Gestodene

Gestodene is an orally active synthetic progestogen compound of the 19-nortestosterone class. Gestodene binds with high affinity to the progesterone receptor, inhibits 5α-reductase, binds to androgen and aldosterone receptors, and inactivates CYP3A. Gestodene acts as a positive allosteric modulator of PAR1, enhances PAR1-mediated signaling pathways, and is capable of increasing the activation potency of PAR1-AP toward PAR1, thereby promoting ERK1/2 phosphorylation, receptor internalization, cell morphological changes, and human platelet aggregation. Gestodene and its A-ring reduced metabolites promote the proliferation, differentiation, and mineralization of neonatal rat osteoblasts. Gestodene itself has no binding capacity for estrogen receptors, and this osteogenic activity depends on intracellular metabolism to generate A-ring reduced products with estrogen-like agonistic activity. Gestodene is useful for research on diseases related to progesterone secretion and diseases related to thrombosis^{[1][2][3][4][5][6][7][8]}. In Vitro:Gestodene exhibits a high relative binding affinity for the progesterone receptor, shows low to moderate binding affinity for the androgen receptor, and has weak binding capacity for the estrogen receptor^[1].
Gestodene inhibits the hydroxylation of ethinyl estradiol in a concentration-dependent manner in human liver microsomes and also inhibits the oxidative metabolism of Cyclosporine and Diazepam^[1].
Gestodene (GDN) (1-500 nM; 1-25 days) stimulates the proliferation of neonatal rat calvarial osteoblasts, increases alkaline phosphatase activity in neonatal rat calvarial osteoblasts, and increases cell-associated osteocalcin content in neonatal rat calvarial osteoblasts; the 5α-reductase inhibitor Finasteride (HY-13635) and the aldosterone ketosteroid dehydrogenase inhibitor Flufenamic acid (HY-B1221) inhibit the Gestodene-induced increase in alkaline phosphatase activity^[2].
Gestodene (50-500 nM; 25 days) increases cell-associated calcium content in neonatal rat calvarial osteoblasts^[2].
Gestodene (1-250 nM; 18 h) shows no binding affinity for estrogen receptors in the cytosolic fraction of neonatal rat calvarial osteoblasts^[2].
Gestodene is extensively metabolized to A-ring reduced derivatives (5α gestodene, 3α,5α gestodene, and 3β,5α gestodene) in rat anterior pituitary, hypothalamus, and ventral prostate homogenates^[3].
Gestodene (3 μM; 3 days; 4-16 h; 30 min) enhances PAR1-AP-induced proliferation, migration, and ERK1/2 phosphorylation in A2058 cells, HaCaT cells, and HDF cells in a PAR1-dependent manner; this enhancing effect is blocked by Vorapaxar (HY-10119)^[4].
Gestodene acts as a positive allosteric modulator of PAR1 in HT29 cells, enhancing PAR1-AP- and thrombin-induced intracellular calcium levels with EC₅₀ values of 8.15 μM and 4.54 μM, respectively, without affecting PAR2 or PAR4 activity^[5].
Gestodene (10 μM) enhances PAR1-AP-induced intracellular calcium levels in MEG-01 cells, reducing the EC₅₀ of PAR1-AP from 6.58 μM to 3.41 μM^[5].
Gestodene (10 μM; 10 min) enhances PAR1-AP-induced ERK1/2 phosphorylation in MEG-01 cells through a PAR1-dependent mechanism^[5].
Gestodene (10 μM) enhances PAR1-AP-induced PAR1 internalization in HT29 cells, and this effect is blocked by Vorapaxar^[5].
Gestodene (10 μM; 30 min) enhances PAR1-AP-induced morphological changes (decreased circularity) in MEG-01 cells, and this effect is blocked by Vorapaxar^[5].
Gestodene (GDN) (10-100 nM; 6 h) significantly increases insulin 2 and glucokinase gene expression in isolated rat pancreatic islets^[8].
Gestodene (100 nM; 6 h) significantly enhances glucose-stimulated insulin secretion in isolated rat pancreatic islets cultured in 11 mM D-glucose; moreover, in the presence of steroid-metabolizing enzyme inhibitors, the Gestodene-induced increase in insulin 2 and glucokinase gene expression in rat pancreatic islets is suppressed, indicating that the stimulatory effect of Gestodene is exerted through enzyme-generated tetrahydro-reduced metabolites^[8].
Gestodene (10 min) acts as a selective positive allosteric modulator of PAR1 in HT29 cells, with no effect on PAR2 or PAR4; it enhances PAR1-AP-induced calcium signaling in A2058 cells in a PAR1-dependent manner and shifts the dose-response curve to the left (EC₅₀ decreases from 3.1 to 0.8 μM)^[4].
Gestodene (3 μM; 24 h) enhances PAR1-AP-induced expression of MMP-1, MMP-2, MMP-3, MMP-10, and fibronectin in HaCaT cells as well as COL1A1 expression in NIH-3T3 cells through a PAR1-dependent signaling pathway^[4].
Gestodene (GES) (10^-10-10^-6 M; 7 days) stimulates the growth of T47D-A breast tumor subclone cells but does not stimulate the growth of T47D-S breast tumor subclone cells^[7].
Gestodene (10^-10-10^-6 M; 7 days) abolishes the estradiol-induced cell proliferation effect in T47D-S human breast tumor subclone cells; the proliferation effect induced in T47D-A cells is partially inhibited by antiestrogens (4-Hydroxytamoxifen, ICI 164384) and is not antagonized by antiprogestins (RU 38486 (HY-13683), Org 31710)^[7]. In Vivo:Gestodene (2 mg/g petrolatum; topical administration; once daily; 8 days) achieves wound closure and enhances collagen deposition by day 8 in a mouse full-thickness skin wound model^[4].
Gestodene (100-600 ng/L; water exposure; renewed daily; 7-day pre-exposure followed by 45 days of continuous exposure) reduces the cumulative egg production per female in adult zebrafish, with no mortality observed, and alters sex steroid levels and mRNA expression of HPG and HPT axis genes in a concentration- and sex-specific manner^[6].