The first combined hormonal contraceptive (CHC) was introduced in 1960 by Gregory Pincus [1 Pincus G, Garcia CR, Rock J, et al. Effectiveness of an oral contraceptive. Science. 1959;30:81–83. [Crossref], [Web of Science ®], [Google Scholar] ] composed by an oral estrogenic and progestin component mestranol and norethinodrel, respectively. Over the last 55 years, the traditional pill has constantly evolved. After the early attempts with mestranol, the use of ethinyl-estradiol (EE) became predominant for decades until a few years ago [2 Grandi G, Cagnacci A, Volpe A. Pharmacokinetic evaluation of desogestrel as a female contraceptive. Expert Opin Drug Metab Toxicol. 2014;10:1–10. [Taylor & Francis Online], [Web of Science ®], [Google Scholar] ]. The EE doses were gradually decreased up to 15 µg. At the same time, numerous different generations of progressively weaker androgenic and even anti-androgenic progestins were tested in order to have products that better fits individual needs. The replacement of EE with estradiol (E2), the estrogen naturally secreted by the granulosa cells of the human ovary, was difficult because of the failure to achieve a satisfactory bleeding control [3 Fruzzetti F, Bitzer J. Review of clinical experience with estradiol in combined oral contraceptives. Contraception. 2010;81:8–15. [Crossref], [PubMed], [Web of Science ®], [Google Scholar] ].

Estradiol in hormonal contraception: real evolution or just same old wine in a new bottle? / Grandi, Giovanni; Facchinetti, Fabio; Bitzer, Johannes. - In: THE EUROPEAN JOURNAL OF CONTRACEPTION AND REPRODUCTIVE HEALTH CARE. - ISSN 1473-0782. - 22:4(2017), pp. 245-246.

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