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Transdermal Estradiol/Norethisterone

A Review of its Pharmacological Properties and Clinical Use in Postmenopausal Women

  • Drug Evaluation
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Summary

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 (t½) of about 1 hour. The t½ 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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References

  • Anonymous. Transdermal estradiol/norethisterone prescribing information, UK, 1993

  • Antunes CMF, Stolley PD, Rosenshein NB, Davies JL, Tonascia JA, et al. Endometrial cancer and estrogen use. Report of a large case-control study. New England Journal of Medicine 300: 9–13, 1979

    Article  PubMed  CAS  Google Scholar 

  • Balfour JA and Heel RC. Transdermal estradiol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of menopausal complaints. Drugs 40: 561–582, 1990

    Article  PubMed  CAS  Google Scholar 

  • Balfour JA, McTavish D. Transdermal estradiol. A review of its pharmacological profile, and therapeutic potential in the prevention of postmenopausal osteoporosis. Drugs and Aging 2: 487–507, 1992

    Article  PubMed  CAS  Google Scholar 

  • Balleisen L, Bailey J, Epping P-H, Schulte H, van de Loo J. Epidemiological study on factor VII, factor VIII and fibrinogen in an industrial population: baseline data on the relation to age, gender, body-weight, smoking, alcohol, pill-using, and menopause. Thrombosis and Haemostasis 54: 475–479, 1985

    PubMed  CAS  Google Scholar 

  • Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. Journal of the American Medical Association 265: 1861–1867, 1991

    Article  PubMed  CAS  Google Scholar 

  • Bates SK. Postmenopausal oestrogen replacement therapy and breast cancer. Journal of the Society of Obstetrics and Gynecology Canada 12: 9–13, 1991

    Google Scholar 

  • Birkhaeuser MH. Long term substitution with combined transdermal hormone therapy: efficacy in the control of postmenopausal somatic and psychological symptoms. Abstract. 6th International Congress on Menopause, Bangkok, October 29–November 2, 1990

  • Bourne T, Hillard TC, Whitehead MI, Crook D, Campbell S. Oestrogens, arterial status, and postmenopausal women. Lancet 335: 1470–1471, 1990

    Article  PubMed  CAS  Google Scholar 

  • Bush TL, Barrett-Connor E, Cowan LD, Criqui MH, Wallace RB, et al. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-Up Study. Circulation 75: 1102–1109, 1987

    Article  PubMed  CAS  Google Scholar 

  • Cagnacci A, Soldani R, Carriero PL, Paoletti AM, Fioretti P, et al. Effects of low doses of transdermal 17β-estradiol on carbohydrate metabolism in postmenopausal women. Journal of Clinical Endocrinology and Metabolism 74: 1396–1400, 1992

    Article  PubMed  CAS  Google Scholar 

  • Campisi D, Bivona A, Paternal S, Valenza M, Albieno R. Oestrogen binding sites in fresh human aortic tissue. International Journal of Tissue Reactions 9: 393, 1987

    PubMed  CAS  Google Scholar 

  • Cheang A, Sitruk-Ware R, Utian WH. A risk-benefit appraisal of transdermal estradiol therapy. Drug Safety 9: 365–379, 1993

    Article  PubMed  CAS  Google Scholar 

  • Chetkowski RJ, Meldrum DR, Steingold KA, Randle D, Lu JK, et al. Biologic effects of transdermal estradiol. New England Journal of Medicine 314: 1615–1620, 1986

    Article  PubMed  CAS  Google Scholar 

  • Christiansen C, Rüs BJ. 17β-Estradiol and continuous norethisterone: a unique treatment for established osteoporosis in elderly women. Journal of Clinical Endocrinology and Metabolism 71: 836–841, 1990

    Article  PubMed  CAS  Google Scholar 

  • Clisham P, Cedars MI, Greendale G, Fu Y, Gambone J, et al. Long-term transdermal estradiol therapy: effects on endometrial histology and bleeding patterns. Obstetrics and Gynecology 79: 196–201, 1992

    PubMed  CAS  Google Scholar 

  • Consensus Development Conference Report. Consensus development conference: prophylaxis and treatment of osteoporosis. American Journal of Medicine 90: 107–110, 1991

    Article  Google Scholar 

  • Cortellaro M, Nencioni T, Boschetti C, Ortolani S, Buzzi F, et al. Cyclic hormonal replacement therapy after the menopause: transdermal versus oral treatment. European Journal of Clinical Pharmacology 41: 555–559, 1991

    Article  PubMed  CAS  Google Scholar 

  • Crook D, Cust MP, Gangar KF, Worthington M, Hillard TC, et al. Comparison of transdermal and oral estrogen-progestin replacement therapy: effects on serum lipids and lipoproteins. American Journal of Obstetrics and Gynecology 166: 950–955, 1992

    PubMed  CAS  Google Scholar 

  • Cust M. Metabolic and psychological effects of oral versus transdermal estrogen/progestogen in postmenopausal women — preliminary report. Abstract. XII World Congress of Gynecology and Obstetrics, Rio de Janiero, October 26, 1988

  • Cust MP, Gangar KF, Crook D, Whitehead MI. New delivery systems for hormone replacement therapy. Recent Advances in Obstetrics and Gynecology 16: 253–270, 1990

    Google Scholar 

  • Dupont WD, Page DL. Menopausal estrogen replacement therapy and breast cancer. Archives of Internal Medicine 151: 67–72, 1991

    Article  PubMed  CAS  Google Scholar 

  • Dupuy HJ. The psychological general well-being index. In Wenger et al. (Eds) Assessment of quality of life in clinical trials of cardiovascular therapies, pp. 170–183, Le Jacq Publ Inc, USA, 1984

    Google Scholar 

  • Falkeborn M, Persson I, Adami H-O, Bergström R, Eaker E, et al. The risk of acute myocardial infarction after oestrogen and oestrogen-progestogen replacement. British Journal of Obstetrics and Gynecology 99: 821–828, 1992

    Article  CAS  Google Scholar 

  • Farish E, Fletcher CD, Hart DM, Dagen MM, Parkin DE. Lipoprotein and apolipoprotein levels in postmenopausal women during treatment with norethisterone. Clinica Chimica Acta 159: 147–151, 1986

    Article  CAS  Google Scholar 

  • Farish E, Rolton HA, Barnes JF, Hart DM. Lipoprotein (a) concentrations in postmenopausal women taking norethisterone. British Medical Journal 303: 694, 1991

    Article  PubMed  CAS  Google Scholar 

  • Fotherby K. Pharmacokinetics of progestational compounds. Maturitas 8: 123–132, 1986

    Article  PubMed  CAS  Google Scholar 

  • Fraser DI. A review of the role of progestogens in hormonal replacement therapy: influence on bleeding patterns. Maturitas 8: 113–121, 1986

    Article  PubMed  CAS  Google Scholar 

  • Fraser DI, Whitehead MI, Endacott J, Morton J, Ryder TA, et al. Are fixed dose estrogen/progestogen combinations ideal for all HRT users? British Journal of Obstetrics and Gynecology 96: 776–782, 1989

    Article  CAS  Google Scholar 

  • Fraser DI, Wordsworth J, Parsons A, Stuart G, Whitehead MI, et al. The optimal dose of oral norethindrone acetate for addition to transdermal estradiol: a multicenter study. Fertility and Sterility 53: 460–468, 1990

    PubMed  CAS  Google Scholar 

  • Fraser D, Whitehead M, Schenkel L, Pryse-Davies J. Does low-dose, transdermal, norethisterone acetate reliably cause endometrial transformation in postmenopausal oestrogen-users? Maturitas 16: 23–30, 1993

    Article  PubMed  CAS  Google Scholar 

  • Gambrell RD. Prevention of endometrial cancer with progestogens. Maturitas 8: 159–168, 1986

    Article  PubMed  Google Scholar 

  • Gangar KR, Fraser D, Cust MP, Whitehead MI. Endometrial histology and bleeding patterns with continuous, transdermal oestradiol and sequential, transdermal low-dose norethisterone acetate. Abstract. XII Congress of Gynecology and Obstetrics, Rio de Janiero, October 23–28, 1988a

  • Gangar K, Fraser D, Whitehead M, Schenkel L, Fankhauser P. Endometrial response to transdermal norethindrone. Abstract. Fertility and Sterility 50 (Suppl.): S90, 1988b

    Google Scholar 

  • Gangar K. Endometrial histology and bleeding patterns during administration of continuous transdermal norethisterone acetate. Preliminary report. Abstract. XII Congress of Gynecology and Obstetrics, Rio de Janiero, October 23–28, 1988c

  • Gangar KF, Vyas S, Whitehead M, Crook D, Meire H, et al. Pulsatility index in internal carotid artery in relation to transdermal oestradiol and time since menopause. Lancet 338: 839–842, 1991

    Article  PubMed  CAS  Google Scholar 

  • Godsland IF, Gangar K, Walton C, Cust MP, Whitehead MI, et al. Insulin resistance, secretion, and elimination in postmenopausal women receiving oral or transdermal hormone replacement therapy. Metabolism 42: 846–853, 1993

    Article  PubMed  CAS  Google Scholar 

  • Grady D, Rubin SM, Petitti DB, Fox CS, Black D, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Annals of Internal Medicine 117: 1016–1036, 1992

    PubMed  CAS  Google Scholar 

  • Henderson BE, Paganini-Hill A, Ross R. Estrogen replacement therapy and protection from acute myocardial infarction. American Journal of Obstetrics and Gynecology 159: 27–31, 1988

    Google Scholar 

  • Hillard TC, Crayford TB, Bourne TH, Collins WP, Whitehead MI, et al. Differential effects of transdermal estradiol and sequential progestogens on impedance to flow within the uterine arteries of postmenopausal women. Fertility and Sterility 58: 959–963, 1992a

    PubMed  CAS  Google Scholar 

  • Hillard TC, Siddle NC, Whitehead MI, Fraser DI, Pryse-Davies J. Continuous combined conjugated equine estrogen-progestogen therapy: effects of medroxyprogesterone acetate and norethindrone acetate on bleeding patterns and endometrial histologic diagnosis. American Journal of Obstetrics and Gynecology 167: 1–7, 1992b

    PubMed  CAS  Google Scholar 

  • Hirvonen E, Malkonen M, Manninen V. Effects of different progestogens on lipoproteins during postmenopausal replacement therapy. New England Journal of Medicine 304: 560–563, 1981

    Article  PubMed  CAS  Google Scholar 

  • Hsueh AJW, Peck EJ, Clark JH. Control of uterine estrogen receptor levels by progesterone. Endocrinology 98: 438–444, 1976

    Article  PubMed  CAS  Google Scholar 

  • Hunter M, Battersby R, Whitehead M. Relationships between psychological symptoms, somatic complaints and menopausal status. Maturitas 8: 217–228, 1986

    Article  PubMed  CAS  Google Scholar 

  • Ingegno MD, Money SR, Thelmo W, Greene GL, Davidian M, et al. Progesterone receptors in the human heart and great vessels. Laboratory Investigation 59: 353–356, 1988

    PubMed  CAS  Google Scholar 

  • Jasonni VM, Bulletti C, Naldi S, Ciotti P, Di Cosmo D, et al. Biological and endocrine aspects of transdermal 17β-estradiol administration in postmenopausal women. Maturitas 10: 263–270, 1988

    Article  PubMed  CAS  Google Scholar 

  • Jenkins CD, Stanton B-A, Niencryk SJ, Rose RM. A scale for the estimation of sleep problems in clinical research. Journal of Clinical Epidemiology 41: 313–321, 1988

    Article  PubMed  CAS  Google Scholar 

  • Keller PJ, Hotz E, Imthurn B. A transdermal regimen for continuous combined hormone replacement therapy in the menopause. Maturitas 15: 195–198, 1992

    Article  PubMed  CAS  Google Scholar 

  • Kuttenn F, Fournier S, Durand JC, Mauvais-Jarvis P. Estradiol and progesterone receptors in human breast fibroadenomas. Journal of Clinical Endocrinology and Metabolism 52: 1225–1229, 1981

    Article  PubMed  CAS  Google Scholar 

  • Laufer LR, DeFazio JL, Lu JKH, Meldrum DR, Eggena P, et al. Estrogen replacement therapy by transdermal estradiol administration. American Journal of Obstetrics and Gynecology 146: 553, 1983

    Google Scholar 

  • Leather AT, Savvas M, Studd JWW. Endometrial histology and bleeding patterns after 8 years of continuous combined estrogen and progestogen therapy in postmenopausal women. Obstetrics and Gynecology 78: 1008–1010, 1991

    PubMed  CAS  Google Scholar 

  • Lee AJ, Lowe GDO, Smith WCS, Tunstall-Pedoe H. Plasma fibrinogen in women: relationships with oral contraception, the menopause and hormone replacement therapy. British Journal of Haematology 83: 616–621, 1993

    Article  PubMed  CAS  Google Scholar 

  • Lin AL, McGill HC Jr, Shain SA. Hormone receptors of the baboon cardiovascular system: biochemical characterization of aortic and myocardial cytoplasmic progesterone receptors. Circulation Research 50: 610–616, 1982

    Article  PubMed  CAS  Google Scholar 

  • Lindgren R, Berg G, Hammar M, Larsson-Cohn U, Olsson AG. Plasma lipid and lipoprotein effects of transdermal administration of estradiol and estradiol/norethisterone acetate. European Journal of Obstetrics Gynecology and Reproductive Biology 47: 213–221, 1992a

    Article  CAS  Google Scholar 

  • Lindgren R, Risberg B, Hammar M, Berg G, Pryse-Davies J. Endometrial effects of transdermal estradiol/norethisterone acetate. Maturitas 15: 71–78, 1992b

    Article  PubMed  CAS  Google Scholar 

  • Loscalzo J. Lipoprotein(a): a unique risk factor for atherothrombotic disease. Arteriosclerosis 10: 671–679, 1990

    Google Scholar 

  • Martin KA, Freeman MW. Postmenopausal hormone replacement therapy. New England Journal of Medicine 328: 115–117, 1993

    Google Scholar 

  • Matthews KA, Meilahn E, Kuller LH, Kelsey SF, Caggiula AW, et al. Menopause and risk factors for coronary heart disease. New England Journal of Medicine 321: 641–646, 1989

    Article  PubMed  CAS  Google Scholar 

  • Meade TW, Haines AP, Imeson JD, Stirling Y, Thompson SG. Menopausal status and haemostatic variables. Lancet 1: 22–24, 1983

    Article  PubMed  CAS  Google Scholar 

  • Meade TW, Dyer S, Howarth DJ, Imeson JD, Stirling Y. Antithrombin III and procoagulant activity: sex differences and effects of the menopause. British Journal of Haematology 74: 77–81, 1990

    Article  PubMed  CAS  Google Scholar 

  • Nabulsi AA, Folsom AR, White A, Patsch W, Heiss G, et al. Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. New England Journal of Medicine 328: 1069–1075, 1993

    Article  PubMed  CAS  Google Scholar 

  • Nichols KC, Schenkel L, Benson H. 17β-Estradiol for postmenopausal estrogen replacement therapy. Obstetrical and Gynecological Survey 39 (Suppl.): 230–245, 1984

    Article  PubMed  CAS  Google Scholar 

  • Ottoson UB, Johansson BG, von Schoultz B. Subfractions of high-density lipoprotein cholesterol during estrogen replacement therapy: a comparison between progestogens and natural progesterone. American Journal of Obstetrics and Gynecology 151: 746–750, 1985

    Google Scholar 

  • Pattison NS, Uptin T, Knox B, France J. Transdermal oestrogen for postmenopausal women: a double blind crossover comparative study with ethinyl oestradiol. Australian and New Zealand Journal of Obstetrics and Gynaecology 29: 62–65, 1989

    Article  PubMed  CAS  Google Scholar 

  • Pelissier C. Long-term hormone substitution with transdermal oestradiol in sequence with combined transdermal norethisterone/oestradiol: a multi-country study. Abstract. 6th International Congress on Menopause, Bangkok, October 29–November 2, 1990

  • Persson I, Adami H-O, Bergkvist L. Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: results of a prospective study. British Medical Journal 298: 147–151, 1989

    Article  PubMed  CAS  Google Scholar 

  • Pryse-Davies J, Schenkel L. Evaluation of endometrial histology after one year of hormone substitution with transdermal oestradiol/progestogen. Abstract. 6th International Congress on Menopause, Bangkok, October 29–November 2, 1990

  • Ribot C, Tremollieres F, Pouilles JM. Effect of 17β-oestradiol and norethisterone acetate on vertebral bone mass and lipid metabolism in early postmenopausal women. Maturitas 15: 217–223, 1992

    Article  PubMed  CAS  Google Scholar 

  • Scanu AM. Lipoprotein(a): a genetic risk factor for premature coronary heart disease. Journal of the American Medical Association 267: 3326–3329, 1992

    Article  PubMed  CAS  Google Scholar 

  • Scanu AM, Fless GM. Lp(a): lipoprotein (a) heterogeneity and biological relevance. Journal of Clinical Investigation 85: 1709–1715, 1992

    Article  Google Scholar 

  • Schenkel L. Long-term treatment with transdermal oestradiol and sequential norethisterone acetate/oestradiol: analysis of bleeding patterns. Abstract. 6th International Congress on Menopause, Bangkok, October 29–November 2, 1990

  • Schenkel L. Characteristics of the combined estradiol-norethisterone acetate TTS. 7th Congress of the European Association of Gynaecologists and Obstetricians, Helsinki, June 28–July 1, 1992

  • Selby PL, McGarrigle HG, Peacock M. Comparison of the effects of oral and transdermal oestradiol administration on oestrogen metabolism, protein synthesis, gonadotrophin release, bone turnover and climacteric symptoms in postmenopausal women. Clinical Endocrinology 30: 241–249, 1989

    Article  PubMed  CAS  Google Scholar 

  • Sillero-Arenas M, Delgado-Rodriguez M, Rodriguez-Canteras R, Bueno-Cavanillas A, Galves-Vargas R. Menopausal hormone replacement therapy and breast cancer: a meta-analysis. Obstetrics and Gynecology 79: 286–294, 1992

    PubMed  CAS  Google Scholar 

  • Silfverstolpe G, Gustafson A, Samsioe G, Svanborg A. Lipid metabolic studies in oophorectomized women. Effects of three different progestogens. Acta Obstetricia et Gynaecologica Scandinavica 88 (Suppl.): 89–95, 1979

    Article  CAS  Google Scholar 

  • Sporrong T, Hellgren M, Samsioe G, Mattson LA. Comparison of four continuously administered progestogen plus oestradiol combinations for climacteric complaints. British Journal of Obstetrics and Gynaecology 95: 1042–1048, 1988

    Article  PubMed  CAS  Google Scholar 

  • Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Preventive Medicine 20: 47–63, 1991

    Article  PubMed  CAS  Google Scholar 

  • Stanczyk FZ, Shoupe D, Nunez V, Marcias-Gonzales P, Vijod MA, et al. A randomised comparison of nonoral estradiol delivery in postmenopausal women. American Journal of Obstetrics and Gynecology 159: 1540–1560, 1988

    PubMed  CAS  Google Scholar 

  • Steinberg KK, Thacker SB, Smith SJ, Zack MM, Flanders WD, et al. A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. Journal of the American Medical Association 265: 1985–1990, 1991

    Article  PubMed  CAS  Google Scholar 

  • Stevenson JC, Cust MP, Gangar KF, Hillard TC, Lees B, et al. Effects of transdermal versus oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women. Lancet 336: 265–269, 1990

    Article  PubMed  CAS  Google Scholar 

  • Stevenson JC, Crook D, Godsland IF. Influence of age and menopause on serum lipids and lipoproteins in healthy women. Atherosclerosis 98: 83–90, 1993

    Article  PubMed  CAS  Google Scholar 

  • Uvebrant M, Mattson L-A, Sandin K. Continuous transdermal administration of combined oestrogen/progestogen for climacteric symptoms. Abstract. 6th International Congress on Menopause, Bangkok, October 29–November 2, 1990

  • Walsh BW, Schiff I, Rosner B, Greenburg L, Ravnikar V, Sacks FM. Effects of postmenopausal estrogen replacement on the concentration and metabolism of plasma lipoproteins. New England Journal of Medicine 325: 1196–1204, 1991

    Article  PubMed  CAS  Google Scholar 

  • Whitehead MI, McQueen J, King RJB, Campbell S. Endometrial histology and biochemistry in climacteric women during oestrogen and oestrogen/progestogen therapy. Journal of the Royal Society of Medicine 72: 322–327, 1979

    PubMed  CAS  Google Scholar 

  • Whitehead MI, Townsend PT, Pryse-Davies J, Ryder TA, King RJB. Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium. New England Journal of Medicine 305: 1599–1604, 1981

    Article  PubMed  CAS  Google Scholar 

  • Whitehead MI, Fraser D. The effects of estrogens and progestogens on the endometrium: a modern approach to treatment. Obstetrics and Gynecology Clinics of North America 14: 299–319, 1987

    PubMed  CAS  Google Scholar 

  • Whitehead MI, Fraser D, Schenkel L, Crook D. Transdermal administration of oestrogen/progestogen hormone replacement therapy. Lancet 335: 310–312, 1990a

    Article  PubMed  CAS  Google Scholar 

  • Whitehead MI. Long-term experience with combined oestradiol/norethisterone acetate — TTS. Abstract. 6th International Congress on Menopause, Bangkok, October 29–November 2, 1990b

  • Wiklund I, Berg G, Hammar M, Karlberg J, Lindgren R, et al. Long-term effect of transdermal hormonal therapy on aspects of quality of life in postmenopausal women. Maturitas 14: 225–236, 1992

    Article  PubMed  CAS  Google Scholar 

  • Williams SR, Frenchek B, Speroff T, Speroff L. Astudy of combined continuous ethinyl estradiol and norethindrone acetate for postmenopausal hormone replacement. American Journal of Obstetric and Gynecology 162: 438–446, 1990

    CAS  Google Scholar 

  • Wolf P, Madans J, Finucane F. Reduction of cardiovascular disease-related mortality among postmenopausal women who use hormones: evidence from a national cohort. American Journal of Obstetrics and Gynecology 164: 489–494, 1991

    PubMed  CAS  Google Scholar 

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Various sections of the manuscript reviewed by: A. Cagnacci, Instituto di Clinica Obstetrica e Ginecologica, Ospedale S. Giovanni di Dio, Cagliari, Italy; M. Cortellaro, Instituto di Medicina Interna, Pad Granelli, Milan, Italy; M. Falkeborn, Department of Geriatrics, University of Uppsala, Uppsala, Sweden; I.F. Godsland, Wynn Institute for Metabolic Research, London, England; P.J. Keller, Department of Obstetrics and Gynecology, University Hospital, Zurich, Switzerland; R. Lindgren, Department of Obstetrics and Gynaecology, University Hospital of Linköping, Linköping, Sweden; M.S. Marsh, Academic Department of Obstetrics and Gynaecology, King’s College of Medicine and Dentistry, London, England; D.E. Meier, Department of Geriatrics and Adult Development, The Mount Sinai School of Medicine, New York, New York, USA; A.D. Mooradian, Department of Internal Medicine, St Louis University Medical Center, St Louis, Missouri, USA; J. Pryse- Davies, Wimbledon, London, England.

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Wiseman, L.R., McTavish, D. Transdermal Estradiol/Norethisterone. Drugs & Aging 4, 238–256 (1994). https://doi.org/10.2165/00002512-199404030-00006

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