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Archives of Gynecology and Obstetrics Aug 2022Endometrial hyperplasia (EH) is the precursor lesion for endometrioid adenocarcinoma of the endometrium (EC), which represents the most common malignancy of the female... (Review)
Review
Endometrial hyperplasia (EH) is the precursor lesion for endometrioid adenocarcinoma of the endometrium (EC), which represents the most common malignancy of the female reproductive tract in industrialized countries. The most important risk factor for the development of EH is chronic exposure to unopposed estrogen. Histopathologically, EH can be classified into EH without atypia (benign EH) and atypical EH/endometrial intraepithelial neoplasia (EIN). Clinical management ranges from surveillance or progestin therapy through to hysterectomy, depending on the risk of progression to or concomitant EC and the patient´s desire to preserve fertility. Multiple studies support the efficacy of progestins in treating both benign and atypical EH. This review summarizes the evidence base regarding risk factors and management of EH. Additionally, we performed a systematic literature search of the databases PubMed and Cochrane Controlled Trials register for studies analyzing the efficacy of progestin treatment in women with EH.
Topics: Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Female; Humans; Progestins; Risk Factors
PubMed: 35001185
DOI: 10.1007/s00404-021-06380-5 -
PLoS Medicine Aug 2021There remains uncertainty about the impact of menopausal hormone therapy (MHT) on women's health. A systematic, comprehensive assessment of the effects on multiple... (Review)
Review
BACKGROUND
There remains uncertainty about the impact of menopausal hormone therapy (MHT) on women's health. A systematic, comprehensive assessment of the effects on multiple outcomes is lacking. We conducted an umbrella review to comprehensively summarize evidence on the benefits and harms of MHT across diverse health outcomes.
METHODS AND FINDINGS
We searched MEDLINE, EMBASE, and 10 other databases from inception to November 26, 2017, updated on December 17, 2020, to identify systematic reviews or meta-analyses of randomized controlled trials (RCTs) and observational studies investigating effects of MHT, including estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT), in perimenopausal or postmenopausal women in all countries and settings. All health outcomes in previous systematic reviews were included, including menopausal symptoms, surrogate endpoints, biomarkers, various morbidity outcomes, and mortality. Two investigators independently extracted data and assessed methodological quality of systematic reviews using the updated 16-item AMSTAR 2 instrument. Random-effects robust variance estimation was used to combine effect estimates, and 95% prediction intervals (PIs) were calculated whenever possible. We used the term MHT to encompass ET and EPT, and results are presented for MHT for each outcome, unless otherwise indicated. Sixty systematic reviews were included, involving 102 meta-analyses of RCTs and 38 of observational studies, with 102 unique outcomes. The overall quality of included systematic reviews was moderate to poor. In meta-analyses of RCTs, MHT was beneficial for vasomotor symptoms (frequency: 9 trials, 1,104 women, risk ratio [RR] 0.43, 95% CI 0.33 to 0.57, p < 0.001; severity: 7 trials, 503 women, RR 0.29, 95% CI 0.17 to 0.50, p = 0.002) and all fracture (30 trials, 43,188 women, RR 0.72, 95% CI 0.62 to 0.84, p = 0.002, 95% PI 0.58 to 0.87), as well as vaginal atrophy (intravaginal ET), sexual function, vertebral and nonvertebral fracture, diabetes mellitus, cardiovascular mortality (ET), and colorectal cancer (EPT), but harmful for stroke (17 trials, 37,272 women, RR 1.17, 95% CI 1.05 to 1.29, p = 0.027) and venous thromboembolism (23 trials, 42,292 women, RR 1.60, 95% CI 0.99 to 2.58, p = 0.052, 95% PI 1.03 to 2.99), as well as cardiovascular disease incidence and recurrence, cerebrovascular disease, nonfatal stroke, deep vein thrombosis, gallbladder disease requiring surgery, and lung cancer mortality (EPT). In meta-analyses of observational studies, MHT was associated with decreased risks of cataract, glioma, and esophageal, gastric, and colorectal cancer, but increased risks of pulmonary embolism, cholelithiasis, asthma, meningioma, and thyroid, breast, and ovarian cancer. ET and EPT had opposite effects for endometrial cancer, endometrial hyperplasia, and Alzheimer disease. The major limitations include the inability to address the varying effects of MHT by type, dose, formulation, duration of use, route of administration, and age of initiation and to take into account the quality of individual studies included in the systematic reviews. The study protocol is publicly available on PROSPERO (CRD42017083412).
CONCLUSIONS
MHT has a complex balance of benefits and harms on multiple health outcomes. Some effects differ qualitatively between ET and EPT. The quality of available evidence is only moderate to poor.
Topics: Estrogen Replacement Therapy; Estrogens; Female; Humans; Menopause; Middle Aged; Progestins; Women's Health
PubMed: 34339416
DOI: 10.1371/journal.pmed.1003731 -
American Journal of Epidemiology Apr 2016Ideally, questions about comparative effectiveness or safety would be answered using an appropriately designed and conducted randomized experiment. When we cannot...
Ideally, questions about comparative effectiveness or safety would be answered using an appropriately designed and conducted randomized experiment. When we cannot conduct a randomized experiment, we analyze observational data. Causal inference from large observational databases (big data) can be viewed as an attempt to emulate a randomized experiment-the target experiment or target trial-that would answer the question of interest. When the goal is to guide decisions among several strategies, causal analyses of observational data need to be evaluated with respect to how well they emulate a particular target trial. We outline a framework for comparative effectiveness research using big data that makes the target trial explicit. This framework channels counterfactual theory for comparing the effects of sustained treatment strategies, organizes analytic approaches, provides a structured process for the criticism of observational studies, and helps avoid common methodologic pitfalls.
Topics: Breast Neoplasms; Causality; Comparative Effectiveness Research; Databases, Factual; Drug Therapy, Combination; Estrogen Replacement Therapy; Female; Humans; Observational Studies as Topic; Postmenopause; Progestins; Propensity Score; Randomized Controlled Trials as Topic
PubMed: 26994063
DOI: 10.1093/aje/kwv254 -
Contraception Dec 2016Women with medical conditions associated with increased risk for thrombosis generally should not use estrogen-containing contraceptives; however, less is known about... (Review)
Review
BACKGROUND
Women with medical conditions associated with increased risk for thrombosis generally should not use estrogen-containing contraceptives; however, less is known about progestin-only contraceptives (POCs) and thrombosis risk.
OBJECTIVES
The objective was to identify evidence regarding the risk of venous thromboembolism (VTE) or arterial thromboembolism [stroke or acute myocardial infarction (AMI)] among women using POCs.
METHODS
We searched the PubMed database for all articles published from database inception through January 2016 for studies examining thrombosis among women using POCs. We included studies which examined women with medical conditions associated with thrombosis risk, as well as studies of women in the general population (either without these conditions or who were not specified to have these conditions). Hormonal contraceptives of interest included progestin-only pills (POPs), injectables, implants and levonorgestrel-releasing intrauterine devices (LNG-IUDs). Outcomes of interest included VTE, stroke and AMI.
RESULTS
There were 26 articles of good to poor quality that met inclusion criteria; 9 studies examined women with medical conditions and 20 examined women in the general population. Two studies found that, among smokers and women with certain thrombogenic mutations, use of depot medroxyprogesterone acetate (DMPA) had elevated odds of VTE compared with nonsmokers or those without mutations, although confidence intervals were wide and overlapped with odds among nonusers. One study found that, among women with previous VTE, use of POCs (including DMPA) was associated with a nonsignificant increased odds of recurrent VTE (all of which were among DMPA users); two other studies that examined POCs other than DMPA did not observe an association with recurrent VTE. Two studies found that use of DMPA among healthy women was also associated with increased odds of VTE. Two studies found that use of POCs for therapeutic indications was associated with increased odds of VTE. Studies did not find increased odds of VTE with POPs for contraceptive purposes, implants or LNG-IUDs nor were there increased odds of stroke or AMI with any POCs.
CONCLUSION
The majority of evidence identified by this systematic review did not suggest an increase in odds for venous or arterial events with use of most POCs. Limited evidence suggested increased odds of VTE with use of injectables (three studies) and use of POCs for therapeutic indications (two studies, one with POCs unspecified and the other with POPs). Any increase in risk likely translates to a small increase in absolute numbers of thrombotic events at the population level.
Topics: Contraception; Female; Humans; Myocardial Infarction; Progestins; Risk Assessment; Stroke; Venous Thromboembolism; Weight Gain
PubMed: 27153743
DOI: 10.1016/j.contraception.2016.04.014 -
American Journal of Obstetrics and... Aug 2020Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone supplementation may reduce the risk of miscarriage in... (Review)
Review
Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone supplementation may reduce the risk of miscarriage in women with recurrent or threatened miscarriage. Cochrane Reviews summarized the evidence and found that the trials were small with substantial methodologic weaknesses. Since then, the effects of first-trimester use of vaginal micronized progesterone have been evaluated in 2 large, high-quality, multicenter placebo-controlled trials, one targeting women with unexplained recurrent miscarriages (the PROMISE [PROgesterone in recurrent MIScarriagE] trial) and the other targeting women with early pregnancy bleeding (the PRISM [PRogesterone In Spontaneous Miscarriage] trial). The PROMISE trial studied 836 women from 45 hospitals in the United Kingdom and the Netherlands and found a 3% greater live birth rate with progesterone but with substantial statistical uncertainty. The PRISM trial studied 4153 women from 48 hospitals in the United Kingdom and found a 3% greater live birth rate with progesterone, but with a P value of .08. A key finding, first observed in the PROMISE trial, and then replicated in the PRISM trial, was that treatment with vaginal micronized progesterone 400 mg twice daily was associated with increasing live birth rates according to the number of previous miscarriages. Prespecified PRISM trial subgroup analysis in women with the dual risk factors of previous miscarriage(s) and current pregnancy bleeding fulfilled all 11 conditions for credible subgroup analysis. For the subgroup of women with a history of 1 or more miscarriage(s) and current pregnancy bleeding, the live birth rate was 75% (689/914) with progesterone vs 70% (619/886) with placebo (rate difference 5%; risk ratio, 1.09, 95% confidence interval, 1.03-1.15; P=.003). The benefit was greater for the subgroup of women with 3 or more previous miscarriages and current pregnancy bleeding; live birth rate was 72% (98/137) with progesterone vs 57% (85/148) with placebo (rate difference 15%; risk ratio, 1.28, 95% confidence interval, 1.08-1.51; P=.004). No short-term safety concerns were identified from the PROMISE and PRISM trials. Therefore, women with a history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone 400 mg twice daily. Women and their care providers should use the findings for shared decision-making.
Topics: Abortion, Habitual; Abortion, Threatened; Administration, Intravaginal; Female; Humans; Pregnancy; Pregnancy Trimester, First; Progesterone; Progestins; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 32008730
DOI: 10.1016/j.ajog.2019.12.006 -
The Cochrane Database of Systematic... Aug 2016Progestin-only contraceptives (POCs) are appropriate for many women who cannot or should not take estrogen. POCs include injectables, intrauterine contraception,... (Review)
Review
BACKGROUND
Progestin-only contraceptives (POCs) are appropriate for many women who cannot or should not take estrogen. POCs include injectables, intrauterine contraception, implants, and oral contraceptives. Many POCs are long-acting, cost-effective methods of preventing pregnancy. However, concern about weight gain can deter the initiation of contraceptives and cause early discontinuation among users.
OBJECTIVES
The primary objective was to evaluate the association between progestin-only contraceptive use and changes in body weight.
SEARCH METHODS
Until 4 August 2016, we searched MEDLINE, CENTRAL, POPLINE, LILACS, ClinicalTrials.gov, and ICTRP. For the initial review, we contacted investigators to identify other trials.
SELECTION CRITERIA
We considered comparative studies that examined a POC versus another contraceptive method or no contraceptive. The primary outcome was mean change in body weight or mean change in body composition. We also considered the dichotomous outcome of loss or gain of a specified amount of weight.
DATA COLLECTION AND ANALYSIS
Two authors extracted the data. Non-randomized studies (NRS) need to control for confounding factors. We used adjusted measures for the primary effects in NRS or the results of matched analysis from paired samples. If the report did not provide adjusted measures for the primary analysis, we used unadjusted outcomes. For RCTs and NRS without adjusted measures, we computed the mean difference (MD) with 95% confidence interval (CI) for continuous variables. For dichotomous outcomes, we calculated the Mantel-Haenszel odds ratio (OR) with 95% CI.
MAIN RESULTS
We found 22 eligible studies that included a total of 11,450 women. With 6 NRS added to this update, the review includes 17 NRS and 5 RCTs. By contraceptive method, the review has 16 studies of depot medroxyprogesterone acetate (DMPA), 4 of levonorgestrel-releasing intrauterine contraception (LNG-IUC), 5 for implants, and 2 for progestin-only pills.Comparison groups did not differ significantly for weight change or other body composition measure in 15 studies. Five studies with moderate or low quality evidence showed differences between study arms. Two studies of a six-rod implant also indicated some differences, but the evidence was low quality.Three studies showed differences for DMPA users compared with women not using a hormonal method. In a retrospective study, weight gain (kg) was greater for DMPA versus copper (Cu) IUC in years one (MD 2.28, 95% CI 1.79 to 2.77), two (MD 2.71, 95% CI 2.12 to 3.30), and three (MD 3.17, 95% CI 2.51 to 3.83). A prospective study showed adolescents using DMPA had a greater increase in body fat (%) compared with a group not using a hormonal method (MD 11.00, 95% CI 2.64 to 19.36). The DMPA group also had a greater decrease in lean body mass (%) (MD -4.00, 95% CI -6.93 to -1.07). A more recent retrospective study reported greater mean increases with use of DMPA versus Cu IUC for weight (kg) at years 1 (1.3 vs 0.2), 4 (3.5 vs 1.9), and 10 (6.6 vs 4.9).Two studies reported a greater mean increase in body fat mass (%) for POC users versus women not using a hormonal method. The method was LNG-IUC in two studies (reported means 2.5 versus -1.3; P = 0.029); (MD 1.60, 95% CI 0.45 to 2.75). One also studied a desogestrel-containing pill (MD 3.30, 95% CI 2.08 to 4.52). Both studies showed a greater decrease in lean body mass among POC users.
AUTHORS' CONCLUSIONS
We considered the overall quality of evidence to be low; more than half of the studies had low quality evidence. The main reasons for downgrading were lack of randomizations (NRS) and high loss to follow-up or early discontinuation.These 22 studies showed limited evidence of change in weight or body composition with use of POCs. Mean weight gain at 6 or 12 months was less than 2 kg (4.4 lb) for most studies. Those with multiyear data showed mean weight change was approximately twice as much at two to four years than at one year, but generally the study groups did not differ significantly. Appropriate counseling about typical weight gain may help reduce discontinuation of contraceptives due to perceptions of weight gain.
Topics: Adolescent; Adult; Body Composition; Body Weight; Contraceptives, Oral, Hormonal; Drug Implants; Female; Humans; Intrauterine Devices, Medicated; Levonorgestrel; Medroxyprogesterone Acetate; Progestins; Prospective Studies; Retrospective Studies; Weight Gain
PubMed: 27567593
DOI: 10.1002/14651858.CD008815.pub4 -
Advanced Drug Delivery Reviews Jul 2021Preterm birth (PTB) is defined as delivery before 37 weeks of gestation. Globally, 15 million infants are born prematurely, putting these children at an increased risk... (Review)
Review
Preterm birth (PTB) is defined as delivery before 37 weeks of gestation. Globally, 15 million infants are born prematurely, putting these children at an increased risk of mortality and lifelong health challenges. Currently in the U.S., there is only one FDA approved therapy for the prevention of preterm birth. Makena is an intramuscular progestin injection given to women who have experienced a premature delivery in the past. Recently, however, Makena failed a confirmatory trial, resulting the Center for Drug Evaluation and Research's (CDER) recommendation for the FDA to withdrawal Makena's approval. This recommendation would leave clinicians with no therapeutic options for preventing PTB. Here, we outline recent interdisciplinary efforts involving physicians, pharmacologists, biologists, chemists, and engineers to understand risk factors associated with PTB, to define mechanisms that contribute to PTB, and to develop next generation therapies for preventing PTB. These advances have the potential to better identify women at risk for PTB, prevent the onset of premature labor, and, ultimately, save infant lives.
Topics: 17 alpha-Hydroxyprogesterone Caproate; Animals; Drug Approval; Drug Development; Female; Humans; Infant, Newborn; Pregnancy; Premature Birth; Progestins; Risk Factors
PubMed: 33895215
DOI: 10.1016/j.addr.2021.04.021 -
International Journal of Sports... Aug 2018To identify the period prevalence of hormonal contraceptive (HC) use and characterize the perceived side effects associated with the menstrual cycle and HC use.
PURPOSE
To identify the period prevalence of hormonal contraceptive (HC) use and characterize the perceived side effects associated with the menstrual cycle and HC use.
METHODS
A total of 430 elite female athletes completed a questionnaire to assess the period prevalence of HC use, the reasons for initiation and discontinuation of HCs, and the side effects experienced by HC and non-HC users. Descriptive statistics, between-groups comparisons, and associations between categorical variables were calculated.
RESULTS
Of athletes studied, 49.5% were currently using HCs and 69.8% had used HCs at some point. Combined oral contraceptives were most commonly used (68.1%), with 30.0% using progestin-only contraceptives (implant = 13.1%, injection = 3.7%, and intrauterine system = 2.8%). Perceived negative side effects were more common with progestin-only HC use (39.1%) compared with combined-HC use (17.8%; P = .001) and were most prevalent in implant users (53.6%; P = .004). HC users reported perceived positive side effects relating to their ability to predict and/or manipulate the timing, frequency, and amount of menstrual bleeding. Non-HC users had a menstrual cycle length of 29 (5) d and 77.4% reported negative side effects during their menstrual cycle, primarily during days 1-2 of menstruation (81.6%).
CONCLUSIONS
Approximately half of elite athletes used HCs, and progestin-only contraceptive users reported greater incidences of negative side effects, especially with the implant. Because of the high interindividual variability in reported side effects, athletes and practitioners should maintain an open dialogue to pursue the best interests of the athlete.
Topics: Adult; Athletes; Contraceptives, Oral, Combined; Contraceptives, Oral, Hormonal; Drug Implants; Emotions; Female; Humans; Injections; Intrauterine Devices, Medicated; Menstrual Cycle; Menstruation Disturbances; Perception; Progestins; Surveys and Questionnaires; Young Adult
PubMed: 29283683
DOI: 10.1123/ijspp.2017-0330 -
BMJ (Clinical Research Ed.) Jun 2023To assess the association between use of menopausal hormone therapy and development of dementia according to type of hormone treatment, duration of use, and age at usage.
OBJECTIVES
To assess the association between use of menopausal hormone therapy and development of dementia according to type of hormone treatment, duration of use, and age at usage.
DESIGN
Nationwide, nested case-control study.
SETTING
Denmark through national registries.
PARTICIPANTS
5589 incident cases of dementia and 55 890 age matched controls were identified between 2000 and 2018 from a population of all Danish women aged 50-60 years in 2000 with no history of dementia or contraindications for use of menopausal hormone therapy.
MAIN OUTCOME MEASURES
Adjusted hazard ratios with 95% confidence intervals for all cause dementia defined by a first time diagnosis or first time use of dementia specific medication.
RESULTS
Compared with people who had never used treatment, people who had received oestrogen-progestogen therapy had an increased rate of all cause dementia (hazard ratio 1.24 (95% confidence interval 1.17 to 1.33)). Increasing durations of use yielded higher hazard ratios, ranging from 1.21 (1.09 to 1.35) for one year or less of use to 1.74 (1.45 to 2.10) for more than 12 years of use. Oestrogen-progestogen therapy was positively associated with development of dementia for both continuous (1.31 (1.18 to 1.46)) and cyclic (1.24 (1.13 to 1.35)) regimens. Associations persisted in women who received treatment at the age 55 years or younger (1.24 (1.11 to 1.40)). Findings persisted when restricted to late onset dementia (1.21 (1.12 to 1.30)) and Alzheimer's disease (1.22 (1.07 to 1.39)).
CONCLUSIONS
Menopausal hormone therapy was positively associated with development of all cause dementia and Alzheimer's disease, even in women who received treatment at the age of 55 years or younger. The increased rate of dementia was similar between continuous and cyclic treatment. Further studies are warranted to determine whether these findings represent an actual effect of menopausal hormone therapy on dementia risk, or whether they reflect an underlying predisposition in women in need of these treatments.
Topics: Humans; Female; Case-Control Studies; Alzheimer Disease; Menopause; Estrogens; Progestins; Denmark; Middle Aged; Aged
PubMed: 37380194
DOI: 10.1136/bmj-2022-072770 -
International Journal of Molecular... Jul 2022Progesterone is a steroid hormone traditionally linked with female fertility and pregnancy. In current reproductive medicine, progesterone and its analogues play crucial... (Review)
Review
Progesterone is a steroid hormone traditionally linked with female fertility and pregnancy. In current reproductive medicine, progesterone and its analogues play crucial roles. While the discovery of its effects has a long history, over recent decades, various novel actions of this interesting steroid have been documented, of which its neuro- and immunoprotective activities are the most widely discussed. Discoveries of the novel biological activities of progesterone have also driven research and development in the field of progesterone analogues used in human medicine. Progestogen treatment has traditionally and predominately been used in maintaining pregnancy, the prevention of preterm labor, various gynecological pathologies, and in lowering the negative effects of menopause. However, there are also various other medical fields where progesterone and its analogues could find application in the future. The aim of this work is to show the mechanisms of action of progesterone and its metabolites, the physiological and pharmacological actions of progesterone and its synthetic analogues in human medicine, as well as the impacts of its production and use on the environment.
Topics: Female; Hormones; Humans; Infant, Newborn; Pregnancy; Progesterone; Progestins
PubMed: 35887338
DOI: 10.3390/ijms23147989