Estradiol valerate/hydroxyprogesterone caproate explained

Estradiol valerate/hydroxyprogesterone caproate (EV/OHPC), sold under the brand names Gravibinon and Injectable No. 1 (or Chinese Injectable No. 1) among others, is a combined estrogen and progestogen medication which is used in the treatment of threatened miscarriage and other indications (e.g., as a means of pseudopregnancy)[1] [2] and as a form of combined injectable birth control to prevent pregnancy.[3] [4] It contains estradiol valerate (EV), an estrogen, and hydroxyprogesterone caproate (OHPC), a progestin.[5] The medication is given by injection into muscle once a day to once a month depending on the indication.

Medical uses

EV/OHPC has been used in the treatment of threatened miscarriage (habitual abortion) and for other indications under the brand name Gravibinon among others in Europe and Latin America.[6] [7] The combination has also been used as a form of pseudopregnancy (high-dose estrogen/progestogen therapy), for instance to treat osteopenia due to hypogonadism, to induce feminization in hypogonadism/delayed puberty, and as a means of hormonal breast enhancement to produce breast enlargement.[8] [9] [10] EV/OHPC is administered daily to once per week or less often for the treatment of threatened miscarriage, for use as a form of pseudopregnancy, and for other indications.

EV/OHPC is used as a combined injectable contraceptive to prevent pregnancy in women under the brand name Injectable No. 1 (or Chinese Injectable No. 1) in China as well.[11] When used as a combined injectable contraceptive, EV/OHPC is given twice in the first month and then once per month thereafter.[12]

Available forms

EV/OHPC is available for general use (e.g., as Gravibinon) in the form of ampoules containing 5 to 10 mg estradiol valerate (EV) and 250 to 500 mg hydroxyprogesterone caproate (OHPC). It is available for use as a combined injectable contraceptive specifically at a dose of 5 mg EV and 250 mg OHPC.

Side effects

EV/OHPC as a combined injectable contraceptive has a relatively short duration and is associated with a high incidence of menstrual irregularity, for instance polymenorrhea (short and hence fast cycles). This may be unacceptable to many women. Twice-monthly administration of half doses has not been found to improve breakthrough bleeding, though cycle length increased to 20 to 24 days.

History

EV/OHPC was reportedly first introduced for medical use in 1955.[13] The medication was developed by Schering and marketed under the brand name Gravibinon for the treatment of habitual abortion in Europe by the late 1960s.[14] [15] [16]

EV/OHPC was the first combined injectable contraceptive to be studied.[17] It was first evaluated by Siegel and colleagues in 1963. The doses used in their study were 10 mg EV and 500 mg OHPC. Around the same time as the Siegel study, a half-dose formulation containing 5 mg EV and 250 mg OHPC was developed and subsequently marketed for use in China under the brand name Injectable No. 1 (or Chinese Injectable No. 1). The formulation was also reported to be marketed in a few countries neighboring China.[18] EV/OHPC was also studied at the same dose by a "major European pharmaceutical company" in 1971, but was found to produce short menstrual cycles of 17 to 18 days with once-monthly administration and 20 to 24 days with twice-monthly administration. As a result of these menstrual disturbances, the company abandoned development of the formulation.

EV/OHPC was one of only two combined injectable contraceptives to have been marketed by 1976, and was one of only three combined injectable contraceptives with considerable clinical experience by 1976.[19] [20] The others were estradiol enanthate/algestone acetophenide (E2-EN/DHPA; brand names Perlutal, Topasel), which had been marketed in Spain and Latin America, and estradiol cypionate/medroxyprogesterone acetate (EC/MPA; code name Cyclo-Provera), which was still experimental by 1976 and did not become formally available for clinical use until the 1990s. By 1994, at which point EC/MPA (brand names Cyclofem and later Lunelle) and estradiol valerate/norethisterone enanthate (EV/NETE; brand name Mesigyna) had been introduced, EV/OHPC had been in use for many years.

EV/OHPC and E2-EN/DHPA have been referred to as first-generation combined injectable contraceptives, while EC/MPA and EV/NETE have been referred to as second-generation combined injectable contraceptives.

Society and culture

Brand names

EV/OHPC has been marketed under the brand names Deluteval (or Deluteval 2X), Gravibinon, Gravibinan, Gravidinona, and Gestadinona for the treatment of threatened abortion and other general uses. It has been marketed under the brand name Injectable No. 1 or Chinese Injectable No. 1 for use as a combined injectable contraceptive.

Availability

EV/OHPC is marketed under the brand names Gravidinona in Mexico and Gestadinona in Brazil for threatened abortion.[21] [22] [23] It was also marketed under the brand name Gravidinona in Chile but was discontinued in this country. EV/OHPC was also marketed under the brand names Gravibinon (Schering) in Austria, Belgium, and Germany and Gravibinan (Schering) in France, Italy, and Turkey for threatened abortion as well, but has been discontinued in these countries.[24] [25] EV/OHPC is marketed for use as a combined injectable contraceptive under the brand name Injectable No. 1 or Chinese Injectable No.1 in the China.

Usage

It was estimated in 1995 that EV/OHPC had been used as a combined injectable contraceptive in China by about 1 million women.[26] However, combined injectable contraceptives like EV/OHPC are unlikely to constitute a large proportion of contraceptive use in the countries in which they are available.

See also

Notes and References

  1. Book: Göretzlehner G, Lauritzen C, Göretzlehner U . Störungen des Menstrual Zyklus und ihre Therapie . Praktische Hormontherapie in der Gynäkologie. https://books.google.com/books?id=E3SuivmVMnQC&pg=PA117. 1 January 2007. Walter de Gruyter. 978-3-11-020864-1. 117, 337, 385, 391–392.
  2. Schindler AE . [Treatment of high risk pregnancy with gravibinon] . Zentralblatt für Gynakologie . 123 . 6 . 353–356 . June 2001 . 11488163 . 10.1055/s-2001-16285 . 71374491 .
  3. Garza-Flores J . Pharmacokinetics of once-a-month injectable contraceptives . Contraception . 49 . 4 . 347–359 . April 1994 . 8013219 . 10.1016/0010-7824(94)90032-9 .
  4. Sang GW . Pharmacodynamic effects of once-a-month combined injectable contraceptives . Contraception . 49 . 4 . 361–385 . April 1994 . 8013220 . 10.1016/0010-7824(94)90033-7 .
  5. Book: Muller. European Drug Index: European Drug Registrations . Fourth . 19 June 1998. CRC Press. 978-3-7692-2114-5. 561–.
  6. Lim CE, Ho KK, Cheng NC, Wong FW . Combined oestrogen and progesterone for preventing miscarriage . The Cochrane Database of Systematic Reviews . 2013 . 9 . CD009278 . September 2013 . 24068368 . 7389506 . 10.1002/14651858.CD009278.pub2 . free . 10453/117991 .
  7. Schindler AE . First trimester endocrinology: consequences for diagnosis and treatment of pregnancy failure . Gynecological Endocrinology . 18 . 1 . 51–57 . January 2004 . 15106366 . 10.1080/09513590310001651795 . 20910537 .
  8. Book: Göretzlehner G, Lauritzen C, Römer T, Rossmanith W . Hormontherapien bei gynäkologischen Erkrankungen . Praktische Hormontherapie in der Gynäkologie. https://books.google.com/books?id=TIs2WhfYzZ4C&pg=PA227. 1 January 2012. Walter de Gruyter. 978-3-11-024568-4. 227–228.
  9. Ulrich U, Pfeifer T, Lauritzen C . Rapid increase in lumbar spine bone density in osteopenic women by high-dose intramuscular estrogen-progestogen injections. A preliminary report . Hormone and Metabolic Research . 26 . 9 . 428–431 . September 1994 . 7835827 . 10.1055/s-2007-1001723 . 260169203 .
  10. Ulrich U, Pfeifer T, Buck G, Keckstein J, Lauritzen C . High-dose estrogen-progestogen injections in gonadal dysgenesis, ovarian hypoplasia, and androgen insensitivity syndrome: Impact on bone density. Adolescent and Pediatric Gynecology. 8. 1. 1995. 20–23. 0932-8610. 10.1016/S0932-8610(12)80156-3.
  11. Toppozada MK . Existing once-a-month combined injectable contraceptives . Contraception . 49 . 4 . 293–301 . April 1994 . 8013216 . 10.1016/0010-7824(94)90029-9 .
  12. Book: Toppozada MK . Monthly Injectable Contraceptives . 93–103 . Goldsmith A, Toppozada M . Long-Acting Contraception . 1983 . 35018604 .
  13. Kaiser R . [Gestagen-estrogen combinations in gynecology. On the history, dosage and use of a hormone principle] . Geburtshilfe und Frauenheilkunde . 53 . 7 . 503–513 . July 1993 . 8370495 . 10.1055/s-2007-1022924 . 71261744 . Progestogen-Estrogen Combinations in Gynecology. History, Dosage, and Use of a Hormone Principle . Zur kombinierten Anwendung von Gestagen en und Östrogenen stand en zunächst ölgelöstes Östradiolbenzoat und Progesteron zur Verfügung. Das erste derartige Mischpräparat kam in Deutschland 1950 auf den Mark t. Dem Wunsch nach verlän gerter Wirkungsdauer entsprach en dann Kristallmischsuspension en verschiedener Korngröße aus Östradiolmonobenzoat + Progesteron, deren Anwendung sich auf klinische Untersuchungen besch ränkte (83). Ölgelöste Depotpräparate mit Östradiolbenzoat oder -valerat + 17-hydroxyprogesteroncaproat wurden ab 1955 in die Therapie eingeführt (45.46). .
  14. Book: Acta Europaea Fertilitatis. 1969. Morgagni Edizioni Scientifiche. 662,665.
  15. Book: Belgisch staatsblad. 1969. 4798 . Belgium .
  16. Pundel JP . [Prolonged amenorrhea after abortion during intensive treatment with progestagens] . fr . Gynécologie Pratique . 22 . 2 . 77–85 . 1971 . 5562318 .
  17. Book: Spinola PG . Benefits of injectable contraception to women's health . Artini PG, Genazzani AR, Petraglia F . Advances in Gynecological Endocrinology. https://books.google.com/books?id=dknDdAonzlUC&pg=PA101. 11 December 2001. CRC Press. 978-1-84214-071-0. 101–102.
  18. Facts about once-a-month injectable contraceptives: memorandum from a WHO meeting . Bulletin of the World Health Organization . 71 . 6 . 677–689 . 1993 . 8313486 . 2393537 .
  19. Book: del Carmen Cravioto M . Combined injectable preparations and introduction as a new method . Bringer J, Hedon B . Fertility and Sterility: A Current Overview . https://books.google.com/books?id=vZirsEgpXiMC&pg=PA47. 15 September 1995. CRC Press. 978-1-85070-694-6. 47–.
  20. Toppozada M . The clinical use of monthly injectable contraceptive preparations . Obstetrical & Gynecological Survey . 32 . 6 . 335–347 . June 1977 . 865726 . 10.1097/00006254-197706000-00001 .
  21. Web site: Hydroxyprogesterone injection Uses, Side Effects & Warnings . drugs.com .
  22. Book: Sweetman SC . Sex hormones and their modulators . Martindale: The Complete Drug Reference . 36th . 2009 . 2082 . Pharmaceutical Press . London. 978-0-85369-840-1.
  23. Web site: Micromedex Products: Please Login.
  24. Book: PDR Generics. 1996. Medical Economics. 978-1-56363-151-1. 1171.
  25. Book: Kleemann A, Engel J . Pharmaceutical Substances: Syntheses, Patents, Applications. 2001. Thieme. 978-3-13-558404-1. 1033.
  26. Book: IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. International Agency for Research on Cancer. Hormonal Contraception and Post-menopausal Hormonal Therapy. 1 January 1999. IARC. 978-92-832-1272-0. 65. 18 September 2018. 28 August 2021. https://web.archive.org/web/20210828080855/https://monographs.iarc.who.int/wp-content/uploads/2018/06/mono72.pdf#page=76. dead.

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