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Prostaglandin F_2α (PGF_2α in prostanoid nomenclature), pharmaceutically termed dinoprost (INN), is a naturally occurring prostaglandin used in medicine to induce labor and as an abortifacient.^[1]

In domestic mammals, it is produced by the uterus when stimulated by oxytocin, in the event that there has been no implantation during the luteal phase. It acts on the corpus luteum to cause luteolysis, forming a corpus albicans and stopping the production of progesterone. Action of PGF_2α is dependent on the number of receptors on the corpus luteum membrane.

The PGF_2α isoform 8-iso-PGF_2α was found in significantly increased amounts in patients with endometriosis, thus being a potential causative link in endometriosis-associated oxidative stress.^[2]

Mechanism of action

PGF_2α acts by binding to the prostaglandin F2α receptor. It is released in response to an increase in oxytocin levels in the uterus, and stimulates both luteolytic activity and the release of oxytocin.^[3] Because PGF_2α is linked with an increase in uterine oxytocin levels, there is evidence that PGF_2α and oxytocin form a positive feedback loop to facilitate the degradation of the corpus luteum.^[4] PGF_2α and oxytocin also inhibit the production of progesterone, a hormone that facilitates corpus luteum development. Conversely, higher progesterone levels inhibit production of PGF_2α and oxytocin, as the effects of the hormones are in opposition to each other.

Pharmaceutical Use

When injected into the body or amniotic sac, PGF_2α can either induce labor or cause an abortion depending on the concentration used. In small doses (1–4 mg/day), PGF_2α acts to stimulate uterine muscle contractions, which aids in the birth process. However, during the second trimester and in higher concentrations (40 mg/day),^[5] PGF_2α can cause an abortion by degrading the corpus luteum, which nourishes the fetus in the womb. Since the fetus is not viable outside the womb by this time, the lack of sustenance starves and aborts the fetus after a day or two.

Synthesis

Industrial Synthesis

In 2012 a concise and highly stereoselective total synthesis of PGF_2α was described.^[6] The synthesis requires only seven steps, a huge improvement on the original 17-steps synthesis of Corey and Cheng,^[7] and uses 2,5-dimethoxytetrahydrofuran as a starting reagent, with S-proline as an asymmetric catalyst.

Biosynthesis

In the body PGF_2α is synthesized in several distinct steps. First, Phospholipase A₂ (PLA₂) facilitates the conversion of phospholipids to Arachidonic Acid, the framework from which all prostaglandins are formed.^[8] The Arachidonic Acid then reacts with two Cyclooxygenase (COX) receptors, COX-1 and COX-2 to form Prostaglandin H₂, an intermediate. Lastly, the compound reacts with Aldose Reductase (AKR1B1) to form PGF_2α.^[8]

Analogues

The following medications are analogues of prostaglandin F_2α:

Latanoprost
Bimatoprost
Travoprost
Carboprost

References

^ The Merck index : an encyclopedia of chemicals, drugs, and biologicals. O'Neil, Maryadele J., Royal Society of Chemistry (Great Britain) (15th ed.). Cambridge, UK: Royal Society of Chemistry. 2013. ISBN 1849736707. OCLC 824530529.
^ Sharma, I.; Dhaliwal, L.; Saha, S.; Sangwan, S.; Dhawan, V. (2010). "Role of 8-iso-prostaglandin F2alpha and 25-hydroxycholesterol in the pathophysiology of endometriosis". Fertility and Sterility. 94 (1): 63–70. doi:10.1016/j.fertnstert.2009.01.141. PMID 19324352.
^ Samuelsson, B.; Goldyne, M.; Granström, E.; et al. (1978). "Prostaglandins and thromboxanes". Annual Review of Biochemistry. 47: 997–1029.
^ Hooper, S.B.; Watkins, W.B.; Thorburn, G.D. (1986). "Oxytocin, oxytocin associated neurophysin, and prostaglandin F2 a concentrations in the uteroovarian vein of pregnant and nonpregnant sheep". Endocrinology. 119: 2590–2597.
^ "Dinoprost tromethamine Injection Advanced Patient Information". Truvn Health Analytics Inc. 2016. Retrieved November 2, 2017.
^ Coulthard, G.; Erb, W.; Aggarwal, V. K. (2012). "Stereocontrolled organocatalytic synthesis of prostaglandin PGF2α in seven steps". Nature. 489 (7415): 278–281. doi:10.1038/nature11411. PMID 22895192.
^ Corey, E.J.; Cheng, X.M. (1995). The Logic of Chemical Synthesis. Wiley.
^ ^a ^b Fortier, M. A.; Krishnaswamy, K.; Danyod, G.; Boucher-Kovalik, S.; Chapdalaine, P. (August 2008). "A postgenomic integrated view of prostaglandins in reproduction: implications for other body systems". Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society. 59 Suppl 1: 65–89. ISSN 1899-1505. PMID 18802217.

UpToDate Contents

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2. 乳酸アシドーシスにおける重炭酸療法 bicarbonate therapy in lactic acidosis
3. 経腟分娩後の出血管理 management of postpartum hemorrhage at vaginal delivery
4. 産褥性子宮内反症 puerperal uterine inversion
5. 胎盤早期剥離：管理 placental abruption management

English Journal

Dynamics of follicular growth and progesterone concentrations in cyclic and anestrous suckling Nelore cows (Bos indicus) treated with progesterone, equine chorionic gonadotropin, or temporary calf removal.

Barreiros TR1, Blaschi W1, Santos GM2, Morotti F2, Andrade ER3, Baruselli PS4, Seneda MM5.Author information 1Laboratório de Biotecnologia da Reprodução Animal, DVPA, UENP, Bandeirantes, Parana, Brazil.2Laboratório de Reprodução Animal, DCV-CCA-UEL, Londrina, Parana, Brazil.3Laboratório de Biotecnologia da Reprodução, UUA-UEMS, Aquidauana, Mato Grosso Do Sul, Brazil.4Departamento de Reprodução Animal, FMVZ-USP, São Paulo, Sao Paulo, Brazil.5Laboratório de Reprodução Animal, DCV-CCA-UEL, Londrina, Parana, Brazil. Electronic address: mseneda@uel.br.AbstractThe objective of this study was to investigate the effects of eCG and temporary calf removal (TCR) associated with progesterone (P4) treatment on the dynamics of follicular growth, CL size, and P4 concentrations in cyclic (n = 36) and anestrous (n = 30) Nelore cows. Cyclic (C) and anestrous (A) cows were divided into three groups. The control group received 2 mg of estradiol benzoate via intramuscular (IM) injection and an intravaginal device containing 1.9 g of P4 on Day 0. On Day 8, the device was removed, and the animals received 12.5 mg of dinoprost tromethamine IM. After 24 hours, the animals received 1 mg of estradiol benzoate IM. In the eCG group, cows received the same treatment described for the control group but also received 400 UI of eCG at the time of device removal. In the TCR group, calves were separated from the cows for 56 hours after device removal. Ultrasound exams were performed every 24 hours after device removal until the time of ovulation and 12 days after ovulation to measure the size of the CL. On the same day as the CL measurement, blood was collected to determine the plasma P4 level. Statistical analyses were performed with a significance level of P ≤ 0.05. In cyclic cows, the presence of the CL at the beginning of protocol resulted in a smaller follicle diameter at the time of device removal (7.4 ± 0.3 mm in cows with CL vs. 8.9 ± 0.4 mm in cows without CL; P = 0.03). All cows ovulated within 72 hours after device removal. Anestrous cows treated with eCG or TCR showed follicle diameter at fixed-timed artificial insemination (A-eCG 10.2 ± 0.3 and A-TCR 10.3 ± 0.5 mm) and follicular growth rate (A-eCG 1.5 ± 0.2 and A-TCR 1.3 ± 0.1 mm/day) similar to cyclic cows (C-eCG 11.0 ± 0.6 and C-TCR 12.0 ± 0.5 mm) and (C-eCG 1.4 ± 0.2 and C-TCR 1.6 ± 0.2 mm/day, respectively; P ≤ 0.05). Despite the similarities in CL size, the average P4 concentration was higher in the A-TCR (9.6 ± 1.4 ng/mL) than in the A-control (4.0 ± 1.0 ng/mL) and C-TCR (4.4 ± 1.0 ng/mL) groups (P < 0.05). From these results, we conclude that eCG treatment and TCR improved the fertility of anestrous cows by providing follicular growth rates and size of dominant follicles similar to cyclic cows. Additionally, TCR increases the plasma concentrations of P4 in anestrous cows.
Theriogenology.Theriogenology.2014 Mar 15;81(5):651-6. doi: 10.1016/j.theriogenology.2013.12.008. Epub 2013 Dec 18.
The objective of this study was to investigate the effects of eCG and temporary calf removal (TCR) associated with progesterone (P4) treatment on the dynamics of follicular growth, CL size, and P4 concentrations in cyclic (n = 36) and anestrous (n = 30) Nelore cows. Cyclic (C) and anestrous (A) cows
PMID 24447340

Increasing length of an estradiol and progesterone timed artificial insemination protocol decreases pregnancy losses in lactating dairy cows.

Pereira MH1, Rodrigues AD1, De Carvalho RJ2, Wiltbank MC3, Vasconcelos JL4.Author information 1Aluno do Programa de Pós-Graduação em Zootecnia, Faculdade de Medicina Veterinária e Zootecnia-Universidade Estadual Paulista, Botucatu 18618-000, Brazil.2Fazendas Reunidas ACP e Filhos, Minas Gerais, Carmo do Rio Claro 37150-000, Brazil.3Department of Dairy Science, University of Wisconsin, Madison 53706.4Department of Animal Production, São Paulo State University, Botucatu 18168-000, Brazil. Electronic address: vasconcelos@fmvz.unesp.br.AbstractOur hypothesis was that increasing the length of an estradiol and progesterone (P4) timed artificial insemination (TAI) protocol would improve pregnancy per artificial insemination (P/AI). Lactating Holstein cows (n=759) yielding 31±0.30kg of milk/d with a detectable corpus luteum (CL) at d -11 were randomly assigned to receive TAI (d 0) following 1 of 2 treatments: (8d) d -10 = controlled internal drug release (CIDR) and 2.0mg of estradiol benzoate, d -3 = PGF2α(25mg of dinoprost tromethamine), d -2 = CIDR removal and 1.0mg of estradiol cypionate, d 0 = TAI; or (9d) d -11 = CIDR and estradiol benzoate, d -4 = PGF2α, d -2 CIDR removal and estradiol cypionate, d 0 TAI. Cows were considered to have their estrous cycle synchronized in response to the protocol by the absence of a CL at artificial insemination (d 0) and presence of a CL on d 7. Pregnancy diagnoses were performed on d 32 and 60. The ovulatory follicle diameter at TAI (d 0) did not differ between treatments (14.7±0.39 vs. 15.0±0.40mm for 8 and 9 d, respectively). The 9d cows tended to have greater P4 concentrations on d 7 in synchronized cows (3.14±0.18ng/mL) than the 8d cows (3.05±0.18ng/mL). Although the P/AI at d 32 [45 (175/385) vs. 43.9% (166/374) for 8d and 9d, respectively] and 60 [38.1 (150/385) vs. 40.4% (154/374) for 8d and 9d, respectively] was not different, the 9d cows had lower pregnancy losses [7.6% (12/166)] than 8d cows [14.7% (25/175)]. The cows in the 9d program were more likely to be detected in estrus [72.0% (269/374)] compared with 8d cows [62% (240/385)]. Expression of estrus improved synchronization [97.4 (489/501) vs. 81% (202/248)], P4 concentrations at d 7 (3.22±0.16 vs. 2.77±0.17ng/mL), P/AI at d 32 [51.2 (252/489) vs. 39.4% (81/202)], P/AI at d 60 [46.3 (230/489) vs. 31.1% (66/202)], and decreased pregnancy loss [9.3 (22/252) vs. 19.8% (15/81)] compared with cows that did not show estrus, respectively. Cows not detected in estrus with small (<11mm) or large follicles (>17mm) had greater pregnancy loss; however, in cows detected in estrus, no effect of follicle diameter on pregnancy loss was observed. In conclusion, increasing the length of the protocol for TAI increased the percentage of cows detected in estrus and decreased pregnancy loss.
Journal of dairy science.J Dairy Sci.2014 Mar;97(3):1454-64. doi: 10.3168/jds.2013-7287. Epub 2014 Jan 4.
Our hypothesis was that increasing the length of an estradiol and progesterone (P4) timed artificial insemination (TAI) protocol would improve pregnancy per artificial insemination (P/AI). Lactating Holstein cows (n=759) yielding 31±0.30kg of milk/d with a detectable corpus luteum (CL) at d -11 wer
PMID 24393173

Efficient association between PGF2α and methyl 4-hydroxybenzoate sex pheromone prior to electroejaculation in dogs.

Santos IP1, Ramos CL, Ramos JL, Oliveira RF, Cunha IC.Author information 1Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes, Rio de Janeiro State, Brazil.AbstractElectroejaculation is a technique that can be used to collect semen from canines, but its use with this group of animals is restricted by low success rate and low semen quality. Here, we evaluated whether pharmacological and sexual sensory stimuli, which may affect ejaculation, can increase electroejaculation efficiency and improve ejaculate quality. We worked with 20 dogs of mixed breed weighing between 5.3 and 22.2 kg, divided into two groups. Both groups were exposed to a spayed female for 10 min, but in the second group, the same spayed female had her vagina impregnated with methyl 4-hydroxybenzoate synthetic pheromone for 10 min and after receiving dinoprost tromethamine IM, 0.1 mg/kg. After stimulation, all dogs were chemically restrained with ketamine, 8 mg/kg, IM; and xylazine, 1 mg/kg, IM, and subjected to electroejaculation protocol. We obtained 100% of antegrade ejaculate in treatments when the spayed female had her vagina impregnated with pheromone and 80% when she did not. Sperm motility was significantly different (p < 0.05) between controls and the test group (10.1 ± 4.5 and 43.0 ± 8.3, respectively). We concluded that the adopted electroejaculation protocol was efficient and that the PGF2α associated with sexual sensory stimulation can improve semen quality in dogs undergoing the procedure.
Reproduction in domestic animals = Zuchthygiene.Reprod Domest Anim.2013 Feb;48(1):160-4. doi: 10.1111/j.1439-0531.2012.02123.x. Epub 2012 Jun 27.
Electroejaculation is a technique that can be used to collect semen from canines, but its use with this group of animals is restricted by low success rate and low semen quality. Here, we evaluated whether pharmacological and sexual sensory stimuli, which may affect ejaculation, can increase electroe
PMID 22734461

「ジノプロスト」

Dinoprost
Clinical data
Synonyms	Amoglandin, Croniben, Cyclosin, Dinifertin, Enzaprost, Glandin, PGF2α, Panacelan, Prostamodin
AHFS/Drugs.com	International Drug Names
Routes of; administration	Intravenous (to induce labor), intra-amniotic (to induce abortion)
ATC code	G02AD01 (WHO);
Pharmacokinetic data
Biological half-life	3 to 6 hours in amniotic fluid, less than 1 minute in blood plasma
Identifiers
	IUPAC name (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)- 3-hydroxyoct-1-enyl]cyclopentyl]hept-5-enoic acid;
CAS Number	551-11-1 38562-01-5;
PubChem CID	5280363;
IUPHAR/BPS	1884;
DrugBank	DB01160 ;
ChemSpider	4444062 ;
KEGG	D01352 ;
ChEMBL	CHEMBL815 ;
ECHA InfoCard	100.209.720
Chemical and physical data
Formula	C20H34O5
Molar mass	354.48 g/mol
3D model (JSmol)	Interactive image;
Solubility in water	200 mg/mL (20 °C)
	SMILES O=C(O)CCC/C=C\C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)CCCCC ;
	InChI InChI=1S/C20H34O5/c1-2-3-6-9-15(21)12-13-17-16(18(22)14-19(17)23)10-7-4-5-8-11-20(24)25/h4,7,12-13,15-19,21-23H,2-3,5-6,8-11,14H2,1H3,(H,24,25)/b7-4-,13-12+/t15-,16+,17+,18-,19+/m0/s1 ; Key:PXGPLTODNUVGFL-YNNPMVKQSA-N ;
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