Judith F. Barnes

Effects of tibolone on lipoprotein(a) and HDL subfractions

OBJECTIVE To determine the effects of tibolone, a synthetic steroid used to alleviate climacteric symptoms and prevent osteoporosis, on lipoprotein metabolism, with particular reference to lipoprotein(a) levels and HDL subfraction profiles. DESIGN Thirty nine postmenopausal women were treated with tibolone (Livial) 2.5 mg/day for 6 months and fasting serum lipoprotein levels were estimated at 0, 2, 4 and 6 months. RESULTS Lipoprotein(a) levels were reduced significantly over the 6 months from a median level of 245 (range < 60-780) mg/l to 152 (range < 60-530) mg/l, a reduction of 39% in the median level. A decrease was observed in approximately two thirds of the women. Reductions were noted in all 6 subjects whose pretreatment levels were high, although concentrations remained at a level associated with increased risk in all but one. There were significant decreases in triglycerides and VLDL cholesterol and no significant change in LDL cholesterol. There was a significant reduction of 18% in HDL cholesterol and a 26% reduction in the HDL2-HDL3 ratio. CONCLUSION The reduction in lipoprotein(a) levels may have a beneficial effect on cardiovascular risk, which could go some way towards balancing the potentially adverse effect on the cardiovascular system caused by the reduction in HDL cholesterol.

Response of plasma low density lipoprotein subfractions to oestrogen replacement therapy following surgical menopause

OBJECTIVE Epidemiological studies suggest that postmenopausal oestrogen replacement reduces the incidence of cardiovascular disease. The purpose of this study was to establish the effects of oestrogen replacement therapy on subfractions of plasma low density lipoprotein in bilaterally oophorectomized women.

Effects of tibolone on serum lipoprotein and apolipoprotein levels compared with a cyclical estrogen/progestogen regimen.

OBJECTIVE The purpose of the study was to examine the effects of tibolone, a synthetic steroid that alleviates climacteric symptoms and prevents bone loss without inducing monthly bleeds, on lipoprotein cardiovascular risk markers and to compare the effects with those of a standard combined estrogen/progestogen preparation. DESIGN Ninety-seven postmenopausal women were randomly allocated to receive either tibolone 2.5 mg/day or conjugated equine estrogens 0.625 mg/day with norgestrel 0.15 mg/day for 12 of each 28 days. Fasting serum levels of lipids, lipoproteins, and apolipoproteins (Apo) were monitored during 18 months of treatment. Women on the cyclical preparation had levels determined during both estrogen-only and combined phases. RESULTS Tibolone caused reductions in triglycerides (33%, p < 0.001), very low density lipoprotein (VLDL) cholesterol (43%, p < 0.001), and high density lipoprotein (HDL) cholesterol (18%, p < 0.001). The HDL2/HDL3 ratio fell by 22% (p < 0.001). Levels of Apo AI and AII were reduced by 18 and 8%, respectively (p < 0.001). The combined preparation caused reductions in VLDL cholesterol (23%, p < 0.001) and low density lipoprotein cholesterol (15%, p < 0.001). There were small reductions in HDL3 cholesterol and in Apo AII and Apo B. All parameters, except for Apo AII and Apo B and lipoprotein (a) [Lp (a)], showed cyclical changes. Lp (a) levels were reduced significantly by both treatments. CONCLUSIONS The cyclical preparation had potentially beneficial effects on LP risk markers. The reduction in HDL induced by tibolone constitutes a potentially adverse change, which may be offset by the substantial falls in triglycerides, VLDL cholesterol, and Lp (a).

A comparison of the effects of two continuous HRT regimens on cardiovascular risk factors

In a study comparing the effects of two continuous HRT regimens on cardiovascular risk markers, 43 postmenopausal women were randomly assigned to receive either tibolone 2.5 mg/day (n=20) or 0.625 mg/day conjugated equine oestrogens plus continuous medroxyprogesterone acetate 5 mg/day (n=23). Serum lipoprotein levels, including LDL and HDL subfractions, oxidisability of LDL and serum nitrate/nitrite levels were determined before and during 12 weeks of therapy. Tibolone significantly reduced triglycerides (17.1%, P<0.01), HDL cholesterol (22.2%, P<0.001), and the ratio HDL(2)/HDL(3) cholesterol (20.2%, P<0.01). Total LDL cholesterol levels did not change significantly, although there was a downward trend in the LDLIII subfraction (12.0% reduction; P=0.06), percentage changes being positively correlated with percentage changes in triglyceride levels (r=0.60, P<0.01). Susceptibility of LDL to oxidation was significantly decreased (P<0.001), changes in lag-time being highly negatively correlated with percentage changes in levels of both LDLIII (r=-0.68, P<0.01) and triglycerides (r=-0.63, P<0.01). Nitrate/nitrite levels did not change. In contrast, the combined therapy caused a significant reduction in LDL cholesterol levels (11.1%; P<0.01) as a result of a significant decrease in the LDLI+II subfraction (12.8%; P<0.05). Changes in LDLI+II and LDLIII were correlated with changes in triglyceride levels (r=-0.52, P<0.05 and r=0.63, P<0.01, respectively). No other parameter was significantly modified. Between treatment effects were significantly different on triglycerides (P<0.01), HDL cholesterol (P<0.001), LDL oxidation (P<0.01) and LDLI+II:LDLIII ratio (P<0.05). The reduction in LDL induced by the continuous combined therapy is likely to be beneficial, despite the apparent shift towards the LDLIII subfraction. Changes in oxidisability and subfraction profile of LDL indicate that tibolone may have a more favourable effect on cardiovascular risk than previously suggested.

Effects of two continuous hormone therapy regimens on C-reactive protein and homocysteine

Objective: To compare the effects of two continuous hormone therapy (HT) regimens on the cardiovascular risk markers, C-reactive protein (CRP) and homocysteine. Design: A prospective study in which 43 postmenopausal women were randomly assigned to either tibolone 2.5 mg/day (n = 20) or 0.625 mg/day conjugated equine estrogens (CEE) plus continuous medroxyprogesterone acetate (MPA) 5 mg/day (n = 23). Serum levels of CRP, homocysteine, vitamin B12, and folate were determined before and during 12 weeks of therapy. Results: C-reactive protein levels were increased by tibolone (76%; P < 0.001) and CEE+MPA (81%; P < 0.001). Neither tibolone nor CEE+MPA had any significant effect on homocysteine levels, but there was a significant difference between the effects of treatment over time (P = 0.046). Both tibolone and CEE+MPA reduced vitamin B12 levels (11%; P < 0.001, and 8%; P < 0.01, respectively), but had no statistically significant effect on folate levels. Individual changes in homocysteine levels were negatively associated with changes in vitamin B12 levels (r = −0.68; P < 0.01) after tibolone therapy. Conclusion: Both tibolone and CEE plus MPA increased CRP levels and reduced levels of vitamin B12. Neither therapy had any significant effect on homocysteine levels. Further long-term studies into the effect of HRT on these markers, and the relationship to cardiovascular disease risk, are required.

The role of megestrol acetate as an alternative to conventional hormone replacement therapy

Objective To investigate the effect of megestrol acetate on menopausal symptoms, lipid metabolism, bone metabolism and coagulation. Methods In a prospective observational study, 71 postmenopausal women, for whom conventional hormone replacement therapy (HRT) was unsuitable, were treated with megestrol acetate 40 mg per day. At 0, 3, 6 and 12 months, fasting lipoproteins, bone biochemistry and thrombophilia profiles were measured and symptom score cards (Greene climacteric scale) completed. Bone mineral density measurement was performed at 0 and 12 months. Results Forty-one women completed the study. Treatment produced significant decreases in psychological (p < 0.001), vasomotor (p < 0.001) and somatic (p < 0.01) symptoms. There were significant reductions in triglycerides (p < 0.001), total cholesterol (p < 0.001), very-low-density lipoprotein (VLDL) (p < 0.05), low-density lipoprotein (LDL) (p < 0.001), high-density lipoprotein (HDL) cholesterol (p < 0.001) and lipoprotein(a) (p < 0.001). Levels of protein C were reduced (p < 0.05) and fibrinogen increased (p < 0.05). Protein S, plasminogen and antithrombin III levels showed an upward trend, which did not reach statistical significance. Biochemical markers of bone turnover did not change, apart from a significant decrease in alkaline phosphatase. Spinal bone density decreased significantly after 12 months, while femoral neck density remained unchanged. Conclusions Megestrol acetate controls menopausal symptoms, has equivocal effects on cardiovascular risk markers and does not increase bone density. It is useful where estrogen is contraindicated.

Effects on climacteric symptoms, bone and lipoprotein metabolism of hormone replacement therapy delivered by estradiol-releasing intravaginal rings: a pilot study

Objective: To assess the efficacy and tolerability of intravaginal rings (IVRs) delivering estradiol. Design: This was a dose-escalating, continuous-dosing, pilot study. Methods: Sixteen women post surgical menopause were recruited at a hospital-based menopause clinic. Over 20 weeks, each patient had IVR devices releasing 50, 75, 100, 150 and 200 μg/day of estradiol inserted consecutively at 4-weekly intervals. Main outcome measures: Climacteric symptoms were assessed, and levels of serum estradiol, lipoproteins and biochemical indices of bone turnover were estimated prior to insertion of the first IVR and at each monthly visit, when the IVR was changed to one of a higher dose. The susceptibility of low-density lipoprotein (LDL) to oxidation was assessed at 0, 12 and 20 weeks. Results: Twelve women completed the study. The rings were well tolerated and serum estradiol levels increased in parallel with each increasing dose. Vasomotor and psychological symptoms and loss of libido were reduced by 76% (p < 0.001), 44% (p < 0.001) and 44% (p < 0.05), respectively, by the end of the study. There were no significant changes in levels of serum lipoproteins, although the ratio of LDL cholesterol to high-density lipoprotein cholesterol decreased by 7.2% (p = 0.01) after 20 weeks. The susceptibility of LDL to oxidation did not change. Urinary excretion of both calcium and deoxypyridinoline cross-links decreased significantly (p < 0.001), indicating a reduction in bone resorption. Conclusions: The rings were effective in controlling climacteric symptoms and had beneficial effects on bone metabolism, but no significant effects on lipoprotein levels or the susceptibility of LDL to oxidation.