Quingestrone

Quingestrone was formerly used in combination with ethinylestradiol or mestranol in combined birth control pills in Italy. The medication was studied in the clinical prevention of miscarriage during pregnancy, but insufficient efficacy was observed at the dosage assessed (100 mg/day orally).{{cite book|title=Vitamins and Hormones|url=https://books.google.com/books?id=rhbTtjo7dM4C&pg=PA332|date=9 February 1973|publisher=Academic Press|isbn=978-0-08-086627-7|pages=332–}}{{cite book| vauthors = Fraser IS |title=Estrogens and Progestogens in Clinical Practice|url=https://books.google.com/books?id=eO5qAAAAMAAJ|year=1998|publisher=Churchill Livingstone|isbn=978-0-443-04706-0}}{{cite journal | vauthors = Goldstein P, Berrier J, Rosen S, Sacks HS, Chalmers TC | title = A meta-analysis of randomized control trials of progestational agents in pregnancy | journal = British Journal of Obstetrics and Gynaecology | volume = 96 | issue = 3 | pages = 265–274 | date = March 1989 | pmid = 2653414 | doi = 10.1111/j.1471-0528.1989.tb02385.x | s2cid = 72030836 }}

{{See also|Progesterone (medication)#Side effects|Progestin#Side effects}}

Along with the retroprogesterone derivative dydrogesterone, quingestrone has been described as a "true" progesterone derivative or progestogen due to its close similarity to natural progesterone.{{cite book | url=https://books.google.com/books?id=AcRsAAAAMAAJ | title=Exfoliative cytology in gynaecological practice | publisher=Appleton-Century-Crofts | vauthors = Wachtel EG | year=1969 | page=134 | isbn=9780407169012 | lccn=77008744}}{{cite journal | vauthors = Appleby B | title = Norethisterone in the control of menopausal symptoms | journal = Lancet | volume = 1 | issue = 7226 | pages = 407–409 | date = February 1962 | pmid = 13861933 | doi = 10.1016/s0140-6736(62)91363-6 | quote = Dr. Appleby would be doing a scientific service if he extended his trial using [...] preferably, a true progesterone derivative, such as [...] progesterone cyclopentyl enol ether ('Enol Luteovis', Vister). }} Similarly to progesterone, dydrogesterone, and hydroxyprogesterone caproate, quingestrone is a pure progestogen and lacks any androgenic effects.{{cite book | vauthors = Baird D, Kerr JM | url=https://books.google.com/books?id=jbwwAAAAIAAJ | title=Combined textbook of obstetrics and gynæcology for students and practitioners | publisher=E. & S. Livingstone | year=1969 |isbn = 9780443000454| lccn=70360656}} As such, it poses no risk of androgenic side effects or virilizing teratogenic effects on female fetuses. Quingestrone is said to influence the hypothalamic–pituitary–adrenal axis similarly to progesterone and medroxyprogesterone acetate, producing adrenal suppression at sufficiently high doses, and this suggests that it possesses weak glucocorticoid activity similarly to progesterone.{{cite book | url=https://books.google.com/books?id=mp3wAAAAMAAJ | title=Neuroendocrinology | publisher=Academic Press | vauthors = Martini L | year=1966 | page=331 | isbn=9780124753525 | lccn=66026256}}{{cite journal| vauthors = Steinetz BG, Beach VL, DiPasquale G, Battista Jr JV |title=Effects of different gestagenic steroid types on plasma-free corticosteroid levels in ACTH-treated rats|journal=Steroids|volume=5|issue=1|year=1965|pages=93–108|issn=0039-128X|doi=10.1016/0039-128X(65)90134-0}}{{cite journal | vauthors = Gaunt R, Steinetz BG, Chart JJ | title = Pharmacologic alteration of steroid hormone functions | journal = Clinical Pharmacology and Therapeutics | volume = 9 | issue = 5 | pages = 657–681 | date = 1968 | pmid = 4175595 | doi = 10.1002/cpt196895657 | quote = An interesting substance which has received little attention is the 3-cyclopentyl enol ether of progesterone (quingestrone). It is a very weak progestational agent, requiring 50 mg. per rat for pregnancy maintenance. 100 At this dose quingestrone reduced adrenal weight in male rats to the level observed after hypophysectomy and prevented any rise in plasma corticosteroids in response to a maximally stimulating dose of ACTH.H5 This strongly suggests a direct adrenal effect although the substance may in addition suppress ACTH secretion. It is doubtful, however, that progestational agents have clinically important effects on the human adrenal in the doses conventionally used. Nevertheless, in view of the prolonged exposure of women to gestogens for contraception, this factor deserves continued surveillance. | s2cid = 38695246 }}

Quingestrone is a very weak progestogen. When administered orally or intraperitoneally in animals, the medication showed 1/80 and 1/20 the potency of subcutaneously injected progesterone, respectively. Similarly, oral doses of quingestrone of 10 to 20 times those of subcutaneous progesterone were insufficient to maintain pregnancy in animals, and oral or intraperitoneal doses of quingestrone 20 to 40 times those of oral or intraperitoneal progesterone were unable to potentiate hexobarbital-induced anesthesia in animals (which progesterone does and is thought to do by inhibiting the hepatic metabolism of barbiturates). With oral administration of equal doses of progesterone and quingestrone in animals, 3 to 4 times less pregnanediol was recovered from urine with quingestrone. The fact that quingestrone is more potent by intraperitoneal than oral administration in animals suggests that it is transformed into a less active metabolite in the intestines.

The effective dosage of quingestrone in the menstrual delay test has been studied.{{cite journal | vauthors = Edgren RA, Sturtevant FM | title = Potencies of oral contraceptives | journal = American Journal of Obstetrics and Gynecology | volume = 125 | issue = 8 | pages = 1029–1038 | date = August 1976 | pmid = 952300 | doi = 10.1016/0002-9378(76)90804-8 }}

Quingestrone has no anesthetic effect in animals, in contrast to progesterone.{{cite book| vauthors = Junkmann K |title=Die Gestagene|url=https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA524|date=1968|publisher=Springer-Verlag|isbn=978-3-642-99941-3|pages=10,275,524}}{{cite journal| vauthors = Ercoli A, Gardi R |title=Δ^4-3-Keto Steroidal Enol Ethers. Paradoxical Dependency of Their Effectiveness on the Administration Route|journal=Journal of the American Chemical Society|volume=82|issue=3|year=1960|pages=746–748|issn=0002-7863|doi=10.1021/ja01488a062}}

Quingestrone has been suggested to act as a prodrug of progesterone via slow hydrolysis in the body.{{cite journal | vauthors = Burton ER, Wachtel EG | title = A clinical trial and cytological assessment of enol LUTEOVIS IN THE TREATMENT OF THREATENED AND RECURRENT ABORTION | journal = The Journal of Obstetrics and Gynaecology of the British Commonwealth | volume = 74 | issue = 4 | pages = 533–536 | date = August 1967 | pmid = 5340429 | doi = 10.1111/j.1471-0528.1967.tb03986.x | s2cid = 31602503 }}{{cite journal| vauthors = Charman WN, Porter CJ |title=Lipophilic prodrugs designed for intestinal lymphatic transport|journal=Advanced Drug Delivery Reviews|volume=19|issue=2|year=1996|pages=149–169|issn=0169-409X|doi=10.1016/0169-409X(95)00105-G}} Indeed, it produces similar metabolites (e.g., pregnanediols and allopregnanediols) as progesterone,{{cite journal | vauthors = Fatouros DG, Karpf DM, Nielsen FS, Mullertz A | title = Clinical studies with oral lipid based formulations of poorly soluble compounds | journal = Therapeutics and Clinical Risk Management | volume = 3 | issue = 4 | pages = 591–604 | date = August 2007 | pmid = 18472981 | pmc = 2374933 }} although with differing ratios,{{Cite web | url=http://www.popline.org/node/474452 |title = POPLINE retirement|date = 2019-09-06}} and notably is the only progestin that is known to produce pregnanediol as a metabolite.{{cite book | url=https://books.google.com/books?id=auc1AQAAIAAJ | title=Current Medicine and Drugs | year=1962 | quote=Enol Luteovis (3 cyclo-pentyl enol ether of progesterone) is the only oral progestin producing pregnanediol as a metabolite. It is not very potent and probably carries very little risk of producing virilizing effects on a female foetus. Thus it is more closely related to progesterone than the other synthetic progestins. | issn=0590-4048}} Subsequent research has cast doubt on the notion that quingestrone is a prodrug of progesterone however, and indicates that it instead is directly metabolized into pregnanediols without intermediate conversion into progesterone.{{cite journal | vauthors = Meli A, Wolff A, Lucker WE, Steinetz BG | title = The Biological Profile of Progesterone 3-Cyclopentyl Enol Ether as Compared with That of Progesterone | journal = Proceedings of the Society for Experimental Biology and Medicine | volume = 118 | issue = 3 | pages = 714–717 | date = March 1965 | pmid = 14264537 | doi = 10.3181/00379727-118-29947 | s2cid = 11891451 }} Based on its chemical structure, quingestrone may be transformed into 3α-dihydroprogesterone and/or 3β-dihydroprogesterone and then further metabolized into pregnanolones and pregnanediols. 3β-Dihydroprogesterone has been reported to possess about the same progestogenic potency as progesterone in the Clauberg test, whereas 3α-dihydroprogesterone was not assessed.{{cite journal | vauthors = Junkermann H, Runnebaum B, Lisboa BP | title = New progesterone metabolites in human myometrium | journal = Steroids | volume = 30 | issue = 1 | pages = 1–14 | date = July 1977 | pmid = 919010 | doi = 10.1016/0039-128X(77)90131-3 | quote = In the Clauberg bioassay the 3β-hydroxy-4-pregnen-20-one shows about the same potency as progesterone (34). In regard to the biological activity of the 3α epimer no data are available. | s2cid = 28420255 }}{{cite journal | vauthors = Pincus G, Miyake T, Merrill AP, Longo P | title = The bioassay of progesterone | journal = Endocrinology | volume = 61 | issue = 5 | pages = 528–533 | date = November 1957 | pmid = 13480263 | doi = 10.1210/endo-61-5-528 | doi-access = free }}

Relative to progesterone, quingestrone shows improved pharmacokinetics, including higher potency, oral activity,{{cite journal | url=https://books.google.com/books?id=IhU-AQAAIAAJ | title=The ... Year Book of Obstetrics and Gynecology | publisher=Year Book Publishers | vauthors = De Lee JB | journal=Yearbook of Obstetrics and Gynecology (O) | year=1965 | page=150 | issn=0084-3911 | lccn=cdr38000020}} and a longer terminal half-life and hence duration of action. This is considered to be due to its higher lipophilicity, being stored into and slowly released from fat. Quingestrone also shows slower metabolism and more stable blood levels, with a longer time to peak concentrations and a less intense peak compared to progesterone.{{cite journal | vauthors = Caie E, Klopper A | title = The Urinary Excretion of Pregnanediol After the Administration of an Oral Gestagen (Progesterone Cyclopentyl Enol Ether) | journal = The Journal of Endocrinology | volume = 28 | issue = 2 | pages = 221–222 | date = January 1964 | pmid = 14112260 | doi = 10.1677/joe.0.0280221 | citeseerx = 10.1.1.1028.4921 }} The bioavailability of quingestrone is highest when it is given as a sesame seed oil solution (compared to an oil suspension (~2-fold less) or micronization (~7-fold less)).

The C3 enol ethers of progesterone are less suited for use via depot injection relative to progestogen esters like hydroxyprogesterone caproate due to their susceptibility to oxidative metabolism.{{cite journal | vauthors = Junkmann K | title = Gestagens of prolonged action | journal = Naunyn-Schmiedebergs Archiv für Pharmakologie und Experimentelle Pathologie | volume = 223 | pages = 244–53 | year = 1954 | issn = 0365-5423 | quote = Among a large no. of pregnane derivs. the esters of 17-α-hydroxyprogesterone (I), itself of weak lutein hormone action, have a strong and long-lasting gestagen action. The optimal results are obtained with I caproate. It permits the administration of depot doses in clear solns. Within the range of dosage used no androgenic effect was noted. It has no influence on growth and on the secondary sex characteristics in infantile and adult castrate male rats. The 3-enol esters of progesterone, which have a somewhat prolonged action, are less suited for depot administration because of their oxidizability.}}

The pharmacokinetics of quingestrone have been reviewed.

{{See also|List of progestogens|Progestogen ester#Progestogen ethers|List of progestogen esters#Ethers of progesterone derivatives}}

Quingestrone, also known as progesterone 3-cyclopentyl enol ether (PCPE) or as 3-cyclopentyloxypregna-3,5-dien-20-one, is a synthetic pregnane steroid and a derivative of progesterone. It is specifically the 3-cyclopentyl enol ether of progesterone. Quingestrone is closely related to progesterone 3-acetyl enol ether and pentagestrone acetate (17α-acetoxyprogesterone 3-cyclopentyl enol ether).

Chemical syntheses of quingestrone have been published.

Quingestrone appears to have been first synthesized in 1936.{{cite journal| vauthors = Westphal U |title=Über Enolacetate des Progesterons und Testosterons|journal=Die Naturwissenschaften|volume=24|issue=44|year=1936|pages=696–697|issn=0028-1042|doi=10.1007/BF01491541|bibcode=1936NW.....24..696W|s2cid=41442733}} It was introduced for medical use in Italy by 1962.

Quingestrone is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}} and {{abbrlink|USAN|United States Adopted Name}}. It is also known by its developmental code name W-3399.

Quingestrone was marketed under the brand name Enol-Luteovis.

Quingestrone is no longer marketed and hence is no longer available in any country.http://www.micromedexsolutions.com/micromedex2/ {{Dead link|date=February 2022}} It was previously available in Italy.

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