Perimenopausal abnormal uterine bleeding.

Abnormal uterine bleeding is a frequent symptom in the perimenopause. Causes are numerous, ranging from physiological reactions due to decreasing/unstable ovarian function to premalignant and malignant conditions. Benign findings such as endometrial polyps and myomas increase with age, leading to more abnormal uterine bleeding in the perimenopause. Cervical and vaginal causes of abnormal uterine bleeding should be excluded by speculum examination. Sexually transmitted diseases or pregnancy should be ruled out. Measurement of haemoglobin and iron levels, human chorion gonadotropin and thyroid hormones are relevant in selected cases. Transvaginal ultrasound is an ideal first step for the evaluation of perimenopausal abnormal uterine bleeding. Saline or gel contrast sonohysterography improves the diagnostic accuracy. Based on the ultrasound findings, invasive procedures such as endometrial biopsy or hysteroscopy can be planned. Once premalignant and malignant causes are excluded, the necessity for treatment can be evaluated in collaboration with the patient. Heavy menstrual bleeding causing anaemia will need immediate treatment. In less severe cases and in intermenstrual bleeding, expectant management can be considered. Hormonal treatment, such as oral progestogens, combined oral contraceptives or insertion of the levonorgestrel intrauterine system, may be a possibility if anovulatory bleeding is interfering with quality of life. The amount of bleeding can be reduced both by antifibrinolytic and non-steroidal anti-inflammatory drugs, progestogens and the levonorgestrel intrauterine system. Focal intrauterine lesions such as endometrial polyps or submucous myomas may require operative hysteroscopic procedures. Endometrial ablation or endometrial resection are good choices in selected cases, but some women will need a hysterectomy to treat their abnormal uterine bleeding in perimenopause.

Birth weight, childhood body mass index and height and risks of endometriosis and adenomyosis.

Background: Body size in adult life is likely associated with risks of endometriosis and adenomyosis, yet little is known about associations with body size earlier in life.Aim: To examine whether birth weight, childhood body mass index (BMI) and height are associated with risks of endometriosis and adenomyosis.Subjects and methods: From the Copenhagen School Health Records Register, 171,447 girls born 1930-1996, with measured weights and heights at ages 7-13 were included. Outcomes were obtained from health registers. Cox regressions were performed to estimate hazard ratios (HR) and 95% confidence intervals (CI).Results: During follow-up, 2149 endometriosis cases and 1410 adenomyosis cases were diagnosed. Childhood BMI was inversely associated with endometriosis (HR = 0.92 [95% CI: 0.88-0.96] per z-score at age 7). In contrast, childhood height was positively associated with endometriosis (HR = 1.09 [95% CI: 1.05-1.14] per z-score at age 7). Associations with childhood body size did not differ by endometriosis location. Childhood BMI and height had limited associations with adenomyosis. Birth weight was not associated with endometriosis or adenomyosis.Conclusion: Lean and tall girls are more often diagnosed with endometriosis, but not adenomyosis. These findings suggest that indicators of endometriosis risk are already apparent at early ages.

Childhood Overweight, Tallness, and Growth Increase Risks of Ovarian Cancer.

BACKGROUND: Adult body size is related to ovarian cancer risks, but size in childhood may also influence risks. We investigated if childhood body mass index (kg/m2), height, and growth patterns were associated with ovarian cancer overall and by histologic subtypes, including effects of birthweight. METHODS: A cohort of 155,958 girls from the Copenhagen School Health Records Register, born 1930 to 1989 with measured weights and heights from 7 to 13 years, were included. During follow-up, 1,041 ovarian cancers were recorded. Overweight was defined using International Obesity Task Force criteria. Cox regressions were performed. RESULTS: Compared with non-overweight girls, at most ages girls with overweight had increased risks of ovarian cancer overall (HR range: 1.24-1.34), mucinous, endometrioid, and clear cell ovarian cancers, but not serous and other ovarian cancers. Childhood height had positive and significant associations with ovarian cancer overall (HR range: 1.07-1.10 per z-score) and the endometrioid subtype but not with the other subtypes. Adjusting for birthweight minimally altered the associations with childhood body size. In growth analyses, girls with overweight or who were tall at 7 and 13 years had increased risks of ovarian cancer overall compared with average-sized girls at both ages. CONCLUSIONS: Ovarian carcinogenesis is linked to childhood overweight, tallness, and growth, with variations across histological subtypes, suggesting that early life plays a role in the origins of this disease. IMPACT: These findings emphasize that healthy body size and growth during childhood are important as they may contribute to reducing ovarian cancer risks.

Birth weight and the risk of histological subtypes of ovarian and endometrial cancers: Results from the Copenhagen School Health Records Register.

BACKGROUND: Studies of birth weight associations with ovarian and endometrial cancer risks are limited with inconsistent results, and none has evaluated associations by histologic subtype. We utilized prospectively collected birth weight information to investigate the association with risk of ovarian and endometrial cancers overall and by histologic subtype. METHODS: 162,559 girls, born from 1930 to 1989, from the Copenhagen School Health Records Register (CSHRR) were followed prospectively via linkage with the Danish health registers. Ovarian (n=666) and endometrial (n=694) cancers were identified from 1978 to 2014. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Women with lower (2.0-3.25 vs. 3.26-3.75kg) and higher (3.75-5.5 vs. 3.26-3.75kg) birth weights had increased risks of ovarian cancer overall [HR (95% CI): 1.27 (1.06-1.52); 1.51 (1.21-1.87), respectively] and serous ovarian cancers [1.54 (1.19-1.98); 1.98 (1.47-2.67), respectively]. A decreased risk of Type II endometrial tumors was suggested per kilogram increase in birth weight [HR (95% CI): 0.63 (0.40-1.00)]. CONCLUSIONS: Our results suggest that both lower and higher birth weights were associated with increased ovarian cancer risk and associations were particularly strong for serous ovarian cancer, the most common subtype. Birth weight was not associated with most types of endometrial cancer.

Childhood body mass index growth trajectories and endometrial cancer risk.

Previously, we found that excess weight already in childhood has positive associations with endometrial cancer; however, associations with changes in body mass index (BMI) during childhood are not well understood. Therefore, we examined whether growth in childhood BMI is associated with endometrial cancer and its sub-types. A cohort of 155,505 girls from the Copenhagen School Health Records Register with measured weights and heights at the ages of 6-14 years and born 1930-1989 formed the analytical population. BMI was transformed to age-specific z scores. Using linear spline multilevel models, each girl's BMI growth trajectory was estimated as the deviance from the average trajectory for three different growth periods (6.25-7.99, 8.0-10.99, 11.0-14.0 years). Via a link to health registers, 1,020 endometrial cancer cases were identified, and Cox regressions were performed. A greater gain in BMI during childhood was positively associated with endometrial cancer but no differences between the different growth periods were detected in models adjusted for baseline BMI. The hazard ratios for the associations with overall growth during childhood per 0.1 z score increase were 1.15 (95% confidence interval [CI]: 1.07-1.24) for all endometrial cancers, 1.12 (95% CI: 1.04-1.21) for estrogen-dependent cancers, 1.16 (95% CI: 1.06-1.26) for endometrioid adenocarcinomas and 1.46 (95% CI: 1.16-1.84) for non-estrogen-dependent cancers. Growth in BMI in early life is positively linked to later endometrial cancer risk. We did not identify any sensitive childhood growth period, which suggests that excess gain in BMI during the entire childhood period should be avoided.

Practice points in gynecardiology: Abnormal uterine bleeding in premenopausal women taking oral anticoagulant or antiplatelet therapy.

A growing number of premenopausal women are currently using antithrombotic and/or (dual) antiplatelet therapy for various cardiovascular indications. These may induce or exacerbate abnormal uterine bleeding and more awareness and knowledge among prescribers is required. Heavy and irregular menstrual bleeding is common in women in their forties and may have a variety of underlying causes that require different treatment options. Thus using anticoagulants in premenopausal women demands specific expertise and close collaboration between cardiovascular physicians and gynecologists. In this article we summarize the scope of the problem and provide practical recommendations for the care for young women taking anticoagulants and/or (dual) antiplatelet therapy. We also recommend that more safety data on uterine bleeding with novel anticoagulants in premenopausal women should be obtained.

EMAS clinical guide: assessment of the endometrium in peri and postmenopausal women.

INTRODUCTION: Invasive as well as non-invasive methods are available for assessment of the endometrium. AIMS: The purpose of this clinical guide is to provide evidence-based advice on endometrial assessment in peri and postmenopausal women. MATERIAL AND METHODS: Literature review and consensus of expert opinion. RESULTS AND CONCLUSIONS: Presuming speculum examination and cervical cytology are assessed, transvaginal ultrasound should be undertaken initially as it is non-invasive and will not only measure endometrial thickness, but will also detect other pelvic pathology such as leiomyomas and ovarian tumours. The main indication for invasive methods is to obtain endometrial tissue to diagnose or exclude the presence of endometrial cancer or pre-malignancies. Biopsy is mainly undertaken as an outpatient procedure, but sampling is 'blind'. Hysteroscopy is used when focal lesions affecting the uterine cavity are suspected such as endometrial polyps or sub-mucous fibroids. None of the available methods are perfect. Ultrasound evaluation is dependent on the experience of the examiner, the equipment and the quality of visualization. Hysteroscopy too is dependent on the examiner and fibroids may obstruct visualization. Blind endometrial biopsy procedures often miss focal lesions. Thus re-examination is necessary when symptoms persist and no explanation for these has been identified. This clinical guide will evaluate the different methods of endometrial assessment, their indications and limitations. Guidance is also given about dealing with inconclusive investigations and persistent symptoms.

Patients with atypical hyperplasia of the endometrium should be treated in oncological centers.

OBJECTIVES: To examine the prevalence of undiagnosed endometrial carcinoma (EC) among women with a preoperative diagnosis of atypical endometrial hyperplasia (AEH) in correlation to age, BMI and menopause. METHODS: Data extracted from the Danish Gynecological Cancer Database (DGCD) covering women diagnosed with AEH between January 1, 2005 and November 1, 2010 undergoing surgery. DGCD is a multidisciplinary, nationwide, clinical database of all cases of gynecological cancer and AEH in Denmark diagnosed after January 1, 2005. Registration is mandatory. Primary outcome was preoperative- and postoperative diagnoses. Secondary outcomes were relationship to BMI, age and menopause. RESULTS: The preoperative diagnosis of AEH was retained in 41% of 773 cases and 59% had endometrial cancer. Of the cancer cases, 18% had more than Stage I disease and 3% were non-endometrioid. Cancer risk was significantly related to age (p<0.0001) and menopause (p<0.0001). The 80% who were postmenopausal had a significantly higher risk of a postoperative cancer diagnosis compared with the premenopausal group (OR 2.8). There was no significant difference regarding BMI (p=0.25). CONCLUSION: More than half of the 773 Danish women primarily diagnosed with AEH had undiagnosed cancer. Failure to diagnose endometrial carcinoma preoperatively can lead to inadequate staging and potentially suboptimal treatment. We recommend that atypical endometrial hyperplasia should be treated as carcinoma in specialized gynecological-oncology centers.

[Need of better preoperative staging of endometrial cancer]. / Behov for bedre præoperativ stadieinddeling af endometriecancer.

Endometrial cancer is one of the most frequent gynaecological cancers in Danish women. The staging of the cancer is done surgically in accordance with guidelines from the International Federation of Gynaecology and Obstetrics. The method has proven insufficient and unsuitable because treatment is frequently decided during surgery and the final staging is done by the pathologist when examining the specimen. Too many patients are over- or under-treated and there is a high demand for new diagnostic tools for preoperative staging of endometrial cancer. We have reviewed recent literature on the subject.

Endometrial safety of ultra-low-dose estradiol vaginal tablets.

OBJECTIVE: To evaluate the endometrial hyperplasia and carcinoma rate after 52-week treatment with ultra-low-dose 10-microgram 17ß-estradiol vaginal tablets in postmenopausal women with vaginal atrophy. METHODS: Endometrial biopsy data from individuals using active treatment (n=205) in a randomized, double-blind, placebo-controlled trial were pooled with the data from an open-label endometrial safety trial (n=336). Patients received 10-microgram estradiol vaginal tablets for 52 weeks. All endometrial biopsy samples were histologically analyzed at baseline and at end of trial by the same laboratory in both trials. RESULTS: A total of 541 women using estradiol were included in the combined analysis of endometrial safety. A total of 456 women completed the trials, and 443 women had a biopsy performed at week 52: 85.6% were categorized as "atrophic endometrium," 12.6% had nonevaluable biopsy samples, 1.1% had polyps, and 0.2% were categorized as "weakly proliferative." One case of complex hyperplasia without atypia was reported in an individual exposed to trial drug for only 9 days. One woman's biopsy sample demonstrated endometrioid adenocarcinoma, grade 2, but the lack of an evaluable screening biopsy sample makes it uncertain whether the carcinoma was preexisting. In total, two events of hyperplasia and carcinoma were reported in 386 evaluable biopsy samples (incidence rate 0.52% per year). CONCLUSION: The reported background incidence rate of endometrial hyperplasia and carcinoma in postmenopausal women is 0% to 1%. The results of this pooled analysis therefore support the endometrial safety of unopposed ultra-low-dose vaginal estrogen. There was no increased risk of endometrial hyperplasia and carcinoma in postmenopausal women undergoing treatment with 10-microgram estradiol vaginal tablets for 1 year under study conditions. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00108849 (VAG-2195) and NCT00431132 (VAG 1748). LEVEL OF EVIDENCE: II.

Effect on endometrium of long term treatment with continuous combined oestrogen-progestogen replacement therapy: follow up study.

OBJECTIVE: To determine effects of five years of treatment with an oral continuous combined regimen of 2 mg 17beta-oestradiol and 1 mg norethisterone acetate on endometrial histology in postmenopausal women. DESIGN: Follow up study in postmenopausal women. SETTING: 31 menopause clinics in the United Kingdom. PARTICIPANTS: 534 postmenopausal women, all with an intact uterus, who had completed nine months of treatment with oral continuous combined 2 mg 17beta-oestradiol and 1 mg norethisterone acetate agreed to take part in a long term follow up study. Women were assigned to different groups on the basis of the treatment status immediately before entering the original study: 360 women had taken sequential oestrogen-progestogen hormone replacement therapy, 164 had taken no hormone replacement therapy, and 10 had taken unopposed oestrogen therapy. METHODS: Endometrial aspiration specimens were taken before the women started the continuous combined regimen, after 9 and 24-36 months, and at the end of the five year treatment period or on withdrawal from the study. MAIN OUTCOME MEASURE: Results of endometrial histology. RESULTS: The duration of treatment with continuous combined hormone replacement therapy was 4.4 (range 1.1-5.9) years. Data on endometrial specimens were available for 526 women after nine months of treatment, 465 women after 24-36 months of treatment, and 398 women who completed the five years treatment (345 women) or were withdrawn between the two latter visits for biopsies (53 women). No cases of endometrial hyperplasia or malignancy were detected at biopsy; 69% of women had an endometrium classified as atrophic or unassessable on completion of the study or withdrawal from it. Before the continuous combined therapy was started, complex hyperplasia was detected in 21 women who had taken sequential hormone replacement therapy before the study and in one who had taken unopposed oestrogen. All of these women had normal results on histological examination of endometrial tissue after nine months of treatment with continuous combined hormone replacement therapy, and hyperplasia did not recur after up to five years of treatment. CONCLUSIONS: Long term treatment (for up to five years) with continuous combined hormone replacement therapy containing oestradiol 2 mg and norethisterone 1 mg daily was associated with neither endometrial hyperplasia nor malignancy. In women who had complex hyperplasia during previous sequential or unopposed regimens, the endometrium returned to normal during treatment with continuous combined hormone replacement therapy. These findings provide reassurance about the long term safety of this continuous combined regimen in terms of the endometrium.