By Georgia Marrion (MNut, BHSci, Adv. Dip Health Sci (Nat).
In women, oestrogen (oestrone [E1], oestradiol [E2] and oestriol [E3]) are necessary sex steroid hormones for a range of reproductive and non-reproductive physiological functions and processes.1,2 Endogenously-derived oestrogen, particularly E1 and E2, are the primary female sex steroid hormones, however this differs between pre- and post-menopausal women. When the body is in balance, E2 is the primary circulating form of oestrogen in premenopausal women, predominantly produced by the ovaries following the conversion of androstenedione by aromatase (CYP19A1) to E1 and its subsequent conversion to E2, with a small amount produced by hepatic, adrenal and breast tissues.1,3,4
In postmenopausal women, E1 also derived from androstenedione, is the primary form, produced mainly in adipose tissue and the adrenal glands, and to a lesser degree, breasts, muscles and bones.3-5 Oestrogen can also be derived from exogenous sources including synthetic hormones (oral contraceptive pill, hormone replacement therapy), industrial chemicals (bisphenol A), phthalates and cadmium.6-9 See Table 1 below:With women continually exposed to both endogenous and exogenous sources of oestrogen, maintaining healthy levels is essential in view of oestrogen’s normal functional effects on body tissues (See Table 2) and the consequent potential for these physiological effects to cause adverse pathologies when present in excessive proportions.15
Within this context, a key clinical consideration regarding oestrogen concentrations and the potential pathological consequences is assessing the functional status of oestrogen’s activation and detoxification pathways and addressing imbalances.15
In the hepatic phase I pathway, oestrogens are irreversibly metabolised (to increase their polarity and water solubility) via hydroxylation reactions by cytochrome P450 enzymes (CYP3A4, CYP2D6, CYP 1B1, 1A and 3A) at the 2-, 4- and 16-positions to form the catechol oestrogens 2‐hydroxyestrone (2‐OH-E1), 4‐hydroxyestrone (4‐OH-E1) and 16-alphahydroxyestrone (16-OH-1), respectively.1,16-19
Subsequently, these metabolites can be metabolised via hepatic phase II conjugation reactions to facilitate their excretion into the urine and bile, predominantly through irreversible glucuronidation (catalysed by UDP- glucuronosyltransferases (UGT) at varying levels in different body tissues; and to a lesser extent via the sulfation pathway (involving sulfotransferases (SULT), before being deposited into bile or urine.1,5,16, 20-23 While these two pathways produce the largest proportion of oestrogen metabolites (EMs), these metabolites can also be conjugated with intracellular glutathione (glutathionation).15,22
Another vital phase II oestrogen detoxification pathway is methylation by catechol-O-methyltransferase enzymes (COMT), 1,5,20, 21 a major methyl group donor and significant pathway for catechol oestrogen conjugation through conversion of 2- and 4-catechols. This is an alternative (and preferred) route which prevents the synthesis of genotoxic and cytotoxic 2OH and 4OH quinone derivatives and their subsequent mutagenic effects on body tissues.15, 20, 21, 23, 24
Healthy oestrogen detoxification also requires effective phase III activity, which involves efflux transporters transferring oestrogen metabolites from phases I and II into urine and bile for elimination.18 Deconjugation of some bile-derived oestrogen metabolites occurs in the large bowel and they are subsequently reabsorbed through enterohepatic recirculation.1,5,20,21
Along with identification of dietary, environmental, lifestyle and genetic factors associated with excessive oestrogen exposure and disruption of these oestrogen activation and detoxification, supporting healthy liver functionality is a key therapeutic factor to promote healthy oestrogen detoxification and modulate the adverse physiological impact of excess oestrogen concentrations on body tissues.
The significant health consequences associated with impaired oestrogen detoxification and relative oestrogen excess in the body emphasises the importance of identifying aetiological factors and supporting relevant endogenous pathways to promote healthy oestrogen balance.*References available on request