This review comprises the pharmacokinetics and pharmacodynamics of natural and synthetic estrogens and progestogens used in contraception and therapy, with special consideration of hormone replacement therapy. The paper describes the mechanisms of action, the relation between structure and hormonal activity, differences in hormonal pattern and potency, peculiarities in the properties of certain steroids, tissue-specific effects, and the metabolism of the available estrogens and progestogens. The influence of the route of administration on pharmacokinetics, hormonal activity and metabolism is presented, and the effects of oral and transdermal treatment with estrogens on tissues, clinical and serum parameters are compared. The effects of oral, transdermal (patch and gel), intranasal, sublingual, buccal, vaginal, subcutaneous and intramuscular administration of estrogens, as well as of oral, vaginal, transdermal, intranasal, buccal, intramuscular and intrauterine application of progestogens are discussed. The various types of progestogens, their receptor interaction, hormonal pattern and the hormonal activity of certain metabolites are described in detail. The structural formulae, serum concentrations, binding affinities to steroid receptors and serum binding globulins, and the relative potencies of the available estrogens and progestins are presented. Differences in the tissue-specific effects of the various compounds and regimens and their potential implications with the risks and benefits of hormone replacement therapy are discussed.

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Intracranial germ cell tumors are rare tumor entities in childhood and adolescents. Extra- and intracranial germ cell tumors are identical in their histologic pattern and occur in preferential midline localizations such as the pineal and the suprasellar region. Germ cell neoplasms show increasing incidence rates over the last 30 years. The majority of intracranial germ cell neoplasms are germinomas. About 90% of the patients with pure germinomas can be salvaged by radiotherapy alone according to modern protocols. Non-germinomatous malignant CNS-germ cell tumors are considered to have a poor prognosis. In order to improve the survival of patients affected by these tumors different treatment approaches adding chemotherapy to conventional surgery and radiotherapy have been initiated by various study groups throughout the world. Due to the rarity of these neoplasms only a very limited number of patients has been enrolled in each study. In 1993 an international working group on these tumors was established by the International Society of Pediatric Oncology (SIOP).

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The newer progestogens desogestrel, norgestimate, gestodene, dienogest and nomegestrol share the common property of having weak or no androgenic effects, but there is great variation between agents in their pharmacokinetic properties and hormonal activities. Both desogestrel (acting as 3-keto-desogestrel) and norgestimate (acting mainly through levonorgestrel) are prodrugs. While nomegestrol is derived from 19-norprogesterone, the other compounds are 19-nortestosterone derivatives: desogestrel, norgestimate and gestodene belong to the subgroup of 13-ethyl-gonanes with an ethinyl group at C17 alpha, and dienogest represents an estrane (13-methyl-gonane) with a cyanomethyl group at C17 alpha. Both dienogest and nomegestrol have antiandrogenic properties. In proportion to the dose, the highest serum concentrations are observed after intake of gestodene. When combined with ethinylestradiol, gestodene and 3-keto-desogestrel accumulate in serum during daily treatment because of slowed-down elimination. This is probably caused both by binding to sex hormone-binding globulin (SHBG) and by inhibition of inactivating enzymes. Dienogest does not accumulate in serum, although at a dose of 2 mg very high serum concentrations of dienogest are reached. The most potent progestogens are gestodene and desogestrel, while the effect of dienogest and nomegestrol on endometrium and cervix is less, even though in a similar range. As the ovulation-inhibiting effect is brought about not only by receptor-mediated interactions but also by a direct inhibition of steroid biosynthesis, dienogest and nomegestrol are much less effective than gestodene, desogestrel and norgestimate. Ethinylated progestogens, particularly gestodene, have been demonstrated to inhibit cytochrome P450 enzymes. Both gestodene and desogestrel may moderately reduce SHBG levels and counteract the stimulating effect of ethinylestradiol on hepatic serum proteins, while dienogest and nomegestrol have no influence. Compared with progestogens with androgenic properties which may restrict the stimulatory action of ethinylestradiol on haemostatic parameters, the newer progestogens do not seem to be superior with respect to haemostasis. There are no data on the direct effect of the compounds on the arterial and venous vessel wall. Due to the less pronounced antagonism on ethinylestradiol-induced changes in lipid metabolism, the newer progestogens appear to be beneficial rather than deleterious, although atherosclerosis was probably not promoted by the older formulations because of the direct effect of ethinylestradiol on the arterial wall. There is no evidence for a lesser impact of the newer progestogens on carbohydrate metabolism, which is mostly impaired by the estrogen component in oral contraceptives. Formulations containing the newer progestogens are, however, preferable in patients with hyperandrogenaemia, the symptoms of which may be improved by the suppression of total and free testosterone and an increase in SHBG; an additional beneficial effect of the antiandrogenic ...