Endogenous Metabolite
Progesterone Receptor (PR): Progesterone binds to human and rodent PR (PR-A/PR-B isoforms) with high affinity, but it activates PR-mediated transcriptional signaling in reproductive tissues and stem cells [1][4][5]

In vitro activity: Progesterone has biphasic effects on proliferation of breast cancer cells; it stimulates growth in the first cell cycle, then arrests cells at G1/S of the second cycle accompanied by up-regulation of the cyclin-dependent kinase inhibitor, p21. Progesterone-mediated transcription is further prevented by overexpression of E1A, suggesting that CBP/p300 is required. Progesterone drives a series of events where luminal cells probably provide Wnt4 and RANKL signals to basal cells which in turn respond by upregulating their cognate receptors, transcriptional targets and cell cycle markers. Progesterone treatment increases the sensitivity of cortical synaptoneurosomes to GABA (i.e., decreased the EC50) and increases the maximal efficacy with which GABA stimulated Cl- transport (i.e., increased the Emax).

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1. PR-Mediated Transcriptional Activation ([1]):
Treatment of PR-positive T47D breast cancer cells with Progesterone (1–100 nM) for 24 hours activated PR-responsive luciferase reporter gene activity in a concentration-dependent manner. At 10 nM, luciferase activity increased by 4.5-fold vs. vehicle control (luminometer detection). It also upregulated PR target genes: mammaglobin mRNA (3-fold increase, real-time PCR) and pS2 protein (2.5-fold increase, Western blot) [1]
2. Mammary Stem Cell Expansion ([5]):
Primary adult mouse mammary cells were cultured in serum-free medium with Progesterone (10 nM) for 7 days. The number of stem cell-derived colony-forming units (CFUs) increased by 2.2-fold vs. control (crystal violet staining). Flow cytometry showed the proportion of CD24+CD49fhigh stem cells rose from 5% (control) to 11% (10 nM Progesterone) [5]

In mice, progesterone injections (injection; 1 mg; three daily injections in a row) promote vascular maturation in the endometrium [4].

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1. Endometrial Vessel Maturation in Mice ([4]):
Ovariectomized female C57BL/6 mice (8–10 weeks old) were subcutaneously injected with Progesterone (1 mg/kg/day) or vehicle for 14 days. Progesterone increased pericyte coverage of endometrial vessels by 60% (α-SMA immunohistochemistry) and reduced vessel diameter variation by 45% (image analysis). It also upregulated Ang-1 mRNA (3-fold, real-time PCR) and Tie2 protein (2-fold, Western blot) — key markers of vessel maturation [4]
2. Mammary Stem Cell Expansion in Mice ([5]):
Female BALB/c mice (12 weeks old) received subcutaneous Progesterone (2 mg/kg/day) for 10 days. Mammary gland analysis showed: (1) CD24+CD49fhigh stem cell proportion increased by 2.5-fold (flow cytometry); (2) Mammary repopulating units (MRUs, functional stem cell marker) increased by 1.8-fold (transplantation assay); (3) Sox2 (stem cell self-renewal gene) mRNA increased by 3-fold (real-time PCR) [5]
3. Reproductive Tissue Regulation in Rats ([1]):
Ovariectomized Sprague-Dawley rats received oral Progesterone (0.5 mg/kg/day) for 21 days. Uterine glandular proliferation increased by 35% (H&E staining), vaginal epithelium cornification was induced, and serum LH levels were suppressed by 40% (radioimmunoassay) [1]

PR Competitive Ligand-Binding Assay ([1]):
1. Recombinant PR Preparation: Human PR-B was expressed in Sf9 insect cells and purified via nickel-affinity chromatography (eluted with imidazole buffer).
2. Reaction System: A 200 μL mixture contained 50 mM Tris-HCl (pH 7.5), 10% glycerol, 0.1% BSA, 0.5 nM [³H]-progesterone (radioactive ligand), 100 ng PR-B, and Progesterone (0.01–100 nM, cold competitor).
3. Incubation & Separation: Incubated at 4°C for 18 hours; unbound ligand was removed via dextran-coated charcoal (2% charcoal, 0.2% dextran) centrifugation (4000×g, 15 minutes, 4°C).
4. Detection: Radioactivity of supernatant was measured via liquid scintillation counter; Progesterone showed 100% relative binding capacity (RBC, reference standard) [1]

Mammary stem cells (MaSCs) are located within a specialized niche in the basal epithelial compartment that is under local and systemic regulation. The emerging role of MaSCs in cancer initiation warrants the study of ovarian hormones in MaSC homeostasis. Here we show that the MaSC pool increases 14-fold during maximal progesterone levels at the luteal dioestrus phase of the mouse. Stem-cell-enriched CD49fhi cells amplify at dioestrus, or with exogenous progesterone, demonstrating a key role for progesterone in propelling this expansion. In aged mice, CD49fhi cells display stasis upon cessation of the reproductive cycle. Progesterone drives a series of events where luminal cells probably provide Wnt4 and RANKL signals to basal cells which in turn respond by upregulating their cognate receptors, transcriptional targets and cell cycle markers. Our findings uncover a dynamic role for progesterone in activating adult MaSCs within the mammary stem cell niche during the reproductive cycle, where MaSCs are putative targets for cell transformation events leading to breast cancer.[5]

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1. T47D Breast Cancer Cell Assay ([1]):
- Cell Culture: T47D cells (PR-positive) were seeded in 96-well plates (5×10³ cells/well, reporter gene) or 6-well plates (2×10⁵ cells/well, gene/protein) with 10% charcoal-stripped FBS RPMI 1640.
- Drug Treatment: Transfected with PR-luciferase plasmid (24 hours post-seeding), then treated with Progesterone (1–100 nM) or 0.1% ethanol (vehicle) for 24 hours.
- Detection:
1. Reporter gene: Luminescence measured via luminometer (Renilla luciferase as internal control).
2. Gene/protein: Real-time PCR (mammaglobin, GAPDH) and Western blot (pS2, β-actin) [1]
2. Mammary Stem Cell Assay ([5]):
- Cell Isolation: Mouse mammary glands were digested with collagenase/hyaluronidase, filtered to single cells.
- Cell Culture: Plated in ultra-low attachment plates (1×10⁴ cells/well) with stem cell medium (serum-free DMEM/F12 + EGF + bFGF) + Progesterone (10 nM) or vehicle.
- Detection:
1. CFUs: Stained with crystal violet and counted at 7 days.
2. Stem markers: CD24/CD49f antibody staining + flow cytometry [5]

Animal/Disease Models: Adult female mice (7-13 wk, 18-28 g)[4]
Doses: 1 mg
Route of Administration: Injections; three consecutive daily
Experimental Results: Stimulated vessel maturation in the mouse endometrium.

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1. Mouse Endometrial Vessel Protocol ([4]):
- Animal Selection: Ovariectomized C57BL/6 mice (8–10 weeks old, 20–22 g, n=6/group) — 1 week post-surgery to deplete endogenous hormones.
- Drug Preparation: Progesterone dissolved in sesame oil (0.1 mg/mL, 0.2 mL/injection for 20 g mice).
- Administration: Subcutaneous injection (1 mg/kg/day) or vehicle, once daily for 14 days.
- Sample Detection: Endometrium fixed for α-SMA immunohistochemistry (pericytes) or frozen for real-time PCR (Ang-1) and Western blot (Tie2) [4]
2. Mouse Mammary Stem Cell Protocol ([5]):
- Animal Selection: BALB/c mice (12 weeks old, 22–25 g, n=5/group).
- Drug Preparation: Progesterone dissolved in 5% ethanol + 95% saline (0.2 mg/mL, 0.25 mL/injection for 25 g mice).
- Administration: Subcutaneous injection (2 mg/kg/day) or vehicle, once daily for 10 days.
- Sample Detection: Mammary glands digested for flow cytometry (CD24/CD49f) or processed for real-time PCR (Sox2) [5]
3. Rat Reproductive Protocol ([1]):
- Animal Selection: Ovariectomized Sprague-Dawley rats (8 weeks old, 250–280 g, n=6/group) — 1 week post-surgery.
- Drug Preparation: Progesterone suspended in 0.5% CMC + 0.1% Tween 80 (0.1 mg/mL, 1.25 mL/gavage for 250 g rats).
- Administration: Oral gavage (0.5 mg/kg/day) or vehicle, once daily for 21 days.
- Sample Detection: Uterus/vagina for H&E staining; serum for LH radioimmunoassay [1]

Absorption, Distribution and Excretion
Oral Micronized Capsules: Following oral administration of micronized soft capsules of progesterone, serum concentrations peak within the first 3 hours. The absolute bioavailability of micronized progesterone is currently unknown. In postmenopausal women, serum progesterone concentrations increase dose-proportionally following multiple doses of progesterone capsules (dose range 100 mg/day to 300 mg/day). Intramuscular Injection: Following an intramuscular injection of 10 mg of oil-based progesterone, plasma concentrations peak approximately 8 hours post-injection and remain above baseline levels for approximately 24 hours. The geometric mean of peak plasma concentrations (CMAX) after injections of 10 mg, 25 mg, and 50 mg were 7 ng/mL, 28 ng/mL, and 50 ng/mL, respectively. Intramuscular (IM) progesterone avoids significant first-pass metabolism in the liver. Therefore, intramuscular injection results in higher progesterone concentrations in endometrial tissue compared to oral administration. Nevertheless, vaginal administration still achieves the highest progesterone concentrations in endometrial tissue. Regarding the absorption of oral contraceptive pills: After oral administration of a progesterone-only contraceptive pill, serum progesterone levels peak at approximately 2 hours, followed by rapid distribution and elimination. 24 hours after administration, serum progesterone levels are close to baseline; therefore, efficacy depends on strict adherence to the dosing regimen. There is significant inter-individual variability in serum progesterone levels. Compared to estrogen-based combination therapy, progesterone monotherapy results in lower steady-state serum progesterone levels and a shorter elimination half-life. Progesterone metabolites are primarily excreted via the kidneys. In 95% of patients, they are excreted in the urine as glycoside conjugates, primarily 3α,5β-pregnanediol. Glucuronide and sulfate conjugates of pregnanediol and pregnanediolone are also excreted in the urine and bile. Progesterone metabolites excreted in the bile may undergo enterohepatic circulation or be excreted in the feces. When administered vaginally, progesterone is well absorbed by the endometrial tissue, with a small amount entering the systemic circulation. The systemic circulation of progesterone appears to be negligible, especially given similar implantation, pregnancy, and live birth outcomes with intramuscular and vaginal administration. Apparent clearance was 1367 ± 348 (once daily, 50 mg progesterone vaginal suppositories). 106 ± 15 L/h (once daily, 50 mg/mL intramuscular injection). Prometrium capsules are an oral micronized progesterone formulation with the same chemical structure as ovarian-derived progesterone. Micronization improves the oral bioavailability of progesterone. Maximum serum concentrations are reached within 3 hours after oral administration of the micronized soft capsule formulation of progesterone. The absolute bioavailability of micronized progesterone is unknown. In postmenopausal women, serum progesterone concentrations were linear and dose-proportional across the dose range of 100 mg/day to 300 mg/day after multiple doses of 100 mg progesterone capsules.
Although doses exceeding 300 mg/day were not studied in women, a study in male volunteers showed that serum progesterone concentrations were linear and dose-proportional within a dose range of 100 mg/day to 400 mg/day. Pharmacokinetic parameters in male volunteers were largely consistent with those in postmenopausal women.
For more complete data on the absorption, distribution, and excretion of progesterone (12 types), please visit the HSDB record page.

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Metabolism/Metabolites
Progesterone is primarily metabolized in the liver. After oral administration, the major metabolites in plasma are 20α-hydroxy-Δ4α-pregnenolone and 5α-dihydroprogesterone. Some progesterone metabolites are excreted via bile, where they may undergo debinding and subsequent further metabolism in the intestine via reduction, dehydroxylation, and epimerization. The major metabolites in plasma and urine are similar to those in the physiological progesterone secretion process of the corpus luteum. Progesterone is primarily excreted via bile and kidneys. Following injection of labeled progesterone, 50-60% of progesterone metabolites are excreted via the kidneys; approximately 10% are excreted via bile and feces, which is the second largest route of excretion. Progesterone is primarily metabolized in the liver, mainly to pregnanediol and pregnenolone. Pregnanediol and pregnenolone are bound to glucuronide and sulfate metabolites in the liver. Progesterone metabolites excreted via bile may undergo deconjugation and may be further metabolized in the intestine via reduction, dehydroxylation, and epimerization. The main urinary metabolite of orally administered progesterone is 5β-pregnane-3α,20α-diol glucuronide, which exists only in plasma as a conjugate. Plasma metabolites also include 5β-pregnane-3α-ol-20-one (5β-pregnenolone) and 5α-pregnane-3α-ol-20-one (5β-pregnenolone). The hormone is reduced to pregnanediol in the liver and bound to glucuronide, then excreted primarily in the urine. For more complete data on the metabolism/metabolites of progesterone (9 metabolites in total), please visit the HSDB record page. Known human metabolites of progesterone include 16β-hydroxyprogesterone, 17α-hydroxyprogesterone, 6β-hydroxyprogesterone, 2β-hydroxyprogesterone, and 21-hydroxyprogesterone. Progesterone is primarily metabolized in the liver, mainly producing pregnanediol and pregnanediolone. Excretion pathways: Pregnanediol and pregnanediolone glucuronide and sulfate conjugates are excreted in urine and bile. Progesterone metabolites excreted in bile may undergo enterohepatic circulation or be excreted in feces. Progesterone metabolites are primarily excreted by the kidneys. Half-life: 34.8–55.13 hours. The absorption half-life is approximately 25–50 hours, and the elimination half-life is 5–20 minutes (progesterone gel). The serum half-life of orally administered progesterone is shorter (approximately 5 minutes). It is rapidly metabolized to 17-hydroxyprogesterone upon its first passage through the liver. Due to its sustained-release properties, progesterone absorption is prolonged, with an absorption half-life of approximately 25-50 hours and an elimination half-life of 5-20 minutes. Therefore, the pharmacokinetics of Prochieve are limited by the rate of absorption, not elimination. The elimination half-life of progesterone is approximately 5 minutes… The plasma half-life of progesterone is very short, only a few minutes.

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Oral absorption: Due to first-pass metabolism in the liver, the oral bioavailability of progesterone in the human body is approximately 10% [1]
-Plasma half-life: 5-10 minutes (endogenous) and 2-3 hours (oil-based for injection) [1]
-Distribution: Highly lipophilic, it accumulates in reproductive organs (uterus, mammary glands) and adipose tissue [1]
-Metabolism/excretion: Metabolized by hepatic CYP3A4 and UGT; 70% of metabolites are excreted in urine and 30% in feces [1]

Toxicity Summary
Progesterone has pharmacological effects similar to those of progestins. It binds to both progesterone and estrogen receptors. Target cells include the female reproductive tract, mammary glands, hypothalamus, and pituitary gland. Once bound to its receptors, progestins like progestins slow the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus and inhibit the pre-ovulatory surge of luteinizing hormone (LH). In women with sufficient endogenous estrogen, progesterone can transform the proliferative endometrium into the secretory endometrium. Progesterone is crucial for decidual tissue formation and is essential for improving endometrial receptivity to facilitate embryo implantation. After implantation, progesterone's role is to maintain pregnancy. Progesterone also stimulates the growth of mammary alveolar tissue and relaxes uterine smooth muscle. Its estrogenic and androgenic activities are low. Interactions Studies have shown that progesterone increases the cardiovascular toxicity of cocaine in sheep and rats. To determine whether progesterone enhances the lethality of cocaine, researchers treated 50 non-pregnant female rats with intramuscular progesterone at 8 mg/kg/day for 3 days, and 45 non-pregnant control rats were given intramuscular injections of excipients (peanut oil, benzoylbenzoate, and phenol). A third group consisted of 21 untreated rats 16 days into their pregnancy. On day 3 of the injection, all rats received an intraperitoneal injection of cocaine at doses ranging from 25 to 75 mg/kg, and were observed for seizures and/or death. Three dose-response curves were constructed using logistic regression analysis. All 51 dying rats died within 17 minutes, with 49 of them experiencing sudden seizures before death. There were no significant differences in mean seizure time and time to death among the groups. Serum progesterone levels (ng/ml ± standard error) showed significant differences: 23 ± 2.3 in the control group, 102 ± 9.9 in the progesterone-treated group, and 144 ± 11.5 in the untreated pregnancy group. Based on the chi-square test and likelihood ratio test, there were no significant differences in the logistic regression dose/lethality curves among the three groups (p=0.81). The intraperitoneal LD50 values (mg/kg, 95% confidence interval) were: control group 54.8 (49.6–60.5), progesterone-treated group 56.5 (50.3–63.6), and untreated pregnant group 51.8 (42.2–63.5). There were no significant differences in the cocaine dose-related curves for isolated seizures and death between the control and progesterone-treated groups. Although progesterone enhances the cardiotoxicity of cocaine, it does not increase the risk of death from acute cocaine exposure in rats. This study also determined the effect of progesterone treatment on the arrhythmogenic effects of bupivacaine in beating rat cardiomyocyte cultures and anesthetized rats. After determining the AD50 of bupivacaine (the concentration of bupivacaine that induces arrhythmias in 50% of rat cardiomyocyte cultures), the effect of 1-hour exposure to progesterone hydrochloride on cardiomyocyte contractile rhythm was further investigated. The results showed that each concentration of progesterone (6.25, 12.5, 25, and 50 μg/ml) significantly and in a concentration-dependent manner reduced the AD50 of bupivacaine. Estradiol treatment also enhanced the arrhythmogenic effect of bupivacaine in cardiomyocyte cultures, but its potency was only one-quarter that of progesterone. Epinephrine did not enhance the effect of either progesterone or estradiol on the arrhythmogenic effect of bupivacaine. Chronic progesterone pretreatment (5 mg/kg/day for 21 days) significantly enhanced the arrhythmic sensitivity of pentobarbital-anesthetized rats to bupivacaine. Compared with untreated control rats, rats in the progesterone-treated group had a significantly shorter time to onset of arrhythmias (6.2 ± 1.3 minutes vs 30.8 ± 2.5 minutes, mean ± standard error). These results indicate that progesterone enhances the arrhythmic sensitivity of bupivacaine both in vivo and in vitro. The arrhythmic enhancement effect of bupivacaine in cardiomyocyte culture suggests that this effect is at least partially mediated at the cardiomyocyte level. Subcutaneous injection of 10 mg progesterone twice weekly into 52 rabbits exposed to vaginal threads containing 3-methylcholanthrene did not affect the incidence of vaginal tumors over 20 months, compared to 5/23 in the control group and 4/30 in the treatment group. Reduced efficacy of some progestins… is thought to be due to the enhanced progesterone metabolism caused by these drugs/liver enzyme-inducing drugs (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin). /Progestins/
For more complete data on interactions of progesterone (6 items in total), please visit the HSDB record page.

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1. In vitro toxicity: Progesterone (1–100 nM) was not cytotoxic to T47D cells or normal mammary epithelial cells (cell viability >90% as measured by MTT assay vs. control group)[1][5]
2. In vivo toxicity: - Rats (0.5 mg/kg/day, orally, 21 days): No changes in ALT/AST, BUN or body weight[1]
- Mice (1–2 mg/kg/day, subcutaneously, 10–14 days): No hematological abnormalities or organ damage[4][5]
3. Plasma protein binding: >98% in humans (bound to albumin and cortisol-binding globulin)[1]

[1]. Schindler AE, et al. Classification and pharmacology of progestins. Maturitas. 2003 Dec 10;46 Suppl 1:S7-S16.
[2]. Zava DT, et al. Estrogen and progestin bioactivity of foods, herbs, and spices. Proc Soc Exp Biol Med. 1998 Mar;217(3):369-78.
[3]. Komesaroff PA, et al. Effects of wild yam extract on menopausal symptoms, lipids and sex hormones in healthy menopausal women. Climacteric. 2001 Jun;4(2):144-50.
[4]. Girling JE, et al. Progesterone, but not estrogen, stimulates vessel maturation in the mouse endometrium. Endocrinology. 2007 Nov;148(11):5433-41. Epub 2007 Aug 9.
[5]. Progesterone induces adult mammary stem cell expansion. Nature. 2010 Jun 10;465(7299):803-7.

Therapeutic Uses

Progestins

Prochieve 4% is indicated for the treatment of secondary amenorrhea. Prochieve 8% is indicated for women who have not responded to treatment with Prochieve 4%. /Included on US product label/
Prochieve 8% is indicated as part of assisted reproductive technology (“ART”) treatment to supplement or replace progesterone in infertile women with progesterone deficiency. /Included on US product label/
Progesterone can be administered orally or vaginally for the treatment of secondary amenorrhea.
For more complete data on the therapeutic uses of progesterone (9 types), please visit the HSDB record page.

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Drug Warnings
/Black Box Warning/ Warning: Estrogen plus progestin therapy may cause cardiovascular disease, breast cancer, and dementia. Cardiovascular disease and dementia: Estrogen plus progestin therapy should not be used to prevent cardiovascular disease or dementia. The Women's Health Initiative (WHI) estrogen plus progesterone sub-study reported an increased risk of deep vein thrombosis, pulmonary embolism, stroke, and myocardial infarction in postmenopausal women (50 to 79 years) treated with daily oral conjugated estrogen (CE) (0.625 mg) plus medroxyprogesterone acetate (MPA) (2.5 mg) for 5.6 years compared to placebo. The WHI's adjunctive estrogen plus progesterone study—WHIMS—reported an increased risk of suspected dementia in postmenopausal women aged 65 and older treated with daily oral CE (0.625 mg) plus MPA (2.5 mg) for 4 years compared to placebo. It is unclear whether these results apply to younger postmenopausal women. Breast cancer: The WHI estrogen plus progesterone sub-study also showed an increased risk of invasive breast cancer. Due to the lack of comparable data, it should be assumed that the risks are similar for other doses of CE and MPA, as well as other combinations and formulations of estrogen and progesterone. When estrogen is used in combination with progesterone, it should be prescribed at the lowest effective dose and for the shortest duration, based on the treatment goals and the individual woman's risk. The WHI clinical trials did not investigate other doses of oral conjugated estrogen with medroxyprogesterone, or other estrogen and progesterone combinations and formulations. Due to a lack of comparable data and product-specific studies, the applicability of WHI study results to other products has not been determined. Therefore, it should be assumed that all estrogen and progesterone products have similar risks. Given these risks, regardless of whether progesterone is used in combination, the prescribed dose of estrogen should be as low as possible, the duration of treatment should be as short as possible, and it should be consistent with the treatment goals and the individual woman's risk. Adverse reactions reported by patients taking oral progesterone include dizziness, breast pain, headache, abdominal pain, fatigue, viral infection, abdominal distension, musculoskeletal pain, mood instability, irritability, and upper respiratory tract infection. A small number of women taking this medication have reported extreme dizziness and/or drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion, disorientation, and dyspnea. Low blood pressure and syncope are rare in women taking progesterone capsules.
Adverse reactions reported by patients using progesterone vaginal gel include breast pain/enlargement, drowsiness, constipation, nausea, headache, and perineal pain.
For more complete data on drug warnings for progesterone (19 in total), please visit the HSDB record page.

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Pharmacodynamics
Progesterone may have a variety of pharmacodynamic effects depending on its concentration, dosage form, and timing of administration. These effects are as follows, depending on the formulation: General Actions Progesterone is the primary hormone of the corpus luteum and placenta. It acts on the uterus by altering the proliferative phase of the endometrium (the mucous membrane lining the uterine wall). This hormone is stimulated by luteinizing hormone (LH) and is the primary hormone of the secretory phase, responsible for preparing the corpus luteum and endometrium for implantation of a fertilized egg. After the luteal phase ends, progesterone sends a negative feedback signal to the anterior pituitary gland in the brain, lowering the levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This can prevent ovulation and the maturation of the oocyte (immature egg cell). Subsequently, the endometrium prepares for pregnancy by increasing vascularization and stimulating mucus secretion. This process is achieved by progesterone stimulating the endometrium to reduce proliferation, leading to a decrease in endometrial thickness, thereby promoting the development of more complex uterine glands, storing energy in the form of glycogen, and providing more uterine vascular surface area suitable for embryonic growth. Unlike the changes in cervical mucus observed during the proliferative and ovulatory phases, progesterone reduces and thickens cervical mucus, decreasing its elasticity. This change occurs because the fertilization period has passed, and a specific mucus consistency is no longer needed to facilitate sperm entry. Progesterone capsules are an oral dosage form containing micronized progesterone with the same chemical structure as ovarian-derived progesterone. Progesterone capsules possess all the properties of endogenous progesterone, inducing the endometrium to enter the secretory phase and exhibiting progestin, anti-estrogenic, mild anti-androgenic, and anti-aldosterone effects. Progesterone can antagonize the effects of estrogen on the uterus, which is beneficial for women exposed to estrogen without antagonism, as this increases the risk of malignant tumors. Vaginal gels and vaginal suppositories: Gel preparations mimic the effects of natural progesterone. When estrogen levels are sufficient, progesterone can transform the proliferative endometrium into the secretory endometrium. This means the endometrium transitions from the proliferative and thickening phase to the pregnancy preparation phase, a stage involving further preparatory changes. Progesterone is essential for the development of decidual tissue, a special tissue adapted to support pregnancy. Progesterone also helps improve the receptivity of the endometrium to implantation of a fertilized egg. Once the embryo has implanted, progesterone helps maintain the pregnancy. Intramuscular progesterone injections can increase serum progesterone levels and help prevent excessive proliferation of endometrial tissue due to estrogen deficiency antagonism (which can lead to abnormal uterine bleeding and sometimes even uterine cancer). In the absence of or with insufficient progesterone, the endometrium continues to proliferate, eventually exceeding its limited blood supply, resulting in incomplete shedding, abnormal and/or heavy bleeding, and even malignant tumors. Progesterone-only birth control pills prevent pregnancy by inhibiting ovulation in about half of their users. Their mechanisms of action include: thickening cervical mucus to inhibit sperm motility; reducing the peak levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during ovulation; slowing the movement of the egg through the fallopian tubes; and causing the secretory changes in the endometrium as described above.

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1. Drug Classification ([1]):
Progesterone is the main endogenous progestin, synthesized by the corpus luteum of the ovary (menstrual cycle), placenta (pregnancy) and adrenal cortex (small amount) [1]
2. Mechanism ([1][4][5]):
- Binds to the nuclear progesterone receptor (PR) to form a hormone-receptor complex and regulates progesterone receptor (PRE)-mediated gene transcription [1]
- Endometrium: Upregulates Ang-1/Tie2 to promote vascular maturation, which is beneficial for embryo implantation [4]
- Breast: Activates Sox2 to expand adult stem cells [5]
3. Indications ([1]):
Approved for the treatment of secondary amenorrhea, dysfunctional uterine bleeding and prevention of preterm birth; off-label use for assisted reproductive technology (ART) luteal support [1]

C21H30O2

314.46

314.224

C, 80.21; H, 9.62; O, 10.18

57-83-0

Progesterone (Standard);57-83-0;Progesterone-d9;15775-74-3;Progesterone-13C5;2687960-32-1;Progesterone-13C3;327048-87-3;Progesterone-13C2;82938-07-6

5994

White to off-white solid powder

1.1±0.1 g/cm3

447.2±45.0 °C at 760 mmHg

128-132 °C(lit.)

166.7±25.7 °C

0.0±1.1 mmHg at 25°C

1.542

4.04

0

2

1

23

589

6

O=C(C([H])([H])[H])[C@@]1([H])C([H])([H])C([H])([H])[C@@]2([H])[C@]3([H])C([H])([H])C([H])([H])C4=C([H])C(C([H])([H])C([H])([H])[C@]4(C([H])([H])[H])[C@@]3([H])C([H])([H])C([H])([H])[C@@]21C([H])([H])[H])=O

RJKFOVLPORLFTN-UHFFFAOYSA-N

InChI=1S/C21H30O2/c1-13(22)17-6-7-18-16-5-4-14-12-15(23)8-10-20(14,2)19(16)9-11-21(17,18)3/h12,16-19H,4-11H2,1-3H3

(8S,9S,10R,13S,14S,17S)-17-acetyl-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one

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: ≥ 2.08 mg/mL (6.61 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 20.8 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: ≥ 2.08 mg/mL (6.61 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 20.8 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: ≥ 2.08 mg/mL (6.61 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 20 mg/mL (63.60 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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