Hydroxyprogesterone acetate

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]

Not to be confused with 17α-Hydroxyprogesterone, Hydroxyprogesterone caproate, or Medroxyprogesterone acetate.
Hydroxyprogesterone acetate
Clinical data
Trade namesProdrox
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 classProgestogen; 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 InfoCard100.005.564
Chemical and physical data
FormulaC23H32O4
Molar mass372.505 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

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
See also: Mestranol/hydroxyprogesterone acetate

Side effects
See also: Progestin § Side effects, and Hydroxyprogesterone caproate § 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
CompoundhPR-AhPR-BrbPRrbGRrbER
Progesterone100100100<1<1
17α-Hydroxyprogesterone1131<1
Hydroxyprogesterone caproate2630284<1
Hydroxyprogesterone acetate38461153 ?
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 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]
Compound Form Dose for specific uses (mg)[lower-alpha 3] DOA[lower-alpha 4]
TFD[lower-alpha 5] POICD[lower-alpha 6] CICD[lower-alpha 7]
Algestone acetophenideOil soln.-–75–15014–32 d
Gestonorone caproateOil soln.25–50––8–13 d
Hydroxyprogest. acetate[lower-alpha 8]Aq. susp.350––9–16 d
Hydroxyprogest. caproateOil soln.250–500[lower-alpha 9]–250–5005–21 d
Medroxyprog. acetateAq. susp.50–1001502514–50+ d
Megestrol acetateAq. susp.-–25>14 d
Norethisterone enanthateOil soln.100–2002005011–52 d
ProgesteroneOil 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 OIDTooltip 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. 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 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 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
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  2. 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. 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.
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  7. 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.
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