-
BioMed Research International 2017To conduct systematic analyses to evaluate the efficacy of progesterone therapy for the prevention of miscarriages in pregnant women experiencing threatened abortion. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To conduct systematic analyses to evaluate the efficacy of progesterone therapy for the prevention of miscarriages in pregnant women experiencing threatened abortion.
METHODS
In November 2016, we performed a systematic literature search and identified 51 articles in PubMed, Embase, and Cochrane databases. We identified nine randomized trials that included 913 pregnant women (including 322 treated with oral dydrogesterone, 213 treated with vaginal progesterone, and 378 control subjects) who met the selection criteria.
RESULTS
The incidence of miscarriage was significantly lower in the total progesterone group than in the control group (13.0% versus 21.7%; odds ratio, 0.53; 95% confidence interval (CI), 0.36 to 0.78; = 0.001; , 0%). Moreover, the incidence of miscarriage was significantly lower in the oral dydrogesterone group than in the control group (11.7% versus 22.6%; odds ratio, 0.43; 95% CI, 0.26 to 0.71; = 0.001; , 0%) and was lower in the vaginal progesterone group than in the control group, although this difference was nonsignificant (15.4% versus 20.3%; odds ratio, 0.72; 95% CI, 0.39 to 1.34; = 0.30; , 0%). However, the incidence of miscarriage was not different between the oral dydrogesterone and vaginal progesterone groups.
CONCLUSION
Progesterone therapy, especially oral dydrogesterone, can effectively prevent miscarriage in pregnant women experiencing threatened abortion.
Topics: Abortion, Threatened; Administration, Oral; Dydrogesterone; Female; Humans; Pregnancy; Progesterone; Vagina
PubMed: 29392134
DOI: 10.1155/2017/3616875 -
Frontiers in Oncology 2019Hormonal therapy in endometrial cancer (EC) is used for patients who wish to preserve fertility and for patients with advanced or recurrent disease in a palliative...
Hormonal therapy in endometrial cancer (EC) is used for patients who wish to preserve fertility and for patients with advanced or recurrent disease in a palliative setting. First line hormonal therapy consists of treatment with progestins, which has a response rate of 25% in an unselected population. Treatment with anti-estrogens is an alternative hormonal therapy option, but there is limited data on the effect and side-effects of anti-estrogens in EC. Therefore, we performed a systematic review to investigate the response rate and toxicity of anti-estrogenic therapy in patients with endometrial cancer. A systematic search in electronic databases was performed to identify studies on selective estrogen receptor modulators (SERM) and down-regulators (SERD) and aromatase inhibitors that reported on response rates (RR) among EC patients. Outcome in estrogen receptor (ER) positive and negative disease was assessed independently. Sixteen studies on advanced stage and recurrent EC were included. Ten studies investigated anti-estrogen monotherapy and seven investigated a combination of anti-estrogenic drugs with either progestin or targeted treatment. Due to heterogeneity in patient population, no meta-analysis was performed. The median age of the patients in the included studies ranged from 61 to 71 years and the proportion of low grade tumors ranged from 38 to 80%. The RR for tamoxifen ranged from 10 to 53%, for other SERMs and SERDs 9-31%, for aromatase inhibitors from 8 to 9%, for combined tamoxifen/progestin treatment 19-58%, for combined chemo- and hormonal therapy 43% and for combination of anti-estrogenic treatment with mammalian target of rapamycin (mTOR) inhibitors 14-31%. Toxicity consisted mainly of nausea and thrombotic events and was higher in combination therapy of chemotherapy and hormonal therapy and hormonal therapy and mTOR inhibitors compared to other therapies. Tamoxifen or a combination of tamoxifen and progestin should be the preferred choice when selecting second line hormonal treatment because the RRs are similar to first line progestin treatment and the toxicity is low. The response can be optimized by selecting patients with endometrioid tumors and positive estrogen receptor status, which should be based on a pretreatment biopsy.
PubMed: 31134155
DOI: 10.3389/fonc.2019.00359 -
The Cochrane Database of Systematic... Oct 2019Endometrial cancer is one of the most common gynaecological cancers in developed countries. Treatment of advanced endometrial cancer usually involves radiotherapy,... (Review)
Review
BACKGROUND
Endometrial cancer is one of the most common gynaecological cancers in developed countries. Treatment of advanced endometrial cancer usually involves radiotherapy, chemotherapy, endocrine therapy or a combination of these. However, survival outcomes are poor in advanced or metastatic disease. Better systemic treatment options are needed to improve survival and safety outcomes for these women. The PI3K/AKT/mTOR pathway is a frequently altered signalling pathway in endometrial cancer. Single-arm studies have reported some encouraging results of the PI3K/AKT/mTOR inhibition in advanced or recurrent endometrial cancer.
OBJECTIVES
To assess the efficacy and safety of PI3K/AKT/mTOR inhibitor-containing regimens in women with locally-advanced, metastatic or recurrent endometrial cancer.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials, MEDLINE and Embase to 16 January 2019; and the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov in July 2018. We also reviewed reference lists from included studies and endometrial cancer guidelines.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) comparing a regimen with a PI3K/AKT/mTOR inhibitor (either alone or in combination with other treatments, such as chemotherapy or hormonal therapy) versus a comparator regimen without a PI3K/AKT/mTOR inhibitor. There were no restrictions on which comparator(s) were included.
DATA COLLECTION AND ANALYSIS
We extracted data independently, and assessed risks of bias and the certainty of the evidence. The primary outcome measures were progression-free survival and toxicity (grade 3/4 where available). We derived hazard ratios (HRs) for time-to-event outcomes and risk ratios (RRs) for dichotomous outcomes. Secondary outcomes included overall survival, objective tumour response rate, quality of life and treatment-related death. We used GRADEproGDT to assess the certainty of the evidence for the most important outcomes (by first-line and second/third-line therapy for progression-free survival and overall survival).
MAIN RESULTS
We included two RCTs involving 361 women. One study assessed the effects of the mTOR inhibitor temsirolimus, in combination with carboplatin/paclitaxel versus carboplatin/paclitaxel and bevacizumab in treatment-naïve women with advanced or recurrent endometrial cancer. The second study compared the mTOR inhibitor ridaforolimus alone versus progestin or investigator choice of chemotherapy in women who had received prior treatment for metastatic or recurrent endometrial cancer. We identified five ongoing studies on the effects of PI3K and AKT inhibitors, metformin and dual mTOR inhibitors.For first-line therapy, an mTOR inhibitor-containing regimen may worsen progression-free survival (HR 1.43, 95% CI 1.06 to 1.93; 1 study, 231 participants; low-certainty evidence), while for second/third-line therapy, an mTOR inhibitor probably improves progression-free survival compared to chemotherapy or endocrine therapy (HR 0.53, 95% CI 0.31 to 0.91; 1 study, 95 participants; moderate-certainty evidence). Data on toxicity were available from both studies: administering an mTOR inhibitor regimen may increase the risk of grade 3/4 mucositis (RR 10.42, 95% CI 1.34 to 80.74; 2 studies, 357 participants; low-certainty evidence), but may result in little to no difference in risk of anaemia or interstitial pneumonitis (low-certainty evidence for both toxicities). Overall, event rates were low. For first-line therapy, an mTOR inhibitor-containing regimen may result in little to no difference in overall survival compared to chemotherapy (HR 1.32, 95% CI 0.98 to 1.781 study, 231 participants; low-certainty evidence). The finding was similar for second/third-line therapy (HR 1.06, 95% CI 0.70 to 1.61; 1 study, 130 participants; low-certainty evidence). Administering mTOR inhibitor-containing regimens may result in little to no difference in tumour response compared to chemotherapy or hormonal therapy in first-line or second/third-line therapy (first line: RR 0.93, 95% CI 0.75 to 1.17; 1 study, 231 participants; second/third line: RR 0.22, 95% CI 0.01 to 4.40; 1 study, 61 participants; low-certainty evidence).Neither study collected or reported quality-of-life data.
AUTHORS' CONCLUSIONS
Two RCTs have been reported to date, with low certainty of evidence. In a recurrent disease setting, mTOR inhibitors may result in improved progression-free survival, but we found no clear benefit in overall survival or tumour response rate. We await the publication of at least five ongoing studies investigating the role of PI3K/AKT/mTOR inhibitors in advanced or recurrent endometrial cancer before any conclusions can be drawn on their use.
PubMed: 31588998
DOI: 10.1002/14651858.CD012160.pub2 -
Ultrasound in Obstetrics & Gynecology :... Mar 2017To assess the efficacy of vaginal progesterone for the prevention of preterm birth and neonatal morbidity and mortality in asymptomatic women with a twin gestation and a... (Meta-Analysis)
Meta-Analysis Review
Vaginal progesterone decreases preterm birth and neonatal morbidity and mortality in women with a twin gestation and a short cervix: an updated meta-analysis of individual patient data.
OBJECTIVE
To assess the efficacy of vaginal progesterone for the prevention of preterm birth and neonatal morbidity and mortality in asymptomatic women with a twin gestation and a sonographic short cervix (cervical length ≤ 25 mm) in the mid-trimester.
METHODS
This was an updated systematic review and meta-analysis of individual patient data (IPD) from randomized controlled trials comparing vaginal progesterone with placebo/no treatment in women with a twin gestation and a mid-trimester sonographic cervical length ≤ 25 mm. MEDLINE, EMBASE, POPLINE, CINAHL and LILACS (all from inception to 31 December 2016), the Cochrane Central Register of Controlled Trials, Research Registers of ongoing trials, Google Scholar, conference proceedings and reference lists of identified studies were searched. The primary outcome measure was preterm birth < 33 weeks' gestation. Two reviewers independently selected studies, assessed the risk of bias and extracted the data. Pooled relative risks (RRs) with 95% confidence intervals (CI) were calculated.
RESULTS
IPD were available for 303 women (159 assigned to vaginal progesterone and 144 assigned to placebo/no treatment) and their 606 fetuses/infants from six randomized controlled trials. One study, which included women with a cervical length between 20 and 25 mm, provided 74% of the total sample size of the IPD meta-analysis. Vaginal progesterone, compared with placebo/no treatment, was associated with a statistically significant reduction in the risk of preterm birth < 33 weeks' gestation (31.4% vs 43.1%; RR, 0.69 (95% CI, 0.51-0.93); moderate-quality evidence). Moreover, vaginal progesterone administration was associated with a significant decrease in the risk of preterm birth < 35, < 34, < 32 and < 30 weeks' gestation (RRs ranging from 0.47 to 0.83), neonatal death (RR, 0.53 (95% CI, 0.35-0.81)), respiratory distress syndrome (RR, 0.70 (95% CI, 0.56-0.89)), composite neonatal morbidity and mortality (RR, 0.61 (95% CI, 0.34-0.98)), use of mechanical ventilation (RR, 0.54 (95% CI, 0.36-0.81)) and birth weight < 1500 g (RR, 0.53 (95% CI, 0.35-0.80)) (all moderate-quality evidence). There were no significant differences in neurodevelopmental outcomes at 4-5 years of age between the vaginal progesterone and placebo groups.
CONCLUSION
Administration of vaginal progesterone to asymptomatic women with a twin gestation and a sonographic short cervix in the mid-trimester reduces the risk of preterm birth occurring at < 30 to < 35 gestational weeks, neonatal mortality and some measures of neonatal morbidity, without any demonstrable deleterious effects on childhood neurodevelopment. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
Topics: Administration, Intravaginal; Cervix Uteri; Female; Humans; Infant; Infant Mortality; Infant, Newborn; Maternal Death; Maternal Mortality; Perinatal Death; Pregnancy; Pregnancy, Twin; Premature Birth; Progesterone; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 28067007
DOI: 10.1002/uog.17397 -
Fertility and Sterility Jun 2023Over the last decade, frozen embryo transfer (FET) has been increasingly used in contemporary fertility units. Despite the rapid increase in FET, there is still... (Meta-Analysis)
Meta-Analysis Review
IMPORTANCE
Over the last decade, frozen embryo transfer (FET) has been increasingly used in contemporary fertility units. Despite the rapid increase in FET, there is still insufficient evidence to recommend an optimized protocol for endometrial preparation especially in patients with lower progesterone (P4) levels. Previous studies have concluded that P4 levels <10 ng/mL are associated with poorer pregnancy outcomes than those reported with high levels of circulating P4.
OBJECTIVE
To identify whether rescue P4 dosing in patients with low P4 can salvage adverse outcomes associated with low P4 levels, resulting in outcomes comparable to patients with adequate progesterone.
DATA SOURCES
The study was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-analyses guidelines and prospectively registered under the PROSPERO database (CRD42022357125). Six databases (Embase, MEDLINE, APA PsycInfo, Global Health, HMIC Health Management Information Consortium, and Google Scholar) and 2 additional sources were searched from inception to August 29, 2022.
STUDY SELECTION AND SYNTHESIS
Prospective and retrospective cohort studies, reporting the association between rescue progesterone and one or more pregnancy outcomes, were included. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS), while the quality of evidence by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. Summative and subgroup data as well as heterogeneity were generated by the Cochrane platform RevMan (V. 5.4).
MAIN OUTCOME MEASURE(S)
To compare ongoing pregnancy rate as primary outcome and clinical pregnancy rate, miscarriage rate, and live birth rate as secondary outcomes between patients with low (<10 ng/mL) receiving rescue progesterone vs. those with adequate levels of P4 (≥10 ng/mL).
RESULT(S)
Overall, 7 observational studies were included in the analysis, with a total of 5927 patients of median age 34 (interquartile range [IQR]: 31.55, 37.13). Overall, patient group comparison, namely those with low P4 that received a rescue dose and those with adequate P4 levels, did not yield significant differences for either the primary or secondary outcomes. For ongoing clinical pregnancy, patients with low P4 receiving the rescue dose vs. those with adequate P4 levels was odds ratio (OR) 0.98 (95% CI: 0.78, 1.24; P = .86, I: 41%), whereas for miscarriage events, OR was 0.98 (95% CI: 0.81, 1.17; P = .80, I: 0). Equally, for clinical pregnancy, OR was 0.91 (95% CI: 0.78, 1.06; P = .24; I: 33%), and for live birth, OR was 0.92 (95% CI: 0.77, 1.09; P = .33; I: 43%). Subgroup analysis on the basis or rescue administration route successfully explained summative heterogeneity.
CONCLUSION(S)
Rescue P4 dosing in patients with low P4 results in ongoing pregnancy rate, clinical pregnancy and live birth rates were comparable to those of patients with adequate P4 levels. However, robust randomized controlled trials assessing rescue treatment in women with low P4 are needed to confirm these findings. Rescue P4 in patients with low circulating P4 around embryo transfer day may result in reproductive outcomes comparable to those with adequate P4 levels.
STUDY REGISTRATION
CRD42022357125 (PROSPERO).
Topics: Pregnancy; Humans; Female; Adult; Progesterone; Abortion, Spontaneous; Prospective Studies; Retrospective Studies; Embryo Transfer; Pregnancy Rate; Live Birth
PubMed: 36781098
DOI: 10.1016/j.fertnstert.2023.02.007 -
Reproductive Biology and Endocrinology... Nov 2021Progesterone supplementation is widely performed in women with threatened miscarriage or a history of recurrent miscarriage; however, the effects of early progesterone... (Meta-Analysis)
Meta-Analysis
Pregnancy-related complications and perinatal outcomes following progesterone supplementation before 20 weeks of pregnancy in spontaneously achieved singleton pregnancies: a systematic review and meta-analysis.
BACKGROUND
Progesterone supplementation is widely performed in women with threatened miscarriage or a history of recurrent miscarriage; however, the effects of early progesterone supplementation on pregnancy-related complications and perinatal outcomes in later gestational weeks remain unknown.
METHODS
Ovid MEDLINE, the Cochrane Library, Embase and ClinicalTrials.gov were searched until April 3rd, 2021. Randomized controlled trials regarding spontaneously achieved singleton pregnancies who were treated with progestogen before 20 weeks of pregnancy and were compared with those women in unexposed control groups were selected for inclusion. We performed pairwise meta-analyses with the random-effects model. The risk of bias was assessed according to the Cochrane Collaboration tool. The primary outcomes included preeclampsia (PE), and gestational diabetes mellitus (GDM), with the results presented as odds ratios (ORs) with 95% confidence intervals (CIs).
RESULTS
We identified nine eligible studies involving 6439 participants. The pooled OR of subsequent PE following early progestogen supplementation was 0.64 (95% CI 0.42-0.98, moderate quality of evidence). A lower OR for PE was observed in the progestogen group when the subgroup analysis was performed in the vaginal subgroup (OR 0.62, 95%CI 0.40-0.96). There was insufficient evidence of a difference in the rate of GDM between pregnant women with early progestogen supplementation and unexposed pregnant women (OR 1.02, 95% CI 0.79-1.32, low quality of evidence). The pooled OR of low birth weight (LBW) following oral dydrogesterone was 0.57 (95% CI 0.34-0.95, moderate quality of evidence). The results were affected by a single study and the total sample size of enrolled women did not reach the required information size.
CONCLUSION
Use of vaginal micronized progesterone (Utrogestan) in spontaneously achieved singleton pregnancies with threatened miscarriage before 20 weeks of pregnancy may reduce the risk of PE in later gestational weeks. Among spontaneously achieved singleton pregnancies with threatened miscarriage or a history of recurrent miscarriage, use of oral dydrogesterone before 20 weeks of pregnancy may result in a lower risk of LBW in later gestational weeks. However, the available data were not sufficient to reach definitive conclusions, which highlighted the need for future studies.
Topics: Abortion, Habitual; Dietary Supplements; Female; Humans; Infant, Newborn; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Progesterone; Randomized Controlled Trials as Topic
PubMed: 34732210
DOI: 10.1186/s12958-021-00846-6 -
Developmental Neuroscience 2023Hypoxic-ischaemic encephalopathy (HIE) in the newborn baby is a major contributor to neonatal mortality and morbidity across the world. Therapeutic hypothermia (TH) is... (Review)
Review
Hypoxic-ischaemic encephalopathy (HIE) in the newborn baby is a major contributor to neonatal mortality and morbidity across the world. Therapeutic hypothermia (TH) is the current standard treatment for moderate to severe HIE, but not all babies benefit. Potential neuroprotective actions of progesterone (PROG) include anti-apoptotic, anti-inflammatory, and anti-oxidative effects and reduction of energy depletion, tissue/cellular oedema, and excitotoxicity. In pre-clinical studies of neonatal HIE, PROG has neuroprotective properties but has not been the subject of systematic review. Here, our objective was to evaluate the evidence base for PROG as a potential therapeutic agent in HIE. The PICO framework was used to define the following inclusion criteria. Population: human neonates with HIE/animal models of HIE; intervention: PROG +/- other agents; comparison: V.S. control; outcome: pathological, neurobehavioural, and mechanistic outcome measures. Medline, EMBASE, and CINHAL were then searched between August to October 2018 using pre-defined medical subject heading and keywords. Study inclusion, data extraction, and risk of bias (ROB) analysis using the SYRCLE ROB tool were carried out by two authors. 14 studies were included in the review. They typically displayed a high ROB. This systematic review suggests that PROG reduced neuropathology and reduced neurobehavioural deficits post-hypoxic-ischaemic (HI) insult in 8 and 3 studies, respectively. However, there was sex dimorphism in the effects of PROG. In addition, there are limitations and biases in these studies, and there remains a need for well-designed large pre-clinical studies with greater methodological quality to further inform the efficacy, safety, dose, timing, and frequency of PROG administration. With such data, large animal studies could be planned combining PROG administration with and without TH.
Topics: Animals; Infant, Newborn; Humans; Neuroprotective Agents; Hypoxia-Ischemia, Brain; Progesterone; Hypothermia, Induced; Neuroprotection
PubMed: 36436500
DOI: 10.1159/000521540 -
Inflammation Research : Official... Mar 2016A systematic review of all literature was done to assess the ability of the progestin dienogest (DNG) to influence the inflammatory response of endometriotic cells. (Review)
Review
OBJECTIVE AND DESIGN
A systematic review of all literature was done to assess the ability of the progestin dienogest (DNG) to influence the inflammatory response of endometriotic cells.
MAIN OUTCOME MEASURES
In vitro and in vivo studies report an influence of DNG on the inflammatory response in eutopic or ectopic endometrial tissue (animal or human).
RESULTS
After strict inclusion criteria were satisfied, 15 studies were identified that reported a DNG influence on the inflammatory response in endometrial tissue. These studies identified a modulation of prostaglandin (PG) production and metabolism (PGE2, PGE2 synthase, cyclo-oxygenase-2 and microsomal PGE synthase-1), pro-inflammatory cytokine and chemokine production [interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, monocyte chemoattractant protein-1 and stromal cell-derived factor-1], growth factor biosynthesis (vascular endothelial growth factor and nerve growth factor) and signaling kinases, responsible for the control of inflammation. Evidence supports a progesterone receptor-mediated inhibition of the inflammatory response in PR-expressing epithelial cells. It also indicated that DNG inhibited the inflammatory response in stromal cells, however, whether this was via a PR-mediated mechanism is not clear.
CONCLUSIONS
DNG has a significant effect on the inflammatory microenvironment of endometriotic lesions that may contribute to its clinical efficacy. A better understanding of the specific anti-inflammatory activity of DNG and whether this contributes to its clinical efficacy can help develop treatments that focus on the inhibition of inflammation while minimizing hormonal modulation.
Topics: Animals; Cytokines; Endometriosis; Epithelial Cells; Female; Hormone Antagonists; Humans; Immunologic Factors; Intercellular Signaling Peptides and Proteins; Nandrolone; Prostaglandins; Stromal Cells
PubMed: 26650031
DOI: 10.1007/s00011-015-0909-7 -
Contraception Sep 2016Postpartum women need effective contraception. Concerns have been raised that use of progestogen-only contraceptives (POCs) may affect breastfeeding performance and... (Review)
Review
BACKGROUND
Postpartum women need effective contraception. Concerns have been raised that use of progestogen-only contraceptives (POCs) may affect breastfeeding performance and infant health outcomes.
OBJECTIVES
We investigated the clinical outcomes of breastfeeding duration, initiation of supplemental feeding and weaning, as well as infant outcomes including infant growth, health and development among breastfeeding women using POCs compared with breastfeeding women not using POCs.
SEARCH STRATEGY
We searched the PubMed database for all articles published from database inception through December 2014.
SELECTION CRITERIA
We included primary research studies of breastfeeding women of any age or parity who received POCs, including progestogen-only pills, injectables, implants or hormonal intrauterine devices (IUDs). The main outcomes were breastfeeding performance (as measured by initiation, continuation, frequency and exclusivity of breastfeeding) and infant health (as measured by growth, development or adverse health effects).
RESULTS
Forty-nine articles reporting on 47 different studies were identified that investigated the use of POCs in breastfeeding women and reported clinically relevant outcomes of infant growth, health or breastfeeding performance. Studies ranged from poor to fair methodological quality and generally failed to show negative effects of the use of POCs on breastfeeding outcomes or on infant growth or development. One randomized controlled trial (RCT) raises concerns that immediate insertion of the levonorgestrel IUD postpartum may be associated with poorer breastfeeding performance when compared with delayed insertion, although two other RCTs evaluating early etonogestrel implants compared with delayed initiation of implants or depot medroxyprogesterone acetate failed to find such an association.
CONCLUSION
The preponderance of evidence fails to demonstrate adverse breastfeeding outcomes or negative health outcomes in infants such as restricted growth, health problems or impaired development. Evidence newly added to this review was largely consistent with previous evidence.
Topics: Breast Feeding; Child Development; Contraception; Contraceptives, Oral, Hormonal; Drug Implants; Female; Humans; Infant; Intrauterine Devices; Levonorgestrel; Medroxyprogesterone Acetate; Progestins; Randomized Controlled Trials as Topic
PubMed: 26410174
DOI: 10.1016/j.contraception.2015.09.010