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Gestonorone caproate

From Wikipedia, the free encyclopedia
Chemical compound
Pharmaceutical compound
Gestonorone caproate
Clinical data
Trade namesDepostat, Primostat
Other namesGestronol hexanoate; Norhydroxy­progesterone caproate; SH-582; SH-80582; NSC-84054; 17α-Hydroxy-19-norpregn-4-ene-3,20-dione hexanoate; 17α-Hydroxy-19-norprogesterone hexanoate
Routes of
administration		Intramuscular injection[1][2][3]
Drug classProgestogen;Progestin;Progestogen ester;Antigonadotropin
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityOral: Low[4]
IM: High[5]
MetabolismReduction (at the C5, C3, and C20 positions)[6]
Metabolites• 19-Norpregnanetriol[6]
• 19-Norpregnanediol-20-one[6]
Eliminationhalf-lifeIM: 7.5 ± 3.1 days[5]
Duration of actionIM: ≥21 days[5]
ExcretionUrine: 28%[5]
Feces: 72%[5]
Identifiers
  • [(8R,9S,10R,13S,14S,17R)-17-acetyl-13-methyl-3-oxo-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] hexanoate
CAS Number
PubChemCID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.013.646Edit this at Wikidata
Chemical and physical data
FormulaC26H38O4
Molar mass414.586 g·mol−1
3D model (JSmol)
  • CCCCCC(=O)OC1(CCC2C1(CCC3C2CCC4=CC(=O)CCC34)C)C(=O)C
  • InChI=1S/C26H38O4/c1-4-5-6-7-24(29)30-26(17(2)27)15-13-23-22-10-8-18-16-19(28)9-11-20(18)21(22)12-14-25(23,26)3/h16,20-23H,4-15H2,1-3H3/t20-,21+,22+,23-,25-,26-/m0/s1
  • Key:XURCMZMFZXXQDJ-UKNJCJGYSA-N

Gestonorone caproate, also known asgestronol hexanoate ornorhydroxyprogesterone caproate and sold under the brand namesDepostat andPrimostat, is aprogestin medication which is used in the treatment ofenlarged prostate andcancer of the endometrium.[5][3][7][1][8] It is given byinjection into muscle typically once a week.[4]

Side effects of gestonorone caproate include worsenedglucose tolerance,decreased libido in men, andinjection site reactions.[5] Gestonorone caproate is a progestin, or asyntheticprogestogen, and hence is anagonist of theprogesterone receptor, thebiological target of progestogens likeprogesterone.[9][10] It has no other importanthormonal activity.[5][11][12][13]

Gestonorone caproate was discovered in 1960 and was introduced for medical use by 1973.[14][15] It has been used widely throughoutEurope, including in theUnited Kingdom, and has also been marketed in certain other countries such asJapan,China, andMexico.[1][16][17][18] However, it has since mostly been discontinued, and it remains available today only in a handful of countries, including theCzech Republic, Japan, Mexico, andRussia.[18][19]

Medical uses

[edit]

Gestonorone caproate is used in thepalliative treatment ofbenign prostatic hyperplasia andendometrial cancer.[5][3][20] It is used at a dose of 100 to 200 mg once a week byintramuscular injection.[5]

Side effects

[edit]
See also:Progestin § Side effects

Side effects of gestonorone caproate have been reported to include worsenedglucose tolerance,decreased libido in men, and localinjection site reactions such asirritation.[5]

Pharmacology

[edit]

Pharmacodynamics

[edit]

Gestonorone caproate is apotent, long-acting, and pureprogestogen,[9][10][13] possessing noandrogenic,anabolic,antiandrogenic,estrogenic,antiestrogenic,glucocorticoid,mineralocorticoid, orteratogenic effects.[5][11][12][13][21] It is approximately 20 to 25 times more potent thanprogesterone orhydroxyprogesterone caproate in animalbioassays when all are given bysubcutaneous injection.[5][13][22] In humans, 100 or 200 mg intramuscular gestonorone caproate has been said to be equivalent to 1,000 mg intramuscular hydroxyprogesterone caproate.[23][24] Hence, gestonorone caproate is approximately 5- to 10-fold more potent than hydroxyprogesterone caproate in humans.[11][23][24] Thebiological effects of gestonorone caproate in women have been studied.[25][26]

Like other potent progestins, gestonorone caproate possesses potentantigonadotropic activity and is capable of markedly suppressing thegonadal production and circulating levels of sex hormones such astestosterone andestradiol.[13][27][28] A clinical study found that 400 mg/week intramuscular gestonorone caproate suppressed testosterone levels by 75% in men, whileorchiectomy as a comparator reduced testosterone levels by 91%.[29][30] Levels ofluteinizing hormone, conversely, remained unchanged.[29] In general, progestogens can maximally suppress testosterone levels by about 70 to 80%.[31][32][33][29][30] In accordance with its lack of glucocorticoid activity, gestonorone caproate has noanticorticotropic effects, and does not influence thesecretion ofadrenocorticotropic hormone.[5]

17α-Hydroxyprogesterone has weakprogestogenic activity, but C17αesterification results in higher progestogenic activity.[6] Of a variety of differentesters, thecaproate (hexanoate) ester was found to have the strongest progestogenic activity, and this formed the basis for the development of gestonorone caproate, as well as other caproateprogestogen esters such as hydroxyprogesterone caproate.[6]

Gestonorone caproate has been found to decrease the weights of theprostate gland andseminal vesicles by 40 to 70% in adult male rats.[5] It has been shown incanines to mediate these effects both via its antigonadotropic effects and by direct actions in these tissues.[5] Gestonorone caproate decreases the uptake of testosterone into the prostate gland.[5] It has also been found to have directantiproliferative effects on humanovarian cancercellsin vitro.[5]

Gestonorone caproate has been reported to act to some extent as a5α-reductase inhibitor, similarly to progesterone.[34][35]

Parenteral potencies and durations of progestogens[a][b]
CompoundFormDose for specific uses (mg)[c]DOA[d]
TFD[e]POICD[f]CICD[g]
Algestone acetophenideOil soln.––75–15014–32 d
Gestonorone caproateOil soln.25–50––8–13 d
Hydroxyprogest. acetate[h]Aq. susp.350––9–16 d
Hydroxyprogest. caproateOil soln.250–500[i]–250–5005–21 d
Medroxyprog. acetateAq. susp.50–1001502514–50+ d
Megestrol acetateAq. susp.––25>14 d
Norethisterone enanthateOil soln.100–2002005011–52 d
ProgesteroneOil soln.200[i]––2–6 d
Aq. soln.?––1–2 d
Aq. susp.50–200––7–14 d
Notes and sources:
  1. ^Sources:[36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54]
  2. ^All given byintramuscular orsubcutaneous injection.
  3. ^Progesterone production during theluteal phase is ~25 (15–50) mg/day. TheOIDTooltip ovulation-inhibiting dose of OHPC is 250 to 500 mg/month.
  4. ^Duration of action in days.
  5. ^Usually given for 14 days.
  6. ^Usually dosed every two to three months.
  7. ^Usually dosed once monthly.
  8. ^Never marketed or approved by this route.
  9. ^abIn divided doses (2 × 125 or 250 mg forOHPC, 10 × 20 mg forP4).

Pharmacokinetics

[edit]

Like the closely related progestins hydroxyprogesterone caproate and19-norprogesterone, gestonorone caproate shows poor activityorally and must be administeredparenterally; specifically, viaintramuscular injection.[4] Gestonorone caproate is administered by intramuscular injection, and acts as a long-lastingdepot by this route.[5][55][56][57] After an intramuscular injection, gestonorone caproate is completely released from the local depot and is highlybioavailable.[5] A singleintramuscular injection of 25 to 50 mg gestonorone caproate inoil solution has been found to have aduration of action of 8 to 13 days in terms of clinicalbiological effect in theuterus in women.[26][58][59] At high doses, theduration of action of gestonorone caproate by intramuscular injection has been found to be at least 21 days.[5] Clinical studies have found gestonorone caproate to be satisfactorily effective as a progestogen when injected once a month, whereas it was poorly effective as an injectable contraceptive when it was injected once every two months.[60][61]

Following a single intramuscular injection of 200 mgradiolabeled gestonorone caproate in 1 mL ofsolution in men with prostate cancer,maximal levels of gestonorone caproate occurred after 3 ± 1 days and were 420 ± 160 ng/mL.[5] Theelimination half-life of gestonorone caproate and itsmetabolites was 7.5 ± 3.1 days.[5] Approximately 5% of theradioactivesteroid content in the blood was unchanged gestonorone caproate.[5] No freegestonorone was observed incirculation or inurine.[5] Gestonorone caproate and its metabolites wereeliminated 72% infeces and 28% inurine.[5][62] Approximately 48 ± 18% of the injected dose had been eliminated after 14 days and approximately 85 ± 12% of the injected dose had been excreted after 30 days.[5]

Themetabolism of unesterified gestonorone (17α-hydroxy-19-norprogesterone) is analogous to that of17α-hydroxyprogesterone, with the corresponding19-norpregnanemetabolites produced.[6] Gestonorone caproate has been found to undergo5α-reduction similarly toprogesterone, 17α-hydroxyprogesterone, and gestonorone, and at a similar rate as thesesteroids.[6] Conversely however, due to its caproate ester,5β-reduction of gestonorone caproate is decreased relative to these steroids.[6] As progesterone ismetabolized mainly into5β-pregnanes, decreased 5β-reduction of gestonorone caproate may be involved in its greaterpotency compared to progesterone.[6] The majormetabolites of gestonorone caproate have been reported to beisomers of 19-norpregnanetriol and 19-norpregnanediol-20-one.[6][21] These metabolites indicate that gestonorone caproate is metabolized mainly byreduction at the C3, C5, and C20 positions.[6] Following an intramuscular injection of 300 mg gestonorone caproate, only a slight increase inurinarypregnanetriolexcretion has been observed.[6]Cleavage of the caproate ester of gestonorone caproate is minimal, which indicates that it is not aprodrug of the unesterified steroid.[6]

Chemistry

[edit]
See also:List of progestogens,Progestogen ester, andList of progestogen esters

Gestonorone caproate, also known as norhydroxyprogesterone caproate, 17α-hydroxy-19-norprogesterone 17α-hexanoate, or 17α-hydroxy-19-norpregn-4-ene-3,20-dione 17α-hexanoate, is asyntheticnorpregnanesteroid and aderivative ofprogesterone.[63][16] It is specifically a combined derivative of17α-hydroxyprogesterone and19-norprogesterone, or ofgestronol (17α-hydroxy-19-norprogesterone), with ahexanoate (caproate)ester at the C17α position.[63][16]Analogues and derivatives of gestonorone caproate includealgestone acetophenide (dihydroxyprogesterone acetophenide),demegestone,nomegestrol acetate,norgestomet, andsegesterone acetate, as well as18-methylsegesterone acetate and thecaproate esterschlormadinone caproate,hydroxyprogesterone caproate,medroxyprogesterone caproate,megestrol caproate, andmethenmadinone caproate.[63][16]

Synthesis

[edit]

Chemical syntheses of gestonorone caproate have been published.[5][7][64]

History

[edit]

Gestonorone caproate was first described in 1960.[14] It was developed bySchering and has been marketed since at least 1968.[12][15]

Society and culture

[edit]

Generic names

[edit]

Gestonorone caproate is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name, andJANTooltip Japanese Accepted Name, whilegestronol hexanoate is itsBANMTooltip British Approved Name.[63][16] It has also been referred to asnorhydroxyprogesterone caproate, and is also known by its former developmental code namesSH-582 andSH-80582.[63][16][17]

Brand names

[edit]

Gestonorone caproate has been marketed exclusively under the brand names Depostat and Primostat.[63][16][17][18][19]

Availability

[edit]
Availability of gestonorone caproate in countries throughout the world as of March 2018. Blue is currently marketed, green is formerly marketed.

Gestonorone caproate has been available widely inEurope, including in theUnited Kingdom, and has also been marketed inJapan,China,Mexico, and certain other countries.[1][16][17][18] However, it has been discontinued in most countries and its availability is more limited today; it appears to remain marketed only in theCzech Republic, Japan, Mexico, andRussia.[18][19][65] It has not been marketed in theUnited States,Canada, and many other countries.[16][17][18][19]

Research

[edit]

Gestonorone caproate was studied in the treatment ofprostate cancer in men at a dosage of 400 mg per week by intramuscular injection but, in contrast to the case ofbenign prostatic hyperplasia, was found to be ineffective.[66][67]

SH-834 was a combination of 90 mgestradiol valerate and 300 mg gestonorone caproate for weekly intramuscular injection that was developed by Schering in the 1960s and 1970s.[68][22][69] It was investigated clinically as a treatment forbreast cancer and was found to be effective.[68][70][69] However, its effectiveness was found to be no better than that of anestrogen alone, and the combination was ultimately never marketed.[71]

Gestonorone caproate was studied bySchering for use as aprogestogen-only injectable contraceptive across a dose range of 2.5 to 200 mg once every one or two months but was never marketed.[61][72][73][74][75][76][77][78] There is very little clinical experience of gestonorone caproate for this indication.[61]

Gestonorone caproate has been studied in the treatment ofovarian cancer (in combination withcyclophosphamide),[5][22][79][80]menstrual cycle-relatedmouth ulcers,[21] and as a component ofmenopausal hormone therapy.[60]

See also

[edit]

References

[edit]
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  4. ^abcBreuer H, Lisboa BP (January 1966). "[Studies on the metabolism of 17-alpha-hydroxy-19-norprogesterone caproate by humans in vivo and of 17-alpha-hydroxy-19-norprogesterone by rats in vitro]" [Studies on the metabolism of 17-alpha-hydroxy-19-norprogesterone caproate by humans in vivo and of 17-alpha-hydroxy-19-norprogesterone by rats in vitro].Acta Endocrinologica (in German).51 (1):114–130.doi:10.1530/acta.0.0510114.PMID 4285463.
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  50. ^Wright JC, Burgess DJ (29 January 2012).Long Acting Injections and Implants. Springer Science & Business Media. pp. 114–.ISBN 978-1-4614-0554-2.
  51. ^Chu YH, Li Q, Zhao ZF (April 1986)."Pharmacokinetics of megestrol acetate in women receiving IM injection of estradiol-megestrol long-acting injectable contraceptive".The Chinese Journal of Clinical Pharmacology.The results showed that after injection the concentration of plasma MA increased rapidly. The meantime of peak plasma MA level was 3rd day, there was a linear relationship between log of plasma MA concentration and time (day) after administration in all subjects, elimination phase half-life t1/2β = 14.35 ± 9.1 days.
  52. ^Runnebaum BC, Rabe T, Kiesel L (6 December 2012).Female Contraception: Update and Trends. Springer Science & Business Media. pp. 429–.ISBN 978-3-642-73790-9.
  53. ^Artini PG, Genazzani AR, Petraglia F (11 December 2001).Advances in Gynecological Endocrinology. CRC Press. pp. 105–.ISBN 978-1-84214-071-0.
  54. ^King TL, Brucker MC, Kriebs JM, Fahey JO (21 October 2013).Varney's Midwifery. Jones & Bartlett Publishers. pp. 495–.ISBN 978-1-284-02542-2.
  55. ^Denis L (6 December 2012).The Medical Management of Prostate Cancer. Springer Science & Business Media. pp. 112–.ISBN 978-3-642-73238-6.Gestonorone caproate, another progestational agent, was investigated at our institution. Eighteen patients with painful metastatic [prostate cancer] with objective relapse after orchiectomy were treated with 400 mg/week i.m.
  56. ^Runnebaum BC, Rabe T, Kiesel L (6 December 2012).Future Aspects in Contraception: Proceeding of an International Symposium held in Heidelberg, 5–8 September 1984 Part 1 Male Contraception. Springer Science & Business Media. pp. 133–.ISBN 978-94-009-4910-2.Gestonorone [caproate] 100 or 200 mg/week i.m.
  57. ^Palanca E, Juco W (2008). "Conservative treatment of benign prostatic hyperplasia".Current Medical Research and Opinion.4 (7):513–520.doi:10.1185/03007997709109342.PMID 66118.S2CID 31798723.A study was carried out in 30 male patients with benign prostate hyperplasia to assess the effectiveness of treatment with a progestational agent, gestonorone caproate (200 mg), given intramuscularly every 7 days over a period of 2 to 3 months.
  58. ^Nevinny-Stickel J (1962). "Die gestagene Wirkung von Hydroxy-nor-Progesteronestern bei der Frau".Gewebs- und Neurohormone [The progestational effects of hydroxy-nor-progesterone esters in women]. Symposion der Deutschen Gesellschaft für Endokrinologie. Springer. pp. 248–255.doi:10.1007/978-3-642-86860-3_27.ISBN 978-3-540-02909-0.Das Hydroxy-nor-Progesteron-Capronat stand in öliger Lösung zm intramuskulären Injektion zur Verfügung. Die Wirkungsdauer betrug 10-13 Tage. Nach Verabreichung von 25 mg waren als beginnende Sekretionszeichen (1) an den geschlängelten Drüsen basale Vacuolen der Epithelien zu sehen. Eine volle Umwandlung der Schleimhaut erfolgte erst auf 50 mg des Capronsäureesters (Abb. l und 2).
  59. ^Horský J, Presl J (1981)."Hormonal Treatment of Disorders of the Menstrual Cycle". In Horsky J, Presl J (eds.).Ovarian Function and its Disorders: Diagnosis and Therapy. Developments in Obstetrics and Gynecology. Springer Science & Business Media. pp. 309–332.doi:10.1007/978-94-009-8195-9_11.ISBN 978-94-009-8195-9.
  60. ^abLindsay R, Hart DM, Purdie D, Ferguson MM, Clark AS, Kraszewski A (February 1978). "Comparative effects of oestrogen and a progestogen on bone loss in postmenopausal women".Clinical Science and Molecular Medicine.54 (2):193–195.doi:10.1042/cs0540193.PMID 340117.S2CID 1799407.
  61. ^abcToppozada M (June 1977). "The clinical use of monthly injectable contraceptive preparations".Obstetrical & Gynecological Survey.32 (6):335–347.doi:10.1097/00006254-197706000-00001.PMID 865726.
  62. ^Nagel R, Kolb K, Kroemer C, Maksimović P, Laudahn G (1973). "Verteilungsstudien und pharmakokinetische Parameter nach i.m. Gabe von Gestonoron-capronat (Depostat) und Cyproteron-acetat (Androcur) beim Menschen".24. Tagung vom 13. Bis 16. September 1972 in Hannover [Distribution studies and pharmacokinetic parameters after i.m. administration of gestonoron-capronate (Depostat) and cyproterone-acetate (Androcur) in man]. Verhandlungsbericht der Deutschen Gesellschaft für Urologie. Vol. 24. pp. 133–138.doi:10.1007/978-3-642-80738-1_36.ISBN 978-3-540-06186-1.ISSN 0070-413X.
  63. ^abcdefElks J (14 November 2014).The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 595–.ISBN 978-1-4757-2085-3.
  64. ^Kleemann A, Engel J (2001).Pharmaceutical substances: syntheses, patents, applications. Thieme. p. 962.ISBN 978-3-13-558404-1.
  65. ^"Find product information about medicines".
  66. ^Smith PH (29 June 2013).Cancer of the Prostate and Kidney. Springer Science & Business Media. pp. 309–.ISBN 978-1-4684-4349-3.
  67. ^Sander S, Nissen-Meyer R, Aakvaag A (1977). "On gestagen treatment of advanced prostatic carcinoma".Scandinavian Journal of Urology and Nephrology.12 (2):119–121.doi:10.3109/00365597809179977.PMID 694436.
  68. ^abNotter G, Berndt G (October 1975). "Hormonal treatment of mammary carcinoma with Progynon-Depot and Depostat".Acta Radiologica.14 (5):433–442.doi:10.3109/02841867509132684.PMID 1202923.
  69. ^abBerndt G, Eckel H, Notter G, St Stender H (May 1971)."[Effect of estrogen-gestagen combination therapy in advanced breast carcinoma with special reference to pulmonary metastases]" [Effect of Estrogen-Gestagen Combination Therapy in Advanced Breast Carcinoma with Special Reference to Pulmonary Metastases].Strahlentherapie (in German).141 (5):540–548.PMID 5088730. Archived fromthe original on 2017-07-29. Retrieved2019-05-20.
  70. ^Berndt G, Stender HS (November 1970). "[The combined estrogen-gestagen treatment of metastasizing mammary carcinoma using with SH 834]".Deutsche Medizinische Wochenschrift.95 (48): 2399+.doi:10.1055/s-0028-1108843.PMID 5529652.S2CID 70908169.
  71. ^Firusian N, Schietzel M (September 1976). "[Additive treatment of metastasizing breast cancer with special reference to postmenopausal age (results of a randomized study)]" [Additive treatment of metastasizing breast cancer with special reference to postmenopausal age (results of a randomized study)].Strahlentherapie (in German).152 (3):235–247.PMID 968923.
  72. ^Toppozada MK (1983). "Monthly Injectable Contraceptives". In Goldsmith A, Toppozada MK (eds.).Long-Acting Contraception. pp. 93–103.OCLC 35018604.
  73. ^Kadam SS (July 2007).Principles of Medicinal Chemistry Volume 2. Pragati Books Pvt. Ltd. pp. 381–.ISBN 978-81-85790-03-9.
  74. ^Karim M, El-mahgoub S (September 1970)."Injectable steroids as a method of contraception".Ain Shams Medical Journal.21 (5):543–550.PMID 12313080.
  75. ^Carlborg L (July 1973)."Effect of norhydroxyprogesterone caproate on cervical sperm penetration and secretion of ovarian steroids in the human female".Upsala Journal of Medical Sciences.78 (3):189–190.doi:10.3109/03009737309178626.PMID 4797435.
  76. ^Hurtado H, Kesseru E, Larrañaga A (2015)."Empleo del capronato de 17-hidroxi-19-norprogesterona como anticonceptivo inyectable de depósito".Revista Peruana de Ginecología y Obstetricia.14 (2):223–233.doi:10.31403/rpgo.v14i1457. Archived fromthe original on 2018-09-19. Retrieved2018-09-19.
  77. ^Nazer J, Valenzuela CY (March 1973)."[Possible biological effects of contraceptives]".Revista Médica de Chile (in Spanish).101 (3):234–236.PMID 4732140.
  78. ^Rodriguez-Restrepo R (1969)."17-alpha-hydroxy 19 norprogesterone capronate as a prolonged-action injectable contraceptive agent".Revista Colombiana de Obstetricia y Ginecologia.20:247–255. Archived fromthe original on 2018-09-19.
  79. ^Guthrie D (July 1979). "The treatment of advanced cystadenocarcinoma of the ovary with gestronol and continuous oral cyclophosphamide".British Journal of Obstetrics and Gynaecology.86 (7):497–500.doi:10.1111/j.1471-0528.1979.tb10799.x.PMID 476014.S2CID 31408925.
  80. ^Darwish DH (August 1978). "The effect of sex steroids on the in vitro synthesis of DNA by malignant ovarian tumours".British Journal of Obstetrics and Gynaecology.85 (8):627–633.doi:10.1111/j.1471-0528.1978.tb14933.x.PMID 687544.S2CID 30816473.
Progestogens
(andprogestins)
PRTooltip Progesterone receptoragonists
Antiprogestogens
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