Estrogen Studies

“Estrogen therapy alters the biology of the inner vessels (of the heart). Hormone replacement therapy protects through vasodilation, anti inflammatory and anti-proliferative effects, providing significant coronary artery benefits.”

Nabel, E. G. (2000). Coronary heart disease in women — an ounce of prevention. New England Journal of Medicine, 343(8), 572-574.

The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial: PEPI was a 3-year, multicenter, randomized, double-blind, placebo-controlled trial performed with 875 healthy postmenopausal women aged 45 to 64.

CONCLUSIONS: Estrogen alone or in combination with a progestin improves lipoproteins and lowers fibrinogen levels. Estrogen with natural bio-identical progesterone has the most favorable effect on HDL-C and no excess risk of endometrial hyperplasia.

Miller, V. T., LaRosa, J., Barnabei, V., Kessler, C., Levin, G., Smith-Roth, A., . . . Kessler, G. (1995). Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA, 273(3), 199-208.

(In other words, when they used natural bio-identical progesterone instead of altered, synthetic MPA (Provera), the result was a better effects on lipids and also no increased risk of uterine cancer.)

Many epidemiological studies show that women who use estrogen therapy after menopause have significantly lower rates of heart disease than postmenopausal women who do not take estrogen. This review assessed the impact of estrogen use among women with particularly high cardiovascular risk. Seven studies of estrogen therapy in women with established coronary heart disease (such as coronary stenosis and prior heart attack) were reviewed:

These studies all find fewer recurrent cardiovascular events and improved survival in the estrogen group when compared to the non-estrogen group. Analysis of the effect of estrogen within different risk categories in the 16-year follow up of the Nurses’ Health Study confirms that the protective effect of estrogen is even more pronounced among women with high baseline risk of heart disease.

Grodstein, F., & Stampfer, M. J. (1998). Estrogen for women at varying risk of coronary disease. Maturitas, 30(1), 19-26. doi:10.1016/S0378-5122(98)00055-3

This study examined the effects of estrogen and progesterone on human foam cell formation, a key early event in arterial plaque buildup.

CONCLUSION: Physiological levels of estrogen and progesterone are associated with a reduction in human macrophage lipid loading in women, which is consistent with an atheroprotective effect.

McCrohon, J. A., Nakhla, S., Jessup, W., Stanley, K. K., & Celermajer, D. S. (1999). Estrogen and progesterone reduce lipid accumulation in human monocyte-derived macrophages. Circulation  , 100(23), 2319-2325.

Postmenopausal hormone use appears to decrease risk for major coronary events in women without previous heart disease.

Grodstein, F., Manson, J. E., Colditz, G. A., Willett, W. C., Speizer, F. E., & Stampfer, M. J. (2000). A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Annals of Internal Medicine, 133(12), 933-941.

(Note: This study also found that when they used synthetic, artificial progestins such as Provera (rather than natural, bio-identical progesterone) and combined it with estrogen pills (rather than creams which aren’t metabolized in the liver), it can increase the risk of stroke in certain patients. Artificial progestins should never be used; bio-identical progesterone is the appropriate choice for every patient. There are a number of variables that determine whether oral estrogen vs. estrogen cream is the right choice for a given patient. These nuances will be thoroughly discussed in person prior to initiating hormone replacement therapy.)

Feb 2006: Findings on estrogen-only therapy from the Women’s Health Initiative trial were published:

Among women who started estrogen replacement therapy between ages 50 to 59, the risk of heart attack or coronary death was lower with estrogen use (Hazard Ratio= 0.63; 95% CI, 0.361.08, P>.05), and the risk of undergoing coronary artery bypass surgery or getting a stent was significantly lower with estrogen than with placebo (HR, 0.55; 95% CI, 0.35?0.86).

Hsia J, et al; Women’s Health Initiative Investigators. Conjugated equine estrogens and coronary heart disease: the Women’s Health Initiative. Arch Intern Med. 2006;166:357?365.

April 2007: A subanalysis was published that combined both arms of the Women’s Health Initiative. They again found that heart disease decreased with hormone replacement therapy: Estrogen users who were less than 10 years past menopause had a Hazard Ratio for Coronary Artery Disease of 0.76 (95% CI, 0.5?1.16).

June 2007: A separate subanalysis was published assessing estrogen use and coronary artery calcification in WHI participants who had undergone hysterectomy and who were 50 to 59 years old at baseline. Coronary artery calcium scores were more favorable among women receiving estrogen than among those receiving placebo (P=.02).

January 2008: The American Association of Clinical Endocrinologists released a statement on hormone replacement therapy, stating it may be beneficial for women in early menopause.

The re-evaluation of the Nurses’ Health Study found that women beginning hormone therapy near menopause had a significantly reduced risk of coronary heart disease (RR= 0.66 for estrogen alone; 0.72 when they added in synthetic progestin).

(Note: Many studies have shown that synthetic progestins negate the beneficial effects of estrogen on heart disease. This is why only natural bio-identical progesterone should be used: it maintains the beneficial effects of estrogen on heart disease, while also protecting against cancer of the breast, uterus and ovaries.)

A meta-analysis of 23 trials of hormone replacement therapy found that women who started taking estrogen either before age 60 or within 10 years of menopause had a significantly lower risk of Coronary Heart Disease (0.68), whereas if they waited until ten years post-menopause there was no benefit regarding CHD or Alzheimer’s (though there are still benefits regarding osteoporosis and skin elasticity).

In the Women’s Health Initiative they found similar results: the hazard ratio for CHD was 0.76 if they started hormones within ten years of menopause, but higher after age 60.

Among 118,404 female registered nurses who responded to a mailed questionnaire and had no history of cancer in 1976, 191 colon cancers and 49 rectal cancers were diagnosed during 8 years of follow-up.

Use of postmenopausal estrogens was associated with a reduced risk of colorectal cancer (Relative Risk = 0.5, 95% CL: 0.3-1.0).

Chute CG, et al: A prospective study of reproductive history and exogenous estrogens on the risk of colorectal cancer in women. Epidemiology 2:201-207, 1991

The results indicate that postmenopausal hormone-replacement therapy might reduce the risk of colorectal cancer.

(age-adjusted relative risk [RR] = 0.4, 95% confidence interval = 0.2-0.9). Adjustments for diet, body mass, and physical activity had little influence on the results.

Gerhardsson de Verdier M et al: Reproductive factors, exogenous female hormones, and colorectal cancer by subsite. Cancer Causes Control 3:355-360, 1992

Menopausal estrogen use was found to protect against development of large bowel cancer with an odds ratio of 0.6 (95% CI, 0.33-0.99). Adjusting for age at diagnosis, parity, hysterectomy, oophorectomy, and cholecystectomy resulted in an adjusted odds ratio of 0.5 (95% CI, 0.27-0.90).

These data support the hypothesis that postmenopausal hormone replacement may decrease the risk of large bowel cancer in women.

Fumer SE, et al: A case-control study of large bowel cancer and hormone exposure in women. Cancer Res 49:4936-4940, 1989

The most extensive study on estrogen vs. colon cancer was published in 1995 in the Journal of the National Cancer Institute:

Estrogen replacement therapy and risk of fatal colon cancer in a prospective cohort of postmenopausal women: The present study attempts a definitive analysis of the relationship between fatal colon cancer and use of Estrogen Replacement Therapy among women in a large prospective study of adults in the United States.

Methods: Women were selected from the 676,526 female participants in Cancer Prevention Study II (CPS-II), a prospective mortality study of about 1.2 million men and women. After 7 years of follow-up, 897 colon cancer deaths were observed in a cohort of 422,373 postmenopausal women who were cancer-free at study entry.

Results: Women who had at some point used Estrogen Replacement Therapy had significantly decreased risk of fatal colon cancer (Relative Risk = 0.71; 95% confidence interval [CI] = 0.61-0.83). The reduction in risk was strongest among current users (RR = 0.55; 95% CI = 0.40-0.76), and there was a significant (P = .0001) trend of decreasing risk with increasing years of use: Women who used estrogen for 1 year or less had a Relative Risk of 0.81 (95% CI = 0.63-1.03), while users of 11 years or more had an RR of 0.54 (95% CI = 0.39-0.76). These associations were not altered in multivariate analyses controlling for other risk factors.

Conclusions: In our data, estrogen therapy, particularly recent and long-term use, was associated with a substantial decrease in risk of fatal colon cancer. These results were consistent with several published studies suggesting a protective role of estrogen replacement therapy in the development of colorectal cancer.

J Natl Cancer Inst. 1995 Apr 5;87(7):517-23.

The results indicate that postmenopausal hormone-replacement therapy might reduce the risk of colorectal cancer.

(age-adjusted relative risk [RR] = 0.4, 95% confidence interval = 0.2-0.9). Adjustments for diet, body mass, and physical activity had little influence on the results.

Gerhardsson de Verdier M et al: Reproductive factors, exogenous female hormones, and colorectal cancer by subsite. Cancer Causes Control 3:355-360, 1992

These findings extend those of two previous prospective studies and provide new evidence to suggest a protective effect of hormone replacement therapy.

As in the previous studies, the adjusted risk of Alzheimer’s Disease among long-term Hormone Replacement Therapy users was reduced to little more than half that of nonusers.

Zandi PP, et al. Hormone replacement therapy and incidence of alzheimer disease in older women: The Cache County study. JAMA. 2002;288:2123-2129.

This study examined whether estrogen replacement therapy affected risk for Alzheimer’s disease in 971 postmenopausal women. We found that estrogen therapy used during early postmenopause may reduce Alzheimer’s risk.

This study looked at women ages 50-63. This is consistent with other studies in showing that you have to start estrogen within approximately eight years of menopause to get significant reduction of Alzheimer’s risk. The risk reduction in this study was rather incredible: The odds ratio for estrogen users was? 0.35, (a 65% reduction in risk!) with a 95% confidence interval?of?0.19 to 0.66? statistically highly significant.

J Neurol Neurosurg Psychiatry. 2005 Jan;76(1):103-5. Postmenopausal hormone therapy and Alzheimer’s disease risk: interaction with age.

Researchers at the Mayo Clinic assessed the risk of neurologic disease among several thousand Midwestern women. They found that having had even one ovary removed before menopause, especially in women younger than 38 years, was associated with a significantly increased risk of cognitive impairment and dementia. However, when estrogen therapy was used after [ovary removal], and taken until at least age 50, no increase in cognitive impairment was found.

Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007;69:1074?1083.

This prospective study followed 472 post- or perimenopausal women for up to 16 years in the Baltimore Longitudinal Study of Aging. The relative risk for Alzheimer’s Disease in Estrogen Replacement Therapy users as compared with nonusers was 0.46 (95% CI, 0.209-0.997), indicating a reduced risk of AD for women who had reported the use of estrogen.

Our finding offers additional support for a protective influence of estrogen in Alzheimer’s Disease.

Kawas C, et al. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer’s disease: the Baltimore Longitudinal Study of Aging. Neurology. 1997;48:1517-1521.

“We studied 1124 elderly women who were initially free of Alzheimer’s disease, Parkinson’s disease, and stroke, and who were taking part in a longitudinal study of aging and health in a New York City community. Onset of Alzheimer’s disease was significantly later in women who had taken estrogen than in those who did not and the relative risk of the disease was significantly reduced (5.8% of estrogen users vs 16.3% of nonusers; RR= 0.40 [95% CI 0.22-0.85], p < 0.01), even after adjustment for differences in education, ethnic origin, and apolipoprotein-E genotype. Women who had used estrogen for longer than 1 year had a greater reduction in risk; none of the women who were taking estrogen at study enrollment has developed Alzheimer’s disease.

Tang MX et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet. 1996;348:429-432.

In this study of hormones, memory, and mood in a healthy elderly population, 14 women who use estrogen and 41 women who do not use estrogen, whose average age was 72.1 years, were given a battery of psychological tests measuring verbal memory, visual memory, concentration and attention, language fluency and semantic memory, and mood.

Estrogen-users had higher total (p < .01) and forward (p < .001) digit span scores compared with non-users, and also had higher backward digit span scores than non-users (p < .05).

Psychoneuroendocrinology. 1998 Aug;23(6):583-603.

Studies on hormone replacement therapy and cognitive function are complicated by differences in how the studies are done.

Is it a preventative study or an interventional study? Did they use estrogen alone or estrogen with a synthetic progestin? How far post-menopause were the women when they started estrogen? But one thing all the studies had in common was that almost none of them used bio-identical estrogen. They all used Premarin (or its’ generic equivalent, conjugated equine estrogen). However, last year a study finally came out comparing the effect of Premarin and bioidentical estrogen on memory. As you might suspect, our brain seems to respond better to the natural human version.

Results: Women receiving 17-beta-Estradiol (i.e. bio-identical estrogen) showed significantly better verbal memory performance compared to women receiving conjugated equine estrogens (i.e. Premarin), regardless of age, IQ, years of education, risk factors for Alzheimer’s Disease (including APOE-4 carriership), duration of endogenous and exogenous estrogen exposure, concurrent progesterone use, or natural or surgical menopause status.

Conclusions: Verbal memory performance was better in menopausal women receiving [bio-identical estrogen] compared to [Premarin] in women with risk factors for Alzheimer’s Didease. Genetic risk for AD as well as other confounders did not affect this finding. The results suggest a differential effect of the type of Hormone Therapy on verbal memory, with [bio-identical estrogen] being a preferential compound.

Differences in verbal memory performance in postmenopausal women receiving hormone therapy: 17beta-estradiol versus conjugated equine estrogens. Am J Geriatr Psychiatry. 2011 September ; 19(9): 792?802.

What is surprising about those results is that only 43 women in their study group were taking bioidentical estrogen? and seven of those women were also taking Provera. There is strong evidence to suggest that Provera worsens verbal memory1,2, and so it’s rather remarkable that they nevertheless got statistically significant results. I suspect a larger trial using just bioidenticals would produce even stronger results.

The potential lethal consequences of osteoporosis are overwhelming. Estrogen is protective, but only when certain serum levels are maintained.

(which is why I recheck serum levels in all my patients after initiating therapy?)

Fitzpatrick LA. Estrogen and bone health. Female Patient. 2004 Oct;29:40-46.

Prospective controlled cohort trial: 2016 healthy women aged 45-58 years, all less than two years menopausal. Staying on hormone replacement for 5 years reduced total fracture risk almost 40% (RR=0.61, 95% CI: 0.39-0.97) and forearm fracture risk 76% (RR=0.24, 95% CI: 0.09-0.69)!

Maturitas. 2000 Oct 31;36(3):181-93. Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women ? results of the Danish Osteoporosis Prevention Study.

A 3-year, multicenter, randomized, double-blinded, placebo-controlled clinical trial studied 875 healthy women aged 45 to 64 years:

CONCLUSIONS: Estrogen replacement therapy increases Bone Mineral Density at clinically important sites (hip and spine).

JAMA. 1996 Nov 6;276(17):1389-96. Effects of hormone therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial.

In older women, a dosage of 0.25 mg/d of 17-beta-estradiol increased bone density of the hip, spine, and total body, and reduced bone turnover, with minimal adverse effects.

(Note: 17-beta estradiol is bio-identical estrogen.)

Prestwood KM, Kenny AM, Kleppinger A, Kulldorff M. Ultralow-dose micronized 17beta-estradiol and bone density and bone metabolism in older women: a randomized controlled trial. JAMA. 2003 Aug;290(8):1042-1048.

Estrogen use by postmenopausal women, especially when started within 3 years of the last menstrual period, prevents bone loss and reduces the risk of osteoporotic fractures.

Withdrawal of estrogen therapy is followed by significant bone loss, suggesting that long-term therapy is needed.

Am J Obstet Gynecol. 1989 Dec;161(6 Pt 2):1842-6. Estrogens in the prevention of osteoporosis in postmenopausal women.

Our results suggest estrogen may promote tooth retention by strengthening the periodontal attachment surrounding the teeth.

Menopause. 2004 Sep-Oct;11(5):556-62. Effect of estrogen use on tooth retention, oral bone height, and oral bone porosity in Japanese postmenopausal women.

Estrogen users had more teeth remaining than nonusers (12.5 versus 10.7 teeth, P = 0.046) after controlling for age, smoking status, and education. Duration of estrogen use was an independent predictor of the number of teeth remaining (P = 0.015): for every 4.2-years of estrogen use there was retention of 1 additional tooth on average.

Long-term estrogen users (more than 8 years) had an average of 3.6 more teeth than women who never used estrogen (P < 0.02).

Postmenopausal estrogen replacement and tooth retention. Am J Med. 1997 Jun;102(6):536-42.

Several studies have demonstrated a relationship between tooth loss and systemic osteoporosis. The recognized benefit of estrogen replacement therapy (ERT) in osteoporosis prompted this review of the effects of ERT on tooth loss.

CONCLUSION: Estrogen replacement therapy may be beneficial in preventing tooth loss and the need for dentures in older women.

Arch Intern Med. 1995 Nov 27;155(21):2325-9. The benefits of estrogen replacement therapy on oral health. The Leisure World cohort.

A study came out recently in the Journal of the American Medical Association showing exactly that: they gave very high doses of dutasteride to 102 men who were also being given testosterone replacement, and here is what they found:Changes in the International Index of Erectile Function and Male Sexual Health Questionnaire composite scores and erectile, orgasmic, ejaculatory, intercourse, or overall satisfaction scores did not differ significantly between the dutasteride and placebo groups.

?In other words, as long as they had enough testosterone circulating, dutasteride did not hurt sexual function. And that was using 2.5mg/day of dutasteride, the highest possible dose. I would actually only use 0.5mg, and probably not even every day, because the half-life is so long that it isn’t necessary to take it daily.

Here are some of the many papers showing that natural progesterone is completely different from synthetic progestins like Provera? (aka medroxyprogesterone acetate or “MPA”):

Climacteric, 2012

Micronized progesterone does not increase cell proliferation in breast tissue in post- menopausal women compared with synthetic medroxyprogesterone acetate (MPA). Experimental evidence suggests that the opposing effects of MPA and micronized progesterone on breast tissue are related to the non-specific effects of MPA, including glucocorticoid activity and differences in the regulation of gene expression.

Micronized progesterone and its impact on the endometrium and breast vs. progestogens. Gompel A, CLIMACTERIC 2012;15(Suppl 1):18?25

Journal of Steroid Biochemistry and Molecular Biology, July 2005

The addition of natural progesterone does not affect breast cancer risk. This finding is consistent with in vivo data suggesting that progesterone does not have a detrimental effect on breast tissue. More importantly, medroxyprogesterone acetate [Provera?] can potentiate the proliferative action of estrogens.

Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. Campagnoli et al. J Steroid Biochem Mol Biol. 2005 Jul;96(2):95-108.

Journal of Steroid Biochemistry and Molecular Biology, December 2005

?synthetic progestins (i.e. Provera?), when added to HRT for menopausal complaints, increase breast cancer risk more than estrogen alone. However, recent findings suggest that natural progesterone, whether produced during pregnancy or administered outside pregnancy, does not increase breast cancer risk, and could even be protective.

J Steroid Biochem Mol Biol. 2005 Dec;97(5):441-50

Breast Cancer Research and Treatment, 2008

This was a large prospective cohort study of over 100,000 women in France. About 70% of the women used HRT for about 7 years, starting at age 52 (on average). They were then followed for about 8 years. This study found that if they combined bio-identical estrogen with synthetic progestins (Provera? /MPA or norethindrone), the risk of cancer was much worse: relative risk of 1.48 to 2.11! However if they combined estrogen with natural progesterone instead of Provera?, the relative risk of breast cancer was 1.00: no increased risk.

Breast Cancer Res Treat. 2008 Jan;107(1):103-11. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. See Table 3.

International Journal of Cancer, 2005

This study assessed the risk of breast cancer in relation to different types of Hormone Replacement Therapy (HRT) in 54,548 postmenopausal women who were part of the E3N-EPIC cohort study.

The relative risk (RR) of developing breast cancer was 1.2 if they used transdermal estrogen alone, and decreased to 0.9 when estrogen was combined with bio-identical progesterone. Those differences did not reach statistical significance: essentially estrogen either alone or with bioidentical progesterone had no effect on breast cancer risk. However, when estrogen was combined with synthetic progestins (such as MPA/Provera?), relative risk of breast cancer increased to 1.4, which was statistically significant.

Fournier A. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005 Apr 10;114(3):448-54.

Climacteric, 2002

To evaluate the risk of breast cancer associated with the use of estradiol plus (bio-identical) progesterone, which is commonly prescribed in France (rather than MPA/Provera), a cohort of 3175 postmenopausal women was followed for a mean of 8.9 years (28,367 woman-years). There was no increase in the risk of breast cancer in the natural, bio-identical hormone users (RR 0.98, 95% confidence interval (CI): 0.65-1.5). The author concluded that HRT with natural estradiol and natural progesterone is beneficial for quality of life, prevention of bone loss and cardiovascular risk profile.

de Ligni?res B et al. Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women. Climacteric. 2002 Dec;5(4):332-40.

Maturitas, 2008

Hormone replacement therapy (HRT) in young postmenopausal women is a safe and effective tool to counteract climacteric symptoms and to prevent long-term degenerative diseases, such as osteoporotic fractures, cardiovascular disease, diabetes mellitus and possibly cognitive impairment. However, the expert selection of specific compounds, doses or routes of administration can provide significant clinical advantages. Recent evidence shows that natural progesterone displays a favorable action on the vessels and on the brain, while this might not be true for synthetic progestins (like Provera?). ?Recent trials (also) indicate that natural progesterone confers less or even no risk of breast cancer, as opposed to synthetic progestins.

Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review. Maturitas. 2008 Jul-Aug;60(3-4):185-201.

Breast Cancer Research and Treatment, 2007

The goal of this study was to compare the effects of oral estradiol given with either MPA or micronized progesterone on risk for breast cancer in a postmenopausal primate model. Compared to placebo, Estrogen + MPA resulted in significantly greater breast tissue proliferation, while Estrogen + bio-identical progesterone did not. These findings suggest that oral micronized progesterone has a more favorable effect on risk biomarkers for breast cancer than medroxyprogesterone acetate. These findings provide growing support for micronized progesterone as an alternative to MPA in hormone therapy regimens.

Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys. Breast Cancer Res Treat. 2007 Jan;101(2):125-34

Climacteric, 2012

Micronized progesterone does not increase cell proliferation in breast tissue in post- menopausal women compared with synthetic medroxyprogesterone acetate (MPA). Experimental evidence suggests that the opposing effects of MPA and micronized progesterone on breast tissue are related to the non-specific effects of MPA, including glucocorticoid activity and differences in the regulation of gene expression.

Micronized progesterone and its impact on the endometrium and breast vs. progestogens. Gompel A, CLIMACTERIC 2012;15(Suppl 1):18?25

Journal of Steroid Biochemistry and Molecular Biology, July 2005

The addition of natural progesterone does not affect breast cancer risk. This finding is consistent with in vivo data suggesting that progesterone does not have a detrimental effect on breast tissue. More importantly, medroxyprogesterone acetate [Provera?] can potentiate the proliferative action of estrogens.

Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. Campagnoli et al. J Steroid Biochem Mol Biol. 2005 Jul;96(2):95-108.

Journal of Steroid Biochemistry and Molecular Biology, December 2005

?synthetic progestins (i.e. Provera?), when added to HRT for menopausal complaints, increase breast cancer risk more than estrogen alone. However, recent findings suggest that natural progesterone, whether produced during pregnancy or administered outside pregnancy, does not increase breast cancer risk, and could even be protective.

J Steroid Biochem Mol Biol. 2005 Dec;97(5):441-50

Breast Cancer Research and Treatment, 2008

This was a large prospective cohort study of over 100,000 women in France. About 70% of the women used HRT for about 7 years, starting at age 52 (on average). They were then followed for about 8 years. This study found that if they combined bio-identical estrogen with synthetic progestins (Provera? /MPA or norethindrone), the risk of cancer was much worse: relative risk of 1.48 to 2.11! However if they combined estrogen with natural progesterone instead of Provera?, the relative risk of breast cancer was 1.00: no increased risk.

Breast Cancer Res Treat. 2008 Jan;107(1):103-11. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. See Table 3.

International Journal of Cancer, 2005

This study assessed the risk of breast cancer in relation to different types of Hormone Replacement Therapy (HRT) in 54,548 postmenopausal women who were part of the E3N-EPIC cohort study. The relative risk (RR) of developing breast cancer was 1.2 if they used transdermal estrogen alone, and decreased to 0.9 when estrogen was combined with bio-identical progesterone. Those differences did not reach statistical significance: essentially estrogen either alone or with bioidentical progesterone had no effect on breast cancer risk. However, when estrogen was combined with synthetic progestins (such as MPA/Provera?), relative risk of breast cancer increased to 1.4, which was statistically significant.

Fournier A. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005 Apr 10;114(3):448-54.

Climacteric, 2002

To evaluate the risk of breast cancer associated with the use of estradiol plus (bio-identical) progesterone, which is commonly prescribed in France (rather than MPA/Provera), a cohort of 3175 postmenopausal women was followed for a mean of 8.9 years (28,367 woman-years). There was no increase in the risk of breast cancer in the natural, bio-identical hormone users (RR 0.98, 95% confidence interval (CI): 0.65-1.5). The author concluded that HRT with natural estradiol and natural progesterone is beneficial for quality of life, prevention of bone loss and cardiovascular risk profile.

de Lignires B et al. Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women. Climacteric. 2002 Dec;5(4):332-40.

Maturitas, 2008

Hormone replacement therapy (HRT) in young postmenopausal women is a safe and effective tool to counteract climacteric symptoms and to prevent long-term degenerative diseases, such as osteoporotic fractures, cardiovascular disease, diabetes mellitus and possibly cognitive impairment. However, the expert selection of specific compounds, doses or routes of administration can provide significant clinical advantages. Recent evidence shows that natural progesterone displays a favorable action on the vessels and on the brain, while this might not be true for synthetic progestins (like Provera?). ?Recent trials (also) indicate that natural progesterone confers less or even no risk of breast cancer, as opposed to synthetic progestins.

Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review. Maturitas. 2008 Jul-Aug;60(3-4):185-201.

Breast Cancer Research and Treatment, 2007

The goal of this study was to compare the effects of oral estradiol given with either MPA or micronized progesterone on risk for breast cancer in a postmenopausal primate model. Compared to placebo, Estrogen + MPA resulted in significantly greater breast tissue proliferation, while Estrogen + bio-identical progesterone did not. These findings suggest that oral micronized progesterone has a more favorable effect on risk biomarkers for breast cancer than medroxyprogesterone acetate. These findings provide growing support for micronized progesterone as an alternative to MPA in hormone therapy regimens.

Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys. Breast Cancer Res Treat. 2007 Jan;101(2):125-34.