Calcium D-Glucarate an effective estrogen regulator? [2021 Update]

What is Calcium D-Glucarate?

 (calcium salt of D-glucaric acid) is produced naturally in small amounts by mammals, and can be found in variety of fruits and vegetables (oranges, apples, grapefruit, and cruciferous vegetables) [1]. Calcium D-glucarate is made by combining glucaric acid with calcium to make supplements that people use for medicine [2].

Calcium D-Glucarate as Estrogen Blocker

Oral supplementation of calcium D-glucarate has been shown to inhibit beta-glucuronidase via its precursor D-glucaro-1,4-lactone [3] (thus increasing glucuronidation process [8]). Elevated beta-glucuronidase activity is associated with an increased risk for various cancers (especially hormone-dependent such as breast, prostate, and colon cancer) [1,4,5]. Therefore, calcium D-glucarate is a promising natural solution for the prevention of certain types of cancer. Clinical applications of oral calcium D-glucarate also include regulation of estrogen metabolism [4,6].

Calcium D-glucarate’s inhibition of beta-glucuronidase activity allows the body to eject hormones such as estrogen before they can become reabsorbed. Supplementation of very large doses of calcium D-glucarate have been shown to decrease serum estrogen levels in rats by 23 percent. [6] However, doses used are so high (approx. 1,000mg/kg) they seem impractical for actual use.

Calcium D-Glucarate Side Effects and Risks

There is not enough information to know if calcium D-glucarate is safe or what the potential side effects might be [2]. Preliminary results of clinical trials in humans show no adverse effects [1]. There are no known drug interactions with calcium D-glucarate, but many drugs and hormones are metabolized in the liver via glucuronidation, thus, supplementing with calcium D-glucarate may increase ejection of these substances and reduce their effectiveness [1]. Testosterone is also a hormone that is glucuronidated, which means calcium D-glucarate may limit the bioavailability of testosterone [7].

Calcium-d-glucarate: Any correlation with Acne and Anxiety?

Calcium-D-glucarate is the calcium salt of D-glucaric acid and is taken as a supplement with the main purpose of enhancing the hepatic detoxifying capacity, thanks to the fact that it increases the metabolic processes of glucuronidation; consequently, it stimulates the entero-hepatic recirculation of bile salts and the excretion of toxic products and catabolites [9].

Although there is no scientific evidence of these precise side effects in the medical literature, some reasoning needs to be done to answer these two questions and the starting point is related to the properties of calcium D-glucarate in regulating cholesterol and sex hormone metabolism.

Calcium-d-glucarate and Acne

Acne is an inflammatory dermatosis involving the pilosebaceous glands that is characterized by excessive sebum production and tissue inflammation. Central roles in the pathogenesis of acne are played by some hormones (such as insulin, insulin-like growth factor-1 (IGF-1), androgens, and, to a lesser extent, estrogens and progesterone), the bacterium Propionibacterium acnes, the lipogenesis process, and a pro-inflammatory lipid profile [10] [11].

Androgens (including testosterone) increase sebum production, which leads to increased pore clogging and a more habitable micro-environment for Propionibacterium acnes; it has also been demonstrated that an imbalance between estrogen and progesterone levels can promote the development of this dermatologic condition [12]. In fact, the expression of both the androgen receptor (AR) and estrogen receptor (ER) has been demonstrated in the sebaceous gland, and for this reason, the levels of these hormones can influence the glands’ activity [13].

Calcium D-glucarate acts by decreasing androgens and estrogens and consequently the production of sebum, and by improving the lipid profile, since it decreases the total cholesterol level by lowering LDL lipoproteins, the main responsible for endothelial inflammation and a pro-inflammatory lipidic profile [9].

On the basis of these considerations, we can assume that calcium D-glucarate may exert a protective or ameliorative role towards acne, due to the overall improvement of hormonal and lipid balance.

Calcium-d-glucarate and Anxiety

Regarding the relationship between Calcium D-glucarate and anxiety levels, it is necessary to differentiate the impact of sex hormones on nervous circuits in males and females because the changes in behavior at the same hormonal concentrations are very different. Both testosterone and estrogens have a protective role against anxiety, but it is in the female that the relationship between levels of sex hormones (and therefore estrogen) and anxiety disorders, is stronger [14].

There is in fact scientific evidence that shows how estrogens can increase the number of serotonin receptors, as well as its synthesis in the brain.

It is also known that the reduction of serotonin and norepinephrine is one of the main causes of anxiety disorders and depression [15]. For this reason, in the presence of a reduction in estrogen levels, females are more susceptible to hormonal changes than males, with greater development of anxiety disorders. Estrogen deficiency results also in NLRP3 inflammasome activation, thereby leading to neuroinflammation in the hippocampus and conditions like depression and anxiety [16].

Calcium d-glucarate Conclusions

These reasonings based on scientific studies, notions of dermatology, and neurophysiology allow us to assume that the integration with calcium D-glucarate does not give or predispose to the development of acne as a side effect, while it could determine the development of anxiety in females, especially if the woman is in an estrogen deficiency phase.

In both cases, calcium D-glucarate could have a protective role by indirectly reducing inflammation, thanks also to the improved hepatic clearance. However, specific studies are needed in order to consolidate these assumptions.

(Other common names: Calcium-D Glucarate, Calcium-D-Glucarate, D-Glucarate (GA), D-glucaro-1,4-lactone (1,4 GL))

[the_ad id=”28979″]

References

1. Calcium-D-glucarate. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12197785 Retrieved 7. May 2013
2. Find a Vitamin or Supplement – “Calcium D – Glucarate” Retrieved from WebMD.com Retrieved 7. May 2013
3. Dwivedi C, Heck WJ, Downie AA, et al. “Effect of calcium glucarate on beta-glucuronidase activity and glucarate content of certain vegetables and fruits.” Biochem Med Metab Biol 1990;43:83-92.
4. Walaszek, Z., et al. “Metabolism, uptake, and excretion of a D-glucaric acid salt and its potential use in cancer prevention.” Cancer detection and prevention 21.2 (1997): 178.
5. Hanausek, Margaret, Zbigniew Walaszek, and Thomas J. Slaga. “Detoxifying cancer causing agents to prevent cancer.” Integrative Cancer Therapies 2.2 (2003): 139-144.
6. Walaszek, Zbigniew, et al. “Dietary glucarate as anti-promoter of 7, 12-dimethylbenz [a] anthracene-induced mammary tumorigenesis.” Carcinogenesis 7.9 (1986): 1463-1466.
7. Pacifici, G. M., A. Gucci, and L. Giuliani. “Testosterone sulphation and glucuronidation in the human liver: interindividual variability.” European journal of drug metabolism and pharmacokinetics 22.3 (1997): 253-258.
8. http://www.anapsid.org/cnd/hormones/glucuronidation.html Retrieved 2. May 2014
9. Calcium-D-glucarate. Altern Med Rev. 2002 Aug;7(4):336-9. PMID: 12197785.
10. Tan JKL, Stein Gold LF, Alexis AF, Harper JC. Current Concepts in Acne Pathogenesis: Pathways to Inflammation. Semin Cutan Med Surg. 2018 Jun;37(3S):S60-S62. doi: 10.12788/j.sder.2018.024. PMID: 30192343.
11. Ju Q, Tao T, Hu T, Karadağ AS, Al-Khuzaei S, Chen W. Sex hormones and acne. Clin Dermatol. 2017 Mar-Apr;35(2):130-137. doi: 10.1016/j.clindermatol.2016.10.004. Epub 2016 Oct 27. PMID: 28274349.
12. Hermanns-Le T, Hermanns JF, Lesuisse M, Pierard GE. Cyclic catamenial dermatoses. Biomed Res Int. 2013;2013:156459.
13. Azmahani A, Nakamura Y, Felizola SJ, et al.: Steroidogenic enzymes, their related transcription factors and nuclear receptors in human sebaceous glands under normal and pathological conditions. J Steroid Biochem Mol Biol. 2014; 144 Pt B: 268-279.
14.  McHenry J, Carrier N, Hull E, Kabbaj M. Sex differences in anxiety and depression: role of testosterone. Front Neuroendocrinol. 2014 Jan;35(1):42-57. doi: 10.1016/j.yfrne.2013.09.001. Epub 2013 Sep 24. PMID: 24076484; PMCID: PMC3946856.
15. Ren J, Friedmann D, Xiong J, Liu CD, Ferguson BR, Weerakkody T, DeLoach KE, Ran C, Pun A, Sun Y, Weissbourd B, Neve RL, Huguenard J, Horowitz MA, Luo L. Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems. Cell. 2018 Oct 4;175(2):472-487.e20. doi: 10.1016/j.cell.2018.07.043. Epub 2018 Aug 23. PMID: 30146164; PMCID: PMC6173627.
16. Xu Y, Sheng H, Bao Q, Wang Y, Lu J, Ni X. NLRP3 inflammasome activation mediates estrogen deficiency-induced depression- and anxiety-like behavior and hippocampal inflammation in mice. Brain Behav Immun. 2016 Aug;56:175-86. doi: 10.1016/j.bbi.2016.02.022. Epub 2016 Feb 27. PMID: 26928197.