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Archives of Gynecology and Obstetrics Apr 2024Short-acting progestin-only injectables containing depot medroxyprogesterone acetate (DMPA) are a safe method of contraception. Although DMPA has been available for... (Review)
Review
PURPOSE
Short-acting progestin-only injectables containing depot medroxyprogesterone acetate (DMPA) are a safe method of contraception. Although DMPA has been available for several decades, there is little data on its influence on the risk of breast cancer. Hence, the aim of this paper was to provide an overview of the existing studies and create clarity regarding a possible association with breast cancer.
METHODS
Literature searches were executed in MEDLINE, Embase, the Cochrane Library, ClinicalTrials.gov and ICTRP. Search terms were related to DMPA and breast cancer. After elimination of duplicates, 3'850 studies were identified and assessed according to inclusion and exclusion criteria. Finally, ten studies were selected and included in this review.
RESULTS
All the selected papers were case-control-studies, except for one pooled analysis and one study comparing observed and expected number of cancer cases. Most of the included studies found no overall elevated breast cancer incidence in DMPA users, only one study found a slightly increased risk and two studies concluded with a significant increase for the overall breast cancer risk.
CONCLUSION
There is little evidence that DMPA may increase the overall risk for breast cancer. However, the incidence of breast cancer is possibly increased in current and more recent users, especially in women younger than 35 years. Long-term use did not result in any risk increase. Nevertheless, further studies will be necessary to confirm these findings and weigh up the individual risks and benefits of this contraceptive method.
Topics: Female; Humans; Medroxyprogesterone Acetate; Delayed-Action Preparations; Breast Neoplasms; Contraceptive Agents, Female; Progestins
PubMed: 37966517
DOI: 10.1007/s00404-023-07265-5 -
BMJ (Clinical Research Ed.) Mar 2024To assess the risk of intracranial meningioma associated with the use of selected progestogens.
OBJECTIVE
To assess the risk of intracranial meningioma associated with the use of selected progestogens.
DESIGN
National case-control study.
SETTING
French National Health Data System (ie, ).
PARTICIPANTS
Of 108 366 women overall, 18 061 women living in France who had intracranial surgery for meningioma between 1 January 2009 and 31 December 2018 (restricted inclusion periods for intrauterine systems) were deemed to be in the case group. Each case was matched to five controls for year of birth and area of residence (90 305 controls).
MAIN OUTCOME MEASURES
Selected progestogens were used: progesterone, hydroxyprogesterone, dydrogesterone, medrogestone, medroxyprogesterone acetate, promegestone, dienogest, and intrauterine levonorgestrel. For each progestogen, use was defined by at least one dispensation within the year before the index date (within three years for 13.5 mg levonorgestrel intrauterine systems and five years for 52 mg). Conditional logistic regression was used to calculate odds ratio for each progestogen meningioma association.
RESULTS
Mean age was 57.6 years (standard deviation 12.8). Analyses showed excess risk of meningioma with use of medrogestone (42 exposed cases/18 061 cases (0.2%) 79 exposed controls/90 305 controls (0.1%), odds ratio 3.49 (95% confidence interval 2.38 to 5.10)), medroxyprogesterone acetate (injectable, 9/18 061 (0.05%) 11/90 305 (0.01%), 5.55 (2.27 to 13.56)), and promegestone (83/18 061 (0.5%) 225/90 305 (0.2 %), 2.39 (1.85 to 3.09)). This excess risk was driven by prolonged use (≥one year). Results showed no excess risk of intracranial meningioma for progesterone, dydrogesterone, or levonorgestrel intrauterine systems. No conclusions could be drawn concerning dienogest or hydroxyprogesterone because of the small number of individuals who received these drugs. A highly increased risk of meningioma was observed for cyproterone acetate (891/18 061 (4.9%) 256/90 305 (0.3%), odds ratio 19.21 (95% confidence interval 16.61 to 22.22)), nomegestrol acetate (925/18 061 (5.1%) 1121/90 305 (1.2%), 4.93 (4.50 to 5.41)), and chlormadinone acetate (628/18 061 (3.5%) 946/90 305 (1.0%), 3.87 (3.48 to 4.30)), which were used as positive controls for use.
CONCLUSIONS
Prolonged use of medrogestone, medroxyprogesterone acetate, and promegestone was found to increase the risk of intracranial meningioma. The increased risk associated with the use of injectable medroxyprogesterone acetate, a widely used contraceptive, and the safety of levonorgestrel intrauterine systems are important new findings.
Topics: Female; Humans; Middle Aged; Progestins; Progesterone; Levonorgestrel; Meningioma; Medroxyprogesterone Acetate; Dydrogesterone; Medrogestone; Promegestone; Case-Control Studies; Meningeal Neoplasms
PubMed: 38537944
DOI: 10.1136/bmj-2023-078078 -
Life Sciences Jul 2023Medroxyprogesterone acetate (MPA) is the most common fertility-sparing treatment in patients with early-stage endometrial cancer. If MPA treatment fails, hysterectomy is...
AIMS
Medroxyprogesterone acetate (MPA) is the most common fertility-sparing treatment in patients with early-stage endometrial cancer. If MPA treatment fails, hysterectomy is recommended. Thus, there is an urgent need for novel treatment approaches for MPA-resistant endometrial cancer patients who wish to preserve their fertility. Ferroptosis is a recently discovered type of regulated cell death caused by the excessive accumulation of reactive oxygen species (ROS), followed by aberrant lipid peroxidation. Recent studies have shown that inducing ferroptosis is a potential therapeutic strategy for cancer. However, the role of ferroptosis in endometrial cancer treatment remains to be discussed. We therefore investigated the effects of ferroptosis inducers on MPA-resistant endometrial cancer cells.
MAIN METHODS
The levels of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), the main mediators of ferroptosis, were examined. Cell viability was evaluated after treatment with the ferroptosis inducers sulfasalazine, erastin, or RSL3. The degree of intracellular oxidative stress after treatment with these drugs was evaluated by the glutathione level, ROS level, ferrous iron level, lipid peroxidation and changes in mitochondrial morphology. The effect of ferroptosis inducers in vivo was also examined.
KEY FINDINGS
The expression of SLC7A11 and GPX4 in MPA-resistant ECC-1 cells decreased in comparison to parental ECC-1 cells. Sulfasalazine, erastin, and RSL3 significantly reduced cell viability and increased intracellular oxidative stress in MPA-resistant ECC-1 cells. Ferroptosis inducers also suppressed in vivo tumor growth more effectively in MPA-resistant ECC-1.
SIGNIFICANCE
Treatment with ferroptosis inducers could be a novel therapeutic approach for MPA-resistant endometrial cancer.
Topics: Female; Humans; Ferroptosis; Medroxyprogesterone Acetate; Reactive Oxygen Species; Sulfasalazine; Endometrial Neoplasms
PubMed: 37160245
DOI: 10.1016/j.lfs.2023.121753 -
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 -
Stem Cell Research & Therapy Jun 2023Mesenchymal stem cell (MSC) therapy is an attractive treatment option for various cancers. Whether MSCs can be used to treat well-differentiated endometrial cancer (EC)...
BACKGROUND
Mesenchymal stem cell (MSC) therapy is an attractive treatment option for various cancers. Whether MSCs can be used to treat well-differentiated endometrial cancer (EC) remains unclear. The aim of this study is to explore the potential therapeutic effects of MSCs on EC and the underlying mechanisms.
METHODS
The effects of adipose-derived MSCs (AD-MSCs), umbilical-cord-derived MSCs (UC-MSCs), and endometrium-derived MSCs (eMSCs) on the malignant behaviors of EC cells were explored via in vitro and in vivo experiments. Three EC models, including patient-derived EC organoid lines, EC cell lines, and EC xenograft model in female BALB/C nude mice, were used for this study. The effects of MSCs on EC cell proliferation, apoptosis, migration, and the growth of xenograft tumors were evaluated. The potential mechanisms by which eMSCs inhibit EC cell proliferation and stemness were explored by regulating DKK1 expression in eMSCs or Wnt signaling in EC cells.
RESULTS
Our results showed that eMSCs had the highest inhibitory effect on EC cell viability, and EC xenograft tumor growth in mice compared to AD-MSCs and UC-MSCs. Conditioned medium (CM) obtained from eMSCs significantly suppressed the sphere-forming ability and stemness-related gene expression of EC cells. In comparison to AD-MSCs and UC-MSCs, eMSCs had the highest level of Dickkopf-related protein 1 (DKK1) secretion. Mechanistically, eMSCs inhibited Wnt/β-catenin signaling in EC cells via secretion of DKK1, and eMSCs suppressed EC cell viability and stemness through DKK1-Wnt/β-catenin signaling. Additionally, the combination of eMSCs and medroxyprogesterone acetate (MPA) significantly inhibited the viability of EC organoids and EC cells compared with eMSCs or MPA alone.
CONCLUSIONS
The eMSCs, but not AD-MSCs or UC-MSCs, could suppress the malignant behaviors of EC both in vivo and in vitro via inhibiting the Wnt/β-catenin signaling pathway by secreting DKK1. The combination of eMSCs and MPA effectively inhibited EC growth, indicating that eMSCs may potentially be a new therapeutic strategy for young EC patients desiring for fertility preservation.
Topics: Humans; Mice; Female; Animals; Wnt Signaling Pathway; beta Catenin; Mice, Nude; Mice, Inbred BALB C; Endometrial Neoplasms; Endometrium; Mesenchymal Stem Cells; Cell Proliferation; Intercellular Signaling Peptides and Proteins
PubMed: 37287079
DOI: 10.1186/s13287-023-03387-4 -
World Journal of Clinical Cases Aug 2023Endometrial cancer is one of the most commonly diagnosed gynecological cancers worldwide, and early-stage high-risk endometrial cancer has a poor prognosis. Adjuvant...
BACKGROUND
Endometrial cancer is one of the most commonly diagnosed gynecological cancers worldwide, and early-stage high-risk endometrial cancer has a poor prognosis. Adjuvant treatments after surgery, such as chemotherapy and radiotherapy, have been widely used in clinical practice to improve patient survival. Medroxyprogesterone acetate is a synthetic progestogen that has been reported to have potential anticancer effects in endometrial cancer. However, its efficacy, safety, and long-term prognostic benefits as an adjuvant treatment for endometrial cancer remain controversial. Therefore, this study aimed to observe the efficacy and prognostic impact of adjuvant medroxyprogesterone acetate treatment in patients with early-stage high-risk endometrial cancer and evaluate its safety.
AIM
To observe the efficacy and prognosis of adjuvant treatment of endometrial cancer with medroxyprogesterone acetate and to evaluate its safety.
METHODS
We collected the clinical data of 200 patients with early-stage high-risk endometrial cancer who were admitted to the Department of Obstetrics and Gynecology of our hospital from January 2018 to December 2022. The control group (100 patients) underwent conventional surgical treatment, and the study group (100 patients) was administered adjuvant medroxyprogesterone acetate tablets on top of the control group. The Kaplan-Meier curve analysis and log-rank test were performed to determine the possible factors influencing the 5-year cumulative survival rate in the patients. The Cox regression analysis was performed to identify the factors influencing the survival prognosis of endometrial cancer.
RESULTS
According to the Cox regression analysis, age [hazard ratio (HR) = 4.636, 95% confidence interval (95%CI): 1.411-15.237], pathological type (HR = 6.943, 95%CI: 2.299-20.977), molecular typing (HR = 5.789, 95%CI: 3.305-10.141), and myometrial infiltration (HR = 5.768, 95%CI: 1.898-17.520) were factors influencing the prognosis of patients with early-stage high-risk endometrial cancer.
CONCLUSION
Age, pathological type, molecular typing, and myometrial infiltration were all relevant factors affecting the prognosis of early-stage high-risk endometrial cancer. The potential long-term prognostic benefit of adjuvant postoperative radiotherapy in patients with early-stage high-risk endometrial cancer is worthy of clinical consideration.
PubMed: 37637703
DOI: 10.12998/wjcc.v11.i23.5447 -
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 -
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