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PloS One 2023Progestin-only injectable contraceptives, mainly depo-medroxyprogesterone acetate intramuscular (DMPA-IM), are the most widely used contraceptive methods in sub-Saharan... (Randomized Controlled Trial)
Randomized Controlled Trial
Misreporting contraceptive use and the association of peak study progestin levels with weight and BMI among women randomized to the progestin-only injectable contraceptives DMPA-IM and NET-EN.
Progestin-only injectable contraceptives, mainly depo-medroxyprogesterone acetate intramuscular (DMPA-IM), are the most widely used contraceptive methods in sub-Saharan Africa. Insufficient robust data on their relative side-effects and serum concentrations limit understanding of reported outcomes in contraception trials. The WHICH clinical trial randomized HIV-negative women to DMPA-IM (n = 262) or norethisterone enanthate (NET-EN) (n = 259) at two South African sites between 2018-2019. We measured serum concentrations of study and non-study progestins at initiation (D0) and peak serum levels, one week after the 24-week injection [25 weeks (25W)], (n = 435) and investigated associations between study progestin levels, and BMI and weight of participants. Peak median serum concentrations were 6.59 (IQR 4.80; 8.70) nM for medroxyprogesterone (MPA) (n = 161) and 13.6 (IQR 9.01; 19.0) nM for norethisterone (NET) (n = 155). MPA was the most commonly quantifiable non-study progestin at D0 in both arms (54%) and at 25W in the NET-EN arm (27%), followed by NET at D0 in both arms (29%) and at 25W in the DMPA-IM arm (19%). Levonorgestrel was quantifiable in both arms [D0 (6.9%); 25W (3.4%)], while other progestins were quantifiable in ≤ 14 participants. Significant negative time-varying associations were detected between MPA and NET concentrations and weight and BMI in both contraceptive arms and a significant increase was detected for peak serum progestin concentrations for normal weight versus obese women. Contraceptive-related reported outcomes are likely confounded by MPA, more so than NET, with reported DMPA-IM effects likely underestimated, at sites where DMPA-IM is widely used, due to misreporting of contraceptive use before and during trials, and 'tail' effects of DMPA-IM use more than six months before trial enrolment. Peak serum levels of MPA and NET are negatively associated with BMI and weight, suggesting another source of variability between trial outcomes and a potential increase in side-effects for normal weight versus overweight and obese women. Trail registration: The clinical trial was registered with the Pan African Clinical Trials Registry (PACTR 202009758229976).
Topics: Female; Humans; Progestins; Medroxyprogesterone Acetate; Contraceptive Agents; Body Mass Index; Norethindrone; Obesity
PubMed: 38134043
DOI: 10.1371/journal.pone.0295959 -
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 -
Nature Communications Jan 2023Effective contraceptives are a global health imperative for reproductive-aged women. However, there remains a lack of rigorous data regarding the effects of... (Randomized Controlled Trial)
Randomized Controlled Trial
Effective contraceptives are a global health imperative for reproductive-aged women. However, there remains a lack of rigorous data regarding the effects of contraceptive options on vaginal bacteria and inflammation. Among 218 women enrolled into a substudy of the ECHO Trial (NCT02550067), we evaluate the effect of injectable intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel implant (LNG), and a copper intrauterine device (Cu-IUD) on the vaginal environment after one and six consecutive months of use, using 16S rRNA gene sequencing and multiplex cytokine assays. Primary endpoints include incident BV occurrence, bacterial diversity, and bacterial and cytokine concentrations. Secondary endpoints are bacterial and cytokine concentrations associated with later HIV seroconversion. Participants randomized to Cu-IUD exhibit elevated bacterial diversity, increased cytokine concentrations, and decreased relative abundance of lactobacilli after one and six months of use, relative to enrollment and other contraceptive options. Total bacterial loads of women using Cu-IUD increase 5.5 fold after six months, predominantly driven by increases in the concentrations of several inflammatory anaerobes. Furthermore, growth of L. crispatus (MV-1A-US) is inhibited by Cu ions below biologically relevant concentrations, in vitro. Our work illustrates deleterious effects on the vaginal environment induced by Cu-IUD initiation, which may adversely impact sexual and reproductive health.
Topics: Female; Humans; Adult; Intrauterine Devices, Copper; Medroxyprogesterone Acetate; Lactobacillus; RNA, Ribosomal, 16S; Bacteria, Anaerobic; Contraceptive Agents
PubMed: 36717556
DOI: 10.1038/s41467-023-36002-4 -
Reproductive Sciences (Thousand Oaks,... Sep 2019C-X3-C motif ligand 1 (CX3CL1) mediates migration, survival, and adhesion of natural killer (NK) cells, monocytes, and T-cells to endothelial/epithelial cells. Aberrant...
C-X3-C motif ligand 1 (CX3CL1) mediates migration, survival, and adhesion of natural killer (NK) cells, monocytes, and T-cells to endothelial/epithelial cells. Aberrant numbers and/or activation of these decidual immune cells elicit preeclampsia development. Decidual macrophages and NK cells are critical for implantation, while macrophage-derived tumor necrosis factor-α (TNF-α), interleukin-1 β (IL-1β), and NK cell-derived interferon-γ (IFN-γ) are associated with preeclampsia development. Thus, serum and decidual levels of CX3CL1 from first-trimester pregnancy and preeclampsia-complicated term pregnancy were examined by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. The effects of incubating primary human first-trimester decidual cells (FTDCs) with estradiol + medroxyprogesterone acetate + either IL-1β or TNF-α and/or IFN-γ on CX3CL1 expression were also assessed by quantitative reverse transcription-polymerase chain reaction and ELISA. The inhibition of each signaling pathway with each kinase and nuclear factor κB (NFκB) inhibitors was evaluated by ELISA. Chemotaxis of CD56CD16 NK cells by various concentrations of CX3CL1 was evaluated. C-X3-C motif ligand 1 is expressed by both cytotrophoblasts and decidual cells in first-trimester decidua. C-X3-C motif ligand 1 expression is increased in term decidua but unchanged in first-trimester and term serum of patients with preeclampsia. Interferon-gamma and either IL-1β or TNF-α synergistically upregulated CX3CL1 expression in FTDCs. Coincubation with IL-1β or TNF-α or IFN-γ, mitogen-activated protein kinase kinase 1 and 2 (MEK1/2), c-JUN N-terminal kinase (JNK), and NFκB inhibitors suppressed CX3CL1 production. C-X3-C motif ligand 1 elicited concentration-dependent enhancement of CD56CD16 NK cell migration. In conclusion, the current study suggests that decidual cell-secreted CX3CL1 is involved in the later development of preeclampsia, whereas circulating CX3CL1 levels do not predict preeclampsia. Mitogen-activated protein kinase kinase 1 and 2, JNK, and NFκB signaling mediate IL-1β-, TNF-α-, and IFN-γ-induced CX3CL1 production by FTDCs.
Topics: Cell Movement; Cells, Cultured; Chemokine CX3CL1; Decidua; Estradiol; Female; Gene Expression Regulation; Humans; Interferon-gamma; Interleukin-1beta; Killer Cells, Natural; Medroxyprogesterone Acetate; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, First; Tumor Necrosis Factor-alpha
PubMed: 30606080
DOI: 10.1177/1933719118815592 -
American Journal of Reproductive... Aug 2022Data on the effects of contraceptives on female genital tract (FGT) immune mediators are inconsistent, possibly in part due to pre-existing conditions that influence... (Randomized Controlled Trial)
Randomized Controlled Trial
PROBLEM
Data on the effects of contraceptives on female genital tract (FGT) immune mediators are inconsistent, possibly in part due to pre-existing conditions that influence immune mediator changes in response to contraceptive initiation.
METHODS
This study included 161 South African women randomised to injectable depot medroxyprogesterone acetate (DMPA-IM), copper intrauterine device (IUD), or levonorgestrel (LNG) implant in the Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial. We measured thirteen cytokines and antimicrobial peptides previously associated with HIV acquisition in vaginal swabs using Luminex and ELISA, before, and at 1 and 3 months after contraceptive initiation. Women were grouped according to an overall baseline inflammatory profile. We evaluated modification of the relationships between contraceptives and immune mediators by baseline inflammation, demographic, and clinical factors.
RESULTS
Overall, LNG implant and copper IUD initiation were associated with increases in inflammatory cytokines, while no changes were observed following DMPA-IM initiation. However, when stratifying by baseline inflammatory profile, women with low baseline inflammation in all groups experienced significant increases in inflammatory cytokines, while those with a high baseline inflammatory profile experienced no change or decreases in inflammatory cytokines.
CONCLUSION
We conclude that pre-contraceptive initiation immune profile modifies the effect of contraceptives on the FGT innate immune response.
Topics: Contraceptive Agents, Female; Cytokines; Female; Genitalia; HIV Infections; Humans; Immunity, Innate; Inflammation; Intrauterine Devices, Copper; Levonorgestrel; Medroxyprogesterone Acetate
PubMed: 35394678
DOI: 10.1111/aji.13542 -
The Lancet. Global Health May 2022Tenofovir disoproxil fumarate (TDF) and intramuscular depot medroxyprogesterone acetate (DMPA-IM) are independently associated with reduced bone mineral density (BMD)....
Intramuscular depot medroxyprogesterone acetate accentuates bone loss associated with tenofovir disoproxil fumarate-containing antiretroviral therapy initiation in young women living with HIV (the BONE: CARE study): a prospective cohort study in Uganda.
BACKGROUND
Tenofovir disoproxil fumarate (TDF) and intramuscular depot medroxyprogesterone acetate (DMPA-IM) are independently associated with reduced bone mineral density (BMD). We aimed to assess the combined effects of DMPA-IM use and TDF initiation on BMD in young adult women living with HIV over two years, compared with age-matched people without HIV.
METHODS
Th BONE: CARE study was a prospective cohort study that recruited women aged 18-35 years from 11 HIV care and general health facilities in Kampala, Uganda. The participants were classified into four groups on the basis of their combination of HIV status, TDF use, and DMPA-IM use, as follows: women living with HIV initiating TDF-containing antiretroviral therapy (ART) with DMPA-IM (HIV positive, DMPA positive, and TDF positive); women living with HIV using DMPA-IM but not eligible for ART as per local guidelines at the time of enrolment into the study (HIV positive, DMPA positive, and TDF negative); women living with HIV initiating TDF-containing ART without DMPA-IM (HIV positive, DMPA negative, and TDF positive); and controls without HIV using non-hormonal contraceptives (HIV negative, DMPA negative, and TDF negative). BMD of the lumbar spine, total hip, and femoral neck were measured using semiannual dual-energy x-ray absorptiometry at enrolment and at intervals every 6 months thereafter. We assessed percentage change in mean BMD.
FINDINGS
Between March 30, 2016, and Oct 19, 2017, we enrolled 265 women living with HIV initiating ART (159 DMPA-IM users and 106 non-hormonal contraceptive users), 187 women living with HIV using DMPA-IM but not ART, and 69 controls without HIV. Mean age was 26·1 years (SD 4·2). BMD declined significantly from baseline in women living with HIV on TDF with versus without DMPA-IM at the lumbar spine (-3·406% [95% CI -3·969 to -2·844] vs -1·111% [-1·929 to -0·293]; p<0·0001), total hip (-3·856% [-4·449 to -3·264] vs -1·714% [-2·479 to -0·949]; p=0·0002), and femoral neck (-4·422% [-5·078 to -3·766] vs -1·999% [-3·022 to -0·976]; p=0·0002), increased in controls at the lumbar spine (1·5% change), and remained unchanged at total hip and femoral neck (-0·1% change). Concurrent use of TDF and DMPA-IM resulted in significantly greater BMD decline (p<0·0001) than TDF alone (lumbar spine -2·677% [95% CI -3·743 to -1·611]; p<0·0001; total hip -2·518% [-3·575 to -1·461]; p<0·0001; and femoral neck -2·907 [-4·132 to -1·683]; p<0·0001) or than controls (lumbar spine -4·970% [-6·391 to -3·549]; p<0·0001; total hip -4·151% [-5·579 to -2·724]; p<0.0001; and femoral neck -4·773% [-6·424 to -3·122]; p<0·0001) INTERPRETATION: Concomitant DMPA-IM use resulted in a doubling of BMD loss in women living with HIV initiating TDF-containing ART. Identification of safer contraceptive and bone-sparing ART options should be prioritised for optimal care of women living with HIV.
FUNDING
National Institute of Allergy and Infectious Diseases of the US National Institutes of Health.
Topics: Adult; Bone Density; Contraceptive Agents, Female; Female; HIV Infections; Humans; Male; Medroxyprogesterone Acetate; Prospective Studies; Tenofovir; Uganda; Young Adult
PubMed: 35427526
DOI: 10.1016/S2214-109X(22)00080-8 -
MSphere Feb 2023Important questions remain on how hormonal contraceptives alter the local immune environment and the microbiota in the female genital tract and how such effects may... (Randomized Controlled Trial)
Randomized Controlled Trial
Important questions remain on how hormonal contraceptives alter the local immune environment and the microbiota in the female genital tract and how such effects may impact susceptibility to HIV infection. We leveraged samples from a previously conducted clinical trial of Malawian women with ( = 73) and without ( = 24) HIV infection randomized to depot medroxyprogesterone acetate (DMPA) or the levonogestrel implant in equal numbers within each group and determined the effects of these hormonal contraceptives (HCs) on the vaginal immune milieu and the composition of the vaginal microbiota. Longitudinal data for soluble immune mediators, measured by multiplex bead arrays and enzyme-linked immunosorbent assays (ELISAs), and vaginal microbiota, assessed by 16S rRNA gene amplicon, were collected prior to and over a period of 180 days post-HC initiation. DMPA and levonogestrel had only minimal effects on the vaginal immune milieu and microbiota. In women with HIV, with the caveat of a small sample size, there was an association between the median log change in the interleukin-12 (IL-12)/IL-10 ratio in vaginal fluid at day 180 post-HC compared to baseline when these women were classified as having a community state type (CST) IV vaginal microbiota and were randomized to DMPA. Long-lasting alterations in soluble immune markers or shifts in microbiota composition were not observed. Furthermore, women with HIV did not exhibit increased viral shedding in the genital tract after HC initiation. Consistent with the results of the ECHO (Evidence for Contraceptive Options and HIV Outcomes) trial, our data imply that the progestin-based HC DMPA and levonorgestrel are associated with minimal risk for women with HIV. (This study has been registered at ClinicalTrials.gov under registration no. NCT02103660). The results of the Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial, the first large randomized controlled clinical trial comparing the HIV acquisition risk of women receiving DMPA, the levonorgestrel (LNG) implant, or the copper intrauterine device (IUD), did not reveal an increased risk of HIV acquisition for women on any of these three contraceptives. Our study results confirm that the two different progestin-based hormonal contraceptives DMPA and levonogestrel will not increase the risk for HIV infection. Furthermore, DMPA and levonogestrel have only minimal effects on the immune milieu and the microbiota in the vaginal tract, attesting to the safety of these hormonal contraceptives.
Topics: Female; Humans; Contraceptive Agents; Cytokines; HIV Infections; Levonorgestrel; Malawi; Medroxyprogesterone Acetate; Microbiota; Progestins; RNA, Ribosomal, 16S; Contraceptive Agents, Hormonal
PubMed: 36622252
DOI: 10.1128/msphere.00585-22 -
Cancers Mar 2023Hormonal therapy has long been a treatment modality for recurrent endometrial cancer. It is appealing for patients with low-grade, slow-growing tumors or in patients for... (Review)
Review
Hormonal therapy has long been a treatment modality for recurrent endometrial cancer. It is appealing for patients with low-grade, slow-growing tumors or in patients for which other treatment types may be too toxic. Hormonal therapy is well tolerated and has response rates ranging from 9 to 33%. Hormonal treatment options take advantage of the estrogen-dependent molecular pathways in endometrial cancers. Current options for hormonal therapies include progesterone therapy (medroxyprogesterone acetate and megestrol acetate) as a single agent or in combination and agents that target the estrogen pathway. Aromatase inhibitors have had modest single-agent activity, but synergistic effects have been found when used in combination with targeted therapy including mTOR inhibitors and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Molecular profiling of endometrial cancers has begun to help individualize treatments. This review will report on existing data and ongoing trials investigating novel hormonal therapy agents.
PubMed: 36980685
DOI: 10.3390/cancers15061799 -
Journal of Acquired Immune Deficiency... Jan 2023Depot medroxyprogesterone acetate (DMPA) is a widely used contraceptive method. HIV pre-exposure prophylaxis with emtricitabine and tenofovir disoproxil fumarate (F/TDF)...
Interaction of Depot Medroxyprogesterone Acetate and Tenofovir Disoproxil Fumarate/Emtricitabine on Peripheral Blood Mononuclear Cells and Cervical Tissue Susceptibility to HIV Infection and Pharmacokinetics.
BACKGROUND
Depot medroxyprogesterone acetate (DMPA) is a widely used contraceptive method. HIV pre-exposure prophylaxis with emtricitabine and tenofovir disoproxil fumarate (F/TDF) is highly effective in reducing HIV acquisition in women. We sought to determine the impact of DMPA on F/TDF pharmacokinetics and pharmacodynamics.
METHODS
Twelve healthy premenopausal cisgender women were enrolled and each completed 4 sequential conditions: (1) baseline, (2) steady-state F/TDF alone, (3) steady-state F/TDF + DMPA, and (4) DMPA alone. Assessments included clinical, pharmacokinetic, viral infectivity (ex vivo challenge of peripheral blood mononuclear cells by X4- and R5-tropic green fluorescent protein pseudoviruses and cervical tissue by HIV BaL ), endocrine, immune cell phenotyping, and renal function.
RESULTS
Compared with baseline, F/TDF (± DMPA) significantly decreased both %R5- and X4-infected CD4 T cells and F/TDF + DMPA decreased cervical explant p24 (all P < 0.05). The %R5- and X4-infected CD4 T cells were higher during DMPA alone than during F/TDF periods and lower than baseline (not statistically significant). Cervical explant p24 fell between baseline and F/TDF values (not statistically significant). There were neither statistically significant differences in F/TDF pharmacokinetics, including total or renal clearance of either antiviral drug, nor changes in glomerular filtration rate with the addition of DMPA. There were few immune cell phenotypic differences across conditions.
CONCLUSIONS
F/TDF decreased HIV infection in both challenge assays, whereas DMPA alone did not enhance HIV infection in either challenge assay. DMPA did not alter F/TDF pharmacokinetics or renal function.
Topics: Female; Humans; Emtricitabine; Tenofovir; HIV Infections; Medroxyprogesterone Acetate; Leukocytes, Mononuclear
PubMed: 36305827
DOI: 10.1097/QAI.0000000000003113 -
Contraception Nov 2018
Topics: Contraception Behavior; Contraceptive Agents, Female; Female; Humans; Injections, Subcutaneous; Medroxyprogesterone Acetate
PubMed: 30145126
DOI: 10.1016/j.contraception.2018.08.009