An open, randomized, controlled study of transdermal hormone replacement therapy on the rate of bone loss in primary biliary cirrhosis. Osteoporosis in primary biliary cirrhosis: a randomized trial of the efficacy and feasibility of estrogen/progestin. Oral antioxidant supplementation for fatigue associated with primary biliary cirrhosis: results of a multicentre, randomized, placebo-controlled, cross-over trial. A two-year double-blind controlled study of the clinical effect of combined and sequential postmenopausal replacement therapy and steroid metabolism during treatment. Effects of "natural oestrogen" replacement therapy on menopausal symptoms and blood clotting. Beneficial effect of azathioprine and prediction of prognosis in primary biliary cirrhosis. Final results of an international trial. Effect of hormone therapy on mortality rates among women with heart failure and coronary artery disease. The benefits of androgens combined with hormone replacement therapy regarding to patients with postmenopausal sexual symptoms. Effects on haemostasis of hormone replacement therapy with transdermal estradiol and oral sequential medroxyprogesterone acetate: a 1-year, double-blind, placebo-controlled study. The Writing Group for the Estradiol Clotting Factors Study.
The prevalence of osteoporosis amongst patients with primary biliary cirrhosis (PBC) is high and may be a serious clinical problem. Hormone replacement therapy (HRT) is effective in preventing bone loss but has not been evaluated in randomized trials in PBC. The primary aim was to study the effect of transdermal HRT in combination with daily vitamin D and calcium supplementation on bone loss compared with vitamin D and calcium supplementation only in postmenopausal women with PBC. The secondary aim was to study the safety of transdermal HRT. SUBJECTS/INTERVENTIONS: Eighteen females with PBC were randomized to receive 2 years therapy with either (i) transdermal oestradiol 50 microg 24 h(-1) two times per week + medroxyprogesterone 2.5 mg day(-1) + alfacalcidol 0.25 microg day(-1) and calcium 1 g day(-1) or (ii) alfacalcidol 0.25 microg day(-1) and calcium 1 g day(-1). Dual-energy X-ray absorptiometry for measurement of bone mineral density (BMD) and sampling of blood and serum for measurements of biochemical markers of liver function was performed before, during and at the end of treatment.
                BMD increased significantly at the lumbar spine (P < 0.05) and the femoral neck (P < 0.05) in the HRT group whereas no significant change was found in the control group. One oestrogen-treated patient was excluded after 1 year because of deteriorating, but reversible, aminotransferases. Dropout frequency because of nonliver-related causes was higher in the HRT group. Otherwise, no difference with respect to adverse liver reactions was found between the groups.
                Transdermal HRT increases BMD in PBC patients with few severe side effects related to the liver. The optimal therapy for the prevention and treatment of osteoporosis in primary biliary cirrhosis (PBC) is unknown. Hormone replacement therapy (HRT) prevents osteoporosis, but may promote cholestasis. We performed a double-blind, randomized, placebo-controlled trial of transdermal estrogen/progestin in postmenopausal women with PBC. The 24-month study enrolled 31 patients, but trial uptake was limited and treatment arm dropout was significant. Placebo-treated patients had a higher percentage loss in femoral neck bone mineral density than actively treated patients (-3.76 +/- 1.37% versus 0.21 +/- 1.01%, respectively, P = .058). New fractures occurred in 2 patients on placebo, and in no patients on treatment. The mean monthly increase in bilirubin was not significantly different between groups, but individual data suggest HRT may worsen cholestasis. In conclusion, women with PBC have strong feelings about HRT, and recruitment for this intervention is difficult. Transdermal estrogen/progestin likely provides protection against bone loss in PBC patients, but may worsen cholestasis. We have previously reported, in an uncontrolled trial, an improvement in fatigue scores in patients with primary biliary cirrhosis given oral antioxidant supplementation. We now present data from a controlled trial.
                Sixty-one patients with primary biliary cirrhosis-associated fatigue were randomized into a double-blind, placebo-controlled, cross-over trial. Participants received 12 weeks each of placebo and antioxidant supplementation (vitamins A, C and E, selenium, methionine and ubiquinone) in random order, separated by a 4-week washout period. The primary trial outcome (fatigue) was assessed using the Fisk scale. Other symptoms of primary biliary cirrhosis were measured using Likert and visual analogue scales.
                Forty-four patients completed both arms of the trial. No significant changes in fatigue were recorded in the active phase of treatment (median improvement in Fisk score, 1; P = 0.61). Small improvements in Fisk scores were recorded during placebo therapy (median improvement, 4; P = 0.03). Neither medication was associated with improvement in any other symptoms related to primary biliary cirrhosis. Adverse effects were more common during active therapy and were mild and self-limiting. One patient died from unrelated causes during active treatment.
                Although oral antioxidant supplementation appears to be safe, we could not find any evidence for a beneficial effect on fatigue or other liver-related symptoms. A total of 151 postmenopausal women were randomly allocated to 3 groups for treatment with hormone replacement therapy. One group received combined therapy (2 mg oestradiol (E2) and 1 mg norethisterone acetate (NETA) daily), the second group was placed on sequential therapy (2 mg E2 for 12 days, 2 mgE2 and 1 mg NETA for 10 days and 1 mg E2 for 6 days), while the third was given placebo. Treatment was administered over 24 cycles of 28 days. The two active treatments were equally effective in relieving climacteric symptoms. In the combined therapy group, 62% of the women experienced spotting and/or breakthrough bleeding during the first 3 cycles; thereafter this proportion decreased to between 3 and 18% in each of the following three-cycle periods. Sixty-four percent (64%) of these women had no more bleeding after the first 3 cycles. Endometrial atrophy was detected in 93% of the women in this group after 24 cycles of therapy. Bleeding irregularities occurred during the first 3 cycles in 27% of the patients treated with sequential therapy and in 21% of those receiving placebo. In the subsequent 3-cycle periods these figures fell to below 10% in the 2 groups. In all 3 groups weight remained stable but blood pressure increased equally in the actively treated groups and the placebo group. The levels of follicle-stimulating hormone (FSH), sex-hormone-binding globulin (SHBG) and the free fraction of E2 in serum were significantly lower in the combined therapy group than in the sequential therapy group. The higher level of free E2 in the latter group may have been caused by a decrease in metabolism associated with the increased SHBG concentration. It was concluded that combined treatment with E2 and NETA might provide an alternative to sequential treatment in postmenopausal women willing to tolerate the initial high risk of breakthrough bleeding/spotting in order to avoid subsequent regular bleeding. In the subgroup of women in whom bleeding irregularities continue, sequential treatment should be considered. In a double-blind study on the value of equine ("natural") oestrogens 30 patients presenting with menopausal symptoms in a group practice were monitored for possible adverse effects on blood clotting, weight, and blood pressure. The women were randomly allocated to two groups and given either three months' hormone treatment followed by three months' placebo or vice versa. An appreciable amelioration of all symptoms on placebo made it difficult to asses the genuine value of oestrogen treatment during the period of study. Both groups made a dramatic clinical improvement during the first three months. Nevertheless, the symptoms of the 15 women who received oestrogen first returned after the cross-over to placebo without any suggestion of a placebo response. In contrast, the other group who took placebo first did not deteriorate after changing to oestrogen. The menopausal index and the karyopyknotic index were not reliable guides to the need for oestrogen treatment. Hot flushes, however, were proportionately reduced on oestrogen and they seemed to be more readily eliminated in individual cases by oestrogen. The results of blood clotting studies indicated that natural oestrogen administration raised the levels of the extrinsic clotting factors VII and X and accelerated the prothrombin time. The findings were similar to those observed after three months synthetic oestrogen administration with oral contraception. Long-term studies and epidemiological surveys of the clinical incidence of thrombotic and other sequelae are needed before large-scale oestrogen replacement treatment can be recommended. The effect of azathioprine on survival of patients with primary biliary cirrhosis was studied prospectively in a multinational, double-blind, randomized clinical trial including 248 patients of whom 127 received azathioprine and 121 placebo. There were 57 deaths in the azathioprine group and 62 in the placebo group. The actual survival was slightly longer during azathioprine than during placebo treatment. Using Cox multiple regression analysis and adjusting for slight imbalance between the two treatment groups, the therapeutic effect of azathioprine was statistically significant (p = 0.01), with azathioprine reducing the risk of dying to 59% of that observed during placebo treatment (95% confidence interval 40%-90%) or improving survival time by 20 mo in the average patient. Furthermore, azathioprine slowed down progressing incapacitation. Side effects of azathioprine were relatively few. The analysis revealed that the following five variables independently implied poor prognosis: high serum bilirubin, old age, cirrhosis, low serum albumin, and central cholestasis. These factors were combined to a "prognostic index" for prediction of outcome in new patients. The index was validated on independent patient data. On the basis of these results we recommend azathioprine as a routine treatment of primary biliary cirrhosis. Randomized, controlled trial data from the Heart and Estrogen-progestin Replacement Study were used to evaluate the effect of estrogen plus progestin use on all-cause mortality in women with heart failure and coronary disease. Over the 4.1-year follow-up, estrogen plus progestin use had no effect on all-cause mortality (hazard ratio 1.0, 95% confidence interval 0.7 to 1.4, p = 0.8) in women with heart failure and coronary disease. To evaluate the benefits and risks of hormone replacement therapy (HRT) combined with methyltestosterone (MT) in postmenopausal women with sexual dysfunction.
                This study was a randomized, double-blind, placebo-controlled and crossover trial. Eighty-five women using HRT were divided into four treatment groups: GI-HRT plus placebo for 4 months; GII-HRT plus MT 2.5mg/day for 4 months; GIII-HRT plus placebo for 2 months and then replaced with HRT plus MT 2.5mg/day for 2 months; GIV-HRT plus MT 2.5mg/day and then replaced with HRT plus placebo for 2 months. Blood was collected at baseline, after 2 months (T1) and 4 months (T2) of treatment for hormone determinations of estradiol, FSH, total and free testosterone, GOT, GPT, glucose, total and fractions of cholesterol and triglycerides. All participants answered clinical questions and a validated questionnaire of modified McCoy's sex scale.
                The association of HRT with MT 2.5mg/day did not significantly change liver enzymes or increase cardiovascular risk factors. The patients of GII, GIIII and GIV when using MT presented amelioration of sex symptoms, mainly satisfaction and desire (p<0.01); however, GIII at T1 (1.3+/-0.3) presented similar problem score results as compared to GIII at T2 (1.5+/-0.6).
                All data suggest that combined HRT-androgen therapy may be beneficial for postmenopausal women receiving HRT who continue to complain of sexual difficulties or for postmenopausal women with sexual complaints who are not undergoing estrogen therapy. After menopause the haemostatic balance shifts towards a latent hypercoagulable state. To evaluate the effects of two regimens of transdermal estradiol (E2) combined with progestin on the balance between procoagulant factors and inhibitors, 255 women in physiological menopause for 1-5 years were randomly allocated to 1 year of treatment with cyclic transdermal E2 (50 micrograms/day for 21 days) plus medroxyprogesterone acetate (MPA) (10 mg/day from days 10 to 21), continuous transdermal E2 (50 micrograms/day for 28 days) plus MPA (10 mg/day from days 14 to 25), or placebo. Fibrinogen, factor VII (FVII), factor VIII:C (FVIII:C), antithrombin III (ATIII), protein C, protein S, heparin cofactor II (HCII) and plasminogen activator inhibitor (PAI-1) levels were measured at baseline and after 6 and 12 cycles. 167 women who took the treatment for at least 6 cycles were evaluable. The continuous treatment group had significantly lower final values of fibrinogen, FVII, ATIII, protein S and HCII than the placebo group; the cyclic treatment reduced fibrinogen in comparison with placebo but the difference was not significant. In conclusion, both regimens produce a clinically relevant decrease of fibrinogen levels; the continuous regimen affects also the levels of FVII and inhibitors suggesting that the haemostatic balance is shifted to a more physiological state.
We did not find evidence to support the use of hormone replacement for women with primary biliary cirrhosis. It seems that hormone replacement is connected with a significant increase in the occurrence of adverse events.