Journal für Reproduktionsmedizin und Endokrinologie – Journal of Reproductive Medicine and Endocrinology – Andrologie • Embryologie & Biologie • Endokrinologie • Ethik & Recht • Genetik Gynäkologie • Kontrazeption • Psychosomatik • Reproduktionsmedizin • Urologie Pharmacology of Progestogens Kuhl H J. Reproduktionsmed. Endokrinol 2011; 8 (Sonderheft 1), 157-177 www.kup.at/repromedizin Online-Datenbank mit Autoren- und Stichwortsuche Offizielles Organ: AGRBM, BRZ, DVR, DGA, DGGEF, DGRM, D·I·R, EFA, OEGRM, SRBM/DGE Indexed in EMBASE/Excerpta Medica/Scopus Krause & Pachernegg GmbH, Verlag für Medizin und Wirtschaft, A-3003 Gablitz Pharmacology of Progestogens Pharmacology of Progestogens * H. Kuhl This review comprises the pharmacokinetics and pharmacodynamics of natural and synthetic progestogens used in contraception and therapy. The paper describes the historic development of progestogens, their mechanisms of action, the relation between structure and hormonal activity, differences in hormonal pattern and potency, peculiarities in the properties of certain compounds, tissue-specific effects, and metabolism. The influence of the route of administration on pharmacokinetics, hormonal activity and metabolism is discussed. The various types of progestogens including tibolone, their receptor interaction, hormonal pattern and the hormonal activity of certain metabolites are described in detail. The structural formula, serum concentrations, binding affinities to steroid receptors and serum binding globulins, and the relative potencies of the available progestins are presented. The different pathways of aromatization of natural androgens as compared to that of norethisterone and tibolone are discussed. Differences in the tissue-specific effects of the various compounds and regimens and their potential implications with the risks and benefits of treatment are described. J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1): 157–76. Key words: progestogens, pharmacokinetics, pharmacodynamics Introduction The Physiological Role of gen-induced endometrial hyperplasia, Progestogens because a long-term unopposed estrogen The close association between pharma- action increases the risk of hyperplasia cokinetics and pharmacodynamics indi- Originally, progestogens which com- and cancer of the endometrium. Con- cates the importance of pharmacological prise the natural progesterone and a se- trary to this, hormonal contraception is knowledge for an appropriate use of sex ries of synthetic progestins, were de- essentially dependent on the presence of steroids for contraception or therapy. fined as compounds that maintain preg- a progestin which not only suppresses However, even though there is a signifi- nancy. In the sixties, progestins were follicular activity and ovulation, but also cant correlation between the serum con- generally used to support early pregnan- changes cervical mucus and impairs en- centrations of sex hormones and, e.g., cies without any evidence of benefit. dometrial and tubal function. the frequency of postmenopausal hot Since many years it is known that in the flushes, the serum level of an individual human only progesterone is capable of Historical Development of woman does not reflect the clinical ef- maintaining pregnancy. fects [2]. Similarly, extensive measure- Progestogens ment of pharmacokinetics of contracep- Endogenous progesterone is essential From the very beginning of the research tive steroids during the use of estrogen/ for the function of the cervix, uterus, en- on hormonal contraception the interest progestin combinations did not reveal dometrium, tubes, the central nervous of scientists was focussed on the anti- any association with the occurrence of system, pituitary, and the breast. As ovulatory effects of corpus luteum ex- irregular bleeding or other complaints progesterone is rapidly metabolized in tracts. Consequently, great efforts were [3]. the intestinal tract, liver and other tis- made to isolate the active principle of sues, its effectiveness is dependent on this organ, and in 1934 four independent This casts considerable doubts on the the galenic preparation, and – if admin- groups of scientists succeeded in isolat- usefulness of regular measurements of istered orally or vaginally – on a high ing progesterone and detecting its hormone levels for the prediction or con- dosage. Therefore, most preparations chemical structure. Subsequent studies trol of therapeutic or adverse effects. contain a synthetic progestogen (proges- and clinical experiences clearly showed Another claim which turned out to be in- tin) which can be used at relatively low that the natural progestogen was hor- correct, was the story of an advantage of doses because its inactivation is slowed monally active only after administration constant hormone levels observed dur- down owing to structural peculiarities. per injection. Finally the need for orally ing parenteral treatment as compared to active progestogens resulted in the syn- the rapid rise and fall after oral adminis- Progestogens are clinically used for spe- thesis of the first useful progestin nor- tration. The striking effectiveness and cial therapeutic indications (e.g., bleed- ethisterone by Carl Djerassi and his co- tolerability of intranasal estradiol ing disorders, benign breast disease, workers. Although orally active estro- therapy which is associated with ex- endometriosis), hormone replacement gens, e.g., diethylstilbestrol (DES) and tremely high peak levels occurring therapy (HRT), and hormonal contra- ethinylestradiol (EE), have been avail- within a few minutes after administra- ception. In hormone replacement able more than a decade earlier, the first tion and a rapid fall thereafter, refuted therapy, the only indication for the use of clinical studies on hormonal contracep- this general opinion [4, 5]. progestogens is the prevention of estro- tion have been carried out using proges- * Updated version, portions of this article from [1]. Reprinted with permission by Taylor & Francis Ltd. Received and accepted: May 1, 2011 From the Department of Obstetrics and Gynecology, Goethe-University, Frankfurt, Germany Correspondence: Herbert Kuhl, PhD, Professor of Experimental Endocrinology, Department of Obstetrics and Gynecology, Goethe-University, D-60590 Frankfurt am Main, Theodor-Stern-Kai 7; e-mail: [email protected] J Reproduktionsmed Endokrinol 2011; 8 (Special Issue 1) 157 For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. Pharmacology of Progestogens In 1950, the group of Carl Djerassi syn- thesized a progesterone analog with an aromatic A-ring. Although this com- pound did neither exert estrogenic not progestogenic activities, it was an im- portant step on the way to the synthesis of norethisterone, because it lacks the 19-methyl group [13]. At that time, the chemical removal of the 19-methyl group was a very complicated process. It Figure 1. Transition from testosterone to norethisterone and the respective relative binding affinities to the was in 1950, when A. J. Birch published progesterone receptor. the reduction of the aromatic A-Ring of tins. At that time, both DES and EE have to the progesterone receptor (Fig. 1). estradiol resulting in the formation of been clinically tested at extremely high In 1950, Arthur J. Birch reported on a 19-nortestosterone [15]. Using the Birch doses which caused various adverse ef- weaker androgenic potency of 19-nor- reduction, Carl Djerassi and his coworker fects, whereas the first progestins have testosterone as compared to testoster- Luis Miramontes succeeded 1951 in been demonstrated to be well tolerated. one, and today we know that there is also converting 3-methoxy-estradiol into a shift from androgenic to anabolic activ- 19-nortestosterone derivative that was However, the story of synthetic pro- ity. The introduction of the 17α-ethinyl subsequently transformed by means of gestogens is more complicated, as the group at C17α into the testosterone mol- several reactions into 17α-ethinyl-19- first orally active compound with pro- ecule leads to ethisterone that shows a nortestosterone (norethisterone) [13]. gestogenic activity was an androgen. It more pronounced binding affinity to the The progestogenic activity of norethiste- was in 1938, when the Schering chem- progesterone receptor, and both rone was about 20-fold higher than that ists H.H. Inhoffen and W. Hohlweg syn- changes, i.e. the 19-nor structure and the of ethisterone. thesized an orally highly active estrogen, ethinylation at C17α, results in a highly 17α-ethinylestradiol, by the addition of active and well tolerated progestin, In the same year, George Rosenkranz und acetylene at the C17α-position of es- norethisterone (Fig. 1). Carl Djerassi also synthesized 19-nor- trone acetate. Subsequently, the yield of progesterone using the Birch reduction, the reaction was largely increased using Animal experiments and clinical studies which was orally inactive, but a potent sodium carbide in liquid ammonia [6]. revealed that 17α-ethinyltestosterone progestogen after parenteral administra- was indeed an orally potent hormone. tion [13]. It is, however, the basic com- Analogous to this, Hans H. Inhoffen and However, the androgenic effect was pound of a series of 19-nor progesterone Walter Hohlweg tried to develop an weaker than that of testosterone and, sur- derivatives that have been used in the past orally active androgen by means of the prisingly, it exerted a considerable pro- (e.g., gestonorone caproate)