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The present work was done to clarify the relevance of altered serum bile acid (BA) profile in healthy women after the administration of the depot oestrogen ethinyloestradiol propanolsulphonate (EES). In the serum of 20 healthy women before and two times after oral EES application, 11 free and 14 taurine- and glycine-conjugated BA were analysed by HPLC with postcolumn derivatisation and fluorescence detection. EES significantly enhanced the total serum BA concentration and that of taurine-conjugated BAs, more pronounced the secondary BAs taurodeoxycholic, tauroursodeoxycholic and taurolithocholic acid. These secondary BAs are produced in the intestine by bacteria due to 7alpha-dehydroxylation of the primary BAs cholic and chenodeoxycholic acid. Because of unchanged free BAs, also produced by intestinal bacteria due to deconjugation, the results were interpreted as a sign of disturbed transport of BAs into the liver. Inhibition of the liver Na(+)-bile salt co-transporter (Ntcp) in the sinusoidal membrane by ethinyloestradiol, formed from the prodrug EES, may be responsible for the altered BA profile in serum.

Antiandrogens or progestins with an antiandrogenic component usually have only a weak antigonadotropic activity. It is thus possible that the antiandrogenic effect on the cellular level is cancelled or at least reduced by an increased ovarian androgen production. The aim of the four submitted clinical studies of the progestin and antiandrogen dienogest alone (0.5-2 mg/day) or of a combined regimen of ethinylestradiol (0.03 mg) plus dienogest (2 mg) (EE/DNG) was to examine the influence on the serum androgen and SHBG concentrations as well as on the serum FSH, LH, progesterone and 17 beta-estradiol concentrations in young women. Like the progesterone derivatives, dienogest has a relatively low antigonadotropic activity. Inhibition of ovulation is mainly produced by peripheral mechanisms such as the reduction of preovulatory 17 beta-estradiol secretion. Dienogest alone has no significant effects on the serum SHBG and androgen concentrations. Unlike this, the combination of EE plus DNG markedly increases SHBG concentrations (to 2.1-3.7 fold the basal levels). The decrease in serum androgens with total testosterone (by 17 and 40%), free testosterone (by 48 and 54%) and dehydroepiandrosterone sulfate (by 51%) corresponds to the values shown in the literature for other oral contraceptives with modern progestins. EE/DNG does not affect the serum concentrations of 5 alpha-dihydrotestosterone (DHT), although the marker of the peripheral transformation from T to DHT, androstanediol glucuronide, is distinctly reduced (by 38%). In a double-blind comparison no differences are found between EE/DNG and a regimen combining 0.02 mg of ethinylestradiol and 0.150 mg of desogestrel. Solely the SHBG concentrations, with EE/DNG, as expected, are significantly higher. In a sequential regimen, dienogest, chlormadinone acetate and desogestrel (progestins without binding to SHBG) enhance the inhibitory effect of ethinylestradiol sulfonate on free testosterone, whereas norethindrone acetate and levonorgestrel (progestins with a strong binding to SHBG) reduce this effect of the estrogen significantly. These results exclude the possibility that the very distinct antiandrogenic effect of dienogest on a cellular level is neutralised or reduced by an increased systemic supply of androgen.

The effects of grapefruit juice on the bioavailability of 17 alpha-ethinylestradiol (EE2) after a single oral administration of 50 micrograms EE2 have been investigated. The pharmacokinetics of EE2 were studied in an open, randomized, cross-over study in which 13 healthy volunteers were administered the drug with herbal tea or grapefruit juice (naringin, 887 mg/ml). In contrast to herbal tea, grapefruit juice increased the peak plasma concentration (Cmax) significantly to 137% (mean; range 64% to 214%, p = 0.0088) and increased the area under plasma concentration-time curve from 0 to 8 hours (AUC0-8) to 128% (mean; range 81% to 180%, p = 0.0186). This study shows that grapefruit juice increases the bioavailable amount of EE2. A possible explanation may be that grapefruit juice inhibits the metabolic degradation of EE2. Whether the increased bioavailability of EE2 following grapefruit juice administration is of clinical importance should be investigated in long-term studies.

The early days of oral contraceptives showed some evidence that these medications may have caused undesirable side effects on the voice, mainly in terms of virilization. In a random study carried out at the university hospitals of Jena and Berlin (Charité), two more recent drugs were tested in this regard, one containing cyproterone acetate (Diane-35) and the other one levonorgestrel (Microgynon), both from Schering. Ninety-one patients took part in extensive clinical and instrumental phoniatric investigations of voice function over a period of one year. No significant side effects on the voice could be proven for the two preparations. Gynecological and clinical effects of both Diane-35 and Microgynon were similar during the one-year study period. Women taking Diane-35 had less intracyclic bleedings and amenorrhea. Also, acne was more favorably influenced by Diane-35.

Serum concentration profiles and pharmacokinetic parameters (cmax, tmax, AUC24, AUC0-00, MRT) of ethinylestradiol (EE2) and levonorgestrel (LNG) were obtained following administration of two combined oral contraceptives. The constituents of the preparations were as follows: Gravistat (0.05 mg EE2, 0.125 mg LNG); Minisiston (0.03 mg EE2, 0.125 mg LNG). In 20 of the volunteers blood samples were taken before and up to 36 hours following the intake of a single table. In 11 women the investigation was carried out at day 21 of a treatment cycle (steady-state condition). In spite of pronounced interindividual variations of the pharmacokinetic data, a clear dependency of EE2 concentration curves on the estrogen dose of the respective preparation could be demonstrated. Under the condition of steady-state (21st day of administration) there was a slight but significant rise of the EE2 peak serum concentrations and a pronounced increase of the LNG levels, closely reflected by elevation of the AUC values. SHBG serum concentration was significantly increased by the 10th day of treatment in all subjects receiving Gravistat, whereas the mean value in the Minisiston-group did not remarkably change. Although LNG is known to be bound to SHBG with high affinity, the missing parallelism between LNG- and SHBG-concentrations suggests other (additional?) mechanisms for the elevated LNG-binding capacity in women taking combined EE2-LNG preparations.

In 8 female sports students (runners) aged 20 and 21 years and 10 women between 20 and 40 years of age, who regularly underwent body building training, serum levels of ethinylestradiol (EE2) and levonorgestrel (LNG) have been determined under conditions of exercise as well as in rest, prior to and following the intake of 1 tablet of Gravistat (0.05 mg EE2, 0.125 mg LNG). Blood samples were obtained at points 0, 2, 6 and 24 hours. Exercise (5000 meter running and intensive body building training of one hour duration, respectively) was started immediately after intake of the steroid combination. There were no significant differences in the serum concentration levels obtained during exercise and rest. But exercise consistently resulted in a slight decrease of EE2 and LNG serum concentrations and the area under curve values.

Caffeine is mainly metabolized by 3-methylcholanthreneinducible cytochrome P-450, whereas metamizol (Analgin) is probably mainly metabolized by the phenobarbital inducible cytochrome P-450 family. Therefore the elimination of caffeine from serum and the elimination of the main metabolites of metamizol in urine reflect the activity of these two cytochrome P-450 families. Sex hormones can influence the activity of cytochrome P-450. Intake of levonorgestrel (0.125 mg) daily for 14 days reduced the metabolism of caffeine slightly, but the elimination of metamizol-metabolites is not influenced. Longterm administration of levonorgestrel (0.250 mg daily) for three months did not change the metabolisms of both model substances tested. In contrast, ethynylestradiol (0.050 mg) alone and also the combination with levonorgestrel markedly retarded the elimination rate of caffeine and metamizol-metabolites. This fact should be taken into consideration in drug therapy.

Pharmacokinetic investigations (c0h, c2h, c6h, c24h, AUC24) were carried out both in the first and last four days of a treatment cycle in patients of different ages, who used oral contraceptives at least for 12 months. 57 women took the preparation Trisiston (three-step-formulation with the components 0.03 mg ethinylestradiol (EE2) + 0.05 mg levonorgestrel (LNG), 0.04 mg EE2 + 0.075 mg LNG, 0.03 mg EE2 + 0.125 mg LNG), 23 subjects used Gravistat (0.05 mg EE2 + 0.125 mg LNG) and 17 patients were under Certostat, a preparation still in clinical evaluation (0.05 mg EE2 + 2.0 mg Dienogest (DNG)). The levels of EE2, LNG and DNG were measured by means of radioimmunoassays. Between the concentrations obtained after administration of a first and single tablet (earlier investigations) and those determined in long-time users during the first 4 days following the tablet-free interval no qualitative and quantitative differences were observed. Between the levels of EE2 and LNG determined in the first and last days of the treatment cycle, marked differences were found in patients under the formulations Trisiston and Gravistat, but not in those taking Certostat. It is concluded that a cyclic and reversible cumulating effect emerges under the influence of LNG-containing contraceptives, the mechanism of which cannot be explained solely by the increase of carrier protein capacity. It seems possibly due to an alteration of steroid metabolism resulting from the interaction between both components.

Serum levels of ethinylestradiol (E2) and levonorgestrel (LNG) have been determined in 10 volunteers of similar age after administration of 1 tablet of the oral contraceptives Gravistat and Ediwal, respectively, each containing 0.05 mg E2 and 0.125 mg LNG, using a cross over design. The studies were carried out at intervals of 4 weeks, within the follicular phase of the menstrual cycle and under standardized conditions. Wide variations were observed between the women in the calculated pharmacokinetic parameters, while there was a relatively close correspondence between the intra-individually obtained values, except for one case.

A radioimmunoassay for ethinylestradiol (EE2) which was developed in the pharmacological department of VEB Jenapharm has been modified and fully validated. It was the purpose of the present study to extend the still limited data concerning EE2-serum levels after a single and repeated ingestion of combination pills with different doses of EE2. 10 volunteers aged 17-25 years with normal body weight and length received a single tablet of either Gravistat (0.05 mg ethinylestradiol + 0.125 mg levonorgestrel) or Minisiston (0.03 mg ethinylestradiol + 0.125 mg levonorgestrel). 11 other women were involved into the study after ingestion of the 21st tablet of a contraceptive cycle. Peak serum levels which were significantly higher in the Gravistat- than in the Minisiston-group were observed 90 to 120 minutes after the oral administration. Detectable EE2 levels were determined in all volunteers after 24 hours. Pharmacokinetic data showed pronounced interindividual variations. Whereas the mean 24 hours levels of EE2 increased progressively during the treatment cycles, kinetic values obtained at the end of the cycle exhibited a significantly higher level than those after ingestion of a single dose. Area under curve (AUC) was calculated by the trapezoidal rule with the aid of a compartment free model.

The effects of two sequential oral contraceptive preparations, Sequostat (6 days ethinylestradiol 0.05 mg, 15 days ethinylestradiol 0.05 mg + norethisterone acetate 1.0 mg) and Sequence-Ovosiston (9 days mestranol 0.1 mg, 12 days mestranol 0.08 mg + chlormadinone acetate 2.0 mg) on triglycerides, total cholesterol, HDL- and LDL-Cholesterol, glucose tolerance, total plasma proteins, plasma protein fractions, plasma transaminases, gamma-glutamyl-transferase, alkaline phosphatase and antithrombin III were studied in two groups of 46 and 29 young women respectively. Investigations were performed prior to the hormonal intake and after treatment for 3, 6 and 12 months. In nearly all parameters studied significant but minimal changes could be demonstrated which in most cases showed a minor degree in the Sequostat-group, while Sequence-Ovosiston exerted a less effect on glucose tolerance. A significant increase of HDL-cholesterol and a reduction of LDL/HDL-cholesterol relation could be demonstrated at least in the first six months, resulting from the estrogen dominance of the contraceptives.

Caffeine is mainly metabolized by 3-methyl-cholanthrene-inducible cytochrome P-450, whereas metamizol (Analgin) is probably mainly metabolized by phenobarbital inducible cytochromes P-450. Therefore the elimination of caffeine from serum and the amount of the main metabolites of metamizol excreted into urine reflect the activity of these two cytochrome P-450 families. Sex hormones can influence the activity of cytochrome P-450. Dienogest is a new gestagen, used for temporary contraception. We investigated the effect of this new sexual hormone alone and in combination with ethynylestradiol on the elimination of both testdrugs. In 10 healthy volunteers dienogest 2 mg daily for 14 days have no effect on the metabolism of model drugs whereas the combination with 0.05 mg ethynylestradiol has an influence on the elimination of caffeine and metamizol.

Intravenous administration of gonadotropin-releasing hormone (GnRH) induces not only a rapid release of pituitary LH and FSH stored, but also stimulates biosynthesis of these hormones by a long acting process. Repeated injection of GnRH after an interval of 90 to 120 minutes evokes an increased response compared with the first period of stimulation. This pattern of reaction is principally maintained on therapy with steroidal contraceptives. The twofold stimulation provides additional information on hypothalamic-pituitary reactivity exceeding the results yielded by the simple GnRH stimulation test. On the contrary examination of prolactin response to twofold TRH-administration gives no increased diagnostic aid.

The isotope dilution technique was used to study the oestrogen component of "Deposiston", a long-acting contraceptive, and its effects on blood volume. Blood volume increased by about ten per cent within 15 days from administration of 3 mg of ethinyloestradiol-sulphonate (1 mg/week). Haematocrit was reduced, at the same time. This haemodynamic initial effect should be always taken into account for any assessment of biochemical parameters in response to hormonal contraception.

The problem of ethinylestradiol sulphonate excretion in human milk was qualitatively and quantitatively studied. In two women 0.0012 or 0.03000 per cent of total radioactivity were detected within the first nine days from application. Parallel thin-layer chromatography revealed the occurrence of ethinyloestradiol sulphonate in both its depot form and as ethinylestradiol.

56 healthy mothers were treated orally with an oestrogen (3 mg ethinyloestradiol-sulfonat) for inhibition of lactation. We found no effect on milk constituents (12 parameters). These results are discussed.

The colpocytologic efficacy of a new estrogen - ethinylestradiolsulfonate - has been studied in postmenopausal and fertile women. According to the depot character of the compound, ranging between ethinylestradiol and quinestrol, it exhibits a high and prolonged proliferative effect on the atropich vaginal epithelia. The weekly application of 1 mg of the substance in a contraceptive regimen causes a high grade of maturation with considerable individual differences. A single dose of 1 mg ethinylestradiolsulfonate quickly influences conditions of estrogen difficiency in the vaginal epithelia.

Endometrium was investigated histologically in 55 fertile women and by electron-microscope in 6 women under the influence of Deposiston (Jenapharm), a sequential contraceptive containing a long acting oestrogen--ethinyloestradiolsulfonate. The drug was administered orally in 1 mg doses on the 5., 12. and 19. day of each cycle. To achieve proper withdrawal bleeding a single oral dose of 10 mg norethisteronacetate was given on the 26. day of the cycle. Whereas Sequenz- Ovosiston (Jenapharm), a "classical" sequential preparation causes only insignificant variations from the physiological endometrium of fertile women, Deposiston developes irregularly proliferated patterns in more than 50% of the patients, due to differences of the elimination rate of ethinyloestradiolsulfonate. The degree of proliferation covers a wide range from a slightly proliferated endometrium to changes similar to hyperplasia of the endometrium with cystically enlarged glands. The secretory transformation takes place 2 or 3 days following the progestogen application. In 2 of the cases a secretory pattern could be found several days before the intake of the progestogen. This indicates break-through-ovulations.

In course of studies for the chronic toxicity of estrogens after oral application two parameters of the unspecific resistance - complement (CH50U and CB50U) and lysozyme - in sera of 30 beagle-dogs were studied. The doses of the daily (over 6 months) applicated hormones were 1,0 mg/kg ethinylöstradiol and 1,0, 0,1 and 0,01 mg/kg ethinylöstradiolsulfonate (depotform). In the majority of all measurements no significant variations of serum complement and -lysozyme could be detected, however after application of high doses of the hormone ethinylöstradiol a little reduction of complement and significant elevations of lysozyme were observed.