Sex hormone binding globulin (SHBG) and pregnancy zone protein (PZP) are two highly oestrogen-inducible serum proteins. SHBG capacity and PZP level were measured in 49 women treated with three different combinations of ethinyloestradiol and norethisterone. SHBG capacity and PZP were measured before and after 6 mth of treatment and both serum factors significantly increased during treatment for all three groups. PZP induction was found to be more sensitive and mainly to reflect the oestrogen component of a combined preparation while SHBG capacity was more sensitive to the modulating effect of the progestogen.

The pharmacokinetics of progesterone after oral administration were investigated. After a single dose of 100 mg, serum concentrations of progesterone around 50-60 nM and of 20 alpha-hydroxy-4-pregnene-3-one around 5-6 nM were recorded within 1-4 hours and elevated levels persisted for 8-12 hours. There were only minor changes in 17 alpha-hydroxyprogesterone concentrations and serum levels of androstenedione and cortisol were unaffected. A significant conversion of circulating progesterone into deoxy-corticosterone was demonstrated. During clinical treatment with oral progesterone the individual serum concentrations of this potent mineralocorticoid were closely correlated to the progesterone concentrations. This observation could be important as regards the etiology of certain clinical disorders characterized by fluid retention. According to competitive binding analyses there was no evidence that progesterone or medroxyprogesterone acetate could cause significant displacement of cortisol from corticosteroid-binding globulin during clinical treatment. The effects of natural and synthetic hormones upon subfractions of high density lipoprotein (HDL) cholesterol and liver proteins were followed in postmenopausal women during replacement therapy with various estrogen-progestogen combinations. The total serum cholesterol level was significantly reduced during treatment with all estrogen regimens. The concentrations of HDL cholesterol, HDL2 cholesterol, apolipoprotein A I and A II were increased in a dose-dependent pattern during unopposed estrogen therapy. The potency of 10 micrograms of ethinyl estradiol was estimated to be equivalent to 3-4 mg of estradiol valerate. Estrogen effects were significantly reversed by levonorgestrel 250 micrograms and also by medroxyprogesterone acetate 10 mg. During treatment with natural progesterone, no changes were recorded in HDL cholesterol or its subfractions. As compared with the lipoproteins, pregnancy zone protein and sex hormone binding globulin (SHBG) were found to be more sensitive to the alkylated than to the non-alkylated estrogen. Both levonorgestrel and medroxyprogesterone acetate clearly reduced SHBG levels after 3 months, whereas micronized progesterone had no such effect. While tamoxifen counteracted the therapeutic and metabolic effects of estrogen the sequential addition of estriol had no apparent influence. Unopposed estrogen treatment enhanced liver lecithin synthesis along pathway I, i.e. reduced the amount of stearic acid and increased the amount of palmitic acid. The effects were dose-dependent and no qualitative differences between ethinyl estradiol and estradiol valerate were recorded.

The relative fatty acid composition of serum lecithin was followed in groups of women during postmenopausal replacement therapy. The effects of estradiol valerate and ethinyl estradiol in two different doses, and the modulating influence of various progestogens and antiestrogens were compared. Unopposed estrogen treatment enhanced liver lecithin synthesis along pathway I, i.e. reduced the amount of stearic acid and increased the amount of palmitic acid. The effect was clearly dose-dependent and even the low dose of 10 micrograms of ethinyl estradiol was more potent than 2 mg of estradiol valerate. No qualitative difference between the two estrogens was recorded. The sequential addition of the antiestrogen tamoxifen significantly reduced the influence of ethinyl estradiol. Liver lecithin synthesis along pathway I may be stimulated by all estrogens and not only by 17C-alkylated compounds. The prostaglandin precursors, dihomogammalinolenic and arachidonic acid, showed a seemingly dose-dependent increase during estrogen treatment. The comparatively weaker effects of estradiol valerate on lipid metabolism should make this non-alkylated estrogen the first choice in clinical practice.

The antiestrogenic effects of tamoxifen and estriol were compared in 39 postmenopausal women during estrogen replacement therapy. Subfractions of HDL cholesterol and its apolipoproteins and the serum levels of two estrogen sensitive liver proteins were followed during three cycles of unopposed estrogen therapy with 10 micrograms ethinyl estradiol daily. During the last 10 days of the following three cycles the women received sequential addition of either 10 mg tamoxifen twice daily or 2 mg estriol twice daily. Tamoxifen clearly reduced the estrogen-induced increase of apolipoprotein AI, HDL2 cholesterol and total HDL cholesterol. In comparison the pregnancy zone protein and sex hormone-binding globulin were more sensitive to the estrogenic as well as to the antiestrogenic effect than the lipoproteins. Tamoxifen also counteracted the therapeutic effect on climacteric symptoms and it seems unlikely that this compound may be clinically useful as an alternative to progestogens during estrogen replacement therapy. The sequential addition of estriol had no apparent effects as compared to unopposed estrogen treatment.

Subfractions of high-density lipoprotein cholesterol and its apolipoproteins were followed up in 58 postmenopausal women during three cycles of unopposed estrogen replacement therapy with 2 mg of estradiol valerate daily. During the last 10 days of the following three cycles the women received sequential addition of either 250 micrograms of levonorgestrel, 10 mg of medroxyprogesterone acetate, or 200 mg of natural micronized progesterone. Both progestogens significantly decreased total high-density lipoprotein cholesterol as well as subfraction 2 of high-density lipoprotein. Data suggest that doses and relative biologic activity of 19-norsteroids and 17-hydroxyprogesterone derivatives are more important for their metabolic effects than are qualitative differences. Natural progesterone had no apparent influence on high-density lipoprotein cholesterol or its subfractions and may develop into an attractive alternative to synthetic progestogens.

The effects of ethinyl estradiol and estradiol valerate were compared in 135 postmenopausal women during estrogen replacement therapy. Subfractions of high-density lipoprotein (HDL) cholesterol and its apolipoproteins and the serum levels of 2 estrogen-sensitive liver proteins were followed during 3 cycles of unopposed treatment with either ethinyl estradiol 10 or 30 micrograms or estradiol valerate 2 mg daily. Estrogen therapy induced significant and dose-dependent changes in all serum factors except HDL3 cholesterol. The effects of 10 micrograms of ethinyl estradiol upon the lipoproteins were 1.5-2.5 times greater than those of 2 mg of estradiol valerate. Sex-hormone-binding globulin and the pregnancy zone protein were the most sensitive markers for the estrogenic effect and these 2 liver-derived plasma proteins were also much more sensitive to ethinyl estradiol than to estradiol valerate. Although satisfactory therapeutic effects were achieved with both estrogens, the marked influence of ethinyl estradiol on liver protein synthesis should make estradiol valerate the first choice in clinical replacement therapy.

The interaction of medroxyprogesterone acetate (MPA) with cortisol binding to corticosteroid-binding globulin (CBG) was studied with the use of an aqueous two-phase system with polyethylene glycol and dextran for equilibrium partition. Competitive binding analyses were also performed for progesterone (P), levonorgestrel, norethisterone, danazol, and tamoxifen. P and danazol were found to exert cortisol displacing activity, whereas MPA and the other tested compounds had no such effect. The glucocorticoid effects reported for MPA could not be explained by displacement. In general, P serum concentrations are lower than those of cortisol, and most binding sites on CBG are occupied by the glucocorticoid. At high P levels displacement and an increase in free cortisol may occur. Danazol displacement of cortisol is hampered by its pronounced albumin binding. In conclusion, none of the tested compounds should increase free and biologically active cortisol during normal clinical treatment.

Malignant transformation is reported in less than 2% of benign cystic teratomas. Although all the elements can undergo this transformation, it is most often seen in squamous epithelium. The malignancy of neural elements is probably the least common event, with only one case previously reported. A case of glioblastoma multiform in a benign cystic teratoma is presented. Its neural derivation was supported by an immunohistochemical staining specific for Glial Fibrillary Acidic Protein (GFAP). Despite very conservative surgery without adjuvant therapy, the patient remains alive and symptom free more than 3 years later.