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PubMed1979

Pituitary and ovarian function in women receiving hormonal contraception.

A study was performed to further evaluate pituitary-ovarian function in women receiving an oral contraceptive preparation. Basal hormone levels (follicle stimulating hormone, luteinizing hormone, estradiol and prolactin) and gonadotropic response to gonadotropic releasing hormone were studied in 12 healthy, regularly ovulating women in the early follicular and mid-luteal phases of their menstrual cycle (non-treatment control period). These same women were then given NORDETTE (ethinyl estradiol 30 microgram +d-Norgestrel 150 microgram) cyclically for 3 months. In the third month of treatment, the tests were repeated on day 21, i.e. after 21 active pills, and on day 28, i.e. after 21 active and 7 inactive tablets. On active preparation, basal luteinizing hormone, follicle stimulating hormone and estradiol and gonadotropin response to gonadotropin releasing hormone were significantly suppressed. However, by day 28 (after completion of the inactive tablets), basal gonadotropin and estradiol concentrations and the gonadotropic response to gonadotropic releasing hormone were not significantly different to their pretreatment levels. No consistent change in prolactin concentration occurred as a result of oral contraceptive therapy. These results indicate that the 'active' component of even a relatively low-dose pill causes considerable suppression of pituitary-ovarian function but that after 7 days of placebo, pituitary function and basal estradiol secretion have virtually returned to normal.

Adolescent↗
PubMed1989

Bioequivalence of two oral contraceptive drugs containing norethindrone and ethinyl estradiol.

Two oral contraceptive drugs, Formulation A and Formulation B, both of similar hormonal content, were compared with each other to determine if they were bioequivalent. Both drugs contain 1 mg of norethindrone (NET) and 0.035 mg of ethinyl estradiol (EE). Application of an interval test for the ratio of the computed parameter means demonstrated equivalence for the two formulations with respect to the 0-24 hour area under the plasma level versus time curve (AUC24), the total area under the curve (AUCtot) and for the maximum plasma concentration (Cmax) for both ethinyl estradiol and norethindrone. The data support the hypothesis for bioequivalence of the two formulations with respect to total absorption.

Adult↗
PubMed1992

Effect of oral contraceptives on plasma beta-endorphin and corticotropin at rest and during exercise.

Concentrations of immunoreactive beta-endorphin and corticotropin in plasma were studied in 27 healthy physically active women at rest and after the exercise test on a treadmill requiring 60% and 90% of the maximal oxygen consumption. Eleven of the subjects were on a combination-type of oral contraceptive pills, and the remaining 16 did not use any pills. Plasma immunoreactive beta-endorphin levels at rest were higher in pill non-users than in pill users. Corticotropin levels at rest did not differ between the pill users and non-users. After the 60% exercise test a slight increase was found in the concentrations of corticotropin and beta-endorphin in the pill non-users but not in the pill users. In the 90% exercise test, plasma beta-endorphin and corticotropin levels increased significantly in both groups. We conclude that the use of oral contraceptives may elevate the threshold of the intensity of exercise required to increase beta-endorphin and corticotropin secretion. Decreased resting concentration of beta-endorphin in pill users can be explained by suppression of normal cyclic ovarian function.

Adrenocorticotropic Hormone↗
PubMed1991

Lack of effect of oral contraceptive use on the pharmacokinetics of quinine.

The pharmacokinetics of quinine after a single 600 mg oral dose of quinine sulphate were studied in seven female subjects who used oral contraceptives and in seven age-matched female controls who did not. There were no significant differences (P greater than 0.05) in the maximum plasma concentration (Cmax) and the time of peak concentration (tmax) between the subjects who used oral contraceptives (Cmax = 5.3 +/- 1.0 (s.d.) mg l-1; tmax = 1.4 +/- 0.7 h) and the control subjects (Cmax = 5.6 +/- 0.9 mg l-1; tmax = 2.1 +/- 0.9 h). The mean elimination half-life of quinine in the oral contraceptives user group (12.5 +/- 1.9 h) was similar (P greater than 0.05) to that in the control group (11.8 +/- 2.7 h). The oral clearance of quinine in the oral contraceptive user group was 0.133 +/- 0.055 l h-1 kg-1 (range 0.073-0.233) and was not significantly different (P greater than 0.05) from that observed in the control group (0.125 +/- 0.025 l h-1 kg-1, range 0.075-0.148).

Adult↗
PubMed1991

Inhibition of antipyrine metabolism by low-dose contraceptives with gestodene and desogestrel.

To examine the effects of the two newest monophasic oral contraceptives on liver microsomal drug metabolism, plasma kinetics and urinary metabolite excretion of antipyrine, a model substrate for liver microsomes, were evaluated. Plasma lipid and lipoprotein levels, and in particular the high-density lipoprotein subfractions, were also monitored in view of their apparent regulation by a P450-dependent system. Ten healthy volunteers were treated with each contraceptive for a period of 3 months in a crossover trial. Both contraceptives significantly reduced antipyrine clearance by 34.6% (gestodene) and 43.3% (desogestrel) by impairing the oxidative metabolism, particularly to the 4-hydroxy and 3-hydroxymethyl metabolites, with little difference between the two associations. In addition, with both a comparable highly significant rise of plasma triglyceride levels, apolipoproteins A-I and A-II and the high-density lipoprotein-3 subfraction was observed. Treatment with these new monophasic contraceptives may reduce the metabolism of concomitantly given drugs undergoing oxidative transformations.

Adult↗
PubMed1990

Influence of oral contraceptives on drug therapy.

Interferences between drugs and oral contraceptives are considered to alter pharmacokinetics and thus the efficacy of steroidal hormones. It should be noted, however, that steroids can also modify the metabolism and pharmacodynamic effects of various substances. To the present knowledge, phase I (i.e., oxidation, demethylation) and phase II reactions (conjugation) are concerned. Drugs sharing those enzymatic systems with oral contraceptives experience either an increase in bioavailability by inhibition of oxidative metabolism or undergo accelerated elimination by induced conjugation. Such interaction may be of practical interest in subjects who take oral contraceptives and are simultaneously treated with antidepressants, antihypertensives, insulin, synthetic glucocorticoids, theophylline, and caffeine.

Biological Availability↗
PubMed1990

The effect of oral contraceptive use and pregnancy on the daily rhythm of cortisol and cortisone.

The effect of oral contraceptives and of pregnancy on the daily rhythm of cortisol, and its metabolite cortisone in plasma and saliva has been investigated. In both conditions the total plasma cortisol levels were raised to the same extent, the mean values in saliva in the oral contraceptive users being intermediate between those in pregnancy and in the controls, particularly in the morning. Salivary cortisone levels were more related to salivary cortisol than to total plasma cortisone which exhibited a rather flat daily rhythm. There was a shift in peak values for salivary cortisol and cortisone towards late morning: this may be due to a delay in the daily activation of the hypothalamic-pituitary-adrenal axis in these patients.

Adult↗
PubMed1986

The lack of effect of sodium valproate on the pharmacokinetics of oral contraceptive steroids.

Patients taking anticonvulsants such as phenobarbitone, phenytoin and carbamazepine together with their oral contraceptive steroid may suffer contraceptive failure because of the enzyme-inducing properties of these anticonvulsants. We have examined, in six women, the effect of sodium valproate, an effective broad spectrum anticonvulsant, on the area under the plasma concentration versus time profile (AUC) of ethinyloestradiol (EE2) and levonorgestrel (Ng). Prior to sodium valproate therapy the mean AUC for EE2 was 880 +/- 109 pg/ml X h (+/- S.E.) and for levonorgestrel it was 29.1 +/- 2.9 ng/ml X h (n = 4). Between two and four months after sodium valproate therapy the mean AUC figures had not changed significantly, the figure for EE2 being 977 +/- 130 pg/ml X h and for levonorgestrel 29.2 +/- 1.9 ng/ml X h (p greater than or equal to 0.1 in each case). We conclude that sodium valproate in the dose used (200 mg b.d.) does not interact with oral contraceptive steroids.

Adolescent↗
PubMed1991

Effects of various IUDs on the composition of cervical mucus.

The influence of three different intrauterine devices on the composition of cervical mucus was studied. The amount of mucin, albumin and immunoglobulin G was estimated. After the insertion of an inert IUD, a decrease in mucin was observed. During copper-IUD use the content of mucin, albumin and IgG was increased in cervical mucus, while weight was not affected. In the levonorgestrel-IUD users, ovulation was inhibited in 2 out of 8 women. Mucus weight was increased. The amounts of mucin, albumin and IgG were not changed. In an in vitro experiment the effect of copper-IUDs on autooxidation of cholesterol was studied. There was an extensive conversion of cholesterol but addition of albumin quenched the oxidation of cholesterol. It is suggested that the increased secretion of albumin induced by copper-IUD users may offer protection against copper-induced cell damage.

Body Weight↗
PubMed1992

Effect of Norplant implants on liver, lipid and carbohydrate metabolism.

In this study involving 100 women, the metabolic changes seen with Norplant use were evaluated. Besides a significant increase in serum bilirubin, there were no other changes in liver function to suggest possible hepatocellular dysfunction at the end of five years. Even the raised mean levels of bilirubin remained within the normal clinical range for the local population. As regards lipid metabolism, total triglycerides, cholesterol and LDL-cholesterol were decreased through the five years of Norplant use. The HDL-cholesterol showed a significant increase in the first year; it then decreased over the years to its preinsertion level at the end of five years. As a result, the HDL-cholesterol/Total cholesterol - HDL-cholesterol showed a significant increase in the first year and then decreased to almost its preinsertion value at the end of five years. The findings appear to indicate Norplant use not to be contributory to cardiovascular risk. The use of Norplant was not associated with any significant effect on carbohydrate metabolism.

Bilirubin↗
PubMed1991

Oral contraceptives stimulate the excretion of clofibric acid glucuronide in women and female rats.

1. Glucuronidation of clofibric acid, the pharmacologically active form of the hypolipidemic drug clofibrate was investigated in a human population, either in vitro with liver homogenates from biopsies, or after ingestion of the drug and determination of the urinary metabolite. No difference in the glucuronidation rate according to age of the patients was observed. Bilirubin but not clofibric acid glucuronidation was significantly higher in women (106% increase), when expressed per gram of tissue. 2. The excretion of clofibryl glucuronide in women who took oral contraceptives was significantly enhanced by 25%. 3. In female rats, treatment with the contraceptive agent norethindrone also stimulated by 48% the formation of clofibrylglucuronide in liver microsomes.

Adult↗
PubMedDate not supplied

Mechanism-based inactivation of human liver microsomal cytochrome P-450 IIIA4 by gestodene.

A series of 17 alpha-acetylenic steroids was examined with regard to ability to inactivate human liver microsomal cytochrome P-450 (P-450) IIA4, an enzyme involved in the oxidation of a number of drugs, carcinogens, and steroids, including estrogens and progestogens. Of the eight compounds tested, gestodene was found to be particularly active as a mechanism-based inactivator of P-450 IIIA4. Inhibition of both microsomal nifedipine oxidation and 17 alpha-ethynylestradiol (EE) 2-hydroxylation was dependent upon NADPH and gestodene concentration. Rates of inactivation were pseudo first order-values of kinactivation = 0.4 min-1 and Ki = 46 microM and a partition ratio of 9 were calculated. The kinactivation is approximately 50-fold greater than estimated for EE and is one of the highest reported for P-450 mechanism-based inactivators. Spectrally detectable P-450 was also destroyed in microsomes, but several experiments indicate that little covalent binding to amino acid residues of P-450 IIIA4 occurs. Microsomal inactivation of P-450 could be blocked by the presence of other P-450 IIIA4 substrates, and several activities catalyzed by other P-450s were not inhibited under conditions in which greater than 90% of P-450 IIIA4 was inactivated. Consideration of structure/activity relationships among the 17 alpha-acetylenic steroids examined indicates that the delta 15 double bond is critical but is not in itself sufficient for the inactivation process, which is postulated to result from attack of P-450 on the substituted acetylenic carbon and lead to porphyrin N-alkylation. The effectiveness of this mechanism-based inactivator may account for reports of increased estrogen and steroid levels in some women using gestodene in oral contraceptives.

Contraceptives, Oral↗
PubMed1992

Concentration of fat, protein, lactose and energy in milk of mothers using hormonal contraceptives.

Energy, protein, lactose and fat were studied in the milk of mothers who were using different types of contraceptives. One hundred and eleven mothers made up the following groups. C: control (barrier and natural methods, or sterilization), n = 22; combined pill: LDP (low dose pill (levonorgestrel 0.15 mg + ethinylestradiol 0.03 mg)), n = 12 and MDP (medium dose pill (levonorgestrel 0.25 mg + ethinylestradiol 0.05 mg)), n = 13; MP (minipill (norethindrone 0.35 mg)), n = 37; DMPA (injectable progesterone (depot medroxiprogesterone acetate 150 mg)), n = 17; and IUD (plastic or copper intrauterine device), n = 10. The mean stages of lactation were, respectively, 15, 17, 5, 9, 5 and 9 weeks. The mean duration of observation for the study groups ranged from 2 to 4 weeks. Milk samples were collected before and after initiation of treatment (mean = 20 days; range = 14-103 days). The stage of lactation and the interval of nursing before sampling were recorded so that statistical account could be taken of these uncontrollable sources of variability. When incorporated as covariates, they showed that no significant differences existed between the groups tested, either before or after treatment.

Adult↗
PubMed1991

Pharmacokinetics of levonorgestrel in 18 women after 1 month of treatment with a triphasic oral contraceptive.

A triphasic levonorgestrel (LNG)- and ethinylestradiol-containing oral contraceptive was administered to 18 women. Plasma samples were obtained throughout a treatment cycle just before drug administration and on the last treatment day (day 21), several plasma samples were collected from each individual up to 48 h postadministration. LNG was determined by radioimmunoassay in all plasma samples. In addition, the concentration of sex-hormone-binding globulin (SHBG) was determined in plasma samples collected from the same subjects during treatment, as well as during a pre- and a posttreatment cycle. During the treatment cycle, plasma levels of LNG determined just before drug administration increased and reached steady state at about day 16. This increase was due to an increased dose of LNG according to the triphasic dose regimen, a concomitantly ethinylestradiol-induced increase in SHBG and due to pharmacokinetic accumulation, since LNG had a terminal half-life of approximately 28.5 h and the dosing interval was 24 h. Steady-state levels and pharmacokinetic parameters of LNG determined on the last day of treatment were in good accordance with previously published results.

Adolescent↗
PubMed1991

Changes in the plasma levels of proteins C and S in young women on low-dose oestrogen oral contraceptives.

The physiological importance of proteins C and S as natural anticoagulants is demonstrated by the increased risk of thromboembolic disease among subjects with hereditary deficiency of both proteins. In the present study the effects were evaluated of low-dose oestrogen oral contraceptives (OC) on the plasma levels of immunological protein S, as free (PS-f), and in reversible complex with C4b-binding protein as well as functional protein C (PC) in a homogeneous group of 20 young healthy women. The participants were randomly given either gestodene (75 micrograms) or desogestrel (150 micrograms) in combination with ethinyl oestradiol (30 micrograms). Blood samples were taken prior to the initiation of the treatment and at the end of the sixth 21-day treatment cycle. The mean concentration of both free and bound PS fell significantly, the decrease still being within the reference range. Conversely, the plasma values for PC rose to a statistically significant extent. There were no significant differences between the two OCs. Hypothetically, the changes in PS-f (active fraction) might be conducive to a procoagulant state, which the increased PC may compensate. The reverse effect of two OCs on the activity of the protein C-protein S anticoagulant system might suggest a different regulation of their synthesis.

Adult↗
PubMed1989

Glucose and insulin levels after six months of treatment with a triphasic oral contraceptive containing ethinyl estradiol and norethindrone.

A prospective study of carbohydrate metabolism was done on 33 women who used a triphasic oral contraceptive (OC) containing ethinyl estradiol and norethindrone for six months. A three-hour oral glucose tolerance test was administered before and after the OC usage, and both the blood glucose and insulin levels were determined. A significant decrease in the fasting glucose level was found with treatment. All other glucose values and insulin levels were unchanged.

Adult↗