Remzi GÖKDENİZ, Ali OVAYOLU, E. Robert GARFİELD

Progesterone inhibits human myometrial contractions by its action on membrane receptors

Amaç: Miyometrialinhibisyon mekanizmaları halen araştırılmaktadır. Bu çalışmanın amacı progesteronun (P4) uterin kontraktilitesi üzerine olan inhibisyon mekanizmasını incelemektir. Yöntem: Prospektif çalışma St. Joseph Hastanesi Üçüncü Basamak Tedavi Hizmetleri Merkezi ve Maricopa Hastanesi, Phoenix; AZ ile Arizona Araştırma Merkezi, ABD de gerçekleştirildi. 2010-2011 yılları sırasında 24 kadın sezaryan operasyonla doğum yaptı. Doğum esnasında kadınlardan (n=24) alınan uterin dokuları organ banyolarında bekletilerek çeşitli ajanlara maruz bırakıldı. Kontraktilite, ajanların eklenmesinden önce ve sonra kayıt edildi ve karşılaştırıldı. Dokular ya yalnız P4 ile, ya progesteron membran reseptörüne (mPR) düşük afinitesi olan progestin (R5020) ile veya bir non-seks steroidi (kolesterol) ile muamele edildi. Diğer dokular ise adenilat siklaz inhibitörü (SQ22536), fosfodiesteraz inhibitörü (rolipram), nitrik oksit (NO) sentaz inhibitörü (L-NAME) veya nükleer P4 reseptör antagonistine (mifepristone, MIF) maruz bırakıldıktan sonra P4 ile muamele edildi. Veriler ANOVA ile analiz edildi. Bulgular: Progesteron (p0.05) çok az inhibe edici etkiye sahipti. Progesteron inhibisyonu MIF, SQ, ODQ, rolipram veya L-NAME (p>0.05) ile bloke edilemedi. Sonuç: Progesteron miyometrial kontraksiyonu genomik olmayan mekanizmalarla; cAMP, cGMP veya NO ile ilişkili olmadan, sadece mPR aracılığı ile hızlı bir şekilde inhibe etmektedir.

Progesteron İnsan miyometrial kontraksiyonlarını membran reseptörleri aracılığı ile inhibe etmektedir

Purpose: The mechanisms for myometrial inhibition are still being investigated. The aim of this article is to examine mechanisms of progesterone (P4) inhibition of uterine contractility. Methods: Prospective study Tertiary care center at St. Joseph s Hospital and at Maricopa Hospital, Phoenix, AZ and research center in Arizona, USA. During 2010-2011 24 women were given birth by cesarean section. Uterine tissues from women (n=24) at term were suspended in organ chambers and exposed to various agents. Contractility was recorded and compared before and after addition of agents. Tissues were treated with P4 alone, a progestin (R5020) with low affinity to the progesterone membrane receptor (mPR), or a non-sex steroid (cholesterol). Other tissues were pretreated with inhibitors of adenylate cyclase (SQ 22536), phosphodiesterase (rolipram), nitric oxide (NO) synthases (L-NAME) or a nuclear P4 receptor antagonist (mifepristone, MIF), followed by P4. Data were analyzed by ANOVA. Results: P4 (P0.05) inhibitory effects. P4 inhibition is not blocked by MIF, SQ, ODQ, rolipram or L-NAME (P>0.05). Conclusions: P4 rapidly inhibits myometrial contractility by nongenomic mechanisms through action on mPR but not via cAMP, cGMP, or NO

PDF

___

1. Fsapo A. Force of labour. In: Iffy L, Kaminetzky HA, editors. Principles and Practice of Obstetrics and Perinatology. John Wiley and Sons, Inc. 1981; 761-799.
2. Chwalisz K, Hegele-Hartung C, Schulz R, Shi SQ, Louton PT. Progesterone control of cervical ripening - experimental studies with the progesterone antagonists onapristone, lilopristone and mifepristone. In: Leppert P, Woessner F, editors. The Extracellular Matrix of the Uterus, Cervix and Fetal Membranes: Synthesis, Degradation and Hormonal Regulation. Perinatology Press. 1991; 119-131.
3. Chwalisz K, Garfield RE. Regulation of the uterus and cervix during pregnancy and labor. Ann NY Acad Sci. 1997; 828: 238-53.
4. Hegele-Hartung C, Chwalisz K, Beier HM, Elger W. Ripening of the uterine cervix of the guinea-pig after treatment with the progesterone antagonist Onapristone (Zk-98.299) - an electron-microscopic study. Hum Reprod. 1989; 4: 369-77.
5. Johnson JW, Austin KL, Jones GS, Davis GH, and King TM. Efficacy of 17 alpha-hydroxyprogesterone caproate in the prevention of premature labor. N Engl J Med. 1975; 293: 675-80.
6. Yemini M, Borenstein R, Dreazen E. Prevention of premature labor by 17 alpha-hydroxyprogesterone caproate in the prevention of premature labor. Am J Obstet Gynaecol. 1985; 151: 574-77.
7. Harrikainen-Sorri AL, Kauppila, A, Tuimala, R. Inefficacy of 17 alpha-hydroxyprogesterone caproate in the prevention of prematurity in twin pregnancy. Obstet Gynaecol. 1980; 56: 692-95.
8. Keirse MJ. Progestogen administration in pregnancy may prevent preterm delivery. Br J Obstet Gynaecol. 1990; 97: 149-54.
9. Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Eng J Med. 2003; 348: 2379-85.
10. da Fonseca EB, Bittar RE, Carvalho MHB, Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am J Obstet Gynaecol. 2003; 188: 419-24.
11. Barnafi L, Larraguibel R. The in vitro effect of progesterone and oestrogens on thespontaneous and oxytocin-induced activity of the human myometrium. Acta Endocrinol. 1974; 76: 172-7.
12. Batra S, Bengtsson B. Effects of diethylstilboestrol and ovarian steroids on the contractile responses and calcium movements in rat uterine smooth muscle. J Physiol. 1978; 276: 329-42.
13. Fu X, Rezapour M, Lofgren M, Ulmsten U, Backstrom T. Antianaphylactic effects of progesterone and oxytocin on term human myometrial contractile activity in-vitro. Obstet Gynaecol. 1993; 82: 532-8.
14. Fu X, Ulmsten U, Backstrom T. Interaction of sex steroids and oxytocin on term human myometrial contractile activity in-vitro. Obstet Gynaecol. 1994; 84: 272-7.
15. Fu X, Rezapour M, Lofgren M, Ulmsten U, Backstrom T. Unexpected stimulatory effect of progesterone on human myometrial contractile activity in-vitro. Obstet Gynaecol. 1993; 82: 23-8.
16. Kostrzewska A, Laudanski T, Batra S. Effect of ovarian-steroids and diethylstilbestrol on the contractile responses of the human myometrium and intramyometrial arteries. Eur J Pharmacol. 1993; 233: 127-34.
17. Kubli-Garfias C, Hoyo-Vadillo C, López-Nieto E, Ponce-Monter H. Inhibition of spontaneous contractions of the rat pregnant uterus by progesterone metabolites. Life Sci. 1990; 47: 1547-53.
18. Löfgren M, Holst J, Bäckström T. Effects in vitro of progesterone and two 5α reduced progestins, 5α-pregnane-3,20-dione and 5α-pregnane-3α-ol-20-one, on contracting human myometrium at term. Acta Obstet Gynecol Scand. 1992; 71: 28-33.
19. Sexton DJ, O'Reilly MW, Friel AM, and Morrison JJ. Functional effects of 17alpha-hydroxyprogesterone caproate (17P) on human myometrial contractility in vitro. Reprod Biol Endocrinol. 2004; 2: 80.
20. Ruddock N, Shi SQ, Jain S, Moore G, Hankins GD, Romero R et al. Progesterone, but not 17alpha hydroxyprogesterone caproate, inhibit human myometrial contractions. Am J Obstet Gynaecol. 2008; 199: 391.e1-391.e7.
21. Kao, CY, Electrophysiological properties of uterine smooth muscle. In Biology of the Uterus, Eds: RM Wynn and WP Jollie, Plenum Medical Book Company, New York. 1989; 403-54.
22. Sanborn BM, Yue C, Wang W, Dodge KL. G protein signalling pathways in the myometrium: affecting the balance between contraction and relaxation. Rev Reprod. 1998; 3: 196-205.
23. Fomin VP, Cox BE, Word RA. Effect of progesterone on intracellular Ca²+ homeostasis in human myometrial smooth muscle cells. Am Physiol Soc. 1999; 276: 379-85.
24. Bernal A. Mechanisms of labour-biochemical aspects. Br J Obstet Gynaecol. 2003; 110: 39-45.
25. Izumi H, Garfield RE. Relaxant effects of nitric oxide and cyclic GMP on pregnant rat uterine longitudinal smooth muscle. Eur J Obstet Reprod Biol. 1995; 60: 171-80.
26. Buhimschi, E, Yallampalli, C, Dong, YL, Garfield RE. Involvement of a nitric oxide-cyclic guanosine monophosphate pathway in control of human uterine contractility during pregnancy. Am J Obstet Gynaecol. 1995; 172: 1577-84.
27. Mesiano S, Chan EC, Fitter JT, Kwek K, Yeo G, Smith R. Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor: a expression in the myometrium. Clin Endocrinol Metabol. 2002; 87: 2924-30.
28. Mesiano S. Myometrial progesterone responsiveness. Semin Reprod Med. 2007; 25: 5-13.
29. Merlino AA, Welsh TN, Tan HQ, Yi LJ, Cannon V, Mercer BM et al. Nuclear progesterone receptors in the human pregnancy myometrium: Evidence that parturition involves functional progesterone withdrawal mediated by increased expression of progesterone receptor-A. J Clin Endocrinol Metabol 2007;92: 1927-1933.
30. Karteris E, Zervou S, Pang YF, Dong J, Hillhouse EW, RandevaHS et al.Progesterone signaling in human myometrium through two novel membrane G protein-coupled receptors: Potential role in functional progesterone withdrawal at term. Mol Endocrinol 2006; 20: 1519-1534.
31. Smith RD, Babiychuk EB, Noble K, Draeger A, Wray S. Increased cholesterol decreases uterine activity: functional effects of cholesterol alteration in pregnant rat myometrium. Am J Physiol Cell Physiol 2005; 288: C982-988.
32. Koike K, Yamashita Y, Horinouchi T, Yamaki F, Tanaka Y. cAMP-independent mechanism is significantly involved in beta2adrenoceptor-mediated tracheal relaxation. Eur J Pharmacol 2004; 492: 65-70.