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Estradiol and Norgestimate

A Review of Their Combined Use as Hormone Replacement Therapy in Postmenopausal Women

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Summary

Abstract

The focus of this review is hormone replacement therapy (HRT) with continuous administration of micronised, oral 17β-estradiol 1 mg/day (herein referred to as continuous estradiol) plus micronised, oral norgestimate 90 μg/day administered for 3 days then withdrawn for 3 days in a 6-day repeating sequence (herein referred to as intermittent norgestimate).

According to data from randomised, comparative trials of 1 year’s duration, continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day relieves climacteric symptoms (vasomotor symptoms and vulvovaginal atrophy) in postmenopausal women. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day appeared as effective as estradiol 1 mg/day alone or continuous estradiol 2 mg/day plus continuous norethisterone acetate 1 mg/day in the treatment of postmenopausal women with vasomotor symptoms. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day was as effective as continuous estradiol 1 mg/day in causing the maturation of vaginal epithelial cells.

In a randomised, double-blind study, bone mineral density (BMD) increased to a significantly greater extent and the rate of bone turnover was slower in postmenopausal women treated with continuous oral estradiol 1 mg/day plus intermittent norgestimate 90 μg/day than in placebo-treated patients.

Two randomised, double-blind studies indicated that the addition of norgestimate 90 μg/day to continuous estradiol 1 mg/day did not attenuate the beneficial effects of estradiol on lipid parameters. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day was associated with increases in mean serum high density lipoprotein (HDL)-cholesterol levels and decreases in total cholesterol, low density lipoprotein (LDL)-cholesterol and lipoprotein (a) levels, compared with baseline. There was no statistically significant increase in triglyceride levels.

In comparative trials, continuous oral estradiol 1 mg/day plus intermittent oral norgestimate 90 μg/day was well tolerated. Headache, breast pain or discomfort, abdominal pain or discomfort, uterine bleeding, dysmenorrhoea, oedema, nausea and depression were the most commonly reported adverse events. Continuous estradiol 1 mg/day plus intermittent oral norgestimate 90 μg/day was associated with a favourable uterine bleeding profile that improved over time. In a randomised trial, 80% of women were free from bleeding (irrespective of spotting) during month 12 of treatment. Norgestimate 90 μg/day was effective in protecting postmenopausal women against induction of endometrial hyperplasia by continuous estradiol 1 mg/day.

In conclusion, data from a limited number of randomised studies indicate that HRT with continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day is effective in relieving climacteric symptoms, increasing BMD and slowing the rate of bone turnover in postmenopausal women. This HRT regimen is well tolerated and is associated with a similar incidence of adverse events to that reported in recipients of continuous estradiol 1 mg/day. The norgestimate component of the regimen provides good endometrial protection and is associated with a favourable bleeding profile. Long-term studies investigating the associated risk of breast cancer and thromboembolic events in recipients of continuous estradiol plus intermittent norgestimate are needed. In the meantime, continuous oral estradiol plus intermittent oral norgestimate can be regarded as an effective new option for HRT in postmenopausal women.

Pharmacodynamic Profile

This review concerns hormone replacement therapy (HRT) in the form of continuous administration of micronised, oral 17β-estradiol 1 mg/day (herein referred to as continuous estradiol) plus micronised, oral norgestimate 90 μg/day administered for 3 days then withdrawn for 3 days in a 6-day repeating sequence (herein referred to as intermittent norgestimate).

Animal studies have shown that progestogens inhibit the synthesis of their own receptors as well as estrogen receptors in the endometrium. By administering norgestimate in an intermittent manner, this inhibition is periodically removed. When norgestimate is withdrawn, the unopposed estrogen increases the number of estrogen and progestogen receptors. The target cells are thus resensitised to both these hormones, allowing a lower total dosage of norgestimate to be administered.

In two randomised trials in postmenopausal women, the addition of intermittent norgestimate 90 μg/day did not negate the beneficial effects of estradiol 1 mg/day on lipid and lipoprotein levels in postmenopausal women. Treatment with continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day was associated with increases in mean serum high density lipoprotein (HDL)- (5 and 10%) and HDL2- (24 and 29%) cholesterol and apolipoprotein A1 levels (7%) and decreases in total cholesterol (2 and 9%), low density lipoprotein (LDL)-cholesterol (5 and 15%) and lipoprotein (a) [11 and 31%], compared with baseline. Although triglyceride levels increased by 4 to 9%, this increase was not statistically significant compared with baseline.

Continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day had a more beneficial effect on the lipid/lipoprotein profile than continuous oral estradiol 2 mg/day plus norethisterone acetate 1 mg/day in a randomised, doubleblind study.

Pharmacokinetic Properties

Following multiple doses of continuous estradiol plus intermittent norgestimate, estradiol reached a peak serum concentration (Cmax) of 46.2 ng/L after approximately 7 hours. The plasma elimination half-life (t½β) of estradiol is approximately 16 hours. Estradiol is metabolised in the liver to estrone, estriol and their conjugates. The metabolites are mainly excreted as sulphate and glucuronide conjugates in the urine, although some enterohepatic recirculation may occur. Norgestimate is extensively metabolised by first-pass mechanisms in the gastrointestinal tract and/or liver to 17-deacetylnorgestimate (norelgestromin). The Cmaxof 17-deacetylnorgestimate of 643 ng/L was reached after 2 hours. The mean t½β of 17-deacetylnorgestimate was 37 hours. Norgestimate metabolites are eliminated in the urine or faeces.

Therapeutic Use

In three randomised, 1-year studies, treatment with continuous estradiol 1 mg/ day plus intermittent norgestimate 90 μg/day was effective in eliminating climacteric symptoms. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day appeared as effective as continuous unopposed estradiol 1 mg/day or continuous estradiol 2 mg/day plus continuous norethisterone acetate 1 mg/day in the treatment of postmenopausal women with vasomotor symptoms, with ≥70% of women free from symptoms at 3 to 4 months. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day was as effective as continuous unopposed estradiol 1 mg/day in causing the maturation of vaginal epithelial cells.

In a randomised, double-blind study, bone mineral density increased to a significantly greater extent and the rate of bone turnover was slower in postmenopausal women treated with continuous oral estradiol 1 mg/day plus intermittent norgestimate 90 μg/day than in placebo-treated patients.

Tolerability

In comparative 1-year trials, continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day was well tolerated. Headache, breast discomfort, abdominal discomfort, uterine bleeding, dysmenorrhoea, oedema, nausea and depression were the most commonly reported adverse events. The incidence of adverse events associated with continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day was similar to that in recipients of continuous estradiol 1 mg/day, with the exception of breast pain, which tended to be more commonly reported in this group. However, slightly fewer recipients of continuous estradiol plus intermittent norgestimate than recipients of continuous estradiol alone withdrew because of adverse events (7 vs 16%).

In a 12-month, randomised study, the incidence of breast discomfort, abdominal pain, oedema and dysmenorrhoea was lower in postmenopausal women treated with continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day than in women treated with continuous estradiol 2 mg/day plus continuous norethisterone acetate 1 mg/day.

Randomised trials indicated that continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day was associated with a uterine bleeding profile that improved over time. In a combined analysis of two randomised, double-blind 1-year trials, 69, 71 and 80% of women were free from bleeding (irrespective of spotting) at 1, 6 and 12 months, respectively. In a randomised 1-year trial, continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day had a bleeding profile that was similar to that of continuous oral estradiol 2 mg/day plus continuous norethisterone acetate 1 mg/day.

In a comparative trial in postmenopausal women, 90 μg/day was the minimal dosage of norgestimate that was required to protect postmenopausal women against induction of endometrial hyperplasia in a regimen of intermittent norgestimate and continuous estradiol 1 mg/day. Endometrial hyperplasia developed in 28% of women treated with continuous estradiol 1 mg/day alone, and in 6, 0 and 0% of women after the addition of intermittent norgestimate 30, 90 and 180 μg/day, respectively.

Dosage and Administration

In the continuous estradiol plus intermittent norgestimate regimen, a single oral tablet containing estradiol 1mg is taken once daily for the first 3 days of therapy, and a different tablet containing estradiol 1mg plus norgestimate 90μg is taken once daily on days 3 to 6. This 6-day sequence is then repeated continuously.

Estradiol 1 mg/day plus intermittent norgestimate 90 μg/day is contraindicated in women with known or suspected pregnancy, undiagnosed abnormal genital bleeding, known or suspected cancer of the breast, known or suspected estrogen-dependent neoplasia, or active or past history of thrombophlebitis or thromboembolic disorders.

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References

  1. Balfour JA, Heel RC. Transdermal estradiol: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of menopausal complaints. Drugs 1990; 40(4): 561–82

    Article  PubMed  CAS  Google Scholar 

  2. Jacobs S, Hillard TC. Hormone replacement therapy in the aged: a state of the art review. Drugs Aging 1996; 8(3): 193–213

    Article  PubMed  CAS  Google Scholar 

  3. Panay N, Studd J. Progestogen intolerance and compliance with hormone replacement therapy in menopausal women. Hum Reprod Update 1997; 3: 159–71

    Article  PubMed  CAS  Google Scholar 

  4. Whitehead MI. The effects of oestrogens and progestogens on the postmenopausal endometrium. Maturitas 1978; 1(5): 87–98

    Article  PubMed  CAS  Google Scholar 

  5. Thom MH, White PJ, Williams RM, et al. Prevention and treatment of endometrial disease in climacteric women receiving oestrogen therapy. Lancet 1979; II: 455–7

    Article  Google Scholar 

  6. Samsioe G. Hormone replacement therapy: aspects of bleeding problems and compliance. Int J Fertil 1996; 41: 11–5

    CAS  Google Scholar 

  7. Casper RF. Regulation of estrogen/progestogen receptors in the endometrium. Int J Fertil 1996; 41: 16–21

    CAS  Google Scholar 

  8. Casper RF. Estrogen with interrupted progestin HRT: a review of experimental and clinical trials. Maturitas 2000; 34: 97–108

    Article  PubMed  CAS  Google Scholar 

  9. Rozenberg S. Clinical evidence supporting the rationale for constant oestrogen, intermittent progestogen hormone replacement therapy. Eur J Obstet Gynecol Reprod Biol 2001; 94: 86–91

    Article  PubMed  CAS  Google Scholar 

  10. Eckert RL, Katzenellenbogen BS. Human endometrial cells in primary tissue culture: modulation of the progesterone receptor level by natural and synthetic estrogens in vitro. J Clin Endocrinol Metab 1981; 52: 699–708

    Article  PubMed  CAS  Google Scholar 

  11. Walters MR, Clark JH. Relationship between the quantity of progesterone receptor and the antagonism of estrogen-induced uterotropic response. Endocrinology 1979; 105: 382–6

    Article  PubMed  CAS  Google Scholar 

  12. West NB, Brenner RM. Progesterone-mediated suppression of estradiol receptors in cynomolgus macaque cervix, endometrium and oviduct during sequential estradiol-progesterone treatment. J Steroid Biochem Mol Biol 1985; 22: 29–37

    CAS  Google Scholar 

  13. Lievertz RW. Pharmacology and pharmacokinetics of estrogens. Am J Obstet Gynecol 1987; 156(5): 1289–93

    PubMed  CAS  Google Scholar 

  14. Baird DT, Fraser IS. Blood production and ovarian secretion rates of estradiol–17β and estrone in women throughout the menstrual cycle. J Clin Endocrinol Metab 1974; 38(6): 1009–17

    Article  PubMed  CAS  Google Scholar 

  15. Foster HF, Balfour JA. Estradiol and dydrogesterone; a review of their combined use as hormone replacement therapy in postmenopausal women. Drugs Aging 1997 Oct; 11(4): 309–32

    Article  PubMed  CAS  Google Scholar 

  16. Phillips A, Demarest K, Hahn DW, et al. Progestational and androgenic receptor binding affinities and in vivo activities of norgestimate and other progestins. Contraception 1990; 41: 399–410

    Article  PubMed  CAS  Google Scholar 

  17. Killinger J, Hahn DW, Phillips A, et al. The affinity of norgestimate for uterine progestogen receptors and its direct action on the uterus. Contraception 1985; 32: 311–9

    Article  PubMed  CAS  Google Scholar 

  18. Phillips A, Hahn DW, Klimek S, et al. A comparison of the potencies and activities of progestogens used in contraceptives. Contraception 1987; 36: 181–92

    Article  PubMed  CAS  Google Scholar 

  19. McGuire JL, Phillips A, Hahn DW, et al. Pharmacologic and pharmacokinetic characteristics of norgestimate and its metabolites. Am J Obstet Gynecol 1990; 163: 2127–31

    PubMed  CAS  Google Scholar 

  20. Phillips A, Hahn DW, Phillips A, et al. Relative binding affinity of norgestimate and other progestins for human sex hormone-binding globulin. Steroids 1990; 55: 373–5

    Article  PubMed  CAS  Google Scholar 

  21. Chapdelaine A, Desmarais J-L, Derman RJ. Clinical evidence of the minimal androgenic activity of norgestimate. Int J Fertil 1989; 34: 347–52

    PubMed  CAS  Google Scholar 

  22. Phillips A, Hahn DW, McGuire JL. Preclinical evaluation of norgestimate, a progestin with minimal androgenic activity. Am J Obstet Gynecol 1992; 167: 1191–6

    PubMed  CAS  Google Scholar 

  23. Bringer J. Norgestimate: a clinical overview of anew progestin. Am J Obstet Gynecol 1992; 166: 1967–77

    Google Scholar 

  24. Vanin CM, MacLusky NJ, Grynpas MD, et al. The effect of three hormone replacement regimens on bone density in the aged ovariectomized rat. Fertil Steril 1995; 63: 643–51

    PubMed  CAS  Google Scholar 

  25. Vanin CM, MacLusky NJ, Chachra D, et al. Lumbar vertebral density and mechanical properties in aged ovariectomized rats treated with estrogen and norethindrone or norgestimate. Am J Obstet Gynecol 1995; 173: 1491–8

    Article  PubMed  CAS  Google Scholar 

  26. Kasra M, Vanin CM, MacLusky NJ, et al. Effects of different estrogen and progestin regimens on the mechanical properties of the rat femur. J Orthop Res 1997; 15: 118–23

    Article  PubMed  CAS  Google Scholar 

  27. Stevenson JC, Crook D, Godsland IF. Hormone replacement therapy and the cardiovascular system: nonlipid effects. Drugs 1994; 47Suppl. 2: 35–41

    Article  PubMed  Google Scholar 

  28. American Heart Association. 2001 Heart and stroke statistical update. Dallas, Texas

    Google Scholar 

  29. North American Menopause Society. A decision tree for the use of estrogen replacement therapy or hormone replacement therapy in postmenopausal women: consensus opinion of the North American Menopause Society. Menopause 2000; 7: 76–86

    Article  Google Scholar 

  30. Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995; 273: 199–208

    Article  Google Scholar 

  31. Lobo RA, Notelovitz M, Bernstein L, et al. Lp(a) lipoprotein: relationship to cardiovascular disease risk factors, exercise and estrogen. Am J Obstet Gynecol 1992; 166: 1182–90

    PubMed  CAS  Google Scholar 

  32. O’Brien T, Nguyen TT. Lipids and lipoproteins in women. Mayo Clin Proc 1997; 72: 235–44

    Article  PubMed  Google Scholar 

  33. Walsh BW, Schiff I, Rosner B, et al. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991; 325: 1196–204

    Article  PubMed  CAS  Google Scholar 

  34. Hirvonen E, Mälkönen M, Manninen V. Effects of different progestogens on lipoproteins during postmenopausal replacement therapy. N Engl J Med 1981; 304: 560–3

    Article  PubMed  CAS  Google Scholar 

  35. Ylikorkala O, Lim P, Caubel P. Effects on serum lipid profiles of continuous 17 β-estradiol, intermittent norgestimate regimens versus continuous combined 17β-estrasdiol/norethisterone acetate hormone replacement therapy. Clin Ther 2000; 22(5): 622–36

    Article  PubMed  CAS  Google Scholar 

  36. Lobo RA, Zacur HZ, Caubel P, et al. A novel intermittent regimen of norgestimate to preserve the beneficial effects of 17 β-estradiol on lipid and lipoprotein profiles. Am J Obstet Gynecol 2000; 182: 41–9

    Article  PubMed  CAS  Google Scholar 

  37. Tikkanen MJ. The menopause and hormone replacement therapy: lipids, lipoproteins, coagulation and fibrinolytic factors. Maturitas 1996 Mar; 23: 209–16

    Article  PubMed  CAS  Google Scholar 

  38. Krauss RM. Effects of progestational agents on serum lipids and lipoproteins. J Reprod Med 1982; 27: 503–10

    PubMed  CAS  Google Scholar 

  39. Campisi D, Bivona A, Paterna S, et al. Oestrogen binding sites in fresh human aortic tissue. Int J Tissue React 1987; 9: 393–8

    PubMed  CAS  Google Scholar 

  40. Ingegno MD, Money SR, Thelmo W, et al. Progesterone receptors in the human heart and great vessels. Lab Invest 1988; 59: 353–6

    PubMed  CAS  Google Scholar 

  41. Gangar KF, Vyas S, Whitehead M, et al. Pulsatility index in the internal carotid artery is influenced by transdermal oestradiol and time since menopause. Lancet 1991; 338: 839–42

    Article  PubMed  CAS  Google Scholar 

  42. Bourne T, Hillard TC, Whitehead MI, et al. Oestrogens, arterial status, and postmenopausal women [letter]. Lancet 1990; 335: 1470–1

    Article  PubMed  CAS  Google Scholar 

  43. Collins P, Rosano GMC, Jiang C, et al. Cardiovascular protection by oestrogen — a calcium antagonistic effect. Lancet 1993; 341: 1264–5

    Article  PubMed  CAS  Google Scholar 

  44. Riedel M, Oeltermann A, Mügge A, et al. Vascular response to 17 β-oestradiol in postmenopausal women. Eur J Clin Invest 1995; 25(1): 44–7

    Article  PubMed  CAS  Google Scholar 

  45. Mosca L. The role of hormone replacement therapy in the prevention of postmenopausal heart disease. Arch Intern Med 2000; 160: 2263–72

    Article  PubMed  CAS  Google Scholar 

  46. Godsland IF, Gangar K, Walton C, et al. Insulin resistance, secretion and elimination in postmenopausal women receiving oral or transdermal hormone replacement therapy. Metabolism 1993; 42: 846–53

    Article  PubMed  CAS  Google Scholar 

  47. O’Sullivan AJ, Ho KKY. A comparison of the effects of oral and transdermal estrogen replacement on insulin activity in postmenopausal women. J Clin Endocrinol Metab 1995; 80(6): 1783–8

    Article  PubMed  Google Scholar 

  48. Prescribing information: Ortho-Prefest® (estradiol/norgestimate) tablets. Raritan (NJ): Ortho-McNeil Pharmaceutical Inc., 1999

  49. Gisclon LG, Curtin CR, Larson KL, et al. Lack of effect of a high-fat meal on the bioavailability of 17 β-estradiol/norgestimate in healthy postmenopausal women. J Clin Pharmacol 2000 Jul; 40: 762–9

    Article  PubMed  CAS  Google Scholar 

  50. Kuhl H. Pharmacokinetics of oestrogens and progestogens. Maturitas 1990; 12: 171–9

    Article  PubMed  CAS  Google Scholar 

  51. Belchetz PE. Hormonal treatment of postmenopausal women. N Engl J Med 1994; 330: 1062–71

    Article  PubMed  CAS  Google Scholar 

  52. Corson SL, Richart RM, Caubel P, et al. Effect of a unique constant-estrogen, pulsed-progestin hormone replacement therapy containing 17 β-estradiol and norgestimate on endometrial histology. Int J Fertil 1999 Nov–Dec; 44: 279–85

    CAS  Google Scholar 

  53. Sulak PJ, Caubel P, Lane R. Efficacy and safety of a constant-estrogen, pulsed-progestin regimen in hormone replacement therapy. Int J Fertil 1999; 44: 286–96

    CAS  Google Scholar 

  54. Rozenberg S, Caubel P, Lim PC. Constant estrogen, intermittent progestogen vs. continuous combined hormone replacement therapy: tolerability and effect on vasomotor symptoms. Int J Gynecol Obstet 2001 Mar; 72: 235–43

    Article  CAS  Google Scholar 

  55. Consensus Development Conference. diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 1993; 94: 646–50

    Google Scholar 

  56. Stevenson JC. Pathogenesis, prevention and treatment of osteoporosis. Obstet Gynecol 1990; 75Suppl. 4: 36S–41S

    PubMed  CAS  Google Scholar 

  57. Cummings SR, Black DM, Rubin SM. Life-time risks of hip, Colles’, or vertebral fracture and coronary heart disease among white postmenopausal women. Arch Intern Med 1989; 149: 2445–8

    Article  PubMed  CAS  Google Scholar 

  58. Greendale GA, Barret-Connor E, Ingles S, et al. Late physical and functional effects of osteoporotic fracture in women; the Rancho Bernardo Study. J Am Geriatr Soc 1995; 43: 955–61

    PubMed  CAS  Google Scholar 

  59. Manson JE, Martin KA. Postmenopausal hormone-replacement therapy. N Engl J Med 2001; 345(1): 34–40

    Article  PubMed  CAS  Google Scholar 

  60. Hillard TC, Whitcroft SJ, Marsh MS, et al. Long-term effects of transdermal and oral hormone replacement therapy on postmenopausal bone loss. Osteoporos Int 1994; 4: 341–8

    Article  PubMed  CAS  Google Scholar 

  61. Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992; 117: 1016–37

    PubMed  CAS  Google Scholar 

  62. Dempster DEW, Lindsay R. Pathogenesis of osteoporosis. Lancet 1993; 341: 797–801

    Article  PubMed  CAS  Google Scholar 

  63. Horowitz M, Wishart JM, Need AG, et al. Effects of norethisterone on bone related biochemical variables and forearm bone mineral in post-menopausal osteoporosis. Clin Endocrinol 1993; 39: 649–55

    Article  CAS  Google Scholar 

  64. Felsenberg D, van der Ouweland F, Friedman MD. Ortho-Prefest for the prevention of bone loss in postmenopausal women [abstract no. 107]. North American Menopause Society 12th Annual Meeting; 2001 Oct 4–6; New Orleans

  65. Barentsen R, Groeneveld FPMJ, Bareman FP, et al. Women’s opinion on withdrawal bleeding with hormone replacement therapy. Eur J Obstet Gynecol Reprod Biol 1993; 51: 203–7

    Article  PubMed  CAS  Google Scholar 

  66. Hammond CB. Women’s concerns with hormone replacement therapy — compliance issues. Fertil Steril 1994; 62Suppl. 2: 157S–60S

    PubMed  CAS  Google Scholar 

  67. Sturdee DW. Current hormone replacement therapy: what are the shortcomings? Advances in delivery. Int J Clin Pract 1999 Sep; 53: 468–72

    PubMed  CAS  Google Scholar 

  68. Udoff L, Langenberg P, Adashi EY. Combined continuous hormone replacement therapy: a critical review. Obstet Gynecol 1995; 86: 306–16

    Article  PubMed  CAS  Google Scholar 

  69. Johannisson E, Lim P. Endometrial effects on a 1-year pulsed progestogen, constant estrogen hormone replacement therapy, Prefest [abstract]. Eur J Obstet Gynecol Reprod Biol 1999; 86: S17

    Google Scholar 

  70. Grady D, Gebretsadik T, Kerlikowske K, et al. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol 1995; 85: 304–13

    Article  PubMed  CAS  Google Scholar 

  71. Clisham PR, Cedars MI, Greendale G, et al. Long-term transdermal estradiol therapy: effects on endometrial histology and bleeding patterns. Obstet Gynecol 1992; 79: 196–201

    PubMed  CAS  Google Scholar 

  72. Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1996; 275: 370–5

    Article  Google Scholar 

  73. Woodruff JD, Pickar JH. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. Am J Obstet Gynecol 1994; 170: 1213–23

    PubMed  CAS  Google Scholar 

  74. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer. Lancet 1997; 350: 1047–59

    Article  Google Scholar 

  75. Bush T, Whiteman M, Flaws JA. Hormone replacement therapy and breast cancer: a qualitative review. Obstet Gynecol 2001; 98: 498–508

    Article  PubMed  CAS  Google Scholar 

  76. Willis DB, Calle EE, Miracle-McMahill HL, et al. Estrogen replacement therapy and risk of fatal breast cancer in a prospective cohort of postmenopausal women in the United States. Cancer Causes Control 1996; 7: 449–57

    Article  PubMed  CAS  Google Scholar 

  77. Adami H-O, Persson I. Hormone replacement and breast cancer: a remaining controversy. JAMA 1995; 274: 178–9

    Article  PubMed  CAS  Google Scholar 

  78. Dupont WD, Page DL. Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med 1991; 151: 67–72

    Article  PubMed  CAS  Google Scholar 

  79. Steinberg KK, Thacker SB, Smith SJ, et al. A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 1991; 265: 1985–90

    Article  PubMed  CAS  Google Scholar 

  80. Grady D, Wenger NK, Herrington D, et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease: the Heart and Estrogen/progestin Replacement Study. Ann Intern Med 2000; 132: 689–96

    PubMed  CAS  Google Scholar 

  81. Lippman JS, Shangold GA. A review of post-marketing safety and surveillance data for oral contraceptives containing norgestimate and ethinyl estradiol. Int J Fertil 1997 Jul–Aug; 42: 230–9

    CAS  Google Scholar 

  82. Burnhill MS. The use of a large-scale surveillance system in Planned Parenthood Federation of America clinics to monitor cardiovascular events in users of combination oral contraceptives. Int J Fertil 1999; 44(1): 19–30

    CAS  Google Scholar 

  83. Col NF, Pauker SG, Goldberg RJ, et al. Individualizing therapy to prevent long-term consequences of estrogen deficiency in postmenopausal women. Arch Intern Med 1999; 159: 1458–66

    Article  PubMed  CAS  Google Scholar 

  84. Nawaz H, Katz DL. American College of Preventive Medicine practice policy statement: perimenopausal and postmenopausal hormone replacement therapy. Am J Prev Med 1999; 17: 250–4

    Article  PubMed  CAS  Google Scholar 

  85. Mosca L, Grundy SM, Judelson D, et al. Guide to preventive cardiology for women: AHA/ACC Scientific Consensus Panel statement. Circulation 1999; 99: 2480–4

    Article  PubMed  CAS  Google Scholar 

  86. Jacobs Institute of Women’s Health Expert Panel on Menopause Counseling. Guidelines for counseling women on the management of menopause. Washington, DC: Jacobs Institute of Women’s Health, 2000ai]

  87. Vihtamaki T, Savilahti R, Tuimala R. Why do postmenopausal women discontinue hormone replacement therapy? Maturitas 1999; 33: 99–105

    Article  PubMed  CAS  Google Scholar 

  88. Barrett-Connor E, Grady D. Hormone-replacement therapy, heart disease, and other considerations. Annu Rev Public Health 1998; 19: 55–72

    Article  PubMed  CAS  Google Scholar 

  89. Bush TL, Barrett-Connor E, Cowan LD, et al. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation 1987; 75(6): 1102–9

    Article  PubMed  CAS  Google Scholar 

  90. Stampfer MJ, Willet WC, Colditz GA, et al. Aprospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J Med 1985; 313: 1044–9

    Article  PubMed  CAS  Google Scholar 

  91. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280: 605–13

    Article  PubMed  CAS  Google Scholar 

  92. Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000; 343: 522–9

    Article  PubMed  CAS  Google Scholar 

  93. Mosca L, Collins P, Herrington DM, et al. Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 2001; 104: 499–503

    Article  PubMed  CAS  Google Scholar 

  94. Wilson PW, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking and cardiovascular morbidity in women over 50; The Framingham study. N Engl J Med 1985; 313: 1038–43

    Article  PubMed  CAS  Google Scholar 

  95. Paganini-Hill A, Ross RK, Henderson BE. Postmenopausal oestrogen treatment and stroke; a prospective study. BMJ 1988; 1988(297): 519–22

    Article  Google Scholar 

  96. Finucane FF, Madans JH, Bush TL, et al. Decreased risk of stroke among postmenopausal hormone users: results from a national cohort. Arch Intern Med 1993; 153: 73–9

    Article  PubMed  CAS  Google Scholar 

  97. Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996; 335: 453–61

    Article  PubMed  CAS  Google Scholar 

  98. Grodstein F, Manson JE, Colditz GA, et al. A prospective observational study of postmenopausal hormone replacement therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000; 133: 933–41

    PubMed  CAS  Google Scholar 

  99. Simon JA, Hsia J, Cauley JA, et al. Postmenopausal hormone replacement and risk of stroke: the Heart and Estrogen-progestin Replacement Study (HERS). Circulation 2001; 103(5): 620–2

    Article  Google Scholar 

  100. Yaffe K, Sawaya G, Lieberburg I, et al. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA 1998; 279: 688–95

    Article  PubMed  CAS  Google Scholar 

  101. Grodstein F, Chen J, Pollen DA, et al. Postmenopausal hormone therapy and cognitive function in healthy older women. J Am Geriatr Soc 2000; 48: 746–52

    PubMed  CAS  Google Scholar 

  102. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer’s Disease Cooperative Study. JAMA 2000; 283: 1007–10015

    Article  PubMed  CAS  Google Scholar 

  103. Runnebaum B, Grunwald K, Rabe T. The efficacy and tolerability of norgestimate/ethinyl estradiol (250 μg of norgestimate/35 μg of ethinyl estradiol): results of an open, multicenter study of 59,701 women. Am J Obstet Gynecol 1992 Jun; 166: 1963–8

    PubMed  CAS  Google Scholar 

  104. Anderson FD. Selectivity and minimal androgenicity of norgestimate in monophasic and triphasic oral contraceptives. Acta Obstet Gynecol Scand 1992; 156Suppl. 1: 15–21

    Article  CAS  Google Scholar 

  105. Schairer C, Lubin J, Troisi R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000; 283: 485–91

    Article  PubMed  CAS  Google Scholar 

  106. Uhler ML, Marks JW, Judd HL. Estrogen replacement therapy and gallbladder disease in postmenopausal women. Menopause 2000; 7(3): 162–7

    Article  PubMed  CAS  Google Scholar 

  107. North American Menopause Society. Achieving long-term continuance of menopausal ERT/HRT: Consensus Opinion of the North American Menopause Society. Menopause 1998; 5: 69–76

    Google Scholar 

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Monique P. Curran & Antona J. Wagstaff

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  1. Monique P. Curran
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  2. Antona J. Wagstaff
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Correspondence to Monique P. Curran.

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Curran, M.P., Wagstaff, A.J. Estradiol and Norgestimate. Drugs Aging 18, 863–885 (2001). https://doi.org/10.2165/00002512-200118110-00007

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