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Calcium D-Glucarate, Your Microbiome, and You: A Closer Look at Hormone Regulation

Calcium D-Glucarate, Your Microbiome, and You: A Closer Look at Hormone Regulation

Calcium D-glucarate is a popular supplement with some buzz these days, used for cancer prevention, liver detoxification, and hormone regulation, but few know why exactly it’s recommended. This article will discuss why it’s used and discuss whether it’s a band-aid or a root cause approach to chronic disease.

First, let’s take a closer look at the compound itself.

Calcium D-glucarate is a calcium salt of D-glucaric acid, a non-toxic compound found in many fruits and vegetables, especially grapefruits, apples, oranges and even cruciferous vegetables, such as broccolini and Collard greens, but in trace amounts. (1)

Calcium D-Glurate and Liver Detoxification

The liver works 24/7 to help carry waste products out of your body.  

The liver has three phases of detoxification, and the middle or second phase, or Phase II, uses a process called glucuronidation, which involves processing end-metabolite hormones such as estrogen so that as end-metabolites they can safely move out of the body. (2, 3)

All steroid hormones, for example, are detoxified in the liver via glucuronidation.

Oral supplementation of Calcium D-glucarate has been shown to inhibit beta-glucuronidase, an enzyme produced by colonic microbiota heavily involved in liver detoxification. (4) This inhibitory enzyme can be produced in excessive amounts when our microbiome is compromised by a pathogenic bacterial foothold.

Beta-Glucuronidase Run Amuck

When our gut microbiota are thrown off, a state otherwise called dysbiosis, a host of byproducts are generated which can lead to dysbiosis-associated changes. (5) Some common agents which can wreak havoc on our microbiome include antibiotics, such as clindamycin, and NSAIDS, such as ibuprofen. (6, 7) And one of these dysbiosis-associated changes include the overproduction of the enzyme beta-glucuronidase. (8)

But the danger here is that if there is excessive beta-glucuronidase in the body due to pathogenic bacteria having taken ahold in the gut, then these end-metabolites of estrogen can be cleaved at the junction of (soon-to-be-excreted) toxin and glucuronic acid, and the toxin can then stay in the body and lead to the formation of carcinogens in the bowel, increasing the risk of cancer.

This whole process can lead to the promotion of enterohepatic recirculation wherein a toxic soup of toxins, hormones and even drugs circulates freely throughout the body. (9

A deeper discussion of enterohepatic recirculation can be saved for a future article, but it has been shown to lead, for example, to higher estrogen levels, which in turn increases the risk for breast cancer. 

In other words, elevated beta-glucuronidase activity is associated with hormone-dependent cancers. 

Calcium D-Glucarate to the Rescue

 

Supposedly, enter the supplement, calcium D-glucarate, to the rescue. Studies indicate that calcium D-Glucarate will actually prevent the excess beta-glucuronidase from cleaving the end-products of estrogen, allowing them to remain glucuronidated and to be excreted properly. 

Beta-glucuronidase actively conjugates estrogens into their active forms, a process which is impaired by dysbiosis and results in less circulating estrogen, which may contribute to conditions such as obesity, metabolic syndrome, PCOS, 

cardiovascular disease, and cancer. (10)

Calcium D-glucarate is thought to confer protective properties against breast cancer via estrogen clearance. 

In mice models, D-glucarates themselves appear to suppress cell proliferation and inflammation, and can also induce cell apoptosis, that is, they can potentially support proper cell death so as to keep malignancy in check. (11)

Other compounds thought to inhibit breast cancer include diindolylmethane (DIM) and isothiocyanates (sulphoraphane) found in cruciferous vegetables. (12) Hence, make sure to eat adequate amounts of these sulfur-rich foods.

In other words, it is thought that oral supplementation of calcium D-glucarate is a way of favoring the body’s natural defense mechanism by upregulating the clearance of carcinogens.

Is Excessive Beta-Glucuronidase A Calcium D-Glucarate Deficiency? 

Is the above a leading question? Somewhat. Is it a rhetorical question: Well, kind of. But the short answer is no. 

And taking calcium D-glucarate, though it may be highly indicated, especially as part of a naturopathic or functional treatment plan, is more a band-aid treatment than a root cause approach. 

In other words, the right question to be asking is, “What exactly is mediating or causing the excessive beta-glucuronidase producing dysbiosis?

In other words, the root cause isn’t even the dysbiosis. The dysbiosis is a symptom of an imbalance that likely has a multifactorial etiology that requires the assistance of a naturopathic physician or other integrative medicine practitioner.

Basically, it can be said that the imbalance is occurring in the gut and that by correcting whatever is causing the dysbiosis, that will lead to an improvement in symptomatology and potentially a resolution.

Hence, taking calcium D-glucarate is a potential first step, that should be part of a root cause oriented approach, to mitigate the effects of high estrogen but it is only a band-aid.

However, it’s best to start with restoring your gut microbiome by way of eliminating the instigators and mediators of dysbiosis, such as multiple rounds of antibiotics or a daily non-steroidal anti-inflammmatory (NSAID) such as ibuprofen, regularly eating your food intolerances, eating a Standard American Diet (S.A.D.), being in constant fight-or-flight, or any other number potential culprits known to compromise gut function.

In other words, because the microbiome is one of the main regulators of estrogen circulation, by taking care of our microbiome, our hormones are more likely to remain in balance.

However, remember to consult your naturopathic doctor, or your integrative medicine practitioner, before considering introducing calcium D-glucarate into your supplement regimen.

Resources

  1. Hanausek M, Walaszek Z, Slaga TJ. Detoxifying cancer causing agents to prevent cancer. Integr Cancer Ther. 2003 Jun;2(2):139-44. doi: 10.1177/1534735403002002005. PMID: 15035900.
  2. Dwivedi C, Heck WJ, Downie AA, Larroya S, Webb TE. Effect of calcium glucarate on beta-glucuronidase activity and glucarate content of certain vegetables and fruits. Biochem Med Metab Biol. 1990 Apr;43(2):83-92. doi: 10.1016/0885-4505(90)90012-p. PMID: 2346674.
  3. Calcium-D-glucarate. Altern Med Rev. 2002 Aug;7(4):336-9. PMID: 12197785.
  4. Gillis CC, Hughes ER, Spiga L, Winter MG, Zhu W, Furtado de Carvalho T, Chanin RB, Behrendt CL, Hooper LV, Santos RL, Winter SE. Dysbiosis-Associated Change in Host Metabolism Generates Lactate to Support Salmonella Growth. Cell Host Microbe. 2018 Jan 10;23(1):54-64.e6. doi: 10.1016/j.chom.2017.11.006. Epub 2017 Dec 21. Erratum in: Cell Host Microbe. 2018 Apr 11;23 (4):570. PMID: 29276172; PMCID: PMC5764812.
  5. Langdon A, Crook N, Dantas G. The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation. Genome Med. 2016 Apr 13;8(1):39. doi: 10.1186/s13073-016-0294-z. PMID: 27074706; PMCID: PMC4831151.
  6. Rogers MAM, Aronoff DM. The influence of non-steroidal anti-inflammatory drugs on the gut microbiome. Clin Microbiol Infect. 2016 Feb;22(2):178.e1-178.e9. doi: 10.1016/j.cmi.2015.10.003. Epub 2015 Oct 16. PMID: 26482265; PMCID: PMC4754147.
  7. Baker JM, Al-Nakkash L, Herbst-Kralovetz MM. Estrogen-gut microbiome axis: Physiological and clinical implications. Maturitas. 2017 Sep;103:45-53. doi: 10.1016/j.maturitas.2017.06.025. Epub 2017 Jun 23. PMID: 28778332.
  8. Court MH. Interindividual variability in hepatic drug glucuronidation: studies into the role of age, sex, enzyme inducers, and genetic polymorphism using the human liver bank as a model system. Drug Metab Rev. 2010 Feb;42(1):209-24. doi: 10.3109/03602530903209288. PMID: 19821798; PMCID: PMC6174030.
  9. Roberts MS, Magnusson BM, Burczynski FJ, Weiss M. Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin Pharmacokinet. 2002;41(10):751-90. doi: 10.2165/00003088-200241100-00005. PMID: 12162761.
  10. Zółtaszek R, Hanausek M, Kiliańska ZM, Walaszek Z. Biologiczna rola kwasu D-glukarowego i jego pochodnych; potencjalne zastosowanie w medycynie [The biological role of D-glucaric acid and its derivatives: potential use in medicine]. Postepy Hig Med Dosw (Online). 2008 Sep 5;62:451-62. Polish. PMID: 18772850.
  11. Zoltaszek R, Kowalczyk P, Kowalczyk MC, et al. Dietary D-glucarate effects on the biomarkers of inflammation during early post-initiation stages of benzo[a]pyrene-induced lung tumorigenesis in A/J mice. Oncol Lett. 2011;2(1):145-154. doi:10.3892/ol.2010.221
  12. Thomson CA, Ho E, Strom MB. Chemopreventive properties of 3,3′-diindolylmethane in breast cancer: evidence from experimental and human studies. Nutr Rev. 2016;74(7):432-443. doi:10.1093/nutrit/nuw010
How Cortisol Inhibits Active Thyroid Hormone and Suppresses Your Immune System

How Cortisol Inhibits Active Thyroid Hormone and Suppresses Your Immune System

Studies show that cortisol, your body’s stress hormone, increases thyroid-stimulating hormone (TSH), (1,2) as well as inhibits the conversion of T4 to T3, which is your body’s metabolically active thyroid hormone (3,4). This process mostly occurs peripherally in the liver, GI tract, skeletal muscle, but also occurs in the thyroid and even the brain itself. However, we need more studies verifying exactly how elevated cortisol levels mechanistically inhibits T4-to-T3 conversion.

Thyroid hormone acts to regulate metabolism by increasing basal metabolic rate, temperature, and heart rate/cardiac output. This, in part, explains why chronic stress can easily lead to hypothyroidism, because cortisol is literally turning off your metabolism. (5)

But why would cortisol inhibit T3 from being formed? Because T3 requires a lot of energy or ATP, to get stuff done in the body, and when the body is stressed, it needs to conserve energy so that it can act out of fight or flight.

Cortisol Is Increased by Stress and Hypoglycemia

There are two main stimuli (6) that lead to the release of cortisol from the zona fasciculata of your adrenal glands:

  1. Stress
  2. Hypoglycemia

What this basically means is that when your blood sugars are low, a stress response is mimicked in your body.

Relaxation (A Destressed State) and Hyperglycemia Inhibit Cortisol

So what inhibits cortisol? You guessed it:

  1. Not being stressed
  2. Hyperglycemia (having blood sugar that is too high)

Stress Can Be Physical or Psychological

Stress is a complex phenomenon which can be physical or psychological. Some examples of stressful events which are physical in nature include trauma, infection, or exercise. We already mentioned hypoglycemia. Psychological examples of stress include fear, bereavement, or anger.

Cortisol is Permissive

Did you know that cortisol is the only hormone in the body that has receptors on almost every cell. It must be pretty important then. And that’s why it goes everywhere, having no particular affinity for anything. There’s a word for this in science: Permissive. (7) When you’re superstressed, all of these cortisol receptors get upregulated, increasing cellular sensitivity. And there is no cellular second messenger, in case you were wondering. The message of cortisol is loud and direct.

The Role of Cortisol

But what does cortisol do in the body? Well, two things, mainly, physiologically:

  1. Proteolysis and Gluconeogenesis: Cortisol breaks down proteins, a process called proteolysis, so that the amino acids can be used to make glucose (gluconeogenesis). Remember, the body is in a state of hypoglycemia.
  2. Stress Lowers Your Immune System: Cortisol wields profound anti-inflammatory effect across the body. Cortisol destroys white blood cells, such as T-cells and eosinophils. Cortisol inhibits the migration of pathogen-engulfing, debris-cleaning macrophages. Cortisol stabilizes mast cells, who can be quite annoying when they unload histamine, as in Type 1 hypersensitivity reactions, such as seasonal allergies.

Cortisol also inhibits an enzyme called phospholipase, which is responsible for making prostaglandins by cleaving the phospholipid bilayer in the cell’s membranes and releasing arachidonic acid, which signals the body to make a host of important inflammatory molecules required by the immune system to do its job. (8) Remind you of the effects of steroids, by chance? Well, that’s because cortisol is an endogenous steroid.

Immunosuppression

Too much cortisol can lead to immunosuppression. (9) And when your immune system is down, that’s when you get sick. Ever get done with school finals for the term, only to be sick during your week off? Well, this is why.

When you experience a stressful event, such as an important exam, a romantic breakup, or a fender-bender, a cascade of hormones (10) are released in the engine of your body over approximately twenty-four hours.

The Cascade of Stress Hormones

  1. Epinephrine: First and immediately after the stressful event, epinephrine, aka adrenaline, is released. Epinephrine increases heart rate, raises blood sugar, and boost sugar metabolism.
  2. Glucagon: After about 20 minutes, glucagon is released from the alpha cells of the pancreas, causing blood sugar to be raised, as well as glycogen to be broken down (glycogenolysis), fats to be broken down (lipolysis), and ketones to be made (ketogenesis). Glucagon acts on the adrenal cortex, as well as the liver and adipose tissue.
  3. Cortisol: Within about 2 to 4 hours, cortisol is released.
  4. Growth Hormone: Then, after about 24 hours, growth hormone (GH) is released. This is one reason that high intensity interval trainings (HIIT), such as CrossFit, is effective for muscle growth, which doesn’t occur until one gets good sleep and after a couple days, because workouts are fast-paced and stressful. GH raises glucose levels and breaks down fat, releasing free fatty acids, produced by the anterior pituitary when we sleep. This is why a good night’s sleep is critical to get the benefits of HIIT.
  5. Insulin: Here’s one thing that’s a bit counterintuitive. Almost every metabolic process in the body is biphasic, balanced and counterbalanced by opposing regulatory feedback mechanisms. The hormones mentioned above will produce glucose in the body, which will increase the osmolarity of the blood. But after about 30 minutes, the body will release insulin, in order to push the excess glucose into the cells so that it can be used.
  6. Antidiuretic Hormone (ADH): After about 30 minutes, the body will also produce antidiuretic hormone (ADH), in order to normalize the blood osmolarity by retaining fluid volume rather than diuresing (a fancy word for urinating).
  7. Aldosterone: Cortisol works alongside the hormone aldosterone, as well, to increase sodium reabsorption in the kidneys, so that electrolyte and hydration status are appropriately maintained. As at least half of our blood is water, proper blood perfusion can occur in the body during fight or flight.

Conclusion

Cortisol, your body’s stress hormone, inhibits the conversion of T4 to T3, that is, your body’s metabolically active thyroid hormone.

If high cortisol levels are chronic, this can lead to hypothyroidism. Cortisol is the body’s endogenous corticosteroid, suppressing the immune system. Chronic stress can lead to frequently getting sick.

 

Resources:

  1. Walter KN, Corwin EJ, Ulbrecht J, et al. Elevated thyroid stimulating hormone is associated with elevated cortisol in healthy young men and womenThyroid Research. 2012;5(1):13. doi:10.1186/1756-6614-5-13.
  2. Hage MP, Azar ST. The Link between Thyroid Function and DepressionJournal of Thyroid Research. 2012;2012:1-8. doi:10.1155/2012/590648.
  3. Szivak TK, Lee EC, Saenz C, et al. Adrenal Stress and Physical Performance During Military Survival TrainingAerospace Medicine and Human Performance. 2018;89(2):99-107. doi:10.3357/amhp.4831.2018.
  4. Kahana L, Keidar S, Sheinfeld M, Palant A. Endogenous Cortisol And Thyroid Hormone Levels In Patients With Acute Myocardial InfarctionClinical Endocrinology. 1983;19(1):131-139. doi:10.1111/j.1365-2265.1983.tb00751.x.
  5. Ranabir S, Reetu K. Stress and hormonesIndian Journal of Endocrinology and Metabolism. 2011;15(1):18. doi:10.4103/2230-8210.77573.
  6. Gandhi K. Approach to hypoglycemia in infants and childrenTranslational Pediatrics. 2017;6(4):408-420. doi:10.21037/tp.2017.10.05.
  7. Mavroudis PD, Corbett SA, Calvano SE, Androulakis IP. Circadian characteristics of permissive and suppressive effects of cortisol and their role in homeostasis and the acute inflammatory responseMathematical Biosciences. 2015;260:54-64. doi:10.1016/j.mbs.2014.10.006.
  8. Goppelt-Struebe M, Wolter D, Resch K. Glucocorticoids inhibit prostaglandin synthesis not only at the level of phospholipase A2 but also at the level of cyclo-oxygenase/PGE isomerase. British Journal of Pharmacology. 1989;98(4):1287-1295. doi:10.1111/j.1476-5381.1989.tb12676.x.
  9. Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insightsMolecular and Cellular Endocrinology. 2011;335(1):2-13. doi:10.1016/j.mce.2010.04.005.
  10. Tsigos C, Kyrou I, Kassi E, et al. Stress, Endocrine Physiology and Pathophysiology. [Updated 2016 Mar 10]. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK278995/