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.     

Influence of vaginal danazol on uterine and brain perfusion during hormonal replacement therapy.

OBJECTIVE: To evaluate the effectiveness of vaginal danazol as progestin supplement to estrogen replacement therapy, and its interference with uterine and carotid artery flow compared with medroxyprogesterone-acetate (MPA), estrogen alone, and placebo. METHODS: Forty healthy women at least 12 months after natural menopause were randomly divided into four treatment groups: Group 1 (n=10), continuous transdermal estradiol (TE) (50 microg/day), plus a monthly 10-day course of MPA (10 mg/day); Group 2 (n=10), continuous TE plus a monthly 10-day course of vaginal danazol (200 mg/day); Group 3 (n=10), TE alone; Group 4 (n=10), placebo. At baseline and during the first, third, and sixth month of treatment, the endometrial thickness was assessed by transvaginal ultrasonography, while the pulsatility index (PI) of the carotid and uterine arteries was assessed by color Doppler. An endometrial biopsy was also performed before and after the treatment. RESULTS: At baseline, no significant differences between ages and other evaluated parameters were present in the four groups. In groups 1, 2, and 3, the values of carotid and uterine PI decreased significantly and similarly during the treatment, while in group 4 they were unchanged. In group 3 only, the endometrium was significantly thicker during treatment than before. No endometrial hyperplasia was present in the four groups at the end of the treatment. CONCLUSIONS: Vaginal danazol seems to be capable of counteracting the mitogenic effect of estrogen on the endometrium without reducing the effectiveness of estrogens to improve peripheral arterial perfusion.     

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.     

Raloxifene therapy does not affect uterine blood flow in postmenopausal women: a transvaginal Doppler study

OBJECTIVE: To monitor the effects of raloxifene therapy on the uterus of postmenopausal women by transvaginal ultrasonography and color flow Doppler. Methods: Twenty-five healthy postmenopausal women were enrolled in this prospective longitudinal study performed at Department of Gynecology and Obstetrics, Faculty of Medicine of Ribeir?o Preto. The patients were treated with raloxifene hydrochloride (60 mg per day) for 6 months. All were submitted to transvaginal ultrasound examination with color flow Doppler (ATL-HDI 3000 equipment) before the beginning and after 1, 3 and 6 months of treatment. Resistance index (RI) and pulsatility index (PI) of the uterine arteries were determined by the Doppler method, being considered as indicators of uterine perfusion. The following variables were analyzed: endometrial thickness, uterine volume, RI, and PI. Data were analyzed statistically by repeated-measures analysis of variance. RESULTS: Before treatment, endometrial thickness was 3.38 +/- 0.73 mm, and similar values were observed after 1, 3 and 6 months of treatment (3.04 +/- 0.82; 3.3 +/- 0.83; and 3.37 +/- 0.79, respectively) (P > 0.05). No significant differences in uterine volume were observed between the pre- and post-treatment periods. Uterine artery perfusion as indicated by RI and PI measured by Doppler also showed no significant variation, with a high impedance flow being maintained throughout treatment. CONCLUSIONS: In the group studied here, raloxifene treatment at the dose of 60 mg per day for 6 months did not induce significant changes in endometrial thickness, uterine volume or uterine artery perfusion, confirming that short-term raloxifene treatment does not affect the uterus of postmenopausal women.     

Doppler velocimetry of the uterine arteries after hysteroscopic rollerball endometrial ablation

The aim of this study was to document the Doppler indices [pulsatility index (PI) and resistance index (RI)] of the uterine arteries in 30 patients who underwent hysteroscopic rollerball endometrial ablation for dysfunctional uterine bleeding by transvaginal pulsed Doppler sonography, and to reveal whether treatment failures (persistent menometrorrhagia) can be predicted by the blood flow characteristics of the uterine arteries in advance. On the basis of the outcome of patients at the end of the first postoperative year, the Doppler indices of the uterine arteries were meaningful 1 year after the operation when PI (1.32 +/- 0.11; mean +/- SD) and RI (0.71 +/- 0.04) in six menometrorrhagic patients were statistically different from PI (2.19 +/- 0.28; 1.95 +/- 0.36 and 1.82 +/- 0.37) and RI (0.87 +/- 0.06; 0.82 +/- 0.06 and 0.81 +/- 0.04) in normally menstruating, amenorrhoeic and hypomenorrhoeic patients respectively (P < 0.05). On the other hand, the patients who would be menometrorrhagic one year after the operation had a thicker endometrium in the first post-operative month. These findings suggest that the angiogenetic role of the persistent endometrial islands after endometrial ablation needs at some time to be reflected as changes in the Doppler parameters of the uterine arteries.      

Endometrial effects of transdermal estradiol/norethisterone acetate.

The efficacy of transdermal norethisterone acetate in sequence with transdermal estradiol has been investigated in a multicenter study of 136 post-menopausal women to determine the incidence of endometrial hyperplasia, the effects on the vaginal cytology and the control of bleeding. Treatment consisted of 12 cycles of 4 weeks each (2 weeks estradiol 50 micrograms/day followed by 2 weeks of a new combined patch delivering norethisterone acetate 0.25 mg/day and estradiol 50 micrograms/day). Endometrial histology was assessed by two pathologists. Of the 136 pre-treatment biopsies 89% provided no material, an inadequate sample or an inactive (atrophic or non-secretory) endometrium. Of the post-treatment biopsies from 110 women who completed the study: 65% showed secretory, 3% proliferative and 24% inadequate material or inactive endometrium. Hyperplasia was found in two biopsies (2%); in one of these focal atypical hyperplasia was agreed by both pathologists, in another a hyperplastic endometrial polyp was diagnosed by one pathologist. The bleeding was regular in 80% of the 1195 cycles and irregular in 11%. No bleeding occurred in 9% of the cycles. Vaginal cytology showed a significant shift towards increased maturation during treatment.     

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.     

Tibolone, oral or transdermal hormone replacement and colour Doppler analysis: a prospective, randomised pilot study

Objective: To compare the plasma thromboxane, the plasma viscosity and the Doppler flow modifications induced by tibolone and by oral or transdermal continuous combined hormone replacement therapy. Methods: Forty-two post-menopausal patients underwent either on: oral daily treatment with tibolone (2.5 mg) (Group I; n=14); or continuous oral administration of 0.625 mg conjugated equine estrogens + medroxyprogesterone 5 mg per day (Group II; n=14); or continuous estradiol transdermal supplementation, at a dose of 50 μg per day, + medroxyprogesterone 5 mg per day (Group III; n=14). The duration of the study was 6 months and the patients were submitted to transvaginal ultrasonographic evaluation of pelvic organs; Doppler analysis of the uterine, internal carotid and ophthalmic arteries; thromboxane and plasma viscosity assays in basal condition, and at 1, 3 and 6 months from the beginning of the study. Results: Although the endometrial thickness increased significantly, there were no cases in which it exceeded the normal range (≤5 mm). In all the three groups, the pulsatility index of the uterine, internal carotid and ophthalmic arteries significantly decreased during the therapy showing a reduced impedance since the first month of treatment. Similar variations were observed for the peak systolic blood flow velocity of the internal carotid and ophthalmic arteries. Hormone replacement therapy and tibolone induced a deep, significant and rapid decrease in plasma thromboxane and plasma viscosity levels. Conclusions: Hormone replacement therapy and tibolone seem to have beneficial effects on vascular and hemorrheological parameters.     

A comparison of effects of sequential transdermal administration versus oral administration of estradiol plus norethisterone acetate on serum NO levels in postmenopausal women

AIM: To compare the effects of sequential transdermal administration versus oral administration of estradiol plus NETA on serum nitric oxide (NO) levels in postmenopausal women (PMW). MATERIALS AND METHODS: Eighty postmenopausal subjects without any prior hormone replacement therapy (HRT) usage were enrolled in this study. All participants were healthy, ambulatory, non-smoker and had similar life styles with dietary habits. HRT was given to participants according to desired HRT administration, in group A (n=50); oral estradiol hemi-hydrate (2 mg)/norethisterone acetate (1 mg), and in group B (n=30); transdermal combined patch comprising estradiol (0.05 mg) alone and estradiol (0.05 mg)/norethisterone acetate (0.25 mg), were given sequential for 12 months. Serum NO levels were studied using Total Oxide Assay Kit (Assay Designs, Inc.) according to manufacturer's instructions prior to and after 12 months from the HRT treatment. RESULTS: The mean serum NO levels prior to the HRT in groups A and B was 0.48+/-0.46 (range, 0.27-0.76 nmol/mL) nmol/mL and 0.47+/-0.48 nmol/mL (range, 0.29-0.693 nmol/mL) (p>0.05). The mean serum NO levels after the HRT in groups A and B was 0.53+/-0.33 nmol/mL (range, 0.29-2.10 nmol/mL) and 2.91+/-0.50 nmol/mL (range, 2.10-3.67 nmol/mL) (p<0.05). A significant difference was found between mean serum NO levels prior to and after the treatment in group B (p<0.05). CONCLUSIONS: Transdermal sequential combined HRT with estradiol hemi-hydrate/NETA was found to be superior to sequential combined oral HRT in increasing serum NO levels.     

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.     

Hormonal replacement regimens and bleeding

Hormone replacement therapy may increase the quality of life of postmenopausal women. Any regimen need to offer long-term endometrial safety. It is a standard to consider the co-administration of a sequential progestogen when estrogen replacement should be initiated in non-hysterectomized women. It is almost impossible to decide which combination of an estrogen and a progestogen seems to be optimal as individual tolerance of HRT may very well limit acceptability despite metabolic benefits and proven endometrial safety of a given combination. Several combinations of oral and transdermal estradiol or conjugated equine estrogens, oral progestogens, transdermal norethisterone acetate and levonorgestrel, and intrauterine levonorgestrel may achieve endometrial safety. It is noteworthy that there is no uniform correlation between the timing of onset of bleeding induced by any sequential estrogen and progestogen replacement and a certain pattern of histology. Therefore, although it is likely, there is no absolute reassurance that regular bleeding on or after day 11 of progestogen administration rules out abnormal histopathology. Transvaginal sonography seems not to be of pivotal importance to screen asymptomatic women on replacement therapy for detection of serious abnormal endometrial findings such as hyperplasia and endometrial cancer. Continuous combined hormone replacement therapy or the use of tibolone may be an alternative in postmenopausal women, who do not want any uterine bleedings after menopause. However, spottings or bleedings most often occur at the beginning of treatment. Vaginal administration of estriol and estradiol for urogenital symptoms of estrogen deficiency may stimulate the endometrium unintentionally. Available data suggest that use of oral estriol may be associated with endometrial hyperplasia and endometrial carcinoma relatively more often compared to sequential HRT. Raloxifene, a benzothiophene derivative acting as a selective estrogen receptor modulator approved for prevention of vertebral osteoporosis, rarely causes uterine bleeding. There is no ideal therapy available to suit women looking for a permanently bleed-free hormonal replacement therapy today.     

Impact of different progestins on endometrial vascularisation of postmenopausal women. A retrospective image analysis-morphometric study

OBJECTIVES: To determine if the vascularisation of the endometrium is dependent on the administered progestin during sequential hormone replacement therapy. METHODS: Nine women received percutaneous estradiol-17 beta, 1.5 mg/day from days 1 to 24 combined with 200 mg/day micronised progesterone from days 11 to 24 of the treatment cycle. Fifteen women received percutaneous estradiol, 1.5 mg/day from days 1 to 24, combined with 10 mg/day chlormadinone acetate from days 11 to 24. Eleven women received percutaneous estradiol, 50 microg/day from days 1 to 28 combined with percutaneous norethisterone acetate, 0.3mg/day form days 14 to 28. Twelve women received intranasal estradiol, 300 microg/day from days 1 to 25 combined with 0.5 mg of promegestone from days 11 to 24. Eleven spontaneous cycling women had an endometrial biopsy during luteal phase and served as controls. Endometrial biopsies were processed routinely between days 18 and 24 and sections were immunostained using anti-CD34 antibody to identify vascular endothelial cells, which were treated with an automatic image analysis system. RESULTS: mean (+/-S.D.) vascular density for controls was 147+/-41.5 vessels/mm(2), with mean vessel area of 143+/-60.9 microm(2). In chlormadinone users endometrial microvascular density and mean vessel area did not differ from the control group (150.2+/-58.6 and 152.9+/-70.5). The other three progestins generated a significant increase of mean vessel density, 179.6+/-51.6 with micronised progesterone, 178.5+/-67.6 with norethisterone and 179.6+/-48.4 with promegestone. The mean vessel area was lower in the latter three groups, respectively, 108.4+/-39.0, 97.5+/-46.5 and 141.6+/-66.7 microm(2), promegestone leading to non significant difference with control. CONCLUSION: regarding vascularisation, chlormadinone and control group gave similar patterns. Promegestone was associated with an increase of the number of vessels, as did micronised progesterone or norethisterone; the mean vascular area was the smallest in the norethisterone group.     

Prevention of postmenopausal bone loss with long-cycle hormone replacement therapy

OBJECTIVE: Postmenopausal bone loss and osteoporotic fractures can be prevented by hormone replacement therapy (HRT). However, opposed HRT may increase the risk of breast cancer above that associated with estrogen alone and in non-hysterectomized women estrogen substitution alone increases the risk of uterine cancer, which triggered renewed interest in long-cycle HRT regimens (estrogen replacement therapy with progesterone-free intervals up to 6 months). The effects on bone of such long-cycle HRT regimens are unknown. The objective of the present study was to compare the effects on bone and the endometrium of long-cycle HRT and conventional HRT. METHODS: Seventy-three healthy non-hysterectomized postmenopausal women were randomized to either conventional HRT (estradiol (E2) 2 mg/d during 12 days, E2 2 mg/d plus 1 mg/d of norethisterone acetate (NETA) during 10 days, E2 1 mg/d for 6 days) or long-cycle HRT treatment (two cycles with E2 2 mg/d during 28 days, followed by one cycle of conventional HRT and repeated every 3 months). Primary endpoint was the change in bone mineral density (BMD) at the lumbar spine (LS) over 24 months. RESULTS: BMD at LS increased significantly versus baseline in both treatment groups (conventional HRT +3.8 +/- 0.6%, long-cycle HRT +3.3 +/- 0.5%, p < 0.0001 for both) with no significant difference between treatment groups over 24 months. Similar significant BMD increases versus baseline were observed at the femoral neck, while biochemical markers of bone turnover (osteocalcin and deoxypyridinoline) were significantly decreased over 24 months. There were no endometrial or breast related adverse events reported. CONCLUSION: Long-cycle HRT may be a valid alternative to conventional HRT with regard to protection against postmenopausal bone loss.     

Carotid and uterine vascular resistance in short-term hormone replacement therapy postmenopausal users

Objective: To compare the short-term effects of oral hormone replacement therapy (HRT) and placebo on carotid and uterine vascular impedance. Methods: 80 postmenopausal women selected from the outpatient clinic of the Hospital Leonor Mendes de Barros in São Paulo, Brazil, were randomized to oral HRT (estradiol 2 mg/norethisterone acetate 1mg—Kliogest^r) or placebo. Carotid and uterine arteries pulsatility indices (PIs) were assessed by color Doppler at baseline, after 4 and 12 weeks of treatment. Seventy-six women completed the trial, 38 in each group. Results: The carotid PI did not decrease significantly in either group. In the uterine arteries, the drop in PI was steeper and greater for HRT women. Drops occurred despite the supposed counteracting effect of norethisterone acetate. In placebo group, there was no significant difference between 4 and 12 weeks of treatment compared with the baseline. The results did not change when analyzed in a real treatment approach. Conclusion: Oral continuous HRT are effective at 12 weeks in reducing impedance to flow in uterine, but not in carotid circulation. These results suggest that the effects of HRT vary by vascular site, and do not have a detectable short-term vascular effect in the carotid area.     

Influence of transdermal estradiol in the regulation of leptin levels of postmenopausal women: a double-blind, placebo-controlled study.

OBJECTIVE: To investigate whether the administration of transdermal estradiol is capable of modifying circulating levels of leptin. DESIGN: Forty postmenopausal women randomly received in a double-blind fashion, a transdermal patch containing either placebo or estradiol (50 microg/day). After 2 months of treatment, they were switched to the alternate treatment for another 2 months. Leptin levels were measured at the end of the placebo and estradiol administration. In a subset of 28 women an evaluation of body composition via bioelectrical impedance and an oral glucose tolerance test (OGTT; 75 g) were also performed at the end of the placebo and estradiol administration. Glucose, insulin, and leptin levels were measured in all OGTT samples. RESULTS: Leptin levels were related directly to body mass index (BMI), fat mass, and insulin, and inversely related to lean mass. In comparison to placebo, transdermal estradiol increased estradiol (from 77.8 +/- 8.4 pmol/l to 183.1 +/- 20.9 pmol/l; p < 0.0001) but did not significantly modify leptin (19.1 +/- 2.4 microg/l vs. 18.6 +/- 2 microg/l) or BMI. Estradiol did not modify fat mass or lean mass, significantly increased intracellular water (31.1 +/- 0.7% vs. 37.2 +/- 2.3%, p < 0.05), and decreased extracellular water (40.5 +/- 0.7% vs. 36.3 +/- 1.7%; p < 0.04). Leptin did not increase during OGTT, but a significant decrease, linearly related to BMI ( r = 0.519; p = 0.0189), was observed at the end of the test. CONCLUSIONS: Low doses of transdermal estradiol exert no influence on fasting leptin levels or BMI. The possibility that different doses of estradiol exert a more pronounced effect on circulating leptin needs to be addressed in comparative studies.     

Lipids and clotting factors during low dose transdermal estradiol/norethisterone use

OBJECTIVE: To demonstrate the effects of 2-year transdermal continuous combined low-dose estradiol (0.025 mg/day) and norethisterone acetate (0.125 mg/day) on lipid/lipoprotein profile and coagulation/fibrinolysis. METHODS: A double-blind, randomized, multicenter, parallel, 1-year trial enrolled 266 healthy women at least 2 years post menopause. Patients received either 0.025 mg estradiol and 0.125 mg norethisterone acetate daily or placebo transdermally. One hundred and thirty five women completed a second year open follow-up (96 had used Estragest TTS, 39 placebo during the first year), where all women had the estradiol/norethisterone patch. Lipid/lipoprotein profile and coagulation/fibrinolysis parameters were studied at 0, 24, 48, 72 and 96 weeks. RESULTS: In women on estradiol/norethisterone total cholesterol, Lp(a) and VLDL cholesterol decreased significantly more than in the placebo group after 24 weeks and LDL cholesterol after 48 weeks. Women on estradiol/norethisterone had no change in HDL, triglycerides or Lp(a), an increased HDL/total cholesterol ratio and decreased LDL, VLDL and total cholesterol at 48 weeks compared to placebo. Women with active treatment also showed a significant reduction compared with the placebo group of Factor VII and antithrombin III at 24 and 48 weeks and a reduction of fibrinogen at 24 weeks. These changes persisted over the second year. CONCLUSIONS: A continuous combined low-dose transdermal patch daily delivering 0.025 mg estradiol and 0.125 mg norethisterone acetate provided beneficial effects on lipid/lipoprotein profile and coagulation/fibrinolysis. The changes were similar to those previously described after higher dose oral and transdermal estrogen/progestogen regimens.     

Endometrial safety of hormone replacement therapy: review of literature

Unopposed estrogens for treating menopausal symptoms were extensively used when epidemiological findings associated them with an increased endometrial cancer risk. Adding progestogens reverse this side effect efficiently but patient, dose, type and especially time during which the progestogen is administered are important. Long-term uterine safety of the long cycle HRT with administration of the progestogen every 3 months remains unclear. Because regular bleeding lowers compliance, continuous combined estrogen-progestogen treatment has become popular. Many different regimens are now available using oral, transdermal, subcutaneous, intravaginal or intra-uterine application of the estrogen and/or progestogen. Available but inadequate studies seem to point towards a slightly decreased endometrial cancer risk with continuous combined preparations compared with non-HRT-users and an increased risk with long-term oral but not vaginal treatment with low-potency estrogen formulations such as estriol. Newer compounds for menopausal health such as tibolone and raloxifene seem to be safe. As for any women with abnormal vaginal bleeding, those on HRT must have an intra-uterine evaluation. Transvaginal ultrasound (TVU) is very accurate in predicting a normal uterine cavity but inaccurate in predicting endometrial pathology because of a low specificity and positive predictive value of a thick echogenic endometrium. In all such cases a three-dimensional visualisation of intra-uterine lesions is more accurate. Periodic examination with TVU and/or endometrial biopsy of HRT exposed endometrium in asymptomatic women is not cost-effective. The available limited data on the use of HRT in hysterectomised women for early stage endometrial cancer show little evidence in terms of recurrence.     

Endometrial safety after 5 years of continuous combined transdermal estrogen and intrauterine levonorgestrel delivery for postmenopausal hormone substitution

OBJECTIVE: To investigate endometrial histology and thickness of the endometrium after long-term use of continuous transdermal estrogen substitution combined with intrauterine release of levonorgestrel (LNG) in postmenopausal women. DESIGN: A 5-year non-comparative prospective clinical trial. SUBJECTS: Out of 182 symptomatic postmenopausal women using estrogen substitution therapy (EST) combined with a novel T-shaped LNG-releasing intrauterine system (Femilis Slim LNG-IUS), to prevent endometrial proliferation and bleeding, only those women (n=102) who used two consecutive LNG-IUSs, were isolated with the aim to study the long-term effects on the endometrium. The mean age of the women was 57 years (range 47-71). The majority of women received percutaneous 17beta estradiol, 1.5mg daily, or an equivalent dose by patch or orally, on a continuous basis. MAIN OUTCOME MEASURES: Endometrial histology and ultrasonographic evidence of endometrial suppression, after a period of approximately 5 years of use. The mean duration of use of the regimen was 70 months (range 25-98). RESULTS: The dominant endometrial histologic picture was that of inactive endometrium characterized by glandular atrophy and stroma decidualization (Kurman classification 5b). No cases of endometrial hyperplasia were found. On transvaginal ultrasound, this corresponds with a thin endometrium (< or = 5 mm). CONCLUSION: The results of this 5-year study in 102 postmenopausal women using EST demonstrates that the LNG-IUS effectively opposes the estrogenic effect on the endometrium resulting in strong suppression during the entire period of EST. Due to its high efficacy and absence of systemic effects on organ tissues (e.g., breasts), target delivery in the uterine cavity could be a preferred route to administer a progestagen in women using EST.     

Uterine findings by transvaginal sonography during percutaneous estrogen treatment in postmenopausal women

Objectives: To evaluate the effect of hormone replacement treatment (HRT) with percutaneous estradiol and cyclical peroral medroxyprogesterone acetate (MPA) every month or every third month on the uterus and endometrium of postmenopausal women. Methods: Uterine size and endometrial thickness were measured by transvaginal sonography in 159 postmenopausal women before HRT, and after 6 and 12 months on HRT during 9–12 days of the MPA administration periods. Results: During HRT, uterine size and endometrial thickness increased. The percentage increase in uterine diameter varied between 3.8% and 19.6%, and endometrial thickness varied between 28.7% and 76.4%, being greater in the group receiving MPA every third month than in the groups receiving MPA every month. Myomas grew during the first 6 months on HRT but increased no further during the next 6 months on HRT. Conclusions: The increases in uterine size, myomas and endometrial thickness during HRT were moderate and not problematic and occurred mainly during the first 6 months on HRT.     

TNFalpha expression in hyperplastic endometrium

PROBLEM: Tumor necrosis factor-alpha (TNFalpha) is produced by the endometrium, and it has been shown that this cytokine has cyclic variations through the menstrual cycle. METHOD OF STUDY: In this study we assessed TNFalpha, estradiol and progesterone levels in the endometrium and serum of 21 patients with recent abnormal uterine bleeding (AUB). Eleven women showed histological diagnosis of endometrial hyperplasia, and ten women showed normal endometrium. RESULTS: The TNFalpha value in the serum of patients with hyperplasia and in normal endometrium did not show significant differences (64.8 +/- 21.4 vs 77.6 +/- 14.8 pg). The amounts of TNFalpha released by hyperplastic endometrial tissue were significantly higher than in control patients (258.8 +/- 78.0 vs 140.6 +/- 79.8 pg/g; P < 0.001). Immunohistochemistry of hyperplastic endometria showed a stronger staining than normal ones. Serum E2 levels in patients with hyperplastic endometrium were 49.5 +/- 31.6 ng/mL, and in controls were 107.3 +/- 66.0 ng/mL. The levels of estradiol released by hyperplastic endometria were significantly lower than in normal endometria (152.7 +/- 60.0 vs 279.9 +/- 178.7 ng/g; P < 0.003). CONCLUSIONS: Hyperplastic endometria produce higher amounts of TNFalpha with respect to controls. These findings may explain the frequent bleeding observed in the patients with endometrial hyperplasia, since TNFalpha promotes apoptosis and endometrial shedding.