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Rabe T et al.  
Oral Contraceptive Pills: Combinations, Dosages and the Rationale behind 50 Years or Oral Hormonal Contraceptive Development

Journal für Reproduktionsmedizin und Endokrinologie - Journal of Reproductive Medicine and Endocrinology 2011; 8 (Sonderheft 1): 58-129

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Keywords: cancerdose reductionEthinylestradiolnon-contraceptive benefitoral hormonal contraceptionProgestineregimenside effects

The first oral hormonal contraceptive Enovid™ (9.85 mg norethynodreland 0.15 mg mestranol)(G.D.Searle, US) was approved for contraception by the FDA in the US in 1959 but was never marketed by Searle for contraception. One year later Searle got approval for a lower dose product Enovid 5mg™ (5 mg norethinodrel and 75 µg mestranol) as a contraceptive pill. On the 1st of January 1961, Bayer HealthCare (then Schering) launched its first oral contraceptive (brandname: Anovlar® by Schering) in Australia, followed a few months later by the launch in West Germany. In the beginning it was approved only on prescription for the “treatment of painful menstrual cycles” in married women until later the indication „contraception“ was added. Shortly after the introduction of the pill in Europe severe cardiovascular side effects were observed in the UK for Enovid™. The development of different formulations of oral contraceptives with less estrogen and progestins was initiated. Furthermore, highly selective derivatives of steroid hormones were investigated to find products well tolerated and with a low profile of undesired side effects. New, preferably neutral products were developed taking into consideration the metabolic profile and safety aspects of cardiovascular disease and cancer, especially breast cancer. Growing knowledge in the field of gene analysis and a deeper understanding of the regulatory changes in the coagulation system led to a discussion as to the influence of oral contraceptives on women having genetic risk factors for thrombophilia. The development of oral hormonal contraceptives during the past 50 years has been accompanied by the continued search for new products. Specific formulas have been analyzed not only to provide data on the safety and reliability of the contraceptive method, in addition to possible non-contraceptive benefits (i.e. regular menstrual cycles, improvement of acne vulgaris, dysmenorrhea and fewer premenstrual symptoms), but also to find new compounds and formulas intended to replace those at the end of their patent lifespan. Methods of Good Clinical Practice have been established and large-scale epidemiological studies initiated (i.e. Study of the Royal College of General Practitioners, 1974) [566]. Several general approaches to OC development can be followed. Synthetic or natural estrogens provide a reliable cycle control and prevent estrogen deficiency symptoms due to the decreased secretion of endogenous estrogen from growth follicles. More selective, highly specific progestins have been developed with pharmacological properties similar to natural progesterone, some with antiandrogenic properties and suitable for transvaginal, transdermal, subdermal or intrauterine application. Furthermore, these new progestins produce fewer undesired effects on the breast and other reproductive organs and exhibit low carcinogenicity. Various additives have been tested for their additional non-contraceptive benefits (i.e. iron, folate, DHEA) either by preventing certain undesired side effects of estrogens and progestins or by improving the general health status. Combinations of estrogen and progestin have evolved from monophasic to multiphasic formulations. Combination products require lower doses of steroids and provide a clinical profile similar to the normal menstrual cycle. New regimens (21 + 7, 22 + 6, 24 + 4, 84 + 7) with and without placebo pills or continuous administration have been used to maintain the contraceptive efficacy of the higher dose products and to achieve a stable bleeding pattern at lower doses. To date only Ortho-McNeil, Bayer HealthCare, MSD and Pfizer have been able to afford scientific research in the field of contraception and develop new products. The loss of patent lawsuits on their part, however, has allowed for the production of generic alternatives of oral contraceptives by other companies thus making it difficult for them to continue research in this specific area due to lack of money. In this comprehensive review the development of oral hormonal contraceptive therapy is analyzed step-by-step considering the rationale behind the development of individual substances, combinations, and the regimens developed for their application.
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