Pharmacokinetics of norethindrone oenanthate in 5 women after a single dose of norethindrone oenanthate and estradiol valerate.
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Adult↗
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[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.
Administration, Oral↗
Chemical reactivity and metabolism of norethindrone-4 beta,5 beta-epoxide by rat liver microsomes in vitro.
A method has been developed to separate norethindrone and norethindrone-4 beta,5 beta-epoxide by high performance liquid chromatography using isocratic solvent systems with either ODS-reverse phase or conventional silica gel columns. Using these techniques it was found that norethindrone epoxide, prepared chemically, was stable in aqueous buffer (pH 7.4) at 37 degrees C for at least 1 h. Under similar conditions, in the presence of a 10-fold molar excess of cysteine or glutathione, the half life for norethindrone epoxide was 15 and 32 min respectively. In 0.01 M perchloric acid at 37 degrees C the t 1/2 of norethindrone epoxide was 17 min. Norethindrone epoxide was rapidly degraded by rat liver microsomal epoxide hydratase to give a metabolite having properties consistant with it being norethindrone-4,5-dihydrodiol. Epoxide hydratase activities were stimulated about three fold by pretreating rats with phenobarbitone. The pH optimum for this reaction was pH 7.4. Conversion of norethindrone epoxide to norethindrone-dihydrodiol was inhibited by the epoxide hydratase inhibitor 1,2-epoxytrichloropropane. Although norethindrone was extensively metabolised in the presence of NADPH and rat liver microsomes, no conversion to norethindrone-4 beta,5 beta-epoxide could be demonstrated, either in the presence or absence of epoxytrichloropropane in the reaction mixture. If norethindrone epoxide was produced under these conditions it was suggested that it either reacted with microsomal proteins at or close to the site or production or was further metabolised. Norethindrone-4 beta,5 beta-epoxide did not cause any loss of cytochrome P-450 when incubated with rat liver microsomes in the absence of NADPH. Only in the presence of NADPH did further metabolism of norethindrone epoxide occur leading to the formation of active metabolites capable of breaking down cytochrome P-450. The initial rate of loss of cytochrome P-450 under these conditions was greater with norethindrone than with norethindrone epoxide as the substrate.
Animals↗
Vaginal bleeding in postmenopausal women taking low-dose norethindrone acetate and ethinyl estradiol combinations. The FemHRT Study Investigators.
OBJECTIVE: To determine the effect of continuous combined treatment with norethindrone acetate and ethinyl estradiol (E2) on vaginal bleeding, spotting, or bleeding and/or spotting in postmenopausal women. METHODS: Two randomized clinical trials were conducted in which participants recorded information on the daily occurrence of vaginal bleeding or spotting. In study 1, 219 postmenopausal women reporting at least ten hot flushes per week were randomized to placebo or one of four treatment groups (0.2 mg norethindrone acetate/1 microg ethinyl E2, 0.5 mg norethindrone acetate/2.5 microg ethinyl E2, 1 mg norethindrone acetate/5 microg ethinyl E2, or 1 mg norethindrone acetate/10 microg ethinyl E2). In study 2, 266 postmenopausal women reporting at least 56 moderate to severe hot flushes were randomized to placebo or one of three treatment groups (0.5 mg norethindrone acetate/2.5 microg ethinyl E2, 1 mg norethindrone acetate/5 microg ethinyl E2, or 1 mg norethindrone acetate/10 microg ethinyl E2). The total duration of treatment was 16 weeks in study 1 and 12 weeks in study 2. In both studies, subjects reported in daily diaries whether they had either bleeding or spotting. RESULTS: In study 1, there was a significantly greater relative risk (RR) for bleeding in the group receiving 1 mg norethindrone acetate/10 microg ethinyl E2 at study weeks 4 and 8 (RR = 1.36 and 95% confidence interval [CI] 1.01, 1.83; RR = 1.37 and 95% CI 1.1, 1.72; respectively) compared with placebo, but not at study weeks 12 or 16. The group receiving 1 mg norethindrone acetate/5 microg ethinyl E2 also had a significantly greater risk at weeks 4 and 8 (RR = 1.5 and 95% CI 1.15, 1.96; RR = 1.33 and 95% CI 1.00, 1.77; respectively), whereas the other dose combinations did not differ from placebo. Results from study 2 were similar to those of study 1. CONCLUSION: Although there was a greater risk for bleeding and/or spotting at the higher doses of norethindrone acetate and ethinyl E2, this risk declined over time. If compliance with hormone replacement therapy regimens is influenced at least in part by vaginal bleeding, the combined norethindrone acetate/ethinyl E2 regimen investigated in these studies may provide a treatment option.
Adult↗
A comparative study of danazol, a regimen of decreasing doses of danazol, and norethindrone in the treatment of objectively proven unexplained menorrhagia.
OBJECTIVE: Our purpose was to compare the efficacy of the recommended dose of danazol, a reduced-dose danazol regimen, and norethindrone in the treatment of objectively proven menorrhagia. Recurrence after discontinuing treatment was also assessed. STUDY DESIGN: The study was a single-blind, randomized, parallel, comparative study. After a placebo run-in period over two menstrual cycles, 57 patients with a baseline mean menstrual blood loss of at least 80 ml per cycle were randomly assigned to receive one of three therapies: danazol, 200 mg/day (n = 19) for three menstrual cycles; danazol, 200 mg/day for one cycle, 100 mg/day for one cycle, and 50 mg/day for one cycle (n = 19); and norethindrone, 5 mg three times daily on days 19 through 26 of the cycle for three consecutive cycles (n = 19). Patients in whom treatment was successful (those experiencing blood loss < 80 ml) were entered in the follow-up phase of the study, receiving placebo for a maximum of four menstrual cycles. RESULTS: The final menstrual blood loss on treatment was significantly less for those patients who received both danazol regimens compared with those who received norethindrone (p = 0.017 for reducing dose danazol vs norethindrone and p = 0.043 for 200 mg of danazol vs norethindrone). Both danazol treatment regimens were significantly more successful in reducing menstrual blood loss to within the normal range than was norethindrone. The reducing-dose danazol regimen was successful in eight of 17 patients (p = 0.027), and 200 mg of danazol was successful in nine of 19 patients (p = 0.029), compared with the two successes of 18 patients treated with norethindrone. Significantly more recipients of 200 mg of danazol than of norethindrone subjectively rated their treatment to be moderately or highly effective (p = 0.033). Both danazol treatment regimens were associated with a higher incidence of adverse events than was norethindrone therapy, although the number of withdrawals were similar and infrequent in the three groups. CONCLUSIONS: Both danazol regimens were significantly more effective than norethindrone in reducing the excessive menstrual blood loss of women with unexplained menorrhagia. A subjective assessment by patients found that only the 200 mg of danazol was judged to be significantly more effective than norethindrone in controlling the heaviness of menstrual bleeding. The reduced-dose danazol regimen did not appear to markedly diminish the incidence of adverse events compared with the 200 mg of danazol regimen.
Adult↗
In vivo and in vitro action of norethindrone on staphylococci.
Norethindrone has been examined in vitro for antibacterial activity against 10 microorganisms. Turbidimetric techniques were used to assay the antibacterial activity of norethindrone. The organisms tested included Staphylococcus aureus, S. epidermidis, Micrococcus conglomeratus, Listeria monocytogenes, Streptococcus faecalis, Salmonella typhosa, Shigella flexnerii, Klebsiella pneumoniae, Escherichia coli, and Proteus vulgaris. Bacteriostatic action was shown only against the gram-positive microorganisms when they were grown anaerobically in Tryptic Soy Broth containing 10 to 50 mug of norethindrone per ml. The bacteriostatic action of norethindrone was exerted primarily during the first 8 hr of incubation and it was reduced by the presence of oxygen. Mestranol at a concentration of 1 to 10 mug/ml failed to exert any significant action on S. aureus. However, incorporation of 5 mug of mestranol per ml in the culture medium enhanced the bacteriostatic action of norethindrone on staphylococci. Enhancement of the bacteriostatic action of norethindrone could not be obtained by the addition of a concentration of 5 mug/ml of testosterone, 17alpha-estradiol, and 17beta-estradiol. Progesterone and 4-pregnen-20beta-ol-3-one under similar conditions showed an additive bacteriostatic effect when they were incorporated into the culture medium containing norethindrone. In vivo studies indicated that female, adult New Zealand rabbits, injected subcutaneously with two injections of 10 to 20 mug of norethindrone, 24 hr apart, and challenged intradermally with S. aureus 4 hr after the second injection, had fewer lesions with smaller areas of swelling and erythema as compared to control, nontreated rabbits. The protective effect of norethindrone on the development of staphylococcal lesion seemed related to hormone concentration. Thus, it was demonstrated with doses of 20, 15, and 10 mug, but not with doses of 1 and 5 mug. When the lesions were excised 48 to 92 hr after infection and when viable cell counts were made, rabbits treated with norethindrone showed significantly lower staphylococcal counts than the control rabbits. During the 1st day after infection with S. aureus, leukocytic counts of the norethindrone-treated rabbits remained normal, whereas control animals showed elevated leukocytic counts.
Animals↗
Growth stimulation and differential regulation of transforming growth factor-beta 1 (TGF beta 1), TGF beta 2, and TGF beta 3 messenger RNA levels by norethindrone in MCF-7 human breast cancer cells.
Transforming growth factor-beta (TGF beta) is a potent growth inhibitor in most epithelial cells. We evaluated the effects of norethindrone (which in combination with estrogen is commonly used in oral contraceptives) and other progestins [medioxyprogesterone acetate (MPA) and R5020, which are not used in oral contraceptives] on cell growth and the expression of TGF beta 1, TGF beta 2, and TGF beta 3 mRNAs in MCF-7 human breast cancer cells. Growth of MCF-7 cells was stimulated by norethindrone (10(-8)-10(-5) M), with maximal growth stimulation at 10(-7) M norethindrone after 7 days of treatment. However, the growth of MCF-7 cells was not affected by MPA (10(-8) M) or R5020 (10(-8) M). Treatment with the antiestrogen 4-hydroxytamoxifen at a concentration of 10(-7) M blocked the growth stimulation induced by norethindrone. The norethindrone-induced growth stimulation was accompanied by a dramatic decrease in TGF beta 2 and TGF beta 3 mRNA levels, whereas the level of TGF beta 1 mRNA was not affected by any of the compounds tested. In addition, treatment with MPA or R5020 did not affect TGF beta 2 and TGF beta 3 mRNA levels. The inhibitory effect of norethindrone on TGF beta 2 and TGF beta 3 mRNA levels could be blocked by the addition of 10(-7) M 4-hydroxytamoxifen. Norethindrone as well as estradiol decreased estrogen receptor mRNA levels and increased progesterone receptor mRNA levels. This is the first report which demonstrates that norethindrone stimulates estrogen-responsive human breast cancer cell growth and inhibits the expression of TGF beta 2 and TGF beta 3 mRNAs. These results suggest that the differential regulation of TGF beta expression by norethindrone may be at least partly responsible for the growth stimulation induced by norethindrone. Thus, the norethindrone component of some oral contraceptives may be sufficiently estrogenic to facilitate the development of breast cancer.
Breast Neoplasms↗
A randomized, double-blind, placebo-controlled, multicenter study that assessed the endometrial effects of norethindrone acetate plus ethinyl estradiol versus ethinyl estradiol alone.
OBJECTIVE: The purpose of this study was to determine the incidence of endometrial hyperplasia in subjects who receive continuous norethindrone acetate and ethinyl estradiol combinations versus unopposed ethinyl estradiol. STUDY DESIGN: Nine hundred forty-five postmenopausal women were randomly selected for 12 months of treatment with one of six blinded norethindrone acetate/ethinyl estradiol combinations (milligrams of norethindrone acetate/micrograms of ethinyl estradiol: 0/5, 0.25/5, 1/5, 0/10, 0.5/10, or 1/10) or to open-label 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate. Endometrial hyperplasia and endometrial proliferation were assessed by biopsy at screening, months 6 and 12. RESULTS: Endometrial hyperplasia developed in 26 subjects: Placebo, 0/5 and 0.25/5 (1 subject each) and 0/10 (23 subjects). Significantly less endometrial proliferation was measured in the 1/5 norethindrone acetate/ethinyl estradiol and other norethindrone acetate/ethinyl estradiol combination groups and in the 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate group, than in unopposed ethinyl estradiol groups (6 months: P <.004; 12 months: P <.001). Treatment with 1/5 norethindrone acetate/ethinyl estradiol and with other norethindrone acetate/ethinyl estradiol combinations significantly reduced endometrial proliferation compared with 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate (6 and 12 months: P <.02). CONCLUSION: Norethindrone acetate protects the endometrium from estrogen-induced hyperplasia and changes in proliferative status. In addition, norethindrone acetate/ethinyl estradiol-treated subjects had significantly less endometrial proliferation compared with 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate-treated subjects.
Double-Blind Method↗
Decreased liver cytochrome P-450 in rats caused by norethindrone or ethynyloestradiol.
1. 19-Nor-17alpha-pregna-1,3,5(10)-trien-20-yne-3,17-diol (ethynyloestradiol) or 17beta-hydroxy-19-nor-17alpha-pregn-4-en-20-yn-3-one (norethindrone) but not 17alpha-ethyl-17beta-hydroxy-19-norandrost-4-en-3-one (norethandrolone) caused a time-dependent loss of cytochrome P-450 when incubated in vitro with rat liver microsomal fractions and NADPH-generating systems. 2. The enzyme system catalysing the norethindrone-mediated loss of cytochrome P-450 had many characteristics of the microsomal mixed-function oxidases. It required NADPH and air, and was inhibited by Co. However, it was unaffected by 1 mM-compound SKF 525A. 3. In microsomal fractions from phenobarbitone-pretreated rats the norethindrone-mediated loss of cytochrome P-450 was increased relative to controls. The norethindrone-mediated cytochrome P-450 loss was less pronounced when the animals were pretreated with 3beta-hydroxy-pregn-5-en-2-one 16alpha-carbonitrile (pregnenolone 16alpha-carbonitrile). Pretreatment with 3-methylcholanthrene rendered the animals resistant to the norethindrone effect. 4. Administration in vivo [100mg/kg, intraperitoneally] of norethindrone or ethinyl oestradiol also produced a time-dependent loss of liver cytochrome P-450. Norethandrolone had a similar, though much less-marked, effect. All three steroids lead to an induction of 5-aminolaevulinate synthase and an accumulation of porphyrins in the liver. 5. The loss of cytochrome P-450 and the accumulation of porphyrins in the liver 2 h after the administration of norethindrone to female rats was similar to that seen in males. 6. Rats pretreated with phenobarbitone and given norethindrone or ethynyloestradiol (100mg/kg, intraperitoneally) formed green pigments in their livers. These had characteristics similar to the green pigments produced in the livers of rats after the administration of 2-allyl-2-isopropylacetamide. No green pigments could be extracted from the livers of control rats or those given norethandrolone, oestradiol or progesterone.
5-Aminolevulinate Synthetase↗
Uterine bleeding in postmenopausal women on continuous therapy with estradiol and norethindrone acetate. Endometrium Study Group.
OBJECTIVE: To investigate the incidence of uterine bleeding during 12 months of treatment with 17beta-estradiol (E2) 1 mg, unopposed or in combination with three doses of norethindrone acetate. METHODS: This study was a prospective, double-masked, randomized, multicenter trial. A total of 1176 healthy postmenopausal women age 45 years and older without evidence of endometrial abnormalities were randomly assigned to receive either unopposed E2 1 mg, or continuous-combined formulations of E2 1 mg and norethindrone acetate 0.1 mg, 0.25 mg, or 0.5 mg. Any spotting or bleeding episodes during the treatment period were recorded in a daily diary and reported by weekly telephone calls. RESULTS: The incidence of bleeding was low in the combination groups, even during the initial 3 months of treatment (24-28%), after which it decreased with increasing doses of norethindrone acetate. Conversely, the incidence of bleeding increased over time with unopposed E2 1 mg. After the initial 3 months, the incidence of bleeding among the combination groups was lowest in the norethindrone acetate 0.5 mg group. Among women initiating therapy close to menopause, fewer reported bleeding with norethindrone acetate 0.5 mg than with the other combination groups. There was a significantly (P<.05) lower discontinuation rate due to bleeding in the norethindrone acetate 0.5 mg group compared with all other treatment groups. CONCLUSION: Continuous-combined formulations of E2 1 mg with norethindrone acetate 0.1, 0.25, or 0.5 mg are associated with a low incidence of uterine bleeding. After the initial 3 months of treatment, bleeding profiles improved with increasing doses of norethindrone acetate.
Adult↗
Interaction of norethindrone and isoniazid following their oral co-administration to the minipig.
Following the oral co-administration of isonicotinic acid hydrazide and norethindrone to minipigs, the hydrazone of norethindrone was detected in plasma as its p-methoxybenzaldehyde derivative, using a high performance liquid chromatographic technique. The suspected precursor of the hydrazone of norethindrone was isonicotinyl hydrazone of norethindrone, a reaction product probably formed between norethindrone and isonicotinic acid hydrazide in the acid environment of the stomach. An in vitro liver metabolite of isonicotinyl hydrazone of norethindrone was isolated following derivatization with p-methoxybenzaldehyde and characterized by high resolution mass spectrometric and radiochemical techniques. The results demonstrated that the hydrazone of norethindrone is a metabolite of isonicotinyl hydrazone of norethindrone.
Administration, Oral↗
Cytotoxic effects of norethindrone-4 beta,5 beta-epoxide to Walker cells in culture and to rat liver in vivo.
1. Norethindrone-4 beta,5 beta-epoxide was toxic to Walker cells in culture. The concentration required to produce a 50% reduction in the increase in cell numbers 72 h after exposure (ID50) was 0.05 mM. In this assay, the parent contraceptive steroid, norethindrone, was at least four times less toxic than the epoxide. 2. Norethandrolone-4 beta,5 beta-epoxide and norethynodrel-5 beta,10 beta-epoxide were as toxic as norethindrone epoxide to the Walker cells. 3. The cytotoxicity of norethindrome epoxide was dependent on the time of exposure of the cells to this compound if excess unreacted epoxide was removed by washing the cells with cysteine. The results are consistant with norethindrone epoxide causing cell death by reacting with sulphydryl groups of cellular proteins. 4. No metabolites toxic to Walker cells could be detected when the cells were incubated with norethindrone, rat liver microsomes and a NADPH generating system. 5. Cells treated with an ID50 of norethindrone epoxide for 1 h showed marked cytoplasmic vacuolation 3 hr after exposure. This vacuolation was much less marked in cells treated with an ID50 of norethindrone or in the controls. Neither group showed any nuclear abnormalities. 6. Norethindrone epoxide when given to rats in large doses (50 mg/kg) by lateral tail vein injection also caused cytoplasmic vacuolar degeneration of the liver hepatocytes, especially in the perilobular areas 3 days after dosing. When this compound was administered at a similar dose level via the hepatic portal vein massive haemorrhagic necrosis of the liver resulted. No damage to either lungs or kidneys was evident, irrespective of the route of administration.
Animals↗
Novel genotoxicity assays identify norethindrone to activate p53 and phosphorylate H2AX.
Norethindrone is a commonly used drug for contraception and hormone replacement therapy, whose carcinogenic potential is still controversial. We applied a novel and particularly sensitive method to screen for DNA damage with special attention to double-strand breaks (DSBs) and identified norethindrone to be likely genotoxic and therefore potentially mutagenic: a p53-reporter assay served as a first, high-throughput screening method and was followed by the immunofluorescent detection of phosphorylated H2AX as a sensitive assay for the presence of DSBs. Norethindrone at concentrations of 2-100 microg/ml activated p53 and phosphorylated H2AX specifically and in a dose-dependent manner. No p53 activation or H2AX phosphorylation was detected using a panel of structurally/functionally related drugs. The overall amount of DNA damage induced by norethindrone was low as compared with etoposide and ionizing radiation. Consistently, norethindrone treatment did not cause a cell cycle arrest. DSBs were not detected with the neutral comet assay, a less sensitive method for DSB assessment than H2AX phosphorylation. Our findings in the p53-reporter and gamma-H2AX assays could not be ascribed to common DSB-causing artifacts in standard genotoxicity screening, including drug precipitation, high cytotoxicity levels and increased apoptosis. Therefore, our study suggests that norethindrone induces DSBs in our experimental setting, both complementing and adding a new aspect to the existing literature on the genotoxic potential of norethindrone. As the effective concentrations of norethindrone used in our assays were approximately 100- to 1000-fold higher than therapeutical doses, the significance of these findings with regard to human exposure still remains to be determined.
Animals↗
Pharmacokinetics of norethindrone acetate in women.
The plasma half-life, MCR and plasma metabolite levels at various time intervals have been studied in six women after an intravenous injection of 3H-norethindrone acetate. The disappearance curve due to norethindrone acetate showed an initial rapid disappearance of 3H with an average half-life of 7.5 minutes and a subsequent slow disapperance with a half-life of 51.5 hours. Norethindrone acetate was cleared from the plasma with an average MCR of 495 L/day. Norethindrone acetate is rapidly metabolised after an intravenous injection. Norethindrone, the main metabolite, disappears from the plasma with an average half-life of 34.8 hours. Norethindrone maintains a high level compared with norethindrone acetate at all time intervals up to 24 hours and an equilibrium is reached between the two at 24 to 48 hours.
Acetates↗
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 4 hr 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.
Animals↗
A randomized comparison of continuous combined transdermal delivery of estradiol-norethindrone acetate and estradiol alone for menopause. CombiPatch Study Group.
OBJECTIVE: To determine whether a continuous estradiol-norethindrone acetate transdermal delivery system reduces incidence of endometrial hyperplasia in postmenopausal women more than transdermal estradiol (E2) alone. METHODS: Six hundred twenty-five postmenopausal women were assigned randomly to one of four treatments, transdermal E2 50 microg/day, or transdermal E2-norethindrone acetate with 50 microg E2 and 140, 250, or 400 microg/day of norethindrone acetate. Follow-up visits to collect information on safety and efficacy were scheduled at 3, 6, 9, and 12 months after initiation of treatment. Endometrial biopsy for histologic evaluation was done at baseline and upon exit from the study (completion or withdrawal). Endometrial histology was evaluated by two independent gynecologic pathologists. In the event of a disparate reading, a third gynecologic pathologist evaluated the tissue using predetermined criteria. RESULTS: Endometrial hyperplasia was found in 37.9% (39 of 103) in the E2 alone group versus 0.8% (one of 123), 1% (one of 98), and 1.1% (one of 89) in the E2-norethindrone acetate 50-140, 50-250, and 50-400 groups, respectively (P < .001). Uterine bleeding was less frequent in the E2-norethindrone acetate 50-140 group than other treatments. The mean number of hot flushes per day decreased to less than one in each treatment group at endpoint. The E2-norethindrone acetate combination patch showed skin tolerance comparable to that of E2 alone. CONCLUSION: Continuous transdermal delivery of E2 combined with norethindrone acetate effectively prevented endometrial hyperplasia in healthy postmenopausal women. Continuous combined transdermal delivery systems provide increased dosing flexibility and might improve convenience and compliance with hormone replacement therapy.
Administration, Cutaneous↗
Norethindrone acetate only partially protects the skeleton of rats treated with the LHRH agonist buserelin from oestrogen-deficiency osteopaenia.
In women with endometriosis there is concern that therapeutic use of LH-releasing hormone (LHRH) analogues, to lower ovarian oestrogen production and control endometrial hyperplasia, leads to unwanted oestrogen-deficiency bone loss. We have developed an animal model of this LHRH-mediated oestrogen-deficiency bone loss in the rat, using buserelin. The aim was to use this model to determine whether the progestogen, norethindrone acetate, could counter oestrogen-deficiency bone loss associated with prolonged treatment with the LHRH agonist buserelin. Four groups of animals which had their bones labelled with 45Ca were studied for 4 weeks: group A, control; group B, buserelin treated; group C, norethindrone acetate treated; group D, norethindrone acetate+buserelin treated. Buserelin was given daily (19.2 pmol/kg body wt); norethindrone was given orally three times/week (1.47 mumol/kg body wt). Bone resorption was monitored by measuring the urinary excretion of hydroxyproline and 45Ca and bone 45Ca content. Buserelin-treated rats developed similarly depressed plasma oestradiol-17 beta values in the presence and absence of progestogen, and both groups given buserelin had significantly smaller uteri than controls or rats given norethindrone without buserelin. However, norethindrone did not prevent buserelin-mediated increases in bone resorption. At the end of the study total body calcium values (mean +/- S.D.) in the four groups were (mg) respectively; 2594 +/- 123; 2260 +/- 92 (P < 0.001 compared with controls); 2616 +/- 221; 2415 +/- 130 (P < 0.02 compared with controls). Rats given norethindrone and buserelin in combination had higher values (P < 0.02) than animals given buserelin alone, but significantly less total body calcium than controls (P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Metabolism of levonorgestrel, norethindrone, and structurally related contraceptive steroids.
There is limited information on the metabolism of levonorgestrel, norethindrone and structurally related contraceptive steroids. Both levonorgestrel and norethindrone undergo extensive reduction of the alpha, beta-unsaturated ketone in ring A. Levonorgestrel also undergoes hydroxylation at carbons 2 and 16. The metabolites of both compounds circulate predominantly as sulfates. In urine, levonorgestrel metabolites are found primarily in the glucuronide form, whereas norethindrone metabolites are present in approximately equal amounts as sulfates and glucuronides. Of the progestogens structurally related to norethindrone, norethindrone acetate, ethynodiol diacetate, norethindrone enanthate, and perhaps lynestrenol, undergo rapid hydrolysis and are converted to the parent compound and its metabolites. There is no convincing evidence that norethynodrel is converted to norethindrone. Of the progestogens structurally related to levonorgestrel, it appears that neither desogestrel nor gestodene are transformed to the parent compound. However, there is evidence that norgestimate can be, at least partly, converted to levonorgestrel. Further studies on the metabolism of these progestogens are required before we can understand their mechanism of action.
Animals↗