Gestational hormone binds to endometrial receptors for estrogen, progesterone, and androgens, occupying all specific binding sites for steroids in steroid target cells, even in the presence of endogenous steroids [1]. Compared to 20 and 40 hours, gestrinone had a greater inhibitory effect on leiomyoma cell development at 60 hours. Following treatment with above 10 μM gestrinone, leiomyoma cells showed signs of decreased density, including smaller cytoplasm, fewer intercellular connections, and nuclear aggregation. At dosages of 0.1-3.0 μM, gestrinone treatment lowers the relative mRNA levels of estrogen alpha in a concentration-dependent manner [2].

Flutamide plus danazol or gestrinone treatment improves the concentrations of uterine progesterone receptors, vaginal keratinization, and endpoints that are sensitive to estrogen. The information presented here suggests that the androgenic properties of danazol and gestrinone hide their estrogenic activity [3]. The average levels of hormone-binding globulin dropped following gestrinone treatment, from 56.4 nM to 28.1 nM, and following 4 weeks of treatment, from 56.4 nM to 7.1 nM [4].

Absorption, Distribution and Excretion
The oral absorption of gestrinone is 30% ±30.
About 40-45% of a dose is excreted in the urine and 30-35% in the feces.
67 L
Renal Excretion accounts for < 1 %.

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Metabolism / Metabolites
Gestrinone undergoes hydroxylation in the liver. Gestrinone is actively metabolized in the liver, mainly by hydroxylation, to conjugated metabolites 16b-hydroxy,13-ethyl (1-OH) and D-homo gestrinone. In vitro studies have shown that the metabolites are active but weaker than the unchanged drug.

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Biological Half-Life
Plasma half-life is 24 hr.

[1]. Gestrinone (R2323) binding to steroid receptors in human uterine endometrial cytosol. Acta Obstet Gynecol Scand. 1986;65(5):439-41.

[2]. Gestrinone inhibits growth of human uterine leiomyoma may relate to activity regulation of ERα, Src and P38 MAPK. Biomed Pharmacother. 2012 Dec;66(8):569-77.

[3]. Studies on the mechanism of action of danazol and gestrinone (R2323) in the rat: evidence for a masked estrogen component. Fertil Steril. 1989 Apr;51(4):705-10.

[4]. A comparison of the effects of danazol and gestrinone on testosterone binding to sex hormone binding globulin in vitro and in vivo. Clin Endocrinol (Oxf). 1986 May;24(5):555-63.

Gestrinone is an oxo steroid.
Gestrinone, also known as ethylnorgestrienone, is a synthetic steroid of the 19-nortestosterone group that is marketed in Europe, Australia, and Latin America, though not the United States or Canada, and is used primarily in the treatment of endometriosis. Gestrinone was developed in the early 1970s and was tested clinically as a weekly oral contraceptive in Europe and North America. Without significant advantages over other oral contraceptives and with its high cost, gestrinone was no longer used after the Stage II clinical trials. However, from 1982 this drug attracted increased interest due to significant therapeutic effects in the treatment endometriosis. Under different endocrine conditions, gestrinone possesses estrogenic, progestational, androgenic, antiestrogenic and antiprogesterone actions.
A non-estrogenic contraceptive which is a weak progestin with strong anti-progesterone properties. It is effective if used once a week orally or can also be used in intravaginal devices.

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Drug Indication
Endometriosis with or without accompanying sterility. Treatment is limited to a single course of 6 months duration per lifetime.

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Mechanism of Action
Gestrinone has weak agonist activity on progesterone receptors in the rabbit endometrium and progesterone antagonist activity in various other pharmacological test systems. In addition, it has moderate agonist activity on prostatic androgen receptors in vitro. In several in vivo experiments, this activity was found to be low. The primary action of gestrinone is on the hypothalamic-pituitary axis where it inhibits gonadotrophin release with a weak inhibitory effect on its synthesis. It also possesses anti-estrogen activity. The suppression of the ovular gonadotrophin peak is observed after the first month of treatment; the resulting decline in ovarian hormone secretion rapidly leads to endometrial atrophy. Aside from its central action, gestrinone also has anti-progesterone activity on cell receptors in both endometrium and extra-uterine ectopic implants. Gestrinone has no direct estrogen and/or uterotrophic effects. A study was done to examine the efficacy of gestrinone in emergency contraception. The data from the study suggest that the mechanism of action of gestrinone used for the purposes of emergency contraception is likely the inhibition of implantation by acting on the endometrium as opposed to the inhibition of ovulation.

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Pharmacodynamics
Gestrinone is a synthetic steroidal hormone which has androgenic, anti-estrogenic and anti-progestogenic properties. The findings of several studies suggest that gestrinone is as effective as danazol in the treatment of infertility associated with endometriosis and is better tolerated, in terms of adverse effects. Gestrinone has moderate anti-estrogen, and anti-gonadal properties, which can lead to increased concentrations of free testosterone, and decrease the level of sex hormone-binding globulin, suppress the FSH and LH hormone peak levels and decrease the LH mean to reduce estrogen levels. In addition, gestrinone has a direct effect on the endometrium and ectopic endometrial receptors, which have the roles of anti-progesterone and anti-estrogen effects lead to endometrial and ectopic endometrial atrophy to achieve therapeutic effects. Gestrinone inhibits the release of pituitary gonadotropins. The effect on ovarian hormone secretion results in the atrophy of endometrial tissue, resulting in the regression of endometriosis. Gestrinone is structurally related to norgestrel and possesses some androgenic and progestogenic activity. However, the gestrinone has an antiprogesterone effect on endometrial tissue. The effect of oral gestrinone, 2.5 mg biweekly for 6 months, was studied in a group of 11 women with mild or moderate endometriosis laparoscopically confirmed. Painful symptoms were alleviated in all patients within 8 weeks from the start of treatment. Gonadotropins, prolactin (PRL) 17 beta-estradiol (17 beta-E2), estrone (E1), progesterone (P), androstenedione (A), and dehydroepiandrosterone sulfate (DHEA-S) remained in the physiological follicular phase range. Total testosterone (TT) and sex hormone-binding globulin (SHBG) decreased, and free testosterone (FT) slightly increased. Metabolic studies showed a decrease in total triglyceride level, very low-density lipoprotein (VLDL) triglycerides, and high-density lipoprotein (HDL) and VLDL cholesterol. Low-density lipoprotein cholesterol and apoprotein B were found to be increased during gestrinone therapy. It can be extrapolated that gestrinone possesses antiestrogenic, androgenic, and progestogenic effects at therapeutic dosages both by acting on both central and peripheral steroid receptors.

C21H24O2

308.42

308.177

16320-04-0

27812

Off-white to light yellow solid powder

1.2±0.1 g/cm3

507.6±50.0 °C at 760 mmHg

154ºC

214.9±22.7 °C

0.0±3.0 mmHg at 25°C

1.607

3.27

1

2

2

23

713

4

C#C[C@]1(O)CC[C@@]2([H])[C@]3([H])CCC4=CC(CCC4=C3C=C[C@]12CC)=O

BJJXHLWLUDYTGC-ANULTFPQSA-N

InChI=1S/C21H24O2/c1-3-20-11-9-17-16-8-6-15(22)13-14(16)5-7-18(17)19(20)10-12-21(20,23)4-2/h2,9,11,13,18-19,23H,3,5-8,10,12H2,1H3/t18-,19+,20+,21+/m1/s1

(8S,13S,14S,17R)-13-ethyl-17-ethynyl-17-hydroxy-1,2,6,7,8,14,15,16-octahydrocyclopenta[a]phenanthren-3-one

A 46 745 A-46-745A46745 Dimetriose R2323 R-2323R 2323Ethylnorgestrienone

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 : ≥ 50 mg/mL (~162.12 mM)
H2O : ~1 mg/mL (~3.24 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.11 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 (8.11 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 (8.11 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.)