Effect of steroid add-back therapy on the proliferative activity of uterine leiomyoma cells under gonadotropin-releasing hormone agonist therapy

Short-term treatment with gonadotropin-releasing hormone agonist (GnRHa) is a useful preoperative medical therapy of uterine leiomyomas. However, adverse effects caused by the hypo-estrogen state sometimes appear, suggesting the necessity of add-back therapy. In this study, we investigated effects of three kinds of add-back therapies on the proliferative activity of uterine leiomyoma cells by examining the expression of Ki-67 in leiomyoma cells by immunostaining. Thirty patients who were to undergo hysterectomy or myomectomy were injected with 3.75?mg depot leuprolide acetate every four weeks until the end of the 12th week. Twenty patients underwent add-back therapy from the 5th week to the end of the 12th week, 8 patients receiving 0.625?mg of conjugated equine estrogen (CEE) /day, 6 patients 5.0?mg of medroxyprogesterone acetate (MPA)/day, 6 patients 0.625?mg CEE plus 2.5?mg of MPA /day. The add-back of CEE or CEE plus MPA suppressed decreases in the proliferative activity of leiomyoma cells caused by GnRHa therapy, but that of MPA did not. These results suggest that the add-back therapy with MPA is of use in preventing the adverse effects caused by hypo-estrogen in the preoperative short-term GnRHa therapy.     

Effect of steroid add-back therapy on the proliferative activity of uterine leiomyoma cells under gonadotropin-releasing hormone agonist therapy.

Short-term treatment with gonadotropin-releasing hormone agonist (GnRHa) is a useful preoperative medical therapy of uterine leiomyomas. However, adverse effects caused by the hypo-estrogen state sometimes appear, suggesting the necessity of add-back therapy. In this study, we investigated effects of three kinds of add-back therapies on the proliferative activity of uterine leiomyoma cells by examining the expression of Ki-67 in leiomyoma cells by immunostaining. Thirty patients who were to undergo hysterectomy or myomectomy were injected with 3.75 mg depot leuprolide acetate every four weeks until the end of the 12th week. Twenty patients underwent add-back therapy from the 5th week to the end of the 12th week, 8 patients receiving 0.625 mg of conjugated equine estrogen (CEE) /day, 6 patients 5.0 mg of medroxyprogesterone acetate (MPA)/day, 6 patients 0.625 mg CEE plus 2.5 mg of MPA /day. The add-back of CEE or CEE plus MPA suppressed decreases in the proliferative activity of leiomyoma cells caused by GnRHa therapy, but that of MPA did not. These results suggest that the add-back therapy with MPA is of use in preventing the adverse effects caused by hypo-estrogen in the preoperative short-term GnRHa therapy.     

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.     

Short-term effects of hormone therapy on serum C-reactive protein levels in postmenopausal women

Objectives: The aim of this study was to investigate the effects of tibolone and conjugated equine estrogens (CEEs) plus medroxyprogesterone acetate (MPA) (CEE + MPA) on levels of serum C-reactive protein (CRP), an independent risk factor for cardiovascular disorders, in postmenopausal women. Study design: In this prospective randomized study, we randomly assigned 58 healthy postmenopausal women to CEE (0.625 mg/day) plus MPA (2.5 mg/day) (CEE + MPA) or tibolone (2.5 mg/day). The serum levels of CRP at 3 months after starting treatment were compared with baseline values for both therapies. Results: After 3 months of treatment the median CRP levels increased by 29% in the CEE + MPA group and by 5% in the tibolone group. But, these changes did not have statistical significance (P=0.15, P=0.06, respectively). Conclusions: Our findings show that neither tibolone nor CEE + MPA caused significant changes in serum CRP levels in postmenopausal women. The potential impact of hormone therapy on serum CRP levels should be investigated in ongoing clinical trials.     

Add-back therapy and gonadotropin-releasing hormone agonists in the treatment of patients with endometriosis: can a consensus be reached? Add-Back Consensus Working Group

OBJECTIVE: To reach a consensus on the role of add-back therapy for patients with endometriosis administered GnRH agonists (GnRH-a). DESIGN: Results of consensus conference reviewing MEDLINE search of English language abstracts of both prospective and retrospective series. SETTING: Consensus conference of 31 specialists in gynecologic surgery and reproductive endocrinology. PATIENT(S): Patients with symptomatic endometriosis who were candidates for GnRH-a therapy in treatment courses ranging in duration from 6 to 12 months. INTERVENTION(S): Oral steroidal and nonsteroidal add-back regimens. MAIN OUTCOME MEASURE(S): Alteration in painful symptoms, extent of disease, vasomotor symptoms, bone mineral density, and serum lipid profile. RESULT(S): When added to GnRH-a for 6 months, both 2.5 mg of norethindrone and 0.625 mg of conjugated equine estrogens with 5 mg/d of medroxyprogesterone acetate provide effective relief of vasomotor symptoms and decrease but do not eliminate bone mineral density loss. During 12 months of GnRH-a therapy, bone mineral density loss is eliminated effectively with an add-back of 5 mg of norethindrone acetate alone or in conjunction with low-dose conjugated equine estrogens. Organic bisphosphonates also may play a role. CONCLUSION(S): In patients with symptomatic endometriosis, the efficacy of GnRH agonists may be preserved and therapy prolonged while overcoming hypoestrogenic side effects with the use of appropriate add-back regimens.     

Effect of hormone replacement therapy and tibolone on serum total homocysteine levels in postmenopausal women

OBJECTIVE: To assess the effect of continuous combined hormone replacement therapy (HRT) or tibolone on serum total homocysteine (tHcy) levels in postmenopausal women. STUDY DESIGN: Ninety-five postmenopausal women aged 41-68 years were included in the study. Seventy-three women with climacteric complaints, osteopenia or osteoporosis received either conjugated equine estrogens 0.625 mg combined with medroxyprogesterone acetate 5 mg (CEE/MPA, n=31) or tibolone 2.5 mg (n=42). Twenty-two healthy women, matched for chronological and menopausal age, served as controls. Serum tHcy levels were assessed at baseline, 6, 12 and 18 months. RESULTS: No difference was recorded between groups regarding demographic characteristics or mean baseline serum tHcy. Serum tHcy levels decreased significantly in the CEE/MPA compared to baseline (change at 18 months: -3.9%, P<0.05). The magnitude of the decrease was higher in the subgroup of women with baseline tHcy levels above the median (change at 18 months: -15.0%, P<0.01). No change in tHcy levels was detected in the tibolone group throughout the study period, either in the whole group (change at 18 months: 1.9%, NS) or in the subgroup with baseline tHcy levels above the median (change at 18 months: -3.23%, NS). CONCLUSION: Continuous CEE/MPA reduces tHcy especially in women with high pretreatment tHcy levels. Tibolone has no effect on serum tHcy levels at least during the first 18 months of therapy. Larger studies with longer follow-up are required to confirm these results.     

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.     

Psychological effects of tibolone and sequential estrogen-progestogen therapy in perimenopausal women.

OBJECTIVE: To investigate changes in psychological symptoms before and after continuous tibolone treatment and sequential estrogen-progestogen therapy in perimenopausal women. METHODS: In this prospective, randomized, controlled study, perimenopausal women were randomly allocated to treatment with either tibolone 2.5 mg/day for 28 days (n = 28), or 0.625 mg conjugated equine estrogens (CEE) for 25 days plus 5 mg medroxyprogesterone acetate (MPA) daily on days 16-25 (n = 33). The differences in Beck's depression scores and serum lipid profiles before and after 1 year of treatment with both regimens were compared. RESULTS: Both groups were similar with respect to demographic characteristics. The differences in Beck's depression scores before and after treatment were statistically significant in the tibolone group (21.3 vs 17.1, p = 0.038) and also in the group receiving standard sequential estrogen-progestogen treatment (15.7 vs. 13.0, p = 0.040). In the sequential estrogen-progesterone group, a statistically significant increase was measured in high-density lipoprotein (HDL)-cholesterol levels after treatment (49.1 vs. 56.8 mg/dl, p = 0.023). CONCLUSION: Tibolone is as effective as sequential estrogen-progesterone therapy in alleviating the psychological symptoms of the perimenopause. In addition, CEE + MPA induces favorable changes in HDL-cholesterol.     

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

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

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.     

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

Objective: To evaluate the efficacy of lower doses of conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for relieving vasomotor symptoms and vaginal atrophy.

Design: A randomized, double-blind, placebo-controlled trial (the Women’s Health, Osteoporosis, Progestin, Estrogen study).

Setting: Study centers across the United States.

Patient(s): Two thousand, six hundred, seventy-three healthy, postmenopausal women with an intact uterus, including an efficacy-evaluable population (n = 241 at baseline).

Intervention(s): Patients received for 1 year (13 cycles; in milligrams per day) CEE, 0.625; CEE, 0.625 and MPA, 2.5; CEE, 0.45; CEE, 0.45 and MPA, 2.5; CEE, 0.45 and MPA, 1.5; CEE, 0.3; CEE, 0.3 and MPA, 1.5; or placebo.

Main Outcome Measure(s): Number and severity of hot flushes and Papanicolaou smear with vaginal maturation index (VMI) to assess vaginal atrophy.

Result(s): In the efficacy-evaluable population, reduction in vasomotor symptoms was similar with CEE of 0.625 mg/d and MPA of 2.5 mg/d (the most commonly prescribed doses) and all lower combination doses. CEE of 0.625 mg/d alleviated hot flushes more effectively than the lower doses of CEE alone. VMI improved in all active treatment groups.

Conclusion(s): Lower doses of CEE plus MPA relieve vasomotor symptoms and vaginal atrophy as effectively as commonly prescribed doses.     

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

Objective: To evaluate vaginal bleeding profiles with lower doses of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) as continuous combined therapy.

Design: The Women’s Health, Osteoporosis, Progestin, Estrogen (Women’s HOPE) study, a randomized, double-blind, placebo-controlled trial.

Setting: Study centers across the United States.

Patient(s): Two thousand six hundred seventy-three healthy, postmenopausal women.

Intervention(s): Women received CEE, 0.625 mg/d; CEE, 0.625 mg/d, plus MPA 2.5 mg/d; CEE, 0.45 mg/d; CEE, 0.45 mg/d, plus MPA, 2.5 mg/d; CEE 0.45 mg/d, plus MPA, 1.5 mg/d; CEE, 0.3 mg/d; CEE, 0.3 mg/d, plus MPA, 1.5 mg/d; or placebo for 1 year.

Main Outcome Measure(s): Bleeding data were analyzed in efficacy-evaluable and intention-to-treat populations.

Result(s): Cumulative amenorrhea and no bleeding rates were higher with lower doses of CEE/MPA than with CEE 0.625/MPA 2.5. A linear trend between time since menopause and cumulative amenorrhea was observed (P<.05) in all CEE/MPA groups except the CEE 0.45/MPA 1.5 group. The proportion of patients who experienced no bleeding in cycle 1 was 89%, 82%, and 80% in the CEE 0.3/MPA 1.5, CEE 0.45/MPA 1.5, and CEE 0.45/MPA 2.5 groups, respectively. These values were significantly greater than the incidence of no bleeding in the CEE 0.625/MPA 2.5 group (P<.05).

Conclusion(s): Lower-dose regimens of CEE and MPA produce higher rates of amenorrhea and no bleeding compared with CEE 0.625/MPA 2.5 and may be appropriate for newly menopausal patients.     

The effect of hormone replacement therapy on the levels of serum lipids, apolipoprotein AI, apolipoprotein B and lipoprotein (a) in Turkish postmenopausal women

Objectives Estrogen replacement therapy alters the lipid profiles favorably for delaying atherosclerosis in postmenopausal women. The effects of estrogen plus progesterone combination therapy on lipids are controversial. This study was designed to evaluate the effect of female sex hormones on lipids and lipoproteins and to clarify the influence of progesterone on the effect of estrogen in postmenopausal women.Methods Of the 60 postmenopausal women admitted to our menopause clinic, 40 had intact uterus and received continuous 0.625 mg conjugated equine estrogen (CEE) plus 2.5 mg medroxyprogesterone acetate (MPA), whereas the remaining 20 were hysterectomized and received 0.625 mg CEE daily. To assess the alterations in lipids and lipoproteins during menopause, 45 healthy premenopausal women were investigated. Lipid and lipoprotein levels were assessed in each subject at baseline and at the 6th and 18th months of therapy.Results In menopause, a shift towards more atherogenic lipid and lipoprotein profiles than those of the premenopausal state was found. Following 18 months of treatment, both regimens reduced total cholesterol (TC) levels as compared with the baseline (6.4 vs. 6.9% in the CEE/MPA and CEE groups, respectively). The CEE group had a more pronounced increase in high-density lipoprotein (HDL) cholesterol than the CEE/MPA group (10.3 vs. 8.8%, respectively). Both groups displayed reduced TC, low-density lipoprotein (LDL) cholesterol and apolipoprotein-B (ApoB) concentrations, whereas triglycerides increased, with a greater tendency to increase in the CEE/MPA group at the end of the trial. Also, the lipoprotein (a) [Lp(a)] levels decreased significantly (27.6 vs. 24.5% in the CEE/MPA and CEE groups, respectively). This decrease was more pronounced in subjects with a relatively higher basal Lp(a) concentration.Conclusion Both treatment regimens caused positive alterations in the lipid and lipoprotein profiles. This association might play a pivotal role in the postmenopausal increases in atherosclerotic diseases and cardioprotective effect of estrogen in postmenopausal women.     

Cognitive function variations in postmenopausal women treated with continuous,combined HRT or tibolone. A comparison

OBJECTIVE: To compare cognitive function in postmenopausal women receiving continuous hormone replacement therapy and those receiving tibolone. STUDY DESIGN: This was a 6-month, prospective, single-blind, single center, randomized study. A total of 50 healthy, postmenopausal women were enrolled. In the end, 40 women completed the 6-month follow-up. One group (23 subjects) received conjugated equine estrogens (CEE), 0.625 mg/d, and medroxyprogesterone acetate (MPA), 5 mg/d. The other group (17 subjects) received tibolone, 2.5 mg/d. Their serum estradiol levels and Cognitive Abilities Screening Instrument (CASI) and Mini-Mental State Examination (MMSE) scores were obtained before starting and after 3 and 6 months of treatment. RESULTS: There was a significant increase in the serum estradiol level in the CEE + MPA group, especially after 3 months of treatment, but there was no increase in the estradiol level in the tibolone group. The CASI and MMSE scores of the CEE + MPA group and the tibolone group after 3 and 6 months of treatment showed no significant difference between the two groups apart from the MMSE at the 3-month follow-up. We saw an increasing trend in CASI and MMSE scores after treatment in both groups; however, the increases were not statistically significant. The rate of increase of both CASI and MMSE scores in the CEE + MPA group was greater than in the tibolone group, though the difference was not significant. CONCLUSION: This preliminary study demonstrated that both CEE + MPA and tibolone can preserve cognitive function and may be able to prevent cognitive decline in postmenopausal women during short-term treatment. Our results also show that continuous, combined CEE + MPA seems to be marginally more effective than tibolone in improving cognitive processes; however, long-term study is needed to follow-up such effect.     

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.     

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.     

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.     

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.     

黑升麻在中重度子宫内膜异位症GnRH-a反加治疗中的疗效评估

目的:比较黑升麻和替勃龙在中重度子宫内膜异位症腹腔镜术后GnRH-a反加治疗中的疗效。方法:前瞻性随机对照比较中重度子宫内膜异位症腹腔镜术后患者90例,分为戈舍瑞林+黑升麻组、戈舍瑞林+替勃龙组、戈舍瑞林组,各30例,分析各组用药3个月后血清雌二醇(E2)、促卵泡激素(FSH)水平;子宫内膜厚度;Kupperman(KMI)评分;视觉疼痛症状评分法(VAS)评分;血清骨钙素(BGP);CA125、肝肾功能、血脂等变化。结果:戈舍瑞林+替勃龙组血清E2水平显著高于戈舍瑞林+黑升麻组及戈舍瑞林组(P均<0.05),FSH显著低于戈舍瑞林+黑升麻组及戈舍瑞林组(P均<0.05),戈舍瑞林+黑升麻组和戈舍瑞林组间无差异(P>0.05);戈舍瑞林组KMI评分明显高于戈舍瑞林+替勃龙组和戈舍瑞林+黑升麻组(P<0.05),而戈舍瑞林+替勃龙组和戈舍瑞林+黑升麻组间无差异(P>0.05);戈舍瑞林+替勃龙组血清BGP浓度显著低于戈舍瑞林组和戈舍瑞林+黑升麻组(P均<0.05),而戈舍瑞林组和戈舍瑞林+黑升麻组间无差异(P>0.05)。各组间EM、VAS评分、CA125、肝肾功能及血脂等均无明显差异(P>0.05)。结论:黑升麻是中重度子宫内膜异位症腹腔镜术后GnRH-a反加治疗安全有效的选择之一。     

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

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