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Home , Estradiol valerate, Estropipate

Maturitas 47 (2004) 269–275

Are all the same?

Herjan J.T. Coelingh Bennink

Pantarhei Bioscience, Institute for Clinical Concept Research in Reproductive , Pantarhei Bioscience, Zeist, The Netherlands Received 26 June 2003; accepted 20 November 2003

Abstract

This paper focuses on the question whether different estrogens (E) have different qualitative pharmacodynamic effects when used by women for contraception, Hormone Replacement Therapy (HRT) or prevention of . In this context estrogens have been defined as the (E2), (E1), (E3), conjugated equine estrogens (CEE), diethyl- (DES) and (EE). Selective Modulator’s (SERM’s) have been excluded from this analysis primarily because of lack of comparative (clinical) data with estrogen agonists. A major problem when addressing the issue of comparability of estrogen agonists is the lack of data from head-to-head estrogen-only comparative studies. Comparative studies have been performed almost exclusively with estrogen agonists combined with a series of different (P), that have been added to protect the from endometrial hyperplasia. Since progestogens are known to exhibit different intrinsic pharmacodynamic properties and interactions with estrogens, it is impossible to judge which role the estrogen plays when qualitative differences between different combined E/P preparations are observed. In summary, no convincing evidence has been found that the estrogens mentioned differ qualitatively. Obviously quantitative differences are present due to differences in e.g. receptor affinity, (half life) and (/vaginal). Since DES has been discarded for human use due to teratogenicity, EE used in all combined E/P oral contraceptives is the most potent estrogen available at present. In HRT, E2 and CEE are equally effective for the treatment of hot flushes and urogenital atrophy and superior to any other treatment option. For long term treatment to prevent osteoporosis and even for short term HRT, estrogen agonists are heavily debated recently because of a small increased risk of , that has been known for a long time already. Well informed and individualised choice of treatment seems the appropriate solution. © 2004 Elsevier Ireland Ltd. All rights reserved.

Keywords: Estrogens; ; ; HRT

1. Introduction estrone and estriol are derived from androgenic precur- sors ( or ) through aroma- Estrogens are endogenous hormones with numer- tization of the A-ring. Estradiol is oxidized reversibly ous physiological action. The most potent naturally to estrone, and both estradiol and estrone can be con- occurring estrogen in humans is 17␤-estradiol (E2), verted to estriol [1]. followed by estrone (E1) and estriol (E3). Estradiol, Estradiol is the predominant estrogen during the premenopausal period, and is mainly secreted by the E-mail address: [email protected] ovaries. After , the main estrogen is es- (H.J.T. Coelingh Bennink). trone. Estrone is synthesized in adipose from

0378-5122/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2003.11.009 270 H.J.T. Coelingh Bennink / Maturitas 47 (2004) 269–275 adrenal . During pregnancy, els remain stable. Mean steady state levels of estradiol estriol is produced in large quantities by the placenta. around 30 pg/ml have been reported with once daily Estradiol occurs in all , regardless of sex dosing at a dose level of 1 mg, and between 55 and or age; its function, however, is related to the control of 80 pg/ml at a dose level of 2 mg per day. Estradiol is female reproduction through cyclic release of anterior extensively metabolized by the . The major un- pituitary hormones and to cyclic changes of the female conjugated and conjugated metabolites are estrone and reproductive tract. During pregnancy, estradiol con- ; these metabolites can contribute to the tributes to uterine growth, placental development, par- estrogenic activity, either directly or after reconver- turition, and the development of the mammary gland. sion to estradiol. The estrone-estradiol ratio after oral Estrogenic activity is shared by many steroidal and dosing is about 5–7, and is irrespective of the estra- compounds, both naturally occurring and diol dose [8–10]. Estradiol is mainly excreted into the synthetic. Conjugated equine estrogens (CEE) are a as glucuronides and sulfate conjugates of estra- mixture of naturally occurring estrogens and contain diol and estrone [1]. The plasma half-life of estradiol estrone sulfate and sulfate as the main con- is very short, i.e. within minutes. Due to entero-hepatic stituents. Synthetic derivatives from natural human es- recirculation, complete elimination of estradiol and trogens have been developed, e.g. ethinyl estradiol (the its metabolites after a single oral dose may take sev- most common estrogen used in contraception) to in- eral days (i.e. up to 72 h following a single oral 2 mg crease after . dose) [11–13]. There is no evidence of accumulation Nonsteroidal compounds with (anti)estrogenic ac- of estradiol following long-term treatment. tivity occur naturally in a variety of plants and fungi. Ethinyl estradiol can also be used orally and is These so-called have only weak activ- more potent than estradiol, because the ethinyl substi- ity, and their therapeutic effects remain as of yet un- tution in the C17 position inhibits the first pass hepatic proven. metabolism. It is rapidly and almost completely ab- (DES) was one of the first nons- sorbed from the gastro-intestinal tract. , like teroidal estrogens to be synthesized. It is structurally some other (semi)synthetic estrogens, is rapidly con- related to estradiol. DES is as potent as estradiol in verted in the liver to ethinyl estradiol. Ethinyl estra- most assays, but has a longer half-life. Nowadays, DES diol has a long half-life, with reported values of up to has no longer widespread use because of its potential 13–27 h. Ethinyl estradiol increases SHBG. However, to induce congenital anomalies. A number of other it does not bind to SHBG but rather to serum albu- synthetic agents, including and plasticizers, min. has a much shorter half-life of also have hormonal or antihormonal activity. The affin- 1.5 h, and is extensively bound to SHBG. ity of these ‘environmental’ estrogens for the estrogen Other oral preparations contain conjugated estro- receptor is relatively weak, but their widespread pres- gens, mainly the sulfate of naturally occurring ence and their potency for bioaccumulation in adipose estrogens. These are absorbed across the intestinal ep- tissue have raised concern about their potential toxic- ithelium after hydrolization in the lower gut. Serum ity for mankind and wildlife [2]. levels of estradiol and estrone that are achieved with are similar to those achieved with oral administration of other naturally occurring 2. Human pharmacokinetics of oral estrogens estrogens. Relative potency of different estrogen preparations Estradiol when given orally in its native crystalline was investigated by von Schoultz, [14] who reported state is poorly absorbed via the gastro-intestinal tract on the effects of estriol, estrone sulfate, 17␤-estradiol, because of its extensive first pass hepatic effect, but and ethinyl estradiol in postmenopausal women on in micronized form it is well absorbed [3–7]. The among others the karypyknotic index of the vagi- steady state pharmacokinetics of unconjugated estro- nal , and on changes in FSH and SHBG gens is complicated by, among others, induction of concentrations. Whereas the directions of the in- -binding globulin (SHBG) upon multiple duced changes were similar with all studied estro- dosing, but once steady state is reached, plasma lev- gens, ethinyl estradiol invariably induced the largest H.J.T. Coelingh Bennink / Maturitas 47 (2004) 269–275 271 response, consistent with its receptor affinity and nu- estrogens via the portal circulation. This may explain clear retention time profile. Ethinyl estradiol is also why the transdermal route is associated with less fa- more potent than conjugated estrogens, micronized vorable changes in lipid profile compared to oral ad- estradiol, and estrogen sulfate () ministration forms [19–22]. with respect to FSH levels and liver proteins, and also more potent than conjugated estrogens, micronized estradiol, estropipate, estradiol valerate, or esterified 4. Hormone replacement therapy estrogens with respect to the effect on bone density [15]. The therapeutic use of estrogens is widespread. Both naturally occurring and synthetic compounds are available for oral and parenteral use. The most com- 3. Transdermal delivery of estrogens mon use of estrogens is in contraception and as hor- mone replacement therapy (HRT) in (post)menopausal Estrogens are well absorbed through the skin, women. and the use of transdermal estrogen preparations via Due to a decline of ovarian function with follicu- patches or gel formulations, is rapidly increasing. lar depletion, the plasma concentrations of estradiol Transdermal delivery formulations provide slow, sus- decrease from 40–400 pg/ml during the menstrual cy- tained release of estrogens, and more constant cle to a level of 5–20 pg/ml at the time of menopause, levels than with oral administration. Conversion of and peripheral conversion of adrenal androstenedione estradiol to estrone is more slowly with parenteral to estrone becomes the principal source of estrogen. administration, and estradiol–estrone ratios of about In most women, this source does not provide enough one are commonly reported with transdermal deliv- estrogen to prevent symptoms of estrogen deficiency. ery, which is similar to the physiological ratio of the The pharmacological principle behind HRT is to in- premenopausal state. crease the circulating levels of estrogens, but addi- Different administration forms each may have their tional treatment with progestogens is mandatory in own distinct pharmacokinetic profile. A direct com- women with an intact uterus to limit the effects of parison between estradiol from a gel, from a patch, estrogen-induced hyperplasia [23–29]. and estradiol valerate from an oral at doses that are normally used in clinical practice revealed quanti- 4.1. Climacteric complaints tative but no qualitative differences in absorption and . The bioavailability of estradiol from Climacteric complaints (mainly vasomotor changes the gel relative to the oral tablet was 61%, and 109% such as hot flushes and night sweats) are one of the as compared with the patch. The gel was also not bioe- earliest symptoms of estrogen deficiency, and are the quivalent with the patch or the tablet [16]. most likely reason for starting HRT. Different avail- There also seem to exist some quantitative differ- able estrogen preparations and administration forms ences between the oral and transdermal administra- all seem to provide dose-dependent, adequate symp- tion forms. Estrogens in general have a presumed fa- tom relief [16,20,30]. Other symptoms that may oc- vorable action on the lipoprotein profile by increas- cur after a longer period of estrogen deficiency in- ing high-density lipoprotein (HDL) and decreasing clude tissue changes in the genital tract and bladder, low-density lipoprotein (LDL) levels. This effect has with resulting changes in sexual function and urinary consistently been demonstrated in large randomized symptoms. Urogential atrophy favorably responds to controlled primary (PEPI) [17] and secondary (HERS) estrogen replacement therapy with similar effects of [18] prevention studies. Due to the presence of estro- different estrogens [31]. gen receptors in the liver, the beneficial effect of es- trogens on the LDL levels is considered to result from 4.2. Osteoporosis direct hepatic actions. With transdermal application the impact on hepatic protein synthesis is reduced, as HRT has been proven effective for the long-term it does not expose the liver to high concentrations of consequences of estrogen depletion, i.e. prevention of 272 H.J.T. Coelingh Bennink / Maturitas 47 (2004) 269–275 postmenopausal osteoporosis. The annual rate of bone a mean number of 5.2 years of follow-up, although loss in the first 5 years after menopause is estimated the fact that the estrogen-only arm is being continued at 3–5% [32,33]. Estrogens prevent bone loss through indicates that the increased risk is possibly not con- inhibition of bone resorption, and are associated with sidered estrogen-related [45]. Also, the mean age of an increase in bone mineral density. The effect of es- the women in the WHI study was rather high (63.2 trogen on the bone is dose-dependent, with no gross years in the active treatment group, and 63.3 years in differences between currently available formulations the placebo arm), which is well above the age that or administration forms [34–40]. Estrogen use is also HRT should be started for prevention. It can further associated with a decrease in the incidence of osteo- be assumed that the frequency of baseline climacteric porotic fractures (e.g. fractures of the hip and verte- complaints, in particular hot flushes, would have been brae). Epidemiological surveys have shown that the rather low in this study population, as it would have incidence of fractures is reduced by 20–45% in HRT been unethical to treat such women with placebo for a users compared to non-users [41–44]. This was re- prolonged time. This would put the WHI study popula- cently confirmed in a randomized placebo controlled tion distinct from the populations commonly described trial [45]. in case control cohort studies, which are mostly se- lected for presence of (severe) climacteric complaints. 4.3. Cardiovascular effects It could very well be that women who present with hot flushes are more susceptible to beneficial arterial Estrogen has been considered to be a protective fac- cardiovascular effects of HRT than women with no tor against , although the un- vasomotor complaints. derlying mechanisms were incompletely understood. Before midlife, death due to cardiovascular disease is 4.4. Colon cancer infrequent in women, but not in men. From the age of 55 onwards, numbers are increasing much more Current or recent HRT use is clearly associated rapidly in women than in males, and beyond the age with a reduced risk of colon cancer, and this effect is of 85 years, the gender ratio is inverted [46]. Whether consistently found both in retrospective cohort stud- estrogen supplementation reduces the risk of cardio- ies [49–51] as well as in prospectively randomized vascular disease and related death in postmenopausal controlled trials [45,52]. The duration of use does women is currently under debate. A meta-analysis of not seem to play a significant role, however past large observational studies has indicated that current use did not provide protection. Different treatment use of HRT is associated with a statistically signifi- regimens—either estrogen alone, or combination cant reduction in coronary heart disease (CHD) (RR, treatment—appear to have similar effects. 0.80; 95% CI, 0.68–0.95) and also in mortality from heart disease (RR, 0.62; 95% CI, 0.40–0.90) [47]. 5. Risks associated with HRT However, the results from prospectively randomized placebo-controlled trials seem to point in another di- The most common side effects with estrogen use rection. The results from HERS showed no reduction include , breast tension/pain, vaginal bleed- in the overall rate of CHD events in women with pre- ing, and , but these side effects existing cardiovascular disease (RR, 0.99; 95% CI, are usually mild and transient. Hair loss seems to 0.81–1.22), although there was a statistically signifi- be specifically associated with Premarin (Prempro, cant time trend, with more CHD events in the HRT Premphase) use [53]. Other, less common, serious ad- group after 1 year of use, but fewer CHD events af- verse effects include breast cancer, thromboembolic ter 2 years of use [18]. The results from the long-term disease, and gallbladder disease. follow up were comparable, i.e. a relative risk of 1.00 (95% CI: 0.77–1.29) [48]. The findings from the WHI 5.1. Breast cancer study are also suggestive of a negative effect (RR, 1.29; 95% CI, 1.02–1.63), and the estrogen plus pro- The risk of breast cancer seems definitely to be in- gestin arm of the study was prematurely stopped after creased among HRT users. A reanalysis of data from H.J.T. Coelingh Bennink / Maturitas 47 (2004) 269–275 273

51 studies [54] showed a slight increase in the relative Table 1 risk of having breast cancer diagnosed in current users Overview of clinical events during HRT with different estrogen of HRT, and in those who ceased use 1–4 years previ- preparations ously. The increase was 1.023 (95% CI, 1.011–1.036) E2 CEE EE with each year of use. Mortality from breast cancer, Hot flushes ↓↓ ↓ however, seems to be reduced [55]. The risk of breast Urogenital atrophy ↓↓ ↓ cancer is related to HRT treatment duration and re- Fractures (bone) ↓↓ ↓(?) turns to that of never-users within 5 years after stop- Colon cancer ↓↓ (?) Breast cancer ↑↑ ping HRT. Again, there seems to be no gross differ- Deep venous /pulmonary ↑↑ ↑ ences with different treatment regimens. embolism Arterial disease (?) (?) (?) 5.2. Thromboembolic disease

It is now generally recognized that there is a two- parisons between different HRT regimens, and also to three-fold increase in the incidence of deep venous the addition of progestogens for uterine protection thrombosis and pulmonary embolism with estrogen makes it difficult to assess the role of different estro- replacement therapy [45,52,56–58]. The risk seems to gen preparations in HRT. Nevertheless, all currently increase with higher doses of estrogen, and is high- available estrogen preparations seem to have a com- est within the first year of use (RR, 3.49; 95% CI, parable benefit–risk profile (see Table 1). 2.33–5.59) [47]. Again, there seem to be no differ- Transdermal estrogens appear to have a smaller ben- ences between different estrogen preparations or ad- eficial effect on the lipid profile than oral estrogens, ministration forms. presumably because the liver is not exposed to high estrogen levels. Whether this has an effect on cardio- 5.3. Gallbladder disease vascular disease risk is as of yet unclear. Currently available estrogens have both benefits Many but not all studies have indicated an increase and harms. Improvement should focus on known in the incidence of gallbladder disease in current and safety issues, i.e. reduction of breast cancer incidence, long-term users of HRT. The risk remains elevated thromboembolic disease, and gallbladder disease. in those who stop treatment [47,59]. This finding is Tolerability—or more specifically, a more favorable consistent with the increase in biliary tract surgery profile—would be important for patient reported in HERS (RR, 1.48; 95% CI, 1.12–1.95) [52]. compliance, especially with long-term treatment. As estrogens have a direct hepatic action, drug–drug interactions remain a source of potential concern. 6. Concluding remarks

Different estrogen formulations are currently avail- able for oral and parenteral, especially transdermal References use. The relative potencies of the various oral prepara- tions differ widely, mainly due to differences in phar- [1] Birkhauser MH. Chemistry, physiology, and pharmacology of macokinetic behavior. The pharmacokinetic profile of sex . J Cardiovasc Pharmacol 1996;28(Suppl 5):S1– S13. transdermal application forms is distinct from that of [2] Williams CL, Stancel GM. Estrogens and progestins. In: oral preparations. The differences seem to be quanti- Hardman JG, Gilman AG, Limbird LE (Eds.), Goodman and tative rather than qualitative. Gilman’s—the pharmacological basis of therapeutics. New A treatment regimen containing CEE with medrox- York: McGraw-Hill; 1995. p. 1411–40. yprogesterone (MPA) was used in all larger [3] Yen SS, Martin PL, Burnier AM, Czekala NM, Greaney Jr MO, Callantine MR. Circulating estradiol, estrone, and randomized placebo-controlled HRT trials, because it levels following the administration of orally constitutes the predominant regimen in the US, where active 17␤-estradiol in postmenopausal women. J Clin the trials were set up. There are no head-to-head com- Endocrinol Metab 1975;40:518–21. 274 H.J.T. Coelingh Bennink / Maturitas 47 (2004) 269–275

[4] Lobo RA. Absorption and metabolic effects of different types of transdermal and oral preparations. Obstet Gynecol of estrogens and progestogens. Obstet Gynecol Clin North 1999;94:61–5. Am 1987;14:143–67. [21] Nachtigall LE. Emerging delivery systems for estrogen [5] Martin PL, Burnier AM, Greaney MO. Oral menopausal replacement: aspects of transdermal and oral delivery. Am J therapy using 17␤-micronized estradiol. Obstet Gynecol Obstet Gynecol 1995;173(3):993–7 (part 2). 1971;39:771–4. [22] Sturdee DW. Current hormone replacement therapy: what [6] Englund DE, Johansson EDB. Oral versus vaginal absorption are the shortcomings? Advances in delivery. Int J Clin Pract of oestradiol in postmenopausal women. Effects of different 1999;53:468–72. particle sizes. Upsala J Med Sci 1981;86:297–307. [23] Ziel HK, Finkle WD. Increased risk of [7] Fink BJ, Strid Christensen M. Bioavailability of oestradiol among users of conjugated estrogens. N Eng J Med and oestriol administered orally to oophorectomised women. 1975;293:1167–70. Maturitas 1981;3:289–94. [24] Brinton LA, Hoover RN. Estrogen replacement therapy and [8] Powers MS, Schenkel L, Darley PE. Pharmacokinetics and endometrial cancer risk: unresolved issues. Obstet Gynecol pharmacodynamics of transdermal dosage forms of estradiol: 1993;81:265–71. comparison with conventional oral estrogens used for [25] Shapiro S, Kelly JP, Rosenberg L, Kaufman DW, Helmrich hormone replacement. Am J Obstet Gynecol 1985;152:1099– SP, Rosenshein NB, et al. Risk of localized and widespread 106. endometrial cancer in relation to recent and discontinued use [9] Selby PL, McGarrigle HG, Peacock M. Comparison of of conjugated estrogens. N Eng J Med 1985;313:969–72. the effects of oral and transdermal oestradiol administration [26] Rose PG. Endometrial carcinoma. N Eng J Med on oestrogen metabolism, protein synthesis, gonadotropin 1996;335:640–9. release, bone turnover and climacteric symptoms in [27] Whitehead MI, Hillard TC, Crook D. The role and use of postmenopausal women. Clin Endocrinol 1989;30:241–9. progestogens. Obstet Gynecol 1990;75:S59–76. [10] Scott RT, Ross B, Anderson C, Archer DF. Pharmacokinetics [28] Varma TR. Effect of long-term therapy with estrogen and of percutaneous estradiol: a crossover study using a gel and on the endometrium of postmenopausal women. a transdermal system in comparison with oral micronized Acta Obstet Gynecol Scand 1985;64:41–6. estradiol. Obstet Gynecol 1991;77(5):758–64. [29] Whitehead M, Lobo RA. Consensus conference: progestagen [11] Bolt HM. Metabolism of estrogens—natural and synthetic. use in postmenopausal women. Lancet 1988;2:1243–4. Pharmac Ther 1979;4:155–81. [30] Notelovitz M, Lenihan JP, McDermott M, Kerber IJ, Nanavati [12] Kuhl H. Pharmacokinetics of oestrogens and progestogens. N, Arce J. Initial 17␤-estradiol dose for treating vasomotor Maturitas 1990;12:171–97. symptoms. Obstet Gynecol 2000;95:726–31. [13] Stumpf PG. Pharmacokinetics of estrogen. Obstet Gynecol 1990;75:9S–14S. [31] Cardozo L, Bachmann G, McClish D, Fonda D, Birgerson [14] Von Schoultz B. Potency of different oestrogen preparations. L. Meta-analysis of estrogen therapy in the management of In: Studd JWW, Whitehead MI (Eds.), The menopause. urogenital atrophy in postmenopausal women. Second report Oxford: Blackwell Scientific Publications; 1988. p. 130–7. of the Hormones and Urogenital Therapy Committee. Obstet Gynecol 1998;92:722–7. [15] Speroff L, Glass RH, Kase NG. Clinical gynecologic endocrinology and . Baltimore: Lippincott Williams [32] Stevenson JC. Pathogenesis, prevention and treatment of and Wilkins; 1999. osteoporosis. Obstet Gynecol 1990;75:36S–41S. [16] Järvinen A, Nykänen S, Paasiniemi L. Absorption and [33] Liu JH. Progestins and their application in the menopause. bioavailability of oestradiol from a gel, a patch and a tablet. What have we learned. Infert Reprod Med Clinical N Am Maturitas 1999;32:103–13. 1999;10:329–42. [17] The Writing Group for the PEPI Trial. Effects of [34] Quigley MET. Estrogen therapy arrests bone loss in elderly estrogen or estrogen/progestin regimens on heart disease women. Am J Obstet Gynecol 1987;156:1516–23. risk factors in postmenopausal women. The Postmenopausal [35] Ettinger B. Low-dosage micronized 17␤-estradiol prevents Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995; bone loss in postmenopausal women. Am J Obstet Gynecol 273(3):199–208. 1992;166:479–88. [18] Hulley S, Grady D, Bush T, Furberg C, Herrington [36] Ettinger B, Genant HK, Steiger P, Madvig P. Low D, Riggs B, et al. Randomized trial of estrogen plus dosage micronized 17␤-estradiol prevents bone loss in progestin for secondary prevention of coronary heart disease postmenopausal women. Am J Obstet Gynecol 1992;166:479– in postmenopausal women. Heart and Estrogen/progestin 88. Replacement Study (HERS) Research Group. JAMA [37] Genant HK, Lucas J, Weiss S, Akin M, Emkey R, 1998;280(7):605–13. McNaney-Flint H, et al. Low-dose esterified estrogen therapy: [19] Crook D. The metabolic consequences of treating effects on bone, plasma estradiol concentrations, endometrium postmenopausal women with non-oral hormone replacement and lipid levels. Arch Intern Med 1997;157:2609–15. therapy. Br J Obstet Gynecol 1997;104(Suppl 16):4–13. [38] Naessen T, Berglund L, Ulmsten U. Bone loss in [20] Mattsson LA, Bohnet HG, Gredmark T. Continuous, elderly women prevented by ultralow doses of parenteral combined hormone replacement: randomized comparison 17␤-estradiol. Am J Obstet Gynecol 1997;177:115–9. H.J.T. Coelingh Bennink / Maturitas 47 (2004) 269–275 275

[39] Christiansen C, Christensen MS, Larsen NE, Transbol [49] Grodstein F, Newcomb PA, Stampfer MJ. Postmenopausal IB. Pathophysiological mechanisms of estrogen effect on and the risk of colorectal cancer: a review bone metabolism. Dose−response relationships in early and meta-analysis. Am J Med 1999;106:574–82. postmenopausal women. J Clin Endocrinol Metab 1982;55: [50] Nanda K, Bastian LA, Hasselblad V, Simel DL. Hormone 1124–30. replacement therapy and the risk of colorectal cancer: a [40] Ettinger B. Use of low dosage 17␤−estradiol for the meta-analysis. Obstet Gynecol 1999;93:880–8. prevention of osteoporosis. Clin Ther 1993;15(6):950– [51] Newcomb PA, Storer BE. Postmenopausal hormone use 62. and risk of large-bowel cancer. J Natl Cancer Inst [41] Consensus Development Conference: diagnosis, prophylaxis, 1995;87(14):1067–71. and treatment of osteoporosis. Am J Med 1993;94(6):646–50. [52] Hulley S, Furberg C, Barrett-Connor E, Cauley J, Grady [42] Consensus Development Conference: prophylaxis and D, Haskell W, et al. Noncardiovascular outcomes during treatment of osteoporosis. Osteoporosis Int 1991;1:114–7. 6.8 years of hormone therapy. Heart and Estrogen/Progestin [43] Riis BJ. How should HRT be used in the prevention and Replacement Study Follow-up (HERS II). JAMA 2002;288: treatment of osteoporosis? In: Birkhäuser MH, Rozenbaum 58–66. H (Eds.), Menopause. European Consensus Development [53] Premarin patient information. Updated 23 January 2003. Conference. Montreux. Switzerland, 8–10 September 1995. Available at http://www.premarin.com (addressed 10 March Paris: Editions Eska; 1996. p.111–6. 2003). [44] World Health Organization. Assessment of fracture risk and [54] Beral V. For the Collaborate Group on Hormonal Factors its application to screening for postmenopausal osteoporosis. in Breast Cancer. Breast cancer and hormone replacement WHO Technical Report Series 843, 1994. therapy. Lancet 1997;350:1047–59. [45] Writing Group for the Women’s Health Initiative [55] Willis DB, Calle EE, Miracle-McMahill HL, Heath Jr CW. Investigators. Risks and benefits of estrogen plus progestin Estrogen replacement therapy and risk of fatal breast cancer in healthy postmenopausal women. Principal results from the in a prospective cohort of postmenopausal women in the Women’s Health Initiative randomized controlled trial. JAMA . Cancer Causes Control 1996;7:449–57. 2002;288:321–33. [56] Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, [46] Manolio TA, Furberg CD, Schemanski L, Psaty BM, O’Leary Marsh S. Risk of venous thromboembolism in users of DH, Tracy RP, et al. Associations of postmenopausal hormone replacement therapy. Lancet 1996;348:977–80. oestrogen use with cardiovascular disease and its risk factors [57] Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM. Risk in older women. Circulation 1993;88:2163–71. of hospital admission for idiopathic venous thromboembolism [47] U.S. Preventive Services Task Force. Postmenopausal among users of postmenopausal oestrogens. Lancet hormone replacement therapy for primary prevention of 1996;348:981–3. chronic conditions: recommendations and rationale. Ann [58] Grodstein F, Stampfer MJ, Goldhaber SZ, Manson JE, Colditz Intern Med 2002;137:834–9. GA, Speizer FE, et al. Prospective study of exogenous [48] Grady D, Herrington D, Bittner V, Blumenthal R, Davidson hormones and risk of pulmonary embolism in women. Lancet M, Hlatky M, et al. Cardiovascular disease outcomes during 1996;348:983–7. 6.8 years of hormone therapy. Heart and estrogen/progestin [59] Grodstein F, Colditz GA, Stampfer MJ. Postmenopausal replacement study follow-up (HERS II). JAMA 2002;288:49– hormone use and cholecystectomy in a large prospective 57. study. Obstet Gynecol 1994;83:5–11.