Estrogen and Testosterone

 The Controversy and Caveats Of Hormones

What a loaded topic for a blog. I guess I just can’t take a break from complicated topics. Hormones are one such controversial topic, meaning there are divided schools of thoughts on how best to modulate them or support their balance. I’ve written previously on the subject of hormonal replacement, including what factors to consider, the pros and cons, and the risks associated with supplementing with them. Timing, population characteristics, and other factors will all come into play regarding the safety of supplementing with synthetic or bioidentical-hormones. In this blog, I’m going to be focusing on the topic of phytoestrogens.

 

What Are Phytoestrogens?

Phytoestrogens are components found in various plants and share structural or functional similarities to mammalian estrogens and their active metabolites. There are various classes of phytoestrogens including:

  1. Lignans, components of plant cell walls and found in foods such as berries, seeds (particularly flaxseeds), grains, nuts and fruits.
  2. Phenolic compounds, which include isoflavones and coumestans (1)

 

How Do Phytoestrogens Work?

Hormone pathway

The most widely accepted mechanism of phytoestrogens are their actions on estrogen receptors (ERs), with a higher preference for estrogen receptor beta (ER-B) than estrogen receptor alpha (ER-a). For this reason, phytoestrogens have mostly been classified as selective estrogen receptor modulators (SERMs), blocking excess activity if estrogen is too high and mimicking estrogen effects if estrogen is too low. (1-3)

However, phytoestrogens’ activity isn’t selective for these estrogen receptors alone, and there is evidence that other receptors related to estrogen response may also be at play. (1-5) For example, it has been demonstrated that phytoestrogens can modulate aromatase activity (1, 6) and increase production of sex hormone-binding globulin (1,7), both affecting estrogen availability. This may be one reason why studies are so conflicting on benefits verses risks. (1-3)

Furthermore, isoflavones, most notably genistein, can inhibit pathways related to cell growth and proliferation, such as the activity of protein tyrosine kinases (PTKs). Various estrogen receptor (ER)-independent properties of genistein, resveratrol and other isoflavones, demonstrate their potential to affect other pathways important for cellular signaling regulating growth and protection. (1) One study even demonstrated phytoestrogens’ ability to modulate peroxisome proliferator-activated receptors, which could have a positive impact on bone health. (8)

Studies are very conflicting in regard to breast cancer, but many human trials point to beneficial effects in modulating breast cancer risk. (1, 2, 7, 8)

For example, a double-blinded trial that included 177 women tested the effects on a phytoestrogen mixture from red clover verses placebo on hormonal levels and mammographic breast density after 1 year. The researchers reported that this mixture provided preliminary support that these phytoestrogens did not cause estrogenic effects on breast tissue or levels of hormones in the blood:

We found that a dietary supplement that provided 26 mg biochanin A, 16 mg formononetin, 1 mg genistein and 0.5 mg daidzein daily for 1 year did not increase mammographic breast density in women aged 49–65 years, unlike conventional oestrogen replacement therapies. Furthermore, there were no effects of the isoflavone supplement on oestradiol, FSH or LH in postmenopausal women, or on hot flushes or other menopausal symptoms. Taken together, our findings suggest that the isoflavone supplement at the dose given was not acting as an oestrogen or as an anti-oestrogen. (9)

 

The Power of Biotransformation

Most phytoestrogens are present in foods in mixtures, providing synergistic effects. I believe that this synergism and the quality of the food are important. For example, eating genetically modified, processed foods that contain pesticides and chemicals could negate any beneficial effects.

However, I believe the bigger component in health implications of estrogens is related to the biotransformation of endogenous hormones and xenoestrogens from the environment that modulate pathways linked to cancer and genotoxicity.(10) In fact, the study listed above with red clover did show a weak association between genetic variants in liver detoxification enzymes (CYP17 and CYP19 genes) risk for breast cancer. The authors report:

Polymorphisms in genes involved in sex hormone metabolism and in genes that encode hormone receptors may have an effect on the production of and exposure to sex hormones, and on the subsequent activation of genes that are responsive to sex hormones. We investigated interactions between treatment and selected polymorphisms in the CYP17 and CYP19 genes, both of which are involved in the sex hormone biosynthesis pathway, and the oestrogen receptor (ESR1) gene. Polymorphisms in these genes have been associated with risk for breast cancer in some but not all studies [65,66]. We saw interesting potential gene–treatment effects for the changes in breast density and ESR1 polymorphism and FSH and CYP19 polymorphism, but the study was not powered to investigate these interactions and a larger study is needed to confirm these findings. (9)

BugsFurthermore, the microbiome may play a role in phytoestrogens’ benefits. (11,12) As I wrote in my upcoming book, BreakFree Medicine, “Another factor to consider with regard to soy is the health of a woman’s gastrointestinal tract. This will affect how well her intestinal bacteria can produce the beneficial compound, “equol,” from soy compounds.”

 

 

So, Do I Drink Red Clover Tea, Eat Soy, Or Take Resveratrol?

When part of a comprehensive, whole-food diet, eating foods with phytoestrogens for healthy people can provide nutrigenomic benefits that positively modulate cellular signaling pathways. For example, the lignans in flax seeds have many benefits and some studies support an association with their ingestion and a decrease risk in breast cancer. (13-14) However, for children and women or men at risk or being treated for cancer, the picture may be a little more complicated depending on the type of phytoestrogen consumed and treatment being applied. (1,7,13)

One of the major tenets of naturopathic and functional medicine is to always to consider the uniqueness of the individual. This means that an individual’s lifestyle, diet, capacity to detoxify hormones, genetic predispositions, liver health, mind-set, microbiome health, and family history will all determine their response to a supplement, medication, essential oil, or any other intervention.

Therefore, with this in mind, I believe it is wise to base decisions on a full history and several TYPES of lab measurements including serum, saliva, and urinary metabolites.

Click here to review various factors to consider for supporting a healthy hormonal balance.

 

References

(1) Patisaul HB, Jefferson W. The pros and cons of phytoestrogens. Frontiers in neuroendocrinology 2010;31(4):400-419. doi:10.1016/j.yfrne.2010.03.003.

(2) NYU Langone Medical Center. 2015:

(3) Addressing the soy and breast cancer relationship: review, commentary, and workshop proceedings. J. Natl. Cancer Inst. September 2006; 98 (18): 1275–1284. doi:10.1093/jnci/djj356. PMID 16985246. Retrieved 2008-12-20.

(4) Involvement of estrogen receptor variant ER-{alpha}36, not GPR30, in nongenomic estrogen signaling. Mol. Endocrinol. 2010. doi: 10.1210/me.2009-0317

(5) Estrogen receptor pathways to AP-1. J. Steroid Biochem. Mol. Biol. 2000;74:311–317. PMID: 11162939

(6) Lignans and flavonoids inhibit aromatase enzyme in human preadipocytes. J Steroid Biochem Mol Biol. 1994 Aug;50(3-4):205-12. PMID: 8049151

(7) Dietary phytoestrogens and cancer: in vitro and in vivo studies. J. Steroid Biochem. Mol. Biol. 1992;41:331–337.

(8) Dose-dependent effects of phytoestrogens on bone. Trends Endocrinol. Metab. July 2005; 16 (5): 207–13. doi:10.1016/j.tem.2005.05.001. PMID 15922618

(9) Red clover-derived isoflavones and mammographic breast density: a double-blind, randomized, placebo-controlled trial [ISRCTN42940165]. Breast Cancer Research 2004;6(3):R170-R179. doi:10.1186/bcr773.

(10) Chapter 6: Estrogen Metabolism by Conjugation. J Natl Cancer Inst Monogr. 2000 (27): 113-124. http://jncimono.oxfordjournals.org/content/2000/27/113.full

(11) Associations of the fecal microbiome with urinary estrogens and estrogen metabolites in postmenopausal women. J Clin Endocrinol Metab. 2014 Dec;99(12):4632-40. doi: 10.1210/jc.2014-2222

(12) The intestinal microbiome: A separate organ inside the body with the metabolic potential to influence the bioactivity of botanicals. DSHEA 2010 Symposium Chicago. January 2011. doi:10.1016/j.fitote.2010.07.012)

(13) Lignans. Linus Pauling Institute. http://lpi.oregonstate.edu/infocenter/phytochemicals/lignans/

(14) Dietary lignan intakes and risk of pre- and postmenopausal breast cancer. Int J Cancer. 2004 Sep 1;111(3):440-3. PMID:15221974

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