Incidence Of Endometrial Hyperplasia Research Articles

Abstract 4102: p27 as a biomarker and determinant of risk for endometrial carcinoma arising in the setting of obesity

Abstract Endometrial carcinoma exhibits the strongest association with obesity of any cancer. Tumor growth is driven by PI3K/AKT activation, and opposed by tumor suppressors, including the tuberous sclerosis complex (TSC) and p27, with inactivation of TSC2 and loss of cytoplasmic misloclization of p27 both being linked to PI3K/AKT signaling. However, little is known about the involvement of p27 in the development of endometrial carcinoma arising in the setting of obesity, expecially its role in early disease progression. We found that p27 was moderatley-to-severely reduced in both “normal” endometrial glands as well as endometrial hyperplasia of obese women. Obese Tsc-2-deficient Eker rats similarly developed endometrial hyperplasia with a high frequency and short latency, and like obese women, endometrial hyperplasia that developed in obese rats exhibited loss of p27. In Eker rats, even a short duration of caloric restriction (2-4 months of age) reduced weight, increased adiponectin and lowered leptin to produce favorable leptin:adiponectin ratio, and reduced circulating insulin levels. Caloric restriction also increased p27 levels, primarily in the nucleus, and significantly decreased endometrial hyperplasia incidence by up to 50%. These data demonstrate that in the setting of obesity, loss of p27 occurs very early in progression to carcinoma. Importantly, p27 can be modulated along with weight by diet, and perhaps other lifestyle interventions that decrease risk for development of carcinoma, suggesting it may be a useful biomarker, and possible determinant of risk for endometrial carcinoma in the setting of obesity. Citation Format: Adrienne S. McCampbell, Megan L. Mittlestedt, Ruhee Dere, Lijun Zhou, Bojana Djordjevic, Pamela T. Soliman, Qian Zhang, Caimiao Wei, Stephen D. Hursting, Karen H. Lu, Cheryl L. Walker, Russell R. Broaddus. p27 as a biomarker and determinant of risk for endometrial carcinoma arising in the setting of obesity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4102. doi:10.1158/1538-7445.AM2014-4102

Effects of Bazedoxifene/Conjugated Estrogens on the Endometrium and Bone: A Randomized Trial

This phase 3 study evaluated the endometrial safety of bazedoxifene (BZA)/conjugated estrogens (CE) and bone mineral density (BMD) effects vs BZA alone, hormone therapy, and placebo (PBO). The Selective estrogens, Menopause, And Response to Therapy (SMART)-5 trial was a multicenter, randomized, double-blind, PBO- and active-controlled study in postmenopausal women with an intact uterus (N = 1843; aged 40-65 years) seeking treatment for menopausal symptoms. Subjects received daily oral BZA 20 mg/CE 0.45 or 0.625 mg, BZA 20 mg, CE 0.45 mg/medroxyprogesterone acetate (MPA) 1.5 mg, or PBO. Primary endpoints were incidence of endometrial hyperplasia and percent change in lumbar spine BMD at 12 months. Secondary endpoints included additional osteoporosis parameters and assessments of tolerability and safety. At 12 months, endometrial hyperplasia incidence was low (<1%) and similar among groups. The BZA/CE group showed significantly greater increases in lumbar spine and total hip BMD vs decreases with PBO (P < .001); the CE/MPA group had increased lumbar spine BMD compared with that in the BZA/CE group. The BZA 20 mg/CE 0.45 and 0.625 mg groups had cumulative amenorrhea rates similar to those with PBO and BZA and significantly higher than those with CE 0.45 mg/MPA 1.5 mg (P < .001). The incidence of breast tenderness with BZA/CE was similar to that with PBO and BZA and significantly lower than with that with CE/MPA (P < .01). Although adverse event (AE) rates were similar among the groups, the incidence of serious AEs overall and AE-related discontinuation rates were higher with CE/MPA than with BZA/CE, BZA, or PBO. BZA/CE showed low rates of endometrial hyperplasia and improved lumbar spine and total hip BMD and was generally safe and well tolerated.

The Incidence of Endometrial Hyperplasia and Cancer in 1031 Patients With a Granulosa Cell Tumor of the Ovary

Concurrent presence of endometrial hyperplasia or cancer in patients with granulosa cell tumors (GCTs) is common, with reported incidences of 25.6% to 65.5%. Consequently, bilateral salpingo-oophorectomy and hysterectomy is usually recommended in patients with a GCT, but this remains debatable. Our aim was to evaluate the need for hysterectomy in patients with GCTs by studying the incidence of pathologically confirmed endometrial abnormalities at the time of diagnosis of GCT and during follow-up. All cases of GCT between 1991 and 2012 were evaluated for endometrial pathology using the Dutch nationwide network and registry of histopathology and cytopathology (PALGA). A total of 1031 cases of GCT were identified at a mean ± SD age of 55 ± 17 years. The incidence of GCTs in the period 1991-2012 was 0.61 per 100,000 women per year. Concurrent endometrial cancer at the time of diagnosis of GCT was found in 58 patients (5.9%) and endometrial hyperplasia in 251 patients (25.5%), including complex hyperplasia in 89 patients (9.1%) and simple hyperplasia in 162 patients (16.5%). Long-term follow-up of 490 patients (47.5%) without a hysterectomy showed that endometrial abnormalities were found in 10 patients (2.0%) of which 2 had endometrial cancer. Interestingly, 8 (80%) of the 10 patients with endometrial abnormalities had recurrent GCT at the time of diagnosis of endometrial hyperplasia or cancer. Our data suggest that after surgical removal of GCT, development of an endometrial abnormality, especially cancer, is very rare. Therefore, hysterectomy is not recommended in patients with a GCT without endometrial abnormalities at the time of diagnosis.

Assessment of the safety of long-term bazedoxifene treatment on the reproductive tract in postmenopausal women with osteoporosis: Results of a 7-year, randomized, placebo-controlled, phase 3 study

ObjectiveTo evaluate the clinical safety of bazedoxifene (BZA) on the reproductive tract in postmenopausal women with osteoporosis over 7 years. Study designThis was a second, blinded, 2-year extension of a 3-year, randomized, double-blind, placebo (PBO)- and active-controlled phase 3 trial. In the core study, subjects were randomized to receive BZA 20 or 40mg, raloxifene 60mg, or PBO. During years 4–5, the raloxifene arm was discontinued and subjects receiving BZA 40mg were transitioned to BZA 20mg. Subjects continued to receive BZA 20mg or PBO during years 6–7. Main outcome measuresThe primary endpoint was the incidence of new vertebral fractures at 7 years (reported separately). Reproductive tract safety findings at 7 years are reported here. Endometrial thickness was assessed by transvaginal ultrasonography for subjects in the endometrial safety substudy. Adverse events (AEs) were recorded throughout the study. ResultsAt 7 years, the adjusted mean (±standard error) change in endometrial thickness was similar with BZA and PBO (−0.11±0.21 and 0.07±0.32mm, respectively). The incidence of endometrial hyperplasia was low (0.1% for both groups). BZA showed significantly lower rates than PBO of endometrial carcinoma (0.1% vs. 0.4%; P=0.020) and vaginitis (6.1% vs. 7.6%; P=0.035). There were more cases of ovarian carcinoma with BZA (n=4 [0.1%]) than PBO (n=0); the difference was not statistically significant. Rates of breast-related and other gynecologic AEs were similar among groups. ConclusionsBZA was associated with a favorable reproductive safety profile in postmenopausal women with osteoporosis over 7 years.

Suspecting Malignancy in Endometrial Polyps: Value of Hysteroscopy

Hysteroscopic polypectomy is the gold standard to treat endometrial polyps and obtain specimens for histological evaluation. There is continuing debate as to when to offer hysteroscopic polypectomy, especially in asymptomatic women with incidental lesions. The aims of this study were to assess the accuracy of hysteroscopy and Vabra sampling in diagnosing atypical hyperplasia and cancer growing on the surface of endometrial polyps and to investigate the association between atypical endometrial polyps and some potential clinical risk factors. This was a retrospective study. We assessed 1039 hysteroscopies and we identified 345 women with endometrial polyps. All patients with endometrial polyps underwent hysteroscopic polypectomy. Data about age, menopausal status, abnormal uterine bleeding (AUB), hormone replacement therapy and tamoxifen use were collected. Hysteroscopic, histological and clinical data were analyzed. The incidence of endometrial hyperplasia or cancer growing on the surface of endometrial polyps was significantly low (1.7%). Hysteroscopy correctly excluded (negative predictive value: 100%) and accurately predicted (positive predictive value: 85.7%) preneoplastic or neoplastic lesions growing within the epithelial layer of endometrial polyps. Vabra sampling was inadequate for the histological diagnosis in 38.5% of cases. Age over 60 years and postmenopausal AUB were associated with an 8.3-fold ( P = 0.022) and 8.8-fold (P = 0.020) increased risk, respectively, of preneoplastic and neoplastic lesions growing on the surface of endometrial polyps. Diagnostic hysteroscopy is a good tool to predict malignancy of the epithelial layer of endometrial polyps. Age over 60 years and AUB are associated with an increased risk of malignant polyps. Few suspicious endometrial polyps should undergo surgical resection.

Effects of bazedoxifene/conjugated estrogens on endometrial safety and bone in postmenopausal women

ABSTRACTObjectives Bazedoxifene/conjugated estrogens (BZA/CE) has demonstrated efficacy in improving vasomotor and vulvar/vaginal atrophy symptoms in postmenopausal women. This study evaluated the endometrial safety of BZA/CE and effects on bone mineral density (BMD) compared with CE/medroxyprogesterone acetate (MPA) and placebo.Methods The Selective estrogens, Menopause, And Response to Therapy (SMART)-4 trial was a 1-year, multicenter, double-blind, randomized, placebo– and active-controlled, phase-3 study in non-hysterectomized, postmenopausal women (n = 1061; aged 40 −< 65 years). Subjects received BZA 20 mg/CE 0.45 or 0.625 mg, CE 0.45 mg/MPA 1.5 mg, or placebo daily. Primary endpoints were the incidence of endometrial hyperplasia and the change in lumbar spine BMD at 1 year. Secondary endpoints included the change in total hip BMD and rates of amenorrhea and breast pain.Results At 1 year, no cases of endometrial hyperplasia were identified in the BZA 20-mg/CE 0.45-mg group, while three cases (1.1%) were confirmed for the BZA 20-mg/CE 0.625-mg group (95% one-sided confidence interval upper limit < 4%). Both BZA/CE doses significantly increased lumbar spine and total hip BMD versus placebo (p ≤ 0.001) and showed low incidences of bleeding and breast tenderness, similar to placebo and significantly lower than for CE 0.45 mg/MPA 1.5 mg (p < 0.05). BZA/CE treatment was generally safe and well tolerated.Conclusions BZA 20 mg/CE 0.45 and 0.625 mg significantly improved BMD while maintaining endometrial safety and showed a favorable safety/tolerability profile over 1 year. BZA/CE may be a promising therapy for treating menopausal symptoms and preventing osteoporosis in non-hysterectomized, postmenopausal women.

Incidence rates of endometrial hyperplasia, endometrial cancer and hysterectomy from 1980 to 2003 within a large prepaid health plan

Obesity strongly increases the risk of endometrial cancer and is projected to increase current and future endometrial cancer incidence. In order to fully understand endometrial cancer incidence, one should also examine both hysterectomy, which eliminates future risk of endometrial cancer, and endometrial hyperplasia (EH), a precursor that prompts treatment (including hysterectomy). Hysterectomy and EH are more common than endometrial cancer, but data on simultaneous temporal trends of EH, hysterectomy and endometrial cancer are lacking. We used linked pathology, tumor registry, surgery and administrative datasets at the Kaiser Permanente Northwest Health Plan to calculate age-adjusted and age-specific rates, 1980-2003, of EH only (N = 5,990), EH plus hysterectomy (N = 904), hysterectomy without a diagnosis of EH or cancer (N = 14,926) and endometrial cancer (N = 1,208). Joinpoint regression identified inflection points and quantified annual percentage changes (APCs). The EH APCs were -5.3% (95% confidence interval [CI] = -7.4% to -3.2%) for 1980-1990, -12.9% (95% CI = -15.6% to -10.1%) for 1990-1999 and 2.4% (95% CI = -6.6% to 12.2%) for 1999-2003. The EH-plus-hysterectomy APCs were -8.6% (95% CI = -10.6% to -6.5%) for 1980-2000 and 24.5% (95% CI = -16.5% to 85.7%) for 2000-2003. Hysterectomy rates did not significantly change over time. The endometrial cancer APCs were -6.5% (95% CI = -10.3% to -2.6%) for 1980-1988 and 1.4% (95% CI = -0.2% to 3.0%) for 1988-2003. Hysterectomy rates were unchanged, but increased endometrial cancer incidence after 1988 and the reversal, in 1999, of the longstanding decline in EH incidence could reflect the influence of obesity on endometrial neoplasia.

Incorporating bazedoxifene/conjugated estrogens into the current paradigm of menopausal therapy

Many women experience bothersome vasomotor and vaginal symptoms during the menopausal transition. Decreasing levels of estrogens during menopause are also associated with reduced bone density and an increased risk of osteoporosis. Combined estrogen/progestin therapy (hormone therapy) effectively treats menopausal symptoms and prevents bone loss, but has been associated with some safety and tolerability concerns. A novel menopausal therapy is the tissue selective estrogen complex, which pairs a selective estrogen receptor modulator with one or more estrogens. In preclinical studies, the tissue selective estrogen complex partnering bazedoxifene (BZA) with conjugated estrogens (CE) antagonized stimulation of breast and endometrial tissue, reduced vasomotor instability, and preserved bone mass in rat and mouse models. The specific attributes seen with BZA/CE were different from those observed with other selective estrogen receptor modulator/estrogen pairings. BZA/CE has undergone clinical evaluation in the Phase III Selective estrogens, Menopause, And Response to Therapy (SMART) trials in postmenopausal women with an intact uterus. Of the various doses of BZA/CE evaluated, BZA 20 mg/CE 0.45 mg and 0.625 mg were associated with a low incidence of endometrial hyperplasia (<1%) similar to placebo, and showed significant improvements in hot flushes and vulvar/vaginal symptoms and increases in bone mineral density. BZA 20 mg/CE 0.45 mg and 0.625 mg were associated with a low incidence of breast-related adverse events and demonstrated no difference from placebo in age-related changes in mammographic breast density. Both BZA/ CE doses showed a favorable tolerability profile, with no increases in uterine bleeding or breast tenderness, and had positive effects on metabolic parameters and quality of life. BZA/CE may be a promising alternative to hormone therapy for the treatment of menopausal symptoms and prevention of osteoporosis in nonhysterectomized postmenopausal women.

Histopathological Pattern of Endometrium on Diagnostic D & C in Patients with Abnormal Uterine Bleeding

Aims and Objectives: To determine histopathologi-cal pattern of endometrium in patients with abnormal uterine bleeding. Study Type: Observational, Cross sectional. Place of Study: Obs and Gynae department, Madina teaching hospital, FSD. Duration of Study: One and a half year from Oct 2008 to Apr 2010. Patients and Methods: Patients presenting to Madina teaching hospital OPD with complaint of abnormal uterine bleeding were assessed via inclusion and ex-clusion criteria to be included in this study. A detailed history was followed by general physical, systemic, and gynecological examination. A pelvic ultrasound was performed followed by diagnostic D&C. Endo-metrial biopsy sent for histopathological examination in Pathology department of Madina teaching hospital, FSD. Data was collected over a period of one and a half year, and shifted to computer for analysis. Statisti-cal package of social sciences (SPSS) version 15 was used for statistical analysis of data. Chi-square good-ness of fit was used as test of statistical significance. Results: The most common pathological pattern iden-tified was proliferative phase endometrium (46.4%). Secretary phase endometrium was second most common pathology (37.6%). Cystic (5.2%), adenomatous (3.8%), and atypical (3.6%) hyperplasia constituted 12.6% of bulk. In 1.4%, endometritis was identified as a cause of abnormal uterine bleeding followed by atrophic endometrium (1%). Polyp was identified in 0.6% of cases followed by endometrial carcinoma (0.4%). Conclusion: Histopathological pattern of endomet-rium in patients with abnormal uterine bleeding is qui-te variable regardless of age, parity and ethnicity. Al-though the incidence of endometrial hyperplasia is grossly variable, yet incidence of endometrial carci-noma is small in all sited studies. Key words: D&C, AUB.

Endometrial histology and predictable clinical factors for endometrial disease in women with polycystic ovary syndrome

ObjectiveThis study was aimed to investigate endometrial histology and to find predictable clinical factors for endometrial disease (hyperplasia or cancer) in women with polycystic ovary syndrome (PCOS).MethodsWe investigated the endometrial histology and analyzed the relationship between endometrial histology and clinical parameters, such as LH, FSH, estradiol, testosterone, fasting and 2 hours postprandial glucose and insulin, insulin resistance, body mass index, endometrial thickness, menstrual status from 117 women with PCOS. Statistical analysis was performed with chi square and t-test, p-value<0.05 was considered as statistically significant. And receiver operating characteristic curve was used to find predictable clinical factors for endometrial disease and to decide the cuff off values.ResultsIn 117 women with PCOS, endometrial histologic profiles are as follows: proliferative phase in 90 women (76.9%), endometrial hyperplasia in 25 women (21.4%), and endometrial cancer in 2 women (1.7%). Of 25 women with endometrial hyperplasia, simple hyperplasia without atypia, complex hyperplasia without atypia and complex hyperplasia with atypia were diagnosed in 15 (12.8%), 6 (5.1%), 4 (3.4%) women, respectively. Age and endometrial thickness were significantly related with endometrial disease, p=0.013 and p=0.001, respectively. At the cut off level of 25.5 years in age, sensitivity and specificity predicting for endometrial disease were 70.4% and 55.6%, respectively (p=0.023). At the cut off level of 8.5 mm in endometrial thickness, sensitivity and specificity were 77.8% and 56.7%, respectively (p=0.000).ConclusionIn women with PCOS, the incidence of endometrial hyperplasia and cancer were 21.4% and 1.7%. The age and endometrial thickness may be used as clinical determining factors for endometrial biopsy.

Hormone therapy: a tale of two cancers – the potential of estrogen/selective estrogen receptor modulator combinations

Expert Rev. Endocrinol. Metab. 5(5), 633–635 (2010) The public debate surrounding the use of hormone therapy in the menopause has reached a polemic divide. Many see menopausal hormone therapy as a choice between the risk of one of two cancers. We learned many years ago that un opposed estrogen exposure would lead to a high incidence of endometrial hyperplasia and cancer in women with a uterus. We can prevent the increased incidence of endometrial cancer by the addition of a progestin; however, this comes at a price of increased breast cancer risk. These risks have caused many to abandon hormone therapy. Fortunately, new agents currently under the US FDA review may eliminate this dichotomy and allow for progestinfree hormone administration in all women, including those with an intact uterus.

Ultra low dose continuous combined hormone replacement therapy with 0.5 mg 17β-oestradiol and 2.5 mg dydrogesterone: Protection of the endometrium and amenorrhoea rate

Objectives and study design The aim of this open, multicentre study was to demonstrate the endometrial safety and assess the bleeding pattern of ultra low dose continuous combined hormone replacement therapy with 0.5 mg 17β-oestradiol and 2.5 mg dydrogesterone in 446 healthy, non-hysterectomised, postmenopausal women with symptoms of oestrogen deficiency. Main outcome measure Aspiration endometrial biopsies were performed at baseline and after 1 year of treatment to assess the incidence of endometrial hyperplasia or a more serious endometrial outcome. Results The only adverse endometrial outcome at the end of the study was one case of simple hyperplasia. This gives an overall incidence of 0.27% (95% CI: 0.01–1.48%) in the per protocol sample ( n = 395). The overall rate of amenorrhoea in the full sample ( n = 446) was 68% and 14% had only one or two bleeding/spotting episodes. The rate of amenorrhoea in months 10–12 ( n = 413) was 88%. The number of bleeding/spotting days per cycle fell during the study. The mean number of bleeding/spotting days was 5.8 and the mean number of days without bleeding was 358.2. Spotting alone was the most prevalent bleeding intensity, whilst heavy bleeding was rare. Conclusions In conclusion, 2.5 mg dydrogesterone continuously combined with 0.5 mg 17β-oestradiol effectively protects the endometrium in postmenopausal women in accordance with the guidelines of the Committee for Medicinal Products for Human Use (CHMP). It has a favourable amenorrhoea rate and is well tolerated by the majority of women.

Incidence of endometrial hyperplasia

The objective of the study was to estimate the age-specific incidence of endometrial hyperplasia: simple, complex, and atypical, in order of increasing likelihood of progression to carcinoma. Women aged 18-90 years with endometrial pathology specimens (1985-2003) at a large integrated health plan were identified using automated data. Incidence rates were obtained by dividing the number of cases by the estimated number of female health plan enrollees who retained a uterus. Endometrial hyperplasia peak incidence was: simple, 142 per 100,000 woman-years, complex, 213 per 100,000 woman-years, both in the early 50s; and atypical, 56 per 100,000 woman-years in the early 60s. Age-adjusted incidence decreased over the study period, especially for atypical hyperplasia. Endometrial hyperplasia incidence without and with atypia peaks in the early postmenopausal years and in the early 60s, respectively. Given that some cases of endometrial hyperplasia likely go undiagnosed, the figures provided should be viewed as minimum estimates of the true incidence.

Abstract A28: Loss of inhibitory IRS-1 phosphorylation is an early event in mTOR-dependent endometrial hyperplasia and carcinoma

Abstract A28 Activation of IGF-I receptor signaling contributes to the development of endometrioid-type endometrial carcinoma in humans and in rodent models. This signaling pathway is under both positive and negative regulation, including S6K phosphorylation of IRS-1 at S636/639, which occurs downstream of mTOR activation to inhibit this adapter protein. We observed activation of mTOR signaling with a high frequency in human endometrial hyperplasia and carcinoma, but an absence of IRS1 phosphorylation at S636/639, despite the high levels of activated S6K in these tumors. To explore when during disease progression mTOR activation and loss of inhibitory IRS-1 phosphorylation occurred, we utilized the Eker rat (Tsc2Ek/+) model for this disease, where endometrial hyperplasia develops as a result of loss of Tsc2, the “gatekeeper” for mTOR signaling. We observed mTOR activation early in progression in hyperplasias and in some histologically normal appearing epithelial cells, suggesting that event(s) in addition to loss of Tsc2 were required for progression to hyperplasia. In contrast, IRS-1 phosphorylation at S636/639 was observed in normal appearing epithelium, but was absent from all hyperplasias, indicating loss of IRS-1 inhibition by S6K occurred during progression to hyperplasia. Furthermore, treatment of Eker rats with an mTOR inhibitor resulted in a decreased incidence of endometrial hyperplasia [54/79 hyperplasias/uterine cross section in vehicle controls to 6/90 in treated rats (p&amp;lt;0.001)] and decreased the proliferative index of hyperplastic endometrial epithelial cells by &amp;gt;95% (p &amp;lt; 0.05). Since progression from normal epithelium to endometrial carcinoma proceeds via the intermediate step of endometrial hyperplasia, these data suggest a progression sequence where activation of mTOR is followed by loss of negative feedback to IRS-1 during the initial stages of development of this disease. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A28.

Risk of complex and atypical endometrial hyperplasia in relation to anthropometric measures and reproductive history.

The authors sought to test the hypothesis that characteristics and exposures which influence the balance of estrogen and progesterone bear on the incidence of endometrial hyperplasia (EH), a noninvasive proliferation of the lining of the uterus. Cases included all female members of Group Health (Washington State) who were diagnosed with complex EH or EH with atypia during the period 1985-2003 and whose diagnoses were confirmed in a pathology review (n = 446). Controls were selected randomly from Group Health membership files and were matched to the cases by age and enrollment status at the reference date. An increased risk of EH was associated with increasing body mass index and nulliparity. There was a suggestion of a decreased risk of EH with atypia among current smokers. No association with diabetes or hypertension was found. The risk factors observed to be associated with EH in this study are similar to those associated with endometrial cancer. Whether these risk factors predispose women to cancer simply by increasing EH incidence or continue to augment cancer risk even after EH is present is currently unknown.

Abnormal Uterine Bleeding

Disorders of the menstrual cycle are common problems in ambulatory medicine. Abnormal uterine bleeding describes bleeding that is excessive or outside the normal menstrual cycle. In the premenopausal woman, the differential diagnosis is broad, and pregnancy must always be considered. Determining whether the bleeding is ovulatory or anovulatory is a central part of the evaluation, as anovulation is one of the most common causes of abnormal uterine bleeding. In patients with anovulatory bleeding, the goal of treatment is to minimize blood loss and prevent complications from chronic unopposed estrogen. In women with oligomenorrhea or amenorrhea, after establishing the etiology, it is necessary to maintain adequate estrogen to support bone health. In the peri- and postmenopausal population, because the incidence of endometrial hyperplasia and malignancy rises, it is important to have a low threshold for endometrial assessment.

What's new in the other general journals

Raloxifene is widely used in primary care to prevent and treat osteoporosis in postmenopausal women. Raloxifene can also protect women from breast cancer, and worked as well as tamoxifen in...

A One-Year Neonatal Mouse Carcinogenesis Study of Quinacrine Dihydrochloride

Quinacrine is an acridine derivative under investigation for its use in nonsurgical female sterilization. Safety issues regarding the carcinogenic potential of quinacrine have been raised because it is mutagenic and clastogenic in vitro. The objective of the study was to evaluate the carcinogenic potential of quinacrine dihydrochloride (quinacrine) in neonatal mice treated with single intraperitoneal doses on postpartum days 8 and 15 and observed for 52 weeks. Neonatal Crl: CD-1 mice of each sex were randomly allocated into four treatment groups (0, 10, 50, and 150 mg/kg), dosed twice with quinacrine suspended in carboxymethylcellulose, observed for 52 weeks post dose, and then euthanized, necropsied, and subjected to a full histopathological examination. In male mice, tumor incidence was not significantly increased at any site at any dose level. In female mice, the incidence of benign uterine endometrial stromal polyps was slightly greater at the mid and high dose (> or = 50 mg/kg), as was the incidence of endometrial hyperplasia. The incidence of polyps in these groups was not significantly greater than in controls by pair-wise comparison but was significantly greater (p = .042) by the linear trend test. The authors conclude that quinacrine administered twice to neonatal mice may have enhanced or accelerated the development of endometrial hyperplasia and uterine stromal polyps at higher doses. Because uterine stromal polyps are a commonly observed benign tumor in older mice, the significance of this finding is unclear and will require a weight of evidence evaluation for a conclusion on the carcinogenic potential of quinacrine.

Defining the extent of cables loss in endometrial cancer subtypes and its effectiveness as an inhibitor of cell proliferation in malignant endometrial cells in vitro and in vivo

Loss of Cables expression is associated with a high incidence of endometrial hyperplasia and endometrial adenocarcinoma in humans. The Cables mutant mouse develops endometrial hyperplasia and following exposure to chronic estrogen develops early endometrial adenocarcinoma. The objectives of the current study were to determine if: 1) loss of Cables expression occurred in high grade endometrioid adenocarcinoma, uterine serous and clear cell carcinoma as observed in endometrial hyperplasia and low grade endometrial adenocarcinoma; 2) overexpression of Cables inhibited cell proliferation in endometrial cancer (EC) cells in vitro and in vivo; and 3) progesterone could regulate the expression of Cables mRNA. Hyperplastic endometrium and low and high grade endometrioid adenocarcinoma showed loss of Cables expression when compared to benign control secretory endometrium. Loss of Cables expression in serous and clear cell tumors was similar to that observed in endometrioid adenocarcinomas with greater than 80% showing loss of protein expression. Treatment of EC lines with progesterone increased cables expression in low-grade EC whereas it had no effect on cables expression in cells derived from high-grade EC. The progesterone-induced increase in cables was abrogated in the presence of a progesterone receptor (PR) antagonist, suggesting the PR mediates the increase. Cables overexpression inhibited cell proliferation of well differentiated EC cells and had no effect on the poorly differentiated EC cells. The capacity to form tumors was dramatically reduced in the Cables overexpressing cell lines compared to those cells containing the control vector. Collectively these results suggest that Cables is an important regulator of cell proliferation and loss of Cables expression contributes to the development of all types of EC.

Levonorgestrel and 17β-estradiol given transdermally for the prevention of postmenopausal osteoporosis

Aim: To evaluate the efficacy and safety of a new transdermal continuous combined hormone replacement therapy (HRT) for the prevention of postmenopausal osteoporosis. Methods: 212 osteopenic (lumbar spine and/or hip (femoral neck) bone mineral density (BMD) between −1.0 and −2.5 S.D. of the premenopausal mean value) postmenopausal women aged 45–65 years participated in a 2-year prospective study. Treatments were 45 μg 17β-estradiol combined with 30 ( n = 69) or 40 μg ( n = 72) levonorgestrel daily or placebo ( n = 71) given as a 7-day patch. All received a daily supplement of 500 mg calcium. BMD at lumbar spine (L2–L4), hip and total body, as well as blood and urinary biochemical markers of bone turnover (serum osteocalcin (sOC), serum bone-specific alkaline phosphatase (sBSAP), urinary calcium (uCa) and urinary CrossLaps (uCTX)) were measured regularly. Results: BMD at the lumbar spine, hip and total body increased by 8, 6 and 3% ( P < 0.001), respectively, in the hormone groups versus placebo. The bone markers all decreased accordingly (sOC: 37%, sBSAP: 34% and uCTX: 65% from baseline (all P < 0.001)), except for uCa that did not change significantly. No significant dose-related effect of levonorgestrel was found. Vaginal bleeding/spotting decreased from 48 to 25% of the HRT-treated women during the study period. Skin tolerance was good in 84% of the women with no difference between the study groups. No incidences of endometrial hyperplasia, uterine or mammary cancer occurred. Conclusion: The transdermal combination of 17β-estradiol and levonorgestrel has a positive effect on BMD in an osteopenic postmenopausal population. Furthermore, a high safety profile was observed.