Androgens and breast cancer risk.

Transdermal testosterone supplementation is a treatment option for postmenopausal women with distressful decreased libido. Side effects are minor, but there is a long-term safety concern with respect to breast cancer, as women with high testosterone serum levels appear to be at a significantly increased risk to have or to develop breast cancer within a few years. Epidemiological studies of sufficient duration to study long-term effects of testosterone supplementation are limited, both in number and in methodological quality and are, therefore, inconclusive. Preclinical studies do not provide evidence for an androgen receptor-mediated stimulating effect of androgens on breast epithelium. However, one biologically plausible possibility, which cannot be ruled out, is that exogenous androgens become mitogenic after aromatization into bioactive oestradiol, either in peripheral fat or within the breast or even within small occult tumours. The evidence available so far makes counselling women interested in testosterone supplementation for distressful low sexual desire, more of an art than science.

The influence of physiological and surgical menopause on coronary heart disease risk markers.

OBJECTIVE: To investigate the influence of physiological and surgical menopause on serum concentrations of coronary heart disease (CHD) risk markers and sex hormones. DESIGN: Physiological menopausal transition was investigated in two studies. In a longitudinal study, 16 women were followed from 2 years before until 2 years after physiological menopause. In a case-control study, 27 early postmenopausal women were compared with 27 age-matched late premenopausal women. Surgical menopause was investigated in 11 women undergoing a prophylactic bilateral salpingo-oophorectomy. The following parameters were measured: serum concentrations of estradiol, follicle-stimulating hormone, inhibin A, inhibin B, asymmetric dimethylarginine, lipids, leptin, homocysteine, C-reactive protein, and coenzyme Q10, as well as weight and body mass index. RESULTS: After physiological and surgical menopause, serum estradiol and inhibin A and B decreased, whereas follicle-stimulating hormone increased (all P values < 0.01). Serum asymmetric dimethylarginine, total and low-density lipoprotein cholesterol, and leptin concentrations were significantly higher in postmenopausal women compared with premenopausal women (all P values < 0.05). Serum homocysteine concentrations increased significantly during the physiological menopausal transition. Total and low-density lipoprotein cholesterol increased after surgical menopause (both P values = 0.01). None of the other parameters studied were influenced significantly by the menopausal transition. No difference in change in the various CHD risk markers investigated was observed between physiological and surgical menopause. CONCLUSIONS: The CHD risk profile was affected unfavorably by both physiological and surgical menopause. Changes in most CHD risk markers were small, despite the substantial changes in hormonal parameters.

Short-term effects of two continuous combined oestrogen-progestogen therapies on several cardiovascular risk markers in healthy postmenopausal women: a randomised controlled trial.

OBJECTIVE: To compare the short-term effects of two oral continuous combined oestrogen-progestogen treatment regimens on blood concentrations of several cardiovascular risk markers in healthy postmenopausal women. STUDY DESIGN: In a 12-week randomised controlled study, 48 healthy non-hysterectomised postmenopausal women, aged 41-58 years, received either no treatment (control group; n=16), or daily oral continuous combined treatment with 1 mg micronised 17beta-oestradiol plus 5 mg dydrogesterone (E/D group; n=18) or 0.625 mg conjugated equine oestrogens plus 5 mg medroxyprogesterone acetate (CEE/MPA group; n=14). Fasting blood sampling was performed at baseline and after 12 weeks of follow-up. RESULTS: Compared with the control group, 12-week treatment with E/D or CEE/MPA reduced fibrinogen (-7.7%, p=0.004 and -3.3%, p=0.083, respectively), factor VII-act (-8.7%, p=0.14 and -9.7%, p=0.06, respectively), homocysteine (-20.5%, p=0.02 and -26.7%, p=0.005, respectively), and IGF-1 (-27.9%, p<0.001 and -18.1%, p=0.002, respectively), but increased factor VII-ag (+10.1%, p=0.03 and +4.4%, p=0.46, respectively), endothelin-1 (+15.2%, p=0.12 and +20.0%, p=0.13, respectively) and C-reactive protein (+88.8%, p=0.18 and +71.0%, p=0.44, respectively). Fibrinolytic factors were not affected by either hormone therapy (HT). CONCLUSIONS: Short-term oral continuous combined therapy with oestradiol/dydrogesterone and conjugated equine oestrogens/medroxyprogesterone acetate had comparable effects on the investigated cardiovascular risk markers.

Effects of non-oral postmenopausal hormone therapy on markers of cardiovascular risk: a systematic review.

OBJECTIVE: To review the effects of non-oral administration of postmenopausal hormone therapy (HT) on risk markers for atherosclerotic and venous thromboembolic disease.Non-oral postmenopausal HT appears not to increase venous thromboembolic risk, whereas the effect on coronary heart disease risk is less clear. DESIGN: Systematic review of literature obtained from MEDLINE, EMBASE, and CENTRAL databases from 1980 until and including April 2006. Terms for "postmenopausal hormone therapy" and for "non-oral administration" were combined in the search. SETTING: Randomized clinical trials. PATIENT(S): Postmenopausal women, both healthy and with established cardiovascular disease or specified cardiovascular risk factors INTERVENTION(S): Non-oral HT (e.g., transdermal or intranasal) compared with oral HT or no treatment/placebo. MAIN OUTCOME MEASURE(S): Lipoprotein(a), homocysteine, C-reactive protein (CRP), cell adhesion molecules, markers of endothelial dysfunction, coagulation, and fibrinolysis. RESULT(S): Seventy-two studies investigating either transdermal or intranasal administration were included. For non-oral HT, decreases in lipoprotein(a), cell adhesion molecules, and factor VII generally were significant, resistance to activated protein C (APCr) was slightly increased, and other markers including CRP and homocysteine did not change. Compared with oral HT, changes in CRP and APCr were smaller, changes in cell adhesion molecules and some fibrinolytic parameters tended to be smaller, whereas changes in other factors including lipoprotein(a) and homocysteine did not differ. CONCLUSION(S): Potentially unfavorable changes seen with oral HT on two important markers, CRP and APCr, are substantially smaller with non-oral HT. Non-oral HT has minor effects on the other cardiovascular risk markers studied. Therefore, compared with oral HT, non-oral HT appears be safer with respect to atherosclerotic and venous thromboembolic disease risk.

3beta-OH-tibolone acutely dilates rat muscle arterioles similar to 3alpha-OH-tibolone.

In an earlier study, we focused on the vasoactive effect of 3alpha-OH-tibolone on spontaneously constricted isolatedfemale rat gracilis muscle arterioles. Vasodilator effects (from 10 to 10 M) of 3alpha-OH-tibolone were similar to those of 17beta-estradiol. It was reported that 3beta-OH-tibolone like estradiol altered GABAB activation in neurons through a membrane estrogen receptor, whereas the 3alpha-OH metabolite did not. We therefore hypothesized that the 3beta-OH metabolite may also have a vasodilating effect in our isolated arteriole model. The results indicate that 3beta-OH-tibolone induces a vasodilator effect in small arterioles that is comparable with that of 3alpha-OH-tibolone at the same concentration. This is intriguing because the binding affinity of 3alpha-OH-tibolone to the estrogen receptor is almost twice that of 3beta-OH-tibolone. Other mechanisms may play a role.

Hemostatic markers in healthy postmenopausal women during intranasal and oral hormone therapy: a randomized trial.

OBJECTIVE: To study changes in the hemostatic balance during intranasal compared with oral administration of 17beta-estradiol (E2) and norethisterone (NET) or NET acetate in postmenopausal women. A wide range of markers of coagulation and fibrinolysis associated with coronary artery disease was tested. DESIGN: In a two-center, randomized, double-blind, comparative trial, 90 healthy postmenopausal women (aged 56.6 +/- 4.7 y) received daily continuous combined hormone therapy, either E2/NET 175 microg/275 mug intranasally as a spray (n = 47) or E2/NET acetate 1 mg/0.5 mg orally as a capsule (n = 43) for 1 year. Hemostatic markers were measured in blood samples taken at baseline and after 12, 24, and 52 weeks of treatment. RESULTS: After 52 weeks of treatment, changes in the intranasal group in markers of coagulation-fibrinogen (-1.3%), factor VII activity (-14.0%), and prothrombin fragment 1 + 2 (+5.8%)-were significantly less (P < 0.05) than the changes in the oral group for these parameters (-6.5%, -20.3%, and +19.0%, respectively). Changes in activated factor VII did not differ between the groups. Neither group showed significant changes in thrombin-antithrombin complex. In the intranasal group, decreases in markers of fibrinolysis-tissue-type plasminogen activator (-10.4%) and plasminogen activator inhibitor-1 antigen (-13.8%)-were significantly less (P < 0.05) than the decreases in the oral group (-17.8% and -38.0%, respectively). A decrease in plasminogen activator inhibitor-1 activity and increases in D-dimer and plasmin-alpha2-antiplasmin complex did not differ between the groups. No differences were found between the groups in homocysteine, which overall was unaltered in both groups. CONCLUSIONS: During intranasal E2/NET therapy, changes in the coagulatory and fibrinolytic markers were to some extent less than those observed during oral therapy.

Breast cancer and climacteric complaints: weighing up risks of hormone therapy against quality of life.

Women with severe menopausal symptoms can, at their request, be treated effectively with hormone therapy. Good information about the advantages and disadvantages of hormone therapy should precede this decision. For women with breast cancer or an inherited increased risk of breast cancer and severe, often therapy-related climacteric symptoms, a high degree of reticence is appropriate in relation to hormone therapy. If the quality of life is seriously affected in these often-young women with these iatrogenic climacteric complaints, then careful consideration must be given to the various treatment modalities.

Effects of a supplement containing isoflavones and Actaea racemosa L. on asymmetric dimethylarginine, lipids, and C-reactive protein in menopausal women.

OBJECTIVE: To investigate the effects of a supplement containing soy isoflavones and Actaea racemosa L. on several coronary heart disease (CHD) risk markers in menopausal women. DESIGN: Randomized, placebo-controlled, double-blind study. SETTING: Nine hospitals in The Netherlands. PATIENT(S): One hundred twenty-four menopausal women. INTERVENTION(S): Daily placebo (n = 64) or supplement containing soy isoflavones and Actaea racemosa L. (n = 60) for 12 weeks. MAIN OUTCOME MEASURE(S): Fasting blood concentrations of asymmetric dimethylarginine (ADMA), lipids, and C-reactive protein (CRP) at baseline and week 12. RESULT(S): In the supplement group, total cholesterol and low-density lipoprotein cholesterol showed a small absolute reduction at week 12 (-0.2, 95% confidence interval [CI] -0.3 to -0.0; and -0.2, 95% CI -0.3 to -0.0; respectively). Concentrations of ADMA, triglycerides, lipoprotein(a), and CRP did not change significantly. Analysis of covariance over the 12-week study period revealed no significant between-group differences for all parameters. No significant correlations were found between the concentrations of isoflavones and the CHD risk markers investigated. CONCLUSION(S): Twelve-week administration of a supplement containing soy isoflavones and Actaea racemosa L. had little or no influence on the CHD risk markers studied. This supplement probably has neither protective nor adverse effects on the cardiovascular system; however, large long-term studies are needed to test this.

Effects on asymmetric dimethylarginine of HMR 3339, a novel selective estrogen receptor modulator: a 12-week, randomized, placebo-controlled, double-blind, dose-ranging study in healthy postmenopausal women.

OBJECTIVE: To investigate the short-term effects of three different doses of the selective estrogen receptor modulator HMR 3339 in comparison with placebo and raloxifene on asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor. DESIGN: This study was a multicenter, randomized, placebo-controlled, double-blind, dose-ranging study. Ninety-four healthy postmenopausal women received daily doses of either placebo (n=16), HMR 3339 2.5 mg (n=20), HMR 3339 10 mg (n=19), HMR 3339 50 mg (n=20), or raloxifene 60 mg (n=19) for 12 weeks. Fasting plasma concentrations of ADMA, arginine, and symmetric dimethylarginine (SDMA) were measured at baseline and after 4 and 12 weeks by high-performance liquid chromatography. RESULTS: HMR 3339 induced a dose-dependent reduction of ADMA and SDMA concentrations, with the largest effects (P<0.01 for both) in the HMR 3339 50 mg group compared with baseline and placebo (at 12 weeks: -7.0% [95% CI, -14.2% to 0.2%] for ADMA and -16.2% [95% CI, -22.4% to -10.0%] for SDMA). Twelve weeks of raloxifene 60 mg significantly reduced SDMA (P=0.03) but not ADMA concentrations. Arginine concentrations were not altered by any treatment. CONCLUSIONS: The reduction of the nitric oxide synthase inhibitor ADMA by HMR 3339 may potentially have a beneficial effect on the cardiovascular system in postmenopausal women.

Effects of intranasal versus oral hormone therapy on asymmetric dimethylarginine in healthy postmenopausal women: a randomized study.

OBJECTIVE: Oral estrogens reduce asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, and an independent risk factor for cardiovascular disease. This study was conducted to compare the effect on ADMA between intranasal and oral 17beta-estradiol (E2) combined with norethisterone (acetate) (NET(A)) administration in postmenopausal women. METHODS: In a two-center, randomized, double-blind, comparative study 90 healthy postmenopausal women (age 56.6+/-4.7 years) received daily continuous combined intranasal E2/NET 175 microg/275 microg (n=47) or oral E2/NETA 1 mg/0.5 mg (n=43) for one year. At baseline, week 12 and 52, plasma concentrations of ADMA, arginine and symmetric dimethylarginine (SDMA) were measured by high-performance liquid chromatography. RESULTS: Oral E2/NETA reduced ADMA concentrations (-7.4%; 95% confidence interval (CI) -10.4 to -4.4%), while intranasal E2/NET had no effect (-0.8%; 95% CI -3.7 to 2.1%) after 52 weeks. In both groups, arginine was transiently decreased compared to baseline at week 12 (intranasal: -6.1%; 95% CI -9.1 to -3.0%; oral: -6.5%; 95% CI -10.9 to -2.1%). Only oral E2/NETA reduced SDMA concentrations. CONCLUSIONS: Oral administration of E2/NETA reduced ADMA and SDMA concentrations, whereas intranasal administration did not. Both treatments transiently reduced arginine. The decrease in ADMA by oral estrogens could be a key phenomenon in the modulation of nitric oxide synthesis by postmenopausal hormone therapy.

Treatment of dysfunctional uterine bleeding in the perimenopause: the effects of adding combined estradiol/norethisterone acetate therapy to goserelin acetate treatment--a randomized, placebo-controlled, double-blind trial.

OBJECTIVE: To assess the effects of adding combined estradiol/norethisterone acetate therapy (CENT) to goserelin acetate treatment (GA) of dysfunctional uterine bleeding (DUB) in perimenopausal women. METHODS: In a randomized, placebo-controlled, double-blind trial followed by an open follow-up study, 31 perimenopausal women with DUB were recruited from gynecological outpatient departments of two Dutch hospitals and randomized for treatment with either GA/placebo or GA/CENT for 6 months followed by 18 months of GA/CENT for all. The main outcome measures were abdominal pain, number of bleeding days, double-layer endometrial thickness (DET), Greene climacteric score (GCS), visual analog scale for well-being, bone mineral density (BMD) and mammographic density (BI-RAD score). RESULTS: Abdominal pain, number of bleeding days and DET decreased in both groups, the between-group difference in decrease not being statistically significant. GCS initially showed significant improvement in the GA/CENT group. BMD decreased significantly in the GA/placebo group (-4.1%) compared with the GA/CENT group (-0.3%). Another 18 months of GA/CENT did not result in a lasting difference in BMD between groups. BI-RAD scores did not differ significantly between or within the two groups. CONCLUSIONS: Adding CENT to GA treatment for DUB in perimenopausal women initially prevented BMD loss and improved climacteric complaints, while having no negative impact on vaginal bleeding, abdominal pain or BI-RAD scores. However, prolonged treatment did not result in a lasting prevention of bone loss.

Less effect of intranasal than oral hormone therapy on factors associated with venous thrombosis risk in healthy postmenopausal women.

OBJECTIVE: To compare the effects of intranasal and oral administration of 17beta-estradiol (E2) and norethisterone(acetate) [NET(A)] in healthy postmenopausal women on activated protein C (APC) resistance and other hemostatic parameters associated with venous thrombosis. METHODS AND RESULTS: In this 2-center, randomized, double-blind, 1-year trial, 90 postmenopausal women (56.6+/-4.7 years of age) received daily either an intranasal spray with 175 microg/275 microg E2/NET (n=47) or 1 mg/0.5 mg oral E2/NETA (n = 43). Normalized APC sensitivity ratios (nAPCsr) were determined with a thrombin generation-based APC resistance test. After 1 year, the increase in nAPCsr was smaller in the intranasal than in the oral group: 11% (95% CI, 1% to 22%) versus 53% (95% CI, 37% to 72%). Overall, the decrease in antithrombin and increase in prothrombin fragment 1+2 (F1+2) were smaller and the decrease in free protein S larger in the intranasal compared with the oral group after 1 year. In both groups, the decreases in protein C and prothrombin, and the increase in d-dimer were similar. CONCLUSIONS: Compared with oral E2/NETA therapy, intranasal administration of E2/NET had less effect on APC resistance and on a number of other parameters associated with venous thrombosis. This observation suggests the possibility of a lower venous thrombosis risk for intranasal E2/NET compared with oral therapy.

Intranasal continuous combined 17 beta-estradiol/norethisterone therapy improves the lipid profile in healthy postmenopausal women.

OBJECTIVE: To compare the effects of continuous combined 17beta-estradiol (E2) plus norethisterone (acetate) [NET(A)] therapy by either intranasal or oral administration on the lipid profile in postmenopausal women. DESIGN: Randomized, double-blind, multicenter trial. SETTING: Gynecologic outpatient department. PATIENT(S): Two-hundred thirty-three healthy postmenopausal women. INTERVENTION(S): Women received continuous combined hormone therapy, either intranasal E2/NET (175 microg/275 microg) as a spray (n = 117) or oral E2/NETA (1 mg/0.5 mg) as a capsule (n = 116), for 1 year. MAIN OUTCOME MEASURE(S): Fasting plasma concentrations of lipids and (apo)lipoproteins; and atherogenic indices at baseline and after 12, 24, and 52 weeks of treatment. RESULT(S): We found a significant (P < .001) decrease from baseline in both treatment groups in total, low-density lipoprotein- (LDL), high-density lipoprotein- (HDL), and HDL2-cholesterol, in triglycerides, apolipoprotein B (apoB), and lipoprotein(a). Levels of HDL3-cholesterol and apolipoprotein A1 (apoA1) were transiently decreased in the intranasal group. In the oral group, compared with the intranasal group, the decrease was larger for ratio total and LDL-cholesterol and lipoprotein(a) and smaller for triglycerides and apoA1. In the oral group, the ratios total/HDL cholesterol and LDL/HDL cholesterol were lowered, and the ratio apoB/LDL was increased, more than in the intranasal group. CONCLUSION(S): Both intranasal and oral E2/NET(A) therapy improved the lipid profile of healthy postmenopausal women, with some effects being more pronounced after oral administration.

The effects of 12 weeks of HMR 3339, a novel selective estrogen receptor modulator, on markers of coagulation and fibrinolysis: a randomized, placebo-controlled, double-blind, dose-ranging study in healthy postmenopausal women.

OBJECTIVE: To investigate the short-term effects of HMR 3339, a novel selective estrogen receptor modulator, on markers of coagulation and fibrinolysis. STUDY DESIGN: In a multicenter, 14-week, randomized, placebo-controlled, double-blind, dose-ranging study, healthy postmenopausal women received daily placebo (n = 22), HMR 3339 2.5 mg (n = 25), HMR 3339 10 mg (n = 24), HMR 3339 50 mg (n = 24), or raloxifene 60 mg (n = 23). Statistical analysis was performed using standard parametric tests. RESULTS: After 12 weeks, compared with placebo, HMR 3339 50 mg induced the largest mean percentage changes in antithrombin (-14.6%, P < .001), protein C (-12.9%, P = .029), and fibrinogen (-26.3%, P = .001). Decreases were observed in the HMR 3339 2.5 mg group, compared with placebo, in tissue-type plasminogen activator (-55.0%, P = .026 after 4 weeks), plasmin-alpha2-antiplasmin complex (-85%, P = .031 and -63.3%, P = .008, respectively, after 4 and 12 weeks), and D-dimer (-91.4%, P = .018 after 12 weeks). Compared with placebo, raloxifene 60 mg decreased total protein S (-8.2%, P = .009) after 4 weeks and antithrombin (-6.0%, P = .034) and fibrinogen (-18.1%, P = .007) after 12 weeks. CONCLUSION: HMR 3339 and raloxifene decreased fibrinogen levels. In the low dosage, HMR 3339 showed potentially beneficial effects on some markers of fibrinolysis. Both drugs impaired the anticoagulatory potential.

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.

Effect of a combination of isoflavones and Actaea racemosa Linnaeus on climacteric symptoms in healthy symptomatic perimenopausal women: a 12-week randomized, placebo-controlled, double-blind study.

OBJECTIVE: To investigate the effects of a novel dietary supplement containing soy isoflavones and Actaea racemosa Linnaeus (formerly called Cimicifuga racemosa L.) on climacteric symptoms in healthy perimenopausal women. DESIGN: In a multicenter, randomized, placebo-controlled, double-blind study, 124 women experiencing at least five vasomotor symptoms every 24 hours were randomized to receive daily either a phytoestrogen-containing supplement (n = 60) or placebo (n = 64) for 12 weeks. The modified Kupperman Index and Greene Climacteric Scale, a visual analogue scale designed to measure quality of life and the daily number and severity of hot flushes, was used in the screening period and in weeks 6 and 12. Changes in these scores from baseline were calculated. RESULTS: At weeks 6 and 12, all scores in both groups had improved compared with baseline, though the overall difference in scores between the groups was not statistically significant. CONCLUSION: The supplement containing soy isoflavones and A racemosa L. had no statistically significant effect on climacteric symptoms in perimenopausal women experiencing at least five vasomotor symptoms per day.

Endothelium-dependent dilatory effects of 3alpha-OH-tibolone in gracilis muscle arterioles of the female Wistar rat.

OBJECTIVE: Tibolone is a synthetic steroid used for the treatment of the symptoms of menopause that, once metabolized, has estrogenic, progestogenic, and androgenic properties. We investigated the direct vasodilatory effects of the major active tibolone metabolite 3alpha-OH-tibolone and its sulfated form on female rat skeletal muscle arterioles, which play an important role in the control of blood pressure. DESIGN: In isolated, pressurized spontaneously constricted arterioles (mean passive diameter 83 +/- 3 microm), we investigated the vasodilatory effect of 3alpha-OH-tibolone and its sulfated form. To study the role of the endothelium and in particular that of nitric oxide, we repeated the experiments with 3alpha-OH-tibolone after removal of the endothelium and on vessels pretreated with the nitric oxide synthesis inhibitor, Nomega-nitro-L-arginine (L-Na). Finally we compared the vasodilatory effect of 3alpha-OH-tibolone with 17beta-estradiol. RESULTS: A dose-dependent dilatation to 3alpha-OH-tibolone was observed starting at a concentration of 10 M. With the sulfated form of 3alpha-OH-tibolone, dilatation was only present at the highest concentration (10 M). In the denuded vessels, the vasodilatory effect was absent at concentrations from 10 to 10 M. The dilatation induced by 3alpha-OH-tibolone was not significantly reduced by L-Na. The vasodilatory effect of 3alpha-OH-tibolone did not differ from that of 17beta-estradiol. CONCLUSIONS: 3alpha-OH-tibolone has a dose-dependent vasodilatory effect on isolated skeletal muscle arterioles from the rat. The sulfated form has no vasodilatory effect in this setup. This finding suggests that during this short incubation time there was no conversion of the sulfated metabolite into its active form by the vascular endothelium. The vasodilatory effect of 3alpha-OH-tibolone is endothelium dependent at physiologic concentrations and comparable to that of 17beta-estradiol.

Effect of raloxifene and hormone therapy on serum markers of brain and whole-body cholesterol metabolism in postmenopausal women.

OBJECTIVE: To compare the 2-year effects of raloxifene (Rlx) with oral postmenopausal hormone therapy (HT) on serum markers of brain and whole-body cholesterol metabolism. METHODS: In a randomized, double-blind, placebo-controlled trial, 95 healthy, non-hysterectomized, early postmenopausal women received either daily Rlx 60 mg (n = 24), Rlx 150 mg (n = 23), HT (conjugated equine estrogens 0.625 mg/medroxyprogesterone acetate 2.5 mg; n = 24), or placebo (n = 24). Fasting blood samples were collected at baseline and after 6, 12, and 24 months of treatment for measurement of serum concentrations of cholesterol by means of gas-liquid chromatography; 24S-hydroxycholesterol (cerebrosterol), lathosterol, and the plant sterol campesterol by means of gas-liquid chromatography-mass spectrometry. The analyses were performed retrospectively from serum samples stored at -70 degrees C for 5 years. RESULTS: Twenty-four months of treatment with raloxifene 150 mg was associated with a significant reduction in serum cholesterol concentrations (-10%, P = 0.007). The ratio of 24S-hydroxycholesterol to cholesterol, a serum marker of brain cholesterol metabolism, showed a significant increase after 6 and 12 months with raloxifene 150 mg but not after 24 months (P = 0.001). The ratio of lathosterol to cholesterol, a marker of whole-body cholesterol synthesis, increased with raloxifene 60 mg (P = 0.163), raloxifene 150 mg (P < 0.001), as well as with HT (P = 0.005). The ratio of campesterol to cholesterol, a marker of cholesterol absorption rate, was significantly reduced with HT (P = 0.002). CONCLUSION: Two-year treatment with raloxifene or HT had no influence on brain cholesterol metabolism, while whole-body cholesterol synthesis, assessed by the ratio of lathosterol to cholesterol, increased during raloxifene and HT.