Medroxyprogesterone (MPA) is a synthetic steroid which is used in the treatment of renal carcinoma. It is a synthetic progestational hormone used in veterinary practice as an estrus regulator.
Physicochemical Properties
| Molecular Formula | C22H32O3 |
| Molecular Weight | 344.48 |
| Exact Mass | 344.235 |
| Elemental Analysis | C, 76.70; H, 9.36; O, 13.93 |
| CAS # | 520-85-4 |
| Related CAS # | Medroxyprogesterone;520-85-4;Medroxyprogesterone-d3;162462-69-3;Medroxyprogesterone-d7; 71-58-9 (acetate) |
| PubChem CID | 10631 |
| Appearance | White to off-white solid powder |
| Density | 1.1±0.1 g/cm3 |
| Boiling Point | 488.0±45.0 °C at 760 mmHg |
| Melting Point | 220-223.5ºC |
| Flash Point | 263.0±25.2 °C |
| Vapour Pressure | 0.0±2.8 mmHg at 25°C |
| Index of Refraction | 1.554 |
| LogP | 3.38 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 3 |
| Rotatable Bond Count | 1 |
| Heavy Atom Count | 25 |
| Complexity | 664 |
| Defined Atom Stereocenter Count | 7 |
| SMILES | CC([C@@]1(O)CC[C@@]2([H])[C@]3([H])C[C@H](C)C4=CC(CC[C@]4(C)[C@@]3([H])CC[C@]12C)=O)=O |
| InChi Key | FRQMUZJSZHZSGN-HBNHAYAOSA-N |
| InChi Code | InChI=1S/C22H32O3/c1-13-11-16-17(20(3)8-5-15(24)12-19(13)20)6-9-21(4)18(16)7-10-22(21,25)14(2)23/h12-13,16-18,25H,5-11H2,1-4H3/t13-,16+,17-,18-,20+,21-,22-/m0/s1 |
| Chemical Name | Pregn-4-ene-3,20-dione, 17-hydroxy-6-alpha-methyl- |
| Synonyms | Medroxyprogesterone; NSC 27408; Medroxyprogesteron; Medroxiprogesteronum; Medroxiprogesterona; Medroxyprogesteronum; Medrossiprogesterone; 17-Hydroxy-6alpha-methylprogesterone; NSC-27408; NSC27408; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | Progesterone receptor |
| ln Vitro |
In T47D cells, medroxyprogesterone (10 nM, 48 h) stimulates the production of Cyclin D1 via the PI3K/Akt signaling pathway, hence promoting cell proliferation [1]. By raising the expression of signaling molecules in HUVECs, medroxyprogesterone (100 nM, 24 h) increases the number of monocyte markers on HUVECs, which may be the cause of atherosclerosis [2]. mRNA levels of adhesion molecules in HUVECs treated with medroxyprogesterone acetate (MPA) or 17β-estradiol + MPA were 1.7- to 2.5-fold higher than those in the control. MPA increased the protein expression of E-selectin, P-selectin, and intercellular adhesion molecule-1 compared with that for the control (83.0 ± 0.7, 34.8 ± 1.2, and 5.4 ± 0.0 ng/mL, respectively), whereas other progestogens or 17β-estradiol additive to progestogens did not significantly change expression. MPA significantly increased U937 monocytoid cell adherence compared with the control (56.0 ± 1.5 vs 46.5 ± 3.5 adherent cells per 10 fields) but did not increase adherence to HUVECs with knocked down intercellular adhesion molecule-1. Conclusions: MPA increases cell adhesion molecule expression on HUVECs, causing increased numbers of monocytoid cells to adhere to HUVECs. These MPA effects may be a risk factor for atherogenesis on endothelial cells in postmenopausal women receiving hormone replacement therapy.[2] |
| ln Vivo |
Although it can enhance thrombosis, medroxyprogesterone (27.7 μg/day, subcutaneous injection) inhibits arterial vascular thrombosis [3]. MPA and MPA + E2-treated animals showed an aggravated thrombotic response shown by significantly reduced time to stable occlusion. The pro-thrombotic effect of MPA was paralleled by increased ETP whereas platelet activation was not affected. Furthermore, MPA + E2 reduced the number of cells positive for alpha-smooth muscle actin and increased hyaluronan in the plaque matrix. Interestingly, total plaque burden was reduced by MPA but unchanged by MPA + E2.[3]. Conclusion and implications: Long-term treatment with MPA and MPA + E2 increased arterial thrombosis despite inhibitory effects of MPA on atherosclerosis in ApoE-deficient mice. Increased thrombin formation, reduced smooth muscle content and remodelling of non-collagenous plaque matrix may be involved in the pro-thrombotic effects. Thus, MPA exhibits differential effects on arterial thrombosis and on atherosclerosis.[3]. Medroxyprogesterone acetate (MPA) and MPA + E2-treated animals showed an aggravated thrombotic response shown by significantly reduced time to stable occlusion. The pro-thrombotic effect of MPA was paralleled by increased ETP whereas platelet activation was not affected. Furthermore, MPA + E2 reduced the number of cells positive for alpha-smooth muscle actin and increased hyaluronan in the plaque matrix. Interestingly, total plaque burden was reduced by MPA but unchanged by MPA + E2. Conclusion and implications: Long-term treatment with MPA and MPA + E2 increased arterial thrombosis despite inhibitory effects of MPA on atherosclerosis in ApoE-deficient mice. Increased thrombin formation, reduced smooth muscle content and remodelling of non-collagenous plaque matrix may be involved in the pro-thrombotic effects. Thus, MPA exhibits differential effects on arterial thrombosis and on atherosclerosis.[4] |
| Enzyme Assay |
The mechanism of medroxyprogesterone acetate (MPA)-induced cell proliferation in human breast cancer cells remains elusive. In this study, researchers examined the mechanism by which MPA affects the cyclin D1 expression in progesterone receptor (PR)-positive T47D human breast cancer cells. MPA (10 nM) treatment for 48 h induced proliferation of the cells (1.6-fold induction). MPA induced cyclin D1 expression (3.3-fold induction), and RU486, a selective PR antagonist, blocked the MPA-induced cell proliferation and cyclin D1 expression (23% inhibition). MPA increased both the protein level (2.2-fold induction) and promoter activity (2.7-fold induction) of cyclin D1 in MCF-7 cells transfected with PRB but not with PRA. Although MPA transcriptionally activated cyclin D1 expression, cyclin D1 promoter does not have progesterone-responsive element-related sequence. We further examined the mechanism for the regulation of the cyclin D1 expression. Because the cyclin D1 promoter contains three putative nuclear factor-kappaB (NFkappaB)-binding motifs and NFkappaB is a substrate of Akt, we investigated the effect of the phosphatidylinositol 3-kinase (PI3K)/Akt/NFkappaB cascade on the responses of cyclin D1 to MPA. MPA induced the transient phosphorylation of Akt (2.7-fold induction at 5 min), and treatment with PI3K inhibitor (wortmannin) attenuated the MPA-induced up-regulation of cyclin D1 expression (40% inhibition) and cell proliferation (40% inhibition). MPA also induced phosphorylation of inhibitor of NFkappaBalpha (IkappaBalpha) (2.3-fold induction), and treatment with wortmannin attenuated the MPA-induced IkappaBalpha phosphorylation (60% inhibition). Treatment with an IkappaBalpha phosphorylation inhibitor (BAY 11-7085) or a specific NFkappaB nuclear translocation inhibitor (SN-50) attenuated the MPA-induced up-regulation of both cyclin D1 expression (80 and 50% inhibition, respectively) and cell proliferation (55 and 34% inhibition, respectively). Because MPA induced a transient phosphorylation of Akt and the cyclin D1 promoter contains no progesterone-responsive element-related sequence, the MPA-induced cell proliferation through PRB by up-regulation of cyclin D1 expression via the PI3K/Akt/NFkappaB cascade may be a nongenomic mechanism.[1] The fungal transformations of medroxyrogesterone (1) were investigated for the first time using Cunninghamella elegans, Trichothecium roseum, and Mucor plumbeus. The metabolites obtained are as following: 6β, 20-dihydroxymedroxyprogesterone (2), 12β-hydroxymedroxyprogesterone (3), 6β, 11β-dihydroxymedroxyprogesterone (4), 16β-hydroxymedroxyprogesterone (5), 11α, 17-dihydroxy-6α-methylpregn-4-ene-3, 20-dione (6), 11-oxo-medroxyprogesterone (7), 6α-methyl-17α-hydroxypregn-1,4-diene-3,20-dione (8), and 6β-hydroxymedroxyprogesterone (9), 15β-hydroxymedroxyprogesterone (10), 6α-methyl-17α, 11β-dihydroxy-5α-pregnan-3, 20-dione (11), 11β-hydroxymedroxyprogesterone (12), and 11α, 20-dihydroxymedroxyprogesterone (13). Among all the microbial transformed products, the newly isolated biotransformed product 13 showed the most potent activity against proliferation of SH-SY5Y cells. Compounds 12, 5, 6, 9, 11, and 3 (in descending order of activity) also showed some extent of activity against SH-SY5Y tumour cell line. The never been reported biotransformed product, 2, showed the most potent inhibitory activity against acetylcholinesterase. Molecular modelling studies were carried out to understand the observed experimental activities, and also to obtain more information on the binding mode and the interactions between the biotransformed products, and enzyme.[4] |
| Cell Assay |
Cell Proliferation Assay[1] Cell Types: T47D Tested Concentrations: 10 nM Incubation Duration: 24 h, 48 h, 72h Experimental Results: Increased cell number at 48 hrs (hours). Western Blot Analysis [1] Cell Types: T47D Tested Concentrations: 10 nM Incubation Duration: 4 h Experimental Results: Induced Cyclin D1 protein expression. RT-PCR[2] Cell Types: HUVEC Tested Concentrations: 100 nM Incubation Duration: 24 hrs (hours) Experimental Results: Increased mRNA and protein expression of adhesion molecules. In HUVECs, adhesion molecule mRNA levels were measured by real-time PCR. Protein expression was quantified by immunocytochemistry and ELISAs. To mimic the monocyte adherence to endothelial cells, we used a flow chamber system to assess progestogen effects on U937 monocytoid cell adherence to HUVEC monolayers. We also examined the suppression effects of adhesion molecules with small interference RNAs.[2] |
| Animal Protocol |
Animal/Disease Models: ApoE-/- mouse model [3] Doses: 27.7 μg/day Route of Administration: sc Experimental Results: diminished atherosclerotic plaque and increased thrombosis. Apolipoprotein E (ApoE)-/- mice were bilaterally ovariectomized and treated with placebo, MPA (27.7 microg day(-1)) and MPA + 17-beta-oestradiol (E2; 1.1 microg day(-1)) for 90 days, on a Western-type diet. Thrombotic response was measured in a photothrombosis model, platelet activation by fluorescence activated cell sorting (FACS) analysis (CD62P) and thrombin generation by the endogenous thrombin potential (ETP). Furthermore, aortic plaque burden and aortic root plaque composition were determined.[3] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion No specific investigation on the absolute bioavailability of medroxyprogesterone (MPA) in humans has been conducted. MPA is rapidly absorbed from the gastrointestinal tract, and maximum MPA concentrations are obtained between 2 to 4 hours after oral administration. Administration of medroxyprogesterone acetate with food increases the bioavailability of MPA. A 10 mg dose of medroxyprogesterone acetate, taken immediately before or after a meal, increased MPA Cmax (50 to 70%) and AUC (18 to 33%). The half-life of MPA was not changed with food. Medroxyprogesterone is approximately 90% protein bound, primarily to albumin; no MPA binding occurs with sex hormone binding globulin. Most MPA metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates. For more Absorption, Distribution and Excretion (Complete) data for MEDROXYPROGESTERONE (10 total), please visit the HSDB record page. Metabolism / Metabolites Following oral dosing, MPA is extensively metabolized in the liver via hydroxylation, with subsequent conjugation and elimination in the urine. ...MPA is almost exclusively eliminated via hepatic metabolism. In 14 patients with advanced liver disease, MPA disposition was significantly altered (reduced elimination). In patients with fatty liver, the mean percent dose excreted in the 24-hour urine as intact MPA after a 10 mg or 100 mg dose was 7.3% and 6.4%, respectively. Biological Half-Life Elimination half-life of oral preparation is 32 to 44 hr. /Acetate/ |
| References |
[1]. Medroxyprogesterone acetate induces cell proliferation through up-regulation of cyclin D1 expression via phosphatidylinositol 3-kinase/Akt/nuclear factor-kappaB cascade in human breast cancer cells. Endocrinology. 2005 Nov;146(11):4917-25. [2]. Medroxyprogesterone acetate enhances monocyte-endothelial interaction under flow conditions by stimulating the expression of cell adhesion molecules. J Clin Endocrinol Metab. 2014 Jun;99(6):2188-97. [3]. Differential effects of medroxyprogesterone acetate on thrombosis and atherosclerosis in mice. Br J Pharmacol. 2009 Dec;158(8):1951-60. [4]. Medroxyprogesterone derivatives from microbial transformation as anti-proliferative agents and acetylcholineterase inhibitors (combined in vitro and in silico approaches). Steroids. 2020 Dec;164:108735. |
| Additional Infomation |
Medroxyprogesterone is a 3-oxo Delta(4)-steroid that is pregn-4-ene-3,20-dione substituted by an alpha-hydroxy group at position 17 and a methyl group at position 6. It has a role as a contraceptive drug, a progestin and a synthetic oral contraceptive. It is a 20-oxo steroid, a 3-oxo-Delta(4) steroid, a 17alpha-hydroxy steroid and a tertiary alpha-hydroxy ketone. Medroxyprogesterone is a Progestin. Medroxyprogesterone is a synthetic derivative of progesterone administered as an acetate salt (medroxyprogesterone acetate) with antiestrogenic activity. As a do all progestins, medroxyprogesterone binds to and activates nuclear receptors which subsequently bind to and activate target genes for transcription. As an antiestrogen, this agent may inhibit the growth-stimulating effects of estrogen on estrogen-sensitive tumor cells. (NCI04) A synthetic progestational hormone used in veterinary practice as an estrus regulator. Mechanism of Action Medroxyprogesterone shares the pharmacologic actions of the progestins. In women with adequate endogenous estrogen, medroxyprogesterone transforms a proliferative endometrium into a secretory one. Medroxyprogesterone has been shown to have slight androgenic activity in animals. Anabolic effects have also been reported, but the drug apparently lacks appreciable estrogenic activity in humans. In animals, the drug exhibits pronounced adrenocorticoid activity, but a clinically important effect has not been observed in humans. Medroxyprogesterone inhibits the secretion of pituitary gonadotropins following usual IM or subcutaneous dosages (eg, 150 or 104 mg every 3 months), thus preventing follicular maturation and ovulation and resulting in endometrial thinning; these effects result in contraceptive activity. Available evidence indicates that these effects do not occur following oral administration of usual dosages (ie, 5-10 mg daily as single daily doses) of the drug. High doses of medroxyprogesterone inhibit pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and will prevent cyclic gonadotropin surges that occur during the normal menstrual cycle. It has been suggested that the drug acts at the hypothalamus since it does not suppress the release of LH and FSH following administration of gonadotropin-releasing hormone and since basal concentrations of LH and FSH remain within the low normal range when the drug is used as a contraceptive. Although the mechanism of action has not been determined, medroxyprogesterone has antineoplastic activity against some cancers (eg, endometrial carcinoma, renal carcinoma). Progestins elicit, to varying degrees, all the pharmacologic responses usually produced by progesterone: induction of secretory changes in the endometrium, increase in basal body temperature (thermogenic action), production of histologic changes in vaginal epithelium, relaxation of uterine smooth muscle, stimulation of mammary alveolar tissue growth, pituitary inhibition, and production of withdrawal bleeding in the presence of estrogen. /Progestins/ Following binding to cytoplasmic receptor protein, steroid is transported to nucleus, and complex is bound there in reactions analogous to those described... for estrogens. However, there is no apparent need for receptor alteration, as with estrogen receptor. /Progesterone/ Although medroxyprogesterone acetate (MPA) is used as an injectable contraceptive, in hormone replacement therapy (HRT) and in treatment of certain cancers, the steroid receptors and their target genes involved in the actions of MPA are not well understood. /Investigators/ show that MPA, like dexamethasone (dex), significantly represses tumour necrosis factor (TNF)-stimulated interleukin-6 (IL-6) protein production in mouse fibroblast (L929sA) cells. In addition, MPA repressed IL-6 and IL-8 promoter-reporter constructs at the transcriptional level, via interference with nuclear factor kappaB (NFkappaB) and activator protein-1 (AP-1). Furthermore, like dex, MPA does not affect NFkappaB DNA-binding activity. /The authors/ also observed significant transactivation by MPA of a glucocorticoid response element (GRE)-driven promoter-reporter construct in both L929sA and COS-1 cells. The MPA-induced nuclear translocation of the glucocorticoid receptor (GR), as well as the antagonistic effects of RU486, strongly suggest that the actions of MPA in these cells are mediated at least in part via the GR. /Investigators/ assessed the transcriptional effects of MPA as compared with those of progesterone and dihydrotestosterone (DHT) in human breast cancer cells. A new progesterone receptor-negative, androgen receptor-positive human breast cancer cell line, designated Y-AR, was engineered and characterized. Transcription assays using a synthetic promoter/reporter construct, as well as endogenous gene expression profiling comparing progesterone, MPA and DHT, were performed in cells either lacking or containing progesterone receptor and/or androgen receptor. In progesterone receptor-positive cells, MPA was found to be an effective progestin through both progesterone receptor isoforms in transient transcription assays. Interestingly, DHT signaled through progesterone receptor type B. Expression profiling of endogenous progesterone receptor-regulated genes comparing progesterone and MPA suggested that although MPA may be a somewhat more potent progestin than progesterone, it is qualitatively similar to progesterone. To address effects of MPA through androgen receptor, expression profiling was performed comparing progesterone, MPA and DHT using Y-AR cells. These studies showed extensive gene regulatory overlap between DHT and MPA through androgen receptor and none with progesterone. Interestingly, there was no difference between pharmacological MPA and physiological MPA, suggesting that high-dose therapeutic MPA may be superfluous. /This/ comparison of the gene regulatory profiles of MPA and progesterone suggests that, for physiologic hormone replacement therapy, the actions of MPA do not mimic those of endogenous progesterone alone. ... It is possible that the increased breast cancer risk and/or the therapeutic efficacy of MPA in cancer treatment is in part mediated by androgen receptor. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~50 mg/mL (~145.14 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.26 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9029 mL | 14.5146 mL | 29.0293 mL | |
| 5 mM | 0.5806 mL | 2.9029 mL | 5.8059 mL | |
| 10 mM | 0.2903 mL | 1.4515 mL | 2.9029 mL |