Effect of hormone replacement therapy, tibolone and raloxifene on serum lipids, apolipoprotein A1, apolipoprotein B and lipoprotein(a) in Greek postmenopausal women.

The aim of this study was to assess the effect of estrogen, two regimens of continuous combined hormone replacement therapy (HRT), tibolone and raloxffene on serum lipid, apolipoprotein A1 and B and lipoprotein(a) levels in Greek postmenopausal women. A total of 350 postmenopausal women were studied in a prospective open design. Women were assigned to one of the following regimens depending on the presence of risk factors for osteoporosis, dimacteric symptoms and an intact uterus: conjugated equine estrogen 0.625 mg (CEE, n = 34), continuous combined CEE 0.625 mg plus medroxyprogesterone acetate (MPA) 5 mg, (n = 80), continuous combined 17beta-estradiol 2 mg plus norethisterone acetate (NETA) 1 mg (n = 58), tibolone 2.5 mg (n = 83) and raloxifene HCl 60 mg (n = 50). Forty-five postmenopausal women with no indications for HRT served as controls. Total cholesterol (TC), low-density lipoprotein (LDL) cholestrol and high-density lipoprotein (HDL) cholesterol, triglyceride (TG), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB) and lipoprotein(a) (Lp(a)) levels were assessed in each subject at baseline, and at 6 and 12 months of therapy. All therapy regimens lowered TC levels compared to baseline (4.2-8.0% decrease). This effect was more prominent in the subgoup of women with high baseline TC levels (9.1-20.4% decrease). LDL cholesterol decreased significantly in CEE, CEE/MPA and raloxifene groups (-11.2%, -11.9% and -11.0%, respectively). Hypercholesterolemic women exhibited a steeper decrease in LDL cholesterol (10.6-27.8% in all therapy groups). TG levels increased significantly in the CEE and CEE/MPA groups (23.7% and 21.8%, respectively), while estradiol/NETA had no effect on TG levels. Tibolone decreased TG levels markedly, by 20.6%, while raloxifene had no TG-lowering effect. HDL cholesterol and ApoA1 were increased by CEE and CEE/MPA (HDL cholesterol, 7.4% and 11.8%, respectively; ApoA1, 17.8% and 7.9%, respectively) and decreased by tibolone (HDL cholesterol, -13.6%; and ApoA1, -9.9%). All therapy regimens except raloxifene lowered Lp(a) levels, with tibolone having the more pronounced effect (-13.2 to -29.0%). In conclusion, each therapy regimen had a diferent effect on lipid-lipoprotein levels, exerting favorable and unfavorable modifications. Hypercholesterolemic women seemed to benefit more from the cholesterol-lowering effect of estrogen replacement therapy/HRT. The choice for a particular regimen should be based on individual needs, indications and lipid-lipoprotein profile.     

Effect of hormone replacement therapy,tibolone and raloxifene on serum lipids,apolipoprotein A1, apolipoprotein B and lipoprotein(a) in Greek postmenopausal women

The aim of this study was to assess the effect of estrogen, two regimens of continuous combined hormone replacement therapy (HRT), tibolone and raloxifene on serum lipid, apolipoprotein A1 and B and lipoprotein(a) levels in Greek postmenopausal women. A total of 350 postmenopausal women were studied in a prospective open design. Women were assigned to one of the following regimens depending on the presence of risk factors for osteoporosis, climacteric symptoms and an intact uterus: conjugated equine estrogen 0.625 mg (CEE, n=34), continuous combined CEE 0.625 mg plus medroxyprogesterone acetate (MPA) 5 mg, (n=80), continuous combined 17β-estradiol 2 mg plus norethisterone acetate (NETA) 1 mg (n=58), tibolone 2.5 mg (n=83) and raloxifene HCl 60 mg (n=50). Forty-five postmenopausal women with no indications for HRT served as controls. Total cholesterol (TC), low-density lipoprotein (LDL) cholestrol and high-density lipoprotein (HDL) cholesterol, triglyceride (TG), apolipoprotein A1 (ApoA₁), apolipoprotein B (ApoB) and lipoprotein(a) (Lp(a)) levels were assessed in each subject at baseline, and at 6 and 12 months of therapy. All therapy regimens lowered TC levels compared to baseline (4.2-8.0% decrease). This effect was more prominent in the subgoup of women with high baseline TC levels (9.1-20.4% decrease). LDL cholesterol decreased significantly in CEE, CEE/MPA and raloxifene groups (?11.2%, ?11.9% and ?11.0%, respectively). Hypercholesterolemic women exhibited a steeper decrease in LDL cholesterol (10.6-27.8% in all therapy groups). TG levels increased significantly in the CEE and CEE/MPA groups (23.7% and 21.8%, respectively), while estradiol/NETA had no effect on TG levels. Tibolone decreased TG levels markedly, by 20.6%, while raloxifene had no TG-lowering effect. HDL cholesterol and ApoA₁ were increased by CEE and CEE/MPA (HDL cholesterol, 7.4% and 11.8%, respectively; ApoA₁, 17.8% and 7.9%, respectively) and decreased by tibolone (HDL cholesterol, ?13.6%; and ApoA₁, ?9.9%). All therapy regimens except raloxifene lowered Lp(a) levels, with tibolone having the more pronounced effect (?13.2 to ?29.0%). In conclusion, each therapy regimen had a different effect on lipid-lipoprotein levels, exerting favorable and unfavorable modifications. Hypercholesterolemic women seemed to benefit more from the cholesterol-lowering effect of estrogen replacement therapy/HRT. The choice for a particular regimen should be based on individual needs, indications and lipid-lipoprotein profile.     

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.     

Hormone replacement therapy and lipid-lipoprotein concentrations.

OBJECTIVE: To evaluate the links between hormone replacement therapy and lipid-lipoprotein concentrations (total cholesterol [T.Ch] triglycerids, high density lipoprotein cholesterol [HDL-C], low density lipoprotein cholesterol [LDL-C] and very low density lipoprotein cholesterol [VLDL-C]) in a total of 6416 postmenopausal women. STUDY DESIGN: Open prospective longitudinal study. Of the 2184 surgical postmenopausal women, 1102 received conjugated equine estrogen (CEE), and 1082 transdermal estradiol (TDE2). Of the 4232 natural postmenopausal women: 1073 received CEE+medroxyprogesterone acetate (MPA), 1068 CEE+dydrogesterone (DD), 1044 TDE2+MPA, 1047 TDE2+DD. Lipid-lipoprotein concentrations were evaluated by using a SPSS program at 1,2,3,4,5,6,7 years of therapy and cumulatively. RESULTS: Cumulative evaluation of the data on estrogen only replacement therapy revealed a significant decrease in T.Ch, LDL-C and VLDL-C, and an increase in HDL-C; however, the increase in HDL-C and triglycerids was significantly higher in CEE than TDE2 (P<0.01). Cumulative evaluation of the data on estrogen progestin hormone replacement therapy revealed a significant decrease in T.Ch, LDL-C and an increase in HDL-C for all; however, triglycerides and VLDL levels decreased in TDE2+MPA and TDE2+DD groups (P<0.05). CONCLUSION: Both the natural and surgical menopause patients were found to have more favorable lipid profiles after treatment with estrogen progesterone combined formulations and estrogen only replacement.     

Effect of conjugated equine estrogen in combination with two different progestogens on the risk factors of coronary heart disease in postmenopausal Chinese women in Taiwan: a randomized one-year study

BACKGROUND: To compare the effect of hormone replacement therapy (HRT) using estrogen plus dydrogesterone or estrogen plus medroxyprogesterone acetate (MPA) on the risk factors for coronary heart disease (CHD) in postmenopausal women. METHODS: A randomized, prospective 1-year clinical trial was designed. All of the postmenopausal women (n = 279) received sequential conjugated equine estrogen (CEE) at a dose of 0.625 mg/day for 25 days (days 1-25) of each month. These women were also randomly assigned to receive either dydrogesterone 10 mg/day (E + D group, n = 140) or MPA 5 mg/day (E + P group, n = 139) for 14 days (days 12-25) of each month. Serum biochemical markers, lipoproteins, plasma prothrombin time (PT), partial prothrombin time (PPT) and antithrombin III-antigen (ATIII-Ag) were analyzed at baseline, and after 6 and 12 months of treatment. RESULTS: Liver function, renal function, PT and PPT did not change significantly during the 12-month trial. The E + D group had a more pronounced increase in high density lipoprotein cholesterol (HDL-C) than the E + P group (10.6% vs. 2.7%) after 12 months of treatment (p < 0.05). Both groups showed reduced concentrations of total cholesterol (T-CHO), low density lipoprotein cholesterol (LDL-C) and ATIII, whereas triglyceride (TG) was increased at the end of the trial (without intergroup difference). CONCLUSIONS: Our study demonstrated a favorable effect on lipoprotein profiles with both hormone replacement therapy regimens. Dydrogesterone appears to be superior to medroxyprogesterone acetate from the perspective of modification of coronary heart disease risk factors.     

Distinct lipid/lipoprotein profiles and hormonal responsiveness in nine ethnic groups of postmenopausal Asian women: the Pan-Asia Menopause (PAM) study.

BACKGROUND: Lipid/lipoprotein profiles, among other factors, are associated with risk of cardiovascular disease. Because cardiovascular disease varies in Asian countries, we hypothesized that lipid profiles differ in ethnic groups of postmenopausal Asian women. To add to the limited body of information currently available, we also investigated the effects of estrogen/progestin therapy on lipid/lipoprotein profiles in postmenopausal Asian women. METHODS: The Pan-Asia Menopause (PAM) study was a prospective, randomized, double-blind clinical trial evaluating 1028 postmenopausal women at 22 investigational centers in 11 Asian countries/territories. Subjects were randomly assigned to one of three doses of continuous combined conjugated estrogens (CE)/medroxyprogesterone acetate (MPA): CE/MPA (in mg/day) = 0.625/2.5, 0.45/1.5 or 0.3/1.5. The treatment period, following baseline evaluations, consisted of six continuous 28-day cycles. Analysis of lipid profiles was a secondary objective of the PAM study. Total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), very low density cholesterol (VLDC-C), triglycerides and lipoprotein(a) were analyzed at a central laboratory by state-of-the-art methods. RESULTS: Mean concentrations of total cholesterol, LDL-C, VLDL-C and triglycerides differed significantly among the nine ethnic groups of postmenopausal women. This difference was independent of body mass index and age, two factors that also influenced lipid/lipoprotein profiles. Mean HDL-C concentrations also differed, but this difference was influenced by body mass index in a weak interaction. All three doses of CE/MPA significantly lowered total cholesterol. Treatment with the high and middle doses significantly lowered LDL-C, and increased HDL-C, VLDL-C and triglycerides. The high dose produced a significant decrease in lipoprotein(a). CONCLUSIONS: The different lipid/lipoprotein profiles in the nine ethnic groups of postmenopausal Asian women evaluated here suggest a relationship to differences in the prevalence of cardiovascular disease reported for different regions in Asia. However, the reported prevalence data on cardiovascular disease morbidity and mortality in the regions corresponding to the nine ethnic groups are insufficient to allow qualitative comparisons with the lipid profiles shown in our study. The lipid/lipoprotein changes in response to estrogen/progestin therapy observed here are consistent with those reported for Western women.     

Effects of the addition of methyltestosterone to combined hormone therapy with estrogens and progestogens on sexual energy and on orgasm in postmenopausal women.

OBJECTIVE: To evaluate the effect of the addition of methyltestosterone to estrogen and progestogen therapy on postmenopausal sexual energy and orgasm. METHODS: Sixty postmenopausal women in a stable relationship with a partner capable of intercourse, and presenting sexual complaints that appeared after menopause, were randomly divided into two groups: EP (n = 29) received one tablet of equine estrogens (CEE) 0.625 mg plus medroxyprogesterone acetate (MPA) 2.5 mg and one capsule of placebo; EP + A (n = 31) received one tablet of CEE 0.625 mg plus MPA 2.5 mg and one capsule of methyltestosterone 2.0 mg; The treatment period was 12 months. The effects of treatment on sexual energy were assessed using the Sexual Energy Change Scale. The ability to reach orgasm in sexual relations with the partner was verified through monthly calendars and by calculating the ratio between monthly frequency of orgasms in sexual relations and monthly sexual frequency. RESULTS: There was a significant relationship between improvement in level of sexual energy and the addition of methyltestosterone to CEE/MPA treatment (p = 0.021). No significant effect on orgasmic capacity was noted after the treatment period. CONCLUSION: Addition of methyltestosterone to CEE/MPA therapy may increase sexual energy, but might not affect the ability to obtain orgasm in sexual relations.     

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.     

Effects of conjugated equine estrogen with and without three different progestogens on lipoproteins, high-density lipoprotein subfractions, and apolipoprotein A-I.

The effects of conjugated equine estrogen and subsequent cyclical progestogen supplementation on lipoprotein and apolipoprotein A-I levels were investigated in three groups of postmenopausal women. Unopposed conjugated equine estrogen (0.625 mg) lowered total cholesterol 4-8% and low-density lipoprotein (LDL) cholesterol 12-19% below pre-treatment levels in all three groups. Levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I were increased 9-13 and 9-18%, respectively, with unopposed estrogen. The increase in HDL cholesterol was mainly due to increases in the high-density lipoprotein2 (HDL2) subfraction. Addition of medroxyprogesterone acetate, norethindrone acetate, or d,l-norgestrel at doses shown previously to provide protection against endometrial hyperplasia reversed some of the beneficial estrogen effects, reducing levels of HDL cholesterol 14-17%, HDL2 cholesterol 22-37%, and apolipoprotein A-I 11-15% from those obtained with unopposed estrogen. The LDL cholesterol levels fell 12-19% with unopposed estrogen but remained 7-12% below baseline when progestogens were added. These observations demonstrate that after 3 months of treatment, all three progestogens reversed some of the favorable effects of unopposed estrogen on lipoproteins but permitted a continued modest reduction in LDL cholesterol.     

Effects of hormone replacement therapy on plasma homocysteine and C-reactive protein levels.

In order to investigate the effect of hormone replacement therapy (HRT) on plasma homocysteine and C-reactive protein (CRP) levels 46 healthy postmenopausal women were prospectively enrolled. HRT, which was either 0.625 mg/day conjugated equine estrogen (CEE) plus 2.5 mg/day medroxyprogesterone acetate (MPA) or 0.625 mg/day CEE alone were administered. After 6 months, estrogen alone significantly increased serum CRP concentrations (p = 0.039), however, estrogen plus progesterone therapy did not significantly alter serum CRP levels. Both regimens significantly decreased plasma homocysteine levels (CEE group p = 0.034, CEE+MPA group p = 0.007). It was concluded that the reduction in plasma homocysteine levels with both regimens might contribute to the cardiovascular benefit of HRT and the CRP raising effect of estrogen might be partially prevented by the addition of progesterone.     

Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate: two-year substudy results

OBJECTIVE: To determine the endometrial safety of 2 years of treatment with lower doses of continuous combined conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA). DESIGN: Randomized, double-blind, placebo-controlled, multicenter metabolic and osteoporosis substudy of the Women's Health, Osteoporosis, Progestin, Estrogen (Women's HOPE) study. SETTING: Nineteen study centers across the United States. PATIENT(S): Healthy, postmenopausal women (n = 822) with an intact uterus were recruited. INTERVENTION(S): Patients received CEE 0.625, CEE 0.625/MPA 2.5, CEE 0.45, CEE 0.45/MPA 2.5, CEE 0.45/MPA 1.5, CEE 0.3, CEE 0.3/MPA 1.5 (all doses mg/day), or placebo for 2 years. Endometrial biopsies were evaluated at baseline and years 0.5, 1, 1.5, and 2 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 estrogen (E). RESULT(S): No cases of endometrial hyperplasia were seen in the four CEE/MPA groups. For the CEE-alone groups, a dose-related increase in incidence rates from 3.17% (CEE 0.3 mg) to 27.27% (CEE 0.625 mg) was seen at 2 years. The number of cases increased from year 1 to year 2. For the CEE-alone groups, the incidence rates and types of hyperplasia diagnosed varied among the pathologists. CONCLUSION(S): Two years of treatment with lower doses of CEE/MPA provided endometrial protection comparable to that seen with commonly prescribed doses. These regimens should be considered for postmenopausal women who are candidates for hormone therapy.     

The comparison of bleeding patterns with high-dose and low-dose hormone replacement therapy in postmenopausal women.

Our objective was to compare vaginal bleeding patterns with lower doses of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA), in a randomized, double-blind, placebo-controlled trial. A total of 112 healthy, postmenopausal women were divided into three groups. Group A received CEE 0.625 mg/day plus MPA 2.5 mg/day; group B received CEE 0.3 mg/day, plus MPA 1.25 mg/day; and another group received placebo. All medications were continued for 13 months and bleeding data were analyzed in each group. The percentage of patients who experienced no bleeding in cycle one was 45.2% in group B. These values were significantly greater than the figure for group A (18.2%) and lower than in the placebo group (66.7%). A linear trend between time since menopause and cumulative amenorrhea was observed in cases in group B and the placebo group in all cycles (p < 0.05). This finding was significant in only cycle 13 in group A. In conclusion, a higher rate of amenorrhea was observed with a lower-dose regimen of CEE/MPA, which may be the appropriate regimen.     

Neither long-term treatment with raloxifene nor hormone replacement therapy modulate cardiac function in healthy postmenopausal women: two randomized, placebo-controlled, 2-year studies

OBJECTIVE: Our purpose was to investigate the long-term effects of raloxifene, compared with opposed and unopposed estrogen replacement therapy, on echocardiographic parameters of left ventricular systolic function in healthy postmenopausal women. A total of 157 women were studied in 2 randomized, double-blind, placebo-controlled, 2-year studies. STUDY DESIGN: In study I, 60 postmenopausal women who had undergone hysterectomy received daily raloxifene, 60 mg (n = 15); raloxifene, 150 mg (n = 15); conjugated equine estrogens (CEE), 0.625 mg (n = 15); or placebo (n = 15). In study II, 97 postmenopausal women who had not undergone hysterectomy received daily raloxifene, 60 mg (n = 24); raloxifene, 150 mg (n = 24); CEE, 0.625 mg, plus medroxyprogesterone acetate (MPA), 2.5 mg (n = 24); or placebo (n = 25). M-mode, quantitative 2-dimensional and Doppler echocardiographic measurements were performed at baseline and after 1 and 2 years. RESULTS: Neither after 1 year nor after 2 years of treatment were echocardiographic parameters found to differ from baseline in both raloxifene groups, as well as in the unopposed CEE and the CEE/MPA groups, compared with the placebo group. CONCLUSION: Within 2 years of raloxifene treatment, no effect on echocardiographic parameters of left ventricular systolic function was found. Unopposed CEE or CEE/MPA also showed no effect.     

Changes in lipids and lipoproteins with long-term estrogen deficiency and hormone replacement therapy

Cross-sectional data of the long-term effects of estrogens, androgens, and progestogens on lipids and lipoproteins were obtained in 556 postmenopausal women aged 24 to 85 years with follow-up for 1 to 44 years. Baseline values were obtained in 155 women from less than 1 year up to 30 years after menopause. Total cholesterol and low-density lipoprotein cholesterol tended to rise during the early postmenopausal years while high-density lipoprotein cholesterol did not change. Triglycerides were related to weight and were significantly different only between untreated women of normal weight (128.3 +/- 7.80 mg/dl) and hormone users weighing greater than 200 pounds (252.9 +/- 9.44 mg/dl), p less than or equal to 0.001. Although mean high-density lipoprotein cholesterol was lower with both C-21 progestogens (64.5 +/- 4.16 mg/dl) and C-19 progestogens (61.9 +/- 3.84 mg/dl), there were no statistically significant differences on comparison with levels in the unopposed estrogen users (67.0 +/- 3.94 mg/dl). Smoking significantly depressed high-density lipoprotein cholesterol in both hormone users (p less than or equal to 0.001) and untreated women (p less than or equal to 0.001). Added progestogens do not adversely affect lipids and lipoproteins over the long term when adequate dosages of estrogens are used.     

The comparison of bleeding patterns with high-dose and low-dose hormone replacement therapy in postmenopausal women

Our objective was to compare vaginal bleeding patterns with lower doses of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA), in a randomized, double- blind, placebo-controlled trial. A total of 112 healthy, postmenopausal women were divided into three groups. Group A received CEE 0.625 mg/day plus MPA 2.5 mg/day; group B received CEE 0.3 mg/day, plus MPA 1.25 mg/day; and another group received placebo. All medications were continued for 13 months and bleeding data were analyzed in each group. The percentage of patients who experienced no bleeding in cycle one was 45.2% in group B. These values were significantly greater than the figure for group A (18.2%) and lower than in the placebo group (66.7%). A linear trend between time since menopause and cumulative amenorrhea was observed in cases in group B and the placebo group in all cycles (p <?0.05). This finding was significant in only cycle 13 in group A. In conclusion, a higher rate of amenorrhea was observed with a lower-dose regimen of CEE/MPA, which may be the appropriate regimen.     

Hormone replacement therapy to improve left ventricular diastolic functions in healthy postmenopausal women.

OBJECTIVES: To investigate the effects of estrogen and estrogen plus progesterone replacement therapy on left ventricular systolic and diastolic function parameters in healthy postmenopausal women. METHODS: Forty-six healthy consecutive postmenopausal women were prospectively enrolled. Hormone replacement therapy (HRT), which was either 0.625 mg/day conjugated equine estrogen (CEE) alone, or with 2.5 mg/day medroxyprogesterone acetate (MPA) was administered depending on the hysterectomy status. Left ventricular systolic and diastolic function parameters were evaluated with echocardiography before and after 6 months of HRT. The paired t-test was used for statistical analysis. RESULTS: Estrogen or estrogen plus progesterone did not significantly alter the left ventricular dimensions and systolic function parameters. However, significant improvements were noted in several diastolic function parameters including late diastolic mitral flow velocity, ratio of early to late mitral flow velocity and isovolumic relaxation time (P=0.003, P=0.001 and P=0.005, respectively, for the CEE group; all P<0.001 for the CEE+MPA group). CONCLUSIONS: Estrogen or estrogen plus progesterone replacement therapy may significantly improve left ventricular diastolic functions in healthy postmenopausal women.     

Comparison of lipid and androgen levels after conjugated estrogen or depo-medroxyprogesterone acetate treatment in postmenopausal women

Thirty-five women who had undergone a natural or surgical menopause were randomized to receive either 0.625 mg of conjugated estrogen to be ingested for 25 days each month or 150 mg of depo-medroxyprogesterone acetate intramuscularly every three months. Plasma lipids were determined before and after one year of therapy. Serum androgens were measured before and after six months of therapy. Conjugated estrogens and depo-medroxyprogesterone acetate had similar effects on plasma lipids. Cholesterol was decreased (P less than .02 for conjugated estrogen therapy and P less than .01 for depo-medroxyprogesterone acetate therapy), as was low-density lipoprotein cholesterol (P less than .02 for conjugated estrogen and P less than .05 for depo-medroxyprogesterone acetate). Conjugated estrogens also significantly increased high-density lipoprotein cholesterol (P less than .02). High-density lipoprotein cholesterol levels were unchanged after depo-medroxyprogesterone acetate therapy. Serum androgens were generally unchanged after depo-medroxyprogesterone acetate or conjugated estrogen therapy. The data from this study suggest that long-term conjugated estrogen and depo-medroxyprogesterone acetate treatment have similar effects on lipid and androgen levels except that high-density lipoprotein cholesterol was not significantly increased by depo-medroxyprogesterone acetate.     

Effect of premenopausal castration and incremental dosages of conjugated equine estrogens on plasma follicle-stimulating hormone, luteinizing hormone, and estradiol.

Plasma levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) were measured serially in 11 premenopausal patients before and after hysterectomy with bilateral salpingo-oophorectomy. One week after operation an incremental dosage regimen of conjugated estrogens (CEE) in tablet form was commenced on a basis of two weeks with therapy (0.3, 0.625, 1.25, and finally 2.5 mg.), with each dose interspersed by two weeks without therapy. FSH, LH and E2 levels were measured at the end of each period with and without therapy. E2 levels fell within 24 hours of operation while FSH and LH levels rose gradually. CEE therapy produced an elevation of E2, but circulating concentrations comparable to the premenopausal values were only maintained during the dosage periods of 0.625 and 1.25 mg. of CEE. In only one instance did CEE succeed in reducing FSH to premenopausal levels, and that was at a dosage of 2.5 mg., in which instance the E2 level was higher than the premenopausal value. LH was never reduced to a premenopausal level. Thus, the data indicate that CEE alone in dosages up to 2.5 mg. per day was unable to reproduce in postmenopausal women the gonadotropin and E2 blood serum levels shown to exist prior to oophorectomy. Usual CEE treatment after menopause, therefore, in itself does not represent physiologic "hormone replacement therapy," if defined as the dosage required to maintain premenopausal circulating concentrations of reproductive hormones.     

Do lipid profiles of postmenopausal women under oral hormone replacement therapy remain stable or reveal a multiphasic course in time?

The object of this study was to compare the effects of oral conjugated estrogen (CEE) alone, CEE plus medroxyprogesterone acetate (MPA) and tibolone on lipid profiles, and investigate whether these effects change in time. Plasma lipid levels were studied for CEE (n = 49), CEE + MPA (n = 50) and tibolone (n = 51). Mean per cent changes at certain intervals were compared with their previous intervals for each therapy. Paired t-test was used for statistical analysis. CEE alone had raised high-density lipoprotein (HDL) and triglyceride levels and lowered total cholesterol and low-density lipoprotein (LDL) levels at the end of the 2-year study period. Addition of MPA to the CEE regimen weakened the effect on HDL and triglyceride, augmented the decrease in total cholesterol and did not affect LDL. The tibolone group revealed similar but more prominent effects in total cholesterol and LDL levels. HDL and triglyceride levels were significantly below baseline in the first 6 months, but HDL changes vanished and triglyceride levels remained decreased at the end of 2 years. These data did not support a correlation between lipid levels and the biphasic incidence of cardiac events that were observed in the Heart and Estrogen/progestin Replacement Study (HERS), but revealed period-dependent changes in the tibolone group.     

Lp(a) lipoprotein: relationship to cardiovascular disease risk factors, exercise, and estrogen.

OBJECTIVE: Lp(a) lipoprotein is a distinct lipoprotein particle that recently has been found to be associated with cardiovascular disease. A study was conducted to assess the influence of cardiovascular disease risk factors on levels of Lp(a) and to evaluate the effects of age, exercise, and estrogen on these levels. STUDY DESIGN: Two studies, a cross-sectional study of older men (n = 105) and women (n = 75) (mean age 76 years) and a prospective study of younger postmenopausal women (mean age 48 years), were carried out. Lp(a) and other lipoproteins were measured in the two studies and differences were sought by statistical analysis. RESULTS: In the cross-sectional study, serum Lp(a) was similar in men and women and was not influenced by age. Lp(a) levels in men and women were higher when there was more than one cardiovascular disease risk factor present (p less than 0.028). We could not demonstrate such a relationship with other lipid and lipoprotein measurements. In the prospective study exercise alone had no influence on Lp(a) levels. Oral estrogen decreased Lp(a) levels marginally (p = 0.08). The decrease in Lp(a) with oral estrogen was associated with increases in triglycerides (p less than 0.01) and very-low-density lipoprotein (p less than 0.06). CONCLUSIONS: These data confirm that elevated Lp(a) levels are an independent risk factor for cardiovascular disease. Lp(a) levels are primarily influenced by genetic factors and it appears estrogen may have a minor influence on its hepatic synthesis.