17-Hydroxyprogesterone

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17-Hydroxyprogesterone
17-Hydroxyprogesterone.svg
17-Hidroxiprogesterona3D.png
Systematic (IUPAC) name
17-Hydroxypregn-4-ene-3,20-dione
Clinical data
Licence data US FDA:link
Pregnancy
category
  • US: B (No risk in non-human studies)
  • B
Legal status
Pharmacokinetic data
Metabolism Liver
Biological half-life 10 days (17-OHPC)[1]
Identifiers
CAS Number 68-96-2 YesY
ATC code G03DA03 (WHO)
PubChem CID: 6238
IUPHAR/BPS 5104
ChemSpider 6002 YesY
UNII 21807M87J2 YesY
ChEBI CHEBI:17252 YesY
ChEMBL CHEMBL1062 YesY
Chemical data
Formula C21H30O3
Molecular mass 330.46 g/mol
  • O=C4\C=C2/[C@]([C@H]1CC[C@@]3([C@@](O)(C(=O)C)CC[C@H]3[C@@H]1CC2)C)(C)CC4
  • InChI=1S/C21H30O3/c1-13(22)21(24)11-8-18-16-5-4-14-12-15(23)6-9-19(14,2)17(16)7-10-20(18,21)3/h12,16-18,24H,4-11H2,1-3H3/t16-,17+,18+,19+,20+,21+/m1/s1 YesY
  • Key:DBPWSSGDRRHUNT-CEGNMAFCSA-N YesY
Physical data
Melting point 219.5 °C (427.1 °F)
  (verify)

17-Hydroxyprogesterone (17-OHP) is an endogenous progestogen as well as chemical intermediate in the biosynthesis of other steroid hormones, including the corticosteroids and the androgens and the estrogens.

Production

It is derived from progesterone via 17-hydroxylase, a P450c17 enzyme, or from 17-hydroxypregnenolone via 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase.

17-OHP increases in the third trimester of pregnancy primarily due to fetal adrenal production.

This steroid is primarily produced in the adrenal glands and to some degree in the gonads, specifically the corpus luteum of the ovary. Normal levels are 3-90 ng/dl in children, and in women, 20-100 ng/dl prior to ovulation, and 100-500 ng/dl during the luteal phase.[2][3]

Biological activity

17-OHP is an agonist of the progesterone receptor (PR) similarly to progesterone, albeit weakly in comparison.[4] In addition, it is an antagonist of the mineralocorticoid receptor (MR) as well as a partial agonist of the glucocorticoid receptor (GR), albeit with very low potency (EC50 >100-fold less relative to cortisol) at the latter site, also similarly to progesterone.[4][5][6]

17-Hydroxyprogesterone caproate

17-OHP is not the same compound as 17-hydroxyprogesterone caproate (17-OHPC), the latter being the caproic acid of 17-hydroxyprogesterone that was first clinically introduced as an injectable version of the steroid under the name of Delalutin in 1956.

The use of 17-OHPC in pregnancy to prevent preterm birth has a long history. A 2006 Cochrane Review concluded "...important maternal and infant outcomes have been poorly reported to date... information regarding the potential harms of progesterone therapy to prevent preterm birth is limited".[7] There was a similar conclusion from a review by Marc Keirse.[8] Three clinical studies of 250 mg/week of i.m. 17-OHPC showed a trend for an increase in pregnancy loss due to miscarriage compared to placebo.[9][10][11][12] There had been speculation that the castor oil in some 17-OHPC formulations may not be beneficial for pregnancy.[13][14]

In contrast, a large NIH study in 2003 looked at the effect of 17-OHPC injections in women at risk for repeat premature birth and found that the treated group experienced premature birth in 37% versus 55% in the controls.[15]

A follow-up study of the offspring showed no evidence that 17-OHPC affected the children in the first years of life.[16] Based on these NIH data, 17 OHPC was approved by the FDA in 2011 as a drug to reduce the risk of premature birth in selected patients at risk. (v.i.)

17-OHPC is a category B drug according to the FDA.

Clinical use

Measurement

Measurements of levels of 17-OHP are useful in the evaluation of patients with suspected congenital adrenal hyperplasia as the typical enzymes that are defective, namely 21-hydroxylase and 11β-hydroxylase, lead to a build-up of 17-OHP. In contrast, the rare patient with 17α-hydroxylase deficiency will have very low or undetectable levels of 17-OHP. 17-OHP levels can also be used to measure contribution of progestational activity of the corpus luteum during pregnancy as progesterone but not 17-OHP is also contributed by the placenta.

Medication

17-OHPC was first introduced in 1956 as Delalutin to reduce pregnancy loss. After decades of use, Squibb, the manufacturer, voluntarily withdrew the brand, however, physicians continued to use 17-OHPC "off label". Renewed interest was sparked with a large NIH-sponsored study in 2003 that found that 17-OHPC reduced the risk of premature birth in selected at-risk pregnant women.[15] With follow-up data showing no evidence of harmful effects on the offspring, the FDA approved the drug, as sponsored by KV Pharmaceutical as Makena, as an orphan drug in February 2011 to reduce the risk of premature birth in women prior to 37 weeks gestation with a single fetus who had at least one previous premature birth.[17] The drug is not effective in preventing premature birth in women with multiples. With the arrival of Makena as an orphan drug, the price of the drug was to increase from $15 to $1,500 per dose meaning a typical treatment would cost $25–30,000, - a pricing strategy that was strongly criticized. The FDA then announced that pharmacies could continue to compound the drug at their usual cost of $10~20 per dose without fear of legal reprisals.,[18] and KV reduced its price to $690 per dose.[19]

17-Hydroxyprogesterone (17-OH-Prog in the diagram) may arise from either of two steroid precursors.

Determination

Earlier immunoassays like RIA (radioimmunoassay) or IRMA (immunoradiometric assay) were used to clinically determine 17-Hydroxyprogesterone. Today more sophisticated methods use gas or liquid chromatography and mass spectrometry (e.g. LC-MS/MS).

Additional images

Synthesis

Hydroxyprogesterone synthesis:[20] U.S. Patent 2,802,839

See also

References

  1. ↑ Pharmacokinetics of 17-hydroxyprogesterone caproate in multifetal gestation.
  2. ↑ Reference Values During Pregnancy
  3. ↑ normal ranges for hormone tests in women
  4. ↑ 4.0 4.1 Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Dodd JM, Flenady V, Cincotta R, Crowther CA; The Cochrane Database of Systematic Reviews 2006 Issue 1
  8. ↑ Keirse MJNC. Progesterone and Preterm: Seventy Years of "Deja vu" or "Still To Be Seen"?. Birth, 2004 September; 31:3.
  9. ↑ Johnson JWC, Austin KL, Jones GS, Davis GH, King TM. Efficacy of 17 alpha-hydroxyprogesterone caproate in the prevention of premature labor. NEJM 1975 October. 293(14):675.
  10. ↑ Yemini M, Borenstein R, Dreazen, et al. Prevention of premature labor by 17 alpha-hydroxyprogesterone caproate. Am J Obstet Gynecol. 1985;151(5):574-7.
  11. ↑ Meis PJ et al. Prevention of Recurrent Preterm Delivery by 17 Alpha-hydroxyprogesterone Caproate. NEJM, 2003: vol 348, no 24, pg 2379-2385.
  12. ↑ Keirse MJNC, Progestogen administration in pregnancy may prevent preterm delivery. Br J Obstet Gynecol 1990 February; 97:149.
  13. ↑ Duke University Medical Center, New England Journal of Medicine, correspondence, vol 349.
  14. ↑ Hauth JC, Gilstrap LC, Brekken AL, Hauth JM. The effect of 17 alpha-hydroxyprogesterone caproate on pregnancy outcome in an active-duty military population. Am J Obstet Gynecol. 1983 May; 146(2): 187.
  15. ↑ 15.0 15.1 Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ FDA press release regarding Makena approval
  18. ↑ http://www.macleans.ca/article.jsp?content=w6411446
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

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