Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cardiovascular effects of medroxyprogesterone acetate and progesterone: a case of mistaken identity?

Nature Clinical Practice Cardiovascular Medicine volume 5, pages 387–395 (2008)Cite this article

Abstract

Heart disease presentation can differ between the sexes because nonobstructive coronary disease and angina unrelated to exercise are considerably more prevalent in women than in men. When the outcomes of large, randomized, controlled trials failed to demonstrate cardiac risk protection, many women and their physicians abandoned hormone replacement therapy as primary or secondary prevention for cardiovascular disease. We are concerned that the apparent blanket condemnation of steroids has not sufficiently distinguished between the cardiovascular actions of estrogen, progesterone and the synthetic progestin medroxyprogesterone acetate. The actions of active metabolites of progestins are not well understood and in some cases have not been explored. We intend to present what is known and what is not known about progesterone per se versus medroxyprogesterone acetate, particularly with regard to cardiovascular effects. This Review considers the mounting evidence that progesterone improves cardiovascular function and proposes its mechanism of action—restoration of a threshold level of progesterone as preventive of microvascular cardiac ischemia—and compares oral and transdermal routes of administration. We hope to stimulate research to determine whether progesterone, with or without estrogen, has a role in reducing cardiovascular risk and treating cardiovascular disease including myocardial ischemia in postmenopausal women.

Key Points

  • Unintentional confusion exists between medroxyprogesterone acetate (MPA) and progesterone in the scientific literature; MPA is in fact a progestin, it is not progesterone

  • Cardiovascular effects of the synthetic 24-carbon MPA are predominantly negative

  • Cardiovascular effects of endogenously identical 21-carbon progesterone are predominantly positive

  • Progesterone—alone or combined with estrogen—has never been tested as a treatment to prevent clinical cardiovascular disease

  • The HERS, WHI, WISDOM, and WISE studies all used MPA, not progesterone, in combination with Premarin®

  • Progesterone has not been tested in a large clinical trial to determine its cardiovascular effects in women, and there is no basis for attributing the adverse cardiovascular effects of synthetic MPA, which is well known to have androgen agonist activity, to progesterone, which does not

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Barrett-Connor E et al. (2005) The rise and fall of menopausal hormone therapy. Ann Rev Public Health 26: 115–140

    Article  Google Scholar 

  2. Mosca L et al. (2004) Evidence-based guidelines for cardiovascular disease prevention in women. Circulation 109: 672–693

    Article  Google Scholar 

  3. Manson JE et al.; WHI and WHI-CACS Investigators (2007) Estrogen therapy and coronary-artery calcification. N Engl J Med 356: 2591–2602

    Article  CAS  Google Scholar 

  4. Quinkler M et al. (2002) Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor. Eur J Endocrinology 146: 789–800

    Article  CAS  Google Scholar 

  5. Stanczyk FZ (2003) All progestins are not created equal. Steroids 68: 879–890

    Article  CAS  Google Scholar 

  6. Lu NZ et al. (2006) The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol Rev 58: 782–797

    Article  CAS  Google Scholar 

  7. Faludi AA et al. (2004) Progesterone abolishes estrogen and/or atorvastatin endothelium dependent vasodilatory effects. Atherosclerosis 177: 89–96

    Article  CAS  Google Scholar 

  8. Schulman SP et al. (2002) Effects of acute hormone therapy on recurrent ischemia in postmenopausal women with unstable angina. J Am Coll Cardiol 39: 231–237

    Article  CAS  Google Scholar 

  9. Popp AW et al. (2006) Prevention of postmenopausal bone loss with long-cycle hormone replacement therapy. Maturitas 53: 191–200

    Article  CAS  Google Scholar 

  10. Ghatge RP et al. (2005) The progestational and androgenic properties of medroxyprogesterone acetate: gene regulatory overlap with dihydrotesterone in breast cancer cells. Breast Cancer Research 7: R1036–R1050

    Article  CAS  Google Scholar 

  11. Miyagawa K et al. (1997) Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nature Med 3: 324–327

    Article  CAS  Google Scholar 

  12. Adams MR et al. (1997) Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis. Arterioscler Thromb Vasc Biol 17: 217–221

    Article  CAS  Google Scholar 

  13. Hermsmeyer RK et al. (2004) Prevention of coronary hyperreactivity in preatherogenic menopausal rhesus monkeys by transdermal progesterone. Arterioscler Thromb Vasc Biol 24: 955–961

    Article  CAS  Google Scholar 

  14. Mishra RJ et al. (2005) Medroxyprogesterone acetate and dihydrotestosterone induce coronary hyperreactivity in intact male rhesus monkeys. J Clin Endocrinol Metab 90: 3706–3714

    Article  CAS  Google Scholar 

  15. Rosano GM et al. (2000) Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. J Am Coll Cardiol 36: 2154–2159

    Article  CAS  Google Scholar 

  16. Wright DW et al. (2007) ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med 49: 391–402

    Article  Google Scholar 

  17. Sitruk-Ware RL (2003) Hormone therapy and the cardiovascular system: the critical role of progestins. Climacteric 6 (Suppl 3): 21–28

    CAS  PubMed  Google Scholar 

  18. Skouby SO et al. (2007) A comparative study of the effect of continuous combined conjugated equine estrogen plus medroxyprogesterone acetate and tibolone on blood coagulability. Hum Reprod 22: 1186–1191

    Article  CAS  Google Scholar 

  19. Canonico M et al.; EStrogen and THromboEmbolism Risk (ESTHER) Study Group (2007) Hormone therapy and venous thromboembolism among postmenopausal women. Circulation 115: 840–845

    Article  CAS  Google Scholar 

  20. Minshall R et al. (2001) Progesterone regulation of vascular thromboxane A(2) receptors in rhesus monkeys. Am J Physiol 281: H1498–H1507

    CAS  Google Scholar 

  21. Otsuki M et al. (2001) Progesterone, but not medroxyprogesterone, inhibits vascular cell adhesion molecule-1 expression in human vascular endothelial cells. Arterioscler Thromb Vasc Biol 21: 243–248

    Article  CAS  Google Scholar 

  22. Simoncini T et al. (2004) Differential signal transduction of progesterone and medroxyprogesterone acetate in human endothelial cells. Endocrinology 145: 5745–5756

    Article  CAS  Google Scholar 

  23. King RJ and Whitehead MI (1986) Assessment of the potency of orally administered progestins in women. Fertil Steril 46: 1062–1066

    Article  CAS  Google Scholar 

  24. Ciriza I et al. (2006) Reduced metabolites mediate neuroprotective effects of progesterone in the adult rat hippocampus: the synthetic progestin medroxyprogesterone acetate (Provera) is not neuroprotective. J Neurobiol 66: 916–928

    Article  CAS  Google Scholar 

  25. Nilsen J and Brinton RD (2003) Divergent impact of progesterone and medroxyprogesterone acetate (Provera) on nuclear mitogen-activated protein kinase signaling. Proc Nat Acad Sci USA 100: 10506–10511

    Article  CAS  Google Scholar 

  26. Hulley S et al. (1998) Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) research group. JAMA 280: 605–613

    Article  CAS  Google Scholar 

  27. Rossouw JE et al. (2007) Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 297: 1465–1477

    Article  CAS  Google Scholar 

  28. Rossouw JE et al.; Writing Group for the Women's Health Initiative Investigators (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 288: 321–333

    Article  CAS  Google Scholar 

  29. Vickers MR et al.; WISDOM Group (2007) Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women. BMJ 235: 339–351

    Google Scholar 

  30. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial (1995) Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 273: 199–208

    Article  Google Scholar 

  31. Buchthal SD et al. (2000) Abnormal myocardial phosphorus-31 nuclear magnetic resonance spectroscopy in women with chest pain but normal coronary angiograms. N Engl J Med 342: 829–835

    Article  CAS  Google Scholar 

  32. Wang L et al. (2006) Coronary risk factors and myocardial perfusion in asymptomatic adults: the Multi-Ethnic Study of Atherosclerosis (MESA). J Am Coll Cardiol 47: 565–572

    Article  Google Scholar 

  33. Wang JJ et al. (2006) Retinal vascular calibre and risk of coronary heart disease-related death. Heart 92: 1583–1587

    Article  CAS  Google Scholar 

  34. Kaski JC (2004) Pathophysiology and management of patients with chest pain and normal coronary arteriograms (cardiac syndrome X). Circulation 109: 568–572

    Article  Google Scholar 

  35. Eichling PS and Sahni J (2005) Menopause related sleep disorders. J Clin Sleep Med 15: 291–300

    Google Scholar 

  36. Wesström J et al. (2005) Sleep apnea and hormone replacement therapy: a pilot study and a literature review. Acta Obstet Gynecol Scand 84: 54–57

    Article  Google Scholar 

  37. Anderson ML et al. (2006) Effects of progesterone on sleep: a possible pharmacological treatment for sleep-breathing disorders? Curr Med Chem 13: 3575–3582

    Article  Google Scholar 

  38. Hays J et al.; Women's Health Initiative Investigators (2003) Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 348: 1839–1854

    Article  CAS  Google Scholar 

  39. Asplund R and Aberg H (1998) Sleep and cardiac symptoms amongst women aged 40–64 years. J Intern Med 243: 209–213

    Article  CAS  Google Scholar 

  40. Kotorii T et al. (1987) Effects of medroxyprogesterone acetate on sleep of healthy young male adults. Jpn J Psychiatry Neurol 41: 261–267

    CAS  PubMed  Google Scholar 

  41. Rosano GM and Fini M (2001) Comparative cardiovascular effects of different progestins in menopause. Int J Fertil Womens Med 46: 248–256

    CAS  PubMed  Google Scholar 

  42. Hudson R et al. (1978) Preclinical evaluation of intrauterine progesterone as a contraceptive agent III. Embryology and toxicology. Contraception 17: 489–497

    Article  CAS  Google Scholar 

  43. Dimera Incorporated (2000 ) DP9 progesterone 2% topical cream to treat angina pectoris. IND 60,595

  44. Parker WH et al. (2005) Ovarian conservation at the time of hysterectomy for benign disease. Obstet Gynecol 106: 219–226

    Article  Google Scholar 

  45. Missmer SA et al. (2004) Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women. J Natl Cancer Inst 96: 1856–1865

    Article  CAS  Google Scholar 

  46. Horwitz KB et al. (1988) Progesterone receptor replenishment inT47D human breast cancer cells: roles of protein synthesis and hormone metabolism. J Biol Chem 258: 7603–7610

    Google Scholar 

  47. Sturm G et al. (1991) Mass spectrometric and high-performance liquid chromatographic studies of medroxyprogesterone acetate metabolites in human plasma. J Chromatogr 562: 351–362

    Article  CAS  Google Scholar 

  48. Shifren JL et al. (2008) A comparison of the short-term effects of oral conjugated equine estrogens vs. transdermal estradiol on c-reactive protein, other serum markers of inflammation and other hepatic proteins in naturally menopausal women. J Clin Endocrinol Metab [10.1210/jc.2007-2193]

  49. Cushman M et al. (1999) Hormone replacement therapy, inflammation, and hemostasis in elderly women. Arterioscler Thromb Vasc Biol 19: 893–899

    Article  CAS  Google Scholar 

  50. Vehkavaara S et al. (2001) Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thromb Haemost 85: 619–625

    Article  CAS  Google Scholar 

  51. Samsioe G et al.; Estalis 50/140 Study Group (2006) Endometrial safety, overall safety and tolerability of transdermal continuous combined hormone replacement over 96 weeks: a randomized open-label study. Climacteric 9: 368–379

    Article  CAS  Google Scholar 

  52. Paris JM et al. (2000) Nomegestrol acetate and vascular reactivity: nonhuman primate experiments. Steroids 65: 621–627

    Article  CAS  Google Scholar 

  53. Cicinelli E et al. (2002) Twice weekly transdermal estradiol and vaginal progesterone as continuous combined hormone replacement therapy in postmenopausal women: a 1-year prospective study. Am J Obstet Gynecol 187: 556–560

    Article  CAS  Google Scholar 

  54. Scarabin PY et al.; EStrogen and THromboEmbolism Risk Study Group (2003) Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 362: 428–432

    Article  CAS  Google Scholar 

  55. Stanczyk FA (1999) Pharmacokinetics of progesterone administered by the oral and parenteral routes. J Reprod Med 44: 141–147

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the contributions of Barbara Wexler to the presentation of this manuscript.

Author information

Authors and Affiliations

  1. RK Hermsmeyer is Founder and TL Thompson is Director of Research at Dimera Incorporated, Portland, OR,

    R Kent Hermsmeyer & Theresa L Thompson

  2. GM Pohost is Chief Medical Officer and Senior Vice-President of Salick Cardiovascular Centers in Los Angeles, CA, USA,

    Gerald M Pohost

  3. JC Kaski is Professor of Cardiovascular Science, St George's, University of London, London, UK.,

    Juan Carlos Kaski

Authors
  1. R Kent Hermsmeyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Theresa L Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gerald M Pohost
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Juan Carlos Kaski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R Kent Hermsmeyer.

Ethics declarations

Competing interests

RK Hermsmeyer is an employee of Dimera Incoporated, which is carrying out clinical trials with a transdermal drug product containing progesterone. He has received grant/research support from, and is a Stock holder/Director and Patent Holder/Applicant for Dimera Incorporated. He has also received grant support from Theraméx Pharmaceuticals of Monaco (now a division of E Merck Darmstadt) and Berlex (now a division of Bayer) for projects with synthetic progestins.

TL Thompson is an employee of and has received grant/research support from Dimera Incoporated, which is carrying out clinical trials with a transdermal drug product containing progesterone.

GM Pohost has received grant/research support from, and is a Stock Holder/Director for Salick Cardiovascular Centers, Los Angeles, CA.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hermsmeyer, R., Thompson, T., Pohost, G. et al. Cardiovascular effects of medroxyprogesterone acetate and progesterone: a case of mistaken identity?. Nat Rev Cardiol 5, 387–395 (2008). https://doi.org/10.1038/ncpcardio1234

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpcardio1234

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing