E. Farish

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 bilateral oophorectomy on lipoprotein metabolism

Summary. The effects of surgical menopause on lipoprotein levels and their dme course were studied in 31 premenopausal women who were undergoing hysterectomy and bilateral oophorectomy for non‐malignant conditions. Lipoprotein levels were measured beforc oophorectomy and afterwards at 6 and 12 weeks, then at intervals of 3 months for 18 months. Low density lipoprotein (LDL) cholesterol levels rose significantly (P<0.05) in the 6 weeks after operation from a mean of 3.57 (SD 0.66) mmol/1 to 4.21 (SD 0.84) mmol/1 with no significant changes thereafter. There were no significant changes in cholesterol in the other density fractions or in triglyceride levels. High density lipoprotein (HDL) subfractions were measured in 10 of the women to assess any change in the relative amounts of cholesterol carried on HDL2 and HDL3, since the protective effect of HDL is believed to be conferred by the HDL2 fraction only. No significant change was found in either fraction. The increase in LDL cholesterol would be expected to result in an appreciable increase in the risk of developing coronary heart disease, but cannot wholly account for the increase in cardiovascular disease associated with oophorectomy.

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).

Lipoprotein and apolipoprotein levels in postmenopausal women on continuous oestrogen/progestogen therapy.

Levels of serum lipoproteins and apolipoproteins were monitored for 48 weeks in two groups of women taking part in a doubleblind trial of continuous oestrogen/progestogen with and without oestriol. There were no differences between the effects of the two treatments on the substances measured. Triglycerides did not change and there was a transient fall in very low density lipoprotein cholesterol. Low density lipoprotein cholesterol fell over the first 24 weeks but rose thereafter to pretreatment levels. There was a decrease in high density lipoprotein (HDL) cholesterol due to a transient fall in HDL2 cholesterol and a gradual decrease in HDL3 cholesterol. Consequently, the only change in lipid levels present after 48 weeks was a decrease in HDL3 cholesterol, the clinical significance of which is uncertain. There was, however, an increase in apoprotein B levels and decreases in apoprotein AI and All levels. These alterations in apoprotein levels may be unfavourable, since apoprotein B levels have been positively correlated and apoprotein AI and All levels negatively correlated with coronary heart disease.

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.

Ten years post-menopausal hormone replacement therapy — Effect on lipoproteins

Serum lipoproteins were measured in 72 post-menopausal women, 40 of whom had been taking the synthetic oestrogen, mestranol, for a period of 10 yr and 32 of whom had been taking identical placebo tablets. Mestranol therapy was found to increase serum triglycerides, decrease low density lipoprotein (LDL) cholesterol and increase high density lipoprotein (HDL) cholesterol. The increase in HDL cholesterol was due principally to a marked increase in the cardioprotective HDL2 fraction. It is concluded that long-term mestranol therapy has a beneficial effect on serum lipoproteins which may help to protect post-menopausal women against fatal ischaemic heart disease.

Org OD 14: long-term effects on serum lipoproteins

For many years oestrogen replacement therapy has been used to relieve climacteric symptoms and prevent the loss of bone that occurs after the menopause. However, oestrogen treatment can lead to endometrial hyperplasia [l] unless it is given with a progestogen, which brings with it the inconvenience of monthly uterine bleedings. In addition, most progestogens have adverse effects on lipoprotein metabolism [2,3]. Org OD 14, a synthetic steroid[(7a, 17cu)-17-hydroxy-7-methyl-l9-norpregn-5(10)en-20-yn-3-one], has been shown to be effective in alleviating climacteric symptoms and preventing post-menopausal osteoporosis and to have no stimulatory effect on the endometrium [4,5]. The steroid has been shown in animal experiments to have a combination of weak oestrogenic, androgenic and progestogenic activities (research files, Organon International, Oss, The Netherlands). Its long-term effects on lipoprotein metabolism have not been reported. We have measured lipoprotein levels in 24 post-menopausal women who had been taking Org OD 14 for a period of 5 yr and compared them with those of a control group.

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.

EFFECTS OF TREATMENT WITH OESTRADIOL/LEVONORGESTREL ON BONE, LIPOPROTEINS AND HORMONE STATUS IN POSTMENOPAUSAL WOMEN

The aim of the study was to investigate the effects of an oestradiol/ levonorgestrel regimen, administered parenterally, on bone metabolism, bone density, lipoprotein metabolism and hormone status. Twenty‐five women who had undergone a surgical menopause had an oestradiol/levonorgestrel‐containing vaginal ring pessary in situ for 6 months. Within the first month there were sustained changes in the biochemical indices of bone metabolism in keeping with a marked reduction in bone turnover and decrease in bone resorption. Bone mineral content in the distal forearm was measured in 14 patients and a small increase was noted in every patient. Levonorgestrel was well absorbed and the serum levels remained almost constant throughout treatment. There was a gradual increase in serum total oestradiol which became significant at 6 months. Dialysable oestradiol levels rose from 26% of total oestradiol at 0 time to 3.3% at 1 month with no further change thereafter. SHBG levels were 23% of pretreatment levels at 6 months. There were sustained decreases in triglyceride, VLDL and HDL cholesterol levels and a transient fall in LDL cholesterol. Total HDL, HDL2 and HDL3 cholesterol levels were reduced by 25, 40 and 21% respectively. The results suggest that levonorgestrel exerts a protective influence on bone either directly or by its effect on the proportion of oestradiol circulating in the free, physiologically active form. The effects on lipoproteins were predominately those of the progestogen component, the lipoprotein risk factors for coronary heart disease being adversely affected.