Estrogen Metabolism And Women’s Health: Implications For Disease And Therapeutic Interventions

Human estrogens, estriol, estradiol and estrone, play im- portant roles in women´s health – not only regulating reproduc- tive functions but also regulating metabolic, brain and cardiovas- cular functions (1). During reproductive years, the main source of estrogens in women are the ovaries, but adipose tissue and even digestive organs as parietal cells of stomach and intestinal microbiome, through B-glucoronidase expression, contribute with a substation amount of estrogen that is not frequently con- sidered when hormonal evaluation in a woman is performed (2). There are also important functions for steroidal hormones pro- duced and metabolized locally, for example in the brain, called “neurosteroids” which plays important role for hormones func- tion in the CNS (3)

Liver is the main organ responsible for hormones metabolism in humans, mainly by phase 1 and 2 of hepatic detoxification. Phase 1 aim to transform hormones from its lipidic structure to a more hydrophilic version through CYP P450 family enzymes ac- tion when an hidroxil radical is added to the molecule; phase 2 is responsible for the conjugation of phase 1 bioproducts mainly to amino acids preparing hormonal metabolites for biliary secretion and excretion by intestines and urine. Phase 1 and 2 enzymes be- yond possible genetic polimorphisms is mostly regulated by the bioavailable nutrional factors: complex B vitamins, folic acid, glutathion, flavonoids, methionine, cystein, magnesium, vita- mine C, glycine, taurine, glutamine and choline but are also under regulation of epigenetic factors like inflammation, obesity, diet and insulin resistance. Phase 3 of detoxification system is the fi- nal and maybe the most important phase, where all these compo- nents of phases 1 and 2 are supposed to be excreted in the intes- tinal level. Estrogen metabolites produced by hepatic metabolism are recognized today as an important part of hormonal regulating system and some of them can even have more estrogen receptor affinity than original estradiol. Some endocrine disruptors as bi- sphenol A can act modifying estrogen metabolism and increasing 4OH-E1 metabolite (4)

Human intestinal microbiome is getting great scientifically interest in recent years. GI tract hosts billions of microbes that are recognized as key regulators of multiple metabolic and im- mune functions but just recently it became clear that they also play important endocrine role regulating entero-hepatic hormone recirculation therefore modifying total estrogen load, which can be a key mechanism for estrogen-related diseases, such as endo- metriosis, menopause, cyclic mastalgia, DTMP, lipedema, breast and endometrial cancer. Specially interest on expression and function of B-glucoronidase, an enzyme expressed by some bac- teria opportunistically present in some dysbiosis of the gut (5). When overly expressed this enzyme de-conjugate estrogen me- tabolites that by entero-hepatic circulation return to portal system therefore not been excreted, increasing estrogen load.

Estrogen metabolism and changes in the intestinal microbi- ome that directly or indirectly influence the endocrine system make it clear that we need to go beyond the endocrine glands and their hormonal production in order to have a broader and more comprehensive view of the influence of the external environment – our habits, lifestyle, availability of nutrients, intestinal health and the global toxic load we are exposed are of great importance so that we can actually establish diagnoses and treatments in a more precise and personalized way.

Keywords: estrogen metabolites, b-glucoronidase, hepatic detoxification, women health
Figure 1: Schematic Hepatic Detoxification Steps (above)
Figure 2: Deconjugated Estrogens and Estrobolome (JNCI J Natl Cancer Inst, 2016, Vol. 108, No. 8)

with more than 5000 active members. Creator and co-founder of the biggest Medical Education Ecosystem in Women’s Health in Menopause, RHEM, an annual event that in its last edition had more than 1200 registrants. In February 2024, Dr Bicca passed the DHA Endocrinology Board Test.

References:
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(2) E R Simpson et al. Sources of Estrogen and their importance. J Steroid Biochem Mol Biol 2003, Sep.
(3) Loredana Raciti et al. Gender and Neurosteroids: Implications for Brains Function, neuroplasticity and rehabilitation. Int J Mol Sci 2023, March; 24 (5): 4758
(4) Eun Jee Kim et al. Association between urinary levels of bi- sphenol-A and estrogen metabolites in Korean adults. Science of the Total Environment 470-471 (2014)1401-1407
(5) Angel-HsinYu Pai et al. Gut Microbiome-Estrobolome pro- file in Reproductive-age women with Endometriosis. Int J Mol 2023 Nov; 23(22): 16301