Hydroxyprogesterone acetate

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Not to be confused with 17α-Hydroxyprogesterone, Hydroxyprogesterone caproate, or Medroxyprogesterone acetate.
Hydroxyprogesterone acetate
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
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

birth control pills.[9]

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

habitual abortion, dysmenorrhea, and premenstrual syndrome.[3][13][14]

OHPA (100 mg) was reportedly marketed in combination with

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

See also: Mestranol/hydroxyprogesterone acetate

Side effects

See also:
Progestin § Side effects, and Hydroxyprogesterone caproate § Side effects

Pharmacology

Pharmacodynamics

OHPA is a

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

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 100 100 100 <1 <1
17α-Hydroxyprogesterone 1 1 3 1 <1
Hydroxyprogesterone caproate 26 30 28 4 <1
Hydroxyprogesterone acetate 38 46 115 3 ?
Notes: Values are percentages (%). Reference ligands (100%) were progesterone for the PRTooltip progesterone receptor, dexamethasone for the GRTooltip glucocorticoid receptor, and estradiol for the ERTooltip 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

biological effect in the uterus in women.[26]

Parenteral potencies and durations of progestogens[a][b]
Compound Form Dose for specific uses (mg)[c] DOA[d]
TFD[e] POICD[f] CICD[g]
Algestone acetophenide Oil soln. - – 75–150 14–32 d
Gestonorone caproate Oil soln. 25–50 – – 8–13 d
Hydroxyprogest. acetate[h] Aq. susp. 350 – – 9–16 d
Hydroxyprogest. caproate Oil soln. 250–500[i] – 250–500 5–21 d
Medroxyprog. acetate Aq. susp. 50–100 150 25 14–50+ d
Megestrol acetate Aq. susp. - – 25 >14 d
Norethisterone enanthate Oil soln. 100–200 200 50 11–52 d
Progesterone Oil soln. 200[i] – – 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. subcutaneous injection
    .
  3. 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. ^ a b In divided doses (2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4).

Chemistry

See also: List of progestogens, Progestogen ester, and List of progestogen esters

OHPA, also known as 17α-hydroxyprogesterone acetate or as 17α-acetoxypregn-4-ene-3,20-dione, is 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

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,

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

INNTooltip 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

References

  1. ^
    ISBN 978-1-4757-2085-3
    .
  2. ^
    ISBN 978-3-642-99941-3
    .
  3. ^
    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. ^
    ISBN 978-1-4020-7149-2
    .
  5. ISBN 978-0-7817-9079-6
    .
  6. ISBN 978-3-527-32669-3
    .
  7. ^
    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. ^ a b c d 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. ^
    OCLC 278011135
    .
  10. ^ a b 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. ^
    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. ^ a b c d e f 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. ^ a b c 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. ^
    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. ^
    PMID 18060946
    .
  16. ^
    PMID 26153441
    .
  17. PMID 4357561
    .
  18. PMID 4129556
    .
  19. PMID 4369808
    .
  20. PMID 77359
    .
  21. S2CID 5895412
    .
  22. ^
    ISBN 978-3-642-73790-9
    .
  23. ^ Barnes AC (1961). Progesterone. Brook Lodge Press. p. 28. Hydroxyprogesterone cap- roate appears to be even less active than Prodox in some respects. It is about 5 times progesterone as an endometrial stimulator [...]
  24. ISBN 978-1-4615-7207-7
    .
  25. ^ a b Veterinary Medicine. 1959. p. 152. Whereas progesterone is relatively inactive when administered orally, ethisterone (anhydrohydroxyprogesterone) and hydroxyprogesterone acetate are highly active.
  26. OCLC 278011135
    .
  27. ISBN 978-3-662-00942-0
    .
  28. ISBN 978-3-642-95583-9
    .
  29. ISBN 978-3-642-96158-8
    .
  30. ISBN 978-94-009-8195-9
    .
  31. 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. ISBN 978-3-11-150424-7
    .
  33. OCLC 278011135
    .
  34. ISBN 978-0-8247-8291-7
    .
  35. ISBN 978-0-12-137250-7
    .
  36. PMID 8013220
    .
  37. PMID 8013216
    .
  38. ISBN 978-1-4613-2241-2
    .
  39. PMID 6452729
    .
  40. PMID 6223851
    .
  41. 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. ISBN 978-3-642-73790-9
    .
  44. ISBN 978-1-84214-071-0
    .
  45. ISBN 978-1-284-02542-2
    .
  46. ^
    ISBN 978-1-59745-150-5
    .
  47. 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. ^ a b "Hydroxyprogesterone injection Uses, Side Effects & Warnings".
  53. ISBN 978-3-88763-075-1
    .
  54. ISBN 978-0-85369-840-1
    .


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