Bleeding patterns in peri and postmenopausal women taking a continuous combined regimen of estradiol with norethisterone acetate or a conventional sequential regimen of conjugated equine estrogens with medrogestone.

OBJECTIVES: The aim of this study was to compare the incidence of women presenting irregular bleeding episodes following 9 months of treatment with a low dose continuous combined hormone replacement therapy consisting of estradiol (E(2)) and norethisterone acetate (NETA) versus a sequential hormone replacement therapy consisting of conjugated equine estrogens (CEE) and medrogestone (MG). Secondary aims were to establish the relationship between menopausal age and the occurrence of irregular bleeding for both therapies and to assess the efficacy of both therapies in alleviating menopausal symptoms. METHODS: This was a stratified and randomised, open label study conducted with late peri and postmenopausal women at 35 sites in Austria and Germany. A total of 446 women were randomly allocated into two cohorts based on time since last bleeding and then stratified to either a low dose continuous combined therapy consisting of 1 mg E(2) and 0.5 mg NETA for 28 days or a sequential therapy consisting of 0.625 mg CEE for 28 days and 5 mg MG for the final 14 days. Bleeding and menopausal complaints were continuously assessed. Treatments were administered for 9 lunar months. RESULTS: The incidence rate of women presenting irregular bleeding episodes including spotting during cycle 9 was 12.2% with 1mgE(2)/0.5mgNETA and 25.8% with 0.625mgCEE/5mgMG (P = 0.0014). In the group of postmenopausal women (time since last bleeding > or = 12 months) the incidence of irregular bleeding during cycle 9 was 11.0% for 1mgE(2)/0.5mgNETA and 25.0% for 0.625mgCEE/5mgMG). In the group of late perimenopausal women (time since last bleeding 6-11 months) the incidence of irregular bleeding was similar for both treatments at cycle 3, but markedly less in patients with 1mgE(2)/0.5mgNETA at cycle 6 and 9, being significantly different compared to patients with 0.625mgCEE/5mgMG at cycle 6 (P < 0.05). The cumulative rate of amenorrhea (no bleeding or spotting) achieved with 1mgE(2)/0.5mgNETA was 89% for the postmenopausal women and 83.7% for the late perimenopausal women. Both treatments relieved menopausal complaints equally effective. CONCLUSIONS: Regarding the occurrence of irregular bleeding, the low dose continuous combined therapy was superior to the sequential therapy (0.625mgCEE/5mgMG). The low dose continuous combined E(2)/NETA regimen is also suitable for late perimenopausal women since more than 80% of the women had no bleeding or spotting after 9 months of treatment.

[Tibolone]. / La tibolone.

INDIRECT MECHANISM OF ACTION: Tibolone (OD 14) is the precursor of its active principles that are its metabolites: 3 alpha and 3 beta hydroxylated derivatives. In vivo, the latter behave like estrogens. Certain tissues (liver, endometrium) may metabolize the 3 beta ol derivative into the delta 4 isomer with progestagenic and androgenic activity. The metabolism of the product in other tissues such as the breast and brain is unknown. ACTIVITY: At the dose of 2.5 mg/day, the product expresses an estrogen activity equivalent to that observed with classical doses of estrogens in the brain, genito-urinary tract, vascular endothelium and bone. In the brain and muscle, it also has a slightly androgenic effect and in the breast an antiestrogenic effect. ON METABOLIC LEVEL: The product acts like a minor androgen (lowering triglycerides and HDL cholesterol without interfering in the cholesterol cell flow) and it stimulates fibrinolysis. ON CLINICAL LEVEL: Tibolone treats the symptoms of estrogen privation and protects against bone loss, without inducing bleeding or mastodynia. There is a lack of large epidemiological studies on prevention of fracture risks, cardiovascular effects and breast. Tolerance in the population studied was excellent (healthy population). However, tolerance remains to be assessed in particular sub-groups (populations at risk of certains pathologies).

Risk of calcium oxalate nephrolithiasis in postmenopausal women supplemented with calcium or combined calcium and estrogen.

BACKGROUND: Recent studies showed that postmenopausal women lost less bone mass when supplemented with calcium or estrogen therapy. However, the safety of the treatments in terms of the risk of calcium oxalate stone formation is unknown. We therefore conducted this study to determine the alteration in calcium oxalate supersaturation after calcium supplement or after combined calcium and estrogen therapy in postmenopausal osteoporotic women. METHODS: Fifty-six postmenopausal women were enrolled in this study. All subjects were more than 10 years postmenopausal with vertebral or femoral osteoporosis by bone mineral density criteria. They were randomly allocated to receive either 625 mg of calcium carbonate (250 mg of elemental calcium) at the end of a meal three times a day (group A, n=26) or calcium carbonate in the same manner plus 0.625 mg/day of conjugated equine estrogen and 5 mg medrogestone acetate from day 1-12 each month (group B, n=30). The age (mean +/- S.E.M.) was 66.3 +/- 1.2 and 65.1 +/- 1.1 years, weight 54.1 +/- 1.2 and 55.3 +/- 2.1 kg, in group A and group B, respectively. Urine specimens (24-h) were collected at baseline and 3 months after treatment for the determination of calcium oxalate saturation by using Tiselius's index (AP(CaOx)) and calcium/citrate ratio. RESULTS: After 3 months of treatment, there was no significant alteration from baseline for urinary excretion of calcium, citrate and oxalate. Urinary phosphate excretion was significantly reduced (6.3 +/- 0.7 vs. 5.1 +/- 0.7 mmol/day for group A and 8.2 +/- 0.9 vs. 5.8 +/- 0.7 mmol/day for group B, P<0.05), whereas net alkaline absorption was significantly elevated (10.1 +/- 3.6 vs. 20.1 +/- 4.4 meq/day for group A and 4.8 +/- 3.2 vs. 19.9 +/- 3.6 meq/day for group B, P<0.05). Calcium/citrate ratio and AP(CaOx) determined at baseline were not different from the corresponding values after treatment in both groups; calcium/citrate: 10.1 +/- 3.1 vs. 10.1 +/- 2.5 for group A and 9.3 +/- 1.8 vs. 11.9 +/- 2.5 for group B and AP(CaOx): 1.1 +/- 0.1 vs. 1.3 +/- 0.2 for group A and 1.2 +/- 0.2 vs. 1.1 +/- 0.1 for group B. There were eight and nine patients with high AP(CaOx), or >2, at baseline and after treatment, respectively. CONCLUSIONS: Calcium supplement with a meal or combined calcium supplement and estrogen therapy is not associated with a significant increased risk of calcium oxalate stone formation in the majority of postmenopausal osteoporotic patients. Determination of urinary saturation for calcium oxalate after calcium and estrogen supplements, especially at the initial phase of treatment, may be helpful in the avoidance of nephrolithiasis.

The effect of medrogestone on plasma lipids and lipoproteins in postmenopausal women using conjugated estrogens: an open randomized comparative study.

OBJECTIVE: To test the hypothesis that the progestogen medrogestone has no effect on changes in lipoprotein metabolism evoked by continuous estrogen replacement therapy, paying special attention to high-density lipoproteins (HDL). DESIGN: Open multicenter randomized comparative trial. PATIENTS: Postmenopausal hysterectomized women aged 49 to 64 years. INTERVENTION: Continuous oral treatment with 0.625 mg daily of conjugated estrogens (CE) alone (n = 55) or CE plus 5 mg of the progestogen medrogestone orally during the last 12 days of each 28-day cycle (n = 59). MAIN OUTCOME MEASURES: At baseline and at cycles 3, 6, and 13 we measured the plasma levels of apolipoprotein (Apo) A1, cholesterol in total HDL and in its subfractions HDL2 and HDL3, using density gradient ultracentrifugation. RESULTS: High-density lipoprotein cholesterol increased from baseline at all assessments in both treatment groups, being significantly greater in the CE group (+15% at cycle 13) than in the CE and medrogestone group (+8%). However, HDL2-cholesterol increased in both treatment groups, but with no significant difference between the two groups. High-density lipoprotein 3 cholesterol increased only in the CE group (+7% at cycle 13); there was no significant change in HDL3-cholesterol in the CE and medrogestone group. Low-density lipoprotein (LDL) cholesterol decreased from baseline at all assessments in both treatment groups (-6% and -9%, respectively, at cycle 13). The change in very low-density (VLDL) lipoprotein cholesterol was not significant in either of the two groups. Medrogestone had no significant effects on the estrogen-induced increases in apo A-1 and triglycerides nor on the decreases in ApoB and LDL-cholesterol. Neither hormone significantly affected VLDL-cholesterol or Lp(a) levels. CONCLUSION: Medrogestone did not eliminate the increase in plasma HDL levels evoked by CE.

[Hormone substitution with premarin plus. Results of an Austrian multicenter treatment study]. / Hormonsubstitution mit Premarin plus. Ergebnisse einer österreichischen multizentrischen Anwendungsbeobachtung.

Estrogen/progestin hormone replacement therapy in menopausal women has 2 important medical rationales. First of all, patients are relieved from the subjective symptoms almost fully. In addition patients benefit from prophylaxis of long term even life threatening sequelae of estrogen deficiency. This paper documents the results of a multicenter phase IV study, performed nationwide in Austria with 158 participating gynaecologists. Objective of this phase IV study was the analysis of efficacy and safety data of a new estrogen/progestin hormone replacement therapy scheme under almost practice conditions in the gynaecological context. The therapy supplied was Premarin plus, containing 28 coated tablets of 0.625 or 1.25 mg conjugated estrogens and in addition 12 tablets for the last cycle days containing 5 mg medrogeston. Thus, the dispensing gynaecologists had the option of an individual estrogen dose adjustment in case the low starting dose showed lack of efficacy. The results are based on the data of 1508 recruited female patients. A very high degree of representativeness is attributable to the high number of recruited patients. Overall judgement of the results shows a very high level of efficacy and a well tolerated scheme of hormone replacement therapy with the option of individual estrogen dose adjustments.

[Estrogen replacement in postmenopause, blood coagulation and fibrinolysis: comparison of a new kind of transdermal estradiol treatment with oral therapy with conjugated estrogens]. / Ostrogensubstitution in der Postmenopause, Blutgerinnung und Fibrinolyse: Vergleich einer neuartigen transdermalen Ostradiol-Behandlung mit der oralen Therapie mit konjugierten Ostrogenen.

Estrogen replacement therapy (ERT) appears to markedly reduce the risk of cardiovascular disease in postmenopausal women. There is evidence that estrogen effects on blood coagulation and fibrinolysis are important mediators of this beneficial effect. It is the acute phase reactants such as factor VII (F VII), von Willebrand factor (vWF) and fibrinogen (Fbg) as well as the main inhibitor of the fibrinolytic system, the plasminogen activator inhibitor (PAI 1), which have been shown to be associated with a particular predisposition or poor prognosis of cardiovascular disease. Additionally, the analysis of stabile reaction products of the coagulation cascade allows for an assessment of the loss of endothelial anticoagulant properties, i.e. endothelial injury. We compared the effects of oral versus transdermal ERT on these key parameters of the hemostatic system. 42 postmenopausal women were randomly assigned to receive either a novel transdermal system releasing 50 micrograms 17-beta-estradiol/24 hours or oral therapy with 0.6 mg conjugated estrogens combined with cyclic medrogestone 5 mg on day 11-21 for three treatment cycles. The study was performed according to the criteria of good clinical practise. We observed no adverse effects on the hemostatic system. Particularly, no increase of coagulatory reaction products, i.e. activity was found. Differences between groups were seen with regard to the extent of favourable effects: While the continuous transdermal ERT significantly reduced factor VII activity, oral ERT had no effect. However, oral ERT significantly reduced PAI 1 concentration by 40% suggesting an improved fibrinolytic capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of conjugated estrogens with and without medrogestone: a prospective study.

OBJECTIVE: To study the possible changes in serum lipids and lipoproteins during hormone replacement therapy with special emphasis on the possible effects brought about by the progestogen. DESIGN: Open-label randomized prospective comparative study. SETTING: Gynecological outpatient department of an university hospital. PATIENTS: Thirty-three healthy hysterectomized postmenopausal women. INTERVENTIONS: Continuous oral supplementation with conjugated estrogens, 0.625 mg daily, was administered either alone (group I; N = 18) or in combination with cyclic medrogestone, 5 mg daily during the last 12 days of each 28 days treatment cycle (group II; N = 15). MAIN OUTCOME MEASURE: Changes in serum lipids, lipoproteins and apolipoproteins after three, six and 13 treatment cycles. RESULTS: After 1 year of treatment significant increases were observed in mean high-density lipoprotein (HDL) cholesterol, its subfractions, and apolipoprotein A-I in group I and II: HDL cholesterol: +25.2% and +12.1%, respectively; HDL2 cholesterol: +47.4% and +23.5%, respectively; HDL3 cholesterol: +18.1% and +11.2%, respectively; apolipoprotein A-I: +23.0 and +14.8%, respectively. Comparing the two study groups no significant differences were found in lipid changes during the study period, except for HDL2 cholesterol. CONCLUSION: Supplementation with conjugated estrogens, with and without medrogestone, and given for a longer period, demonstrated a beneficial influence on serum lipoproteins with almost no differences between the two treatment regimens.

A new peroral estrogen/progestin combination for postmenopausal hormonal substitution: an open multicentric field study.

An open prospective multicentric trial has been conducted over 6 months in 241 postmenopausal volunteers. One-hundred forty-one women had an intact uterus. All patients received a fixed peroral combination of conjugated estrogens CE (1.25 mg per day from day 1 to day 21) and medrogestone (5 mg per day from day 12 to day 21) followed by 7 days without substitution (day 22 to day 28). After 3 months of treatment, the managing physician could, according to the patient's clinical response, reduce the dosage of CE to 0.625 mg daily. This dose reduction took place in 79 patients (38.9%). The trial was designed to study efficacy, compliance and side-effects of this combination. Of the patients 68.9% showed a very good, 27.7% a good and 1.9% a satisfactory improvement of their preexisting subjective complaints. Of the patients 28.6% suffered from minor side-effects leading to drop-outs in 7.8% of the cases. Of the women participating in the study 92.2% completed the trial without from the treatment scheme. No serious complications have been noted. After 6 months of treatment, a regular bleeding pattern has been observed in 71.5% of the 144 non-hysterectomized women, an irregular pattern in 9.7% and amenorrhoea in 18.8%. Total cholesterol showed no change, whereas HDL rose significantly from 1.58 to 1.72 mmol/l (P < 0.01) resulting in a drop of Total-Cholesterol-HDL-Ratio of -8.8% (P < 0.01). LDL decreased from 3.71 +/- 1.56 to 3.45 +/- 1.39 (P < 0.05). Considering the two patient groups with and without estrogen reduction after 3 months, HDL increase was significant in both groups but was dose dependent. The HDL increase compared to the initial value was 5.7% with 0.625 mg CE and +10.8% with 1.25 mg CE, respectively. The fixed peroral combination of CE and medrogestone tested was effective, easy to administer and safe. The bleeding pattern observed was mostly regular. The pattern of serum lipids changed favorably in a significant way. Therefore, the use of this new peroral estrogen/progestin combination can be recommended for routine substitution in postmenopausal women.

Effects of medrogestone and conjugated oestrogens on serum lipid and lipoprotein concentrations.

Twenty patients, aged 30-60 yr, who had undergone bilateral ovariectomy, were treated orally with 5 mg medrogestone (6,17-dimethylpregna-4,6-diene-3,20-dione) and 1.25 mg conjugated oestrogens per day, according to a constant dosage pattern during the cycle (22 + 6 days). The lipids and lipoproteins were determined twice before the start of therapy and 3, 6 and 12 mth thereafter. The lipids were quantified enzymatically and the lipoproteins by quantitative lipoprotein electrophoresis. Whilst cholesterol and triglyceride concentrations showed no detectable change, a slight but significant increase was seen in the high-density alphalipoprotein (HDL) cholesterol concentrations. The low-density beta-lipoprotein (LDL) cholesterol level showed a moderate fall. There was a resultant reduction in the beta/alpha-lipoprotein ratio. Accordingly, the apoprotein A1 concentrations were found to be elevated, while apoprotein B tended to fall to lower levels during therapy. When these changes are measured by the lipid metabolism risk criterion for the occurrence of coronary heart disease applicable to post-menopausal patients, the effects of the above-mentioned combination may be regarded as entirely favourable.

[Oral contraceptives: pharmacotherapy of normal women (author's transl)]. / Hormonale Kontrazeption: Pharmakotherapie der gesunden Frau

PIP: Side effects, especially cardiovascular, of oral contraception in healthy women are discussed. A causal relationship between ovulation inhibitors and thromboembolic disease has been demon demonstrated epidemiologically and experimentally. Thrombus formation may be due to disturbances of blood coagulation, lesions, of the vascular wall, or blood flow disorders; the "pill" influences all 3 components. The role of the "pill" in the etiology of hypertension has not been explained, but there is no doubt of its existence. Although the risk to a healthy woman with no predisposing factors is small, it is real, and must be considered by the patient and her physician.^ieng

Medrogestone: a prospective study in the pharmaceutical management of benign prostatic hyperplasia.

Medrogestone is a progestational agent that may reduce outflow obstruction secondary to benign prostatic hyperplasia. Five of 8 patients taking 15 mg. oral medrogestone twice daily and 5 of 7 patients taking 7.5 mg. oral medrogestone twice daily experienced an increase in mean urine flow (averaging 55.8 and 30.1 per cent, respectively), while no change was noted in 4 untreated patients. Five of the 8 patients taking 15 mg. and 6 of the 7 patients taking 7.5 mg. experienced an increase in peak urine flow (averaging 60 and 37.6 per cent, respectively), while 2 of the 4 controls had an improvement of only 12.2 per cent. Repetitive residual urines and digital examination were inaccurate to assay sequential changes in prostatic size. Certain side effects, such as hypertension, abnormal glucose tolerance and impotence, were encountered in isolated patients but in no instance was the side effect hazardous to the health of the test subject and in each instance it could be reversed by withdrawal of the medication.