The Science of Lowering Estrogen For Weight Loss: How Receptor Action Determines Fat Storage
Through the estrogen receptors that are so densely situated in fat cells, estrogen promotes fat storage in sites beneath the skin. It does so by shutting down the cell’s adrenaline receptors (this will be important later), receptors that would normally sense the ‘request’ for circulating energy and release fatty acids into the bloodstream. However, this is not a uniform effect across all the fat reservoirs of the body, the altered receptor profile we found in visceral fat (around the abdomen) means that testosterone is the major hormonal driver of fat storage here and, through competing with this ‘male’ hormone at these sites, estrogen actually inhibits fat storage here. Conversely, it increases it around the triceps, buttocks, hips and breasts, with effects observed across all mammals studied.
- So far:
- estrogen increases fat storage overall, especially so at the upper arms, buttocks and thighs but reduces fat storage on the abdomen. In other words, estrogen delivers the ‘female shape’.
Reduce estrogen for less fat storage?
I’ll set the scene. It’s the early-noughties and reducing estrogen had become The Thing To Do when working with females seeking weight loss. Gyms were separated into the trainers who were ‘estrogen-literate’ and those stuck in the past. Learning about the importance of estrogen was a milestone for those of us in the functional nutrition field; it was exciting to learn how intestinal balance could cause an increase in a chemical called beta-glucoridase, which interfered with the intestinal elimination of estrogen. Other papers showed DIM favourably altered estrogen metabolism and further research demonstrated that resveratrol had anti-estrogenic effects.
It quickly became gospel that one gave these ladies DIM, calcium-D-glurarate and resveratrol. You also avoided soy because ‘soy increases estrogen dominance’. There was only problem with this great advice; it rarely delivered results for the ladies I worked with.
Cue a deep dive into the science to see what I was missing…. There were some surprises in store. Turns out that removing estrogen receptors from mammals saw a massive increase in fat storage. That’s right… lowering estrogen made the subjects fat! My search dug up more and more papers that each struck a dagger into the heart of this otherwise beautiful theory. Turns out that, while there are important concerns with anti-nutrients, soy’s effects on estrogen may actually be beneficial. Equally, turns out that resveratrol could work as an estrogen agonist in some cases and a blocker in others. Among the complexity, one thing was clear: there is no one-size-fits-all approach to estrogen management.
- The black-and-white idea that ‘estrogen is bad, estrogen increases fat’ was far too simplistic
- Estrogen can have both positive and negative effects on fat
From confusion to clarity: estrogen receptor-a and estrogen receptor-b
The most important research paper I found was a Danish study that studied the density of the different types of receptors in the gluteal regions versus the abdomen. In short, that the gluteal fat cells had a high density of beta-receptors and the abdominal fat had very little. Importantly, whenever estrogen binds with the beta receptor, fat storage increases. This is found in multiple other studies (here and here). It is also relevant that activation of the estrogen-receptor beta can slow down mitochondrial energy production (with downstream effects across the body, most notably the metabolic rate).
So could the dual roles of estrogen be explained by the two different types of receptor? Yes. Estrogen receptor alpha has pro-metabolic effects, reducing food intake but increasing metabolic output (and therefore inducing a leaner body shape). It also encourages the formation of fat-burning brown fat over depot-style white fat and has adds to the effect of leptin at the hypothalamus, where it conveys a message of ‘energy safety’ that permits the usage of energy throughout the body. It also curbs the activity of a wide array of lipogenic enzymes. No wonder women with reduced activity in the alpha receptor store more weight at the abdomen.
Estrogen receptor beta is found all over, but in particularly high densities in the bone, cardiovascular system uterus, bladder and ovaries. As a side note, higher densities of the beta receptors are also found in the basal forebrain, hippocampus and cerebral cortex of the adult, areas that are heavily involved in brain activity (sharpness) and implicated in neurodegenerative diseases. This may explain why the classic phytoestrogens – those that bind extensively with the beta receptor – show benefits in cardiovascular health, bone strength and brain function but yet offer little to stem excess fat storage in my post-menopausal clients. Importantly for this discussion, estrogen receptor beta is found in high amounts in the thighs and buttocks, where it increases the uptake of fat from the bloodstream (this ‘sponge effect’ is why the average pre-menopausal woman, with her higher estrogen levels, has a dramatically lower cardiovascular risk and better lipid profile).
(Note: there are actually more receptors than just alpha and beta, but discussing the other adds nothing to the explanation at this point).
If we lose sensitivity at estrogen receptor alpha, the hypothalamus does not get the estrogenic signal it expects. In response, it increases the release of GnRH (Gonadotrophin-Releasing Hormone) to correct this shortage; the end result is that the ovaries are stimulated more than normal and estrogen levels rise. The beta receptors remain perfectly sensitive to the estrogen. Lots of binding occurs, so lots of fat storage occurs. Equally, lots of brain activity activity (to the point that sleep may suffer and the individual may feel some ongoing, low-grade agitation) and increased activity in sebaceous glands and uterine lining (which will be the subject of an upcoming article on endometriosis). Meanwhile, reduced sensitivity at the alpha receptors + increased delivery of estrogen = normal function at the hypothalamus. And the ‘only’ price to pay for restoring this balance was substantially increased fat storage at the areas rich in beta receptors (back of the arms, buttocks and thighs) and increase activity in certain areas of the brain and body.
- Estrogen has dual roles in reducing fat storage overall, especially at the abdomen, but maintaining fat storage at the hips and buttocks
- The different effects of estrogen in women is determined by the interaction of estrogen with the two receptors
- Estrogen’s interaction with estrogen receptor beta is responsible for the fat storage effects. This is not a ‘bad’ thing, as this moves energy out of the liver and bloodstream (providing a cardioprotective role) but the cost is increased fat storage
What affects sensitivity at the alpha receptor?
The research discussed above makes it clear how the ‘classic’ estrogen dominance picture (high blood levels of estrogen, agitation/insomnia, increased fat storage beneath arms and at buttocks/thighs) can start from reduced sensitivity at the alpha receptor in the hypothalamus, and the subsequent attempts at compensation.
Therefore, provided that serious endocrinological disruption has been ruled out, we can expect great results from focusing on this alpha receptor (ER-a) and the elimination of any factors that downregulate its activity. The key factors here:
- Inflammation. Inflammation has been shown to reduce both ER-a expression and its effects on releasing fatty acids from fat cells (a huge deal in weight management)
- Endotoxins. This could technically be classified as inflammation, as the effect of endotoxins on human metabolism is mediated by inflammation. But endotoxins stand out as a subject worthwhile of discussion by itself, as this links both stress and microbial balance to the inflammatory response (stress increases the movement of endotoxins into the bloodstream, while microbial imbalance in the gut can increase the amount of these endotoxins queueing up to do so). It is also relevant that endotoxins appears to have a particularly pronounced ability to downregulate ER-a above that of other inflammatory sources (in pre-menopausal conditions, at least). Further links worth touching on is the way that endotoxins can downregulate ER-a in the brain’s immune cells, an action that blocks them from launching their usual anti-inflammatory control.
- Stress. One of the central aspects of the stress response is the release of cortisol, which helps the body cope with the impacts of stress, turn off the stress response when it is no longer needed and support recovery from the otherwise costly effects of stress. It turns out that, when the cortisol receptor is bound, it reduces expression of ER-a while increasing ER-b. This makes perfect sense when we consider cortisol’s pro-coping purpose (the stress response exits to meet demands when energy availability is overwhelmed and, thus, it figures that it would increase energy storage in fat cells and reduce baseline energy expenditure so that the person has more ‘energy insurance’ for next time).
- Progesterone. The balancing effects of progesterone on menstrual fluctuations are well known, although its effects are often overly summarized as ‘counteracting the effects of estrogen’. It turns out it is a little more complex, with progesterone both enhancing the expression of ER-a to limit dominance of the ER-b activity. However, progesterone demonstrates true modulatory capacity in that it also limits overactivity of ER-a-induced pathways (hence the anti-carcinogenic profile of progesterone). While management of progesterone is beyond the scope of this article, optimal levels can only be expected after successful ovulation, underscoring the importance of healthy cycles in managing estrogen activity. It is no coincidence that inflammation, endotoxemia and stress are the biggest disruptors of healthy menstrual activity
- Estrogen receptor alpha is downregulated by inflammation, endotoxemia, stress and low progesterone
Clinical usage: how does the ‘alpha receptor technique’ work out on the frontline?
Theory is fine, but what happens in real-life when we apply this approach? I have been managing ER-a status for several years now, with support always consisting of what I’d call the ‘obvious/basic’ support (addressing results from initial Organic Acids test, considering any obvious calls to support adrenal output, sleep and digestion) together with a hop extract (one that provides a concentrated serving of 8-prenyl-naringenin, the only plant phytoestrogen that shows strong binding to ER-a). Overall, the responses have been pleasing.
In pre-menopausal women, frontline patterns tend to fall fairly evenly into three groups:
- Great response. In around one third of women with higher blood levels of estrogen, we see a linear fat loss that has comes disproportionately from the ‘estrogen’ zones (mainly around the buttocks and thighs). We also see improved energy, sleep, mood and mental sharpness. Interestingly, the fat loss almost never starts in the first two cycles (which seem quite vulnerable to a change in patterns before things settle in).
- Systemic response but no fat loss. This accounts for around half of the initial responses. This group show improvements in brain balance (energy, sleep, mood focus) and may also see improvement in symptoms that ebb and flow with their cycle (bloating, spots, etc) but they don’t see the fat loss we wanted. This would suggest that there are other factors interfering with the activity at fat cells. Further interventions down the line support this too, as I have often found that further metabolic support (that focuses on insulin sensitivity, adrenaline sensitivity intake of seed oils, PPAR signalling and dysbiosis) normally allows us to finally achieve the fat loss we are after. It’s worth remembering that ER-b signalling helps maintain fat stores through several mechanisms and one of these is by reduction of adrenaline sensitivity at fat cells; if the individual has had high levels of adrenaline (and continues to do so), we cannot expect this to reset. This, in essence, doubles the effect of ER-b on keeping fat in cells.
- No response. This represents around a sixth. While it is occasionally the case that we see no change, I will often see a small drop in blood levels of estrogen but it is not anywhere that seen in those that respond. It appears that the intervention is simply not enough if there is still a lot of ‘fuel being poured on the fire’. Looking further into this, one clear pattern is that individuals with particularly high stress levels (and low HRV scores), ongoing mould exposure and insufficient calorific intake are hugely-overrepresented in this group (in fact, no individual is yet to respond if any of these factors is present).
I would have expected dysbiosis status to make a big difference in responses, and there is definitely an increased tendency of those with these gut issues to show a limited response, but it was not the be-all-and-end-all that I would have expected.
In post-menopausal women (whose issues are not excess estrogen activity at the ER-b, instead simply low ER-a across the board), the responses have been more uniform but still show some divergence:
- Good systemic response with moderate fat loss. This is most post-menopausal women. Although supporting both ER-a and ER-b signalling has been one of the most reliable interventions for overall wellbeing, it is important to note that the fat loss response has not been as pronounced as with pre-menopausal women; it is actually more reliable to see fat loss in post-menopausal women, it has simply occurred at slower rates in those I’ve worked with. I would hypothesize that this is down to a reduced ability to kick-start a stronger ER-a response (as it will always be limited by the phytoestrogen support, as there is much less estrogen in the blood stream to capitalize in these rebooted receptors). However, hot flushes are a very common problem in post-menopausal women and these have been reliably reduced. Some find that they go entirely, although even in the ‘good responders’ there are those that still have some lingering issues here (often we are able to tend to this with further phytoestrogen support like Red Clover, or with the addition of Black Cohosh, although sometimes they have needed to consult their doctor for direct hormonal support).
- Mixed bag. There have been a handful of post-menopausal women who haven’t noticed any differences but, of those who do not show a ‘good’ response, most still find some benefit. The key thing here is how inconsistent the improvement has been (with some finding some improved mental sharpness, others finding improved sleep) but never an across-the-board improvement. Equally, hot flushes are one symptom that I rarely see improve here; the little-discussed fact that these are mediated through altered interaction between estrogen and adrenergic receptors certainly provides clues as to what might explains this; once again, we see this group over-represented but those with high activation of the stress response. So too those with unresolved mould issues or those consuming insufficient calories (as above), which speaks to the importance for all to resolve these major obstacles. While I have seen a couple of ‘non-responsive’ women do well through obtaining hormonal therapy from their doctors, the strong pattern here is that even the stronger option does not cut it (further supporting the idea that other metabolic factors are simply having too strong an impact).
- A hop phytonutrient works on the frontline to achieve ER-a dependent improvements, but is not the entire picture (and will fail if energy metabolism is still affected by other major obstacles)
- Pre-menopausal women show no need for ongoing support once normal activity has been restored
Further implications: is ER-a management relevant for women with estrogen-type fat storage but normal levels of estrogen?
The literature and the frontline effects discussed above show how, when the factors that brought about the issues are resolved, the use of a hop phytoestrogen can help ‘reset’ the alpha receptor.
A 2012 research paper indicates that this ‘reset’ effect may be relevant even in women without high blood levels of estrogen, with particular relevance in those ladies who have:
- a) gone through a period of metabolic stress (one that resulted in high levels of cortisol, sustained over a period of time)
- b) found that their body shape/fat storage profile has been different since
This paper shows clearly how, once ER-b signalling is dominant, it actually upregulates local cortisol formation in the fat cells (which, due to cortisol’s effect in increasing expression of ER-b, can result in a self-perpetuating party of fat retention that is entirely local and therefore not reflected in blood/saliva readings of cortisol). At the time of writing (Nov 2021), I am still in the early stages of seeing how the ER-a management would pan out in clinic for these scenarios, but initial responses are encouraging.
- After ER-b dominance occurs, it can induce local production of cortisol (which triggers a self-perpetuating cycle)
Functional management of hormones is always a complex matter, and estrogen is no different. However, one thing that is obvious is how limiting it is to speak of the role of ‘estrogen’ on fat storage without differentiating between its opposite effects at the alpha and beta receptor.
Also obvious is how the fundamental mechanics of estrogen on energy management have been largely ignored by dogmatic professionals, despite the spectacular failings of these old, half-baked ideas and the growing body of evidence that reveals a system that is elegant, understandable and ready to employ on the frontline.
The evidence shows clearly that management of the estrogen receptor alpha is one of the most important aspects in turning off a cycle that could otherwise induce an ongoing obstacle and is capable of providing great results, but how these results can be expected only as part of a holistic approach that tends to all aspects of energy management of fat cells.