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Andrew T. Kicman - One of the best experts on this subject based on the ideXlab platform.
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doping in sport 3 metabolic conversion of oral Norethisterone to urinary 19 norandrosterone
Steroids, 2009Co-Authors: Christopher J. Walker, David A. Cowan, Vivian H.t. James, Joanne C.y. Lau, Andrew T. KicmanAbstract:The detection of 19 norandrosterone (19-NA) in a competitor's urine sample is taken as prima facie evidence of administration of nandrolone or other 19-norsteroid but a potential problem is that administration of Norethisterone, a progestogen used for menstrual disorders and for hormonal contraception, also results in the excretion of 19-NA that can exceed the laboratory reporting threshold of 2 ng/mL The contribution of Norethisterone to urinary 19-NA with and without 19-norandrostenedione. a known Norethisterone tablet impurity, requires evaluation. Preparations containing, either <2 ng or 1 mu g 19-norandrostenedione impurity per 5mg of Norethisterone, administered to female volunteers (n=10) in doses comparable to those used for menstrual disorders (5mg three times daily for 10 days), resulted in maximal 19-NA concentrations of 51 and 63 ng/mL, respectively. The maximal concentration of 19-NA, 2h post-administration of a single 1 mu g dose of 19-norandrostenedione, was 2.4 ng/mL These results prove unequivocally that Norethisterone is metabolized to 19-NA and that there is only a minor contribution from the impurity 19-norandrostenedione. Administration to women (n=30) of a single contraceptive tablet containing Norethisterone (I mg) with one of the highest proportions of the impurity 19-norandrostenedione (similar to 0.5 mu g, 0.05%, w/w) resulted in a urinary 19-NA concentration of 9.1 ng/mL, with a maximum concentration ratio of 19-NA to the Norethisterone metabolite 3 alpha,5 beta-tetra hydroNorethisterone of 0.36. We provide data that should remove the need for time-consuming follow-up investigations to consider whether doping with 19-norandrogens has occurred. (C) 2008 Elsevier Inc. All rights reserved.
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Doping in sport: 3. Metabolic conversion of oral Norethisterone to urinary 19-norandrosterone
Steroids, 2008Co-Authors: Christopher J. Walker, David A. Cowan, Vivian H.t. James, Joanne C.y. Lau, Andrew T. KicmanAbstract:The detection of 19 norandrosterone (19-NA) in a competitor's urine sample is taken as prima facie evidence of administration of nandrolone or other 19-norsteroid but a potential problem is that administration of Norethisterone, a progestogen used for menstrual disorders and for hormonal contraception, also results in the excretion of 19-NA that can exceed the laboratory reporting threshold of 2 ng/mL The contribution of Norethisterone to urinary 19-NA with and without 19-norandrostenedione. a known Norethisterone tablet impurity, requires evaluation. Preparations containing, either
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Doping in sport--2. Quantification of the impurity 19-norandrostenedione in pharmaceutical preparations of Norethisterone.
Steroids, 2008Co-Authors: Christopher J. Walker, David A. Cowan, Vivian H.t. James, Joanne C.y. Lau, Andrew T. KicmanAbstract:The finding of measurable amounts of 19-norandrostenedione in Norethisterone tablets prompted us to develop an assay to quantify this steroid. 19-Norandrostenedione is an anabolic steroid whose use in sport is prohibited by the World Anti-Doping Agency (WADA). The assay was developed using isotope dilution and liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the quantification of 19-norandrostenedione in Norethisterone formulations, with [3,4-(13)C(2)]-19-norandrostenedione as the internal standard. The results showed amounts up to 1.01+/-0.01microg (mean+/-S.E.M.) per tablet in those containing 5mg of Norethisterone or Norethisterone acetate (0.02%, w/w) and up to 0.5+/-0.01microg (mean+/-S.E.M.) per tablet (0.05%, w/w) in oral contraceptive tablets containing 0.35-1.5mg of Norethisterone or Norethisterone acetate. No tablet tested exceeded the British Pharmacopoeia limit of 0.1% for this impurity.
Donna Mctavish - One of the best experts on this subject based on the ideXlab platform.
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Transdermal Estradiol/Norethisterone
Drugs & Aging, 1994Co-Authors: Lynda R Wiseman, Donna MctavishAbstract:Synopsis The combined transdermal estradiol/Norethisterone therapeutic system is designed to deliver both estradiol and Norethisterone into the systemic circulation at a constant rate for up to 4 days when affixed to the skin. Transdermal administration avoids hepatic first- pass metabolism, allowing therapeutic concentrations of the progestogen and estrogen to be maintained in postmenopausal women following low dose administration. Transdermal Norethisterone does not appear to alter the potentially beneficial effects of transdermal estradiol on total cholesterol low- density lipoprotein (LDL) or triglyceride levels, or metabolic parameters of bone resorption or vaginal cytology. Protection of the endometriumfrom the effects of unopposed estradiol is achieved by sequential treatment with transdermal estradiol/Norethisterone for 2 weeks of each 28- day cycle, and the majority of patients experience a regular vaginal bleeding pattern with this treatment regimen. Menopausal symptoms are improved to a similar extent during the transdermal estradiol- only and combined estradiol/Norethisterone treatment phases. The transdermal therapeutic system has been well accepted by patients in clinical trials. It is generally well tolerated, the most common adverse effect being local irritation at the site of application. Estrogen- and progestogen- related systemic adverse events are reported in a small proportion of patients. Thus, the combined estradiol/Norethisterone transdermal delivery system offers a more convenient and consistent method of progestogen administration. Together with its therapeutic efficacy when administered at lower dosages than oral therapy, it is likely to further improve patient compliance during hormone replacement therapy. Pharmacological Properties The combined estradiol/Norethisterone therapeutic system is designed to deliver 0.05 mg/day estradiol and 0.25 mg/day Norethisterone (given as the acetate) at a constant rate for up to 4 days. Following application of the delivery system to intact skin, steady-state plasma concentrations of Norethisterone (the active gestogen), were between 1.6 and 3.2 nmol/L 2 days after the first application. Steady-state concentrations of estradiol of 0.15 to 0.18 nmol/L were reached within 24 hours, and were similar to estradiol levels in the early follicular stage of the ovulatory cycle in premenopausal women. Estradiol is rapidly cleared from the circulation following transdermal administration, with a plasma elimination half-life (t_½) of about 1 hour. The t_½ of Norethisterone varies between 6 and 8 hours. Metabolism of both estradiol and Norethisterone occurs mainly in the liver, the major metabolites being estrone, estriol and their conjugates, and the 5β,3α-Norethisterone derivative, respectively. Metabolites are mainly excreted as sulphate and glucuronide conjugates in the urine, although some enterohepatic recirculation may occur. Plasma concentrations of estradiol and Norethisterone return to pretreatment values within 24 and 48 hours of patch removal, respectively. Transdermal estradiol therapy appears to have a positive effect on cardiovascular disease risk factors in postmenopausal women, which may be mediated in part by the beneficial changes in lipid and lipoprotein profiles observed in patients receiving transdermal estradiol for ≥ 3 months. Addition of sequential transdermal Norethisterone does not appear to significantly affect the reduced plasma levels of total and low density lipoprotein (LDL) cholesterol induced by estradiol, and triglyceride levels are reduced by a similar extent during both the estrogen-only and combined estrogen/Norethisterone treatment phases. Transdermal estradiol appears to have a favourable effect on carbohydrate metabolism and no net adverse effect is observed following coadministration of transdermal Norethisterone. The effects of combined transdermal estradiol/Norethisterone on haemostatic factors and arterial status have yet to be determined. During transdermal estradiol/Norethisterone therapy, vaginal cytology is converted to a pattern similar to that found in premenopausal women, with increased numbers of superficial and decreased numbers of basal and parabasal cells. Transdermal estradiol inhibits bone resorption, as evidenced by a reduction in the urinary ratios of calcium and hydroxyproline to creatinine, and stabilisation of, or small increases in, bone mineral density in postmenopausal women receiving long term treatment. Concomitant progestogen therapy does not appear to impair, and may enhance, the bone conserving effects of estrogens; however, further investigation is necessary to confirm the latter findings. Clinical Use The clinical efficacy of the combined transdermal estradiol/Norethisterone delivery system in preventing endometrial hyperplasia and controlling climacteric symptoms has been investigated in noncomparative clinical trials of up to 3 years’ duration. In most studies, transdermal estradiol 0.05 mg/day was administered for the first 2 weeks of a 28-day cycle, followed by combined transdermal estradiol/Norethisterone 0.05/0.25 mg/day for the last 2 weeks. The combined transdermal estradiol/Norethisterone delivery system provided endometrial protection from unopposed estradiol. Biopsy samples from more than 400 treated women showed proliferative endometrium in 1.5 to 7% and secretory endometrium in 57 to 100%. The incidence of hyperplasia in women receiving this treatment regimen was less than 2%. Sequential transdermal Norethisterone induced a regular vaginal bleeding pattern in about 80% of women. Regular bleeding episodes occurred in 80 to 90% of cycles, with irregular episodes in about 5 to 11%. Amenorrhoea occurred in about 6 to 9% of cycles during therapy. In 2 small studies in which 30 women received continuous transdermal estradiol/Norethisterone, the incidence of amenorrhoea was 53 and 100% after 6 months. Climacteric symptoms including hot flushes, sweating, sleep disturbance, vaginal discomfort, poor concentration and irritability were significantly improved compared with baseline in patients receiving transdermal estradiol with sequential transdermal Norethisterone. Tolerability The most frequently reported adverse effects in women using transdermal estradiol or combined transdermal estradiol/Norethisterone delivery systems are dermatological reactions. Transient mild erythema and itching at the site of application are the most common events. However, severe cutaneous irritation necessitating withdrawal of treatment is experienced by about 6% of patients using the estradiol-only or combined delivery systems. The occurrence of skin reactions can be minimised by selection of new sites when applying patches. Adverse systemic events associated with estrogen or progestogen therapy occurred in a small proportion of women and included breast tenderness, vaginal spotting or bleeding, fluid retention, headache, nausea, gastrointestinal disturbances, bodyweight gain and depression. Of these events, unacceptable vaginal bleeding was the most common reason for patients discontinuing combined estradiol/Norethisterone therapy (affecting 6 to 10%). Transdermal estradiol did not stimulate hepatic metabolism and therefore no increases in plasma levels of renin substrate, sex hormone-, thyroxin-, and cortisol-binding globulins or clotting factors were observed; however, a slight decrease in sex hormone-binding globulins was observed during combined transdermal estradiol/Norethisterone treatment. Dosage and Administration For treatment of postmenopausal symptoms and symptoms of estrogen deficiency due to surgical menopause, and for prevention of postmenopausal osteoporosis in women with an intact uterus, transdermal estradiol 0.05 mg/day is recommended for the first 14 days of a 28-day cycle, followed by 14 days of combined transdermal estradiol 0.05/Norethisterone 0.25 mg/day. The transdermal delivery system should be applied to clean dry intact skin and should be changed twice weekly. Contraindications to the use of estradiol include carcinoma of the breast or endometrium, vaginal bleeding of unknown origin, previous estrogen-associated, or active thromboembolic disease or thrombophlebitis. Caution is advised in patients with past or present endometriosis, uterine leiomyomata, impaired hepatic or renal function, conditions likely to be influenced by fluid retention, or a history of depression or pregnancy-associated jaundice.
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Transdermal Estradiol/Norethisterone
Drugs & aging, 1994Co-Authors: Lynda R Wiseman, Donna MctavishAbstract:Synopsis The combined transdermal estradiol/Norethisterone therapeutic system is designed to deliver both estradiol and Norethisterone into the systemic circulation at a constant rate for up to 4 days when affixed to the skin. Transdermal administration avoids hepatic first- pass metabolism, allowing therapeutic concentrations of the progestogen and estrogen to be maintained in postmenopausal women following low dose administration. Transdermal Norethisterone does not appear to alter the potentially beneficial effects of transdermal estradiol on total cholesterol low- density lipoprotein (LDL) or triglyceride levels, or metabolic parameters of bone resorption or vaginal cytology. Protection of the endometriumfrom the effects of unopposed estradiol is achieved by sequential treatment with transdermal estradiol/Norethisterone for 2 weeks of each 28- day cycle, and the majority of patients experience a regular vaginal bleeding pattern with this treatment regimen. Menopausal symptoms are improved to a similar extent during the transdermal estradiol- only and combined estradiol/Norethisterone treatment phases. The transdermal therapeutic system has been well accepted by patients in clinical trials. It is generally well tolerated, the most common adverse effect being local irritation at the site of application. Estrogen- and progestogen- related systemic adverse events are reported in a small proportion of patients. Thus, the combined estradiol/Norethisterone transdermal delivery system offers a more convenient and consistent method of progestogen administration. Together with its therapeutic efficacy when administered at lower dosages than oral therapy, it is likely to further improve patient compliance during hormone replacement therapy.
Christopher J. Walker - One of the best experts on this subject based on the ideXlab platform.
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doping in sport 3 metabolic conversion of oral Norethisterone to urinary 19 norandrosterone
Steroids, 2009Co-Authors: Christopher J. Walker, David A. Cowan, Vivian H.t. James, Joanne C.y. Lau, Andrew T. KicmanAbstract:The detection of 19 norandrosterone (19-NA) in a competitor's urine sample is taken as prima facie evidence of administration of nandrolone or other 19-norsteroid but a potential problem is that administration of Norethisterone, a progestogen used for menstrual disorders and for hormonal contraception, also results in the excretion of 19-NA that can exceed the laboratory reporting threshold of 2 ng/mL The contribution of Norethisterone to urinary 19-NA with and without 19-norandrostenedione. a known Norethisterone tablet impurity, requires evaluation. Preparations containing, either <2 ng or 1 mu g 19-norandrostenedione impurity per 5mg of Norethisterone, administered to female volunteers (n=10) in doses comparable to those used for menstrual disorders (5mg three times daily for 10 days), resulted in maximal 19-NA concentrations of 51 and 63 ng/mL, respectively. The maximal concentration of 19-NA, 2h post-administration of a single 1 mu g dose of 19-norandrostenedione, was 2.4 ng/mL These results prove unequivocally that Norethisterone is metabolized to 19-NA and that there is only a minor contribution from the impurity 19-norandrostenedione. Administration to women (n=30) of a single contraceptive tablet containing Norethisterone (I mg) with one of the highest proportions of the impurity 19-norandrostenedione (similar to 0.5 mu g, 0.05%, w/w) resulted in a urinary 19-NA concentration of 9.1 ng/mL, with a maximum concentration ratio of 19-NA to the Norethisterone metabolite 3 alpha,5 beta-tetra hydroNorethisterone of 0.36. We provide data that should remove the need for time-consuming follow-up investigations to consider whether doping with 19-norandrogens has occurred. (C) 2008 Elsevier Inc. All rights reserved.
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Doping in sport: 3. Metabolic conversion of oral Norethisterone to urinary 19-norandrosterone
Steroids, 2008Co-Authors: Christopher J. Walker, David A. Cowan, Vivian H.t. James, Joanne C.y. Lau, Andrew T. KicmanAbstract:The detection of 19 norandrosterone (19-NA) in a competitor's urine sample is taken as prima facie evidence of administration of nandrolone or other 19-norsteroid but a potential problem is that administration of Norethisterone, a progestogen used for menstrual disorders and for hormonal contraception, also results in the excretion of 19-NA that can exceed the laboratory reporting threshold of 2 ng/mL The contribution of Norethisterone to urinary 19-NA with and without 19-norandrostenedione. a known Norethisterone tablet impurity, requires evaluation. Preparations containing, either
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Doping in sport--2. Quantification of the impurity 19-norandrostenedione in pharmaceutical preparations of Norethisterone.
Steroids, 2008Co-Authors: Christopher J. Walker, David A. Cowan, Vivian H.t. James, Joanne C.y. Lau, Andrew T. KicmanAbstract:The finding of measurable amounts of 19-norandrostenedione in Norethisterone tablets prompted us to develop an assay to quantify this steroid. 19-Norandrostenedione is an anabolic steroid whose use in sport is prohibited by the World Anti-Doping Agency (WADA). The assay was developed using isotope dilution and liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the quantification of 19-norandrostenedione in Norethisterone formulations, with [3,4-(13)C(2)]-19-norandrostenedione as the internal standard. The results showed amounts up to 1.01+/-0.01microg (mean+/-S.E.M.) per tablet in those containing 5mg of Norethisterone or Norethisterone acetate (0.02%, w/w) and up to 0.5+/-0.01microg (mean+/-S.E.M.) per tablet (0.05%, w/w) in oral contraceptive tablets containing 0.35-1.5mg of Norethisterone or Norethisterone acetate. No tablet tested exceeded the British Pharmacopoeia limit of 0.1% for this impurity.
Mats Hammar - One of the best experts on this subject based on the ideXlab platform.
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lipids and clotting factors during low dose transdermal estradiol Norethisterone use
Maturitas, 2005Co-Authors: Jan Brynhildsen, Mats HammarAbstract:Objective: To demonstrate the effects of 2-year transdermal continuous combined low-dose estradiol (0.025 mg/day) and Norethisterone acetate (0.125 mg/day) on lipid/lipoprotein profile and coagulation/fibrinolysis. Methods: A double-blind, randomized, multicenter, parallel, 1-year trial enrolled 266 healthy women at least 2 years post menopause. Patients received either 0.025 mg estradiol and 0.125 mg Norethisterone acetate daily or placebo transdermally. One hundred and thirty five women completed a second year open follow-up (96 had used Estragest TTS, 39 placebo during the first year), where all women had the estradiol/Norethisterone patch. Lipid/lipoprotein profile and coagulation/fibrinolysis parameters were studied at 0, 24, 48, 72 and 96 weeks. Results: In women on estradiol/Norethisterone total cholesterol, Lp(a) and VLDL cholesterol decreased significantly more than in the placebo group after 24 weeks and LDL cholesterol after 48 weeks. Women on estradiol/Norethisterone had no change in HDL, triglycerides or Lp(a), an increased HDL/total cholestrol ratio and decreased LDL, VLDL and total cholesterol at 48 weeks compared to placebo. Women with active treatment also showed a significant reduction compared with the placebo group of Factor VII and antithrombin III at 24 and 48 weeks and a reduction of fibrinogen at 24 weeks. These changes persisted over the second year. Conclusions: A continuous combined low-dose transdermal patch daily delivering 0.025 mg estradiol and 0.125 mg Norethisterone acetate provided beneficial effects on lipid/lipoprotein profile and coagulation/fibrinolysis. The changes were similar to those previously described after higher dose oral and transdermal estrogen/progestogen regimens.
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Low dose transdermal estradiol/Norethisterone acetate treatment over 2 years does not cause endometrial proliferation in postmenopausal women.
Menopause, 2002Co-Authors: Jan Brynhildsen, Mats HammarAbstract:Objective: We investigated the effects of 2-year transdermal continuous combined estradiol (0.025 mg/day) and Norethisterone acetate (0.125 mg/day) (Estragest TTS) on bleeding and on the endometrium. Design: This double-blind, randomized, multicenter, parallel, 1-year trial enrolled 266 healthy women at least 2 years past menopause with intact uteri. Patients received a transdermal patch delivering either 0.025 mg estradiol and 0.125 mg Norethisterone acetate daily or placebo. Of the 266 women initially included, 135 (96 Estragest TTS, 39 placebo) completed a second year open follow-up, where all women had the estradiol/Norethisterone patch. Endometrial biopsies were performed at weeks 0, 48 (n = 171), and 96 (n =109). Effects on endometrial morphology and uterine bleeding were studied. Results: The overall incidence of endometrial hyperplasia after treatment with the estradiol/Norethisterone acetate patch for one year was 0.8% with only one case of atypical hyperplasia. There were no clinically significant changes in endometrial thickness in either treatment group. The proportion of bleed-free patients with the estradiol/Norethisterone acetate transdermal system increased from 55% in cycles 1-3 to 83% in cycles 10-12. By the 12th cycle, 92% of patients receiving estradiol/Norethisterone acetate patches were bleed-free. No additional hyperplasia was seen during the second year follow-up. Conclusions: A continuous combined transdermal patch delivering 0.025 mg estradiol/day and 0.125 mg Norethisterone acetate/day provided good endometrial protection. The dose maintained a consistently high rate of amenorrhea in postmenopausal women.
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low dose transdermal estradiol Norethisterone acetate treatment over 2 years does not cause endometrial proliferation in postmenopausal women
Menopause, 2002Co-Authors: Jan Brynhildsen, Mats HammarAbstract:Objective: We investigated the effects of 2-year transdermal continuous combined estradiol (0.025 mg/day) and Norethisterone acetate (0.125 mg/day) (Estragest TTS) on bleeding and on the endometrium. Design: This double-blind, randomized, multicenter, parallel, 1-year trial enrolled 266 healthy women at least 2 years past menopause with intact uteri. Patients received a transdermal patch delivering either 0.025 mg estradiol and 0.125 mg Norethisterone acetate daily or placebo. Of the 266 women initially included, 135 (96 Estragest TTS, 39 placebo) completed a second year open follow-up, where all women had the estradiol/Norethisterone patch. Endometrial biopsies were performed at weeks 0, 48 (n = 171), and 96 (n =109). Effects on endometrial morphology and uterine bleeding were studied. Results: The overall incidence of endometrial hyperplasia after treatment with the estradiol/Norethisterone acetate patch for one year was 0.8% with only one case of atypical hyperplasia. There were no clinically significant changes in endometrial thickness in either treatment group. The proportion of bleed-free patients with the estradiol/Norethisterone acetate transdermal system increased from 55% in cycles 1-3 to 83% in cycles 10-12. By the 12th cycle, 92% of patients receiving estradiol/Norethisterone acetate patches were bleed-free. No additional hyperplasia was seen during the second year follow-up. Conclusions: A continuous combined transdermal patch delivering 0.025 mg estradiol/day and 0.125 mg Norethisterone acetate/day provided good endometrial protection. The dose maintained a consistently high rate of amenorrhea in postmenopausal women.
Lynda R Wiseman - One of the best experts on this subject based on the ideXlab platform.
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Transdermal Estradiol/Norethisterone
Drugs & Aging, 1994Co-Authors: Lynda R Wiseman, Donna MctavishAbstract:Synopsis The combined transdermal estradiol/Norethisterone therapeutic system is designed to deliver both estradiol and Norethisterone into the systemic circulation at a constant rate for up to 4 days when affixed to the skin. Transdermal administration avoids hepatic first- pass metabolism, allowing therapeutic concentrations of the progestogen and estrogen to be maintained in postmenopausal women following low dose administration. Transdermal Norethisterone does not appear to alter the potentially beneficial effects of transdermal estradiol on total cholesterol low- density lipoprotein (LDL) or triglyceride levels, or metabolic parameters of bone resorption or vaginal cytology. Protection of the endometriumfrom the effects of unopposed estradiol is achieved by sequential treatment with transdermal estradiol/Norethisterone for 2 weeks of each 28- day cycle, and the majority of patients experience a regular vaginal bleeding pattern with this treatment regimen. Menopausal symptoms are improved to a similar extent during the transdermal estradiol- only and combined estradiol/Norethisterone treatment phases. The transdermal therapeutic system has been well accepted by patients in clinical trials. It is generally well tolerated, the most common adverse effect being local irritation at the site of application. Estrogen- and progestogen- related systemic adverse events are reported in a small proportion of patients. Thus, the combined estradiol/Norethisterone transdermal delivery system offers a more convenient and consistent method of progestogen administration. Together with its therapeutic efficacy when administered at lower dosages than oral therapy, it is likely to further improve patient compliance during hormone replacement therapy. Pharmacological Properties The combined estradiol/Norethisterone therapeutic system is designed to deliver 0.05 mg/day estradiol and 0.25 mg/day Norethisterone (given as the acetate) at a constant rate for up to 4 days. Following application of the delivery system to intact skin, steady-state plasma concentrations of Norethisterone (the active gestogen), were between 1.6 and 3.2 nmol/L 2 days after the first application. Steady-state concentrations of estradiol of 0.15 to 0.18 nmol/L were reached within 24 hours, and were similar to estradiol levels in the early follicular stage of the ovulatory cycle in premenopausal women. Estradiol is rapidly cleared from the circulation following transdermal administration, with a plasma elimination half-life (t_½) of about 1 hour. The t_½ of Norethisterone varies between 6 and 8 hours. Metabolism of both estradiol and Norethisterone occurs mainly in the liver, the major metabolites being estrone, estriol and their conjugates, and the 5β,3α-Norethisterone derivative, respectively. Metabolites are mainly excreted as sulphate and glucuronide conjugates in the urine, although some enterohepatic recirculation may occur. Plasma concentrations of estradiol and Norethisterone return to pretreatment values within 24 and 48 hours of patch removal, respectively. Transdermal estradiol therapy appears to have a positive effect on cardiovascular disease risk factors in postmenopausal women, which may be mediated in part by the beneficial changes in lipid and lipoprotein profiles observed in patients receiving transdermal estradiol for ≥ 3 months. Addition of sequential transdermal Norethisterone does not appear to significantly affect the reduced plasma levels of total and low density lipoprotein (LDL) cholesterol induced by estradiol, and triglyceride levels are reduced by a similar extent during both the estrogen-only and combined estrogen/Norethisterone treatment phases. Transdermal estradiol appears to have a favourable effect on carbohydrate metabolism and no net adverse effect is observed following coadministration of transdermal Norethisterone. The effects of combined transdermal estradiol/Norethisterone on haemostatic factors and arterial status have yet to be determined. During transdermal estradiol/Norethisterone therapy, vaginal cytology is converted to a pattern similar to that found in premenopausal women, with increased numbers of superficial and decreased numbers of basal and parabasal cells. Transdermal estradiol inhibits bone resorption, as evidenced by a reduction in the urinary ratios of calcium and hydroxyproline to creatinine, and stabilisation of, or small increases in, bone mineral density in postmenopausal women receiving long term treatment. Concomitant progestogen therapy does not appear to impair, and may enhance, the bone conserving effects of estrogens; however, further investigation is necessary to confirm the latter findings. Clinical Use The clinical efficacy of the combined transdermal estradiol/Norethisterone delivery system in preventing endometrial hyperplasia and controlling climacteric symptoms has been investigated in noncomparative clinical trials of up to 3 years’ duration. In most studies, transdermal estradiol 0.05 mg/day was administered for the first 2 weeks of a 28-day cycle, followed by combined transdermal estradiol/Norethisterone 0.05/0.25 mg/day for the last 2 weeks. The combined transdermal estradiol/Norethisterone delivery system provided endometrial protection from unopposed estradiol. Biopsy samples from more than 400 treated women showed proliferative endometrium in 1.5 to 7% and secretory endometrium in 57 to 100%. The incidence of hyperplasia in women receiving this treatment regimen was less than 2%. Sequential transdermal Norethisterone induced a regular vaginal bleeding pattern in about 80% of women. Regular bleeding episodes occurred in 80 to 90% of cycles, with irregular episodes in about 5 to 11%. Amenorrhoea occurred in about 6 to 9% of cycles during therapy. In 2 small studies in which 30 women received continuous transdermal estradiol/Norethisterone, the incidence of amenorrhoea was 53 and 100% after 6 months. Climacteric symptoms including hot flushes, sweating, sleep disturbance, vaginal discomfort, poor concentration and irritability were significantly improved compared with baseline in patients receiving transdermal estradiol with sequential transdermal Norethisterone. Tolerability The most frequently reported adverse effects in women using transdermal estradiol or combined transdermal estradiol/Norethisterone delivery systems are dermatological reactions. Transient mild erythema and itching at the site of application are the most common events. However, severe cutaneous irritation necessitating withdrawal of treatment is experienced by about 6% of patients using the estradiol-only or combined delivery systems. The occurrence of skin reactions can be minimised by selection of new sites when applying patches. Adverse systemic events associated with estrogen or progestogen therapy occurred in a small proportion of women and included breast tenderness, vaginal spotting or bleeding, fluid retention, headache, nausea, gastrointestinal disturbances, bodyweight gain and depression. Of these events, unacceptable vaginal bleeding was the most common reason for patients discontinuing combined estradiol/Norethisterone therapy (affecting 6 to 10%). Transdermal estradiol did not stimulate hepatic metabolism and therefore no increases in plasma levels of renin substrate, sex hormone-, thyroxin-, and cortisol-binding globulins or clotting factors were observed; however, a slight decrease in sex hormone-binding globulins was observed during combined transdermal estradiol/Norethisterone treatment. Dosage and Administration For treatment of postmenopausal symptoms and symptoms of estrogen deficiency due to surgical menopause, and for prevention of postmenopausal osteoporosis in women with an intact uterus, transdermal estradiol 0.05 mg/day is recommended for the first 14 days of a 28-day cycle, followed by 14 days of combined transdermal estradiol 0.05/Norethisterone 0.25 mg/day. The transdermal delivery system should be applied to clean dry intact skin and should be changed twice weekly. Contraindications to the use of estradiol include carcinoma of the breast or endometrium, vaginal bleeding of unknown origin, previous estrogen-associated, or active thromboembolic disease or thrombophlebitis. Caution is advised in patients with past or present endometriosis, uterine leiomyomata, impaired hepatic or renal function, conditions likely to be influenced by fluid retention, or a history of depression or pregnancy-associated jaundice.
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Transdermal Estradiol/Norethisterone
Drugs & aging, 1994Co-Authors: Lynda R Wiseman, Donna MctavishAbstract:Synopsis The combined transdermal estradiol/Norethisterone therapeutic system is designed to deliver both estradiol and Norethisterone into the systemic circulation at a constant rate for up to 4 days when affixed to the skin. Transdermal administration avoids hepatic first- pass metabolism, allowing therapeutic concentrations of the progestogen and estrogen to be maintained in postmenopausal women following low dose administration. Transdermal Norethisterone does not appear to alter the potentially beneficial effects of transdermal estradiol on total cholesterol low- density lipoprotein (LDL) or triglyceride levels, or metabolic parameters of bone resorption or vaginal cytology. Protection of the endometriumfrom the effects of unopposed estradiol is achieved by sequential treatment with transdermal estradiol/Norethisterone for 2 weeks of each 28- day cycle, and the majority of patients experience a regular vaginal bleeding pattern with this treatment regimen. Menopausal symptoms are improved to a similar extent during the transdermal estradiol- only and combined estradiol/Norethisterone treatment phases. The transdermal therapeutic system has been well accepted by patients in clinical trials. It is generally well tolerated, the most common adverse effect being local irritation at the site of application. Estrogen- and progestogen- related systemic adverse events are reported in a small proportion of patients. Thus, the combined estradiol/Norethisterone transdermal delivery system offers a more convenient and consistent method of progestogen administration. Together with its therapeutic efficacy when administered at lower dosages than oral therapy, it is likely to further improve patient compliance during hormone replacement therapy.
