Gestonorone caproate

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Gestonorone caproate
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]
Elimination half-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
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 as gestronol hexanoate or norhydroxyprogesterone caproate and sold under the brand names Depostat and Primostat, is a

enlarged prostate and cancer of the endometrium.[5][3][7][1][8] It is given by injection into muscle typically once a week.[4]

hormonal 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 throughout Europe, including in the United Kingdom, and has also been marketed in certain other countries such as Japan, China, and Mexico.[1][16][17][18] However, it has since mostly been discontinued, and it remains available today only in a handful of countries, including the Czech Republic, Japan, Mexico, and Russia.[18][19]

Medical uses

Gestonorone caproate is used in the

benign prostatic hypertrophy and endometrial cancer.[5][3][20] It is used at a dose of 100 to 200 mg once a week by intramuscular injection.[5]

Side effects

See also:
Progestin § Side effects

decreased libido in men, and local injection site reactions such as irritation.[5]

Pharmacology

Pharmacodynamics

Gestonorone caproate is a

biological effects of gestonorone caproate in women have been studied.[25][26]

Like other potent progestins, gestonorone caproate possesses potent

anticorticotropic effects, and does not influence the secretion of adrenocorticotropic hormone.[5]

caproate (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 caproate progestogen esters such as hydroxyprogesterone caproate.[6]

Gestonorone caproate has been found to decrease the weights of the

antiproliferative effects on human ovarian cancer cells in vitro.[5]

Gestonorone caproate has been reported to act to some extent as a

5α-reductase inhibitor, similarly to progesterone.[34][35]

Parenteral potencies and durations of progestogens[a][b]
Compound Form Dose for specific uses (mg)[c] DOA[d]
TFD[e] POICD[f] CICD[g]
Algestone acetophenide Oil soln. - – 75–150 14–32 d
Gestonorone caproate Oil soln. 25–50 – – 8–13 d
Hydroxyprogest. acetate[h] Aq. susp. 350 – – 9–16 d
Hydroxyprogest. caproate Oil soln. 250–500[i] – 250–500 5–21 d
Medroxyprog. acetate Aq. susp. 50–100 150 25 14–50+ d
Megestrol acetate Aq. susp. - – 25 >14 d
Norethisterone enanthate Oil soln. 100–200 200 50 11–52 d
Progesterone Oil 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. subcutaneous injection
    .
  3. OID
    Tooltip 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. ^ a b In divided doses (2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4).

Pharmacokinetics

Like the closely related progestins hydroxyprogesterone caproate and

duration 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 mg

gestonorone was observed in circulation or in urine.[5] Gestonorone caproate and its metabolites were eliminated 72% in feces and 28% in urine.[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]

The

5β-pregnanes, decreased 5β-reduction of gestonorone caproate may be involved in its greater potency compared to progesterone.[6] The major metabolites of gestonorone caproate have been reported to be isomers of 19-norpregnanetriol and 19-norpregnanediol-20-one.[6][21] These metabolites indicate that gestonorone caproate is metabolized mainly by reduction at the C3, C5, and C20 positions.[6] Following an intramuscular injection of 300 mg gestonorone caproate, only a slight increase in urinary pregnanetriol excretion has been observed.[6] Cleavage of the caproate ester of gestonorone caproate is minimal, which indicates that it is not a prodrug of the unesterified steroid.[6]

Chemistry

See also: List of progestogens, Progestogen ester, and List 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 a

caproate esters chlormadinone caproate, hydroxyprogesterone caproate, medroxyprogesterone caproate, megestrol caproate, and methenmadinone caproate.[63][16]

Synthesis

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

History

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

Society and culture

Generic names

Gestonorone caproate is the

INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, and JANTooltip Japanese Accepted Name, while gestronol hexanoate is its BANMTooltip British Approved Name.[63][16] It has also been referred to as norhydroxyprogesterone caproate, and is also known by its former developmental code names SH-582 and SH-80582.[63][16][17]

Brand names

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

Availability

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 in Europe, including in the United Kingdom, and has also been marketed in Japan, 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 the Czech Republic, Japan, Mexico, and Russia.[18][19][65] It has not been marketed in the United States, Canada, and many other countries.[16][17][18][19]

Research

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

SH-834 was a combination of 90 mg estradiol 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 for breast cancer and was found to be effective.[68][70][69] However, its effectiveness was found to be no better than that of an estrogen alone, and the combination was ultimately never marketed.[71]

Gestonorone caproate was studied by Schering for use as a progestogen-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 of

menopausal hormone therapy.[60]

See also

References

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    . Gestonorone caproate is a depot gestagen, five times more potent than 17α-hydroxyprogesterone caproate.
  12. ^ a b c Schering, A. G. (1968). Depostat (SH 582): A New Treatment for Prostatic Hypertrophy. https://scholar.google.com/scholar?cluster=13658296147916476056
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    . The preparations used were Proluton Depot (17a-hydroxy-progesterone caproate) and in 3 patients SH 5132 (17a-hydroxy-19-norprogesterone caproate); 100 mg of the latter corresponds to 1000 mg of Proluton Depot.
  24. ^
    S2CID 7181971
    . Thirteen patients with primary adenocarcinoma of the uterine corpus were treated for 21 days with 17alpha-hydroxy-progesterone-caproate (Primolut Depot®, Schering), 1000 mg daily, or 17alpha-hydroxy-19-nor-progesterone-caproate (Depostat®, Schering), 200 mg daily. These doses can be considered as equivalent.
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    . Another synthetic gestogen, 17-hydroxy-19-norprogesterone caproate (Depostat-Schering), 400 mg by i.m. weekly injections suppressed T levels to 25% of pretreatment values (Sander er al., 1978).
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    . 17α-Hydroxyprogesterone caproate is a depot progestogen which is entirely free of side actions. The dose required to induce secretory changes in primed endometrium is about 250 mg. per menstrual cycle.
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    . 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. ISBN 978-94-009-4910-2
    . Gestonorone [caproate] 100 or 200 mg/week i.m.
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    . 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. 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).
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