-
Steroids Jun 2022The glucocorticoid receptor (GR) regulates transcription of genes involved in multiple processes. Medroxyprogesterone acetate (MPA), widely used in the injectable...
The glucocorticoid receptor (GR) regulates transcription of genes involved in multiple processes. Medroxyprogesterone acetate (MPA), widely used in the injectable contraceptive Depo-MPA (DMPA), has off-target effects via the GR, which may result in side-effects in endocrine therapy. However, very little is known about the GR activity of other progestins used in endocrine therapy. This study compared GR activities for several progestins, using whole cell binding, dose-response, and GR phosphorylation assays, in both a cell line model and peripheral blood mononuclear cells (PBMCs). MPA, etonogestrel (ETG) and nestorone (NES) exhibit greater relative binding affinities for the GR than levonorgestrel (LNG) and norethisterone/norethindrone (NET) and are partial GR agonists for transactivation but agonists for transrepression on synthetic promoters in COS-1 cells. MPA is a potent agonist for endogenous GR-regulated GILZ and IL6 genes in PBMCs. While ETG and NES also display agonist activity on IL6, they have little effect on GILZ. In contrast, LNG and NET exhibit little to no activity in transactivation models, while both exhibit some transrepressive activity but are generally less potent and/or efficacious than MPA. Antagonist and phosphorylation assays confirmed that MPA and NES act via the GR on endogenous genes in PBMCs. Our results suggest GR-mediated dose-dependent and gene-specific transcriptional side-effects are likely to occur at physiologically relevant concentrations in vivo for MPA, may possibly occur selectively for ETG and NES, but are unlikely to occur for LNG and NET. This suggests that these progestins will exhibit differential side-effects in endocrine therapy via the GR.
Topics: Animals; COS Cells; Chlorocebus aethiops; Glucocorticoids; Interleukin-6; Leukocytes, Mononuclear; Levonorgestrel; Medroxyprogesterone Acetate; Norethindrone; Progestins; Receptors, Glucocorticoid
PubMed: 35271867
DOI: 10.1016/j.steroids.2022.108998 -
Contrast Media & Molecular Imaging 2022. To study the therapeutic effects of metformin in combination with medroxyprogesterone in the early endometrial cancer patients with fertility requirements. A total of...
. To study the therapeutic effects of metformin in combination with medroxyprogesterone in the early endometrial cancer patients with fertility requirements. A total of 120 patients with early endometrial cancer admitted to and treated in our hospital were enrolled and evenly assigned into two groups according to different therapeutic regimens, namely, metformin group (metformin combined with medroxyprogesterone acetate) and control group (medroxyprogesterone acetate alone). The objective response rate (ORR) and disease control rate (DCR) were 71.7% (43/60) and 90.0% (54/60) in the metformin group and 53.3% (32/60) and 78.3% (47/60) in the control group, respectively. Adverse reactions such as gastrointestinal reaction, headache, and insomnia were mainly observed in patients. The body mass index (BMI) declined from (34.43 ± 4.34) kg/m to (24.77 ± 2.39) kg/m in the metformin group and from (33.37 ± 4.49) kg/m to (31.28 ± 3.55) kg/m in the control group after treatment. After treatment, serum levels of vascular endothelial growth factor (VEGF), angiotensin-2 (Ang-2), carbohydrate antigen 125 (CA125), and CA19-9 in the metformin group were significantly lower than those in the control group ( = 0.005, < 0.001, = 0.002, and < 0.001). During follow-up, the pregnancy rate was 81.7% (49/60) in the metformin group and 61.7% (37/60) in the control group, and the former was prominently higher than the latter ( = 0.025). Metformin in combination with progesterone is effective in treating early endometrial cancer patients with fertility requirements, which significantly reduced the BMI of patients and increased the pregnancy rate after treatment.
Topics: Endometrial Neoplasms; Female; Humans; Medroxyprogesterone Acetate; Metformin; Pregnancy; Pregnancy Rate; Progesterone; Vascular Endothelial Growth Factor A
PubMed: 35854762
DOI: 10.1155/2022/1961016 -
American Journal of Reproductive... Sep 2021Access to safe, effective, and affordable contraception is important for women's health and essential to mitigate maternal and fetal mortality rates. The progestin-based... (Review)
Review
BACKGROUND
Access to safe, effective, and affordable contraception is important for women's health and essential to mitigate maternal and fetal mortality rates. The progestin-based contraceptive depot medroxyprogesterone acetate (DMPA) is a popular contraceptive choice with a low failure rate and convenient administration schedule.
AIM
In this review, we compiled observational data from human cohorts that examine how DMPA influences the mucosal biology of the female genital tract (FGT) that are essential in maintaining vaginal health, including resident immune cells, pro-inflammatory cytokines, epithelial barrier function, and the vaginal microbiome MATERIALS AND METHODS: This review focused on the recent published literature published in 2019 and 2020.
RESULTS
Recent longitudinal studies show that DMPA use associates with an immunosuppressive phenotype, increase in CD4+CCR5+ T cells, and alterations to growth factors. In agreement with previous meta-analyses, DMPA use is associated with minimal effects of the composition of the vaginal microbiome. Cross-sectional studies associate a more pro-inflammatory relationship with DMPA, but these studies are confounded by inherent weaknesses of cross-sectional studies, including differences in study group sizes, behaviors, and other variables that may affect genital inflammation.
DISCUSSION & CONCLUSION
These recent results indicate that the interactions between DMPA and the vaginal mucosa are complex emphasizing the need for comprehensive longitudinal studies that take into consideration the measurement of multiple biological parameters.
Topics: Contraceptive Agents, Female; Delayed-Action Preparations; Female; Genitalia, Female; Humans; Medroxyprogesterone Acetate; Microbiota; Mucous Membrane; Vagina
PubMed: 33991137
DOI: 10.1111/aji.13455 -
Alternative Therapies in Health and... Jul 2023The high resistance rate and high recurrence rate of progesterone only as a treatment for endometrial cancer (EC) limit its clinical application. Metformin (MET) may...
CONTEXT
The high resistance rate and high recurrence rate of progesterone only as a treatment for endometrial cancer (EC) limit its clinical application. Metformin (MET) may have antitumor ability. Combining MET and medroxyprogesterone acetate (MPA) may strengthen their inhibitory effects on proliferation of EC cells, but MET's mechanisms remain unclear.
OBJECTIVE
The study intended to identify the specific molecular mechanism that MET combined with MPA uses against EC progression.
DESIGN
The research team performed a controlled animal study.
SETTING
The study took place at Xuzhou Medical University in Xuzhou, China.
ANIMALS
The animals were16 female non-obese diabetic-severe combined immunodeficient (NOD-SCID) nude mice, about 12 to 16 g in weight.
INTERVENTIONS
The research team divided randomly, the mice into four groups and induced EC in all groups, four in each group: (1) The control group which received received normal saline, (2) the MPA group, which received 100 mg/kg of MPA; (3) the MET group, which received metformin at the rate of 200 mg/kg, each gavage volume was 0.1ml; (4) the MET+MPA group, which received 100 mg/kg of MPA and 200 mg/kg of MET.
OUTCOME MEASURES
The research team: (1) used a CCK-8 kit, an EdU assay, and a flow-cytometry assay to measure cancer-cell proliferation, count, and viability; determine the cell cycle; and measure apoptosis; (2) performed a Western blot analysis to determine the expression of the PR, CD133, pAkt, totalAkt, p-mTOR, and totalTOR antibodies; and (3) determined the size and volume of tumors in vivo and used immunohistochemical staining to determine expression of the Ki67 protein.
RESULTS
The MET+MPA group had a significantly lower number of cancer cells than the MET or MDA groups (both P < .001). That group also had significantly more stagnated cancer cells in the G0/G1 phase and significantly fewer cancer cells in the S phase or G2/M phase control, MET, or MPA groups (all P < .01). The MET+MPA group's PCNA and Ki-67 protein expression was significantly lower than that of the MET and MPA group. The EDU assay yielded similar results. Additionally, the MET+MPA group had significantly higher PR expression than that of to MET or MPA group (both P < .001). The MET and MPA groups' expression of CD133, p-Akt, and p-mTOR were significantly lower than those of the control group, while the MET+MPA group's levels were significantly lower than those of the MET and MPA groups. In-vivo experiments revealed that the MET and MPA groups did show decreased tumor size and volume. The MET+MPA group had tumor weights that were significantly lower and tumor volumes were significantly smaller than those of the MET and MPA groups (all P < .001). Immunohistochemical analysis revealed that the MET+MPA group's levels of the Ki-67 antigen were significantly lower than those of the MET and MPA groups.
CONCLUSIONS
MET inhibited the proliferation of EC cells by increasing MPA-sensitivity, which was dependent on the inhibition of the CD133 expression and the Akt/mTOR pathway. In addition, if MET acts as an effective progestin sensitizer, it certainly offers promising therapeutic prospects for patients with early-stage EC or overgrown endometrium who have fertility requirements.
Topics: Humans; Female; Animals; Mice; Medroxyprogesterone Acetate; Metformin; Mice, Nude; Proto-Oncogene Proteins c-akt; Receptors, Progesterone; Mice, Inbred NOD; Mice, SCID; Endometrial Neoplasms; Cell Proliferation; TOR Serine-Threonine Kinases; Apoptosis; Cell Line, Tumor
PubMed: 37171945
DOI: No ID Found -
Frontiers in Pharmacology 2021Medroxyprogesterone and donepezil could be used as respiratory stimulants in ventilated patients. However, no randomized placebo-controlled trial is available to...
Effects of Donepezil and Medroxyprogesterone Versus Placebo on Weaning in Adult Patients With Non-Pulmonary Etiologies Receiving Invasive Mechanical Ventilation: A triple-blind Randomized Clinical Trial.
Medroxyprogesterone and donepezil could be used as respiratory stimulants in ventilated patients. However, no randomized placebo-controlled trial is available to confirm this approach and compare these drugs. The aim of the current study was to evaluate the effects of donepezil or medroxyprogesterone compared to the placebo in improvement in respiratory status and weaning facilitation in critically ill adult patients receiving mechanical ventilation. This randomized, triple-blind trial was conducted on 78 ventilated patients in intensive care units (ICU). Patients who were intubated due to pulmonary disorders were ruled out. Patients were randomized in a 1:1:1 ratio to receive 5 mg donepezil (n = 23) or 5 mg medroxyprogesterone (n = 26), or placebo (n = 24) twice a day until weaning (maximum 10 days). The primary endpoints were weaning duration, and duration of invasive mechanical ventilation. Secondary endpoints included rate of successful weaning, changes in arterial blood gas (ABG) parameters, GCS and sequential organ failure assessment (SOFA) score, hemoglobin (Hgb), ICU-mortality, and duration of ICU stay, were measured before and after the intervention and if successful weaning was recorded. : Of 78 studied patients who were randomized, 59 weaned successfully. 87% patients in donepezil and 88.5% patients in medroxyprogesterone groups were successfully weaned compared to 66.7% patients in the placebo group. However, this difference was not statistically significant ( = 0.111). Changes in pH, mean duration of intubation, and weaning duration were statistically different in donepezil compared with the control group ( < 0.05). No significant difference in ABG, Hgb, GCS and SOFA score, and duration of intubation were seen in the medroxyprogesterone group, but weaning duration was significantly reduced to 1.429 days compared with the control group ( = 0.038). The results of this clinical trial have demonstrated that the administered dose of medroxyprogesterone and donepezil can expedite the weaning process by reducing the weaning duration compared to placebo. Furthermore, the total duration of invasive ventilation was significantly lower in the donepezil group compared to the control group. Future clinical trials with a larger sample size will determine the exact role of medroxyprogesterone and donepezil in mechanically ventilated patients. https://irct.ir/IRCT20190810044500N2 (April 1, 2020).
PubMed: 34938176
DOI: 10.3389/fphar.2021.735594 -
Journal of Obstetrics and Gynaecology... Feb 2021Despite increased public awareness and use of opioid agonist therapy (OAT), there is little published data on contraception among women on methadone or...
OBJECTIVE
Despite increased public awareness and use of opioid agonist therapy (OAT), there is little published data on contraception among women on methadone or buprenorphine/naloxone. This study aimed to characterize patterns of contraception use among this population.
METHODS
We conducted a cross-sectional survey between May 2014 and October 2015 at 6 medical clinics, pharmacies, and community organizations in British Columbia. Trained surveyors used the Canadian Sexual Health Survey (CSHS) to collect information on contraceptive practices and barriers to health care access. Descriptive analysis was performed on the subset of women on OAT who were at risk for unintended pregnancy.
RESULTS
Of the 133 survey respondents, 80 (60.2%) were at risk for unintended pregnancy. Among the 46 respondents with a recent pregnancy, 44 (95.7%) reported it as unintended. Of those at risk for unintended pregnancy, the most common contraceptive methods used were "no method," male condom, and depo-medroxyprogesterone at 28.8%, 16.3%, and 12.5%, respectively. Only 5% reported dual protection with a barrier and hormonal or intrauterine method. Barriers to contraception access included difficulty booking appointments with providers and cost, although 97% of all respondents reported feeling comfortable speaking with a physician about contraception.
CONCLUSION
We found that most respondents using OAT reported prior pregnancies that were unintended, and used less effective contraceptive methods. Health care professionals who provide addiction care are uniquely positioned to address their patients' concerns about contraception. Incorporating family planning discussions into OAT services may improve understanding and use of effective contraceptive methods. Addressing unmet contraceptive needs may enable women on OAT to achieve their reproductive goals.
Topics: Adult; British Columbia; Buprenorphine, Naloxone Drug Combination; Contraception; Contraception Behavior; Cross-Sectional Studies; Family Planning Services; Female; Health Services Accessibility; Humans; Male; Methadone; Middle Aged; Opiate Substitution Treatment; Opioid-Related Disorders; Pregnancy; Pregnancy, Unplanned; Substance-Related Disorders
PubMed: 32980283
DOI: 10.1016/j.jogc.2020.06.027 -
American Journal of Obstetrics and... Apr 2020Contraceptive choice is a preference-sensitive decision that is affected by contraceptive attributes, patient experience, and reproductive history. Familiarity with and...
BACKGROUND
Contraceptive choice is a preference-sensitive decision that is affected by contraceptive attributes, patient experience, and reproductive history. Familiarity with and acceptability of specific contraceptive methods may influence patient decisions.
OBJECTIVE
The purpose of this study was to describe the acceptability of and previsit familiarity with long-acting reversible contraception (intrauterine devices and contraceptive implants) compared with depo-medroxyprogesterone acetate and oral contraceptive pills in women seeking contraceptive care and to investigate the relationship between acceptability and contraceptive choice.
STUDY DESIGN
This was a secondary analysis of a study that was designed to compare 2 contraceptive care programs conducted at 3 Midwest federally qualified health centers. After contraceptive counseling, participants completed a baseline interviewer-administered survey before the healthcare provider visit. We asked participants questions about previsit familiarity with and acceptability of the intrauterine device, implant, depo-medroxyprogesterone acetate, and oral contraceptive pills. We assessed familiarity using 2 questions: (1) Before today have you ever heard of the [method]? (2) Do you know any woman who has/has used the [method]? Acceptability was assessed for each method on a 0-10 scale, with 0 being "strongly dislike" and 10 being "strongly like." We dichotomized the scores into high acceptability (7-10) and low/moderate acceptability (0-6) for analysis. We examined differences in demographic and reproductive characteristics between women with high and low long-acting reversible contraception acceptability using the chi-square test. We used univariate and multivariable Poisson regressions to examine the relationship among participants' characteristics, method acceptability, and method choice. We adjusted for any covariate that changed the effect size of acceptability by >10%.
RESULTS
There were 1007 women included in the analysis: 900 women (89%) reported that they had heard of the intrauterine device, and 592 women (59%) knew someone who had used the intrauterine device. Eight hundred sixty-five (86%) women had heard of the implant, and 636 women (63%) knew someone who had used it. Knowledge of depo-medroxyprogesterone acetate and oral contraceptive pills was high (>98% for both). Five hundred seventy-six women (57%) found 1 or both long-acting reversible contraception methods highly acceptable. Women with high long-acting reversible contraception acceptability were more likely to be adolescents or aged 30-45 years, white, Hispanic, married/cohabitating, and uninsured and were less likely to desire a child in the next 1-3 years. They were more likely to desire a hormonal intrauterine device (90.5% vs 9.5%), copper intrauterine device (81.1% vs 18.9%), or implant (89.8% vs 10.2%) compared with women with low acceptability (P<.001). In adjusted analyses, women with high acceptability of an intrauterine device were more likely to desire an intrauterine device (adjusted relative risk, 9.62; 95% confidence interval, 6.42-14.42). Women with high acceptability of an implant were also more likely to desire one (adjusted relative risk, 8.74; 95% confidence interval, 6.17-12.38). Women were more likely to desire an intrauterine device or an implant if they knew someone who used the method. Previous use of the method and demographic factors were not associated with method choice.
CONCLUSION
Previsit familiarity with intrauterine devices and implants was high in our federally qualified health centers population, although not as high as depo-medroxyprogesterone acetate and oral contraceptive pills. In adjusted analyses, women who found an intrauterine device or implant highly acceptable and who knew someone who had used the method were more likely to choose those respective methods at the end of their visit.
Topics: Adolescent; Adult; Black or African American; Age Factors; Choice Behavior; Contraceptive Agents, Hormonal; Contraceptives, Oral; Delayed-Action Preparations; Drug Implants; Female; Health Knowledge, Attitudes, Practice; Hispanic or Latino; Humans; Intrauterine Devices; Long-Acting Reversible Contraception; Marital Status; Medroxyprogesterone Acetate; Middle Aged; Patient Acceptance of Health Care; Recognition, Psychology; White People; Young Adult
PubMed: 31838124
DOI: 10.1016/j.ajog.2019.11.1266 -
Pharmacogenetics and Genomics Jan 2022In AIDS Clinical Trials Group study A5338, concomitant rifampicin, isoniazid, and efavirenz was associated with more rapid plasma medroxyprogesterone acetate (MPA)... (Clinical Trial)
Clinical Trial
OBJECTIVE
In AIDS Clinical Trials Group study A5338, concomitant rifampicin, isoniazid, and efavirenz was associated with more rapid plasma medroxyprogesterone acetate (MPA) clearance compared to historical controls without tuberculosis or HIV therapy. We characterized the pharmacogenetics of this interaction.
METHODS
In A5338, women receiving efavirenz-based HIV therapy and rifampicin plus isoniazid for tuberculosis underwent pharmacokinetic evaluations over 12 weeks following a 150-mg intramuscular injection of depot MPA. Data were interpreted with nonlinear mixed-effects modelling. Associations between individual pharmacokinetic parameters and polymorphisms relevant to rifampicin, isoniazid, efavirenz, and MPA were assessed.
RESULTS
Of 62 A5338 participants in four African countries, 44 were evaluable for pharmacokinetic associations, with 17 CYP2B6 normal, 21 intermediate, and 6 poor metabolizers, and 5 NAT2 rapid, 20 intermediate, and 19 slow acetylators. There were no associations between either CYP2B6 or NAT2 genotype and MPA Cmin at week 12, apparent clearance, Cmax, area under the concentration-time curve (AUC) or half-life, or unexplained interindividual variability in clearance, and uptake rate constant or mean transit time of the slow-release fraction (P > 0.05 for each). In exploratory analyses, none of 28 polymorphisms in 14 genes were consistently associated with MPA pharmacokinetic parameters, and none withstood correction for multiple testing.
CONCLUSIONS
Study A5338 suggested that more frequent depot MPA dosing may be appropriate for women receiving rifampicin, isoniazid, and efavirenz. The present results suggest that knowledge of CYP2B6 metabolizer or NAT2 acetylator status does not inform individualized DMPA dosing in this setting.
Topics: Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Drug Interactions; Female; HIV Infections; Humans; Isoniazid; Medroxyprogesterone Acetate; Pharmacogenetics; Rifampin; Tuberculosis
PubMed: 34369424
DOI: 10.1097/FPC.0000000000000448 -
Reproductive Sciences (Thousand Oaks,... Mar 2022Uterine leiomyomas (fibroids) are common benign tumors in women. The tryptophan metabolism through the kynurenine pathway plays important roles in tumorigenesis in...
Uterine leiomyomas (fibroids) are common benign tumors in women. The tryptophan metabolism through the kynurenine pathway plays important roles in tumorigenesis in general. Leiomyomas expressing mutated mediator complex subunit 12 (mut-MED12) were reported to contain significantly decreased tryptophan levels; the underlying mechanism and the role of the tryptophan metabolism-kynurenine pathway in leiomyoma tumorigenesis, however, remain unknown. We here assessed the expression and regulation of the key enzymes that metabolize tryptophan. Among these, the tissue mRNA levels of tryptophan 2,3-dioxygenase (TDO2), the rate limiting enzyme of tryptophan metabolism through the kynurenine pathway, was 36-fold higher in mut-MED12 compared to adjacent myometrium (P < 0.0001), and 14-fold higher compared to wild type (wt)-MED12 leiomyoma (P < 0.05). The mRNA levels of other tryptophan metabolizing enzymes, IDO1 and IDO2, were low and not significantly different, suggesting that TDO2 is the key enzyme responsible for reduced tryptophan levels in mut-MED12 leiomyoma. R5020 and medroxyprogesterone acetate (MPA), two progesterone agonists, regulated TDO2 gene expression in primary myometrial and leiomyoma cells expressing wt-MED12; however, this effect was absent or blunted in leiomyoma cells expressing G44D mut-MED12. These data suggest that MED12 mutation may alter progesterone-mediated TDO2 expression in leiomyoma, leading to lower levels of tryptophan in mut-MED12 leiomyoma. This highlights that fibroids can vary widely in their response to progesterone as a result of mutation status and provides some insight for understanding the effect of tryptophan-kynurenine pathway on leiomyoma tumorigenesis and identifying targeted interventions for fibroids based on their distinct molecular signatures.
Topics: Adult; Female; Gene Expression Regulation, Neoplastic; Humans; Leiomyoma; Mediator Complex; Middle Aged; Mutation; Progestins; Tryptophan Oxygenase; Tumor Cells, Cultured
PubMed: 35064560
DOI: 10.1007/s43032-022-00852-y -
Contraception May 2024To summarize and update information regarding drug-drug interactions (DDIs) between antiretrovirals (ARVs) and hormonal contraceptives (HCs). (Review)
Review
OBJECTIVE
To summarize and update information regarding drug-drug interactions (DDIs) between antiretrovirals (ARVs) and hormonal contraceptives (HCs).
DESIGN
Systematic review METHODS: We searched seven databases for peer-reviewed publications from January 1, 2015, through December 31, 2023, including studies of women using ARVs and HCs concurrently with outcomes including therapeutic effectiveness or toxicity, pharmacokinetics (PK), or pharmacodynamics. We summarized findings and used checklists to assess evidence quality.
RESULTS
We included 49 articles, with clinical, ARV or HC PK outcomes reported by 39, 25, and 30 articles, respectively, with some articles reporting outcomes in two or more categories. Fifteen of 18 articles assessing DDIs between efavirenz and progestin implants, emergency contraception, or combined hormonal intravaginal rings found higher pregnancy rates, luteal progesterone levels suggesting ovulation, or reduced progestin PK values. Five studies documented that CYP2B6 single nucleotide polymorphisms exacerbated this DDI. One cohort detected doubled bone density loss with concomitant depot medroxyprogesterone acetate (DMPA) and tenofovir disoproxil fumarate (TDF)-containing ART use versus TDF alone. No other studies described DDIs impacting clinical outcomes. Few adverse events were attributed to ARV-HC use with none exceeding Grade 2. Evidence quality was generally moderate, with dis-similar treatment and control groups, identifying and controlling for confounding, and minimizing attrition bias in the study design being the most frequent limitations.
CONCLUSION
Most ARVs and HCs may be used safely and effectively together. TDF-DMPA DDIs warrant longer-term study on bone health and consideration of alternate combinations. For efavirenz-based ART, client counselling on relative risks, including both potential increase in pregnancy rate with concomitant efavirenz and implant use and lower pregnancy rates compared to other HCs even with concomitant efavirenz use, should continue to allow users comprehensive method choice.
PubMed: 38762199
DOI: 10.1016/j.contraception.2024.110490