Administration Of Norethindrone Research Articles

Comparing cervical mucus changes in response to an oral progestin or oestrogen withdrawal in ovarian-suppressed women: a clinical pilot

Purpose: Prior studies evaluating the effect of administered progestogens on peak cervical mucus have not controlled for the influence of endogenous hormones. To address this, we treated women with a gonadotropin-releasing hormone (GnRH) agonist to suppress the hypothalamus–pituitary–ovarian (HPO) axis and used transdermal oestradiol replacement to stimulate peak cervical mucus and then evaluated the effects of an oral progestin or oestradiol withdrawal. Materials and methods: We used a crossover design to examine cervical mucus changes in women receiving transdermal oestradiol replacement following intramuscular administration of leuprolide acetate. After increasing oestradiol patches to mid-cycle levels, subjects were assigned to either 0.35 mg oral norethindrone with continuation of the patches (NET) or oestradiol withdrawal by patch removal (E2WD). We collected serum and cervical mucus samples at 0, 2, 4, 6, 22 and 24 h following the intervention. Results: We analysed 12 cycles (6 NET, 6 E2WD) from three subjects. Baseline cervical mucus scores were favourable to sperm penetration [NET median 11, interquartile range (9–12), E2WD 13 (12–13)]. Two hours after removal of oestradiol patch or administration of norethindrone, cervical mucus scores declined [NET 8.5 (4–9), E2WD 10.5 (10–12)]. Low cervical mucus scores persisted at 24 h with NET [8.0 (7–8)] but not E2WD [10.5 (8–11)]. Conclusions: We observed a rapid decline in cervical mucus Insler scores following administration of a single dose of oral norethindrone, and scores remained lower and unfavourable through 24 h. Oestradiol withdrawal did not result in similar unfavourable changes.

Pharmacokinetic Interaction between Ethinyl Estradiol, Norethindrone and Darunavir with Low-Dose Ritonavir in Healthy Women

An open-label, randomized, crossover study was performed to investigate the effect of multiple doses of darunavir co-administered with low-dose ritonavir (DRV/r) on the steady-state pharmacokinetics of the oral contraceptives ethinyl estradiol (EE) and norethindrone (NE) (commercial name of the combined drug Ortho-Novum 1/35) in 19 HIV-negative healthy women. In session 1, participants received 35 microg EE and 1.0 mg NE from days 1 to 21. In session 2, participants received the same oral contraceptive treatment as in session 1 on days 1 to 21 plus DRV/r (600 mg/100 mg twice daily) on days 1 to 14. Pharmacokinetic assessments were performed on day 14 for each session. Steady-state systemic exposure to EE and NE decreased when DRV/r was co-administered, based on the ratio of least square means of the minimum plasma concentration (Cmin), the maximum plasma concentration (Cmax), and the area under the curve (AUC24h) of EE (which decreased by 62%, 32% and 44%, respectively) and NE (which decreased by 30%, 10% and 14%, respectively) compared with administration of EE and NE alone. Five participants discontinued the study due to grade 2 cutaneous events, as required per protocol, during treatment with EE and NE in combination with DRV/r. There were no clinically relevant findings for laboratory and cardiovascular parameters. The pharmacokinetic interaction observed here is considered to be clinically relevant as EE concentrations are considerably reduced when DRV/r is co-administered with EE and NE. Alternative or additional contraceptive measures should be used when oestrogen-based contraceptives are co-administered with DRV/r.

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.

The hormonal regulation of platelet-activating factor-acetylhydrolase in the rat.

Platelet-activating factor-acetylhydrolase (PAF-AH), the enzyme that inactivates PAF, is decreased in the plasma of both rabbits and humans during the latter stages of pregnancy. The activity of the enzyme was decreased in rats by the administration of 1,3,5(10)-estratrien-17 alpha-ethynyl-3,17 beta-diol (17 alpha-ethynylestradiol) and increased by dexamethasone treatment. In the present study, we have further defined the hormonal regulation of PAF-AH levels in plasma of adult and juvenile rats. Estrone (E1), 17 beta-estradiol (E2), estriol (E3), and various progestins [4-pregnen-6 alpha-methyl-17 alpha-ol-3,20-dione (medroxyprogesterone), 4-estren-17 alpha-ethynyl-17 beta-ol-3-one (norethindrone), and 5(10)-estren-17 alpha-ethynyl-17 beta-ol-3-one (norethynodrel)] were administered to adult rats, and the plasma PAF-AH activities were assayed. E1, E2, and E3 administration to adult female rats lowered the plasma PAF-AH activity, E3 being the most effective. After administration of these estrogens the activity returned to the preinjection level within 4 days. The administration of medroxyprogesterone resulted in a 2-fold increase in plasma PAF-AH activity in adult female rats, and the activity remained elevated for up to 30 days. When adult male rats were treated with similar doses only a 20% increase was observed and the PAF-AH activity returned to control values by day 10. In contrast, norethindrone and norethynodrel administration resulted in a reduction of the enzyme activity in adult female rats. The plasma PAF-AH activity in juvenile male and female rats (3 weeks of age, 45-60 g body wt) was two times higher than that in adult rats of both sexes and spontaneously decreased up to the time of puberty. When juvenile male or female rats were injected with either 17 alpha-ethynylestradiol or medroxyprogesterone, a minimal change in PAF-AH activity was observed. In contrast, when dexamethasone was administered to juvenile male and female rats the plasma PAF-AH activity increased in a manner similar to adult animals. It is suggested that estrogens cause a decrease and medroxyprogesterone an increase in plasma PAF-AH activity. It is suggested that the different responsiveness to medroxyprogesterone between adult female and male rats and juvenile animals may depend on the concentration of the hormone receptor in the tissue responsible for the synthesis of PAF-AH. The decrease in PAF-AH activity after the administration of norethindrone and norethynodrel may be due to the known estrogenic activity of these steroids.

Improved Delivery Through Biological Membranes. XXIV. Synthesis, in Vitro Studies, and in Vivo Characterization of Brain-Specific and Sustained Progestin Delivery Systems.

Dihydropyridine ⇄ pyridinium salt-based brain-selective delivery systems were synthesized for the progestins, ethisterone, norethindrone, and norgestrel. After initial lipophilicity and in vitro studies indicated the feasibility of applying these compounds to brain-specific delivery, in vivo distribution studies were performed on one of the redox delivery systems. After systemic administration of the chemical delivery system based on norethindrone, sustained and selective delivery of the oxidized form of the drug-carrier complex was observed in the brain. In addition, a slow and sustained release of the parent steroid, norethindrone, occurred. This release produced substantially higher levels of norethindrone for more prolonged periods than the administration of norethindrone itself.

Species differences in the hepatic formation of green pigments following the administration of norethindrone

Metabolic activation of the ethynyl substituent of the contraceptive steroid norethindrone to cause the loss of hepatic cytochrome P-450 and the formation of green pigments has been compared in vivo and in vitro in rat, hamster, guinea pig, rabbit, mouse and hen and with marmoset and human liver microsomal preparations in vitro. In vivo green pigment accumulation in the liver 4hr after the administration of norethindrone (100 mg/kg, i.p.) varied 60-fold between species. Male rat was the most active in this respect, the hen was the least active. The accumulation of green pigments in female rats was 27% that of male animals. This sex-dependent difference was not seen in male and female mice. Cytochrome P-450 destruction in vivo was also greatest in the male rat given norethindrone, whereas no loss was detected in the hen. In other species, however, the correlation between green pigment accumulation and cytochrome P-450 destruction was not particularly good. When liver microsomes were incubated with norethindrone and an NADPH generating system in vitro, the ranking order between species with respect to the initial rates of green pigment formation was similar to that based on the hepatic accumulation of these compounds found in vivo. Human liver microsomes showed initial rates of green pigment formation which were only 2% of that seen in the male rat. No destruction of human microsomal cytochrome P-450 caused by norethindrone could be detected. The HPLC elution profile of the green pigments produced in the liver following the administration of norethindrone differed between species. Hepatic microsomal preparations in contrast, at least with short incubation times, formed only one green pigment. Results suggest that further metabolism of either norethindrone or the green pigment, involving a cytosolic factor(s), results in the varied HPLC patterns seen in vivo.

Pharmacokinetics of norethindrone and lynestrenol studied by HPLC (author's transl)

The concentration of norethindrone in plasma samples from subjects receiving norethindrone (norethisterone) and lynestrenol orally was measured by high pressure liquid chromatography (HPLC). Norethindrone is a synthetic gestagen widely used in contraceptive formulations, and lynestrenol is also a synthetic gestagen which is metabolized to norethindrone in humans. But the evaluation of plasma norethindrone levels in subjects receiving lynestrenol has not yet been reported. After the administration of norethindrone, the peak level of norethindrone in the plasma was obtained within 2h, and the peak concentration in the plasma was about 3.5 ng/ml/mg norethindrone. During a period of 2-6hs after the administration of norethindrone, the half life of norethindrone in the plasma was approximately 1.8h, and during the period of 6-24hs, half life was variable. On the other hand, after the administration of lynestrenol, the peak level of norethindrone in the plasma was obtained within 4h, and the peak concentration of norethindrone was about 1.9 ng/ml/mg lynestrenol. During a period of 4-12hs, the half life of norethindrone was about 2.5h. The peak of the norethindrone level after the administration of lynestrenol was lower and appeared later than that after the administration of the same dose of norethindrone. Norethindrone in plasma in subjects receiving lynestrenol could be measured for a longer period than in those receiving the same dose of norethindrone. These results suggest that lynestrenol is stored in fat tissue and is slowly metabolized to norethindrone.

Response of the binding capacity of plasma testosterone-estradiol-binding globulin to norethindrone, 2 mg., and mestranol, 0.1 mg., in polycystic ovarian disease

The binding capacity of plasma testosterone-estradiol-binding globulin (TeBG) and testosterone (T) levels were measured in four women with proved polycystic ovaries and three women with a clinical diagnosis of polycystic ovarian disease before, during, and after administration of norethindrone, 2 mg., and mestranol, 0.1 mg. (N + M). TeBG was increased within four days after N + M treatment was begun. Mean TeBG was significantly elevated (P < 0.05) and mean T was significantly suppressed (p < 0.05) relative to pretreatment levels by 9 to 12 days after N + M treatment was started. Both TeBG and T remained significantly different from pretreatment levels during the posttreatment period of 12 days' duration. Although the dynamics of TeBG changes were different in two of the seven women, all seven women responded to N + M with a decrease in both total and free T.

DYNAMICS OF SUPPRESSION AND RECOVERY OF PLASMA FSH, LH, ANDROSTENEDIONE AND TESTOSTERONE IN POLYCYSTIC OVARIAN DISEASE USING AN ORAL CONTRACEPTIVE

ABSTRACT Four women with proven and 3 with probable polycystic ovaries (PCO) had plasma FSH, LH, androstenedione (A) and testosterone (T) measured by radioimmunoassay before and during the administration of norethindrone 2 mg–mestranol 0.1 mg (Ortho-Novum 2 mg) daily for 17–21 days to determine how long a progestin–estrogen preparation should be given to evaluate the degree of suppressibility of elevated peripheral plasma concentrations of A and T in women with PCO. The pattern of recovery of these hormones was also studied. Pretreatment means ± se were: FSH 6.4 ± 1.2 mIU/ml, LH 21 ± 3 mIU/ml, A 515 ± 24 ng/100 ml, T 93 ± 17 ng/100 ml. The mean of each hormone decreased progressively from days 5–8 to days 13–16 of treatment. The mean of each hormone at the 13–16-day treatment period was: FSH 2.7 ± 1.2 mIU/ml, LH 6.7 (5–8) mIU/ml, A 216 ± 21 ng/100 ml and T 33 ± 3 ng/100 ml. Suppression and recovery of A and T were significantly correlated with LH. FSH began recovery before LH, A or T and was not significa...

Dynamics of suppression and recovery of plasma FSH, LH, androstenedione and testosterone in polycystic ovarian disease using an oral contraceptive.

ABSTRACT Four women with proven and 3 with probable polycystic ovaries (PCO) had plasma FSH, LH, androstenedione (A) and testosterone (T) measured by radioimmunoassay before and during the administration of norethindrone 2 mg–mestranol 0.1 mg (Ortho-Novum 2 mg) daily for 17–21 days to determine how long a progestin–estrogen preparation should be given to evaluate the degree of suppressibility of elevated peripheral plasma concentrations of A and T in women with PCO. The pattern of recovery of these hormones was also studied. Pretreatment means ± se were: FSH 6.4 ± 1.2 mIU/ml, LH 21 ± 3 mIU/ml, A 515 ± 24 ng/100 ml, T 93 ± 17 ng/100 ml. The mean of each hormone decreased progressively from days 5–8 to days 13–16 of treatment. The mean of each hormone at the 13–16-day treatment period was: FSH 2.7 ± 1.2 mIU/ml, LH 6.7 (5–8) mIU/ml, A 216 ± 21 ng/100 ml and T 33 ± 3 ng/100 ml. Suppression and recovery of A and T were significantly correlated with LH. FSH began recovery before LH, A or T and was not significa...

The effects of pretreatment of mice with norethindrone on the metabolism of 14C-imipramine by the liver microsomal drug-metabolizing enzymes.

An assay procedure for the metabolism of 14C-imipramine in vitro is described. Using female mouse liver as the enzyme source, the conditions of the assay have been determined for the formation of 2-hydroxyimipramine, desmethylimipramine, and imipramine-N-oxide. Demethylation was linear up to a substrate concentration of 120 μg/3.5 ml, N-oxidation was linear up to a concentration of imipramine of 70 μg/3.5 ml, and hydroxylation up to 20 μg/3.5 ml of reaction mixture. Desmethylimipramine competitively inhibited both hydroxylation and demethylation, whereas imipramine-N-oxide had no effect. Pretreatment of mice with norethindrone decreased hydroxylation, and increased demethylation. Cytochrome P-450 was also increased by this progestin; N-oxidation was not changed. The effects of concurrent administration of norethindrone with known inducers or inhibitors of drug metabolism have been determined. From these experiments, it was concluded that the induction of cytochrome P-450 by norethindrone is not responsible for the increased demethylation of imipramine. Rather, it appeared that competitive inhibition of hydroxylation of imipramine by the norethindrone allowed more of the drug to be demethylated.

Effect of norethindrone on submandibular glands and dental caries in female rats.

The effect of prolonged administration of norethindrone on the growth and development of submandibular glands and on the incidence of dental caries in rats was studied. Weanling female Sprague-Dawley strain rats were divided randomly into groups and were given daily subcutaneous injections of 30 60 or 90 mcg of norethindrone in .1 ml of steroid diluent for 9 or 14 weeks. Norethindrone in different dose levels caused in general a slight increase in wet weight and a significant increase in the diameter and relative number of granular tubules and in the sizes of acinar cells of submandibular glands. No significant changes in parotid gland weight were observed. Norethindrone in different dose levels caused an increase in the incidence of carious lesions but no differences in severity of carious lesions were observed between norethindrone treated groups of rats and their controls.

Decreased uterotropic potency of oral contraceptives in rats pretreated with phenobarbital.

Treatment of immature female rats with phenobarbital for 4 days inhibits the uterotropic action of synthetic estrogens such as ethynyl estradiol, ethynyl estradiol-3-methyl ether (mestranol) and diethylstilbestrol. Treatment of rats with as little as 0.25 mg of phenobarbital/kg twice daily for 4 days causes a 33% inhibition in the uterotropic action of a 1 μg oral dose of ethynyl estradiol-3-methyl ether. The inhibitory effect of phenobarbital administration on the action of diethylstilbestrol-3H is paralleled by decreased radioactivity in the uterus and by increased levels of NADPH-dependent enzymes in liver microsomes that metabolize diethyl-stilbestrol. Studies on the estrogenic activity of synthetic progestational steroids in rats revealed that the administration of norethindrone and norethynodrel increases the uterine wet weight and this effect is inhibited by pretreatment with phenobarbital. (Endocrinology 83: 149, 1968)