- Progesterone Receptor (PR) - High binding affinity (Kᵢ = 0.2–0.5 nM) [13]
- Activates PR-mediated transcription without androgenic/estrogenic effects [13]
- 5α-Reductase - Inhibits 5α-reductase type 2 (Kᵢ = 2.1 μM) [13]
- Neurosteroid Biosynthesis - Induces allopregnanolone production in brain and serum [6]

Strong oral progestins like drogesterone are useful for treating a range of gynecological disorders linked to low progesterone levels. Despite having a comparable pharmacological profile and chemical structure to natural progesterone. Even at far smaller dosages, it has an oral effect. Compared to the majority of other synthetic progestins, it has the extra advantage of being free of estrogenic, androgenic, anabolic, corticosteroid, and other negative hormonal effects. In addition, estrogen replacement treatment (HRT) that uses testosterone is approved to prevent the damaging effects of unopposed estrogen on the endometrium in women who have an intact uterus. In addition to being generally well-tolerated and safe, dysgesterone also lacks some of the androgenic adverse effects that are associated with other progestins, like medroxyprogesterone [1].

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1. PR-Mediated Transactivation - Cell Line: Human endometrial carcinoma cells (Ishikawa) transfected with PR luciferase reporter. - Protocol: Cells treated with Dydrogesterone (0.1–10 μM) for 24 hours. - Results: - EC₅₀ = 0.8 μM for PR activation [13]
- No cross-activation of androgen receptor (AR) or glucocorticoid receptor (GR) [13]
2. 5α-Reductase Inhibition - Enzyme Source: Recombinant human 5α-reductase type 2. - Protocol: Incubation with Dydrogesterone (0.1–10 μM) and [³H]-testosterone (1 nM) at 37°C for 1 hour. - Results: - Kᵢ = 2.1 μM for 5α-dihydrotestosterone (DHT) reduction [13]
- Inhibition >50% at 10 μM [13]
3. Neurosteroid Modulation - Cell Line: Rat hippocampal neurons exposed to Dydrogesterone (1–10 μM) for 48 hours. - Results: - Increased allopregnanolone levels by 2–3-fold (LC-MS/MS) [6]
- Upregulated γ-aminobutyric acid (GABA) receptor subunit expression [6]

1. Stress-Induced Abortion Prevention - Animal Model: CBA/J mice mated with DBA/2J males, stressed on gestation day 5. - Treatment: Single intraperitoneal injection of Dydrogesterone (1–5 mg/kg) before stress. - Results: - Reduced abortion rate from 65% (control) to 18% (5 mg/kg) [5]
- Increased plasma progesterone-induced blocking factor (PIBF) by 2.5-fold [5]
- Shifted Th1/Th2 cytokine balance toward Th2 (IL-4↑, IFN-γ↓) [5]
2. Bone Metabolism Regulation - Animal Model: Ovariectomized rats treated with Dydrogesterone (0.1–1 mg/kg/day, oral) for 12 weeks. - Results: - Prevented bone mineral density (BMD) loss (DEXA scan) [3]
- Reduced osteoclast activity (tartrate-resistant acid phosphatase, TRAP) [3]
3. Neurosteroid Production in Brain - Animal Model: Female rats received Dydrogesterone (1 mg/kg/day, oral) for 2 weeks. - Results: - Allopregnanolone levels increased in frontal lobe (+40%) and hippocampus (+35%) [6]
- Improved anxiety-like behavior in elevated plus maze test [6]

1. Progesterone Receptor Binding Assay - Reagents: Human uterine cytosol, [³H]-progesterone (1 nM), and Dydrogesterone. - Protocol: - Cytosol incubated with [³H]-progesterone and Dydrogesterone (0.01–1 μM) at 4°C for 2 hours. - Bound ligands separated by dextran-coated charcoal. - Analysis: Dydrogesterone displaced [³H]-progesterone with higher affinity than progesterone (Kᵢ = 0.2 nM) [13]
2. 5α-Reductase Activity Assay - Reagents: Recombinant human 5α-reductase type 2, NADPH, and [³H]-testosterone (1 nM). - Protocol: - Enzyme incubated with Dydrogesterone (0.1–10 μM) and substrate at 37°C for 60 minutes. - Reaction terminated with ethyl acetate; DHT formation measured by liquid scintillation counting. - Results: Dydrogesterone inhibited 5α-reductase with Kᵢ = 2.1 μM [13]

1. Endometrial Cell Proliferation Inhibition - Cell Line: Human endometrial stromal cells (HESC) treated with Dydrogesterone (0.1–10 μM) for 72 hours. - Assays: - MTT Assay: IC₅₀ = 3.5 μM [13]
- Western Blot: Downregulated cyclin D1 and PCNA expression [13]
- TUNEL Assay: Induced apoptosis (apoptotic index increased from 8% to 22%) [13]
2. Neurosteroid Induction in Neurons - Cell Line: Rat primary hippocampal neurons exposed to Dydrogesterone (1 μM) for 48 hours. - Assays: - LC-MS/MS: Allopregnanolone levels increased by 2.8-fold [6]
- qPCR: Upregulated steroidogenic acute regulatory protein (StAR) mRNA [6]

1. Stress-Induced Abortion Model - Animal: Pregnant CBA/J mice (day 5 post-coitus). - Treatment: - Dydrogesterone (1–5 mg/kg, intraperitoneal) administered 1 hour before sound stress (95 dB, 30 minutes). - Control groups: vehicle-treated stressed mice and non-stressed mice. - Assessment: - Abortion rate calculated on day 13 [5]
- Plasma PIBF levels measured by ELISA [5]
- Uterine tissue analyzed for Th1/Th2 cytokine expression [5]
2. Osteoporosis Prevention in Rats - Animal: Ovariectomized Sprague-Dawley rats (200–250 g). - Treatment: - Dydrogesterone (0.1–1 mg/kg/day, oral) dissolved in corn oil for 12 weeks. - Control groups: sham-operated and vehicle-treated ovariectomized rats. - Assessment: - BMD measured by dual-energy X-ray absorptiometry (DEXA) [3]
- Serum osteocalcin and TRAP levels analyzed by colorimetry [3]

Absorption, Distribution and Excretion
Rapidly absorbed in the gastrointestinal tract, with a bioavailability of 28%. Following oral administration of labeled dydrogesterone, an average of 63% of the dose is excreted in the urine. Excretion is completed within 72 hours. Following oral administration of dydrogesterone, plasma concentrations of dihydrodydrogesterone (DHD) are significantly higher than those of the mother. The AUC and Cmax ratios of DHD to dydrogesterone are approximately 40 and 25, respectively. DHD is rapidly absorbed. The Tmax values for dydrogesterone and DHD range from 0.5 to 2.5 hours. The hemolytic concentration of dihydrodydrogesterone is 13 ng/mL, with a Cmin of 4.1 ng/mL and a Cmax of 63 ng/mL. The hemolytic concentration of dydrogesterone is 0.38 ng/mL, with a Cmin <0.1 ng/mL and a Cmax of 2.5 ng/mL. It has been reported that the progesterone is distributed into breast milk. The potential effects of progestins in breast milk on breastfed infants have not been determined. /Progestin Overview/

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Metabolism/Metabolites
Dydrogesterone is completely metabolized to 20-dihydrodydrogesterone (DHD) metabolites.
In the human body, dydrogesterone is completely metabolized. The major metabolite of dydrogesterone is 20α-dihydrodydrogesterone (DHD), which is mainly present in urine as a glucuronide conjugate. A common characteristic of all identified metabolites is that they retain the 4,6-dien-3-one configuration of the parent compound and lack 17α-hydroxylation. This explains their lack of estrogenic and androgenic activity.
Dydrogesterone is not excreted in urine as pregnanediol like progesterone. Therefore, it remains feasible to analyze endogenous progesterone production based on pregnanediol excretion.

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Biological Half-Life
Dydrogesterone: 5-7 hours, 20-dihydrodydrogesterone (DHD) metabolite: 14-17 hours
The mean terminal half-lives of dydrogesterone and DHD are 5 to 7 hours and 14 to 17 hours, respectively.

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- Absorption: - Rapid oral absorption; peak plasma concentration (Cₘₐₓ) is reached within 2-3 hours [7]
- Absolute bioavailability: approximately 28-30% in humans [7]
- Metabolism: - Primarily metabolized in the liver by aldosterone reductase 1C (AKR1C) to 20α-dihydrodydrogesterone [7]
- A small amount is metabolized by CYP3A4 (contributing 20-30%) [7]
- Half-life: - Terminal half-life (t₁/₂): 5-7 hours in humans [7]
- Excretion: - 60-70% is excreted in urine as conjugates; 20-30% is excreted in feces [7]

Acute toxicity: - LD₅₀: >5000 mg/kg (oral in rats)[9] - Subchronic toxicity: - No significant hepatotoxicity or nephrotoxicity was observed in rats at daily doses up to 10 mg/kg[9] - No genotoxicity or carcinogenicity was found in animal studies[9] - Plasma protein binding: - Approximately 93% bound to sex hormone-binding globulin (SHBG)[10]

[1]. Dydrogesterone, From Wikipedia, the free encyclopedia.

Dydrogesterone is a 3-oxo-Δ⁴ and 20-oxosteroid with progestin activity. It is a synthetic progestin without androgenic or estrogenic activity. Unlike many other progestins, dydrogesterone does not cause a rise in body temperature or inhibit ovulation. It is a synthetic progestin without androgenic or estrogenic activity. Unlike many other progestins, dydrogesterone does not cause a rise in body temperature or inhibit ovulation. Indications: Used to treat irregular menstrual cycles and menstrual disorders caused by progesterone deficiency. Also used to prevent spontaneous abortion in patients with a history of recurrent miscarriage. Mechanism of Action: Dydrogesterone is a progestin that regulates the healthy growth and normal shedding of the endometrium by acting on progesterone receptors in the uterus. Dydrogesterone is an orally effective progestin. For women who have not undergone hysterectomy, progesterone supplementation can significantly reduce estrogen-induced endometrial hyperplasia and the risk of cancer by decreasing endometrial growth. Progesterone should not be equated with progesterone, as some progesters have estrogenic activity, some have mild androgenic activity, and some are purely progesterone; correspondingly, their mechanisms of ovulation inhibition may differ slightly. On the other hand, 17-hydroxy or acetoxy compounds elicit responses closer to progesterone. They have little or no estrogenic or androgenic activity and may produce catabolic and mild diuretic effects. 19-normethyl derivatives are more effective in delaying normal menstruation. Increasing evidence suggests that substance P (SP) is involved in neurogenic inflammation and pain perception primarily through its high-affinity neurokinin 1 receptor (NK-1R). Interestingly, decreased pain sensitivity is associated with elevated plasma progesterone levels. We hypothesize that progesterone may attenuate nociception and associated inflammatory responses through an NK-1R-dependent pathway. To test our hypothesis, we incubated splenic lymphocytes from female CBA/J mice with different concentrations of the progesterone derivative dydrogesterone. We then analyzed the expression of NK-1R and T helper (Th1) cytokines using flow cytometry. Next, we subcutaneously injected 1.25 mg of dydrogesterone (dissolved in 200 μL of sesame oil) into CBA/J mice; control mice received a sham injection. A tail-flick test was performed every 30 minutes after injection to detect the pain threshold. Lymphocytes were isolated from blood and the uterus, and their NK-1R surface expression was analyzed. We performed immunohistochemical analysis to investigate the distribution of NK-1R in uterine tissue. Dydrogesterone reduced the percentage of NK-1R-positive lymphocytes both in vitro and in vivo. Furthermore, in vitro experiments showed that dydrogesterone treatment increased Th2 cytokine levels while decreasing Th1 cytokine levels. The prolonged tail-flick latency after dydrogesterone injection supports the view that decreased NK-1R expression on lymphocytes is associated with an increased pain threshold. In summary, these results clearly reveal the pathways by which dydrogesterone or progesterone regulates the interactions of the nervous, endocrine, and immune systems in inflammation and pain. For more complete data on the mechanisms of action of dydrogesterone (6 studies), please visit the HSDB records page.

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1. Mechanism of action: - PR-mediated transcription: Activates PR to induce decidualization and endometrial maturation [13]
- Immunomodulation: Promotes the Th2 cytokine spectrum to prevent fetal rejection [5]
- Neurosteroid production: Enhances the synthesis of allogeneic ketones to regulate GABAergic signaling [6]
2. Clinical applications: - Approved for: - Threatened/recurrent miscarriage (10-40 mg/day) [8]
- Endometriosis (10-30 mg/day) [8]
- Menopausal hormone therapy (10 mg/day) [8]
3. Side effects: - Common: Headache, dizziness, abdominal pain [10]
- Rare: Venous thromboembolism (incidence <0.1%) [10]

C21H28O2

312.45

312.208

C, 80.73; H, 9.03; O, 10.24

152-62-5

Levonorgestrel;797-63-7;Dydrogesterone-d6

9051

White to light yellow solid powder

1.1±0.1 g/cm3

462.8±45.0 °C at 760 mmHg

168-173°C

172.2±25.7 °C

0.0±1.1 mmHg at 25°C

1.557

3.58

0

2

1

23

628

6

CC(=O)[C@H]1CC[C@@H]2[C@@]1(CC[C@@H]3[C@H]2C=CC4=CC(=O)CC[C@@]34C)C

JGMOKGBVKVMRFX-HQZYFCCVSA-N

InChI=1S/C21H28O2/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/h4-5,12,16-19H,6-11H2,1-3H3/t16-,17+,18-,19+,20+,21+/m0/s1

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

Dydrogesterone; Isopregnenone; dydrogesterone; 152-62-5; Isopregnenone; Hydrogesterone; Duphaston; Hydrogestrone; Gynorest; Gestatron; Hydrogesterone; Duphaston; Hydrogestrone; Dufaston; Isopregnenone; Solvay Brand of Dydrogesterone

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)

DMSO : ~33.33 mg/mL (~106.67 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.00 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 25.0 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: ≥ 2.5 mg/mL (8.00 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 25.0 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: ≥ 2.5 mg/mL (8.00 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.

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