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Psychoneuroendocrinology Jul 2022Medroxyprogesterone acetate (MPA) is a progestin widely used in humans as hormone replacement therapy and at other indications. Many progestin metabolites, as the...
Medroxyprogesterone acetate (MPA) is a progestin widely used in humans as hormone replacement therapy and at other indications. Many progestin metabolites, as the progesterone metabolite allopregnanolone, have GABA-receptor modulatory effects and are known to affect memory, learning, appetite, and mood. In women, 4 years chronic treatment with MPA doubles the frequency of dementia and in rats, MPA causes cognitive impairment related to the GABAergic system. Activation of the membrane bound GABA receptor results in a chloride ion flux that can be studied by whole-cell patch-clamp electrophysiological recordings. The purpose of this study was to clarify the modulatory effects of MPA and specific MPA metabolites, with structures like known GABA-receptor modulators, on different GABA-receptor subtypes. An additional aim was to verify the results as steroid effects on GABA response in single cells taken from rat hypothalamus. HEK-293 cell-lines permanently expressing the recombinant human GABA-receptor subtype α1β2γ2L or α5β3γ2L or α2β3γ2S were created. The MPA metabolites 3α5α-MPA,3β5α-MPA and 3β5β-MPA were synthesised and purified for electrophysiological patch-clamp measurements with a Dynaflow system. The effects of MPA and tetrahydrodeoxycorticosterone were also studied. None of the studied MPA metabolites affected the responses mediated by α1β2γ2L or α5β3γ2L GABA receptors. Contrary, MPA clearly acted both as a positive modulator and as a direct activator of the α5β3γ2L and α2β3γ2S GABA receptors. However, in concentrations up to 10 μM, MPA was inactive at the α1β2γ2L GABA receptor. In the patch-clamp recordings from dissociated cells of the preoptic area in rats, MPA increased the amplitude of responses to GABA. In addition, MPA alone without added GABA, evoked a current response. In conclusion, MPA acts as a positive modulator of specific GABA receptor subtypes expressed in HEK cells and at native GABA receptors in single cells from the hypothalamic preoptic area.
Topics: Animals; Cognition; Female; HEK293 Cells; Humans; Medroxyprogesterone Acetate; Progestins; Rats; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 35395561
DOI: 10.1016/j.psyneuen.2022.105754 -
Obstetrics and Gynecology May 2022Investigate the association between use of depot medroxyprogesterone acetate (DMPA) (an injectable progestin-only contraceptive) and leiomyoma development.
OBJECTIVE
Investigate the association between use of depot medroxyprogesterone acetate (DMPA) (an injectable progestin-only contraceptive) and leiomyoma development.
METHODS
We conducted a cohort study in the Detroit, Michigan, area that involved four clinic visits at 20-month intervals over 5 years (2010-2018) and used a standardized ultrasonography protocol to prospectively measure leiomyomas 0.5 cm or more in diameter. Participants were 1,693 self-identified Black women aged 23-35 years with no prior leiomyoma diagnosis and no hysterectomy. For this substudy, years since last use of DMPA was ascertained from questionnaire data at every visit. Leiomyoma incidence was defined as the first visit with an observed leiomyoma among women who were leiomyoma-free at enrollment. Depot medroxyprogesterone acetate associations were examined with Cox models. Leiomyoma growth was calculated as the change in log-volume for leiomyomas matched at successive visits and was modeled using linear mixed models accounting for clustered data. Leiomyoma loss, defined as a reduction in leiomyoma number in successive visits, was modeled using Poisson regression. All models used time-varying exposure and covariates.
RESULTS
Of participants with at least one follow-up visit (N=1,610), 42.9% had ever used DMPA. Participants exposed to DMPA within the previous 2 years experienced reduced leiomyoma development during the subsequent observation interval compared with never users, including lower leiomyoma incidence (5.2% vs 10.7%), adjusted hazard ratio 0.6 (95% CI 0.4-1.0), 42.0% lower leiomyoma growth (95% CI -51.4 to -30.7) and 60% greater leiomyoma loss (adjusted risk ratio 1.6, 95% CI 1.1-2.2). Excess leiomyoma loss was also seen for those who used DMPA 2-4 years before the visit compared with never users, 2.1-fold increase (95% CI 1.4-3.1).
CONCLUSION
Recent use of DMPA was associated with reduced leiomyoma development and increased leiomyoma loss. Such changes in early leiomyoma development in young women could delay symptom onset and reduce the need for invasive treatment.
Topics: Cohort Studies; Contraceptive Agents, Female; Delayed-Action Preparations; Female; Humans; Incidence; Leiomyoma; Medroxyprogesterone; Medroxyprogesterone Acetate
PubMed: 35576339
DOI: 10.1097/AOG.0000000000004745 -
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 -
Molecular and Cellular Endocrinology Mar 2023The pro-inflammatory cytokine, chemokine (C-C motif) ligand 20 (CCL20), is emerging as a therapeutic target for immune-based therapies. Cooperative regulation of CCL20...
The pro-inflammatory cytokine, chemokine (C-C motif) ligand 20 (CCL20), is emerging as a therapeutic target for immune-based therapies. Cooperative regulation of CCL20 by glucocorticoids and progestins used in endocrine therapy and pro-inflammatory mediators could modulate immune function and affect disease outcomes. We show that glucocorticoids as well as medroxyprogesterone acetate (MPA), the progestin widely used in injectable contraception in sub-Saharan Africa, cooperate with pro-inflammatory mediators to upregulate CCL20 protein and/or mRNA in human peripheral blood mononuclear cells (PBMCs) and human cervical cell lines. Changes in CCL20 mRNA levels were shown to be synergistic, as assessed by Chou analysis, cell- and gene-specific and to involve transcriptional regulation, with a requirement for a nuclear factor kappa B (NF-κB) site and glucocorticoid receptor (GR) involvement. The novel results suggest a mechanism whereby MPA, like glucocorticoids, may impact inflammation both systemically and in the genital tract in patients using MPA and/or glucocorticoid therapy.
Topics: Humans; Medroxyprogesterone Acetate; Glucocorticoids; Leukocytes, Mononuclear; Progestins; Receptors, Glucocorticoid; RNA, Messenger; Chemokine CCL20
PubMed: 36646303
DOI: 10.1016/j.mce.2023.111855 -
Current Opinion in Obstetrics &... Dec 2019To provide an overview of recent research and guidelines regarding contraception and breastfeeding. (Review)
Review
PURPOSE OF REVIEW
To provide an overview of recent research and guidelines regarding contraception and breastfeeding.
RECENT FINDINGS
Recent studies assessed lactogenesis, breastfeeding rates, and milk supply concerns in patients starting postpartum hormonal contraception. One study showed a small but statistically significant increase in milk supply concerns between users and nonusers of postpartum hormonal contraception. Mean time to lactogenesis and breastfeeding rates were similar between patients with immediate and delayed insertion of the levonorgestrel (LNG) implant in one study and the LNG intrauterine device (IUD) in another study. Two studies assessed nursing knowledge and attitudes toward postpartum contraception in breastfeeding women, showing that postpartum nurses had incorrect knowledge of contraceptive safety in this patient population. Both studies demonstrated persistent erroneous beliefs that depot medroxyprogesterone acetate (DMPA) adversely affects breastfeeding. In postpartum patients intending to breastfeed, more than half intended to initiate contraception within 6 weeks postpartum and few indicated effect on breastfeeding as a factor in their decision.
SUMMARY
There are no significant differences in lactogenesis, breastfeeding, and infant growth parameters between immediate postpartum (IPP) and delayed insertion of LNG implants and IUDs. Labor and delivery and postpartum nurses have persistent erroneous beliefs that DMPA negatively affects breastfeeding. Patients desire to use contraception postpartum but prenatal counseling rates and practices are of variable content and quality.
Topics: Breast Feeding; Contraception; Contraceptive Agents; Delayed-Action Preparations; Female; Gynecology; Health Knowledge, Attitudes, Practice; Hormonal Contraception; Humans; Infant; Infant, Newborn; Intrauterine Devices; Lactation; Levonorgestrel; Medroxyprogesterone Acetate; Milk, Human; Postpartum Period; Practice Guidelines as Topic; Pregnancy
PubMed: 31436540
DOI: 10.1097/GCO.0000000000000571 -
Best Practice & Research. Clinical... Aug 2014Progestin-only contraceptive injectables and implants are highly effective, longer-acting contraceptive methods that can be used by most women in most circumstances.... (Review)
Review
Progestin-only contraceptive injectables and implants are highly effective, longer-acting contraceptive methods that can be used by most women in most circumstances. Globally, 6% of women using modern contraception use injectables and 1% use implants. Injectables are the predominant contraceptive method used in sub-Saharan Africa, and account for 43% of modern contraceptive methods used. A lower-dose, subcutaneous formulation of the most widely used injectable, depot-medroxyprogesterone acetate, has been developed. Implants have the highest effectiveness of any contraceptive method. Commodity cost, which historically limited implant availability in low-resource countries, was markedly lowered between 2012 and 2013. Changes in menstrual bleeding patterns are extremely common with both methods, and a main cause of discontinuation. Advice from normative bodies differs on progestin-only contraceptive use by breastfeeding women 0-6 weeks postpartum. Whether these methods are associated with HIV acquisition is a controversial issue, with important implications for sub-Saharan Africa, which has a disproportionate burden of both human immunodeficiency virus (HIV) and maternal mortality.
Topics: Breast Feeding; Contraception; Contraceptive Agents, Female; Delayed-Action Preparations; Drug Implants; Female; Humans; Injections, Intramuscular; Injections, Subcutaneous; Medroxyprogesterone Acetate; Pregnancy; Progesterone Congeners
PubMed: 24996766
DOI: 10.1016/j.bpobgyn.2014.05.003 -
Maturitas Jul 2022To compare the difference between micronised progesterone (MP) and medroxyprogesterone acetate (MPA) in combination with transdermal oestradiol (t-E) on cardiovascular... (Randomized Controlled Trial)
Randomized Controlled Trial
Impact of micronised progesterone and medroxyprogesterone acetate in combination with transdermal oestradiol on cardiovascular markers in women diagnosed with premature ovarian insufficiency or an early menopause: a randomised pilot trial.
OBJECTIVE
To compare the difference between micronised progesterone (MP) and medroxyprogesterone acetate (MPA) in combination with transdermal oestradiol (t-E) on cardiovascular disease (CVD) risk markers in women diagnosed with an early menopause and premature ovarian insufficiency (EMPOI).
BACKGROUND
The European Society for Cardiology has identified carotid femoral pulse wave velocity (cfPWV) as the gold standard cardiogenic biomarker for risk stratification of arterial disease. Menopause has been shown to augment the age-dependent increase in arterial stiffness, with hormone replacement therapy (HRT) being the mainstay of management of women diagnosed with EMPOI.
STUDY DESIGN
A pilot randomised prospective open-label trial. Women were randomised to either cyclical MP (Utrogestan® 200mg) or MPA (Provera® 10mg) in conjunction with t-E (Evorel® Patches 50mcg/day) for 12 months. Seventy-one subjects were screened, and baseline data are available for 57 subjects.
MAIN OUTCOME MEASURE
Carotid-femoral pulse wave velocity (cfPWV).
RESULTS
PWV did not significantly change from baseline in either treatment arm. MP + t-E demonstrated a positive effect on traditional CVD markers, with a significant improvement seen in cardiac output (CO) (0.71±1.01mL/min, 95% CI 0.20 to 1.21) and reduction in diastolic blood pressure (DBP) (-3.43±6.31mmHg, 95% Cl -6.57 to -0.29) and total peripheral resistance (TPR) (-0.15±0.19mmHg⋅min⋅mL, 95% CI -0.24 to -0.05) after 12 months. MPA + t-E, in contrast, did not demonstrate significant changes from baseline in traditional haemodynamic parameters.
CONCLUSION
The positive changes in traditional markers were not reflected in the cardiogenic biomarker, cfPWV, which has demonstrated a higher positive predictive value for cardiovascular events than traditional measurements.
Topics: Biomarkers; Cardiovascular Diseases; Estradiol; Female; Humans; Medroxyprogesterone Acetate; Menopause; Menopause, Premature; Pilot Projects; Primary Ovarian Insufficiency; Progesterone; Prospective Studies; Pulse Wave Analysis
PubMed: 35688490
DOI: 10.1016/j.maturitas.2022.01.012 -
Clinical Obstetrics and Gynecology Dec 2014As birth spacing has demonstrated health benefits for a woman and her children, contraception after childbirth is recognized as an important health issue. The potential... (Review)
Review
As birth spacing has demonstrated health benefits for a woman and her children, contraception after childbirth is recognized as an important health issue. The potential risk of pregnancy soon after delivery underscores the importance of initiating postpartum contraception in a timely manner. The contraceptive method initiated in the postpartum period depends upon a number of factors including medical history, anatomic and hormonal factors, patient preference, and whether or not the woman is breastfeeding. When electing a contraceptive method, informed choice is paramount. The availability of long-acting reversible contraceptive methods immediately postpartum provides a strategy to achieve reductions in unintended pregnancy.
Topics: Amenorrhea; Birth Intervals; Breast Feeding; Condoms; Contraception; Contraceptive Agents, Female; Contraceptive Devices, Female; Contraceptives, Oral, Hormonal; Desogestrel; Drug Implants; Female; Humans; Intrauterine Devices, Copper; Levonorgestrel; Medroxyprogesterone Acetate; Postpartum Period; Sterilization, Tubal; Venous Thromboembolism
PubMed: 25264698
DOI: 10.1097/GRF.0000000000000055 -
Handbook of Experimental Pharmacology 2020Drugs may cause bone loss by lowering sex steroid levels (e.g., aromatase inhibitors in breast cancer, GnRH agonists in prostate cancer, or depot medroxyprogestone...
Drugs may cause bone loss by lowering sex steroid levels (e.g., aromatase inhibitors in breast cancer, GnRH agonists in prostate cancer, or depot medroxyprogestone acetate - DMPA), interfere with vitamin D levels (liver inducing anti-epileptic drugs), or directly by toxic effects on bone cells (chemotherapy, phenytoin, or thiazolidinedions, which diverts mesenchymal stem cells from forming osteoblasts to forming adipocytes). However, besides effects on the mineralized matrix, interactions with collagen and other parts of the unmineralized matrix may decrease bone biomechanical competence in a manner that may not correlate with bone mineral density (BMD) measured by dual energy absorptiometry (DXA).Some drugs and drug classes may decrease BMD like the thiazolidinediones and consequently increase fracture risk. Other drugs such as glucocorticoids may decrease BMD, and thus increase fracture risk. However, glucocorticoids may also interfere with the unmineralized matrix leading to an increase in fracture risk, not mirrored in BMD changes. Some drugs such as selective serotonin reuptake inhibitors (SSRI), paracetamol, and non-steroidal anti-inflammatory drugs (NSAIDs) may not per se be associated with bone loss, but fracture risk may be increased, possibly stemming from an increased risk of falls stemming from effects on postural balance mediated by effects on the central nervous system or cardiovascular system.This paper performs a systematic review of drugs inducing bone loss or associated with fracture risk. The chapter is organized by the Anatomical Therapeutic Chemical (ATC) classification.
Topics: Bone Density; Bone and Bones; Fractures, Bone; Humans; Medroxyprogesterone Acetate; Pharmaceutical Preparations
PubMed: 31889220
DOI: 10.1007/164_2019_340 -
Endocrine Reviews Feb 2018Access to effective affordable contraception is critical for individual and public health. A wide range of hormonal contraceptives (HCs), which differ in composition,... (Review)
Review
Access to effective affordable contraception is critical for individual and public health. A wide range of hormonal contraceptives (HCs), which differ in composition, concentration of the progestin component, frequency of dosage, and method of administration, is currently available globally. However, the options are rather limited in settings with restricted economic resources that frequently overlap with areas of high HIV-1 prevalence. The predominant contraceptive used in sub-Saharan Africa is the progestin-only three-monthly injectable depot medroxyprogesterone acetate. Determination of whether HCs affect HIV-1 acquisition has been hampered by behavioral differences potentially confounding clinical observational data. Meta-analysis of these studies shows a significant association between depot medroxyprogesterone acetate use and increased risk of HIV-1 acquisition, raising important concerns. No association was found for combined oral contraceptives containing levonorgestrel, nor for the two-monthly injectable contraceptive norethisterone enanthate, although data for norethisterone enanthate are limited. Susceptibility to HIV-1 and other sexually transmitted infections may, however, be dependent on the type of progestin present in the formulation. Several underlying biological mechanisms that may mediate the effect of HCs on HIV-1 and other sexually transmitted infection acquisition have been identified in clinical, animal, and ex vivo studies. A substantial gap exists in the translation of basic research into clinical practice and public health policy. To bridge this gap, we review the current knowledge of underlying mechanisms and biological effects of commonly used progestins. The review sheds light on issues critical for an informed choice of progestins for the identification of safe, effective, acceptable, and affordable contraceptive methods.
Topics: Animals; Contraception; Contraceptive Agents, Female; Disease Susceptibility; Dose-Response Relationship, Drug; Female; Genitalia, Female; HIV Infections; HIV-1; Humans; Medroxyprogesterone Acetate; Progestins
PubMed: 29309550
DOI: 10.1210/er.2017-00103