HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women; a 5 year randomized trial

OBJECTIVES: We investigated the incidence of new non-vertebral fractures during HRT or low-dose vitamin (Vit) D3 supplementation in a 5-year prospective trial. METHODS: A total of 464 early postmenopausal women, (a subgroup of the Kuopio Osteoporosis Study, n = 13,100) were randomized to four groups: (1) HRT, a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate; (2) Vit D (300 IU/day and 100 IU/day during the fifth years); (3) HRT + Vit D; and (4) placebo. Lumbar (L2-4) and femoral neck bone mineral densities (BMD) were determined by dual X-ray absorptiometry (DXA) at baseline, after 2.5 and 5 years of treatment. All new symptomatic non-vertebral, radiographically defined fractures were recorded. RESULTS: Altogether, 368 women (79%) completed the 5 year treatment. In all, 32 women had 39 non-vertebral fractures during a mean of 4.3 year follow-up (HRT 4, Vit D 10, HRT + Vit D 8 and placebo 17). The reduction in the incidence of new non-vertebral fractures was significant in women with HRT alone (P = 0.032) when adjusted by baseline BMD and previous fractures; observed also with the intention-to-treat principle (P = 0.048). When the HRT groups were pooled, HRT showed a significantly lower incidence of new non-vertebral fractures (P = 0.042) than women receiving placebo and also after adjusting as above (P = 0.016); both in valid-case and in the intention-to-treat analysis. In the Vit D group, the fracture incidence was non-significantly decreased (P = 0.229) in comparison with the placebo group. The estimated risk of new non-vertebral fractures among women treated with HRT alone was 0.29 (95% CI, 0.10-0.90) and with Vit D 0.47 (95% CI, 0.20-1.14) and with HRT + Vit D 0.44 (95% CI, 0.17-1.15), in comparison with the placebo group (adjusted by femoral BMD and previous fractures). CONCLUSIONS: This study is the first prospective trial confirming the beneficial effect of HRT on prevention of peripheral fractures in non-osteoporotic postmenopausal women. The effect of low-dose Vit D remains to be proved.     

Dydrogesterone does not reverse the effects of estradiol on endothelium-dependant vasodilation in postmenopausal women: a randomised clinical trial

OBJECTIVES: The purpose of this study was to evaluate endothelium-dependent flow-mediated dilation (FMD) in the brachial artery and the plasma levels of endothelin-1 in postmenopausal women at risk for coronary artery disease before and after treatment with both estradiol and estradiol plus dydrogesterone. METHODS: Sixteen postmenopausal women (PMW) (mean age 58+/-9 years) with more than two risk factors for coronary artery disease, were randomized to receive either oral estradiol (2 mg) for 28 days or oral estradiol (2 mg) for 14 days and oral estradiol (2 mg) and dydrogesterone (10 mg) for 14 days, in a double-blind, placebo-controlled, single cross-over study. Patients were crossed-over the complementary treatment 7 days after completing the first treatment. The study of forearm blood flow and the measurement of plasma endothelin-1 levels was carried out before and after each treatment. RESULTS: Estradiol significantly increased FMD as compared to baseline; the addition of dydrogesterone did not affect the effect of estradiol on FMD. Similarly reactive hyperemic flow increased after estradiol alone or in association with dydrogesterone compared to baseline. Plasma levels of endothelin-1 were significantly reduced by estradiol both when administered alone or in association with dydrogesterone. CONCLUSIONS: Hormone replacement therapy with estradiol and dydrogesterone improves endothelial function and reduces plasma levels of endothelin-1 in PMW at risk for coronary artery disease.     

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.     

Effects of tibolone and combined 17beta-estradiol and norethisterone acetate on serum C-reactive protein in healthy post-menopausal women: a randomized trial

BACKGROUND: Serum C-reactive protein (CRP) is an independent risk factor for the development of cardiovascular diseases in healthy post-menopausal women. Oral unopposed and progestin-combined 17beta-estradiol (E(2)) increase serum CRP in post-menopausal women. The aim of this study was to compare the effects of tibolone, a steroid with estrogenic, androgenic or progestogenic properties, with a combination of E(2) and norethisterone acetate (E(2) + NETA) on serum CRP levels in healthy post-menopausal women. METHODS: A total of 139 post-menopausal women (mean age: 55 years, range 44-48) was randomly assigned to receive tibolone 1.25 mg/day (n = 52), tibolone 2.5 mg/day (n = 39) or E(2) 2 mg/day plus NETA 1 mg/day (n = 48) for 2 years. Serum CRP was measured at baseline and at 6, 12 and 24 months. RESULTS: Both doses of tibolone and E(2) + NETA increased serum CRP by a similar extent as soon as 6 months with a sustained effect over the 24 month treatment period. For example, after 6 months of treatment, serum CRP increased by a median of +106% (P < 0.001), +89% (P < 0.05) and +139% (P < 0.001) for tibolone 1.25 mg/day, tibolone 2.5 mg/day and E(2) + NETA respectively. CONCLUSIONS: Tibolone and E(2) + NETA significantly increase serum CRP levels in healthy post-menopausal women to a comparable extent. Relationships between induced elevated CRP levels with tibolone and E(2) + NETA and cardiovascular events require further studies.     

Changes in endometrial blood vessels in the endometrium of women with hormone replacement therapy-related irregular bleeding

BACKGROUND: Irregular bleeding affects up to 60% of hormone replacement therapy (HRT) users. The mechanism of this bleeding is not understood. Reduced endometrial microvascular integrity appears to underlie breakthrough bleeding in pre-menopausal women and the aim of this study was to establish whether similar changes are seen in HRT users and hence to elucidate a possible mechanism of irregular bleeding. METHODS: Endometrium from 34 HRT users with amenorrhoea, irregular bleeding or regular bleeding was assessed for endometrial endothelial cell density (anti-CD34), number of blood vessels per mm(2), vascular basal lamina components (laminin, collagen IV and heparan sulphate proteoglycan) and in 32 subjects and 23 controls for perivascular smooth muscle alpha (SMA). Findings were compared with a control population of 29 post-menopausal women not using HRT, other sex steroids or tamoxifen and with no vaginal bleeding. Staining intensity was assessed in a blinded fashion in all immunohistochemical studies. RESULTS: Four significant differences in endometrial blood vessels were observed between HRT users and controls: (i) a significantly lower density of endometrial endothelial cells (EC staining for CD34) per mm(2) was present in HRT users compared with controls (P < 0.001); (ii) endothelial cells (EC) were predominantly organized within blood vessels (83%) in controls but in HRT users EC were dispersed in the tissues with only 29% in organized vessels (P <0.001); (iii) supportive perivascular cell SMA was significantly reduced in 23 post-menopausal HRT users compared with 23 post-menopausal controls (n = 29, P = 0.013) and (iv) an atrophic or inactive histological pattern of endometrium was more frequently seen in the controls (P < 0.001). CONCLUSIONS: These findings support the hypothesis that exposure to HRT profoundly alters endometrial blood vessels, reducing structural integrity thereby predisposing to irregular bleeding in HRT users.     

Effects of estradiol and norethisterone on lipids, insulin resistance and carotid flow

OBJECTIVES: To evaluate the lipid profile, insulin resistance and vasomotricity, and the interaction between these factors, in postmenopausal women receiving hormone therapy. METHODS: A prospective, randomized, double-blind study was carried out in which 77 postmenopausal women received one of the three treatment regimens: (A) 2mg oral micronized estradiol (E2) (n=25); (B) 2mg oral E2+1mg oral norethisterone acetate (NETA) (n=28); or C) placebo (n=24), daily for 6 months. Evaluations were carried out at baseline and at the end of treatment on lipid and lipoprotein profiles, homeostasis model assessment of insulin resistance (HOMA-IR) and pulsatility index (PI) of the internal carotid artery by Doppler ultrasonography. RESULTS: Mean increases of 15.6% and 2.4% and a reduction of 6.4% in high-density lipoprotein (HDL) levels were found for the E2, E2+NETA and placebo groups, respectively. Reductions of 9.5% and 3.7% and an increase of 12.1% in low-density lipoprotein (LDL), and reductions of 20.0% and 3.8% and an increase of 28.8% in the LDL:HDL ratio were found for the E2, E2+NETA and placebo groups, respectively (p<0.001 in all cases). Insulin levels and HOMA-IR decreased 12.8% and 12.3% in the E2 group and increased 12.9% and 16.0% in the E2+NETA group (p<0.05), respectively. Carotid PI following treatment was 1.18+/-0.23, 1.38+/-0.20 and 1.41+/-0.21 for the E2, E2+NETA and placebo groups, respectively (p=0.0006). CONCLUSIONS: Oral estrogen therapy led to an improvement in lipid profile, insulin resistance and carotid blood flow, which was cancelled when NETA was associated.     

Changes in body composition during post-menopausal hormone therapy: a 2 year prospective study

BACKGROUND: Post-menopausal hormone therapy (pHT) induces changes in both body composition and bone mineral density (BMD). METHODS: In 109 post-menopausal women beginning either tibolone 2.5 mg (n=29), tibolone 1.25 mg (n=42) or estradiol 2 mg plus norethisterone acetate 1 mg (E2 + NETA) (n=38), we assessed body composition, total and regional BMD by dual energy X-ray absorptiometry, and the serum bone alkaline phosphatase (BAP), osteocalcin and the urinary excretion to type I collagen C-telopeptide (CTX) at baseline and after 2 years. RESULTS: At baseline, BMD at all sites correlated negatively with age and years since menopause, and positively with lean mass and fat mass (r=0.42, P<0.001 and r=0.26, P=0.006 at the total femur). During treatment, BMD increased at all sites (P<0.001), and serum BAP, osteocalcin, and urinary CTX decreased in all groups (P<0.001). Lean mass increased whereas android fat and android obesity index decreased. The increase in BMD at all sites correlated positively with changes of lean mass at 2 years. CONCLUSIONS: Both fat mass and lean mass are related to BMD in post-menopausal women, the relationship being strongest with lean mass; an increase in lean mass and a change in distribution of body fat are observed during treatment with E2 + NETA and tibolone.     

Association between single nucleotide polymorphisms of estrogen receptor alpha gene and efficacy of HRT on bone mineral density in post-menopausal Japanese women

BACKGROUND: Although HRT for post-menopausal women can protect against bone loss, variations in bone responses exist. We studied whether single nucleotide polymorphisms (SNP) of the estrogen receptor-alpha (ERalpha) gene contribute to the effect of HRT on lumbar spine bone mineral density (BMD). METHODS: Subjects were 84 post-menopausal women who had been taking HRT for 3 years to treat osteopenia or osteoporosis. Eighteen SNP in the ERalpha gene were characterized by a single nucleotide primer extension assay. RESULTS: Genotyping of the 84 individuals revealed that all SNP were quite common, the minor allele frequency being > or = 20%. A SNP in intron 6 (IVS6+14144) was significantly associated with the response to HRT for the first 3 years after starting treatment (P = 0.043, 0.025 and 0.032 for the first, second and third years respectively). Haplotype analysis revealed that a combination of SNP IVS6+14144 and IVS4+4238 was significantly correlated with the response to HRT; women with haplotype G-G (IVS6 14144-IVS4 4238) showed a significantly higher response (P = 0.014, 0.043 and 0.010 for the first second and third year respectively). CONCLUSIONS: These results suggest that a specific SNP and the haplotype of the selected SNP could be used to predict the effect of HRT on lumbar BMD.     

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.     

Effects of different progestin regimens in hormone replacement therapy on blood coagulation factor VII and tissue factor pathway inhibitor

BACKGROUND: Long-term hormone replacement therapy (HRT) reduces cardiovascular risk, but an early increased risk was reported in women with coronary heart disease. In such women the arterial intima can express tissue factor, and changes in coagulation factor VII (factor VII) and tissue factor pathway inhibitor (TFPI) may be deleterious. METHODS: We measured factor VII clotting activity, activated factor VII, and concentrations of factor VII and TFPI during 12 months in healthy post-menopausal women randomized to: (i). cyclic oral estrogen/progestin (n = 25); (ii). long-cycle oral estrogen/quarterly progestin (n = 32); (iii). continuous oral estrogen/progestin (n = 21); (iv). continuous oral estrogen/intrauterine progestin (n = 22); (v). no HRT (n = 26). Blood was collected at baseline, 3, 6 and 12 months. Additional sampling was done before progestin intake in the long cycle group. RESULTS: No variations were observed in the reference group. There was a substantial decrease in TFPI concentrations in the HRT groups irrespective of the type of progestin. In women receiving long-cycle treatment, all factor VII measures increased during the unopposed estrogen periods, and the increase was reversed after progestin intake. The integrated response, AUC, for TFPI was significantly lower in the HRT groups compared with the reference group. CONCLUSION: The observed changes may increase the early thrombotic risk associated with HRT use.     

Prevention of postmenopausal bone loss with long-cycle hormone replacement therapy

OBJECTIVE: Postmenopausal bone loss and osteoporotic fractures can be prevented by hormone replacement therapy (HRT). However, opposed HRT may increase the risk of breast cancer above that associated with estrogen alone and in non-hysterectomized women estrogen substitution alone increases the risk of uterine cancer, which triggered renewed interest in long-cycle HRT regimens (estrogen replacement therapy with progesterone-free intervals up to 6 months). The effects on bone of such long-cycle HRT regimens are unknown. The objective of the present study was to compare the effects on bone and the endometrium of long-cycle HRT and conventional HRT. METHODS: Seventy-three healthy non-hysterectomized postmenopausal women were randomized to either conventional HRT (estradiol (E2) 2 mg/d during 12 days, E2 2 mg/d plus 1 mg/d of norethisterone acetate (NETA) during 10 days, E2 1 mg/d for 6 days) or long-cycle HRT treatment (two cycles with E2 2 mg/d during 28 days, followed by one cycle of conventional HRT and repeated every 3 months). Primary endpoint was the change in bone mineral density (BMD) at the lumbar spine (LS) over 24 months. RESULTS: BMD at LS increased significantly versus baseline in both treatment groups (conventional HRT +3.8 +/- 0.6%, long-cycle HRT +3.3 +/- 0.5%, p < 0.0001 for both) with no significant difference between treatment groups over 24 months. Similar significant BMD increases versus baseline were observed at the femoral neck, while biochemical markers of bone turnover (osteocalcin and deoxypyridinoline) were significantly decreased over 24 months. There were no endometrial or breast related adverse events reported. CONCLUSION: Long-cycle HRT may be a valid alternative to conventional HRT with regard to protection against postmenopausal bone loss.     

The effect of a change in the dose of trimegestone on the pattern of bleeding in estrogen-treated post-menopausal women: 6 month extension of a dose-ranging study

BACKGROUND: Abnormal bleeding pattern is one major reason for non-compliance with hormone replacement therapy (HRT) in post-menopausal women. We have previously documented that the dose of trimegestone is the main determinant of the pattern of bleeding in women treated with estradiol (E(2)) and sequential combined trimegestone administered in four doses. The objectives of this study were to test the effect of changing the dose of trimegestone and the duration of treatment on the pattern of bleeding in these women who then entered a 6 month extension phase where a single dose of trimegestone was given sequentially combined with E(2). METHODS: The menstrual diaries of 134 post-menopausal women who completed a dose-ranging study of trimegestone and then entered a 6 month extension phase were analysed. In the 6 month extension study, all women were given one dose of trimegestone (0.25 mg) in a sequential fashion (day 15-28) combined with continuous E(2) (2 mg/day). RESULTS: Women who had received trimegestone 0.25 mg/day during the first 6 months experienced no change in the bleeding pattern in the 6 month extension. Women who had been treated with 0.5 mg/day dose experienced earlier onset, and more prolonged bleeding (P < 0.0001) following the change to 0.25 mg/day. Women who previously received trimegestone doses of 0.05 and 0.1 mg experienced a later onset of bleeding, which was lighter and of shorter duration (P < 0.001) during the extension phase as compared with the first 6 months. CONCLUSION: The dose of trimegestone, and not the duration of treatment, appears to be the important determinant of the pattern of bleeding in post-menopausal women on this HRT regimen.     

Positive effects on cardiovascular and breast metabolic markers of oral estradiol and dydrogesterone in comparison with transdermal estradiol and norethisterone acetate

Objectives: To assess differences in two sequential combined hormone replacement therapy (HRT) products on selected cardiovascular and breast metabolic markers. The products were different concerning the route of administration of estradiol and its combined progestin, either oral or transdermal, and the androgenic properties of progestogens, respectively, dydrogesterone and norethisterone acetate. Methods: One hundred and nineteen healthy non-hysterectomized postmenopausal women were included in this open, multi-center, two parallel group trial. They were randomized to a treatment of six 28-day cycles with oral estradiol sequentially combined with dydrogesterone (oE2/D10) or a sequential combination patch of estradiol plus norethisterone acetate (tdE/NETA). At baseline and after six cycles the high-density lipoprotein cholesterol (HDL-C), the sex hormone binding globulin (SHBG) and the total insulin-like growth factor-I (IGF-I) blood levels were determined by a central laboratory. A total of 89 women were compliant to the protocol. Results: After six cycles, a statistically significant difference (P<0.001) concerning HDL-C, SHBG and IGF-I levels was found between the two treatment groups. The HDL-C levels were increased in the oE2/D10 group and decreased in the tdE/NETA group, with a final difference of about 0.3 mmol/l. The oE2/D10 treatment induced a sharp increase (about 57 mmol/l) in SHBG levels. IGF-I levels decreased with both the products, but the difference in favor of the oE2/D10 treatment was of about 30 ng/ml. Moreover, patients on tdE/NETA with an IGF-I baseline value below the median showed an increase. Conclusion: Oral estradiol sequentially combined with dydrogesterone, a non-androgenic progestogen, induced positive changes of some cardiovascular (HDL-C) and breast (SHBG and IGF-I) metabolic markers. These effects were significantly different from those obtained with a transdermal estradiol associated to an androgenic progestogen.     

The effects of 17 beta-oestradiol plus dydrogesterone compared with conjugated equine oestrogens plus medroxyprogesterone acetate on lipids, apolipoproteins and lipoprotein(a)

OBJECTIVE: To compare the effects of 17 beta-oestradiol plus dydrogesterone with conjugated equine oestrogens plus medroxyprogesterone acetate on serum lipids, apolipoproteins and lipoprotein(a) in postmenopausal women. METHODS: A multi-centre, prospective, randomised, double-blind, comparative one-year study in 362 healthy postmenopausal women aged 39-74 years with an intact uterus. Fasting blood samples were taken at baseline and after 28 and 52 weeks of treatment. Participants received daily oral treatment with continuous combined 1 mg micronised 17 beta-oestradiol/5 mg dydrogesterone (E/D: n=180) or 0.625 mg conjugated equine oestrogens/5 mg medroxyprogesterone acetate (CEE/MPA: n=182). RESULTS: Significant differences between the two groups after 52 weeks were observed for total cholesterol (E/D: -1.7%; CEE/MPA: -7.3%), LDL-cholesterol (E/D: -4.5%; CEE/MPA: -11.3%), HDL-cholesterol (E/D: +15.3%; CEE/MPA: +7.5%), triglycerides (E/D: +9.8%; CEE/MPA: +16.6%), VLDL-triglycerides (E/D: -3.3%; CEE/MPA: +10.0%), lipoprotein(a) (E/D: 0.0%; CEE/MPA: -25.2%) and for the ratio apolipoprotein B/LDL-cholesterol (E/D: +0.9%; CEE/MPA +5.9%). CONCLUSIONS: E/D and CEE/MPA differ in their anti-atherogenic effects on lipids and lipoproteins. This however can not easily be translated to differences in clinical cardiovascular outcomes.     

Changes in gonadal steroid receptors in the cardinal ligaments of prolapsed uteri: immunohistomorphometric data

BACKGROUND:The precise mechanism of uterine prolapse is poorly understood. This immunohistochemical study was performed on paraffin-embedded sections of the cardinal ligaments in an attempt to evaluate the differential expression of gonadal steroid receptors in human cardinal ligaments of prolapsed uteri compared with non-prolapsed controls. METHODS: Specimens from women with pelvic organ prolapse (POP) stage III (n = 33), together with the appropriate controls (n = 25), were stained for estrogen receptor alpha (ERalpha), ERbeta, progesterone receptor (PR), androgen receptor (AR) and Ki-67. The control materials were samples of the cardinal ligaments obtained from pre- and post-menopausal women with no prolapse, who were not using hormonal therapy. RESULTS The prolapsed ligaments expressed 1.5-2.5 times more ERalpha-positive cells (statistically significant in post-menopausal women not taking HRT, P < 0.001), a 3-4 times greater percentage of AR-positive cells (P = 0.004 and P = 0.008 in pre-menopausal and post-menopausal women not taking HRT, respectively) and twice the percentage of PR-positive cells (statistically significant in the pre-menopausal group, P = 0.03) compared with the no prolapse group. Expression of ERbeta was twice as high in the ligaments of pre-menopausal women with no prolapse compared with those with prolapse (P = 0.02), and no significant difference was found in the post-menopausal groups. The use of HRT was significantly associated with low AR and high PR expression. Ki-67 expression was not detected in these specimens. CONCLUSIONS: The clearly discernible levels of expression of ERalpha, ERbeta, AR and PR in the prolapsed cardinal ligaments may suggest a relationship to the process of tissue stretch 'trauma', rather than an effect of the menopausal status, HRT use or cell proliferation. The use of HRT in post-menopausal women appears to offset some of the changes observed with the prolapse.     

Sublingual administration of micronized estradiol and progesterone, with and without micronized testosterone: effect on biochemical markers of bone metabolism and bone mineral density

OBJECTIVES: The purpose of this investigation was to evaluate the relative efficacy of the sublingual administration of micronized estradiol (E2), progesterone (P4), and testosterone (T) on bone mineral density and biochemical markers of bone metabolism. DESIGN: In this double-blind, prospective study, postmenopausal women were randomly assigned to one of four treatment groups: hysterectomized women were assigned to either 1) micronized E2 (0.5 mg) or 2) micronized E2 (0.5 mg) + micronized T (1.25 mg). Women with intact uteri were assigned to either 3) micronized E2 (0.5 mg) + micronized P4 (100 mg) or 4) micronized E2 (0.5 mg) + micronized P4 (100 mcg) + micronized T (1.25 mg). For the purpose of this study, the four treatment groups were combined into two groups for all comparisons. The E2 and E2+P4 groups were combined into the HRT alone group (n=30), and the E2+T and E2+P4+T groups were combined into the HRT + T group (n=27). Hormones were administered sublingually as a single tablet twice a day for 12 months. Bone mineral density was measured in the anterior-posterior lumbar spine and total left hip via dual energy x-ray absorptiometry. Bone metabolism was assessed via serum bone-specific alkaline phosphatase and urinary deoxypyridinoline and cross-linked N-telopeptide of type I collagen, both normalized to creatinine. Data were analyzed via a repeated measures analysis of variance and a Student's t test (alpha=0.05). RESULTS: The subjects were of similar age (54.0 +/- 0.8 years), height (64.0 +/- 0.3 in), weight (157.6 +/- 4.2 lb), and had similar baseline follicle-stimulating hormone (66.4 +/- 3.2 mIU/L), E2 (26.4 +/- 1.5 pg/ml), P4 (0.3 +/- 0.1 ng/ml), total T (19.0 +/- 1.5 ng/dL), and bioavailable T (3.7 +/- 0.3 ng/dL) levels. During therapy, serum levels increased (p < 0.05) for each hormone. Bone mineral density and bone markers at baseline were similar for each treatment group. Bone-specific alkaline phosphatase decreased (p < 0.05) by -14.3 +/- 4.1% in the HRT alone group and by -8.2 +/- 4.6% in the HRT + T group. Deoxypyridinoline levels decreased significantly in the HRT alone and HRT + T groups, - 14.4 +/- 6.8% and -26.9 +/- 7.6%, respectively. Significant reductions (p < 0.05) in cross-linked N-telopeptide of type I collagen were also observed in both groups, -24.4 +/- 6.5% and -39.5 +/- 8.6%, respectively. Bone mineral density in the lumbar spine increased (p < 0.05) by +2.2 +/- 0.5% the HRT alone group and by + 1.8 +/- 0.6% in the HRT + T group. Total hip bone mineral density was maintained in the HRT alone group (+0.4 +/- 0.4%) and increased (p < 0.05) in the HRT + T group (+ 1.8 +/- 0.5%). CONCLUSIONS: Sublingual micronized HRT favorably decreases serum and urine markers of bone metabolism, prevents bone loss, and results in a slight increase in spine and hip bone mineral density. Although the addition of testosterone to HRT for 1 year did not result in added benefit to the spine bone mineral density, it did result in a significant increase in hip bone mineral density. Longer duration of therapy may have further improved these outcomes.     

Effects of transdermal and oral postmenopausal hormone therapy on vascular function: a randomized, placebo-controlled study in healthy postmenopausal women

OBJECTIVE: To compare the effect of transdermal and oral estrogen therapy, the latter with or without the addition of gestodene, on plasma concentrations of markers of endothelial function and on ultrasonographic parameters of vascular function in healthy postmenopausal women. DESIGN: In a 15-month, randomized, double-blind, placebo-controlled study, 152 healthy hysterectomized postmenopausal women received daily doses of placebo (n = 49), 50 microg of transdermal 17ss-estradiol (tE2, n = 33), 1 mg of oral E2 (oE2, n = 37), or 1 mg of oral estradiol combined with 25 microg of gestodene (oE2+ G, n = 33) for 13 cycles of 28 days, followed by four washout cycles with placebo in each group. At baseline and in cycles 4, 13, and 17, we measured plasma levels of endothelial markers and ultrasonographic markers of vascular function (pulsatility index [PI] and, at baseline and cycle 13, arterial stiffness). RESULTS: Compared with placebo, we found reductions in soluble vascular cell adhesion molecule (oE2, P < 0.01; oE2+ G, P < 0.001), sE-selectin (oE2 + G, P < 0.05), von Willebrand factor (tE2, P < 0.05), and divergent effects in PI and stiffness parameters in the carotid artery. We found no effect on PI in the retinal and femoral arteries, or on stiffness parameters in the femoral and brachial artery. CONCLUSIONS: Oral hormone therapy reduced plasma levels of adhesion molecules, whereas transdermal estrogen therapy reduced von Willebrand factor. Effects on ultrasonographic parameters of vascular function in the carotid artery were inconclusive.     

Early impact of hormone replacement therapy on vascular hemodynamics detected via ocular colour Doppler analysis

Objective: To determine the effects of hormone replacement therapy (HRT) on ocular blood flow.

Study design: In a prospective controlled study, 40 healthy women who presented to the menopause clinic between December 2000 and December 2001 were randomly assigned into the study. The HRT-receiving group was administered estradiol 17-valerate 2 mg the first 11 days, and estradiol 17-valerate 2 mg plus ciproterone acetate 1 mg the next 10 days of the monthly cycle for 6 months. The control group did not receive any HRT for 6 months. The ocular colour Doppler analysis were performed at baseline and after 3 and 6 months. The ocular Doppler analysis was performed in the first half of the cycle in the HRT-receiving group.

Results: Central retinal artery and ophthalmic artery basal Doppler index (peak systolic velocity, end-diastolic velocity, resistive index and pulsatility index) values of the two groups at the beginning of the study did not show any statistically significant difference. Both the right and the left central retinal artery pulsatility index (PI) values of the study group, who received HRT at the end of the third and sixth months, showed a statistically significant decline (paired-samples test, P < 0.05), while the decrease in the resistive indexes was not significant.

Conclusion: These results suggest that 6 months of combined hormone replacement therapy with estradiol 17-valerate 2 mg plus ciproterone acetate 1 mg improves ocular vascular Doppler indices which may be a reflection of cerebral vascular status.     

Continuous combined hormone replacement therapy with 1 mg 17beta-oestradiol and 5 mg dydrogesterone (Femoston-conti): endometrial safety and bleeding profile

OBJECTIVES: The aim of the study was to confirm the endometrial safety and describe the bleeding profile of continuous combined 1 mg 17beta-oestradiol and 5 mg dydrogesterone in post-menopausal women. METHODS: An open, multicentre study was carried out in 290 healthy, non-hysterectomised post-menopausal women receiving oral continuous combined 1 mg 17beta-oestradiol and 5 mg dydrogesterone (Femoston-conti) for 1 year. Aspiration endometrial biopsies were performed at baseline and at the end of the study; those classified as hyperplasia or malignancy were considered treatment failures. RESULTS: Only one woman developed simple hyperplasia without atypia at the end of the study; the treatment failure rate was therefore 0.4%. Cross-sectional analysis showed that the percentage of women without bleeding increased from 71% during the first cycle to around 80% by the end of the study. Approximately 50% of the bleeding episodes occurred in the form of spotting; severe bleeding was rare and only seven women withdrew prematurely from the study due to uterine bleeding. Overall, 41% of the women were amenorrhoeic throughout the study. CONCLUSIONS: Continuous combined 1 mg 17beta-oestradiol and 5 mg dydrogesterone provides excellent endometrial safety and is associated with an acceptable bleeding profile.