Hydroxyprogesterone acetate

Last updated
Hydroxyprogesterone acetate
17-Acetoxyprogesterone.svg
Clinical data
Trade names Prodrox
Other namesOHPA; 17α-Hydroxyprogesterone acetate; 17α-Acetoxyprogesterone; Acetoxyprogesterone; 17α-Hydroxypregn-4-ene-3,20-dione 17α-acetate; 17α-Acetoxypregn-4-ene-3,20-dione
Routes of
administration 		By mouth
Drug class Progestogen; Progestin; Progestogen ester
ATC code
Identifiers
  • [(8R,9S,10R,13S,14S,17R)-17-acetyl-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-17-yl] acetate
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard 100.005.564 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C23H32O4
Molar mass 372.505 g·mol−1
3D model (JSmol)
  • O=C4\C=C2/[C@]([C@H]1CC[C@@]3([C@@](OC(=O)C)(C(=O)C)CC[C@H]3[C@@H]1CC2)C)(C)CC4
  • InChI=1S/C23H32O4/c1-14(24)23(27-15(2)25)12-9-20-18-6-5-16-13-17(26)7-10-21(16,3)19(18)8-11-22(20,23)4/h13,18-20H,5-12H2,1-4H3/t18-,19+,20+,21+,22+,23+/m1/s1
  • Key:VTHUYJIXSMGYOQ-KOORYGTMSA-N

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. [1] [2] [3] [4] [5] [6] [7] [8] It has reportedly also been used in birth control pills. [9]

Contents

OHPA is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.

OHPA was discovered in 1953 and was introduced for medical use in 1956. [10] [11] [12]

Medical uses

OHPA has been used in the treatment of a variety of gynecological disorders, including secondary amenorrhea, functional uterine bleeding, infertility, habitual abortion, dysmenorrhea, and premenstrual syndrome. [3] [13] [14]

OHPA (100 mg) was reportedly marketed in combination with mestranol (80 μg) as a sequential combined birth control pill under the brand name Hormolidin. [9] The preparation was available in the early 1970s. [9] The firm that manufactured it, known as Gador, was based in Argentina. [9]

Available forms

Side effects

Pharmacology

Pharmacodynamics

OHPA is a progestogen and acts as an agonist of the progesterone receptor (PR), both PRA and PRB isoforms (IC50 = 16.8 nM and 12.6 nM, respectively). [15] It has more than 50-fold higher affinity for the PR isoforms than 17α-hydroxyprogesterone, a little less than half the affinity of progesterone, and slightly higher affinity than OHPC. [16] Additional studies have reported on the affinity of OHPA for the PR. [17] [18] [19] [20] [21]

OHPA is of relatively low potency as a progestogen, which may explain its relatively limited use. [22] It is 100-fold less potent than medroxyprogesterone acetate, 400-fold less potent than chlormadinone acetate, and 1,200-fold less potent than cyproterone acetate in animal assays. [22] In terms of producing full progestogenic changes on the endometrium in women, 75 to 100 mg/day oral OHPA is equivalent to 20 mg/day parenteral progesterone, and OHPA is at least twice as potent as oral ethisterone in such regards. [3] It is also reportedly more potent than OHPC. [15] [23] OHPA has been found to be effective as an oral progestogen-only pill at a dosage of 30 mg/day. [24]

Relative affinities (%) of hydroxyprogesterone and related steroids
Compound hPR-A hPR-B rbPR rbGR rbER
Progesterone 100100100<1<1
17α-Hydroxyprogesterone 1131<1
Hydroxyprogesterone caproate 2630284<1
Hydroxyprogesterone acetate38461153 ?
Notes: Values are percentages (%). Reference ligands (100%) were progesterone for the PR Tooltip progesterone receptor, dexamethasone for the GR Tooltip glucocorticoid receptor, and estradiol for the ER Tooltip estrogen receptor. Sources: See template.

Pharmacokinetics

OHPA has very low but nonetheless significant oral bioavailability and can be taken by mouth. [25] The pharmacokinetics of OHPA have been reviewed. [2]

A single intramuscular injection of 150 to 350 mg OHPA in microcrystalline aqueous suspension has been found to have a duration of action of 9 to 16 days in terms of clinical biological effect in the uterus in women. [26]

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 caproate Oil 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: [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45]
  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).

Chemistry

OHPA, also known as 17α-hydroxyprogesterone acetate or as 17α-acetoxypregn-4-ene-3,20-dione, is a synthetic pregnane steroid and a derivative of progesterone. [1] [46] It is the acetate ester of 17α-hydroxyprogesterone, as well as a parent compound of a number of progestins including chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, and megestrol acetate. [4] [46]

Synthesis

Chemical syntheses of OHPA have been described. [2]

History

In 1949, it was discovered that 17α-methylprogesterone had twice the progestogenic activity of progesterone when administered parenterally, [47] and this finding led to renewed interest in 17α-substituted derivatives of progesterone as potential progestins. [12] Along with OHPC, OHPA was synthesized by Karl Junkmann of Schering AG in 1953 and was first reported by him in the medical literature in 1954. [10] [11] [48] [49] [12] OHPC shows very low oral activity [16] and was introduced for use via intramuscular injection by Squibb in 1956 under the brand name Delalutin. [12] Although a substantial prolongation of action occurs when OHPC is formulated in oil, [16] the same was not observed to a significant extent with OHPA, and this is likely why OHPC was chosen by Schering for development over OHPA. [7]

Subsequently, Upjohn unexpectedly discovered that OHPA, unlike OHPC and progesterone, is orally active and shows marked progestogenic activity with oral administration, [25] a finding that had been missed by the Schering researchers (who were primarily interested in the oil solubility of such esters). [7] [12] OHPA was found to possess two to three times the oral activity of 17α-methylprogesterone. [50] Upjohn reported the oral activity of OHPA in the medical literature in 1957 and introduced the drug for medical use as Prodox in 25 mg and 50 mg oral tablet formulations later the same year. [3] [12] [13] OHPA was indicated for the treatment of a variety of gynecological disorders in women. [3] [13] [14] However, it saw relatively little use, which was perhaps due its comparatively low potency relative to a variety of other progestins such as medroxyprogesterone acetate and norethisterone. [22] [14] These progestins were introduced around the same time and hence may have been favored. [22] [14]

In 1960, OHPA was introduced also as Prodox as an oral progestin for veterinary use for the indication of estrus suppression in dogs. [8] [51] However, probably due its high cost and the inconvenience of daily oral administration, the drug was not a market success. [8] It was superseded for this indication by medroxyprogesterone acetate (brand name Promone) in 1963, which could be administered by injection conveniently once every six months, although this preparation was discontinued in 1966 for various reasons and hence was not a market success either. [8]

Society and culture

Generic names

Hydroxyprogesterone acetate is the generic name of the drug and its INN Tooltip International Nonproprietary Name. [1]

Brand names

OHPA is or was marketed under the brand name Prodox initially for clinical use and then for veterinary use. [1] Other brand names of OHPA include Gestageno, Gestageno Gador, Kyormon, Lutate-Inj, Prodix, and Prokan. [1] OHPA may also be or have been marketed in combination with estradiol enantate under the brand names Atrimon and Protegin in Argentina and Nicaragua. [52]

Availability

OHPA is no longer marketed and hence is no longer available in any country. [53] [54] [52]

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">Gestonorone caproate</span> Chemical compound

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. It is given by injection into muscle typically once a week.

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

Hydroxyprogesterone caproate, sold under the brand name Delalutin 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 approval of this drug substance was withdrawn by the US Food and Drug Administration (FDA) in April 2023. In May 2024, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency recommended suspending the marketing authorizations of medications containing 17-hydroxyprogesterone caproate in the European Union.

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">Dimethisterone</span> Chemical compound

Dimethisterone, formerly sold under the brand names Lutagan and Secrosteron among others, is a progestin medication which was used in birth control pills and in the treatment of gynecological disorders but is now no longer available. It was used both alone and in combination with an estrogen. It is taken by mouth.

<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">Medroxyprogesterone acetate</span> Injectable form of birth control

Medroxyprogesterone acetate (MPA), also known as depot medroxyprogesterone acetate (DMPA) in injectable form and sold under the brand name Depo-Provera among others, is a hormonal medication of the progestin type. It is used as a method of birth control and as a part of menopausal hormone therapy. It is also used to treat endometriosis, abnormal uterine bleeding, paraphilia, and certain types of cancer. The medication is available both alone and in combination with an estrogen. It is taken by mouth, used under the tongue, or by injection into a muscle or fat.

<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">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">Quingestrone</span> Progestin medication

Quingestrone, also known as progesterone 3-cyclopentyl enol ether (PCPE) and sold under the brand name Enol-Luteovis, is a progestin medication which was previously used in birth control pills in Italy but is now no longer marketed. It is taken by mouth.

<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.

<span class="mw-page-title-main">17α-Methylprogesterone</span> Chemical compound

17α-Methylprogesterone (17α-MP), or 17α-methylpregn-4-ene-3,20-dione, is a steroidal progestin related to progesterone that was synthesized and characterized in 1949 but was never marketed. Along with ethisterone (1938) and 19-norprogesterone (1951), 17α-MP was one of the earliest derivatives of progesterone to be identified as possessing progestogenic activity. Similarly to progesterone and derivatives like 17α-hydroxyprogesterone and 19-norprogesterone, 17α-MP was found to possess poor oral bioavailability, but showed improved progestogenic activity relative to progesterone when administered via other routes. In addition to its activity as a progestogen, 17α-MP has also been found to possess some antiglucocorticoid activity.

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

Megestrol caproate, abbreviated as MGC, is a progestin medication which was never marketed. It was developed in Russia in 2002. In animals, MGC shows 10-fold higher progestogenic activity compared to progesterone when both are administered via subcutaneous injection. In addition, MGC has no androgenic, anabolic, or estrogenic activity. The medication was suggested as a potential contraceptive and therapeutic agent.

<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">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.

Estradiol benzoate/estradiol valerate/hydroxyprogesterone caproate (EB/EV/OHPC), sold under the brand name Sin-Ol, is a combination medication of estradiol benzoate (EB), an estrogen, estradiol valerate (EV), an estrogen, and hydroxyprogesterone caproate (OHPC), a progestin, which was reportedly used as a combined injectable contraceptive in women in the early 1970s. It contained 1 mg EB, 10 mg EV, and 250 mg OHPC in oil solution, was provided in the form of 3 mL ampoules, and was administered by intramuscular injection at regular intervals. The medication was manufactured by the pharmaceutical company Reuffer in Mexico.

References

  1. 1 2 3 4 5 Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 664–. ISBN   978-1-4757-2085-3.
  2. 1 2 3 Junkmann K (27 November 2013). "Konstitution und chemische und physikalische Eigenschaften der Gestagene" [Constitution and chemical and physical properties of progestogens]. Die Gestagene (in German). Springer-Verlag. pp. 6, 278. ISBN   978-3-642-99941-3.
  3. 1 2 3 4 5 Davis ME, Wied GL (1957). "17-alpha-HYDROXYPROGESTERONE acetate; an effective progestational substance on oral administration". The Journal of Clinical Endocrinology and Metabolism. 17 (10): 1237–44. doi:10.1210/jcem-17-10-1237. PMID   13475464. It is the purpose of this paper to introduce and describe a new steroid for oral administration, 17-a-hydroxyprogesterone acetate*, and to compare it with the most widely used oral substance with progestational properties, 20,21-anhydro-17-/3-hydroxyprogesterone. * Prodox, Upjohn Co., Kalamazoo, Michigan [...] It was found that 17-a-hydroxyprogesterone acetate has a progestational activity which is at least twice that of anhydrohydroxyprogesterone.
  4. 1 2 Lobo R, Crosignani PG, Paoletti R (31 October 2002). Women's Health and Menopause: New Strategies - Improved Quality of Life. Springer Science & Business Media. pp. 91–. ISBN   978-1-4020-7149-2.
  5. ↑ Stoller JK, Michota FA, Mandell BF (2009). The Cleveland Clinic Foundation Intensive Review of Internal Medicine. Lippincott Williams & Wilkins. pp. 13–. ISBN   978-0-7817-9079-6.
  6. ↑ Ravina E (11 January 2011). "Hormone Analogs". The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. pp. 194–. ISBN   978-3-527-32669-3.
  7. 1 2 3 Sneader W (23 June 2005). Drug Discovery: A History. John Wiley & Sons. pp. 204–. ISBN   978-0-471-89979-2. In 1954, Karl Junkmann of Schering AG reported that the acetylation of the 17-hydroxyl group of ethisterone provided a derivative suitable for formulating in oil for injection intramuscularly as a depot medication.79 There resulted widespread interest in preparing the acetates (and other esters) of various hydroxy-steroids. One such ester, Upjohn's 17-acetoxyprogesterone, provided to be a promising progestogen even though its hydroxy precursor was inactive. Unfortunately, it turned out that no significant prolongation of action was obtained by formulating it in oil. The Upjohn researchers, however, made the unexpected discovery that their acetoxy derivative was orally active, an observation that had been missed by the Schering group, who were primarily interested in the oil solubility of such esters.
  8. 1 2 3 4 Lauderdale JW, Sokolowski JH, eds. (1978). Proceedings of the Symposium on Cheque® for Canine Estrus Prevention, Brook Lodge, Augusta, Michigan, March 13-15, 1978. Upjohn Company. p. 16. [...] The first product was 17alpha-acetoxyprogesterone4 (Figure 1) marketed under the trade name of Prodox.® Prodox was introduced in 1960, was designed for oral use and was not a marketing success. The reasons are not clear as to lack of clear success, but one predominant reason was the high cost. For the average size dog, the cost of preventing estrus for a year was approximately $90. In addition, the inconvenience of daily oral administration may have prevented some market acceptance, especially at that cost. In 1963, Upjohn introduced injectable medroxyprogesterone acetate6 (Figure 1) under the trade name of Promone. Injections were to be made every six months, and this procedure was well accepted by both veterinarians and pet owners. However, Promone sales were discontinued in April, 1966 in the United States for basically two reasons. First was a prolonged and unpredictable return to estrus. This appeared to be due to very slow and variable absorption from the injection site. As a result of this variable absorption rate, one would expect a variable return to estrus. Even after [...]
  9. 1 2 3 4 Rudel HW, Kinel FA (September 1972). "Oral Contraceptives. Human Fertility Studies and Side Effects". In Tausk M (ed.). Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents. Vol. II. Pergamon Press. pp. 385–469. ISBN   978-0080168128. OCLC   278011135.
  10. 1 2 Davis ME (1930). M. Edward Davis Reprints. p. 406. Chemically pure progesterone was the only substance with progestational properties in general use which could be administered parenterally until Junkmann (1) developed in 1953, 17-alpha-hydroxyprogesterone acetate and 17-alpha-hydroxyprogesterone caproate.
  11. 1 2 Wied GL, Davis ME (1958). "Comparative activity of progestational agents on the human endometrium and vaginal epithelium of surgical castrates". Ann. N. Y. Acad. Sci. 71 (5): 599–616. Bibcode:1958NYASA..71..599W. doi:10.1111/j.1749-6632.1958.tb46791.x. PMID   13583817. In the group of new parenteral progestational agents, three substances developed by Karl Junkmann1,2 are the most outstanding and interesting: 17a-hydroxyprogesterone caproate and 17a-hydroxyprogesterone acetate, introduced in 1953, and the most potent of all new parenteral progestational agents, 17-ethynyl-19-nortestosterone enanthate, introduced in 1956.
  12. 1 2 3 4 5 6 Applezweig N (1962). Steroid Drugs. Blakiston Division, McGraw-Hill. pp. 101–102. Junkmann of Schering, AG., however, was able to show that long chain esters of 17a-hydroxyprogesterones such as the 17a-caproate produced powerful long-acting progestational effect. [...] Subsequently, a series of events led to the exploitation of 17a-hydroxyprogesterone derivatives as highly effective and orally active progestogens. Groups at Upjohn, Merck & Co., and Syntex independently found means of readily acetylating the 17-hydroxy group. Later, Upjohn announced it found that 17a-acetoxyprogesterone was orally active in humans and subsequently marketed this compound under the name of Prodox.
  13. 1 2 3 Medical Digest. Medical Digest. Incorporated. 1958. Prodox Tablets ( Upjohn) A new derivative of progesterone for oral administration. Indications: Secondary amenorrhea, functional uterine bleeding, in- fertility, habitual abortion, dysmen-orrhea and premenstrual tension. Supplied: Tablets containing 25 mg. or 50 mg. of hydroxyprogesterone a c e t a te, in bottles of 25 tablets.
  14. 1 2 3 4 Greenblatt RB (1959). "Hormonal control of functional uterine bleeding". Clinical Obstetrics and Gynecology. 2 (1): 232–46. doi:10.1097/00003081-195903000-00021. PMID   13639329. [...] ethisterone, 25 mg. (Lutocylol; Pranone) 17-acetoxyprogesterone, 25 mg. (Prodox), 6-methyl-17-acetoxyprogesterone, 5 mg. (Provera), norethindrone, 5 mg. (Norlutin), norethinodrel, 5 mg. (Enovid). [...]
  15. 1 2 Attardi BJ, Zeleznik A, Simhan H, Chiao JP, Mattison DR, Caritis SN (2007). "Comparison of progesterone and glucocorticoid receptor binding and stimulation of gene expression by progesterone, 17-alpha hydroxyprogesterone caproate, and related progestins". American Journal of Obstetrics and Gynecology. 197 (6): 599.e1–7. doi:10.1016/j.ajog.2007.05.024. PMC   2278032 . PMID   18060946.
  16. 1 2 3 Shaik IH, Bastian JR, Zhao Y, Caritis SN, Venkataramanan R (2015). "Route of administration and formulation dependent pharmacokinetics of 17-hydroxyprogesterone caproate in rats". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 46 (2): 169–174. doi:10.3109/00498254.2015.1057547. PMC   4809632 . PMID   26153441.
  17. ↑ Lontula K, Luukkainen JT, Vihko R (November 1973). "Progesterone-binding protein in human myometrium. Ligand specificity and some physicochemical characteristics". Biochim. Biophys. Acta. 328 (1): 145–53. doi:10.1016/0005-2795(73)90340-1. PMID   4357561.
  18. ↑ McGuire JL, Bariso CD, Shroff AP (January 1974). "Interaction between steroids and a uterine progestogen specific binding macromolecule". Biochemistry. 13 (2): 319–22. doi:10.1021/bi00699a014. PMID   4129556.
  19. ↑ Smith HE, Smith RG, Toft DO, Neergaard JR, Burrows EP, O'Malley BW (September 1974). "Binding of steroids to progesterone receptor proteins in chick oviduct and human uterus". J. Biol. Chem. 249 (18): 5924–32. doi: 10.1016/S0021-9258(20)79907-2 . PMID   4369808.
  20. ↑ Blanford AT, Wittman W, Stroupes SD, Westphal U (March 1978). "Steroid--protein interactions--XXXVIII. Influence of steroid structure on affinity to the progesterone-binding globulin". J. Steroid Biochem. 9 (3): 187–201. doi:10.1016/0022-4731(78)90149-8. PMID   77359.
  21. ↑ Wilks JW, Spilman CH, Campbell JA (June 1980). "Steroid binding specificity of the hamster uterine progesterone receptor". Steroids. 35 (6): 697–706. doi:10.1016/0039-128x(80)90094-x. PMID   7404605. S2CID   5895412.
  22. 1 2 3 4 Neumann F, Düsterberg B, Laurent H (6 December 2012). "Development of progestogens". In Runnebaum BC, Rabe T, Kiesel L (eds.). Female Contraception: Update and Trends. Springer Science & Business Media. pp. 133–134. ISBN   978-3-642-73790-9.
  23. ↑ Barnes AC (1961). Progesterone. Brook Lodge Press. p. 28. Hydroxyprogesterone caproate appears to be even less active than Prodox in some respects. It is about 5 times progesterone as an endometrial stimulator [...]
  24. ↑ Lönnerdal B (6 December 2012). "Effect of Oral Contraceptives on Lactation". In Hamosh M, Goldman AS (eds.). Human Lactation 2: Maternal and Environmental Factors. Springer Science & Business Media. pp. 454–. ISBN   978-1-4615-7207-7.
  25. 1 2 Veterinary Medicine. 1959. p. 152. Whereas progesterone is relatively inactive when administered orally, ethisterone (anhydrohydroxyprogesterone) and hydroxyprogesterone acetate are highly active.
  26. ↑ 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. ↑ Knörr K, Beller FK, Lauritzen C (17 April 2013). Lehrbuch der Gynäkologie. Springer-Verlag. pp. 214–. ISBN   978-3-662-00942-0.
  28. ↑ 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.
  29. ↑ Labhart A (6 December 2012). Clinical Endocrinology: Theory and Practice. Springer Science & Business Media. pp. 554–. ISBN   978-3-642-96158-8.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ Pschyrembel W (1968). Praktische Gynäkologie: für Studierende und Ärzte. Walter de Gruyter. pp. 598, 601. ISBN   978-3-11-150424-7.
  33. ↑ 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.
  34. ↑ 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.
  35. ↑ Brotherton J (1976). Sex Hormone Pharmacology. Academic Press. p. 114. ISBN   978-0-12-137250-7.
  36. ↑ 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.
  37. ↑ 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.
  38. ↑ 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.
  39. ↑ 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.
  40. ↑ 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.
  41. ↑ Wright JC, Burgess DJ (29 January 2012). Long Acting Injections and Implants. Springer Science & Business Media. pp. 114–. ISBN   978-1-4614-0554-2.
  42. ↑ 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.
  43. ↑ 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.
  44. ↑ Artini PG, Genazzani AR, Petraglia F (11 December 2001). Advances in Gynecological Endocrinology. CRC Press. pp. 105–. ISBN   978-1-84214-071-0.
  45. ↑ 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.
  46. 1 2 Jurow R, Shoupe D (7 November 2007). "Long-Acting Progestin Injectables: Comparison ofDepo-Provera With Depo-SubQProvera 104". In Shoupe D, Kjos SL (eds.). The Handbook of Contraception: A Guide for Practical Management. Springer Science & Business Media. pp. 103–. ISBN   978-1-59745-150-5.
  47. ↑ Plattner PA, Heusser H, Herzig PT (1949). "Uber steroide und sexualhormone. 159. Die synthese von 17-methyl-progesteron". Helvetica Chimica Acta. 32 (1): 270–275. doi:10.1002/hlca.19490320138. PMID   18115956.
  48. ↑ ACRH. U.S. Dept. of Energy. 1960. p. 71. [The] minimal activity [of 17(a)-hydroxyprogesterone] is magnified to an unexpected degree by the esterification of this steroid with caproic acid to produce 17(a)-hydroxyprogesterone-17-n-caproate, first reported by Karl Junkmann in 1954.6,7
  49. ↑ Dorfman RI (1966). Methods in Hormone Research. Academic Press. p. 86. Junkmann (1954) reported that the acetate, butyrate, and caproate forms had both increased and prolonged activity, [...]
  50. ↑ Kirk RE, Othmer DF, Mark HF (1965). Encyclopedia of chemical technology. Interscience Publishers. p. 78. Subsequent acetylation with acetic anhydride and tosyl acid followed by Oppenauer oxidation afforded 17a-acetoxy- progesterone (95) in good yield (115). Tests showed this compound to possess 2-3 times the oral activity of 17-methylpregn-4-ene-3,20-dione (78) and to be many times more potent than progesterone (116,117).
  51. ↑ Pure-bred Dogs, American Kennel Gazette. American Kennel Club. 1961. p. 33. According to Dr. Gordon G. Stocking, director of Upjohn's Veterinary Division, Prodox is a synthetic version of progesterone — one of the hormones that regulates the human female reproductive system. It is 100 per cent effective and has produced no ill-effects on 200 or more dogs on which it has been tested. As a result of its findings, says Dr. Stocking, Upjohn is making the product available through veterinarians.
  52. 1 2 "Hydroxyprogesterone injection Uses, Side Effects & Warnings".
  53. ↑ Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 532–. ISBN   978-3-88763-075-1.
  54. ↑ Sweetman SC, ed. (2009). "Sex hormones and their modulators". Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. p. 2110. ISBN   978-0-85369-840-1.


This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.