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A new method for the radioimmunoassay of plasma aldosterone is described. The assay is performed directly on plasma without extracting or purifying the aldosterone. The method fulfilled the usual requirements for the demonstration of accuracy. Extensive data on the properties of the antisera are given.
The relationship between unbound and total cortisol has been studied in patients with a variety of clinical conditions. We report on a simple, rapid and reliable method for evaluating the percentage unbound cortisol in serum or plasma which can be used in conjunction with total plasma cortisol to obtain a more complete understanding of the patients' adrenal status. Comparison of a patient's percentage unbound and total cortisol with a nomogram showing the normal relationship between percentage unbound and total cortisol indicates the patient's concentration of cortisol binding globulin. The concentration of unbound cortisol, the biologically active moiety, is the product of the percentage unbound and total cortisol concentration. The following values for the unbound cortisol concentration (microgram/dl) were obtained (mean +/- S.D.). Twenty-four normal subjects, 8--10 a.m., 1.2 +/- 0.4; 14 women receiving an oral contraceptive, 1.4 +/- 0.5; 6 patients with adrenal insufficiency, 0.2 +/- 0.1; 9 hyperthyroid patients, 1.7 +/- 0.8; 5 acute ill patients, 3.8 +/- 2.4; and a patient with Cushing's syndrome, 6.1. In normal subjects the values decreased at 4 p.m. (0.4 +/- 0.1) and after dexamethasone administration (0.1 +/- 0.1), and increased following the intravenous injection of adrenocorticotropic hormone (3.6 +/- 0.7). In pregnant women the unbound cortisol increased as the pregnancy progressed, first trimester: 1.2 +/- 0.3, second trimester: 1.6 +/- 0.2, third trimester: 2.4 +/- 0.5.
The corticosteroid-binding globulin (CBG) is a plasma protein which is present both in liver, where it is mainly synthesized, and in cells of different target tissues for glucocorticoids. Using monospecific antibodies raised against human CGB, we could demonstrate the antigenic identity of the protein in human bronchoalveolar fluid. We found that the bronchoalveolar fluid/serum concentration ratio of CBG was similar to that of albumin. Since albumin is not synthesized in pulmonary cells, it was concluded that, in healthy human, CBG enters bronchoalveolar fluid by diffusion through alveolar cells. It is suggested that the expression of the CBG gene in pulmonary cells could occur during the pathological state.
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Plasma levels of cortisol and corticosteroid binding globulin (CBG) were studied during one year in eleven healthy women using NORPLANT-2 implants. NORPLANT-2 implants release approximately 50 ug of levonorgestrel/day. A significant diurnal variation of cortisol levels was found during the study. No significant change in cortisol levels compared to pretreatment levels was found. Levels of CBG showed no diurnal variation, but decreased significantly during use of the implants. This was most probably due to a direct effect of the levonorgestrel, as the levels of estradiol did not change compared to pretreatment levels, except for the values after 6 months that were significantly lower than pretreatment levels. A "free cortisol index" calculated as: level of cortisol/level of CBG, was unchanged during treatment compared to pretreatment levels. It is concluded that although CBG levels were reduced, no significant change in cortisol patterns was seen during use of the implants.
Recently, in the laboratories of Schering in Germany a competitive progesterone antagonist, ZK 98,734, was synthetized, which is characterized by a similar antigestagenic activity as RU 38,486, synthezised by Roussel-Uclaf in France, as assessed by inhibition of nidation tests in rats and guinea pigs. However, this compound has a substantially lower antiglucocorticoid activity measured in cell culture systems than RU 38,486. The purpose of this study was to present a comparison of biochemical and physical properties of the complexes formed by the human uterine progesterone receptor with 3H-ZK 98,734 on one hand and with other well-established progestins on the other hand. ZK 98,734 competed in the same order of magnitude as progesterone or RU 38,486 for the 3H-R5020 binding site of progestin receptor, whereas R5020, Org 2058 or progesterone were unable to compete against 3H-ZK 98,734. This apparent contradiction could be explained by means of FPLC-chromatography and sucrose density centrifugation technique. FPLC-chromatography with an anion exchange column (Mono Q, Pharmacia, Uppsala, Sweden) showed that 3H-ZK 98,734 forms at least two stable complexes with uterine cytosol, on one hand with serum albumin, which presents almost 90% of bound radioactivity, and on the other hand with the two native progestin receptor forms, corresponding to 4S and 8S receptor forms in sucrose density gradient analysis. Competition experiments in liver cytosol of adrenalectomized rats with increasing concentrations of unlabeled ligands other than dexamethasone showed that ZK 98,734, RU 38,486 and cortisol displaced 3H-dexamethasone efficiently from the binding sites in the cytosol. Furthermore, results concerning the specificity of 3H-cortisol binding to serum proteins in diluted pregnant serum demonstrated that ZK 98,734 did not compete with 3H-cortisol for serum binding.
The serum concentrations of ethinylestradiol (EE) during the first 4 h and 24 h after intake of an oral contraceptive containing 30 micrograms EE and 75 micrograms gestodene (EE/GSD) were compared to those after intake of a preparation containing the same EE dose and 150 micrograms desogestrel (EE/DG) in each of 11 women on days 1, 10, and 21 of their 1st, 3rd, 6th, and 12th cycles. There were great interindividual variations, but during treatment with EE/GSD the EE levels were higher and the EE peaks occurred by 30 min later than during treatment with EE/DG. The areas under the EE serum concentration-versus-time curves (AUC) between 0 and 4 h were higher by 37% (p less than 0.03) and between 0 and 24 h higher by 70% (p less than 0.002) during treatment with EE/GSD. During each treatment cycle, the EE levels rose between day 1 and 10. The serum levels of corticosteroid-binding globulin (CBG), which is known to be influenced only by the estrogenic component of the combination pill, increased significantly (p less than 0.01) during each treatment cycle. CBG was elevated on day 21 of the 6th and 12th cycle by 150 to 155% and by 120 to 130% with EE/GSD and EE/DG, respectively. The difference between the two drugs was significant (p less than 0.02). During the pill-free intervals of 7 days between the treatment cycles, the CBG levels decreased but were still elevated by 85% with EE/GSD and 50% with EE/DG at the beginning of the following cycle as compared to the control cycle. The serum levels of cortisol were also significantly more elevated (p less than 0.05) during treatment with EE/GSD as compared to EE/DG. Despite the same EE dose during treatment, the higher EE levels with EE/GSD as compared to EE/DG seem to be due to a retardation of the inactivation and elimination of EE caused by the progestogen component. The rise in the EE levels during each cycle seems to be due to a reduction in the oxidative metabolism by EE itself.
The effect of seven low-dose oral contraceptive preparations on sex hormone binding globulin (SHBG), cortisol binding globulin (CBG), total and absolute free testosterone were investigated in groups of 10 healthy volunteers. All preparations contained about the same amount of ethinylestradiol but they differed in type and/or dose of progestagen. The progestagens studied were: levonorgestrel (LNG; in mono- and triphasic preparations), norethisterone (NET; in monophasic preparation), desogestrel (DSG; in mono- and biphasic preparations) and gestodene (GSD; in triphasic preparation), all 19-nortestosterone derivatives, and the anti-androgen cyproterone acetate (CPA) in a monophasic preparation. Differences observed in SHBG level, which reflect the estrogen-androgen balance, can be attributed to the intrinsic androgenic (or anti-androgenic) properties of the progestagens, and were in agreement with the results of published receptor binding studies, performed in vitro. Based on our results the following ranking (high to low) can be made with respect to the androgenicity of the preparations: monophasic LNG greater than or equal to monophasic NET = triphasic LNG greater than or equal to triphasic GSD = biphasic DSG = monophasic DSG greater than monophasic CPA. An anti-estrogenic effect of the 19-nortestosterone derived progestagens can be excluded by the effect on CBG, a marker for estrogenic activity. All preparations containing a 19-nortestosterone derived progestagen, independent of their type and dose, induce a similar rise in CBG, whereas the preparation with cyproterone acetate induced an even higher CBG level. Irrespective of the effect on total testosterone, which varies between the preparations, the absolute free testosterone level decreased to a comparable degree for all preparations.(ABSTRACT TRUNCATED AT 250 WORDS)
The metabolic effect of the monthly injectable contraceptive containing dihydroxyprogesterone acetophenide (DHPA) 150 mg + estradiol enanthate (EEn) 10 mg was compared to that of other regularly used contraceptive methods (pills containing: ethinylestradiol (EE) 0.050 mg + levonorgestrel (LNG) 0.250 mg, EE 0.030 mg + LNG 0.150 mg; EE 0.030/0.040/0.030 mg + LNG 0.050/0.075/0.0125 mg; norethisterone enanthate (NEE) 200 mg i.m.; non-hormonal methods). Serum triglycerides, HDL/LDL-cholesterol, copper, ceruloplasmin, total and free cortisol, CBG, total and free testosterone and SHBG in chronic users were determined. A total of 237 women took part in this study. Taking users of non-hormonal methods as control, triglyceride levels were higher, and total and free testosterone levels were lower in women using DHPA 150 mg + EEn 10 mg and in those taking contraceptive pills (p less than 0.05 - 0.01). Such modifications were slightly less in the group using the injectable. The effects of DHPA 150 mg + EEn 10 mg on HDL/LDL-cholesterol copper, ceruloplasmin, CBG, total and free cortisol and SHBG were rare or non-existent. Nevertheless, the contraceptive pills (even the low-dose formulations) correlate with modifications of all those variables, which were highly significant in comparison with the injectable (p less than 0.01) and with non-hormonal methods (p less than 0.01); there were no differences between the last two methods. The results suggest that the metabolic effect of DHPA 150 mg + EEn 10 mg is not higher than that of the commonly used oral contraceptives. On the other hand, they do not suggest that the dose contained in this injectable is exaggerated. There is no evidence that it produces accumulation of effects in the organism. These findings should be taken into account when referring to the long-term safety of this injectable.
Serum ethinyl estradiol (EE2), sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) concentrations were studied in healthy young women randomly allocated to one of two low-dose combination oral contraceptives containing 30 micrograms EE2 and either 75 micrograms gestodene (F) or 150 micrograms desogestrel (M) per unit. There was either no (formerly non-pill users) or one (pill users) wash-out cycle before the study started with a pill-free pretreatment cycle in which the hormone status and basal SHBG and CBG levels were measured. Treatment was for three months. During treatment cycles 1 and 3, there were three test days each. Seven serum samples were obtained up to four hours and one sample 24 hours after intake of the first, tenth and the last (21st) pill. Additional samples were taken prior to morning ingestion of pills 5 and 15. For each individual and each test day, a representative serum pool has been constructed for SHBG and CBG analysis. EE2 concentrations were analyzed in all individual samples by means of a specific and sensitive RIA using anti-EE2-6 beta-CMO-BSA antiserum. Area under the curves (AUC) up to 4 and 24 hours, Cmax and tmax were evaluated and compared between the two treatment groups (n = 40 for F, n = 43 for M). SHBG and CBG concentrations were measured using commercially available immunoassay kits. Groups were large enough to detect a difference in group means of 75% of one standard deviation (alpha = 0.05, 1-beta = 0.9) of target variables, which is equivalent to 28 pg EE2/ml for Cmax, 69 pg.h.ml-1 for AUCEE2 0-4h, 257 pg.h.ml-1 for AUCEE2 0-24h, 39 nmol/l SHBG and 13.4 micrograms CBG/ml. Results clearly demonstrate that there were no differences between the two treatment groups in any of the target variables at any of the six test days distributed over a three-month period. Mean SHBG and CBG pretreatment levels of about 70 nmol/l and 37 micrograms/ml, respectively, increased to about 210 nmol/l and 88 micrograms/ml during the first treatment cycle and to about 230 nmol/l and 93 micrograms/ml during the third treatment cycle. Whereas the time of maximum EE2 serum levels did not differ significantly between test days, Cmax, AUCEE2 0-4h and AUCEE2 0-24h values increased by 30-35% or 40-50%, respectively, when test days 10 and 21 were compared to test day 1. Similar results were found for the third treatment cycle.(ABSTRACT TRUNCATED AT 400 WORDS)
The metabolic and hemostatic effects of two oral contraceptives containing 150 mcg desogestrel and 20 mcg ethinyl-estradiol (EE) (MERCILON) or 30 mcg EE (MARVELON) were compared in order to examine the effect of reducing the EE dose in contraceptive pills. Forty-nine women participated in this randomized study during 6 cycles. In both groups, there was a significant increase in triglycerides, HDL-cholesterol and apoprotein A1; the same increase was observed for SBP and CBG. Slight and transient variations of fasting blood glucose levels were seen in the 30 mcg EE group and in the two groups for fasting insulin levels. The increase in renin substrate was significantly higher with the 30 mcg EE than with the 20 mcg EE pill. In both groups, plasminogen increased significantly, but antithrombin III, total and free protein S and fibrinogen decreased significantly only in women taking the 30 mcg EE pill, whereas there was no significant change in the 20 mcg EE group. Reducing the dose of EE in oral contraceptives from 30 mcg to 20 mcg minimizes their impact on renin substrate and hemostatic parameters.
The absence of an effect of high oral doses of vitamin C on the systemic availability of ethinylestradiol in women using a levonorgestrel-containing combination oral contraceptive (0.15 mg levonorgestrel and 0.03 mg ethinylestradiol) was demonstrated in a recent study. However, it is conceivable that the oral administration of gram quantities of vitamin C could also interfere with the sulfation of levonorgestrel (LNG) metabolites during phase II biotransformation, because sulfates represent a major part of the conjugated metabolites of LNG in the serum. This possible interaction was investigated in the aforementioned study, comparing Cmax and AUC(0-12h) values of LNG on the first and 15th day of two successive treatment cycles with and without co-medication of vitamin C. In addition, the serum protein binding of LNG and the concentration of the binding proteins SHBG and CBG were compared between both treatments. Corresponding parameters obtained during treatment with the oral contraceptive alone and during co-administration of vitamin C were evaluated statistically for possible differences. No effect of vitamin C was observed for any of the parameters investigated. Thus, the repeated oral administration of gram quantities of vitamin C does not impair the sulfation of hydroxylated metabolites of LNG. There was also no observable effect on the serum protein binding of LNG and the concentrations of SHBG and CBG in the serum. The results obtained in this study population (American women) for LNG are in good agreement with those obtained from a previous study in European women, who had taken a combination oral contraceptive containing the same doses of LNG and ethinylestradiol.
A cross-over study of two oral contraceptive formulations, containing 30 micrograms ethinylestradiol in combination with 150 micrograms desogestrel (Marvelon) or 75 micrograms gestodene (Femovan), has been performed to compare the serum distribution and pharmacokinetics of gestodene and the active metabolite of desogestrel, namely 3-ketodesogestrel. Serum concentrations of both sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) were also measured and were increased more than 3-fold and 2-fold, respectively, on day 21 of the treatment cycle, with no statistically significant difference between treatment groups. In addition, 35 days after ingestion of either oral contraceptive had ceased, the serum SHBG and CBG concentrations were similar to the pretreatment values. During treatment cycles, increased serum SHBG levels were associated with a redistribution of 3-ketodesogestrel and gestodene such that the non-protein-bound (NPB) and albumin-bound fractions were reduced in concert with an increase in the relative proportions bound to SHBG. The proportion of gestodene bound to SHBG was consistently higher than that observed for 3-ketodesogestrel, and this undoubtedly reflects the higher affinity of SHBG for gestodene (Kd = 1.2 nM at 37 degrees C) when compared to 3-ketodesogestrel (Kd = 4.7 nM at 37 degrees C). It also probably accounts, in part, for the much higher total serum levels of gestodene (8.58 nmol/L) when compared to 3-ketodesogestrel (2.37 nmol/L) during the treatment cycles. Consequently, the absolute amounts of NPB, non-SHBG-bound, and SHBG-bound gestodene are significantly higher than those measured for 3-ketodesogestrel. It is concluded that ethinylestradiol-induced increases in serum SHBG levels during treatment with Marvelon or Femovan, influenced the distribution and total amount of 3-ketodesogestrel and gestodene in serum, respectively, and that this, combined with the higher affinity of SHBG for gestodene, results in a greater amount of bioavailable gestodene compared to 3-ketodesogestrel, despite the smaller dose of gestodene administered.
The aim of the present study was to compare changes in the endogenous androgen environment in healthy women while on low-dose oral contraceptives (OCs). One-hundred healthy women were randomized to receive one of four OCs during six months: 21 tablets of Cilest, Femodeen, Marvelon, or Mercilon. During the luteal phase of the pretreatment cycle, body weight and blood pressure were recorded and the following parameters were measured: sex hormone-binding globulin (SHBG), corticosteroid-binding globulin (CBG), testosterone (T), free testosterone (FT), 5 alpha-dihydrotestosterone (DHT), androstenedione (A), dehydroepiandrosterone-sulphate (DHEA-S) and 17 alpha-hydroxyprogesterone (170HP) while also the free androgen index (FAI) was calculated. Measurements were repeated during the 3rd week of pill intake in the 4th and the 6th pill month. There were no differences on body mass and blood pressure with the use of the four OCs. The mean serum DHEA-S decreased significantly in all groups though less in the Mercilon group when compared to Cilest and Marvelon (approximately 20% vs 45%). Mean serum SHBG and CBG increased significantly in all four groups approximately 250% and 100%, respectively. In each group CBG also increased significantly but less in women taking Mercilon (-75%) as compared to the others (-100%). Current low-dose OCs were found to have similar impact on the endogenous androgen metabolism with significant decreases of serum testosterone, DHT, A, and DHEA-S. They may be equally beneficial in women with androgen related syndromes such as acne and hirsutism.
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