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 mug/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.

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.

The effect of estradiol and a combined estradiol/progestagen preparation on insulin sensitivity in healthy postmenopausal women.

Abnormalities of carbohydrate metabolism and insulin sensitivity have been reported in estrogen deficiency. Estrogen replacement appears to result in an improvement in these parameters, although progestagens may antagonize these effects. We have examined the effects of transdermal estradiol and oral norethisterone on insulin sensitivity using the hyperinsulinemic euglycemic clamp method by performing a randomized, double blind, placebo-controlled study in 22 healthy women after a surgically induced menopause. After baseline measurements, subjects were randomized to receive either transdermal 17beta-estradiol (50 microg) or matching placebo patches for 6 weeks. The subjects were then further randomized to receive either estradiol in combination with oral norethisterone (1 mg) or a matching oral placebo preparation, crossing over after 6 weeks, with assessment of insulin sensitivity at the end of each treatment. No significant increase in insulin sensitivity was observed after 6 weeks of transdermal 17beta-estradiol treatment (95% confidence interval, -0.54, 1.86; P = 0.27). Addition of norethisterone for a further 6 weeks had no detectable effect on insulin sensitivity (95% confidence interval, -1.65, 1.10; P = 0.65). The results of this study using transdermal estradiol do not support previous reports that unopposed estrogens exert potentially beneficial effects on insulin sensitivity and suggest that the addition of an oral progestagen confers no clinically important risk or benefit. It is therefore unlikely that effects on insulin sensitivity contribute appreciably to the cardioprotective benefits attributed to hormone replacement therapy.

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).

Long-term effects of continuous combined HRT on bone turnover and lipid metabolism in postmenopausal women.

This study was undertaken to investigate the effect of 10 years of hormone replacement therapy (HRT) on bone turnover and lipid metabolism in postmenopausal women. The single-centre trial was initiated as a 1-year, double-masked, randomized, parallel-group study of continuous combined HRT with 2 mg 17 beta-estradiol and 1 mg norethisterone acetate administered once daily with or without 1 mg estriol. Following preliminary results which showed no difference between the addition and omission of estriol, patients continued on an open-label extension phase of continuous combined HRT without estriol for a further 9 years. Of the 52 women who entered the original double-masked study, 32 entered the open-label extension phase. The 10-year analysis was based on 27 patients. Major increases in bone mineral density (BMD) of the lumbar spine were seen during the first 3 years of treatment, remaining statistically significant compared with baseline at all visits throughout the 10-year follow-up (p < or = 0.025). Statistical modelling confirmed that there were no decreases in BMD after these initial increases. BMD remained 5.5% higher than baseline values after 10 years of continuous combined HRT. Mean total cholesterol levels were significantly reduced after 10 years of therapy (p = 0.012), with no significant changes in serum triglyceride and low-density lipoprotein (LDL)-cholesterol levels from baseline values at this time. High-density lipoprotein (HDL)-cholesterol levels, however, were reduced by 15.4% (p < 0.001). In conclusion, 10 years of continuous combined HRT resulted in a significant and sustained increase in BMD. This treatment regimen therefore appears to be well suited for the long-term prevention of osteoporosis in postmenopausal women.

Urogenital ageing and its effect on sexual health in older British women.

OBJECTIVE: To provide information on the extent of problems of urogenital ageing in older British women. DESIGN: A MORI survey of a representative population sample of older British women. SETTING: Home interviews. PARTICIPANTS: Two thousand and forty-five women aged 55-85+. RESULTS: Urogenital symptoms had affected 48.8% of the women at some time, but no more than 11% were currently affected by individual symptoms; however, these were often of long duration. The majority (73%) were not sexually active, with lack of a partner being a factor for many. There was also a decreasing prevalence of sexual activity with increasing age. Those sexually active in the 65-74 year old age group (n = 148) tended to have a similar sexual frequency (at least once per month) compared with the younger women studied. Approximately 12% of those who reported dyspareunia and/or vaginal dryness claimed a severe problem; 33% did not seek professional advice and 36% resorted to an over the counter remedy. Use of hormone replacement therapy was generally of relatively short duration. There was a declining gradient of ever-use with age. CONCLUSIONS: The extent of significant urogenital symptoms is relatively low, but some women are seriously affected and use self-help as well as professional assistance. The extent of sexual activity in older women and factors affecting this have been defined, and the effect of urogenital symptoms on sexual activity demonstrated.

Effects of postmenopausal hormone replacement therapy on lipoproteins including lipoprotein(a) and LDL subfractions.

The purpose of this study was to examine the effects on lipoprotein risk markers for CHD of oestradiol given alone and in combination with the androgenic progestogen, norethisterone. Eighty postmenopausal women were randomly allocated to receive oestradiol (2 mg/day) alone or with continuous norethisterone (1 mg/day). Serum lipoprotein levels, including lipoprotein(a), were monitored during 12 months on treatment in all the women, and in a sub-set of 32 patients cholesterol was measured in the two major density subfractions of LDL. Oestradiol caused a transient rise in triglycerides, a small decrease in LDL cholesterol (significant only at 3 and 6 months, P < 0.05) and a consistent significant increase in HDL cholesterol (16%, P < 0.01). There was a downward trend in lipoprotein(a) levels which did not achieve statistical significance. The combined preparation caused significant, sustained decreases in triglycerides (31%, P < 0.01), total cholesterol (15%, P < 0.001), VLDL (42%, P < 0.01), LDL (9%, P < 0.05) and HDL (11%, P < 0.001). Lipoprotein(a) was also reduced (39%, P < 0.05). In the sub-set of patients in which LDL subfractions were measured, the reduction in LDL induced by oestradiol monotherapy was significant only at the 3-month visit (6%, P < 0.05). This was due to a decrease in the 'light' (1.025 < d < 1.044 g/ml) subfraction (10%, P < 0.05) and resulted in an apparent shift in subfraction distribution towards the 'heavy' (1.044 < d < 1.060 g/ml) subfraction, although there was no absolute increase in the latter. None of these changes was statistically significant at 12 months. Oestradiol/norethisterone caused sustained decreases in both 'light' (15%, P < 0.05) and 'heavy' (29%, P < 0.05) subfractions, with no significant change in the relative amounts. The changes in 'light' and 'heavy' LDL in this group were highly correlated with changes in triglyceride levels (r = -0.57, P < 0.05 and r = 0.82, P < 0.01 respectively). Therefore, at the end of 1 year's treatment with unopposed oestradiol the only statistically significant change was an increase in HDL cholesterol. Addition of norethisterone to the preparation reversed this potentially beneficial change, but favourably influenced triglycerides, VLDL, LDL subfraction profile and lipoprotein(a), which may counteract the adverse effect on HDL.

Immunohistochemical and hysteroscopic assessment of postmenopausal women with uterine bleeding whilst taking Tibolone.

The gonadomimetic steroid Tibolone, is currently widely used for the treatment of menopausal symptoms. Up to 20% of women have been reported to have episodes of bleeding whilst on therapy. We investigated 37 cases who experienced bleeding episodes whilst on Tibolone and compared these to six cases who experienced no bleeding whilst on therapy and who underwent similar investigations in the course of a clinical study. All women underwent a diagnostic hysteroscopy and an endometrial biopsy, under a local anaesthetic. The endometrium was assessed by histology and with immunohistochemical markers for cellular proliferation (Ki67, PCNA), Heat Shock Protein 27 (HSP27) and bcl-2. There were 17 women with intracavitary lesions on hysteroscopy (including one in the control group), 10 with polyps, five with fibroids, two with congenital uterine anomalies. Histological diagnosis was not obtained in 16 cases. The high incidence of uterine polyps in the group who bled on Tibolone suggests an etiologic relation. The staining pattern with HSP27 demonstrated an oestrogenic effect. There were no differences in the bcl-2 immunoreactivity between those who bled and those who did not bleed on treatment which suggests absence of a link. Similarly, there were no differences in the expression of the proliferation markers. We conclude that episodes of bleeding in patients receiving Tibolone for hormone replacement therapy, whilst warranting investigation, should not cause undue concern.

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.

Investigation of the bleeding patterns of postmenopausal women treated with Estrapak-50.

Diary cards of patients in two similar trials of Estrapak-50 hormone replacement therapy were analysed with regard to the characteristics of progestogen-associated bleeding (PAB) and breakthrough bleeding (BTB). Forty out of 52 patients in Study A and 74 out of 92 patients in Study B had diaries suitable for analysis. One patient in Study A and two patients in Study B who withdrew from treatment did so because of unacceptable bleeding problems. Similar results were obtained from both trials. After 6 months of treatment approximately 90% of patients in study A and approximately 70% of patients in study B had PAB on or before day 11. Twenty-seven percent and 49% in studies A and B, respectively, bled prior to day 8, which in the majority of instances affected one treatment cycle. Duration of PAB varied from 1 to 14 days (median 7 days) and the pattern of bleeding in the second cycle was predictive of bleeding in subsequent cycles. Although over 1/3 of women reported some heavy bleeding days, this usually only affected one treatment cycle, and the majority of bleeding was only spotting or light flow. BTB patterns did not raise suspicions of endometrial pathology. Bleeding patterns were both acceptable to patients and, in as much as the current literature indicates that bleeding patterns can be interpreted, were consistent with adequate progestogenic protection of the endometrium.

Lipoprotein(a) and postmenopausal oestrogen.

Epidemiological studies have shown that postmenopausal oestrogen therapy substantially reduces the risk of cardiovascular and cerebrovascular disease and this is partly mediated by oestrogen-associated changes in lipoproteins, particularly high-density lipoprotein. In this study, we investigated whether changes in lipoprotein(a) might help to account for the reduction in coronary heart disease and stroke associated with postmenopausal oestrogen therapy. The study group consisted of 18 women who had hysterectomy and bilateral oophorectomy at least 2 months prior to recruitment and had received no previous hormonal therapy. Serum samples were collected for measurement of lipoprotein(a) before and after 4 months of treatment with oestradiol valerate (2 mg/day). Lipoprotein(a) levels ranged from 35 to 720 mg/l (median 180 mg/l) before treatment and from 55 to 780 mg/l (median 130 mg/l) after oestradiol treatment and showed no consistent pattern of change. It would appear, therefore, that treatment with unopposed oestrogen in relatively low doses not have a marked effect on lipoprotein(a), at least in the short term.

Reversible menopause induced by the GnRH analogue buserelin: effects on lipoprotein metabolism.

GnRH agonists can induce a reversible pharmacological menopause and can be used to treat endometriosis, a fairly common gynaecological problem which responds well to oestrogen deprivation. Premature menopause is associated with adverse lipid changes and an increased risk of coronary heart disease. Therefore we set out to investigate changes in lipoprotein metabolism in a group of premenopausal women being treated with the GnRH analogue buserelin for active endometriosis. We monitored lipoprotein levels, high density lipoprotein subfractions and apolipoproteins AI, AII and B during a 12-month course of treatment and for 6 months afterwards. Treatment caused a sustained increase in HDL3 cholesterol levels and a small increase in low density lipoprotein cholesterol, which was significant at the six-month visit only. Apolipoprotein B levels rose significantly and there were marginal increases in apolipoproteins AI and AII. All changes and trends were reversed after cessation of treatment. We conclude that the treatment did not profoundly affect lipoprotein metabolism, neither LDL nor HDL cholesterol, the established important risk markers for coronary heart disease appreciably altered.

Short-term changes in lipoproteins and apoproteins during cyclical oestrogen-progestogen replacement therapy.

Lipoproteins and apoproteins were measured weekly in a group of 18 post-menopausal women treated with a cyclical hormone replacement regimen comprising 28 days on conjugated equine oestrogens (0.625 mg/day) with the addition of norgestrel (0.15 mg/day) for the last 12 days of the cycle. There were no significant changes in total triglyceride, very low-density-lipoprotein (VLDL) cholesterol or high-density-lipoprotein (HDL) cholesterol levels. Low-density lipoprotein (LDL) and total cholesterol levels fell, the differences being significant after two weeks. The LDL/HDL cholesterol ratio also fell significantly over 1 week of treatment. There were no significant changes in either HDL2 or HDL3 cholesterol. The HDL2/HDL3 cholesterol ratio did, however, alter significantly, increasing during the oestrogen-only phase. Apart from this ratio, none of the parameters measured showed any significant differences as between the oestrogen-only phases and the oestrogen/norgestrel phases. There were no significant changes from baseline values in the levels of apoproteins AI, AII or B. The apoprotein AI/AII ratio was significantly increased, the levels being higher during the oestrogen phase of the cycle. There was no significant change in the apoprotein B/AI ratio. The apoprotein B/LDL cholesterol ratio showed a statistically significant increase after 4 weeks. There was no evidence of any cyclical changes. We conclude that the results of this study are generally favourable with regard to coronary heart disease risk but that the change in the apoprotein B/LDL ratio merits further investigation.

Org OD 14 and the endometrium.

Long-term therapy with (7 alpha,17 alpha)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one (Org OD 14; tibolone, Livial) has no influence on the endometrium in post-menopausal women. This was concluded from endometrial biopsies taken from 39 post-menopausal women treated with 2.5 mg/day for periods of from 3 months to 5 years 11 months at three centres. These results accord with the data published so far on 129 women who have been treated for up to 2 years. A review of the data relating to a total of 168 patients treated with Org OD 14 is presented. The endometrial pattern observed at the start of therapy showed no change during treatment in 90% of patients. In 15 cases slight proliferation was apparent after treatment, this being a similar pattern to that seen in the initial days of a normal cycle. In a considerable number of patients no tissue could be obtained, indicating an atrophic pattern. The picture following Org OD 14 therapy was the same as that observed in untreated normal post-menopausal women.

Prevention of bone loss by hormone replacement therapy is probably not due to stimulation of calcitonin secretion.

Weekly fasting serum calcitonin levels and biochemical indices of bone metabolism were measured in 13 postmenopausal women being given hormone replacement therapy over a period of 8 weeks. All of the biochemical indices except urinary hydroxyproline creatinine ratios fell significantly, indicating that the treatments were effective in reducing bone turnover. Calcitonin levels fell significantly and, within the individual, levels were positively correlated with adjusted calcium levels. These findings do not support the theory that estrogen conserves bone by stimulating calcitonin secretion.

Effects of bilateral oophorectomy on lipoprotein metabolism.

The effects of surgical menopause on lipoprotein levels and their time course were studied in 31 premenopausal women who were undergoing hysterectomy and bilateral oophorectomy for non-malignant conditions. Lipoprotein levels were measured before 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 less than 0.05) in the 6 weeks after operation from a mean of 3.57 (SD 0.66) mmol/l to 4.21 (SD 0.84) mmol/l 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.