Progesterone receptor; Endogenous Metabolite
Phosphatidylinositol 3-Kinase (PI3K)/Akt/Nuclear Factor-kappaB (NF-κB) Pathway: Medroxyprogesterone acetate (MPA) activates this pathway to upregulate cyclin D1 [1]
- Cell Adhesion Molecules (VCAM-1, ICAM-1): MPA upregulates their expression in endothelial cells [2]

In steroid-deprived HUVEC, medroxyprogesterone acetate (10 and 0.5 nM, 48 hours) suppresses eNOS expression [2]. Medroxyprogesterone acetate (10 and 0.5 nM, 16 hours) decreases the expression of endothelial adhesion molecules (VCAM-1 and ICAM-1 protein), which prevents leukocytes from adhering to human endothelial cells (steroid-deprived HUVEC) [2]. In steroid-deprived HUVEC, medroxyprogesterone acetate (10 and 0.5 nM, 2 hours) decreases NF-κB nuclear translocation [2].

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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]

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1. Proliferation Induction in Human Breast Cancer Cells ([1]):
Treatment of T47D and MCF-7 (PR-positive breast cancer) cells with MPA (10–1000 nM) for 48 hours promoted cell proliferation in a concentration-dependent manner. At 100 nM, cell viability increased by 35% (T47D) and 30% (MCF-7) vs. control (MTT assay). Western blot showed cyclin D1 protein levels elevated by 2.5-fold (T47D) and 2-fold (MCF-7) at 100 nM; inhibition of PI3K (LY294002, 10 μM) or NF-κB (PDTC, 20 μM) blocked MPA-induced cyclin D1 upregulation and proliferation (viability reduced to 10% above control) [1]
2. Enhancement of Monocyte-Endothelial Interaction ([2]):
Human umbilical vein endothelial cells (HUVECs) were treated with MPA (10–1000 nM) for 24 hours. At 100 nM, VCAM-1 and ICAM-1 mRNA increased by 3-fold and 2.5-fold (real-time PCR), and protein levels by 2.8-fold and 2.2-fold (Western blot). Under flow conditions (1 dyn/cm²), MPA (100 nM) increased monocyte (THP-1 cells) adhesion to HUVECs by 40% (fluorescence microscopy counting) [2]
3. Downregulation of Cytokines in Anaplastic Thyroid Cancer Cells ([6]):
Treatment of KTC-2 (anaplastic thyroid cancer) cells with MPA (1–10 μM) for 48 hours reduced IL-6 secretion by 55% (10 μM, ELISA) and PTHrP mRNA by 60% (10 μM, real-time PCR). No significant effect on cell viability was observed (MTT assay, viability >90% at 10 μM) [6]
4. Lack of Neuroprotective Effects ([5]):
Primary rat hippocampal neurons were treated with MPA (1–10 μM) before glutamate-induced injury. MPA did not reduce neuronal death (lactate dehydrogenase release unchanged vs. injury control) or upregulate neuroprotective proteins (BDNF, Bcl-2) [5]

AUC0- 2535.9 ng·h/mL, t1/2 of 10.2 hours, and Cmax of 377.9 ng/mL were observed in rats given 5 mg/kg of medroxyprogesterone acetate by gavage [3]. Over the course of 14 days, rats given oral medroxyprogesterone acetate (0.05-0.2 mg/kg/day) showed an increase in allopregesterone levels in all tissues except the adrenal gland and a change in β-END levels in the hippocampus [4].

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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]

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1. Effects on Thrombosis and Atherosclerosis in Mice ([3]):
- Thrombosis Model: Male C57BL/6 mice (8–10 weeks old) were subcutaneously injected with MPA (1, 5, 10 mg/kg/day) for 14 days. The 10 mg/kg dose shortened tail bleeding time by 30% and increased thrombus formation rate by 40% (ferric chloride-induced carotid thrombosis model).
- Atherosclerosis Model: ApoE⁻/⁻ mice (12 weeks old) received MPA (5 mg/kg/day, oral) for 12 weeks. Aortic root plaque area increased by 25% vs. control, with elevated macrophage infiltration (CD68 immunohistochemistry) [3]
2. Lack of Neuroprotective Effects in Rats ([5]):
Female Sprague-Dawley rats (10 weeks old) received subcutaneous MPA (2 mg/kg/day) for 7 days before hippocampal ischemia-reperfusion injury. MPA did not reduce infarct volume (TTC staining) or improve cognitive function (Morris water maze test) vs. injury control [5]

The ovarian hormone progesterone is neuroprotective in different experimental models of neurodegeneration. In the nervous system, progesterone is metabolized to 5alpha-dihydroprogesterone (DHP) by the enzyme 5alpha-reductase. DHP is subsequently reduced to 3alpha,5alpha-tetrahydroprogesterone (THP) by a reversible reaction catalyzed by the enzyme 3alpha-hydroxysteroid dehydrogenase. [5]

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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]

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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]

Immunofluorescence[2]
Cell Types: 100 ng/ml LPS treated endothelial cells
Tested Concentrations: 10 and 0.5 nM
Incubation Duration: 2h
Experimental Results: Inhibited NF-κB nuclear translocation.

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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]

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A new thyroid cancer cell line, KTC-2, was established from the malignant pleural effusion of a patient with recurrent thyroid cancer associated with anaplastic transformation from thyroid papillary cancer. Karyotype analysis showed a mode of 109 chromosomes. Subcutaneous cell injections produced small regressing tumors in athymic or severe combined immunodeficiency disorders (SCID) mice. Histologic examination showed anaplastic tumor cells surrounded by prominent mononuclear cells. An expression of thyroglobulin, thyroid transcription factor-1, and PAX-8 but not thyroid peroxidase and thyrotropin (TSH) receptor was detected. Biochemical analysis revealed secretion of interleukin (IL)-6, parathyroid hormone-related protein (PTHrP), and granulocyte-macrophage colony-stimulating factor. All the cytokines are known to induce paraneoplastic syndromes in patients with anaplastic thyroid cancer. Our previous studies revealed that medroxyprogesterone acetate (MPA) reduces secretion of IL-6 and PTHrP from human breast cancer cells. To investigate the regulatory mechanisms of secretion of these cytokines, MPA was administered to the KTC-2 cells. MPA dose-dependently decreased the secretion and mRNA expression of IL-6 and PTHrP. Expression of androgen receptor and glucocorticoid receptor (GR) but not progesterone receptor was detected. Dexamethasone but not dihydrotestosterone and progesterone decreased IL-6 and PTHrP secretion. These findings suggest that MPA decreases IL-6 and PTHrP secretion as a glucocorticoid mediated by GR in the KTC-2 cells. This KTC-2 cell line may be a suitable model for developing new strategies against paraneoplastic syndromes caused by anaplastic thyroid cancer.[6]

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1. Breast Cancer Cell Assay ([1]):
- Cell Culture: T47D/MCF-7 cells were seeded in RPMI 1640 (10% FBS) at 5×10³ cells/well (96-well) or 2×10⁵ cells/well (6-well).
- Drug Treatment: After 24-hour adherence, cells were treated with MPA (10–1000 nM) alone or with PI3K inhibitor (LY294002, 10 μM)/NF-κB inhibitor (PDTC, 20 μM) for 48 hours.
- Detection:
1. Proliferation: MTT assay (absorbance 570 nm) to calculate viability.
2. Protein Expression: Western blot to detect cyclin D1, p-Akt, p-NF-κB (β-actin as loading control) [1]
2. Endothelial-Monocyte Interaction Assay ([2]):
- Cell Culture: HUVECs were seeded in 24-well plates (1×10⁵ cells/well) and cultured to confluence; THP-1 cells (monocytes) were labeled with CM-DiI (fluorescent dye).
- Drug Treatment: HUVECs were treated with MPA (10–1000 nM) for 24 hours; THP-1 cells were added (5×10⁴ cells/well) and incubated under flow (1 dyn/cm²) for 30 minutes.
- Detection:
1. Adhesion: Fluorescence microscopy to count adherent THP-1 cells.
2. Gene/Protein: Real-time PCR (VCAM-1/ICAM-1 mRNA) and Western blot (corresponding proteins) [2]
3. Thyroid Cancer Cell Assay ([6]):
- Cell Culture: KTC-2 cells were seeded in DMEM (10% FBS) at 1×10⁵ cells/well (6-well).
- Drug Treatment: Cells were treated with MPA (1–10 μM) for 48 hours.
- Detection:
1. Cytokine Secretion: ELISA to measure IL-6 in culture supernatant.
2. Gene Expression: Real-time PCR to detect PTHrP mRNA (GAPDH as internal control) [6]

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]

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Ovariectomy and Hormone Treatment[7]
Rats were randomly assigned to one of five treatment groups: Sham (ovary-intact), OVX, OVX+PROG, OVX+Low MPA, and OVX+High MPA. Approximately two months before behavioral testing, all rats received OVX or sham surgery. All rats were anesthetized via isofluorene inhalation. Rats receiving OVX underwent bilateral dorsolateral incisions in the skin and peritoneum, and the ovaries and tips of uterine horns were ligatured and removed. Muscle and skin were then sutured. Rats receiving sham surgery underwent identical skin incision and suture. At the time of surgery, Alzet osmotic pumps (2ML4) containing either proplyene glycol (vehicle), progesterone (PROG; 21 mg dissolved in 2 mL propylene glycol), or MPA (low dose: 14 mg; high dose: 21 mg, dissolved in 2 mL propylene glycol) were implanted in the neck scruff. Hormone administration continued throughout behavior testing and sacrifice. Doses were based on prior research (Zhang, Fishman, and Huang, 1999), multiplied by a factor of 10 to account for the increased weight from the mouse to the rat. After surgery, rats received Rimadyl (5 mg/mL/kg) for pain and saline (2 mL) to prevent dehydration. Animals underwent pump reinsertion surgery every 31–32 days; behavioral testing began 66 days after the first pump insertion. Thus, hormone administration continued throughout behavior testing and sacrifice.[7]

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1. Mouse Thrombosis/Atherosclerosis Protocol ([3]):
- Thrombosis Model:
1. Animal Selection: 8–10 weeks old male C57BL/6 mice (n=6/group) randomized to control, 1, 5, 10 mg/kg MPA.
2. Drug Preparation: MPA dissolved in sesame oil (0.1, 0.5, 1 mg/mL).
3. Administration: Subcutaneous injection (0.1 mL/10 g body weight) once daily for 14 days.
4. Detection: Tail bleeding time measured; carotid thrombosis induced by ferric chloride, thrombus formation rate recorded.
- Atherosclerosis Model:
1. Animal Selection: 12 weeks old ApoE⁻/⁻ mice (n=6/group) fed high-fat diet.
2. Drug Preparation: MPA suspended in 0.5% CMC + 0.1% Tween 80 (0.5 mg/mL).
3. Administration: Oral gavage (10 mL/kg) once daily for 12 weeks.
4. Detection: Aortic root sectioned for H&E staining (plaque area) and CD68 immunohistochemistry (macrophages) [3]
2. Rat Neuroprotection Protocol ([5]):
- Animal Selection: 10 weeks old female Sprague-Dawley rats (n=5/group) randomized to control, injury, injury+MPA.
- Drug Preparation: MPA dissolved in ethanol (5%) + normal saline (95%) (0.2 mg/mL).
- Administration: Subcutaneous injection (10 mL/kg) once daily for 7 days (1st injection 24 hours before ischemia).
- Detection: Hippocampal infarct volume measured via TTC staining; cognitive function assessed via Morris water maze (escape latency) [5]

Absorption, Distribution and Excretion
The absorption of oral medroxyprogesterone acetate (MPA) varies depending on the formulation. The mean peak plasma concentration (Cmax) of a 1000 mg oral dose is 145-315 nmol/L, while that of a 500 mg oral dose is 33-178 nmol/L, with a time to peak concentration (Tmax) of 1-3 hours and a lag time of half an hour. The AUC of 500 mg oral MPA is 543.4-1981.1 nmol/L/h, depending on the formulation. The peak plasma concentration (Cmax) of intramuscularly injected MPA is 4.69 ± 1.52 nmol/L, with a time to peak concentration of 4.75 ± 2.09 days and an AUC of 81.58 ± 27.64 days·mol/L. The peak plasma concentration (Cmax) of subcutaneously injected medroxyprogesterone acetate (MPA) was 3.83 ± 1.56 nmol/L, the time to peak concentration (Tmax) was 6.52 ± 2.07 days, and the area under the curve (AUC) was 72.26 ± 38.73 days·mol/L. However, the pharmacokinetics of MPA may vary depending on the injection site. Most medroxyprogesterone acetate (MPA) is excreted in the urine as glucuronide conjugates, with a small amount excreted as sulfate conjugates. Glucuronide conjugates can also be detected in feces. Due to the insignificant differences in the urinary metabolite profile and the lack of availability of radiolabeled studies, it is difficult to determine the exact ratio of metabolites to the parent compound in urine and feces. The volume of distribution of medroxyprogesterone acetate is 20 ± 3 liters. The mean clearance of medroxyprogesterone acetate (MPA) is 1668 ± 146 L/day or 21.9 ± 4.3 L/kg/day. Due to significant inter-patient variability in MPA pharmacokinetics, its clearance has been reported to be 1600–4000 L/day. Metabolites/Metabolic Substances: Medroxyprogesterone acetate is β-hydroxylated to produce metabolites 6-β-hydroxy (M-2), 2-β-hydroxy (M-4), and 1-β-hydroxymedroxyprogesterone acetate (M-3). M-2 and M-4 are further metabolized to 2β,6β-dihydroxymedroxyprogesterone (M-1). M-3 is further metabolized to 1,2-dehydromedroxyprogesterone acetate (M-5). Known metabolites of medroxyprogesterone acetate include M-3, medroxyprogesterone acetate, and M-2. Primary metabolic pathway: Hepatic. Excretion pathway: After oral administration, MPA is primarily metabolized in the liver via hydroxylation, followed by conjugation reactions, and ultimately excreted in the urine. Most MPA metabolites are excreted in the urine as glucuronide conjugates, with only a small amount excreted as sulfate. Half-life: 50 days. Biological half-life: The absorption half-life of orally administered medroxyprogesterone acetate (MPA) is 15-30 minutes, and the biological half-life is 40-60 hours. The absorption half-life of intramuscularly injected MPA is 0.86±0.30 days, and the elimination half-life is 24.03±21.74 days. The absorption half-life of subcutaneously injected MPA is 1.05±0.56 days, and the elimination half-life is 30.90±15.11 days.

Toxicity Summary
Progesterone can freely diffuse into target cells in the female reproductive tract, mammary glands, hypothalamus, and pituitary gland, and bind to progesterone receptors. After binding to these receptors, progesterone slows the release frequency of gonadotropin-releasing hormone (GnRH) from the hypothalamus and inhibits the pre-ovulatory surge of luteinizing hormone (LH).

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1. In vitro toxicity:
- MPA (10 μM) showed no cytotoxicity to KTC-2 cells (cell viability >90%, MTT assay) [6]
- MPA (1–10 μM) did not induce neuronal necrosis (lactate dehydrogenase release <15% vs. control group) [5]
2. In vivo toxicity:
- Mice treated with MPA (1–10 mg/kg/day, 14–84 days) showed no changes in ALT/AST, BUN, or body weight [3]
- Rats treated with MPA (2 mg/kg/day, 7 days) showed no liver or kidney damage (serum biochemical indicators were normal) [5]

[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.
[5]. Reduced metabolites mediate neuroprotective effects of progesterone in the adult rat hippocampus. The synthetic progestin medroxyprogesterone acetate (Provera) is not neuroprotective. J Neurobiol.2006 Aug;66(9):916-28;
[6]. Medroxyprogesterone acetate decreases secretion of interleukin-6 and parathyroid hormone-related protein in a new anaplastic thyroid cancer cell line, KTC-2. Thyroid.2003;13(3):249-58;
[7]. Medroxyprogesterone acetate impairs memory and alters the GABAergic system in aged surgically menopausal rats. Neurobiol Learn Mem.2010;93(3):444-53.

According to the International Agency for Research on Cancer (IARC) of the World Health Organization, medroxyprogesterone acetate may be carcinogenic. It may also be developmentally toxic depending on state or federal labeling requirements. Medroxyprogesterone acetate is an odorless, white to off-white microcrystalline powder. (NTP, 1992) Medroxyprogesterone acetate is an acetate ester formed by the condensation of the 17α-hydroxy group of medroxyprogesterone with the carboxyl group of acetic acid. It is a progestin widely used for menopausal hormone therapy and as a progestin-only contraceptive. It has multiple functions, including progestin, androgen, female contraceptive, synthetic oral contraceptive, adjuvant, inhibitor, antioxidant, and antitumor drug. It is a steroid ester, acetate ester, 20-oxosteroid, 3-oxo-Δ⁴steroid, and corticosteroid. Its function is related to medroxyprogesterone. Medroxyprogesterone acetate (MPA) is a progesterone derivative with higher metabolic stability and therefore better pharmacokinetic properties. MPA can be used to treat secondary amenorrhea, endometrial hyperplasia, abnormal uterine bleeding, osteoporosis, menopausal vasomotor symptoms, vulvar and vaginal atrophy, contraception, and to relieve pain associated with endometriosis. It can also be used for palliative treatment of endometrial cancer and renal cell carcinoma. Medroxyprogesterone acetate was approved by the FDA on June 18, 1959. Medroxyprogesterone acetate is a synthetic acetic acid derivative of the sex hormone progesterone. Medroxyprogesterone acetate (NCI04) Medroxyprogesterone acetate (INN, USAN, BAN), also known as 17'-hydroxy-6'-methylprogesterone acetate, is usually abbreviated as MPA. It is a steroidal progestin and a synthetic derivative of the human hormone progesterone. It can be used as a contraceptive, a hormone replacement therapy drug, and to treat endometriosis and many other indications. MPA is a more potent derivative of its parent compound, medroxyprogesterone (MP). Although medroxyprogesterone acetate is sometimes used as a synonym, the commonly used drug is MPA, not MP. It is a synthetic progestin derived from 17-hydroxyprogesterone. It is a long-acting contraceptive, effective both orally and intramuscularly, and has also been used to treat breast and endometrial tumors.

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Drug Indications
Medroxyprogesterone acetate (MPA) oral tablets are indicated for the treatment of secondary amenorrhea, reducing the incidence of endometrial hyperplasia in postmenopausal women, and treating abnormal uterine bleeding caused by hormonal imbalances rather than organic lesions. Oral tablets containing MPA and conjugated estrogen are indicated for the prevention of postmenopausal osteoporosis and the treatment of moderate to severe menopausal symptoms, such as vasomotor symptoms, vulvar atrophy, and vaginal atrophy. Subcutaneous injection of MPA is indicated for the prevention of pregnancy and the treatment of endometriosis-related pain. Intramuscular injection of medroxyprogesterone acetate (MPA) is indicated for the prevention of pregnancy, and at high concentrations, it can be used for the palliative treatment of endometrial or renal cancer.
FDA Label
Mechanism of Action
Medoxyprogesterone acetate (MPA) inhibits the production of gonadotropins, thereby preventing follicle maturation and ovulation, which is why it exerts its contraceptive effect. This effect also thins the endometrium. MPA reduces nuclear estrogen receptors and DNA synthesis in endometrial epithelial cells. MPA can also induce p53-dependent apoptosis in certain cancer cell lines and inhibit GABA-A receptors.
Pharmacodynamics
Medoxyprogesterone acetate (MPA) inhibits the production of gonadotropins, reduces nuclear estrogen receptors and DNA synthesis in endometrial epithelial cells, and induces p53-dependent apoptosis in cancer cell lines. The half-life of oral MPA tablets is 40-60 hours; other formulations may have longer half-lives, thus resulting in a longer duration of action. MPA has a wide therapeutic window, with daily oral doses ranging from 5 mg to weekly injections of 1000 mg.
Long-term use of MPA is associated with decreased bone mineral density. Patients who take MPA during adolescence may have lower peak bone mass than untreated patients, which may increase the risk of osteoporosis and fractures in the future.

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1. Drug background ([1][3]):
medroxyprogesterone acetate is a synthetic progestin widely used for contraception, hormone replacement therapy and treatment of hormone-sensitive cancers (e.g., breast cancer, endometrial cancer) [1][3]
2. Mechanism of action ([1][2][6]):
-In breast cancer cells: activates the PI3K/Akt/NF-κB pathway, upregulates cyclin D1, and promotes cell proliferation [1]
-In endothelial cells: upregulates VCAM-1/ICAM-1, enhances monocyte adhesion, and promotes vascular inflammation [2]
-In thyroid cancer cells: downregulates the secretion of IL-6 and PTHrP, which may inhibit tumor progression [6]
3. Limitations ([5]):
Unlike progesterone (endogenous progestin), MPA lacks neuroprotective effects because it cannot be metabolized into neuroactive reduced metabolites [5]

C24H34O4

386.52

386.245

, 74.58; H, 8.87; O, 16.56

71-58-9

Medroxyprogesterone acetate;71-58-9; 520-85-4

6279

White to off-white solid powder

1.1±0.1 g/cm3

496.4±45.0 °C at 760 mmHg

206-207 °C(lit.)

213.2±28.8 °C

0.0±1.3 mmHg at 25°C

1.539

4.11

0

4

3

28

767

7

C[C@H]1C[C@@H]2[C@H](CC[C@]3([C@H]2CC[C@@]3(C(=O)C)OC(=O)C)C)[C@@]4(C1=CC(=O)CC4)C

PSGAAPLEWMOORI-PEINSRQWSA-N

InChI=1S/C24H34O4/c1-14-12-18-19(22(4)9-6-17(27)13-21(14)22)7-10-23(5)20(18)8-11-24(23,15(2)25)28-16(3)26/h13-14,18-20H,6-12H2,1-5H3/t14-,18+,19-,20-,22+,23-,24-/m0/s1

(6S,8R,9S,10R,13S,14S,17R)-17-acetyl-6,10,13-trimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 1 mg/mL (2.59 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 1 mg/mL (2.59 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (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 10.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 1 mg/mL (2.59 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 10.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)