Abstract
Objective:
To determine whether 17-α hydroxyprogesterone (17-OHPC) alters tumor necrosis factor-α (TNF-α) production and the expression of cyclooxygenase type 2 (COX-2) in myometrium exposed to lipopolysaccharide (LPS).
Study Design:
Lower segment myometrial biopsies were obtained from non-laboring patients at term. Tissues were cultured in serum-free media with 17-OHPC (1 μM) and LPS (1 μg/ml), either alone or in combination. At 24 h, the production of tumor necrosis factor-α (TNF-α) and the expression of COX-2 was determined using enzyme linked immunosorbent assay and real-time (RT-PCR). Statistical analysis was performed using non-parametric testing. A P-value of <0.05 was considered significant.
Result:
17-OHPC had no effect on TNF-α production and COX-2 expression when compared with untreated myometrial explants (P=0.61 and P=0.95). LPS induced production of TNF-α (P=0.03) and expression of COX-2 (P=0.02). Treatment with 17-OHPC did not block LPS-induced TNF-α production (P=0.37) or COX-2 expression (P=0.12).
Conclusion:
In this pilot study, 17-OHPC did not affect the production of TNF-α or COX-2 expression in human myometrium.
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References
Da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M . Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increase risk: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol 2003; 188: 419–424.
Slater DM, Dennes WJ, Campa JS, Poston L, Bennett PR . Expression of cyclo-oxygenase types-1 and -2 in human myometrium throughout pregnancy. Mol Hum Reprod 1999; 5 (9): 880–884.
Sooranna SR, Lee Y, Kim LU, Mohan AR, Bennett PR, Johnson MR . Mechanical stretch activates type 2 cyclooxygenase via activator protein-1 transcription factor in human myometrial cells. Mol Hum Reprod 2004; 10 (2): 109–113.
Gravett MG, Novy MJ, Rosenfeld RG, Reddy AP, Jacob T, Turner M et al. Diagnosis of intra-amniotic infection by proteomic profiling and identification of novel biomarkers. JAMA 2004; 292 (4): 462–469.
Goldenberg RL, Hauth JC, Andrews WW . Intrauterine infection and preterm delivery. N Engl J Med 2000; 342 (20): 1500–1507.
Houben M, Nikkels P, van Bleek G, Visser G, Rovers M, Kessel H et al. The association between intrauterine inflammation and spontaneous vaginal delivery at term: a cross-sectional study. PLoS ONE 2009; 4 (8): e6572.
Peltier M, Tee S, Smulian J . Effect of progesterone on proinflammatory cytokine production by monocytes stimulated with pathogens associated with preterm birth. Am J Reprod Immunol 2008; 60 (4): 346–353.
Watari M, Watari H, DiSanto M, Chacko S, Shi G, Strauss J . Pro-inflammatory cytokines induce expression of matrix-metabolizing enzymes in human cervical smooth muscle cells. Am J Pathol 1999; 154 (6): 1755–1762.
Inglis S, Jeremias J, Kuno K, Lescale K, Peeper Q, Chervenak F et al. Detection of tumor necrosis factor-alpha, interleukin-6, and fetal fibronectin in the lower genital tract during pregnancy: relation to outcome. Am J Obstet Gynecol 1994; 171 (1): 5–10.
Sadowsky D, Adams K, Gravett M, Witkin S, Novy M . Preterm labor is induced by intraamniotic infusions of interleukin-1beta and tumor necrosis factor-alpha but not by interleukin-6 or interleukin-8 in a nonhuman primate model. Am J Obstet Gynecol 2006; 195: 1578–1589.
Pu J, Zeng WY . Relationship among TNF-alpha gene promoter -308 site polymorphism, the levels of maternal serum TNF-alpha, and the mRNA expression placental TNF-alpha in preterm labor. Sichuan Da Xue Xue Bao Yi Xue Ban 2009; 40 (1): 77–80.
Erkinheimo TL, Saukkonen K, Narko K, Jalkanen J, Ylikorkala O, Ristimaki A . Expression of cyclooxygenase-2 and prostanoid receptors by human myometrium. J Clin Endocrinol Metab 2000; 85: 3468–3475.
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 Engl J Med 2003; 348 (24): 2379–2385.
Facchinetti F, Dante G, Venturini P, Paganelli S, Volpe A . 17α-hydroxy-progesterone effects on cervical proinflammatory agents in women at risk for preterm delivery. Am J Perinatol 2008; 25: 503–506.
Tyson-Capper AJ, Europe-Finner GN . Novel targeting of cyclooxygenase-2 (COX-2) pre-mRNA using antisense morpholino oligonucleotides directed to the 3′ acceptor and 5′ donor splice sites of exon 4: suppression of COX-2 activity in human amnion-derived WISH and myometrial cells. Mol Pharm 2006; 69 (3): 796–804.
Sexton D, O’Reilly M, Friel A, Morrison J . Functional effects of 17alpha- hydroxyprogesterone caproate (17P) on human myometrial contractility in vitro. Reprod Biol Endocrinol 2004; 2 (1): 80.
Hardy DB, Janowski BA, Corey DR, Mendelson CR . Progesterone receptor plays a major antiinflammatory role in human myomterial cells by antagonism of nuclear factor-κB activation of cyclooxygenase 2 expression. Mol Endocrinol 2006; 20: 2724–2733.
Hatthachote P, Gillespie JI . Complex interactions between sex steroids and cytokines in the human pregnant myometrium: evidence for an autocrine signaling system at term. Endocrinology 1999; 140 (6): 2533–2540.
Li A, Lee RH, Felix JC, Minoo P, Goodwin TM . Alteration of secretory leukocyte protease inhibitor in human myometrium during labor. Am J Obstet Gynecol 2009; 200 (3): 311. e1–311. e10.
Jain JK, Li A, Minoo P, Nucatola DL, Felix JC . The effect of nonoxynol-9 on human endometrium. Contraception 2005; 71: 137–142.
Li A, Felix JC, Hao J, Minoo P, Jain JK . Menstrual-like breakdown and apoptosis in human endometrial explants. Hum Reprod 2005; 20: 1709–1719.
Li A, Felix JC, Minoo P, Amezcua CA, Jain JK . Effect of mifepristone on proliferation and apoptosis of Ishikawa endometrial adenocarcinoma cells. Fertil Steril 2005; 84: 202–211.
Jain JK, Li A, Nucatola DL, Minoo P, Felix JC . Nonoxynol-9 induces apoptosis of endometrial explants by both caspase-dependent and -independent apoptotic pathways. Biol Reprod 2005; 73: 382–388.
Nap AW, Dunselman GA, de Goeij AF, Evers JL, Groothuis PG . Inhibiting MMP activity prevents the development of endometriosis in the chicken chorioallantoic membrane model. Hum Reprod 2004; 19 (10): 2180–2187.
Ruddock NK, Shi S-Q, Jain S, Moore G, Hankins G, Romero R et al. Progesterone, but not 17-alpha hydroxyprogesterone caproate, inhibits human myometrial contractions. Am J Obstet Gynecol 2008; 199: 391.e1–391.e7.
Keiser S, Veillon E, Parrish M, Bennett W, Cockrell K, Fournier L et al. Effects of 17-hydroxyprogesterone on tumor necrosis factor-α-induced hypertension during pregnancy. Am J Hypertens 2009; 22 (10): 1120–1125.
Veillon E, Keiser S, Parrish M, Bennett W, Cockrell K, Ray L et al. 17-hydroxyprogesterone blunts the hypertensive response associated with reductions in uterine perfusion pressure in pregnant rats. Am J Obstet Gynecol 2009; 201 (3): 324. e1–323. e6.
Amory J, Lawler R, Shields L . Hydroxyprogesterone caproate and progesterone increase tumor necrosis factor-alpha production in lipopolysaccharide stimulated whole blood from non-pregnant women. J Perinat Med 2005; 33 (6): 506–509.
Johnson JWC, Lee PA, Zachary AS, Calhoun S, Migeon CJ . High-risk prematurity-progestin treatment and steroid studies. Obstet Gynecol 1979; 54 (4): 412–418.
Hartikainen-Sorri A, Kauppila A, Tuimala R . Inefficacy of 17 alpha-hydroxyprogesterone caproate in the prevention of prematurity in twin pregnancy. Obstet Gynecol 1980; 56 (6): 692–695.
Attardi BJ, Zeleznik A, Simhan H, Chiao JP, Mattison DR, Caritis SN . Comparison of progesterone and glucocorticoid receptor binding and stimulation of gene expression by progesterone, 17-alpha hydroxyprogesterone caproate, and related progestins. Am J Obstet Gynecol 2007; 197 (6): 599.e1–599.e7.
Benjamin D, Jost JP . Reversal of methylation-mediated repression with short-chain fatty acids: evidence for an additional mechanism to histone deacetylation. Nucleic Acids Res 2001; 29 (17): 3603–3610.
Lockwood CJ, Kuczynski E . Risk stratification and pathological mechanisms in preterm delivery. Paediatr Perinat Epidemiol 2001; 15 (Suppl 2): 78–89.
Jansen PW, Tiemeier H, Jaddoe VWV, Hofman A, Steegers EAP, Verhulst FC et al. Explaining educational inequalities in preterm birth: the generation r study. Arch Dis Child Fetal Neontal Ed 2009; 94 (1): F28–F34.
Moutquin JM . Socio-economic and psychosocial factors in the management and prevention of preterm labour. BJOG 2003; 110 (Suppl 20): 56–60.
Goffinet F . Primary predictors of preterm labour. BJOG 2005; 112 (Suppl 1): 38–47.
ESHRE Capri Workshop Group. Multiple gestation pregnancy. Hum Reprod 2000; 15: 1856–1864.
ACOG Committee opinion no. 419. American College of Obstetricians and Gynecologists. Obstet Gynecol 2008; 112: 963–965.
Acknowledgements
We thank Drs Frank Stanczyk and Durlin Hickok and Adeza Biomedical Corporation for providing the 17-OHPC used in our experiment. We also acknowledge grant funding from Health Research Associates.
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Patel, S., Li, A., Goodwin, T. et al. Effect of 17-α hydroxyprogesterone caproate on the production of tumor necrosis factor-α and the expression of cyclooxygenase-2 in lipopolysaccharide-treated gravid human myometrial explants. J Perinatol 30, 584–589 (2010). https://doi.org/10.1038/jp.2010.23
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DOI: https://doi.org/10.1038/jp.2010.23