Hormones & gut health, a continuous balancing act

Oct 24

Functional medicine and independent nutrition research both advocate a bioindividuality-based approach to resolving disease. This means that rather than just managing the downstream effects of obscure-cause dysfunctions, body systems are assessed through specific testing methodologies to determine how well they function in each particular individual, based on his/her genetics and lifestyle. Thankfully, rather than prescribing palliative drugs, a growing number of allopathic doctors seem to be breaking with the conventional healthcare model to integrate testing for cellular disruptions upstream of health conditions, most notably by looking into GI tract activity - what comes in, what goes out, and what does what in between. After all, health and disease - and really all things human, begin in the gut and circle back to it. In light of this Hippocratic healing paradigm, it would be preposterous to attempt realigning hormones without assessing gut functionality, or, inversely, fixing gut issues without questioning whether our neuro-hormonal messaging system is performing ideally.

Our gut is often referred to as our second brain: the wall of the GI tract is home to our ENS, enteric nervous system, a network of 100 million neurons that govern GI functions, either in tandem with the sympathetic and parasympathetic nervous systems (all three together make up our autonomic nervous system), or in complete autonomy from them. Much like the brain, the gut also exhibits a symbiotic relationship with the endocrine system: aside from housing endocrine/exocrine organs like the pancreas and liver, the GI tract is populated with cells that secrete important hormones of their own, which continually interact with endocrine hormones.

Our digestive system is in charge of extracting, absorbing and processing nutrients from the foods we eat. Hormone synthesis relies integrally on absorption and metabolism of nutrients: steroids are made from liver cholesterol; peptides are made by assembling amino acids into chains; amino hormones are synthesized from the amino acids tyrosine and tryptophan; eicosanoids are manufactured from fatty acids. Along with basic macronutrient digestion, the absorption of co-factors such as minerals and vitamins is quintessential to hormone manufacturing and to their metabolic efficiency. Any such shortage impacts the synthesis of hormones and/or their ability to bind to target cell receptors and inform biological processes. Moreover, since used up hormones can become pathogenic, the gut is in charge of safely escorting them out of the body through detoxification pathways that are nutrient-dependent. Below are some examples of how digestion affects the entire lifecycle of hormones.

The vital bond between stomach and thyroid

A little biochemistry is in order here. In response to the ingestion of food, specialized cells in the stomach lining, called parietal cells, secrete HCl, or hydrochloric acid, which starts degrading foods and kills incoming bacteria, yeast and viruses. A PH of 2.0 is necessary for the stomach to activate a protease (protein specific) enzyme called pepsin, which starts digestion of proteins by hydrolyzing them into smaller chains called polypeptides. As the food moves into the duodenum (the first section of the small intestine), stomach acid also prompts the pancreas to release digestive juices and protease enzymes into it, to break down proteins into its constituent amino acids; these will be later reassembled into chains that make up proteins with different biological functions (think blood, muscle, hair, nails, skin, bones, membranes, hormones, antibodies, enzymes, etc.). The blueprint for the assemblage of these proteins is bio-individual: instructions are provided courtesy of our DNA.

This entire acid-dependent process is paramount to the production of peptide hormones, which are fabricated by assembling amino acids into chains, and much like structural, transport, defensive or catalytic proteins, they are the product of genetic translation (according to mRNA transcripts). Peptide hormones are ubiquitous in the body; they are secreted by endocrine organs like the hypothalamus, pituitary, thyroid, adrenals, pancreas and ovaries, but also by the kidneys, heart, adipose tissues and the gut. Examples of peptides are FSH, LH, calcitonin, growth hormone, insulin, glucagon, renin, insulin growth factor, leptin, ghrelin, secretin and cholecystokinin.

Analogously to peptides, amino hormones such as adrenaline, melatonin, dopamine, and thyroid hormones T3 and T4, are derived from amino acids (tyrosine and tryptophan), which are produced from the breakdown of protein, as described above. Without the proper level of acidity and the presence of pepsin and other digestive enzymes, the stomach cannot break down protein containing the amino acids needed to make T3 and T4, leading to thyroid insufficiency and the ensuing cascade of hormonal disruptions. Optimal absorption of tryptophan, which is an essential amino acid (we can only get it from dietary sources), is also critical since it serves as a precursor to serotonin, a neurotransmitter produced in our digestive tract tissues that regulates mood, appetite, and sleep.

Common stomach afflictions like GERD, gastroesophageal reflux disease, the chronic regurgitation of hydrochloric acid into the esophagus, and heartburn, both historically attributed to an excess of acid in the stomach, have been instead shown to be caused by low stomach acid production, or hypochlorhydria, and are therefore among the gut-related underlying causes and effects of hormonal imbalances. Under normal conditions, the LES, lower esophageal sphincter, a one-way valve located at the base of the esophagus, opens to let food pass into the stomach and closes to prevent stomach content from backing up, cued by a sufficient amount of stomach acid. Transient relaxation of the LES due to low stomach acid, which causes it to lose its rhythmicity and open erratically, is the most common cause of GERD that is not otherwise induced by hiatal hernia, abdominal distension, infections or intolerances. Hypochlorhydria may arise from atrophy of the stomach mucosa due to hypothyroidism and inadequate thyroid hormone secretion, since the T3 hormone is needed for the growth of stomach parietal cells, the ones that make stomach acid; aging, nutrient deficiencies, inflammation and high BMI (even in non-obese individuals) are all conditions that may dampen acid production, with high levels of stress hormones being a common denominator through all of them. Hypochloridria can also be medically induced by prolonged use of a class of drugs called PPIs (proton pump inhibitors), paradoxically prescribed to treat the symptoms of GERD: this is a perfect example of how suppressing symptoms rather than probing into root causes ends up worsening the condition.

As alluded to above, research has shown gastric disorders to be associated with hypothyroidism via a thyroid hormone-dependent HCl production mechanism; however, motility of the GI tract is also choreographed by another thyroid hormone called motilin, whose secretion is inconsistent in an underactive thyroid. The GI tract has an abundance of thyroid hormone receptors, and low output of these hormones hampers esophageal motility, causing the LES to lose tone and allow acid to back up into the esophagus. Additionally, hypothyroidism-induced inflammation, excess weight and overeating also tamper with LES modulation. CAG, chronic autoimmune gastritis, a condition characterized by a progressive degradation of acid-producing parietal cells, correlates with Hashimoto’s hypothyroidism (on a tangential note, co-morbidity of autoimmune conditions is extremely common). The term thyrogastric syndrome is in fact used to define the relationship between thyroid disease and chronic autoimmune gastritis; interestingly, iodine is both a constituent of thyroid hormones and gastric parietal cells. Grave’s disease, which is autoimmune hyperthyroidism, is also associated with GI tract disorders. In hyperthyroidism, increased levels of gastric mucosal ghrelin, called the ‘hunger hormone’ are associated with gastrointestinal dysmotility. Ghrelin increases gastric emptying, which leads to diarrhea and malabsorption of nutrients essential to hormone functions.

Stomach absorption of vitamins and minerals that are needed for hormonal efficiency is at the mercy of thyroid function/acid production, while the opposite is also true. B12, for instance, is absorbed by GIF, gastric intrinsic factor, a glycoprotein produced by the same parietal cells in the stomach that make HCl; B12 regulates our circadian rhythm by stimulating production of melatonin by the pineal gland. Vitamins of the B group all assist with liver detoxification of estrogens by enhancing bile production; B3 in particular is needed for the production of HCl. CAG and hypothyroidism imply the impairment of both hydrochloric acid and intrinsic factor production, with consequent malabsorption of B12 and other B vitamins, as well as the very minerals the thyroid needs: magnesium, zinc, calcium, iron and selenium.

Significant hormonal changes such as those brought on by menopause, pregnancy, obesity or chronic stress, precipitate shifts in neuro-hormonal signaling that cause malfunction of the LES, creating a vicious cycle of GERD and hormone disruptions, with thyroid issues being both upstream and downstream of fluctuations. Both high and low estrogen levels can cause LES relaxation; estrogen and progesterone have an inverse relationship, when one goes up the other one goes down, hence, while both hormones contribute to regulating esophageal motility, high levels of either one increase relaxation of LES to a degree of malfunction. To make matters worse on digestion, high estrogen and low progesterone impair thyroid function, going back full circle to parietal cell damage and low stomach acid.

The liver’s critical role in hormonal balance

Hormones have a lifecycle, like all molecules in nature: they are synthesized, perform their biological actions, and are then degraded and eliminated through urine and feces, or destroyed. Their longevity depends on their nature, functions and mechanisms of action. Unlike peptide hormones, which are primarily released in direct bursts, stick around only a few minutes to do their job, and are promptly eliminated, steroid hormones linger around the body longer and their elimination is more complex. Steroid hormones, which include estrogens, progesterone, testosterone, aldosterone, DHEA and cortisol, are synthesized from the uptake of liver cholesterol (both HDL and LDL) and its enzymatic conversion to pregnenolone inside cell mitochondria. This takes place primarily in the adrenal and gonad tissues. Since steroids are hydrophobic, in order to move around the bloodstream, they need to be bound to carrier plasma proteins that safely shuttle them around in the aqueous human body environment. Estrogen and androgens are carried by a specific protein with high affinity, SHBG, sex hormone-binding globulin. Protein binding also impacts the elimination process, as I will detail ahead.

So you can fully appreciate the diligent labor of the liver in maintaining hormonal balance, I will quickly go over a few facts on estrogen metabolism, though this topic will require further elucidations in subsequent discussions addressing weight loss and aging.

What we refer to as estrogen, is actually a class of hormones that collectively covers the most prominent role in women’s sexual development and reproductive health, and to a smaller extent in men’s. Estrogens are mainly produced in the ovaries (during fertile years) and adrenals (our back-up sex hormone factory after menopause); adipose tissues also secrete estrogens. Although there are several estrogen metabolites, the three main and commonly acknowledged ones are Estrone (E1), Estradiol (E2) and Estrone (E3). Estradiol, produced by the ovaries, is the strongest form of estrogen, followed by estrone and estriol, the weakest of the three. Conversions of estradiol to estrone and estriol take place primarily inside the liver and partially in the small intestine. Now, the fact that estrogens can convert from one form to another and back is both a blessing and a curse. It is however important to note that estrogens are, collectively, the only end hormone, as they cannot be converted to any other hormone, and must be eliminated if in excess of functional needs.

Going further down the estrogen conversion pathway, we encounter their metabolites (breakdown products), which include: 2-Hydroxyestrone, a protective hormone, and 16 alpha-hydroxyestrone, a cancer promoting type of estrogen produced by the conversion of estriol in states of liver toxicity or estrogen dominance, which occurs when the hormonal scale tips in favor of estrogens compared to progesterone and androgens, This condition can be due to a natural decline in progesterone (estrogen and progesterone have an inverse relationship), but also to xenoestrogens, or estrogen mimickers, endocrine disrupting chemicals that get into our system and pose as our endogenous hormones by binding to their target receptors, causing cancer and other metabolic dysfunctions. This day and age we are continuously exposed to an exorbitant amount of endocrine disrupting toxins that come from our environment: pesticides in conventional produce; added hormones and antibiotics in mainstream meats and cheeses; BPA, PVC and phthalates in plastic; chlorine and countless other chemicals in drinking water; parabens and fragrances in cosmetics; NPEs, benzenes and fragrances in laundry detergents, resorcinol in hair dyes, etc. - the list goes on and on [I will link the EWG database for a complete list in the source section below].

What further complicates things, biologically, is that these toxins accumulate in our adipose tissues and draw water into them; the more endocrine disruptors we collect, the more estrogen dominant we become, which ramps up adipose cell growth and replication, in a noxious vicious cycle. In other words, estrogens in excess will make you fat and that fat can kill you in more ways than one. This is where our almighty liver comes to the rescue, and the reason why caring for our liver is paramount to hormonal balance and health. The liver has the life-saving task of ridding the body of excess estrogens. Liver detoxification of hormones takes place in two steps: Phase I, in which these compounds are broken down into potentially toxic metabolites; and Phase II, in which other compounds are added to the toxic metabolites in order to render them harmless and make them water-soluble, so they can be excreted into the bile and eliminated through feces and urine. A disruption in either pathway, as is the case in both alcoholic and non-alcoholic fatty liver disease, can cause estrogens to be returned to their active metabolic form and go back into circulation. Alcohol increases the action of an enzyme called aromatase, which rapidly converts testosterone to estrogen. Estrogen clearance may also be Impaired by the depletion of certain necessary nutrients or amino acids that are critical to these two steps such as B vitamins and magnesium, both necessary for the production of a powerful antioxidant called glutathione that allows estrogen breakdown. As detailed further ahead in this article, there are intestinal conditions leading to constipation and/or diarrhea that interfere with liver activity, allowing for recirculation of toxins in the lymphatic system and reabsorption of estrogens into the bloodstream, through a tricky enzyme called beta-glucuronidase.

The liver also plays an essential role in bile production, which is secreted through the gallbladder, its storage organ. Along with escorting toxins out of the body, bile breaks down fats for digestion, and is therefore critical for the absorption of essential fatty acids, needed for healthy cell membranes and used to make eicosanoid hormones that control inflammatory responses. Intestinal absorption of fat soluble nutrients such as vitamins A,D,E and K is also bile-dependent. Vitamin D, which is also defined as a pro-hormone, plays a crucial role in the production and activity of steroid hormones, assists insulin in balancing blood sugar and regulates parathyroid hormone activity, among many other things; Vitamins A and E facilitate iodine absorption in the thyroid; Vitamin K2 helps reduce thyroid-blocking excess estrogens in the body. When fat digestion is impaired, as is the case in gallbladder disease, fat-soluble vitamins A, D, E and K are not properly metabolized, leaving the body deprived of their beneficial effects on hormone pathways.

The gut microbiome, our big little hormone equalizer

According to the most recent scientific calculations, the human body is composed of roughly 37 billion human cells and 48 trillion among bacteria, fungi and other microorganisms; these single-cell populations are collectively referred to as the microbiota or microbiome. Most of the microbiome we are naturally gifted with is lodged in our gut tissues, mostly in our large intestine, and it is in fact referred to as our gut flora. A healthy, well-balanced microbiome is composed of 85% beneficial bacteria and 15% pathogens, which co-exist peacefully, to the benefit of our well-being, till they don’t: any alteration in their ratio, called dysbiosis, that gives power to the bad guys, is a precipitating factor in countless health issues.

Because of the microscopic size of these organisms, the microbiome collectively weighs in at a mere 1 to 3 percent of the human body mass, yet it astonishingly influences every single function in the body, from digestion, hormonal activity, gene expression and immunity to emotional and reproductive behaviors. Shockingly, while our human genome is composed of about 22.000 protein-coding genes, our microbiome exerts a massive epigenetic influence on our gene expression by contributing 360 times more encoding genes to our DNA sequence. We are in fact learning how our metabolic phenotype (the product of genetic and epigenetic conributions) reflects myriad functions encoded in our individual human genome and gut microbial genes. Some of those genes create essential metabolites such as B vitamins, carotenoids, vitamin K, enzymes, beneficial Omega-6 fats like CLA, and vitamin D.

One crucial function of benefic intestinal microbes is their role in modulating inflammation by stimulating the release of chemicals that ignite and restrain the inflammatory processes as needed. This is particularly important to hormonal health, since gut inflammation leads to things like IBD (inflammatory bowel disease), immune disorders, metabolic dysfunctions and, vice-versa, these conditions lead to hormone upheaval. Much of the modern scientific research focuses on the role of gut bacteria on inflammation. Inflammation drives a condition called LGS, leaky gut syndrome, or abnormal intestinal permeability, a dysfunction of the intestinal endothelium. A leaky gut is no longer capable of keeping toxic by-products of digestion from translocating into the bloodstream, particularly one type of endotoxins called LPS, lipopolysaccharides, which are metabolites of dead and dying bacteria cell walls. LPS adversely impact glucose metabolism and secretion of reproductive hormones, and blunt Growth Hormone receptors. A leaky gut may lead to protein malabsorption, which typically triggers muscle breakdown in an effort to compensate, leading to hypothyroidism along with several other hormonal dysfunctions.

Of particular interest to hormonal health is a subset of our microbiome called estrobolome, capable of influencing the behavior of estrogens in the body. The estrobolome produces an enzyme called β-glucuronidase, needed for carbohydrate metabolism and for a detoxification pathway called glucuronidation, which expels disease-causing biological waste products and hormones. Beta-glucuronidase has the unique ability to prevent used up estrogens from being excreted by the liver, by reconverting them to their active form so they can be reabsorbed by the body. If levels of the good estrogens run low, this may be a protective compensatory mechanism. However, in states of estrogen dominance, in which less desirable estrogens abound, as is largely the case this day and age, excess beta-glucuronidase sabotages proper detoxification of cancer-causing estrogen metabolites. In essence, proper balance is key. Dietary recommendations to support correct glucuronidation will be covered in details in the estrogen dominance discussion.

Diversity of bacterial species and strains is key to keeping the microflora in balance. Heterogeneity can be achieved through dietary modifications, namely by favoring prebiotic and probiotic foods, as well as eliminating processed foods and all sources of sugar. A dynamic microbiome assists in hormone production and detoxification by regulating food intake, balancing blood glucose, recycling bile acids, normalizing bowel motility and boosting vitamin and mineral absorption throughout the GI tract. Different species may encode different combinations of the pathways for biosynthesis of vitamins. For example, the Bacteroidetes and Proteobacteria strains are capable of independently synthesizing non-dietary Vitamin B6, crucial to hormonal balance, and its absorption is largely microbiome-dependent. B6 aids in protein metabolism, hormone signaling and hormone conversion; it is crucial for the synthesis of dopamine and serotonin; it promotes the flow of fat and bile to and from the liver. B6 stimulates androgen hormone production and its receptors in the body, signaling the testes to produce testosterone; it also has the ability to bind to estrogen, progesterone and testosterone in the detoxification process, helping safely eliminate these steroids from the body. In dysbiotic states, as is the case with SIBO, small intestinal bacterial overgrowth, in which strains of microbes from the colon migrate and seize the small bowel, absorption of these nutrients is impaired until the condition is treated by balancing gut flora.

The microbiome has such a controlling role in the body, and it is so tenaciously active in hormonal processes, that it has the ability to outsmart us by communicating with the brain directly, through signaling molecules called neuropeptides. Since the microbiome depend on us, their host, for survival, in dysbiotic states, noxious bacteria steer us in the direction of poor health by urging the brain to engage in dietary and lifestyle behaviors conducive to their own parasitic survival, leading to obesity, metabolic disorders and emotional disturbances. Conversely, a healthy and diverse microbiome will communicate with the brain inducing it to seek beneficial nourishment and maintain a balanced emotional state. This cross-talk mechanism is what is known as the gut-brain axis. Dietary manipulation of specific microbiome strains for fat loss is the subject of recent research on the pathogenesis of obesity. Studies are homing in on two specific strains of metabolically active microbiota called Firmicutes and Bacteroidites, for their opposing roles, the former driving obesity, the latter ramping up metabolism.

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Link to the Environmental Working Group database: https://www.ewg.org/consumer-guides

Sources:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991651/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858318/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680557/

https://pubmed.ncbi.nlm.nih.gov/24844564/

https://pubmed.ncbi.nlm.nih.gov/31149284/

https://pubmed.ncbi.nlm.nih.gov/20351569/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2782772/

https://pubmed.ncbi.nlm.nih.gov/28778332/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3298082/