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]
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 cancercellsin vitro.[5]
Gestonorone caproate has been reported to act to some extent as a
5α-reductase inhibitor, similarly to progesterone.[34][35]
^
abIn 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
radioactivesteroid 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-norpregnanemetabolites 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
urinarypregnanetriolexcretion 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]
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
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]
^
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.
PMID4285463.
^
abSchoonees R, de Klerk JN, Murphy GP (1969). "The effect of depostat (SH 582) on the baboon prostate". Journal of Surgical Oncology. 1 (4): 317–324.
doi:
10.1002/jso.2930010404.
PMID5000209.
S2CID33568137.
^
abcHorský J, Presl J (1981).
"Genital 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. 70–129.
doi:
10.1007/978-94-009-8195-9_11.
ISBN978-94-009-8195-9. Gestonorone caproate is a depot gestagen, five times more potent than 17α-hydroxyprogesterone caproate.
^
abcdeAubrey DA, Khosla T (September 1971). "The effect of 17-alpha-hydroxy-19-norprogesterone caproate (SH582) on benign prostatic hypertrophy". The British Journal of Surgery. 58 (9): 648–652.
doi:
10.1002/bjs.1800580904.
PMID4105896.
S2CID40905771.
^
abKaiser R (1960). "Klinische Erfahrungen mit Norprogesteronderivaten". ZBL. Gynäk. 82: 2009.
^
abSubbiah N, Mortensen J (February 1973). "The treatment of benign enlargement of the prostate with nor progesterone caproate (primostat)". The Australian and New Zealand Journal of Surgery. 42 (3): 304–307.
doi:
10.1111/j.1445-2197.1973.tb06805.x.
PMID4129814.
^
abcFerguson 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.
PMID102602.
^
abMoe 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.
PMID4261828.
S2CID7181971. 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.
^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.
PMID5369019.
S2CID41105630.
^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.
PMID4117491.
S2CID7679705.
^
abcSander 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.
PMID694436.
^
abKjeld 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.
PMID519881.
S2CID5836155. 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).
^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.
PMID6237116.
^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.
PMID7000222.
^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.
PMID64267.
^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.
PMID1177428.
^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.
ISBN978-0-8247-8291-7.
^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.
PMID6452729.
^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.
PMID6223851.
^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.
^Denis L (6 December 2012).
The Medical Management of Prostate Cancer. Springer Science & Business Media. pp. 112–.
ISBN978-3-642-73238-6. 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.
^Palanca E, Juco W (2008). "Conservative treatment of benign prostatic hyperplasia". Current Medical Research and Opinion. 4 (7): 513–520.
doi:
10.1185/03007997709109342.
PMID66118.
S2CID31798723. 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.
^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.
ISBN978-3-540-02909-0. 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).
^
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.
PMID340117.
S2CID1799407.
^
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.
PMID865726.
^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.
ISBN978-3-540-06186-1.
ISSN0070-413X.
^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.
PMID5529652.
S2CID70908169.
^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.
PMID968923.
^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.
PMID476014.
S2CID31408925.
^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.
PMID687544.
S2CID30816473.