Endometrial bleeding during hormone therapy: the effect of progestogens

Postmenopausal women using continuous combined estrogen/progestin therapy (ccEPT) are likely to have irregular bleeding or spotting. The use of estrogen with 12-14 days of a progestin is called cyclic (scEPT). This method results in regular endometrial bleeding at a scheduled time. The mechanism(s) involved in this regimen that result in bleeding could be similar to a spontaneous menstrual bleeding episode in a menachal woman, but there are no data in this regard. This aspect of regular scheduled bleeding in postmenopausal women will not be addressed in this article due to the paucity of information. The effect of cyclic progestogen with continuous estrogen on the endometrium could result in similar local mechanisms for endometrial bleeding as seen wth ccEPT. The mechanism(s) involved in endometrial bleeding is unknown. Several reports have highlighted a number of potential pathophysiologic mechanisms. Most of the investigation into the mechanisms involved in endometrial bleeding has been in women using progestin only contraceptive methods not ccEPT. The use of ccEPT could be construed as similar but not identical to that of a continuous progestin only contraceptive since the progestin in ccEPT is delivered daily. The potential mechanism(s) involved in endometrial bleeding includes the following: changes in the ratio of vascular endothelial growth factor to Thrombospondin-1 (pro- versus anti-angiogenic factors); alterations in metalloproteinases and tissue inhibitor of metalloproteinases (TIMP); changes in tissue factor a known haemostasis mediator in the endometrium; and increased endometrial leukocytes with a particular emphasis on uterine natural killer (uNK) cells. Each of these potential causes has been the subject of both in vivo and in vitro investigations. There is no clear linkage between any of these hypotheses and the onset or cessation of uterine bleeding in ccEPT users. No good therapeutic option to control the bleeding or spotting exists at this time. Evaluation and monitoring of the patient regarding endometrial safety is of paramount importance.     

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.     

Changes in the withdrawal bleeding pattern and endometrial histology during 17β-estradiol —dydrogesterone therapy in postmenopausal women: a 2 year prospective study

Objective: To describe changes in the withdrawal bleeding pattern and endometrial histology during a sequential 17β-estradiol —dydrogesterone regimen in postmenopausal women. Design: Open-label, non-comparative, prospective study. Setting: Gynecological outpatient department of a university hospital. Patients: Twenty-seven healthy nonhysterectomized postmenopausal women. Interventions: Continuous micronized 17β-estradiol supplementation, 2 mg daily, and cyclic administration of dydrogesterone, 10 mg daily for the first half of each 28 day treatment cycle. Main Outcome Measures: Changes in the characteristics of the withdrawal bleeding pattern and the endometrial biopsy histology during 2 years of treatment. Results: The initial withdrawal bleeding was comparable to normal menstruation with respect to amount and duration. During the 2 years of treatment the bleeding showed a significant tendency to become shorter with less blood loss. This was mainly the result of the decrease (P < 0.001) in the number of days per cycle with bleeding grade II (normal menstruation). None of the women developed endometrial hyperplasia, and in almost all women the given hormone replacement therapy regimen induced secretory or atrophic changes of the endometrium. Conclusions: This sequential 17β-estradiol —dydrogesterone regimen can be regarded as safe with respect to the prevention of endometrial disease and appeared to foster patient compliance.     

Endometrial breakdown in women using Norplant is associated with migratory cells expressing matrix metalloproteinase-9 (gelatinase B)

Norplant, subdermally implanted slow-release levonorgestrel, is an effective and widely used contraceptive agent but has a high rate of discontinuation due to unacceptable abnormal uterine bleeding. Matrix metalloproteinases (MMPs) are expressed in normal cycling endometrium and are postulated to be responsible for the tissue breakdown at menstruation. We have compared the immunolocalization of MMP-9 and migratory cells in endometrium from Indonesian women using Norplant with normal controls. Positive MMP-9 immunostaining was observed intracellularly within stromal and intravascular leukocytes and extracellularly in areas of tissue lysis adjacent to these migratory cells. The MMP-9 positive cells were identified as neutrophils, eosinophils, CD3+ T-cells and macrophages. Quantitative assessment revealed that the number of MMP-9 positive cells, neutrophils and eosinophils were significantly increased in those endometrial biopsies from Norplant users displaying a shedding morphology and in normal controls at menstruation. There was no correlation between the number of MMP-9 positive cells and the number of bleeding days reported. Endometrial immunostaining for tissue inhibitor of metalloproteinases was similar in Norplant users and normal controls. These results suggest that MMP-9, an enzyme capable of degrading basement membrane components, may be involved in endometrial breakdown in women using Norplant.     

Why does menopausal hormone therapy lead to irregular uterine bleeding? Changes to endometrial blood vessels

BACKGROUND: Abnormal bleeding is common in hormone therapy (HT) users. We aimed to determine how HT alters endometrial blood vessels and stromal factors known to regulate vascular growth and integrity. METHODS: Prospective observational study of 165 post-menopausal women in Western Australia. The following were measured in endometrial biopsies: vascular density (vessels/mm(2)), total vessel area (total area enclosed by peripheral vascular immunostaining for perivascular pericytes in mm(2)), total luminal area (mm(2)) and vessel wall area (total vessel area minus luminal area), stromal expression of matrix metalloproteinases (MMP) -1, -3, -9 and -14, their tissue inhibitors (TIMPs) -1-4 and vascular endothelial growth factor (VEGF) by immunohistochemistry. RESULTS: Total vessel area was greater during bleeding compared with HT users with no bleeding (P = 0.028) or with a prior irregular bleeding (P = 0.039). Total vessel area was greater in non-HT users compared with HT users with no bleeding (P = 0.021). In HT users, vessel luminal area was greater during bleeding compared with HT users with no bleeding (P = 0.030) and vessel wall area was also increased (P = 0.025). During bleeding there was an increase in stromal TIMP-2 staining (P = 0.044). No significant changes in endometrial MMP or VEGF were seen. CONCLUSIONS: Abnormal bleeding in HT users is associated with changes in endometrial vessel size and in stromal expression of factors known to regulate vascular growth and integrity. These changes may contribute to abnormal bleeding.     

Focal expression and final activity of matrix metalloproteinases may explain irregular dysfunctional endometrial bleeding

Irregular dysfunctional bleeding of the endometrium (ie, metrorrhagia without organic lesion) is common in women, whether treated or not with ovarian hormones. Several matrix metalloproteinases (MMPs) become normally expressed and/or activated at menstruation and cause extracellular matrix breakdown. We therefore explored whether episodes of irregular dysfunctional bleeding could be associated with untimely MMP activity. By histology, foci of stromal breakdown were exclusively found in the endometrium of metrorrhagic women at bleeding. In these foci, 1) expression of estrogen receptor-alpha and progesterone receptor was altered; 2) collagenase-1 (MMP-1), stromelysin-1 (MMP-3), and gelatinase B (MMP-9) became detected in stromal cells, together with MMP-9 in neutrophils; and 3) gelatinase A (MMP-2) was more expressed and immunolocalized at the membrane of stromal cells. By biochemistry, endometrial lysates from nonbleeding metrorrhagic patients contained more latent and active MMP-2 and -9 than age-matched controls; at bleeding, collagenase activity, MMP-9, and active MMP-2 were strikingly increased whereas tissue inhibitor of metalloproteinases-1 (TIMP-1) was considerably decreased. As a functional assay, in situ gelatin zymography revealed large areas of gelatinolytic activity only in endometrium of bleeding patients. Altogether, these results strongly suggest that inappropriate focal expression and activation of several MMPs, combined with decreased inhibition, trigger irregular dysfunctional endometrial bleeding.     

The role of matrix metalloproteinases and leukocytes in abnormal uterine bleeding associated with progestin-only contraceptives

Progestin-only contraceptives are associated with menstrual bleeding disturbances; a major reason why these agents are discontinued. The pathogenesis of abnormal uterine bleeding associated with progestin-only contraceptives remains ill-defined. Matrix metalloproteinases (MMPs) and leukocytes are postulated to be involved in the process of normal menstruation. Immunolocalization of MMPs and leukocytes in (Norplant), and injectable depot medroxyprogesendometrium from women using the progestinterone acetate (DMPA), are widely used, safe and only contraceptives, Norplant or depot medroxyprogesterone acetate (DMPA) compared with normal controls, revealed foci of positive MMP-1 and -3 immunostaining in stromal cells and adjacent extracellular matrix, the presence of MMP-9 in various subtypes of leukocytes and alterations in mast cell phenotype. In women using progestin-only contraceptives, extent of endometrial MMP, neutrophil and eosinophil immunolocalization and the mast cell activation state was similar to or greater than that observed in perimenstrual control women. However, differences in MMP immunostaining were observed in endometrial samples from women using different progestin-only contraceptive agents; in particular, significantly higher MMP-1 immunostaining was observed associated with the use of Norplant compared with DMPA. No correlation was observed with the number of bleeding days recorded. These results suggest that MMP and leukocytes may be involved in endometrial breakdown in women using progestin-only contraceptives.     

Serum Mg and Zn levels in postmenopausal women

Approximately 30% of a woman's life is spent in the postmenopausal period. This is when steroid hormone deficiency is often accompanied by mineral homeostasis perturbations and deficiencies that could be related to the intensity of any clinical symptoms. The aim of this study was to assess how serum Mg and Zn levels in postmenopausal women correlate with climacteric symptoms, body mass index (BMI), and the time interval since the final menstruation. The study involved 171 healthy, postmenopausal women, who had had their final menstruation at least one year prior to the study and who did not use menopausal hormone therapy. Both hypomagnesaemia and hypozincaemia were detected in the postmenopausal women involved in this study. The analysis revealed statistically significant differences between serum Mg levels, depending on the time interval since the final menstruation (p<0.05). No statistically significant differences were found in serum Mg and Zn levels between women as regards the severity of the climacteric symptoms or BMI (p>0.05). In conclusion, serum Mg and Zn concentrations in postmenopausal women, not using MHT, were low. The average serum Mg levels decreased considerably with the time since the final menstruation. No correlation between BMI and worsening of climacteric symptoms and serum Mg and Zn concentrations in postmenopausal women, not using MHT was found.     

Circulating sex hormones and endometrial stromelysin-1 (matrix metalloproteinase-3) at the start of bleeding episodes in levonorgestrel-implant users

Unpredictable endometrial bleeding is the major side-effect of levonorgestrel-releasing s.c. implants (Norplant), otherwise a method of choice for long-term contraception. The mechanisms responsible for bleeding are still unknown and no reliable treatment is available. Several matrix metalloproteinases (MMP) are expressed and activated in human endometrium only at menstruation and specific synthetic inhibitors of MMP fully prevent the tissue breakdown that occurs in menstrual-like endometrial explants. To investigate whether MMP are inappropriately expressed and activated in Norplant-treated endometria during bleeding episodes, volunteers were recruited to provide blood and endometrial biopsies at the start of bleeding episodes and during non-bleeding intervals. Whereas serum concentrations of levonorgestrel and sex hormones showed no change at bleeding, except for a slight decrease of oestradiol concentration, the expression and activation of stromelysin-1 released by explants cultured for 1 day were consistently increased at the start of bleeding episodes. Furthermore, stromelysin-1 was immunolocalized in stromal cells within breakdown areas of several bleeding endometria, but not in non-bleeding endometria. These observations suggest that the expression and activation of stromelysin-1 participate in the initiation of bleeding episodes upon Norplant contraception. New strategies in the prevention and treatment of abnormal bleeding based on MMP control should be envisaged.     

Steroids and endometrial breakthrough bleeding: future directions for research

Abnormal endometrial bleeding continues to be a significant problem for women using long-acting gestagens and not only reduces the use of these agents, thus restricting the options available to women, but also reduces the quality of their lives. This symposium addressed a range of basic and clinical studies that have tried over the past 3 years to define the problem. Two areas have been identified. The first is the structure of the blood vessels themselves and the second is the environment of the endometrium in relation to these vessels. This reflects a shift in research interest away from factors that simply control epithelial-mesenchyme interactions. The expression of angiogenic inhibitors and stimulators is being defined and the critical role of the matrix and the immunocompetent cells of the endometrium elucidated. The disappointing results of simple oestrogen supplementation were confirmed. Three broad areas of research were considered to be important for future studies. The first of these is not related to molecular and cellular function but rather to understanding better the attitudes of women to vaginal bleeding in the multicultural diverse situations in which this event occurs. It was recognized that a broader constituency was not interested in this problem with the increasing use of continuous combined regimes of hormone replacement therapy in the developed world. Studies that listen to and educate women about this problem are needed to ensure that these techniques are felt to be better owned by the women themselves. Molecular and cellular studies were identified that attempted to define the factors necessary for the development and maintenance of healthy, non-leaky vessels. These included studies of the pro- and anti-angiogenic agents expressed in endometrium and a definition of their interactions with matrix metalloproteinases in maintaining vessel integrity. Finally there was recognition of the need to understand how neutrophils traffic through the endometrium and to determine how they effect endometrial bleeding.     

Matrix metalloproteinase-1 and -3 and mast cells are present in the endometrium of women using progestin-only contraceptives

Progestin-only contraceptives are associated with menstrual bleeding disturbances; a major reason why these agents are discontinued. The pathogenesis of such abnormal uterine bleeding associated with progestin-only contraceptives remains ill-defined. Matrix metalloproteinases (MMP)s and mast cells (MC)s are postulated to be involved in endometrial breakdown observed in normal menstruation. In this study comparisons were made of the immunolocalization of MMP-1 and -3 and MC in endometrium from women using Norplant or depot medroxyprogesterone acetate (DMPA) with normal controls. Positive MMP immunostaining was observed focally in stromal cells and adjacent extracellular matrix. Quantitative assessment revealed significantly higher MMP-1 immunostaining associated with the use of Norplant compared with DMPA or menstrual phase controls. Endometrial MMP-1 immunostaining in DMPA users was similar to that in menstrual controls. Positive MMP-3 immunolocalization was observed in a minority of endometrial samples. Activated MC, shown by the presence of extracellular MC tryptase, predominated in the endometrium of Norplant and DMPA users as also observed in menstrual phase controls. There was no correlation between MMP immunostaining, number of MC and number of bleeding days reported. These results indicate that in women using progestin-only contraceptives, endometrial MMP-1, -3 and MC demonstrate similarities to menstrual phase controls but also variation with different progestins.     

Endometrial polyps in pre- and postmenopausal women: factors associated with malignancy

OBJECTIVE: To evaluate the prevalence of premalignant and malignant polyps and their association with menopausal status, hormone therapy and clinical characteristics in perimenopausal and postmenopausal women. METHODS: A surgical database was used to select pre- and postmenopausal women >or=40 years of age, submitted to hysteroscopic resection of endometrial polyps. The medical records of 475 women were reviewed and clinical characteristics and histological diagnosis of resected polyps were assessed. RESULTS: The majority of women had benign endometrial lesions, 78.53% of which were endometrial polyps and 13.47% polyps with simple or complex endometrial hyperplasia without atypia. Polyps with endometrial hyperplasia with atypia comprised 1.05% of cases, while 2.74% were carcinomatous polyps. Analysis using prevalence ratios showed that premalignant and malignant lesions were associated with age and postmenopausal bleeding. Women >60 years of age had a prevalence ratio 3.28 times greater (95%CI: 1.19-9.07) of premalignant or malignant polyps. When only postmenopausal women were evaluated for the effect of age, those over 60 years of age had a prevalence 5.31 times greater (95%CI: 1.22-23.09), while those with postmenopausal bleeding had an age-adjusted prevalence ratio of 3.71 (95%CI: 1.21-11.34) compared to asymptomatic women. No significant association was found between arterial hypertension, diabetes mellitus, obesity, use of hormone therapy or tamoxifen and premalignancy or malignancy. CONCLUSIONS: There was a low prevalence of premalignant and malignant lesions in endometrial polyps. Older women and those with postmenopausal bleeding had a greater prevalence of malignancy and in these cases hysteroscopic resection of endometrial polyps is mandatory.     

A simple method for determining the optimal dosage of progestin in postmenopausal women receiving estrogens

Progestin is often added to regimens of estrogen therapy in postmenopausal women to reduce the risk of endometrial hyperstimulation, but it may cause undesirable metabolic effects. Therefore, a low dosage is recommended. At present, the only way to determine whether the dosage of progestin is causing the desired secretory transformation of the endometrium is by endometrial sampling, which is invasive. We studied 102 postmenopausal women undergoing estrogen therapy who also took a progestin for 12 days each month, and we correlated the day of onset of bleeding with the endometrial histology over a three-month period. A bleeding pattern suitable for interpretation was observed in 96 women. Regardless of the preparation and dosage of the estrogen and progestin used, wholly or predominantly proliferative endometrium was always associated with bleeding on or before day 10 after the addition of progestin; wholly or predominantly secretory endometrium, or a lack of endometrial tissue, was associated with bleeding on day 11 or later. We conclude that the bleeding pattern reflected the histologic condition of the endometrium and that adjustment of the dosage of progestin so that regular bleeding is induced on or after day 11 may obviate the need for endometrial biopsy.     

Clinical relevance of benign endometrial cells in postmenopausal women

Our objective was to determine if the finding of benign endometrial cells on a Papanicolaou (Pap) smear of a postmenopausal woman is associated with endometrial/uterine pathology, independent of symptomatology and hormone replacement therapy (HRT) status. The medical records of 146 postmenopausal patients who had a Pap smear showing normal-appearing endometrial cells between January 9, 1997 and January 12, 2000 were reviewed. Uterine pathology for each patient was determined by reviewing the results of endometrial sampling (endometrial biopsy or dilatation and curettage), hysterectomy, or pelvic sonogram, which were performed within 24 mo of the cytologic smear. The results were then correlated with clinical symptomatology and HRT status of each patient at the time the cytologic smear was obtained. Of the 146 Pap smears coded with "endometrial cells in a postmenopausal woman," 50 were excluded due to prior hysterectomy, perimenopausal status, and absence of further follow-up. Of the remaining 96 women, 27 (28%) had benign pathologic findings including polyps, leiomyomata, and simple hyperplasia without atypia, whereas 11 (12%) had significant pathologic findings including hyperplasia with atypia, adenocarcinoma, mixed Mullerian tumor, and leiomyosarcoma. Of the 11 patients with significant pathology, only one patient did not have abnormal vaginal bleeding but instead had a 30-wk-size irregular uterus on examination, and only 2 patients received hormone replacement therapy. In conclusion, Reporting endometrial cells on Pap smears in postmenopausal women did not lead to the diagnosis of any cases of significant pathology that would have gone unsuspected clinically. Moreover, HRT status did not affect the incidence of normal endometrial cells on Pap smears in postmenopausal women, nor did it aid in distinguishing which postmenopausal women had endometrial/uterine pathology. This calls into question the usefulness of the current Bethesda guideline to report "benign endometrial cells in a postmenopausal woman."     

Endometrial leukocytes and menstruation

This review examines evidence supporting the concept that menstruation occurs as a result of an inflammatory process. In the endometrium, leukocyte numbers rise in the late secretory phase following the fall in serum progesterone concentrations. It is postulated that products released following activation of these leukocytes are critically important for menstruation. Mast cells, eosinophils, neutrophils and macrophages in particular are involved. Endometrial granular lymphocytes may also play a role, although their increase in numbers is somewhat earlier during the menstrual cycle than that of the others, suggesting perhaps a primary role in embryo implantation. Leukocyte products include a range of proteases, chemokines and cytokines which in concert result in focal production and activation of matrix metalloproteinases by endometrial cells and the subsequent breakdown of tissue that characterizes menstruation. Regulation of leukocyte entry, proliferation, differentiation and activation within the endometrium is not yet well understood, although both chemokines and cytokines produced locally by endometrial cells are clearly implicated. The role of progesterone in regulating these events is still not understood although the lack of progesterone receptors on endometrial leukocytes suggests indirect actions.     

Transvaginal sonography of the endometrium in women with postmenopausal bleeding

Objective: The purpose of this study was to determine the value of screening transvaginal ultrasonography for the evaluation of endometrial abnormalities in women with postmenopausal bleeding. Materials and methods: 250 women with postmenopausal bleeding underwent transvaginal ultrasonographic examinations before undergoing dilatation and curettage. Women who had any pelvic symptoms or were on hormone replacement therapy were excluded. Results: In 151 women, the histologic diagnosis was atrophic endometrium. In these patients, the mean endometrial thickness was 3.4 ± 1.2 mm. In 24 patients with endometrial carcinoma, the mean endometrial thickness was 16.5 ± 6.2 mm. The measurement included both endometrial layers (i.e. double layer). Thirty six cases of other pelvic pathologic conditions were discovered on ultra sonography. Conclusions: We believe that is reasonable to have a cutoff limit for normal postmenopausal endometrium at 5 mm. Endovaginal ultrasound is a valuable diagnostic instrument, as sensitive as dilatation and curettage, for detecting pathological conditions in the uterine mucosa.     

Decreased tissue inhibitor of metalloproteinase in the endometrium of women using depot medroxyprogesterone acetate: a role for altered endometrial matrix metalloproteinase/tissue inhibitor of metalloproteinase balance in the pathogenesis of abnormal uterine bleeding?

BACKGROUND: Abnormal uterine bleeding is commonly associated with progestin-only contraceptives, including depot medroxyprogesterone acetate (DMPA), and remains the main reason why these agents are discontinued. Matrix metalloproteinases (MMP), enzymes which degrade specific extracellular matrix components, and leukocytes are implicated in menstruation. Alteration in endometrial MMP-9 and leukocytes has been described in users of other progestin-only contraceptives, suggesting a potential role in the pathogenesis of abnormal uterine bleeding. METHODS: This study describes the immunohistochemical localization of MMP-9, the tissue inhibitors of metalloproteinases (TIMP)-1, TIMP-2 and TIMP-3, and leukocytes [CD3+ T lymphocytes, CD68+ macrophages and CD56+ uterine natural killer cells (uNK cells)] in the endometrium of women using DMPA. Comparison is made with perimenstrual endometria from normal cycling women. RESULTS: Similar to the perimenstrual period, an influx of MMP-9 positive cells (identified as neutrophils and CD3+ T cells on the basis of dual immunofluorescence), macrophages and uNK cells was observed in the endometrium of DMPA users. However, significantly more endometrial T lymphocytes were observed in DMPA users. Immunoreactive TIMP, present in all endometrial compartments, demonstrated a significantly decreased immunostaining intensity score in endometrial epithelium (TIMP-1 and TIMP-2), stroma (TIMP-1, TIMP-2 and TIMP-3), endothelium (TIMP-1 and TIMP-2) and vascular smooth muscle (TIMP-1) of DMPA users compared with controls. No correlation was observed between the parameters studied and bleeding patterns reported by subjects. CONCLUSIONS: These findings provide additional evidence for the importance of the MMP/TIMP balance in the loss/maintenance of endometrial integrity and in the complex pathological mechanisms involved in the troubling side-effect of menstrual bleeding disturbance.     

An immunohistochemical comparison of endometrial polyps from postmenopausal women exposed and not exposed to HRT

OBJECTIVE: Our study set out to test the null hypothesis that oestrogen containing continuous combined hormone replacement therapy (HRT) would not affect the hormone receptor expression (oestrogen and progesterone receptors-ER, PR) or markers of cell proliferation/apoptosis (Ki67 and Bcl-2) in endometrial polyps from postmenopausal women exposed and not exposed to HRT. DESIGN: Immunohistochemical staining for ER, PR, Ki67 and Bcl-2 was performed on polyps obtained from two groups of postmenopausal women. SETTING: Polyps were obtained from postmenopausal women attending an outpatient hysteroscopy clinic in a district general hospital (Bradford Royal Infirmary, UK). POPULATION: Twenty-five postmenopausal women presenting with abnormal bleeding subsequently diagnosed with endometrial polyps (16 from women not exposed to HRT, 9 from women exposed to HRT). METHODS: Semiquantitative immunohistochemistry was performed. MAIN OUTCOME MEASURES: Significant differences or correlations in either hormone receptor expression or markers of cell proliferation/apoptosis between the two groups of polyps. RESULTS: There were no significant differences for hormone receptor expression (ER and PR) between endometrial polyps exposed and not exposed to HRT. Bcl-2 expression was higher than Ki67 in both groups, but polyps from HRT users had increased levels reflecting decreased apoptosis in these polyps. CONCLUSIONS: HRT has no demonstrable effect on polyp ER and PR expression. However, HRT does appear to inhibit apoptosis and cell proliferation in endometrial polyps, which may affect polyp growth.     

Diagnosis of abnormal uterine bleeding with imaging

The major role of ultrasound in the evaluation of abnormal uterine bleeding, other than that occurring during pregnancy, is in postmenopausal women. Because postmenopausal bleeding can be the presenting symptom of endometrial cancer, any woman with this symptom should be evaluated to diagnose or exclude carcinoma. Over the last two decades, the role of ultrasound in the evaluation of postmenopausal bleeding has changed markedly, from little or no role in 1990 to a major role today. In the intervening years, numerous studies have shown that ultrasound is at least as sensitive as endometrial biopsy for endometrial cancer and that ultrasound can reliably exclude cancer without the need for biopsy in some women with postmenopausal bleeding. In particular, numerous studies have shown that women with an endometrial thickness of 4 mm or less have an extremely low likelihood of endometrial cancer and thus do not need to undergo endometrial biopsy. Ultrasound can also help in the selection of an appropriate biopsy technique. In a woman with postmenopausal bleeding and a thick endometrium, a sonohysterogram can determine whether the endometrium is diffusely thick or has focal areas of thickening. With diffuse thickening, a blind endometrial biopsy is appropriate. When there are one or more focal areas of thickening, hysteroscopic biopsy is likely to be the better choice. We present two clinical algorithms, either of which is an acceptable approach to the use of ultrasound and/or endometrial biopsy in women with postmenopausal bleeding: the "ultrasound-first" approach and the "biopsy-first" approach.     

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.