medroxyprogesterone acetate (MPA), 2.5 or 5.0 mg/day, for 1 year. RESULTS: After 1 year, no bleeding was reported by over 89% of women. More women in the 5.0 mg/day MPA group than in the 2.5 mg/day MPA group reported no bleeding (93.8% versus 89.5%; P<.089). Of those women who had had their last menstrual period 3 years ago or less, a significantly higher percentage in the 5.0 mg/day MPA group (72.4%) did not experience bleeding after three cycles compared with the 2.5 mg group (59.0%; P<.001). Although the percentage of patients without bleeding was also higher in the 5.0 mg/day MPA group after six cycles and 1 year, the differences between groups were not statistically significant. Of the women who had their last menstrual period more than 3 years ago, 94.7% of those in the 5.0 mg/day MPA group and 90.7% of those in the 2.5 mg/day MPA group reported no bleeding at 1 year. CONCLUSION: A continuous combined regimen of CEE plus 5.0 mg MPA may be more suitable for women closer to the onset of menopause or for women starting therapy who are unwilling to tolerate irregular bleeding. The improved bleeding profile with CEE and 5.0 mg/day MPA is likely to enhance compliance with hormone replacement therapy.

Recent insights into the varying activity of estrogens.

Recent advances have added substantially to our understanding of the biology of estrogens. Estrogens are no longer considered to differ only in potency. Two estrogens can have similar effects in one tissue and very different effects in another. Additionally, an estrogen can have different effects in different tissues. It is now recognized that there are at least two estrogen receptors, ER-alpha and ER-beta, and that it is quite likely that estrogens also work through non-genomic mechanisms. The development of new methods of chromatographic separation has aided substantially in our ability to characterize the composition of Premarin, including the identification of estradiene, the fourth-most abundant estrogen in Premarin. Recent studies have contributed to our understanding of the unique profile of Delta(8,9) dehydroestrone sulfate, another of the Premarin estrogens. It was found that Delta(8,9) dehydroestrone sulfate is an active estrogen with a distinct pharmacological profile that results in significant clinical activity in vasomotor, neuroendocrine and bone preservation parameters. However, it displayed little or no efficacy, at the dose studied, on other peripheral parameters normally affected by classical estrogens. Increasing knowledge of the unique profiles of the Premarin components, as well as their complex interaction, will help to increase our understanding of the clinical profile of Premarin.