Norethisterone for prolonged uterine bleeding associated with etonogestrel implant (IMPLANET): a randomized controlled trial.

Abnormal uterine bleeding is the third most common clinical presentation in gynecology OPD. Histopathological evaluation of the endometrial tissue plays a significant role in diagnosis and management of Abnormal Uterine Bleeding.
 Aim: To find out cause of abnormal uterine bleeding with the help of histopathological report of endometrial biopsy.
 Methodology: This is retrospective observational study done at NGMC from ( 1st June 2018 to -30th June 2019) of 100 patients endometrial biopsy sent for histopathological evaluation and diagnosis reports were correlated with age and bleeding pattern and patients were managed accordingly.
 Result: A total of 100 endometrial specimens submitted with clinical diagnosis of Abnormal Uterine Bleeding were studied. Patients age group ranged from 18 – 65 yrs and most of them were seen in the age group of 41–50 yrs (43%).The commonest complaint was menorrhagia i.e. 48% .The commonest endometrial pattern observed in the study was, proliferative phase endometrium (38%).
 Conclusion: Endometrial biopsy is one of the most useful diagnostic tools to find out cause of uterine bleeding in AUB cases and also helps in management of AUB patient.

Chronic treatment with 17 beta-oestradiol (E2) implants has been found to counteract the formation of more acidic isoforms of the gonadotrophins in post-menopausal women. Oral medication with an oestrogen in combination with a progestagen is a common hormone replacement therapy (HRT) in post-menopausal women. The present study investigated the effect of such a therapy on the concentration and charge of the gonadotrophin isoforms in serum. Serum samples were obtained from 20 post-menopausal women, mean age 60 years (range 50-72 years), treated with continuous daily oral medication of 2 mg E2 combined with 1 mg norethisterone acetate (NETA). FSH, LH and E2 in the serum was measured with fluoroimmunoassays. The median charge and charge heterogeneity of the FSH and LH isoforms were determined for each serum by electrophoresis in 0.1% agarose suspension. Sera from 20 post-menopausal women without a history of HRT served as controls. The results were compared with those from previous studies on post-menopausal women treated with E2 implants and on women with normal menstrual cycles. The E2 level in the oral-E2 + NETA treated women was 198-610 pmol/l, within the range expected during the mid-luteal phase of the normal menstrual cycle and similar to that of the group of women with an E2 implant. The mean LH level was similar to that of the luteal phase of the cycle and significantly lower than that of the controls (P < 0.001), the E2 implant group (P < 0.001) and at the follicular phase of the cycle (P < 0.01). The mean FSH level was similar to that of the follicular phase and the E2 implant group but lower than that of the controls (P < 0.001) and higher than at the luteal phase of the cycle (P < 0.01). The mean values for median charge of both FSH and LH were less acidic than those of the controls (P < 0.001) but more acidic than those for the E2 implant group (P < 0.01; P < 0.001) and for different phases of the menstrual cycle (P < 0.05; P < 0.001). The mean degree of charge heterogeneity of FSH was larger (P < 0.01), while that of LH was smaller (P < 0.01), than for the controls. The mean concentrations of SHBG in the oral E2 + NETA group, the E2 implant group and the controls were similar. Chronic oral therapy with 2 mg 17 beta-oestradiol combined with 1 mg norethisterone in post-menopausal women efficiently decreased the serum gonadotrophin levels but only partly counteracted the formation of the more acidic isoforms of FSH and LH after menopause. The differences in the charge for both FSH and LH between the E2 implant and the oral E2 + NETA treated groups may be due to the differences in route of administration of E2 or to the effect of norethisterone or both.

Abnormal uterine bleeding (AUB) is an acute/chronic variation in the normal menstrual cycle that affects adolescents, women of reproductive age and perimenopausal women. AUB affects approximately 3–30% of reproductive-aged women worldwide, and reduces their quality of life and productivity whilst increasing the overall healthcare burden. Its management requires thorough medical evaluation and individualized treatment. Depending on the severity and cause of AUB, its treatment ranges from lifestyle modifications and hormonal therapies to more invasive procedures or surgery. Although hormonal therapy is the preferred first-line measure in AUB, the available pharmacological options have various adverse effects. There exists a need for safer and more efficient treatment regimens with high patient compliance to effectively treat AUB. Norethisterone, also known as norethindrone, is a widely used synthetic analogue of progestogen. Controlled release formulations of norethisterone/ norethisterone acetate help maintain constant drug levels in the blood and exert minimal side-effects; therefore, they are promising therapeutic agents for effective AUB management. The present review summarizes the epidemiology and diagnosis of AUB, with a focus on the safety, efficacy and tolerability of norethisterone/ norethisterone acetate in AUB management. We also report a case of AUB in a 40-year-old woman, who was treated with NETA tablets. The treatment resulted in favourable outcomes, and patient satisfaction.

The etonogestrel contraceptive implant is one of the most effective contraceptives available, with a failure rate of 0.05%. Approved for 3 years of use, it has a high 2-year continuation rate (53%–90%). Up to 11.3% of women in clinical trials discontinued use of this implant before 3 years because of bothersome bleeding (prolonged bleeding and frequent episodes). This double-blind randomized, placebo-controlled trial was designed to determine whether 14 days of treatment with a combination of oral contraceptive pills (OCPs) would stop bleeding in users of the implant with bothersome bleeding. The OCP regimen was a low-dose combination of levonorgestrel and ethinyl estradiol. The primary study outcome was the proportion of women in each group who stopped bleeding during treatment and continued to report no bleeding at the end of 14 days of therapy. Prespecified secondary outcomes included number of days until temporary cessation of bleeding, number of days without bleeding during therapy, and number of days to recurrence of bleeding after therapy was discontinued. The investigators hypothesized that the intervention would result in temporary interruption of bleeding in 80% of the treatment group compared with 20% in the control group; using 80% power, a sample size of 26 women (13 in each group) was required. The study was performed according to the intention-to-treat principle. Most subjects (78%) were young white women. Baseline characteristics of groups were similar. Mean age was 21 to 22 years (range, 18–44 years). A total of 66 women were screened between November 2013 and December 2014; 32 of these were randomized to an OCP group or to a placebo group. Users of the etonogestrel implant with bothersome bleeding episodes for at least 7 consecutive days were randomized to receive 14 pills of combined OCPs (150 μg levonorgestrel and 30 μg ethinyl estradiol, n = 16, or an identical-appearing placebo, n = 16). Significantly, more women in the OCP group than in the placebo group were likely to have a temporary interruption of bleeding during the study period (14 of 16 [87.5% ± 16.2%] in the OCP group vs 6 of 16 [37.5% ± 23.7%] in the placebo group); the odds ratio was 11.7, with a 95% confidence interval of 1.9 to 70.2 (P < 0.01). Among women who had a temporary interruption of bleeding during OCP therapy, 85.7% had bleeding recurrence within 10 days after treatment ended. Use of a low-dose combination OCP in etonogestrel implant users who had reported bothersome bleeding before treatment usually stops bleeding within 14 days. However, bleeding resumes in most patients within 10 days of treatment cessation.

Background: Abnormal uterine bleeding (AUB) is a common gynecological condition that significantly affects women's quality of life. It is a leading cause of consultation in gynecological practice and can be associated with various underlying pathologies, ranging from benign conditions such as fibroids and polyps to more serious diseases like endometrial cancer. The evaluation and diagnosis of AUB are crucial for determining appropriate management strategies. Hysteroscopy, a minimally invasive diagnostic procedure, allows for direct visualization of the uterine cavity and is increasingly used for the evaluation of AUB. When combined with histopathological examination, it offers a more comprehensive assessment and aids in establishing a definitive diagnosis. Objective: The aim of this study is to evaluate the role of hysteroscopy in diagnosing the causes of abnormal uterine bleeding and to correlate the hysteroscopic findings with histopathological results. Methods: This study is a retrospective analysis conducted at Department of Obstetrics and Gynaecology, Katihar Medical College, and Hospital, Katihar, Bihar, India for one year, involving 150 women presenting with abnormal uterine bleeding. All participants underwent hysteroscopy, and tissue samples were collected for histopathological examination. The correlation between hysteroscopic findings and histopathological diagnoses was analyzed. The data were reviewed to identify the most common causes of AUB and the concordance between hysteroscopic and histopathological findings. Results: The study found that the most common causes of AUB were endometrial polyps (30%), fibroids (25%), and endometrial hyperplasia (20%). Hysteroscopy successfully identified these conditions, with a high degree of correlation to histopathological findings. However, discrepancies between hysteroscopic and histopathological diagnoses were noted in a small percentage of cases, particularly in women with endometrial hyperplasia and carcinoma. Conclusion: Hysteroscopy, in conjunction with histopathological examination, is a valuable tool in the diagnosis and management of abnormal uterine bleeding. It not only helps in identifying the structural abnormalities in the uterine cavity but also provides a definitive diagnosis when combined with histopathological analysis. The combined approach significantly improves the accuracy of diagnosis and guides targeted therapeutic interventions, particularly in cases where the etiology of bleeding is uncertain.

To present evidence- and consensus-based recommendations for the diagnosis abnormal uterine bleeding. A literature search for the diagnosis of abnormal uterine bleeding was systematically conducted in PubMed from its inception to May 2024 to identify meta-analyses, reviews, randomized controlled trials, and clinical trials, followed by an additional systematic search using keywords. Based on this evidence, an expert panel developed background, clinical, and future research questions. Based on a systematic search and the collected evidence, we developed five background questions, three clinical questions, and one future research question, with recommendations and/or statements. Evidence and recommendations are provided for clinical questions. Additionally, we developed a flowchart for diagnosis showing the steps of the examinations to be performed. The flowchart and nine recommendations/statements specify an efficient diagnostic procedure to differentiate abnormal causative diseases of uterine bleeding optimized for actual Japanese situations.

This systematic review aims to assess the efficacy of aromatase inhibitors (AIs) in treating pain symptoms caused by endometriosis. A comprehensive literature search was conducted to identify all the published studies evaluating the efficacy of type II nonsteroidal aromatase inhibitors (anastrozole and letrozole) in treating endometriosis-related pain symptoms. The MEDLINE, EMBASE, PubMed, and SCOPUS databases and the Cochrane System Reviews were searched up to October 2010. This review comprises of the results of 10 publications fitting the inclusion criteria; these studies included a total of 251 women. Five studies were prospective non-comparative, four were randomized controlled trials (RCTs) and one was a prospective patient preference trial. Seven studies examined the efficacy of AIs in improving endometriosis-related pain symptoms, whilst three RCTs investigated the use of AIs as post-operative therapy in preventing the recurrence of pain symptoms after surgery for endometriosis. All the observational studies demonstrated that AIs combined with either progestogens or oral contraceptive pill reduce the severity of pain symptoms and improve quality of life. One patient preference study demonstrated that letrozole combined with norethisterone acetate is more effective in reducing pain and deep dyspareunia than norethisterone acetate alone. However, letrozole causes a higher incidence of adverse effects and does not improve patients' satisfaction or influence recurrence of symptoms after discontinuation of treatment. A RCT showed that combining letrozole with norethisterone acetate causes a lower incidence of adverse effects and lower discontinuation rate than combining letrozole with triptorelin. Two RCTs demonstrated that, after surgical treatment of endometriosis, the administration of AIs combined with gonadotropin releasing hormone analogue for 6 months reduces the risk of endometriosis recurrence when compared with gonadotropin releasing hormone analogue alone. In conclusion, AIs effectively reduce the severity of endometriosis-related pain symptoms. Since endometriosis is a chronic disease, future investigations should clarify whether the long-term administration of AIs is superior to currently available endocrine therapies in terms of improvement of pain, adverse effects and patient satisfaction.

8-OH-DPAT does not interfere with habituation to motion-induced emesis in cats

The levonorgestrel-releasing intrauterine device (LNG IUS) is more effective than oral medication as a treatment for heavy menstrual bleeding (HMB). It is associated with a greater reduction in HMB, improved quality of life and appears to be more acceptable long term but is associated with more minor adverse effects than oral therapy.When compared to endometrial ablation, it is not clear whether the LNG IUS offers any benefits with regard to reduced HMB and satisfaction rates and quality of life measures were similar. Some minor adverse effects were more common with the LNG IUS but it appeared to be more cost effective than endometrial ablation techniques.The LNG IUS was less effective than hysterectomy in reducing HMB. Both treatments improved quality of life but the LNG IUS appeared more cost effective than hysterectomy for up to 10 years after treatment.

Progesterone is essential for the maintenance of a healthy pregnancy. Any defect in the secretion of human chorionic gonadotropin or progesterone is associated with a significantly increased risk of first-trimester abortion. Progesterone is frequently prescribed to patients presenting with per vaginal (PV) bleeding in early pregnancy and a history of recurrent pregnancy loss. Pregnant women up to 12weeks of gestation with a history of more than two early pregnancy losses and presenting with vaginal bleeding were included in this study. All subjects were randomized to receive either vaginal progesterone 600mg/day or oral dydrogesterone 30mg/day. A detailed history-including menstrual history, previous pregnancies, previous miscarriages, and other risk factors-was obtained. The mean time required for the cessation of PV bleeding and continuation of pregnancy up to 24weeks and till term was compared. A total of 200 patients were randomized to vaginal progesterone 600mg/day (n = 100) or oral dydrogesterone 30mg/day (n = 100). While 74 patients had two miscarriages in the progesterone group, 68 patients had two miscarriages in the dydrogesterone group. The time required for complete cessation of bleeding was significantly lesser among patients who received oral dydrogesterone compared to those who received intravaginal progesterone (53.90 ± 9.09 vs. 94.60 ± 7.29h, p < 0.0001). Numerically higher number of patients receiving oral dydrogesterone had a successful continuation of pregnancy up to 24weeks of gestation, as well as till full term compared to progesterone group (70 vs. 75). Oral dydrogesterone is preferred over vaginal progesterone in patients presenting with vaginal bleeding during early pregnancy and a history of recurrent early pregnancy loss.

Although anticoccidial-resistant Eimeria spp. have been reported in avian industry, it has yet to be officially identified in dairy goats in Taiwan. This paper describes Eimeria strains, identified from a five-week-old kid, found to be resistant to sulfonamide drugs, due to the fact that the number of oocysts per gram of feces (O.P.G.) remained to be 9200 after seven consecutive days of treatment and only dropped to zero after another two consecutive days of treatment with toltrazuril. We believe this is the first paper to identify the emergence of an anticoccidial-resistant Eimeria spp. strain, and further investigation should be warranted. This paper would help farmers and veterinarians consider an alternative treatment protocol when dealing with coccidiosis in the goat industry.

To compare the effects of frequently used two different regimens of combined continuous hormone replacement therapy; 0.625 mg conjugated equine estrogen (CEE) + 2.5 mg medroxyprogesterone acetate (MPA) and 1 mg 17beta estradiol (E2) + 0.5 mg norethindrone acetate (NETA), on endometrial histopathology and postmenopausal uterine bleeding. Two hundred and forty-six outpatient subjects aged 41-57 years were enrolled in the study conducted at the menopause clinic between November 2003 and November 2004. One hundred and thirty-nine patients were assigned to receive 0.625 mg conjugated equine estrogen + 2.5 mg medroxyprogesterone acetate (CEE/MPA), whereas 107 patients were to receive 17beta estradiol + 0.5 mg norethindrone acetate (E2/NETA). Inclusion criteria of the study were: normal values of endometrial thickness at basal evaluation, women with intact uterus, at least 12 months of amenorrhea, normal vaginal smear, bilateral mammography and biochemical blood parameters. All women were questioned every 3 months for vaginal bleeding/spotting. Endometrial sampling was performed by Pipelle catheter in the 12th month of therapy. For the first 3 months, vaginal bleeding/spotting rate for the CEE/MPA group was 38.7%, whereas it was higher (45%) in the E2/NETA group. For the second 3-month period, vaginal bleeding/spotting frequencies were 41.1 and 37.8%, respectively. In the third 3-month period 30.6 and 29.6%, and in the fourth 3-month period, 18.5 and 12.5% of the patients reported vaginal bleeding or spotting. None of the results of endometrial sampling have shown findings of cancer histopathology. Compared to CEE/MPA regimen, E2/NETA therapy has not shown more favorable effects on postmenopausal bleeding abnormalities. Irregular endometrial proliferation was seen more with the E2/NETA regimen.

Digital adherence technology interventions to reduce poor end-of-treatment outcomes and recurrence among adults with drug-sensitive tuberculosis in Ethiopia: a three-arm, pragmatic, cluster-randomised, controlled trial.

Introduction: Concerns remain over bleeding with direct factor Xa and thrombin inhibitors in cases of overdose or medical emergency. This study tested the ability of PCCs to reverse bleeding induced by apixaban, rivaroxaban or dabigatran in a standardized rat tail resection model. Methods: Individual groups of anesthetized rats (8-10) were anticoagulated with apixaban, rivaroxaban or dabigatran and subsequently treated with vehicle, 3-factor (Profilnine), 4-factor (Beriplex) or activated 4-factor PCC (FEIBA). Five minutes post-PCC administration, a tail snip was performed and bleeding time was measured. Upon cessation of bleeding, a blood samples were collected for ex vivo analysis and the rat was humanely euthanized. Results: In comparison to saline control (6.8 + 1.1 sec) apixaban (300μg/kg) prolonged bleeding time (17.1±5.6; p=0.024). Beriplex at doses ≤10U/kg did not shorten bleeding time while 10U/kg Profilnine did. FEIBA prolonged bleeding beyond that seen with apixaban alone (22.6±11.4 and 37.5±5.2 min for 5 and 10U/kg doses; p&lt;0.001 apixaban + 10U/kg FEIBA vs. apixaban). 100 and 300μg/kg rivaroxaban prolonged bleeding time (20.8±2.5, p=0.002 vs. saline; 25.0±10.0 min, p&lt;0.001 vs. saline). Profilnine was more effective than Beriplex or FEIBA in reversing rivaroxaban-induced bleeding. Dabigatran-induced bleeding was prevented by Beriplex or Profilnine but enhanced by FEIBA (50.3±8.3 vs. 15.9±1.2 min; p&lt;0.001). Treatment of apixaban or rivaroxaban anticoagulated rats with FEIBA + 10mg/kg epsilon aminocaproic acid, produced bleeding times comparable to those of non-anticoagulated rats (apixaban: 6.7±5.0 min; rivaroxaban: 7.7±6.4 min). Ex vivo analysis of blood samples did not show any relevance with the observed bleeding or its modulation. Discussion: PCCs appear useful for neutralizing bleeding induced by direct factor Xa and thrombin inhibitors, but each PCC exhibits a distinct neutralization profile. Co-administration of a fibrinolytic inhibitor may enhance effectiveness of hemorrhage reversal by PCCs.

Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone structure of topotecan, which is in equilibrium with the inactive ring-opened hydroxy acid, is essential for this activity. We performed a pharmacokinetics study as part of phase II clinical trials in patients with various types of solid tumors, giving topotecan at 1.5 mg/m2 per day by 30-min infusion for 5 consecutive days, with courses being repeated every 3 weeks. Previously validated limited-sampling models, using concentration measurements in samples obtained 2 h after infusion, were used to calculate the area under the plasma concentration-time curves (AUCs) for both chemical forms. Samples were obtained from a total of 36 patients over 136 treatment days. The mean AUC of the closed-ring form (AUC(closed)) was 8.74 (range 2.3-16.3 microM min per day, and the mean AUC of the ring-opened form (AUC(open)) was 11.5 (range 3.2-46.0) microM min per day (interpatient variability 34-61%). In each patient the AUC values achieved on the 1st day of administration were similar to and, thus, predictive for those achieved during the following days, with a day-to-day variation of 7.39% being recorded for the AUC(closed) and that of 12.6% for the AUC(open). There was no drug accumulation during the 5 consecutive treatment days of each cycle. However, despite the large interpatient pharmacokinetic variability, the importance of regular drug monitoring on this schedule can be questioned, as the pharmacodynamic variability was relatively small.