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11α-Hydroxyprogesterone

From Wikipedia, the free encyclopedia

11α-Hydroxyprogesterone
11α-Hydroxyprogesterone.svg
Clinical data
Synonyms11α-OHP; 11α-Hydroxypregn-4-ene-3,20-dione; 4-Pregnen-11α-ol-3,20-dione; δ4-Pregnen-11α-ol-3,20-dione
Identifiers
CAS Number
PubChem CID
ChemSpider
ChEBI
ChEMBL
Chemical and physical data
FormulaC21H30O3
Molar mass330.4611 g/mol g·mol−1
3D model (JSmol)

11α-Hydroxyprogesterone (11α-OHP), or 11α-hydroxypregn-4-ene-3,20-dione is an endogenous steroid and metabolite of progesterone.[1][2][3] It is a weak antiandrogen, and is devoid of androgenic, estrogenic, and progestogenic activity.[4][5][6] It was investigated as a topical antiandrogen for the treatment of androgen-dependent skin conditions in the early 1950s, and was found to produce some benefit.[7] In 1995, 11α-OHP, along with its epimer 11β-hydroxyprogesterone, was identified as a very potent competitive inhibitor of both isoforms (1 and 2) of 11β-hydroxysteroid dehydrogenase (11β-HSD).[2][3] It is notably not metabolized by 11β-HSD2.[8] 11α-OHP is a more potent inhibitor of 11β-HSD than enoxolone (glycyrrhetinic acid) or carbenoxolone in vitro (IC50 = 0.9 nM; IC50 = 5 nM in transfected cells).[8][9][10] The compound has been found to be highly active in conferring mineralocorticoid sodium-retaining activity of corticosterone in vivo in rat bioassays and in increasing blood pressure, effects that it mediates by preventing the 11β-HSD-mediated inactivation of endogenous corticosteroids.[2][3] Because of its inhibition of 11β-HSD and consequent potentiation of corticosteroids, 11α-OHP has recently been patented for the treatment of skin diseases, particularly psoriasis in combination with clobetasol propionate and minoxidil.[5]

11α-OHP is used as a precursor in chemical syntheses of cortisone and hydrocortisone.[11][12][13]

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Transcription

This presentation is a brief overview of the use of Proluton, a synthetic progesterone in the field of obstetrics. We will first introduced Proluton and review how it can be applied in obstetric conditions. We will also go over current guidelines and conclude by discussing its safety profile. This is a flow chart of our discussion. What is Proluton? How does it work? Proluton, or 17 alpha-hydroxyprogesterone caproate is a synthetic progestogen. It is manufactured by the esterification of a progesterone metabolite, which increases its progestogenic activity. It is also known as hydroxyprogesterone hexanoate. In order to understand how Proluton can be used in obstetrics, it is important to understand the role of progesterone in pregnancy. Progesterone induces changes within the lining of the uterus to allow the implantation of a fertilized egg. It then prevents rejection of the embryo by immune modulation. It also prevents the contraction of the uterus by suppressing contractile genes, inflammatory mediators, and oxytocin to prevent uterine contraction. Progesterone exerts its effects on the cervix as well. Effacement of the cervix occurs through reorganization of collagen as well as inflammation, and these events are effected by the various enzymes and proteins shown on the slide. What progesterone does is to prevent collagen reorganization and inflammation by inhibiting and up regulating proteins to maintain cervical competency. With that in mind, we can see how Proluton, as a progestogenic agent, can possibly help with various obstetric conditions. In this presentation, we will focus only on preterm labor and short cervix. Preterm birth is defined as delivery at less than 37 weeks. In the US, the number of preterm births have been on the rise and was reported to be top 12.5% in 2004. This has resulted in over $26 million in cost. Despite medical advancements, such as Proluton, which was introduced in 1970, prematurity rates continues to rise. One of the reasons is due to having only 25% of obstetricians offering it to their patients. The lack of clinical use is mainly due to conflicting results from experimental studies. Let us now discuss the results. While the cause of spontaneous preterm birth is unknown, a history of spontaneous preterm birth is one of the strongest predictors for preterm birth in a subsequent pregnancy. It is speculated that labors are caused by the breakdown of factors maintaining uterine quiescence, fetal distress, and progesterone withdrawal. In this RCT study by Meis, et al., Proluton was shown to be effective in preterm labor. 459 patients at high risk for preterm birth because of a prior preterm birth was randomized to receive weekly Proluton or placebo at 16 to 20 weeks until 36 weeks. The results were measured using the outcome of preterm labor of less than 37 weeks. Those included in the study have a history of spontaneous preterm delivery between 20 to 36 weeks, of a liveborn singleton, and the current pregnancy between 15 to 20 weeks plus three days. Those with multifetal gestation and any known fetal anomaly were excluded. Results from this trials show that use of Proluton significantly reduced the risk of preterm delivery compared to placebo. The benefits of Proluton extended beyond merely prolonging the length of gestation. Of the infants exposed to Proluton, there was reduced perinatal morbidity, necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen. Twins are another high-risk for preterm birth. A randomized controlled trial conducted by Rouse, et al. reported no differences between Proluton versus placebo. Similar findings for triple gestations were recently demonstrated in another randomized control trial. It reported no differences in preterm birth rate across all weeks of gestational age. A second more recent study by combs even reported an increase in neonatal morbidity. Thus no benefit has been found to support using Proluton in triplet gestations. In terms of threatened preterm labor, there is conflicting evidence on the use of Proluton in management. The RCT by Facchinetti, et al. in 2007 showed an increase in the average time to delivery. However, another multicentered RCT by Rosenberg, et al. in 2012 reported no differences in the average time of delivery with the use of Proluton. Besides these two studies, there have been other research done with progesterone, and they too have not yielded positive results with respect to threatened preterm labor. Finally, Proluton has not shown to be effective with tocolysis in acute preterm labor. To summarize, Proluton has been shown to benefit patients with a previous history of preterm birth and not effective in multigestational pregnancies, threatened preterm labor, or as adjunct to tocolysis. The next potential use of Proluton that we are going to discuss is the use in pregnant women with short cervix. Short cervix has been shown to be an independent risk factor for preterm delivery. A pregnant woman can be diagnosed as having short cervix if she is shown to have cervical length less than or equal to 25 millimeters in pelvic ultrasound. In treatment of short cervix, there are high-level evidence that cerclage and vaginal progesterone are efficacious in attenuating cervical shortening and lowering the risk of preterm delivery. However, the role of Proluton in this setting is unclear. A secondary analysis of a randomized control trial by Berghella, et al. in 2010 showed that in patients who have been given cerclage, there is no statistically significant difference in outcome in patients given Proluton. In patients without cerclage, Proluton decreased risk of preterm delivery before 24 weeks and reduced perinatal mortality, but showed no difference in other outcomes, including preterm delivery before 35 weeks. A retrospective study by Raphael, et al. in 2011 also showed no significant difference in outcomes achieved by giving Proluton to patients with cerclage. Finally, a randomized trial by Keeler, et al. in 2009 comparing the efficacy of the cerclage and Proluton showed that they have similar efficacy for patients with cervix shorter than or equal to 25 millimeters. However, cerclage was shown to be more efficacious when the cervical length is less than or equal to 50 millimeters. Considering the currently available evidence, it can be concluded that in patients with short cervix who have been given cerclage, Proluton did not improve outcomes. On the other hand, in patients with short cervix without cerclage, some studies indicate the Proluton is useful to reduce risk, but only if they also have a history of preterm delivery. However, all the studies done on Proluton in the setting of short cervix only involved a rather small number of patients. There is currently no high-level evidence on the use of Proluton for short cervix. In agreement, ACOG stated that Proluton is not for women with short cervix and no prior preterm birth. And RCOG does not recommend routine use of progesterone supplementation following cerclage. We will proceed to discuss the safety profile of Proluton. Although the FDA lumped Proluton together with other progesterone-like drugs which have shown an increased risk of hypospadias, recent studies have demonstrated that Proluton is safe to use with no evidence of teratogenicity, androgenic activity, glucocorticoid activity, and virilization of female fetuses. According to a ACOG guidelines, Proluton usage is recommended for patients with history of a spontaneous preterm birth less than 37 weeks with current singleton pregnancy. Proluton is to be initiated between 16 week 0 days and 20 weeks 6 days of pregnancy. RCOG endorses current recommendations that in women at high risk of preterm delivery progesterone administration should be restricted to clinical trials. The two most recent ongoing multicentered clinical trials include the following studies investigating the use of Proluton in women with a previous preterm birth and the use of Proluton in women with premature rupture of membranes. Conclusion-- in this presentation, we have to show you how the mechanism of Proluton opens up several possibilities for its use in obstetrics, especially in preterm labor and short cervix. We have adequate evidence for its use for women with a prior history of preterm labor but not for those with short cervix. Thank you.

See also

References

  1. ^ Ford, Donald H. (1954). "EFFECT OF 11α-HYDROXYPROGESTERONE ON REPRODUCTIVE SYSTEM OF NORMAL AND PREGNANT ADULT WISTAR RATS*". The Journal of Clinical Endocrinology & Metabolism. 14 (10): 1268–1270. doi:10.1210/jcem-14-10-1268. ISSN 0021-972X.
  2. ^ a b c Souness GW, Latif SA, Laurenzo JL, Morris DJ (1995). "11 alpha- and 11 beta-hydroxyprogesterone, potent inhibitors of 11 beta-hydroxysteroid dehydrogenase (isoforms 1 and 2), confer marked mineralocorticoid activity on corticosterone in the ADX rat". Endocrinology. 136 (4): 1809–12. doi:10.1210/endo.136.4.7895695. PMID 7895695.
  3. ^ a b c Souness GW, Morris DJ (1996). "11 alpha- and 11 beta-hydroxyprogesterone, potent inhibitors of 11 beta-hydroxysteroid dehydrogenase, possess hypertensinogenic activity in the rat". Hypertension. 27 (3 Pt 1): 421–5. doi:10.1161/01.hyp.27.3.421. PMID 8698448.
  4. ^ Lerner, Leonard J. (1975). "Androgen antagonists". Pharmacology & Therapeutics B. 1 (2): 217–231. doi:10.1016/0306-039X(75)90006-9. ISSN 0306-039X. 11α Hydroxyprogesterone, while devoid of androgenic, estrogenic and progestational activity, is weakly anti androgenic in castrate rats.
  5. ^ a b Nguyen, Kim Thoa; Virus, Cornelia; Günnewich, Nils; Hannemann, Frank; Bernhardt, Rita (2012). "Changing the Regioselectivity of a P450 from C15 to C11 Hydroxylation of Progesterone". ChemBioChem. 13 (8): 1161–1166. doi:10.1002/cbic.201100811. ISSN 1439-4227. 11α-Hydroxyprogesterone is an important pharmaceutical compound with anti-androgenic and blood-pressure-regulating activity. [...] 11α-Hydroxyprogesterone can therefore influence blood pressure regulation.12 Furthermore, 11α-hydroxyprogesterone exhibits an anti-androgenic activity with minimal estrogenic and progestational side effects.13 This substance was also recently patented for its role in treating skin diseases, especially for psoriasis in combination with clobetasol propionate and minoxidil.14.
  6. ^ Tindall, D.J.; Chang, C.H.; Lobl, T.J.; Cunningham, G.R. (1984). "Androgen antagonists in androgen target tissues". Pharmacology & Therapeutics. 24 (3): 367–400. doi:10.1016/0163-7258(84)90010-X. ISSN 0163-7258.
  7. ^ Larry E. Millikan (19 April 2016). Drug Therapy in Dermatology. CRC Press. p. 403. ISBN 978-0-203-90831-0. Topical antiandrogens have also been tried, including topical progesterone, which proved ineffective. However, small studies with topical 11α-hydroxyprogesterone and 17α-estradiol showed some benefit [38,39].
  8. ^ a b Morita, H; Zhou, M; Foecking, M F; Gomez-Sanchez, E P; Cozza, E N; Gomez-Sanchez, C E (1996). "11 beta-Hydroxysteroid dehydrogenase type 2 complementary deoxyribonucleic acid stably transfected into Chinese hamster ovary cells: specific inhibition by 11 alpha-hydroxyprogesterone". Endocrinology. 137 (6): 2308–2314. doi:10.1210/endo.137.6.8641180. ISSN 0013-7227. PMID 8641180. 11 alpha-Hydroxyprogesterone (11 alpha OH-P) was an order of magnitude more potent a competitive inhibitor of the 11 beta HSD-2 than was glycyrrhetinic acid (GA) (approximate IC50 = 0.9 vs. 15 nM).
  9. ^ Tomlinson, Jeremy W.; Walker, Elizabeth A.; Bujalska, Iwona J.; Draper, Nicole; Lavery, Gareth G.; Cooper, Mark S.; Hewison, Martin; Stewart, Paul M. (2004). "11β-Hydroxysteroid Dehydrogenase Type 1: A Tissue-Specific Regulator of Glucocorticoid Response". Endocrine Reviews. 25 (5): 831–866. doi:10.1210/er.2003-0031. ISSN 0163-769X. PMID 15466942. In intact cells 11α-hydroxyprogesterone is a more potent inhibitor of 11β-HSD1 than glycyrrhetinic acid or 11β-hydroxyprogesterone (117, 118).
  10. ^ Bujalska, Iwona; Shimojo, Masako; Howie, Alex; Stewart, Paul M. (1997). "Human 11β-hydroxysteroid dehydrogenase: Studies on the stably transfected isoforms and localization of the type 2 isozyme within renal tissue". Steroids. 62 (1): 77–82. doi:10.1016/S0039-128X(96)00163-8. ISSN 0039-128X.
  11. ^ Peter J. Dunn; Andrew Wells; Michael T. Williams (2 February 2010). Green Chemistry in the Pharmaceutical Industry. John Wiley & Sons. pp. 2–. ISBN 978-3-527-62969-5.
  12. ^ Clemens Lamberth; Jürgen Dinges (17 May 2016). Bioactive Carboxylic Compound Classes: Pharmaceuticals and Agrochemicals. Wiley. pp. 250–. ISBN 978-3-527-69396-2.
  13. ^ Kishan Gopal Ramawat; Jean-Michel Mérillon (16 October 2008). Bioactive Molecules and Medicinal Plants. Springer Science & Business Media. pp. 5–. ISBN 978-3-540-74603-4.
This page was last edited on 5 June 2019, at 21:52
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