Hostname: page-component-5d59c44645-mrcq8 Total loading time: 0 Render date: 2024-03-02T16:48:24.929Z Has data issue: false hasContentIssue false

Synthetic Hormones and Clot Formation

Published online by Cambridge University Press:  12 August 2016

Albe C. Swanepoel*
Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Private Bag x323, Pretoria, Arcadia0007, South Africa
Amcois Visagie
Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Private Bag x323, Pretoria, Arcadia0007, South Africa
Etheresia Pretorius*
Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Private Bag x323, Pretoria, Arcadia0007, South Africa
Get access


Combined oral contraceptives (COCs), colloquially referred to as “the pill,” have been regarded as a medical breakthrough, as they have improved the lives of countless women, from simplifying family planning to the treatment of acne, endometriosis, polycystic ovarian syndrome, and dysmenorrhea. Unfortunately, COC usage has been associated with an increased occurrence of venous thrombosis and therefore a systemic hypercoagulable state in susceptible females. Here we discuss the health risks of COC usage and use viscoelastic and morphological techniques to investigate the effect of different COC constituents on clot formation, particularly fibrin network packaging and whole blood viscoelasticity. Viscoelastic properties of whole blood showed gender-specific changes while morphological alterations were person-specific, regardless of gender. Using scanning electron microscopy and thromboelastography provides great insight regarding fibrin packaging and the development of a hypercoagulable state in high-risk individuals. We proposed a three-step approach where (1) an individual’s coagulation profile baseline is determined, after which (2) the “ideal” combination of constituents is prescribed, and (3) the coagulation profile of the individual is monitored to assess possible risk of thrombosis. Only in following such an individualized patient-oriented approach will we be able to avoid the many health issues due to COC usage in susceptible females.

Biological Applications
© Microscopy Society of America 2016 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)


Al-Jefout, M. & Nawaiseh, N. (2016). Continuous norethisterone acetate versus cyclical drospirenone 3 mg/ethinyl estradiol 20 μg for the management of primary dysmenorrhea in young adult women. J Pediatr Adolesc Gynecol 29(2), 143147.Google Scholar
Arowojolu, A.O., Gallo, M.F., Lopez, L.M. & Grimes, D.A. (2012). Combined oral contraceptive pills for treatment of acne. The Cochrane Library.Google Scholar
Bird, S.T., Hartzema, A.G., Etminan, M., Brophy, J.M. & Delaney, J.A. (2013). Polycystic ovary syndrome and combined oral contraceptive use: A comparison of clinical practice in the United States to treatment guidelines. Gynecol Endocrinol 29(4), 365369.Google Scholar
Bucay, I., O’Brien, E.T. III, Wulfe, S.D., Superfine, R., Wolberg, A.S., Falvo, M.R. & Hudson, N.E. (2015). Physical determinants of fibrinolysis in single fibrin fibers. PLOS ONE 10(2), e0116350.CrossRefGoogle ScholarPubMed
Collet, J., Park, D., Lesty, C., Soria, J., Soria, C., Montalescot, G. & Weisel, J. (2000). Influence of fibrin network conformation and fibrin fiber diameter on fibrinolysis speed: Dynamic and structural approaches by confocal microscopy. Arterioscler Thromb Vasc Biol 20(5), 13541361.Google Scholar
Collins, F.S. & Varmus, H. (2015). A new initiative on precision medicine. N Engl J Med 372(9), 793795.Google Scholar
Daniels, K., Daugherty, J. & Jones, J. (2014). Current contraceptive status among women aged 15–44: United States, 2011–2013. NCHS Data Brief 173, 18.Google Scholar
Department of Economic and Social Affairs (2013). World contraceptive pattern. United Nations (Ed.). Available at (retrieved January 12, 2016).Google Scholar
Farmer, R., Lawrenson, R., Thompson, C., Kennedy, J. & Hambleton, I. (1997). Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 349(9045), 8388.CrossRefGoogle ScholarPubMed
Filatova, O.V., Sidorenko, A.A. & Agarkova, S.A. (2015). The rheological properties of blood depending on age and sex. Fiziol Cheloveka 41(4), 110118.Google Scholar
Georgescu, C. (2015). Polycystic ovary syndrome endocrine and cardio-metabolic abnormalities: How to manage? Acta Endocrinol 11(1), 7783.Google Scholar
Graziottin, A. (2015). The shorter, the better: A review of the evidence for a shorter contraceptive hormone-free interval. Eur J Contracept Reprod Health Care 21(2), 93105.Google Scholar
Gronich, N., Lavi, I. & Rennert, G. (2011). Higher risk of venous thrombosis associated with drospirenone-containing oral contraceptives: A population-based cohort study. Can Med Assoc J 183(18), E1319E1325.Google Scholar
Harper, J.C. (2009). Should dermatologists prescribe hormonal contraceptives for acne? Dermatol Ther 22(5), 452457.Google Scholar
Huber, J. & Walch, K. (2006). Treating acne with oral contraceptives: Use of lower doses. Contraception 73(1), 2329.Google Scholar
Jick, S.S. & Hernandez, R.K. (2011). Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: Case-control study using United States claims data. BMJ 342, d2151.CrossRefGoogle ScholarPubMed
Jones, R.K. (2011). Beyond Birth Control: The Overlooked Benefits of Oral Contraceptive Pills . New York: Alan Guttmacher Institute.Google Scholar
Jordan, W. (1961). Pulmonary embolism. Lancet 278, 1146.Google Scholar
Khan, S.A. (2015). Drug therapy for endometriosis-associated pain. US Pharm 1, 21.Google Scholar
Kim, N., Yoo, H.-N., Hyun, H.S., Lee, D.-Y., Yoon, B.-K. & Choi, D.-S. (2015). Efficacy and safety of a 24-day regimen of drospirenone-containing combined oral contraceptive in Korean women. Obstet Gynecol Sci 58(5), 397400.Google Scholar
Koltun, W., Lucky, A.W., Thiboutot, D., Niknian, M., Sampson-Landers, C., Korner, P. & Marr, J. (2008). Efficacy and safety of 3 mg drospirenone/20 mcg ethinylestradiol oral contraceptive administered in 24/4 regimen in the treatment of acne vulgaris: A randomized, double-blind, placebo-controlled trial. Contraception 77(4), 249256.Google Scholar
Koltun, W., Maloney, J.M., Marr, J. & Kunz, M. (2011). Treatment of moderate acne vulgaris using a combined oral contraceptive containing ethinylestradiol 20 μg plus drospirenone 3 mg administered in a 24/4 regimen: A pooled analysis. Eur J Obstet Gynecol Reprod Biol 155(2), 171175.Google Scholar
Lidegaard, Ø., Edström, B. & Kreiner, S. (2002). Oral contraceptives and venous thromboembolism: A five-year national case-control study. Contraception 65(3), 187196.Google Scholar
Lidegaard, Ø., Løkkegaard, E., Svendsen, A.L. & Agger, C. (2009). Hormonal contraception and risk of venous thromboembolism: National follow-up study. BMJ 339, b2890.Google Scholar
Lidegaard, Ø., Nielsen, L.H., Skovlund, C.W., Skjeldestad, F.E. & Løkkegaard, E. (2011). Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001–9. BMJ 343, d6423.Google Scholar
Mabrouk, M., Solfrini, S., Frascà, C., Del Forno, S., Montanari, G., Ferrini, G., Paradisi, R. & Seracchioli, R. (2012). A new oral contraceptive regimen for endometriosis management: Preliminary experience with 24/4-day drospirenone/ethinylestradiol 3 mg/20 mcg. Gynecol Endocrinol 28(6), 451454.Google Scholar
Manzoli, L., De Vito, C., Marzuillo, C., Boccia, A. & Villari, P. (2012). Oral contraceptives and venous thromboembolism. Drug Saf 35(3), 191205.Google ScholarPubMed
Mathur, R., Levin, O. & Azziz, R. (2008). Use of ethinylestradiol/drospirenone combination in patients with the polycystic ovary syndrome. Ther Clin Risk Manag 4(2), 487492.Google Scholar
Morotti, M., Remorgida, V., Venturini, P.L. & Ferrero, S. (2014). Progestogen-only contraceptive pill compared with combined oral contraceptive in the treatment of pain symptoms caused by endometriosis in patients with migraine without aura. Eur J Obstet Gynecol Reprod Biol 179, 6368.Google Scholar
Parkin, L., Sharples, K., Hernandez, R.K. & Jick, S.S. (2011). Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: Nested case-control study based on UK General Practice Research Database. BMJ 342, d2139.Google Scholar
Petitti, D.B. (2003). Combination estrogen–progestin oral contraceptives. N Engl J Med 349(15), 14431450.Google Scholar
Proctor, M.L., Roberts, H. & Farquhar, C.M. (2001). Combined oral contraceptive pill (OCP) as treatment for primary dysmenorrhoea. Cochrane Database Syst Rev (4), CD002120.Google Scholar
Rushton, D.H., Dover, R., Sainsbury, A.W. & Norris, M.J. (2001). Why should women have lower reference limits for haemoglobin and ferritin concentrations than men? BMJ 322(7298), 1355.Google Scholar
Stegeman, B.H.B. (2013). Hormonal Contraceptives and Venous Thrombosis. Leiden, Netherlands: Department of Thrombosis and Hemostasis, Faculty of Medicine, Leiden University Library (LUMC), Leiden University.Google Scholar
Stegeman, B.H., de Bastos, M., Rosendaal, F.R., van Hylckama Vlieg, A., Helmerhorst, F.M., Stijnen, T. & Dekkers, O.M. (2013). Different combined oral contraceptives and the risk of venous thrombosis: Systematic review and network meta-analysis. BMJ 347, f5298.CrossRefGoogle ScholarPubMed
Tafi, E., Leone Roberti Maggiore, U., Alessandri, F., Bogliolo, S., Gardella, B., Vellone, V.G., Grillo, F., Mastracci, L. & Ferrero, S. (2015). Advances in pharmacotherapy for treating endometriosis. Expert Opin Pharmacother 16(16), 24652483.Google Scholar
Thorogood, M., Mann, J., Murphy, M. & Vessey, M. (1992). Risk factors for fatal venous thromboembolism in young women: A case-control study. Int J Epidemiol 21(1), 4852.Google Scholar
van Hylckama Vlieg, A., Helmerhorst, F., Vandenbroucke, J., Doggen, C. & Rosendaal, F. (2009). The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: Results of the MEGA case-control study. BMJ 339, b2921.CrossRefGoogle ScholarPubMed
van Hylckama Vlieg, A. & Middeldorp, S. (2011). Hormone therapies and venous thromboembolism: Where are we now? J Thromb Haemost 9(2), 257266.Google Scholar
Vandenbroucke, J.P., Koster, T., Rosendaal, F., Briët, E., Reitsma, P. & Bertina, R. (1994). Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 344(8935), 14531457.CrossRefGoogle ScholarPubMed
Witjes, H., Creinin, M.D., Sundström-Poromaa, I., Martin Nguyen, A. & Korver, T. (2015). Comparative analysis of the effects of nomegestrol acetate/17 β-estradiol and drospirenone/ethinylestradiol on premenstrual and menstrual symptoms and dysmenorrhea. Eur J Contracept Reprod Health Care 20(4), 296307.Google Scholar
Zorbas, K.A., Economopoulos, K.P. & Vlahos, N.F. (2015). Continuous versus cyclic oral contraceptives for the treatment of endometriosis: A systematic review. Arch Gynecol Obstet 292(1), 3743.Google Scholar
Supplementary material: File

Swanepoel supplementary material

Tables S1-S4

Download Swanepoel supplementary material(File)
File 29 KB
Supplementary material: Image

Swanepoel supplementary material

Figure 1

Download Swanepoel supplementary material(Image)
Image 55 KB