Outcomes often have unsuspecting origins. Nowhere is this more evident than in metabolic endotoxemia and hormones. Brevity is the soul of whit. However, when it comes to hormones, brevity is the soul of ignorance.
What is the impact of metabolic endotoxemia?
One does not need to jump all the way to obesity and disease to see the manifestations of the diet —> gut microbiome —> metabolic endotoxemia —> dysfunction. It is right up in your face. Most just don’t recognize it.
It is essential to understand that the alteration of the gut microbiome is the direct result of dietary and oral intervention. Whether it be twinkies, muffins, cookies, or broccoli, spinach, or brussel sprouts, or antibiotics, the effect changes the bacteria that live in the gastrointestinal tract, also known as the gut microbiome.
Hormones are often the first to manifest the metabolic dysfunctions that eventually result in disease. Hormone imbalances, deficiencies, dysfunction can point right back to the same gut-sourced metabolic endotoxemia. In many ways, hormones imbalances are just the manifestation of the underlying problem, the check engine light, if you will, that precedes the very large physical manifestations of obesity or other diseases.
Diet, gut microbiome, metabolic endotoxemia, hormone imbalance, cancer connection
I want to briefly highlight a few well-known hormones and their connections back to metabolic endotoxemia. Why? Because metabolic endotoxemia is a foundational contributor to many of the common hormone imbalances which create the metabolic dysfunction that manifests itself in obesity. As a result, local microenvironments become more tumor favorable—called tumor microenvironments. The result is many chronic diseases associated with aging, but most specifically—cancer.
I have written extensively on the topic of low testosterone and obesity in men. I have written two books on the subject, Man Boob Nation–an Integrative medicine approach to low testosterone published in 2014, and Total Testosterone Transformation published in 2017, so check them out for a deeper dive on the topic. Metabolic endotoxemia leads to low testosterone in men. This metabolic endotoxemia-induced low testosterone even has a name–the GELDING theory [i]. The connection here is an obvious and direct one. Imbalances in gut bacteria lead to a leaky gut and an increase in systemic LPS, metabolic endotoxemia, which correlates directly with an increase in obesity. Obesity increases inflammatory signaling, specifically interleukin-6 (IL-6), to drive testosterone levels down. That is an inverse relationship between systemic inflammation, IL-6, and Testosterone. More, an increase in obesity drives estrogen production, which also contributes to a decrease in testosterone levels [ii] [iii]. In short, the gut microbiome drives metabolic endotoxemia to increase obesity, which increases systemic inflammation that increases estrogen, all of which decrease testosterone [iv]. The proof is in the low testosterone pudding here, and the theory concept no longer applies to this GELDING.
In this discussion of these individual hormones and cancer, they are not the primary cause. Instead, these hormones and hormone imbalances help to change and create the local environment that helps to make the environment that allows cancer to survive and thrive. The connection to cancer here with the GELDING theory is one of low testosterone. The result is an increase in obesity, an increase in inflammation, and an increase in estrogen. All of which set the stage for a favorable carcinogenic environment.
I can hear the question now, what about testosterone and prostate cancer. Hormones can be one of the significant contributors to the carcinogenic process through alterations in the local environment. In prostate cancer, it is the receptor that is the problem, not the actual testosterone levels. In hormones, sometimes it is not what the hormone levels are, high or low. The balance and individual hormones in the body may be perfect if ever such a thing exists, but the body may do EVERYTHING wrong with it. That is precisely the case with prostate cancer and testosterone.
Progesterone is a hormone that is a powerful anti-inflammatory. In similar ways to testosterone, metabolic endotoxemia can induce low progesterone in women. As in the GELDING theory with low testosterone, gut sourced metabolic endotoxemia in women increases IL-6 within the ovary to inhibit progesterone production [v]. The result is low progesterone. Low progesterone production results in a hormone imbalance called estrogen dominance—normal to high estrogen levels with low progesterone levels. The result is weight increase, obesity, insulin resistance, estrogen dominance, and contribution to estrogen-sensitive cancers. It is the same gut source, same metabolic endotoxemia, but different sex, which affects different hormones, yet impacts cancer the same.
Even estrogen gets in on the gut microbiome, metabolic endotoxemia, systemic inflammation, hormone imbalance, cancer connection. The sequence is easy to see and understand if you look at just the obesity —> estrogen —> cancer connection. Take menopause, for example. Estrogen is increased in obese post-menopausal women, and estrogen is associated with an increased risk of breast cancer. The how is interesting. The increase in fat in post-menopause women increases the activity of the enzyme—aromatase. This aromatase enzyme is responsible for increasing estrogen production from testosterone and DHEA—all from post-menopausal fat. The primary estrogen manufacturing site in post-menopause women is in abdominal and visceral fat [vi].
Don’t think that this connection is forgotten on men. It is not. In men, 90% of estrogen production comes from abdominal fat. Abdominal fat is an estrogen-producing factory in men. The estrogen is produced from the same testosterone and DHEA. Abdominal obesity increases the same aromatase enzyme activity mentioned in the previous paragraph for women, which increases systemic estrogen production—all from abdominal fat. In men, this can contribute to an increase in systemic inflammation and a decrease in systemic testosterone levels [vii]. The result is a broad spectrum of metabolic dysfunction and disease potential. Beyond low testosterone, the high abdominal fat estrogen production opens the doorway to cancers responsive to estrogen. Many of the estrogenic cancers are listed below.
But what about a link back to the gut microbiome and, as a result, diet or anything put in the mouth? This series is about metabolic endotoxemia, after all. We know that the gut microbiome is linked to metabolic endotoxemia, which drives systemic inflammation and obesity for both men and women. Obesity, via an increase in fat cell number and size, further increases inflammation production to provide a self-feeding loop of inflammation—inflammation causes obesity, and obesity causes inflammation. Remember, fat cells are biologically active, producing many hormones and inflammation signaling. For example, we know that an increase in abdominal fat in men and women increases aromatase activity. The result is an increase in estrogen production that originates from the gut microbiome, and it is our diet through poor nutrition, or pure nutrition, sets the stage one way or another.
Insulin dysfunction will be discussed in greater detail in the following post, so stay tuned. Insulin is often thought of merely in terms of metabolism and disease, such as diabetes. But, insulin is a hormone produced by the pancreas that regulates glucose homeostasis—balance. Metabolic endotoxemia disrupts glucose homeostasis by increasing insulin resistance (liver, muscle, adipose tissue). The result of insulin resistance is an increase in systemic insulin—hyperinsulinemia. As it relates to healthy metabolism and disease, specifically cancer, this is never good. The cancer impact is an increase in insulin receptors, an increase in insulin receptor affinity, and even a cross affinity with the hormone insulin growth factor-1 (IGF-1) and vice versa. The result is a pro-growth environment for cancer. Again, look for more specific details on this connection to cancer to follow.
Cortisol is the stress hormone that we all know too well, and that was before the pile on from the COVID-19 pandemic of 2020. Cortisol dominates our body’s survival response through the control of the fight or flight stress response. In similar effect to insulin, but in contrast to the inhibition effects found with progesterone and testosterone, metabolic endotoxemia stimulates an increase in cortisol production; the gut microbiome —> metabolic endotoxemia —> systemic inflammation (IL-6) —> increase in cortisol connection [viii]. In addition to the direct endotoxin increase in systemic cortisol, there is an indirect increase in cortisol from an increase in fat that is the result of gut microbiome —> metabolic endotoxemia —> systemic inflammation —> insulin resistance —> obesity —> increase in cortisol connection [ix]. This gut sourced endotoxemia increase in cortisol, whether direct or indirect, supercharges the immune alterations, metabolic dysfunction, epigenetic changes, and hormone imbalances that contribute to many of the diseases we see today, including what we treat here at An Oasis of Healing—cancer.
Even though the impact of the previously mentioned hormones on metabolism is significant and well known, there is no greater impact on metabolism than the thyroid. Thyroid drives the metabolic show. Thyroid dysfunction from metabolic endotoxemia directly connects diet —> gut microbiome —> metabolic endotoxemia —> metabolic dysfunction. This metabolic dysfunction is a direct result of thyroid dysfunction. Thyroid effects are broad to include mitochondria, energy production, and metabolism, to name a few. In metabolic endotoxemia, the interaction between LPS and TLR4 triggers systemic inflammation that is auto directed against the thyroid in Hashimoto’s thyroiditis and Graves autoimmune thyroid disease [x]. Though the mechanisms are similar, the area of activity affected in the autoimmune disease is different between the two forms of autoimmune thyroid disease.
Thyroid dysfunction is a common condition in cancer. It is called non-thyroidal illness syndrome or NTIS, also known as sick thyroid syndrome. If inflammation is the bed cancer lays in, the inflammation that cancer further perpetuates creates NTIS and contributes to cancer growth potential. Another loop cycle of inflammation. How can this be? It comes down to genomic versus non-genomic thyroid signaling. In cancer, non-genomic thyroid signaling becomes a prominent alternative growth stimulus pathway for cancer. You read that right. Thyroid hormone, primarily T4 and reverse T3, can stimulate cancer growth non-genomically. The specifics and discussion of the mechanism here are beyond the scope of this post, but check out the talk I gave for ZRT labs for a deep dive on the topic of genomic versus non-genomic thyroid signaling in cancer.
Hormones are not just for hot flashes and erectile dysfunction. They don’t just have an effect on mood and energy. Their effects include these common and many other hormonal symptoms; but, they are not limited to these inconvenient symptoms. Hormones are part of the dysfunction that permeates the body because of metabolic endotoxemia. In fact, hormone imbalances may be the first evidence of the dysfunction that connects diet —> gut microbiome —> metabolic endotoxemia —> to disease. Hormone imbalances and associated symptoms are the check engine light, if you will, pointing to more significant underlying dysfunction under the hood in the metabolic engine of the body. Instead of a symptom that may need treatment, metabolic endotoxemia-induced hormone dysfunction may be the first evidence of the foundation for impending disease—cancer.
[i] Tremellen K. Gut Endotoxin Leading to a Decline IN Gonadal function (GELDING) – a novel theory for the development of late onset hypogonadism in obese men. Basic Clin. Androl. 2016;26,7. https://doi.org/10.1186/s12610-016-0034-7
[ii] Aguirre LE, Colleluori G, Fowler KE, et al. High aromatase activity in hypogonadal men is associated with higher spine bone mineral density, increased truncal fat and reduced lean mass. European Journal of Endocrinology. 2015 Aug;173(2):167-174. DOI: 10.1530/eje-14-1103.
[iii] Hayes FJ, Seminara SB, Decruz S, Boepple PA, Crowley WF Jr. Aromatase inhibition in the human male reveals a hypothalamic site of estrogen feedback. J Clin Endocrinol Metab. 2000 Sep;85(9):3027-35. doi: 10.1210/jcem.85.9.6795.
[iv] Tremellen K, McPhee N, Pearce K, Benson S, Schedlowski M, Engler H. Endotoxin-initiated inflammation reduces testosterone production in men of reproductive age. Am J Physiol Endocrinol Metab. 2018 Mar 1;314(3):E206-E213. doi: 10.1152/ajpendo.00279.2017.
[v] Tremellen K, Syedi N, Tan S, Pearce K. Metabolic endotoxaemia–a potential novel link between ovarian inflammation and impaired progesterone production. Gynecol Endocrinol. 2015 Apr;31(4):309-12. doi: 10.3109/09513590.2014.994602.
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[viii] de Punder K, Pruimboom L. Stress induces endotoxemia and low-grade inflammation by increasing barrier permeability. Front Immunol. 2015;6:223. Published 2015 May 15. doi:10.3389/fimmu.2015.00223
[ix] Osto M, Zini E, Franchini M, Wolfrum C, Guscetti F, Hafner M, Ackermann M, Reusch CE, Lutz TA. Subacute endotoxemia induces adipose inflammation and changes in lipid and lipoprotein metabolism in cats. Endocrinology. 2011 Mar;152(3):804-15. doi: 10.1210/en.2010-0999.
[x] Fröhlich E, Wahl R. Microbiota and Thyroid Interaction in Health and Disease. Trends Endocrinol Metab. 2019 Aug;30(8):479-490. doi: 10.1016/j.tem.2019.05.008.
Dr. Nathan Goodyear is dedicated to disease prevention, disease resolution, and the Wellness Lifestyle through a solution-based, Integrative Medicine approach founded in science. Dr. Goodyear received his Bachelor of Arts from Louisiana Tech University and his Doctor of Medicine from LSU Health Sciences Center.
He is Board Certified in Obstetrics and Gynecology and served as the Chief Resident in Obstetrics and Gynecology at the University of Tennessee. Dr. Goodyear has practiced Integrative Medicine since 2006. Dr. Goodyear is a Fellow in Functional and Regenerative Medicine and served on the board of the American Functional Medicine Association. Dr Goodyear is licensed by the Arizona Homeopathic and Integrative Medical Board in the State of Arizona. Dr. Goodyear is a published author, Man Boob Nation–an Integrative medicine approach to low Testosterone published in 2014, and Total Testosterone Transformation published in 2017