Effects of hormonal replacement therapy on plasma sex hormone-binding globulin, androgen and insulin-like growth factor-1 levels in postmenopausal women

Plasma sex hormone-binding globulin (SHBG) levels are important in the regulation of plasma free and albumin-bound androgens and estrogens. In postmenopausal women associated to the decrease of estrogen production, a decrease of plasma SHBG levels occurs. Hormone replacement therapy (HRT) in postmenopausal women modulates plasma SHBG levels, in relationship with the different regimens and routes of administration. The present study aimed to compare the effect of different HRT on plasma SHBG levels in relationship with the changes of plasma androgen [dehydroepiandrosterone sulphate (DHEAS), testosterone (T), androstenedione (A)] and insulin-like growth factor-1 (IGF-1) levels. In a retrospective study 443 postmenopausal women were studied and divided into 2 groups. The group 1 (n = 170) was subdivided in 4 groups of women as follows: A) treated with transdermal 17-beta estradiol + medroxyprogesterone acetate, B) treated with oral conjugated estrogens, C) treated with sequential HRT (estradiol valerate (EV) + norgestrel), and D) treated with a combined HRT (micronized estradiol (E2) + noretisterone acetate). Women of group 2 (n = 273) did not receive HRT and served as controls. All groups of women treated with different HRT showed plasma estradiol levels significantly higher than controls (p < 0.01), showing the highest values in women treated with oral HRT. Plasma SHBG levels were not significantly different between patients treated with transdermal 17-beta estradiol + medroxyprogesterone acetate and controls. On the other hand, all the groups of patients treated with oral conjugated estrogen with or without progestagens showed plasma SHBG levels significantly higher than controls (p < 0.01). Plasma SHBG levels were higher in the group treated with estrogen alone than in groups of women treated with sequential or combined HRT. Plasma DHEAS, T and A levels in patients treated with different HRT regimens were in the same range of levels as control women. Plasma IGF-1 levels were not significantly affected by the various HRT regimens and remained in the same range as controls. In conclusion, plasma SHBG levels increase following oral HRT while are not affected by transdermal HRT. Plasma IGF-1 and androgen levels are not influenced from oral or transdermal HRT.     

Transdermal estrogen replacement therapy: beneficial effects on hemostatic risk factors for cardiovascular disease

OBJECTIVES: To assess the effect of estrogen replacement therapy on hemostatic risk factors for cardiovascular disease (CVD) in postmenopausal women during 2 years of treatment. METHODS: In an open prospective study, patients (n = 42) were investigated before and during 2 years of treatment, and compared to an untreated postmenopausal control group (n = 18) followed during the same period, healthy premenopausal women (n = 20) being included as a reference group for premenopausal values. The patients underwent treatment with transdermal 17 beta-estradiol (E2) (50 micrograms/24 h), oral medroxyprogesterone acetate (5 mg/day) being added for 12 days every second month. RESULTS: After 2 years of treatment there was a significant increase in t-PA antigen (P = 0.01) and a significant decrease in F VII antigen (P = 0.01). PAI-1 antigen concentrations decreased slightly. Fibrinogen concentrations were already significantly decreased at 3-month follow-up (P = 0.01), and were still low after 2 years. By contrast, at 2-year follow-up the postmenopausal control group manifested significant increases in F VII and PAI-1 antigen and slight increases in fibrinogen, which resulted in significant differences between patients and controls. Regression analysis showed the increase in the serum estradiol concentrations to be inversely correlated to the decreases in the plasma concentrations of F VII antigen (r = -0.34, P = 0.001) and fibrinogen (r = -0.35, P = 0.001). There were no changes in AT III or protein C in any group. CONCLUSIONS: The increase in serum estradiol concentrations due to replacement therapy did not adversely affect the studied components of the fibrinolytic and protein C defense system against thrombosis, and resulted in beneficial decreases in F VII antigen and fibrinogen. These findings may help to explain the beneficial effects of estrogen replacement therapy in terms of protection from cardiovascular disease.     

Bursts of high-frequency synchronized electrical activity in the dog neocortex during food-related operant conditioning

BACKGROUND: Many studies have shown that estrogen replacement with oral micronized 17 beta-estradiol reduces the risk of cardiovascular disease. The aim of the present study was to evaluate the efficacy of transdermal estrogen replacement therapy in improving the risk profile of cardiovascular disease in postmenopausal women. METHODS: Two hundred and fifty postmenopausal women were enrolled from the "Bene Essere Donna" Center and grouped according to the absence (Group I, n = 175; mean age 54.6 +/- 3.5) or presence of mild to moderate hypertension (Group II, n = 75; mean age 54.1 +/- 4.5). Total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, glucose and fibrinogen levels were tested in all women. The total study population was treated with estrogen replacement therapy for 12 months: hysterectomized women received 17 beta-estradiol (0.05 mg/die), while non-hysterectomized women received 17 beta-estradiol 0.05 mg/die plus 5 mg/die of medroxyprogesterone acetate for 12 days during every 28-day cycle. After 12 months, blood pressure and blood chemistry were measured as baseline. RESULTS: Total cholesterol, LDL cholesterol and glucose levels decreased in both groups. HDL cholesterol levels increased significantly only in the sub-group of Group II treated with estrogen plus progesterone. Triglycerides glucose and fibrinogen blood levels decreased in both groups. No cardiovascular events were recorded during the first year of follow-up. CONCLUSION: Transdermal estrogen replacement therapy should be considered as a therapeutic support in order to contrast the elevated cardiovascular risk in postmenopausal women.     

Effects of estrogen replacement therapy on the lipoprotein profile in postmenopausal women with ESRD

BACKGROUND: Patients with ESRD have excessive cardiovascular morbidity and mortality. In postmenopausal women with normal renal function, estrogen replacement therapy decreases cardiovascular mortality by 50%, in part because of their beneficial effects on the lipoprotein profile. Because of similarities in the lipoprotein profile between healthy, postmenopausal women, and women with ESRD, we examined the effects of estrogen replacement on lipoproteins in 11 postmenopausal women with ESRD. METHODS: In a randomized, placebo-controlled crossover study (8 week treatment arms) using 2 mg daily of oral, micronized estradiol, 11 postmenopausal women with ESRD were treated. Neither baseline lipid nor lipoprotein abnormalities were used as entry criteria for study participation. RESULTS: Blood estradiol levels were 19 +/- 4 with placebo and 194 +/- 67 pg/ml (P = 0.024) with estradiol treatment. Total HDL cholesterol concentrations increased from 52 +/- 19 mg/dl to 61 +/- 20 mg/dl (16%), with placebo and estradiol treatments, respectively (P = 0.002). Apolipoprotein A1 increased by 24.6% (P = 0.0002) with estradiol intervention. HDL2 concentrations were 19 +/- 13 with placebo and 24 +/- 16 with estradiol treatment (P = 0.046). There were no differences in total or LDL cholesterol, other lipoprotein fractions including Lp(a), and triglycerides with 2 mg daily estradiol treatment. No significant side effects were observed. CONCLUSIONS: Therefore, using standard dosage regimens for estrogen replacement therapy in postmenopausal women with ESRD, HDL cholesterol is increased to an extent that would be expected to improve their cardiovascular risk profile. Further studies are needed to assess whether estrogen replacement therapy decreases the incidence or severity of cardiovascular disease in ESRD patients to a similar degree compared with other women.     

Development of endometrial cancer in women on estrogen and progestin hormone replacement therapy

The presenting symptoms, hormonal regimens, treatment modalities, tumor pathology, and follow-up of 25 women developing endometrial cancer while receiving postmenopausal estrogen and progestin therapy were investigated retrospectively. Patients were interviewed and hormone therapies were confirmed through medical records. Pathology specimens were reviewed. Patients received conjugated estrogens (n = 20) or another estrogen (n = 5). For those on conjugated estrogens, the mean daily dose was 0.68 mg, monthly duration was 24.9 days, and monthly dose was 17.0 mg. Women also received medroxyprogesterone acetate (n = 23) or norethindrone acetate (n = 2). The most common regimen was sequential medroxyprogesterone acetate, at a mean daily dose of 7.5 mg, monthly duration of 9.3 days, and monthly dose of 68 mg (mean duration = 5.7 years). Most tumors were low stage and grade, with few demonstrating grade 3 disease (n = 2) or greater than 50% myometrial invasion (n = 2). Twenty-three (92%) had disease limited to the uterus, while two had stage IIIA disease. All are alive and disease-free after a median follow-up of 26 months. Estrogen and progestin therapy does not prevent endometrial cancer in all patients. Women who developed this tumor on sequential therapy in general received less than the recommended guidelines for daily dosage and monthly duration of progestin. Most patients had early-stage and low-grade disease. Continued vigilance in the care of women on hormone replacement therapy is necessary even when combination therapy is prescribed.     

A comparison of estrogen replacement, pravastatin, and combined treatment for the management of hypercholesterolemia in postmenopausal women

OBJECTIVES: To evaluate and compare the lipid-altering effects of conjugated estrogens and pravastatin, alone and in combination, in postmenopausal women with hypercholesterolemia. METHODS: This was a double-blind, randomized, placebo-controlled clinical trial with 4 parallel groups. Participants (N = 76) were randomly assigned to receive conjugated estrogens, 0.625 mg/d; pravastatin sodium, 20 mg/d; conjugated estrogens plus pravastatin; or a placebo for 16 weeks. RESULTS: Primary end points were changes in serum lipid parameters. Among participants treated with conjugated estrogens, levels of non-high density lipoprotein cholesterol (non-HDL-C) (13.0%) and calculated low density lipoprotein cholesterol (LDL-C) (13.5%) decreased, while levels of HDL-C (22.5%) and triglycerides (4.2%) increased. Participants in the pravastatin group achieved reductions of 23.7% and 25.4% in non-HDL-C and calculated LDL-C levels, respectively. Levels of HDL-C increased slightly (3.7%) and triglycerides decreased by 12.1%. Among participants treated with a combination of conjugated estrogens plus pravastatin, the non-HDL-C (-25.2%) and calculated LDL-C (-28.7%) responses were similar to those of the pravastatin group, and the HDL-C response (21.2%) was similar to that observed in the conjugated estrogens group. Triglyceride levels remained similar to baseline (-0.9%) in the combined treatment group. CONCLUSIONS: Administration of conjugated estrogens resulted in potentially antiatherogenic changes in levels of non-HDL-C, HDL-C, and calculated LDL-C. The HDL-C response to combined treatment was similar to that observed in women taking conjugated estrogens alone, while the non-HDL-C and LDL-C responses to combined treatment were similar to those produced by pravastatin therapy alone. These findings support the position of the National Cholesterol Education Program that estrogen replacement, with a progestin where indicated, should be given consideration as a therapeutic option for the management of hypercholesterolemia in postmenopausal women.     

Tennis elbow. Current concepts of treatment and rehabilitation

OBJECTIVE: Estrogens are known to exhibit antioxidative effects. At present little information exists on the influence of co-administered progestins upon this effect. Therefore we investigated the influence of levonorgestrel, a potent antiestrogenic progestin, on the inhibition of the low-density lipoprotein (LDL) oxidation by 17 beta-estradiol or 17 beta-estradiol valerate in vitro and ex vivo. METHODS: After isolation from blood, the in vitro oxidation of LDL was induced by copper ions and measured continuously by monitoring the formation of conjugated dienes. In 21 female ovariectomized White New Zealand rabbits the antioxidative action of 17 beta-estradiol alone or in combination with levonorgestrel after subcutaneous infusion for 3 days was determined using the copper-induced LDL-oxidation as an endpoint. Eleven postmenopausal women were exposed to sequential estrogen-progestin replacement therapy (day 1-21:2 mg estradiol valerate/day, day 10-21: 0.15 mg levonorgestrel/day). Blood samples were collected at three times: on day 1, on day 10, on day 22 (after the combination phase). The lag time of ex vivo oxidation of LDL, the plasma estradiol and estrone levels were estimated. RESULTS: In the chosen cell-free system, 17 beta-estradiol increased the lag time of the LDL-oxidation in a dose-dependent manner. Levonorgestrel showed neither pro-oxidative nor antioxidative effects when administered alone in different concentrations. Co-administration of different doses of levonorgestrel did not modify the antioxidative action of estrogen either. The two ex-vivo models confirmed these results. In rabbits the co-administered 19-nortestosterone derivative levonorgestrel did not impair or reverse the estradiol-dependent effect. In postmenopausal women the daily oral administration of levonorgestrel in conjunction with 17 beta-estradiol valerate did not diminish the antioxidative action of this estrogen given for the first 9 days. CONCLUSION: The antioxidative potential of estradiol and estradiol valerate is maintained in the presence of levonorgestrel.     

Hormone replacement therapy improves cardiovascular risk by lowering plasma viscosity in postmenopausal women

Hormone replacement therapy may protect against cardiovascular disease through several mechanisms that have variable actions on the major determinants of plasma viscosity. Plasma viscosity is an important predictor of incident and recurrent cardiovascular events and mortality in coronary heart disease patients. The effect of estrogen alone or in combination with progestin on plasma viscosity is not known. Using a randomized, double-blind design, we examined the impact of the following daily hormone regimens on plasma viscosity in 23 women: (1) 1 mg estradiol and 2.5 mg medroxyprogesterone (n=7); (2) 1 mg estradiol alone (n=8); and (3) placebo (n=8). Plasma viscosity, fibrinogen, and standard lipoprotein levels were determined at baseline and after 12 weeks of intervention. Plasma viscosity was measured at 37 degreesC with a coaxial microviscometer. Fibrinogen was measured by the Clauss method. Significant changes in plasma viscosity (mPa.s) levels occurred among treatment groups (P<0.01) after the intervention. Plasma viscosity was significantly reduced with estrogen replacement therapy (P<0.01). These data demonstrate that estrogen replacement therapy lowers plasma viscosity. This study suggests an additional mechanism for the cardiovascular protection conferred to postmenopausal women on estrogen replacement therapy.     

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.     

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.     

Effect of various estrogen treatment schedules on antithrombin III levels

Antithrombin III levels were determined in 18 normal indiviuals of both sexes, 24 pregnant women (at term), 20 patients treated with oral contraceptives and 21 postmenopausal patients treated with Premarin. There was no sex difference in antithrombin III levels in the untreated control group. Pregnant women at term had the lowest levels of antithrombin III. The second lowest values were exhibited by women on oral contraceptives. Both of these groups differed significantly (p less than 0.05) from the controls. Premarin treated postmenopausal women had somewhat lower levels of antithrombin III than controls but these were statistically not significant.     

Circulating hormone levels in menopausal women receiving different hormone replacement therapy regimens. A comparison

OBJECTIVE: To measure and compare plasma levels of sex hormones after the administration of different hormone replacement therapy (HRT) regimens. STUDY DESIGN: Ninety women with natural menopause were randomized into this comparative study. Eighty-five women completed one year of follow-up. Patients were randomly assigned to five groups. The first received 0.6 mg/d of conjugated equine estrogen (CEE) cyclically (n = 15). The second received 50 micrograms/d of transdermal estradiol (E2) cyclically (n = 17), and the third received 0.6 mg/d of CEE continuously (n = 17). All these groups also received 2.5 mg of medroxyprogesterone acetate (MPA) sequentially for the last 12 days of HRT, while the fourth therapy group received 0.625 mg/d of CEE and 2.5 mg/d of MPA continuously (n = 19). The fifth group constituted a treatment-free control group (n = 22). Levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2, estrone (E1), prolactin (PRL), testosterone (T), androstenedione (A4), dehydroepiandrosterone sulfate (DHEA-S) and sex hormone binding globulin (SHBG) were determined prior to HRT and during the last week of the 6th and 12th months of HRT, between days 21 and 24 of estrogen administration. RESULTS: After HRT we found decreases in FSH, LH and PRL levels, increases in E2, E1 and SHBG, and no modifications in T, A4 and DHEA-S plasma levels. There were no significant differences between the treatment groups in FSH, LH, E2, PRL, T, A4 or DHEA-S. E1 and SHBG were significantly higher in the groups with oral HRT. CONCLUSION: All the observed changes in hormone levels are to be expected after HRT except for the decrease in PRL levels. Finally, although MPA dosage was not the focus of the present study, our results suggest that the dosage of 2.5 mg/d of MPA in sequential regimens is clearly inadequate to protect the endometrium from hyperplastic changes.     

Hepatitis G virus RNA is common in AIDS patients'' plasma but is not associated with abnormal liver function tests or other clinical syndromes

OBJECTIVE: To determine whether postmenopausal oestrogen replacement therapy affects carotid artery pulsatility index. DESIGN: A prospective double-blind placebo controlled trial. SETTING: University associated teaching hospital. PARTICIPANTS: Twenty-eight postmenopausal women who were more than 12 months postmenopausal and who had not taken exogenous oestrogen. INTERVENTIONS: Independent randomisation to receive oral oestradiol (2 mg daily) or placebo for 20 to 24 weeks. MAIN OUTCOME MEASURES: Internal carotid artery Doppler pulsatility index, measured within one centimetre of the carotid bifurcation. RESULTS: Replicate data were available from 27 women. The mean pulsatility index decreased by -0.11 in 15 women receiving oestradiol, compared with a mean rise of 0.05 in the 12 women who received placebo (P = 0.006, 95% CI for treatment difference 0.06-0.31). CONCLUSIONS: Oestrogen replacement decreases postmenopausal carotid artery pulsatility index, probably reflecting decreased peripheral vascular resistance. This is a further mechanism whereby hormone replacement therapy may impart cardiovascular protection.     

Oral 17 beta-estradiol continuously combined with dydrogesterone lowers serum lipoprotein(a) concentrations in healthy postmenopausal women

Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerosis. Serum Lp(a) concentrations increase after menopause, and postmenopausal estrogen replacement appears to decrease Lp(a) levels. In a randomized, double blind study, we examined the effects of 6-month treatment with daily 17 beta-estradiol (E2; 2 mg, orally) continuously combined with one of four dosages [2.5 mg (n = 41), 5 mg (n = 38), 10 mg (n = 38), and 15 mg (n = 20)] of dydrogesterone on fasting serum Lp(a) concentrations in 137 healthy postmenopausal women. At baseline, no significant differences were noted among the four treatment groups. During the study period of 6 months the median serum Lp(a) concentration decreased significantly from 128 mg/L (range, 5-1660) to 110 mg/L (range, 1-1530) in the total population, corresponding to a reduction of 13% (P < 0.001). The percent changes in serum Lp(a) correlated positively with the percent changes in serum E2 at 3 as well as 6 months of therapy (r = 0.38; P < 0.001 and r = 0.35; P < 0.001, respectively). A dose response of dydrogesterone on serum Lp(a) was not found. In addition, serum lipids and (apo)lipoproteins improved significantly in all four treatment groups. In conclusion, oral E2 continuously combined with dydrogesterone has beneficial effects on the lipid and lipoprotein profile and is effective in lowering Lp(a) concentrations in postmenopausal women.     

The accuracy and precision of four infrared aural canal thermometers during cardiac surgery

Hormone replacement therapy has been shown to decrease the risk of coronary heart disease (CHD) in menopausal women. In this cross-sectional study, we addressed the following question: What effects would combined oral hormone replacement therapy have on plasma lipid and lipoprotein profiles independent of the other known CHD risk factors? We analyzed the plasma lipoproteins of two groups of menopausal women who were randomly selected from a large database of individuals. One group (n = 10) was not taking any hormone replacement therapy (NO HRT), while the second group (n = 8) was taking a daily dose of 0.625 mg conjugated estrogen and 2.5 mg medroxyprogesterone orally (PremPro, Wyeth-Ayerst, Philadelphia, PA) for at least 6 months (HRT). The two groups were not different in age, body weight, percent body fat, body mass index (BMI), waist to hip ratio, blood pressure, or insulin and glucose levels. High-density lipoprotein (HDL)-cholesterol was significantly higher (P < .05) in the HRT group. The total cholesterol (TC) to HDL-cholesterol ratio was significantly lower for HRT versus NO HRT (P < .05). Apolipoprotein (apo) A-1, the apo A-1/B ratio, and lecithin:cholesterol acyltransferase (LCAT) activity were significantly higher in HRT (P < .05). Lipoprotein subclass profiles measured by nuclear magnetic resonance (NMR) spectroscopy showed an increase in larger HDL subpopulations (H3 and H4) in HRT (P < .05), which are considered antiatherogenic. No differences were seen in the cholesterol concentration or size of low-density lipoprotein (LDL) subpopulations in HRT compared with NO HRT. These results indicate that the combined estrogen and progesterone treatment leads to beneficial effects on plasma lipoproteins. The beneficial effects include (1) increases in HDL-cholesterol and predominance of HDL2, (2) no adverse effects on LDL subpopulation distribution, and (3) increases in apo A-1 levels and LCAT activity, which indicate an improvement in reverse cholesterol transport.     

Alteration of the ADP/ATP translocase isoform pattern improves ATP expenditure in developing rat liver mitochondria

OBJECTIVES: To evaluate and to compare the bleeding patterns obtained with two regimens of hormone replacement therapy given to early postmenopausal women with asymptomatic uterine leiomyomas. METHODS: In this randomised prospective 1-year study 50 early postmenopausal women with one to four asymptomatic uterine leiomyomas were enrolled into two study-groups to take two regimens of hormone replacement therapy for 12 28-day cycles: (A) Tibolone, 2.5 mg/day; (B) conjugated equine estrogens (CEE), 0.625 mg/day plus medroxyprogesterone acetate (MPA), 5 mg/day. The bleeding patterns and the changes in uterine volume of the 47 outpatients who completed the study were evaluated and compared. RESULTS: Amenorrhea incidence was higher in group A (75.0% of the cycles) than in group B (65.6% of the cycles), while irregular bleeding and irregular spotting incidences were higher in group B (29.7 and 4.7% of the cycles, respectively) compared to group A (22.6 and 2.4% of the cycles, respectively). The mean bleeding and spotting lengths were not statistically different between patients in group A and those in group B. Finally, at the end of the study period transvaginal ultrasonography showed no significant change in leiomyoma size. CONCLUSIONS: The results demonstrate that, in early postmenopausal patients with asymptomatic uterine leiomyomas, Tibolone treatment seems to be preferable compared to CEE-MPA continuous combined treatment in relation to the lesser occurrence of irregular bleeding. Furthermore, neither Tibolone nor CEE-MPA therapy, at the doses used here, promote fibroid growth.     

Synthesis and structure-activity relationships of 3-hydrazono-1H-2-indolinones with antituberculosis activity

OBJECTIVES: To evaluate endometrial responses to three different forms of amenorrhea-inducing HRT in postmenopausal women. MATERIAL AND METHODS: Fifty-one postmenopausal women completing a one-year HRT trial with percutaneous estradiol gel containing 1.5 mg estradiol daily combined with a levonorgestrel-releasing intrauterine device (LNG-IUD) (n=18), or natural progesterone 100 mg daily orally (n= 19) or vaginally (n=15) during 1-25 calendar days of each month. Endometrial thickness and uterine size were measured by transvaginal ultrasound, and endometrial cytology/histology was assessed from specimens taken by needle aspiration before the study and at 12 months. RESULTS: Before medication, the median endometrial thickness was 2.0 mm in the LNG-IUD group, 2.4 mm in the oral P group and 2.5 mm in the vaginal P group. At 12 months of therapy the respective values, 3.0, 2.7 and 2.4 mm, did not differ significantly from the initial values. LNG-IUD induced epithelial atrophy in all women, which was accompanied by stromal decidualization in 12 women. On the contrary, only four women in the oral P group and five women in the vaginal P group had an inactive or atrophic endometrium. The remaining cases were dominated by proliferative features. No hyperplasia was seen in any of the groups. CONCLUSION: LNG-IUD appeared to be an effective method of counteracting the stimulatory effect of estrogen on the endometrium, whereas natural progesterone given orally or vaginally was not sufficiently effective in this function at the doses used. The vaginal and oral administrations of progesterone did not differ from each other in this respect.     

Differential impact of conventional oral or transdermal hormone replacement therapy or tibolone on body composition in postmenopausal women

OBJECTIVE: To compare the effects on body composition and body weight of tibolone vs two different sequential oral or transdermal oestrogen-progestogen hormone replacement therapies versus no therapy. PATIENTS AND METHODS: One hundred postmenopausal women were assigned to a control group (n = 26), or randomized to 1) tibolone (TIB) 2.5 mg/day (n = 28), 2) oral oestradiol 2 mg/day (PO) plus sequential dydrogesterone 10 mg/day for 14 of 28 days per cycle (n = 26), or 3) transdermal oestradiol patch (TTS) releasing 50 micrograms/day plus oral sequential dydrogesterone 10 mg/day for 14 of 28 days per cycle (n = 20). Body composition was measured at the base-line and every 6 months for 2 years by DXA (Hologic QDR 1000 W). RESULTS: Total body fat mass increased (P < 0.05) in controls (+3.6 +/- 1.5%) and in TTS treated (+4.7 +/- 2.2%), but not in PO (-1.2 +/- 2.4%) and TIB (-1.6 +/- 2.2%) treated subjects. This increase in total fat mass in controls and TTS treated women was mostly due to an increase in fat mass of the trunk (P < 0.05), but not legs. As a result, a redistribution of body fat to the trunk occurred in controls, TTS and TIB, but not in PO treated women (P < 0.05). Total lean body mass decreased (P < 0.02) in controls (-1.7 +/- 0.7%) and PO (-1.4 +/- 0.6%) but not in TTS (+0.3 +/- 0.8%) and TIB (+0.4 +/- 0.5%) treated subjects. CONCLUSIONS: The menopause is associated with an increase in total body fat and a decline in lean body mass. Oral oestradiol/dydrogesterone and tibolone prevent total body fat changes, whereas transdermal oestradiol/oral dydrogesterone and tibolone prevent the lean mass changes. Furthermore, oral oestradiol/dydrogesterone prevents the shift to a central, android fat distribution.     

Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis

Although estrogen replacement therapy is associated with reduced risk of coronary heart disease and reduced extent of coronary artery atherosclerosis, the effects of combined (estrogen plus progestin) hormone-replacement therapy are uncertain. Some observational data indicate that users of combined hormone replacement consisting of continuously administered oral conjugated equine estrogens (CEE) and oral sequentially administered (7 to 14 days per month) medroxyprogesterone acetate (MPA) experience a reduction in risk similar to that of users of CEE alone. However, the effects of combined, continuously administered CEE plus MPA (a prescribing pattern that has gained favor) on the risk of coronary heart disease or atherosclerosis are not known. We studied the effects of CEE (monkey equivalent of 0.625 mg/d) and MPA (monkey equivalent of 2.5 mg/d), administered separately or in combination, on the extent of coronary artery atherosclerosis (average plaque size) in surgically postmenopausal cynomolgus monkeys fed atherogenic diets and treated with these hormones for 30 months. Treatment with CEE alone resulted in atherosclerosis extent that was reduced 72% relative to untreated (estrogen-deficient) controls (P < .004). Atherosclerosis extent in animals treated with CEE plus MPA or MPA alone did not differ from that of untreated controls. Although treatment had marked effects on plasma lipoprotein patterns, statistical adjustment for variation in plasma lipoproteins did not alter the between-group relationships in atherosclerotic plaque size, suggesting that these factors do not explain substantially the atheroprotective effect of estrogen or the MPA-associated antagonism. Although the mechanism(s) remains unclear, we conclude that oral CEE inhibits the initiation and progression of coronary artery atherosclerosis and that continuously administered oral MPA antagonizes this atheroprotective effect.     

Continuous, low dosage estradiol administration with a vaginal ring: a placebo-controlled study

Estrogen replacement therapy is used in postmenopausal women with symptoms of urogenital atrophy. The aim of this study was to detect differences in efficacy of a low-dose estradiol-releasing vaginal ring and a placebo ring in the relief of symptoms of estrogen deficiency and reduction of urogenital atrophy (pH and vaginal mucosal maturation) in postmenopausal women. DESIGN: This was a multicentre double-blind, placebo-controlled study. PATIENT SAMPLE: 84 postmenopausal women, of whom 67 completed the full 24 weeks of treatment. RESULTS: Vaginal pH decreased significantly (p = 0.0006) in the estradiol group compared with the placebo group. Similarly, in the estradiol group the mean maturation value increased significantly (p = 0.0004), while incidence of pallor and friability were significantly reduced. Patients in the estradiol group reported significantly greater relief of dyspareunia. CONCLUSION: The results indicate that the estradiol-releasing vaginal ring is effective and well tolerated in the treatment of local estrogen deficiency.