Gestonorone caproate

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Gestonorone caproate
Gestronol caproate.svg
Gestonorone caproate molecule ball.png
Clinical data
Trade names Depostat, 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 class Progestogen; Progestin; Progestogen ester; Antigonadotropin
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability Oral: Low [4]
IM: High [5]
Metabolism Reduction (at the C5, C3, and C20 positions) [6]
Metabolites • 19-Norpregnanetriol [6]
• 19-Norpregnanediol-20-one [6]
Elimination half-life IM: 7.5 ± 3.1 days [5]
Duration of action IM: ≥21 days [5]
Excretion Urine: 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
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.013.646 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C26H38O4
Molar mass 414.586 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 as gestronol hexanoate or norhydroxyprogesterone caproate and sold under the brand names Depostat and Primostat, is a progestin medication which is used in the treatment of enlarged prostate and cancer of the endometrium. [5] [3] [7] [1] [8] It is given by injection into muscle typically once a week. [4]

Contents

Side effects of gestonorone caproate include worsened glucose tolerance, decreased libido in men, and injection site reactions. [5] Gestonorone caproate is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. [9] [10] It has no other important 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 palliative treatment of 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

Side effects of gestonorone caproate have been reported to include worsened glucose tolerance, decreased libido in men, and local injection site reactions such as irritation. [5]

Pharmacology

Pharmacodynamics

Gestonorone caproate is a potent, long-acting, and pure progestogen, [9] [10] [13] possessing no androgenic, anabolic, antiandrogenic, estrogenic, antiestrogenic, glucocorticoid, mineralocorticoid, or teratogenic effects. [5] [11] [12] [13] [21] It is approximately 20 to 25 times more potent than progesterone or hydroxyprogesterone caproate in animal bioassays when all are given by subcutaneous 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] The biological effects of gestonorone caproate in women have been studied. [25] [26]

Like other potent progestins, gestonorone caproate possesses potent antigonadotropic activity and is capable of markedly suppressing the gonadal production and circulating levels of sex hormones such as testosterone and estradiol. [13] [27] [28] A clinical study found that 400 mg/week intramuscular gestonorone caproate suppressed testosterone levels by 75% in men, while orchiectomy as a comparator reduced testosterone levels by 91%. [29] [30] Levels of luteinizing 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 no anticorticotropic effects, and does not influence the secretion of adrenocorticotropic hormone. [5]

17α-Hydroxyprogesterone has weak progestogenic activity, but C17α esterification results in higher progestogenic activity. [6] Of a variety of different esters, the 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 prostate gland and seminal vesicles by 40 to 70% in adult male rats. [5] It has been shown in canines 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 direct 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 [lower-alpha 1] [lower-alpha 2]
CompoundFormDose for specific uses (mg) [lower-alpha 3] DOA [lower-alpha 4]
TFD [lower-alpha 5] POICD [lower-alpha 6] CICD [lower-alpha 7]
Algestone acetophenide Oil soln.-–75–15014–32 d
Gestonorone caproateOil soln.25–50––8–13 d
Hydroxyprogest. acetate [lower-alpha 8] Aq. susp.350––9–16 d
Hydroxyprogest. caproate Oil soln.250–500 [lower-alpha 9] –250–5005–21 d
Medroxyprog. acetate Aq. susp.50–1001502514–50+ d
Megestrol acetate Aq. susp.-–25>14 d
Norethisterone enanthate Oil soln.100–2002005011–52 d
Progesterone Oil soln.200 [lower-alpha 9] ––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 by intramuscular or subcutaneous injection.
  3. ↑ Progesterone production during the luteal phase is ~25 (15–50) mg/day. The 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. 1 2 In divided doses (2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4).

Pharmacokinetics

Like the closely related progestins hydroxyprogesterone caproate and 19-norprogesterone, gestonorone caproate shows poor activity orally and must be administered parenterally; specifically, via intramuscular injection. [4] Gestonorone caproate is administered by intramuscular injection, and acts as a long-lasting depot by this route. [5] [55] [56] [57] After an intramuscular injection, gestonorone caproate is completely released from the local depot and is highly bioavailable. [5] A single intramuscular injection of 25 to 50 mg gestonorone caproate in oil solution has been found to have a duration of action of 8 to 13 days in terms of clinical biological effect in the uterus in women. [26] [58] [59] At high doses, the 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 radiolabeled gestonorone caproate in 1 mL of solution in men with prostate cancer, maximal levels of gestonorone caproate occurred after 3 ± 1 days and were 420 ± 160 ng/mL. [5] The elimination half-life of gestonorone caproate and its metabolites was 7.5 ± 3.1 days. [5] Approximately 5% of the radioactive steroid content in the blood was unchanged gestonorone caproate. [5] No free 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 metabolism of unesterified gestonorone (17α-hydroxy-19-norprogesterone) is analogous to that of 17α-hydroxyprogesterone, with the corresponding 19-norpregnane metabolites produced. [6] Gestonorone caproate has been found to undergo 5α-reduction similarly to progesterone, 17α-hydroxyprogesterone, and gestonorone, and at a similar rate as these steroids. [6] Conversely however, due to its caproate ester, 5β-reduction of gestonorone caproate is decreased relative to these steroids. [6] As progesterone is metabolized mainly into 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

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 synthetic norpregnane steroid and a derivative of progesterone. [63] [16] It is specifically a combined derivative of 17α-hydroxyprogesterone and 19-norprogesterone, or of gestronol (17α-hydroxy-19-norprogesterone), with a hexanoate (caproate) ester at the C17α position. [63] [16] Analogues and derivatives of gestonorone caproate include algestone acetophenide (dihydroxyprogesterone acetophenide), demegestone, nomegestrol acetate, norgestomet, and segesterone acetate, as well as 18-methylsegesterone acetate and the 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 generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, and JAN Tooltip Japanese Accepted Name, while gestronol hexanoate is its BANM Tooltip 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 availability.png
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 ovarian cancer (in combination with cyclophosphamide), [5] [22] [79] [80] menstrual cycle-related mouth ulcers, [21] and as a component of menopausal hormone therapy. [60]

See also

Related Research Articles

<span class="mw-page-title-main">Progestogen (medication)</span> Medication producing effects similar to progesterone

A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.

<span class="mw-page-title-main">Hydroxyprogesterone caproate</span> Medication

Hydroxyprogesterone caproate, sold under the brand names Proluton and Makena among others, is a medication used to reduce the risk of preterm birth in women pregnant with one baby who have a history of spontaneous preterm birth. In March 2023, the manufacturer, Covis Pharma, agreed to withdraw the drug from the US market. The approvals of Makena and its generics were withdrawn by the US Food and Drug Administration (FDA) in April 2023.

Combined injectable contraceptives (CICs) are a form of hormonal birth control for women. They consist of monthly injections of combined formulations containing an estrogen and a progestin to prevent pregnancy.

<span class="mw-page-title-main">Algestone acetophenide</span> Chemical compound

Algestone acetophenide, also known more commonly as dihydroxyprogesterone acetophenide (DHPA) and sold under the brand names Perlutal and Topasel among others, is a progestin medication which is used in combination with an estrogen as a form of long-lasting injectable birth control. It has also been used alone, but is no longer available as a standalone medication. DHPA is not active by mouth and is given once a month by injection into muscle.

<span class="mw-page-title-main">Norethisterone enanthate</span> Chemical compound

Norethisterone enanthate (NETE), also known as norethindrone enanthate, is a form of hormonal birth control which is used to prevent pregnancy in women. It is used both as a form of progestogen-only injectable birth control and in combined injectable birth control formulations. It may be used following childbirth, miscarriage, or abortion. The failure rate per year in preventing pregnancy for the progestogen-only formulation is 2 per 100 women. Each dose of this form lasts two months with only up to two doses typically recommended.

<span class="mw-page-title-main">Segesterone acetate</span> Progestin medication

Segesterone acetate (SGA), sold under the brand names Nestorone, Elcometrine, and Annovera, is a progestin medication which is used in birth control and in the treatment of endometriosis in the United States, Brazil, and other South American countries. It is available both alone and in combination with an estrogen. It is not effective by mouth and must be given by other routes, most typically as a vaginal ring or implant that is placed into fat.

<span class="mw-page-title-main">19-Norprogesterone</span> Chemical compound

19-Norprogesterone, also known as 19-norpregn-4-ene-3,20-dione, is a steroidal progestin and close analogue of the sex hormone progesterone, lacking only the C19 methyl group of that molecule. It was first synthesized in 1944 in the form of a mixture that also included unnatural stereoisomers of progesterone, and this mixture was found to be at least equivalent to progesterone in terms of progestogenic activity. Subsequent investigations revealed that 17-isoprogesterone and 14-iso-17-isoprogesterone are devoid of progestogenic activity. 19-Norprogesterone was resynthesized in 1951 with an improved method, and was confirmed to be the component of the mixture synthesized in 1944 that was responsible for its progestogenic activity. In 1953, a paper was published showing that 19-norprogesterone possessed 4- to 8-fold the activity of progesterone in the Clauberg assay in rabbits, and at the time of this discovery, 19-norprogesterone was the most potent progestogen known.

<span class="mw-page-title-main">Hydroxyprogesterone acetate</span> Chemical compound

Hydroxyprogesterone acetate (OHPA), sold under the brand name Prodox, is an orally active progestin related to hydroxyprogesterone caproate (OHPC) which has been used in clinical and veterinary medicine. It has reportedly also been used in birth control pills.

<span class="mw-page-title-main">Hydroxyprogesterone heptanoate</span> Chemical compound

Hydroxyprogesterone heptanoate (OHPH), also known as hydroxyprogesterone enanthate (OHPE) and sold under the brand names H.O.P., Lutogil A.P., and Lutogyl A.P. among others, is a progestin medication used for progestogenic indications. It has been formulated both alone and in together with estrogens, androgens/anabolic steroids, and other progestogens in several combination preparations. OHPH is given by injection into muscle at regular intervals.

<span class="mw-page-title-main">Progestogen ester</span> Drug class

A progestogen ester is an ester of a progestogen or progestin. The prototypical progestogen is progesterone, an endogenous sex hormone. Esterification is frequently employed to improve the pharmacokinetics of steroids, including oral bioavailability, lipophilicity, and elimination half-life. In addition, with intramuscular injection, steroid esters are often absorbed more slowly into the body, allowing for less frequent administration. Many steroid esters function as prodrugs.

<span class="mw-page-title-main">Oxogestone phenpropionate</span> Chemical compound

Oxogestone phenpropionate, also known as xinogestone, as well as 20β-hydroxy-19-norprogesterone 20β-(3-phenylpropionate), is a progestin related to the 19-norprogesterone derivatives which was developed as an injectable hormonal contraceptive, specifically a progestogen-only injectable contraceptive, in the 1960s and early 1970s but was never marketed. It was studied at a dose of 50 to 75 mg once a month by intramuscular injection but was associated with a high failure rate with this regimen and was not further developed. OPP is the 20β-(3-phenylpropionate) ester of oxogestone, which, similarly, was never marketed.

Progestogen-only injectable contraceptives (POICs) are a form of hormonal contraception and progestogen-only contraception that are administered by injection and providing long-lasting birth control. As opposed to combined injectable contraceptives, they contain only a progestogen without an estrogen, and include two progestin preparations:

<span class="mw-page-title-main">Levonorgestrel butanoate</span> Chemical compound

Levonorgestrel butanoate (LNG-B), or levonorgestrel 17β-butanoate, is a steroidal progestin of the 19-nortestosterone group which was developed by the World Health Organization (WHO) in collaboration with the Contraceptive Development Branch (CDB) of the National Institute of Child Health and Human Development as a long-acting injectable contraceptive. It is the C17β butanoate ester of levonorgestrel, and acts as a prodrug of levonorgestrel in the body. The drug is at or beyond the phase III stage of clinical development, but has not been marketed at this time. It was first described in the literature, by the WHO, in 1983, and has been under investigation for potential clinical use since then.

<span class="mw-page-title-main">Gestadienol acetate</span> Chemical compound

Gestadienol acetate an orally active progestin which was described in the literature in 1967 and was never marketed. It has no androgenic or estrogenic effects. The effects of gestadienol acetate on the endometrium and its general pharmacology were studied in a clinical trial in women. It has also been studied in a clinical trial for benign prostatic hyperplasia in men, but was ineffective.

<span class="mw-page-title-main">Estradiol benzoate/progesterone</span> Drug combination

Estradiol benzoate/progesterone (EB/P4), sold under the brand names Duogynon and Sistocyclin among others, is a combination medication of estradiol benzoate (EB), an estrogen, and progesterone (P4), a progestogen. It has been formulated both as short-acting oil solutions and long-acting microcrystalline aqueous suspensions and is given by injection into muscle either once or continuously at regular intervals.

<span class="mw-page-title-main">Methenmadinone caproate</span> Chemical compound

Methenmadinone caproate is a progestin medication which was developed in Czechoslovakia in the 1960s and was studied for potential use in combined injectable contraceptives in the 1970s but was never marketed. It was studied as a combined injectable contraceptive in combination with estradiol valerate at doses of 60 mg and 10 mg, respectively, once a month by intramuscular injection. MMC is the C17α caproate (hexanoate) ester of methenmadinone and an analogue of methenmadinone acetate. In addition to MMA, analogues of MMC include chlormadinone caproate, gestonorone caproate, hydroxyprogesterone caproate, medroxyprogesterone caproate, and megestrol caproate.

<span class="mw-page-title-main">Lynestrenol phenylpropionate</span> Chemical compound

Lynestrenol phenylpropionate (LPP), also known as ethynylestrenol phenylpropionate, is a progestin and a progestogen ester which was developed for potential use as a progestogen-only injectable contraceptive by Organon but was never marketed. It was assessed at doses of 25 to 75 mg in an oil solution once a month by intramuscular injection. LPP was associated with high contraceptive failure at the low dose and with poor cycle control. The medication was found to produce estrogenic effects in the endometrium in women due to transformation into estrogenic metabolites.

<span class="mw-page-title-main">Gestonorone acetate</span> Chemical compound

Gestonorone acetate, or gestronol acetate, also known as norhydroxyprogesterone acetate, is a progestin of the 19-norprogesterone and 17α-hydroxyprogesterone groups which was developed in the early 1960s but was never marketed. It is the C17α acetate ester of gestronol (17α-hydroxy-19-norprogesterone).

<span class="mw-page-title-main">Estradiol valerate/gestonorone caproate</span> Combination drug

Estradiol valerate/gestonorone caproate (EV/GC), known by the developmental code names SH-834 and SH-8.0834, is a high-dose combination medication of estradiol valerate (EV), an estrogen, and gestonorone caproate, a progestin, which was developed and studied by Schering in the 1960s and 1970s for potential use in the treatment of breast cancer in women but was ultimately never marketed. It contained 90 mg EV and 300 mg GC in each 3 mL of oil solution and was intended for use by intramuscular injection once a week. The combination has also been studied incidentally in the treatment of ovarian cancer.

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  20. ↑ Smith HJ, Williams H (10 October 2005). Smith and Williams' Introduction to the Principles of Drug Design and Action, Fourth Edition. CRC Press. pp. 493–. ISBN   978-0-203-30415-0.
  21. 1 2 3 Ferguson MM, McKay Hart D, Lindsay R, Stephen KW (October 1978). "Progeston therapy for menstrually related aphthae". International Journal of Oral Surgery. 7 (5): 463–470. doi:10.1016/S0300-9785(78)80038-6. PMID   102602.
  22. 1 2 3 Ward HW (June 1972). "Progestogen therapy for ovarian carcinoma". The Journal of Obstetrics and Gynaecology of the British Commonwealth. 79 (6): 555–559. doi:10.1111/j.1471-0528.1972.tb14200.x. PMID   4555897. S2CID   2586346.
  23. 1 2 Karlstedt K (April 1971). "Progesterone treatment for local recurrence and metastases in carcinoma corporis uteri". Acta Radiologica. 10 (2): 187–192. doi: 10.3109/02841867109129755 . PMID   5556820. 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. 1 2 Moe N (1972). "Short-term progestogen treatment of endometrial carcinoma. Histological, histochemical and hormonal studies". Acta Obstetricia et Gynecologica Scandinavica. 51 (1): 55–62. doi:10.3109/00016347209154968. PMID   4261828. 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.
  25. ↑ Jürgensen O, Taubert HD (February 1969). "[Clinical observations on the effect of depot gestagen 17 alpha-hydroxy-19-nor-progesterone caproate in women with eumenorrhea]" [Clinical observations on the effect of the depot gestagen 17α-hydroxy-19-nor-progesterone capronate in women with eumenorrhea]. Klinische Wochenschrift. 47 (3): 162–165. doi:10.1007/BF01746052. PMID   5369019. S2CID   41105630.
  26. 1 2 Ferin J (September 1972). "Effects, Duration of Action and Metabolism in Man". In Tausk M (ed.). Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents. Vol. II. Pergamon Press. pp. 13–24. ISBN   978-0080168128. OCLC   278011135.
  27. ↑ Raspé G, Brosig W (22 October 2013). International Symposium on the Treatment of Carcinoma of the Prostate, Berlin, November 13 to 15, 1969: Life Science Monographs. Elsevier. p. 169. ISBN   978-1-4831-8711-2.
  28. ↑ Makrigiannis D, Gaca A (1971). "Evaluation of Depostat in prostatic adenoma on the ground of clinical and sphincterotonometric studies". International Urology and Nephrology. 3 (1): 21–29. doi:10.1007/BF02081794. PMID   4117491. S2CID   7679705.
  29. 1 2 3 Sander S, Nissen-Meyer R, Aakvaag A (1978). "On gestagen treatment of advanced prostatic carcinoma". Scandinavian Journal of Urology and Nephrology. 12 (2): 119–121. doi:10.3109/00365597809179977. PMID   694436.
  30. 1 2 Kjeld JM, Puah CM, Kaufman B, Loizou S, Vlotides J, Gwee HM, et al. (November 1979). "Effects of norgestrel and ethinyloestradiol ingestion on serum levels of sex hormones and gonadotrophins in men". Clinical Endocrinology. 11 (5): 497–504. doi:10.1111/j.1365-2265.1979.tb03102.x. PMID   519881. S2CID   5836155. 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).
  31. ↑ Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA (25 August 2011). Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set. Elsevier Health Sciences. pp. 2938–. ISBN   978-1-4160-6911-9.
  32. ↑ Knuth UA, Hano R, Nieschlag E (November 1984). "Effect of flutamide or cyproterone acetate on pituitary and testicular hormones in normal men". The Journal of Clinical Endocrinology and Metabolism. 59 (5): 963–969. doi:10.1210/jcem-59-5-963. PMID   6237116.
  33. ↑ Jacobi GH, Altwein JE, Kurth KH, Basting R, Hohenfellner R (June 1980). "Treatment of advanced prostatic cancer with parenteral cyproterone acetate: a phase III randomised trial". British Journal of Urology. 52 (3): 208–215. doi:10.1111/j.1464-410x.1980.tb02961.x. PMID   7000222.
  34. ↑ Orestano F, Altwein JE (December 1976). "Testosterone metabolism in benign prostatic hypertrophy: in vivo studies of gestonorone caproate and cyproterone acetate". British Journal of Urology. 48 (6): 485–491. doi:10.1111/j.1464-410X.1976.tb06687.x. PMID   64267.
  35. ↑ Orestano F, Altwein JE, Knapstein P, Bandhauer K (June 1975). "Mode of action of progesterone, gestonorone capronate (Depostat) and cyproterone acetate (Androcur) on the metabolism of testosterone in human prostatic adenoma: in vitro and in vivo investigations". Journal of Steroid Biochemistry. 6 (6): 845–851. doi:10.1016/0022-4731(75)90313-1. PMID   1177428.
  36. ↑ Knörr K, Beller FK, Lauritzen C (17 April 2013). Lehrbuch der Gynäkologie. Springer-Verlag. pp. 214–. ISBN   978-3-662-00942-0.
  37. ↑ Knörr K, Knörr-Gärtner H, Beller FK, Lauritzen C (8 March 2013). Geburtshilfe und Gynäkologie: Physiologie und Pathologie der Reproduktion. Springer-Verlag. pp. 583–. ISBN   978-3-642-95583-9.
  38. ↑ Labhart A (6 December 2012). Clinical Endocrinology: Theory and Practice. Springer Science & Business Media. pp. 554–. ISBN   978-3-642-96158-8.
  39. ↑ Horský J, Presl J (1981). "Hormonal Treatment of Disorders of the Menstrual Cycle". In Horsky J, Presl K (eds.). Ovarian Function and its Disorders: Diagnosis and Therapy. Springer Science & Business Media. pp. 309–332. doi:10.1007/978-94-009-8195-9_11. ISBN   978-94-009-8195-9.
  40. ↑ Ufer J (1969). The Principles and Practice of Hormone Therapy in Gynaecology and Obstetrics. de Gruyter. p. 49. ISBN   9783110006148. 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.
  41. ↑ Pschyrembel W (1968). Praktische Gynäkologie: für Studierende und Ärzte. Walter de Gruyter. pp. 598, 601. ISBN   978-3-11-150424-7.
  42. ↑ Ferin J (September 1972). "Effects, Duration of Action and Metabolism in Man". In Tausk M (ed.). Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents. Vol. II. Pergamon Press. pp. 13–24. ISBN   978-0080168128. OCLC   278011135.
  43. ↑ Henzl MR, Edwards JA (10 November 1999). "Pharmacology of Progestins: 17α-Hydroxyprogesterone Derivatives and Progestins of the First and Second Generation". In Sitruk-Ware R, Mishell DR (eds.). Progestins and Antiprogestins in Clinical Practice. Taylor & Francis. pp. 101–132. ISBN   978-0-8247-8291-7.
  44. ↑ Brotherton J (1976). Sex Hormone Pharmacology. Academic Press. p. 114. ISBN   978-0-12-137250-7.
  45. ↑ Sang GW (April 1994). "Pharmacodynamic effects of once-a-month combined injectable contraceptives". Contraception. 49 (4): 361–385. doi:10.1016/0010-7824(94)90033-7. PMID   8013220.
  46. ↑ Toppozada MK (April 1994). "Existing once-a-month combined injectable contraceptives". Contraception. 49 (4): 293–301. doi:10.1016/0010-7824(94)90029-9. PMID   8013216.
  47. ↑ Goebelsmann U (1986). "Pharmacokinetics of Contraceptive Steroids in Humans". In Gregoire AT, Blye RP (eds.). Contraceptive Steroids: Pharmacology and Safety. Springer Science & Business Media. pp. 67–111. doi:10.1007/978-1-4613-2241-2_4. ISBN   978-1-4613-2241-2.
  48. ↑ Becker H, Düsterberg B, Klosterhalfen H (1980). "[Bioavailability of cyproterone acetate after oral and intramuscular application in men (author's transl)]" [Bioavailability of Cyproterone Acetate after Oral and Intramuscular Application in Men]. Urologia Internationalis. 35 (6): 381–385. doi:10.1159/000280353. PMID   6452729.
  49. ↑ Moltz L, Haase F, Schwartz U, Hammerstein J (May 1983). "[Treatment of virilized women with intramuscular administration of cyproterone acetate]" [Efficacy of Intra muscularly Applied Cyproterone Acetate in Hyperandrogenism]. Geburtshilfe und Frauenheilkunde. 43 (5): 281–287. doi:10.1055/s-2008-1036893. PMID   6223851.
  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. 1 2 Lindsay 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. 1 2 3 Toppozada 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.
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  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. 1 2 Notter 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. 1 2 Berndt 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 from the original on 2017-07-29. Retrieved 2019-05-20.
  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.
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  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.
  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 from the 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.
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