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PubMed1990

Protein binding of the contraceptive steroids gestodene, 3-keto-desogestrel and ethinylestradiol in human serum.

The protein binding of ethinylestradiol (EE2), gestodene (GEST) and 3-keto-desogestrel (KDG) has been determined by ultrafiltration in the serum of women who had either taken a gestodene (n = 37) or desogestrel (n = 28) containing oral contraceptive for a time period of at least 3 months. GEST and KDG were analyzed in individual serum pools whereas EE2 was repeatedly measured in two serum pools, each one representing one treatment group. The respective free fractions of the three steroids were 0.6 +/- 0.1% (GEST), 2.5 +/- 0.2% (KDG), 1.7 +/- 0.6% (EE2, in the gestodene-group) and 1.5 +/- 0.2% (EE2, in the desogestrel-group). EE2 was exclusively bound to albumin, whereas GEST and KDG were also bound to sex-hormone-binding globulin (SHBG). The distribution of the two progestins over the serum binding proteins was determined after heat-treatment of serum samples. For GEST, the contribution of albumin and SHBG was 24.1 +/- 9.1 and 75.3 +/- 9.1%, respectively and for KDG it was 65.9 +/- 11.9 and 31.6 +/- 12.0%, respectively. SHBG and corticosteroid-binding globulin (CBG) concentrations were measured in the serum samples obtained from both treatment groups. In the gestodene-group 180 +/- 61 nmol/l (SHBG) and 89 +/- 13 mg/l (CBG) were measured, the corresponding values in the desogestrel-group were 226 +/- 64 nmol/l (SHBG) and 93 +/- 14 mg/l (CBG). SHBG concentrations were correlated with the total concentration of GEST and its free fraction and a positive (r = 0.395) and negative (r = -0.491) correlation respectively was found. Only a weak negative correlation (r = -0.291) was found for SHBG and the free fraction of KDG in the serum. These data demonstrate that the three contraceptive steroids EE2, GEST and KDG were all bound extensively to serum proteins, however, with pronounced differences concerning their distribution over the various binding proteins.

Blood Proteins↗
PubMed1975

Metabolism of 2-3H- and 4-14C-17alpha-ethynylestradiol 3-methyl ether (mestranol) by women.

A mixture of 2-3H and 4-14C-mestranol was administered orally to five women and 2-3H-mestranol alone to one woman. Reactions involving position 2 were extensive as judged by liberation of 3H into body water (14-45% of the dose). 17alpha-Ethynylestradiol, 2-hydroxy-17alpha-ethynylestradiol, 2-methoxy-17alpha-ethynylestradiol, 2-hydroxy-17alpha-ethynylestradiol 3-methyl ether and 16geta-hydroxy-17alpha-ethynylestradiol were measured in the "glucuronide" and pH1 fractions and mestranol, D-homoestrone-17a and D-homoestradiol-17abeta were also measured in the "glucuronide" fraction frum the urine to two of the women by reverse isotope dilution. Radioactive 2-methoxyestradiol accounted for less than 0.011% of the 14C dose in the "glucuronide" fraction of one of the women, consistent with the extent of de-ethynylation previously reported (Steroids, 25, 343 (1975).

Adult↗
PubMed1977

The detection and measurement of D-norgestrel in human milk using Sephadex LH 20 chromatography and radioimmunoassay.

An accurate sensitive method for the assay of D-norgestrel in human milk is described. The steroid is isolated from an ether extract of milk by Sephadex LH 20 chromatography in the system iso-octane-benzene-methanol (70:20:10 v/v). The radioimmunoassay utilises a specific antibody produced in rabbits against D-'norgestrel 3-(O-carboxymethyl) - oxime coupled to bovine serum albumin with D-norgestrel 3-(0-carboxymethyl) -oxime/ [125I]-iodohistamine conjugate as radioligand. Accuracy, sensitivity and blank value are satisfactory. Milk samples were obtained from three subjects treated with 30 microgram/day D-norgestrel, treatment commencing two weeks following parturition. Significant amounts of D-norgestrel were found, ranging between 92-135 pg/ml milk at the end of the first two-week treatment regimen. In two of three subjects, lower, but significant concentrations (53 pg and 35 pg/ml respectively) of steroid were found at the end of four weeks treatment. In the third subject, D-norgestrel could not be detected at this time. As a check on the specificity of the assay, three samples were submitted to additional chromatographic purification on alumina thin layer in the system benzene-cyclohexane-ethanol (70:27:3 v/v). Although this additional chromatographic step yielded somewhat lower values, agreement between the respective sets of results was good. The significance and implications of these findings are discussed.

Chromatography, Gel↗
PubMed1979

A comparison of medroxyprogesterone serum concentrations by the oral or intramuscular route in patients with persistent or recurrent endometrial carcinoma.

A randomized study, comparing serum medroxyprogesterone concentrations by the oral and intramuscular routes, was performed on 22 patients with persistent or recurrent endometrial adenocarcinoma by six institutions of the Gynecologic Oncology Group. The oral group (11 patients) received cutaneous Provera (medroxyprogesterone), 50 mg three times a day, and the intramuscular group (11 patients) received 300 mg of Depo-Provera (medroxyprogesterone) weekly for at least 2 months. Serum levels were evaluated at 0, 2, 4, 6, 8, 10, and 12 hours after administration and every day for the first week and weekly thereafter for 8 weeks. The mean serum levels (nanograms per milliliter) of medroxyprogesterone in the oral group were consistently higher than the corresponding mean levels of the intramuscular group. In addition, from the first through eighth weeks, the measurements (medians) for the oral group were statistically higher than those for the intramuscular group. Although the study indicates a significant increase in serum levels achieved by the oral route, the follow-up period of patients under study is too early to evaluate its clinical effectiveness as compared to the intramuscular route.

Adenocarcinoma↗
PubMed1976

Biliary metabolites of estriol in the rat.

Following the subcutaneous administration of estriol-6,7-3H to rats, biliary metabolites were identified and quantitated. Approximately 70% of the metabolites were excreted in the form of "glucosiduronate" conjugates. 3,17beta-Dihydroxy-2-methoxy-1,3,5(10)-estratrien-16-one was the major metabolite in this conjugate fraction. Significant amounts of 3,17beta-dihydroxy-1,3,5(10)-estratrien-16-one and 2,3,17beta-trihydroxy-1,3,5(10)-estratrien-16-one, as well as smaller quantities of 1,3,5(10)-estratriene-2,316alpha,17beta, tetrol and 2-methoxy-1,3,5(10)-estratriene-3, 16alpha, 17beta-triol, were also found. In 17alpha-ethinylestradiol-treated animals, the rate of excretion of radioactivity and the proportion of 16-oxo-17beta-ol metabolites found in the "glucosiduronate" fraction were reduced.

Animals↗
PubMed1975

Anti-inflammatory steroids, lysosomal stabilization and parachor.

Parachor is an additive constitutive property of a molecule and is related to the molar volume and the surface tension. The parachor of a steroid can be calculated from its constituent atoms and bonds. The parachor of a biologically active molecule is related to the ability of that molecule to permeate hydrophobic regions of cells, especially cellular membranes. An examination of the parachor values of a large number of steroids shows that these values are correlated with a number of different biological activities, from independent sources. The ability of steroids to release lysosomal enzymes from isolated lysosomes in vitro is inversely related to the parachor of the steroid. A similar relationship holds for the release of lysosomal beta-glucoronidase (EC 3.2.1.31) from isolated lysosomes of rat preputial gland following in vivo administration of steroids. The relative anti-inflammatory potencies of steroids by several assay methods are directly proportional to their parachors. The relative ability of corticosteroids to uncouple oxidative phosphorylation and to swell isolated mitochondria in vitro show a direct proportionality with the steroidal parachor. The percutaneous absorptions of steroids show good correlation with parachors, stratum corneum-water partition coefficients and amylcaproate-water partition coefficients; but not with hexadecane-water partition coefficients. The application of parachor as a structure-activity correlation parameter in drug design is likely to yield useful information. The advantages and limitations of the calculated parachor method are discussed.

Androgens↗
PubMed1975

[The experimental studies on the estrogenic activities of 17alpha-ethynyl-17beta-hydroxy-19-norandrost-4-en-3-one (ENT) (author's transl)].

Today, ENT is a popular synthetic progesteron for clinical use, and is well known to have some estrogenic activity. Estradiol-17beta (E2) or 17alpha-ethynyl estradiol (EE2) binding to the specific protein in the nuclear fraction of hypothalamus were examined by 3H-E2 exchange assay reported by Anderson. The possible mode of the estrogenic actions of ENT are as follows: 1) Conversion of ENT to EE2. 2) Estrogenic of ENT per se without changing the chemical structure. 3) Conversion of ENT to other estrogenic compounds except for EE2. In this experiment, 3H-ENT or 3H-testosterone (3H-T) was incubated with human placental microsomes and NADPH generating system for 1 hr at 37 degrees C, 3H-delta4AD, 3H-T and 3H-ENT were incubated also with homogenates of rat hypothalamus under the same conditions. Isolation and purification of the metabolites were performed by using phenolic separation and paper chromatography. Identification of EE2, a metabolite of ENT, was established by measuring the radiochemical homogenity with the authentic standard on paper chromatography. In another experiment where alkali was not used during the extraction procedure to avoid making artificial products, the conversion rate of ENT to EE2 was measured. This experimental data indicated that ENT was converted to 1beta-OH-ENT and to EE2 by human placental microsomes. The former compound was easily converted to EE2 in the presence of NaOH or by incubation with bile. In the incubation with hypothalamic preparation neither aromatization nor 1beta-hydroxylation of delta4AD, T and ENT were detected. In the exchange assays of E2 receptor, the animals were killed 1 hr after the administration of 25 mug of various steroids. The hypothalamic nuclear fraction was incubated with various 3H-steroids for 30 min at 37 degrees C. After washing this nuclear pellet, the radioactivity was counted. Administration of E2 in vivo resulted in the increase of the amount of 3H-EE2 bound to the nuclear fraction in vitro. But only a small increase of binding was observed in the similar experiment with 3H-ENT. 3H-EE2 was exchanged more abundantly after ENT administration than after EE2 injection. From the above results, it was concluded that the estrogenic effect of ENT is attributed to the EE2 converted in vivo. In addition, a possibility was proposed that ENT or its metabolites other than EE2 could regulate some step in the mechanism of estrogen action.

Androstenedione↗
PubMed1977

Oestrogenic activity of oestradiol-decanoate after oral administration to rodents.

Oestradiol-decanoate, dissolved in arachis oil and orally administered to rodents, produces oestrogenic effects. Compared on a molecular basis the ester has 0.1-1.0 times the activity of ethinyl oestradiol, dependent on the species and the parameter studied. The effects of oestradiol-decanoate are less or absent when the oil is omitted. It is likely that absorption of the steroid ester takes place via the intestinal lymphatics in conjunction with the oil.

Administration, Oral↗
PubMed1979

Plasma medroxyprogesterone acetate levels following intramuscular or oral administration in patients with endometrial adenocarcinoma.

The concentration of medroxyprogesterone acetate (MPA) in plasma samples taken 24 h after intramuscular or oral administration of 100 mg daily doses of the drug to patients with endometrial adenocarcinoma was measured by radioimmunoassay. In general, a plasma level of about 4 ng/ml was found 24 h after the dose, independent of the route of drug administration. However, in three of the patients to whom intramuscular MPA was given, considerably higher values were found. A maximal plasma level was achieved three hours after ingestion of 100 mg MPA. This was followed by a rapid decline to 20-25% of the peak value after about 12 h. A rather small day-to-day intraindividual variation was found in daily blood samples taken just before administration of the next dose. However, considerable differences were found between individuals and it is concluded that this variation in plasma levels may be reflected in the clinical efficacy of the treatment. Thus further studies in which plasma values and clinical effectiveness are correlated seem to be indicated.

Adenocarcinoma↗
PubMed1975

Microbiological hydroxylation of norethisterone.

Hydroxylation of norethisterone by a large number of fungi has been investigated. 1alpha-Hydroxy-, 6beta-hydroxy-, 10beta-hydroxy-, 10beta,11beta-dihydroxy-15alpha-and 15beta-hydroxy-derivatives were formed from norethisterone. The microbiological dehydrogenation of 10beta-hydroxy-norethisterone resulting in 10beta,17beta-dihydroxy-17-ethynyl-1,4-estradien-3-one was also observed. The structure of transformation products was established by chemical and spectroscopical methods.

Chemical Phenomena↗
PubMedDate not supplied

Radioimmunoassay of norethindrone (17 alpha-ethynyl-17 beta-hydroxy-4-estren-3-one) and ethynyl-estradiol (17 alpha-ethynyl-1,3,5, (10)-estratien-3, 17 beta-diol). Application to human plasma determination of norethindrone after oral administration of this steroid.

The experiment conditions for the evaluation of Norethindrone (17 alpha-Ethynyl-17 beta-hydroxy-4-estren-3-one, NET) and Ethynyl-estradiol (17 alpha-ethynyl-1, 3, 5 (10) estratrien-3, 17 beta-diol, EE) by radioimmunoassay are described. A minimal quantity of 25 pg of these two steroids could be evaluated using different reduced metabolites of NET, very little cross reaction is observed with 200 pg of these metabolites. No effect was observed with estradiol for the EE-antiserum. The NET-antiserum was used to evaluate this steroid and ethynodiol diacetate after oral administration to female volunteers. Maximal values in the plasma (2-3% of the administered dose) was found between 1-3 h after administration and at 24 h a concentration of 0.1-0.3% still remained in the plasma.

Administration, Oral↗