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HRT stops vaginal atrophy, hot flashes, and bone loss
Three applications form the basis for HRT in postmenopausal women:
- Hot flashes subside. Hot flashes occur with varying intensity in about 85% of women, and are effectively treated with estrogen, whether given orally, transdermally, or vaginally.1,2 As long as an appropriate blood level of the hormone is reached, hot flashes diminish.3-5 This reduction is dose-related.
- Measurable improvements in vaginal atrophy. Estrogen’s efficacy in relieving dryness, itching, burning, and dyspareunia is well demonstrated, regardless of the route of administration.3,6,7 A fall in vaginal pH from 6.0 to 5.0 after estrogen administration has been documented,8 as has the increase in the number of superficial cells of the vagina with exogenous estrogen.9
- HRT maintains or increases bone mineral density (BMD). Most estrogen preparations on the US market have been shown to improve BMD.10-15 “Improvement” means no significant loss, or an increase, in BMD. In the WHI, both vertebral and nonvertebral fractures diminished unequivocally in women using estrogen—alone or with a progestin.16,17 Other clinical trials also have shown increased BMD, as well as decreased urinary and serum markers of bone turnover.
Do new data link progestin to cancer?
Although compelling evidence supports the use of progestational agents in addition to estrogen to prevent endometrial hyperplasia and endometrial cancer,18 a 2005 report19 suggests that chronic, long-term use of estrogen with a progestin may increase the risk of endometrial carcinoma. Because this is the only study in which this risk has been found, corroboration is required.
Until then, give progestin at a sufficient dose and duration to inhibit endometrial hyperplasia.20-25
Effects on heart disease may be age-related
With notable exceptions, the overall conclusion of clinical trials and observational studies to date is that estrogen helps prevent coronary heart disease (CHD).26-30 This finding was first observed in the late 1980s with evidence that estrogen increases high-density lipoprotein (HDL) cholesterol and reduces total and low-density lipoprotein (LDL) cholesterol.31
Some experts argue that these observational trials are biased because many of the women taking estrogen had modified their lifestyles to maintain their weight, control their diet, and exercise regularly.32 Indeed, the randomized, placebo-controlled Heart and Estrogen Replacement Study (HERS) and both arms of the WHI trial found no evidence for a significant increase or decrease in CHD events.33-35
Time from menopause to HRT may be key
Both the HERS and WHI trials enrolled older women who had entered menopause a few months to several years before starting HRT.36 In addition, the estrogen-progestin arm of the WHI trial lacked sufficient power to detect a significant difference in CHD outcomes.37
The WHI findings contrast those of the large, ongoing, observational Nurses Health Study, which has shown a consistent decrease in CHD incidence in women who began HRT with the onset of menopausal symptoms.27-30 The most recent data suggest that the interval between menopause and the start of HRT may explain the different findings in randomized, controlled trials and observational studies.38 The WHI data support this theory: CHD was lower in women who began taking HRT within 5 years of menopause, compared with women who initiated HRT more than 5 years afterward.36 In addition, data from the estrogen-only arm of the WHI show fewer CHD events in women younger than 60.34
Several other studies support this hypothesis:
- The surgically postmenopausal cynomolgus macaque had a lower rate of atherosclerotic plaque development when estrogen was given, with or without a progestin.39,40
- In the Rancho Bernardo study, women who had used HRT had less cardiac calcification documented by computed tomography, compared with nonusers.41
- Estrogen has been shown, by measurement of carotid intimal medial thickness, to inhibit atherosclerotic plaque in humans.42
- Older women with established atherosclerosis do not undergo any significant change in plaque size with the use of exogenous estrogen.43
Although these findings support the use of estrogen or estrogen-progestin early after menopause as a way of preventing CHD, further clinical trials are needed.44
Stroke risk is small but real
Both arms of the WHI found an increased incidence of stroke in women using hormones, compared with nonusers.16,36 The exact mechanisms underlying this increased risk are unclear.
The actual attributable risk was an increase of 0.7 cases of stroke per 1,000 women per year over placebo in the estrogen-progestin arm,36 and 1.2 cases per 1,000 in the estrogen-only arm.16 The relative hazards were 1.31 (95% confidence interval [CI] 1.02–1.68) and 1.30 (95% CI 1.10–1.77), respectively.
Note that women in the estrogen-only arm had a greater incidence of hypertension and diabetes mellitus—known risk factors for stroke—than did women in the estrogen-progestin arm.16,36
VTE risk is twice as high in HRT users
Postmenopausal women who take estrogen have a higher risk of venous thromboembolism (VTE) than those who do not. This risk translated into a relative hazard of 2.06 (1.57–2.70) in the WHI estrogen-progestin arm, or an attributable risk of 3.6 cases per 1,000 women, compared with 1.8 cases per thousand in the control group.36
The absolute increased risk is 1.8 cases per 1,000 women, or, as expressed in the study itself, 18 cases per 10,000 women per year.
I have deliberately reduced the attributable risk to the number of cases per thousand because I believe this number is more easily understood by the patient and accurately demonstrates the low risk.
In the estrogen-only arm of the WHI, the hazard ratio for VTE was 1.33 (0.99–1.79), or an absolute increased risk of 0.7 cases per thousand—although this finding was not significant. The attributable risk was 2.7 cases per 1,000 women, compared with 2.0 cases per thousand among controls.16
Like stroke, the risk of VTE may be confounded by other factors besides use of exogenous estrogen.
No cause and effect for HRT and breast cancer
Nothing frightens women as much as breast cancer, and articles focusing on the relationship between breast cancer and HRT have drawn widespread attention. However, despite voluminous literature, the etiology of breast cancer remains elusive—and there is no evidence that either estrogen or progestins cause the disease.45,46 Rather, there is only an association between the use of estrogen, progestin, and breast cancer. Linking the finding of an increased risk with an implication of causality would be inappropriate.
Breast cancer risk with HRT is not consistently elevated, in studies
In fact, a qualitative review of observational studies from 1975 to 2000 found no significant increase or decrease in the risk of breast cancer with estrogen or estrogen-progestin in 80% of the reports.47
Risk factors for breast cancer (TABLE 1) include family history, obesity, late childbirth, and hormone therapy—but obesity and family history have higher relative risks than the use of HRT.48
TABLE 1
Relative risk of breast cancer
| CHARACTERISTIC | RELATIVE RISK |
|---|---|
| 2 family members with breast cancer | 14 |
| 1 family member with breast cancer | 2.2 |
| Obesity | 1.8 |
| Young age at menarche | 1.6 |
| Hormone therapy | 1.3 |
| >30 years of age at birth of first child | 1.3 |
| Menopause | 0.7 |
WHI arms find different risks
In the widely publicized WHI, women in the estrogen-progestin arm had an overall relative hazard for breast cancer of 1.24 (95% CI 1.01–1.54), but there was no increased risk in women who had never before used hormones.36 Women who had previously used hormones for 5 years or more did have an increased risk.36 The incidence of breast cancer in the study population was 3 cases per 1,000 women, and the excess number was 0.7 more cases with the use of estrogen-progestin (TABLE 2).
Conversely, in the estrogen-only arm of the WHI,16 the relative hazard for breast cancer was 0.77 (95% CI 0.59–1.01), and the reduction in risk was almost statistically significant. There are at least 2 potential explanations for the lower incidence of breast cancer in this arm:
- Without a progestin, estrogen increases breast density only minimally, allowing for easier mammographic interpretation.
- Women susceptible to breast cancer because of their previous use of estrogen may not have been present in the at-risk population in sufficient numbers to cause an increase.
TABLE 2
Extra cases of breast cancer, by risk factor
| RISK FACTOR | BREAST CANCERS DIAGNOSED OVER 20 YEARS FROM AGES 50 TO 70 (PER 1,000) | EXTRA BREAST CANCERS (PER 1,000) |
|---|---|---|
| Never used HRT | 45 | - |
| >5 years HRT | 47 | 2 |
| >10 years HRT | 51 | 6 |
| >15 years HRT | 57 | 12 |
| Late menopause (age 60) | 59 | 14 |
| Alcohol (2 drinks/day) | 72 | 27 |
| No daily exercise | 72 | 27 |
| Weight gain (>20 kg) | 90 | 45 |
| Reprinted from THE LANCET, Vol. 350: 1047–1059, 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. Copyright 1997, with permission from Elsevier | ||
HRT may promote, rather than induce, breast cancer
The role of hormones in the etiology of breast cancer is difficult to assess. The Million Women Study49 found that the elevated risk of breast cancer disappeared within 1 year of stopping HRT. This finding implies that hormones may be a promoter, rather than inducer, of neoplasms in the breast.
Breast cancer may be present in many women, but apparent in few
When autopsies were performed on women in their 40s who had died from other diseases, the incidence of breast cancer was 39%, but the clinical detection rate was only 1% for this population.50 This discrepancy suggests that neoplastic cells may be present in the body at any time, but become clinically apparent only under certain conditions.51
More recent data suggest that undifferentiated stem cells in the breast become dysfunctional and result in cancer.52 This theory is supported by the various histologic types of cancer found in the breast.
A weak link
Although it may be compelling to link hormone use with breast cancer, the association is weak and the incidence is lower than in other known relationships such as obesity. At present, the cause of breast neoplasia appears to be multifactorial.
1. Freedman RR. Pathophysiology and treatment of menopausal hot flashes. Semin Reprod Med. 2005;23:11-25.
2. Utian WH. Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: a comprehensive review. Health Qual Life Outcomes. 2005;3:47.-
3. Archer DF. Percutaneous 17beta-estradiol gel for the treatment of vasomotor symptoms in postmenopausal women. Menopause. 2003;10:516-521.
4. Archer DF. Low-dose hormone therapy for postmenopausal women. Clin Obstet Gynecol. 2003;46:317-324.
5. Nelson HD. Commonly used types of postmenopausal estrogen for treatment of hot flashes: scientific review. JAMA. 2004;291:1610-1620.
6. Ballagh SA. Vaginal rings for menopausal symptom relief. Drugs Aging. 2004;21:757-766.
7. Speroff L. Efficacy and tolerability of a novel estradiol vaginal ring for relief of menopausal symptoms. Obstet Gynecol. 2003;102:823-834.
8. Notelovitz M. Urogenital atrophy and low-dose vaginal estrogen therapy. Menopause. 2000;7:140-142.
9. Utian WH, Burry KA, Archer DF, 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.
10. Christiansen C. Effects of drospirenone/estrogen combinations on bone metabolism. Climacteric. 2005;8(suppl 3):35-41.
11. Delmas PD, Confavreux E, Garnero P, et al. A combination of low doses of 17 beta-estradiol and norethisterone acetate prevents bone loss and normalizes bone turnover in postmenopausal women. Osteoporos Int. 2000;11:177-187.
12. Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH. Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. JAMA. 2002;287:2668-2676.
13. Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH. Bone response to treatment with lower doses of conjugated estrogens with and without medroxyprogesterone acetate in early postmenopausal women. Osteoporos Int. 2005;16:372-379.
14. Ravn P, Bidstrup M, Wasnich RD, et al. Alendronate and estrogen-progestin in the long-term prevention of bone loss: four-year results from the early postmenopausal intervention cohort study. A randomized, controlled trial. Ann Intern Med. 1999;131:935-942.
15. Recker RR, Davies KM, Dowd RM, Heaney RP. 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.
16. Anderson GL, Limacher M, Assaf AR, 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.
17. Cauley JA, 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.
18. Archer DF. The effect of the duration of progestin use on the occurrence of endometrial cancer in postmenopausal women. Menopause. 2001;8:245-251.
19. Lacey JV, Jr, Brinton LA, Lubin JH, Sherman ME, Schatzkin A, Schairer C. Endometrial carcinoma risks among menopausal estrogen plus progestin and unopposed estrogen users in a cohort of postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2005;14:1724-1731.
20. Archer DF, Furst K, Tipping D, Dain MP, Vandepol C. A randomized comparison of continuous combined transdermal delivery of estradiol-norethindrone acetate and estradiol alone for menopause. CombiPatch Study Group. Obstet Gynecol. 1999;94:498-503.
21. Bouchard P, De Cicco-Nardone F, Spielmann D, Garcea N. Bleeding profile and endometrial safety of continuous combined regimens 1mg 17beta-estradiol/trimegestone versus 1or 2 mg 17beta-estradiol/norethisterone acetate in postmenopausal women. Gynecol Endocrinol. 2005;21:142-148.
22. Kurman RJ, Felix JC, Archer DF, Nanavati N, Arce J, Moyer DL. Norethindrone acetate and estradiol-induced endometrial hyperplasia. Obstet Gynecol. 2000;96:373-379.
23. 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.
24. Sturdee DW, Ulrich LG, Barlow DH, et al. The endometrial response to sequential and continuous combined oestrogen-progestogen replacement therapy. BJOG. 2000;107:1392-1400.
25. Ylikorkala O, Wahlstrom T, Caubel P, Lane R. Intermittent progestin administration as part of hormone replacement therapy: long-term comparison between estradiol 1mg combined with intermittent norgestimate and estradiol 2 mg combined with constant norethisterone acetate. Acta Obstet Gynecol Scand. 2002;81:654-660.
26. Espeland MA, Bush TL, Mebane-Sims I, et al. Rationale, design, and conduct of the PEPI Trial. Postmenopausal Estrogen/Progestin Interventions. Control Clin Trials. 1995;16(suppl):3S-19S.
27. Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med. 1996;335:453-461.
28. Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses’ health study. N Engl J Med. 1991;325:756-762.
29. Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med. 2000;133:933-941.
30. Grodstein F, Manson JE, Stampfer MJ. Postmenopausal hormone use and secondary prevention of coronary events in the nurses’ health study. a prospective, observational study. Ann Intern Med. 2001;135:1-8.
31. Bush TL, Cowan LD, Barrett-Connor E, et al. Estrogen use and all-cause mortality. Preliminary results from the Lipid Research Clinics Program Follow-Up Study. JAMA. 1983;249:903-906.
32. Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other considerations. Annu Rev Public Health. 1998;19:55-72.
33. 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.
34. Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease: the Women’s Health Initiative. Arch Intern Med. 2006;166:357-365.
35. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523-534.
36. Rossouw JE, Anderson GL, Prentice RL, 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.
37. Naftolin F, Taylor HS, 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.
38. Grodstein F, Manson JE, Stampfer MJ. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. J Womens Health (Larchmt). 2006;15:35-44.
39. Clarkson TB, Appt SE. Controversies about HRT-lessons from monkey models. Maturitas. 2005;51:64-74.
40. Wagner JD, Clarkson TB. The applicability of hormonal effects on atherosclerosis in animals to heart disease in postmenopausal women. Semin Reprod Med. 2005;23:149-156.
41. Barrett-Connor E, Laughlin GA. Hormone therapy and coronary artery calcification in symptomatic postmenopausal women: the Rancho Bernardo Study. Menopause. 2005;12:40-48.
42. Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001;135:939-953.
43. Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med. 2000;343:522-529.
44. Harman SM, Brinton EA, Cedars M, et al. KEEPS: the Kronos Early Estrogen Prevention Study. Climacteric. 2005;8:3-12.
45. Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med. 2001;344:276-285.
46. Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med. 2006;354:270-282.
47. Bush TL, Whiteman M, Flaws JA. Hormone replacement therapy and breast cancer: a qualitative review. Obstet Gynecol. 2001;98:498-508.
48. Morimoto LM, White E, Chen Z, et al. Obesity, body size, and risk of postmenopausal breast cancer: the Women’s Health Initiative (United States). Cancer Causes Control. 2002;13:741-751.
49. Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362:419-427.
50. Black WC, Welch HG. Advances in diagnostic imaging and overestimations of disease prevalence and the benefits of therapy. N Engl J Med. 1993;328:1237-1243.
51. Folkman J, Kalluri R. Cancer without disease. Nature. 2004;427:787.-
52. Dontu G, Al-Hajj M, Abdallah WM, Clarke MF, Wicha MS. Stem cells in normal breast development and breast cancer. Cell Prolif. 2003;36 Suppl 1:59-72.
HRT stops vaginal atrophy, hot flashes, and bone loss
Three applications form the basis for HRT in postmenopausal women:
- Hot flashes subside. Hot flashes occur with varying intensity in about 85% of women, and are effectively treated with estrogen, whether given orally, transdermally, or vaginally.1,2 As long as an appropriate blood level of the hormone is reached, hot flashes diminish.3-5 This reduction is dose-related.
- Measurable improvements in vaginal atrophy. Estrogen’s efficacy in relieving dryness, itching, burning, and dyspareunia is well demonstrated, regardless of the route of administration.3,6,7 A fall in vaginal pH from 6.0 to 5.0 after estrogen administration has been documented,8 as has the increase in the number of superficial cells of the vagina with exogenous estrogen.9
- HRT maintains or increases bone mineral density (BMD). Most estrogen preparations on the US market have been shown to improve BMD.10-15 “Improvement” means no significant loss, or an increase, in BMD. In the WHI, both vertebral and nonvertebral fractures diminished unequivocally in women using estrogen—alone or with a progestin.16,17 Other clinical trials also have shown increased BMD, as well as decreased urinary and serum markers of bone turnover.
Do new data link progestin to cancer?
Although compelling evidence supports the use of progestational agents in addition to estrogen to prevent endometrial hyperplasia and endometrial cancer,18 a 2005 report19 suggests that chronic, long-term use of estrogen with a progestin may increase the risk of endometrial carcinoma. Because this is the only study in which this risk has been found, corroboration is required.
Until then, give progestin at a sufficient dose and duration to inhibit endometrial hyperplasia.20-25
Effects on heart disease may be age-related
With notable exceptions, the overall conclusion of clinical trials and observational studies to date is that estrogen helps prevent coronary heart disease (CHD).26-30 This finding was first observed in the late 1980s with evidence that estrogen increases high-density lipoprotein (HDL) cholesterol and reduces total and low-density lipoprotein (LDL) cholesterol.31
Some experts argue that these observational trials are biased because many of the women taking estrogen had modified their lifestyles to maintain their weight, control their diet, and exercise regularly.32 Indeed, the randomized, placebo-controlled Heart and Estrogen Replacement Study (HERS) and both arms of the WHI trial found no evidence for a significant increase or decrease in CHD events.33-35
Time from menopause to HRT may be key
Both the HERS and WHI trials enrolled older women who had entered menopause a few months to several years before starting HRT.36 In addition, the estrogen-progestin arm of the WHI trial lacked sufficient power to detect a significant difference in CHD outcomes.37
The WHI findings contrast those of the large, ongoing, observational Nurses Health Study, which has shown a consistent decrease in CHD incidence in women who began HRT with the onset of menopausal symptoms.27-30 The most recent data suggest that the interval between menopause and the start of HRT may explain the different findings in randomized, controlled trials and observational studies.38 The WHI data support this theory: CHD was lower in women who began taking HRT within 5 years of menopause, compared with women who initiated HRT more than 5 years afterward.36 In addition, data from the estrogen-only arm of the WHI show fewer CHD events in women younger than 60.34
Several other studies support this hypothesis:
- The surgically postmenopausal cynomolgus macaque had a lower rate of atherosclerotic plaque development when estrogen was given, with or without a progestin.39,40
- In the Rancho Bernardo study, women who had used HRT had less cardiac calcification documented by computed tomography, compared with nonusers.41
- Estrogen has been shown, by measurement of carotid intimal medial thickness, to inhibit atherosclerotic plaque in humans.42
- Older women with established atherosclerosis do not undergo any significant change in plaque size with the use of exogenous estrogen.43
Although these findings support the use of estrogen or estrogen-progestin early after menopause as a way of preventing CHD, further clinical trials are needed.44
Stroke risk is small but real
Both arms of the WHI found an increased incidence of stroke in women using hormones, compared with nonusers.16,36 The exact mechanisms underlying this increased risk are unclear.
The actual attributable risk was an increase of 0.7 cases of stroke per 1,000 women per year over placebo in the estrogen-progestin arm,36 and 1.2 cases per 1,000 in the estrogen-only arm.16 The relative hazards were 1.31 (95% confidence interval [CI] 1.02–1.68) and 1.30 (95% CI 1.10–1.77), respectively.
Note that women in the estrogen-only arm had a greater incidence of hypertension and diabetes mellitus—known risk factors for stroke—than did women in the estrogen-progestin arm.16,36
VTE risk is twice as high in HRT users
Postmenopausal women who take estrogen have a higher risk of venous thromboembolism (VTE) than those who do not. This risk translated into a relative hazard of 2.06 (1.57–2.70) in the WHI estrogen-progestin arm, or an attributable risk of 3.6 cases per 1,000 women, compared with 1.8 cases per thousand in the control group.36
The absolute increased risk is 1.8 cases per 1,000 women, or, as expressed in the study itself, 18 cases per 10,000 women per year.
I have deliberately reduced the attributable risk to the number of cases per thousand because I believe this number is more easily understood by the patient and accurately demonstrates the low risk.
In the estrogen-only arm of the WHI, the hazard ratio for VTE was 1.33 (0.99–1.79), or an absolute increased risk of 0.7 cases per thousand—although this finding was not significant. The attributable risk was 2.7 cases per 1,000 women, compared with 2.0 cases per thousand among controls.16
Like stroke, the risk of VTE may be confounded by other factors besides use of exogenous estrogen.
No cause and effect for HRT and breast cancer
Nothing frightens women as much as breast cancer, and articles focusing on the relationship between breast cancer and HRT have drawn widespread attention. However, despite voluminous literature, the etiology of breast cancer remains elusive—and there is no evidence that either estrogen or progestins cause the disease.45,46 Rather, there is only an association between the use of estrogen, progestin, and breast cancer. Linking the finding of an increased risk with an implication of causality would be inappropriate.
Breast cancer risk with HRT is not consistently elevated, in studies
In fact, a qualitative review of observational studies from 1975 to 2000 found no significant increase or decrease in the risk of breast cancer with estrogen or estrogen-progestin in 80% of the reports.47
Risk factors for breast cancer (TABLE 1) include family history, obesity, late childbirth, and hormone therapy—but obesity and family history have higher relative risks than the use of HRT.48
TABLE 1
Relative risk of breast cancer
| CHARACTERISTIC | RELATIVE RISK |
|---|---|
| 2 family members with breast cancer | 14 |
| 1 family member with breast cancer | 2.2 |
| Obesity | 1.8 |
| Young age at menarche | 1.6 |
| Hormone therapy | 1.3 |
| >30 years of age at birth of first child | 1.3 |
| Menopause | 0.7 |
WHI arms find different risks
In the widely publicized WHI, women in the estrogen-progestin arm had an overall relative hazard for breast cancer of 1.24 (95% CI 1.01–1.54), but there was no increased risk in women who had never before used hormones.36 Women who had previously used hormones for 5 years or more did have an increased risk.36 The incidence of breast cancer in the study population was 3 cases per 1,000 women, and the excess number was 0.7 more cases with the use of estrogen-progestin (TABLE 2).
Conversely, in the estrogen-only arm of the WHI,16 the relative hazard for breast cancer was 0.77 (95% CI 0.59–1.01), and the reduction in risk was almost statistically significant. There are at least 2 potential explanations for the lower incidence of breast cancer in this arm:
- Without a progestin, estrogen increases breast density only minimally, allowing for easier mammographic interpretation.
- Women susceptible to breast cancer because of their previous use of estrogen may not have been present in the at-risk population in sufficient numbers to cause an increase.
TABLE 2
Extra cases of breast cancer, by risk factor
| RISK FACTOR | BREAST CANCERS DIAGNOSED OVER 20 YEARS FROM AGES 50 TO 70 (PER 1,000) | EXTRA BREAST CANCERS (PER 1,000) |
|---|---|---|
| Never used HRT | 45 | - |
| >5 years HRT | 47 | 2 |
| >10 years HRT | 51 | 6 |
| >15 years HRT | 57 | 12 |
| Late menopause (age 60) | 59 | 14 |
| Alcohol (2 drinks/day) | 72 | 27 |
| No daily exercise | 72 | 27 |
| Weight gain (>20 kg) | 90 | 45 |
| Reprinted from THE LANCET, Vol. 350: 1047–1059, 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. Copyright 1997, with permission from Elsevier | ||
HRT may promote, rather than induce, breast cancer
The role of hormones in the etiology of breast cancer is difficult to assess. The Million Women Study49 found that the elevated risk of breast cancer disappeared within 1 year of stopping HRT. This finding implies that hormones may be a promoter, rather than inducer, of neoplasms in the breast.
Breast cancer may be present in many women, but apparent in few
When autopsies were performed on women in their 40s who had died from other diseases, the incidence of breast cancer was 39%, but the clinical detection rate was only 1% for this population.50 This discrepancy suggests that neoplastic cells may be present in the body at any time, but become clinically apparent only under certain conditions.51
More recent data suggest that undifferentiated stem cells in the breast become dysfunctional and result in cancer.52 This theory is supported by the various histologic types of cancer found in the breast.
A weak link
Although it may be compelling to link hormone use with breast cancer, the association is weak and the incidence is lower than in other known relationships such as obesity. At present, the cause of breast neoplasia appears to be multifactorial.
HRT stops vaginal atrophy, hot flashes, and bone loss
Three applications form the basis for HRT in postmenopausal women:
- Hot flashes subside. Hot flashes occur with varying intensity in about 85% of women, and are effectively treated with estrogen, whether given orally, transdermally, or vaginally.1,2 As long as an appropriate blood level of the hormone is reached, hot flashes diminish.3-5 This reduction is dose-related.
- Measurable improvements in vaginal atrophy. Estrogen’s efficacy in relieving dryness, itching, burning, and dyspareunia is well demonstrated, regardless of the route of administration.3,6,7 A fall in vaginal pH from 6.0 to 5.0 after estrogen administration has been documented,8 as has the increase in the number of superficial cells of the vagina with exogenous estrogen.9
- HRT maintains or increases bone mineral density (BMD). Most estrogen preparations on the US market have been shown to improve BMD.10-15 “Improvement” means no significant loss, or an increase, in BMD. In the WHI, both vertebral and nonvertebral fractures diminished unequivocally in women using estrogen—alone or with a progestin.16,17 Other clinical trials also have shown increased BMD, as well as decreased urinary and serum markers of bone turnover.
Do new data link progestin to cancer?
Although compelling evidence supports the use of progestational agents in addition to estrogen to prevent endometrial hyperplasia and endometrial cancer,18 a 2005 report19 suggests that chronic, long-term use of estrogen with a progestin may increase the risk of endometrial carcinoma. Because this is the only study in which this risk has been found, corroboration is required.
Until then, give progestin at a sufficient dose and duration to inhibit endometrial hyperplasia.20-25
Effects on heart disease may be age-related
With notable exceptions, the overall conclusion of clinical trials and observational studies to date is that estrogen helps prevent coronary heart disease (CHD).26-30 This finding was first observed in the late 1980s with evidence that estrogen increases high-density lipoprotein (HDL) cholesterol and reduces total and low-density lipoprotein (LDL) cholesterol.31
Some experts argue that these observational trials are biased because many of the women taking estrogen had modified their lifestyles to maintain their weight, control their diet, and exercise regularly.32 Indeed, the randomized, placebo-controlled Heart and Estrogen Replacement Study (HERS) and both arms of the WHI trial found no evidence for a significant increase or decrease in CHD events.33-35
Time from menopause to HRT may be key
Both the HERS and WHI trials enrolled older women who had entered menopause a few months to several years before starting HRT.36 In addition, the estrogen-progestin arm of the WHI trial lacked sufficient power to detect a significant difference in CHD outcomes.37
The WHI findings contrast those of the large, ongoing, observational Nurses Health Study, which has shown a consistent decrease in CHD incidence in women who began HRT with the onset of menopausal symptoms.27-30 The most recent data suggest that the interval between menopause and the start of HRT may explain the different findings in randomized, controlled trials and observational studies.38 The WHI data support this theory: CHD was lower in women who began taking HRT within 5 years of menopause, compared with women who initiated HRT more than 5 years afterward.36 In addition, data from the estrogen-only arm of the WHI show fewer CHD events in women younger than 60.34
Several other studies support this hypothesis:
- The surgically postmenopausal cynomolgus macaque had a lower rate of atherosclerotic plaque development when estrogen was given, with or without a progestin.39,40
- In the Rancho Bernardo study, women who had used HRT had less cardiac calcification documented by computed tomography, compared with nonusers.41
- Estrogen has been shown, by measurement of carotid intimal medial thickness, to inhibit atherosclerotic plaque in humans.42
- Older women with established atherosclerosis do not undergo any significant change in plaque size with the use of exogenous estrogen.43
Although these findings support the use of estrogen or estrogen-progestin early after menopause as a way of preventing CHD, further clinical trials are needed.44
Stroke risk is small but real
Both arms of the WHI found an increased incidence of stroke in women using hormones, compared with nonusers.16,36 The exact mechanisms underlying this increased risk are unclear.
The actual attributable risk was an increase of 0.7 cases of stroke per 1,000 women per year over placebo in the estrogen-progestin arm,36 and 1.2 cases per 1,000 in the estrogen-only arm.16 The relative hazards were 1.31 (95% confidence interval [CI] 1.02–1.68) and 1.30 (95% CI 1.10–1.77), respectively.
Note that women in the estrogen-only arm had a greater incidence of hypertension and diabetes mellitus—known risk factors for stroke—than did women in the estrogen-progestin arm.16,36
VTE risk is twice as high in HRT users
Postmenopausal women who take estrogen have a higher risk of venous thromboembolism (VTE) than those who do not. This risk translated into a relative hazard of 2.06 (1.57–2.70) in the WHI estrogen-progestin arm, or an attributable risk of 3.6 cases per 1,000 women, compared with 1.8 cases per thousand in the control group.36
The absolute increased risk is 1.8 cases per 1,000 women, or, as expressed in the study itself, 18 cases per 10,000 women per year.
I have deliberately reduced the attributable risk to the number of cases per thousand because I believe this number is more easily understood by the patient and accurately demonstrates the low risk.
In the estrogen-only arm of the WHI, the hazard ratio for VTE was 1.33 (0.99–1.79), or an absolute increased risk of 0.7 cases per thousand—although this finding was not significant. The attributable risk was 2.7 cases per 1,000 women, compared with 2.0 cases per thousand among controls.16
Like stroke, the risk of VTE may be confounded by other factors besides use of exogenous estrogen.
No cause and effect for HRT and breast cancer
Nothing frightens women as much as breast cancer, and articles focusing on the relationship between breast cancer and HRT have drawn widespread attention. However, despite voluminous literature, the etiology of breast cancer remains elusive—and there is no evidence that either estrogen or progestins cause the disease.45,46 Rather, there is only an association between the use of estrogen, progestin, and breast cancer. Linking the finding of an increased risk with an implication of causality would be inappropriate.
Breast cancer risk with HRT is not consistently elevated, in studies
In fact, a qualitative review of observational studies from 1975 to 2000 found no significant increase or decrease in the risk of breast cancer with estrogen or estrogen-progestin in 80% of the reports.47
Risk factors for breast cancer (TABLE 1) include family history, obesity, late childbirth, and hormone therapy—but obesity and family history have higher relative risks than the use of HRT.48
TABLE 1
Relative risk of breast cancer
| CHARACTERISTIC | RELATIVE RISK |
|---|---|
| 2 family members with breast cancer | 14 |
| 1 family member with breast cancer | 2.2 |
| Obesity | 1.8 |
| Young age at menarche | 1.6 |
| Hormone therapy | 1.3 |
| >30 years of age at birth of first child | 1.3 |
| Menopause | 0.7 |
WHI arms find different risks
In the widely publicized WHI, women in the estrogen-progestin arm had an overall relative hazard for breast cancer of 1.24 (95% CI 1.01–1.54), but there was no increased risk in women who had never before used hormones.36 Women who had previously used hormones for 5 years or more did have an increased risk.36 The incidence of breast cancer in the study population was 3 cases per 1,000 women, and the excess number was 0.7 more cases with the use of estrogen-progestin (TABLE 2).
Conversely, in the estrogen-only arm of the WHI,16 the relative hazard for breast cancer was 0.77 (95% CI 0.59–1.01), and the reduction in risk was almost statistically significant. There are at least 2 potential explanations for the lower incidence of breast cancer in this arm:
- Without a progestin, estrogen increases breast density only minimally, allowing for easier mammographic interpretation.
- Women susceptible to breast cancer because of their previous use of estrogen may not have been present in the at-risk population in sufficient numbers to cause an increase.
TABLE 2
Extra cases of breast cancer, by risk factor
| RISK FACTOR | BREAST CANCERS DIAGNOSED OVER 20 YEARS FROM AGES 50 TO 70 (PER 1,000) | EXTRA BREAST CANCERS (PER 1,000) |
|---|---|---|
| Never used HRT | 45 | - |
| >5 years HRT | 47 | 2 |
| >10 years HRT | 51 | 6 |
| >15 years HRT | 57 | 12 |
| Late menopause (age 60) | 59 | 14 |
| Alcohol (2 drinks/day) | 72 | 27 |
| No daily exercise | 72 | 27 |
| Weight gain (>20 kg) | 90 | 45 |
| Reprinted from THE LANCET, Vol. 350: 1047–1059, 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. Copyright 1997, with permission from Elsevier | ||
HRT may promote, rather than induce, breast cancer
The role of hormones in the etiology of breast cancer is difficult to assess. The Million Women Study49 found that the elevated risk of breast cancer disappeared within 1 year of stopping HRT. This finding implies that hormones may be a promoter, rather than inducer, of neoplasms in the breast.
Breast cancer may be present in many women, but apparent in few
When autopsies were performed on women in their 40s who had died from other diseases, the incidence of breast cancer was 39%, but the clinical detection rate was only 1% for this population.50 This discrepancy suggests that neoplastic cells may be present in the body at any time, but become clinically apparent only under certain conditions.51
More recent data suggest that undifferentiated stem cells in the breast become dysfunctional and result in cancer.52 This theory is supported by the various histologic types of cancer found in the breast.
A weak link
Although it may be compelling to link hormone use with breast cancer, the association is weak and the incidence is lower than in other known relationships such as obesity. At present, the cause of breast neoplasia appears to be multifactorial.
1. Freedman RR. Pathophysiology and treatment of menopausal hot flashes. Semin Reprod Med. 2005;23:11-25.
2. Utian WH. Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: a comprehensive review. Health Qual Life Outcomes. 2005;3:47.-
3. Archer DF. Percutaneous 17beta-estradiol gel for the treatment of vasomotor symptoms in postmenopausal women. Menopause. 2003;10:516-521.
4. Archer DF. Low-dose hormone therapy for postmenopausal women. Clin Obstet Gynecol. 2003;46:317-324.
5. Nelson HD. Commonly used types of postmenopausal estrogen for treatment of hot flashes: scientific review. JAMA. 2004;291:1610-1620.
6. Ballagh SA. Vaginal rings for menopausal symptom relief. Drugs Aging. 2004;21:757-766.
7. Speroff L. Efficacy and tolerability of a novel estradiol vaginal ring for relief of menopausal symptoms. Obstet Gynecol. 2003;102:823-834.
8. Notelovitz M. Urogenital atrophy and low-dose vaginal estrogen therapy. Menopause. 2000;7:140-142.
9. Utian WH, Burry KA, Archer DF, 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.
10. Christiansen C. Effects of drospirenone/estrogen combinations on bone metabolism. Climacteric. 2005;8(suppl 3):35-41.
11. Delmas PD, Confavreux E, Garnero P, et al. A combination of low doses of 17 beta-estradiol and norethisterone acetate prevents bone loss and normalizes bone turnover in postmenopausal women. Osteoporos Int. 2000;11:177-187.
12. Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH. Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. JAMA. 2002;287:2668-2676.
13. Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH. Bone response to treatment with lower doses of conjugated estrogens with and without medroxyprogesterone acetate in early postmenopausal women. Osteoporos Int. 2005;16:372-379.
14. Ravn P, Bidstrup M, Wasnich RD, et al. Alendronate and estrogen-progestin in the long-term prevention of bone loss: four-year results from the early postmenopausal intervention cohort study. A randomized, controlled trial. Ann Intern Med. 1999;131:935-942.
15. Recker RR, Davies KM, Dowd RM, Heaney RP. 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.
16. Anderson GL, Limacher M, Assaf AR, 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.
17. Cauley JA, 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.
18. Archer DF. The effect of the duration of progestin use on the occurrence of endometrial cancer in postmenopausal women. Menopause. 2001;8:245-251.
19. Lacey JV, Jr, Brinton LA, Lubin JH, Sherman ME, Schatzkin A, Schairer C. Endometrial carcinoma risks among menopausal estrogen plus progestin and unopposed estrogen users in a cohort of postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2005;14:1724-1731.
20. Archer DF, Furst K, Tipping D, Dain MP, Vandepol C. A randomized comparison of continuous combined transdermal delivery of estradiol-norethindrone acetate and estradiol alone for menopause. CombiPatch Study Group. Obstet Gynecol. 1999;94:498-503.
21. Bouchard P, De Cicco-Nardone F, Spielmann D, Garcea N. Bleeding profile and endometrial safety of continuous combined regimens 1mg 17beta-estradiol/trimegestone versus 1or 2 mg 17beta-estradiol/norethisterone acetate in postmenopausal women. Gynecol Endocrinol. 2005;21:142-148.
22. Kurman RJ, Felix JC, Archer DF, Nanavati N, Arce J, Moyer DL. Norethindrone acetate and estradiol-induced endometrial hyperplasia. Obstet Gynecol. 2000;96:373-379.
23. 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.
24. Sturdee DW, Ulrich LG, Barlow DH, et al. The endometrial response to sequential and continuous combined oestrogen-progestogen replacement therapy. BJOG. 2000;107:1392-1400.
25. Ylikorkala O, Wahlstrom T, Caubel P, Lane R. Intermittent progestin administration as part of hormone replacement therapy: long-term comparison between estradiol 1mg combined with intermittent norgestimate and estradiol 2 mg combined with constant norethisterone acetate. Acta Obstet Gynecol Scand. 2002;81:654-660.
26. Espeland MA, Bush TL, Mebane-Sims I, et al. Rationale, design, and conduct of the PEPI Trial. Postmenopausal Estrogen/Progestin Interventions. Control Clin Trials. 1995;16(suppl):3S-19S.
27. Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med. 1996;335:453-461.
28. Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses’ health study. N Engl J Med. 1991;325:756-762.
29. Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med. 2000;133:933-941.
30. Grodstein F, Manson JE, Stampfer MJ. Postmenopausal hormone use and secondary prevention of coronary events in the nurses’ health study. a prospective, observational study. Ann Intern Med. 2001;135:1-8.
31. Bush TL, Cowan LD, Barrett-Connor E, et al. Estrogen use and all-cause mortality. Preliminary results from the Lipid Research Clinics Program Follow-Up Study. JAMA. 1983;249:903-906.
32. Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other considerations. Annu Rev Public Health. 1998;19:55-72.
33. 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.
34. Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease: the Women’s Health Initiative. Arch Intern Med. 2006;166:357-365.
35. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523-534.
36. Rossouw JE, Anderson GL, Prentice RL, 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.
37. Naftolin F, Taylor HS, 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.
38. Grodstein F, Manson JE, Stampfer MJ. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. J Womens Health (Larchmt). 2006;15:35-44.
39. Clarkson TB, Appt SE. Controversies about HRT-lessons from monkey models. Maturitas. 2005;51:64-74.
40. Wagner JD, Clarkson TB. The applicability of hormonal effects on atherosclerosis in animals to heart disease in postmenopausal women. Semin Reprod Med. 2005;23:149-156.
41. Barrett-Connor E, Laughlin GA. Hormone therapy and coronary artery calcification in symptomatic postmenopausal women: the Rancho Bernardo Study. Menopause. 2005;12:40-48.
42. Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001;135:939-953.
43. Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med. 2000;343:522-529.
44. Harman SM, Brinton EA, Cedars M, et al. KEEPS: the Kronos Early Estrogen Prevention Study. Climacteric. 2005;8:3-12.
45. Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med. 2001;344:276-285.
46. Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med. 2006;354:270-282.
47. Bush TL, Whiteman M, Flaws JA. Hormone replacement therapy and breast cancer: a qualitative review. Obstet Gynecol. 2001;98:498-508.
48. Morimoto LM, White E, Chen Z, et al. Obesity, body size, and risk of postmenopausal breast cancer: the Women’s Health Initiative (United States). Cancer Causes Control. 2002;13:741-751.
49. Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362:419-427.
50. Black WC, Welch HG. Advances in diagnostic imaging and overestimations of disease prevalence and the benefits of therapy. N Engl J Med. 1993;328:1237-1243.
51. Folkman J, Kalluri R. Cancer without disease. Nature. 2004;427:787.-
52. Dontu G, Al-Hajj M, Abdallah WM, Clarke MF, Wicha MS. Stem cells in normal breast development and breast cancer. Cell Prolif. 2003;36 Suppl 1:59-72.
1. Freedman RR. Pathophysiology and treatment of menopausal hot flashes. Semin Reprod Med. 2005;23:11-25.
2. Utian WH. Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: a comprehensive review. Health Qual Life Outcomes. 2005;3:47.-
3. Archer DF. Percutaneous 17beta-estradiol gel for the treatment of vasomotor symptoms in postmenopausal women. Menopause. 2003;10:516-521.
4. Archer DF. Low-dose hormone therapy for postmenopausal women. Clin Obstet Gynecol. 2003;46:317-324.
5. Nelson HD. Commonly used types of postmenopausal estrogen for treatment of hot flashes: scientific review. JAMA. 2004;291:1610-1620.
6. Ballagh SA. Vaginal rings for menopausal symptom relief. Drugs Aging. 2004;21:757-766.
7. Speroff L. Efficacy and tolerability of a novel estradiol vaginal ring for relief of menopausal symptoms. Obstet Gynecol. 2003;102:823-834.
8. Notelovitz M. Urogenital atrophy and low-dose vaginal estrogen therapy. Menopause. 2000;7:140-142.
9. Utian WH, Burry KA, Archer DF, 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.
10. Christiansen C. Effects of drospirenone/estrogen combinations on bone metabolism. Climacteric. 2005;8(suppl 3):35-41.
11. Delmas PD, Confavreux E, Garnero P, et al. A combination of low doses of 17 beta-estradiol and norethisterone acetate prevents bone loss and normalizes bone turnover in postmenopausal women. Osteoporos Int. 2000;11:177-187.
12. Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH. Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. JAMA. 2002;287:2668-2676.
13. Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH. Bone response to treatment with lower doses of conjugated estrogens with and without medroxyprogesterone acetate in early postmenopausal women. Osteoporos Int. 2005;16:372-379.
14. Ravn P, Bidstrup M, Wasnich RD, et al. Alendronate and estrogen-progestin in the long-term prevention of bone loss: four-year results from the early postmenopausal intervention cohort study. A randomized, controlled trial. Ann Intern Med. 1999;131:935-942.
15. Recker RR, Davies KM, Dowd RM, Heaney RP. 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.
16. Anderson GL, Limacher M, Assaf AR, 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.
17. Cauley JA, 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.
18. Archer DF. The effect of the duration of progestin use on the occurrence of endometrial cancer in postmenopausal women. Menopause. 2001;8:245-251.
19. Lacey JV, Jr, Brinton LA, Lubin JH, Sherman ME, Schatzkin A, Schairer C. Endometrial carcinoma risks among menopausal estrogen plus progestin and unopposed estrogen users in a cohort of postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2005;14:1724-1731.
20. Archer DF, Furst K, Tipping D, Dain MP, Vandepol C. A randomized comparison of continuous combined transdermal delivery of estradiol-norethindrone acetate and estradiol alone for menopause. CombiPatch Study Group. Obstet Gynecol. 1999;94:498-503.
21. Bouchard P, De Cicco-Nardone F, Spielmann D, Garcea N. Bleeding profile and endometrial safety of continuous combined regimens 1mg 17beta-estradiol/trimegestone versus 1or 2 mg 17beta-estradiol/norethisterone acetate in postmenopausal women. Gynecol Endocrinol. 2005;21:142-148.
22. Kurman RJ, Felix JC, Archer DF, Nanavati N, Arce J, Moyer DL. Norethindrone acetate and estradiol-induced endometrial hyperplasia. Obstet Gynecol. 2000;96:373-379.
23. 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.
24. Sturdee DW, Ulrich LG, Barlow DH, et al. The endometrial response to sequential and continuous combined oestrogen-progestogen replacement therapy. BJOG. 2000;107:1392-1400.
25. Ylikorkala O, Wahlstrom T, Caubel P, Lane R. Intermittent progestin administration as part of hormone replacement therapy: long-term comparison between estradiol 1mg combined with intermittent norgestimate and estradiol 2 mg combined with constant norethisterone acetate. Acta Obstet Gynecol Scand. 2002;81:654-660.
26. Espeland MA, Bush TL, Mebane-Sims I, et al. Rationale, design, and conduct of the PEPI Trial. Postmenopausal Estrogen/Progestin Interventions. Control Clin Trials. 1995;16(suppl):3S-19S.
27. Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med. 1996;335:453-461.
28. Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses’ health study. N Engl J Med. 1991;325:756-762.
29. Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med. 2000;133:933-941.
30. Grodstein F, Manson JE, Stampfer MJ. Postmenopausal hormone use and secondary prevention of coronary events in the nurses’ health study. a prospective, observational study. Ann Intern Med. 2001;135:1-8.
31. Bush TL, Cowan LD, Barrett-Connor E, et al. Estrogen use and all-cause mortality. Preliminary results from the Lipid Research Clinics Program Follow-Up Study. JAMA. 1983;249:903-906.
32. Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other considerations. Annu Rev Public Health. 1998;19:55-72.
33. 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.
34. Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease: the Women’s Health Initiative. Arch Intern Med. 2006;166:357-365.
35. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523-534.
36. Rossouw JE, Anderson GL, Prentice RL, 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.
37. Naftolin F, Taylor HS, 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.
38. Grodstein F, Manson JE, Stampfer MJ. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. J Womens Health (Larchmt). 2006;15:35-44.
39. Clarkson TB, Appt SE. Controversies about HRT-lessons from monkey models. Maturitas. 2005;51:64-74.
40. Wagner JD, Clarkson TB. The applicability of hormonal effects on atherosclerosis in animals to heart disease in postmenopausal women. Semin Reprod Med. 2005;23:149-156.
41. Barrett-Connor E, Laughlin GA. Hormone therapy and coronary artery calcification in symptomatic postmenopausal women: the Rancho Bernardo Study. Menopause. 2005;12:40-48.
42. Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001;135:939-953.
43. Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med. 2000;343:522-529.
44. Harman SM, Brinton EA, Cedars M, et al. KEEPS: the Kronos Early Estrogen Prevention Study. Climacteric. 2005;8:3-12.
45. Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med. 2001;344:276-285.
46. Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med. 2006;354:270-282.
47. Bush TL, Whiteman M, Flaws JA. Hormone replacement therapy and breast cancer: a qualitative review. Obstet Gynecol. 2001;98:498-508.
48. Morimoto LM, White E, Chen Z, et al. Obesity, body size, and risk of postmenopausal breast cancer: the Women’s Health Initiative (United States). Cancer Causes Control. 2002;13:741-751.
49. Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362:419-427.
50. Black WC, Welch HG. Advances in diagnostic imaging and overestimations of disease prevalence and the benefits of therapy. N Engl J Med. 1993;328:1237-1243.
51. Folkman J, Kalluri R. Cancer without disease. Nature. 2004;427:787.-
52. Dontu G, Al-Hajj M, Abdallah WM, Clarke MF, Wicha MS. Stem cells in normal breast development and breast cancer. Cell Prolif. 2003;36 Suppl 1:59-72.