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Progestogen use and breast cancer
Published in Barry G. Wren, Progress in the Management of the Menopause, 2020
As already mentioned above, the progestins prescribed for HRT vary from country to country, and the coprescription of progestins together with estrogens is only a recent phenomenon in most countries. The progestin molecule most often prescribed in the United States remains medroxyprogesterone acetate (MPA), a 170H-progesterone derivative exhibiting some glucocorticoid activity and a partial androgenic effect35,36. In Europe, several combinations of estrogens and progestins have been developed and the progestational molecules are often derivatives of 19-nortestosterone which have lost their main androgenic effect, but still bind to the androgen receptor. These well-known 19-nortestosterone compounds include both the estrane derivatives such as norethisterone, and the gonane category such as norgestrel. Progesterone itself, and its derivatives such as dydrogesterone and the 19-norprogesterone compounds, are also largely prescribed in Europe.
Hormonal and natural contraceptives: a review on efficacy and risks of different methods for an informed choice
Published in Gynecological Endocrinology, 2023
Andrea R. Genazzani, Tiziana Fidecicchi, Domenico Arduini, Andrea Giannini, Tommaso Simoncini
Progestins are classified in categories according to their structural origins. They have been divided in generations according to the time of first synthesis. Among those used in the field of HC, pregnanes (17-hydroxyprogesterone derivatives and 19-norprogesterone derivatives, i.e. chlormadinone acetate) and estranes (testosterone derivatives, i.e. norethindrone, norethynodrel, norethindrone acetate, and ethynodiol diacetate) are considered first generation progestins. Only few of these are still used in HC due to their androgenic properties that cause bothersome side effects, as oily skin, acne, and reduced levels of high density lipoproteins (HDL) [30]. Second-generation progestins are called gonanes and derive from testosterone. This includes some of the most widely used progestins, such as levonorgestrel. Third generation include desogestrel, gestodene, norgestimate/norelgestromin, and etonogestrel. These molecules progressively lose the androgenic activity, acquiring a non-androgenic or an antiandrogenic effect. The newest progestins are the fourth-generation ones, that include nonethylated estranes (i.e. dienogest and drospirenone, a spironolactone derivative) and 19-norprogesterones-derivatives pregnanes (i.e. nomegestrol acetate) [29–31].
Synthesis and structure–activity relationships of 2- and/or 4-halogenated 13β- and 13α-estrone derivatives as enzyme inhibitors of estrogen biosynthesis
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Ildikó Bacsa, Bianka Edina Herman, Rebeka Jójárt, Kevin Stefán Herman, János Wölfling, Gyula Schneider, Mónika Varga, Csaba Tömböly, Tea Lanišnik Rižner, Mihály Szécsi, Erzsébet Mernyák
The use of the estrone-based inhibitors of the mentioned steroidogenic enzymes in the therapy is limited because of their retained estrogenic activity. The availability of inhibitors acting selectively without hormonal behavior would be of particular interest. Literature data reveal that estrogenic effect of estrone is a 5–35% extent of that of 17β-estradiol8–10. Chloro substitution at position C-4 of estrone or 17β-estradiol retains the estrogenicity, however, 4-bromo and 4-iodo, as well as 2-chloro, -bromo, and -iodo compounds exert suppressed effect compared to that of the parent compounds. Data vary according to the methods applied, but it can be stated that estrogenic effect decreases with the increasing size of the introduced halogen. C-2 substituted estrone or 17β-estradiol compounds are usually less estrogenic than their C-4 counterparts. The 2,4-disubstituted analogs, nevertheless, exert negligible estrogenic potential8,10,11. Certain other chemical modifications of the estrane skeleton, such as the inversion of the configuration at C-13 or the opening of ring D, may result in the complete loss of hormonal activity12–15. We have promising preliminary results concerning the design, synthesis and biochemical evaluation of 17β-HSD1 inhibitors based on hormonally inactive 13α-estrane core16. 13α-Estrone (9, Scheme 2) itself was proved to be a potent inhibitor with an IC50 comparable to that of the natural substrate E1. Additionally, the previously synthesised 13α-estrone derivatives (10a,b–12a,b) brominated or iodinated in the A-ring exerted low micromolar or submicromolar inhibitory potential17. Chlorinations in the 13α-estrone series leading to 10c–12c have not been performed up to now. Concerning recent promising results, that 13α-estrone derivatives might possess valuable 17β-HSD1 inhibitory potential, it seemed rational to evaluate these compounds as potential aromatase or STS inhibitors, too.
Synthesis of substituted 15β-alkoxy estrone derivatives and their cofactor-dependent inhibitory effect on 17β-HSD1
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Bianka Edina Herman, Anita Kiss, János Wölfling, Erzsébet Mernyák, Mihály Szécsi, Gyula Schneider
Treatment of Δ15-17-one compound 6 with aqueous potassium hydroxyde in methanol afforded 3,15β-dimethoxy-estra-1,3,5(10)-trien-17-one via 1,4 addition in practically quantitative yield. On the basis of an earlier observation from W. S. Johnson and W. F. Johns23, we extended this 1,4-addition process to 1,2-ethanediol, 1,3-propanediol and 1,4-butanediol to receive from compound 6 the corresponding 3-methoxy-15β-(2’-hydroxy)ethoxy-, and 3-methoxy-15β-(3’-hydroxy)propoxy-estra-1,3,5(10)-triene-17-ones (8 and 9), from compound 7 the 3-benzyloxy-15β-(2’-hydroxy)ethoxy-, 3-benzyloxy-15β-(3’-hydroxy)propoxy-, and 3-benzyloxy-15β-(4’-hydroxy)butoxy-estra-1,3,5(10)-trien-17-ones (10‒12). The addition of different nucleophiles is highly stereospecific, giving 15β substituted estranes in all cases12,23. Jones oxidation of these compounds (8‒12) furnished the corresponding 3-methoxy-, and 3-benzyloxy-15β-(carboxyl)-alkoxy-estra-1,3,5(10)-trien-17-one derivatives (13‒17). The 1,4-addition process of compounds 6 and 7 with 3-hydroxypropionitrile afforded the corresponding 3-methoxy-, and 3-benzyloxy-15β-(2’-cyano)ethoxy-estra-1,3,5(10)-trien-17-ones (18, 19). Cleavage of the 3-benzyloxy group of 19 yielded 20, which reacted with sulfamoyl chloride to yield 21. Esterification of 15β-(carboxyl)alkoxy derivatives by diazomethane yielded the corresponding methyl esters 22–24. The 15β-(carboxyl)alkoxy compounds were reacted with oxalyl chloride to give carboxylic acid chloride which, upon reaction with ammonium hydroxide, morpholine or N-cyclohexyl, N-methylamine yielded the corresponding carboxamides 25‒33. The 3-benzyloxy-15β-(2’-hydroxy)ethoxy- and 3-benzyloxy-15β-(3’-hydroxy)propoxy-estra-1,3,5(10)-triene-17-ones (10 and 11) reacted with different alkyl- and aryl isocyanates to furnish alkyl- and aryl urethane derivatives 34‒40.