HoldsUp

Dr. Tyna Moore · 2026-04-30 · Tyna Moore (host), David Roberts, John Gilday

Stop the "Toxic" Estrogen Loop: The Secret to Safer HRT

52 research-tied claims examined: 6 contradicted 9 overstated 2 context 26 supported 1 corroborated online 8 unverified

26

Supported by research

0:00:00David Robertssupportedhigh

Chewing broccoli breaks plant cell walls to release the enzyme myrosinase, which converts glucoraphanin into sulforaphane.

"So, if you have a head of broccoli, start chewing it. The glucoraphanin, the precursor molecules in there, you break the cell wall through the chewing, and it releases an enzyme that converts that glucoraphanin into sulforaphane." (said at 0:00:00)

The biochemical mechanism is well-established. In intact broccoli, the glucosinolate precursor glucoraphanin and the enzyme myrosinase (a thioglucosidase) are segregated in separate cellular compartments. Mechanical disruption such as chewing or chopping breaks down plant cell walls and compartments, allowing myrosinase to interact with glucoraphanin and catalyze its hydrolysis into the bioactive isothiocyanate sulforaphane.

0:03:36John Gildaysupportedmoderate

The estrogen metabolite 4-hydroxyestrone can form DNA adducts and is genotoxic.

"one of those pathways, 4-hydroxyestrone, can be a DNA adduct. So it's it's genotoxic." (said at 0:03:36)

4-Hydroxyestrone is a catechol estrogen metabolite that undergoes metabolic oxidation to reactive catechol estrogen-3,4-quinones. These reactive electrophiles react directly with DNA bases (primarily purines like adenine and guanine) to form depurinating DNA adducts, leading to apurinic sites, mutations, and genotoxicity.

0:05:00John Gildaysupportedvery low

Loss of estrogen leads to loss of NRF2 induction, SIRT1 activation, and AMPK activation.

"And then as you lose this protective function, um you know, some of these other pathways that come into play are really important like NRF2. You lose NRF2 induction, um you lose SIRT1 activation, um uh AMPK as well." (said at 0:05:00)

Preclinical models of estrogen deficiency (such as ovariectomy) and translational human tissue studies demonstrate that the loss of estrogen signaling impairs the activation and downstream pathways of NRF2, SIRT1, and AMPK. Conversely, administration of estradiol or estrogen receptor agonists restores NRF2 nuclear translocation and antioxidant expression, upregulates SIRT1, and increases AMPK phosphorylation.

0:07:11John Gildaysupportedvery low

SIRT1 is a histone deacetylase that functions in genome gatekeeping and participates in repairing double-stranded DNA breaks.

"SIRT1 is is a genome gatekeeper. And so, if you're if you get double-stranded breaks in your in your um in your DNA, um SIRT1 is part of the complex that goes and repairs those that DNA. ... It's a histone deacetylase." (said at 0:07:11)

SIRT1 is well established as an NAD(+)-dependent class III histone deacetylase that plays a crucial role in maintaining genomic stability and facilitating the repair of DNA double-strand breaks (DSBs). In response to DNA damage, SIRT1 is recruited to DSB sites and promotes repair through pathways including homologous recombination (HR) and non-homologous end joining (NHEJ). Because evidence for this molecular mechanism comes from cell culture and animal experimental models, the certainty of evidence under standard clinical GRADE criteria is very low.

0:07:50John Gildaysupportedhigh

AMP kinase acts as a metabolic sensor measuring AMP to ATP ratios and triggers mitophagy and autophagy.

"And then AMP kinase is a metabolic sensor. So it it measures the amount of AMP to ATP. So when you're running out of energy, it turns on a bunch of pathways to to clean up shop, to start reusing some of the broken parts around your garage and start making a good car again. So that's this meta- mitophagy, autophagy." (said at 0:07:50)

The speaker's statement is supported. AMP-activated protein kinase (AMPK) is a well-established cellular energy sensor that is allosterically activated by rising AMP:ATP (and ADP:ATP) ratios during energy depletion. Upon activation, AMPK promotes cellular quality control by directly activating ULK1 and inhibiting mTORC1, thereby inducing both general macroautophagy and mitochondrial-specific autophagy (mitophagy) to recycle damaged components and restore energetic homeostasis.

0:24:44John Gildaysupportedvery low

NRF2 induction promotes the sealing of tight junctions in enterocytes, reducing endotoxin translocation and inflammation.

"if you study um tight junctions at all, um a central feature of that, and you can read it in any review, is that NRF2 induction causes tight junctions to seal. And so, as soon as you get the tight junctions in your enterocytes sealed, you've just established the stage one of of lowering inflammation." (said at 0:24:44)

Preclinical in vitro and animal models support the claim that Nrf2 activation promotes intestinal tight junction integrity (upregulating tight junction proteins such as ZO-1, occludin, and claudins) and attenuates mucosal inflammation and barrier permeability. Genetic silencing or knockdown of Nrf2 abolishes these protective effects on epithelial barrier integrity. However, this evidence is derived entirely from cellular and rodent experimental models, meaning clinical certainty in humans remains very low.

0:25:45David Robertssupportedvery low

In a mouse study, administering sulforaphane to aged mice reversed their microbiome composition to resemble that of young mice.

"it's a mice study where they um you know, had young young mice and old mice, and uh they measured the microbiome of each, and then they gave the old mice sulforaphane, and then and then measured their microbiome again, and it was it it and it was the same as the young mice. So, basically, their microbiome age um decreased so to so that they had the microbiome of young mice." (said at 0:25:45)

A 2020 study evaluated the effects of sulforaphane administration in young (6–8 weeks) and old (21–22 months) mice for two months. The authors found that dietary sulforaphane restored the gut microbiome profile in aged mice to mimic that of young mice, enriching bacterial taxa associated with improved intestinal barrier function and reduced inflammation. Because the evidence is derived solely from an animal model, certainty is very low regarding applicability to humans.

0:01:02Tyna Moore (host)supportedmoderate

Diindolylmethane (DIM) can inhibit or lower estrogen levels.

"everybody talks about DIM, and she's adamant that DIM can inhibit your estrogen, and this is not what we're going for necessarily when a woman's perimenopausal or menopausal and estrogen's leaving the building, and then she's taking DIM, which might be driving it down lower." (said at 0:01:02)

Clinical and pre-clinical studies demonstrate that diindolylmethane (DIM) exhibits antiestrogenic properties and can lower circulating estradiol levels and active estrogen signaling. In a prospective trial evaluating 1 year of daily DIM supplementation in female BRCA carriers (median age 47 years, 78% postmenopausal), mean serum estradiol significantly decreased from 159 pmol/L to 102 pmol/L. In randomized trials, DIM significantly enhanced the metabolic clearance of estrogen into less estrogenic pathways (increasing the urinary 2-hydroxyestrone to 16α-hydroxyestrone ratio) and increased sex hormone-binding globulin (SHBG) levels, which reduces biologically available estrogen.

0:31:47Tyna Moore (host)supportedmoderate

Sulforaphane induces the expression of heat shock proteins.

"And then I was reading that sulforaphane induces heat shock proteins. Do I have that right? GUEST2: Yep, it does." (said at 0:31:47)

Published experimental and clinical biomarker studies show that sulforaphane induces the heat shock response and upregulates the expression of several heat shock proteins (including Hsp27, Hsp70, and Hsp60). Mechanistic in vitro work demonstrates that sulforaphane activates heat shock transcription factor 1 (HSF1) to increase Hsp27 levels, while human trials and ex vivo assays using peripheral blood mononuclear cells have documented upregulation of HSP27 and HSP70 mRNA following sulforaphane treatment.

0:39:50Tyna Moore (host)supportedhigh

Estrogen loss induces interleukin-6 (IL-6), which promotes the development of osteoporosis.

"IL-6 is also what's driving osteoporosis GUEST2: Yes. Yes. the estrogen loses makes you induce IL-6." (said at 0:39:50)

The claim is supported by scientific evidence. Studies in animal models and human cellular biology demonstrate that estrogen deficiency upregulates pro-inflammatory cytokines, specifically interleukin-6 (IL-6), which promotes osteoclastogenesis (the formation and activation of bone-resorbing osteoclasts) and accelerates bone loss, contributing to postmenopausal osteoporosis.

0:42:25Tyna Moore (host)supportedhigh

Middle-aged women have the highest suicide rate among all female age groups.

"And then you read the studies and our age cohort is women in middle age is the highest has the highest suicide rate of women of any other age group." (said at 0:42:25)

Epidemiological surveillance data from the Centers for Disease Control and Prevention (CDC) and the National Vital Statistics System (NVSS) demonstrate that suicide rates among females in the United States peak during middle age (specifically ages 45–64), representing the highest suicide rate among all female age groups. This age-specific distribution differs notably from males, where suicide mortality rates are highest among elderly age cohorts.

0:42:50Tyna Moore (host)supportedvery low

Sulforaphane upregulates brain-derived neurotrophic factor (BDNF).

"And then I was in the research I was doing I realized that sulforaphane upregulates BDNF, too, which is awesome." (said at 0:42:50)

Preclinical laboratory research supports the claim that sulforaphane upregulates brain-derived neurotrophic factor (BDNF). In vitro neuronal cultures and rodent models demonstrate that sulforaphane stimulates BDNF transcription and expression through Nrf2 pathway activation and epigenetic mechanisms such as histone deacetylase (HDAC) inhibition. However, evidence is currently limited to cellular and animal models, and clinical trials confirming BDNF upregulation in humans remain lacking.

0:46:46David Robertssupportedhigh

Researchers at Johns Hopkins discovered sulforaphane in 1992.

"Johns Hopkins actually, I mean, they discovered sulforaphane in 1992, but they created the chemoprotective center, which uh up until 5 6 years ago was the broccoli sprout growing operation for the research." (said at 0:46:46)

In 1992, researchers at Johns Hopkins University School of Medicine (led by Paul Talalay and Yuesheng Zhang) isolated and identified sulforaphane from broccoli as a potent inducer of phase II chemoprotective and detoxication enzymes (published in the Proceedings of the National Academy of Sciences). While the chemical compound had been isolated from other plants and synthesized decades earlier, the landmark discovery of sulforaphane in broccoli and its role in cancer chemoprotection was made at Johns Hopkins in 1992.

0:58:02David Robertssupportedmoderate

Less than 1% of standard oral berberine and curcumin is absorbed across the intestinal barrier.

"John mentioned curcumin and berberine and those are um those are both lipid soluble. So like uh less than 1% of what you take gets through the gut barrier. Um it's like oil and vinegar basically. Um and so so ba- what we try to do and what we do is make um and you know, make it possible so that enough gets through the gut barrier um to like move the needle on the biology. And so if you take uh not you know, regular berberine, um it it you know, less than 1% gets through. Like I think it's .6 uh .7%" (said at 0:58:02)

Published pharmacokinetic evidence confirms that standard oral berberine and curcumin have very low oral bioavailability and intestinal absorption, typically below 1%. For berberine, animal and human pharmacokinetic studies report absolute oral bioavailability of less than 1% (frequently measured at approximately 0.68%), driven by poor intestinal membrane permeability, active P-glycoprotein efflux, low aqueous solubility, and extensive first-pass intestinal and hepatic metabolism.

0:45:00John Gildaysupportedvery low

Pure sulforaphane induces cell death and apoptosis in cell cultures at concentrations of approximately 10 micromolar.

"there's some papers out there showing sulforaphane has some um apoptosis induction, you know, at like 10 micromol, you know... if you order sulforaphane from Sigma where it's 100% sulforaphane, it does start showing cell death at 10 micromol." (said at 0:45:00)

In vitro studies evaluating sulforaphane in cell cultures demonstrate that concentrations around 10 to 30 μM induce cell cycle arrest, inhibition of cell proliferation, reactive oxygen species generation, and apoptotic cell death across various cell lines. Because this evidence is derived exclusively from in vitro cell culture models, certainty for broader biological/in vivo implications is rated very low.

1:01:00David Robertssupportedmoderate

Microwaving frozen dinners in plastic containers can leach millions of microplastics.

"frozen dinners that you microwave, those can leach, you know, the plastic containers, and they can leach millions of microplastics." (said at 1:01:00)

Laboratory testing of plastic food containers subjected to microwave heating demonstrates that millions of microplastics (and billions of nanoplastics) can leach into food simulants. A 2023 study published in Environmental Science & Technology found that 3 minutes of microwave heating of plastic containers released up to 4.22 million microplastic particles and 2.11 billion nanoplastic particles per square centimeter of plastic area, representing the highest release among tested usage scenarios.

1:01:21David Robertssupportedmoderate

Pyramid-shaped nylon tea bags can release up to 2 billion microplastics into a single cup of tea.

"those pyramid-shaped um shiny tea bags. But those are it's nylon. HOST: The worst. It's the worst. GUEST1: And so yeah, and I didn't do the study, but it showed to up to 2 billion microplastics just from one tea." (said at 1:01:21)

A landmark 2019 study by researchers at McGill University evaluated the release of plastic particles from commercial plastic (nylon and polyethylene terephthalate) teabags steeped in water at 95 °C. The researchers found that steeping a single plastic teabag released approximately 11.6 billion microplastics and 3.1 billion nanoplastics into a single cup, confirming that plastic teabags release billions of microplastic particles during normal brewing.

1:02:00David Robertssupportedhigh

Disposable paper cups are lined with plastic that releases microplastics when heated.

"those paper cups are lined with plastic. HOST: Yeah. GUEST1: And so it gets heated up. Um and so yeah, it's just you're getting three different places where you're getting microplastics" (said at 1:02:00)

Disposable paper cups are manufactured with an inner waterproof lining made of plastics (commonly polyethylene [PE] or polylactic acid [PLA]). Experimental analyses demonstrate that exposure to hot liquids causes this lining to degrade and release tens of thousands of microplastic particles and microfibers per liter into beverages.

1:03:53David Robertssupportedhigh

BPA acts as an estrogen mimic in the body.

"they can basically have these plasticizers like BPA which is um an estrogen mimic" (said at 1:03:53)

Extensive in vitro, animal, and mechanistic literature establishes that bisphenol A (BPA) acts as a xenoestrogen (estrogen mimic). BPA binds to classical nuclear estrogen receptors (ERα and ERβ) as well as membrane-bound estrogen receptors (such as GPER/GPR30), activating estrogen-dependent transcriptional and signaling pathways that regulate cellular proliferation, gene expression, and endocrine function.

1:04:20David Robertssupportedlow

BPA and estrogen mimics can cause earlier puberty onset in girls and irregular menstrual cycles in women.

"And then those uh BPAs, those estrogen mimics start getting released. And and so it's can be responsible for thing things like when a girl's going into puberty earlier. It can be responsible for women um having irregular menstrual cycles." (said at 1:04:20)

Epidemiological studies, systematic reviews, and toxicological research support the plausibility that bisphenol A (BPA) and related estrogenic endocrine-disrupting chemicals (EDCs) can contribute to earlier pubertal onset in girls and menstrual cycle irregularities in women. A 2026 systematic review and meta-analysis of observational studies found that higher postnatal BPA exposure was significantly associated with increased odds of early pubertal onset in girls (pooled OR = 4.45, 95% CI: 1.69–11.72), although substantial heterogeneity was present and causal direction cannot be firmly established from observational designs alone. Narrative reviews and cohort studies similarly associate BPA exposure with disruption of female reproductive hormone pathways, polycystic ovary syndrome (PCOS), and menstrual cycle alterations (such as heavy bleeding or cycle length irregularity). Certainty is graded low due to residual confounding, exposure measurement variability, and observational designs in human populations.

1:07:40John Gildaysupportedvery low

Sulforaphane activates the lysosomal receptor mucolipin 1 (TRPML1) through a redox-sensitive cysteine, releasing calcium and triggering lysosomal exocytosis via a synaptotagmin complex and LAMP-2.

"it's through a receptor called mucolipin 1. And so it has a redox sensitive cysteine that's just the same as what I was talking about earlier about on Keap1 and on IKKβ for NF-κB pathway. So this is in actually in the lysosome membrane and when you activate that you release calcium from the uh lysosome and it initiates a signaling cascade where um the same the same pathway where you get um neurotransmitters dumped in into uh the synaptic cleft in your brain. Um it's for neurotransmission. It's a synaptotagmin complex and LAMP-2. It fuses with the cell surface and actually um releases the lysosome right into the extracellular space." (said at 1:07:40)

Preclinical in vitro research demonstrates that sulforaphane (SFN) acts on the lysosomal cation channel mucolipin 1 (MCOLN1/TRPML1) through redox-sensitive mechanisms, promoting lysosomal calcium (Ca2+) release. This calcium signaling engages the machinery involved in lysosomal exocytosis and trafficking (including synaptotagmin complexes and lysosomal-associated membrane proteins) and triggers downstream pathways such as TFEB activation. Because this mechanism has only been demonstrated in cell culture and animal models, certainty is graded as very low.

1:09:30John Gildaysupportedhigh

TFEB is the master transcription factor that regulates lysosome biogenesis.

"there's a master transcription factor that regulates lysosome production. It's called TFEB" (said at 1:09:30)

Published cell biology research establishes transcription factor EB (TFEB) as the master transcription factor coordinating lysosomal biogenesis and autophagy. TFEB binds Coordinated Lysosomal Expression and Regulation (CLEAR) motifs in promoters across the lysosomal gene network, driving lysosomal biogenesis, acidification, and cellular clearance pathways.

1:09:40John Gildaysupportedvery low

Resveratrol induces genes regulated by TFEB to enhance lysosomal system capacity.

"resveratrol is very good at inducing this whole set of genes that are are made to make your lysosomal system a better conveyor belt." (said at 1:09:40)

Preclinical in vitro and animal studies support that resveratrol promotes the activation and nuclear translocation of transcription factor EB (TFEB)—a master transcriptional regulator of the autophagy-lysosome pathway (the CLEAR gene network)—thereby upregulating genes involved in lysosomal biogenesis, autophagosome formation, and lysosomal degradation capacity. However, evidence is currently limited to cellular and animal models, and clinical evidence in humans remains unestablished.

1:13:18David Robertssupportedmoderate

Resveratrol increases nitric oxide production to improve circulation.

"so does resveratrol. Um so you get nitric oxide so you get better circulation." (said at 1:13:18)

Preclinical and clinical evidence supports the claim that resveratrol stimulates nitric oxide production and improves endothelial-dependent circulation. Mechanistic studies demonstrate that resveratrol enhances endothelial nitric oxide synthase (eNOS) activity and nitric oxide (NO) bioavailability, mediating vasodilation and increased blood flow. Systematic reviews and meta-analyses of randomized controlled trials further confirm that resveratrol supplementation significantly improves flow-mediated dilation (FMD), a standard clinical measure of nitric oxide-dependent vascular function and circulation.

1:17:48John Gildaysupportedvery low

EGCG (epigallocatechin gallate) is an effective inhibitor of LPS-induced inflammatory stimulation.

"if people are interested in in blocking some of that is uh EGCG is one of the best inhibitors of that" (said at 1:17:48)

Published in vitro and animal studies consistently demonstrate that epigallocatechin-3-gallate (EGCG) suppresses lipopolysaccharide (LPS)-induced inflammatory activation. In cell culture (such as macrophages and dendritic cells) and rodent endotoxemia models, EGCG inhibits Toll-like receptor 4 (TLR4) signaling, attenuates NF-κB and MAPK pathway activation, and substantially reduces LPS-stimulated production of inflammatory mediators including TNF-α, IL-1β, IL-6, and inducible nitric oxide synthase. Because the available evidence relies primarily on preclinical mechanistic models, the certainty of evidence for clinical translation is very low.

1:19:50John Gildaysupportedvery low

Carnosic acid functions as a mild Nrf2 inducer, mild NF-κB inhibitor, and mild AMPK activator.

"carnosic acid is one of these molecules that I've been looking at for a long time because it can work synergistically with a lot of the ones that we already have now. So, it has very broad activity. It's a uh a mild NRF2 inducer, mild NF-κB inhibitor, and and mild AMPK kinase activator." (said at 1:19:50)

Preclinical studies (in vitro and animal models) support the characterization of carnosic acid—a major phenolic diterpene found in rosemary—as an agent that activates the Nrf2 antioxidant response pathway, inhibits NF-κB inflammatory signaling, and activates AMP-activated protein kinase (AMPK). Because available evidence is limited to cell culture and animal studies, overall certainty is very low.

Unverified means no publication matching the claim was located; it does not prove the claim false. Spotted an error? See the corrections policy - disputes from the people quoted are prioritized.