Cautions against soy for folks on transfem HRT

Soy isoflavones are an established estrogen disruptor in that its constituents have anti-estrogen effects with high binding affinity and low transactivation potential at estrogen receptors.

Isoflavones are polyphenolic compounds that possess both estrogen-agonist and estrogen-antagonist properties (see Biological Activities). For this reason, they are classified as phytoestrogens - plant-derived compounds with estrogenic activity. […] Soy isoflavones are known to have weak estrogenic or hormone-like activity due to their structural similarity with 17-#-estradiol. […] Soy isoflavones can preferentially bind to and transactivate estrogen receptor-# (ER-#) - rather than ER-# - mimicking the effects of estrogen in some tissues and antagonizing (blocking) the effects of estrogen in others.

As a transfem person on hormone replacement therapy, I became interested in whether this could be granularly determined to pose a problem for feminization when consumed in high enough quantities regularly. SERMs antagonistic activity at ER are known to slow or prevent breast development in transfem enby people, so its not like this outside the realm of possibility for soy isoflavones.

At the time, I had been relying on Soylent meal replacement shakes for dinner daily. I found that Soylent bottles may contain up to 20g of soy protein isolate, which would equate to ~46mg of phytoestrogen isoflavones per bottle, a non-insignificant amount. Given some isoflavones and their metabolites in SPI have half lives of hours, I found myself concerned of its interference.

These results show that SPI is an efficient isoflavone delivery vehicle capable of providing significant proportions of the total dose into the circulation in the active aglycone form for distribution to receptor-bearing tissues and subsequent pharmacological effects that determine possible health benefits and/or risks.

I shot an email over to Soylent, and after some back and forth involving political posturing surrounding the whole soy boy fiasco, I was able to extract some useful information out of them. They linked a meta-analysis on the topic, citing human studies, which was far better than the animal models I put to them. Ironically, they tried to use this to back up their claim of it being safe, and did not address my specific speculative concern whatsoever.

In regard to isoflavone metabolism, a striking difference among individuals is that only about 25% of non-Asians and 50% of Asians host the intestinal bacteria that convert daidzein into the isoflavonoid equol [80]. In 2002, Setchell et al. (2002) proposed that those individuals who host these bacteria are more likely to benefit from soyfood consumption [81]. Since that time this hypothesis has been hotly debated. Equol does appear to offer health benefits over its precursor daidzein [82,83] in possibly several different areas but especially in the alleviation of hot flashes [84,85,86]. However, it also may be that in some cases it is the equol-producing phenotype (i.e., the ability to produce equol) rather than equol itself, that is responsible for the more beneficial response to isoflavone ingestion [87].

This doesn’t give me much confidence. I have no idea if I posess this digestive ability. I have no idea how I’d find out. This is a complex issue likely involving genetics, diet and the intestinal microbiome. If I were to, the evidence showing that in postmenopausal women, hot flashes are reduced with sufficient soy consumption only increases my concern. This demonstrates the isoflavones’ agonistic properties, which isn’t bad by itself, but digging into sources reveals more detail on the pharmacodynamics of their SERM properties.

Isoflavone glycoside binds weakly to both receptors and estrogen receptor-dependent transcriptional expression is poor. […] The concentration required for maximal gene expression is much higher than expected from the binding affinities of the compounds, and the maximal activity induced by these compounds is about half the activity of 17 beta-estradiol.

For someone interested in their hormonal balance being as effective as it can be, this doesn’t sound good. Isoflavones would outnumber those of endogenous estrogens, potentially overwhelming them to the point where those isoflavones preferentially bind to receptors despite their weak affinity. Then once they do, their reduced transactivational potential would result in a net reduction in estrogenic activity.

Other digestive metabolites of SPI result in antiestrogenic activity. ENL seems to have antiestrogenic effects on human breast cancer cell lines when exposed in tandem with E2. However, the amount introduced to the tissue was far higher than would be systemic from ‘high intake’ of soyfoods (though that measurement is highly dependant on when the food was eaten, and they didnt control for that). Another study which showed clear correlation in humans between intake of soyfoods, plasma concentration of ENL and reduced breast cancer risk, but there is evidence from other studies that is mixed. (I don’t recall the sources for these.)

Clearly, though, there are signficant hormonal effects exhibited by consuming soy in sufficient amounts. The meta-analysis strongly shows this when talking about breast cancer risk:

the prospective epidemiologic data show that post-diagnosis soy intake improves prognosis. More specifically, a meta-analysis of five prospective studies, two from the United States [255,256] and three from China [257,258,259], involving over 11,000 women with breast cancer, found soy consumption after a diagnosis of their disease was associated with statistically significant reductions in breast cancer recurrence (HR, 0.85; 95% CI: 0.77, 0.93) and mortality (HR, 0.79; 95% CI: 0.72, 0.87)

Breast cancer cell proliferation is mediated through estrogenic activity. SERMs like tamoxifene are commonly prescribed for this purpose. That SPI is linked with reduced risk of breast cancer recurrence tells me that again, there is reduced estrogenic activity.

What else did the Soylent representative tell me?

The processing of the soy protein we use and the processing of our product does reduce the isoflavones content to a degree. Our Soylent Ready to Drink meal replacement does contain approximately 20mg of isoflavone/bottle. To put it in perspective, the average daily intake of isoflavones in Japan, a country where soy foods are commonly consumed is between 30-50mg [1].

This is what I wanted to hear. Unfortunately, I never was able to get a firm estimate on concentration of isoflavones that would result in outcomes such as reduced hot flashes or breast cancer risk. Its encouraging that they’ve put in effort to reduce the concentration in light of concerns, but unfortunately, it wasn’t enough to convince me to keep drinking their product.

So, be forewarned. This can apply to any soy product, soy protein isolate-containing supplement. If you’re concerned about optimal feminization from HRT, consider staying away from or at least reducing your intake.

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