Progesterone, but not 17-alpha-hydroxyprogesterone caproate, inhibits human myometrial contractions Nicole K. Ruddock, MD; Shao-Qing Shi, MD; Sangeeta Jain, MD; Gradie Moore, MD; Gary D. V. Hankins, MD; Roberto Romero, MD; Robert E. Garfield, PhD OBJECTIVE: The aim was to determine whether progesterone (P4) or 17- alpha-hydroxyprogesterone caproate (17P) directly inhibit human uterine contractility in vitro and thereby clarify their mechanisms of action. STUDY DESIGN: Myometrial tissues were suspended in organ chambers and exposed for 2 to 20 hours to varying concentrations of P4 or 17P or solvent. Contractile activity was registered, stored, and analyzed. Dose re- sponse curves were then generated for P4 or 17P at various times. RESULTS: P4 significantly inhibited spontaneous contractility dose dependently. The inhibition was not blocked by RU486 but was revers- ible after washing. Surprisingly, 17P dose dependently stimulated con- tractility. HPLC and GC-MS methods were used to determine the de- tectable concentrations of progestins in the baths. CONCLUSION: P4, at concentrations equivalent to those present in the placenta and uterus, inhibit spontaneous myometrial contractility in vitro by nongenomic mechanisms. Key words: 17-alpha-hydroxyprogesterone caproate, myometrium, preterm labor, progesterone, uterine contractility Cite this article as: Ruddock NK, Shi S-Q, Jain S, et al. Progesterone, but not 17-alpha-hydroxyprogesterone caproate, inhibits human myometrial contractions. Am J Obstet Gynecol 2008;199:391.e1-391.e7. P rogesterone (P4) has long been thought to regulate uterine contrac- tility 1 and cervical function 2,3 and there- fore the onset and progression of la- bor. Several early studies suggested that 17-alpha-hydroxyprogesterone caproate (17P), a synthetic caproate ester of the progesterone metabolite, might be used to treat preterm labor. 4,5 More recent studies support a role for both 17P and P4 in the prevention of preterm labor for women at risk for preterm delivery. 6,7 Meis et al 6 in a multicenter study showed a significant reduction of preterm deliv- ery in women with a history of prior pre- term deliveries who were treated with weekly injections of 17P (250 mg), com- pared with placebo from weeks 16-20 to week 36 or delivery. These findings were corroborated by da Fonseca et al 7 using daily supplemen- tation with P4 (100 mg) in vaginal sup- positories from 24 to 34 weeks of gesta- tion. In the study by Meis et al, 6 the authors suggested that 17P may suppress uterine contractility. Uterine contrac- tions were measured in the study by da Fonseca et al after P4 treatment and a reduction in contractile activity in the P4-treated group vs the control group was noted. Although clinical studies have sup- ported a role for progestins in preven- tion of preterm labor, their mechanism of action, optimal timing, and duration of treatment are unclear. Current Amer- ican College of Obstetrics and Gynecol- ogy (ACOG) guidelines restrict proges- tin use to women who have had a documented preterm delivery prior to 37 weeks (ACOG committee opinion 291). There is no evidence to support the use of progestins in patients with multiple gestations, 8 but there may be some ben- efit for asymptomatic women with shortened cervical length less than 15 mm. 9 Tocolysis is useful for short-term pro- longation after the onset of labor; how- ever, these treatments are associated with maternal side effects without the benefit of improved neonatal morbidity and mortality. 10 Exogenous progestins probably sup- press uterine contractility through both genomic and nongenomic mechanisms. Progesterone is known to regulate the expression of many genes thought to be involved in controlling contractility in myometrial cells. 11,12 In addition, pro- gesterone is thought to bind to mem- brane receptors and regulate cell activity by nongenomic mechanisms. 13 The aim of this study was to determine whether 17P or P4 directly inhibit hu- man uterine contractility in vitro and thereby clarify their mechanisms of ac- tion. Previous studies examining the ef- fects of 17P and P4 on uterine contrac- tility in vitro have been inconclusive with some reports of stimulation, other stud- ies showing inhibition or no effects. 14-19 From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX (Drs Ruddock, Jain, Hankins, and Moore); Department of Obstetrics and Gynecology, St. Joseph’s Hospital and Medical Center, Phoenix, AZ (Drs Shi and Garfield); Department of Obstetrics and Gynecology (Dr Romero), Hutzel Hospital/The Wayne State University, Detroit, MI. Presented at the 28th Annual Meeting of the Society for Maternal-Fetal Medicine, Dallas, TX, Jan. 28-Feb. 2, 2008. Received Feb. 29, 2008; revised May 13, 2008; accepted June 25, 2008. Reprints: Dr R.E. Garfield, PhD, Department of Obstetrics and Gynecology, St. Joseph’s Hospital and Medical Center, 445 N 5th Street, Phoenix, AZ 85004. robert.garfield@chw.edu. This study was supported by a contract with the Perinatology Research Branch, National Institutes of Health. 0002-9378/$34.00 © 2008 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2008.06.085 SMFM Papers www. AJOG.org OCTOBER 2008 American Journal of Obstetrics & Gynecology 391.e1