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PubMed1978

Bioavailability of norethindrone in human subjects.

A competitive protein binding assay for norethindrone was developed to measure plasma levels in human subjects. The plasma levels were considerably higher in women than in men, especially at low dose levels. The plasma levels were directly related to the dose in men; but greater variations in the plasma levels were observed in women. The plasma half-life was about 5 h in both sexes with single oral doses of 5 to 20 mg. A comparative bioavailability study with norethindrone from 2 different manufacturers, formulated in the same manner, showed no significant differences in absorption characteristics and provided sufficient data for pharmacokinetic analysis.

Adult↗
PubMed1990

Two-year carbohydrate metabolism studies in women using a norethindrone or levonorgestrel triphasic oral contraceptive.

Carbohydrate metabolism was prospectively studied in 28 women using triphasic oral contraceptives (TOC) for two years. They were tested using a 100-gram oral glucose tolerance test with measurements of plasma glucose and insulin levels during the three-hour test. The women were randomly assigned to either a norethindrone-containing TOC or a levonorgestrel-containing TOC. Both types of drugs contained the estrogen ethinyl estradiol. No significant changes were noted in the norethindrone TOC group. The levonorgestrel TOC two-year test had a significant elevation of the 0.5- and 2-hour plasma glucose values and the fasting insulin value. These data show that the two triphasic oral contraceptive preparations affect carbohydrate metabolism differently.

Adult↗
PubMed1990

Comparison of norethindrone and medroxyprogesterone acetate with natural progesterone and estradiol in stimulating prolactin production from cultured endometrial stromal cells.

Progestins stimulate prolactin production from endometrial stromal cells in culture. We compared the potencies of the synthetic progestins norethindrone and medroxyprogesterone acetate to natural progesterone in inducing stromal prolactin production. Modifications of the culture system provided an increase in stromal cell yield, thus permitting multiple comparisons from the treatment of cells from a common endometrial sample. The effects of high-dose estradiol also were evaluated in this system. The findings suggest relative potencies of 50:1 for medroxyprogesterone acetate and progesterone. Norethindrone gave intermediate and more variable responses. Estradiol potentiated prolactin production from only submaximal progestins doses. The differences between the progestin effects, in large measure, were due to differential culture growth as reflected by culture mass. Compared to controls and estradiol alone, all the progestins induced much greater prolactin production. Thus during decidualization, progestins probably promote both stromal growth and intracellular prolactin production. High-dose estradiol may not interfere with these events.

Analysis of Variance↗
PubMed1983

HPLC-RIA of a metabolite of norethindrone in human plasma, 17 alpha-ethinyl-5 beta-estrane-3 alpha, 17 beta-diol, following conjugate hydrolysis.

An HPLC-RIA method for the assay of a reduced metabolite of norethindrone, 17 alpha-ethinyl-5 beta-estrane-3 alpha, 17 beta-diol, is described. Conjugated metabolites were extracted from human plasma and subjected to hydrolysis prior to analysis. With a daily dose of 2 mg of norethindrone, the mean plasma level of the metabolite was 24.8 ng/ml with a range of 22.8 ng/ml to 33.9 ng/ml.

Chromatography, High Pressure Liquid↗
PubMed1999

A multicenter randomized comparison of cycle control and laboratory findings with oral contraceptive agents containing 100 microg levonorgestrel with 20 microg ethinyl estradiol or triphasic norethindrone with ethinyl estradiol.

OBJECTIVE: This study was undertaken to compare the effects of 2 oral contraceptive regimens on menstrual cycle control and laboratory findings. METHODS: In a multicenter randomized study 100 microg levonorgestrel with 20 microg ethinyl estradiol (Alesse or Loette) was given to 155 healthy women. A triphasic preparation of 500, 750, and 1000 microg norethindrone with 35 microg ethinyl estradiol (Ortho-Novum 7/7/7 or TriNovum) was given to 167 women for 1 to 4 cycles of treatment. RESULTS: Overall, the percentages of normal menstrual cycles and the percentages of cycles with intermenstrual and withdrawal bleeding were similar between the 2 treatment groups. In the levonorgestrel with ethinyl estradiol group, there was a statistically significantly longer latent period and a statistically significantly shorter withdrawal bleeding episode. Adverse events were similar between treatment groups, and none were serious. Most mean changes from baseline laboratory values were comparable between groups, although the mean increase in cholesterol concentration was statistically significantly lower in the levonorgestrel with ethinyl estradiol group. Changes in triglyceride and glucose concentrations were not statistically significantly different between groups. CONCLUSIONS: Levonorgestrel (100 microg) with ethinyl estradiol (20 microg) provides menstrual cycle control equivalent to that obtained with triphasic norethindrone with ethinyl estradiol (75% higher estrogen dose) with similar safety and tolerability.

Adult↗
PubMed1979

Metabolic and endocrine studies in women using norethindrone acetate implant.

Subcutaneously administered implant-D containing 40 mg of Norethindrone acetate in a single silastic implant was offered to 79 subjects who desired spacing of their family. The effect of constant release of steroid from this device on metabolic and endocrine functions was studied. Each subject in the pretreatment state served as her own control. The device was removed at 8 months initially and subsequently at 5-6 months. The clinical acceptability of this method was fairly high. The results reported in this study show that Norethindrone acetate administered in this way did not cause any adverse reactions on endocrine and metabolic functions as gauged by the parameters analysed.

Adult↗
PubMed1995

The effect of monophasic combinations of ethinyl estradiol and norethindrone on gonadotropins, androgens and sex hormone binding globulin: a randomized trial.

The effects of different monophasic combinations of ethinyl estradiol and norethindrone on FSH, LH, sex hormone binding globulin, total testosterone, androstenedione, and dehydroepiandrosterone sulfate levels in non-obese, non-hirsute women were compared. Retrospective analysis of frozen serum from a prospective randomized trial in which women received one of three oral contraceptive pills containing ethinyl estradiol 50 micrograms/norethindrone 1 mg, ethinyl estradiol 35 micrograms/norethindrone 1 mg or ethinyl estradiol 35 g/norethindrone 0.5 mg for nine cycles was conducted. Blood samples were obtained prior to treatment and during the third, sixth and ninth pill cycles. Ethinyl estradiol 50 micrograms/norethindrone 1 mg and ethinyl estradiol 35 micrograms/norethindrone 1 mg suppressed FSH, LH, and total testosterone and increased sex hormone binding globulin to a similar degree. Ethinyl estradiol 35 micrograms/norethindrone 0.5 mg resulted in less suppression of FSH, LH, and total testosterone, but greater elevation of sex hormone binding globulin. Dehydroepiandrosterone sulfate was suppressed to a similar degree with ethinyl estradiol 35 micrograms/norethindrone 1 mg and ethinyl estradiol 35 micrograms/norethindrone 0.5 mg, but ethinyl estradiol 50 micrograms/norethindrone 1 mg resulted in the least suppression of dehydroepiandrosterone sulfate. Ethinyl estradiol 35 micrograms/norethindrone 1 mg caused greater suppression of androstenedione than did the other two oral contraceptives. Oral contraceptive-induced changes in gonadotropins, androgens, and sex hormone binding globulin can be predicted by considering the relative amounts of estrogen and progestin in the pill. When combined with 1 mg of norethindrone, 50 micrograms of ethinyl estradiol did not result in greater suppression of FSH, LH, or total testosterone or in greater elevation of sex hormone binding globulin than did 35 micrograms of ethinyl estradiol.

Adolescent↗
PubMed2004

Progesterone receptor ligand binding pocket flexibility: crystal structures of the norethindrone and mometasone furoate complexes.

Although progesterone, the natural ligand of the progesterone receptor (PR), has a hydrogen atom at the 17alpha position, other potent steroid agonists such as norethindrone and mometasone furoate have larger substituents at this position that are accommodated by the PR ligand binding pocket. Crystallographic analysis of PR ligand binding domain complexes clearly demonstrated that these moieties were accommodated by local shifts of the protein main chain and by adoption of alternative side chain rotamer conformations of ligand-proximal amino acids. These conformational changes imparted a ligand-specific volume to the binding pocket, from 490 A3 in the metribolone complex to 520 A3 in the norethindrone complex, 565 A3 in the progesterone complex, and 730 A3 in the mometasone furoate complex. Despite these marked alterations in binding pocket volume, critical interactions essential for establishment of an active AF2 conformation were maintained.

Binding Sites↗
PubMed1977

Plasma concentrations of ethynyl oestradiol and norethindrone after oral administration to women.

Plasma concentrations of ethynyl oestradiol and norethindrone in women were measured by radioimmunoassays after oral administration of 50 microng and 1000 microng respectively. The maximum values were obtained 1 h after administration. The calculated half-life was 6 1/2 h for ethynyl oestradiol and 7 h for norethindrone. At most 2-3% of the administered dose was present in the plasma at 1 h and had decreased to about 0-5% by 24 h.

Administration, Oral↗
PubMed1990

The effects of combining norethindrone with a gonadotropin-releasing hormone agonist in the treatment of symptomatic endometriosis.

Treatment of endometriosis with gonadotropin-releasing hormone agonists (GnRH-a) is associated with side effects secondary to the induced hypoestrogenic state. In an effort to ameliorate these symptoms, 10 patients with symptomatic endometriosis self-administered the GnRH-a [D-His6(Imbzl)-Pro9-NET]-GnRH in combination with norethindrone daily for 24 weeks. Painful symptoms were significantly suppressed after therapy (P less than 0.005). Objective review of photographs taken at laparoscopy before and after therapy demonstrated significant reduction of visible implants (P less than 0.005). Vasomotor symptoms were minimized when compared with a group of 16 patients previously treated with GnRH-a alone. Bone mineral density of the distal radius assessed by single photon absorptiometry was not reduced during therapy, although lumbar spine bone density assessed by quantitative computerized tomography was minimally but reversibly reduced. No metabolic derangements were detected. The combination of norethindrone with GnRH-a is a well tolerated and effective means of treating symptomatic endometriosis.

Adult↗
PubMed1990

Effect of progesterone (norethindrone) only oral contraceptive on mouse uterus--a SEM study.

Impact of progesterone (norethindrone) only oral contraceptive (MICRONOR) on mouse uterus was investigated by SEM. The three dimensional SEM photographs revealed that, flat wave like mucous folds of the uterus (control) become more thick and highly convoluted after 50 days of MICRONOR feeding. The uteri became highly secretory as indicated by increased thickness of nonciliated secretory cell population with their increased microvilli. Low doses of norethindrone in combination with circulating estrogen, instead of causing regression, maintained a steady and highly secretory state which may interfere implantation/gamete transport.

Animals↗
PubMed1986

Lipid, carbohydrate, and androgen metabolism in women using a triphasic oral contraceptive containing norethindrone for one year.

A clinical trial was conducted to determine the effects of a norethindrone-containing triphasic oral contraceptive, Ortho-Novum 7/7/7, on lipid, carbohydrate, and androgen metabolism in 22 women during 12 cycles of use. Examinations were made in two consecutive cycles before treatment and after 3, 6, 9, and 12 cycles of treatment. Treatment consisted of ethinyl estradiol, 35 micrograms/d for 21 days, together with norethindrone in stepwise-increasing doses of 0.5, 0.75, and 1.0 mg/d, with each dose given for seven days. Only a minimal impact on lipid metabolism was observed during treatment. There were no unfavorable changes in any HDL-related measurement. HDL-cholesterol and alpha levels were not altered in any cycle. The HDL:LDL ratio was not significantly altered during treatment. LDL cholesterol levels were also unaltered during treatment, but there were slight elevations in other LDL-related measurements in some cycles. Total cholesterol, phospholipid, and triglyceride levels were elevated in cycle 9, and triglyceride levels also increased in cycle 3, but no significant changes were observed in these levels at any other sampling times. Carbohydrate metabolism did not change significantly as indicated by mean fasting levels of glucose, insulin, and HbA1c or by levels of these parameters after a glucose load. Changes observed in androgenic parameters indicate the lack of androgenicity. The results of this study demonstrate that Ortho-Novum 7/7/7 use results in a minimal impact on lipid metabolism, no change in carbohydrate metabolism, and no potential for androgenic side effects.

Adult↗
PubMed1984

Quantitation of delta 4-reduced metabolite of norethindrone in human plasma by HPLC-RIA.

An HPLC-RIA method for the measurement of the delta 4-reduced metabolite of norethindrone is described. The sensitivity of the method was such as to permit the quantitation of pg amounts (30 pg with an inter-assay CV of less than 7%). Nineteen volunteers received a single oral dose of 1 mg of norethindrone and, blood samples withdrawn at timed intervals, were pooled for each time period and assayed. The plasma concentrations of the dihydro metabolite ranged from 460 pg/ml at 30 min to 20 pg/ml at 24h.

Biotransformation↗
PubMedDate not supplied

Norethindrone--a review of therapeutic applications.

Norethindrone is utilized for numerous noncontraceptive therapies, especially during the menopause. Through an analysis of the literature we have described the pharmacological profile of norethindrone and the potential therapeutic implications of low-dose therapies, with an emphasis on endometrial pathology, climacteric symptoms, lipid metabolism, and bone density.

Adult↗
PubMed1983

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↗
PubMed1979

Accumulation of norethindrone and individual metabolites in human plasma during short- and long-term administration of a contraceptive dosage.

Blood levels of free, sulfate, and glucuronide conjugates of norethindrone (NE) and its ring A reduced metabolites 17alpha-ethynyl-5beta-estrane-3alpha, 17beta-diol and 17alpha-ethynyl-5alpha-estrane-3alpha, 17beta-diol were measured in a female volunteer who received six consecutive daily doses of 2.5 mg. of NE and in four female volunteers undergoing chronic treatment with Orthonovum 2 mg. (2 mg. of NE and 0.1 mg. of mestranol [ME]). The blood levels were quantified by gas chromatograph-mass spectrometry. During treatment for 6 days with 2.5 mg. of NE daily, the 3 hour blood levels of NE and the ring A reduced metabolites increased in a stepwise fashion. During long-term treatment the concentrations of NE, NE sulfate, and the conjugates of the ring A reduced metabolites were seen to build up to a peak at approximately the midpoint of the treatment phase of each cycle, and drop to near baseline during the time when no drug was administered. Individuals varied as to their tendency to accumulate the drug and metabolites, and as to the relative proportion of metabolites formed.

Adult↗
PubMed1979

Subdermal norethindrone pellets -- a method for contraception?

The mode of action of compressed pellets containing 85 per cent norethindrone (NET) and 15 per cent cholesterol was studied. Four pellets were inserted subcutaneously, in each of five healthy volunteers and left in place for 200--229 days. The NET content of the pellets varied between 23.9 mg and 25.6 mg; and the cholesterol content between 4.2 mg and 4.5 mg. Plasma levels of NET, estradiol and progesterone were determined by radioimmunoassays. Plasma levels of NET varied mostly between 1--2 ng/ml the first month after insertion. After two months plasma levels of NET ranged between 0.5 ng/ml and 1 ng/ml in all volunteers and there was a gradual decrease of the plasma NET levels throughout treatment. Pronounced day-to-day variations in plasma NET levels were recorded. The release rates of NET was calculated to be between 187 micrograms/day and 243 micrograms/day among the five volunteers. Ovulations occurred in four out of five subjects during treatment. This study indicates that the release of gestagen from four NET pellets was only initially high enough to completely inhibit ovulation and that to accomplish full contraceptive efficacy, a higher dose, i.e. more pellets, would have to be inserted.

Adult↗