 | |
| Clinical data | |
|---|---|
| Trade names | Dimetriose, Dimetrose, Nemestran, others |
| Other names | Ethylnorgestrienone; A-46745; R2323; R-2323; RU-2323; 17α-Ethynyl-18-methyl-δ9,11-19-nortestosterone; 17α-Ethynyl-18-methylestra-4,9,11-trien-17β-ol-3-one; 13β-Ethyl-18,19-dinor-17α-pregna-4,9,11-trien-20-yn-17β-ol-3-one |
| AHFS/Drugs.com | International Drug Names |
| Pregnancy category |
|
| Routes of administration | By mouth,vaginal[1] |
| Drug class | Progestogen;Progestin;Antiprogestogen;Androgen;Anabolic steroid;Steroidogenesis inhibitor;Antiestrogen |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Protein binding | Toalbumin[1] |
| Metabolism | Liver (hydroxylation)[1] |
| Eliminationhalf-life | 27.3 hours[1] |
| Excretion | Urine andbile[1] |
| Identifiers | |
| |
| CAS Number | |
| PubChemCID | |
| DrugBank |
|
| ChemSpider |
|
| UNII | |
| KEGG |
|
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.210.606 |
| Chemical and physical data | |
| Formula | C21H24O2 |
| Molar mass | 308.421 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
| (verify) | |
Gestrinone, sold under the brand namesDimetrose andNemestran among others, is a medication which is used in the treatment ofendometriosis.[3][4] It has also been used to treat other conditions such asuterine fibroids andheavy menstrual bleeding and has been investigated as a method ofbirth control.[5][6][1] Gestrinone is used alone and is not formulated in combination with other medications.[7] It is takenby mouth orin through the vagina.[1][8]
Side effects of gestrinone includemenstrual abnormalities,estrogen deficiency, andsymptoms ofmasculinization likeacne,seborrhea,breast shrinkage,increased hair growth, andscalp hair loss, among others.[1][8][9][10] Gestrinone has a complexmechanism of action, and is characterized as a mixedprogestogen andantiprogestogen, a weakandrogen andanabolic steroid, a weakantigonadotropin, a weaksteroidogenesis inhibitor, and a functionalantiestrogen.[11][1][12][13]
Gestrinone was introduced for medical use in 1986.[14] It has been used extensively inEurope but appears to remains marketed only in a few countries throughout the world.[10][15][7] The medication is not available in theUnited States.[16] Due to itsanabolic effects, the use of gestrinone in competition has been banned by theInternational Olympic Committee.[17]
Gestrinone is approved for and used in the treatment ofendometriosis. It is described as similar in action and effect todanazol, which is also used in the treatment of endometriosis, but is reported to have fewer androgenicside effects in comparison.[18][19] Gestrinone has also been used to shrinkuterine fibroids and to reducemenorrhagia.[5][6]
Due to itsantigonadotropic effects and ability to inhibitovulation, gestrinone has been studied as a method ofhormonal birth control in women.[1] Large studies across thousands ofmenstrual cycles have found it to be effective in preventingpregnancy.[1] However, although effective, the pregnancy rate in the largest study conducted was 4.6 per 100 woman-years, which is too high of a failure rate for the medication to be recommended as a safe method of birth control.[1] The medication has also been investigated as anemergency post-coital contraceptive.[20]
The medication iscontraindicated inpregnancy, duringlactation, and in patients with severe cardiac,chronic kidney disease or liver disease. It is also contraindicated in patients who experienced metabolic and/or vascular disorders during previous estrogen or progestogen therapy, or who are allergic to the medication. The medication is contraindicated in children.
The main side effects of gestrinone areandrogenic andantiestrogenic in nature.[1][10] In one study of 2.5 mg oral gestrinone twice per week in women, it causedseborrhea in 71%,acne in 65%,breast hypoplasia in 29%,hirsutism in 9%, andscalp hair loss in 9%.[1] In another study, the rate of androgenic side effects was similarly 50%.[1] Other androgenic side effects that have been reported includeoily skin andhair,weight gain,voice deepening, andclitoral enlargement, the latter two of which as well as hirsutism may be irreversible.[8][9][10]
Gestrinone also inhibitsgonadotropinsecretion and causesamenorrhea oroligomenorrhea in a high percentage of women.[1] Similarly, circulatingestradiol levels have been found to be reduced by 50%, which may result inestrogen deficiency and associatedsymptoms.[10] Studies of 2.5 mg oral gestrinone twice per week have found a rate of amenorrhea of 50 to 58%, while a study of 5 mg oral gestrinone per day found a rate of amenorrhea of 100%.[1]
It has been found that vaginal gestrinone shows fewer androgenic side effects andweight gain than oral gestrinone with equivalent effectiveness in endometriosis.[1] Gestrinone appears to show similar effectiveness todanazol in the treatment of endometriosis but with fewer side effects, in particular androgenic side effects.[1][18][19]
Themechanism of action of gestrinone is complex and multifaceted.[1][18] It shows highaffinity for theprogesterone receptor (PR), as well as lower affinity for theandrogen receptor (AR).[1][18] The medication has mixedprogestogenic andantiprogestogenic activity – that is, it is apartial agonist of the PR or aselective progesterone receptor modulator (SPRM) – and is a weakagonist of the AR, or ananabolic–androgenic steroid (AAS).[11][1][12][13] Similarly to danazol, gestrinone acts as a weakantigonadotropin via activation of the PR and AR in thepituitary gland and suppresses the mid-cycle surge ofluteinizing hormone (LH) andfollicle-stimulating hormone (FSH) during themenstrual cycle without affecting basal levels of these hormones.[1][18] It also inhibitsovariansteroidogenesis and, via activation of the AR in theliver, decreases circulating levels ofsex hormone-binding globulin (SHBG), thereby resulting in increased levels of freetestosterone.[1][18][21] In addition to the PR and AR, gestrinone has been found to bind to theestrogen receptor (ER) with relatively "avid" affinity.[22] The medication has functional antiestrogenic activity in theendometrium.[11][1][12][13] Unlike danazol, gestrinone does not appear to bind to SHBG orcorticosteroid-binding globulin (CBG).[22]
| Compound | PRTooltip Progesterone receptor | ARTooltip Androgen receptor | ERTooltip Estrogen receptor | GRTooltip Glucocorticoid receptor | MRTooltip Mineralocorticoid receptor | SHBGTooltip Sex hormone-binding globulin | CBGTooltip Corticosteroid binding globulin |
|---|---|---|---|---|---|---|---|
| Norethisterone | 155–156 | 43–45 | <0.1 | 2.7–2.8 | 0.2 | ? | ? |
| Norgestrienone | 63–65 | 70 | <0.1 | 11 | 1.8 | ? | ? |
| Levonorgestrel | 170 | 84–87 | <0.1 | 14 | 0.6–0.9 | ? | ? |
| Gestrinone | 75–76 | 83–85 | <0.1, 3–10 | 77 | 3.2 | ? | ? |
| Notes: Values are percentages (%). Referenceligands (100%) wereprogesterone for thePRTooltip progesterone receptor,testosterone for theARTooltip androgen receptor,E2 for theERTooltip estrogen receptor,DEXATooltip dexamethasone for theGRTooltip glucocorticoid receptor,aldosterone for theMRTooltip mineralocorticoid receptor,DHTTooltip dihydrotestosterone forSHBGTooltip sex hormone-binding globulin, andcortisol forCBGTooltip Corticosteroid-binding globulin.Sources:[23][24][25][26] | |||||||
Gestrinone isbound toalbumin in the circulation.[1] It ismetabolized in theliver mainly byhydroxylation.[1] Four hydroxylatedactive metabolites with reduced activity relative to gestrinone have been found to be formed.[1] Theelimination half-life of gestrinone is 27.3 hours.[1] The medication isexcreted inurine andbile.[1]
Gestrinone, also known as 17α-ethynyl-18-methyl-19-nor-δ9,11-testosterone, as well as 17α-ethynyl-18-methylestra-4,9,11-trien-17β-ol-3-one or as 13β-ethyl-18,19-dinor-17α-pregna-4,9,11-trien-20-yn-17β-ol-3-one, is asyntheticestranesteroid and aderivative oftestosterone.[27][15] It is more specifically a derivative ofnorethisterone (17α-ethynyl-19-nortestosterone) and is a member of thegonane (18-methylestrane) subgroup of the19-nortestosterone family of progestins.[28][11][29][30] Gestrinone is the C18methyl derivative ofnorgestrienone (17α-ethynyl-19-nor-δ9,11-testosterone) and the δ9,11analogue oflevonorgestrel (17α-ethynyl-18-methyl-19-nortestosterone) and is also known as ethylnorgestrienone due to the fact that it is the C13βethyl variant of norgestrienone.[10][31] It is also the C17αethynyl and C18 methyl derivative of the AAStrenbolone.[32][33]
The androgenic properties of gestrinone are more exploited in its derivativetetrahydrogestrinone (THG; 17α-ethyl-18-methyl-δ9,11-19-nortestosterone), adesigner steroid which is far more potent as both an AAS and progestogen in comparison.[34] THG was banned by theFood and Drug Administration (FDA) in 2003.[35]
Gestrinone was introduced for medical use in 1986.[14]
Gestrinone is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANTooltip British Approved Name, andJANTooltip Japanese Accepted Name.[27][15][4][7] It is also known by its developmental code namesA-46745 andR-2323 (orRU-2323).[27][15][4][7]
Gestrinone is or has been marketed under the brand names Dimetriose, Dimetrose, Dinone, Gestrin, and Nemestran.[27][15][7]
Gestrinone is or has been marketed inEurope,Australia,Latin America, andSoutheast Asia,[15][7] though notably not in theUnited States.[16]
Side effects [of gestrinone] are due to the androgenic and anti-estrogenic effects including, voice changes, hirsutism, and clittoral enlargement.
The clinical side effects are dose dependent and similar but less intense than those caused by danazol.12 They include nausea, muscle cramps, and androgenic effects such as weight gain, acne, seborrhea, oily hair/skin, and irreversible voice changes.
Side-effects [of gestrinone] include androgenic and antiestrogenic sequelae. Although most side-effects are mild and transient, several, such as voice changes, hirsutism, and clitoral hypertrophy, are potentially irreversible.
