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.     

Can climacteric women self-adjust therapeutic estrogen doses using symptoms as markers ?

Objectives: To investigate if disappearance of climacteric symptoms during hormone replacement therapy (HRT) also means good therapeutic level of serum estradiol. The study group comprised of 32 postmenopausal women who had frequent climacteric symptoms. Methods: The women increased the daily treatment doses of percutaneous estradiol every 2 weeks until they felt comfortable with it. Each woman continued at that treatment dose for up to 3 months. Blood samples for estradiol assay were drawn at baseline, every time before the estradiol dosage was increased and at the end of the study. Climacteric symptoms were scored according to the Kupperman menopausal index. Results: Despite the relief of climacteric symptoms, serum estradiol concentration was at a menopausal level (<50 pg/ml) in 22% of the women. In all, 45% of the subjects showed serum estradiol remaining under 60 pg/ml, 29% of the women showed levels of 60–100 pg/ml and 26% showed serum estradiol concentration more than 100 pg/ml. Conclusions: The disappearence of climacteric symptoms during HRT does not quarantee that estrogen levels are sufficiently high for obtaining long term benefits of HRT.     

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.     

Hysteroscopic findings in postmenopausal abnormal uterine bleeding: a comparison between HRT users and non-users

Objectives: The aim of our study was to investigate hysteroscopic findings in a sample of 410 menopausal women (hormonal replacement therapy, HRT users n=219 and HRT non-users n=191) and to evaluate the relationship between the presence of intrauterine disease, the use of HRT and the presence of AUB. Methods: Two hundred and nineteen women on HRT underwent standard office hysteroscopy by means of the Hamou hysteroscope (in 94 cases for abnormal uterine bleeding (AUB) and in 125 cases for periodic endometrium monitoring). One hundred and ninety-one women who had never received HRT were submitted to office hysteroscopy (154 for AUB and 37 for other reasons). Results: Intrauterine diseases are more frequent in patients who do not use HRT (P=0.02). Endometrial polyps is a frequent disease present in 30% of the sample (23.7% of HRT users and 30.8% of HRT non-users). Myomas were present in 8.7% of all patients examined (6.8% of HRT users and 11% of HRT non-users). Irregular bleeding in menopause is often associated with endouterine abnormalities: in symptomatic patients the frequency of endouterine diseases was 41% while in asymptomatic patients was 28% (P=0.003). In patients taking HRT (n=219) endouterine disease is demonstrated in 37% with AUB and in 26% without AUB (P=0.07). Conclusion: Benign intrauterine diseases (endometrial polyps and submucous myomas) are more frequent in postmenopausal women who do not use HRT. In patients taking HRT irregular bleeding is associated with intrauterine diseases; however, the absence of AUB does not exclude the presence of endometrial polyps or myomas.     

Adverse endometrial effects during long cycle hormone replacement therapy

Objectives: treatment with unopposed estrogen is known to increase the risk of endometrial hyperplasia, atypia, and carcinoma, and therefore the administration of a progestin during hormone replacement therapy (HRT) is recommended. The addition of a progestestin may cause unwanted side effects. Progestin administration of various durations are therefore used in HRT. Study design: data were obtained about endometrial histopathology, bleeding interval and compliance in 240 early postmenopausal women receiving HRT with a progestin administered for 10 days during 12 week or 4 week cycles of estrogen administration. These regimens were studied for as long as 4 years. The daily estrogen given was 17β-estradiol 2 mg per day which was reduced to 1 mg day during the last 6 days of each cycle. The progestin used was norethindrone acetate, given at a dose of 1 mg per day. Results: the incidence of endometrial hyperplastic changes, i.e. simple or complex hyperplasia, atypia or cancer, was significantly higher in the 12 weeks cycle than in the monthly cycle group (P=0.003), with an overall annual incidence of 5.6% in the 12 weeks cycle group and 1% in the monthly cycle group. One case of atypical hyperplasia and one case of endometrial adenocarcinoma was observed in the long cycle group. Long cycle treatment produced more irregular bleeding pattern. Accordingly, the rate of drop-out due to bleeding was significantly higher in the long cycle group (P<0.01). Conclusion: we conclude that the long cycle HRT modality investigated did not improve compliance and may increase the risk of endometrial hyperplasia and eventually cancer compared to conventional HRT with a monthly cycle. Caution using long cycle HRT regimens is advisable, and careful monitoring of the endometrium during treatment is recommended.     

Insulin-like growth factor-binding protein-1: a biochemical marker of endometrial response to progestin during hormone replacement therapy

Objectives: To compare immunohistochemical localization of insulin-like growth factor binding protein-1 (IGFBP-1) in endometrial stromal cells with endometrial morphology during three regimens of continuous combined hormone replacement therapy. Methods: Endometrial samples for morphological examination and immunohistochemical staining with monoclonal antibody against IGFBP-1 were obtained from 30 menopausal women before treatment and after 12 and 24 months of continuous combined hormone replacement therapy. All women received percutaneous estradiolgel releasing 1.5 mg estradiol daily. Regarding progestins, patients were divided into three groups: one group (n = 15) had a 20 μg/24 h levonorgestrel-releasing intrauterine device (LNG-IUD); the women in the other two groups received micronised natural progesterone either 100 mg orally (n = 7) or 100–200 mg vaginally (n = 8) daily, 25 days per calendar month. Results: Before treatment the endometrium of all women was atrophic or subatrophic and no IGFBP-1 could be detected in any of the samples which contained enough stromal cells for evaluation. After 12 and 24 months of treatment, epithelial atrophy with decidual transformation in stroma was detected in all specimens in the LNG-IUD group, and IGFBP-1 was localized in decidualized stromal cells in all samples. In the other two groups, no signs of progestin effect were detected by microscopic examination in any of the endometrial samples and IGFBP-1 staining was completely negative in all of them. Conclusion: A striking difference occurred in both morphological and biochemical response in the endometrium of women treated with LNG-IUD compared with those receiving oral or vaginal micronised progesteron during continuous combined HRT. Micronised progesterone at doses used in this study turned out to be ineffective to prevent the proliferative effect of estrogen. Immunohistochemical localization of IGFBP-1 in endometrial stromal cells strongly correlated with decidual reaction in all endometrial specimens exposed to LNG-IUD, suggesting that the immunostaining of IGFBP-1 can be used as a means of assessing the strength of progestin effect in the endometrium during HRT.     

Endometrial histology and bleeding patterns in post-menopausal women taking sequential, combined estradiol and dydrogesterone

Objectives: To determine the endometrial response and bleeding patterns in post-menopausal women who were given a sequential hormone replacement regimen with estradiol 2 mg and dydrogesterone 10 mg. Methods: One-hundred-and-eighty-eight (188) post-menopausal women with amenorrhea of 6 months or longer, with FSH/estradiol (E2) levels in the post-menopausal range and normal endometrium were entered in the study. All patients received a daily dose of 2 mg E2 during day 1–14 of each 28 day cycle and 2 mg E2 combined with 10 mg dydrogesterone during cycle day 15–28. The total duration of treatment was 12 months (13 cycles of 28 days). Results: The rate of adequate progestational response (secretory or atrophic) in the 146 patients who remained in the study for at least 356 days with 90% study medication compliance and received an endometrial biopsy after 13 cycles of study medication was 97.2%. Three patients had proliferative endometrium and one simple hyperplasia. Cyclic bleedings in the 153 women who remained on study medication for at least 76 days occurred in over 85% of all cycles; the day of onset occurring regularly on day 13 or 14 of the combined period; the mean duration of bleeding per cycle was approximately 5 days with most patients having (very) slight bleeding. Sixty percent of patients had no intermittent bleedings over the whole 12-month study period. The average incidence of intermittent bleeding in the remaining patients was only 2.7 and generally of very slight quantities and of short duration. Per evaluable cycle the percentage of patients with an intermittent bleeding varies from 4.6 to 9.8%. Only two patients discontinued therapy because of bleeding problems. A clear decrease in the incidence of typical menopausal symptoms, i.e. hot flushes and night sweats was observed by the first visit after 6 weeks of treatment. Conclusions: The endometrial safety of 2 mg E2 sequentially combined with 10 mg dydrogesterone is very good as determined by the histologic response of the endometrium. The incidence of cyclic bleedings with this combination therapy is very high as is the regularity of day of onset and duration of bleeding. Blood loss during intermittent bleedings was mild and of short duration.     

Effective bleeding control and symptom relief by lower dose regimens of continuous combined hormone replacement therapy: A randomized comparative dose-ranging study

Objectives: We compared two different continuous combined hormone replacement therapy (HRT) regimens of estradiol valerate (E₂V) and medroxyprogesterone acetate (MPA) with a combination of micronized estradiol (E₂) and norethisterone acetate (NETA) to determine bleeding pattern, control of climacteric symptoms, lipid profile, endometrial and general safety in a 1-year multicenter study. Methods: 440 postmenopausal women were randomized to three treatment groups to receive: 1 mg E₂V+2.5 mg MPA; 1 mg E₂V+5 mg MPA; or 2 mg of E₂+1 mg NETA. After the first 6 months, the E₂V dose was increased to 2 mg in both E₂V/MPA groups. Information on bleeding was recorded on diaries by the women and intensity of climacteric symptoms was assessed using VAS scales. Physical and laboratory examinations, endometrial biopsy and vaginal ultrasonography were performed at baseline and follow-up visits. Results: Significantly fewer bleeding days were experienced in the first 3 months by women taking E₂V/MPA compared with women taking E₂/NETA. When the dose of E₂V was increased in the E₂V/MPA groups, an increase in maximum bleeding intensity was observed in the group receiving 2.5 mg of MPA, but not in the group taking 5 mg of MPA. All dose combinations effectively relieved climacteric symptoms and beneficial effects on the lipid profile were seen after 6 months in all groups. Tolerability and endometrial safety were good and no cases of hyperplasia were observed. More women discontinued treatment prematurely in the E₂/NETA group compared with either of the E₂V/MPA groups. The overall continuation rates ranged from 70 to 86%. Conclusions: These results confirm that lower dose combinations of continuous combined HRT are usually sufficient to control symptoms or avoid breakthrough bleeding. However, if higher E₂V dose is needed for symptom control, it should be combined with the higher dose of progestin (5 mg) to avoid bleeding disturbances. Flexible treatment regimens should be available for individualized HRT.     

The efficacy of two dosages of a continuous combined hormone replacement regimen

OBJECTIVES: To evaluate the efficacy of a low-dose combination of estradiol (E2) and norethisterone acetate (NETA) on bone markers, lipid and bleeding profiles and menopausal symptoms. METHOD: Ninety-six healthy Chinese postmenopausal women were allocated randomly to receive 1 mg E2/0.5 mg NETA (low-dose hormone replacement therapy (HRT)) or 2 mg E2/1 mg NETA (high-dose HRT) for 6 months. RESULTS: Bone resorption markers (collagen I N-terminal telopeptides (NTX) and deoxypyridinoline (dPyr)) were significantly reduced; -66 and -32%, respectively, in high-dose HRT versus -55 and -24%, respectively, in low-dose HRT. Bone-specific alkaline phosphatase remained unchanged with either combination of hormones. Total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels were decreased significantly (-12 and -13%, respectively, in high-dose HRT vs. -7 and -8% in low-dose HRT). High density lipoprotein cholesterol (HDL-C) was decreased to a lesser extent in low-dose HRT and triglycerides (TG) levels remained unchanged. Both the low and high-dose HRT were effective in alleviating menopausal symptoms. After 6 months of treatment, 2% of women in the low-dose HRT were bleeding compared with 23% in the high-dose HRT. Breast pain occurred in 2% of women in low-dose HRT compared with 15% in high-dose HRT. The endometrium in the majority of the women remained normal. CONCLUSION: Menopausal symptoms were reduced effectively in postmenopausal women on either low-dose or high-dose HRT. TC, LDL-C levels and bone resorption markers were reduced in a dose-dependent manner. Low-dose HRT provided a better bleeding profile and the incidence of breast pain was low.     

Effect of hormone replacement therapy on serum levels of tumor markers in healthy postmenopausal women

Objective: The effect of hormone replacement therapy (HRT) on serum levels of tumor markers is barely defined. The aim of this study was to evaluate the effect of HRT on levels of tumor markers CA 125, CA 15-3, CA 19-9, CEA and -FP. Methods: Retrospective analysis of prospectively collected data in healthy postmenopausal women under oral estrogen replacement therapy (ERT, conjugated equine estrogen (CEE) 0.625 mg (n=21) or estradiol 2 mg (n=31)), and continuous combined estrogen and progesterone regimen (HRT, CEE 0.625 mg plus medroxyprogesterone acetate 2.5 mg (n=34) or estradiol 2 mg plus norethisterone acetate 1 mg (n=37)). One hundred and twenty-three healthy women among a sampled population of 654 postmenopausal patients with complete records, initial normal tumor marker levels, and at least 1 year of follow-up were included into the study. Tumor markers were measured with 1-year interval. Results: Fifty-two (41.5%) patients were under ERT and 71 (58.5%) were under combined HRT. The number of months since menopause, age and age at menopause did not influence tumor marker levels at first admission. All of the tumor marker levels were in normal range after 1 year. Pretreatment CA 125 II, CA 15-3 and CEA levels were significantly low (median and range) 5.0 (1.0–11.8) versus 7.45 (1.0–18.1) U/ml for CA 125, 27.05 (7.3–37.5) versus 32.6 (12.5–37.9) U/ml for CA 15-3, 0.88 (0.58–2.8) versus 1.34 (0.53–2.41) ng/ml for CEA in women with hysterectomy when compared to women without hysterectomy. There was no effect of ERT on CA 125 II, CA 19-9, CEA and -FP levels. E2 led to a significant decrease in post-treatment CA 15-3 levels [32.9 (8.1–34.9) vs. 18.1 (6.7–31.4); P<0.001]. CA 125 levels were only significantly reduced in hysterectomised women using continuously combined HRT [7.9 (2.6–17.7) vs. 5.6 (1.3–19.2) for CEE+MPA, and 7 (1–18.1) vs. 5.8 (1.8–17.4) for E2+NETA; P<0.05]. There was a small, but not significant, increase in CA 125 levels in women under ERT. Conclusion: Although there was a statistically significant decrease in CA 15-3 levels in current E2 and E2+NETA users, and a decrease in CA 125 levels in combined regimens, this change is clinically not relevant in healthy postmenopausal women. This data will be useful for the caregivers in the management and follow-up of cancer survivors who preferred replacement therapy as the only treatment of their postmenopausal symptoms.     

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.     

Factors associated with endometrial bleeding in continuous hormone replacement therapy

OBJECTIVE: To identify clinical and laboratory parameters associated with the occurrence of endometrial bleeding within the first 6 months of treatment in postmenopausal women taking continuous hormone replacement therapy. DESIGN: We performed a prospective study of 55 postmenopausal women who had amenorrhea for at least 12 months before baseline screening and were taking 0.625 mg conjugated estrogen and 5 mg medroxyprogesterone acetate daily on a continuous basis. Postmenopausal duration was defined as the interval, in months, between the last menstruation and the commencement of treatment. All subjects were instructed to monitor bleeding episodes in a diary and were followed up monthly for at least 12 months. RESULTS: Thirty-four women (62%) experienced bleeding within the first 6 months of treatment. Using a multivariate approach, a woman with a postmenopausal duration of 24 months or less had a relative risk of 8.2 (95% confidence limits: 1.3, 53.1) of bleeding, as compared with those with a postmenopausal duration of more than 24 months. Furthermore, pretreatment endometrial thickness greater than 5 mm (p < 0.05) and serum estradiol levels greater than 25 pg/mL (p < 0.01) were noted to be significantly correlated with the occurrence of bleeding in women with a postmenopausal duration of more than 24 months. CONCLUSIONS: Women with a postmenopausal duration of 24 months or less, a pretreatment endometrial thickness greater than 5 mm, and serum estradiol level greater than 25 pg/mL are at risk to have endometrial bleeding within the first 6 months of continuous hormone replacement therapy.     

Comparison of two HRT regimens with bimonthly and monthly progestin administration in postmenopause

OBJECTIVES: Here we report the results of a study in which natural estrogens were given transdermally cyclically and continuously for 1 year, and a progestin of the latest generation, namely nomegestrol acetate, was given for 10 days every month and for 15 days every 2 months. METHODS: The patients were a group of 34 post-menopausal women (51-56 years), 18 of whom (group A) were treated with continuous transdermal estradiol (50 micrograms/day) and cyclic oral nomegestrol at a dose of 5 mg/day for 15 days every 2 months for 1 year. The other 16 women (group B) were treated with cyclic transdermal estradiol for 3 weeks with oral nomegestrol for 10 days (12-21)/month. Endometrial thickness was evaluated by transvaginal ultrasonography before and after treatment. At the end of treatment, an endometrial biopsy was performed. Serum total cholesterol, HDL, LDL and triglycerides were assessed at baseline and every 4 months. The characteristics of the cycle were deduced from the diary cards recorded by the women. RESULTS: No significant differences were found in the mean interval between the last dose of nomegestrol and the start of bleeding or in the duration of bleeding. The total number of days of bleeding per year was significantly lower in group A than group B (27 +/- 12 vs. 52 +/- 18; P < 0.01). Total serum cholesterol and LDL significantly decreased after 1 year of treatment in both groups, HDL-cholesterol and triglycerides were found increased at most of the time points studied. CONCLUSIONS: The present protocol involving continuous transdermal administration of estrogen combined with oral progestin every 2 months gave good control of the menstrual cycle, did not increase the risk of endometrial pathology and met with good patient compliance.     

A survey of physicians' attitude towards women with postmenopausal bleeding

Objective: To study how gynaecologist manage postmenopausal bleeding in women not using HRT. The impact on the physicians’ attitude of risk factors for endometrial cancer and of the endometrial thickness was essentially accounted for. Methods: Two different case-types were defined by modifying the risk level of developing endometrial cancer. Also the level of endometrial thickness, assessed by ultrasound, was made to vary. In total four case-types were constructed. One case-type was sent at random to each Belgian gynaecologist (n=970). Results: Response rate: 55%. The proportion of physicians who would not investigate the patients’ endometrium varied between 2% (high-risk patient with abnormal ultrasound) and 34% (low risk patient, normal ultrasound). Significant differences were observed in relation to the level of risk factors for endometrial cancer and in relation to endometrial thickness. No significant relationship was found between the choice of the method of endometrial investigation and the risk situation or the ultrasound result. Conclusions: The attitude of Belgian gynaecologists towards postmenopausal bleeding is modified by the presence of risk factors and by the level of endometrium thickness. About one third of physicians would not further investigate the endometrium of a patient with a low risk profile and a normal endometrium as assessed by ultrasound.     

Postmenopausal women without previous or current vasomotor symptoms do not flush after abruptly abandoning estrogen replacement therapy

BACKGROUND: Most but not all women suffer from vasomotor symptoms around menopause. The exact mechanisms behind these symptoms are unknown, but the rate of decline in estrogen concentrations has been suggested to affect the risk of hot flushes. OBJECTIVE: The objective was to assess whether vasomotor symptoms were induced in women without previous such symptoms, when the women were given combined estradiol and progestagen therapy for 3 months, whereafter therapy was abruptly withdrawn. MATERIALS AND METHOD: After randomization, 40 postmenopausal women without previous or current vasomotor symptoms were treated transdermally with either 50 micrograms/day 17 beta-estradiol or placebo during 14 weeks. During the 13th and 14th weeks, treatment was combined with oral medroxyprogesterone acetate 10 mg/day. Serum estradiol and follicle-stimulating hormone (FSH) concentrations were analysed before and after 12 weeks of therapy. Climacteric symptoms were assessed at the same intervals as well as 8 weeks after the end of therapy. RESULTS: All women had low pretreatment levels of estradiol and high FSH concentrations. During estradiol therapy estradiol levels increased significantly, whereas FSH only decreased slightly. No woman developed vasomotor symptoms after withdrawal of therapy. CONCLUSION: Postmenopausal women without previous or current vasomotor symptoms did not develop such symptoms when estrogen replacement therapy was first instituted and then abruptly stopped. Probably other factors than the rate with which estrogen concentrations decrease determine whether or not a woman will develop vasomotor symptoms. Evidently, estrogens can be prescribed to a woman who has no vasomotor symptoms, without much risk of inducing such symptoms if she decides to abandon therapy, even after 3 months of treatment.     

Clinical profile of a new hormone replacement therapy containing 2 mg 17 beta-estradiol and 10 mg dydrogesterone

Objective: Patient’s acceptability, compliance, and effectiveness of a new sequential hormone replacement regimen containing 2 mg 17β-estradiol and 10 mg dydrogesterone, were assessed in a 3-month, open, multicentre study involving 110 menopausal women. Methods: A specially designed menopause score was used to assess the severity of menopausal symptoms, each symptom being graded at baseline and after 3 months on a four-point scale. Bleeding data were recorded by the patient on a diary card. Serum hormone levels including FSH, LH, E2, P, PRL, DHEA-S, T, SHBG were checked at the initial visit and at the end of the study. Results: After 3 months of treatment, all but four of the 34 climacteric symptoms investigated showed a significant improvement. There were no significant changes noted in body weight. The average duration and flow of bleeding showed no significant changes during hormone replacement therapy (HRT). There were no serious adverse events related to treatment. Conclusion: The 17β-estradiol/dydrogesterone combination HRT reduced effectively climacteric symptoms, showed no significant changes in endometrial thickness as determined by transvaginal ultrasonography and provided excellent cycle control.     

The effect of the duration of progestin use on the occurrence of endometrial cancer in postmenopausal women.

OBJECTIVE: Women who have ever used estrogen replacement therapy (ERT), even at a low dose, have an increased incidence of endometrial cancer. The addition of a progestin to ERT reduces the incidence of endometrial cancer. The duration of progestin administration is more important than the dose. DESIGN: A MEDLINE review of the literature was performed using the search terms endometrial cancer, epidemiology, and hormone replacement therapy (HRT). RESULTS: Women who have ever used ERT have an increased incidence of endometrial cancer. The use of HRT for more than 5 years, with a progestin use of <10 days per cycle, has a relative risk = 1.8. Continuous combined HRT, or sequential or cyclic HRT with >10 days of progestin per cycle, appears to decrease the incidence of endometrial cancer to that found in nonusers of HRT. CONCLUSIONS: The use of HRT in postmenopausal women with a uterus reduces the incidence of endometrial cancer. The duration of progestin administration should be 14 days or more per cycle based on recent epidemiologic data.     

A comparative study of transvaginal uterine ultrasound and endometrial biopsy for evaluating the endometrium of postmenopausal women taking hormone replacement therapy.

OBJECTIVE: Compare transvaginal uterine ultrasound and endometrial biopsy in evaluating the endometrium of postmenopausal women who are taking estrogen replacement therapy (ERT) or hormone replacement therapy (HRT; estrogen and progestin). DESIGN: Prospective multicenter study done in the United States with 148 healthy women with an intact uterus. A total of 121 women used hormonal preparations prescribed by personal physicians. Continuous combined HRT regimens, nonoral forms of ERT or HRT, and intrauterine devices were not allowed for 3 months before the study began. Endometrial biopsy samples were taken within 3 days of transvaginal ultrasound measurement. The uterus was scanned transversely and longitudinally. Endometrial thickness was measured at the thickest part of the longitudinal plane. RESULTS: Endometrial thickness ranged from 1.0 to 25.0 mm. The range in 126 women with a normal endometrium (determined by diagnoses of endometrial biopsies) was 1.0-25.0 mm (median, 5.0 mm); in 15 women with an abnormal endometrium, the range was 2.8-23.0 mm (median, 6.2 mm). A significant difference (p = 0.006) in endometrial thickness was seen between the 38 subjects taking ERT and HRT (median, 6.1 mm) with unexpected bleeding or spotting and the 26 untreated women in the control group (median, 4.0 mm). Overall, results were clinically inconclusive. CONCLUSIONS: Results of ultrasound as a screening technique in postmenopausal women who were taking ERT or HRT did not correlate well with results of endometrial biopsy. Unscheduled bleeding in postmenopausal women should be investigated regardless of results of ultrasonographically determined endometrial thickness. Abnormalities may be found with an endometrial thickness of less than 4 mm with or without HRT and even with no bleeding.     

Hormonal replacement therapy after stem cell transplantation

Objective: To evaluate HRT compliance and efficacy in the treatment of symptomatic ovarian failure in pre-menopausal women after stem cell transplantation (SCT) for malignancies. Methods: Thirty-one females were selected and prospectively followed in a university bone marrow transplantation unit and gynecologic outpatient clinic in a university teaching hospital. The patients received regular gynecological examinations, hormonal assessment every 6 months including plasma levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), 17-beta estradiol (E2), and transvaginal pelvic ultrasonography, mammography, and computerized bone mineralometry every 12 months. Self-assessment form of menopausal symptoms perception was filled in by all patients before HRT and during the observation period. Results: All patients developed gonadal failure after SCT. The menopausal symptoms more frequently reported were: vasomotor (90%), muscleskeletal symptoms (61%), vulvo-vaginal atrophy (54%), and mood changes (54%). Fifteen premenopausal women out of 31 (51.6%) received systemic HRT on the basis of age (<45 years), absence of medical contraindication or subjective refusal, and complete remission of underlying malignancies post-SCT. The remaining patients (48.4%) did not receive HRT mainly for patient’s refusal (29%), relapse of malignancy (13%) or liver toxicity (9.6%). HRT was effective in HRT treated patients promptly relieving unpleasant symptoms of gonadal failure. HRT was tolerated without minimal complications or serious side effects. Conclusions: Dramatic improvement in menopausal symptoms was observed in women on HRT although treatment was feasible only in nearly half of the patients. HRT alleviates unnecessary discomfort and improves the well-being of female patients post-transplant also by preventing menopause related complications. Feasibility and patients’ compliance of HRT should be carefully evaluated in long-term survivors after stem cell transplantation.     

Ultrasonographic endometrial monitoring during continuous-sequential hormonal replacement therapy regimen in postmenopausal women

Objective: To evaluate the endometrial thickness in different periods of a continuous–sequential HRT regimen and to correlate the ultrasonographic findings with the histological patterns. Methods: The study was structured in two phases. In the 1st phase, 37 postmenopausal women (group A) treated by at least 6 months with a conventional continuous–sequential hormonal replacement therapy (cs–HRT) regimen were enrolled. In all patients, the endometrial thickness was measured at the 7th, 14th, 21st and 25th day of the cycle using transvaginal ultrasonography (TV-USG). In the 2nd phase of the study, other 41 postmenopausal women (group B) were enrolled and treated with the same sc-HRT regimen. At entry and after six cycles of cs–HRT, an endometrial biopsy was performed. The endometrial pattern was related with endometrial thickness. Either the evaluations were performed immediately after progestogen withdrawal bleeding, as showed by 1st phase results. Results: The results of the 1st phase of the study showed a mean endometrial thickness significantly lower at 7th day of the cycle compared to 14th, 21st and 25th day (4.3±1.2 versus 6.6±2.9, 7.8±4.2 and 7.4±4.6 mm±SD, respectively). After six cycles of cs–HRT (2nd phase of the study), the mean endometrial thickness was significantly increased in comparison with basal values (4.2±1.5 versus 2.8±1.2 mm±SD; P<0.05). Endometrial biopsies showed 13 cases (39.4%) of atrophy and 20 cases (60.6%) of proliferative endometrium. Mean endometrial thickness in case of atrophy was lower than in presence of a proliferative endometrium (3.7±1.2 versus 4.4±1.4 mm±SD; not significant). Endometrial thickness was <4 mm in 16 cases (11 of atrophic and five of proliferative endometrium), between 4 and 5 mm in 15 cases (13 of proliferative and two of atrophic endometrium) and between 5 and 6 mm in two cases (either case of proliferative endometrium). Conclusions: The best timing for monitoring endometrial thickness during cs–HRT regimens is the period immediately after withdrawal bleeding improving the reliability of the ultrasonographic exam to identify endometrial pathologies.