Skip to main content
SpringerLink
Log in

Sildenafil Increases Uterine Blood Flow in Nonpregnant Nulliparous Women

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

This study investigated the effect of sildenafil on uterine volumetric blood flow (UVF) and vascular impedance in nonpregnant, nulliparous women. Fifteen women were randomized in a double-blind fashion to receive either placebo or sildenafil (25 or 100 mg) during the luteal phase of the menstrual cycle. Color Doppler ultrasound of both uterine arteries was performed at baseline and at 1 and 3 hours postdosing to calculate resistance index (RI) and UVF. Those who received sildenafil significantly increased UVF and decreased RI over the 3-hour monitoring period. When UVF responses to sildenafil were examined as a function of baseline UVF, a significant increase in UVF was observed in only those participants with higher baseline UVF. Overall, women in the luteal phase demonstrated a significant increase in UVF in response to sildenafil. However, this increase appears to be directly associated with basal UVF.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hollis B, Prefumo F, Bhide A, Rao S, Thilaganathan B. First-trimester uterine artery blood flow and birth weight. Ultrasound Obstet Gynecol. 2003;22(4):373–376.

    Article  CAS  PubMed  Google Scholar 

  2. Melchiorre K, Wormald B, Leslie K, Bhide A, Thilaganathan B. First-trimester uterine artery Doppler indices in term and preterm pre-eclampsia. Ultrasound Obstet Gynecol. 2008;32(2): 133–137.

    Article  CAS  PubMed  Google Scholar 

  3. Rang S, van Montfrans GA, Wolf H. Serial hemodynamic measurement in normal pregnancy, preeclampsia, and intrauterine growth restriction. Am J Obstet Gynecol. 2008;198(5): e511–e519.

    Article  Google Scholar 

  4. Lang U, Baker RS, Braems G, Zygmunt M, Künzel W, Clark KE. Uterine blood flow—a determinant of fetal growth. Eur J Obstet Gynecol Reprod Biol. 2003;110((suppl 1)):S55–S61.

    Article  PubMed  Google Scholar 

  5. Lang U, Baker RS, Khoury J, Clark KE. Effects of chronic reduction in uterine blood flow on fetal and placental growth in the sheep. Am J Physiol Regul Integr Comp Physiol. 2000;279((1)):R53–R59.

    Article  CAS  PubMed  Google Scholar 

  6. Boyle DW, Lecklitner S, Liechty EA. Effect of prolonged uterine blood flow reduction on fetal growth in sheep. Am J Physiol Regul Integr Comp Physiol. 1996;270(1): R246–R253.

    Article  CAS  Google Scholar 

  7. Hossain N, Paidas MJ. Adverse pregnancy outcome, the uteroplacental interface, and preventive strategies. Semin Perinatol. 2007;31(4):208–212.

    Article  PubMed  Google Scholar 

  8. Figueroa R, Maulik D. Prenatal therapy for fetal growth restriction. Clin Obstet Gynecol. 2006;49(2):308–319.

    Article  PubMed  Google Scholar 

  9. Nakatsuka M, Takata M, Tada K, et al. A long-term transdermal nitric oxide donor improves uteroplacental circulation in women with preeclampsia. J Ultrasound Med. 2002;21(8): 831–836.

    Article  PubMed  Google Scholar 

  10. Nakatsuka M, Tada K, Kimura Y, et al. Clinical experience of long-term transdermal treatment with nitric oxide donor for women with preeclampsia. Gynecol Obstet Invest. 1999;47(1): 13–19.

    Article  CAS  PubMed  Google Scholar 

  11. Sieroszewski P, Suzin J, Karowicz B, Ska A. Ultrasound evaluation of intrauterine growth restriction therapy by a nitric oxide donor (l-arginine). J Matern Fetal Neonatal Med. 2004; 15(6):363–366.

    Article  CAS  PubMed  Google Scholar 

  12. Miller SL, Jenkin G, Walker DW. Effect of nitric oxide synthase inhibition on the uterine vasculature of the late-pregnant ewe. Am J Obstet Gynecol. 1999;180(5):1138–1145.

    Article  CAS  PubMed  Google Scholar 

  13. Van Buren GA, Yang DS, Clark KE. Estrogen-induced uterine vasodilatation is antagonized by l-nitroarginine methyl ester, an inhibitor of nitric oxide synthesis. Am J Obstet Gynecol. 1992;167(3):828–833.

    Article  PubMed  Google Scholar 

  14. Sher G, Fisch JD. Effect of vaginal sildenafil on the outcome of in vitro fertilization (IVF) after multiple IVF failures attributed to poor endometrial development. Fertil Steril. 2002;78(5): 1073–1076.

    Article  PubMed  Google Scholar 

  15. Sher G, Fisch JD. Vaginal sildenafil (Viagra): a preliminary report of a novel method to improve uterine artery blood flow and endometrial development in patients undergoing IVF. Hum Reprod. 2000;15(4):806–809.

    Article  CAS  PubMed  Google Scholar 

  16. Lewis JF, Kuo LC, Nelson JG, Limacher MC, Quinones MA. Pulsed Doppler echocardiographic determination of stroke volume and cardiac output: clinical validation of two new methods using the apical window. Circulation. 1984;70(3): 425–431.

    Article  CAS  PubMed  Google Scholar 

  17. Neunteufl T, Katzenschlager R, Hassan A, et al. Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease. Atherosclerosis. 1997; 129(1):111–118.

    Article  CAS  PubMed  Google Scholar 

  18. Uehata A, Lieberman EH, Gerhard MD, et al. Noninvasive assessment of endothelium-dependent flow-mediated dilation of the brachial artery. Vasc Med. 1997;2(2):87–92.

    Article  CAS  PubMed  Google Scholar 

  19. Reynolds LP, Caton JS, Redmer DA, et al. Evidence for altered placental blood flow and vascularity in compromised pregnancies. J Physiol. 2006;572(pt 1):51–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Morris NH, Sooranna SR, Learmont JG, et al. Nitric oxide synthase activities in placental tissue from normotensive, pre-eclamptic and growth retarded pregnancies. Br J Obstet Gynaecol. 1995;102(9):711–714.

    Article  CAS  PubMed  Google Scholar 

  21. Seligman SP, Buyon JP, Clancy RM, Young BK, Abramson SB. The role of nitric oxide in the pathogenesis of preeclampsia. Am J Obstet Gynecol. 1994;171(4):944–948.

    Article  CAS  PubMed  Google Scholar 

  22. Smarason AK, Allman KG, Young D, Redman CW. Elevated levels of serum nitrate, a stable end product of nitric oxide, in women with pre-eclampsia. Br J Obstet Gynaecol. 1997;104(5): 538–543.

    Article  CAS  PubMed  Google Scholar 

  23. Luzi G, Caserta G, Iammarino G, Clerici G, Di Renzo GC. Nitric oxide donors in pregnancy: fetomaternal hemodynamic effects induced in mild pre-eclampsia and threatened preterm labor. Ultrasound Obstet Gynecol. 1999;14(2):101–109.

    Article  CAS  PubMed  Google Scholar 

  24. Refuerzo JS, Sokol RJ, Aranda JV, et al. Sildenafil citrate and fetal outcome in pregnant rats. Fetal Diagn Ther. 2006; 21(3):259–263.

    Article  PubMed  Google Scholar 

  25. Wareing M, Myers JE, O’Hara M, Baker PN. Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction. J Clin Endocrinol Metab. 2005;90(5):2550–2555.

    Article  CAS  PubMed  Google Scholar 

  26. Villanueva-Garcia D, Mota-Rojas D, Hernandez-Gonzalez R, et al. A systematic review of experimental and clinical studies of sildenafil citrate for intrauterine growth restriction and pre-term labour. J Obstet Gynaecol. 2007;27(3):255–259.

    Article  CAS  PubMed  Google Scholar 

  27. Salhab WA, Shaul PW, Cox BE, Rosenfeld CR. Regulation of types I and III NOS in ovine uterine arteries by daily and acute estrogen exposure. Am J Physiol Heart Circ Physiol. 2000;278(6):H2134–H2142.

    Article  CAS  PubMed  Google Scholar 

  28. Rosenfeld CR, Cox BE, Roy T, Magness RR. Nitric oxide contributes to estrogen-induced vasodilation of the ovine uterine circulation. J Clin Invest. 1996;98(9):2158–2166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rosenfeld CR, White RE, Roy T, Cox BE. Calcium-activated potassium channels and nitric oxide coregulate estrogen-induced vasodilation. Am J Physiol Heart Circ Physiol. 2000;279(1):H319–H328.

    Article  CAS  PubMed  Google Scholar 

  30. Coleman MA, McCowan LM, North RA. Mid-trimester uterine artery Doppler screening as a predictor of adverse pregnancy outcome in high-risk women. Ultrasound Obstet Gynecol. 2000;15(1):7–12.

    Article  CAS  PubMed  Google Scholar 

  31. Dugoff L, Lynch AM, Cioffi-Ragan D, et al. First trimester uterine artery Doppler abnormalities predict subsequent intrauterine growth restriction. Am J Obstet Gynecol. 2005; 193(3 suppl 1):1208–1212.

    Article  PubMed  Google Scholar 

  32. Fratelli N, Rampello S, Guala M, Platto C, Frusca T. Transabdominal uterine artery Doppler between 11 and 14 weeks of gestation for the prediction of outcome in high-risk pregnancies. J Matern Fetal Neonatal Med. 2008;21(6):403–406.

    Article  CAS  PubMed  Google Scholar 

  33. Özkaya U, Özkan S, Özeren S, Çorakç A. Doppler examination of uteroplacental circulation in early pregnancy: can it predict adverse outcome? J Clin Ultrasound. 2007; 35(7):382–386.

    Article  PubMed  Google Scholar 

  34. Li H, Gudnason H, Olofsson P, Dubiel M, Gudmundsson S. Increased uterine artery vascular impedance is related to adverse outcome of pregnancy but is present in only one-third of late third-trimester pre-eclamptic women. Ultrasound Obstet Gynecol. 2005;25(5):459–463.

    Article  CAS  PubMed  Google Scholar 

  35. Kahler C, Schleussner E, Moller A, Seewald HJ. Nitric oxide donors: effects on fetoplacental blood flow. Eur J Obstet Gynecol Reprod Biol. 2004;115(1):10–14.

    Article  PubMed  CAS  Google Scholar 

  36. Werns SW, Walton JA, Hsia HH, Nabel EG, Sanz ML, Pitt B. Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease. Circulation. 1989;79(2):287–291.

    Article  CAS  PubMed  Google Scholar 

  37. Inoue T, Matsuoka H, Higashi Y, et al. Flow-mediated vasodilation as a diagnostic modality for vascular failure. Hypertens Res. 2008;31(12):2105–2113.

    Article  PubMed  Google Scholar 

  38. Kuvin JT, Patel AR, Sliney KA, et al. Peripheral vascular endothelial function testing as a noninvasive indicator of coronary artery disease. J Am Coll Cardiol. 2001;38(7): 1843–1849.

    Article  CAS  PubMed  Google Scholar 

  39. Matsushima Y, Takase B, Uehata A, et al. Comparative predictive and diagnostic value of flow-mediated vasodilation in the brachial artery and intima media thickness of the carotid artery for assessment of coronary artery disease severity. Int J Cardiol. 2007;117(2):165–172.

    Article  PubMed  Google Scholar 

  40. Perrone-Filardi P, Cuocolo A, Brevetti G, et al. Relation of brachial artery flow-mediated vasodilation to significant coronary artery disease in patients with peripheral arterial disease. Am J Cardiol. 2005;96(9):1337–1341.

    Article  PubMed  Google Scholar 

  41. Angerer P, Negut C, Stork S, von Schacky C. Endothelial function of the popliteal artery in patients with coronary artery disease. Atherosclerosis. 2001;155(1):187–193.

    Article  CAS  PubMed  Google Scholar 

  42. Spacil J, Ceska R, Haas T. Flow-dependent vasomotor dysfunction of the popliteal artery related to common carotid artery intima-media thickness. Angiology. 2001;52(10):689–695.

    Article  CAS  PubMed  Google Scholar 

  43. Roberts JM, Redman CWG. Pre-eclampsia: more than pregnancy-induced hypertension. The Lancet. 1993; 341(8858):1447–1451.

    Article  CAS  Google Scholar 

  44. Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol. 1989;161(5):1200–1204.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Obstetrics, Gynecology and Reproductive Sciences, University of Vermont, 89 Beaumont Avenue, Burlington, Vermont, 05405, USA

    Sarah A. Hale PhD, Cresta W. Jones MD, George Osol PhD, Adrienne Schonberg RN & Ira M. Bernstein MD

  2. Medical Biostatistics, University of Vermont, Burlington, Vermont, USA

    Gary J. Badger MS

Authors
  1. Sarah A. Hale PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cresta W. Jones MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. George Osol PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Adrienne Schonberg RN
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gary J. Badger MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ira M. Bernstein MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ira M. Bernstein MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hale, S.A., Jones, C.W., Osol, G. et al. Sildenafil Increases Uterine Blood Flow in Nonpregnant Nulliparous Women. Reprod. Sci. 17, 358–365 (2010). https://doi.org/10.1177/1933719109354648

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719109354648

Key words

Search

Navigation