Plasma estrogens in postmenopausal women

The concentration of plasma estrone and estradiol was measured in different groups of postmenopausal women; including physiologic menopause, castration menopause, and those who in addition to menopause had diabetes, hypertension, or cardiac disease. The mean values for estrone were 41 pg. per milliliter and for estradiol 13 pg. per milliliter. There was no statistical difference in the levels of plasma estrogen in all groups of postmenopausal women studied. In 3 individuals, studies of estrogens in ovarian vein blood suggested a nonovarian origin of estrogen.     

Apoptosis in the endometrium of postmenopausal women receiving tibolone

BACKGROUND/AIM: Tibolone, a synthetic derivative of the 19-nortestosterone family, induces atrophy of the endometrium, especially via its progestogenic Delta(4) isomer. The aim of the study was to determine whether tibolone induces apoptosis in the endometrium of postmenopausal women. METHODS: Twenty healthy postmenopausal women (mean age +/- SD 52.4 +/- 4.21 years) who had amenorrhea for at least 1 year and who had no history of any systemic illness and estrogen replacement therapy were enrolled in the study. All patients were offered office endometrial samplings, and then tibolone was prescribed (2.5 mg/day p.o., once daily) to all patients. Repeat endometrial samples were obtained after completion of the 6-month course of tibolone therapy. All samples were immunohistochemically analyzed for the presence of apoptotic cells. RESULTS: There was no significant difference in the median proportion of apoptotic nuclei between the pre- and posttreatment samples (2 vs. 3%; p > 0.05). CONCLUSIONS: The results showed that tibolone did not affect the rate of apoptosis in the postmenopausal endometrium. Further studies are needed to clarify the role of apoptosis in overall effects of hormonal compounds on the postmenopausal endometrium.     

Effects of tibolone on the breast of postmenopausal women

For decades, hormone therapy (HT) has been the mainstay for managing menopausal symptoms. However, the prolonged use of either single estrogen therapy (ET) or a combination therapy of estrogen and progestogen (EPT) might be associated with a slightly increased risk of breast cancer. Alternative therapies that are effective in the prevention and/or treatment of menopause, having associated morbidities but no unwanted effects, are of primary interest in clinical practice. Tibolone (Livial; NV Organon, Oss, The Netherlands) is structurally related to 19-nortestosterone derivatives and is a new postmenopausal regimen with a unique pharmacological profile, licensed for the relief of climacteric symptoms and the prevention of osteoporosis in postmenopausal women. Tibolone exhibits weak estrogenic, progestogenic, and androgenic activities, which in theory might influence the breast. The effect of tibolone on breast tissue, however, is obscure. The purpose of this study was to assess the effects of tibolone on breast safety, and the collected data include preclinical models, clinical observation, and epidemiologic study. Although in vitro studies showed conflicting results (with the majority being favorable effects) regarding the effects of tibolone on breast cells, in vivo studies showed favorable effects of tibolone on the breast in animal models. Similarly, an epidemiologic study indicated an increased risk of breast cancer when tibolone was used to manage climacteric symptoms of postmenopausal women, but accumulated data obtained from radiologic studies (mammography) showed a possible protective effect of tibolone on the breast. Taken together, we conclude that tibolone, if not superior to conventional HT, may be more acceptable to clinicians as a therapeutic drug option for use with symptomatic menopausal women. Only time will tell whether tibolone will be the preferred option.     

Ovarian production of estrogens in postmenopausal women

We investigated the possible secretory capacity of the ovaries of 79 postmenopausal women with and without endometrial carcinoma using chemical, enzymehistochemical and ultrastructural methods. The mean serum levels of estrone, estradiol and total estrogens were higher in ovarian effluent blood than the corresponding values in cubital venous blood. There was a positive correlation between the difference of total estrogens in ovarian and cubital vein sera and, on the other hand, enzymehistochemical and ultrastructural findings in ovarian tissue. No statistical differences were found in the peripheral mean values of estrone and total estrogens between the two groups. The mean level of estradiol, however, seemed to be higher and that of estriol lower in the carcinoma patients than in the control groups.     

Effects of tibolone on plasma homocysteine levels in postmenopausal women

OBJECTIVE: To investigate the effects of tibolone on levels of plasma homocysteine, an independent risk factor for cardiovascular disorders, in postmenopausal women. DESIGN: Prospective, randomized clinical study. SETTING: University hospital. PATIENT(S): Postmenopausal healthy women. INTERVENTION(S): Tibolone (2.5 mg/d) or calcium (1250 mg/d) and conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (5 mg/d) were administered orally for 6 months. Blood samples were collected at the start and the end of therapy. MAIN OUTCOME MEASURE(S): Plasma homocysteine levels. RESULT(S): Administration of tibolone and calcium caused only a 4% decrease in plasma homocysteine levels compared with initial levels. In contrast, conjugated equine estrogens plus medroxyprogesterone acetate caused a 29% decrease in plasma homocysteine levels. CONCLUSION(S): Despite the reported beneficial effect of tibolone on the serum lipid profile, tibolone had no statistically significant effect on serum homocysteine levels in postmenopausal women. The possible cardiovascular protective role of tibolone might be unrelated to its effects on homocysteine levels.     

Long-term effects of tibolone on ocular functions in postmenopausal women

Hormone replacement therapy has been widely used for the prevention of postmenopausal osteoporosis and treatment of climacteric symptoms for many years, but its effect on ocular functions remains unclear. The aim of the study was to evaluate the long-term effects of tibolone on ocular functions in postmenopausal women. A total of 77 healthy women with at least 1 year of spontaneous menopause were enrolled in the study. Forty women were treated with tibolone for 6 months and 37 women were left untreated. All these patients underwent ophthalmic examination including visual acuity, intraocular pressure (IOP), tear functions, blue-on-yellow and white-on-white Humphrey visual field (HVF), visual evoked potentials (VEP) and electroretinography (ERG). There were significant differences in mean deviation of blue-on-yellow HVF, and oscillatory potentials (O1, O2, and O4) in the ERGs of the chronic tibolone users and the control (P < 0.0001, P = 0.001, P < 0.0001 and 0.05, respectively). However, no significant differences were observed in visual acuity, IOP, tear functions, white-on-white HVF and VEP. We concluded that, although tibolone had no effects on visual acuity, IOP, tear functions and VEP, it might cause some early adverse effects on the electrophysiologic and structural characteristics of the retina, which are detected by these sensitive assays. Randomized placebo-controlled studies with larger groups are needed in future research.     

Long term effects of tibolone on the genital tract in postmenopausal women

Objectives To assess the effects of six years tibolone therapy on the genital tract in postmenopausal women against matched voluntary controls.
Design Prospective, non-randomised, open label study of the efficacy of tibolone.
Methods Symptoms were assessed by questionnaires every six months. Assessment of genital tract cellular activity comprised annual vaginal smear and endometrial biopsy/smear in the tibolone group (   n = 58  ) and vaginal smear alone in the control group (   n = 55  ). As a recent protocol addition, transvaginal ultrasound assessment of endometrial thickness was performed in all women who gave consent. endometrial biopsy was performed in control women if the endometrial thickness was > 5 mm. Karyopyknotic index and maturation index were calculated from the vaginal smears.
Results The rate of amenorrhoea between six months and six years treatment was 90% in the tibolone group compared with 91% in the controls (P was not significant). There was improvement in reported vaginal symptomatology in the treatment group but not in the controls. Median endometrial thickness increased slightly in the tibolone treated group (3.2 mm tibolone vs 2.5 mm control;   P < 0.05  ). There were no cases of cytologically proven endometrial stimulation in asymptomatic women in either group. Both vaginal karyopyknotic index and maturation index increased significantly in the tibolone treated group over six years, but not in the control group.
Conclusions Tibolone is effective at maintaining an inactive endometrium while providing oestrogenisation of the lower genital tract over a six year period.     

Immunoreactive plasma estrogens and vaginal hormone cytology in postmenopausal women

The vaginal hormone cytology and the serum estrogen levels (as determined by radioimmunoassay) of 39 post-menopausal patients were compared. All cytologic parameters showed high statistical correlations with radioimmunoassay values, but these general associations could not be applied to individual patients. A more detailed analysis showed that an atrophic smear (eg, karyopyknotic index [KI], < 10%; parabasal level, > 20%; maturation value [MV], < 40%) indicate estrogen deficiency in the postmenopause. When the KI is 20%-40%, the parabasal cells less than 20% or the MV 40%-60%, the evaluation of estrogen status, on the basis of hormone cytology alone, is indeterminate. The three cytologic indices studied seem much more useful for detecting estrogen deficiency than estrogen excess in the postmenopause. The fact that immunochemical characteristics are not always related to biologic behavior must also be considered when interpreting these findings.     

Long term effects of tibolone on the genital tract in postmenopausal women.

OBJECTIVES: To assess the effects of six years tibolone therapy on the genital tract in postmenopausal women against matched voluntary controls. DESIGN: Prospective, non-randomised, open label study of the efficacy of tibolone. METHODS: Symptoms were assessed by questionnaires every six months. Assessment of genital tract cellular activity comprised annual vaginal smear and endometrial biopsy/smear in the tibolone group (n = 58) and vaginal smear alone in the control group (n = 55). As a recent protocol addition, transvaginal ultrasound assessment of endometrial thickness was performed in all women who gave consent. Endometrial biopsy was performed in control women if the endometrial thickness was > 5 mm. Karyopyknotic index and maturation index were calculated from the vaginal smears. RESULTS: The rate of amenorrhoea between six months and six years treatment was 90% in the tibolone group compared with 91% in the controls (P was not significant). There was improvement in reported vaginal symptomatology in the treatment group but not in the controls. Median endometrial thickness increased slightly in the tibolone treated group (3.2 mm tibolone vs 2.5 mm control; P < 0.05). There were no cases of cytologically proven endometrial stimulation in asymptomatic women in either group. Both vaginal karyopyknotic index and maturation index increased significantly in the tibolone treated group over six years, but not in the control group. CONCLUSIONS: Tibolone is effective at maintaining an inactive endometrium while providing oestrogenisation of the lower genital tract over a six year period.     

Effects of tibolone on plasma levels of nitric oxide in postmenopausal women

OBJECTIVE: To determine the effects of tibolone on nitric oxide (NO) plasma levels in postmenopausal women.DESIGN: Randomized, double-blind, placebo-controlled, cross-over trial.SETTING: Healthy volunteers in an academic research environment.PATIENT(S): Eighteen healthy women who have been in postmenopause for 1-4 years.INTERVENTION(S): Women received either tibolone 2.5 mg/day (group A) or placebo (group B) for 1 month; then the treatment was inverted for the second month.MAIN OUTCOME MEASURE(S): Plasma concentration of NO stable oxidation products and blood pressure were evaluated at baseline, month 1, and month 2.RESULT(S): Baseline concentration of NO metabolites were similar in both groups. At month 1, mean concentration of NO metabolites increased significantly in group A alone. At the end of month 2, NO metabolite levels in group A returned to baseline, whereas in group B they increased significantly.CONCLUSION(S): Tibolone induced a sustained increase in plasma levels of NO in postmenopausal women, suggesting that tibolone may exert a direct cardiovascular protective effect in postmenopausal women.     

结合雌激素对绝经后妇女血液流变学影响的探讨

目的 探讨不同剂量结合雌激素对绝经后妇女血液流变学及临床症状的影响。方法 将66例绝经后妇女分为三组,其中A组每日服用CEE 0.625 mg+ 安宫黄体酮(MPA)2 mg+ 钙尔奇 D 600 mg,B纽每日服用CEE 0.3 mg+MPA 2mg+钙尔奇D 600 mg,C组为对照组,每日单用钙尔奇D 600 mg,观察治疗前后血液流变学及Kupgermn评分的变化。结果 A组血浆粘度、纤维蛋白原明显低于对照组,B组全血高切粘度、低切粘度和血浆粘度明显低于对照组。两组用雌激素后,与自身对照,全血高切粘度和红细胞变形能力均明显改善,两组更年期症状均明显改善,A组阴道出血率54.5％,明显高于B组。结论 结合雌激素加孕激素可以改善绝经后妇女血液流变学指标,每日结合雌激素0.3 mg加安宫黄体酮2 mg与CEE 0.625 mg加MPA 2 mg效果相似。     

Hormone replacement therapy with tibolone: effects on sexual functioning in postmenopausal women

OBJECTIVE: Because hormonal changes in postmenopausal women may be accompanied by sexual problems and a worsening of various aspects of libido, the aim of this study was to assess the effect of tibolone (Liviel(R)) on sexual life. METHODS: Postmenopausal first-time users of hormone replacement therapy (HRT) were included in this open, multicenter study. Patients were treated with tibolone 2.5 mg daily for at least 4 months. Both at baseline and after 4 months of treatment, patients were asked to complete two different questionnaires rating the women's subjective assessment of their sexual problems or desires. RESULTS: One hundred and eighty-four women were enrolled to receive HRT with tibolone. Overall, a significant increase in women's satisfaction with their sexual lives and a significant improvement in different aspects of libido was found. CONCLUSION: Tibolone has beneficial effects on several aspects of sexual life in postmenopausal women. These effects may be due to both an increase in genital blood flow and the central estrogenic/androgenic activity.     

Conjugated estrogens and hypercoagulability.

A group of 11 menopausal women receiving 1.25 mg. of conjugated estrogens daily had coagulation tests to determine the development of hypercoagulability after taking 5 and 21 tablets. There was no essential change in thrombin generation or fibrinolytic activity as measured by euglobin lysis time. There was a shift toward hypercoagulability in all three parameters of the thrombelastograms. The decrease of the antithrombin III activity was not as pronounced following the administration of conjugated estrogens as had been the change associated with oral contraceptives. Fibrin monomers were observed in some women during the first week of Premarin therapy.     

Steady-state pharmacokinetics of conjugated equine estrogens in healthy, postmenopausal women

OBJECTIVE: To determine the steady-state exposure of conjugated and unconjugated estrogen components following oral administration of conjugated equine estrogens (2 0.625-mg tablets). STUDY DESIGN: A prospective, open-label, single-treatment study conducted at 1 clinical site with 12 healthy, postmenopausal women. Each subject received 7 daily doses of 2 conjugated equine estrogen (0.625-mg) tablets, and blood samples were taken on the last day of dosing for pharmacokinetic analysis of estrogen components. RESULTS: The major estrogen components after estrogen dosing (as determined by steady-state plasma concentration-time curves) were estrone (100 ng x h/mL), equilin (43.1 ng x h/mL) and delta8,9-dehydroestrone (13.6 ng x h/mL). Several 17beta-reduced forms of estrogen also had consistent plasma concentrations during a steady-state dosing interval. Mean t(max) values ranged from 6.2 to 9.0 hours after dosing, and the 24-hour profiles of the various plasma estrogen concentrations at steady state showed limited fluctuations. CONCLUSION: Oral dosing of conjugated equine estrogen at steady state resulted in consistent concentrations of estrogen components during a dosing interval.     

Effects of tibolone on thromboxane B(2) levels in postmenopausal women.

This study was carried out in 16 premenopausal (control) and 24 postmenopausal women (study group) to investigate the effect of menopause and tibolone treatment (2.5 mg/day for 6 months) on plasma thromboxane B(2) (TxB(2)), a well-known vasoconstrictor and stimulator of platelet aggregation. The TxB(2) levels were measured using [(125)I] RIA kit. Statistical significance was analyzed by Student's t test for paired and unpaired data, and Pearson's correlation analysis. Plasma TxB(2) concentrations of postmenopausal women were higher than those of premenopausal women. Tibolone treatment decreased plasma TxB(2) in postmenopausal women. There was no correlation between TxB(2) and blood pressure and heart rate. It was concluded that tibolone, decreasing the plasma concentrations of TxB(2), might have beneficial effects on prostaglandin metabolism and thus reduce the risk of cardiovascular disease.