V. Mijatovic

Both Raloxifene and Estrogen Reduce Major Cardiovascular Risk Factors in Healthy Postmenopausal Women: A 2-Year, Placebo-Controlled Study

Currently raloxifene, a selective estrogen receptor modulator, is being investigated as a potential alternative for postmenopausal hormone replacement to prevent osteoporosis and cardiovascular disease. We compared the 2-year effects of raloxifene on a wide range of cardiovascular risk factors with those of placebo and conjugated equine estrogens (CEEs). Analyses were based on 56 hysterectomized but otherwise healthy postmenopausal women aged 54. 8+/-3.5 (mean+/-SD) years who entered this double-blind study and who were randomly assigned to raloxifene hydrochloride 60 mg/d (n=15) or 150 mg/d (n=13), placebo (n=13), or CEEs 0.625 mg/d (n=15). At baseline and after 6, 12, and 24 months of treatment, we assessed serum lipids, blood pressure, glucose metabolism, C-reactive protein, and various hemostatic parameters. Compared with placebo, both raloxifene and CEEs lowered the level of low density lipoprotein cholesterol by 0.53 to 0.79 mmol/L (all P<0.04) and lowered, at 24 months, the level of fibrinogen by 0.71 to 0.86 g/L (all P<0.05). The effects of raloxifene and CEEs did not differ significantly. In contrast to raloxifene, from 6 months on CEEs increased high density lipoprotein cholesterol by 0.25 to 0.29 mmol/L and reduced plasminogen activator inhibitor-1 antigen by 30.6 to 48.6 ng/mL (all P<0.02 versus both placebo and raloxifene). CEEs transiently increased C-reactive protein by 1.0 mg/L at 6 months (P<0.05 versus placebo) and prothrombin-derived fragment F1+2 by 0. 79 nmol/L at 12 months (P<0.001 versus placebo). Finally, from 12 months on, CEEs increased triglycerides by 0.33 to 0.56 mmol/L (all P<0.05 versus both placebo and raloxifene). Our findings suggest that in healthy postmenopausal women, raloxifene and estrogen monotherapy have similar beneficial effects on low density lipoprotein cholesterol and fibrinogen levels. These treatments differ, however, in their effects on high density lipoprotein cholesterol, triglycerides, and plasminogen activator inhibitor-1 and possibly in their effects on prothrombin fragment F1+2 and C-reactive protein.

Long-term effects of combined hormone replacement therapy on markers of endothelial function and inflammatory activity in healthy postmenopausal women

OBJECTIVE To study the effects of combined hormone replacement therapy on markers of endothelial function and inflammatory activity. DESIGN Prospective, randomized, controlled study. SETTING Academic hospital. PATIENT(S) Healthy postmenopausal women with an intact uterus. INTERVENTION(S) For the first 12 months, the hormone replacement therapy group (n = 14) received oral E2, 1 mg daily, sequentially combined with 5 or 10 mg of dydrogesterone. Thereafter, they received oral E2, 2 mg daily, sequentially combined with 10 mg of dydrogesterone. The control group (n = 13) received no treatment. Data were collected at baseline and at 3, 12, and 15 months. MAIN OUTCOME MEASURE(S) Parameters of endothelial function and inflammatory activity. RESULT(S) During 12 months of follow-up, we observed decreases of 15% in plasma levels of endothelin-l, of 21% in soluble thrombomodulin, of 14% in von Willebrand factor, and of 12% in clottable fibrinogen in the hormone replacement therapy group compared with the control group. There was a 5% decrease in soluble E-selectin tevels. All significant changes were observed by 3 months and sustained after 15 months. Brachial artery flow-mediated vasodilatation and C-reactive protein levels did not change significantly. CONCLUSION(S) Long-term combined hormone replacement therapy with E2 and dydrogesterone in healthy women was associated with sustained improvement in some aspects of endothelial function and in clottable fibrinogen levels.

Randomized, double-blind, placebo- controlled study of the effects of raloxifene and conjugated equine estrogen on plasma homocysteine levels in healthy postmenopausal women

OBJECTIVE To investigate the long-term effects of raloxifene on fasting plasma homocysteine levels in postmenopausal women compared with conjugated equine estrogen (CEE). DESIGN Randomized, double-blind, placebo-controlled study. SETTING Outpatient department of a university hospital. PATIENT(S) Fifty-two hysterectomized, healthy postmenopausal women. INTERVENTION(S) Oral raloxifene in two dosages (60 mg/d [n=13] and 150 mg/d [n=13]), oral CEE (0.625 mg/d [n=13], and placebo (n=13) were given for 24 months. MAIN OUTCOME MEASURE(S) Fasting plasma homocysteine concentrations. RESULT(S) Plasma homocysteine levels were not altered in the placebo group. After 12 months, a significant reduction versus baseline in the mean plasma homocysteine level (-16%) was found only in the raloxifene 150-mg group. The mean change in plasma homocysteine levels within this group also was significantly different from the changes versus baseline found in the placebo group (+2%) and the raloxifene 60-mg group (-2%), but not different from those found in the CEE group (-8%). After 24 months, plasma homocysteine levels were decreased significantly in the raloxifene 150-mg and CEE groups compared with both baseline (-13% and -10%, respectively) and placebo values (-15% and -11%, respectively). No significant change in plasma homocysteine levels was observed in the raloxifene 60-mg group. CONCLUSION(S) Raloxifene has a favorable, dose-related effect on plasma homocysteine levels in postmenopausal women.

Ambulatory--not office--blood pressures decline during hormone replacement therapy in healthy postmenopausal women.

Hormone replacement therapy (HRT, estrogen plus progestagen) in postmenopausal women has beneficial effects on the cardiovascular system. However, effects on blood pressure, determined with office measurements, remain controversial. We studied the effects of HRT in 29 healthy normotensive postmenopausal women (mean age 52.3 [3.8] years, median duration of amenorrhea 34.5 months), using ambulatory blood pressure monitoring at baseline and at 3 and 12 months of follow-up. Women were randomized to two groups: an HRT group (N = 14), treated with 1 mg 17beta-estradiol once daily and 5 or 10 mg dydrogesterone once daily during the third and fourth week of every 4 weeks; and a control group (C-group, N = 15), which did not receive therapy. Blood pressures did not differ between the groups at baseline (HRT group 117.1 (9.2)/74.4 (6.6) mm Hg, C-group 113.8 (11.2)/71.3 (7.4) mm Hg). During the follow-up period, changes from baseline of office blood pressures did not differ significantly between the groups. However, changes (95% CI) of mean 24-h blood pressures differed significantly between the two groups after 1 year of follow-up: a decrease of blood pressures was observed in the HRT group (delta systolic/delta diastolic = -5.54 [-8.86 to -2.21]/-4.23 [-6.66 to -1.80] mm Hg), whereas an increase was found in the C-group (+3.33 [-0.69 to +7.35]/+1.67 [-1.75 to +5.09] mm Hg; P [HRT v control group] = .001/.005). We conclude that HRT may have blood pressure lowering properties in healthy, normotensive postmenopausal women.

Postmenopausal hormone replacement, risk estimators for coronary artery disease and cardiovascular protection

Menopause, regardless of age at onset, is associated with a marked increase in coronary artery disease (CAD) risk. A large body of observational clinical studies repeatedly demonstrated favorable associations between postmenopausal hormone replacement therapy (HRT) and cardiovascular morbidity, mortality, and risk factors. Estrogens may act in a gender-specific way on vascular endothelial cells and other components of the vessel wall, enhancing the synthesis and release of nitric oxide (NO) and other vasodilators, and by inhibiting the synthesis and release of vasoconstricting agents, thus favoring vasodilation. Menopause-related changes in metabolic cardiovascular risk factors are identifiable, as are HRT-related changes in these factors. The metabolic effects include changes in lipoprotein (a), coagulation and fibrinolysis as well as homocysteine metabolism. The various actions of estrogen alone and combined with progestogen on the vascular system are reviewed. Furthermore, the outcome of the recently published Heart and estrogen/progestin replacement study (HERS) data are put in perspective. In addition, we outline the present data on the effects of raloxifene, a new second generation selective estrogen receptor modulator (SERM), which has been shown to favorably alter several markers of cardiovascular risk in postmenopausal women.

Hormone replacement therapy and cardioprotection: basic concepts and clinical considerations

A large body of epidemiological evidence shows that estrogen use after the menopause reduces the incidence of cardiovascular disease up to 50%. The use of progestin as co-medication in HRT appears not to attenuate the cardioprotective effects of estrogen. Menopause-related changes in metabolic cardiovascular risk factors are identifiable, as are HRT-related changes in these factors. Estrogens may act in a gender-specific way on vascular endothelial cells and other components of the vessel wall enhancing the synthesis and release of NO and other vasodilators and by inhibiting the synthesis and release of vasoconstricting agents, thus favoring vasodilation. Angiographic studies demonstrated in postmenopausal women with ischemic heart disease a reduction in coronary stenosis by estrogen monotherapy. Several studies, including the PEPI-trial, failed to demonstrate any major effect of HRT on blood pressure. The information on HRT and cardioprotection which is available so far is very promising and merits recommending HRT not only in healthy women but also in women with cardiovascular disease as well as in women with increased risk for this disease.

Endometriosis : The way forward

Endometriosis, a common cause of morbidity, affects 10% of women of reproductive age. In this review we focus on the new developments in pathogenesis, diagnosis and treatment options, reviewing the literature published about this enigmatic disorder over the past three years. More specifically, new theories of the pathogenesis of the syndrome of Sampson and Cullen are discussed. The new era of genomics may characterize endometriosis and transform clinical management of the disease. Literature suggesting that endometriosis may have an environmental origin is reviewed. New approaches to medical therapy of endometriosis have been developed, including the levonorgestrel-releasing intrauterine device, aromatase inhibitors, immunomodulatory drugs, angiogenesis inhibitors, selective estrogen and progesterone receptor modulators, and statins. Subfertility is another well-known result of endometriosis and often complex decisions must be made regarding management of the endometriosis patient who wishes to conceive. Laparoscopic surgery and assisted reproduction – with or without gonadotropin-releasing hormone-agonist treatment – are reviewed. Finally we speculate about new developments in the field of endometriosis in the coming three years.

A 2-year, randomized, comparative, placebo-controlled study on the effects of raloxifene on lipoprotein(a) and homocysteine

OBJECTIVES Lipoprotein(a) (Lp(a)) and homocysteine (Hcy) are independent cardiovascular risk factors, which have been shown to be lowered by hormone replacement therapy (HRT). In this 2-year study, the long-term effects of raloxifene (Rlx) in two doses, on Lp(a) and Hcy, were studied and compared with the effects of continuously combined hormone replacement therapy (ccHRT). METHODS In a prospective, randomized, double-blind, placebo-controlled 2-year study, 95 healthy, non-hysterectomized, early postmenopausal women, received daily either oral Rlx 60 mg (N=24) or 150 mg (N=23), ccHRT (conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg; N=24) or placebo (N=24). Fasting serum Lp(a) and plasma Hcy concentrations were measured at baseline and at 6, 12 and 24 months. RESULTS The mean individual changes compared to baseline after 24 months were for Lp(a): Rlx 60: - 5%, Rlx 150: -7%, ccHRT: -34%, placebo: +1% and for Hcy: Rlx 60: -3%, Rlx 150: -4%, ccHRT: -4%, placebo: +6%. ANCOVA was significant for Lp(a) under ccHRT versus placebo (P=0.001) and for Lp(a) under ccHRT versus each of the two Rlx groups (P<0.05). CONCLUSIONS Long-term treatment with Rlx was not as effective as ccHRT in lowering Lp(a). Although not significant and without an obvious dose-related response, the Hcy values showed the same trend for each treatment arm, which is in line with data reported earlier.

Update on management of genitourinary syndrome of menopause: A practical guide

The term genitourinary syndrome of menopause (GSM) emerged following a consensus conference held in May 2013. GSM is a more descriptive term than vulvovaginal atrophy (VVA) and does not imply pathology. However there are concerns that GSM is all encompassing and includes not only symptoms resulting from estrogen deficiency, but also those arising from the effects of ageing and other processes on the bladder and pelvic floor. Focusing on symptoms related to estrogen deficiency, the update provides a practical guide for health and allied health professionals on the impact of GSM on women and their partners, assessment, management and areas for future research. As GSM is a chronic condition, long term therapy is required. Hormonal, nonhormonal, laser and alternative and complementary therapies are described.

Hormone replacement therapy in postmenopausal women with specific risk factors for coronary artery disease

Hormone replacement therapy (HRT) in postmenopausal women is associated with a reduction in the risk of developing coronary artery disease (CAD) of about 50%. Women with an elevated risk for CAD appear to benefit most by HRT. The HRT-associated cardiovascular protection may be related to favourable changes in several important cardiovascular risk estimators, such as circulating blood concentrations of cholesterol, lipoprotein(a) (Lp(a)) and homocysteine. This paper reviews the literature presently available on the effects of HRT on cholesterol, Lp(a) and homocysteine concentrations, and special attention will be given to the effects on their elevated concentrations. The effect of HRT in women with hypertension is reviewed as well. From this overview it can be concluded that risk factors such as cholesterol, Lp(a), and homocysteine can be favourably modulated by HRT, and especially, that the strongest reductions can be achieved in those women with the highest concentrations. Although clinical trials still need to demonstrate the impact of lowering concentrations of Lp(a) and homocysteine, HRT appears to be a promising risk reduction strategy in this respect.