By Rob Goodier

NEW YORK (Reuters Health) June 21 - In older women, higher levels of endogenous estrogen at baseline predicted a lower risk of heart disease in the Women's Health Initiative trials, a new analysis shows.

"Regardless of treatment, our hormone levels predicted your chance of heart disease," Dr. Douglas Bauer, who led the new research at the University of California in San Francisco, told Reuters Health.  Dr. Bauer and his team presented their findings Sunday at the 93rd annual meeting of Endocrine Society in Boston.

The WHI trials studied two treatments: estrogen, and estrogen plus progestin.  The estrogen-alone trail randomized 10,739 women to take either conjugated equine estrogens, or a placebo, and tracked them for about 7 years.

The estrogen-plus-progestin trial randomized 16,608 women to take either estrogen plus medroxyprogesterone acetate, or a placebo, and tracked them for more than five years.

Overall, 748 women had heart disease events (e.g., myocardial infarction, silent MI, or cardiac death) during follow-up, including 416 subjects in the estrogen-alone trial and 332 in the estrogen-plus-progestin trial.

When Dr. Bauer and his colleagues analyzed baseline quartiles of serum estradiol (E2) levels, they found that heart disease risk decreased with higher E2 levels (p for trend, <0.05).

Futhermore, "baseline levels of total E2 did not modify the relationship between treatment and coronary heart disease risk" in either trial, the researchers said in their abstract for the meeting.

In the estrogen-plus-progestin trial, women in the highest quartile of E2 levels had a 70% lower risk of heart disease compared to those in the lowest quartile (hazard ratio: 0.3).  In the estrogen-alone trial, women with the highest E2 levels were 50% less likely to suffer a cardiac event compared to those with the lowest E2 levels (HR: 0.5).

"This is more likely to be useful in women trying to predict their risk of heart disease than in trying to determine the best treatment," Dr. Bauer said.  "In the future, you could, perhaps, measure estrogen to tell the likelihood of heart disease."

Bio-identical hormone replacement therapy (BHRT) is becoming more popular among women, and providers should have adequate knowledge regarding this treatment. This article reviews traditional hormone replacement therapy, BHRT, its premise, treatment options, and its overall strengths and weaknesses.

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By Jason E. Barker, ND

In the eyes of holistic physicians, hormones are the “fountain of youth” in the human body. Their job is to regulate the functions of different tissues and organs as well as blood pressure control, reproductive function, body mass, immune function, cognitive performance, how we deal with stress and so much more. Hormones are chemical messengers that are released from one area of the body to communicate a signal in another area.
The hormonal “orchestra” must stay in balance in order for the tissues that they regulate to function optimally and stay in harmony. When hormones become depleted or imbalanced (from aging, stress, pollutants, lifestyle) we begin to experience serious health issues.
While the majority of information about hormonal health tends to focus on reproductive function and conditions associated with PMS, menopause and andropause, other areas of the body are just as greatly affected.
The heart is one organ that hormone balance has a direct effect upon. Newer research is exploring how inadequate hormone levels negatively affect heart health, and how achieving hormone balance can offset this.

Estrogens and the Heart
Estrogens are perhaps most often associated with female reproductive issues. Yet this group of hormones also plays complex roles in non-reproductive tissues including the brain and cardiovascular system. Estrogen receptor molecules are found in the vasculature where they exert positive effects on the ability of blood vessels to dilate and respond to changes in blood pressure (vascular reactivity), as well as lipid-lowering and antithrombotic (clot-preventing) effects.1
Epidemiologic studies show less cardiovascular disease occurring in pre-menopausal women in comparison to same-aged men and postmenopausal women, an effect attributed to the difference in estrogen levels between pre- and postmenopausal women and men.2 Further, as cardiovascular disease increases drastically after menopause and becomes the most common cause of death in women,3-4 the need to have adequate/balanced estrogen levels becomes especially important.
Other such epidemiological studies do not show a benefit in the reduction of coronary heart disease (CHD) in postmenopausal women using hormone replacement therapy; however, one notable area of bias is the fact that larger trials used orally dosed estrogens, which leads to a pro-coagulant effect while non-orally dosed estrogens do not exhibit this. Additionally, these studies utilized the synthetic progestin medroxyprogesterone acetate (MPA), which interferes with the beneficial effects of estrogen in the blood vessels, whereas natural progesterone does not have this effect.5
On the other hand, naturally derived estradiol and progesterone therapy can have beneficial effects on lipoprotein and cardiovascular indices. In women with mild to moderate hypertension, women treated with these hormones did not experience any negative changes in blood pressure, heart rate, lipids, plasma renin or aldosterone activity levels, nor most importantly antithrombin II levels, suggesting that percutaneous delivery of naturally derived estrogen and progesterone represents a possibly safe HRT treatment for postmenopausal women.6

Progestins vs. Progesterone
There is much confusion in the lay literature regarding this hormone. The term “progesterone” is meant to refer only to naturally derived progesterone hormone, whereas the term “progestin” refers to synthetic analogs of progesterone. Unfortunately, these two terms are often used interchangeably in the mass media to much detriment as they have strikingly different physiological effects; progestins are detrimental to blood vessel walls and thus the cardiovascular system whereas progesterone has not been shown to have this effect.
More specifically, the effects of progestins on blood vessels revealed endothelial (blood vessel lining) disruption, activation of platelets and subsequent clotting, and accumulation of monocytes in vessel walls, whereas progesterone or estrogens (conjugated equine estrogens and 17 beta-estradiol) showed none of these effects.7 These and other studies confirm the damaging effects of progestins on the cardiovascular system.
The progestins medroxyprogesterone acetate and norethisterone acetate (NETA) also inhibit the beneficial effects of estrogens on the cardiovascular system, and induce changes in lipid profiles, development of atheromas (underlying lesions in atherosclerosis) and vasodilation of blood vessels. These antagonist actions are not noted when progesterone is used in combination with estrogens where there is a neutral effect.8
Supporting “bioidentical” progesterone levels naturally in the body takes on even greater importance when considering the immediate downstream metabolism of progesterone into the hormone cortisol. Cortisol is the body’s main anti-inflammatory hormone (with other effects) and is responsible for quenching inflammatory processes. This is especially important in cardiovascular disease, which is initiated by inflammatory processes.9
It is hypothesized that as stress levels elevate and the demand for cortisol increases, this may have a depleting effect on the body’s progesterone stores and thereby creates further hormone imbalance in the form of depressed progesterone levels. This is known as the “progesterone steal,” wherein the body steals progesterone in order to make cortisol. Continual demands for cortisol in turn draw upon progesterone, setting one up for hormonal imbalance as progesterone is used up to manufacture stress-related hormones.

Testosterone’s Protective Effect
Lower levels of testosterone are associated with increased cardiovascular mortality; they are also associated with several conditions (insulin resistance, metabolic syndrome and diabetes) that lead to cardiovascular disease.10 In the case of heart failure, which is in reality a multisystem disease, it is estimated that 26-37 percent of men with this condition are deficient in testosterone.11
Androgen (testosterone) levels determine one’s anabolic state, muscular strength, and anti-inflammatory and vasodilatory effects; heart failure is characterized by a shift towards catabolism (tissue breakdown), production of pro-inflammatory cytokines, loss of muscle mass and vasodilatory incapacity.12 The use of testosterone replacement therapy in heart failure has beneficial effects. Men with moderately severe heart failure who used only 5 milligrams testosterone for 12 months experienced improvements in functional capacity and heart failure symptoms.12
Testosterone therapy in women with chronic heart failure also improved their functional capacity, muscular strength and parameters of insulin resistance, with no detectable side effects.13

Measuring Hormone Levels
This article is only a short review of the multiple effects that a few key hormones have on the heart and cardiovascular system. Hormonal health extends beyond the heart to every tissue in the body. Hormonal decline and imbalance is an issue that all adults will face at midlife and left unaddressed has the potential to create many additional health problems. Obtaining a salivary hormone test (Comprehensive Hormone Panel) is an ideal way to establish baseline hormone levels in order to determine the extent of replacement and or balance needed.

Restoring Balanced Levels
There are several botanicals that support testosterone levels. Luteolin (Perilla frutescens), myricetin (Myrica cerifera), beta sitosterol, Nettle (Urtica dioica) and Eurycoma longifolia jack found in AndroAMP work to support testosterone levels in several ways.
Luteolin inhibits the conversion of testosterone into estrogen via aromatase inhibition, preventing testosterone from converting into estrogen.14 Myricetin and beta sitosterol inhibit the enzyme 5 alpha-reductase, preventing the conversion of testosterone into the metabolite 5 hydroxtestosteone.15-16 Nettle binds to Sex Hormone Binding Globulin (SHBG) preventing it from locking onto free testosterone and limiting its biological activity.17 Lastly, Eurycoma longifolia jack can improve androgenic activity such as libido and sexual activity.18-19
Vitamin D3 also has been shown to provide a supportive effect on testosterone levels. A trial involving overweight men on a weight reduction plan examined the effects of supplementing vitamin D3 for one year on the subjects’ testosterone levels. After a year of supplementation, average vitamin D levels increased significantly as did all (total, bioactive and free) testosterone indices, suggesting that vitamin D supplementation can boost testosterone levels in men.20
Bioidentical hormones are naturally derived hormonal preparations that can directly support hormone levels. Progesterone cream can be used to directly support progesterone in both women and men, all the while offsetting the effects of excess estrogen and preventing a drain of progesterone due to the “progesterone steal.” As physicians trained in the art and science of bioidentical hormone replacement know, bioidentical estrogens (Bi-Est cream), from a compounding pharmacy, can be used to support estrogen-dependent physiological processes in postmenopausal women. Saliva testing also can determine baseline hormonal levels.

Conclusion
Cardiovascular health is dependent upon proper hormonal balance. It is ideal to test levels of estrogen, testosterone, progesterone and cortisol and to restore optimal levels if they are inadequate in order to help ensure the success of any heart-supportive regimen.

References
1. Billeci AM, Paciaroni M, Caso V, Agnelli G. Hormone replacement therapy and stroke. Curr Vasc Pharmacol. 2008 Apr;6(2):112-23.
2. Masood DE, Roach EC, Beauregard KG, Khalil RA. Impact of sex hormone metabolism on the vascular effects of menopausal hormone therapy in cardiovascular disease. Curr Drug Metab. 2010 Oct 1;11(8):693-714.
3. Schenck-Gustafsson K, Brincat M, Erel CT, et al. EMAS position statement: Managing the menopause in the context of coronary heart disease. Maturitas. 2011 Jan;68(1):94-7.
4. Ballard VL, Edelberg JM. Harnessing hormonal signaling for cardioprotection. Sci Aging Knowledge Environ. 2005 Dec 21;2005(51):re6.
5. Kuttenn F, Gerson M, de Lignères B. Effects of hormone replacement therapy in menopause on cardiovascular risk. Need for a European study. Presse Med. 2002 Mar 16;31(10):468-75.
6. Spritzer PM, Vitola D, Vilodre LC, Wender MC, Reis FM, Ruschel S, Castro I. One year follow-up of hormone replacement therapy with percutaneous estradiol and low-dose vaginal natural progesterone in women with mild to moderate hypertension. Exp Clin Endocrinol Diabetes. 2003 Aug;111(5):267-73.
7. Thomas T, Rhodin J, Clark L, Garces A. Progestins initiate adverse events of menopausal estrogen therapy. Climacteric. 2003 Dec;6(4):293-301.
8. Sitruk-Ware R. Progestins and cardiovascular risk markers. Steroids. 2000 Oct-Nov;65(10-11):651-8.
9. Bucova M, Bernadic M, Buckingham T. C-reactive protein, cytokines and inflammation in cardiovascular diseases. Bratisl Lek Listy. 2008;109(8):333-40.
10. Yeap BB. Curr Opin Endocrinol Diabetes Obes. 2010 Jun;17(3):269-76. Androgens and cardiovascular disease.
11. Naghi JJ, Philip KJ, Dilibero D, et al. Testosterone Therapy: Treatment of Metabolic Disturbances in Heart Failure. J Cardiovasc Pharmacol Ther. 2010 Nov 19.
12. Malkin CJ, Pugh PJ, West JN, et al. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur Heart J. 2006 Jan;27(1):57-64.
13. Iellamo F, Volterrani M, Caminiti G, et al. Testosterone therapy in women with chronic heart failure: a pilot double-blind, randomized, placebo-controlled study. J Am Coll Cardiol. 2010 Oct 12;56(16):1310-6.
14. Wang C, Mäkelä T, Hase T, et al. Lignans and flavonoids inhibit aromatase enzyme in human preadipocytes. J Steroid Biochem Mol Biol. 1994 Aug;50(3-4):205-12.
15. Prager N, Bickett K, French N, et al. A randomized, double-blind, placebo-controlled trial to determine the effectiveness of botanically derived inhibitors of 5-alpha-reductase in the treatment of androgenetic alopecia. J Altern Complement Med. 2002 Apr;8(2):143-52.
16. Hiipakka RA. Structure-activity relationships for inhibition of human 5alpha-reductases by polyphenols. Biochem Pharmacol. 2002 Mar 15;63(6):1165-76.
17. Schottner M, Gansser D, Spiteller G, et al. Lignans from the roots of Urtica dioica and their metabolites bind to human sex hormone binding globulin (SHBG). Planta Med. 1997;63:529-32.
18. Ang HH, Cheang HS, Yusof AP. Effects of Eurycoma longifolia Jack (Tongkat Ali) on the initiation of sexual performance of inexperienced castrated male rats. Exp Anim. 2000;49:35-8.
19. Ang HH, Ikeda S, Gan EK. Evaluation of the potency activity of aphrodisiac in Eurycoma longifolia Jack. Phytother Res. 2001;15:435-6.
20. Pilz S, Frisch S, Koertke H, et al. Effect of Vitamin D supplementation on testosterone levels in men. Hormone and Metabolic Research. December 10, 2010.

Does Progesterone Increase Breast Cancer Risk?

There appears to be some controversy brewing about progesterone possibly increasing the risk of breast cancer. This is based on a secondary follow-up of a French study (Fournier et al J Clin Oncol 26 (8):1260-1268, 2008) investigating breast cancer incidence in approximately 80 thousand women who had used various forms of estrogens and progestogens for hormone replacement therapy. It is being suggested that progesterone increases breast cancer risk, contrary to popular thinking that this hormone is safe and helps prevent breast cancer. The following is my argument in favor of natural progesterone as a preventative for breast cancer, with reference to the Fournier studies that address this issue.

Fournier and colleagues (Breast Cancer Res Treat 107: 103-111, 2008) originally published their clinical study looking at the relationship of different progestogens, in combination with estrogen, on the risk of developing breast cancer. First, I think it important to define a progestogen; it is any molecule with a structure similar to the natural hormone progesterone that binds to and activates intracellular progesterone receptors. This would include all forms of synthetic progestins in addition to natural progesterone. What Fournier and colleagues found in the first study is that of all the progestogens studied, natural progesterone had the lowest risk, which was actually lower than no treatment at all.

Fournier and colleagues then did a second follow-up study (J Clin Oncol 26 (8): 1260-1268, 2008) in the same patient population as the first study (80,391 postmenopausal women), but looked not only at the different types of hormones that were used (estrogens and progestogens), but breast cancer risk in relationship to the type of tumors (ductal or lobular) that occurred in some of these women. They also looked at whether or not the tumors contained receptors for estrogen or progestogens, which includes four categories: ER+/PR+, ER+/PR-, ER-/PR+, and ER-/PR-. Most breast cancers (60-70%) present with receptors for both estrogens and progestogens (ER+/PR+), and about 20-30% fall into the other categories (about 10-15% are ER-/PR-). This is an area I would consider myself somewhat of an expert in as I helped develop the technology for detecting ER and PR in breast cancers in the late 1970's, ran three different breast cancer testing laboratories that did this type of testing (from the mid 1970s to mid 1990s), and am published extensively using breast cancer cell lines and human clinical samples post breast cancer surgery.

What Fournier and group found is that the combination of estrogens and progestogens for more than 5 years is associated with increased risk of breast cancer. Broken down in ductal vs lobular cancers, the use of estrogens plus progestogen (including natural progesterone) was associated with an increased risk for breast cancer. While this could be interpreted to indicate that natural progesterone increases breast cancer risk, it should be kept in mind that the data shows it's the combination of estrogen and natural progesterone that increases risk. In fact, risk with estrogen plus progesterone is actually less than the risk of estrogen alone (1.7 vs 2.1, respectively), and that of all the progestogens, natural progesterone has the lowest risk. So there is a different way of looking at this data. It is important to keep in mind that this study did NOT look at natural progesterone by itself, only estrogen plus progesterone. Another way of interpreting this data is that natural progesterone decreased the risk of breast cancer caused by long term use of estrogens (i.e. risk 2.1 to 1.7).

It is important to also keep in mind that the Fournier studies did NOT look at the effect of progesterone alone, or compare the effects of oral vs topical progesterone. Most of these studies are based on oral progesterone use.

Based on what we have seen in hundereds of thousands of salivary and capillary blood progesterone levels following different routes of progesterone administration, the topical route of administration delivers much more progesterone to tissues than the oral route. Oral progesterone therapy only raises progesterone to subluteal levels (1-5ng/ml) (Nahool and Levits references) and this is also reflected in lower salivary and capillary whole blood progesterone levels. Luteal levels of progesterone (>10ng/ml) need to be achieved for progesterone to act as an estrogen antagonist to prevent estrogen from excessively stimulating breast cell proliferation. Women who have an excess of estrogen relative to progesterone (low progesterone/estradiol ratio), are more likely to have atypical benign breast disease that is at increased risk of developing into breast cancer (Sitruk-Ware et al J Clin Endocrinol Metab 44, 771, 1977). Low endogenous luteal progesterone levels in premenopuase women (much more prevalent in peri-menopausal woman) have also been associated with increase breast cancer risk (Micheli et al Int J Cancer 112, 312-318, 2004).

Oral progesterone is mostly destroyed in the gastrointestinal track before it enters the blood circluation and delivered to the tissues. Based on saliva and capillary blood progesterone levels, topically delivered progesterone is 20-100 times more efficiently delivered to tissues. Studies in humans have shown that physiological amounts of progesterone (20-50mg) administered topically deliver physiological amounts progesterone to the breast tissue and suppress estrogen-stimulated cell proliferation (Chank KJ et al Fert Sterility 63: 785-791, 1995 and De Boever et al Endocrinol of Cystic Breast Disease, 1983). My concern is that women using estrogens and ORAL progesterone as hormone replacement may not be getting enough progesterone to tissues to counter the growth-promoting effects of the estrogens. Unfortunately, the estradiol level, relative to progesterone (i.e. progesterone/estradiol ratio), was not evaluated in these studies. In vivo, during the luteal phase of the menstrual cycle, the level of progesterone is approximately 100-200 times higher than estradiol in all body fluids that have been studied (serum, capillary whole blood, saliva, urine). Lower levels are associated with increased risk for benign breast disease, higher proliferative rates, and increased breast cancer risk (Sitruk-Ware et al J Clin Endocrino Metab 44, 771, 1977; Micheli et al Int J Cancer 112, 313-318, 2004).

The Fournier studies referenced above looked at ORAL, not topical, progesterone. Based on salivary, capillary blood, and tissue progesterone levels from the studies mentioned above, topical progesterone is far more effective in delivering a physiological amount of progesterone to the breast and controlling estrogen-stimulated cell proliferation.

It is unfortunate that in spite of all the science and clinical studies behind it, only one small study (Plu-Bureau G et al Cancer Detect Preve 23(4), 290-296, 1999) that I am aware of looked at the risk of breast cancer with TOPICAL progesterone in a manner similar to what Dr. John Lee recommended for progesterone use (10-30 mg topical progesterone daily). In that study, they showed the risk to be reduced by half (0.5) in those using topical progesterone for 3 years or more. This is entirely consistent with the notion that when progesterone is delivered topically at a physiological level, it is protective.

When I talk to very high levels of people about why they should at least study the relationship of topically delivered progesterone to breast cancer risk, I am told they don't think it could possibly be effective because topical progesterone doesn't increase serum levels. This is true for all nonpolar sex-steroid hormones used clinically as replacement therapies, including estradiol, progesterone, and testosterone. While topical delivery of these hormones does not increase serum levels significantly, this route of administration does result in marked increase in levels of these hormones in saliva, capillary blood, and tissue.

When it is finally realized that topical hormone deliver of progesterone is a very efficient way to deliver progesterone to tissues, and that serum is not reflective of this delivery, progress will be made in avoidance of over-treatment (often occurs with topical delivery as a result of tracking success with serum levels that do not increase significantly), and delivery of a physiological amount of progesterone to tissues that is breast protective. Dr. John Lee, and many of those who follow his protocols for physiological delivery of topical progesterone, have reported very few breast cancer cases in their clinical practice. While this is anecdote, their use of topical progesterone in physiological amounts deserves more attention by the medical establishment.

Posted by David Zava, PhD at 10:39 AM

Clinical studies continually demonstrate an effectiveness of bioidentical progesterone for symptom relief for menopause, hot flashes, anxiety, sleep disturbances, and mood swings. More and more research repeatedly indicates that adequate progesterone is needed for fertility, cardiovascular health, nervous system function, and bone health, and also protects against the development of cancer of the uterus in women using estrogen therapy. Bioidentical progesterone has historically been used to support regular menstruation and provide help for infertility.

Much of the research cited below is provided by www.womeninbalance.org and we invite you to visit this site for more information about natural hormone research.