Gestonorone caproate

Medical uses

Gestonorone caproate is used in the palliative treatment of benign prostatic hyperplasia and endometrial cancer. It is used at a dose of 100 to 200 mg once a week by intramuscular injection.

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.

Pharmacology

Pharmacodynamics

Gestonorone caproate is a potent, long-acting, and pure progestogen, possessing no androgenic, anabolic, antiandrogenic, estrogenic, antiestrogenic, glucocorticoid, mineralocorticoid, or teratogenic effects. It is approximately 20 to 25 times more potent than progesterone or hydroxyprogesterone caproate in animal bioassays when all are given by subcutaneous injection. In humans, 100 or 200 mg intramuscular gestonorone caproate has been said to be equivalent to 1,000 mg intramuscular hydroxyprogesterone caproate. Hence, gestonorone caproate is approximately 5- to 10-fold more potent than hydroxyprogesterone caproate in humans. The biological effects of gestonorone caproate in women have been studied.

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. 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%. Levels of luteinizing hormone, conversely, remained unchanged. In general, progestogens can maximally suppress testosterone levels by about 70 to 80%. In accordance with its lack of glucocorticoid activity, gestonorone caproate has no anticorticotropic effects, and does not influence the secretion of adrenocorticotropic hormone.

17α-Hydroxyprogesterone has weak progestogenic activity, but C17α esterification results in higher progestogenic activity. 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.

Gestonorone caproate has been found to decrease the weights of the prostate gland and seminal vesicles by 40 to 70% in adult male rats. It has been shown in canines to mediate these effects both via its antigonadotropic effects and by direct actions in these tissues. Gestonorone caproate decreases the uptake of testosterone into the prostate gland. It has also been found to have direct antiproliferative effects on human ovarian cancer cells in vitro.

Gestonorone caproate has been reported to act to some extent as a 5α-reductase inhibitor, similarly to progesterone.

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. Gestonorone caproate is administered by intramuscular injection, and acts as a long-lasting depot by this route. After an intramuscular injection, gestonorone caproate is completely released from the local depot and is highly bioavailable. 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. At high doses, the duration of action of gestonorone caproate by intramuscular injection has been found to be at least 21 days. 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.

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. The elimination half-life of gestonorone caproate and its metabolites was 7.5 ± 3.1 days. Approximately 5% of the radioactive steroid content in the blood was unchanged gestonorone caproate. No free gestonorone was observed in circulation or in urine. Gestonorone caproate and its metabolites were eliminated 72% in feces and 28% in urine. 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.

The metabolism of unesterified gestonorone (17α-hydroxy-19-norprogesterone) is analogous to that of 17α-hydroxyprogesterone, with the corresponding 19-norpregnane metabolites produced. Gestonorone caproate has been found to undergo 5α-reduction similarly to progesterone, 17α-hydroxyprogesterone, and gestonorone, and at a similar rate as these steroids. Conversely however, due to its caproate ester, 5β-reduction of gestonorone caproate is decreased relative to these steroids. As progesterone is metabolized mainly into 5β-pregnanes, decreased 5β-reduction of gestonorone caproate may be involved in its greater potency compared to progesterone. The major metabolites of gestonorone caproate have been reported to be isomers of 19-norpregnanetriol and 19-norpregnanediol-20-one. These metabolites indicate that gestonorone caproate is metabolized mainly by reduction at the C3, C5, and C20 positions. Following an intramuscular injection of 300 mg gestonorone caproate, only a slight increase in urinary pregnanetriol excretion has been observed. Cleavage of the caproate ester of gestonorone caproate is minimal, which indicates that it is not a prodrug of the unesterified steroid.

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. 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. 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.

Synthesis

Chemical syntheses of gestonorone caproate have been published.

History

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

Society and culture

Generic names

Gestonorone caproate is the generic name of the drug and its , , and , while gestronol hexanoate is its . It has also been referred to as norhydroxyprogesterone caproate, and is also known by its former developmental code names SH-582 and SH-80582.

Brand names

Gestonorone caproate has been marketed exclusively under the brand names Depostat and Primostat.

Availability

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. 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. It has not been marketed in the United States, Canada, and many other countries.

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.

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. It was investigated clinically as a treatment for breast cancer and was found to be effective. However, its effectiveness was found to be no better than that of an estrogen alone, and the combination was ultimately never marketed.

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. There is very little clinical experience of gestonorone caproate for this indication.

Gestonorone caproate has been studied in the treatment of ovarian cancer (in combination with cyclophosphamide), menstrual cycle-related mouth ulcers, and as a component of menopausal hormone therapy.

References

References

1. (21 February 2009). "Meyler's Side Effects of Endocrine and Metabolic Drugs". Elsevier.
2. (6 December 2012). "Concise Dictionary of Pharmacological Agents: Properties and Synonyms". Springer Science & Business Media.
3. William Andrew Publishing. (22 October 2013). "Pharmaceutical Manufacturing Encyclopedia, 3rd Edition". Elsevier.
4. Muller. (19 June 1998). "European Drug Index: European Drug Registrations". CRC Press.
5. (22 November 2006). "Chemistry and Pharmacology of Anticancer Drugs". CRC Press.
6. (1981). "Ovarian Function and its Disorders: Diagnosis and Therapy". Springer Science & Business Media.
7. (1960). "Klinische Erfahrungen mit Norprogesteronderivaten". ZBL. Gynäk.
8. (10 October 2005). "Smith and Williams' Introduction to the Principles of Drug Design and Action, Fourth Edition". CRC Press.
9. (22 October 2013). "Hormones and Embryonic Development: Advances in The Biosciences". Elsevier Science.
10. (1969). "The effect of depostat (SH 582) on the baboon prostate". Journal of Surgical Oncology.
11. (September 1971). "The effect of 17-alpha-hydroxy-19-norprogesterone caproate (SH582) on benign prostatic hypertrophy". The British Journal of Surgery.
12. (June 1972). "Progestogen therapy for ovarian carcinoma". The Journal of Obstetrics and Gynaecology of the British Commonwealth.
13. (April 1971). "Progesterone treatment for local recurrence and metastases in carcinoma corporis uteri". Acta Radiologica.
14. (1972). "Short-term progestogen treatment of endometrial carcinoma. Histological, histochemical and hormonal studies". Acta Obstetricia et Gynecologica Scandinavica.
15. (February 1969). "[Clinical observations on the effect of depot gestagen 17 alpha-hydroxy-19-nor-progesterone caproate in women with eumenorrhea]". Klinische Wochenschrift.
16. (22 October 2013). "International Symposium on the Treatment of Carcinoma of the Prostate, Berlin, November 13 to 15, 1969: Life Science Monographs". Elsevier.
17. (1971). "Evaluation of Depostat in prostatic adenoma on the ground of clinical and sphincterotonometric studies". International Urology and Nephrology.
18. (1978). "On gestagen treatment of advanced prostatic carcinoma". Scandinavian Journal of Urology and Nephrology.
19. (November 1979). "Effects of norgestrel and ethinyloestradiol ingestion on serum levels of sex hormones and gonadotrophins in men". Clinical Endocrinology.
20. (25 August 2011). "Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set". Elsevier Health Sciences.
21. (November 1984). "Effect of flutamide or cyproterone acetate on pituitary and testicular hormones in normal men". The Journal of Clinical Endocrinology and Metabolism.
22. (June 1980). "Treatment of advanced prostatic cancer with parenteral cyproterone acetate: a phase III randomised trial". British Journal of Urology.
23. (December 1976). "Testosterone metabolism in benign prostatic hypertrophy: in vivo studies of gestonorone caproate and cyproterone acetate". British Journal of Urology.
24. (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.
25. (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]". Acta Endocrinologica.
26. (6 December 2012). "The Medical Management of Prostate Cancer". Springer Science & Business Media.
27. (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.
28. (2008). "Conservative treatment of benign prostatic hyperplasia". Current Medical Research and Opinion.
29. (September 1972). "Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents". Pergamon Press.
30. (1962). "Gewebs- und Neurohormone". Springer.
31. (1981). "Ovarian Function and its Disorders: Diagnosis and Therapy". Springer Science & Business Media.
32. (1973). "24. Tagung vom 13. Bis 16. September 1972 in Hannover".
33. (27 November 2013). "Die Gestagene". Springer-Verlag.
34. (14 November 2014). "The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies". Springer.
35. (January 2000). "Index Nominum 2000: International Drug Directory". Taylor & Francis.
36. (2 July 2013). "Hagers Handbuch der Pharmazeutischen Praxis: Band 8: Stoffe E-O". Springer-Verlag.
37. (2001). "Pharmaceutical substances: syntheses, patents, applications". Thieme.
38. Schering, A. G. (1968). Depostat (SH 582): A New Treatment for Prostatic Hypertrophy. https://scholar.google.com/scholar?cluster=13658296147916476056
39. (February 1973). "The treatment of benign enlargement of the prostate with nor progesterone caproate (primostat)". The Australian and New Zealand Journal of Surgery.
40. "List of Progestins".
41. "Micromedex Products: Please Login".
42. (2009). "Martindale: The Complete Drug Reference". Pharmaceutical Press.
43. "Find product information about medicines".
44. (29 June 2013). "Cancer of the Prostate and Kidney". Springer Science & Business Media.
45. (1977). "On gestagen treatment of advanced prostatic carcinoma". Scandinavian Journal of Urology and Nephrology.
46. (October 1975). "Hormonal treatment of mammary carcinoma with Progynon-Depot and Depostat". Acta Radiologica.
47. (May 1971). "[Effect of estrogen-gestagen combination therapy in advanced breast carcinoma with special reference to pulmonary metastases]". Strahlentherapie.
48. (November 1970). "[The combined estrogen-gestagen treatment of metastasizing mammary carcinoma using with SH 834]". Deutsche Medizinische Wochenschrift.
49. (September 1976). "[Additive treatment of metastasizing breast cancer with special reference to postmenopausal age (results of a randomized study)]". Strahlentherapie.
50. (June 1977). "The clinical use of monthly injectable contraceptive preparations". Obstetrical & Gynecological Survey.
51. (1983). "Long-Acting Contraception".
52. (July 2007). "Principles of Medicinal Chemistry Volume 2". Pragati Books Pvt. Ltd..
53. (September 1970). "Injectable steroids as a method of contraception". Ain Shams Medical Journal.
54. (July 1973). "Effect of norhydroxyprogesterone caproate on cervical sperm penetration and secretion of ovarian steroids in the human female". Upsala Journal of Medical Sciences.
55. (2015). "Empleo del capronato de 17-hidroxi-19-norprogesterona como anticonceptivo inyectable de depósito". Revista Peruana de Ginecología y Obstetricia.
56. (March 1973). "[Possible biological effects of contraceptives]". Revista Médica de Chile.
57. (1969). "17-alpha-hydroxy 19 norprogesterone capronate as a prolonged-action injectable contraceptive agent.". Revista Colombiana de Obstetricia y Ginecologia.
58. (July 1979). "The treatment of advanced cystadenocarcinoma of the ovary with gestronol and continuous oral cyclophosphamide". British Journal of Obstetrics and Gynaecology.
59. (August 1978). "The effect of sex steroids on the in vitro synthesis of DNA by malignant ovarian tumours". British Journal of Obstetrics and Gynaecology.
60. (October 1978). "Progeston therapy for menstrually related aphthae". International Journal of Oral Surgery.
61. (February 1978). "Comparative effects of oestrogen and a progestogen on bone loss in postmenopausal women". Clinical Science and Molecular Medicine.