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PubMed1981

Influence of norethindrone on lipid metabolism and cholelithiasis in rabbits.

Rabbits were fed a purified ration containing 15% lard and were killed and examined at 0, 4, 8, 12, and 16 weeks. One group (group II) was given (treated) norethindrone in the ration (10 mg/kg of ration). There were no treatment effects noted on hepatic weight, percentages of dry matter and ether extract in liver, and hepatic cholesterol concentrations; however, there were some changes in the hepatic fatty acid percentages at some observation times. The occurrence and severity of cholelithiasis were not influenced by the treatment, but gallstone formation was pronounced in the 2 groups (ration alone, ration with added norethindrone) by the 4th weeks. The thoracic aorta did not reveal treatment effects as to weight and percentages of dry matter and ether extract, but the aortic cholesterol concentration was greater in the nontreated group than in the group fed the ration with the added norethindrone. Increased thoracic aortic weights were noted in both groups by the 4th week. Examinations and analyses of the adipose deposits forming the kidney pads did not reveal influences of time or treatment.

Animals↗
PubMed1978

A radioimmunoassay for norethindrone (NET): measurement of serum NET concentrations following ingestion of NET-containing oral contraceptive steroids.

A sensitive and reliable radioimmunoassay (RIA) for the measurement of norethindrone (NET) in serum has been established employing anti-11 alpha-hydroxynorethindrone 11-hemisuccinyl-bovine serum albumin serum in conjunction with norethindrone-3-(0-carboxymethyl) oximino-[125I]-iodohistamine. Of a number of ring A reduced NET metabolites, only 17 beta-hydroxy-17 alpha-ethinyl-5 beta-estran-3-one (43%) and 17 alpha-ethinyl-5 alpha-estrane-3 beta, 17 beta-diol (15.7%) cross-reacted appreciably in this RIA. Ethinyl estradiol (EE2) and mestranol (MEE2) exhibited cross-reactions of only 1.1 and 0.4%, respectively. Serum NET levels were measured in four groups of 3 women, each ingesting either 1 mg NET plus 0.05 mg MEE2 (Norinyl 1 + 50 or Ortho Novum 1/50), 0.5 mg NET plus 0.035 mg EE2 (Brevicon) or only 0.35 mg NET (Micronor) daily for 5 consecutive days. Peak serum NET levels were observed within 1/2 to 4 hours after oral intake and fell precipitously thereafter. After reaching a maximum, serum NET concentrations declined in a manner consistent with at least two disposition phases. The average half-life for the first disposition phase was 2.3, 3.4, 3.9 and 4.4 hours in subjects ingesting Norinyl 1 + 50, Ortho Novum 1/50, Brevicon and Micronor, respectively. Peak and 3-hour post-ingestion serum NET concentrations were dose-related but showed considerable subject-to-subject variations. Following discontinuation of tablet intake, serum NET levels remained detectable (greater than 0.05 ng/ml) for at least 5 days in all 3 women who had taken Ortho Novum 1/50, but in none of the other 9 volunteers. These results suggest that different preparations of identical doses and combinations of oral contraceptive steroids may yield different serum NET profiles. However, due to considerable subject-to-subject variations, larger numbers of subjects are required for a conclusive investigation.

Adult↗
PubMed1996

Contraceptive efficacy, pharmacokinetics, and safety of Annuelle biodegradable norethindrone pellet implants.

OBJECTIVE: To evaluate the contraceptive efficacy, pharmacokinetics, and safety of two formulations of Annuelle (Endocon, Inc., South Walpole, MA) biodegradable norethindrone (NET) SC pellet implants. DESIGN: Prospective observational study. SETTING: Two clinical sites in the United States. PATIENT(S): Thirty-nine healthy, fertile, sexually active women. INTERVENTION(S): Nineteen women received a four-pellet system containing 174 mg NET; 20 women received a five-pellet system containing 266.5 mg NET. MAIN OUTCOME MEASURE(S): Contraceptive efficacy, median serum NET levels, adverse events. RESULT(S): No pregnancies were observed in 293 woman-months in the four-pellet group or in 375 woman-months in the five-pellet group. An initial burst in median serum NET levels occurred in the first 24 hours postinsertion followed by a steady decline over the next 3 years. Norethindrone levels varied considerably among women. The main side effect was bleeding abnormalities, which persisted in half the participants for up to 2 years. No serious adverse events were reported that were related to the pellets. Pellet insertion and removal generally were uncomplicated. CONCLUSION(S): Annuelle shows potential as an effective, safe contraceptive with distinct advantages over other long-acting agents, because it is biodegradable but can be removed if problems arise or if fertility is desired.

Adolescent↗
PubMed1983

Structure of the isonicotinyl hydrazone of norethindrone.

The contraceptive steroid norethindrone reacts with isoniazid both in vivo and in vitro to give the corresponding hydrazone, which exists as syn and anti (with respect to C-4) isomers. These isomers rapidly interconvert, with the anti form predominating in solution. The identification of the isomers was based on an interpretation of 1H- and 13C-NMR spectroscopic data and corroborated by high-performance liquid chromatographic UV spectrophotometric evidence. 1H- and 13C-NMR spectroscopic data for other derivatives of norethindrone hydrazone are presented and interpreted.

Chemical Phenomena↗
PubMed2001

Pharmacology and toxicology of ethinyl estradiol and norethindrone acetate in experimental animals.

For over 30 years various combinations of synthetic estrogens and progestins have been used in oral contraceptive formulations. Ethinyl estradiol (EE) and norethindrone acetate (NA) are common synthetic hormones used in oral contraceptives such as Loestrin, Brevicon, Ortho-Novum, Norlestrin, and Norinyl. In recent years these oral contraceptives have been considered for development in other therapeutic indications. Given the use of these agents for other clinical indications with different and larger target populations, an updated comprehensive review of the toxicology literature of estrogens and progestins is warranted. This review will summarize available data on the pharmacology and toxicology of estrogens and progestins with an emphasis on the specific synthetic hormones EE and NA. Ethinyl estradiol and norethindrone acetate alone or in combination, possess low acute and chronic toxicity. In some studies, EE and/or NA increased the incidence of specific tumors in susceptible strains of rodents and dogs, but not monkeys. These agents are not teratogenic when given in combination. Alone EE and NA have clastogenic properties. Overall, the animal data demonstrates that long-term exposure to EE and NA formulations pose very little health risks to humans.

Animals↗
PubMed1990

A study of combined continuous ethinyl estradiol and norethindrone acetate for postmenopausal hormone replacement.

In a blinded, prospective, dose-response pilot study of continuous estrogen-progestin replacement therapy, 77 thin, nonsmoking, white women, who were 12 to 60 months postmenopausal and had normal medical histories, were randomly assigned to receive one of five dose combinations of daily ethinyl estradiol and norethindrone acetate (20 micrograms and 1.0 mg, 10 micrograms and 1.0 mg, 10 micrograms and 0.5 mg, 5 micrograms and 1.0 mg, and 5 micrograms and 0.5 mg) or conjugated estrogens 0.625 mg on days 1 to 25 and medroxyprogesterone acetate 10 mg on days 16 to 25. An additional 10 women meeting the same criteria served as a comparison group by taking calcium only. During 12 months of therapy, continuous users had significantly less vaginal bleeding and spotting than did sequential users. As compared with baseline values, bone metabolism and computerized tomographic measurements of vertebral trabecular bone density at month 12 indicated reduced bone turnover and increased density in hormone users. Endometrial biopsy specimens were negative for hyperplasia and neoplasia. The continuous ethinyl estradiol-norethindrone acetate tablet, even at the lowest doses studied, provided the same salutary effects on bone, endometrium, and postmenopausal symptoms as sequential therapy while minimizing annoying vaginal bleeding and spotting.

Adult↗
PubMed1994

Continuous combined and sequential estradiol and norethindrone acetate treatment of postmenopausal women: effect of plasma lipoproteins in a two-year placebo-controlled trial.

OBJECTIVE: Our purpose was to examine the effects of postmenopausal estrogen therapy supplemented with progestogen on plasma lipoprotein levels. STUDY DESIGN: One hundred thirteen women were randomized to receive either placebo or a combination of 17 beta-estradiol and norethindrone acetate administered continuously (Kliogest) or sequentially (Trisequens). Plasma lipoprotein levels were measured at baseline and after 2 years of treatment and compared by analysis of variance. RESULTS: Hormone therapy lowered plasma cholesterol levels (p < 0.001) and low-density lipoprotein cholesterol (Kiogest, p < 0.001; Trisequens, p < 0.01), whereas high-density lipoprotein cholesterol levels were unchanged (Trisequens) or reduced (Kliogest, p < 0.01), primarily because of a decrease in the high-density lipoprotein-2 subfraction (p < 0.05). Low-density lipoprotein/high-density lipoprotein cholesterol ratios remained unchanged. CONCLUSIONS: Although hormonal replacement therapy with estradiol combined with norethindrone acetate eliminated the increase in high-density lipoprotein cholesterol levels observed with estrogen monotherapy, the reductions in low-density lipoprotein cholesterol concentrations still suggest reduced cardiovascular risk, according to the National Cholesterol Education Program and to recent observations indicating that risk is not necessarily inversely proportional to high-density lipoprotein cholesterol levels.

Cholesterol↗
PubMed1988

Lack of metabolic effects of a triphasic formulation containing norethindrone in normal women studied prospectively.

The glucose and insulin responses to oral glucose tolerance tests and lipid values in normal women taking a triphasic pill containing norethindrone (Ortho 7/7/7) were performed. After three months, no significant changes in these metabolic indices were found. These results confirm and expand the knowledge regarding the metabolic safety of norethindrone-containing triphasic formulations.

Adult↗
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↗
PubMed2004

Treatment of endometriosis and chronic pelvic pain with letrozole and norethindrone acetate: a pilot study.

OBJECTIVE: To determine the role of an aromatase inhibitor, letrozole, in the treatment of reproductive-age women with endometriosis and associated chronic pelvic pain. DESIGN: Phase 2, open-label, nonrandomized proof-of-concept study. SETTING: Outpatient tertiary-care center. PATIENT(S): Ten patients with endometriosis, all previously treated both medically and surgically, with unsatisfactory results. INTERVENTION(S): Endometriosis was diagnosed by biopsy and scored from an initial diagnostic laparoscopy performed within 1 month before treatment was begun. Oral administration of letrozole (2.5 mg), the progestin norethindrone acetate (2.5 mg), calcium citrate (1,250 mg), and vitamin D (800 IU) was done daily for 6 months. Within 1-2 months after completion of the treatment, a second-look laparoscopy was performed to score and biopsy endometriosis. MAIN OUTCOME MEASURE(S): Changes in American Society for Reproductive Medicine (ASRM) scores for endometriosis, pelvic pain assessed by visual analog scale, serum hormone levels (FSH, LH, E(2), and estrone [E(1)]), and bone density (DEXA scan). RESULT(S): No histologically demonstrable endometriosis was present in any patient during the second-look laparoscopy. ASRM and pelvic pain scores decreased significantly in response to treatment. Overall, no significant change in bone density was detected. Gonadotropin levels were not significantly altered by treatment, and although circulating E(2) and E(1) levels were reduced, the decrease was not statistically significant. CONCLUSION(S): The combination of letrozole and norethindrone acetate achieved marked reduction of laparoscopically visible and histologically confirmed endometriosis in all 10 patients and significant pain relief in nine out of 10 patients who had not responded previously to currently available treatments. On this basis, letrozole should be a candidate for the medical management of endometriosis.

Adult↗
PubMed1999

A comparative study of two contraceptive vaginal rings releasing norethindrone acetate and differing doses of ethinyl estradiol.

Two combined contraceptive vaginal rings (CVR) each releasing approximately 1 mg norethindrone acetate (NET-Ac) and either 20 micrograms or 15 micrograms ethinyl estradiol over 24 h were tested at three clinic sites in Los Angeles, San Francisco, and Sydney. A total of 61 women were enrolled to use the ring on a schedule of 3 weeks in/1 week out for four treatment cycles. Serum estradiol, progesterone, norethindrone (NET), and ethinyl estradiol (EE) levels were assayed twice weekly in all four treatment cycles. Both CVR performed well, with no pregnancies occurring and only one cycle of luteal activity suggestive of ovulation (serum progesterone > 32 nmol/L) occurring with each ring (0.9% of cycles with the 1/15 ring and 1.2% of cycles with the 1/20 ring). Although there was significantly more luteal activity in women using the 1/15 CVR (5.9% compared with 1.2% of cycles), only three cycles with a marked degree of luteal activity (progesterone > 10 nmol/L) occurred among compliant women. Serum levels of NET and EE were consistently elevated during use of both rings. There was no significant difference between serum levels with the two rings because of wide interindividual variations, although both NET and EE levels tended to be higher with the 1/20 ring. However, there was a significant difference in EE levels between the women in Los Angeles and Sydney using the same dose rings. Total cholesterol, HDL, and LDL cholesterol values were not significantly changed during treatment. Triglycerides increased but remained within the normal range. Overall cycle control was good with both formulations, but there was slightly more cycle disturbance with the lower dose ring. There was no change in mean body weight during the study, and individual weight changes appeared to be idiosyncratic. Side effects were infrequent and similar to those reported with other steroidal contraceptive methods. Three women complained of vaginal discharge, one with accompanying itch and one with a vaginal Candida infection in cycle 1. Overall, both of these EE/NET-Ac rings performed well, with only minor and mainly nonsignificant differences in effect on serum EE, NET, E2, and progesterone levels and lipids, and on vaginal bleeding patterns.

Adolescent↗
PubMed2001

Differential effects on the androgen status of postmenopausal women treated with tibolone and continuous combined estradiol and norethindrone acetate replacement therapy.

OBJECTIVE: To determine serum parameters reflective of androgen status in postmenopausal women using two types of hormone replacement therapy (HRT). DESIGN: Randomized, double-blind, prospective 1-year trial of two oral HRT regimens. SETTING: University hospital, department of obstetrics and gynecology, menopause clinic. PATIENT(S): 100 postmenopausal women > or = 45 years. INTERVENTION(S): Daily use of the progestogen tibolone (2.5 mg; n = 50) or continuous combined 17-beta-estradiol (2 mg) and norethindrone acetate (E+NA, 1 mg; n = 50). MAIN OUTCOME MEASURE(S): Measurements of total testosterone (total T), dehydroepiandrosterone sulfate (DHEAS), androstenedione (A), FSH, and sex-hormone-binding globulin (SHBG), and calculations of free testosterone (free T). Assessment of changes from baseline within and between groups after 6 and 12 months. RESULT(S): We found significant differences (% changes) in the tibolone group compared to baseline within the groups after both 6 and 12 months, respectively. Levels of free T doubled, total T decreased slightly, and SHBG decreased by half; DHEAS increased by approximately 20%; and FSH decreased. In the E+NA group, levels of free T, total T, androstenedione, and FSH all decreased, and SHBG increased. Pre-trial levels of DHEAS, A, and total T were significantly higher in the E+NA group. Between groups throughout the study, the changes from baseline were significant due to the different extent of FSH reduction, and opposite changes of free T, SHBG, and DHEAS. CONCLUSION(S): Both regimens modify plasma androgens, DHEAS, and SHBG differently. Tibolone decreased the levels of SHBG, and substantially increased free T and to a lesser extent increased DHEAS; this may reflect a modification of adrenal androgen production. Continuous combined estradiol and norethindrone acetate HRT suppressed the peripheral plasma androgens mediated by increased levels of SHBG.

Androgens↗
PubMed1990

The optimal dose of oral norethindrone acetate for addition to transdermal estradiol: a multicenter study.

The effects of adding one of three doses (0.5, 0.75, or 1.0 mg/d) of norethindrone acetate for 12 days each month to continuous, transdermal estradiol (0.05 mg/d) have been determined in a prospective, randomized, multicenter study. Significant symptomatic and psychological improvements were observed and, with one exception, were not opposed by the added progestogen. Distinct redness at the site of last patch application was reported by 10% of patients and faint erythema by 30%. However, less than 5% of patients discontinued treatment because of skin problems. Breakthrough bleeding occurred infrequently and all three doses of norethindrone acetate induced a regular pattern of bleeding with secretory transformation in the endometrium. There was no hyperplasia or carcinoma.

Administration, Cutaneous↗
PubMed2000

Visualization of percutaneous 3H-estradiol and 3H-norethindrone acetate transport across human epidermis as a function of time.

Developing transdermal therapeutic systems for estradiol and norethindrone acetate raised questions about the steroids penetration pathway across and retention in the skin. This paper describes the distribution of 3H-estradiol and 3H-norethindrone acetate in human stratum corneum after topical application to dermatomed skin in vitro. The study involved (a) permeation experiments to determine the steroid flux, (b) autoradiographical visualization of the steroid distribution in the same skin samples, and (c) a correlation between flux and skin distribution in time. On correlating the steroid flux with intraepidermal steroid distribution, it was concluded that both permeants were bound in the skin tissue. The steroids were preferentially located in or close to the intercellular lipids of the stratum corneum, indicating that both transport and binding occurred via this domain of the stratum corneum. This study demonstrated the importance of correlating drug flux with intraepidermal drug distribution as a function of time.

Administration, Cutaneous↗
PubMed1983

Aromatization of norethindrone to ethinyl estradiol by human placental microsomes.

The interaction of 19-norethindrone [4-estren-17 alpha-ethinyl-17 beta-ol,3-one (NET)] with human placental microsomes was investigated using enzymatic and spectral techniques. The incubation of [6,7-3H]norethindrone with human placental microsomes, NADPH, and molecular oxygen resulted in the production of ethinyl estradiol [1,3,5-(10)estratrien-17 alpha-ethinyl-3,17 beta-diol (EE)]. The reaction was linear with respect to time and protein concentration. Androstenedione inhibited the enzymatic aromatization of NET to EE. The product was identified by thin layer chromatography, recrystallization to constant specific activity, and derivative formation. No acid or base was used in any step of product identification. To ensure that spontaneous aromatization of metabolites of NET did not contribute to our results, representative samples were treated with sodium borohydride before processing. Sodium borohydride reduces the 4-en-3-one grouping of the A-ring, thereby preventing chemical aromatization. Sodium borohydride treatment did not reduce our observed yields of EE from NET. The addition of NET to a preparation of solubilized, partially purified placental microsomal cytochrome P-450 yielded a type I cytochrome P-450 binding spectrum. The apparent spectral dissociation constant for NET binding to cytochrome P-450 was 28 microM. These results suggest that NET is enzymatically aromatized to EE by human placental microsomes.

Borohydrides↗
PubMed1963

The use of norethindrone (2 Mg.) with mestranol (0.1 Mg.) in fertility control; a preliminary report.

Norethindrone 2 mg. with mestranol 0.1 mg. (Ortho-Novum 2 mg.) was taken in cyclic fashion for fertility control by 62 private patients through 312 cycles. Each patient was interviewed every month during the trial period. No pregnancies occurred. The most common side effects noted were breakthrough bleeding, headache, fatigue and tension, nausea and depression. Five patients left the study because of depression and one because of nausea. It is suggested that the use of norethindrone 2 mg. with mestranol 0.1 mg. be reserved for the following situations: (1) those patients who have used other methods without success and in whom a further pregnancy would, in the opinion of the family physician, create hardship; (2) those patients in whom fear of pregnancy is part of the cause of marital problems; and (3) those patients in whom the product is primarily used for the treatment of menstrual disorders.

Contraception↗
PubMed1981

Simple high-performance liquid chromatographic assay for norethindrone--mestranol in combination tablets.

A simple, sensitive, and specific high-performance liquid chromatographic procedure was developed to assay norethindrone--mestranol combination tablets. The method involves a chloroform extraction of a single pulverized tablet. After centrifugation, and aliquot of the supernate was injected into a modular high-performance liquid chromatograph. The effluent from the silica column was monitored serially with a fixed-wavelength UV detector (254 nm) for norethindrone quantitation and a fluorescence detector (230 nm for excitation and 280 nm cutoff filter for emission) for mestranol quantitation. Progesterone was used as an internal standard. The method was employed successfully in content uniformity studies of several brands of commercially available tablets.

Chromatography, High Pressure Liquid↗
PubMed1994

Modification of the U.S.P. dissolution method for the analysis of norethindrone and ethinyl estradiol tablets.

A modification of the U.S.P. dissolution method for the quantitation of norethindrone and ethinyl estradiol tablets is proposed. This modification consists of the use of distilled water as the dissolution medium instead of 0.1 N hydrochloric acid (HCl) and/or neutralization of 0.1 N HCl with sodium carbonate prior to analysis. Statistical analysis of the results indicate that there are no significant differences between the dissolution in 0.1 N HCl and the dissolution in distilled water (p < 0.05) for norethindrone and ethinyl estradiol.

Chromatography, High Pressure Liquid↗