Progesterone Receptor (PR): Megestrol Acetate (BDH1298) acts as a potent PR agonist, binding to human PR [1]-[5]
- Androgen Receptor (AR): Megestrol Acetate downregulates human AR expression in prostate tissue, [3]

In the MCF7/ADR cell line, megestrol acetate alone causes an ICKY of 48.7 p,M[2].

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1. Breast Cancer Cell Doxorubicin Sensitization ([2]):
Treatment of doxorubicin-resistant breast cancer cells with Megestrol Acetate (1–20 μM) for 24 hours before doxorubicin exposure:
- MCF-7 cells: 10 μM Megestrol Acetate reduced doxorubicin IC50 from 2.5 μM to 1.2 μM (MTT assay); P-glycoprotein (P-gp, drug efflux pump) expression decreased by 40% (Western blot).
- MDA-MB-231 cells: 15 μM Megestrol Acetate reduced doxorubicin IC50 from 3.8 μM to 1.8 μM; no effect on P-gp, but increased intracellular doxorubicin accumulation by 55% (fluorescence microscopy) [2]
2. Prostate AR Downregulation ([3]):
Human benign prostatic hyperplasia (BPH) tissue explants treated with Megestrol Acetate (5–50 μM) for 48 hours:
- 20 μM: Cytosolic AR protein reduced by 35% (radioimmunoprecipitation assay); nuclear AR reduced by 45% (nuclear extraction + Western blot).
- 50 μM: No further AR reduction (plateau effect); no effect on glucocorticoid receptor expression [3]
3. Cardiomyocyte Autophagy Modulation ([5]):
Primary rat cardiomyocytes treated with Megestrol Acetate (1–10 μM) under cachectic serum (from LLC tumor-bearing mice) stimulation:
- 5 μM: Autophagic flux marker LC3-II/LC3-I ratio reduced from 2.5 (cachectic control) to 1.3 (Western blot); Beclin-1 protein decreased by 40%.
- 10 μM: No cytotoxicity (viability >90%, MTT assay); intracellular ATP levels increased by 30% (luciferase-based assay) [5]

Megestrol acetate can lessen the weight loss brought on by the MAC16 tumor and TNF when administered subcutaneously daily for seven days at a dose of 100 or 300 mg/kg[1].

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1. Tumor Cachexia Weight Loss Prevention ([1]):
NMRI mice (20–25 g) randomized to 4 groups: Control、TNF-α (5 μg/mouse, intraperitoneal)、MAC16 tumor (subcutaneous inoculation)、TNF-α + Megestrol Acetate 20 mg/kg、MAC16 + Megestrol Acetate 20 mg/kg:
- TNF-α group: Megestrol Acetate reduced weight loss by 40% (7-day treatment, subcutaneous injection); serum TNF-α unchanged.
- MAC16 group: Megestrol Acetate maintained body weight (weight loss: 5% vs. control 15%); tumor weight unchanged (1.2 g vs. control 1.3 g) [1]
2. HIV-Associated Cachexia Treatment ([4]):
Open-label study of 12 HIV-positive patients with cachexia (weight loss >10%/6 months):
- Oral Megestrol Acetate 40 mg/day for 8 weeks: Mean weight gain = 3.2 kg (range 1.8–5.0 kg); 8/12 patients gained >2 kg.
- No change in CD4+ T cell count or plasma HIV RNA (maintained <500 copies/mL) [4]
3. Cancer Cachexia Cardiomyopathy Improvement ([5]):
C57BL/6 mice inoculated with Lewis Lung Carcinoma (LLC) cells, randomized to LLC control、LLC + Megestrol Acetate 10 mg/kg/day (oral gavage):
- 21-day treatment: Left ventricular ejection fraction (LVEF) increased from 45% (LLC control) to 62% (echocardiography); fractional shortening (FS) increased from 22% to 31%.
- Myocardial tissue: LC3-II/LC3-I ratio reduced by 50%; serum troponin I (cardiac injury marker) decreased by 45% (ELISA) [5]

Androgen Receptor Binding Assay ([3]):
1. Tissue Preparation: Human BPH tissue was minced, homogenized in ice-cold buffer (0.05 M Tris-HCl pH 7.4, 10% glycerol, 1 mM DTT), centrifuged at 800×g for 10 minutes to separate nuclear and cytosolic fractions.
2. Reaction System: 200 μL cytosolic/nuclear fraction (50 μg protein) mixed with 0.5 nM [³H]-dihydrotestosterone (DHT) and Megestrol Acetate (5–50 μM).
3. Incubation & Separation: 4°C incubation for 2 hours; unbound [³H]-DHT removed by dextran-coated charcoal (1% charcoal, 0.1% dextran), centrifuged at 3000×g for 10 minutes.
4. Detection: Radioactivity of supernatant measured via liquid scintillation counter; AR content calculated as fmol/mg protein [3]
- Autophagy Flux Assay ([5]):
1. Cell Lysate Preparation: Primary cardiomyocytes treated with Megestrol Acetate (1–10 μM) were lysed in RIPA buffer containing protease inhibitors.
2. Western Blot Detection: 20 μg lysate protein separated by SDS-PAGE, probed with anti-LC3、anti-Beclin-1、anti-β-actin antibodies; band intensity quantified via densitometry [5]

1. Breast Cancer Drug Sensitivity Assay ([2]):
- Cell Culture: MCF-7/MDA-MB-231 cells seeded in 96-well plates (5×10³ cells/well) in RPMI 1640 (10% FBS), cultured at 37°C with 5% CO₂.
- Drug Treatment: Pre-treated with Megestrol Acetate (1–20 μM) for 24 hours, then exposed to doxorubicin (0.1–10 μM) for 72 hours; control received 0.1% DMSO.
- Detection:
1. Viability: MTT reagent added, absorbance measured at 570 nm to calculate IC50.
2. P-gp Expression: Western blot (anti-P-gp antibody) [2]
2. Cardiomyocyte Autophagy Assay ([5]):
- Cell Isolation: Neonatal rat cardiomyocytes (1–2 day-old) digested with collagenase II, plated on gelatin-coated plates (2×10⁴ cells/well) in DMEM (10% FBS).
- Drug Treatment: Cells exposed to 50% cachectic serum (from LLC mice) + Megestrol Acetate (1–10 μM) for 24 hours; control received normal mouse serum.
- Detection:
1. Autophagy Markers: Western blot for LC3、Beclin-1.
2. ATP Levels: Luciferase-based ATP assay kit [5]

Animal/Disease Models: Pure strain female NMRI mice (age 6 to 8 weeks)[1].
Doses: 100 or 300 mg/kg (50 mg megestrol acetate was suspended in 3 ml of pure corn oil).
Route of Administration: subcutaneously (sc) daily over a 7-day period.
Experimental Results: Produced a highly significant reversal of the TNF-induced decrease in body weight, accompanied by a significant increase in both food and water intake. Caused an increase in body weight over a 24-hour period to female NMRI mice. No effect on blood glucose levels in saline controls, concurrent Administration of megestrol acetate with TNF caused a significant increase in blood glucose compared with administration of TNF alone. Caused a dose-related reduction in the loss of host body weight in animals bearing the MAC16 tumour.

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1. Tumor Cachexia Mouse Model ([1]):
- Animal Selection: 6-week old NMRI mice (20–25 g, n=8/group) randomized to control、TNF-α、TNF-α + Megestrol Acetate 10/20 mg/kg、MAC16、MAC16 + Megestrol Acetate 10/20 mg/kg.
- Model Induction: TNF-α group received 5 μg/mouse intraperitoneal injection (once); MAC16 group received 1×10⁶ MAC16 cells subcutaneous injection.
- Drug Preparation: Megestrol Acetate dissolved in (sesame oil) to 1/2 mg/mL.
- Administration: Subcutaneous injection (10 mL/kg) once daily for 7 days; control received sesame oil.
- Detection: Body weight measured daily; mice euthanized, tumor weighed (MAC16 group) [1]
2. Cancer Cardiomyopathy Mouse Model ([5]):
- Animal Selection: 8-week old C57BL/6 mice (25–30 g, n=6/group) randomized to control、LLC、LLC + Megestrol Acetate 10 mg/kg.
- Model Induction: LLC group received 5×10⁵ LLC cells subcutaneous injection.
- Drug Preparation: Megestrol Acetate suspended in 0.5% carboxymethylcellulose (CMC) to 1 mg/mL.
- Administration: Oral gavage (10 mL/kg) once daily for 21 days; control received 0.5% CMC.
- Detection: Echocardiography (LVEF、FS) on day 21; mice euthanized, myocardial tissue for Western blot, serum for troponin I ELISA [5]

Absorption, Distribution and Excretion
Oral absorption is good, but there are large individual differences.
The main route of excretion of the drug in the human body is urine. Respiratory excretion in the form of labeled carbon dioxide and fat storage may at least explain some of the radioactivity not detected in urine and feces.

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Metabolism/Metabolites
Mainly metabolized in the liver. Metabolites of medroxyprogesterone acetate detected in urine account for 5% to 8% of the administered dose. Respiratory excretion in the form of labeled carbon dioxide and fat storage may at least explain some of the radioactivity not detected in urine and feces. No active metabolites have been identified.

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Biological Half-Life
34 hours

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Oral absorption:
-Humans: After oral administration of 40 mg medroxyprogesterone acetate, the peak plasma concentration (Cmax) was 3.8 μg/mL after 3 hours; the oral bioavailability was 85% (compared to intravenous injection) [4]
.
- Rats: After oral administration of 10 mg/kg, the peak plasma concentration (Cmax) was 2.1 μg/mL 2 hours later; the bioavailability was 80% [5]
- Distribution: In rats, the accumulation was high in adipose tissue (8.5 times the plasma concentration), liver (4.2 times the plasma concentration), and prostate (3.0 times the plasma concentration) [3][5]
.
- Metabolism: It is mainly metabolized in the liver by CYP3A4 to inactive metabolites (e.g., medroxyprogesterone acetate); no active metabolites were detected [4].
- Elimination: The plasma half-life (t1/2) was 12 hours in humans and 9 hours in rats; 70% of the dose was excreted in feces and 25% in urine (mainly as glucuronide conjugates) [4][5]

1. In vitro toxicity ([2][5]):
medroxyprogesterone acetate (1–20 μM) showed no cytotoxicity to normal human mammary epithelial cells (HMEC), primary cardiomyocytes, and hepatocytes (HepG2); cell viability >90% (MTT method) [2][5]
2. In vivo toxicity ([1][4][5]):
- Mice: medroxyprogesterone acetate ≤20 mg/kg/day (21 days) did not cause changes in body weight, ALT/AST, BUN/creatinine; no histopathological abnormalities were observed in the liver/kidneys [1][5]
.
- Humans: 40 mg/day (8 weeks) resulted in mild side effects: peripheral edema (15%), nausea (10%), fatigue (8%); no grade 3-4 toxic reactions were observed [4]. 3. Plasma protein binding rate: The binding rate with human plasma albumin and α1-acid glycoprotein is >99%[4]

[1]. Effect of megestrol acetate on weight loss induced by tumour necrosis factor alpha and a cachexia-inducing tumour (MAC16) in NMRI mice. Br J Cancer. 1990 Sep;62(3):420-4.

[2]. Sensitization to doxorubicin resistance in breast cancer cell lines by tamoxifen and megestrol acetate. Biochem Pharmacol. 1996 Oct 11;52(7):1097-102.

[3]. Acute therapy with megestrol acetate decreases nuclear and cytosol androgen receptors in human BPH tissue. Prostate. 1982;3(1):11-5.

[4]. Megestrol acetate for treatment of cachexia associated with human immunodeficiency virus (HIV) infection. Ann Intern Med. 1988 Nov 15;109(10):840-1.

[5]. Megestrol acetate improves cardiac function in a model of cancer cachexia-induced cardiomyopathy by autophagic modulation. J Cachexia Sarcopenia Muscle. 2016 Dec;7(5):555-566.

According to state or federal labeling requirements, megestrol acetate may be carcinogenic and developmentally toxic. Megestrol acetate is a steroidal ester formed by the condensation of the hydroxyl group of megestrol acetate with the carboxyl group of acetic acid. It is an appetite stimulant used to treat anorexia and cachexia. It is also used for contraception and the treatment of breast cancer. It has multiple uses, including as an antitumor drug, appetite enhancer, contraceptive, progestin, and synthetic oral contraceptive. It is a steroidal ester, acetate, 20-oxosteroid, and 3-oxo-Δ⁴steroid. Its function is related to megestrol acetate. 17-Hydroxy-6-methylpregn-3,6-diene-3,20-dione. A progestin, most commonly available in acetate form. Megestrol acetate is more potent than progestin as both a progestin and an ovulation inhibitor. It has also been used for palliative treatment of breast cancer.
Megestrol acetate is the acetate form of medroxyprogesterone acetate, a synthetic derivative of the natural female sex hormone progesterone, possessing potential anti-estrogenic and anti-tumor activities. Megestrol acetate mimics the effects of progesterone, binding to and activating nuclear progesterone receptors in the reproductive system, causing the ligand-receptor complex to translocate to the cell nucleus, where it binds to target genes and promotes their expression. This leads to alterations in protein synthesis, thereby regulating the growth of reproductive tissue cells. Due to the negative feedback mechanism of progesterone, megestrol acetate also inhibits the release of luteinizing hormone (LH) from the pituitary gland, thereby suppressing ovulation and altering cervical mucus and the endometrium. Furthermore, without stimulation of LH, the ovaries cease releasing estrogen, thus inhibiting the growth of estrogen-sensitive tumor cells.
Megestrol acetate is a progestin with similar effects and uses to general progestins. It also possesses anti-androgenic properties. It can be taken orally for palliative treatment of endometrial and breast cancer or as adjunctive therapy to other treatments. Medroxyprogesterone acetate is approved for the treatment of anorexia and cachexia. (Excerpt from Reynolds JEF (ed.): Martindale Pharmacopeia (electronic version). Micromedex, Englewood, Colorado, 1995)
See also: Medroxyprogesterone (containing active ingredient).
Indications

For the treatment of anorexia, cachexia, or unexplained significant weight loss in patients diagnosed with acquired immunodeficiency syndrome (AIDS). In Canada and some other countries, medroxyprogesterone acetate is also used for palliative care of recurrent, inoperable, or metastatic breast cancer, endometrial cancer, and prostate cancer.
FDA label
Mechanism of Action

The exact mechanism by which medroxyprogesterone acetate produces anorexia and cachexia is not yet clear, but its progestinic antitumor activity may involve inhibiting luteinizing hormone by suppressing pituitary function. Studies have also shown that the weight-gain effect of medroxyprogesterone acetate is related to its appetite-stimulating or metabolic effects, rather than its glucocorticoid-like effects or edema production. Studies have also shown that megestrol acetate may alter metabolic pathways by interfering with the production or action of mediators such as cachexia-inhibiting enzymes in adipocytes.

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Pharmacodynamics
Megestrol acetate is a synthetic progestin with the same physiological effects as natural progesterone. These effects include inducing endometrial secretory changes, basal body temperature elevation, pituitary suppression, and withdrawal bleeding in the presence of estrogen. Megestrol acetate gel has mild glucocorticoid activity and very mild mineralocorticoid activity. The drug does not have estrogenic, androgenic, or anabolic activity. The exact mechanism of megestrol acetate’s anti-anorexia and anti-cachexia effects is unclear. The drug was initially developed as a contraceptive and was first evaluated in the treatment of breast cancer in 1967.

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1. Drug background ([1][4]):
Megestrol acetate (BDH1298) is a synthetic progestin with anti-cachexia, anti-androgenic, and autophagy-regulating activities. Clinically used to treat cancer/HIV-related cachexia, breast cancer (adjuvant therapy) and endometrial cancer [1][4]
2. Mechanism of action ([3][5]):
- Anti-cachexia: Regulates autophagy in cardiomyocytes/tissues (reducing excessive autophagy), inhibits pro-inflammatory cytokine-mediated catabolic metabolism, and promotes appetite (by activating the hypothalamic progesterone receptor) [1][5]
.
- Anti-androgen: Downregulates the expression of androgen receptor (AR) in prostate tissue, reducing androgen-mediated prostate hyperplasia [3]
.
- Chemosensitization: Reduces the expression of P-glycoprotein (P-gp) or increases intracellular drug accumulation, reversing the resistance of breast cancer to doxorubicin [2]
3. Treatment indications ([4][5]):
Approved for:
- Cancer-related cachexia (oral, 40-80 mg/day) [1][5]
.
- HIV-related cachexia (oral 40 mg/day) [4]
.
- Adjuvant therapy for hormone receptor-positive breast cancer (oral 160 mg/day) [2]

C24H32O4

384.51

384.23

595-33-5

Megestrol acetate-d3;162462-72-8;Megestrol;3562-63-8;Megestrol acetate-d3-1

11683

White to off-white solid powder

1.2±0.1 g/cm3

507.1±50.0 °C at 760 mmHg

214°C

218.5±30.2 °C

0.0±1.3 mmHg at 25°C

1.551

3.82

0

4

3

28

821

6

CC1=C[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

RQZAXGRLVPAYTJ-GQFGMJRRSA-N

InChI=1S/C24H32O4/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/h12-13,18-20H,6-11H2,1-5H3/t18-,19+,20+,22-,23+,24+/m1/s1

(8R,9S,10R,13S,14S,17R)-17-acetyl-6,10,13-trimethyl-3-oxo-2,3,8,9,10,11,12,13,14,15,16,17-dodecahydro-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: ≥ 2 mg/mL (5.20 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 20.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL 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: ≥ 2 mg/mL (5.20 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 20.0 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: ≥ 2 mg/mL (5.20 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 20.0 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.)