Rationale for use of lower estrogen doses for postmenopausal hormone therapy

In placebo-controlled clinical trials low dose estrogens have been shown to reduce hot flashes an average of 65%. Low dosage is effective in preventing bone loss in early menopause and both low and ultralow estrogen dosages can prevent bone loss among women many years beyond menopause. Epidemiological studies indicate less risk of cardiovascular disease and venous thromboembolism in women who use low dose estrogens compared to standard dose. Low dosages of estrogens are less likely to produce unacceptable side effects, such as vaginal bleeding or breast tenderness. When prescribing low dosage estrogen, one can safely use less progestogen, either less daily dosage or less frequent cycles. Older women on ultralow estrogen may not require regular progestogen because the endometrium is not stimulated. In conclusion, there is a strong rationale for use of lower estrogen dosage in HT. Low dosage estrogen can relieve vasomotor symptoms and can prevent postmenopausal bone loss. Women taking low dosages of estrogens are less likely to have unacceptable side effects, such as vaginal bleeding or breast tenderness. Moreover, the potential harm caused by standard dosages of estrogen with progestin, including coronary heart disease, venous thromboembolism, stroke, and breast cancer may be mitigated by use of lower estrogen doses that do not require daily or monthly progestin opposition.     

Hormone replacement therapy: the benefits in tailoring the regimen and dose

Despite the clear benefits of long-term hormone replacement therapy (HRT), the majority of patients tend to undergo short-term treatment. The cyclical bleedings induced by the sequential progestogen administration are often unacceptable namely in the elderly postmenopausal women. At the standard doses HRT preparations can also induce annoying hormone-related side effects, both in sequential and continuous combined regimens. Lower HRT schedules are reported to be highly effective in the relief of climacteric symptoms, inducing minimal endometrial stimulation with high rates of amenorrhea. Continuous administration of low doses of progestins is safe for endometrium protection and minimizes progestin-related side effects. Indeed, it has been demonstrated that low dose HRT can prevent the increase in bone turnover and the consequent bone loss in postmenopausal women. The choice of lower HRT dosages can also be useful for the number of potential disadvantages of standard HRT doses, mainly for long-term treatments. Low dose regimens should be considered as a starting dose to minimize the occurrence of side effects, improving compliance and, therefore, HRT effects on the prevention of long-term consequences of estrogen deprivation.     

Estrogen with interrupted progestin HRT: a review of experimental and clinical studies

This review outlines the basic principles of a novel interrupted progestin HRT regimen in which estrogen is administered continuously, and progestin is given in a 3-days on, 3-days off pulsed fashion. The rationale for this regimen is to prevent receptor down-regulation and allow increased estrogen and progestin sensitivity during the progestin-free periods. Background information is provided including the reasons for poor patient acceptance of HRT, and the concerns of the potential association of HRT with breast and endometrial cancer. Experimental studies in the rat are described which provide evidence in support of the rationale for the interrupted progestin regimen. Clinically, two pilot studies examining symptom control, bleeding rates and safety of the interrupted progestin regimen, as well as preliminary results of a third study examining the usefulness of this regimen for addback therapy in GnRH agonist treated patients, are outlined. The preliminary results of phase III trials are presented. These clinical studies all demonstrated good symptom control, low bleeding rates, endometrial protection, and excellent patient acceptance. The combination of continuous estrogen with interrupted progestin appears to result in increased sensitivity to estrogen and progestin in estrogen responsive tissues. As a result, lower doses of estrogen and progestin may be used for HRT with good biological effects. Further clinical studies, preferably in prospective randomized trials, are required to demonstrate an advantage of this new regimen compared to continuous combined HRT.     

Prevention of bone loss and hypoestrogenic symptoms by estrogen and interrupted progestogen add-back in long-term GnRH-agonist down-regulated patients with endometriosis and premenstrual syndrome

OBJECTIVE: To examine the utility of a low-dose estrogen and pulsed progestogen hormone replacement therapy (HRT) regimen for add-back during long-term gonadotropin-releasing hormone-agonist (GnRH-agonist) therapy. DESIGN: A pilot clinical trial conducted at a tertiary referral, academic, reproductive sciences center. The study included 15 patients with endometriosis and 5 patients with severe premenstrual syndrome (PMS). Patients with endometriosis received leuprolide acetate depot 3.75 mg IM monthly until their symptoms had resolved (2-3 months), at which time HRT was initiated along with the GnRH-agonist. Patients with severe PMS received the same treatment with the addition of HRT after 1 month. The HRT regimen consisted of 1 mg oral micronized estradiol daily and 0.35 mg norethindrone daily for 2 days alternating with 2 days without norethindrone. The main outcome measure included bone density assessment in the lumbar spine and femoral neck by dual-energy x-ray absorptiometry at 6- to 12-month intervals. The mean follow-up duration +/- SD while on GnRH-agonist treatment was 31.2 +/- 17 months (for endometriosis patients) and 37.7 +/- 8.4 months (for patients with severe PMS). RESULTS: Bone mineral density was stable after initiation of HRT for the entire follow-up period. No patient had return of pelvic pain or resumption of mood swings after HRT add-back. After the first 3 months of HRT, all women remained amenorrheic. CONCLUSIONS: Long-term GnRH-agonist down-regulation is safe and effective when combined with HRT add-back. Furthermore, on the basis of this small study, the low-dose pulsed progestogen, continuous estrogen HRT regimen seems to be safe for use as add-back therapy in terms of bone health.     

Hormone replacement therapy: the perspectives for the 21st century.

Nowadays different lines of evidence demonstrate the benefits of postmenopausal hormone replacement therapy (HRT). HRT is extremely effective in treating subjective symptoms and can really improve the quality of life of climacteric women. HRT and dementia: Estrogens are potentially relevant to the pathogenesis and treatment of Alzheimer's disease. The effects of different progestogens on cognitive functions and Alzheimer's disease are largely unknown. The prevention of Alzheimer disease might be a major indication to long term HRT. Large prospective, randomized trials will confirm these preliminary data. HRT and osteoporosis: HRT has been strongly correlated with higher bone mineral density and lower fracture incidence. Definite answers in terms of minimum effective dosages, timing and duration of HRT for fracture prevention are needed. HRT and cardiovascular disease: Different lines of evidence suggest that HRT can exert cardioprotective effects with substantial reduction of morbidity and mortality for cardiovascular disease in postmenopausal women. The effects and the role of progestogens in cardiovascular disease prevention are still debated. Prospective, randomized, controlled studies are needed to assess the impact of different HRT regimens on cardiovascular events. HRT and cancer: The major issue in the relationship between HRT and cancer is breast cancer. Long-term and current HRT use are followed by a slight, though significant increase in the risk of breast cancer. Progestogens can modify the cellular response of normal as well as cancer breasts. The possible protective effect of continuous progestogen addition is very interesting and needs further investigation. Alternative to classical HRT: Selective estrogen receptor modulators (SERM). SERMs such as raloxifene (RAL) are a new class of drugs that exert site specific estrogenic or antiestrogenic effects in different target tissues. RAL prevents bone loss and reduces serum cholesterol in postmenopausal women. In contrast to estrogen RAL does not stimulate breast or uterine tissues. In vitro RAL is highly effective at inhibiting the growth of estrogen-dependent breast adenocarcinoma cells. SERMs are expected to represent a major breakthrough for postmenopausal health. CONCLUSION: HRT can be offered either as a preventive tool or as individualized care on the basis of personal needs. New therapeutic options like the SERMs will offer a substantial medical advancement for the treatment of postmenopausal women.     

Strategies for effectively addressing women's concerns about the menopause and HRT

HRT has many benefits for postmenopausal women yet acceptance and compliance with therapy is low. This paper sets out some of the main concerns women have regarding HRT and highlights ways that physicians can effectively deal with these concerns. Physicians dealing with women concerned about starting or continuing HRT should conduct patient-centered consultations employing good counseling skills. Dealing effectively with women's concerns means addressing their attitude to HRT, listening to the patients' fears in an understanding and non-dismissive way, and focusing on good communication. Common concerns relating to unwanted effects such as bleeding, fear of cancer, weight gain, thrombosis, general systemic effects, and the use of medical intervention generally, can be dealt with if the physician follows the principles for conducting a patient-centered interview. When it comes to decisions about starting and continuing on HRT, it is important that women are treated with understanding, their concerns are taken seriously, and they are given time to air their views and ask questions. Tailoring treatments to individual patients can overcome many of the problems women have with HRT, however it is important that the decision to start HRT, and the most suitable regimen and delivery system to use, be decided in partnership with the patient. This should result in the patient having a better understanding of HRT, and may improve compliance.     

Perspectives in hormone replacement therapy

Estrogens have been convincingly shown to be highly effective in preventing and reversing menopause-related conditions, such as hot flushes, urogenital complaints, and postmenopausal bone loss. Observational studies report that long-term, estrogen-containing, postmenopausal hormone replacement therapy (HRT) leads to a substantial reduction in hip fractures, myocardial infarction, and possibly colonic cancer, with important consequences for health and quality of life. Estrogen replacement may postpone the onset of Alzheimer's disease and extend life. While many of these effects are biologically plausible, with a variety of cellular mechanisms being involved, only ongoing and future large-scale randomized clinical trials can and should define the effects of HRT more precisely. Long-term compliance is a key issue for long-term benefits, and offering women a choice of administration routes and regimens can only be beneficial in this respect. Pills, patches, gels, and implants are all widely prescribed. Intravaginal or intranasal forms of administration, which are very easy to use and adaptable on an individual level, are among the new options which could improve long-term continuation of HRT use. Fear of breast cancer and recurrence of vaginal bleeding are real concerns for many women considering HRT. This has led to research into lower-dose, estrogen-containing regimens, into continuous combined regimens, and into the potential of estrogen receptor alpha or beta binding molecules that may help to prevent such problems from arising. The prospects for safe and effective postmenopausal HRT with either estrogens or estrogen-like drugs are very promising when these drugs are used in a patient-tailored, risk profile-based manner.     

Progestogen intolerance and compliance with hormone replacement therapy in menopausal women

It is vital that we maximize compliance if patients are to receivethe full benefits from hormone replacement therapy (HRT). Oneof the main factors for reduced compliance is that of progestogenintolerance. Progestogens have a variety of effects apart fromthe one for which their use was intended, that of secretorytransformation of the endometrium. Endometrial effects varybetween individuals and between different progestogens, leadingto bleeding problems. Symptoms of fluid retention are producedby the sodium-retaining effect on the renin-aldosterone system.The nor-testosterone-derived progestogens can have adverse effectson skin, lipids, vasculature and insulin resistance. Negativemood effects are produced by most progestogens due to the effecton neurotransmitters via central nervous system progesteronereceptors. Manipulation of the dosage and duration of progestogen,continuous administration of a low dose of progestogen and areduction in the number of progestogenic episodes can be usedto improve compliance. The progestogen and progesterone releasingcoils and vaginal progesterone gel minimize systemic side effectsand bleeding. Adverse effects can also be avoided by makinguse of the progesterone receptor-specific progestogens suchas the pregnanes (e.g. cyproterone), nor-pregnanes (e.g. nomegestrol)and progesterone itself. Hysterectomy remains an option forthe severely progestogen-intolerant woman. In the future, progestogenintolerance may not be an issue if selective oestrogen receptormodulators provide a complete alternative to HRT.     

Current perspectives on the benefits of HRT in menopausal women

AIMS: Women in the West can now expect to live one third of their life in a postmenopausal state, and consequently in a state of estrogen deficiency. This can have a number of consequences, and many women suffer vasomotor symptoms during the climacteric. Estrogen deficiency can also result in changes to the skin, hair, urogenital, cardiovascular and skeletal systems. This article reviews some of the main actions of replacement estrogen in postmenopausal women, and discusses the major benefits of estrogen replacement therapy (ERT) and hormone replacement therapy (HRT). REVIEW: HRT is well documented to reduce vasomotor symptoms in women suffering from estrogen deficiency, and can have beneficial effects on the skin and the prevention of skin aging. HRT has beneficial effects on urogenitary function including reductions in urinary incontinence and vaginal atrophy. HRT is used as a first-line treatment to prevent or reverse the development of postmenopausal osteoporosis and can reduce the risk of fractures if taken for 5-10 years from the menopause. In epidemiological studies, ERT was associated with a reduction in the risk of coronary heart disease. Estrogens seem to affect the cardiovascular system directly and indirectly such as reducing some of the coronary risk factors. In recent years, estrogen has been linked to beneficial effects in the CNS including an association with a reduction in the risk of developing Alzheimer's Disease. Despite these benefits, HRT compliance remains low, and physicians need to address this if patients are to gain the benefits.     

Hormonal replacement regimens and bleeding

Hormone replacement therapy may increase the quality of life of postmenopausal women. Any regimen need to offer long-term endometrial safety. It is a standard to consider the co-administration of a sequential progestogen when estrogen replacement should be initiated in non-hysterectomized women. It is almost impossible to decide which combination of an estrogen and a progestogen seems to be optimal as individual tolerance of HRT may very well limit acceptability despite metabolic benefits and proven endometrial safety of a given combination. Several combinations of oral and transdermal estradiol or conjugated equine estrogens, oral progestogens, transdermal norethisterone acetate and levonorgestrel, and intrauterine levonorgestrel may achieve endometrial safety. It is noteworthy that there is no uniform correlation between the timing of onset of bleeding induced by any sequential estrogen and progestogen replacement and a certain pattern of histology. Therefore, although it is likely, there is no absolute reassurance that regular bleeding on or after day 11 of progestogen administration rules out abnormal histopathology. Transvaginal sonography seems not to be of pivotal importance to screen asymptomatic women on replacement therapy for detection of serious abnormal endometrial findings such as hyperplasia and endometrial cancer. Continuous combined hormone replacement therapy or the use of tibolone may be an alternative in postmenopausal women, who do not want any uterine bleedings after menopause. However, spottings or bleedings most often occur at the beginning of treatment. Vaginal administration of estriol and estradiol for urogenital symptoms of estrogen deficiency may stimulate the endometrium unintentionally. Available data suggest that use of oral estriol may be associated with endometrial hyperplasia and endometrial carcinoma relatively more often compared to sequential HRT. Raloxifene, a benzothiophene derivative acting as a selective estrogen receptor modulator approved for prevention of vertebral osteoporosis, rarely causes uterine bleeding. There is no ideal therapy available to suit women looking for a permanently bleed-free hormonal replacement therapy today.     

Concurrent administration of sustained-release bezafibrate may counteract the increased thrombotic risk associated with oral estrogen therapy.

Although hormone replacement therapy (HRT) can have many favorable effects on serum lipids and on vascular endothelium that presumably mediate the decreased risk for heart attack and stroke associated with HRT in observational epidemiology, oral estrogen also has various pro-coagulant effects: increases in serum triglycerides and factor VII activity, decreases in serum antithrombin III and protein S. This may explain the increased risk for venous thromboembolism observed with HRT and oral contraceptives, as well as the temporary increase in coronary risk noted when women with preexisting coronary disease initiate HRT. The well-tolerated hypolipidemic agent bezafibrate has anticoagulant actions that are diametrically opposed to the procoagulant effects of oral estrogen: namely, reductions in serum triglycerides and factor VII activity, and an increase in antithrombin III. However, bezafibrate could be expected to complement the protective effects of oral estrogen on serum lipids and on serum IGF-I activity. Thus, there is reason to believe that concurrent bezafibrate administration would minimize any thrombotic risk associated with HRT or oral contraception, while amplifying the health benefits of oral estrogen, and would make it more feasible to administer these therapies in women at increased vascular risk. These predictions require confirmation in controlled clinical studies. Certain natural hypolipidemic agents may also have potential as adjuvants to oral estrogen, but their effects on hemostasis require further investigation.     

Endometrial safety of hormone replacement therapy: review of literature

Unopposed estrogens for treating menopausal symptoms were extensively used when epidemiological findings associated them with an increased endometrial cancer risk. Adding progestogens reverse this side effect efficiently but patient, dose, type and especially time during which the progestogen is administered are important. Long-term uterine safety of the long cycle HRT with administration of the progestogen every 3 months remains unclear. Because regular bleeding lowers compliance, continuous combined estrogen-progestogen treatment has become popular. Many different regimens are now available using oral, transdermal, subcutaneous, intravaginal or intra-uterine application of the estrogen and/or progestogen. Available but inadequate studies seem to point towards a slightly decreased endometrial cancer risk with continuous combined preparations compared with non-HRT-users and an increased risk with long-term oral but not vaginal treatment with low-potency estrogen formulations such as estriol. Newer compounds for menopausal health such as tibolone and raloxifene seem to be safe. As for any women with abnormal vaginal bleeding, those on HRT must have an intra-uterine evaluation. Transvaginal ultrasound (TVU) is very accurate in predicting a normal uterine cavity but inaccurate in predicting endometrial pathology because of a low specificity and positive predictive value of a thick echogenic endometrium. In all such cases a three-dimensional visualisation of intra-uterine lesions is more accurate. Periodic examination with TVU and/or endometrial biopsy of HRT exposed endometrium in asymptomatic women is not cost-effective. The available limited data on the use of HRT in hysterectomised women for early stage endometrial cancer show little evidence in terms of recurrence.     

HRT and gynaecologic cancer after WHI: old stuff or new doubts?

Previous studies had shown that there is little concern about endometrial cancer risk with hormone replacement therapy (HRT), whereas the risk of ovarian cancer is still debated. A new paper based on the women's health initiative (WHI) study devoted to gynaecologic cancers has been published in the October 2003 issue of JAMA, leading to the conclusion that also for endometrial and ovarian cancer risk, as the first WHI publication did for breast cancer risk, the previous large studies have been confirmed. About follow-up the authors conclude that, "The increased burden of endometrial biopsies required to assess vaginal bleeding further limits the acceptability of this regimen." These conclusions deserve a thorough analysis and must be read in the light of the burden of available epidemiological and clinical data and of recommended clinical practice. In the WHI trial the use of continuous combined HRT has resulted in a considerable increase of both imaging and invasive exams, to investigate women with bleeding or spotting, but the findings of these exams have been invariably negative. As far as, all published studies agree on the fact that continuous combined HRT either has no effect or significantly reduces the risk of both endometrial hyperplasia and cancer, there should be no reason to close-watching endometrium of women using this regimen with a different strategy from that employed on any healthy woman.     

Impact on postmenopausal symptoms of adding continuous C-21 versus C-19 progestin to estrogen

OBJECTIVE: To compare the effects of (i) continuous low dosage C-19 progestin (dl-norgestrel, NG) plus cyclical conjugated estrogen (CEE) versus (ii) continuous low dosage C-21 progestin [medroxyprogesterone acetate (MPA)] plus CEE on postmenopausal vaginal bleeding, mood and somatic, psychosomatic and psychological symptoms. METHODS: Nine hypercholesterolemic postmenopausal women with intact uteri were randomly assigned in a prospective, double-blind, two-period cross-over study of CEE (25/28 days) plus either (i) NG, (0.05 mg/day) or (ii) MPA (2.5 mg/day) for 1 year and after an appropriate wash-out period were switched to the alternative regimen for another year. Four hysterectomized control subjects received the CEE only. RESULTS: Administration of CEE + MPA versus CEE + NG resulted in a significantly higher percent of cycles which were free of vaginal bleeding (97 vs 85%), spotting (92 vs 79%) and either spotting or bleeding (92 vs 76%, P < 0.01). All three regimens significantly reduced the overall combined scores for postmenopausal somatic, psychosomatic and psychological symptoms (P < 0.05). CONCLUSIONS: Vaginal bleeding and/or spotting were significantly less frequent with CEE + MPA versus CEE + NG. However, each of the three hormonal regimens improved mood and significantly reduced postmenopausal symptoms in comparison to untreated control values.     

Exogenous progestagens and the human breast

The role of progestins (or progestagens) on the breast tissue remains controversial. However, according to the molecule and the duration of application, cell differentiation and apoptosis may predominate over proliferation. Progestins are also used as second-line agents for the treatment of metastatic breast cancer. In young women with benign breast disease, long-term treatment with 19-nortestosterone progestins had a trend to decrease breast cancer risk contrarily to what was observed in postmenopausal women receiving estrogens. Several compounds with progestational activity have been used for HRT. Small differences in the structure of the molecules may lead to pronounced differences in activities, some progestins exerting androgenic effects and some exerting estrogenic or glucocorticoid like activities. While most progestins do not bind to the estrogen receptors, it has been shown that some androgenic progestins stimulate MCF7 cells proliferation while progestins derived from progesterone did not induce cell multiplication in the same cell lines. Therefore, different progestins may induce different effects on the breast cells. Whether the progestins available to date are able to bind specifically to the progesterone receptors PR-A or PR-B and whether this is of clinical relevance to breast cell proliferation is still unclear. Although the relationship between progestin use and breast cancer risk is still the subject of debate and controversy, the data reported to date suggest that 5 years of treatment carry a low risk but further duration of use increases the risk. Further studies are still needed, randomised long-term prospective studies as well as from the laboratory, especially to determine whether a sequential or continuous regimen would be preferable as far as breast-cell response and apoptosis are concerned, and what are the effects of the various molecules used for HRT.     

The effect of hormone replacement therapy on bone mass in patients with ovarian failure due to bone marrow transplantation

Long permanent remissions in malignant hematopoietic disorders can often be achieved by autologous bone marrow transplantation (ABMT) or by allogenic bone marrow transplantation (BMT). Previous studies have shown that such therapies may induce osteoporosis due to iatrogenic ovarian failure. The administration of hormone replacement therapy (HRT) in these women could prevent the adverse effects of long-term ovarian failure without remarkable side effects. The aim of this study was to evaluate how the bone mass is affected by HRT in patients undergoing ABMT or BMT adjusting the results for age, weight, and height. Subjects and methods: Thirteen women with previous ABMT/BMT were treated with a standard dose (0.625 mg/day) of conjugated equine estrogen (CEE) or with 50 μg/day of 17-β-estradiol in transdermal therapeutic systems (TTS) plus 5 mg/day of medroxyprogesterone acetate sequentially added to the last 12 days of estrogen therapy. Bone mass was measured prior to and 12 months following HRT. Blood samples were collected before therapy and during the 6th and 12th treatment months. Results: The mean time elapsed between bone transplantation and HRT initiation was 13.0 months (range 3–26 months). Before treatment nine patients were osteopenic and after HRT bone mass increased in all cases. Following ABMT/BMT, hepatic hyperenzymemia was detected in three patients. After 6 and 12 months of treatment no significant changes were observed in hepatic enzymes. Conclusion: Although hepatic hyperenzymemia is commonly considered as a contraindication for HRT, our results suggest that HRT is safe for these patients and that such therapy should be initiated after transplantation in women to prevent adverse effects of long-term ovarian failure.     

Hormonal contraception without estrogens

The long-term clinical effects of ethinyl estradiol and the impact on environmental safety of the alkylated estrogen components used in combined contraceptive pills remain the subject of debate. The development of improved methods for the use of progestogen-only contraception would represent a viable and desirable option. Several progestogen compounds are not alkylated, and these can be delivered through a variety of routes. Some of the progestogen-only methods are well established in clinical use. Estimates for both perfect and typical effectiveness are less than one pregnancy per 100 woman-years with oral, injectable, implantable and intrauterine methods. In practice, with the oral progestogen-only method, perfect and typical effectiveness range from three to five pregnancies per 100 woman-years. The main side effect with all progestogen-only methods is unpredictable vaginal bleeding during the first months of use, and this may lead to discontinuation. Nevertheless, continuation of use is more frequent if patients are well informed of this side effect before treatment begins. No cardiovascular- and cancer-related side effects have been proven.     

Post-menopausal women and osteoporosis: available choices for maintenance of skeletal health

Objective: To briefly summarize the therapeutic choices for osteoporosis prevention which are currently available to post-menopausal women. Methods: Results of randomized clinical trials and epidemiological studies in post-menopausal women, and pre-clinical studies in ovariectomized rats were summarized. Results: Estrogen combined with progestogen in hormone replacement therapy (HRT) is effective in relieving perimenopausal symptoms and maintaining bone mineral density. However, the increased breast cancer risk associated with long-term HRT use makes it a less desirable option for many women. Selective estrogen receptor modulators (SERMs), such as raloxifene, are also effective in maintaining bone density, without stimulating the breast or uterus. However, SERMs do not relieve perimenopausal hot flashes. Conclusion: HRT is effective for acute relief of perimenopausal symptoms, but for women who are unwilling or unable to take HRT long-term, SERMs such as raloxifene are a useful therapy for the prevention of osteoporosis.     

Endometrial response to raloxifene compared with placebo, cyclical hormone replacement therapy, and unopposed estrogen in postmenopausal women.

OBJECTIVE: To determine the endometrial effects of raloxifene 60 mg/day in postmenopausal women as assessed by vaginal bleeding and endometrial thickness. DESIGN: Data from 1157 postmenopausal women were analyzed from a database consisting of four independent, double-blind, randomized, placebo-controlled trials (range = 6-30 months duration), a 24-month open-label randomized, cyclical hormone replacement therapy (HRT)-controlled trial, and a 6-month double-blind, randomized, unopposed estrogen-controlled trial. Vaginal bleeding rate was derived from self-reported adverse events collected at least every 6 months. Endometrial thickness was measured by ultrasonography at regular intervals. RESULTS: Raloxifene 60 mg/day was not significantly different from placebo with regard to the incidence of vaginal bleeding, the baseline-to-endpoint change in endometrial thickness, or the proportion of women experiencing an increase in endometrial thickness above baseline after either 12 or 24 months of therapy. Unexpected bleeding was reported significantly more frequently in the unopposed estrogen groups compared with the raloxifene group (raloxifene 60 mg/day, 0% versus estrogen, 50%; p = 0.002). A significantly greater baseline-to-endpoint increase in endometrial thickness was observed in both the HRT and estrogen groups compared with their respective raloxifene comparison group (raloxifene 60 mg/day, 0.01 +/- 2.0 mm versus HRT, 1.8 +/- 3.2; p < 0.001; raloxifene 60 mg/day, 1.1 +/- 1.7 mm versus estrogen, 7.8 +/- 3.8; p < 0.001). No cases of endometrial hyperplasia or cancer were diagnosed in the placebo or raloxifene 60 mg/day groups. Endometrial hyperplasia was diagnosed in one case in the HRT group and in two cases in the estrogen group. CONCLUSION: Raloxifene 60 mg/day for up to 30 months is not associated with vaginal bleeding or increased endometrial thickness in postmenopausal women.