A comparison of effects of sequential transdermal administration versus oral administration of estradiol plus norethisterone acetate on serum NO levels in postmenopausal women

AIM: To compare the effects of sequential transdermal administration versus oral administration of estradiol plus NETA on serum nitric oxide (NO) levels in postmenopausal women (PMW). MATERIALS AND METHODS: Eighty postmenopausal subjects without any prior hormone replacement therapy (HRT) usage were enrolled in this study. All participants were healthy, ambulatory, non-smoker and had similar life styles with dietary habits. HRT was given to participants according to desired HRT administration, in group A (n=50); oral estradiol hemi-hydrate (2 mg)/norethisterone acetate (1 mg), and in group B (n=30); transdermal combined patch comprising estradiol (0.05 mg) alone and estradiol (0.05 mg)/norethisterone acetate (0.25 mg), were given sequential for 12 months. Serum NO levels were studied using Total Oxide Assay Kit (Assay Designs, Inc.) according to manufacturer's instructions prior to and after 12 months from the HRT treatment. RESULTS: The mean serum NO levels prior to the HRT in groups A and B was 0.48+/-0.46 (range, 0.27-0.76 nmol/mL) nmol/mL and 0.47+/-0.48 nmol/mL (range, 0.29-0.693 nmol/mL) (p>0.05). The mean serum NO levels after the HRT in groups A and B was 0.53+/-0.33 nmol/mL (range, 0.29-2.10 nmol/mL) and 2.91+/-0.50 nmol/mL (range, 2.10-3.67 nmol/mL) (p<0.05). A significant difference was found between mean serum NO levels prior to and after the treatment in group B (p<0.05). CONCLUSIONS: Transdermal sequential combined HRT with estradiol hemi-hydrate/NETA was found to be superior to sequential combined oral HRT in increasing serum NO levels.     

The comparison of effects of tibolone and conjugated estrogen-medroxyprogesterone acetate therapy on sexual performance in postmenopausal women

OBJECTIVE: To compare the effects of two different postmenopausal regimens on sexual performance. METHODS: A single blind prospective clinical study was planned on fifty natural postmenopausal women with no absolute contraindication for hormone replacement therapy (HRT). A total of 25 women were randomized for tibolone therapy (group T) and the rest 25 for continuous conjugated estrogen (CE) 0. 625 mg plus medroxyprogesterone acetate (MPA) 2.5 mg (group E) for a year. Two women in group T and four women in group E were excluded from the study as they didn't attend the control visit. At baseline and after a year, sexual performance parameters (sexual desire, coital frequency, orgasm frequency, vaginal dryness/dyspareunia) and after therapy subjective well-being, vasomotor symptoms, and side effects were assessed by score method designed by us. RESULTS: Treatment with either preparation significantly improved subjective well-being, vasomotor symptoms and vaginal dryness. The rates of overall side effects between two groups were not found statistically different (P=0.84). Tibolone therapy increased sexual desire and coital frequency (P=0.001, P=0.014). CONCLUSIONS: Both tibolone and continuous combined CE/MPA effectively improve the findings of hypoestrogenism and subjective well being. Moreover, tibolone effectively increases sexual performance. It is seen that tibolone with acceptable androgenic side effects can be an appropriate selection for HRT in postmenopausal women with decreased sexual desire.     

Two-year prospective and comparative study on the effects of tibolone on lipid pattern, behavior of apolipoproteins AI and B.

OBJECTIVE: To investigate long-term lipid and lipoprotein changes in postmenopausal women treated with tibolone in a prospective study using appropriate control groups. DESIGN: Seventy-six of 105 postmenopausal women initially selected for this study completed the 2-year follow-up. Patients were allocated into three groups. The first received 2.5 mg/day tibolone continuously (n = 27; group T), the second received 0.625 mg/day conjugated equine estrogen plus 2.5 mg/day of medroxyprogesterone (group E-P) continuously (n = 25), and a third group contained an additional 24 women who did not receive replacement therapy; these constituted the untreated control group (group C). Plasma lipids and lipoproteins were determined in all patients before joining the study and also at 12 and 24 months after being included. RESULTS: Women treated with tibolone experienced the greatest decreases in cholesterol, both total and high density lipoprotein (HDL), and triglycerides (TG), whereas the highest increase in HDL was observed in the group E-P. A decrease in low density lipoprotein levels was detected in both therapy groups, whereas a significant increase was observed in the control group. TG were increased after E-P therapy. In all the groups, apolipoprotein AI showed parallel trends to HDL and apolipoprotein B to low density lipoprotein. CONCLUSIONS: Both therapy groups, tibolone and E-P, induced changes in levels of plasma lipids, lipoproteins and apolipoproteins. Long-term tibolone treatment is associated with a marked and significant decrease in HDL apolipoprotein AI and TG, an effect that defines the major difference with standard HRT. Clearly, further studies are necessary to establish the definite risk/benefit ratio of tibolone with respect to its overall effect on lipid metabolism.     

Differential effects of oral conjugated equine estrogen and transdermal estrogen on atherosclerotic vascular disease risk markers and endothelial function in healthy postmenopausal women

BACKGROUND: Recent studies have revealed that HRT may increase the risk for atherosclerotic vascular disease (ASVD). METHODS: We investigated the effects of HRT via different administration routes on the markers for ASVD and endothelial function in healthy postmenopausal women. The oral HRT group (n=18) received conjugated equine estrogen 0.625 mg/day; the transdermal HRT group (n=18) received 17beta-estradiol (E2) gel 0.6 mg/day for 6 months. The control group (n=30) had no treatment for 6 months. RESULTS: The C-reactive protein (CRP) rose from 0.129+/-0.116 to 0.752+/-0.794 mg/dl (P<0.01) in the oral HRT group but remained unchanged in the transdermal HRT and control groups. The flow-mediated vasodilation (FMD) in the brachial artery was increased significantly by HRT from 6.0% before oral HRT to 14.7% after oral HRT (P<0.001) and from 5.9% before transdermal HRT to 13.9% after transdermal HRT (P=0.001). CONCLUSIONS: These data suggest that oral estrogen induces ASVD risk by increasing acute inflammation; however, transdermal estrogen avoids this untoward effect. Additionally, transdermal estrogen exerts a positive effect on endothelial function similar to that of oral estrogen. Therefore, the transdermal route might be favourable in terms of ASVD risks.     

Comparative effects of estrogens plus androgens and tibolone on bone, lipid pattern and sexuality in postmenopausal women

BACKGROUND: The main goals of estrogen replacement therapy (ERT) are the prevention of osteoporosis and cardioprotection and the improvement of quality of life (QL). Androgens and tibolone therapy may increase bone mineral density (BMD) to a greater extent than ERT and offer an increase in QL. Lipid and cardiovascular effects, however, are still a major concern. AIM: To evaluate whether the addition of a weak androgen to ERT may improve postmenopausal bone loss and sexual activity without adverse effects on lipid pattern and to compare these effects with those observed after tibolone therapy. SUBJECTS AND METHODS: This prospective study enrolled 120 surgical postmenopausal women; of these, 96 completed the 1-year follow-up. Patients were allocated to one of four groups. The first group (A; n = 23) received 4 mg of estradiol valerate plus 200 mg of enanthate of dihydroandrosterone im monthly. The second group (E; n = 26) received 50 microg/day of transdermal 17-b-estradiol continuously; the third (T; n = 23) received 2.5 mg of tibolone every day; and finally, the fourth group (C; n = 24) constituted a treatment-free control group. Bone mass (dual X-ray absorptiometry), serum total cholesterol, HDL, LDL, triglycerides, apolipoproteins A1 and B and sexual activity were evaluated before starting therapy and at the end of follow-up. RESULTS: All active treatment groups showed an increase in BMD. This increase was higher in the A treatment group (4.08% P < 0.01). Sexuality improved significantly with therapy; however, tibolone and androgens increased scores to a greater extent than ERT. Androgen therapy was associated with significant increases in total cholesterol, LDL and triglycerides. Cholesterol and LDL fall into groups E and T, HDL into groups A and T and triglycerides in group T only. CONCLUSION: The combined regimen of androgens and ERT increased vertebral bone mass and enhance sexual activity in postmenopausal women equal to that of tibolone and to a greater extent than ERT alone; its effects on lipids, however, are clearly adverse.     

Effects of raloxifene and hormone replacement therapy on markers of serum atherogenicity in healthy postmenopausal women.

OBJECTIVE: To determine the effect of raloxifene (RLX) and hormone replacement therapy (HRT) on non-high density lipoprotein cholesterol (non-HDL-C) levels and the apolipoprotein-B/apolipoprotein-A1 (apo-B/apo-A1) concentration ratio, markers of serum atherogenicity, in postmenopausal women. METHODS: Three hundred and ninety healthy postmenopausal women aged 45-72 years were enrolled in a double-blind, randomized, placebo-controlled, parallel trial at eight outpatient sites in the United States. Women were randomly assigned to receive continuous combined HRT (0.625 mg/day conjugated equine estrogen and 2.5 mg/day medroxyprogesterone acetate), 60 or 120 mg/day raloxifene, or placebo for 6 months. Serum concentrations of non-HDL cholesterol and the apo-B/apo-A1 concentration ratio were measured in serum samples obtained at baseline and at 6 months of treatment. RESULTS: At 6 months, non-HDL-C and apo-B/apo-A1 were significantly reduced by 60 mg/day RLX (10 and 11%, respectively), 120 mg/day RLX (9 and 12%, respectively) and HRT (10 and 12%, respectively), compared with placebo. The effect of all treatments to lower non-HDL-C and apo-B/apo-A1 was greatest in women with hypercholesterolemia (total-C>240 mg/dl) at baseline. Among women with undesirable (>160 mg/dl) non-HDL cholesterol at baseline, RLX and HRT lowered the percentage of these women remaining above this threshold after 6 months (placebo, 89%; 60 mg/day RLX, 61%; 120 mg/day RLX, 74%; HRT, 58%). Similar results were observed for women with high (>190 mg/dl) non-HDL cholesterol at baseline. CONCLUSION: In healthy postmenopausal women, RLX and HRT lower serum non-HDL-C and apo-B/apo-A1, indicators of serum atherogenicity, to a similar extent.     

Serum estrogen level after hormone replacement therapy and body mass index in postmenopausal and bilaterally ovariectomized women

OBJECTIVE: The objective of this study was to determine the relationships of serum estrogen levels after hormone replacement therapy (HRT) every other day and every day with body mass index (BMI) in postmenopausal and bilaterally ovariectomized women. METHODS: Eighty-six postmenopausal and 51 bilaterally ovariectomized women who had been suffering from vasomotor symptoms such as hot flush or atrophy of the vagina were randomly treated with HRT every other day or every day. Seventy-four patients received oral administration of 0.625 mg conjugated equine estrogen (CEE) and 2.5 mg medroxyprogesterone acetate (MPA) every other day, and 63 patients received oral administration of 0.625 mg CEE and 2.5 mg MPA every day as conventional HRT. RESULTS: Eighty-four postmenopausal and 50 bilaterally ovariectomized women completed this study. Serum estradiol levels after HRT every day in postmenopausal and bilaterally ovariectomized women were significantly (P <0.05 and <0.01, respectively) correlated with BMI, while those after HRT every other day were not correlated with BMI. The differences between estradiol levels after 12 months of treatment and initial estradiol levels were also significantly (P <0.01) correlated with BMI in both postmenopausal and bilaterally ovariectomized women who received HRT every day but not in women who received HRT every other day. Serum estrone level after HRT every day and the difference between estrone level after 12 months of treatment and initial estrone level were significantly (P <0.05 and <0.01, respectively) correlated with BMI only in bilaterally ovariectomized women. CONCLUSION: Serum estradiol levels after HRT every day increase more in overweight women than in non-overweight postmenopausal and bilaterally ovariectomized women. The results of the present study regarding the relationship between serum estradiol levels after HRT and BMI should be useful for selecting dosages of drugs to be used in HRT.     

Raloxifene lowers serum lipoprotein(A) in healthy postmenopausal women: a randomized, double-blind, placebo-controlled comparison with conjugated equine estrogens.

OBJECTIVE: Long-term postmenopausal estrogen replacement therapy lowers the risk of osteoporotic fractures and coronary artery disease but increases the risk of endometrial cancer and probably breast cancer. Raloxifene, a nonsteroidal estrogen receptor ligand, seems to have a tissue-specific antiestrogenic action on endometrium and breast and the desired estrogenic action on bone and lipid metabolism. The purpose of this study was to investigate the effects of 24-month treatment with orally administered raloxifene in two doses (60 mg and 150 mg daily) and conjugated equine estrogens in a standard oral dose (0.625 mg daily) on serum lipoprotein(a) [Lp(a)], an independent risk factor for coronary artery disease, in healthy postmenopausal women who had undergone hysterectomy. DESIGN: A randomized, double-blind, placebo-controlled study was performed with 56 women. RESULTS: In the placebo group serum Lp(a) levels did not change throughout the study. After 6 months, serum Lp(a) was significantly reduced versus baseline in the raloxifene 150 (-17%; p = 0.003) and conjugated equine estrogens (-26%; p = 0.003) groups, but this reduction was significantly different from placebo only in the conjugated equine estrogens group. At 12 and 24 months, serum Lp(a) levels were significantly lowered versus baseline in all active treatment groups. However, these reductions were significantly different from placebo only in the raloxifene 150 and conjugated equine estrogens groups. After 24 months, serum Lp(a) was reduced versus baseline with 30% (p = 0.001) in the raloxifene 150 group and 35% (p = 0.001) in the conjugated equine estrogens group. CONCLUSIONS: Long term raloxifene treatment significantly lowers serum Lp(a) levels in postmenopausal women and thus might reduce the risk of coronary artery disease.     

The effects of hormone replacement therapy on plasma lipids in type II diabetes

Objectives: The effects of hormone replacement therapy on cardiovascular risk factors in postmenopausal women with non-insulin dependent diabetes mellitus (type II diabetes) is uncertain. Methods: The effects of estrogen replacement therapy (ERT, conjugated equine estrogen 0.625 mg orally daily), combined estrogen and continuous progestogen therapy (HRT, 0.625 mg of conjugated equine estrogens plus medroxyprogesterone acetate 5 mg daily) or placebo was compared in 20 postmenopausal type II diabetic women and 20 normal postmenopausal women in a double blind, randomised, crossover study. Patients receiving insulin were excluded from the study and all lipid modifying drugs were ceased at least 4 weeks prior to randomisation. Other medication including oral hypoglycaemics was kept constant for the duration of the study. Results: Women with type II diabetes were a similar age (58.7±1.3 years) to the non-diabetic women (59.6±1.6 years) but they had a significantly greater body mass index, a higher incidence of treated hypertension, higher fasting plasma glucose levels, higher triglycerides and lower HDL cholesterol levels than non-diabetic women. ERT reduced total cholesterol and LDL cholesterol by a similar extent (8.9–12.3%) in normal and type II diabetic women and increased HDL cholesterol to a similar extent in both groups (11.0 and 8.9% respectively). ERT did not significantly alter fasting triglyceride levels in either group. The addition of medroxyprogesterone acetate 5 mg daily abolished the increase in HDL cholesterol associated with ERT in both groups but did not significantly affect any of the other lipid measurements. ERT and HRT did not significantly alter fasting insulin levels nor alter fasting glucose levels in either non-diabetic women or women with type II diabetes. Conclusions: ERT and HRT have similar effects on lipids in women with type II diabetes and non-diabetic women after 1 month of therapy.     

Postmenopausal hormone therapy and mammographic breast density

OBJECTIVE: The aim of this study was to evaluate the effects of different types of hormone replacement therapy (HRT) on mammographic density. MATERIALS AND METHODS: In a prospective 1-year study, 103 postmenopausal women were randomized to receive tibolone 2.5 mg/die, continuous conjugated equine estrogens 0.625 mg/die plus medroxyprogesterone acetate (MPA) 5mg/die or placebo. Mammograms were performed at baseline and after 12 months of treatment. Mammographic density was quantified according to the Wolfe classification. RESULTS: After 12 months of HRT 16 of the 35 patients (45.1%) receiving continuous combined hormonal therapy showed an increase of breast density change in the Wolfe classification. After treatment with tibolone, an up grading in breast density, according to Wolfe's classification, was found in 2 of the 43 patients (2.3%). No changes were recorded in the 25 patients of the control group. The difference between the group treated with continuous combined hormonal therapy and the control group was highly significant (p<0.001). The difference in breast density between patients in treatment with tibolone and the control group was not statistically significant (p=0.34). DISCUSSION: Continuous combination HRT may be more commonly associated with an increase of mammography density than tibolone treatment.     

Effects of HRT on serum levels of IGF-I in postmenopausal women.

OBJECTIVES: It is thought that insulin-like growth factor-1 (IGF-I) stimulates bone formation. We aimed to determine the effects of oral and transdermal hormone replacement therapy (HRT) on serum IGF-I levels and to investigate the effects of basal IGF-I levels on the levels obtained at the end of the therapy. METHODS: Sixty-six postmenopausal women were administered either oral (n=44) or transdermal (n=22) HRT for 6 months. Serum levels of IGF-I were determined before and after HRT in all subjects. Groups were divided into two subgroups according to the median value of serum IGF-I levels (basal IGF-I levels above or below the median value). The increase of IGF-I levels after HRT were calculated (%) for all women. Mean increases of subgroups were compared. Furthermore, study groups were divided into three subgroups according to the changing of IGF-I (increase>25%, between 25% increase and 25% decrease and decrease>25%). Mean basal IGF-I levels of these three subgroups were compared. RESULTS: Mean serum levels of IGF-I before and after HRT were not significantly different in both oral and transdermal groups (P>0.05). Mean increases of IGF-I after HRT for the patients with low basal IGF-I levels, were 65% in oral and 77% in transdermal groups. However, mean increase of the patients with high basal IGF-I levels were -8 and -16% respectively. Moreover, mean level of basal IGF-I was significantly low in women who have more than a 25% increase after HRT (P<0.05). CONCLUSION: HRT seems to significantly increase serum levels of IGF-I in postmenopausal women with low basal levels of IGF-I.     

Assessment of DNA damage in postmenopausal women under hormone replacement therapy

OBJECTIVE: To evaluate the possible DNA damage in peripheral blood leukocytes of postmenopausal women under different hormone replacement therapies (HRT), comet assay, a standard method for assessing genotoxicity has been used. METHOD: 46 women were categorized in three groups-Group A: 15 surgical menopausal women who underwent surgery for benign conditions, receiving conjugated equine estrogen, 0.625 mg/day (CEE) for 2.3 +/- 1.5 years, Group B: 16 spontaneous menopausal women receiving conjugated equine estrogen, 0.625 mg/day plus medroxyprogesteron acetate, 5mg/day (CEE + MPA) for 2.4 +/- 1.0 years and Group C: 15 spontaneous menopausal women receiving tibolone, 2.5mg/day for 2.4 +/- 1.3 years. Control group consisted of 15 spontaneous menopausal women who never had HRT. RESULTS: Significant differences in terms of DNA damage were observed between Group A and B with controls as mean total comet scores 23.93 +/- 5.84, 19.44 +/- 6.19 and 10.07 +/- 2.40, but no significance (P > 0.05) were detected between Group C and controls as mean total comet scores 12.07 +/- 3.65 and 10.07 +/- 2.40, respectively. CONCLUSION: Reduced DNA damage were observed with tibolone compared to CEE or CEE + MPA therapy. Studies of this approach are needed.     

Long-term effects of oral and transdermal hormone replacement therapy on plasma homocysteine levels

OBJECTIVE: To compare the long-term effects of oral and transdermal hormone replacement therapy (HRT) on serum homocysteine levels in postmenopausal women. DESIGN: An open, prospective, controlled study. Seventy-five healthy postmenopausal women were recruited as eligible for the study. Fifty women seeking HRT were randomized to receive continuous 17beta-estradiol, either by oral (2 mg daily; n = 25) or transdermal (50 microg daily; n = 25) administration, plus 10 mg dydrogesterone daily for 14 days of each 28-day cycle. Twenty-five women unwilling to receive hormone treatment received only calcium supplementation, representing the control group. Fasting blood samples were analyzed at baseline and then after 6, 12, and 24 months to determine plasma homocysteine levels. RESULTS: Fifty-nine women completed the study. After 6 months of therapy, homocysteine concentrations showed a statistically significant reduction in the treated groups versus both baseline and controls, and no further significant variations were found thereafter. The mean reduction in the homocysteine levels throughout the study was 13.6% in the oral and 8.9% in the transdermal group, respectively, without significant difference between the two routes of estradiol administration. Women with the highest baseline levels of homocysteine experienced the greatest reduction. No significant variations in homocysteine concentrations were found in the control group. CONCLUSIONS: Oral and transdermal estradiol sequentially combined with dydrogesterone shows comparable effectiveness in reducing plasma homocysteine levels in postmenopausal women. Women with the highest pretreatment concentrations of homocysteine benefit the most by the lowering effect of HRT.     

Substitution of transdermal estradiol during oral estrogen-progestin therapy in postmenopausal women: effects on hypertriglyceridemia

OBJECTIVE: We investigated effects of changing from oral estrogen to transdermal estradiol on the lipid and lipoprotein profile of postmenopausal women who developed hypertriglyceridemia (serum concentrations exceeding 150 mg/dL) during estrogen-progestin therapy. DESIGN: Sixty-one postmenopausal Japanese women receiving 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate daily for 12 months had developed serum triglyceride concentrations exceeding 150 mg/dL after 12 months of treatment. Thirty-six of them, chosen randomly for study, were assigned at random to either a group that continued this oral regimen or another that changed to transdermal estradiol while continuing 2.5 mg of oral medroxyprogesterone acetate for the next 3 months (n = 18 for each). Blood lipids were compared between groups. RESULTS: Serum concentrations of triglyceride and very-low-density lipoprotein triglyceride decreased significantly after changing to transdermal estradiol (triglyceride, from 226.0 +/- 43.9 to 110.5 +/- 44.1 mg/dL, P < 0.01). No changes were seen in concentrations of low-density lipoprotein cholesterol or high-density lipoprotein cholesterol. CONCLUSION: Changing to transdermal estradiol may improve triglyceride metabolism in women who developed hypertriglyceridemia during oral estrogen-progestin therapy, with minimal effect on cholesterol profiles.     

Effects of transdermal estrogen replacement therapy on plasma levels of nitric oxide and plasma lipids in postmenopausal women

OBJECTIVE: Our purpose was to assess the effects of transdermal estrogen replacement therapy (TERT) on plasma levels of nitric oxide (NO) and plasma lipids in postmenopausal women. MATERIALS AND METHODS: The study designed as a randomized, double-blind, placebo-controlled trial, involved 43 postmenopausal healthy women who had previously undergone hysterectomy. Women received either transdermal 100 microg 17beta-estradiol (Climara forte TTS) or placebo once a week for 3 months. Plasma levels of NO metabolites, estradiol (E2), total cholesterol (TC), triglicerides (TG), low-density lipoproteins (LDL), high-density lipoproteins (HDL), HDL2 and HDL3 were measured in blood samples of all women which were collected before, after 24 h and after 3 months of therapy. RESULTS: We found significantly increased NO levels 24 h after therapy in TERT group. Moreover significantly higher NO levels were determined at 3rd month of therapy. Serum HDL and HDL2 levels of ERT group were significantly increased at 3rd month of therapy. Alteration of serum levels of HDL3, LDL and TC were not significantly different in groups. TG levels were significantly decreased in TERT group. DISCUSSION: NO-related mechanism may help to explain the cardio-protective effect of TERT in the postmenopausal period. TERT seems to have favorable effects on plasma lipids in surgical menopausal women.     

Association of serum complement (C3, C4) and immunoglobulin (IgG,IgM) levels with hormone replacement therapy in healthy post-menopausal women

BACKGROUND: Recently published data suggest that hormone replacement therapy (HRT) may increase cardiovascular risk during the early months of therapy. Activation of the immune system is known to be involved in several types of cardiovascular disease. In this cross-sectional study, serum C3, C4, IgG and IgM levels were evaluated in healthy post-menopausal women receiving two different short-term HRT regimens, and in untreated women. METHODS: Serum C3, C4, IgM and IgG levels were assessed in 18 women receiving transdermal 17beta-estradiol (50 micro g/day) + continuous oral medroxyprogesterone acetate (MPA; 2.5 mg/day), in 56 women taking oral conjugated equine estrogen (CEE; 0.625 mg/day) + continuous MPA, and in 80 control women not receiving HRT. RESULTS: The mean serum C3 level was significantly higher in women using oral CEE + MPA than in women receiving transdermal 17beta-estradiol + MPA, and those not on HRT (P = 0.02 and P < 0.001 respectively). Furthermore, women taking oral CEE + MPA had significantly higher mean levels of C4 compared with untreated women (P < 0.01). IgG and IgM levels were similar among women either of the two HRT regimens and between women not on HRT. CONCLUSIONS: Oral HRT may be involved in the development of cardiovascular disease through inflammatory mechanisms, as suggested by increased serum levels of C3 and C4.     

Hormonal replacement regimens and bleeding

Hormone replacement therapy may increase the quality of life of postmenopausal women. Any regimen need to offer long-term endometrial safety. It is a standard to consider the co-administration of a sequential progestogen when estrogen replacement should be initiated in non-hysterectomized women. It is almost impossible to decide which combination of an estrogen and a progestogen seems to be optimal as individual tolerance of HRT may very well limit acceptability despite metabolic benefits and proven endometrial safety of a given combination. Several combinations of oral and transdermal estradiol or conjugated equine estrogens, oral progestogens, transdermal norethisterone acetate and levonorgestrel, and intrauterine levonorgestrel may achieve endometrial safety. It is noteworthy that there is no uniform correlation between the timing of onset of bleeding induced by any sequential estrogen and progestogen replacement and a certain pattern of histology. Therefore, although it is likely, there is no absolute reassurance that regular bleeding on or after day 11 of progestogen administration rules out abnormal histopathology. Transvaginal sonography seems not to be of pivotal importance to screen asymptomatic women on replacement therapy for detection of serious abnormal endometrial findings such as hyperplasia and endometrial cancer. Continuous combined hormone replacement therapy or the use of tibolone may be an alternative in postmenopausal women, who do not want any uterine bleedings after menopause. However, spottings or bleedings most often occur at the beginning of treatment. Vaginal administration of estriol and estradiol for urogenital symptoms of estrogen deficiency may stimulate the endometrium unintentionally. Available data suggest that use of oral estriol may be associated with endometrial hyperplasia and endometrial carcinoma relatively more often compared to sequential HRT. Raloxifene, a benzothiophene derivative acting as a selective estrogen receptor modulator approved for prevention of vertebral osteoporosis, rarely causes uterine bleeding. There is no ideal therapy available to suit women looking for a permanently bleed-free hormonal replacement therapy today.     

Effect of long-term hormone replacement therapy on angiotensin-converting enzyme activity and bradykinin in postmenopausal women with essential hypertension and normotensive postmenopausal women

OBJECTIVE: Hormone replacement therapy (HRT) reduces the incidence of cardiovascular disease in postmenopausal women. Three-month short-term HRT in postmenopausal women with essential hypertension increased the plasma concentrations ofbradykinin with decreased serum angiotensin-converting enzyme (ACE) activity, which may be partially responsible for the cardioprotective effects of HRT. The objective was to determine whether 12-month long-term HRT in postmenopausal women with essential hypertension would maintain the decreased ACE activity and increased bradykinin levels and whether long-term HRT would increase the plasma bradykinin concentrations of normotensive postmenopausal women who had shown no significant changes in the 3-month HRT study, despite their decreased serum ACE activity. DESIGN: Twenty hypertensive and 15 normotensive postmenopausal women were treated with conjugated estrogens (0.625 mg/day) and medroxyprogesterone (2.5 mg/day) for 12 months. Twenty hypertensive and 15 normotensive postmenopausal women were used as controls. The controls were not treated with HRT. Serum ACE activity and plasma bradykinin concentrations were measured at baseline and at 12 months. RESULTS: Long-term HRT in both hypertensive and normotensive postmenopausal women significantly decreased serum ACE activity from 15.5+/-0.7 IU/L and 16.0+/-0.9 IU/L, respectively, at baseline to 13.3+/-0.5 IU/L and 14.2+/-0.9 IU/L, respectively, 12 months after the start of HRT (p < 0.05 and p < 0.05, respectively). Long-term HRT in both hypertensive and normotensive postmenopausal women also significantly increased plasma bradykinin concentrations from 22.1+/-4.4 pg/mL and 19.2+/-3.0 pg/mL, respectively, at baseline to 86.7+/-21.2 pg/mL and 73.5+/-23.0 pg/mL, respectively, 12 months after the start of HRT (p < 0.01 and p < 0.05, respectively). No significant changes in serum ACE activity or plasma bradykinin concentrations were observed in the control groups. CONCLUSIONS: Long-term HRT in hypertensive and normotensive postmenopausal women decreases their serum ACE activity and increases their plasma bradykinin concentrations. Thus, maintenance of elevated bradykinin with decreased serum ACE activity by HRT may be useful in reducing the risk of cardiovascular disease in both hypertensive and normotensive postmenopausal women.     

Evaluation of mammographic density and (99m)Tc-sestamibi scintimammographic uptake in postmenopausal women on hormone replacement therapy

OBJECTIVE: To evaluate changes in mammographic density and (99m)Tc-sestamibi scintimammographic uptake in postmenopausal women on hormone replacement therapy (HRT). METHODS: Seventy-five postmenopausal women were prospectively studied and allocated into three groups: 50 women were randomized to either Group 1 (G1, n=25), which received 2mg of 17beta-oestradiol continuously combined with 1mg of norethisterone acetate (E2/NETA, Kliogest, Medley) or Group 2 (G2), which received 2.5mg/day of tibolone (Livial, Organon). The remaining 25 women, who were asymptomatic and had no desire to undergo HRT, constituted the control group (G3). Each patient was submitted to both mammography and scintimammography at baseline and after six months. Mammographic density was evaluated by using the BI-RADS classification system. The classification system of Barros et al. was used in the interpretation of scintimammography. For statistical analysis, the Chi-square test, ANOVA and Pearson's correlation were used. RESULTS: At six months, increased mammographic density was observed in 48% of G1, 12% of G2 and 16% of G3 patients (p<0.001). The increase in sestamibi uptake was 56% in G1, 28% in G2 and 24% in G3 (p<0.001). Increases in both density and uptake were significantly higher in the group on E2/NETA than among tibolone users and the controls. CONCLUSION: In postmenopausal women, HRT with E2/NETA was associated with increased mammographic density and increased (99m)Tc-sestamibi scintimammographic uptakes, suggesting greater mithochondrial activity in the cells of the mammary duct. This was not observed in users of 2.5 mg of tibolone, demonstrating that the effects on the breast were reduced. The same was observed in the control group.     

Effect of tibolone on breast symptoms resulting from postmenopausal hormone replacement therapy

Objective: To evaluate the incidence of breast symptoms in a population treated with various hormone replacement therapy (HRT) regimens and to detect the variations in breast symptomatology after HRT changing to tibolone administration. Methods: This prospective placebo-controlled clinical trial was conducted on healthy women on HRT reporting breast symptoms. A questionnaire was given to each woman to detect breast symptomatology. Breast tenderness and mastalgia were evaluated using a visual analogue scale (VAS). According to the choice of the each woman with breast symptoms, the HRT was changed to tibolone (2.5 mg/day per os) or to calcium carbonate (1 tab/day, placebo group). The duration of treatment was of 12 months. After 6 and 12 months breast symptomatology was re-evaluated. Results: Among the 600 screened women, 64 (10.7%) were suffering from breast symptomatology. After 6 and 12 months of treatment with tibolone or placebo, mean VAS score for breast tenderness and for mastalgia resulted significantly (P<0.05) decreased, without differences between groups, in comparison with basal value. Only one woman had no improvement from the breast symptoms with tibolone administration. Conclusions: Shifting from classical HRT to tibolone is followed by a significant reduction of breast symptomatology in postmenopausal women with breast complaints similar to that obtained with treatment withdrawal.