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JAMA Network Open Jan 2022Meta-analyses have reported conflicting data on the safety of hormonal contraception, but the quality of evidence for the associations between hormonal contraceptive use... (Review)
Review
IMPORTANCE
Meta-analyses have reported conflicting data on the safety of hormonal contraception, but the quality of evidence for the associations between hormonal contraceptive use and adverse health outcomes has not been quantified in aggregate.
OBJECTIVE
To grade the evidence from meta-analyses of randomized clinical trials (RCTs) and cohort studies that assessed the associations between hormonal contraceptive use and adverse health outcomes among women.
DATA SOURCES
MEDLINE, Embase, and the Cochrane Database of Systematic Reviews were searched from database inception to August 2020. Search terms included hormonal contraception, contraceptive agents, progesterone, desogestrel, norethindrone, megestrol, algestone, norprogesterones, and levonorgestrel combined with terms such as systematic review or meta-analysis.
EVIDENCE REVIEW
The methodological quality of each meta-analysis was graded using the Assessment of Multiple Systematic Reviews, version 2, which rated quality as critically low, low, moderate, or high. The Grading of Recommendation, Assessment, Development and Evaluations approach was used to assess the certainty of evidence in meta-analyses of RCTs, with evidence graded as very low, low, moderate, or high. Evidence of associations from meta-analyses of cohort studies was ranked according to established criteria as nonsignificant, weak, suggestive, highly suggestive, or convincing.
RESULTS
A total of 2996 records were screened; of those, 310 full-text articles were assessed for eligibility, and 58 articles (13 meta-analyses of RCTs and 45 meta-analyses of cohort studies) were selected for evidence synthesis. Sixty associations were described in meta-analyses of RCTs, and 96 associations were described in meta-analyses of cohort studies. Among meta-analyses of RCTs, 14 of the 60 associations were nominally statistically significant (P ≤ .05); no associations between hormonal contraceptive use and adverse outcomes were supported by high-quality evidence. The association between the use of a levonorgestrel-releasing intrauterine system and reductions in endometrial polyps associated with tamoxifen use (odds ratio [OR], 0.22; 95% CI, 0.13-0.38) was graded as having high-quality evidence, and this evidence ranking was retained in the subgroup analysis. Among meta-analyses of cohort studies, 40 of the 96 associations were nominally statistically significant; however, no associations between hormonal contraceptive use and adverse outcomes were supported by convincing evidence in the primary and subgroup analyses. The risk of venous thromboembolism among those using vs not using oral contraception (OR, 2.42; 95% CI, 1.76-3.32) was initially supported by highly suggestive evidence, but this evidence was downgraded to weak in the sensitivity analysis.
CONCLUSIONS AND RELEVANCE
The results of this umbrella review supported preexisting understandings of the risks and benefits associated with hormonal contraceptive use. Overall, the associations between hormonal contraceptive use and cardiovascular risk, cancer risk, and other major adverse health outcomes were not supported by high-quality evidence.
Topics: Adult; Cohort Studies; Contraceptive Agents, Hormonal; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Long Term Adverse Effects; Meta-Analysis as Topic; Pregnancy; Randomized Controlled Trials as Topic; Systematic Reviews as Topic; Women's Health
PubMed: 35029663
DOI: 10.1001/jamanetworkopen.2021.43730 -
European Journal of Obstetrics,... Jun 2022To report the pregnancy outcomes of women with prior endometrial cancer and endometrial hyperplasia managed with fertility-sparing treatments. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To report the pregnancy outcomes of women with prior endometrial cancer and endometrial hyperplasia managed with fertility-sparing treatments.
METHODS
Medline and Embase databases were searched. Inclusion criteria were studies reporting the pregnancy outcomes of women who had undergone fertility-sparing treatments for endometrial hyperplasia or early endometrioid endometrial cancer. Outcomes explored were pregnancy, miscarriage and livebirth rates according to the type of progestin treatment used. Subgroup analyses according to the type of diagnostic follow-up were also performed. Meta-analyses of proportions using a random effects model were used to combine data.
RESULTS
Twenty-nine studies (1036 women) were included, and 82.8% [95% confidence interval (CI) 72.3-91.2] of women achieved complete remission. Pregnancy rates were 56.3% (95% CI 41.6-70.5) with megestrol (MA) or medroxyprogesterone acetate (MPA), 63.1% (95% CI 37.0-85.6) with levonorgestrel-releasing intrauterine device (LNG-IUD), 57.9% (95% CI 37.7-76.8) with MA or MPA and metformin, 59.8% (95% CI 48.3-70.7) with MPA and LNG-IUD, 15.4% (95% CI 4.3-42.2) with gonadotropin-releasing hormone analogue (GnRHa) combined with LNG-IUD or letrozole, and 40.7% (95% CI 24.5-59.3) with LNG-IUD and GnRHa. Miscarriage rates were 17.4% (95% CI 12.2-23.4), 14.3% (95% CI 6.4-24.7), 57.9% (95% CI 37.7-76.8), 26.9% (95% CI 14.6-39.3), 100% (95% CI 34.0-100) and 18.2% (95% CI 5.1-47.7), respectively, and livebirth rates were 68.8% (95% CI 56.0-80.3), 80.8% (95% CI 69.5-90.0), 69.9% (95% CI 56.1-82.0), 25.97 (95% CI 14.6-39.3), 0% (95% CI 0-66.0) and 81.8% (95% CI 52.3-94.8), respectively. Finally, stratifying the analysis considering the endometrial sampling method alone, the pregnancy rate was 68.6% (95% CI 51.2-83.6; 10 studies, I = 83.5%) in women who underwent hysteroscopy and 60.5% (95% CI 53.4-67.5; 13 studies, I = 39.8%) in women managed with dilatation and curettage biopsy; the miscarriage and livebirth rates were 13.2% (95% CI 8.0-19.5; I = 0%) and 81.2% (95% CI 67.4-91.8; I = 67.3%), respectively, for hysteroscopy, and 25.2% (95% CI 17.8-33.3; I = 15.5%) and 67.5% (95% CI 58.8-75.5; I = 0%), respectively, for dilatation and curettage biopsy.
CONCLUSION
Fertility-sparing treatment in women with endometrial cancer or hyperplasia is associated with an overall good response to therapy, good chance of achieving pregnancy and a good livebirth rate. Diagnostic follow-up with hysteroscopy was associated with a higher pregnancy rate, although this requires confirmation in adequately powered randomized trials.
Topics: Abortion, Spontaneous; Endometrial Hyperplasia; Endometrial Neoplasms; Female; Fertility Preservation; Humans; Hyperplasia; Intrauterine Devices, Medicated; Levonorgestrel; Medroxyprogesterone Acetate; Precancerous Conditions; Pregnancy; Pregnancy Outcome
PubMed: 35526471
DOI: 10.1016/j.ejogrb.2022.04.019 -
Cancers Apr 2022Endometrial cancer (EC) rarely develops in young women. Most cases are associated with known risk factors: BMI > 30, history of Polycystic Ovary Syndrome (PCOs), and... (Review)
Review
Endometrial cancer (EC) rarely develops in young women. Most cases are associated with known risk factors: BMI > 30, history of Polycystic Ovary Syndrome (PCOs), and race differentiation. The molecular EC classification based on The Cancer Genome Atlas Research Network divides these heterogeneous cancers into four types: Polymerase Epsilon Mutation (POLE), Microsatellite Instability (MSI), Copy Number Low (CNL), and Copy Number High (CNH). This division was introduced to allow for early assessment of neoplastic changes and clinical management, including targeted therapies. The basic technique for imaging endometrium changes is transvaginal sonography. Hysteroscopy is the standard for obtaining endometrial material for histological evaluation. The MRI result permits assessment of the extent of EC cancer infiltration. In young women who want to preserve fertility, apart from surgery, conservative management is often implemented after strict selection based on clinical and pathological data. This pharmacological treatment involves the administration of progestogens MPA (medroxyprogesterone acetate) and MA (megestrol acetate). The use of metformin may increase the effectiveness of such treatment. An alternative option is to apply progestogens locally—via the levonorgestrel-releasing intrauterine device. In addition to pharmacological treatment, hysteroscopic resection may be used—part of the uterine muscle adjacent to the pathologically changed endometrium may also undergo resection. An alternative is the administration of estrogen receptor modulators (e.g., SERMs) or aromatase inhibitors, or GnRH agonists.
PubMed: 35454829
DOI: 10.3390/cancers14081922 -
The Cochrane Database of Systematic... May 2024Endometrial cancer is one of the most common gynaecological cancers in the world. Rates of endometrial cancer are rising, in part because of rising obesity rates.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Endometrial cancer is one of the most common gynaecological cancers in the world. Rates of endometrial cancer are rising, in part because of rising obesity rates. Endometrial hyperplasia is a precancerous condition in women that can lead to endometrial cancer if left untreated. Endometrial hyperplasia occurs more commonly than endometrial cancer. Progesterone tablets that are currently used to treat women with endometrial hyperplasia are associated with adverse effects in up to 84% of women. A levonorgestrel intrauterine device may improve compliance, but it is invasive, is not acceptable to all women, and is associated with irregular vaginal bleeding in 82% of cases. Therefore, an alternative treatment for women with endometrial hyperplasia is needed. Metformin, a drug that is often used to treat people with diabetes, has been shown, in some human studies, to reverse endometrial hyperplasia. However, the effectiveness and safety of metformin for treatment of endometrial hyperplasia remain uncertain. This is an update of a review first published in 2017.
OBJECTIVES
To determine the effectiveness and safety of metformin in treating women with endometrial hyperplasia.
SEARCH METHODS
We searched the Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, PubMed, Embase, Google Scholar, OpenGrey, LILACS, and two trials registers from inception to 5 September 2022. We searched the bibliographies of all relevant studies, and contacted experts in the field for any additional trials.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) and cross-over trials comparing metformin (used alone or in combination with other medical therapies) versus placebo, no treatment, any conventional medical treatment, or any other active intervention for women with histologically confirmed endometrial hyperplasia of any type.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for eligibility, extracted data from included studies, assessed the risk of bias in the included studies, and assessed the certainty of the evidence for each outcome. We resolved disagreements by discussion or by deferring to a third review author. When study details were missing, review authors contacted the study authors. The primary outcome of this review was regression of endometrial hyperplasia histology (with or without atypia) towards normal histology.
MAIN RESULTS
We included seven RCTs, in which a total of 387 women took part. In the comparison, Metformin plus megestrol versus megestrol alone, we rated the certainty of the evidence as low for the outcome, regression of endometrial hyperplasia. We rated the quality of the evidence as very low for the rest of the outcomes, in all three comparisons. Although there was a low risk of selection bias, there was a high risk of bias in the blinding of personnel and outcome assessment (performance bias and detection bias) in many studies. This update identified four new RCTs and six ongoing RCTs. Metformin versus megestrol We are uncertain whether metformin increases the regression of endometrial hyperplasia towards normal histology over megestrol (odds ratio (OR) 4.89, 95% confidence interval (CI) 1.56 to 15.32; P = 0.006; 2 RCTs, 83 participants; I² = 7%; very low-certainty evidence). This evidence suggests that if the rate of regression with megestrol is 61%, the rate of regression with metformin would be between 71% and 96%. It is unresolved whether metformin results in different rates of abnormal uterine bleeding or hysterectomy compared to megestrol. No study in this comparison reported progression of hyperplasia to endometrial cancer, recurrence of endometrial hyperplasia, health-related quality of life, or adverse effects during treatment. Metformin plus megestrol versus megestrol monotherapy The combination of metformin and megestrol may enhance the regression of endometrial hyperplasia towards normal histology more than megestrol alone (OR 3.27, 95% CI 1.65 to 6.51; P = 0.0007; 4 RCTs, 258 participants; I² = 0%, low-certainty evidence). This suggests that if the rate of regression with megestrol monotherapy is 54%, the rate of regression with the addition of metformin would be between 66% and 84%. In one study, 3/8 (37.5%) of participants who took metformin had nausea that settled without further treatment. It is unresolved whether the combination of metformin and megestrol results in different rates of recurrence of endometrial hyperplasia, progression of endometrial hyperplasia to endometrial cancer, or hysterectomy compared to megestrol monotherapy. No study in this comparison reported abnormal uterine bleeding, or health-related quality of life. Metformin plus levonorgestrel (intrauterine system) versus levonorgestrel (intrauterine system) monotherapy We are uncertain whether there is a difference between groups in the regression of endometrial hyperplasia towards normal histology (OR 0.29, 95% CI 0.01 to 7.56; 1 RCT, 46 participants; very low-certainty evidence). This evidence suggests that if the rate of regression with levonorgestrel monotherapy is 96%, the rate of regression with the addition of metformin would be between 73% and 100%. It is unresolved whether the combination of metformin and levonorgestrel results in different rates of abnormal uterine bleeding, hysterectomy, or the development of adverse effects during treatment compared to levonorgestrel monotherapy. No study in this comparison reported recurrence of endometrial hyperplasia, progression of hyperplasia to endometrial cancer, or health-related quality of life.
AUTHORS' CONCLUSIONS
Review authors found insufficient evidence to either support or refute the use of metformin, specifically megestrol acetate, given alone or in combination with standard therapy, for the treatment of women with endometrial hyperplasia. Robustly designed and adequately powered randomised controlled trials, yielding long-term outcome data are still needed to address this clinical question.
Topics: Humans; Metformin; Female; Endometrial Hyperplasia; Randomized Controlled Trials as Topic; Hypoglycemic Agents
PubMed: 38695827
DOI: 10.1002/14651858.CD012214.pub3 -
The Senior Care Pharmacist Jul 2022To evaluate the efficacy and safety of megestrol for off-label use in older patients with weight loss. Retrospective, nonblinded cohort study. Upstate University...
To evaluate the efficacy and safety of megestrol for off-label use in older patients with weight loss. Retrospective, nonblinded cohort study. Upstate University Hospital is a 420-bed facility and academic medical center with a level 1 trauma center. Upstate Community Hospital is a 314-bed acute care/hospital/ambulatory care center and long-term care hospital that also provides teaching services. Patients 65 years of age and older without malignancy or acquired immunodeficiency syndrome who were initiated and continued megestrol therapy at the Upstate University hospitals for at least two weeks were included. Of the 1,290 patients initially screened, 16 patients on megestrol were evaluated. An age- and gender-matched control group of 16 patients was utilized for comparison of changes in weight and other variables. Patients in the megestrol group have received daily doses of megestrol between 160 mg to 800 mg for an average duration of 19 days. Patients in the control group had no history or current use of megestrol utilization. The primary outcome was an increase in weight. Secondary outcome measures included albumin and thromboembolic events. Changes in weight and albumin were also compared with the control group. At a mean duration of 19 days, there was no significant difference in weight gain (0.95 kg, OR = 1.33 [95% CI -1.615-3.527]). Albumin decreased by (0.4 g/dL OR = 0.916 [95% CI 0.12-0.78]) and none of the patients developed a thromboembolic event. In older hospitalized patients, megestrol did not increase weight, and did not improve albumin. No thromboembolic events were observed, but this may be because of a limited duration of observation of therapy and the routine use of anticoagulation prophylaxis in the inpatient setting.
Topics: Aged; Albumins; Cohort Studies; Hospitalization; Humans; Megestrol; Retrospective Studies
PubMed: 35752918
DOI: 10.4140/TCP.n.2022.284 -
The American Journal of Geriatric... Jun 2020
Topics: Drug Therapy, Combination; Humans; Megestrol; Megestrol Acetate; Mental Disorders
PubMed: 32122805
DOI: 10.1016/j.jagp.2020.01.188 -
Journal of Cachexia, Sarcopenia and... Oct 2023In cancer cachexia trials, measures of physical function are commonly used as endpoints. For drug trials to obtain regulatory approval, efficacy in physical function...
In cancer cachexia trials, measures of physical function are commonly used as endpoints. For drug trials to obtain regulatory approval, efficacy in physical function endpoints may be needed alongside other measures. However, it is not clear which physical function endpoints should be used. The aim of this systematic review was to assess the frequency and diversity of physical function endpoints in cancer cachexia trials. Following a comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990-2021), records were retrieved. Eligible trials met the following criteria: adults (≥18 years), controlled design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a physical function endpoint. Physical function measures were classified as an objective measure (hand grip strength [HGS], stair climb power [SCP], timed up and go [TUG] test, 6-min walking test [6MWT] and short physical performance battery [SPPB]), clinician assessment of function (Karnofsky Performance Status [KPS] or Eastern Cooperative Oncology Group-Performance Status [ECOG-PS]) or patient-reported outcomes (physical function subscale of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaires [EORTC QLQ-C30 or C15]). Data extraction was performed using Covidence and followed PRISMA guidance (PROSPERO registration: CRD42022276710). A total of 5975 potential studies were examined and 71 were eligible. Pharmacological interventions were assessed in 38 trials (54%). Of these, 11 (29%, n = 1184) examined megestrol and 5 (13%, n = 1928) examined anamorelin; nutritional interventions were assessed in 21 trials (30%); and exercise-based interventions were assessed in 6 trials (8%). The remaining six trials (8%) assessed multimodal interventions. Among the objective measures of physical function (assessed as primary or secondary endpoints), HGS was most commonly examined (33 trials, n = 5081) and demonstrated a statistically significant finding in 12 (36%) trials (n = 2091). The 6MWT was assessed in 12 trials (n = 1074) and was statistically significant in 4 (33%) trials (n = 403), whereas SCP, TUG and SPPB were each assessed in 3 trials. KPS was more commonly assessed than the newer ECOG-PS (16 vs. 9 trials), and patient-reported EORTC QLQ-C30 physical function was reported in 25 trials. HGS is the most commonly used physical function endpoint in cancer cachexia clinical trials. However, heterogeneity in study design, populations, intervention and endpoint selection make it difficult to comment on the optimal endpoint and how to measure this. We offer several recommendations/considerations to improve the design of future clinical trials in cancer cachexia.
Topics: Humans; Cachexia; Hand Strength; Neoplasms; Quality of Life; Research Design
PubMed: 37671529
DOI: 10.1002/jcsm.13321 -
Nutrition in Clinical Practice :... Feb 2023The majority of evidence on efficacy of appetite-stimulating medications is limited to specific populations and the outpatient treatment setting. However, hospitalized... (Review)
Review
BACKGROUND
The majority of evidence on efficacy of appetite-stimulating medications is limited to specific populations and the outpatient treatment setting. However, hospitalized adults remain at risk for poor appetite and inadequate intake.
METHOD
The purpose of this review was to assess recent evidence on the efficacy of dronabinol, megestrol acetate, and mirtazapine (used to stimulate appetite) on promoting change in intake; somatic symptoms, such as appetite and nausea; and weight change during hospital stay. The population was limited to hospitalized adults or adults who demonstrated a need for appetite stimulation during hospitalization.
RESULTS
Of the 382 articles screened, four met inclusion criteria (one randomized control trial, two retrospective cohort studies, and one retrospective case series). Based on the studies included, these appetite stimulants have limited efficacy on improving appetite and meal intake. There was no significant change in weight.
CONCLUSION
Current data lack standardization, generalizability, and comparability, and higher quality evidence is needed before conclusions can be identified on the efficacy of dronabinol, megestrol acetate, and mirtazapine in the inpatient setting.
Topics: Humans; Adult; Appetite; Megestrol Acetate; Retrospective Studies; Dronabinol; Mirtazapine; Appetite Stimulants
PubMed: 35076955
DOI: 10.1002/ncp.10839 -
Pharmaceuticals (Basel, Switzerland) Feb 2022Cisplatin is a well-known chemotherapeutic agent used to treat various types of cancers; however, it can also induce anorexia, which results in reduced food intake, loss... (Review)
Review
Cisplatin is a well-known chemotherapeutic agent used to treat various types of cancers; however, it can also induce anorexia, which results in reduced food intake, loss of body weight, and lower quality of life. Although drugs such as megestrol acetate and cyproheptadine are used to decrease this severe feeding disorder, they can also induce side effects, such as diarrhea and somnolence, which limit their widespread use. Various types of herbal medicines have long been used to prevent and treat numerous gastrointestinal tract diseases; however, to date, no study has been conducted to analyze and summarize their effects on cisplatin-induced anorexia. In this paper, we analyze 12 animal studies that used either a single herbal medicine extract or mixtures thereof to decrease cisplatin-induced anorexia. Among the herbal medicines, Ginseng Radix was the most used, as it was included in seven studies, whereas both Glycyrrhizae Radix et Rhizoma and Angelicae Gigantis Radix were used in four studies. As for the mechanisms of action, the roles of serotonin and its receptors, cytokines, white blood cells, ghrelin, and leptin were investigated. Based on these results, we suggest that herbal medicines could be considered a useful treatment method for cisplatin-induced anorexia.
PubMed: 35215322
DOI: 10.3390/ph15020208