Phytoestrogen Liquiritigenin

Biologically, estrogen is essential to humans’ health, male or female, but unlike other hormones whose levels gradually decreases with aging and affects male and female equally, estrogen deficiency affects menopausal women, women with ovariohysterectomy or total oophorectomy (WMOO) more than other segments of the general population and same contributes to their cardiovascular, neurodegenerative diseases, as well as bone and metabolic issues.

Currently, the estrogen deficiency in WMOO is principally achieved through Hormone Therapy, which notwithstanding its adverse effects, there is insufficient evidence to assess the risk of its long-term application in premenopausal or postmenopausal women younger than 50 years of age (1).

Phytoestrogens are nonsteroidal plant compounds that possess estrogenic activity and can mimic estrogen. However, phytoestrogens when taken in the form of food sources such as soybean, flaxseeds, hops, Radix Glycyrrhizae, etc, their intake has been associated with adverse reporting and that is due to hundreds of other phytochemicals in them, (2, 3, 4, 5).

Generally speaking, estrogen achieves its actions through two totally opposite mechanisms: pro-inflammatory and anti-inflammatory (6).

These actions are mainly achieved through the two (2) types of estrogen receptors: Alpha and Beta, whereas alpha is generally associated with growth and beta with anti-inflammatory/anti-growth, as seen in the beneficial actions of estrogen in bone and fat metabolism vs. breast cancer or endometrial hyperplasia/cancer.

As examples, estrogen in the right amount strengthens the immune system but in higher amounts causes hyperactivity of the immune system, resulting in autoimmune diseases such as lupus, which is pretty much exclusive to women.

Conversely, estrogen in the right amount protects bones and, to some extent, counters weight gain but in lower amounts contributes to osteoporosis and obesity.

The same applies to the cardiovascular and nervous system. Estrogen, in the right amount, plays a fundamental role in all biological systems.

Equally, phytoestrogens in the “right amount” will have tremendous heath benefits. However, too little would not do much, if anything at all, and too much could promote the same growth concerns as human estrogen.

Pytoestrogen also have their own unique identity, some phytoestrogens (naringenin) can act as full agonist of estrogen receptor alpha (7) and thus promote growth and others phytoestrogen extracts, such as soy phytoestrogens, have shown to interfere with thyroid function (8).

Liquiritigenin is a unique bioactive phytoestrogen extract isolated from the roots of plants belonging to Radix Glycyrrhizae (licorice) and it is a selective agonist for estrogen receptor Beta (PubChem) and according to US National Institutes of Health (NCATS), liquiritigenin has a 20-fold higher affinity for ER-beta than for ER-alpha.

https://drugs.ncats.io/drug/T194LKP9W6

However and sadly, practically all of the research on Liquiritigenin has been done with the synthetic type to develop medications to combat cancer, diabetes, liver diseases, etc. (As some examples: 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19).

Liquiritigenin is natural phytoestrogen and its most profound benefit is its inherent natural capacity to combat estrogen deficiency and while the estimated number of menopausal women is reaching the 1 Billion mark, suffering from menopausal syndromes, but the natural estrogenic benefit of liquiritigenin has been cast aside in favor of its synthetic form to develop pharmaceutical medication through studies of laboratory animals!

As to the ideal benefits of Liquiritigenin, an anti-inflammatory is paramount to Liquiritigenin "enhancement” of immune system.

Phytoestrogens, generally, stimulate the immune system and immune stimulation is synonymous with activation of the immune system’s inflammatory stimuli and if it is not regulated, ultimately may result in chronic inflammation and undesirable health consequences. (20, 21)

However, immune enhancement is an immune response more closely linked to clinical inflammation. 

Omega-3 is perhaps the most potent anti-inflammatory nutrient, which generally reduces the inflammation in the organism through down-regulating inflammation.

Needless to state that inflammation (clinical) is also a mechanism by which the immune system operates and when Omega-3 is added to Liquiritigenin, it does not down-regulate the immune reaction rather it enhances it.

In a Randomized Controlled Trial, a mix of Flavonoid and fish oil Supplement has shown to produce an immune enhancing effect in adult obese and overweight women (22). Liquiritigenin is a Flavanoid.

Additionally, when combining the estrogen (17β-oestradiol) with Omega-3, there was a synergistic bone-protective efficacy for bone formation. (23)

Equally important, when it comes to estrogen receptors alpha, Omeg-3 fatty acids shift signaling and that estrogen (estradiol ) synergistically enhances the inhibitory effect of Omega-3 in human breast cancer cells growth. (24)

Additionally, in relation to estrogen and its cancer potentials, IL-1 beta and/or IL-6 take the leading roles in promoting cancer cell growth (25, 26). 

Omega-3 is a potent natural ingredient that modulates the activities of these interleukins. (27)

However, when it comes to menopausal women and their potential metabolic syndromes, Omega-3 plays a double-edged sword.

Peroxisome proliferator-activated receptors (PPARs) are transcription factors regulating the expression of genes involved in cellular metabolism and inflammation

PPARs are ligands for polyunsaturated fatty acids (Omega-3). (28)

However, Peroxisome proliferator-activated receptor gamma (PPAR-gamma) plays a key role in adipocyte differentiation. 

PPAR-gamma is expressed at high levels in adipose tissue and present at low levels in pre-adipocytes (3T3-L1), which is induced dramatically by the PPAR-gamma activators. (29)

Docosahexaenoic acid (DHA-Omega-3) increases the activity of peroxisome proliferator activated receptor-gamma (PPAR) γ (30) and thus contributes to adipocytes (fat cells) proliferation and hypertrophy.

Moreover, different EPA:DHA ratios have shown different impacts on the adipose tissue metabolism and that fish oil rich in EPA, but not in DHA counters changes induced by obesity (31).

Menopausal women are susceptible to metabolic syndrome. As such, supplements intended to combat complication of menopausal metabolic syndromes should have a proper (higher) ratio of EPA Omega-3 to DHA Omega-3.

However, DHA Omega-3 has pronounced benefits for brain and nervous system and its reduction in a menopausal supplement has to be compensated by another competent nutrient.

Citicoline’s (CDP-choline) is a logical choice to support mental health and cognitive functioning through modulatory activity on neurotransmitter production and function. (32)

Choline benefits in anxiety and diseases such as Alzheimer’s and Parkinson’s is paramount (33, 34, 35).

Additionally, in the nervous system, biological estrogen's neuroprotective effects are strongly dependent on its interactions with the cholinergic system (36). Choline is the building block of cholinergic system.Choline is also equally paramount to Liquiritigenin for an adequate Cholinergic system and thus confers Liquiritigenin an enhanced neuroprotective aspects.

In the nervous system, biological estrogen's neuroprotective effects is strongly dependent on its interactions with the cholinergic system and that WMOO estrogen deficiency changes the dietary requirement for choline and applying the choline guidelines of general population to the WMOO is an error in of itself. 

The current established Adequate Intake of choline is not sufficient for WMOO to prevent organ dysfunction (37).

Liquiritigenin benefits in memory and cognitive impairment is through cholinergic system with choline being the building block of the cholinergic system (38).

The mixture of Liquiritigenin, Omega-3 and Choline is a novel compound that works synergistically and confers benefits different than its components, when they in their own state, and preferably acts to increase the estrogenic activity and the same time preferably supports bone metabolism, the cardiovascular, immune and nervous system.

References:

(1) Long-term hormone therapy for perimenopausal and postmenopausal women Cochrane Database Syst Rev. 2017 Jan 17;1(1):CD004143

(2) Soy allergy in perspective Current Opinion in Allergy and Clinical Immunology: June 2008 - Volume 8 - Issue 3 - p 270-27

(3) Anaphylaxis to flaxseed in a non-atopic adult patient Annals of Allergy, Asthma & Immunology. March 25, 2022.

(4) Verzele M. 100 years of hop chemistry and its relevance to brewing J Inst Brewing 1986;92:32-48.

(5) Effects of Licorice on the Cardiovascular System Foods. 2019 Oct; 8(10): 495.

(7) Salem, M. L. Estrogen, a double-edged sword. Current drug targets. Inflammation and allergy 3, 97–104 (2004)

(8) The nutritional flavanone naringenin triggers antiestrogenic effects by regulating estrogen receptor alpha-palmitoylation Endocrinology. 2008 May;149(5):2567-75.

(9) The Effect of Soy Phytoestrogen Supplementation on Thyroid Status The Journal of Clinical Endocrinology & Metabolism, Volume 96, Issue 5, 1 May 2011, Pages 1442–1449

(10) Liquiritigenin inhibits hepatic fibrogenesis. Phytomedicine. 2019 Sep;62:152780

(11) Liquiritigenin decreases tumorigenesis. Exp Biol Med (Maywood). 2021 Feb;246(4):459-466. doi: 10.1177/1535370220957255.

(12) Liquiritigenin attenuates isoprenaline induced myocardial fibrosis in mice. Mol Med Rep. 2021 Oct;24(4):686. doi: 10.3892/mmr.2021.12326. Epub 2021 Jul 30.

(13) Liquiritigenin Decreases Aβ Levels and Ameliorates Cognitive Decline. Neurotox Res. 2021 Apr;39(2):349-358.

(14) Phytochemical and Pharmacological Role of Liquiritigenin and Isoliquiritigenin. Front Aging Neurosci. 2018 Nov 1;10:348.

(15) Liquiritigenin Inhibits Colorectal Cancer Proliferation, Invasion, and Epithelial-to-Mesenchymal Transition. Oncol Res. 2019 Feb 5;27(2):139-146. 2018 Feb 22.

(16) Liquiritigenin Reduces Blood Glucose Level and Bone Adverse Effects in Hyperglycemic Adult Zebrafish. Nutrients. 2019 May 9;11(5):1042.

(17) Liquiritigenin prevents palmitate-induced beta-cell apoptosis. Biomed Pharmacother. 2018 May;101:348-354.

(18) Antihyperuricemic effect of liquiritigenin in potassium oxonate-induced hyperuricemic rats. Biomed Pharmacother. 2016 Dec;84:1930-1936. doi

(19) Liquiritigenin reduces osteoclast activity in zebrafish model of glucocorticoid-induced osteoporosis. J Pharmacol Sci. 2020 Aug;143(4):300-306.

(20)Proc Natl Acad Sci U S A. 2002 May 28;99(11):7616-21. The phytoestrogen genistein induces thymic and immune changes: a human health concern?

(21) The Journal of Nutrition, Volume 136, Issue 3, March 2006, Pages 704–708 Genistein, Estrogen Receptors, and the Acquired Immune Response

(22) A Mixed Flavonoid-Fish Oil Supplement Induces Immune-Enhancing and Anti-Inflammatory Transcriptomic Changes - A Randomized Controlled Trial Nutrients. 2016 May; 8(5): 277.

(23) Synergistic attenuation of ovariectomy-induced bone loss by combined use of fish oil and 17β-oestradiol 12Br J Nutr. 2017 Feb;117(4):479-489.

(24) N-3 poly-unsaturated fatty acids shift estrogen signaling to inhibit human breast cancer cell growth. PLoS One. 2012;7(12):e52838

(25) Interleukin-1β and Cancer. Cancers (Basel). 2020 Jul; 12(7): 1791.

(26) Review Tumour Biol. Role of interleukin-6 in cancer progression and therapeutic resistance. 2016 Sep;37(9):11553-11572.

(27) Modulation of Inflammatory Cytokines by Omega-3 Fatty Acids. Lipids in Health and Disease pp 133–143

(28) PPAR-α as a Key Nutritional and Environmental Sensor for Metabolic Adaptation. Adv Nutr. 2013 Jul; 4(4): 439–452

(29) Peroxisome proliferator-activated receptor (PPAR) gamma and adipocyte differentiation. Endocrinology. 1994 Aug;135(2):798-800.

(30) Effect of DHA-rich fish oil on PPARγ target genes. J Clin Lipidol. Nov-Dec 2015;9(6):770-777

(31)- Fish Oil Enriched in EPA, but Not in DHA, Reverses the Metabolic Syndrome and Adipocyte Dysfunction. Nutrients. 2021 Mar; 13(3): 754.

(32) SienceDirect. Textbook of Natural Medicine (Fifth Edition), 2020

(33) Choline as a prevention for Alzheimer’s disease

Aging (Albany NY). 2020 Feb 15; 12(3): 2026–2027.

(34) New strategies in the management of Parkinson's disease

Neuropsychobiology. 1982;8(6):289-96.

(35) Choline in anxiety and depression: the Hordaland Health Study The American Journal of Clinical Nutrition, Volume 90, Issue 4, October 2009, Pages 1056–1060

(36) Perspective: Estrogen and the Risk of Cognitive Decline: A Missing Choline(rgic) Link? Advances in Nutrition, Volume 13, Issue 2, March 2022, Pages 376–387

(37) Sex and menopausal status influence human dietary requirements for the nutrient choline The American Journal of Clinical Nutrition, Volume 85, Issue 5, May 2007, Pages 1275–1285

(38) Liquiritigenin ameliorates memory and cognitive impairment through cholinergic Arch Pharm Res. 2017 Oct;40(10):1209-1217.

Copyright. All Rights Reserved.

Hamid R. Momayez Zadeh 

News Release via PRWEB, April 13, 2022