Preparation of deuterium and tritium labelled norethynodrel, norethindrone, and 6-methyleneandrostenedione.
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Biology↗
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Results for “Norethindrone--pharmacodynamics”
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Norethisterone acetate and ethinylestradiol in early human pregnancy.
In a double-blind randomized trial, 25 women (8-9 weeks pregnant) received 20 mg norethisterone acetate (NET-AC) and 0.04 mg ethinylestradiol (EE2), 25 women receiving placebo. The patients were followed by ultrasound and the products at curettage studied macroscopically and microscopically. In an open trial, ten patients (5-9 weeks pregnant) received NET-AC + EE2, 11 serving as controls. The concentrations of plasma progesterone, estradiol-17 beta, 17 alpha-hydroxyprogesterone, norethisterone, and FSH were followed. The frequency of intrauterine hemorrhage in early pregnancy was not affected by NET-AC + EE2. Ultrasound was not reliable when studying the occurrence of decidual hemorrhages during early pregnancy. The pharmacokinetics and bioavailability of NET remain unchanged during early pregnancy. The treatment with NET-AC + EE2 had no effect on the heights and the time courses of the mean plasma values of progesterone, estradiol-17 beta, 17 alpha-hydroxyprogesterone, and FSH. No differences were found between treated and nontreated patients in the pathology of the placenta or decidua as determined by both macroscopic and microscopic examinations. The hypothesis of Papp and Gardo, that decidual hemorrhages may be induced in early pregnancy as a consequence of a "withdrawal effect" of hormonal pregnancy tests, is not supported by the results of this investigation.
17-alpha-Hydroxyprogesterone↗
Selected aspects of the pharmacokinetics and metabolism of ethinyl estrogens and their clinical implications.
Careful studies in an adequate sample of subjects show a very marked degree of variability in the pharmacokinetics of ethinyl estradiol--specifically, in parameters such as area under the curve, half-life, and time to peak. This variability is seen in differences between different populations, as well as from one individual to another. These studies also show variability in area under the curve and other parameters in the same person from time to time. Such differences may equal or exceed the differences between low dose (35 micrograms) and high-dose (50 micrograms) formulations. The levels of plasma ethinyl estradiol produced by a 50 micrograms dose of mestranol are similar to those from 35 micrograms of ethinyl estradiol. Thus a high-dose pill may be no higher than a low-dose pill if the nature of the estrogen is not kept in mind. Qualitative differences in the oxidative metabolites of estrogens may be of significance with respect to oncogenic potential.
Biological Availability↗
Pharmacokinetics of norethisterone oenanthate in humans.
The pharmacokinetics of a dose of 200 mg NET-OEN were studied after intramuscular injection into nine subjects. Blood levels of NET and NET-OEN increased rapidly, reaching peaks in most subjects within seven days. At all times after injection, serum levels of NET exceeded those of NET-OEN. The half-life of absorption varied from 5.4 to 22.3 days and the half-life of elimination varied from 7.5 to 22.5 days; there was a significant correlation (R = 0.78) between these two half-lives. There were significant correlations between the absorption half-lives and the peak values of NET and NET-OEN, the time to reach peak values and the time for which NET was detectable in serum. In all subjects NET was detectable in the circulation for a longer time after injection (mean value 74 days) than NET-OEN (mean value 43 days). The time for which the two steroids were detectable in the circulation showed a significant correlation with the elimination half-lives but there was no correlation with the peak values attained, the time taken to reach peak values and bioavailability. There was a two-fold variation between the subjects in the bioavailability of NET, less than 5% of the bioavailable NET was released after day 60.
Absorption↗
Pharmacokinetic and pharmacodynamic studies with vaginal devices releasing norethisterone at a constant, near zero order.
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Absorption↗
Phase I clinical trial of two contraceptive preparations. Norethisterone enanthate (NEN) and norethisterone acetate (NET).
A Phase I Clinical Trial was conducted in 20 fertile Cuban women using for contraception: Norethisterone Enanthate injectable (NEN) and Norethisterone Acetate minipill (NET). Women had daily blood sampling during a control cycle and during the second month of treatment with either drug. Discontinuation rate was very low (1/20). The preovulatory LH and FSH peaks were abolished in all treated women, basal levels remaining unchanged. The incidence of menstrual disorders as amenorrhea, spotting and inter-menstrual bleeding was greater in subjects using NEN than in those on NET. No pregnancy was reported. Blood pressure was unaltered. Renal, hepatic and thyroid function were unchanged. Cholesterol levels were unchanged and triglycerides significantly decreased with both preparations. Women on either NEN or NET underwent OGTT before and after 2 months treatment. In NEN group glycemia was unchanged but insulin levels increased significantly at 120 minutes. In NET group glycemia and insulin levels were significantly increased at all times during post-treatment OGTT. Both forms of Norethisterone were well accepted by this group of women despite menstrual irregularities. Significant changes were found in the group using NET with regard to carbohydrate metabolism.
Blood Glucose↗
Serum levels and pharmacokinetics of norethisterone after ingestion of lynestrenol: its relation to dose and stage of the menstrual cycle.
The peak concentration, peak time, the area under the serum concentration time curve (AUC) and half-life of serum norethisterone (NET) after a single application of lynestrenol (LYN) to female volunteers demonstrated that 0.7 mg NET is bioequivalent to 1 mg LYN which is rapidly converted to NET. There was a decrease of the peak values and an increase of half-life of NET during the periovulatory and luteal phase which was, however, not significant due to the great individual differences. The shift of the peak time to longer intervals and the increase of half-life of NET after ingestion of higher LYN doses indicate a certain limitation of the metabolic capacity of the liver. One of the volunteers who complained of nausea and vertigo after the administration of 5 mg LYN, showed the highest serum values of NET. The large interindividual variations of the serum levels of synthetic steroids demonstrate a possible risk of contraceptive safety in women with low steroid levels and possibly a coherence between extremely high serum levels of synthetic steroids and side effects.
Adult↗
Plasma levels and pharmacokinetics of norethindrone and ethinylestradiol administered in solution and as tablets to women.
Twenty-four normal adult female volunteers were dosed orally with a solution and tablet formulation containing the contraceptive combination of norethindrone (NET, 1.0 mg) and ethinylestradiol (EE2, 0.12 mg) in a crossover bioequivalence study. Blood was sampled sequentially following single oral doses and the plasma separated for analysis of NET and EE2 by specific radioimmunoassays. Comparisons of both drugs following a dose in solution and tablets were made with respect to the following parameters: (a) plasma concentrations at each sample time; (b) maximum plasma concentration (Cpmax); (c) time to maximum plasma concentration (Tmax); (d) total area under the plasma concentration vs. time curve (AUC), and (e) plasma half-life (t1/2). It was found that the tablet and solution doses were bioequivalent with respect to EE2 absorption. However, absorption of NET from solution and tablet doses exhibited significant differences with respect to plasma levels at certain time points as well as AUC (which were higher following the tablet dose), but Cpmax, Tmax and t1/2 were not significantly different. Pharmacokinetic analysis of both drugs following the tablet dose was carried out using a two-compartment open model. The absorption rate constant (ka) and peripheral to central compartment transfer rate constant (k21) were similar for NET and EE2, but statistically significant differences were observed with respect to the distribution rate constant (alpha), the central to peripheral transfer rate constant (k12), the overall elimination rate constant (ke1), and volume of distribution (V1/F). The elimination rate constant (beta) for both drugs showed a difference of borderline statistical significance.
Adolescent↗
Pharmacokinetics of different doses of norethisterone oenanthate.
Doses of norethisterone oenanthate of 300, 150, 100 and 50 mg were administered to four groups of subjects. Due to wide intersubject variations there were no statistically significant differences in the pharmacokinetic parameters for the different groups but there were significant correlations between the dose and the mean values for these parameters. There was little difference between the groups in the duration for which ovarian function was suppressed due to the inter-subject variation being greater than the inter-dose effect. The duration of the antifertility action of norethisterone oenanthate cannot be increased by increasing the dose above the standard 200 mg; however, with an injection interval of 60 to 70 days, it seems likely that the dose could be reduced to 150 mg.
Adult↗
Pharmacokinetics of norethisterone in humans.
The pharmacokinetics of a dose of 1mg norethisterone administered with 50 micrograms ethynyloestradiol was studied in 83 subjects. The dose was rapidly absorbed and there were wide variations in the serum NET concentrations at any particular time after dosing; the concentrations at 24 h varied from 100 to 1700 pg/ml. There was a significant negative correlation between the serum NET concentration and the time after dosing in all women. There were large inter-subject variations in the pharmacokinetic parameters, the elimination half-life and bioavailability showing 3- and 5- fold variability, respectively. Mean values for the parameters were t1/2, 7.6 h; bioavailability, 53.6 ng/ml/h; C max, 4.63 ng/ml; clearance, 22.6 l/h; and Vd 2361. There were a number of statistically significant correlations between the pharmacokinetic parameters and analysis of the correlations suggested that clearance was an important determinant of the bioavailability and of C max whereas the elimination half-life was the determinant of the NET concentration at 24 h. The pharmacokinetics of NET are compared with those of ethynyloestradiol. The wide variation in pharmacokinetics is likely to be important in determining inter-subject variations in efficacy and, particularly, side-effects of oral contraceptives especially now that low-dose formulations are widely used.
Biological Availability↗
Assessment of a new low-dose once-a-month injectable contraceptive.
Norethisterone (NET) in combination with mestranol (ME), in a macrocrystalline aqueous suspension that provides sustained release of steroids, was assessed as a once-a-month injectable contraceptive in ten healthy women of reproductive age. The ovarian function was studied before and after the intramuscular administration of 12mg NET plus 1.2mg ME, delivered as crystals of 150 micron average size. Serial blood samples were taken throughout the injection intervals in all women to measure serum progesterone (P), estradiol (E2), and NET. The NET/ME preparation effectively inhibited ovulation in 23 out of the 25 injection intervals studied. The administration of this formulation induced in some women a small degree of follicular maturation not followed by luteal activity. The endometrial bleeding patterns after each injection showed a bleeding-free period of two to three weeks. The overall data demonstrate that the parenteral administration of a macrocrystalline steroid preparation of NET/ME can bring about a sustained release contraceptive system at a substantially lower dose than those currently employed in once-a-month injectable contraception.
Adult↗
Effects of different doses of norethisterone on ovarian function, serum sex hormone binding globulin and high density lipoprotein-cholesterol.
The ovarian effects of different doses of norethisterone (NET) were compared in 45 normally menstruating women in order to find the lowest effective dose of the Chinese NET "visiting pill". Subjects were randomly divided into 3 groups. Each subject in each group was taking 0.5, 1.5 or 3.0 mg per day from days 5 to day 18 of the cycle. Blood samples were taken on days 5, 8, 11, 14, 17, 20, 23, 26 and 29 of the cycle. Serum oestradiol (E2), progesterone (P), sex hormone binding globulin (SHBG), high density-lipoprotein cholesterol (HDL-C), and NET concentrations were measured. Ovulation, delayed ovulation, ovulation inhibition and follicular activity were classified by the analysis of the peripheral serum levels of sex hormones. Ovulation occurred in 7 women in the 0.5 mg group, in 2 women in the 1.5 mg group and in none of the 3.0 mg group. Mean serum SHBG levels were reduced progressively by 6.6% (Group 0.5), 15.5% (Group 1.5) and 23.4% (Group 3.0). There were no significant changes in HDL-C levels in any group. There was a significant correlation of mean serum NET concentrations with dose. The lack of complete inhibition of ovulation in most women in the 1.5 mg and 0.5 mg groups might suggest that the dose of NET required when used as a visiting pill could not be reduced below 3.0 mg.
Adult↗
Animal toxicity studies performed for risk assessment of the once-a-month injectable contraceptive Mesigyna.
Results from toxicity studies performed for risk assessment of the combined injectable hormonal preparation Mesigyna are reviewed. Both components of Mesigyna, i.e., estradiol valerate (E2Val) and norethisterone enanthate (NET-EN), have been thoroughly investigated as individual compounds and some limited toxicity data have been obtained for the combination. Most findings which were gathered in these studies from different animal species occurred in the gonads, accessory genital and endocrine organs and can be related to the known species-specific pharmacological activity of a typical estrogen or progestin, respectively. No additional or unexpected information which might indicate a possible estrogen/progestin interaction was gained from the administration of the combined preparation to animals. Based on the results from toxicity testing, there were no objections to the long-term therapeutic use of Mesigyna for hormonal contraception. The predictive value of the effects (including the tumorigenicity) observed in the common laboratory animals with regard to human safety is critically discussed, taking the vast amount of previous experience with hormonal contraceptives into consideration. The conclusion is drawn that there is no animal model for safety assessment of sex steroids that adequately represents the human situation. Quantitative extrapolations from animal toxicity findings to humans, therefore, are not possible. Especially, the value of long-term studies and of toxicity studies on estrogen/progestin combinations is put into question. Like endocrine pharmacology studies, the toxicity studies with these steroid hormones are useful for the characterization of the possible endocrine pharmacological profile only.
Animals↗
A comparative study on the return to ovulation following chronic use of once-a-month injectable contraceptives.
A comparative study was undertaken involving 21 Mexican women who discontinued the use of medroxyprogesterone acetate 25 mg plus oestradiol cypionate 5 mg (Cyclofem) and norethisterone enanthate 50 mg plus oestradiol valerate 5 mg (Mesigyna) to assess the time required for the return to menses and ovulation. All subjects were exposed to once-a-month injectable contraceptives for two years and were followed for 120 days after the last injection. The urinary concentration of oestrone glucuronide and pregnanediol glucuronide was determined daily in all subjects beginning one month after the last injection. The results disclosed that ovulatory cycles were documented after 120 days of the last injection in six women of each studied group. Similar endometrial bleeding patterns were observed in both groups, indicating that the two drugs have alike pharmacokinetic and pharmacodynamic effects.
Adult↗
Variability of pharmacokinetic parameters for contraceptive steroids.
Studies of the pharmacokinetics of three contraceptive steroids, ethynyloestradiol, norethisterone and norethisterone oenanthate, in large groups of women are reviewed. Extremely wide variations were observed between women in the various calculated pharmacokinetic parameters. Studies carried out in small groups of subjects may give misleading results. It is difficult to ascribe any meaning and interpretation to most of the derived values but they do provide a means of comparing aspects of the metabolism of the various steroids. It is difficult to relate the pharmacokinetic values to the various biological actions of the steroids. However, the wide variations between subjects in the pharmacokinetic parameters must indicate equally wide variations in the biological activity of the steroids. Subjects in whom the bio-availability is low or where the rate of metabolism is rapid might be expected to respond differently, both in terms of efficacy and side-effects, from subjects with high values for bio-availability and a slow metabolism.
Biological Availability↗
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↗
Pharmacokinetics of oestrogens and progestogens.
There are large inter- and intra-individual variations in the serum concentrations of natural and synthetic sex steroids irrespective of the route of administration. Oral ingestion of steroids has a stronger effect on hepatic metabolism than parenteral administration, as the local concentration in liver sinusoids are 4-5 times higher during the first liver passage. Oestradiol and oestrone are interconvertible, dependent on the local concentrations in liver and target organs, and oestrone sulphate serves as a large reservoir. The oestrone/oestradiol ratio has no physiological significance, as oestrone is only a weak oestrogen. Oestrone is both a precursor and a metabolite of oestradiol. Oestriol is extensively conjugated after oral administration. Therefore, the oestriol serum levels are similar after oral intake of 10 mg and after vaginal application of 0.5 mg oestriol resulting in similar systemic effectiveness. Conjugated oestrogens can easily enter the hepatocytes but are hormonally active only after hydrolyzation into the parent steroids. Ethinylestradiol which exerts strong effects on hepatic metabolism and inhibits metabolizing enzymes, should not be used for hormone replacement therapy. Among the progestogens, the progesterone derivatives have less effects on liver metabolism than the norethisterone derivatives (13-methyl-gonanes and 13-ethyl-gonanes). The highly potent 13-ethyl-gonanes are effective at very low doses, because of a slow inactivation and elimination rate due to the ethinyl group.
Estrogens↗
Single- and multiple-dose pharmacokinetics of a low-dose oral contraceptive in women with chronic renal failure undergoing peritoneal dialysis.
OBJECTIVE: Our purpose was to compare the pharmacokinetic parameters of oral administration of a 35 micrograms ethinyl estradiol, 1 mg norethindrone pill in peritoneal dialysis patients and normal women. STUDY DESIGN: A single-dose study was performed with five patients and four controls, followed by a multiple-dose study with five subjects in each group. Pharmacokinetic parameters were calculated by noncompartmental analysis and statistical analysis performed with Mann-Whitney U testing. RESULTS: There is no difference in the pharmacokinetic parameters for norethindrone in peritoneal dialysis patients compared with normal women. During multiple dosing an increased area under the concentration curve and decreased apparent oral clearance was observed for ethinyl estradiol in peritoneal dialysis patients compared with normal women. CONCLUSION: Peritoneal dialysis patients have decreased apparent oral clearance of ethinyl estradiol, leading to slightly higher serum concentrations compared with women with normal renal function. The clearance of norethindrone is the same in peritoneal dialysis patients and normal women.
Adult↗