SESSION IV. HORMONAL EFFECTIVENESS OF ORAL CONTRACEPTIVE STEROIDS Chairman: M. Breckwoldt
Binding of oral contraceptive progestogens to serum proteins and cytoplasmic receptor Michael Juchem* and Kunhard Pollow, MD, PhD Mainz, West Germany Some progestogens widely used in oral contraceptives are characterized at the level of high-affinity receptor binding as well as binding to sex hormone-binding globulin and corticosteroid-binding globulin. With regard to binding to sex hormone-binding globulin, gestodene, levonorgestrel, and to a lesser extent 3-ketodesogestrel (which is only formed from the prodrug desogestrel in the body), show a behavior that is manifested in the relatively high affinity to sex hormone-binding globulin, whereas desogestrel and norgestimate do not display any measurable affinity for this specific steroid-binding serum protein. Furthermore, levonorgestrel and gestodene dissociate very much more slowly from the binding sites of sex hormone-binding globulin than 3-ketodesogestrel. A natural affinity of all these synthetic progestogens tested for corticosteroid-binding globulin could not be established. Gestodene, levonorgestrel, and 3-ketodesogestrel bind to the progesterone, glucocorticoid, and androgen receptor with high affinity, apart from slight differences, whereas estrogen receptor affinity could not be demonstrated in any of the progestogens investigated. In relation to aldosterone, the relative binding affinity values of gestodene, levonorgestrel, and the natural progestogen progesterone are relatively high, whereas 3-ketodesogestrel does not display any measurable affinity for this receptor species. (AM J OSSTET GVNECOL 1990;163: 2171-83.)
Key words: Sex hormone-binding globulin, competition studies, steroid receptors, gestodene, desogestrel, levonorgestrel, norgestimate
A generally accepted classical principle of therapy with pharmacologically active substances is that the greatest possible effectiveness is to be reached at the lowest dosage. The idea behind this approach is based on the assumption that the lower the therapeutic dose, the less the burden on the body as a whole, especially in terms of possible adverse drug effects. With regard to oral contraceptives, efforts have been made over many years to reduce the overall amount of estrogenically and progestogenically active steroid components applied over the menstrual cycle and to find synthetic steroids that offer not only efficacy but also a large measure of tolerance. The proportion of estrogen in the oral contraceptives of the most recent generation has been reduced; for example, it is down to 30 f.Lg per pill in the most widespread form of ethinyl estradiol, above all to lower markedly the incidence of adverse drug effects caused From the Department of Experimental Endocrinology, Johannes Gutenberg University. Reprint requests: Kunhard Pollow, MD, PhD, Department of Experimental Endocrinology, Johannes Gutenberg University, Langenbeckstrasse 1, 6500 Mainz 1, Federal Republic of Germany. *This work is part of the PhD thesis of M. Juchem. 610124390
by estrogens. Regarding the gestagen constituent in oral contraceptives, however, there is no uniformity with regard to the steroid used or to the dosage. The synthetic progestogens most frequently used are levonorgestrel, desogestrel, gestodene, cyproterone acetate, and norgestimate. Thus levonorgestrel, the classic orally active synthetic progestogen, presents the advantage of balancing overshoot and adverse effects of the estrogen component besides providing a markedly reduced dosage. I The antiandrogenically active cyproterone acetate had the advantage of processing a highly antiandrogenic activity component, in addition to its potent gestagenic effects, which allowed an additional effective treatment in androgenization manifestations of the skin in potential users of oral contraceptives!'; Desogestrel,6.9 gestodene,IO·13 and norgestimate,11 further agents from the 19-nortestosterone series, which are now available for clinical application in oral contraceptives, appeared to set new standards with regard to activities and hormonal profiles. The dosage of progestogens used in oral contraceptives shows a large range of variation. However, a dose reduction of a certain progestogen is limited by its hormonal effectiveness, because the component used in oral contraceptives has to suppress ovulation reliably.
2172 Juchem and Pollow
December 1990 Am J Obstet Gynecol
Table I. Relative binding affinities (%) of various progestogens in comparison with cortisol and DHT for binding to human CBG and SHBG Cortisol DHT Progesterone Medroxyprogesterone acetate Cyproterone acetate Org2058 R5020 Levonorgestrel Gestodene 3-Ketodesogestrel Desogestrel Norgestimate
CGB
SHBG
100
Binding of oral contraceptive progestogens to serum proteins and cytoplasmic receptor Michael Juchem* and Kunhard Pollow, MD, PhD Mainz, West Germany Some progestogens widely used in oral contraceptives are characterized at the level of high-affinity receptor binding as well as binding to sex hormone-binding globulin and corticosteroid-binding globulin. With regard to binding to sex hormone-binding globulin, gestodene, levonorgestrel, and to a lesser extent 3-ketodesogestrel (which is only formed from the prodrug desogestrel in the body), show a behavior that is manifested in the relatively high affinity to sex hormone-binding globulin, whereas desogestrel and norgestimate do not display any measurable affinity for this specific steroid-binding serum protein. Furthermore, levonorgestrel and gestodene dissociate very much more slowly from the binding sites of sex hormone-binding globulin than 3-ketodesogestrel. A natural affinity of all these synthetic progestogens tested for corticosteroid-binding globulin could not be established. Gestodene, levonorgestrel, and 3-ketodesogestrel bind to the progesterone, glucocorticoid, and androgen receptor with high affinity, apart from slight differences, whereas estrogen receptor affinity could not be demonstrated in any of the progestogens investigated. In relation to aldosterone, the relative binding affinity values of gestodene, levonorgestrel, and the natural progestogen progesterone are relatively high, whereas 3-ketodesogestrel does not display any measurable affinity for this receptor species. (AM J OSSTET GVNECOL 1990;163: 2171-83.)
Key words: Sex hormone-binding globulin, competition studies, steroid receptors, gestodene, desogestrel, levonorgestrel, norgestimate
A generally accepted classical principle of therapy with pharmacologically active substances is that the greatest possible effectiveness is to be reached at the lowest dosage. The idea behind this approach is based on the assumption that the lower the therapeutic dose, the less the burden on the body as a whole, especially in terms of possible adverse drug effects. With regard to oral contraceptives, efforts have been made over many years to reduce the overall amount of estrogenically and progestogenically active steroid components applied over the menstrual cycle and to find synthetic steroids that offer not only efficacy but also a large measure of tolerance. The proportion of estrogen in the oral contraceptives of the most recent generation has been reduced; for example, it is down to 30 f.Lg per pill in the most widespread form of ethinyl estradiol, above all to lower markedly the incidence of adverse drug effects caused From the Department of Experimental Endocrinology, Johannes Gutenberg University. Reprint requests: Kunhard Pollow, MD, PhD, Department of Experimental Endocrinology, Johannes Gutenberg University, Langenbeckstrasse 1, 6500 Mainz 1, Federal Republic of Germany. *This work is part of the PhD thesis of M. Juchem. 610124390
by estrogens. Regarding the gestagen constituent in oral contraceptives, however, there is no uniformity with regard to the steroid used or to the dosage. The synthetic progestogens most frequently used are levonorgestrel, desogestrel, gestodene, cyproterone acetate, and norgestimate. Thus levonorgestrel, the classic orally active synthetic progestogen, presents the advantage of balancing overshoot and adverse effects of the estrogen component besides providing a markedly reduced dosage. I The antiandrogenically active cyproterone acetate had the advantage of processing a highly antiandrogenic activity component, in addition to its potent gestagenic effects, which allowed an additional effective treatment in androgenization manifestations of the skin in potential users of oral contraceptives!'; Desogestrel,6.9 gestodene,IO·13 and norgestimate,11 further agents from the 19-nortestosterone series, which are now available for clinical application in oral contraceptives, appeared to set new standards with regard to activities and hormonal profiles. The dosage of progestogens used in oral contraceptives shows a large range of variation. However, a dose reduction of a certain progestogen is limited by its hormonal effectiveness, because the component used in oral contraceptives has to suppress ovulation reliably.
2172 Juchem and Pollow
December 1990 Am J Obstet Gynecol
Table I. Relative binding affinities (%) of various progestogens in comparison with cortisol and DHT for binding to human CBG and SHBG Cortisol DHT Progesterone Medroxyprogesterone acetate Cyproterone acetate Org2058 R5020 Levonorgestrel Gestodene 3-Ketodesogestrel Desogestrel Norgestimate
CGB
SHBG
100
