Continuous Combined Replacement Therapy Research Articles

Continuous combined replacement therapy in postmenopausal women: effect on plasma lipoproteins, bone mass and the endometrium

The purpose of this study was to examine the effects of Hormone Replacement Therapy (HRT) on plasma lipoprotein levels, bone mass and the endometrium. Thirty healthy women were enrolled in the study for climacteric symptoms and received a combination of 17beta-estradiol and norethisterone acetate continuously for 2 years. An untreated group, consisting of 25 healthy postmenopausal women presenting the same symptoms and not willing to receive HRT, were also studied and served as controls. Plasma lipoprotein levels, bone mineral density as well as thickness of the endometrium measured by ultrasound and biopsy of the endometrium were evaluated at baseline and after 1 and 2 years. There were no differences between the two groups regarding clinical and demographic baseline data. After 2 years of HRT, total cholesterol and LDL-cholesterol levels were significantly reduced (p<0.05). Changes in serum triglyceride and HDL-cholesterol levels were not statistically significant. Levels of lipoprotein (a) showed a statistically significant decrease at 1(st) and 2(nd) year (p<0.05) in both groups while levels of ApoA1 and ApoB were significantly lower only in the HRT group compared to the baseline values. After 2 years of HRT, biomarkers of bone metabolism showed a significant decline, while endometrium was atrophic in 93.3% of the cases. Hormone replacement therapy (17beta-estradiol combined with norethisterone acetate) was associated with favorable changes in the lipid status and bone metabolism. Endometrium was atrophic in most of the treated subjects.

Transvaginal sonographic monitoring of the uterine effects of raloxifene and a continuous combined replacement therapy in postmenopausal women

Objective: To study the effect of 17β-estradiol+norethisterone acetate and raloxifene on the endometrium and uterine volume in postmenopausal women. Methods: Patients were randomly assigned to 17β-estradiol 2 mg+norethisterone acetate 1mg (E 2+NETA) daily ( n=90) or raloxifene HCl 60 mg (Evista) daily ( n=43). Transvaginal sonography was done at baseline and at 6, 12 and 18 months, and at 6 and 12 months in-patients treated with E 2+NETA and EVISTA respectively. Patients were asked to record bleeding-spotting episodes. Whenever required patients were referred for hysteroscopy±biopsy of the endometrium. Results: Patients under E 2+NETA had a higher bleeding-spotting incidence (48.6%) compared with EVISTA (7.7%). Endometrial thickness increased significantly under E 2+NETA as compared with baseline; however, at end point thickness reverted to baseline values. Evista had a non-stimulatory effect on the endometrium. Changes in uterine volume were not statistically significant. Conclusions: Both treatment regimens provided comparable uterine safety. However, raloxifene exhibited a more favorable safety profile on the uterus as expressed in the bleeding-spotting incidence and the effect on endometrial thickness and uterine volume. Transvaginal sonography appears to be a dependable method for monitoring the effect of treatment on the uterus.

A Controlled Trial Between Hormone Replacement Therapy and Toremifene in Aged Post-Menopausal Women 65 Years Old or More

Objectives: Hormone replacement therapy (HRT) is the treatment of choice for menopause and its complications such as osteoporosis, heart diseases and aging. Recently, anti-estrogens such as raloxifene and toremifene have been successfully used in the treatment of menopause complications. To determine the effect of toremifene as compared to continuous combined replacement therapy in aged post menopausal women a controlled study was performed.

Effect of Hormone Replacement Therapy on Breast Cancer Risk: Estrogen Versus Estrogen Plus Progestin

Background: Hormone replacement therapy (HRT) given as unopposed estrogen replacement therapy (ERT) gained widespread popularity in the United States in the 1960s and 1970s. Recent prescribing practices have favored combination HRT (CHRT), i.e., adding a progestin to estrogen for the entire monthly cycle (continuous combined replacement therapy [CCRT]) or a part of the cycle (sequential estrogen plus progestin therapy [SEPRT]). Few data exist on the association between CHRT and breast cancer risk. We determined the effects of CHRT on a woman’s risk of developing breast cancer in a population-based, case‐control study. Methods: Case subjects included those with incident breast cancers diagnosed over 4 1 ⁄ 2 years in Los Angeles County, CA, in the late 1980s and 1990s. Control subjects were neighborhood residents who were individually matched to case subjects on age and race. Case subjects and control subjects were interviewed in person to collect information on known breast cancer risk factors as well as on HRT use. Information on 1897 postmenopausal case subjects and on 1637 postmenopausal control subjects aged 55‐72 years who had not undergone a simple hysterectomy was analyzed. Breast cancer risks associated with the various types of HRT were estimated as odds ratios (ORs) after adjusting simultaneously for the different forms of HRT and for known risk factors of breast cancer. All P values are two-sided. Results: HRT was associated with a 10% higher breast cancer risk for each 5 years of use (OR 5 = 1.10; 95% confidence interval [CI] = 1.02‐1.18). Risk was substantially higher for CHRT use (OR5 = 1.24; 95% CI = 1.07‐1.45) than for ERT use (OR 5 = 1.06; 95% CI = 0.97‐1.15). Risk estimates were higher for SEPRT (OR 5 = 1.38; 95% CI = 1.13‐1.68) than for CCRT (OR5 = 1.09; 95% CI = 0.88‐1.35), but this difference was not statistically significant. Conclusions: This study provides strong evidence that the addition of a progestin to HRT enhances markedly the risk of breast cancer relative to estrogen use alone. These findings have important implications for the risk‐ benefit equation for HRT in women using CHRT. [J Natl Cancer Inst 2000; 92:328‐32]

Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin.

Hormone replacement therapy (HRT) given as unopposed estrogen replacement therapy (ERT) gained widespread popularity in the United States in the 1960s and 1970s. Recent prescribing practices have favored combination HRT (CHRT), i.e., adding a progestin to estrogen for the entire monthly cycle (continuous combined replacement therapy [CCRT]) or a part of the cycle (sequential estrogen plus progestin therapy [SEPRT]). Few data exist on the association between CHRT and breast cancer risk. We determined the effects of CHRT on a woman's risk of developing breast cancer in a population-based, case-control study. Case subjects included those with incident breast cancers diagnosed over 4(1/2) years in Los Angeles County, CA, in the late 1980s and 1990s. Control subjects were neighborhood residents who were individually matched to case subjects on age and race. Case subjects and control subjects were interviewed in person to collect information on known breast cancer risk factors as well as on HRT use. Information on 1897 postmenopausal case subjects and on 1637 postmenopausal control subjects aged 55-72 years who had not undergone a simple hysterectomy was analyzed. Breast cancer risks associated with the various types of HRT were estimated as odds ratios (ORs) after adjusting simultaneously for the different forms of HRT and for known risk factors of breast cancer. All P values are two-sided. HRT was associated with a 10% higher breast cancer risk for each 5 years of use (OR(5) = 1.10; 95% confidence interval [CI] = 1.02-1.18). Risk was substantially higher for CHRT use (OR(5) = 1.24; 95% CI = 1.07-1.45) than for ERT use (OR(5) = 1. 06; 95% CI = 0.97-1.15). Risk estimates were higher for SEPRT (OR(5) = 1.38; 95% CI = 1.13-1.68) than for CCRT (OR(5) = 1.09; 95% CI = 0. 88-1.35), but this difference was not statistically significant. This study provides strong evidence that the addition of a progestin to HRT enhances markedly the risk of breast cancer relative to estrogen use alone. These findings have important implications for the risk-benefit equation for HRT in women using CHRT.

Estrogen-Progestin Replacement Therapy and Endometrial Cancer

Pike, Malcolm C.; Peters, Ruth K.; Cozen, Wendy; Probst-Hensch, Nicole M.; Felix, Juan C.; Wan, Peggy C.; Mack, Thomas M. Author Information

Estrogen-progestin replacement therapy and endometrial cancer.

It has been known for more than 20 years that estrogen replacement therapy substantially increases a woman's risk of developing endometrial cancer. To reduce this increased risk, progestins have been added to estrogen replacement therapy for between 5 and 15 days (usually 7 or 10 days) per "month" in a sequential fashion (sequential estrogen-progestin replacement therapy) or with each dose of estrogen replacement therapy (continuous combined replacement therapy). At the present time, however, little is known about the effects of varying the number of days that progestin is used in sequential estrogen-progestin replacement therapy. We sought to determine the effects of sequential estrogen-progestin replacement therapy and continuous combined replacement therapy on a woman's risk of developing endometrial cancer. A population-based, case-control study of 833 case subjects and 791 control subjects was conducted. Women were postmenopausal, white, and aged 50-74 years when first diagnosed with invasive endometrial cancer or were aged 50-74 years at the matching date for control subjects. All subjects were interviewed in person with the aid of a month-by-month calendar. Relative risks were estimated by odds ratios (ORs); ORs were adjusted simultaneously for the different forms of hormone replacement therapy and for the known endometrial cancer risk factors. The adjusted OR was 2.17 (95% confidence interval [CI] = 1.91-2.47) per 5 years of estrogen replacement therapy use (based on 422 users among the case subjects and 262 users among the control subjects). For women who received sequential estrogen-progestin replacement therapy with the progestin given for less than 10 days (effectively 7 days) per month, the adjusted OR was only slightly reduced to 1.87 (95% CI = 1.32-2.65) per 5 years of use (74 case subjects and 47 control subjects). However, when progestin was given for 10 or more days (effectively 10 days), there was essentially no increased risk (adjusted OR = 1.07 per 5 years of use; 95% CI = 0.82-1.41) (79 case subjects and 88 control subjects). Continuous combined replacement therapy was also associated with essentially no increased risk (adjusted OR = 1.07 per 5 years of use; 95% CI = 0.80-1.43) (94 case subjects and 81 control subjects). The progestin in sequential estrogen-progestin replacement therapy needs to be given for at least 10 days to block effectively any increased risk of endometrial cancer. Continuous combined estrogen-progestin therapy is similarly effective. Neither regimen reduces a woman's underlying risk of endometrial cancer. The sharp distinction between the effects of less than 10 days (effectively 7 days) and 10 or more days (effectively 10 days) of progestin use in sequential estrogen-progestin replacement therapy suggests that the extent of endometrial sloughing may play a critical role in determining endometrial cancer risk.

Low Doses of 17β-Estradiol and Norethisterone Acetate as Continuous Combined Replacement Therapy in Postmenopausal Women: Lipid Metabolic Effects

Our objective was to investigate the effects on serum and lipoprotein lipids of low doses of 17β-estradiol (E2) and norethisterone acetate (NETA) administered as continuous combined hormone replacement therapy (HRT) in postmenopausal women. A one-center prospective randomized double-blind comparison of three hormone replacement combinations was carried out during 12 months. Subjects were 60 healthy postmenopausal women with climacteric symptoms. Treatment was continuous combined regimens as one tablet every day given to three treatment groups denoted group A (1 mg E2 + 0.25 mg NETA). group B (1 mg E2 + 0.5 mg NETA). and group C (2 mg E2 + 1 mg NETA). A significant decrease in total cholesterol (0.40-0.61 mmol/L) and low-density lipoprotein (LDL)-cholesterol (0.12-0.33 mmol/L) was found in all groups. High-density lipoprotein (HDL)-cholesterol decreased (0.11-0.15 mmol/L) after 12 months but the HDL/LDL ratio remained unchanged. Serum triglyceride levels were reduced in all groups (0.07-0.31 mmol/L) but the reduction did not reach statistical significance. The levels of serum lipoprotein(a) showed a slight reduction at the end of the study (10-14 mg/L). Small changes occurred in apolipoprotein-AI levels. Apolipoprotein-B increased in group B (p < 0.05) and was unchanged in groups A and C. Low doses of E2 and NETA as continuous combined HRT induced small metabolic effects. No significant differences were observed between the treatment groups. The significance of the changes in lipid metabolism in elderly women on long-term therapy cannot be fully evaluated from our study but has to be confirmed further in larger epidemiological studies.

Superior compliance and efficacy of continuous combined oral estrogen-progestogen replacement therapy in postmenopausal women

OBJECTIVE: We assessed compliance, relief of climacteric symptoms, and impact on lumbar bone mineral density in two groups of 140 patients treated with a sequential estrogen-progestogen or a continuous combined replacement therapy in comparison with controls. STUDY DESIGN: Patients were randomized to 2 mg of estradiol valerate daily and 5 mg of medroxyprogesterone acetate daily for 12 days per month sequentially to induce withdrawal bleeding (group A) or 2 mg of estradiol, 1 mg of estriol, and 1 mg of norethisterone acetate daily continuously to maintain amenorrhea (group B) or a control group (group C). RESULTS: Compliance was 93% after 1 year and 73% after 2 years in group B and 66% and 49% in group A after 1 and 2 years, respectively. Improvement of climacteric symptoms was similar in groups A and B. Uterine bleeding in 24% of patients in group A and 3% in group B was the most frequent reason for discontinuation of drug intake. Only continuous combined therapy (group B) increased bone mineral density after 1 and 2 years compared with baseline: -13% and 17% ( p = 0.01). In groups A and C no significant changes in bone mineral density were recorded. Compliance was unrelated to the age of menopause. CONCLUSION: Continuous combined therapy is superior to sequential estrogen progestogen replacement in compliance and prevention of bone loss but not with regard to relief of climacteric symptoms.

A Transdermal Regimen for Continuous Combined Hormone Replacement Therapy in the Menopause

Transdermal systems for oestrogen therapy in the menopause have become very popular. The compliance, however, is impeded by the cyclic addition of oral progestins which leads to monthly withdrawal bleeds. In this pilot study a skin patch releasing 0.05 mg oestradiol and 0.25 mg norethisterone acetate per day, which was originally designed for sequential therapy, was used in a continuous manner. Results were quite favourable. Menopausal complaints were efficiently relieved and the Kupperman score dropped from 27.6 to 5.0. Out of 10 women, 1 had mild breakthrough bleeding, and 7 patients recorded one or several spotting episodes, mainly within the first 3 treatment months. No endometrial hyperplasia was observed and there was no significant change in plasma lipids, i.e. cholesterol, triglycerides, HDL-, HDL2-, HDL3-cholesterol, LDL-cholesterol and apolipoproteins A1 and B. The regimen might be a useful alternative to oral continuous combined replacement therapy.

A transdermal regimen for continuous combined hormone replacement therapy in the menopause

Transdermal systems for oestrogen therapy in the menopause have become very popular. The compliance, however, is impeded by the cyclic addition of oral progestins which leads to monthly withdrawal bleeds. In this pilot study a skin patch releasing 0.05 mg oestradiol and 0.25 mg norethisterone acetate per day, which was originally designed for sequential therapy, was used in a continuous manner. Results were quite favourable. Menopausal complaints were efficiently relieved and the Kupperman score dropped from 27.6 to 5.0. Out of 10 women, 1 had mild breakthrough bleeding, and 7 patients recorded one or several spotting episodes, mainly within the first 3 treatment months. No endometrial hyperplasia was observed and there was no significant change in plasma lipids, i.e. cholesterol, triglycerides, HDL-, HDL2-, HDL3-cholesterol, LDL-cholesterol and apolipoproteins A1 and B. The regimen might be a useful alternative to oral continuous combined replacement therapy.