Lower Doses of Oral Estrogen and Progestogens as Treatment for Postmenopausal Women

ABSTRACT

Estrogen, with or without a progestin, is effective for the treatment of menopausal symptoms. Larger doses of estrogen/progestin have been used than required for the amelioration of menopausal symptoms. Both positive and negative outcomes of hormone therapy are reported in postmenopausal women. The positive aspects have been those associated with a reduction in menopausal symptoms such as hot flashes, and improvement in vulvovaginal atrophy with maintenance of bone mineral density. The problems have included an increased risk of venous thrombosis and breast cancer. The anticipation is that as the dose of oral estrogen and progestins is lowered, the benefits can be maintained and the side effects reduced. Recent clinical trials have found that lower doses of estrogen and/or progestin reduce or improve menopausal symptoms and maintain bone mineral density. The impact of lower doses of hormones on heart disease, and venous thromboembolism and stroke remain to be determined in future studies.

Oral estrogen - progestogen - menopausal symptoms - lipids - bone - lower doses

REFERENCES

• 1 Archer D F. The effect of the duration of progestin use on the occurrence of endometrial cancer in postmenopausal women.  Menopause. 2001;  8 245-251
• 2 Rossouw J E, Anderson G L, Prentice R L et al.. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial.  JAMA. 2002;  288 321-333
• 3 Archer D F, Pickar J H, Bottiglioni F. Bleeding patterns in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate. Menopause Study Group.  Obstet Gynecol. 1994;  83 686-692
• 4 Ettinger B, Selby J, Citron J T, Vangessel A, Ettinger V M, Hendrickson M R. Cyclic hormone replacement therapy using quarterly progestin.  Obstet Gynecol. 1994;  83 693-700
• 5 Ettinger B, Pressman A, Van Gessel A. Low-dosage esterified estrogens opposed by progestin at 6-month intervals.  Obstet Gynecol. 2001;  98 205-211
• 6 Archer D F, Dorin M H, Heine W, Nanavati N, Arce J C. Uterine bleeding in postmenopausal women on continuous therapy with estradiol and norethindrone acetate. Endometrium Study Group.  Obstet Gynecol. 1999;  94 323-329
• 7 Speroff L, Rowan J, Symons J, Genant H, Wilborn W. The comparative effect on bone density, endometrium, and lipids of continuous hormones as replacement therapy (CHART study). A randomized controlled trial.  JAMA. 1996;  276 1397-1403
• 8 Casper R F, Chapdelaine A. Estrogen and interrupted progestin: a new concept for menopausal hormone replacement therapy.  Am J Obstet Gynecol. 1993;  168 1188-1194
• 9 Corson S L, Richart R M, Caubel P, Lim P. Effect of a unique constant-estrogen, pulsed-progestin hormone replacement therapy containing 17beta-estradiol and norgestimate on endometrial histology.  Int J Fertil Womens Med. 1999;  44 279-285
• 10 Casper R F, MacLusky N J, Vanin C, Brown T J. Rationale for estrogen with interrupted progestin as a new low-dose hormonal replacement therapy.  J Soc Gynecol Investig. 1996;  3 225-234
• 11 Staland B. Continuous treatment with a combination of estrogen and gestagen-a way of avoiding endometrial stimulation. Clinical experiences with Kliogest.  Acta Obstet Gynecol Scand. 1985;  130 29-35
• 12 Sturdee D W, Ulrich L G, Barlow D H et al.. The endometrial response to sequential and continuous combined oestrogen-progestogen replacement therapy.  BJOG. 2000;  107 392-400
• 13 Stadberg E, Mattsson L A, Uvebrant M. 17 beta-estradiol and norethisterone acetate in low doses as continuous combined hormone replacement therapy.  Maturitas. 1996;  23 31-39
• 14 Utian W H, Shoupe D, Bachmann G, Pinkerton J V, Pickar J H. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate.  Fertil Steril. 2001;  75 1065-1079
• 15 Hulley S, Furberg C, Barrett-Connor E et al.. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II).  JAMA. 2002;  288 58-66
• 16 Manson J E, Hsia J, Johnson K C et al.. Estrogen plus progestin and the risk of coronary heart disease.  N Engl J Med. 2003;  349 523-534
• 17 Grodstein F, Manson J E, Colditz G A, Willett W C, Speizer F E, Stampfer M J. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease.  Ann Intern Med. 2000;  133 933-941
• 18 Gold E B, Sternfeld B, Kelsey J L et al.. Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40-55 years of age.  Am J Epidemiol. 2000;  152 463-473
• 19 Hlatky M A, Boothroyd D, Vittinghoff E et al.. Quality-of-life and depressive symptoms in postmenopausal women after receiving hormone therapy: results from the Heart and Estrogen/Progestin Replacement Study (HERS) trial.  JAMA. 2002;  287 591-597
• 20 Freedman R R. Physiology of hot flashes.  Am J Human Biol. 2001;  13 453-464
• 21 Freedman R R. Pathophysiology and treatment of menopausal hot flashes.  Semin Reprod Med. 2005;  23 117-125
• 22 Utian W H, Burry K A, Archer D F et al.. Efficacy and safety of low, standard, and high dosages of an estradiol transdermal system (Esclim) compared with placebo on vasomotor symptoms in highly symptomatic menopausal patients. The Esclim Study Group.  Am J Obstet Gynecol. 1999;  181 71-79
• 23 Speroff L, Symons J, Kempfert N, Rowan J. femhrt Study Investigators. The effect of varying low-dose combinations of norethindrone acetate and ethinyl estradiol (femhrt) on the frequency and intensity of vasomotor symptoms.  Menopause. 2000;  7 383-390
• 24 Notelovitz M, Mattox J H. Suppression of vasomotor and vulvovaginal symptoms with continuous oral 17beta-estradiol.  Menopause. 2000;  7 310-317
• 25 Simon J, Klaiber E, Wiita B, Bowen A, Yang H M. Differential effects of estrogen-androgen and estrogen-only therapy on vasomotor symptoms, gonadotropin secretion, and endogenous androgen bioavailability in postmenopausal women.  Menopause. 1999;  6 138-146
• 26 Rebar R W, Trabal J, Mortola J. Low-dose esterified estrogens (0.3 mg/day): long-term and short-term effects on menopausal symptoms and quality of life in postmenopausal women.  Climacteric. 2000;  3 176-182
• 27 Utian W H, Lederman S A, Williams B M, Vega R Y, Koltun W D, Leonard T W. Relief of hot flushes with new plant-derived 10-component synthetic conjugated estrogens.  Obstet Gynecol. 2004;  103 245-253
• 28 Rovati L C, Setnikar I, Genazzani A R. Dose-response efficacy of a new estradiol transdermal matrix patch for 7-day application: a randomized, double-blind, placebo-controlled study. Italian Menopause Research Group.  Gynecol Endocrinol. 2000;  14 282-291
• 29 MacLennan A, Lester S, Moore V. Oral estrogen replacement therapy versus placebo for hot flushes: a systematic review.  Climacteric. 2001;  4 58-74
• 30 MacLennan A, Lester A, Moore V. Oral oestrogen replacement therapy versus placebo for hot flushes.  Cochrane Database Syst Rev. 2001;  1 CD002978
• 31 Tice J A, Ettinger B, Ensrud K, Wallace R, Blackwell T, Cummings S R. Phytoestrogen supplements for the treatment of hot flashes: the Isoflavone Clover Extract (ICE) Study: a randomized controlled trial.  JAMA. 2003;  290 207-214
• 32 Kang H J, Ansbacher R, Hammoud M M. Use of alternative and complementary medicine in menopause.  Int J Gynaecol Obstet. 2002;  79 195-207
• 33 Notelovitz M, Cassel D, Hille D et al.. Efficacy of continuous sequential transdermal estradiol and norethindrone acetate in relieving vasomotor symptoms associated with menopause.  Am J Obstet Gynecol. 2000;  182(1 pt 1) 7-12
• 34 Schiff I, Regestein Q, Tulchinsky D, Ryan K J. Effects of estrogens on sleep and psychological state of hypogonadal women.  JAMA. 1979;  242 2405-2414
• 35 Barnabei V M, Grady D, Stovall D W et al.. Menopausal symptoms in older women and the effects of treatment with hormone therapy.  Obstet Gynecol. 2002;  100 1209-1218
• 36 Kravitz H M, Ganz P A, Bromberger J, Powell L H, Sutton-Tyrrell K, Meyer P M. Sleep difficulty in women at midlife: a community survey of sleep and the menopausal transition.  Menopause. 2003;  10 19-28
• 37 Freedman R R, Roehrs T A. Lack of sleep disturbance from menopausal hot flashes.  Fertil Steril. 2004;  82 138-144
• 38 Notelovitz M. Urogenital aging: solutions in clinical practice.  Int J Gynaecol Obstet. 1997;  59 S35-S39
• 39 Notelovitz M. Estrogen therapy in the management of problems associated with urogenital ageing: a simple diagnostic test and the effect of the route of hormone administration.  Maturitas. 1995;  22 S31-S33
• 40 Nachtigall L E. Comparative study: replens versus local estrogen in menopausal women.  Fertil Steril. 1994;  61 178-180
• 41 Grady D, Herrington D, Bittner V et al.. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II).  JAMA. 2002;  288 49-57
• 42 Hulley S, Grady D, Bush T et al.. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group.  JAMA. 1998;  280 605-613
• 43 Anderson G L, Limacher M, Assaf A R et al.. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial.  JAMA. 2004;  291 1701-1712
• 44 Lobo R A, Bush T, Carr B R, Pickar J H. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism.  Fertil Steril. 2001;  76 13-24
• 45 Davidson M H, Maki K C, Marx P et al.. Effects of continuous estrogen and estrogen-progestin replacement regimens on cardiovascular risk markers in postmenopausal women.  Arch Intern Med. 2000;  160 3315-3325
• 46 Lobo R A, Pickar J H, Wild R A, Walsh B, Hirvonen E. Metabolic impact of adding medroxyprogesterone acetate to conjugated estrogen therapy in postmenopausal women. The Menopause Study Group.  Obstet Gynecol. 1994;  84 987-995
• 47 The 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
• 48 Herrington D M, Vittinghoff E, Lin F et al.. Statin therapy, cardiovascular events, and total mortality in the Heart and Estrogen/Progestin Replacement Study (HERS).  Circulation. 2002;  105 2962-2967
• 49 Hodis H N, Mack W J, Lobo R A et al.. Estrogen in the prevention of atherosclerosis. A randomized, double- blind, placebo-controlled trial.  Ann Intern Med. 2001;  135 939-953
• 50 Herrington D M, Reboussin D M, Klein K P et al.. The estrogen replacement and atherosclerosis (ERA) study: study design and baseline characteristics of the cohort.  Control Clin Trials. 2000;  21 257-285
• 51 Grodstein F, Clarkson T B, Manson J E. Understanding the divergent data on postmenopausal hormone therapy.  N Engl J Med. 2003;  348 645-650
• 52 Wagner J D, Clarkson T B. The applicability of hormonal effects on atherosclerosis in animals to heart disease in postmenopausal women.  Semin Reprod Med. 2005;  23 149-156
• 53 Naftolin F, Taylor H S, Karas R et al.. The Women’s Health Initiative could not have detected cardioprotective effects of starting hormone therapy during the menopausal transition.  Fertil Steril. 2004;  81 1498-1501
• 54 Harman S M, Brinton E A, Clarkson T et al.. Is the WHI Relevant to HRT Started in the Perimenopause?.  Endocrine. 2004;  24 195-202
• 55 Feldman L, McMullan C, Abernathy T. Angina and socio-economic status in Ontario: how do characteristics of the county you live in influence your chance of developing heart disease?.  Can J Public Health. 2004;  95 228-232
• 56 Alter D A, Iron K, Austin P C. SESAMI Study Group . Influence of education and income on atherogenic risk factor profiles among patients hospitalized with acute myocardial infarction.  Can J Cardiol. 2004;  20 1219-1228
• 57 Rossouw J E, Jooste P L, Steenkamp H J, Thompson M L, Jordaan P C, Swanepoel A S. Socio-economic status, risk factors and coronary heart disease. The CORIS baseline study.  S Afr Med J. 1990;  78 82-85
• 58 Manson J E, Greenland P, LaCroix A Z et al.. Walking compared with vigorous exercise for the prevention of cardiovascular events in women.  N Engl J Med. 2002;  347 716-725
• 59 Archer D F, Pickar J H. Hormone replacement therapy: effect of progestin dose and time since menopause on endometrial bleeding.  Obstet Gynecol. 2000;  96 899-905
• 60 Ferenczy A, Gelfand M. The biologic significance of cytologic atypia in progestogen-treated endometrial hyperplasia.  Am J Obstet Gynecol. 1989;  160 126-131
• 61 Kurman R J, Kaminski P F, Norris H J. The behavior of endometrial hyperplasia. A long-term study of “untreated” hyperplasia in 170 patients.  Cancer. 1985;  56 403-412
• 62 Kurman R J, Felix J C, Archer D F, Nanavati N, Arce J, Moyer D L. Norethindrone acetate and estradiol-induced endometrial hyperplasia.  Obstet Gynecol. 2000;  96 373-379
• 63 Woodruff J D, Pickar J H. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. The Menopause Study Group.  Am J Obstet Gynecol. 1994;  170(5 pt 1) 1213-1223
• 64 The 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;  275 370-375
• 65 Pickar J H, Thorneycroft I, Whitehead M. Effects of hormone replacement therapy on the endometrium and lipid parameters: a review of randomized clinical trials, 1985 to 1995.  Am J Obstet Gynecol. 1998;  178 1087-1099
• 66 Pickar J H, Yeh I, Wheeler J E, Cunnane M F, Speroff L. Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate.  Fertil Steril. 2001;  76 25-31
• 67 Pickar J H, Yeh I T, Wheeler J E, Cunnane M F, Speroff L. Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate: two-year substudy results.  Fertil Steril. 2003;  80 1234-1240
• 68 Archer D F, Dorin M, Lewis V, Schneider D L, Pickar J H. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding.  Fertil Steril. 2001;  75 1080-1087
• 69 Graser T, Koytchev R, Muller A, Oettel M. Comparison of the efficacy and endometrial safety of two estradiol valerate/dienogest combinations and Kliogest for continuous combined hormone replacement therapy in postmenopausal women.  Climacteric. 2000;  3 109-118
• 70 Hovik P, Sundsbak H P, Gaasemyr M, Sandvik L. Comparison of continuous and sequential oestrogen-progestogen treatment in women with climacteric symptoms.  Maturitas. 1989;  11 75-82
• 71 Heikkinen J, Vaheri R, Timonen U. Long-term safety and tolerability of continuous-combined hormone therapy in postmenopausal women: results from a seven-year randomized comparison of low and standard doses.  J Br Menopause Soc. 2004;  10 95-102
• 72 Mattsson L A, Skouby S O, Heikkinen J, Vaheri R, Maenpaa J, Timonen U. A low-dose start in hormone replacement therapy provides a beneficial bleeding profile and few side-effects: randomized comparison with a conventional-dose regimen.  Climacteric. 2004;  7 59-69
• 73 Ferenczy A, Gelfand M M, van de Weijer P H, Rioux J E. Endometrial safety and bleeding patterns during a 2-year study of 1 or 2 mg 17 beta-estradiol combined with sequential 5-20 mg dydrogesterone.  Climacteric. 2002;  5 26-35
• 74 Bruhat M, Rudolf K, Vaheri R, Kainulainen P, Timonen U, Viitanen A. Effective bleeding control and symptom relief by lower dose regimens of continuous combined hormone replacement therapy: a randomized comparative dose-ranging study.  Maturitas. 2001;  40 259-271
• 75 Ettinger B, Genant H K, Steiger P, Madvig P. Low-dosage micronized 17 beta-estradiol prevents bone loss in postmenopausal women.  Am J Obstet Gynecol. 1992;  166 479-488
• 76 Ettinger B. Use of low-dosage 17 beta-estradiol for the prevention of osteoporosis.  Clin Ther. 1993;  15 950-962
• 77 Lindsay R, Hart D M, Clark D M. The minimum effective dose of estrogen for prevention of postmenopausal bone loss.  Obstet Gynecol. 1984;  63 759-763
• 78 Lindsay R, Gallagher J C, Kleerekoper M, Pickar J H. Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women.  JAMA. 2002;  287 2668-2676
• 79 Recker R R, Davies K M, Dowd R M, Heaney R P. The effect of low-dose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women. A randomized, controlled trial.  Ann Intern Med. 1999;  130 897-904
• 80 Genant H K, Lucas J, Weiss S et al.. Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Estratab/Osteoporosis Study Group.  Arch Intern Med. 1997;  157 2609-2615
• 81 Cauley J A, Zmuda J M, Ensrud K E et al.. Timing of estrogen replacement therapy for optimal osteoporosis prevention.  J Clin Endocrinol Metab. 2001;  86 5700-5705
• 82 Cauley J A, Robbins J, Chen Z et al.. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial.  JAMA. 2003;  290 1729-1738