Search

Due to their high oral bioavailability synthetic progestagens are used for therapy, hormone replacement therapy and contraception There are different types of progestogens. There are progesterone derivatives, nortestosterone derivatives (13-methyl-gonanes and 13-ethyl-gonanes), spirolactone derivatives and norpregnance derivatives which differ in their efficacy and hormonal profile. All progestagens show antiestrogenic activities, inhibit the estrogen-induced proliferation of the endometrium and, hence, decrease the risk of endometrial hyperplasia. With the exception of Dienogest, the derivatives of 19-nortestosterone are characterized by a 17-alpha-ethynyl group and show slight androgenic properties which may antagonise some estrogen-dependent alterations of hepatic serum parameters. Tibolone which is a derivative of norethynodel also belongs to this group. Among the nortestosterone derivatives, there are the so-called "Prodrugs". Prodrugs are rapidly transformed after intake to the active progestagens. Progesterone derivatives partly exert moderate androgenic or antiandrogenic effects, while the spirolactone derivative Drospirenone shows antimineralocorticoid and antiandrogenic activities. The progesterone derivatives as well as Gestodene and Desogestrel have certain glucocorticoid activities which, at the doses used, are not clinically relevant, but possibly may influence vascular function. The effects of 19-norpregnane derivatives are comparable with those of progesterone derivatives. According to their different hormonal profiles and activities, the various available progestogens allow the choice of preparations which are best suitable for the individual woman for contraception or hormone replacement therapy.

Hormone replacement therapy is well known for its beneficial effects on climacteric symptoms and is also used for the prevention of osteoporosis. In a prospective open label study we evaluated the efficacy and safety of hormone replacement therapy with 17 beta estradiol dydrogesterone (Femoston, 17 beta estradiol/continuously and dydrogesterone/sequentially). We observed 704 women who were treated with 17 beta estradiol-dydrogesterone over three months. 448 of the women previously had not used hormone replacement therapy, 224 women had been treated with a different hormone replacement therapy before they were entered into the study; for 20 women this information was not available. The physicians were asked to assess the severity of climacteric symptoms at baseline and after three months of hormone replacement therapy. In addition, the following parameters were evaluated before and at the end of the study: blood pressure, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, blood glucose, alkaline phosphatase and gamma glutamyltransferase. Twelve women did not tolerate 17 beta estradiol-dydrogesterone and therefore dropped out of the study. Climacteric symptoms clearly improved after treatment with 17 beta estradiol-dydrogesterone. During our open label prospective study, a significant decrease in blood pressure and serum levels of total cholesterol, LDL cholesterol and the LDL/HDL ratio were observed, whereas serum levels of HDL cholesterol increased significantly. Surprisingly, triglyceride levels also decreased significantly. Serum levels of alkaline phosphatase decreased significantly in women who had received a different hormone replacement therapy before they took 17 beta estradiol-dydrogesterone. We conclude that hormone replacement therapy with 17 beta estradiol-dydrogesterone is highly effective and well tolerated. Hormone replacement therapy with 17 beta estradiol-dydrogesterone appears to have a positive effect on blood pressure and the serum lipid profile. We therefore hypothesise that prolonged treatment with 17 beta estradiol-dydrogesterone may reduce morbidity and mortality secondary to cardiovascular diseases.

In a prospective open-label multicenter trial, safety, tolerance, cycle control and changes in lipid metabolism before and during intake of a low-dose hormonal contraceptive (gestodene 75 mcg + ethinylestradiol 30 mcg) have been investigated under normal conditions of a general or gynecology practice (232 testing physicians, 1321 women). The atherogenic index remained almost unchanged over six cycles observed (3.3 before drug intake vs. 3.28 after drug intake, cycle 6). HDL cholesterol levels increased significantly in the period between prestudy and cycle 6 (+4.4%, p < 0.0001). A very good cycle control was demonstrated, and reliable contraception was achieved, combined with excellent general tolerance. The preparation conclusively suits very well for oral hormonal contraception.

Sera from 500 female blood donors, aged 18-40 years, were examined by quantitative lipoprotein electrophoresis. 218 women had been taking oral contraceptives for more than 3 months; the remaining 282 not on contraceptives acted as controls. The two groups were similar as to age distribution, weight and smoking habits. There were five sub-groups according to the composition of the contraceptives. It was found that all contraceptives had a favourable influence on the atherogenic beta-lipoprotein fraction. The pure progestogen preparations were less advantageous because they in particular reduced the concentration of potentially anti-atherogenic alpha-lipoproteins.

Initial effects of the following hormonal contraceptives on certain serum proteins in 29 women were checked under standardised conditions through the first three cycles on the pill: Deposiston (ethinyloestradiol-sulphonate/norethisterone-acetate), Gravistat (ethinyloestradiol/norgestrel), Non-Ovlon (ethinyloestradiol/norethisterone-actate).--Effects were found to differ strongly by fractions. Differences were recorded also from action over time. Changes and deviations were confirmed to depend on oestrogen levels.

Adult, female baboons (Papio hamadryas) were administered orally once 18 h p.c., either 1.6 mg STS 557 (17 alpha-cyanomethyl-17 beta-hydroxy-estra-4;9(10)-dien-3-one) or 1.6 mg levonorgestrel. Investigations of the bone-marrow cells of these animals showed, compared to untreated controls, no signs of increased chromosome aberrations caused by the substances. The relative frequency of chromosome aberrations were estimated for controls: STS 557: levonorgestrel with 0.60 +/- 0.35 : 0.55 +/- 0.39 : 0.92 +/- 0.46%, respectively. The differences between the three groups investigated in the exact Fisher-test (2 alpha = 0.05) were not significant.

The synthesis of new gona-4,9(10)-dienes with a 17 alpha-CH2X-substituent (X = CN, N3, Cl or Br) is described. The progestagenic activity of these substances was studied in the McPhail assay using immature rabbits. The compound XVI (X = CN, STS 557) is the most potent one, showing an activity about ten times higher than D-norgestrel. Differences in the activity caused by different routes of application are discussed.