Bio-identical (Natural) Hormone Replacement Therapy
and Other Natural Hormone-Balancing Therapies
Which One is Right for You?
Are Your Symptoms Caused by Low or Imbalanced Hormones?
Women and men both go through “the climacteric,” a period in mid-life when sex hormone production declines.
In women, this change is called “menopause.” In men, the change is often referred to as “andropause.” Many symptoms of the climacteric are similar in men and women.
In women, peri-menopause (“around the time of menopause”) symptoms can include mood swings, weight gain, fatigue, hot flashes, breast tenderness, vaginal dryness, decreased libido (sex drive), urinary leakage or urgency and sleep difficulties. Menstrual periods may becomes less frequent, irregular and farther apart OR they can become heavier and more frequent. Peri-menopause usually begins in a woman’s 40’s but can start as early as the 30’s or as late as the 50’s.
Menopause symptoms in women are similar to peri-menopause symptoms except that menstrual periods cease. Headaches, heart palpitations, cognitive decline and difficulty sleeping may also occur. Bone mineral loss is often accelerated during this time, leading to osteoporosis.
Andropause symptoms in men can include include night sweats, low libido (sex drive), weight gain, depression, anxiety, hot flashes, gynecomastia (enlarged male breasts), fatigue, irritability, and weight gain. Other male climacteric symptoms include erectile dysfunction, loss of stamina and lean muscle mass, cognitive decline and decreased bone mineral density. Men with lower testosterone have a higher risk of coronary artery disease. (1-4)
The change in men is more gradual than in women and symptoms are often attributed to “natural aging” instead of hormone decline.
What is Bio-identical Hormone Replacement Therapy (bHRT)?
Bio-identical Hormone Replacement Therapy (bHRT) is a way to resolve symptoms and/or restore sex hormones to more youthful levels using hormones that are identical to those produced by the human body. Bio-identical hormone replacement therapy (bHRT) differs from convention HRT (cHRT) which uses horse estrogens (Premarin = Pregnant Mares Urine), synthetic and semi-synthetic hormones that are different from human hormones.
Proponents of bHRT believe that many of the unwanted side effects of conventional HRT are due to the “foreignness” of the molecules, not to hormone replacement therapy itself. This may make bHRT a safer form of hormone replacement therapy. (5-10)
How is Bio-Identical HRT Different from Conventional HRT?
Bio-identical hormone replacement is different from conventional HRT in the following ways.
- “Identical to human” hormones are used in bHRT. Conventional HRT typically uses horse hormones and synthetic and semi-synthetic hormones. These hormones are not the same molecules as those produced by the human body.It should be noted that there are bio-identical FDA approved hormones available by prescription. Not all “bio-identical” hormones need to be “compounded,” or made up individually by a compounding pharmacist.
- Based on Testing. bHRT is prescribed based on individual hormone test results. Conventional HRT does not use testing but bases treatment on improvement of symptoms.
- “Pulsed dosing” is often used in bHRT to duplicate the natural rhythm of hormone production and release. Some studies have shown this pattern of use to be safer and just as effective as continuous HRT. (11-12) Conventional HRT typically uses continuous doses of hormones. Continuous doses are associated with higher risk of breast cancer in some studies. (13)
What are the advantages of bHRT?
Is bHRT Safer than conventional HRT?
Conventional hormone replacement therapy, especially in women, is associated with a number of increased health risks including heart disease, stroke, breast cancer, deep vein thrombosis, gallbladder disease and acid reflux. (14-20) Conventional HRT decreases the risk of osteoporosis and can alleviate some symptoms of menopause including hot flashes and vaginal dryness (21-22) but many experts do not believe these improvements justify the increased risks.
Proponents of bio-identical hormone replacement therapy believe that bHRT is safer than conventional hormone therapy and some studies have shown this. (5-10) However, the number of studies done with bHRT is small compared to the studies done with conventional HRT. Large-scale studies of safety and efficacy of bHRT are lacking.
In spite of a small number of studies confirming safety and efficacy, the case for bio-identical hormones also makes sense in theory. Consider these facts:
Conventional hormone replacement therapy typically employs estrogens from pregnant mare’s urine. Horse hormones are significantly different than human hormones. Conventional hormone replacement also typically uses synthetic progesterone. The difference in synthetic and bio-identical progesterone is significant. It is therefore believed that most if not all of the negative side effects of conventional hormone replacement is due to their “foreign to humans” molecular structure, not to hormone replacement itself. Some studies on bio-identical versus non-bio-identical progesterone confirm that there is a different effect in humans with natural progesterone appearing to have less risk of associated cancers. (5-10)
Further, conventional hormone replacement is almost always prescribed as a “one-size-fits-all” recommendation without the use of any laboratory testing to verify hormone levels. Practitioners of bio-identical hormone replacement typically start with blood, saliva or urine hormone testing and customize hormone prescriptions based on an individual’s unique requirements. Testing can help guide the prescription and prevent levels of hormones from being excessive.
Finally, risks associated with hormone therapy can be monitored, but this is rarely if ever done in conventional hormone prescribing. However, risks such as total hormone levels, ratios of hormones to each other and hormone metabolites can be potent predictors of heart disease and cancer risks. Even without hormone replacement therapy, these risk factors may be worth monitoring in all middle-aged men and women.
To answer the question of safety, there are theoretical reasons to believe that bio-identical HRT should be safer than conventional HRTand some actual studies show better safety.
Is bHRT Effective?
Studies have verified the effectiveness of bHRT for relieving many of the symptoms of menopause. (7-9, 23-24)
My personal clinical experience over the past 23 years is that bHRT can achieve every positive effect that conventional HRT achieves with less risk of negative side effects. Because I monitor risk factors, I have also seen reductions in cardiac and cancer risk markers and improvements in bone mineral density.
Is bHRT Proven?
Studies have demonstrated the effectiveness of bio-identical hormone replacement therapy. (7-9, 23-28)
Anti-Aging Claims for bHRT
Proponents of bHRT claim that keeping hormones at “youthful” levels can extend life expectancy and help delay the effects of aging. These claims have been popularized by public figures like Suzanne Somers in her book “The Sexy Years.” In spite of these claims, there is no proof that continued use of sex hormones, especially estrogen and progesterone in women, have-extending properties. There IS evidence that DHEA in both men and women (25-28) and testosterone in men (29-33) may have a positive influence on health, longevity and hormone balance.
While claims of living better and longer with bHRT are numerous, proof is lacking. This leaves bHRT and its anti-aging effects in the realm of theory at this point.
Delivery System: Oral Versus Transdermal Hormones
In addition to the “form” (natural or synthetic) of hormone, the method of administration has been shown to make a significant difference in safety and efficacy.
Orally administered hormones, especially estrogens, can increase risk of blood clots and deep vein thrombosis, increase hs-CRP (a marker of inflammation), decrease free testosterone and thyroid hormone and increase cortisol.(34) Oral estrogen is also associated with an increased risk of gallbladder disease and acid reflux. (15,18)
Many hormones used transdermally — applied to the skin or mucous membranes — do not appear to have these unwanted effects. (35) Therefore, when considering bHRT, the form that it is used in is also of importance.
How Best to Address Your Menopausal Symptoms and Concerns?
Symptoms of peri-menopause and menopause in women and andropause in men are a sign from the body that something is “off kilter.” For example, hot flashes in women correspond to an increase in oxidative stress and decreased nitric oxide levels (NO), both risk factors for cardiovascular disease. (36-37)
These symptoms and resulting negative physical changes are not an inevitable part of aging and should not be ignored. They can be addressed and improved through a variety of means, including but not limited to bio-identical hormone replacement therapy.
Diet changes, exercise and personal health practices can all help to improve symptoms of menopause and andropause. (38-39) There are nutritional and herbal supplements are proven to help correct menopause and andropause symptoms. (40-42) Bioidentical hormone replacement is one way to address declining hormone levels, but it is not the only way.
The decision to use bHRT is a personal one that should be made in conjunction with an holistic physician. Your degree of symptoms, personal thoughts about bHRT, willingness to make other lifestyle changes and use nutritional and herbal supplements should all factor into the “decision equation.” Here are some additional factors to consider when making this decision.
Possible “Pro’s” of bHRT
- Faster. Herbs and other factors can help balance hormones, but the effects of bHRT might be more dramatic and faster. (NOTE: I cannot find scientific studies to support this; it is my clinical observation — Dr. Myatt)
- Easier. Taking an Rx. may be easier than making lifestyle changes, although any good holistic physician should recommend positive lifestyle changes as part of an overall health program.
- Safer. Some studies point to the improved safety of bHRT over conventional HRT. (14-20)
- Better hormone balance. Some hormones such as DHEA and testosterone have independent health benefits. (25-33, 43) These hormones are typically not used in conventional HRT but may be prescribed by a physician who uses bHRT.
Possible “Cons” of bHRT
- Cost. bHRT is not necessarily expensive and can be as little as $30/month depending on what hormones are needed. However, an Rx. will represent an ongoing expense. Most practitioners prescribing bHRT require initial hormone testing (to customize your Rx.) and follow-up testing to ensure that your hormones are at optimal (safe and effective) levels. Testing plus the Rx. itself will be an ongoing expense.
- Safety. Although bHRT appears safer than conventional HRT, there is some evidence that no type of hormone replacement in women has been proven to be “protective” or safer than natural menopause.
Alternatives to bHRT
Hormone Testing: Saliva vs. Blood vs. Urine
Conventional hormone replacement does not use testing. The recommended “end point” (goal of treatment) is alleviation of symptoms. Therefore, when a woman has stopped having hot flashes, for example, the dose is considered to be correct.
Most bHRT practitioners begin treatment with some form of hormone testing, using either saliva, blood or urine to evaluate hormone levels. Although there are many claims about the superiority of one form of testing over another, scientific studies are lacking.
Saliva testing is the least accurate measure of sex hormones. Numerous studies have failed to find a reliable correlation between saliva hormone levels and physiologic (body) hormone levels with the exception of cortisol measurement. (17,44-54)
Blood testing does not reveal the hourly variation and 24-hour cyclical nature of hormone release but it has been better studied. For this reason, blood testing is probably the second-best method of hormone testing.
Twenty-four hour urine testing may be the preferred method of hormone testing. In addition to evaluating hormone output including the 24-hour variation (a “video” instead of a “snapshot,”), urine testing also looks at biochemical intermediates which are independent indicators of hormone levels and hormone metabolism. Some intermediates, such as the 2:16alpha-hydroxyestrone ratio, may be potent predictors of increased risk for hormone-related cancers. (55-56) Fortunately, once known, these risks can be modified.
Dr. Myatt’s Hormone Balance Programs:
Which One is Right for You?
All bHRT programs in both men and women begin with a Brief Telephone Consultation. Together, we determine which program is right for you.
Depending on your age, symptoms, beliefs and what you hope to achieve, we work together to design and implement a complete program to optimize both hormone balance and overall health.
For some men and women, this will include the use of bio-identical hormone replacement therapy, as determined by laboratory testing (24-hour urine). The form may differ depending on which hormones are needed, but usually include both transdermal and oral hormone replacements.
Hormone balance and relief of symptoms can often be achieved without the use of hormone replacement therapy. The decision to use hormones should not be taken lightly and should be made in consultation with a physician who is well-versed in both bHRT and non-hormonal methods of achieving hormone balance.
Which Hormone-Balancing Program is Right for You ?
The Bronze program is for:
• Peri-menopausal women
• Post-menopausal women
• Men over 35
For women and men desiring better hormone balance without the use of
bio-identical hormone replacement.
You will receive a Personalized Health Report and Phone Follow-Up of 60 mins
The Silver program is for:
• Peri-menopausal women
• Post-menopausal women
• Men over 35
For women and men desiring better hormone balance AND bone mineral density protection without using
bio-identical hormone replacement.
You will receive a Personalized Health Report and Phone Follow-Up of 120 mins
The Gold program is for:
• Peri-menopausal women
• Post-menopausal women
• Men over 35
For women and men desiring sex hormone optimization and breast/prostate cancer risk reduction using bHRT.
You will receive a Personalized Health Report and Phone Follow-Up of 360 mins
The Platinum program is for:
• Peri-menopausal women
• Post-menopausal women
• Men over 35
For women and men desiring anti-aging, full-scope endocrine balancing (including sex, thyroid and adrenal hormones) and
breast /prostate cancer risk reduction using bHRT.
You will receive a Personalized Health Report and unlimited Phone Follow-Up
* saliva hormone testing not available in New York state.
1.) Corona G, Rastrelli G, Monami M, Guay A, Buvat J, Sforza A, Forti G, Mannucci E, Maggi M.
Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study.
Eur J Endocrinol. 2011 Nov;165(5):687-701. Epub 2011 Aug 18.
2.) Corona G, et al “Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction” ECE 2010; Poster 149.
3.) Ohlsson C, Barrett-Connor E, Bhasin S, Orwoll E, Labrie F, Karlsson MK, Ljunggren O, Vandenput L, Mellström D, Tivesten A.High Serum Testosterone Is Associated With Reduced Risk of Cardiovascular Events in Elderly Men, J Am Coll Cardiol, 2011; 58:1674-1681
4.) Tivesten A, Mellström D, Jutberger H, Fagerberg B, Lernfelt B, Orwoll E, Karlsson MK, Ljunggren O, Ohlsson C. Low serum testosterone and high serum estradiol associate with lower extremity peripheral arterial disease in elderly men. The MrOS Study in Sweden. J Am Coll Cardiol. 2007 Sep 11;50(11):1070-6. Epub 2007 Aug 24.
5.) Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008 Jan;107(1):103-11. Epub 2007 Feb 27.
6.) Fournier A, Berrino F, Riboli E, Avenel V, Clavel-Chapelon F. 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.
7.) Holtorf K. The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? Postgrad Med. 2009 Jan;121(1):73-85.
8.) Mahmud K. Natural hormone therapy for menopause. Gynecol Endocrinol. 2010 Feb;26(2):81-5.
9.) Moskowitz D. A comprehensive review of the safety and efficacy of bioidentical hormones for the management of menopause and related health risks. Altern Med Rev. 2006 Sep;11(3):208-23.
10.) Schmidt JW, Wollner D, Curcio J, Riedlinger J, Kim LS. Hormone replacement therapy in menopausal women: Past problems and future possibilities. Gynecol Endocrinol. 2006 Oct;22(10):564-77.
11.) Ichikawa A, Sumino H, Ogawa T, Ichikawa S, Nitta K. Effects of long-term transdermal hormone replacement therapy on the renin-angiotensin- aldosterone system, plasma bradykinin levels and blood pressure in normotensive postmenopausal women. Geriatr Gerontol Int. 2008 Dec;8(4):259-64.
12.) Vilodre LC, Osório Wender MC, Sisson de Castro JA, dos Reis FM, Ruschel S, Magalhães JA, Spritzer PM. Endometrial response to a cyclic regimen of percutaneous 17beta-estradiol and low-dose vaginal micronized progesterone in women with mild-to-moderate hypertension.
Gynecol Endocrinol. 2003 Aug;17(4):323-8.
13.) Beral V, Bull D, Reeves G; Million Women Study Collaborators. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2005 Apr 30-May 6;365(9470):1543-51.
14.) Canonico M, Fournier A, Carcaillon L, et al. Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study. Arterioscler Thromb Vasc Biol. 2010;30(2):340-345.
15.) Cirillo DJ, Wallace RB, Rodabough RJ, et al. Effect of estrogen therapy on gallbladder disease. JAMA. 2005;293(3):330-339.
16.) Eilertsen AL, Høibraaten E, Os I, Andersen TO, Sandvik L, Sandset PM. The effects of oral and transdermal hormone replacement therapy on C-reactive protein levels and other inflammatory markers in women with high risk of thrombosis. Maturitas. 2005;52(2):111-118.
17.) Files JA, Ko MG, Pruthi S. Bioidentical Hormone Therapy.Mayo Clin Proc. 2011 July; 86(7): 673–680.
18.) Jacobson BC, Moy B, Colditz GA, Fuchs CS. Postmenopausal hormone use and symptoms of gastroesophageal reflux. Arch Intern Med. 2008;168(16):1798-1804.
19.) Jernström H, Bendahl PO, Lidfeldt J, Nerbrand C, Agardh CD, Samsioe G. A prospective study of different types of hormone replacement therapy use and the risk of subsequent breast cancer: the women’s health in the Lund area (WHILA) study (Sweden). Cancer Causes Control. 2003 Sep;14(7):673-80.
20.) [No authors listed] 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. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 1997 Oct 11;350(9084):1047-59.
21.) de Villiers TJ, Stevenson JC. The WHI: the effect of hormone replacement therapy on fracture prevention. Climacteric. 2012 Jun;15(3):263-6.
22.) Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD. Postmenopausal hormone replacement therapy: scientific review. JAMA. 2002 Aug 21;288(7):872-81.
23.) Cramer EH, Jones P, Keenan NL, Thompson BL. Is naturopathy as effective as conventional therapy for treatment of menopausal symptoms? J Altern Complement Med. 2003 Aug;9(4):529-38.
24.) Ruiz AD, Daniels KR, Barner JC, Carson JJ, Frei CR. Effectiveness of compounded bioidentical hormone replacement therapy: an observational cohort study. BMC Womens Health. 2011 Jun 8;11:27.
25.) Genazzani AR, Pluchino N, Begliuomini S, Stomati M, Bernardi F, Pieri M, Casarosa E, Palumbo M, Genazzani AD, Luisi M. Long-term low-dose oral administration of dehydroepiandrosterone modulates adrenal response to adrenocorticotropic hormone in early and late postmenopausal women. Gynecol Endocrinol. 2006 Nov;22(11):627-35.
26.) Labrie F. DHEA, important source of sex steroids in men and even more in women.
Prog Brain Res. 2010;182:97-148.
27.) Pluchino N, Ninni F, Stomati M, Freschi L, Casarosa E, Valentino V, Luisi S, Genazzani AD, Potì E, Genazzani AR. One-year therapy with 10mg/day DHEA alone or in combination with HRT in postmenopausal women: effects on hormonal milieu. Maturitas. 2008 Apr 20;59(4):293-303. Epub 2008 Apr 3.
28.) Stomati M, Monteleone P, Casarosa E, Quirici B, Puccetti S, Bernardi F, Genazzani AD, Rovati L, Luisi M, Genazzani AR. Six-month oral dehydroepiandrosterone supplementation in early and late postmenopause. Gynecol Endocrinol. 2000 Oct;14(5):342-63.
29.) Aaronson AJ, Morrissey RP, Nguyen CT, Willix R, Schwarz ER. Update on the safety of testosterone therapy in cardiac disease. Expert Opin Drug Saf. 2011 Sep;10(5):697-704. Epub 2011 Mar 22.
30.) De Maddalena C, Vodo S, Petroni A, Aloisi AM. Impact of testosterone on body fat composition. J Cell Physiol. 2012 Apr 11. doi: 10.1002/jcp.24096. [Epub ahead of print]
31.) Toma M, McAlister FA, Coglianese EE, Vidi V, Vasaiwala S, Bakal JA, Armstrong PW, Ezekowitz JA. Testosterone supplementation in heart failure: a meta-analysis. Circ Heart Fail. 2012 May
32.) Vermeulen A. Ageing, hormones, body composition, metabolic effects. World J Urol. 2002 May;20(1):23-7.
33.) Vermeulen A, Goemaere S, Kaufman JM. Testosterone, body composition and aging. J Endocrinol Invest. 1999;22(5 Suppl):110-6. 1;5(3):315-21. Epub 2012 Apr 17.
34.) Shifren JL, Desindes S, McIlwain M, Doros G, Mazer NA. A randomized, open-label, crossover study comparing the effects of oral versus transdermal estrogen therapy on serum androgens, thyroid hormones, and adrenal hormones in naturally menopausal women. Menopause. 2007 Nov-Dec;14(6):985-94.
35.) L’hermite M, Simoncini T, Fuller S, Genazzani AR. Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review. Maturitas. 2008 Jul-Aug;60(3-4):185-201. Epub 2008 Sep 5.
36.) Leal M, Díaz J, Serrano E, Abellán J, Carbonell LF. Hormone replacement therapy for oxidative stress in postmenopausal women with hot flushes. Obstet Gynecol. 2000 Jun;95(6 Pt 1):804-9.
37.) Leal Hernández M, Abellán Alemán J, Carbonell Meseguer LF, Díaz Fernández J, García Sánchez FA, Martínez Selva JM. Influence of the presence of hot flashes during menopause on the metabolism of nitric oxide. Effects of hormonal replacement treatment]. Med Clin (Barc). 2000 Jan 22;114(2):41-5.
38.) North American Menopause Society. Treatment of menopause-associated vasomotor symptoms: position statement of The North American Menopause Society. Menopause. 2004 Jan-Feb;11(1):11-33.
39.) McKee J, Warber SL. Integrative therapies for menopause. South Med J. 2005 Mar;98(3):319-26.
40.) Low Dog T. Menopause: a review of botanical dietary supplements. Am J Med. 2005 Dec 19;118 Suppl 12B:98-108.
41.) Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: a review of randomized, controlled trials. Ann Intern Med. 2002 Nov 19;137(10):805-13.
42.) Geller SE, Studee L.Botanical and dietary supplements for menopausal symptoms: what works, what does not. J Womens Health (Larchmt). 2005 Sep;14(7):634-49.
43.) Øverlie I, Moen MH, Holte A, Finset A. Androgens and estrogens in relation to hot flushes during the menopausal transition. Maturitas. 2002 Jan 30;41(1):69-77.
44.) Gröschl M. Current status of salivary hormone analysis. Clin Chem. 2008 Nov;54(11):1759-69. Epub 2008 Aug 29.
45.) Hagen J, Gott N, Miller DR. Reliability of saliva hormone tests. J Am Pharm Assoc . 2003 Nov-Dec;43(6):724-6.
46.) Davison S. Salivary testing opens a Pandora’s box of issues surrounding accurate measurement of testosterone in women. Menopause. 2009;16:630-631.
47.) Flyckt RL, Liu J, Frasure H, Wekselman K, et al. Comparison of salivary versus serum testosterone levels in postmenopausal women receiving transdermal testosterone supplementation versus placebo. Menopause. 2009 Jul-Aug;16(4):680-8.
48.) Granger DA, Shirtcliff EA, Booth A, et al. The “trouble” with salivary testosterone. Psychoneuroendocrinology. 2004 Nov;29(10):1229-40.
49.) Mörelius E, Nelson N, Theodorsson E. Saliva collection using cotton buds with wooden sticks: a note of caution. Scand J Clin Lab Invest. 2006;66(1):15-8.
50.) 6.Lewis JG. Steroid analysis in saliva: an overview. Clin Biochem Rev. 2006 Aug;27(3):139-46.
51.) Stanczyk FZ, Paulson RJ, Roy S. Percutaneous administration of progesterone: blood levels and endometrial protection. Menopause. 2005 Mar;12(2):232-7.
52.) Lewis JG, McGill H, Patton VM, et al. Caution on the use of saliva measurements to monitor absorption of progesterone from transdermal creams in postmenopausal women. Maturitas. 2002 Jan 30;41(1):1-6.
53.) Wren BG, McFarland K, Edwards L, et al. Effect of sequential transdermal progesterone cream on endometrium, bleeding pattern, and plasma progesterone and salivary progesterone levels in postmenopausal women. Climacteric. 2000 Sep;3(3):155-60.
54.) Wood P. Salivary steroid assays – research or routine? . Ann Clin Biochem. 2009 May;46(Pt 3):183-96. Epub 2009 Jan 28.
55.) Kabat GC, Chang CJ, Sparano JA, Sepkovie DW, Hu XP, Khalil A, Rosenblatt R, Bradlow HL.Urinary estrogen metabolites and breast cancer: a case-control study. Cancer Epidemiol Biomarkers Prev. 1997 Jul;6(7):505-9.
56.) Muti P, Bradlow HL, Micheli A, Krogh V, Freudenheim JL, Schünemann HJ, Stanulla M, Yang J, Sepkovic DW, Trevisan M, Berrino F. Estrogen metabolism and risk of breast cancer: a prospective study of the 2:16alpha-hydroxyestrone ratio in premenopausal and postmenopausal women. Epidemiology. 2000 Nov;11(6):635-40.