Endogenous oestrogens – a ‘family’ of oestrogens

Oestrogens are a cohort of sex steroid hormones derived from cholesterol. Among the endogenous physiological oestrogens, three primary forms exist: oestrone (E1), oestradiol (E2) and oestriol (E3). E2 holds prominence as the primary oestrogenic compound circulating during a woman’s reproductive years, and it remains dominant until menopause. Following menopause, E1 gains significance as a key oestrogenic compound, while E3 assumes a major role during pregnancy, even though it’s considered the least potent oestrogen^{(Reference Cui, Shen and Li16)}.

The synthesis of oestrogens in ovarian granulosa cells hinges on the activation of an enzyme named aromatase (CYP19A1), which belongs to the cytochrome P450 superfamily. This enzyme facilitates the aromatisation process, wherein androgens, particularly testosterone and androstenedione, are transformed into oestradiol and oestrone. Notably, studies on animals lacking this enzyme have revealed an inability to produce oestrogens^{(Reference Jones, Thorburn and Britt17,Reference Dalla, Antoniou and Papadopoulou-Daifoti18)} . In women during their reproductive years, the ovaries, corpus luteum and placenta serve as primary sites for oestrogen production. Additionally, smaller amounts of oestrogens are synthesised by non-gonadal organs such as the liver, heart, skin, brain, adipose tissues, intestines and adrenal glands^{(Reference Barakat, Oakley and Kim19)}. In prepubescent females and males, oestrogens are produced in non-gonadal locations, where their functional effects are typically exerted locally through paracrine and/or intracrine mechanisms^{(Reference Cui, Shen and Li16)}.

Following the onset of menopause, adipose tissue stromal cells and preadipocytes exhibit high expression levels of aromatase, 17b-hydroxysteroid dehydrogenases (17bHSD) and CYP1B1. Among these, 17bHSD plays a role in converting weak androgens and/or oestrogens into their more potent counterparts to include the conversion of androstenedione into testosterone and oestrone into oestradiol^{(Reference Hilborn, Stål and Jansson20)}. Due to the substantial mass of adipose tissue, its contribution to whole-body steroid metabolism is notably significant.

E2 levels in humans and rodents

In pre-menopausal individuals, the levels of E2, or oestradiol, exhibit a range of 15–400 pg/ml, a variance largely contingent on the phase of the menstrual cycle. Conversely, E2 levels plummet to less than 10 pg/ml during menopause. Rodents have been used to study and learn more about the physiological functions of oestrogens. Rodents undergo a reproductive cycle, termed the oestrous cycle, divided into four distinct phases—proestrus, oestrus, metestrus and diestrus—spanning about 4–5 d. Throughout this cycle, the concentration of circulating E2 within rodents displays significant fluctuations. Among these phases, proestrus showcases the highest E2 concentration, roughly ranging between 30–60 pg/ml. Even during diestrus and metestrus, E2 remains detectable with the use of sensitive instrumentation, albeit at levels not surpassing 5 pg/ml. Remarkably, during the oestrus stage, E2 has been found to be undetectable^{(Reference Frick21–Reference Wall, Desai and Khant Aung24)}.

Oestrogens modulate homeostasis through binding and activation of oestrogen receptors

Oestrogens exert their effects through the mediation of oestrogen receptors (ERs), which comprise nuclear receptors, surface membrane receptors, and are found in various forms such as ERα (ESR1), ERβ (ESR2), G protein-coupled receptors (GRP30 and Gq-mER) and ER-X. Nuclear ERs function as transcription factors, overseeing the modulation of specific gene transcription. On the other hand, surface membrane ERs, once activated by oestrogens, instigate rapid intracellular signalling pathways^{(Reference Cui, Shen and Li16)}. Beyond their interaction with ERs, oestrogens can also regulate enzymatic activities and engage with non-steroid-hormone-nuclear receptors, consequently initiating signalling pathways that are independent of ERs^{(Reference Cui, Shen and Li16)}.

Effects of endogenous oestrogens on obesity, diabetes and the metabolic syndrome

Many women exhibit features of the metabolic syndrome (abdominal adiposity, insulin resistance and dyslipidemia) with the onset of oestrogen deficiency at menopause. There are direct effects of oestrogen deficiency on body fat distribution, insulin action, effect on arterial wall and fibrinolysis that may contribute to an increased prevalence of the metabolic syndrome in post-menopausal women compared to pre-menopausal women^{(Reference Park, Zhu, Palaniappan and Heshka25)}. Fabre et al., postulated that membrane-initiated ERα extra-nuclear signalling contributes to female, but not to male, protection against high-fat-diet-induced obesity and associated metabolic disorders in mouse^{(Reference Fabre, Tramunt and Montagner26)}.

Exogenous oestrogens obtained through the diet

Oestrogens can also be introduced into the body from external sources, either through the consumption of certain foods or exposure to various environmental factors. These exogenous oestrogen exposures are capable of exhibiting oestrogen-like activities, which involve binding to ERs and other nuclear hormone receptors. There are two distinct categories of exogenous oestrogens: xenoestrogens, which are synthetic oestrogens, and phytoestrogens, which are phytochemicals derived naturally from plants. Phytoestrogens possess the potential to exert both beneficial effects and function as endocrine disruptors^{(Reference Wang, Ha and Yoshitake27)}. The roles and effects of phytoestrogens will be explored in greater detail further below. Xenoestrogens also bind to and activate ERs and currently data suggests these exert endocrine disruption and may have long-term negative effects as will also be discussed below.

Phytoestrogens have the ability to bind to and activate oestrogen receptors

Phytoestrogens exhibit the ability to bind to and activate ERs. Interestingly, data suggest phytoestrogens demonstrate a preference for oestrogen receptor beta activation (ERβ), as evidenced by the ratios of binding affinity of these compounds relative to binding to ERα v. ERβ: Genistein β/α = 20, Daidzein β/α = 7, S-Equol β/α = 32, Coumestrol β/α = 7, Naringenin β/α = 11, Apigenin β/α = 20^{(Reference Minutolo, Macchia and Katzenellenbogen31,Reference Paterni, Granchi and Katzenellenbogen32)} . Moreover, phytoestrogens are known to also bind to serotonergic receptors and insulin-like growth factor receptors exerting biological effects which are impacted by the duration and age for which exposure has occurred. Phytoestrogens possess the capability to enhance the binding of free radicals and can directly or indirectly influence the activation of tyrosine kinases, cyclic adenosine monophosphate pathways, phosphatidylinositol-3 kinase (PI3K), DNA methylation, as well as histone and RNA expression^{(Reference Domínguez-López, Yago-Aragón and Salas-Huetos28)}.

Detrimental or beneficial phytoestrogen function(s)?

The discussion surrounding whether phytoestrogens yield positive or negative effects is ongoing. Crucially, it is important to recognise that the timing, type, duration and level of exposure plays pivotal roles in determining whether these oestrogenic compounds offer advantages or pose risks. Moreover, the context matters significantly as to whether phytoestrogens are therapeutic for conditions like alleviating menopausal symptoms, reducing osteoporosis, or potentially exerting anti-tumorigenic properties. When low endogenous levels of oestrogens exist, there are data suggesting phytoestrogenic benefits; however, the potential for off-target or side effects post-consumption/exposure remains less understood^{(Reference Patisaul and Jefferson33)}. Moreover, when phytoestrogens are consumed in combination with drugs, phytoestrogens can interfere with the drug efficacy and function, implying that additional data and caution may be necessary to ascertain if phytoestrogen intake affects the safety of other medications. It is worth noting that the beneficial effects of phytoestrogens could differ in pre-menopausal women with higher endogenous oestrogen levels^{(Reference Patisaul and Jefferson33)} when compared to post-menopausal women. Additionally, the impact of phytoestrogens on men, who naturally have lower circulating levels of oestrogens, is also less understood.

The timing of phytoestrogen exposure emerges as a critical factor influencing their potential positive or negative effects. Exposure can occur during foetal development, adulthood, in the presence or absence of endogenous oestrogens, and in both females and males. However, establishing an association between dietary phytoestrogens and endocrine biomarkers remains inconclusive, partly due to variations in the type and concentration of compounds, the bioavailability of phytoestrogens, and whether they affect circulating v. urinary excretion of metabolites^{(Reference Patisaul and Jefferson33,Reference Patisaul34)} .

Xenoestrogen’s ‘estrogen-like’ activity

Xenoestrogens not only engage with and activate ERs and oestrogen-related receptors, but they also interact with androgen receptors and retinoid receptors. Moreover, xenoestrogens can directly or indirectly bind to non-steroid receptors, including neurotransmitter receptors like serotonin, dopamine and norepinephrine receptors. They can also interact with orphan receptors, such as the aryl hydrocarbon receptor (AhR), triggering enzymatic pathways that influence steroid biosynthesis and metabolism^{(Reference Bulzomi and Marino56)}. Many xenoestrogens possess a phenolic structure resembling that of E2, allowing them to interact with ERs as either agonists or antagonists^{(Reference Bolli and Marino57)}. Their binding affinities for ERs span from sub-nanomolar to micromolar values, and once bound, they can function as full agonists or partial agonists/antagonists^{(Reference Delfosse, Grimaldi and le Maire42)}. Xenoestrogens can also serve as hormone precursors, thereby impacting steroid metabolism and functioning as steroid-sensitive substrates^{(Reference Wang, Chen and Chen58)}. However, the relationship between BPA and metabolic outcomes is complicated by a non-monotonic dose response curve. Various epidemiological studies assumed a linear relationship between BPA exposure and diabetes risk but lately it has been postulated by the regulatory agencies that BPA can mitigate adverse effects at much lower doses than the calculated safe dose^{(Reference Song, Chou and Baecker59,Reference Gore, Chappell and Fenton60)} .

Xenoestrogens may negatively influence various health conditions, including breast and prostate cancer, endometriosis, infertility, diabetes, metabolic syndrome, early puberty and obesity. Xenoestrogens can interfere with the development of the female reproductive tract by competitively inhibiting endogenous oestrogens and selectively binding to ERs. Specific substances, such as nine PCBs, three pesticides, a furan, and two phthalates, have been linked to gradual damage to the follicular pool and associated with earlier onset of menopause^{(Reference Vabre, Gatimel and Moreau61)}. Xenoestrogens can also contribute to the formation of ovarian cysts, leading to a condition known as polycystic ovary syndrome^{(Reference Götz, Thieme and Dörner62)}. Adolescents residing in areas with significant industrial development and PCB exposure experienced earlier menarche and thelarche compared to their unexposed peers^{(Reference Grindler, Allsworth and Macones63)}. A National Health and Nutrition Examination study showed higher BPA exposure is associated with obesity in the adult population of the United States^{(Reference Carwile and Michels64)}. Riffee et al., explored the relationship between bisphenol exposure and lipid profile parameters and exercise-induced glucose uptake mechanisms and indicated that BPA and bisphenol S are highly correlated with oxidative stress generation and impaired lipid metabolism^{(Reference Riffee, Wade and Sine65)}.

Foetal development

Xenoestrogens have been demonstrated to provide detrimental effects on foetal development, with evidence indicating negative impacts on neuronal and endocrine function^{(Reference Paterni, Granchi and Minutolo66)}. These compounds have also been associated with cancer-promoting mutations within cells during foetal development^{(Reference Palmlund67)}. Furthermore, exposure to xenoestrogens during pregnancy has been linked to alterations in the genetic sequence within the placenta, thereby adversely affecting foetal growth and overall development^{(Reference Vilahur, Bustamante and Byun68,Reference García-Arevalo, Alonso-Magdalena and Rebelo Dos Santos69)} . A study by Garcia-Arvelo et al., exposed mice to BPA subcutaneously and fed a high-fat diet and the authors found the male offspring had fasting hyperglycaemia, glucose intolerance and high levels of NEFA in the plasma compared with the controls^{(Reference García-Arevalo, Alonso-Magdalena and Rebelo Dos Santos69)}. An epigenomic-wide analysis of cord blood DNA methylation indicated that there may be sex specific epigenomic responses to BPA exposure in offspring as well^{(Reference Miura, Araki and Minatoya70)}.

The term used to define the timing for which an individual is exposed to xenoestrogens is referred to as the ‘term window’^{(Reference Diamanti-Kandarakis, Bourguignon and Giudice40)}. Determining the ‘term window’ is extremely challenging and yet may be critical in determining if and when the impact of the exposure is manifested and to what harm the organism may experience due to the exposure. The ‘term window’ is the period of developmental susceptibility during which the developing organism can be altered by environmental factors resulting in structural, functional and/or cellular changes^{(Reference Diamanti-Kandarakis, Bourguignon and Giudice40)}.

How to minimise exposure

Given the documented adverse effects of xenoestrogen exposure, one effective strategy to minimise risk is to reduce the use of cosmetic products that contain parabens and phthalates. Additionally, using glass or ceramic containers for storing food, as opposed to plastic, is recommended due to the heightened presence of xenoestrogens in plastics. It’s advisable to avoid using plastic containers in the microwave to prevent potential leaching of BPA into microwaved products. Additionally, refraining from heating plastics, even in direct sunlight, is recommended to mitigate exposure^{(Reference Yang, Yaniger and Jordan71,Reference Bittner, Yang and Stoner72)} .

Moreover, adjusting dietary consumption of foods which contain high levels of xenoestrogens can aid in decreasing exposure. Specifically, restricting the intake of canned fish which can contain elevated levels of mercury and PCBs, would be prudent^{(Reference Darnerud, Eriksen and Jóhannesson73,Reference Hites, Foran and Schwager74)} . Health professionals and nutrition experts advocate for consumption of fresh fish which is high in n-3 long-chain PUFA^{(Reference Yokoyama, Origasa and Matsuzaki75,Reference Troesch, Eggersdorfer and Laviano76)} . Additionally, various studies indicate that consuming fish might protect against the effects of methyl mercury^{(Reference Hibbeln, Davis and Steer77–Reference Myers, Davidson and Cox79)}. For instance, research conducted in the Seychelles Child Development Study suggests a positive correlation between fish consumption and cognition^{(Reference Davidson, Myers and Cox78,Reference Myers, Davidson and Cox79)} . Moreover, opting for pesticide-free fruits and vegetables is advisable whenever possible. If this is not feasible, then ensuring that fruit and vegetables are washed thoroughly prior to consumption could minimise exposure^{(Reference Mukherjee, Pandya and Baxi80–Reference Kuiper, Lemmen and Carlsson82)}.