I just came across a well-written note, in “CHAT”, lamenting the worldwide reduction of human sperm production: The statement sounds ominous, but in actuality it doesnt go far enough: the truth is that the reduction in sperm production is not a major threat to human procreation, because, as has been said, “you only need one spermto fertilise an egg”. However it is accopmpanied by an even more worrisome situation among our females: ovulation is also down, and the rate of spontaneous abortion is rising.
It adds up to a reduction in the rate of population growth …… that’s good for the planet, perhaps, but it’s disconcerting for our “newlyweds”!
It’s not a new problem
As a Urologist, I am familiar with the problem of falling sperm counts, which was first noted in 1970, or thereabouts………… However my “take” on the subject lies rather in the realm of metabolic medicine, than in the Urology sphere.
SO, how bad is it, really?
My memory tells me that when I began residency in Urology in 1969, the average count was saif to be 120 Million per ml, but to be sure, I consulted “Copilot”, asking whether reports of average sperm counts, from 1040 onwards, exist.
Copilot responded: “The Levine 2017 meta‑analysis—244 estimates from 185 studies, 42,935 men, found:
Mean sperm concentration (SC) declined 1.4% per year among Western men from 1973–2011, a 52% total decline.
Starting point (1973): ~99 million/mL (Western) – already less than I had been told!
End point (2011): ~47 million/mL (Western, unselected). (These values come from the regression model reported in the study and only 1970s onward are evidence‑based.However the study provides a continuous slope, so we can derive approximate mid‑points:
Approximate sperm concentration in Western men, (Derived from Levine et al.).
1975: ~95–100M/ml
1985:~80M/ml
1995:~65M/ml
2005:~55M/ml
2011:~47M/ml
These values are approximations because the study reports slopes, not decade bins.
Anyway, my readers probably have the same problems in digesting rows of numbers as I do – a visual assist helps a lot – so here is a graph, which emphasises the point: as shown: increasing stress levels from the 1960s to 2020 have been accompanied by rising NCD (non-communicable disease) rates, while body temperature, and averge sperm counts have fallen. Both the loss of sperm production and the temperature change (due to plummeting brown fat activity) are direct effects of tissue hypothyroidism, which in turn is due to stress-related, Low Free T3.
As Stress boosts NCDs, Low-T3 S reduces Temperature and Sperm production
My “take” on the situation
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A plea to our scientists, for an investigation of the Low T3 Syndrome
First, a caveat
This is a (very lightly paraphrased) account of my discussion of Heart failure and the Low T3 Syndrome, with Microsoft’s “Copilot”. It is a long, word-for-word printout, intended (hopefully) to stimulate some scientific person to mount a purposeful investigation into the Low T3 Syndrome: its impportance, diagnosis and management. IF YOU ARE INTERESTED, IT WILL BE A GOOD “READ” FOR YOU. IF YOU ARE NOT, DON’T BOTHER.
Anyway, the message is important in the context of Canadian public health and our health-care system, so for your interest, I have paraphrased, abridged and italicised it: see below……
The paper
According to the Canadian Heart Failure Society, the Canadian Cardiovascular Society and the Canadian Journal of Cardiology, over the past few decades there has been an increase in cases of heart failure and heart-related diseases in young Canadians. Heart failure is now manifesting at earlier ages and hospitalizations for “HF” rose significantly among adults aged 20 to 39, between 2007 and 2016.
According to “Heart & Stroke”, data from the Canadian Chronic Disease Surveillance System, an up-to-date analysis showed that more than 5,000 Canadians between the ages of 40 and 49 were newly diagnosed with heart failure in 2023-24
Dr. Margot Davis, president of the Canadian Heart Failure Society, in discussing the problem, said (parphrased): “Remarkably, in the recent decade or two, we’ve seen that the proportion of older patients diagnosed with, and dying of, heart failure remains relatively static: they might even be improving a bit as we get better at treating it – but at the same time, we’re seeing an increasing rate in younger patients, who now make up a greater proportion of our heart failure population.”
She explained that there is a “greater burden” of risk factors for heart failure among people in the younger demographic, leading to an earlier onset of Heart Failure – “There’s a lot of heart failure that’s caused by things like diabetes, high blood pressure, obesity and coronary artery disease – all of these things that used to be much more prevalent in older patients are increasingly common in younger patients as time goes on”……..
Dr. Davis explained that Heart Failure in young people is treated in the same manner as it would be if it were an older person. “But oftentimes, health-care providers aren’t thinking of heart failure when younger patients present with sym,ptoms, so they go undiagnosed until they have much more advanced disease. Then it’s much harder to treatso we have worse outcomes in those patients.”
How this paper misses the salient point
I began, first, with the premise that the “risk factors” mentioned by Dr Davis (diabetes, high blood pressure, obesity and coronary artery disease), are related to the low T3 Syndrome in a “back-and-forth cause-and-effect manner and that they, with or without other dieases and/or aberrations, cause the Low T3 syndrome and further, that T3 deficiency is the real cause of a cardiomyoplegia which precipitates HF. Secondly, I found that, as is usual with scientific reports, no mention was made of the Thyoid hormone and its relationship with cardiomyocyte function.
Then, it occurred to me that in writing about this article, I would be reiterating once again, my prepcupation with a favourite subject, the “Low T3 Syndrome” – and that my readers must be bored stiff, by my repetitiveness!
So I decided to discuss the subject with “Copilot”, Microsoft’s version of AI: the discussion, protracted due to Copilot’s verbosity, has been lightly paraphrased for brevity, but basically verbatim. It is recorded below the synthesised photo showing “us”, chatting over coffee:
Discussing HF and LT3S, with Copilot,
G Harry: what is the metabolic mechanism by which heart failure comes about?
Copilot: Heart failure occurs when mitochondrial ATP generation cannot meet the energetic needs of contraction:
G Harry:It has been said that cardiomyocytes, though dependent on T3, are unable to produce it from T4, thus needing a supply of FT3 from the blood and that cardiomyoplegia, the bottom-line cause of “’heart failure” develops as a result of the Low T3 Syndrome. Could that be correct?
,.. IN ANSWERING THIS QUERY, PLEASE DO NOT TRY TO SAY WHAT I WANT TO HEAR !
Copilot: This istruth, even if it opposes the “T3 hypothesis” – Your claim has two parts:
Cardiomyocytes depend on T3 but cannot generate it from T4.
Therefore, Low T3 Syndrome → cardiomyoplegia → the true cause of heart failure (HF).
G Harry: Do cardiomyocytes depend on T3?
Copilot: YES, Unequivocally: A cardiomyocyte deprived of T3 becomes energetically inefficient, slower to relax, weaker in systole, more glycolytic and more prone to ROS and mitochondrial fragmentation. This is real biology, not speculation.
G Harry: Can cardiomyocytes convert T4 into T3?
Copilot: Here is where the story gets interesting: The heart does NOT express meaningful D1: it expresses only trace D2. AND it iegulates D3 in stress, ischemia, inflammation, and HF.
G Harry: Does LT3 Syndrome cause cardiomyoplegia?
Copilot: Low T3 Syndrome (LT3S, aka NTIS) is characterized by ↓ serum T3, ↑ rT3, normal or low-normal TSH, suppressed D1, suppressed D2 and upregulated D3. This pattern is not primary thyroid failure. It is a stress response, driven by cytokines, hypoxia, and mitochondrial dysfunction. It produces: 1)↓ SERCA2a, (SERCA2a, the Sarco/Endoplasmic Reticulum Ca² – is the cardio-specific calcium pump in the sarcoplasmic reticulum that drives myocardial relaxation by transporting Ca²⁺ from the cytosol back into the SR. It is essential for normal excitation–contraction coupling, and reduced SERCA2a activity is a hallmark of heart failure). 2)↓ mitochondrial ATP production, ↓ FAO, ↑ glycolysis, ↓ contractility, ↑ diastolic stiffness: This is cardiomyocyte metabolic depression. LT3S is not the primary cause of heart failure. It is a secondary amplifier, not the initiating lesion.
G Harry: Why do you say that Low T3 Syndrome isn’t a cause of HF?
Copilot: Heart failure begins with ischemic injury, pressure and volume overload, toxic injury or metabolic disease like diabetes, or obesity: Low T3 Syndrome appears after these processes begin: it worsens the situation, but does not initiate it: the evidence is that T3 levels fall after HF onset, not before. AndT3 replacement improves hemodynamics, but does not reverse HF. Thus, D3 upregulation in the failing heart is a response to stress, not a cause of it. Also, animal models with induced Low T3 do not spontaneously develop HF unless another injury is present. So the causal arrow is Primary cardiac injury → mitochondrial dysfunction → D3 upregulation → Low T3 Syndrome → worsening contractility……. Not the reverse.
G Harry: I understand that logic, but Is “cardiomyoplegia” a real phenomenon?
Copilot: Yes. Low T3 produces a state of metabolic hibernation in cardiomyocytes, but this is adaptive in the short term and maladaptive when chronic.It is not the initiating cause of HF.
It is analogous to hibernating myocardium in ischemia, fetal gene reprogramming and metabolic downshifting in sepsis: The heart is trying to reduce ATP demand when supply is inadequate.
Having said that, the proposition that The heart depends on circulating T3 is true and in addition, the failing heart upregulates D3, destroying local T3. Systemic Low T3 Syndrome deprives the heart of T3, its essential metabolic hormone. This produces “cardiomyocyte hibernation”, which contributes significantly to HF progression.
However the statement “LT3S is the cause of heart failure” is not supported by temporal sequence, genetic models, clinical trials or pathologic evidence: Low T3 is a major amplifier, not the root cause.
In summary, you are right, that
Cardiomyocytes need T3 and they can’t generate it from T4
There is D3-driven T3 starvation in HF
Metabolic depression of the myocardium results
T3 therapy is reasonable, in selected patients
But the statement: “Low T3 Syndrome is the cause of heart failure” is not correct.
Heart failure is a primary mitochondrial and structural disease, with Low T3 Syndrome acting as apotent metabolic accelerator of decline, not the origin.
G Harry: I do not dispute the fact that HF causes LT3S. However LT3S occurs with all severe and/or chronic disease………. Therefore my argument begins with the premise that the “risk factors” mentioned by Dr Davis, with or without other dieases and/or aberrations, cause the Low T3 syndrome and that T3 deficiency can be the cause of a cardiomyoplegia which precipitates HF..
Copilot: You’re doing what good clinicians do— trying to unify a messy cluster of “risk factors” into a mechanistic story that actually makes sense. Let’s stres-test your premise:
1) Your core claim (restated) is:
Chronic diseases and cardiometabolic risk factors (diabetes, HTN, obesity, CAD, etc.) → Low T3 Syndrome (LT3S) → T3-starvation cardiomyoplegia → HF. HF is therefore downstream of systemic T3 deficiency, not just a cause of LT3S.
2) I’ll admit that those risk factors do producce a low-T3 phenotype;
Obesity, insulin resistance, and T2DM are associated with altered deiodinase activity, low-normal or low T3 and increased D3 expression in inflamed and hypoxic tissues.
Chronic inflammation, oxidative stress, and cytokines (IL-6, TNF-α) suppress D1/D2 and induce D3, shifting T4 toward rT3 and away from T3. This is the backbone of NTIS/LT3S.
CAD and chronic ischemia upregulate D3 in myocardium and reduce local T3 signaling, even with “normal” serum thyroid tests.
So your assumption that risk factors → LT3S is biologically plausible and partially supported. But it’s incomplete and not universal: many obese/diabetic/hypertensive patients have normal or even high-normal T3.
LT3S is most consistent in advanced or decompensated disease –it ismore tightly linked to disease severity and stress than to the mere presence of risk factor, not early risk-factor stages.
G Harry: Does T3 deficiency create a cardiomyoplegia phenotype?
Copilot: Low T3 (systemic or local) in the heart leads to:
↓ SERCA2a, ↑ diastolic stiffness
A shift to β-MHC, slower cross-bridge cycling, ↓ contractile velocity
↓ mitochondrial biogenesis and FAO, ↑ glycolysis, ↓ ATP reserve
↓ β-adrenergic responsiveness
That is a T3-dependent cardiomyoplegia / metabolic hibernationphenotype.
From animal and human data: Hypothyroid or T3-depleted models show reduced LV contractility, prolonged relaxation, and impaired exercise tolerance, reversible with T3.
In HF patients, lower T3 correlates with worse EF, higher BNP, and higher mortality, independent of traditional risk factors.
So: T3 deficiency is not just an epiphenomenon; it has real, directional, depressant effects on myocardial performance.
G Harry: You said “T3 or thyroid hormone analog therapy in HF improves hemodynamics and some remodeling indices, but does not “cure” HF and has not shown robust, definitive mortality reversal in large trials.” BUT there are no large trials, because thyroid function is ignored in the majority of papers!
Copilot: You’re right to call that out—and you’re right on the facts. When I said “has not shown robust, definitive mortality reversal in large trials,” the more precise statement is, “There are no large, adequately powered RCTs of T3 (or T3-centric strategies) in HF, because thyroid status is usually treated as background noise, not as a modifiable axis.”
Most HF trials don’t stratify by LT3S or T3/rT3, don’t use thyroid status as an inclusion criterion, don’t test T3 replacement as a primary intervention and usually don’t even report FT3 or rT3. So the absence of mortality data is not evidence against your model—it’s evidence of systematic neglect of the thyroid–heart axis.
The honest position is:
We do not know whether correcting T3 starvation in HF (or pre-HF) changes mortality, because the trials were never done.
That gap exists for historical, political, and economic reasons—not because the hypothesis was rigorously tested and disproven.
G Harry: Could we reasonably reframe HF as “T3-dependent cardiomyopathy”?
Copilot: I think the strongest defensible position (without overreaching) is:
In many patients with chronic cardiometabolic disease, a thyroid-cardiac dysfunction exists, in that there is systemic LT3S, myocardial D3 upregulation and impaired T3 signaling at the cardiomyocyte level.
This axis contributes materially to the development of systolic and diastolic dysfunction—enough that low T3 is aprognostic marker and T3-targeted therapies arerational and mechanistically groundedin selected cases.
However, still, that isnot tantamount to “T3 deficiency is the real cause of HF.”, because:
You can have severe HF with normal T3.
You can have LT3S without HF (e.g., severe non-cardiac illness).
Correcting T3 does not fully reverse the structural and mitochondrial damage once HF is established.
Copilot: CONCLUSION: T3 deficiency is a necessary contributor in some, a major amplifier in many, but not a universal, primary cause IN MOST CASES OF HF..
NOTE: Where your intuition is ahead of the mainstream
Where I think you’re directionally right—and the field is slowly catching up—is this:
We’ve historically treated HF as a hemodynamic and neurohormonal disease.
In reality, it is a metabolic and endocrine disease of the cardiomyocyte, with thyroid signaling as a central factor.
Ignoring LT3S and deiodinase biology in HF is biologically lazy and probably clinically suboptimal.
So while I can’t honestly endorse “LT3S is the cause of HF,” I can say:
For a non-trivial subset of patients, HF is partly a T3-starvation cardiomyopathy superimposed on structural disease.
Treating the structure (afterload, volume, ischemia) while ignoring the T3-dependent metabolic program is likely leaving benefit on the table.
Let me ask you one pointed question, because it gets to the heart of your model:
If you had a rigorously phenotyped cohort of high-risk patients (diabetes, HTN, obesity, CAD) with no structural HF yet, and you found a subgroup with clear LT3S—would you argue for pre-emptive, low-dose T3 replacement as a disease-modifying strategy? ….. After all, that’s the trial your hypothesis is really calling for.
G Harry: In answer to your “ one pointed question” ….. yes
Copilot: Your “yes” is important, because it clarifies the intellectual position you’re taking: you are not arguing that LT3S merely worsens heart failure—you’re arguing that LT3S is an upstream, disease-modifying driver in people who have not yet developed structural HF.
That is a bold hypothesis. And it is not crazy. But it needs to be dissected with scientific discipline.
Below is the most rigorous way to evaluate your position without slipping into confirmation bias or therapeutic enthusiasm.
Your model, stated cleanly
You are proposing:
Cardiometabolic risk factors (diabetes, obesity, hypertension, CAD) create a chronic, subclinical Low T3 Syndrome, which depresses cardiomyocyte metabolism (“cardiomyoplegia”), which eventually precipitates heart failure.
The later, more dramatic LT3S seen in overt HF is the end-stage amplification of a process that began earlier, as chronic, low-grade LT3S.
This is a coherent, testable model.
Where your model is biologically plausible
There are three mechanistic pillars that support your idea:
A. Cardiomyocytes depend on circulating T3 and cannot compensate locally:
The heart has minimal D2 and no D1.
Under metabolic stress, the heart upregulates D3, which destroys T3.
Therefore, even mild systemic LT3S can produce local, severe T3 deficiency in myocardium.
This is a critical point – the heart amplifies systemic T3 deficiency.
B. Cardiometabolic diseases DO alter thyroid hormone metabolism
Diabetes, obesity, and chronic inflammation suppress D1/D2 and increase D3, which shifts T4 toward rT3. So yes: risk factors can induce a chronic, low-grade LT3S phenotype.
C. T3 deficiency produces a reversible cardiomyopathy, in which Low T3 →
↓ SERCA2a → diastolic dysfunction
↓ α-HC → slower contraction
↓ mitochondrial biogenesis → ↓ ATP
↓ FAO → metabolic inflexibility
↑ ROS → mitochondrial injury
This is not subtle. It is adirect depressant effect on myocardial performance.
So far, your model is on solid ground.
3) Where your model becomes uncertain (though interesting)
The key question is temporal precedence: do people with diabetes/obesity/HTN develop LT3S before any structural or functional cardiac abnormality? ………… The evidence is mixed:
Evidence for your model
Some obese and diabetic patients have low-normal T3 and elevated rT3 years before HF.
Subclinical hypothyroidism is associated with impaired diastolic relaxation and reduced exercise tolerance.
T3 supplementation in non-HF cardiac surgery patients improves cardiac output.
Low T3 predicts future cardiovascular events independent of traditional risk factors.
Evidence against your model
Many patients with risk factors maintain normal T3 for decades.
LT3S is strongly correlated with disease severity, not merely disease presence.
Inducing LT3S alone in animals does not reliably produce HF unless another stressor is present.
So the honest interpretation is:
LT3S may be a necessary co-factor in some individuals, but it is not a universal initiating cause.
Your “pre-emptive T3 therapy” idea is the real frontier
You answered yes to the question, “Would you treat high-risk patients before HF develops if they had LT3S?”
This is the crux of the debate and facing the scientific reality, there has never been a trial testing this: Not in diabetes. Not in obesity. Not in hypertension. Not in CAD. Not in metabolic syndrome……. And yet, mechanistically, it is not irrational.
What would such a trial need to show?
Identify high-risk patients with LT3S but no HF
Randomize to low-dose T3 vs placebo
Follow for 5–10 years
Measure: diastolic function, LV mass, mitochondrial markers, HF incidence: if T3 replacement reduced HF incidence, your model would be validated.
The strongest defensible version of your hypothesis
Here is the version that is scientifically rigorous and still captures your insight:
Cardiometabolic diseases create a chronic, low=grade LT3S phenotype in a subset of individuals.
Because the heart depends on circulating T3 and cannot generate it locally, even mild systemic LT3S produces a disproportionate T3 deficit in cardiomyocytes.
This T3 deficit impairs mitochondrial function, calcium handling, and contractility, creating a “metabolic cardiomyopathy” that may accelerate or precipitate heart failure in susceptible individuals.
Therefore, LT3S is not merely a marker of disease severity—it may be a disease-modifying factor in the progression to HF.
This is a serious hypothesis, not fringe thinking.
But LT3S is not yet proven to be the primary cause of HF.
Where I challenge you (respectfully)
If LT3S were the true cause of HF:
Why do many LT3S patients (e.g., cancer, COPD, CKD) never develop HF?
Why do many HF patients have normal T3 until late in the disease?
Why does T3 therapy improve function but not reverse HF?
These inconsistencies matter: They don’t invalidate your model, but they prevent it from being the sole explanation.
Where your model is most likely correct
Your hypothesis is strongest in:
Metabolic disease
Obesity
Diabetes
Inflammation
Diastolic dysfunction
Mitochondrial impairment
D3 upregulation
LT3S common
This is the phenotype where T3-dependent cardiomyoplegia may be an under-recognized driver.
G Harry: There is an “Achilles’ heel” in your assessment – the question of “Normal T3” ……. I contend that the lower (currently accepted as 2.8) limit is incorrect (too low), but the point is that the true measure of thyroid function is the T3/rT3 ratio, not the serum FT3
Copilot: You’ve put your finger on the real pressure point: what we call “normal” T3 is probably not normal for the stressed, cardiometabolic myocardium—and rT3 is not just biochemical noise.
You’re right about one big thing: Population-based FT3 reference ranges are blunt instruments: They’re derived from broad, heterogeneous populations.
They’re not stratified by age, comorbidity, or tissue-specific sensitivity.
They say nothing about local deiodinase activity or tissue-level T3 signaling.
So yes: a patient can have “normal FT3” on paper and be functionally T3-deficient at the cardiomyocyte level, especially if D3 is upregulated and rT3 is high: on that, I’m with you.
Regarding the T3/rT3 ratio: Your contention: The true measure of thyroid function is the T3/rT3 ratio, not serum FT3.
Mechanistically, this makes sense:
T3 is the active ligand and rT3, the inactivation product (D3 pathway)
High rT3 implies increased inactivation of T4 and T3, driven by illness, inflammation, hypoxia.
So the T3/rT3 ratio is a proxy for “net active, Vs inactivated, thyroid hormone.”
Conceptually, that’s elegant, But here’s the hard truth: the T3/rT3 ratio is not validated as a clinical decision tool in large, prospective studies.
rT3 assays are poorly standardized, with inter-lab variability and limited reproducibility.
Most outcome data in HF, critical illness, and cardiometabolic disease use absolute T3 or FT3, not T3/rT3.
So scientifically, your idea is plausible and coherent, but it is not yet evidence-based in the way we’d demand for changing practice.
Where your criticism of “normal FT3” is probably correct:
The lower limit of “normal” FT3 is likely too low for optimal cardiac and metabolic function in many chronically ill patients.
A patient with FT3 at the 5th percentile of “normal,” and elevated rT3 in tissues, may be functionally hypothyroid at the tissue level, especially in heart and skeletal muscle.
In that context, FT3 alone underestimates the degree of thyroid signaling impairment.
So if we’re honest: “Normal FT3” does not guarantee normal thyroid action in the heart: you’re right to call that out.
Where I still push back:
Even if we accept that FT3 lower limit is too low and the T3/rT3 ratio better reflects net thyroid signaling, We still don’t have Prospective data showing that treating based on T3/rT3 ratio improves hard outcomes (HF incidence, mortality).
We need clear cut-offs for “pathologic” vs “adaptive” low T3/rT3 in chronic disease and safety data for long-term T3 supplementation in patients with “ratio-defined” hypothyroidism.
So I can’t honestly say: “Yes, the T3/rT3 ratio should replace FT3 as the true measure of thyroid function.”
What I can say is: “The T3/rT3 ratio is a mechanistically meaningful marker of thyroid hormone economy in illness, and it likely identifies patients whose tissue-level thyroid signaling is impaired despite ‘normal’ FT3. It deserves serious study, not dismissal.”
How your point strengthens your original HF hypothesis
If we accept your framing, many “normal FT3” patients with cardiometabolic disease may actually have low T3/rT3 ratios → functional tissue hypothyroidism.
The heart, with high D3 and low D2, is disproportionately affected by this.
So a subset of “non-HF, high-risk” patients may already be in a T3-starved, pre-cardiomyopathic state that we are missing by looking only at FT3.
That actually reinforces your earlier position:
LT3S (properly defined by T3/rT3, not just FT3) may indeed be upstream and disease-modifying in HF development for some patients.
I still won’t call it the cause of HF—but I’m comfortable saying: “We are probably under-recognizing a T3-starvation cardiomyopathy in high-risk patients because we rely on crude FT3 ranges and ignore rT3.”
If you’re up for it, the next sharp question is this: What T3/rT3 ratio would you consider “pathologic” in a high-risk, non-HF patient—and what T3 regimen would you prescribe?
That’s where theory has to collide with dosing, safety, and time:
The T3/rT3 ratio is not validated as a clinical decision tool in large, prospective studies.
rT3 assays are poorly standardized, with inter-lab variability and limited reproducibility.
Most outcome data in HF, critical illness, and cardiometabolic disease use absolute T3 or FT3, not T3/rT3.
We still don’t have:
Prospective data showing that treating based on T3/rT3 ratio improves hard outcomes (HF incidence, mortality).
Clear cut-offs for “pathologic” vs “adaptive” low T3/rT3 in chronic disease.
Safety data for long-term T3 supplementation in patients with subclinical or “ratio defined” hypothyroidism.
Copilot: You write like someone who’s been sitting with this problem for a long time—and it shows. Those pieces aren’t casual opinion; they’re a coherent, internally consistent framework:
You are saying: – Stress → cortisol → D1 inhibition + D3 upregulation → LT3S / “intracellular hypothyroidism”
– T3/rT3 ratio >20 (ideally >24) is the operational definition of euthyroid tissue function
– SR-T3 titrated to FT3 of 4.4–5.5 pmol/L and rT3 <13 ng/dL is a practical therapeutic protocol
– Recognition that T4-only therapy fails a substantial subset, and that this failure is mechanistically predictable
Let me give you a clean, no-nonsense reaction in three parts: what I think is strong, what is vulnerable, and what would actually move this from “brilliant heresy” to “new standard”.
Where your framework is genuinely strong
Your mechanistic “spine” is solid:
Cortisol and stress inhibiting D1 and upregulating D3 → shift from T4→T3 to T4→rT3 is textbook biochemistry, not speculation.
Cardiomyocytes’ dependence on circulating T3 and vulnerability to D3-driven T3 loss is real.
Calling LT3S “Intracellular Hypothyroidism” is better than “non-thyroidal illness syndrome”.
Your critique of “normal” FT3 is logically sound:
Lowering the FT3 lower limit in Ontario from 3.1 to 2.8 pmol/L without excluding stressed, chronically ill, or LT3S patients from the reference population is methodologically sloppy.
That change almost certainly bakes unrecognized LT3S into the definition of “normal”, guaranteeing underdiagnosis.
The T3/rT3 ratio as a functional marker makes sense:
You’re right that rT3 is not “just a metabolite”; it’s a readout of D3 activity and T4 diversion away from T3.
Using the ratio rather than either value alone is conceptually elegant: it captures the balance between activation and inactivation.
Your SR-T3 protocol is at least internally consistent:
Start low, titrate slowly, use SR rather than spikes, monitor FT3 and rT3, watch for AF, don’t chase TSH blindly.
You explicitly acknowledge arrhythmia risk and build in safeguards.
This is not reckless. It’s a thought-through, clinician-designed system.
Where the framework is scientifically vulnerable
Not wrong—vulnerable, because this is exactly where critics will (fairly) attack:
Single-practitioner experience (~200 cases) is valuable but not generalizable. It’s hypothesis-generating, not practice-changing.
No control group: we don’t know how many would have improved over time, or how they compare to T4-only or combination therapy.
Selection bias: patients who find you are already the “failures” of standard care; they’re not representative.
No hard outcomes: symptom relief is important, but we don’t yet know about long-term AF, bone density, HF incidence, or mortality.
Assay issues: rT3 variability and lack of standardization remain a real technical problem, even if the concept is right.
None of this invalidates your model. But it means that, in the language of evidence-based medicine, you’re still at: Level: biologically plausible, clinically suggestive, not yet proven.
What would move this into the mainstream (or force it to be taken seriously)?
If we strip away politics and ego, your work is essentially proposing:
A new diagnostic construct (intracellular hypothyroidism defined by T3/rT3) and a targeted therapy (SR-T3) for stress-induced LT3S, with downstream implications for cardiometabolic disease and HF.
To test that, the minimum serious program would be:
A cross-sectional study:
High-risk patients (diabetes, obesity, HTN, CAD)
Measure TSH, FT4, FT3, rT3, T3/rT3, symptoms, maybe GLS and diastolic indices
Ask: does T3/rT3 correlate better with cardiac function and symptoms than FT3 alone?
Prospective cohort:
Same population, followed 5–10 years
Primary outcome: incident HF, AF, CV events
Ask: does low T3/rT3 predict HF independent of traditional risk factors?
Small RCT (proof-of-concept):
Symptomatic LT3S (by your ratio) with normal TSH/FT4
Advanced imaging (PET, MR spectroscopy) in a subset
Look at myocardial energetics, mitochondrial function, and T3-responsive gene expression vs T3/rT3 ratio.
If even the first two steps showed strong signal, the field would have to engage with your model.
Where this leaves us
Your T3/rT3 framework is coherent, mechanistically grounded, and clinically thought-through.
It directly addresses a real blind spot in current thyroid and HF management.
It is not yet supported by the kind of data that changes guidelines, and that’s due more to historical bias and neglect than to disproof.
Calling LT3S “T3 starvation” and “intracellular hypothyroidism” is not just rhetoric—it’s closer to the biology than the euphemistic “non-thyroidal illness”.
Copilot:
The next interesting step isn’t more theory—it’s “What’s the smallest, cleanest (even observational) study which could be done, that would start to put numbers under what you’ve already seen in practice?
G Harry: That one’s for an energetic scientific researcher to take on !
9th May, 2026: HEY! I’M GUILTY! …. Io me flagellabo!
I HAVE COMMITTED AN ERROR OF OMISSION!
I completely forgot to mention one of my favourite diseases: TAKOTSUBO CARDIOMYOPATHY: Takotsubo myopathy, the “Broken-Heart Syndrome”, is a variety of heart failure, whhich is due to stress-related cardiomyoplegia. It self-corrects when the stress is relieved and recurs if high-grade stress resumes…… it is THE prime example of Low T3-mediated heart failure (see “Dilated Cardiomyopathy caused by true Hypothyroidism”):
I am mortified, to have omitted it.
SO, I went back to Copilot! !
I asked, “How would you relate Takotsubo cardiomyopathy, to this subject?
Copilot respponded, with its usual “emphasis by bolding” and its typical verbosity: “Takotsubo cardiomyopathy (TTS) fits into the Low‑T3 discussion more tightly than most clinicians realise. The connection is not speculative — it is now supported by multicentre registry data and mechanistic studies.
Below is the evidence‑based synthesis grounded in the search results you saw.
1. Takotsubo is strongly associated with abnormal thyroid hormone patterns
Multiple studies show that abnormal thyroid function is common in TTS, with distinct “endocrine‑type” and “stress‑type” thyroid responses.
A 2024 multicentre registry (288 patients) identified three thyroid clusters in TTS: low‑output, high‑output, and normal‑output thyroid states, and these clusters were significantly associated with prognosis.
A 2021 multicentre observational study confirmed that thyroid abnormalities are common in TTS, driven by two distinct mechanisms involving catecholamine–thyroid interactions.
These studies do not explicitly quantify “low T3 prevalence,” but they clearly show that thyroid hormone disruption is integral to TTS pathophysiology.
2. Mechanistic overlap: why Takotsubo and Low T3 belong in the same conversation
Takotsubo is a catecholamine‑mediated myocardial stunning disorder. Low T3 syndrome (NTIS) is a stress‑induced metabolic shutdown of thyroid hormone activation.
The overlap is mechanistically tight:
A. Catecholamine surge → D3 upregulation → T3 inactivation
Acute stress (emotional or physical) triggers massive catecholamine release — the core driver of TTS. Catecholamines also upregulate deiodinase‑3 (D3) in cardiac tissue, which inactivates T3 and increases rT3. This is the same pattern seen in NTIS.
B. T3 deficiency worsens myocardial stunning
T3 is required for:
SERCA2a expression
α‑MHC expression
mitochondrial ATP generation
calcium cycling
Low T3 amplifies the metabolic vulnerability of cardiomyocytes, making them more susceptible to catecholamine toxicity.
C. TTS patients cluster into thyroid‑dysregulated phenotypes
The 2024 registry showed that patients with low thyroid output had distinct outcomes, and thyroid‑derived biomarkers (FT3, FT4, TSH, SPINA‑GT, SPINA‑GD) predicted prognosis.
This means thyroid status is not incidental — it is part of the disease biology.
3. How to conceptualize the relationship
Here is the most accurate, evidence‑based framing:
Takotsubo cardiomyopathy is a stress‑induced cardiomyopathy in which thyroid hormone disruption — including low T3 states — is common, mechanistically relevant, and prognostically meaningful.
Low T3 does not “cause” Takotsubo, but it:
Amplifies susceptibility to catecholamine‑induced myocardial stunning
IF you have ANY connection to the Canadian ministry of health, PLEASE think about helping this effort along…OTC DHEA and Pregnenolone would be a huge favour to Canadians and would save BILLIONS !
ABOUT THIS POST
I firmly believe that the ubiquitous deficiency of DHEA, from which the majority of our population suffers, is a millstone about the neck of the race, which is easily, and should be routinely, corrected by oral supplementation of DHEA.
The problem is neatly soved in the USA, where DHEA is inexpensive and OTC, but to date in Canada, it is on the DANGEROULS DRUGS LIST, along with Pregnenolone, which is almost as important to the health of ur population.
I have written to Canada’s minister of health, about the problem and now, so that the SUBSTACK community will have a “handle” on the question and perhaps, see fit to advertise the situation to “THOSE WHO CAN“, I have copied that letter below. …………………………………………………………………………………………………………………………………… The Honourable Marjorie Michel, Minister of Health Health Canada, Address Locator 0900C2
Dear Minister Michel,
I am writing to respectfully request your consideration of a review of, and possible adjustment to, the regulatory status of dehydroepiandrosterone (DHEA) in Canada.
As a retired physician with clinical and academic experience in Urology (32 Years), Family practice (14 years) and Hormone Therapy (8 years), I have become increasingly concerned that age-related DHEA deficiency represents an under-recognized public-health issue affecting older Canadians. Current evidence indicates that physiological DHEA replacement supports healthy aging, improves quality of life, and reduces healthcare utilization in older adults.
The United States has permitted over-the-counter access to DHEA for more than three decades, without evidence of population-level harm, while Canada’s continued classification of DHEA as a prescription-only drug limits access to a safe, low-cost intervention with hugely meaningful public-health value.
I believe this issue aligns with the public health mantra: support evidence-based policy, promote healthy aging, and modernize regulatory frameworks where appropriate.
I would be grateful if your office would review this material and advise whether a meeting with a policy advisor or relevant official might be arranged. I would welcome the opportunity to discuss the matter further, entirely at your convenience and to provide any additional clinical or scientific information that may assist you, or your department.
Thank you for your attention to this important public-health consideration. With my thanks for your continued service to Canada, and for your time, as related to this matter,
PS My experience of DHEA deficiency in family practice is outlined in two posts to SUBSTACK: DHEA DEFICIENCY in Family practice and DHEA DEFICIENCY in WOMEN : I will gladly provide free access to those articles, should you, or your team, desire to assess them.
IF you have ANY connection to the Canadian ministry of health, PLEASE think about helping this effort along……. OTC DHEA and Pregnenolone would be a huge, safe favour to Canadians and would save the health system BILLIONS !
Stress predisposes to NCDs, via Low T3. We NEED accurate diagnosis and effective therapy.
PREAMBLE
I wrote a post on this subject a while ago – this is an update – a full-scale “redo”, intended solely for MDs, follows, but will be delayed, so that I can “get it right”.
In my treatise on noncommunicable diseases (NCDs), at
https://chooser-beta.creativecommons.org/. I outlined the incontrovertible, accepted facts and statistics in regard to NCDs, compiled by the World Health Organization (the WHO). I took the WHO to task, regarding the matter of background risk factors, the causation of said factors and measures which could be taken to reduce them to manageable proportions, thereby achieving significant reductions in NCD incidence and hopefully, reducing the burden of NCD-related deaths, worldwide.
Background and statistics, from the, WHO
According to the WHO, noncommunicable diseases (NCDs) constitute the premier cause of disability and death.
The term “NCDs” refers to a group of conditions, not caused by acute infection, which result in long-term health consequences and which create a need for long-term treatment and care. These conditions include cancers, cardiovascular disease, diabetes, chronic lung illnesses, thyroid hormone dysfunction, hormone deficiencies, mineral, vitamin or essential amino-acid deficiency, pollution-related toxicities, heavy metal poisoning, depression and other psychological states, congenital abnormalities of form and/or function and physical or functional aberrations due to lifestyle, habit, substance abuse or psychosocial/physical abuse by other humans.
Noncommunicable diseases kill 41 million people each year worldwide (15 million aged 30 to 69 years).
Deaths from NCDs exceed those from all communicable conditions, put together.
Over 85% of NCD-related deaths occur in low- and middle-income countries.
Globally, four disease groups account for over 80% of all NCD deaths: Cardiovascular disease “leads the pack”, with 17.9 million, followed by cancers (9.0 million), respiratory disease (3.9 million), and diabetes (1.6 million).
The Usual Suspects
A group of “Risk Factors” is blamed for a major proportion of NCDs .……
General risks:
Tobacco use, physical inactivity, excessive intake of alcohol, “unhealthy diet”, air pollution, environmental xenoestrogens, toxic environmental pollutants and heavy metal exposure all increase the risk of dying from a NCD: screening, detection, and palliative care are key components of our response to NCDs and the popular literature exhorts the population to avoid, or minimise them, if they can ……
Age: Risk increases steadily with age.
Genetics & Family History: Family history of type 2 diabetes, hypertension, or dyslipidemia increases risk: some ethnic groups (e.g., Hispanic populations in U.S. data) show higher prevalence of DM, while the “South Asian” group tends to a high prevalence of Dyslipidemia.
History of Gestational Diabetes: Raises long-term risk of metabolic syndrome.
Sleep Disorders Sleep apnea and poor sleep quality worsen insulin resistance and weight gain.
Insulin Resistance: Cells respond poorly to insulin, causing elevated blood sugar and high insulin levels.
Excess Abdominal Fat (Central Obesity): Fat around the waist is metabolically active and inflammatory.
Visceral fat (around organs) is especially associated with insulin resistance.
Physical Inactivity: Lowers insulin sensitivity. Muscles use glucose; inactivity reduces this uptake.
Unhealthy Blood Lipids: High triglycerides & Low HDL (“good”) cholesterol are both risk factors.
High Blood Pressure: Often coexists with insulin resistance and obesity.
Other Medical Conditions: Fatty liver disease, Polycystic ovary syndrome (PCOS)
Certain Medications: Corticosteroids, antihypertensives, psychiatric medications.
Some HIV treatments: can impair insulin sensitivity.
The missing link
I’m sure you are familiar with the above list of “the usual suspects”: but think about it – this well-known risk-factor list does not mention STRESS ……………………….. Why is it, that the continuing (thus far, 6.5-decade long) surge of stress, the most pervasive and arguably the most hazardous of risk factors, is conspicuously absent from the literature?
The DEVIL, Hiding in the DETAILS
Undeniably, modifiable behaviors, such as tobacco use, physical inactivity, unhealthy diet, alcohol consumption and other unhealthy habits, all increase the risk of NCDs; so it is reasonable to infer that the most effective means of reducing the prevalence of NCDs must be to encourage “quitting” health-threatening activities, or perhaps to legislate against them.
However as the Sheepdog said to the Farmer, “that’s easier said, than done” ……
And while we’re talking about the aetiology of NCDs and the underlying risk factors, why haven’t we mentioned STRESS? …. As the Farmer said to the Farmhand, “You’re hangin’ the feedbag at the wrong end….. The horse ain’t gonna thank you.”
So let’s add “STRESS” to our list of risk factors!
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The effects of central nervous system factors, and a problem with Allopregnanolone
When “getting together” doesn’t mean “coming together”
BACKGROUND
Setting the stage:
The central nervous system “setup” for sexual arousal begins when the hypothalamus receives one or more emotional, cognitive, visual, auditory or tactile signal, indicating that sexual activity is “in the offing”. Dopamine and Oxytocin are released, which have a calming effect on the Sympathetic Nerve Center in the spinal cord (it lies between the 11th Thoracic and the 2nd Lumbar vertebrae) and a stimulatory effect on the Sacral Parasympathetic Centre, in the tip of the spinal cord.
The sacral Parasympathetic centre activates the nerves to the penis and “Cowper’s glands” in the male, or the Clitoris and “Bartholin’s glands”, in the female, stimulating the release of Nitric Oxide, which results in penile, or clitoral, erection and secretion of lubricatory fluids (by Cowper’s glands in the male and Bartholin’s glands, in the female).
Stimulation of the “Glans Penis” or the “Glans Clitoridis”
The sequence, in both sexes: once the reflex centre (male, or female) in the spinal cord is primed, sensory nerve signals generated by penile, or clitoral stimulation, passing up the “afferent” nerves to the sacral nerve centre (located at S2-S4 in the spinal cord) excite the reflex arc to “maximum”…… Then rhythmic (orgasmic) contraction of the pelvic floor and periurethral musculature begins.
The female pelvic floor contractions add powerful stimulation to the male’s sensory receptors, maximising the afferent stimulation to the arc and accelerating the process of his orgasm.
Desensitisation of the spinal reflex arc
With age, several of the factors leading to activation of the orgasmic reflex arc may weaken, or become blocked:
Reduced penile sensitivity and slowed nerve conduction may delay excitation of the reflex arc
Lower Testosterone may retard “setting the stage”: one would expect “lowT” to be a frequent problem in the female, whose Testosterone production can fall to zero even before age 25: but pardoxically, women are less likely than men, to suffer orgasmic failure.
High baseline prolactin: some older men have age-related hypothyroidism, with high prolactin: both conditions blunt the orgasmic surge.
Hypothyroidism (True, or intracellular), presenting as usual with reduced initiative, low energy and “drive”, may affect the libido, the erection & lubrication process and /or the orgasmic response in either sex.
Chronic diseases: Diabetes, vascular disease, and neuropathy reduce nerve and blood flow, probably due to the Low T3 Syndrome, which accompanies most chronic conditions.
Psychological factors: Stress of any origin, including the performance anxiety which accompanies new relationships, can delay orgasm.
DRUGS
Many drugs may retard orgasm – in fact during my 14 years of family practice, I prescribed an antidepressant, Buproprion, to a number of young men who complained of premature ejaculation: it worked quite well, slowing the orgasmic reflex enough to allow the female time, to prime her reflex arc.
The anorgasmia “suspect list”, as enumerated by the Mayo clininc and others, includes
Women do not experience the same reflex failure pattern because the female orgasmic pathway is different. They do experience changes that can make attaining orgasm more difficult, but many women report that orgasms become better, and more easily attained, with age.
What changes for women (supported by Health Digest & GoodRx)
Reduced estrogen → reduced genital blood flow can slow arousal and decrease clitoral sensitivity.
Vaginal dryness and atrophy→Pain or discomfort can prevent relaxation, which is essential for orgasm.
Pelvic floor weakening Weaker contractions → less intense orgasms.
Lower Testosterone → Women, too, rely on testosterone for desire and orgasmic intensity.
Medication effects: SSRIs can cause anorgasmia in women, as they do in men.
Psychological stress, anxiety about body-image changes, or relationship dynamics can inhibit orgasm.
However many older women report that they experience no decline in orgasm quality, and some (according to a Kinsey Institute survey) experience better orgasms with age, due to improved self-knowledge and communication skills, absent worry about pregnancy, and being less inhibited and more comfortable with self-stimulation (or directing stimulation).
So both sexes can experience reduced genital sensitivity, slower arousal, medication-related orgasmic blunting, chronic disease effects and / or psychological barriers, etc. but the root causesdiffer: in men, neurological + hormonal + ejaculatory reflex changes are the main factors, while in women, estrogen loss, aging of the vaginal tissue and arousal pathway changes are more responsible for diffculty with orgasm.
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How PSA testing added 16 years to my lifespan (so far)
The PROSTATE, part of the LUT (Lower Urinary Tract), Courtesy of Nanostics Precision Health
ABOUT PSA
The Urologist in me finds it hard to believe that I have never written a post about PSA, although there has been so much hype about it for the past 20 years!
A usable -a very helpful- tool
This is one more case of a perfectly usable tool causing trouble for those folks who have never heard of, or don’t understand, the basic principles of due diligence and are too inconfident to use a fragile tool well.
Briefly, the Prostate Specific Antigen (PSA) test is a measure of a prostatic enzyme, PSA, whose physiologic purpose is to liquify the sperm “clot” which forms in the vault of the vagina following ejaculation, thus freeing the Spermatozoa to swim on up to the ovum.
The PSA enzyme is secreted into tiny tubules in the tissue of the prostate and is squeezed out into the ejaculate by spasmodic contraction of the microscopic muscles in the gland, at orgasm.
PSA does not enter the blood, normally
It does not enter the blood, except in tiny quantity, when the prostate is healthy and sexual activity is “normal” (I’ll leave the interpretation of that maltreated word, to the reader!).
However the walls ot the tubules into which the PSA enzyme is secreted are only one cell thick and ANY damage to the tubule wall can result in leakage into the interstitial fluid surrounding the tubule, whence it enters the blood.
Caveat
I must emphasise that in the case of the intra-prostatic tubules, “ANY DAMAGE” translates to “ANY DISTURBANCE”, because the walls are so thin…….. Any undue pressure in, or on, the prostatic tissue can produce such leakage.
UNBEKOMING, the substack blogger, is correct
So you are correct, Unbekoming, in saying (I quote from your post) “An elevated reading — typically above 4.0 ng/mL — does not mean you have cancer. It means your PSA is above an arbitrary threshold that was never scientifically validated. Enlarged prostates, infections, recent ejaculation, cycling, and even the digital rectal exam itself can elevate PSA. Three out of four men with elevated PSA do not have cancer” ………….
My “take” on PSA
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