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PubMed1989

Carbohydrate studies in women using a norethindrone triphasic oral contraceptive for eighteen months.

Twenty women were tested before and after eighteen months of use of triphasic oral contraceptive (TOC) containing norethindrone and ethinyl estradiol (7-7-7). The evaluation was with an oral glucose tolerance test and plasma glucose and insulin levels were measured. The results showed a lower fasting glucose and elevated one-hour insulin values after TOC use. These results suggest improved safety with these contraceptives.

Contraceptives, Oral↗
PubMed1985

Contraceptive efficacy of bioabsorbable pellets of norethindrone (NET) as subcutaneous implants: phase II clinical study.

The contraceptive efficacy of norethindrone (NET) fused pellets was evaluated over 12 months in a Phase II clinical study with three and four pellets, each pellet containing 35 mg of NET. Volunteers were healthy, fertile, sexually active women. The release rate of NET from three and four pellets, respectively, was 150.3 +/- 7.2 micrograms and 212.5 +/- 8.6 micrograms NET/day. Following the implantation of NET pellets, serum NET levels did not show any 'burst effect' and were sustained at levels between 0.4 and 0.6 ng NET/ml serum with three pellets and 0.6-0.7 ng NET/ml serum with four pellets. With three and four pellets, respectively, 40% and 27% of the women had normal menstrual cycles; 20% and 14% were amenorrheic; 27% and 37% had mid-menstrual spotting or bleeding; and 13% and 22% had prolonged episodes of bleeding. Cardiovascular, hepatic, and renal functions were normal throughout the study. Ovulation was inhibited in 85% and 92% of the cycles with three and four pellets, respectively. In women using three pellets, two pregnancies occurred, one at the 6th cycle and another at the 12th cycle. In women using four pellets, no pregnancies occurred during the entire period of study.

Adult↗
PubMed1981

An investigation of the interaction between isoniazid and the contraceptive steroid norethindrone in vivo.

Isonicotinic acid hydrazide (isoniazid) was shown to react readily with 17 alpha-ethinyl-17 beta-hydroxyestr-4-en-3-one (norethindrone) to form the isonicotinyl hydrazone of the steroid under conditions likely to exist in the stomach. The hydrazone was detected in guinea-pig, but not rat, plasma following its oral administration. Rat liver tissue metabolized the compound more rapidly than guinea-pig liver in vitro which probably accounts for the failure to detect the hydrazone in rat plasma.

Animals↗
PubMed2002

Randomized, double-masked, 2-year comparison of tibolone with 17beta-estradiol and norethindrone acetate in preventing postmenopausal bone loss.

In this 2-year, randomized study, we compared the efficacy and tolerability of tibolone 2.5 mg (n = 75), tibolone 1.25 mg (n = 76) and estradiol 2 mg plus norethindrone acetate 1 mg (E2/NETA: n = 74) for preventing bone loss in postmenopausal women. Bone mineral density (BMD), measured by dual-energy X-ray absorptiometry, and bone remodeling markers were assessed every 6 months. Side-effects were assessed quarterly. After 24 months, the mean increase (+/- SD) in lumbar spine BMD from baseline was 3.6% +/- 2.9%, 1.9% +/- 3.5% and 6.8% +/- 4.5% in the tibolone 2.5 mg, tibolone 1.25 mg and E2/NETA groups, respectively. All pairwise differences were significant. The proportion of responders (women with a change from baseline in lumbar spine BMD of > or = -2% after 2 years) was 95.7%, 89.0% and 98.5% with tibolone 2.5 mg, tibolone 1.25 mg and E2/NETA, respectively. Similar results were obtained for femoral BMD, although the difference between tibolone 2.5 mg and E2/NETA was not significant at 24 months. Decreases in bone remodeling markers were similar in the three groups. Vaginal bleeding was more common in the E2/ NETA group (33.8%) than with tibolone 2.5 mg (12.0%) or tibolone 1.25 mg (9.2%), as was breast pain (23.0%, 2.7% and 2.6%, respectively). Each treatment effectively prevented bone loss. Overall, tolerability of tibolone was better than with E2/NETA, because of less frequent vaginal bleeding and breast pain. This may promote long-term adherence.

Androgen Antagonists↗
PubMed1992

Contraceptive compliance with a levonorgestrel triphasic and a norethindrone monophasic oral contraceptive in adolescent patients.

OBJECTIVE: This study was undertaken to assess the impact of two low-dose oral contraceptive pills on compliance and side effects in adolescent patients. STUDY DESIGN: The use of a levonorgestrel-containing triphasic pill (N = 114) was compared with that of a monophasic (1 + 35) norethindrone-containing pill (N = 110) at two different sociodemographic sites. RESULTS: No significant difference in compliance or pill satisfaction was observed between the pills. Socioeconomic factors were the overriding predictors of compliance. At 3 and 12 months of follow-up, there were significantly fewer complaints of overall side effects (p less than 0.001 and p = 0.004, respectively), breakthrough bleeding (p = 0.017 and p = 0.018), and pill amenorrhea (p = 0.002 and p less than 0.001) among users of the triphasic pill. Mean weight change at 12 months was +1.1 kg for the monophasic pill and -0.1 kg for the triphasic pill. All known pregnancies occurred among noncompliant city clinic patients. CONCLUSIONS: Adolescents experienced fewer side effects with the triphasic pill than with the monophasic one, but compliance was the same.

Adolescent↗
PubMed1980

Radioimmunoassay of plasma ethinylestradiol in the presence of circulating norethindrone.

A reliable radioimmunoassay (RIA) for the measurement of ethinylestradiol (EE2) in plasma after the separation of norethindrone (NET) by column chromatography has been developed. The procedure involves diethyl ether extraction, followed by celite column partition chromatography to separate NET from EE2. An antiserum against ethinylestradiol-7-(3-thiopropionic acid)-bovine serum albumin conjugate was employed. Tritiated EE2 was used as the radioligand. The separation of bound from free 3H-EE2 was carried out with dextran-coated charcoal. This RIA procedure was used to measure plasma EE2 at specified time intervals in three women following oral administration of a tablet containing EE2 (0.12 mg) and NET (1.0 mg). The results show that EE2 is rapidly absorbed after oral administration. Peak concentrations of plasma EE2 were reached within 1.0 to 1.5 hours and then declined biphasically. The EE2 alpha phase half-life values in three subjects were 1.5, 2.8 and 3.8 hours. By comparison, the half-life values for the beta phase for the same three women were 6.2, 12.3 and 14.5 hours, respectively. Plasma samples were also analyzed for NET by RIA. The half-life values for the beta phase for EE2 and NET in the three subjects were similar.

Administration, Oral↗
PubMed1981

Effect of food restriction (undernutrition) on pharmacokinetics of norethindrone in rabbits.

Our previous studies have shown that the plasma norethindrone (NET) elimination is faster in women of low socio-economic group as compared to those of high socio-economic group. Undernutrition being very common in low socio-economic group, using an animal model, efforts were made to determine whether these differences were due to differences in the nutritional status of these two group of women. The experimental animals consisted of a set of twelve female rabbits, divided equally into two groups. One group (A) was fed on a stock diet ad libitum while the second group (B) received the diet in restricted amounts (half of that consumed by animals of group A). At the end of three months, radiolabelled NET was administered intravenously and plasma drug levels were determined at frequent intervals up to 24 hours. The plasma values were subjected to pharmacokinetic analysis. Food restriction to the extent of 50% resulted in a 20% deficit of body weight as compared to controls. The half-lives of alpha and beta phases were shortened in the restricted group resulting in an enhanced metabolic clearance rate of NET in this group. Though the differences were not statistically significant, the volume of distribution tended to be lower and the dose excreted in urine higher when food restriction was imposed.

Animal Nutritional Physiological Phenomena↗
PubMed1984

Multicenter clinical trial of implanted norethindrone pellets for long-acting contraception in women. Program for Applied Research on Fertility Regulation.

Long-acting, biodegradable, subcutaneous implants of fused pellets composed of norethindrone (NET) and pure cholestrol were evaluated in 50 healthy, normally menstruating volunteers from five clinics. Evaluation of serum NET levels indicated a steady release rate over the 6-cycle follow-up period. There were no serious local reactions to the pellets. Menstrual cycle length remained unchanged, but the incidence of intermenstrual bleeding and/or spotting was higher during the initial 2-3 months of pellet use. Following pellet removal menstrual cycle parameters returned to their pre-pellet implantation values. Serum gonadotropin assays indicated the incidence of ovulatory cycles increased over the follow-up period. No significant changes in serum lipoproteins, SMAC-12 or enzyme profiles were observed. Although women were advised to use additional methods of contraception, three became pregnant while using the implants. Fibrous tissue was noted to form around the pellets, thus limiting the release of NET. Additional trials of higher NET doses are being evaluated.

Adolescent↗
PubMed1985

Serum gonadotropin and ovarian steroid levels in women during administration of a norethindrone-ethinylestradiol triphasic oral contraceptive.

We studied the inhibitory effect of a triphasic oral contraceptive (OC) regimen on the pituitary and ovarian function in 29 normal, healthy women. ORTHO* 7/7/7 Tablets contain a constant low dose of ethinylestradiol (EE) and a step-wise increasing level of norethindrone (NE). The pills for the first, middle and last weeks of the 21-day regimen contained, respectively, 0.5, 0.75, and 1.00 mg NE, and all contained 0.035 mg EE. The subjects were divided into 3 groups on the basis of their histories of OC use. Ten had not taken an OC in the previous 2 months, 10 were switched to this study from a fixed-dosage combination OC containing 0.050 mg estrogen, and 9 had been taking ORTHO 7/7/7 Tablets for 5 or more cycles. Serum levels of FSH, LH, estradiol and progesterone were measured and statistically compared with those from 5 normal, untreated women. The results from all study cycles showed that the four hormone profiles were significantly suppressed as compared to the normal patterns. Thus, one mode of action of this new triphasic OC is to inhibit ovulation by suppression of pituitary-ovarian function. This OC treatment appeared to be equally effective among women with varying prior histories of OC therapy.

Adult↗
PubMed1989

Pharmacokinetics of norethindrone: effect of particle size.

In 24 healthy women between the ages of 19 and 35 years who had not used oral contraceptive preparations for at least 60 days, it was found that the smaller the particle size of norethindrone (NET) administered, the higher was the plasma NET level obtained. Three different preparations having particle sizes of NET smaller than 250 microns, 44 microns or 10 microns were tested in a crossover pattern. The time required to reach maximum plasma concentration (Tmax) became shorter with decreasing particle size, 1.69 hr, 1.52 hr and 1.06 hr, respectively. As particle size was reduced, the maximum NET plasma concentration (Cmax) increased for the 3 different 1 mg NET preparations, i.e. 8.66 ng/ml, 10.53 ng/ml and 15.73 ng/ml. A trial with a 2 mg NET preparation made with NET utilizing the 44 microns same material displayed a Tmax similar to the 1 mg NET preparation having the same particle size while the Cmax reached a level of 17.56 ng/ml. The area under the plasma concentration versus time curve from 0-24 hrs and the extrapolated total area under the curve, increased with decreasing particle size. The use of a smaller particle size allows for more rapid dissolution or oral contraceptive tablets when measured in vitro; however, there is no evidence that such faster dissolution leads to a significant difference in efficacy. Oral contraceptive tablets have, since their inception, utilized both large and small NET particle size material in various preparations.

Administration, Oral↗
PubMed1990

Action of estradiol on müllerian duct regression induced by treatment with norethindrone of female chick embryos.

Treatment of genetically female chick embryos with norethindrone (NET), a progesterone-like steroid chemically related to testosterone, caused two types of Müllerian duct (MD) deficiencies. The first consisted in an absence of the caudal part of the ducts owing to their partial agenesia occurring between Days 5 and 7 of embryonic life. This is nonspecific since it was observed after a treatment with almost all steroidal sex hormones. In particular, this was obtained with estradiol which also increases the frequency and extent of agenesia caused by the NET, as reported here. The second type of deficiency appeared between Days 12 and 14 and was due to a regression destroying the more or less large part of the MDs having escaped agenesia, i.e., for most of the cephalic half. This resulted from the influence of the anti-Müllerian hormone originating from the ovary and normally inhibited by the ovarian estrogens. This protective action of endogenous estrogens was inhibited by the NET, but an additional treatment with estradiol removed this inhibition and prevented duct regression. Our results suggest that estrogen protects the duct from the regression induced indirectly by NET, by acting both at gonad and MD levels.

Animals↗
PubMed1993

Norethindrone alters apolipoprotein E concentration and isoform expression in rat plasma high-density lipoproteins.

The administration of norethindrone, a synthetic progestin, to female rats caused marked decreases in the cholesterol and protein contents of high-density lipoproteins (HDL). A 84% decrease in the total apolipoprotein (apo) E of HDL was associated with a 80% decrease in the proportions of apoE isoforms E1 and E2, whereas E3 and E4 were unchanged. This appears to be the first demonstration of hormonally-induced modification of the apoE phenotype.

Animals↗
PubMed2004

Effect of zonisamide on the pharmacokinetics and pharmacodynamics of a combination ethinyl estradiol-norethindrone oral contraceptive in healthy women.

BACKGROUND: Several antiepileptic drugs have clinically significant pharmacokinetic interactions with oral contraceptives (OCs) that may result in contraceptive failure. OBJECTIVE: The aim of this study was to assess the effect of zonisamide on the pharmacokinetics of the individual components of a combination OC (ethinyl estradiol [EE] 0.035 mg and norethindrone [NOR] 1 mg) and on pharmacodynamic variables that may be increased in the event of reduced contraceptive efficacy (concentrations of serum luteinizing hormone [LH], follicle-stimulating hormone [FSH], and progesterone). METHODS: This was a single-center, open-label, 1-sequence, crossover study. Healthy, premenopausal women received the combination OC for three 28-day cycles (combination OC for 21 days, followed by placebo for 7 days). Following stabilization on the OC during the first cycle, blood was collected during cycle 2 for the determination of serum EE and NOR profiles (day 14) and serum LH, FSH, and progesterone concentrations (days 13-15). Starting on day 15 of cycle 2, zonisamide was administered orally at 100 mg/d and titrated to a target dose of 400 mg/d. EE and NOR profiles and serum LH, FSH, and progesterone concentrations were obtained again in cycle 3 (in the presence of zonisamide) and compared with those from cycle 2 (in the absence of zonisamide). RESULTS: Thirty-seven healthy premenopausal women (mean age, 26.1 years [range, 18-51 years]; mean body weight, 65.5 kg [range, 50.4-93.1 kg]; mean height, 165.8 cm [range, 152.4-182.9 cm]) received > or =1 dose of zonisamide. Of the 33 subjects (89.2%) who completed the study, 26 (78.8%) underwent titration to a stable zonisamide dose of 400 mg/d. For EE, the mean (SD) AUC over a 24-hour dosing interval (AUC(tau)) was 1139 (317) pg.h/mL in cycle 2 and 1143 (312) pg.h/mL in cycle 3; the mean C(max) in the respective cycles was 133 (39) and 141 (46) pg/mL. For NOR, the corresponding values were 140 (48) and 159 (46) ng.h/mL for AUC(tau) and 21 (5.4) and 23 (6.7) ng/mL for C(max). The 90% Cls for the geometric mean ratios (cycle 3:cycle 2) for AUC(tau) and C(max) fell within the accepted range for lack of interaction (0.80-1.25). There were no increases in LH, FSH, or progesterone concentrations between cycle 2 and cycle 3. CONCLUSIONS: In these healthy volunteers, steady-state zonisamide dosing had no clinically significant effect on the pharmacokinetics of EE or NOR. There was no pharmacodynamic evidence that zonisamide is likely to reduce the contraceptive effectiveness of OCs containing EE and NOR.

Adult↗
PubMed1988

Prospective study of carbohydrate metabolism in women using a triphasic oral contraceptive containing norethindrone and ethinyl estradiol for 3 months.

Thirty-five women with normal carbohydrate metabolism were administered a 3-hour oral glucose tolerance test before and after 3 months' use of a triphasic oral contraceptive that contained ethinyl estradiol and norethindrone. The results show no significant change in either the plasma glucose or the insulin values. This is the first published study with regard to this type of triphasic oral contraceptive, and the study supports claims of the preparation's improved safety.

Adolescent↗
PubMed1979

The rabbit as an animal model to study pharmacokinetics of norethindrone in women.

The pharmacokinetics of norethindrone (NET) were studied in adult female rabbits and rhesus monkeys with a view to developing an animal model closely resembling humans in the handling of NET. Plasma levels of NET were determined in rabbits and monkeys after administering either labelled NET or a NET minipill. Pharmacokinetic parameters were evaluated by using a two-compartment open model and by graphical and regression analysis of plasma NET data. In rabbits, the drug absorption was found to be rapid and NET peak levels were attained within 0.5 to 1.0 hour. The clearance half-lives were 1.3 hours for 'alpha' and 10.0 hours for 'beta'. In monkeys, plasma NET values showed an inconsistent pattern and the approximate t 1/2 was found to lie between 4 and 6 hours. The observed pharmacokinetics of NET in rabbits rather than in monkeys were closer to those in humans. On this basis, it would appear that the rabbit is a suitable animal model for studying effects of nutritional factors on the pharmacokinetics of NET.

Animals↗
PubMed1990

Effects of norethindrone on gonadotropin and ovarian steroid secretion when used for cycle programming during in vitro fertilization.

Norethindrone (NET) has been used for cycle programming and may result in attenuated responses to controlled ovarian hyperstimulation. The effects of NET on gonadotropin secretion, its bioavailability to the ovary, and its effect on ovarian steroidogenesis in vivo and in vitro were assessed. Endogenous secretion of luteinizing hormone and follicle-stimulating hormone was attenuated by 59% and 50%, respectively, after 2 weeks of orally administered NET. Twelve hours after a single 10-mg oral dose, significant levels of NET were measured in samples of peripheral (8.8 +/- 1.9 ng/mL) and ovarian venous blood (10.5 +/- 3.1 ng/mL), follicular fluid (7.1 +/- 2.1 ng/mL), and homogenates of ovarian tissue (8.0 +/- 0.6 ng/g). Furthermore, NET was detectable in follicular fluid 2 weeks after its withdrawal (863 +/- 149 pg/mL). However, there were no effects of NET on follicular fluid levels of estradiol and progesterone in vivo or on luteinized granulosa cell steroidogenesis in vitro. We conclude that when used for cycle programming in in vitro fertilization, NET does not inhibit ovarian steroidogenesis but does affect the hypothalamic-pituitary axis.

Adult↗