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Semin Thromb Hemost 2024; 50(01): 091-095
DOI: 10.1055/s-0043-1764382
Review Article

Contraceptives and Thrombosis: An Intertwined Revolutionary Road

Doris Barcellona
1   Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy
2   Departmental Unit of Thrombosis and Haemostasis, Azienda Ospedaliero-Universitaria di Cagliari, Cagliari, Italy
,
Francesco Marongiu
1   Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy
2   Departmental Unit of Thrombosis and Haemostasis, Azienda Ospedaliero-Universitaria di Cagliari, Cagliari, Italy
,
Elvira Grandone
3   Thrombosis and Haemostasis Unit, I.R.C.C.S. ‘Casa Sollievo della Sofferenza’, San Giovanni Rotondo, Foggia, Italy
4   Department of Medical and Surgical Sciences, University of Foggia, Foggia, FG, Italy
5   Department of Obstetrics, Gynaecology and Perinatal Medicine, First I.M. Sechenov Moscow State Medical University, Moscow, Russian Federation
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Abstract

The development of oral contraceptives (OCs) began in 1921 and continued in the following years until the first regulatory approval from the Food and Drug Administration was granted in 1960. However, it took several years to realize that OCs presented an important but not frequent risk of venous thrombosis. Several reports ignored this dangerous effect and only in 1967 the Medical Research Council clearly stated this as an important risk. Later, research led to the formulation of second-generation OCs containing progestins, which nevertheless presented an increased thrombotic risk. In early 1980s, OCs containing third-generation progestins were introduced into the market. Only in 1995, it became clear that these new compounds induced a higher thrombotic risk than that related to the second-generation progestins. It appeared clear that the modulating action of progestins was against the procoagulant activity of estrogens. Lastly, at the end of the 2000s, OCs containing natural estrogens and a fourth-generation progestin (dienogest) became available. The prothrombotic effect of those natural products was not different from that of preparations containing second-generation progestins. Moreover, research over the years has produced much data on risk factors associated with OCs use such as age, obesity, cigarette smoking, and thrombophilia. These findings allowed us to better assess the individual thrombotic risk (both arterial and thrombotic) of each woman before offering an OC. Furthermore, research has shown that in high-risk people the use of single progestin is not dangerous as far as thrombosis is concerned. In conclusion, the OCs road has been long and difficult but has led to a great and unthinkable scientific and social enrichment since the 1960s.

Keywords

estrogens - progestins - oral contraceptives - thrombosis


Publication History

Article published online:
13 March 2023

© 2023. Thieme. All rights reserved.

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  • References

  • 1 Djerassi C. Ludwig Haberlandt–“Grandfather of the Pill”. Wien Klin Wochenschr 2009; 121 (23-24): 727-728
    CrossrefPubMedSearch in Google Scholar
  • 2 Haberlandt E. Ludwig Haberlandt—a pioneer in hormonal contraception. Wien Klin Wochenschr 2009; 121 (23-24): 746-749
    CrossrefPubMedSearch in Google Scholar
  • 3 Makepeace AW, Weinstein GL, Freidman MH. The effect of progestin and progesterone on ovulation in the rabbit. Exp Biol Med 1937; 35: 269-270
    CrossrefPubMedSearch in Google Scholar
  • 4 Margaret S. Woman and the New Race. New York: Brentano's; 1920
    Search in Google Scholar
  • 5 Diczfalusy E. Gregory Pincus and steroidal contraception revisited. Acta Obstet Gynecol Scand Suppl 1982; 105: 7-15
    CrossrefPubMedSearch in Google Scholar
  • 6 Chang MC, Hafez ES, Merrill A, Pincus G, Zarrow MX. Studies of the biological activity of certain 19-nor steroids in female animals. Endocrinology 1956; 59 (06) 695-707
    CrossrefPubMedSearch in Google Scholar
  • 7 Greep RO. Min Chueh Chang—October 10, 1908-June 5, 1991. Biogr Mem Natl Acad Sci 1995; 68: 45-61
    PubMedSearch in Google Scholar
  • 8 Dhont M. History of oral contraception. Eur J Contracept Reprod Health Care 2010; 15 (Suppl. 02) S12-S18
    CrossrefPubMedSearch in Google Scholar
  • 9 Jordan WM, Anand JK. Pulmonary embolism. Lancet 1961; 2: 1146-1147
    CrossrefPubMedSearch in Google Scholar
  • 10 Amador E, Zimmerman TS, Wacker WE. FDA report on Enovid. Ad hoc Advisory Committee for the evaluation of a possible etiologic relation with thromboembolic conditions. JAMA 1963; 185: 776
    CrossrefPubMedSearch in Google Scholar
  • 11 Langer E. Enovid: contraceptive pill and recent FDA report clearing it stir continued medical dispute. Science 1963; 141 (3584): 892-894
    CrossrefPubMedSearch in Google Scholar
  • 12 Tyler ET. Eight years' experience with oral contraception and an analysis of use of low-dosage norethisterone. BMJ 1964; 2 (5413): 843-847
    CrossrefPubMedSearch in Google Scholar
  • 13 Thomson JM, Poller L. Oral contraceptive hormones and blood coagulability. BMJ 1965; 2 (5456): 270-273
    CrossrefPubMedSearch in Google Scholar
  • 14 Poller L. Thrombosis and factor VII activity. J Clin Pathol 1957; 10 (04) 348-350
    CrossrefPubMedSearch in Google Scholar
  • 15 Zilkha KJ. Cerebrovascular accidents and oral contraception. BMJ 1964; 2 (5417): 1132-1133
    CrossrefPubMedSearch in Google Scholar
  • 16 Egeberg O, Owren PA. Oral contraception and blood coagulability. BMJ 1963; 1 (5325): 220-221
    CrossrefPubMedSearch in Google Scholar
  • 17 Tchaikovski SN, Rosing J. Mechanisms of estrogen-induced venous thromboembolism. Thromb Res 2010; 126 (01) 5-11
    CrossrefPubMedSearch in Google Scholar
  • 18 Risk of thromboembolic disease in women taking oral contraceptives. A preliminary communication to the Medical Research Council by a Subcommittee. BMJ 1967; 2 (5548): 355-359
    CrossrefPubMedSearch in Google Scholar
  • 19 Benagiano G, Carrara S, Filippi V. Safety, efficacy and patient satisfaction with continuous daily administration of levonorgestrel/ethinylestradiol oral contraceptives. Patient Prefer Adherence 2009; 3: 131-143
    CrossrefPubMedSearch in Google Scholar
  • 20 Lidegaard Ø, Nielsen LH, Skovlund CW, Skjeldestad FE, Løkkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ 2011; 343: d6423
    CrossrefPubMedSearch in Google Scholar
  • 21 Skouby SO, Petersen KR. Clinical experience with the recently developed progestogens. Int J Fertil 1991; 36 (Suppl. 01) 32-37
    PubMedSearch in Google Scholar
  • 22 Teichmann A. Metabolic profile of six oral contraceptives containing norgestimate, gestodene, and desogestrel. Int J Fertil Menopausal Stud 1995; 40 (Suppl. 02) 98-104
    PubMedSearch in Google Scholar
  • 23 Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995; 346 (8990): 1589-1593
    CrossrefPubMedSearch in Google Scholar
  • 24 World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 1995; 346 (8990): 1582-1588
    CrossrefPubMedSearch in Google Scholar
  • 25 Oedingen C, Scholz S, Razum O. Systematic review and meta-analysis of the association of combined oral contraceptives on the risk of venous thromboembolism: The role of the progestogen type and estrogen dose. Thromb Res 2018; 165: 68-78
    CrossrefPubMedSearch in Google Scholar
  • 26 Kuhl H. Comparative pharmacology of newer progestogens. Drugs 1996; 51 (02) 188-215
    CrossrefPubMedSearch in Google Scholar
  • 27 Odlind V, Milsom I, Persson I, Victor A. Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills?. Acta Obstet Gynecol Scand 2002; 81 (06) 482-490
    PubMedSearch in Google Scholar
  • 28 Fruzzetti F, Cagnacci A. Venous thrombosis and hormonal contraception: what's new with estradiol-based hormonal contraceptives?. Open Access J Contracept 2018; 9: 75-79
    CrossrefPubMedSearch in Google Scholar
  • 29 Junge W, Mellinger U, Parke S, Serrani M. Metabolic and haemostatic effects of estradiol valerate/dienogest, a novel oral contraceptive: a randomized, open-label, single-centre study. Clin Drug Investig 2011; 31 (08) 573-584
    CrossrefPubMedSearch in Google Scholar
  • 30 Klipping C, Duijkers I, Parke S, Mellinger U, Serrani M, Junge W. Hemostatic effects of a novel estradiol-based oral contraceptive: an open-label, randomized, crossover study of estradiol valerate/dienogest versus ethinylestradiol/levonorgestrel. Drugs R D 2011; 11 (02) 159-170
    CrossrefPubMedSearch in Google Scholar
  • 31 Dinger J, Do Minh T, Heinemann K. Impact of estrogen type on cardiovascular safety of combined oral contraceptives. Contraception 2016; 94 (04) 328-339
    CrossrefPubMedSearch in Google Scholar
  • 32 Lidegaard Ø. Hormonal contraception, thrombosis and age. Expert Opin Drug Saf 2014; 13 (10) 1353-1360
    CrossrefPubMedSearch in Google Scholar
  • 33 Practice Committee of the American Society for Reproductive Medicine. Electronic address: ASRM@asrm.org, Practice Committee of the American Society for Reproductive Medicine. Combined hormonal contraception and the risk of venous thromboembolism: a guideline. Fertil Steril 2017; 107 (01) 43-51
    CrossrefPubMedSearch in Google Scholar
  • 34 Tanis BC, van den Bosch MA, Kemmeren JM. et al. Oral contraceptives and the risk of myocardial infarction. N Engl J Med 2001; 345 (25) 1787-1793
    CrossrefPubMedSearch in Google Scholar
  • 35 van Vlijmen EF, Wiewel-Verschueren S, Monster TB, Meijer K. Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2016; 14 (07) 1393-1403
    CrossrefPubMedSearch in Google Scholar
  • 36 Glisic M, Shahzad S, Tsoli S. et al. Association between progestin-only contraceptive use and cardiometabolic outcomes: a systematic review and meta-analysis. Eur J Prev Cardiol 2018; 25 (10) 1042-1052
    CrossrefPubMedSearch in Google Scholar