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Scientific Reports Jan 2023To identify biomarkers of hormonal contraceptive (HC) use in urine and saliva, we conducted a pilot study with 30 women initiating levonorgestrel (LNG) containing...
To identify biomarkers of hormonal contraceptive (HC) use in urine and saliva, we conducted a pilot study with 30 women initiating levonorgestrel (LNG) containing combined oral contraceptives (COCs) or depot medroxyprogesterone acetate (DMPA) (15/group). Based on established COC pharmacokinetics, we collected serum and urine samples before COC ingestion and during Days one and three of use, or before DMPA injection and on Days 21 and 60 post-injection. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure serum/urine LNG and MPA. LNG was undetectable at baseline (specificity 100%); post ingestion, most urine samples had detectable LNG levels (sensitivity: 80% 6 h post Dose one, 93% 6 h post Dose three). We used a DetectX LNG immunoassay kit and showed 100% sensitivity measuring urine LNG. Urine MPA levels were undetectable in 14/15 women at baseline (specificity 91%); post-injection all urine samples had detectable MPA levels (sensitivity: 100% days 21 and 60). Results suggest urine sampling can be used to identify a biomarker of LNG and MPA use. Based on evidence from other steroidal hormonal studies showing changes affecting the transcriptome profile of saliva at 24 h, we used the same (COC, DMPA) timepoints to collect saliva. We performed transcriptome analysis and detected several differentially expressed genes in DMPA users' saliva on Days 21 and 60 compared to baseline; none among COC users. We plan further research of differential gene expression in saliva as a HC biomarker of DMPA use, and will explore longer periods of COC use and saliva collection times, and application of microRNA sequencing to support using saliva as a COC biomarker.
Topics: Female; Humans; Chromatography, Liquid; Pilot Projects; Tandem Mass Spectrometry; Levonorgestrel; Medroxyprogesterone Acetate; Contraceptives, Oral, Combined
PubMed: 36604469
DOI: 10.1038/s41598-022-24215-4 -
The Cochrane Database of Systematic... Jun 2014Steroidal contraceptive use has been associated with changes in bone mineral density in women. Whether such changes increase the risk of fractures later in life is not... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Steroidal contraceptive use has been associated with changes in bone mineral density in women. Whether such changes increase the risk of fractures later in life is not clear. Osteoporosis is a major public health concern. Age-related decline in bone mass increases the risk of fracture, especially of the spine, hip, and wrist. Concern about bone health influences the recommendation and use of these effective contraceptives globally.
OBJECTIVES
Our aim was to evaluate the effect of using hormonal contraceptives before menopause on the risk of fracture in women.
SEARCH METHODS
Through April 2014, we searched for studies of fracture or bone health and hormonal contraceptives in MEDLINE, POPLINE, CENTRAL, EMBASE, and LILACS, as well as ClinicalTrials.gov and ICTRP. We examined reference lists of relevant articles for other trials. For the initial review, we wrote to investigators to find additional trials.
SELECTION CRITERIA
Randomized controlled trials (RCTs) were considered if they examined fractures, bone mineral density (BMD), or bone turnover markers in women with hormonal contraceptive use prior to menopause. Eligible interventions included comparisons of a hormonal contraceptive with a placebo or with another hormonal contraceptive that differed in terms of drug, dosage, or regimen. They also included providing a supplement to one group.
DATA COLLECTION AND ANALYSIS
We assessed all titles and abstracts identified through the literature searches. Mean differences were computed using the inverse variance approach. For dichotomous outcomes, the Mantel-Haenszel odds ratio (OR) was calculated. Both included the 95% confidence interval (CI) and used a fixed-effect model. Due to differing interventions, no trials could be combined for meta-analysis. We applied principles from GRADE to assess the evidence quality and address confidence in the effect estimates. In addition, a sensitivity analysis included trials that provided sufficient data for this review and evidence of at least moderate quality.
MAIN RESULTS
We found 19 RCTs that met our eligibility criteria. Eleven trials compared different combined oral contraceptives (COCs) or regimens of COCs; five examined an injectable versus another injectable, implant, or IUD; two studied implants, and one compared the transdermal patch versus the vaginal ring. No trial had fracture as an outcome. BMD was measured in 17 studies and 12 trials assessed biochemical markers of bone turnover. Depot medroxyprogesterone acetate (DMPA) was associated with decreased bone mineral density (BMD). The placebo-controlled trials showed BMD increases for DMPA plus estrogen supplement and decreases for DMPA plus placebo supplement. COCs did not appear to negatively affect BMD, and some formulations had more positive effects than others. However, no COC trial was placebo-controlled. Where studies showed differences between groups in bone turnover markers, the results were generally consistent with those for BMD. For implants, the single-rod etonogestrel group showed a greater BMD decrease versus the two-rod levonorgestrel group but results were not consistent across all implant comparisons.The sensitivity analysis included 11 trials providing evidence of moderate or high quality. Four trials involving DMPA showed some positive effects of an estrogen supplement on BMD, a negative effect of DMPA-subcutaneous on lumbar spine BMD, and a negative effect of DMPA on a bone formation marker. Of the three COC trials, one had a BMD decrease for the group with gestodene plus EE 15 μg. Another indicated less bone resorption in the group with gestodene plus EE 30 μg versus EE 20 μg.
AUTHORS' CONCLUSIONS
Whether steroidal contraceptives influence fracture risk cannot be determined from existing information. The evidence quality was considered moderate overall, largely due to the trials of DMPA, implants, and the patch versus ring. The COC evidence varied in quality but was low overall. Many trials had small numbers of participants and some had large losses. Health care providers and women should consider the costs and benefits of these effective contraceptives. For example, injectable contraceptives and implants provide effective, long-term birth control yet do not involve a daily regimen. Progestin-only contraceptives are considered appropriate for women who should avoid estrogen due to medical conditions.
Topics: Bone Density; Bone Remodeling; Contraceptives, Oral, Hormonal; Estrogens; Female; Fractures, Bone; Humans; Medroxyprogesterone Acetate; Premenopause; Progestins; Randomized Controlled Trials as Topic
PubMed: 24960023
DOI: 10.1002/14651858.CD006033.pub5 -
The Journal of Steroid Biochemistry and... Mar 2024Progestins used in hormonal contraceptives and menopausal hormone therapy (MHT) have been linked to increased breast cancer risk. Whether the association holds for all...
Progestins used in hormonal contraceptives and menopausal hormone therapy (MHT) have been linked to increased breast cancer risk. Whether the association holds for all progestins is unclear and the underlying mechanisms remain poorly understood. We directly compared the effects of four progestins (medroxyprogesterone acetate (MPA), norethisterone acetate (NET-A), levonorgestrel (LNG) and drospirenone (DRSP)) to each other and the natural progestogen progesterone (P) on selected cancer hallmarks. To provide mechanistic insight into these effects, we assessed the role of the progesterone receptor (PR), and the extracellular signal-related kinase (ERK1/2) and c-Jun N terminal (JNK) signaling pathways. We showed that the increased proliferation of the luminal T47D breast cancer cell line by P and all progestins, albeit to different extents, was inhibited by PR knockdown and inhibition of both the ERK1/2 and JNK pathways. While knockdown of the PR also blocked the upregulation of MKI67 and CCND1 mRNA expression by selected progestogens, only a role for the ERK1/2 pathway could be established in these effects. Similarly, only a role for the ERK1/2 pathway could be confirmed for progestogen-induced colony formation, whereas both the ERK1/2 and JNK pathways were required for cell migration in response to the three older progestins implicated in the etiology of breast cancer, MPA, NET-A and LNG. Together our results show that all the progestins elicit their effects on cell proliferation via a mechanism requiring the PR, ERK1/2 and JNK pathways. While the ERK1/2 and JNK pathways are also required for increased cell migration by the older progestins, only a role for the ERK1/2 pathway could be established in their effects on colony formation. Notably, the cytoplasmic PR was not needed for activation of the ERK1/2 pathway by the progestogens. Given that DRSP showed significantly lower proliferation than MPA and NET-A, and that it had no effect on breast cancer cell migration and colony formation, hormonal formulations containing the newer generation progestin DRSP may provide a better benefit/risk profile towards breast cancer than those containing the older generation progestins.
Topics: Humans; Female; Progestins; Breast Neoplasms; MAP Kinase Signaling System; Progesterone; Medroxyprogesterone Acetate; Levonorgestrel; Receptors, Progesterone; Receptors, Estrogen
PubMed: 38048919
DOI: 10.1016/j.jsbmb.2023.106440 -
Reproductive Health Aug 2020Self-administered subcutaneous depot medroxyprogesterone acetate (DMPA-SC) is poised to increase access to contraception; however, governments are concerned about the...
Adolescent and covert family planning users' experiences self-injecting contraception in Uganda and Malawi: implications for waste disposal of subcutaneous depot medroxyprogesterone acetate.
BACKGROUND
Self-administered subcutaneous depot medroxyprogesterone acetate (DMPA-SC) is poised to increase access to contraception; however, governments are concerned about the waste management of used units. Self-injectors in Malawi and Uganda are currently instructed to store used units in containers and return them to health workers for disposal. However, this may not be feasible in low-resource settings, especially for younger or covert self-injectors. We describe adolescent (15-19 years) and adult (20-49 years) self-injectors' disposal experiences in Uganda and Malawi. When possible, we compare covert and overt users' experiences.
METHODS
We conducted cross-sectional qualitative studies in 2019 with 50 self-injectors in Uganda and 60 in Malawi. We purposively selected approximately half adolescents and included those trained by clinic-based providers and community health workers. We conducted semi-structured interviews and thematic data analysis and compared the findings across settings.
RESULTS
Just under half of both samples were adolescents, substantially more of whom were covert users in Uganda (68%) than Malawi (~ 10%). Most participants reported being told to store used units in a container and return them to health workers. About two-thirds of Uganda participants had disposed of at least one unit by the interview, most commonly returning them to health workers. Over one-third of Malawi participants had disposed of at least one unit by the interview, slightly more disposed into latrines compared to returning to health workers. Participants in both settings reported compliance with health workers' disposal instructions as a primary reason for their disposal method. One-fifth of Uganda participants, mostly adolescent covert users, and one-quarter in Malawi said they were told they could dispose into latrines, and often did so. The majority in both settings said they would prefer to dispose units in latrines because they worried about needlestick injuries to others and because it was convenient. Some Uganda adolescent covert users felt returning units to health workers was challenging due to privacy concerns.
CONCLUSIONS
While most self-injectors disposed of used units as instructed, findings from both studies suggest that returning units to health workers is not preferred and may not be feasible for some adolescent covert users. More convenient disposal solutions should be identified.
Topics: Adolescent; Adult; Community Health Workers; Contraception; Contraceptive Agents, Female; Cross-Sectional Studies; Family Planning Services; Female; Humans; Injections, Subcutaneous; Malawi; Medroxyprogesterone Acetate; Patient Satisfaction; Uganda; Young Adult
PubMed: 32746860
DOI: 10.1186/s12978-020-00964-1 -
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 -
Journal of Korean Medical Science Feb 2013
Topics: Castration; Cyproterone Acetate; Gonadotropin-Releasing Hormone; Humans; Male; Medroxyprogesterone Acetate; Physicians; Prostatic Neoplasms; Psychotherapy; Sex Offenses
PubMed: 23401647
DOI: 10.3346/jkms.2013.28.2.171 -
Contraception Nov 2018As low- and middle-income countries (LMICs) consider adding self-administration of subcutaneous depot medroxyprogesterone acetate (DMPA-SC) to their contraceptive method...
OBJECTIVE
As low- and middle-income countries (LMICs) consider adding self-administration of subcutaneous depot medroxyprogesterone acetate (DMPA-SC) to their contraceptive method mix, learning about family planning clients' and providers' experiences with self-injectable DMPA-SC during trials will inform introduction and scale-up efforts.
STUDY DESIGN
We conducted semistructured interviews with 30 randomly selected adult women enrolled in the self-administration group of a 12-month randomized controlled trial studying DMPA-SC continuation rates in rural Malawi. We asked about their experiences learning to self-inject, self-injecting, remembering when to reinject, and storing and disposing of DMPA-SC. We also interviewed 12 providers - clinic-based providers (CBPs) and community-based health surveillance assistants (HSAs) - who trained clients to self-inject DMPA-SC during the trial. We asked about their experiences training and supporting women to self-inject DMPA-SC during the trial and their recommendations for scale-up of self-administered DMPA-SC.
RESULTS
Clients and providers reported positive experiences with DMPA-SC self-injection. Clients felt that DMPA-SC self-injection saved them time and money, and providers felt that it reduced their workload and saved them time. We found that both CBPs and HSAs successfully trained clients to self-inject DMPA-SC and that clients safely and appropriately stored and disposed of DMPA-SC.
CONCLUSIONS
Our findings contribute to the growing body of evidence of the feasibility of DMPA-SC self-injection in LMIC settings. We recommend that providers plan to train clients for at least 30min, emphasize the activating and injecting steps during training, use up to four practice injections per client trained and give self-injectors calendars to help them remember when to reinject.
IMPLICATIONS
DMPA-SC self-administration should be made available in LMIC settings, but because it is a new practice, implementation guidance is needed. We offer practical recommendations for introducing and scaling up DMPA-SC self-administration based on clients' and providers' experiences during a trial investigating this practice in Malawi.
Topics: Adult; Contraceptive Agents, Female; Female; Humans; Injections, Subcutaneous; Malawi; Medroxyprogesterone Acetate; Self Administration; Young Adult
PubMed: 29706227
DOI: 10.1016/j.contraception.2018.02.011 -
Reproductive Health Aug 2013Use of depot medroxyprogesterone acetate (DMPA), often known by the brand name Depo-Provera, has increased globally, particularly in multiple low- and middle-income... (Review)
Review
BACKGROUND
Use of depot medroxyprogesterone acetate (DMPA), often known by the brand name Depo-Provera, has increased globally, particularly in multiple low- and middle-income countries (LMICs). As a reproductive health technology that has scaled up in diverse contexts, DMPA is an exemplar product innovation with which to illustrate the utility of the AIDED model for scaling up family health innovations.
METHODS
We conducted a systematic review of the enabling factors and barriers to scaling up DMPA use in LMICs. We searched 11 electronic databases for academic literature published through January 2013 (n = 284 articles), and grey literature from major health organizations. We applied exclusion criteria to identify relevant articles from peer-reviewed (n = 10) and grey literature (n = 9), extracting data on scale up of DMPA in 13 countries. We then mapped the resulting factors to the five AIDED model components: ASSESS, INNOVATE, DEVELOP, ENGAGE, and DEVOLVE.
RESULTS
The final sample of sources included studies representing variation in geographies and methodologies. We identified 15 enabling factors and 10 barriers to dissemination, diffusion, scale up, and/or sustainability of DMPA use. The greatest number of factors were mapped to the ASSESS, DEVELOP, and ENGAGE components.
CONCLUSIONS
Findings offer early empirical support for the AIDED model, and provide insights into scale up of DMPA that may be relevant for other family planning product innovations.
Topics: Contraceptive Agents, Female; Delayed-Action Preparations; Female; Health Services Accessibility; Humans; Medroxyprogesterone Acetate; Models, Theoretical; Reproductive Health Services
PubMed: 23915274
DOI: 10.1186/1742-4755-10-39 -
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 -
The Journal of Family Planning and... Jan 2002
Review
Topics: Bone Density; Contraceptive Agents, Female; Education, Medical, Continuing; Female; Humans; Injections; Medroxyprogesterone Acetate; Osteoporosis; Risk Factors
PubMed: 16259806
DOI: 10.1783/147118902101195910