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BMJ Global Health Jul 2022Subcutaneous depot medroxyprogesterone acetate (DMPA-SC) is an innovative contraceptive method aimed at meeting women's unique circumstances and needs, largely due to... (Review)
Review
Subcutaneous depot medroxyprogesterone acetate (DMPA-SC) is an innovative contraceptive method aimed at meeting women's unique circumstances and needs, largely due to its ability to be self-injected. Substantial research and advocacy investments have been made to promote roll-out of DMPA-SC across sub-Saharan Africa. To date, research on the demand for DMPA-SC as a self-injectable method has been conducted largely with healthcare providers, via qualitative research, or with highly specific subsamples that are not population based. Using three recent rounds of data from Performance Monitoring for Action, we examined population-representative trends in demand, use, and preference for self-injection among current non-users in Burkina Faso, the Democratic Republic of Congo (Kinshasa and Kongo Central regions), Kenya, and Nigeria (Lagos and Kano States). We found that while over 80.0% of women had heard of injectables across settings, few women had heard of self-injection (ranging from 13.0% in Kenya to 24.8% in Burkina Faso). Despite initial increases in DMPA-SC prevalence, DMPA-SC usage began to stagnate or even decrease in all settings in the recent three years (except in Nigeria-Kano). Few (0.0%-16.7%) current DMPA-SC users were self-injecting, and the majority instead were relying on a healthcare provider for administration of DMPA-SC. Among current contraceptive non-users wishing to use an injectable in the future, only 1.5%-11.4% preferred to self-inject. Our results show that self-injection is uncommon, and demand for self-injection is very limited across six settings, calling for further qualitative and quantitative research on women's views on DMPA-SC and self-injection and, ultimately, their contraceptive preferences and needs.
Topics: Contraceptive Agents, Female; Democratic Republic of the Congo; Female; Humans; Injections, Subcutaneous; Medroxyprogesterone Acetate; Nigeria; Self Administration
PubMed: 35835480
DOI: 10.1136/bmjgh-2022-008862 -
Therapeutic Advances in Musculoskeletal... Oct 2014Drug-induced osteoporosis is a significant health problem and many physicians are unaware that many commonly prescribed medications contribute to significant bone loss... (Review)
Review
Drug-induced osteoporosis is a significant health problem and many physicians are unaware that many commonly prescribed medications contribute to significant bone loss and fractures. In addition to glucocorticoids, proton pump inhibitors, selective serotonin receptor inhibitors, thiazolidinediones, anticonvulsants, medroxyprogesterone acetate, aromatase inhibitors, androgen deprivation therapy, heparin, calcineurin inhibitors, and some chemotherapies have deleterious effects on bone health. Furthermore, many patients are treated with combinations of these medications, possibly compounding the harmful effects of these drugs. Increasing physician awareness of these side effects will allow for monitoring of bone health and therapeutic interventions to prevent or treat drug-induced osteoporosis.
PubMed: 25342997
DOI: 10.1177/1759720X14546350 -
BMC Women's Health Mar 2024Robust information on relative effects of hormonal contraceptives on endogenous androgens is important for understanding beneficial and adverse effects, method choice... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of depot medroxyprogesterone acetate, the copper IUD and the levonorgestrel implant on testosterone, sex hormone binding globulin and free testosterone levels: ancillary study of the ECHO randomized clinical trial.
BACKGROUND
Robust information on relative effects of hormonal contraceptives on endogenous androgens is important for understanding beneficial and adverse effects, method choice and development of new methods.
METHODS
In this ancillary study at the East London, South Africa site of the ECHO multicentre randomized trial, we compared effects of three contraceptive methods on serum androgen levels among contraceptive users aged 18 to 35 years. Participants were allocated by centrally-managed randomization to open label depot medroxyprogesterone acetate (DMPA-IM), copper intrauterine device (IUD) or levonorgestrel implant. The primary outcome was free testosterone at 6 months.
RESULTS
We analysed stored baseline and 6-month serum samples in 398/615 participants (DMPA-IM 131/205, IUD 135/205 and implant 132/205). Median testosterone levels at baseline were DMPA-IM 0.82, IUD 0.9 and implant 0.87 nmol/L; at 6 months, DMPA 0.68 (lower than IUD, mean percentage difference 28.35, (p < 0.001), IUD 0.86 (unchanged) and implant 0.66, lower than IUD, mean percentage difference - 22.98, p < 0.001). Median SHBG levels at baseline were DMPA 52.4, IUD 50.5 and implant 55.75 nmol/L; at 6 months, DMPA 40.65, lower than IUD (mean percentage difference 21.19, p = 0.005), IUD 49.1 (unchanged), and implant 23.35 nmol/L, lower than IUD (mean percentage difference - 50.04, p < 0.001 and than DMPA (mean percentage difference - 39.45, p < 0.001). Free testosterone levels at baseline were DMPA 10, IUD 12 and implant 11 pmol/L; at 6 months, DMPA 11, less than IUD (mean percentage difference 13.53, p = 0.047), IUD 12 and implant 14, higher than IUD (mean percentage difference 14.15, p = 0.038) and than DMPA, (mean percentage difference 29.60, p < 0.001).
CONCLUSIONS
This is the first randomized trial to show lower SHBG and higher free testosterone with the levonorgestrel implant than with DMPA, and contrasts with reports of increased SHBG with combined oral ethinyl estradiol/levonorgestrel use, and reduced androgens (and impaired sexual function) reported with the etonorgestrel implant. The higher free testosterone with the LNG implant might improve sexual function, mood and bone health as well as increasing side-effects such as acne and hirsutism, and is consistent with the greater sexual activity (with respect to multiple sex partners, new sex partner and unprotected sex) with the implant compared with DMPA documented in the ECHO study.
ECHO TRIAL REGISTRATION
ClinicalTrials.gov , number NCT02550067 15/09/2015. Contraception, or family planning, is central to the role of women in societies. It is most important to have accurate information on the relative side-effects of various contraceptive options in order to empower women to make informed choices regarding their preferred method. Hormonal contraceptives contain various forms of the female sex hormones, estrogens and/or progestogens. These hormones have direct effects on the users, as well as modifying the levels of the users' own circulating sex hormones, both the 'female' and the 'male' sex hormones (androgens). In this study, consenting participants requesting contraception, were allocated randomly to receive either depot medroxyprogesterone acetate (DMPA-IM) a 3-monthly progestogen injection, the copper intrauterine device (IUD), a non-hormonal contraceptive inserted within the womb, or the levonorgestrel implant, a device placed under the skin which releases a progestogen for 5 years. We measured the participants' androgen levels after 6 months, and found for the first time that the active form of testosterone (free testosterone) was 29% higher with the implant than with DMPA-IM. The level with the IUD was intermediate, and significantly different from the other two methods. This finding is relevant to the effects experienced by users of these methods, because free testosterone has effects on sexual function, bone health and mood, as well as on conditions such as acne and hair distribution patterns.
Topics: Female; Humans; Acne Vulgaris; Androgens; Contraceptive Agents, Female; Intrauterine Devices, Copper; Levonorgestrel; Medroxyprogesterone Acetate; Progestins; Sex Hormone-Binding Globulin; Testosterone; Adolescent; Young Adult; Adult
PubMed: 38459552
DOI: 10.1186/s12905-024-02990-8 -
British Journal of Cancer Sep 2023The effectiveness of conservative treatment of endometrial carcinoma (EC) with oral progesterone therapy, such as medroxyprogesterone acetate (MPA), can be blunted due...
BACKGROUND
The effectiveness of conservative treatment of endometrial carcinoma (EC) with oral progesterone therapy, such as medroxyprogesterone acetate (MPA), can be blunted due to primary or acquired resistance, but the underlying mechanisms remain incompletely defined.
METHODS
Genome-wide CRISPR screening was performed to identify potential regulators in response to MPA in Ishikawa cells. Crystal violet staining, RT-qPCR, western blotting, ChIP-qPCR and luciferase assays were employed to elucidate the p53-AarF domain-containing kinase 3 (ADCK3) regulatory axis and its roles in sensitizing EC cells to MPA treatment.
RESULTS
ADCK3 is identified as a previously unrecognized regulator in response to MPA in EC cells. Loss of ADCK3 in EC cells markedly alleviated MPA-induced cell death. Mechanistically, loss of ADCK3 primarily suppresses MPA-mediated ferroptosis by abrogating arachidonate 15-lipoxygenase (ALOX15) transcriptional activation. Moreover, we validated ADCK3 as a direct downstream target of the tumor suppressor p53 in EC cells. By stimulating the p53-ADCK3 axis, the small-molecule compound Nutlin3A synergized with MPA to efficiently inhibit EC cell growth.
CONCLUSIONS
Our findings reveal ADCK3 as a key regulator of EC cells in response to MPA and shed light on a potential strategy for conservative EC treatment by activating the p53-ADCK3 axis to sensitize MPA-mediated cell death.
Topics: Female; Humans; Medroxyprogesterone Acetate; Tumor Suppressor Protein p53; Clustered Regularly Interspaced Short Palindromic Repeats; Endometrial Neoplasms; Cell Line, Tumor
PubMed: 37402867
DOI: 10.1038/s41416-023-02347-2 -
Current HIV/AIDS Reports Aug 2023The long-acting reversible intramuscularly-injected contraceptive depot medroxyprogesterone acetate (DMPA-IM) is widely used by cisgender women in Africa. Although... (Review)
Review
PURPOSE OF REVIEW
The long-acting reversible intramuscularly-injected contraceptive depot medroxyprogesterone acetate (DMPA-IM) is widely used by cisgender women in Africa. Although DMPA-IM provides reliable contraception, potential effects on the female genital tract (FGT) mucosa have raised concern, including risk of HIV infection. This review summarises and compares evidence from observational cohort studies and the randomised Evidence for Contraceptive Options in HIV Outcomes (ECHO) Trial.
RECENT FINDINGS
Although previous observational studies found women using DMPA-IM had higher abundance of bacterial vaginosis (BV)-associated bacteria, increased inflammation, increased cervicovaginal HIV target cell density, and epithelial barrier damage, sub-studies of the ECHO Trial found no adverse changes in vaginal microbiome, inflammation, proteome, transcriptome, and risk of viral and bacterial STIs, other than an increase in Th17-like cells. Randomised data suggest that DMPA-IM use does not adversely change mucosal endpoints associated with acquisition of infections. These findings support the safe use of DMPA-IM in women at high risk of acquiring STIs, including HIV.
Topics: Female; Humans; Medroxyprogesterone Acetate; Contraceptive Agents, Female; HIV Infections; Bacteria; Inflammation; Mucous Membrane; Observational Studies as Topic
PubMed: 37341916
DOI: 10.1007/s11904-023-00662-0 -
International Journal of Molecular... Jun 2023Progestin-only long-acting reversible-contraceptive (pLARC)-exposed endometria displays decidualized human endometrial stromal cells (HESCs) and hyperdilated thin-walled...
Progestin-only long-acting reversible-contraceptive (pLARC)-exposed endometria displays decidualized human endometrial stromal cells (HESCs) and hyperdilated thin-walled fragile microvessels. The combination of fragile microvessels and enhanced tissue factor levels in decidualized HESCs generates excess thrombin, which contributes to abnormal uterine bleeding (AUB) by inducing inflammation, aberrant angiogenesis, and proteolysis. The- zinc finger and BTB domain containing 16 (ZBTB16) has been reported as an essential regulator of decidualization. Microarray studies have demonstrated that levels are induced by medroxyprogesterone acetate (MPA) and etonogestrel (ETO) in cultured HESCs. We hypothesized that pLARC-induced ZBTB16 expression contributes to HESC decidualization, whereas prolonged enhancement of ZBTB16 levels triggers an inflammatory milieu by inducing pro-inflammatory gene expression and tissue-factor-mediated thrombin generation in decidualized HESCs. Thus, ZBTB16 immunostaining was performed in paired endometria from pre- and post-depo-MPA (DMPA)-administrated women and oophorectomized guinea pigs exposed to the vehicle, estradiol (E), MPA, or E + MPA. The effect of progestins including MPA, ETO, and levonorgestrel (LNG) and estradiol + MPA + cyclic-AMP (E + MPA + cAMP) on levels were measured in HESC cultures by qPCR and immunoblotting. The regulation of levels by MPA was evaluated in glucocorticoid-receptor-silenced HESC cultures. was overexpressed in cultured HESCs for 72 h followed by a ± 1 IU/mL thrombin treatment for 6 h. DMPA administration in women and MPA treatment in guinea pigs enhanced ZBTB16 immunostaining in endometrial stromal and glandular epithelial cells. The findings indicated that: (1) ZBTB16 levels were significantly elevated by all progestin treatments; (2) MPA exerted the greatest effect on levels; (3) MPA-induced expression was inhibited in glucocorticoid-receptor-silenced HESCs. Moreover, overexpression in HESCs significantly enhanced prolactin (), insulin-like growth factor binding protein 1 (), and tissue factor () levels. Thrombin-induced interleukin 8 ( and prostaglandin-endoperoxide synthase 2 ( mRNA levels in control-vector-transfected HESCs were further increased by overexpression. In conclusion, these results supported that ZBTB16 is enhanced during decidualization, and long-term induction of ZBTB16 expression by pLARCs contributes to thrombin generation through enhancing tissue factor expression and inflammation by enhancing and levels in decidualized HESCs.
Topics: Female; Humans; Animals; Guinea Pigs; Progestins; Interleukin-8; Thrombin; Contraceptive Agents; Thromboplastin; Glucocorticoids; Cyclooxygenase 2; Endometrium; Estradiol; Inflammation; Stromal Cells; Cells, Cultured; Decidua; Medroxyprogesterone Acetate
PubMed: 37445713
DOI: 10.3390/ijms241310532 -
Cleveland Clinic Journal of Medicine Dec 2021Long-acting reversible contraceptives (ie, intrauterine devices and the etonogestrel subdermal implant) have become increasingly popular methods of contraception because...
Long-acting reversible contraceptives (ie, intrauterine devices and the etonogestrel subdermal implant) have become increasingly popular methods of contraception because of their convenience and safety profile. At the same time, the use of depot medroxyprogesterone acetate, one of the most prescribed contraceptives in the United States since its approval in 1992, is on the wane. The history and pros and cons of these contraceptive methods are reviewed.
Topics: Contraception; Contraceptive Agents, Female; Female; Humans; Intrauterine Devices; Medroxyprogesterone Acetate; United States
PubMed: 34857607
DOI: 10.3949/ccjm.88a.20110 -
BMC Women's Health Dec 2022Injectable contraceptives have contributed substantially to Nigeria's rise in modern family planning methods usage. They are one of the most commonly used and preferred...
BACKGROUND
Injectable contraceptives have contributed substantially to Nigeria's rise in modern family planning methods usage. They are one of the most commonly used and preferred means of contraception among women in the country. Enabling policies are required to assure contraceptive access, security, and use. This study aimed to investigate the policy environment and how it supports or limits Nigeria's introduction and scale-up of subcutaneous depot-medroxyprogesterone acetate (DMPA-SC).
METHODS
The design of this mixed-methods study was cross-sectional. Desk reviews of policy papers, key informant interviews, and in-depth interviews were used to obtain information from respondents about the introduction of DMPA-SC in Nigeria and how existing policies influenced its scale-up. Data on DMPA-SC and other injectables were gathered from Nigeria's national electronic logistics management information system.
RESULTS
The findings suggest that policies such as task-shifting and task-sharing, cost-free policies, reproductive health policies, and others created an enabling environment for the scale-up of DMPA-SC adoption in Nigeria. The inclusion of DMPA-SC on the essential medicines list and the approved patent medicines list facilitated the scale-up process by ensuring private sector participation, removing economic barriers to access, fostering greater collaboration among health worker cadres, improving intersectoral partnerships, and improving logistics and client access. Despite significant anomalies in some implementing policies, injectable contraceptive consumption data demonstrate a progressive increase in DMPA-SC use during the study period. The results also indicate that policy initiatives have a favorable impact on the use of DMPA-SC throughout the country.
CONCLUSION
The existence of policies, the active participation of stakeholders, and the political will of the Nigerian health system's leadership have all aided in the scaling-up of the DMPA-SC. Understanding how to build an enabling policy climate is critical for providing women with family planning options. These lessons from Nigeria emphasize the importance of these levers, which should be considered by teams intending to introduce innovative health products, particularly in developing countries.
Topics: Female; Humans; Medroxyprogesterone Acetate; Contraceptive Agents, Female; Nigeria; Cross-Sectional Studies; Policy
PubMed: 36544189
DOI: 10.1186/s12905-022-02109-x -
Clinical Pharmacology and Therapeutics Oct 2021Depot medroxyprogesterone acetate is an injectable hormonal contraceptive, widely used by women of childbearing potential living with HIV and/or tuberculosis. As...
Depot medroxyprogesterone acetate is an injectable hormonal contraceptive, widely used by women of childbearing potential living with HIV and/or tuberculosis. As medroxyprogesterone acetate is a cytochrome P450 (CYP3A4) substrate, drug-drug interactions (DDIs) with antiretroviral or antituberculosis treatment may lead to subtherapeutic medroxyprogesterone acetate concentrations (< 0.1 ng/mL), resulting in contraception failure, when depot medroxyprogesterone is dosed at 12-week intervals. A pooled population pharmacokinetic analysis with 744 plasma medroxyprogesterone acetate concentrations from 138 women treated with depot medroxyprogesterone and antiretroviral/antituberculosis treatment across three clinical trials was performed. Monte Carlo simulations were performed to predict the percentage of participants with subtherapeutic medroxyprogesterone acetate concentrations and to derive alternative dosing strategies. Medroxyprogesterone acetate clearance increased by 24.7% with efavirenz coadministration. Efavirenz plus antituberculosis treatment (rifampicin + isoniazid) increased clearance by 52.4%. Conversely, lopinavir/ritonavir and nelfinavir decreased clearance (28.7% and 15.8%, respectively), but lopinavir/ritonavir also accelerated medroxyprogesterone acetate's appearance into the systemic circulation, thus shortening the terminal half-life. A higher risk of subtherapeutic medroxyprogesterone acetate concentrations at Week 12 was predicted on a typical 60-kg woman on efavirenz (4.99%) and efavirenz with antituberculosis treatment (6.08%) when compared with medroxyprogesterone acetate alone (2.91%). This risk increased in women with higher body weight. Simulations show that re-dosing every 8 to 10 weeks circumvents the risk of subtherapeutic medroxyprogesterone acetate exposure associated with these DDIs. Dosing depot medroxyprogesterone every 8 to 10 weeks should eliminate the risk of subtherapeutic medroxyprogesterone acetate exposure caused by coadministered efavirenz and/or antituberculosis treatment, thus reducing the risk of contraceptive failure.
Topics: Alkynes; Anti-Retroviral Agents; Antitubercular Agents; Benzoxazines; Contraceptive Agents, Hormonal; Contraceptive Effectiveness; Cyclopropanes; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Delayed-Action Preparations; Drug Administration Schedule; Drug Combinations; Drug Interactions; Female; HIV Infections; Humans; Isoniazid; Lopinavir; Medroxyprogesterone Acetate; Nelfinavir; Rifampin; Ritonavir; Tuberculosis
PubMed: 34151439
DOI: 10.1002/cpt.2324 -
Human Reproduction (Oxford, England) May 2015Does medroxyprogesterone acetate (MPA) impair human dendritic cell (DC) activation and function?
STUDY QUESTION
Does medroxyprogesterone acetate (MPA) impair human dendritic cell (DC) activation and function?
SUMMARY ANSWER
In vitro MPA treatment suppressed expression of CD40 and CD80 by human primary DCs responding to Toll-like receptor 3 (TLR3) agonist stimulation (i.e. DC activation). Moreover, this MPA-mediated decrease in CD40 expression impaired DC capacity to stimulate T cell proliferation (i.e. DC function).
WHAT IS KNOWN ALREADY
MPA is the active molecule in Depo-Provera(®) (DMPA), a commonly used injectable hormonal contraceptive (HC). Although DMPA treatment of mice prior to viral mucosal tissue infection impaired the capacity of DCs to up-regulate CD40 and CD80 and prime virus-specific T cell proliferation, neither DC activation marker expression nor the ability of DCs to promote T cell proliferation were affected by in vitro progesterone treatment of human DCs generated from peripheral blood monocytes.
STUDY DESIGN, SIZE, DURATION
This cross-sectional study examined MPA-mediated effects on the activation and function of human primary untouched peripheral blood DCs.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Human DCs isolated from peripheral blood mononuclear cells by negative immunomagnetic selection were incubated for 24 h with various concentrations of MPA. After an additional 24 h incubation with the TLR3 agonist polyinosinic:polycytidylic acid (poly I:C), flow cytometry was used to evaluate DC phenotype (i.e. expression of CD40, CD80, CD86, and HLA-DR). In separate experiments, primary untouched human DCs were sequentially MPA-treated, poly I:C-activated, and incubated for 7 days with fluorescently labeled naïve allogeneic T cells. Flow cytometry was then used to quantify allogeneic T cell proliferation.
MAIN RESULTS AND THE ROLE OF CHANCE
Several pharmacologically relevant concentrations of MPA dramatically reduced CD40 and CD80 expression in human primary DCs responding to the immunostimulant poly I:C. In addition, MPA-treated DCs displayed a reduced capacity to promote allogeneic CD4(+) and CD8(+) T cell proliferation. In other DC: T cell co-cultures, the addition of antibody blocking the CD40-CD154 (CD40L) interaction mirrored the decreased T cell proliferation produced by MPA treatment, while addition of recombinant soluble CD154 restored the capacity of MPA-treated DCs to induce T cell proliferation to levels produced by non-MPA-treated controls.
LIMITATIONS, REASON FOR CAUTION
While our results newly reveal that pharmacologically relevant MPA concentrations suppress human DC function in vitro, additional research is needed to learn if DMPA similarly inhibits DC maturation and function in the human female genital tract.
WIDER IMPLICATIONS OF THE FINDINGS
Identification of a mechanism by which MPA impairs human DC activation and function increases the biological plausibility for the relationships currently suspected between DMPA use and enhanced susceptibility to genital tract infection.
STUDY FUNDING/COMPETING INTERESTS
Funding provided by the NIH (grant R01HD072663) and The Ohio State University College of Medicine. The authors have no conflicts of interest to declare.
Topics: B7-1 Antigen; CD40 Antigens; Cell Proliferation; Cell Survival; Contraceptive Agents, Female; Dendritic Cells; Female; Humans; Medroxyprogesterone Acetate; Monocytes; T-Lymphocytes; Toll-Like Receptor 3
PubMed: 25740884
DOI: 10.1093/humrep/dev035