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17α-Hydroxyprogesterone caproate is a synthetic steroid hormone that is similar to medroxyprogesterone acetate and megestrol acetate. It is an ester derivative of 17α-hydroxyprogesterone formed from caproic acid (hexanoic acid).

17α-Hydroxyprogesterone caproate was previously marketed under the trade name Delalutin by Squibb, which was approved by the U.S. Food and Drug Administration (FDA) in 1956 and withdrawn from marketing in 1999.

The US FDA approved Makena from KV Pharmaceutical (previously named as Gestiva) on February 4, 2011 for prevention of preterm delivery in women with a history of preterm delivery, sparking a pricing controversy.

Safety[edit]

The use of 17-hydroxyprogesterone caproate in pregnancy to prevent preterm birth is not recommended without further study according to two authorities. 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".^[1] There was a similar conclusion from a review by Marc Keirse of Flinders University.^[2] Three clinical studies in singleton pregnancies of 250 mg/week of intramuscular 17-hydroxyprogesterone caproate have all shown a trend for an increase in pregnancy loss due to miscarriage compared to placebo.^[3]^[4]^[5]^[6] The FDA expressed concern about miscarriage at the 2006 advisory committee meeting; the committee voted unanimously that further study was needed to evaluate the potential association of 17OHP-C with increased risk of second trimester miscarriage and stillbirth.^[7] A toxicology study in rhesus monkeys resulted in the death of all rhesus fetuses exposed to 1 and 10 times the human dose equivalent of 17-hydroxyprogesterone caproate.^[8] as of 2008^[update], 17-hydroxyprogesterone caproate is a category D progestin according to the FDA (that is, there is evidence of fetal harm). There is speculation that the castor oil in the 17-hydroxyprogesterone caproate formulation may not be beneficial for pregnancy.^[9]^[10]

Synthesis[edit]

Hydroxyprogesterone caproate can be prepared by the following sequence:^[11]

Makena[edit]

See also: KV Pharmaceutical#Makena pricing controversy

A 2011 decision by the USFDA was going to result in driving "up the [US] cost of an available medication from about $300 to $30,000 — about a 100-fold increase — with minimal added clinical benefit".^[12] However, the USFDA said it would not go after compounding pharmacies that filled prescriptions, and KV Pharmaceutical announced a lower price.^[12]

Notes[edit]

^ Dodd JM, Flenady V, Cincotta R, Crowther CA; The Cochrane Database of Systematic Reviews 2006 Issue 1
^ Keirse MJNC. Progesterone and preterm: seventy years of "déjà vu" or "still to be seen"?. Birth, 2004 September; 31:3.
^ 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.
^ 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.
^ Meis PJ et al. Prevention of Recurrent Preterm Delivery by 17 Alpha-hydroxyprogesterone Caproate. NEJM, 2003: vol 348, no 24, pg 2379-2385.
^ Keirse MJNC, Progestogen administration in pregnancy may prevent preterm delivery. Br J Obstet Gynecol 1990 February; 97:149.
^ Advisory Committees: CDER 2006 Meeting Documents
^ Hendrix AG, et al. Embriotoxicity of sex steroidal hormones in nonhuman primates: II. Hydroxyprogesterone caproate, estradiol valerate. Teratology 1987 February. 35 (1): 129.
^ Duke University Medical Center, New England Journal of Medicine, correspondence, vol 349.
^ 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.
^ Ringold, H. J.; Loken, B.; Rosenkraz, G.; Sondheimer, F. (1956). J. Amer. Chem. Soc. 78 (4): 816. doi:10.1021/ja01585a030.
^ ^a ^b Armstrong J (May 2011). "Unintended consequences — the cost of preventing preterm births after FDA approval of a branded version of 17OHP". N. Engl. J. Med. 364 (18): 1689–91. doi:10.1056/NEJMp1102796. PMID 21410391.

Sources[edit]

FDA Reproductive Health Drugs Advisory Committee. August 29, 2006 Meeting to discuss NDA 21-945 Gestiva (Adeza Biomedical)
17α-hydroxyprogesterone caproate injection, 250 mg/mL, for the proposed indication: prevention of preterm delivery in women with a history of a prior preterm delivery.
Adeza Biomedical (October 23, 2006) Receives FDA Approvable Letter For Gestiva
Adeza gets orphan drug designation for Gestiva (January 31, 2007)
Cytyc Acquires Adeza Biomedical Corporation (April 3, 2007)
Adeza's name changed to Cytyc Prenatal Products Corp.

UpToDate Contents

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1. 自然早産のリスクを低下させるためのプロゲステロン補充 progesterone supplementation to reduce the risk of spontaneous preterm birth
2. 症候性または進行した慢性リンパ性白血病に対する初期治療の選択 selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia
3. 頸管無力症 cervical insufficiency
4. 自然早産の予測のための妊娠中期の子宮頸管長測定 second trimester evaluation of cervical length for prediction of spontaneous preterm birth
5. 慢性リンパ性白血病の病態生理および遺伝学的特徴 pathophysiology and genetic features of chronic lymphocytic leukemia

English Journal

Use of hydroxyprogesterone caproate to prevent preterm labour in uterine didelphys: a case report.

Ng KS, Ng BK, Lim PS, Shafiee MN, Abdul Karim AK, Omar MH.
Hormone molecular biology and clinical investigation.Horm Mol Biol Clin Investig.2015 Dec 18. pii: /j/hmbci.ahead-of-print/hmbci-2015-0060/hmbci-2015-0060.xml. doi: 10.1515/hmbci-2015-0060. [Epub ahead of print]
Congenital uterine anomalies have been associated with poor reproductive outcome, which include recurrent miscarriage, abruptio placenta, intra-uterine growth restriction and preterm delivery. Here, we report a case: 36 years old, G3P2, known case of uterine didelphys, with history of preterm birth,
PMID 26684353

17-Hydroxyprogesterone caproate in triplet pregnancy: an individual patient data meta-analysis.

Combs CA1, Schuit E2,3, Caritis SN4, Lim AC5, Garite TJ1,6, Maurel K1, Rouse D7,8,9, Thom E7,10, Tita AT8,11, Mol B5,12; A Global Obstetrics Network (GONet) collaboration.
BJOG : an international journal of obstetrics and gynaecology.BJOG.2015 Dec 10. doi: 10.1111/1471-0528.13779. [Epub ahead of print]
BACKGROUND: Preterm birth complicates almost all triplet pregnancies and no preventive strategy has proven effective.OBJECTIVE: To determine, using individual patient data (IPD) meta-analysis, whether the outcome of triplet pregnancy is affected by prophylactic administration of 17-hydroxyprogestero
PMID 26663620

Does 17-alpha hydroxyprogesterone caproate prevent recurrent preterm birth in obese women?

Heyborne KD1, Allshouse AA2, Carey JC3.
American journal of obstetrics and gynecology.Am J Obstet Gynecol.2015 Dec;213(6):844.e1-6. doi: 10.1016/j.ajog.2015.08.014. Epub 2015 Aug 12.
OBJECTIVE: We sought to determine if maternal weight or body mass index (BMI) modifies the effectiveness of 17-alpha hydroxyprogesterone caproate (17OHP-C).STUDY DESIGN: We performed a secondary analysis of the Maternal-Fetal Medicine Units Network Trial for the Prevention of Recurrent Preterm Deliv
PMID 26275354

Japanese Journal

P1-25-13 反復中期流早産既往妊婦に対し,17Alpha-Hydroxyprogesterone Caproateの投与が妊娠期間延長に有効であった3例(Group58 HELLP・早産・胎盤異常(症例),一般演題,第63回日本産科婦人科学会学術講演会)

日本産科婦人科學會雜誌 63(2), 644, 2011-02-01
NAID 110008509357

分娩後の無発情および鈍性発情の牛と水牛におけるホルモン処置による発情誘起と妊孕率(臨床繁殖学)

The journal of veterinary medical science 70(12), 1327-1331, 2008-12-25
NAID 110007021712

Development and validation of a high-performance liquid chromatography-mass spectrometric assay for the determination of 17α-hydroxyprogesterone caproate (17-OHPC) in human plasma

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 856(1), 141-147, 2007-09-01
NAID 10025807529

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リンク元	「ヒドロキシプロゲステロン」
関連記事	「caproate」「hydroxyprogesterone」

「ヒドロキシプロゲステロン」

17-Hydroxyprogesterone caproate
Systematic (IUPAC) name
	[(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] hexanoate
Clinical data
Legal status	?
Identifiers
CAS number	630-56-8
ATC code	?
PubChem	CID 169870
ChemSpider	148552
Chemical data
Formula	C27H40O4
Mol. mass	428.6041 g/mol
	SMILES O=C4\C=C2/[C@]([C@H]1CC[C@@]3([C@@](OC(=O)CCCCC)(C(=O)C)CC[C@H]3[C@@H]1CC2)C)(C)CC4;
	InChI InChI=1S/C27H40O4/c1-5-6-7-8-24(30)31-27(18(2)28)16-13-23-21-10-9-19-17-20(29)11-14-25(19,3)22(21)12-15-26(23,27)4/h17,21-23H,5-16H2,1-4H3/t21-,22+,23+,25+,26+,27+/m1/s1 ; Key:DOMWKUIIPQCAJU-LJHIYBGHSA-N ;
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