Impact on uterine bleeding and endometrial thickness: tibolone compared with continuous combined estradiol and norethisterone acetate replacement therapy

Objective: To evaluate endometrial thickness and the incidence of uterine bleeding in postmenopausal women using either tibolone 2.5 mg or continuous combined 2 mg estradiol and 1 mg norethisterone acetate (E+NETA) daily as hormone replacement therapy. DESIGN: We compared diary records of self-reported uterine bleeding and measurements of endometrial thickness, area, and volume by transvaginal sonography at baseline and after 1, 3, 6, and 12 months in a 1-year, prospective, randomized, double-blind, single-center trial of 100 postmenopausal women aged 46-69 years. Bleeding frequencies and endometrial thickness were assessed by Chi-square tests and analysis of covariance, respectively. RESULTS: Self-reported bleeding was significantly less in the tibolone group. Bleeding episodes were reported by 27.7% of women in the tibolone group and by 59.2% in the E+NETA group. The mean number of days with bleeding was 5.8 +/- 27.0 in the tibolone group and 35.6 +/- 58.6 in the E+NETA group. Six women in the tibolone group and seven in the E+NETA group discontinued the study; three in the E+NETA group because of bleeding. The mean endometrial thickness at baseline was 2.56 +/- 0.81 mm in the tibolone group and 2.58 +/- 1.04 mm in the E+NETA group. After 1 year, the corresponding figures were 3.32 +/- 1.58 mm and 3.07 +/- 1.68 mm. Thus, 86% of women in the tibolone group and 93% in the E+NETA group had an endometrial thickness of less than 5 mm. CONCLUSIONS: Use of tibolone 2.5 mg daily for 1 year was associated with significantly less bleeding and spotting compared with daily continuous combined 2 mg estradiol and 1 mg norethisterone acetate in postmenopausal women in the presence of both minimal and nonprogressive increase of endometrial thickness associated with the two regimens.     

Transvaginal sonographic monitoring of the uterine effects of raloxifene and a continuous combined replacement therapy in postmenopausal women

OBJECTIVE: To study the effect of 17beta-estradiol+norethisterone acetate and raloxifene on the endometrium and uterine volume in postmenopausal women. METHODS: Patients were randomly assigned to 17beta-estradiol 2 mg+norethisterone acetate 1mg (E2+NETA) daily (n=90) or raloxifene HCl 60 mg (Evista) daily (n=43). Transvaginal sonography was done at baseline and at 6, 12 and 18 months, and at 6 and 12 months in-patients treated with E2+NETA and EVISTA respectively. Patients were asked to record bleeding-spotting episodes. Whenever required patients were referred for hysteroscopy+/-biopsy of the endometrium. RESULTS: Patients under E2+NETA had a higher bleeding-spotting incidence (48.6%) compared with EVISTA (7.7%). Endometrial thickness increased significantly under E2+NETA as compared with baseline; however, at end point thickness reverted to baseline values. Evista had a non-stimulatory effect on the endometrium. Changes in uterine volume were not statistically significant. CONCLUSIONS: Both treatment regimens provided comparable uterine safety. However, raloxifene exhibited a more favorable safety profile on the uterus as expressed in the bleeding-spotting incidence and the effect on endometrial thickness and uterine volume. Transvaginal sonography appears to be a dependable method for monitoring the effect of treatment on the uterus.     

Low dose transdermal estradiol/norethisterone acetate treatment over 2 years does not cause endometrial proliferation in postmenopausal women

OBJECTIVE: We investigated the effects of 2-year transdermal continuous combined estradiol (0.025 mg/day) and norethisterone acetate (0.125 mg/day) (Estragest TTS) on bleeding and on the endometrium. DESIGN: This double-blind, randomized, multicenter, parallel, 1-year trial enrolled 266 healthy women at least 2 years past menopause with intact uteri. Patients received a transdermal patch delivering either 0.025 mg estradiol and 0.125 mg norethisterone acetate daily or placebo. Of the 266 women initially included, 135 (96 Estragest TTS, 39 placebo) completed a second year open follow-up, where all women had the estradiol/norethisterone patch. Endometrial biopsies were performed at weeks 0, 48 (n = 171), and 96 (n =109). Effects on endometrial morphology and uterine bleeding were studied. RESULTS: The overall incidence of endometrial hyperplasia after treatment with the estradiol/norethisterone acetate patch for one year was 0.8% with only one case of atypical hyperplasia. There were no clinically significant changes in endometrial thickness in either treatment group. The proportion of bleed-free patients with the estradiol/norethisterone acetate transdermal system increased from 55% in cycles 1-3 to 83% in cycles 10-12. By the 12th cycle, 92% of patients receiving estradiol/norethisterone acetate patches were bleed-free. No additional hyperplasia was seen during the second year follow-up. CONCLUSIONS: A continuous combined transdermal patch delivering 0.025 mg estradiol/day and 0.125 mg norethisterone acetate/day provided good endometrial protection. The dose maintained a consistently high rate of amenorrhea in postmenopausal women.     

Circulating leptin and ghrelin are differentially influenced by estrogen/progestin therapy and raloxifene

BACKGROUND: Leptin and ghrelin are increasingly being recognized as cardiotropic hormones, promoting or inhibiting the atherosclerotic process, respectively. Apoptosis may be one pathway through which the actions of these hormones are mediated. Sex hormones are reported to influence the secretion and action of ghrelin and leptin. OBJECTIVE: To evaluate (1) the association of circulating ghrelin and leptin with selected markers of receptor-mediated apoptosis and (2) the effect of estrogen monotherapy, low dose estrogen-progestin therapy, tibolone and raloxifene on serum ghrelin and leptin in healthy postmenopausal women. METHODS: Eighty eight postmenopausal women aged 44-62 years were randomly allocated to daily (1) conjugated equine estrogens 0.625 mg (CEE), (2) 17beta-estradiol 1mg plus norethisterone acetate 0.5 mg (E(2)/NETA), (3) tibolone 2.5mg, (4) raloxifene HCl 60 mg or (5) no treatment. Serum markers of apoptosis sFas, Fas-ligand (Fas-L) and caspase-1 were measured at baseline. Serum leptin and ghrelin were measured at baseline and at 3 months. RESULTS: Body Mass Index (BMI) and estradiol levels correlated positively, while FSH correlated negatively with serum leptin (BMI: r=0.646, p=0.005, estradiol: r=0.432, p=0.001, FSH: r=-0.401, p=0.002). Insulin levels associated positively with circulating leptin (r=0.394, p=0.011) and negatively with circulating ghrelin (r=-0.401, p=0.009). Serum leptin decreased significantly in E2/NETA group (baseline: 2.882+/-0.76 ng/ml, 3 months: 2.687+/-0.66 ng/ml, p=0.043), while it increased significantly in the raloxifene group (baseline: 2.671+/-0.54 ng/ml, 3 months: 2.839+/-0.47 ng/ml). Ghrelin levels decreased significantly only in the raloxifene group (baseline: 1634+/-592 pg/ml, 3 months: 1408+/-534 pg/ml). CONCLUSION: Apoptosis may be a pathway through which leptin exerts a pro-atherogenic effect. Low dose HT may act cardioprotectively by decreasing leptin levels in healthy recently menopaused women.     

Endometrial response to raloxifene compared with placebo, cyclical hormone replacement therapy, and unopposed estrogen in postmenopausal women.

OBJECTIVE: To determine the endometrial effects of raloxifene 60 mg/day in postmenopausal women as assessed by vaginal bleeding and endometrial thickness. DESIGN: Data from 1157 postmenopausal women were analyzed from a database consisting of four independent, double-blind, randomized, placebo-controlled trials (range = 6-30 months duration), a 24-month open-label randomized, cyclical hormone replacement therapy (HRT)-controlled trial, and a 6-month double-blind, randomized, unopposed estrogen-controlled trial. Vaginal bleeding rate was derived from self-reported adverse events collected at least every 6 months. Endometrial thickness was measured by ultrasonography at regular intervals. RESULTS: Raloxifene 60 mg/day was not significantly different from placebo with regard to the incidence of vaginal bleeding, the baseline-to-endpoint change in endometrial thickness, or the proportion of women experiencing an increase in endometrial thickness above baseline after either 12 or 24 months of therapy. Unexpected bleeding was reported significantly more frequently in the unopposed estrogen groups compared with the raloxifene group (raloxifene 60 mg/day, 0% versus estrogen, 50%; p = 0.002). A significantly greater baseline-to-endpoint increase in endometrial thickness was observed in both the HRT and estrogen groups compared with their respective raloxifene comparison group (raloxifene 60 mg/day, 0.01 +/- 2.0 mm versus HRT, 1.8 +/- 3.2; p < 0.001; raloxifene 60 mg/day, 1.1 +/- 1.7 mm versus estrogen, 7.8 +/- 3.8; p < 0.001). No cases of endometrial hyperplasia or cancer were diagnosed in the placebo or raloxifene 60 mg/day groups. Endometrial hyperplasia was diagnosed in one case in the HRT group and in two cases in the estrogen group. CONCLUSION: Raloxifene 60 mg/day for up to 30 months is not associated with vaginal bleeding or increased endometrial thickness in postmenopausal women.     

Serum androgen levels and insulin resistance in postmenopausal women: association with hormone therapy, tibolone and raloxifene

OBJECTIVE: To assess endogenous androgen and insulin resistance status in postmenopausal women receiving continuous combined hormone therapy (HT), tibolone, raloxifene or no therapy. METHODS: A total of 427 postmenopausal women aged 42-71 years were studied in a cross-sectional design. Among them 84 were taking HT (46 women conjugated equine estrogens 0.625 mg; medroxyprogesterone acetate, 5 mg, CEE/MPA; and 38 women 17beta-estradiol 2 mg; norethisterone acetate 1 mg, E2/NETA); 83 were taking tibolone 2.5 mg; 50 were taking raloxifene HCl 60 mg; and 210 women were not receiving any therapy. Main outcome measures were FSH, LH, estradiol, total testosterone, SHBG, free androgen index (FAI), Delta4-Androstendione (Delta4-A), Dehydroepiandrosterone sulphate (DHEAS) and HOMA insulin resistance index (HOMA-IR). RESULTS: In women not on hormone therapy smoking and older age was associated with lower DHEAS levels. FAI values increased linearly with increasing BMI. Age and BMI were positive determinants of HOMA-IR, while no association was identified between endogenous sex steroids and insulin resistance. CEE/MPA therapy was associated with higher SHBG, lower FAI and lower HOMA-IR values compared to women not on therapy (age and BMI-adjusted SHBG: CEE/MPA 148.8 nmol/l, controls 58.7 nmol/l, p < 0.01; age-adjusted FAI: CEE/MPA 0.8, controls 3.2, p < 0.05; age-adjusted HOMA-IR: CEE/MPA 1.3, controls 2.6, p < 0.05). On the contrary, E2/NETA treatment had no effect on these parameters. Women on tibolone had lower SHBG, higher FAI and similar HOMA-IR values compared to controls (age and BMI-adjusted SHBG: 24.1 nmol/l, p < 0.01; FAI: 6.0, p < 0.05; HOMA-IR: 2.3, p = NS). Raloxifene users did not exhibit any difference with respect to sex steroids and HOMA-IR levels. CONCLUSIONS: CEE/MPA users had lower free testosterone and improved insulin sensitivity. Tibolone on the other hand associated with higher free testosterone, while raloxifene did not relate to any of these parameters.     

Conventional-dose hormone therapy (HT) and tibolone, but not low-dose HT and raloxifene, increase markers of activated coagulation

OBJECTIVES: Hormone therapy (HT) is associated with a modest, but significantly increased risk for arterial and venous thromboembolism. We have compared the effects of estrogen, tibolone, and raloxifene on relevant markers of coagulation activation and investigated whether there is a dose-response relationship of oral HT. METHODS: Randomized, open-label, comparative study of 202 healthy women who were assigned to receive treatment for 12 weeks with either low-dose hormone therapy containing 1 mg 17beta-estradiol + 0.5 mg norethisterone acetate (NETA) (n=50), conventional-dose HT containing 2 mg 17beta-estradiol and 1 mg NETA (n=50), 2.5 mg tibolone (n=51), or 60 mg raloxifene (n=51). RESULTS: The groups were comparable with regard to demographic characteristics and laboratory variables at baseline. D-dimer increased markedly in the conventional-dose HT group, but remained unchanged in the low-dose HT group. Tibolone was associated with a medium increase, whereas raloxifene was associated with a decrease in D-dimer levels. Changes in prothrombin fragment 1 + 2 showed a similar pattern for all four groups, whereas no significant differences in changes of thrombin-antithrombin complex were observed. CONCLUSIONS: Our data suggest that low-dose HT is associated with less activation of coagulation than conventional-dose HT. This finding may be of clinical importance since randomized clinical trials showing increased risk of thrombosis have utilized conventional-dose HT.     

Regression of endometrial thickness in combination with reduced withdrawal bleeding as a progestational effect of tibolone in postmenopausal women on oestrogen replacment therapy

For 176 postmenopausal women on HRT with progestogen addition ‘on demand’ medroxyprogesterone acetate (MPA), noresthisterone and tibolone were used to protect the endometrium in 214 cases. Tibolone is a gonadomimetic steroid with combined progestogenic and estrogenic effects. In this study tibolone has been used as a progestogen. The results of these three progestogens were compared. The endometrial thickness before and after the use of progestogen was determined by vaginosonography. In 175 out of 214 cases progestogen addition during oestrogen therapy caused endometrial regression. Withdrawal bleeding was observed 166 times. If the endometrial thickness on the onset of progestogen addition was 5 mm or more, in nearly all cases withdrawal bleeding occurred when MPA or norethisterone was used. If tibolone was used, no withdrawal bleeding occurred in over half the cases studied. We report the first observation of induced endometrial regression without withdrawal bleeding.     

Effects of genistein on hot flushes in early postmenopausal women: a randomized, double-blind EPT- and placebo-controlled study

OBJECTIVE: We evaluated and compared the effects of the phytoestrogen genistein, estrogen-progestogen therapy (EPT), and placebo on hot flushes and endometrial thickness in postmenopausal women. DESIGN: Ninety healthy, postmenopausal women, 47 to 57 years of age, were randomly assigned to receive for 1 year continuous EPT (n = 30; 1 mg 17beta-estradiol combined with 0.5 mg norethisterone acetate), the phytoestrogen genistein (n = 30; 54 mg/day), or placebo (n = 30). Endometrial safety was evaluated by intravaginal ultrasounds at baseline, 6 and 12 months. RESULTS: By comparison with placebo, daily flushes reduced significantly by a mean of 22% (95% CI: -38 to -6.2; P < 0.01) after 3 months, by a mean of 29% (95% CI: -45 to -13; P < 0.001) after 6 months, and by a mean of 24% (95% CI: -43 to -5; P < 0.01) after 12 months of genistein treatment. Flush score decreased by a mean of 53% (95% CI: -79 to -26; P < 0.001) after 3 months, by a mean of 56% (95% CI: -83 to -28; P < 0.001) after 6 months, and by a mean of 54% (95% CI: -74 to -33; P < 0.001) after 12 months of EPT, as compared with placebo. No side effect was observed on the uterus of the participants. CONCLUSIONS: The present study confirms that genistein might have positive effects on hot flushes without a negative impact on endometrial thickness and suggests a future role of this phytoestrogen as a strategically therapeutic alternative in the management of postmenopausal symptoms.     

Bleeding patterns during continuous estradiol with different sequential progestogens therapy

OBJECTIVE:: To evaluate the effects on monthly bleeding of four different progestogens administered in association with transdermal estradiol in a continuous sequential estrogen-progestin therapy (CS-EPT). DESIGN:: This prospective, open, randomized, clinical trial included 100 healthy postmenopausal women. Patients were randomized into four treatment groups, each consisting of 25 women. Treatment consisted of 50 mug/day transdermal 17beta-estradiol for all women combined to receive four different progestogens (group A: medroxyprogesterone acetate, 10 mg/day; group B: nomegestrol acetate, 5 mg/day; group C: dydrogesterone, 10 mg/day; group D: micronized progesterone, 200 mg/day) per os from the 14th to 25th day of each 28-day cycle. The duration of treatment was 12 cycles. Patients were asked to record in a daily diary the occurrence of any vaginal bleeding, the days of application of each patch, the days of assumption of the different progestogens, and the exact moment of bleeding onset. RESULTS:: A total of 937 cycles could be evaluated. In 690 cycles (73.6%), regular progestogen-related bleeding was reported. Among the other cycles, we observed 73 episodes of amenorrhea (7.8%, each one lasting one cycle), 78 episodes of irregular bleeding (8.3%), and 96 episodes of spotting (10.2%). Patients receiving nomegestrol acetate had a significantly higher incidence of regular progestogen-associated bleeding in comparison with those receiving medroxyprogesterone acetate or natural progesterone, and patients receiving dydrogesterone had a significantly higher incidence of regular progestogen-associated bleeding in comparison with those receiving natural progesterone. CONCLUSION:: Our data suggest that CS-EPT generally leads to regular withdrawal bleeding in women without uterine pathology. Micronized progesterone seems to induce more irregular bleeding episodes.     

Comparative effects of tibolone and conjugated equine estrogens with and without medroxyprogesterone acetate on the reproductive tract of female cynomolgus monkeys

OBJECTIVE: To measure the effects of 2 years' treatment with tibolone on the reproductive tract of female monkeys (Macaca fascicularis) in comparison with conventional hormone replacement therapy. DESIGN: Ovariectomized adult female monkeys were randomized for 2 years of treatment into five groups: controls (n = 31); tibolone at 0.05 mg/kg (LoTIB group; n = 30); tibolone at 0.2 mg/kg (HiTIB group; n = 31); conjugated equine estrogens (CEE) at 0.042 mg/kg (CEE group; n = 28); or CEE + medroxyprogesterone acetate (MPA) at 0.167 mg/kg (CEE + MPA group; n = 29). Endpoints included vaginal cytology; uterine weight; histopathologic evaluation of the uterus, vagina, and cervix; histomorphometry of the endometrium; and immunohistochemical detection of the proliferation marker Ki67 and progesterone receptor in endometrial tissue. RESULTS: Endometrial atrophy was found in 29 of 30 and 23 of 31 animals in the LoTIB and HiTIB groups, respectively, compared with 0 of 28 and 11 of 29 in the CEE and CEE + MPA groups, respectively. All ovariectomized control animals had atrophic endometria. No complex or atypical hyperplasia was seen. Simple endometrial hyperplasia of a significant degree was seen in 3 of 31 HiTIB-treated animals, 1 of 30 LoTIB-treated animals, 26 of 28 CEE-treated animals, and 16 of 29 CEE + MPA-treated animals, and in none of the control animals. Marked simple endometrial hyperplasia and Ki-67 expression was induced by CEE and partially antagonized by MPA. LoTIB and HiTIB slightly increased endometrial thickness, whereas CEE and CEE + MPA induced a marked increase of 350% and 200%, respectively. Neither LoTIB nor HiTIB increased endometrial proliferation (Ki67 labeling) or induced vaginal keratinization. Endometrial bleeding was not seen in tibolone-treated animals but was present in 10 of 29 animals given CEE + MPA. CONCLUSIONS: The effect of tibolone on the uterus and lower reproductive tract was minimal. The lack of a proliferative response of the endometrium to tibolone, coupled with the lower incidence of endometrial bleeding, suggests that tibolone may have advantages over CEE and CEE + MPA regarding endometrial safety and efficacy.     

The effect of raloxifene and tibolone on the uterine blood flow and endometrial thickness: a transvaginal Doppler study

OBJECTIVES: To evaluate and compare the effect of different than classical hormone therapy medications, such as raloxifene and tibolone, on the uterine arteries and endometrium of postmenopausal women using transvaginal ultrasonography. METHODS: The prospective study included 62 healthy, postmenopausal women recruited from the Menopausal Clinic of the 2nd Department of Obstetrics and Gynecology of the University of Athens. Subjects were randomly allocated to receive raloxifene HCl in a daily dose of 60 mg orally (Group A-31 women) or tibolone in a daily dose of 2.5 mg orally (Group B-31 women). The study period was 6 months and all subjects were assessed using transvaginal ultrasonography before treatment initiation as well as after 3 and 6 months for evaluation of the endometrial thickness and the pulsatility (PI) and resistance (RI) indices at the level of the uterine arteries. RESULTS: No significant differences in RI, PI and endometrial thickness were observed in the raloxifene group during the 6-month treatment. In the tibolone group, PI and RI values decreased linearly from baseline to the end of the study, whereas the endometrial thickness was significantly increased during the first 3 months remaining unaltered thereafter. Comparisons between the two study groups revealed significant percent change of values in the pre-treatment to month-3 period and no difference with regard to pre-treatment, month-3 and month-6 absolute values. CONCLUSION: Raloxifene and tibolone exert dissimilar effects on uterine blood supply parameters and endometrial thickness.     

Effects of tibolone and combined 17beta-estradiol and norethisterone acetate on serum C-reactive protein in healthy post-menopausal women: a randomized trial

BACKGROUND: Serum C-reactive protein (CRP) is an independent risk factor for the development of cardiovascular diseases in healthy post-menopausal women. Oral unopposed and progestin-combined 17beta-estradiol (E(2)) increase serum CRP in post-menopausal women. The aim of this study was to compare the effects of tibolone, a steroid with estrogenic, androgenic or progestogenic properties, with a combination of E(2) and norethisterone acetate (E(2) + NETA) on serum CRP levels in healthy post-menopausal women. METHODS: A total of 139 post-menopausal women (mean age: 55 years, range 44-48) was randomly assigned to receive tibolone 1.25 mg/day (n = 52), tibolone 2.5 mg/day (n = 39) or E(2) 2 mg/day plus NETA 1 mg/day (n = 48) for 2 years. Serum CRP was measured at baseline and at 6, 12 and 24 months. RESULTS: Both doses of tibolone and E(2) + NETA increased serum CRP by a similar extent as soon as 6 months with a sustained effect over the 24 month treatment period. For example, after 6 months of treatment, serum CRP increased by a median of +106% (P < 0.001), +89% (P < 0.05) and +139% (P < 0.001) for tibolone 1.25 mg/day, tibolone 2.5 mg/day and E(2) + NETA respectively. CONCLUSIONS: Tibolone and E(2) + NETA significantly increase serum CRP levels in healthy post-menopausal women to a comparable extent. Relationships between induced elevated CRP levels with tibolone and E(2) + NETA and cardiovascular events require further studies.     

One-year endometrial safety evaluation of a continuous combined transdermal matrix patch delivering low-dose estradiol-norethisterone acetate in postmenopausal women

OBJECTIVE: To evaluate the safety and endometrial protection of low-dose transdermal estradiol (E2)/norethisterone acetate (NETA) patches (Estalis 25/125) in terms of post-treatment incidence of endometrial hyperplasia/cancer after 1 year of treatment in postmenopausal women with intact uteri. METHODS: Patients were randomized to receive either transdermal E2/NETA (delivering daily doses of E2 25 microg and NETA 125 microg; applied every 3-4 days) or oral E2/NETA (E2 1mg and NETA 0.5 mg; given daily) in this open-label study. The primary variable was the incidence of endometrial hyperplasia/cancer based on endometrial biopsies; secondary variables included vaginal bleeding/spotting patterns, patch adhesion, safety and tolerability. RESULTS: Six hundred and seventy-seven patients were randomized (507 in the transdermal group and 169 in the oral group; one did not receive study drug) and >80% completed the study. There were no cases of endometrial hyperplasia or cancer in either group and the upper limit of the one-sided 95% confidence interval in the transdermal group was 0.85%. Over time, both treatments were associated with a decreasing frequency of spotting/bleeding days. The overall incidence of adverse events (AEs) was comparable in both groups, and the majority was mild-to-moderate in intensity. Breast tenderness was the most frequently reported AE (transdermal 19.9% versus oral 28.4%). AEs related to the gastrointestinal system were more frequent with oral E2/NETA, and episodes of spotting and bleeding were more frequent with transdermal E2/NETA. Local skin tolerability of the transdermal matrix system was good. CONCLUSIONS: Transdermal E2/NETA (25 and 125 microg) provided adequate endometrial protection in postmenopausal women when evaluated according to CPMP/CHMP criteria, achieved a high rate of amenorrhea, and was well tolerated.     

Endometrial safety and bleeding pattern during a five-year treatment with long-cycle hormone therapy

OBJECTIVE: To determine compliance, the incidence of untoward effects, and endometrial safety in postmenopausal women treated with 3-month sequential hormone therapy for up to 5 years. DESIGN: A prospective, uncontrolled multicenter study of 129 women treated with 0.625 mg conjugated estrogens daily plus 10 mg medroxyprogesterone acetate for 14 days every third month. Endometrial biopsy samples were taken before the initiation of the study and then yearly during the next 5 years. Bleeding patterns were recorded. RESULTS: Upon completion of the first 12 months of treatment, 76 of 126 biopsied women (60%) had secretory endometrium. After 5 years, this finding was reversed in biopsy specimens completed by 59 women, among whom 32 (56%) had insufficient or atrophic endometrium. We did not find any hyperplasia when the biopsy specimen was taken according to the protocol. One endometrial cancer was found by biopsy after 12 months, but the subsequent hysterectomy showed no sign of cancer. Ultrasound determinations of mean endometrial thickness during therapy showed a thin endometrium (mean = 4 mm, range = 1-13 mm). Amenorrhea was reported by 6.2% of 129 women after 12 months of treatment. Among the 59 women who completed the study, 71.2% had regular bleeding patterns every third month, 25.4% reported amenorrhea, and 3.4% had irregular bleeding patterns. CONCLUSIONS: The addition of 10 mg of medroxyprogesterone acetate for 14 days every third month to treatment with 0.625 mg of conjugated estrogens daily was well tolerated, and was associated with high endometrial safety.     

A novel statistical approach to analysis of bleeding patterns during continuous hormone replacement therapy

Previous studies have shown that continuous oral oestrogen-progestogen therapy, which is a relatively new treatment regimen, does not induce endometrial hyperstimulation. However, bleeding disturbances are common during the early months of therapy and in the present study we used both conventional methods of statistical analysis and a stochastic model to describe the bleeding patterns. Four groups of 15 post-menopausal women were given different oral formulations continuously for 1 yr. The oestrogen component in all cases was 2 mg 17 beta-estradiol. The progestogen used was norethisterone acetate at a dose of either 1 mg or 0.5 mg (Groups A and B) or megestrol acetate at a dose of either 5 mg and 2.5 mg (Groups C and D). Each woman kept a daily record of all bleeding episodes, 80% of which occurred during the first 4 mth of therapy. Analysis of variance showed that the high doses of the two progestogens were associated with less spotting and menstrual-like bleeding than the low doses. Stochastic analysis of the bleeding data confirmed that women on the high progestogen doses experienced fewer bleeding episodes than those on the low doses. It also showed that women receiving the high progestogen doses who weighed under 67 kg or had had their last menstruation over 5 yr previously bled less than the other women in the high-dose groups.     

Absent correlation between vaginal bleeding and oestradiol levels or endometrial morphology during tibolone use in early postmenopausal women

OBJECTIVE: To investigate a potential correlation between vaginal bleeding and oestradiol (E2) levels/endometrial morphology in early postmenopausal women using tibolone (Livial(R)). METHODS: A 2-year randomised placebo-controlled study of 94 healthy women, 1-3 years after spontaneous menopause, receiving either placebo (n=23), 1.25 mg/day (n=36) or 2.5 mg/day (n=35) tibolone. Episodes of vaginal bleeding throughout the 2-year study period were recorded. Age, age of menopause, months since menopause and body mass index were recorded. Serum E2 levels were assessed at baseline and at 3-month intervals throughout the study period. In case of vaginal bleeding, endometrium morphology was assessed by Vabra Curettage. RESULTS: Fifty-one percent (n=18, P<0.05) of women in the 2.5 mg/day tibolone group and 44% (n=16, P=0.07) in the 1.25 mg/day tibolone group presented with at least one period of vaginal bleeding, compared with 22% (n=5) in the placebo group. The women who bled in the placebo group were younger (P<0.01), had menopause at an earlier age (P<0.05), had a shorter duration since menopause (P<0.05) and had a higher median E2 serum level prior to bleeding (P<0.05). In contrast, in both tibolone groups, no determinants could be found for the vaginal bleeding. Ninety percent of the first bleedings occurred within 9 months after starting the treatment. At Vabra endometrium sampling, there was no evidence of endometrial stimulation. CONCLUSIONS: In the present study, early postmenopausal women using 1.25 or 2.5 mg/day tibolone are 2-2.5 times more likely to present with vaginal bleeding compared with placebo (P<0.05) without evidence of higher serum E2 levels or endometrial stimulation.     

Prevention of osteoporosis and uterine effects in postmenopausal women taking raloxifene for 5 years

OBJECTIVE: Raloxifene hydrochloride (60 mg/day) is a selective estrogen receptor modulator indicated for the prevention and treatment of postmenopausal osteoporosis. Raloxifene treatment for 3 years increases bone mineral density (BMD) and, unlike tamoxifen (a triphenylethylene selective estrogen receptor modulator), does not stimulate the endometrium in healthy postmenopausal women. The effect of longer duration of treatment with raloxifene is not known. Therefore, the main objectives of these analyses are (1) to compare the effect of 5 years of treatment with raloxifene (60 mg/day) with placebo in terms of the likelihood of developing osteoporosis and (2) to evaluate the effect of 5 years of raloxifene treatment on the endometrium and incidence of vaginal bleeding. DESIGN: The current analyses include integrated data from two identically designed, prospective, double-blinded trials including postmenopausal women (mean age, 55 years) randomly assigned to either placebo (n = 143) or raloxifene (60 mg/day; n = 185). Osteoporosis and osteopenia were diagnosed according to World Health Organization criteria, using the manufacturer's database for the lumbar spine and the National Health and Nutrition Examination Survey's 1998 reference base for the hip. Endometrial thickness was determined using transvaginal ultrasonography. Clinical diagnoses of endometrial hyperplasia or endometrial cancer were confirmed by blinded review of histopathology reports. RESULTS: Compared with the case of placebo, raloxifene treatment for 5 years reduced bone turnover markers (osteocalcin: -10.9%, P < 0.001; bone-specific alkaline phosphatase: -7.2%, P = 0.042; urinary C-telopeptide: -11.1%, P = 0.034) and was associated with increased BMD in the lumbar spine (2.8%; P < 0.001) and total hip BMD (2.6%; P < 0.001). Women taking raloxifene were less likely to develop osteoporosis (relative risk [RR] for raloxifene v placebo: 0.13; 95% CI: 0.00, 0.37; P = 0.001) or osteopenia (RR: 0.23; 95% CI: 0.00, 0.81; P = 0.038) at the lumbar spine and were more likely to convert to normal BMD status at the lumbar spine (RR: 4.01; 95% CI: 1.34, 11.23; P = 0.043) and total hip (RR: 3.92; 95% CI: 1.12,14.27; P = 0.011) at 5 years, compared with the case of placebo. Raloxifene also significantly reduced total cholesterol (-5.5%; P < 0.001) and low-density lipoprotein cholesterol (-8.7%; P < 0.001), compared with the case of placebo. No significant changes in high-density lipoprotein cholesterol (P = 0.257) or triglycerides (P = 0.620) were detected. Incidence of hot flashes was higher among women taking raloxifene compared with those taking placebo [raloxifene, 47 (28.8%); placebo, 21 (16.8%); P = 0.017]. Women taking placebo or raloxifene reported a similar incidence of vaginal bleeding (P = 0.999) or of mean endometrial thickness of more than 5 mm at baseline and at each visit, up to the 5-year endpoint (P >/= 0.349). No diagnoses of endometrial hyperplasia or endometrial cancer were made in either treatment group. CONCLUSIONS: Five years of raloxifene treatment in healthy postmenopausal women preserves BMD, significantly reduces the likelihood of development of osteoporosis, and was not associated with an increased rate of vaginal bleeding, endometrial hyperplasia, or endometrial carcinoma, compared with the case of placebo.     

Pilot study to evaluate a new regimen to treat climacteric complaints with cyclic combined oestradiol valerate/medroxyprogesterone acetate

Nineteen post-menopausal women suffering from climacteric complaints were treated with a cyclic regimen comprising 25 days on 2 mg oestradiol valerate and 5 mg medroxyprogesterone acetate daily, followed by a 5-day treatment-free interval. The mean duration of treatment was 20.2 mth. Control of bleeding was good; 9 women had slight monthly bleeding, 8 no bleeding at all, and 2 had only irregular spotting during the follow-up period. An endometrial biopsy was taken in 9 'women in whom the mean duration of treatment was 30 mth. All endometrial biopsies showed an atrophic endometrium. A larger, randomized comparative study is now planned.     

Clitoral circulation in postmenopausal women with sexual dysfunction: a pilot randomized study with hormone therapy

OBJECTIVE: The aim of the present pilot, randomized, study was to assess hemodynamic status of clitoral erectile tissues in postmenopausal women reporting female sexual dysfunction (FSD), namely libido and arousal disorders, under hormone therapy (HT). Vaginal health and sexual function were also investigated. STUDY DESIGN: Fifty patients presenting for clinical evaluation of menopausal status and suffering from FSD were randomly assigned to receive tibolone (2.5 mg) or 1 mg 17beta-estradiol .5 mg NETA (EPT) for 6 months. The observational period lasted 7 months during which women underwent to duplex Doppler ultrasonography to obtain clitoral hemodynamic data, were evaluated by using the vaginal health score index (VHIS) and filled in the two-factor Italian McCoy female sexuality questionnaire (MFSQ). RESULTS: Tibolone significantly increased clitoral peak systolic and end diastolic velocity (p<.001 for both), while no significant difference was evident in clitoral circulation of women under EPT at the end of the study. Both tibolone and EPT significantly increased VHIS (p<.001), an effect already evident following 3 months of HT. The atrophic state was significantly improved at 6 months (p<.001) with no significant differences between the two HT regimens. After 3 months, both tibolone and EPT significantly increased the sexuality score (p<.001, for both), but such an effect was significantly more pronounced in FSD women treated with tibolone in comparison with those assuming EPT (p<.002). Between the 3rd and the 6th month, tibolone caused a further significant improvement of sexuality score (p<.001), while women under EPT did not show any significant further change displaying a lower score (p<.001) at the end of the study in comparison with women assuming tibolone. CONCLUSIONS: Clitoral circulation in postmenopausal women reporting FSD is significantly increased under tibolone in comparison with EPT with a better improvement of sexual function, as measured by MFSQ, following 6 months of treatment.