Stop the Breast Cancer Epidemic

Breast cancer is the most prevalent malignancy in women. Healthy lifestyle choices can substantially reduce risk.

Menopausal women, however, continue to use hormone drugs that were long ago shown to increase breast cancer risk.

Premarin® is a drug that contains estrogens unnatural to the human body.

While Premarin® alone does not appear to increase the risk of breast cancer,¹ the FDA obstructs women’s access to what we believe are safer forms of natural estrogens, like estriol.

The hormone drugs that concern us most are synthetic progestogens that continue to be prescribed, despite evidence that they can increase breast cancer risk.^2-4

Back in the early 1990s, we published findings from studies showing that natural progesterone provided benefits to menopausal and postmenopausal woman (including reduced breast cancer risk) in contrast to a synthetic progestogen (medroxyprogesterone acetate).^5,6

Our recommendation was bolstered in 2002 and 2004 with publications from the Women’s Health Initiative showing higher breast cancer incidence in women prescribed synthetic progestogens (with or without Premarin®).^1,2

Our concerns about the risks posed by FDA-approved hormone drugs have remained largely consistent for the past 25 years.

Life Extension® advocates for the use of bioidentical hormones as opposed to horse urine-derived estrogens and synthetic progestogens.

On page 28 of this month’s issue, we describe an alternative for those women who choose not to replace hormones lost to menopause.

This editorial describes what women can do to reduce their breast cancer risk.

The Estrogen Dilemma

As women enter their menopausal years they face a difficult decision.

Their bodies’ production of estrogen, progesterone and other youth-promoting hormones, like DHEA, rapidly declines.

While individual effects of menopause vary, most women suffer because their glands no longer produce the hormones needed to regulate critical physiological processes.

Depression, irritability, and short-term memory lapses are common menopausal complaints, along with hot flashes, night sweats, and insomnia.

Synthetic hormone drugs that were once widely prescribed have been shown to produce deadly side effects, yet they remain on the market courtesy of the FDA.

More women now seek natural hormone replacement strategies to find relief from menopausal symptoms.

Rather than repeat what we’ve written since the early 1990s about safer ways to replace female hormones, we performed an analysis of recent published data.

These latest findings help corroborate what we wrote 25 years ago.

It is now crystal clear that women can better balance risk with benefit by using bioidentical hormones or plant extracts that have menopausal relief properties.

Evidence From 2002-2017

A scientist frustrated with the lack of consensus about menopausal hormone therapy wrote a review article in 2017 that sought to pull together research that began with the famous Women’s Health Initiative trial in 2002.⁷

The Women’s Health Initiative trial was designed to test whether the beneficial associations seen in women starting hormone replacement near menopause would be found in women beyond menopause.

The trial was terminated early because most findings turned out opposite of what conventional doctors expected.

The 2002 report revealed higher breast cancer risk and no cardiovascular benefit in women prescribed the combination of horse urine-derived estrogen with a synthetic progestogen used in a commonly prescribed drug called Prempro®.²

Two years later, however, another arm of the Women’s Health Initiative trial suggested that horse urine estrogens used alone prevented coronary heart disease in women who began hormone therapy under age 60, along with a reduction in breast cancer overall.^1,7

The author of this 2017 review expressed frustration that beneficial findings from this arm of the Women’s Health Initiative trial have been overlooked.⁷

Estrogen therapy has been available for more than 60 years for menopausal symptoms such as painful intercourse, cognitive impairment, reduced tissue atrophy, and bone density loss.¹ The author of the 2017 review article sought to wrap this up by concluding:

“Critically, the ‘facts’ that most women and clinicians consider in making the decision to use, or not use, HRT (hormone replacement therapy) are frequently wrong or incorrectly applied.”⁷

We at Life Extension largely concur that fears of breast cancer from the 2002 report from the Women’s Health Initiative trial frightened many menopausal women away from hormone replacement therapy, including bioidentical estrogens and natural progesterone (not synthetic progestogen).

The villain in the 2002 report, based on our review of the published literature, was the synthetic progestogen (medroxyprogesterone acetate) that is used in Provera® and Prempro® drugs.

Specific Synthetic Progestogens Implicated

An analysis of 14 prior studies looked at women who used only estradiol (a natural estrogen) and compared them with women prescribed estradiol + different progestogens or natural progesterone.⁸

This study found no increased breast cancer risk in estradiol-only or estradiol + natural-progesterone groups.⁸

There were huge differences, however, based on the type of synthetic progestogen drug and how long it was used.

Women prescribed some of the most popular synthetic progestogen drugs (medroxyprogesterone, norethisterone and levonorgestrel) for less than five years had 1.39-fold increased odds of breast cancer.⁸

Women who used these synthetic progestogens for more than five years had 2.25-fold increased odds of breast cancer.⁸

Medroxyprogesterone is the synthetic progestogen used in Provera® and Prempro® (combination of horse-urine estrogens and progestogens).

Provera® and Prempro® have been leading drugs prescribed long-term to women in all phases of menopause. As it related to use of synthetic progestogen drugs, the authors of this analysis concluded:

“The breast cancer risk rises progressively by prolonged use, furthermore, comparing to sequential therapy, continuous therapy carries a higher risk.”⁸

Mammogram Density Change with Estrogen-Progestin Drugs

In women with dense breast tissue, it’s more difficult to detect tumors using mammograms.

Researchers sought to ascertain if estrogen + synthetic progestogen drug therapy increases mammographic density and breast cancer incidence.

This case-control study looked at postmenopausal women randomly assigned to daily conjugated equine (horse-urine) estrogen 0.625 mg + synthetic progestogen (medroxyprogesterone acetate 2.5 mg) or placebo.⁹

Among women in the estrogen + synthetic progestogen arm, each 1% positive change in mammographic density increased breast cancer risk 3%.

For women in the highest quintile of mammographic density change (>19.3% increase), breast cancer risk increased a startling 3.6-fold.⁹

What was discovered in this study, however, is that the estrogen + synthetic-progestogen drugs only increased breast cancer in women who also showed increased mammographic density.⁹

The authors concluded by stating:

“All of the increased risk from estrogen plus progestin use was mediated through mammographic density change.”⁹

These findings suggest that women using hormone replacement drugs should make sure they are not increasing mammographic density.

This study adds to a growing body of published evidence for women to avoid synthetic progestogens (and if for no other reason than common sense, to avoid horse urine-derived estrogens when natural-to-the-human-body estrogens are available).

Menopausal Hormone Therapy and Reproductive Cancer Risk

A nationwide Swedish population-based study was done on more than 290,000 women (age 40 and over) that compared those who had used menopausal hormone therapy with those who had not.

The results, published in 2017, found a 31% higher incidence of breast, endometrial or ovarian cancer in women who used any menopausal hormone therapy compared to the general Swedish population.¹⁵

The greatest incidence of these cancers occurred in women who had used an estrogen + synthetic progestogen, which corresponds with previous studies showing synthetic progestogens, and not estrogen itself, is the culprit.

This large study also found that women using estrogen have lower rates of gastrointestinal cancers. This Swedish study concluded:

“MHT [menopausal hormone therapy], notably EP-MHT [estrogen-synthetic progestogen], was associated with a limited increase in overall cancer risk. The increased risk of female reproductive organ cancers was almost balanced by a decreased risk of gastro-intestinal cancers.”¹⁵

As you will read later, studies published in 2017 are showing estrogen by itself has interesting protective mechanisms against digestive tract cancers.

Obesity-Associated Breast Cancer

There is a strong association between increased body mass index (BMI) and higher breast cancer incidence in postmenopausal women. Also, obese women are at higher risk of all-cause and breast cancer-specific mortality when compared to non-obese women with breast cancer.¹⁷

Some factors that obese women have to contend with are very high levels of estrogens due to excessive aromatization activity in fat tissues.¹⁷

In obese postmenopausal women with estrogen-receptor positive tumors, estrogen replacement therapy should be discontinued¹⁸ and the aromatase-inhibitor drug letrozole should be initiated.^19,20

Other factors that fuel breast tumors in overweight women are:¹⁷

• Overexpression of inflammatory cytokines
• Insulin resistance
• Activation of insulin-like growth factor (IGF) pathways
• Fat cell-derived adipokines
• High cholesterol
• Excess oxidative stress

Increased blood levels of glucose,²¹ insulin,²² IGF,²³ cholesterol,²⁴ and inflammatory factors²⁵ leads to accelerated tumor formation and exacerbates their aggressiveness.

These cancer cell proliferation factors suggest to us that breast cancer patients (and overweight women) should neutralize them via:

• Anti-inflammatory drugs (aspirin) and nutrient extracts (curcumin and green tea)^26-28
• AMPK activating drugs (metformin)²⁹ and natural products (Gynostemma pentaphyllum and hesperidin)³⁰
• mTOR suppressing nutrients such as Withaferin A^31,32
• Reduce intake of dietary sugars and starches^33-35
• Initiate cholesterol-lowering diet and/or drugs^36-38
• Increase intake of antioxidants^39-41

In postmenopausal women who are not taking exogenous hormones, general obesity is a significant predictor for breast cancer.^17,42

Women can reduce this breast cancer risk by avoiding being overweight and avoiding high-glycemic/high fat foods.^17,43

Women using estrogen and synthetic progestogen hormone therapy for more than five years have elevated risks of both invasive ductal and lobular breast cancer.¹⁷ These cases have higher cancer-related mortality.

A review published in early 2018 suggests that natural progesterone-based menopausal hormone replacement therapy can help maintain bone density and, compared to synthetic progestogens, possibly reduce risk of breast cancer.⁴⁴

Role of Alcohol and Other Lifestyle Factors

A study of postmenopausal women evaluated the impact of various lifestyle factors on breast cancer incidence including alcoholic beverage consumption, body mass index, and reported levels of physical activity.

Findings from this 2017 published study revealed that, in women age 65 and over, the following lifestyle factors were associated with greater odds of breast cancer as follows:⁴⁵

• Lifetime alcohol intake: 79% increase
• High body mass index: 83% increase
• Low level physical activity: 31% increase

The authors concluded their 2017 report by stating:

“Interventions targeting modifiable lifestyle factors may reduce the burden of post-menopausal breast cancer among older women.”⁴⁵

As it relates to alcohol consumption, this represents a troublesome conundrum, as some studies show that those who abstain completely from alcohol have shorter lifespans, often related to increased risk of occlusive arterial disorders such as ischemic stroke.^46-48

Even moderate alcohol consumption has been shown in previous studies to increase breast cancer risk, however.^49-51

How to Neutralize Deadly Estrogen Metabolites

One cancer-causing mechanism of alcohol is how it impacts the way the body metabolizes estrogens, specifically the 2/16 a hydroxyestrone ratio.

High levels of 16 a hydroxy-estrone have been correlated to greater risk of breast cancer.^52-54

Consumption of cruciferous vegetables containing compounds like indole-3-carbinol (I3C) enables the body to convert estrogens into more 2-hydroxyestrone which has a far weaker estrogen effect than 16 a -hydroxyestrone.⁵⁵

Other studies show that higher alcohol consumption increases estradiol levels in pre- and postmenopausal women.^56-58

The consistency of findings relating alcohol intake to higher and more dangerous estrogen metabolites points to the importance of testing one’s urinary levels of total estrogens including 2-hydroxyestrone and 16 a -hydroxyestrone.

If blood or urinary levels of estrogens and/or metabolites (such as 16 a -hydroxyestrone) are imbalanced in women who choose to continue drinking alcohol, then perhaps the use of an estrogen drug should be discontinued.

Women with elevated 16 a-hydroxyestrone should eat more cruciferous vegetables or take supplements that provide plant extracts such as I3C.

What Should Hormone-Deprived Women Do?

We at Life Extension have long advocated for a compounded estrogen drug that consists of about 80% estriol and 20% estradiol.

This ideally should be in the form of a cream that is rubbed on to the skin for direct absorption into the bloodstream.

In response to a petition filed by a pharmaceutical company, the FDA has obstructed the use of the estriol form of estrogen. This provided the company who lobbied the FDA with a more exclusive market to sell their horse urine-derived estrogen drug (Premarin®).

We suggest that synthetic progestogens should be avoided and natural (bioidentical) progesterone cream applied as per our Female Hormone Replacement protocol (www.LifeExtension.com/female).

Summary

The data described in this article help corroborate Life Extension’s longstanding position to avoid synthetic progestogen drugs.

Natural progesterone cream makes a lot more sense as it relates to protecting against estrogen-induced cancers and helping to maintain bone density.

For women suffering menopausal issues who don’t want to use estrogen, or can’t find a doctor to properly prescribe bioidenticals, a new plant extract has shown remarkable benefits in human studies.

To read the science behind this new botanical formulation, turn to page 28 of this month’s issue.

For longer life,

William Faloon, Co-Founder

Life Extension Buyers Club

References

1. 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(14):1701-12.
2. 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(3):321-33.
3. Stanczyk FZ, Bhavnani BR. Reprint of “Use of medroxyprogesterone acetate for hormone therapy in postmenopausal women: Is it safe?”. J Steroid Biochem Mol Biol. 2015;153:151-9.
4. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. Jama. 2003;289(24):3243-53.
5. Available at: https://www.lifeextension.com/magazine/1996/1/96jan1. Accessed July 31, 2018.
6. Available at: https://www.lifeextension.com/magazine/1999/3/report1/page-01. Accessed July 31, 2018.
7. Langer RD. The evidence base for HRT: what can we believe? Climacteric. 2017;20(2):91-6.
8. Yang Z, Hu Y, Zhang J, et al. Estradiol therapy and breast cancer risk in perimenopausal and postmenopausal women: a systematic review and meta-analysis. Gynecol Endocrinol. 2017;33(2):87-92.
9. Byrne C, Ursin G, Martin CF, et al. Mammographic Density Change With Estrogen and Progestin Therapy and Breast Cancer Risk. J Natl Cancer Inst. 2017;109(9).
10. Ellingjord-Dale M, Vos L, Tretli S, et al. Parity, hormones and breast cancer subtypes - results from a large nested case-control study in a national screening program. Breast Cancer Res. 2017;19(1):10.
11. Tamimi RM, Baer HJ, Marotti J, et al. Comparison of molecular phenotypes of ductal carcinoma in situ and invasive breast cancer. Breast Cancer Res. 2008;10(4):R67.
12. Clark SE, Warwick J, Carpenter R, et al. Molecular subtyping of DCIS: heterogeneity of breast cancer reflected in pre-invasive disease. Br J Cancer. 2011;104(1):120-7.
13. Fan C, Oh DS, Wessels L, et al. Concordance among gene-expression-based predictors for breast cancer. N Engl J Med. 2006;355(6):560-9.
14. Voduc KD, Cheang MC, Tyldesley S, et al. Breast cancer subtypes and the risk of local and regional relapse. J Clin Oncol. 2010;28(10):1684-91.
15. Simin J, Tamimi R, Lagergren J, et al. Menopausal hormone therapy and cancer risk: An overestimated risk? Eur J Cancer. 2017;84:60-8.
16. Marjoribanks J, Farquhar C, Roberts H, et al. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2017;1:Cd004143.
17. Engin A. Obesity-associated Breast Cancer: Analysis of risk factors. Adv Exp Med Biol. 2017;960:571-606
18. Available at: http://www.medscape.com/viewarticle/463856. Accessed August 1, 2018.
19. Geisler J, Helle H, Ekse D, et al. Letrozole is superior to anastrozole in suppressing breast cancer tissue and plasma estrogen levels. Clin Cancer Res. 2008;14(19):6330-5.
20. Folkerd EJ, Dixon JM, Renshaw L, et al. Suppression of plasma estrogen levels by letrozole and anastrozole is related to body mass index in patients with breast cancer. J Clin Oncol. 2012;30(24):2977-80.
21. Ryu TY, Park J, Scherer PE. Hyperglycemia as a risk factor for cancer progression. Diabetes Metab J. 2014;38(5):330-6.
22. Iqbal MA, Siddiqui FA, Gupta V, et al. Insulin enhances metabolic capacities of cancer cells by dual regulation of glycolytic enzyme pyruvate kinase M2. Mol Cancer. 2013;12:72.
23. Muti P, Quattrin T, Grant BJ, et al. Fasting glucose is a risk factor for breast cancer: a prospective study. Cancer Epidemiol Biomarkers Prev. 2002;11(11):1361-8.
24. Llaverias G, Danilo C, Mercier I, et al. Role of cholesterol in the development and progression of breast cancer. Am J Pathol. 2011;178(1):402-12.
25. Colotta F, Allavena P, Sica A, et al. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;30(7):1073-81.
26. Redondo S, Santos-Gallego CG, Ganado P, et al. Acetylsalicylic acid inhibits cell proliferation by involving transforming growth factor-beta. Circulation. 2003;107(4):626-9.
27. Ravindran J, Prasad S, Aggarwal BBCurcumin and cancer cells: how many ways can curry kill tumor cells selectively? Aaps j. 2009;11(3):495-510.
28. Rahmani AH, Al Shabrmi FM, Allemailem KS, et al. Implications of Green Tea and Its Constituents in the Prevention of Cancer via the Modulation of Cell Signalling Pathway. Biomed Res Int. 2015;2015:925640.
29. Choi YK, Park KG. Metabolic roles of AMPK and metformin in cancer cells. Mol Cells. 2013;36(4):279-87.
30. Available at: https://www.lifeextension.com/magazine/2018/2/reverse-major-factor-in-degenerative-aging/page-01. Accessed July 26, 2018.
31. Kim SH, Hahm ER, Arlotti JA, et al. Withaferin A inhibits in vivo growth of breast cancer cells accelerated by Notch2 knockdown. Breast Cancer Res Treat. 2016;157(1):41-54.
32. Thaiparambil JT, Bender L, Ganesh T, et al. Withaferin A inhibits breast cancer invasion and metastasis at sub-cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation. Int J Cancer. 2011;129(11):2744-55.
33. Ho VW, Leung K, Hsu A, et al. A low carbohydrate, high protein diet slows tumor growth and prevents cancer initiation. Cancer Res. 2011;71(13):4484-93.
34. Augustin LS, Dal Maso L, La Vecchia C, et al. Dietary glycemic index and glycemic load, and breast cancer risk: a case-control study. Ann Oncol. 2001;12(11):1533-8.
35. Wen W, Shu XO, Li H, et al. Dietary carbohydrates, fiber, and breast cancer risk in Chinese women. Am J Clin Nutr. 2009;89(1):283-9.
36. Pelton K, Coticchia CM, Curatolo AS, et al. Hypercholesterolemia induces angiogenesis and accelerates growth of breast tumors in vivo. Am J Pathol. 2014;184(7):2099-110.
37. Danilo C, Frank PG. Cholesterol and breast cancer development. Curr Opin Pharmacol. 2012;12(6):677-82.
38. Kumar AS, Benz CC, Shim V, et al. Estrogen receptor-negative breast cancer is less likely to arise among lipophilic statin users. Cancer Epidemiol Biomarkers Prev. 2008;17(5):1028-33.
39. Michels KB, Holmberg L, Bergkvist L, et al. Dietary antioxidant vitamins, retinol, and breast cancer incidence in a cohort of Swedish women. Int J Cancer. 2001;91(4):563-7.
40. Olsson ME, Andersson CS, Oredsson S, et al. Antioxidant levels and inhibition of cancer cell proliferation in vitro by extracts from organically and conventionally cultivated strawberries. J Agric Food Chem. 2006;54(4):1248-55.
41. Singletary KW, Jung KJ, Giusti M. Anthocyanin-rich grape extract blocks breast cell DNA damage. J Med Food. 2007;10(2):244-51.
42. Rose DP, Komninou D, Stephenson GD. Obesity, adipocytokines, and insulin resistance in breast cancer. Obes Rev. 2004;5(3):153-65.
43. Mullie P, Koechlin A, Boniol M, et al. Relation between Breast Cancer and High Glycemic Index or Glycemic Load: A Meta-analysis of Prospective Cohort Studies. Crit Rev Food Sci Nutr. 2016;56(1):152-9.
44. Mirkin S. Evidence on the use of progesterone in menopausal hormone therapy. Climacteric. 2018;21(4):346-54.
45. McClain KM, McCullough LE, Bradshaw PT, et al. Age-Specific Indicators of a Healthy Lifestyle and Postmenopausal Breast Cancer. J Womens Health (Larchmt). 2017;26(11):1176-84.
46. Available at: https://www.alcoholproblemsandsolutions.org/alcohol-and-health-medical-findings. Accessed July 26, 2018.
47. Di Castelnuovo A, Costanzo S, Bagnardi V, et al. Alcohol dosing and total mortality in men and women: an updated meta-analysis of 34 prospective studies. Arch Intern Med. 2006;166(22):2437-45.
48. Jimenez M, Chiuve SE, Glynn RJ, et al. Alcohol consumption and risk of stroke in women. Stroke. 2012;43(4):939-45.
49. Allen NE, Beral V, Casabonne D, et al. Moderate alcohol intake and cancer incidence in women. J Natl Cancer Inst. 2009;101(5):296-305.
50. Chen WY, Rosner B, Hankinson SE, et al. Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk. Jama. 2011;306(17):1884-90.
51. Li CI, Chlebowski RT, Freiberg M, et al. Alcohol consumption and risk of postmenopausal breast cancer by subtype: the women’s health initiative observational study. J Natl Cancer Inst. 2010;102(18):1422-31.
52. Muti P, Bradlow HL, Micheli A, et al. Estrogen metabolism and risk of breast cancer: a prospective study of the 2:16alpha-hydroxyestrone ratio in premenopausal and postmenopausal women. Epidemiology. 2000;11(6):635-40.
53. Seeger H, Wallwiener D, Kraemer E, et al. Comparison of possible carcinogenic estradiol metabolites: effects on proliferation, apoptosis and metastasis of human breast cancer cells. Maturitas. 2006;54(1):72-7.
54. Osborne MP, Bradlow HL, Wong GY, et al. Upregulation of estradiol C16 alpha-hydroxylation in human breast tissue: a potential biomarker of breast cancer risk. J Natl Cancer Inst. 1993;85(23):1917-20.
55. Michnovicz JJ, Adlercreutz H, Bradlow HL. Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans. J Natl Cancer Inst. 1997;89(10):718-23.
56. Hartman TJ, Sisti JS, Hankinson SE, et al. Alcohol Consumption and Urinary Estrogens and Estrogen Metabolites in Premenopausal Women. Horm Cancer. 2016;7(1):65-74.
57. Purohit V. Moderate alcohol consumption and estrogen levels in postmenopausal women: a review. Alcohol Clin Exp Res. 1998;22(5):994-7.
58. Frydenberg H, Flote VG, Larsson IM, et al. Alcohol consumption, endogenous estrogen and mammographic density among premenopausal women. Breast Cancer Res. 2015;17:103.
59. Hassan MM, Botrus G, Abdel-Wahab R, et al. Estrogen Replacement Reduces Risk and Increases Survival Times of Women With Hepatocellular Carcinoma. Clin Gastroenterol Hepatol. 2017;15(11):1791-9.
60. Csizmadi I, Collet JP, Benedetti A, et al. The effects of transdermal and oral oestrogen replacement therapy on colorectal cancer risk in postmenopausal women. Br J Cancer. 2004;90(1):76-81.
61. Hannaford P, Elliott A. Use of exogenous hormones by women and colorectal cancer: evidence from the Royal College of General Practitioners’ Oral Contraception Study. Contraception. 2005;71(2):95-8.
62. Brusselaers N, Maret-Ouda J, Konings P, et al. Menopausal hormone therapy and the risk of esophageal and gastric cancer. Int J Cancer. 2017;140(7):1693-9.
63. Calle EE, Miracle-McMahill HL, Thun MJ, et al. Estrogen replacement therapy and risk of fatal colon cancer in a prospective cohort of postmenopausal women. J Natl Cancer Inst. 1995;87(7):517-23.
64. Chan JA, Meyerhardt JA, Chan AT, et al. Hormone replacement therapy and survival after colorectal cancer diagnosis. J Clin Oncol. 2006;24(36):5680-6.
65. Available at: https://www.nytimes.com/2002/07/10/us/hormone-replacement-study-a-shock-to-the-medical-system.html. Accessed July 26, 2018.
66. Available at: https://www.whi.org/sitepages/whi%20home.aspx. Accessed July 26, 2018.
67. Zeng Z, Jiang X, Li X, et al. Conjugated equine estrogen and medroxyprogesterone acetate are associated with decreased risk of breast cancer relative to bioidentical hormone therapy and controls. PLoS One. 2018;13(5):e0197064.