Intracellular thyroid 3 deficiency, which I refer to as Intracellular Hypothyroidism (IH), has been called many names (see below), but has never been recognized as a bona fide metabolic abnormality deserving of its own title.
This is perhaps a part of the reason why it has not been taken seriously by mainstream medicine and why its diagnostic panel has not been added to the family doctors’ armamentarium, now 9 years since it was definitively described in 2014.
It is time for doctors, indeed for the entire population, to elevate this miserable, dangerous, vexing, disturbing, upsetting, ubiquitous metabolic abnormality to its rightful place as a syndrome on its own, so that it can be seen as the pervasive, morbid condition which plagues so many of us.
This article therefore is (hopefully) intended to educate our people and their doctors: to help us navigate this life, free of the yoke of intracellular thyroid 3 hormone starvation.

History of IH
Our understanding of the metabolism of thyroid hormones within our cells has been nicely explained by Dr. Kent Holtorf, who in 2014, first described of the effects of intracellular T3 starvation, ascribing it to failure of thyroid hormone transport into cellular tissue [1].
Subsequently, writing with Erika Schwartz as the metabolic process became clearer, he briefly considered giving IH the title “reverse T3 dominance”: rT3 was credited with an active role in blockading access of T3 to thyroid receptors [2].
His final paper on the subject [3] succinctly explains the true situation; to quote him,
”D1 converts T4 to active T3 throughout the body, but not in the pituitary, where T4-T3 conversion is controlled by D2.
D1 but not D2 is suppressed and down-regulated (decreasing T4 to T3 conversion) by cortisol, secreted in response to physiologic and emotional stress.”

Simply put, the situation is clear: under stress, no T3 is produced intracellularly, because D1 is blocked by cortisol.
Also, any pre-existing T3 is destroyed by D3, again with cortisol as the trigger: thus intracellular T3 starvation results.

Stress-related, intracellular T3 starvation, previously termed “Reverse T3 dominance” by Kent Holtorf and Erika Schwartz, is called “Functional Hypothyroidism” by the Metabolic Medicine community. It is also known as “Subclinical Hypothyroidism”, “Euthyroid Sick Syndrome” and “Nonthyroidal Illness Syndrome”, by mainstream medicine.
However the most appropriate term is Intracellular Hypothyroidism (IH), because the condition actually is insufficient T3 within the cells [4].

We now know that the aberration is due to two intracellular effects of cortisol: blockade of Deiodinase 1, with failure of conversion of T4 into T3 and activation of Deiodinase 3, which converts T4 to reverse T3 and T3 to T2.
As defined, IH (intracellular T3 deficiency) results from the actions of cortisol, which is released by the adrenal glands in response to stress: Cortisol blocks Deiodinase 1, preventing conversion of T4 to T3 and it activates Deiodinase 3, which converts T4 to rT3 and pre-existing T3 to T2: rT3 and T2 are both metabolically inactive [5].  

Intracellular Hypothyroidism is ubiquitous. Conjecturally, it is the most pervasive metabolic aberration.
It may result from, or may cause, illness, but notwithstanding, it accompanies all life-threatening illnesses.
IH is found in the vast majority of chronic debilitating conditions, in prolonged depression and in morbid obesity, in anorexia nervosa and starvation.
It complicates severe physical injury, major surgery, significant psychoshock and any acute illness severe enough for admission to an intensive care unit.
It is associated with heart failure, cardiomyopathy [6,7], Long Covid [8], PTSD, Chronic Fatigue Syndrome [9], ME, Fibromyalgia, the post-finasteride syndrome, infertility with recurrent abortion, major depression, schizophrenia, chronic true hypothyroidism and a host of other conditions, including neurological and neuromuscular diseases, such as Multiple Sclerosis, Parkinson’s disease, Alzheimer’s disease, Hoffman’s syndrome [10], stiff person syndrome [11].
It is reasonable to conclude that IH accompanies each and every severe disease, but “the message has been lost in translation”: as an example, an extremely thorough, erudite and otherwise admirable report on ALS [12], published in 2021, considers all possible etiologies of ALS: the reported battery of tests included thyroid profiles, but there was no mention made of reverse T3, without which IH cannot be diagnosed.

IH may be short-lived, existing only as long as the stressful episode persists, or may be a long-term accompaniment to chronic stress [13].
It tends to self-perpetuation, because the confusion, psychological uncertainty and anxiety which hypothyroidism produces keep the person’s “subconsciously perceived” stress high even after the original stressful situation has gone.
Thus it is often confused with chronic fatigue syndrome (CFS) and it is probably the cause of “Long Covid” symptoms [8].

IH can be asymptomatic, especially in confident people who have high self-esteem and tend to endure mild symptoms without complaint [13]: some people are able to hide, or ignore, their low-thyroid symptoms.
However asymptomatic IH is easily diagnosed on the basis of the T3/rT3 ratio.
Caveat: in uncomplicated true hypothyroidism, the TSH is elevated to >2.5 [14] and serum FT4 and FT3 are low, whereas in IH, TSH and FT4 may be normal, but FT3 is at, or below, the low end of the “normal” T3 range and reverse T3 is sufficiently increased to reduce the T3/rT3 ratio to less than 20.0 [15].
The diagnosis of IH is usually missed by doctors, because TSH is traditionally believed to be the only necessary diagnostic parameter for thyroid function and in IH, TSH production is normal, because the pituitary gland is unaffected by the condition.
Therefore a “thyroid profile“, including TSH, free T4 (F T4), free T3 (FT3) and rT3 should be included in every diagnostic test series, regardless of the reason for the investigation.

Comparison with true hypothyroidism:
True hypothyroidism (TH) may coexist with IH, in which case investigation usually suggests a diagnosis of TH, because:
(1) TSH is elevated to > 2.5
(2) FT4 is low, or below the normal range,
(3) FT3 is at, or below, the low end of the normal range,
(4) rT3 production is restricted by the low T4, so it is only minimally elevated and the T/rT3 ratio is borderline.

Thus in combined true and intracellular hypothyroidism, the IH is often masked until T4 is prescribed and a follow-up thyroid profile is done. The situation then becomes obvious, because:
(1) TSH has returned to normal,
(2) FT4 has increased,
(3) FT3 remains low,
(4) rT3 has increased, due to preferential conversion of exogenous T4 to reverse T3 and the T3/rT3 ratio is less than 20.

The “normal” ranges for TSH, FT3 and rT3, as advertised by traditional allopathic medicine are all suspect: see “Think About Normal” [15], at, or via “research gate”.

Calculation of the T3/rT3 ratio, from the thyroid profile results:
T3 is reported in Picomoles per litre (Pm/L) and rT3 is reported in Nanograms per decilitre (ng/DL)
To obtain the ratio, we first convert the T3 value to ng/DL, by dividing FT3 by 0.0154.
We then divide the T3 (ng/DL) by the rT3 value: this gives us the “T3/rT3 ratio”*.
The accepted normal ratio is >20 and the preferred optimum is >24.
Intracellular hypothyroidism is diagnosed if the ratio is <20.

*Cameron Sutherland’s T3/rT3 ratio table is available online, at /media/driveD/AUser/Documents/A WORK AIDS/Cameron Sutherland’s T3 – rT3 Worksheet: see a truncated version, below.
Brief perusal of this T3/rT3 ratio table will show that if serum T3 is 5.2, a normal T3/r T3 balance will obtain unless the rT3 value is > 17 and that when serum T3 is 6.2, a normal balance obtains until rT3 exceeds 19.

Rating the severity of IH:
It is reasonable to rate the severity of intracellular hypothyroidism thus: 7-10 = Severe, 11-15 = Moderate, 16-20 = Mild.
However the degree of IH varies with the individual’s stress level and it is in the patient’s interest to assume the worst.

Treatment protocol – choice of therapy:
(1) When IH, or combined TH and IH, is diagnosed, triiodothyronine should be prescribed rather than thyroxine [3], because since exogenous thyroxine will be preferentially converted into reverse T3, the intracellular T3 concentration will not increase and the IH will not be resolved [4].
(2) Appropriate therapy for any associated disease, if available, should be prescribed concomitantly.

The choice of triiodothyronine (T3) format is important: a tablet, “Cytomel”, is available, but the T3 is rapidly released and absorbed [16], producing a “Spike” of serum T3 two-and-one half hours post-dose, with resumption of the patient’s symptoms, in the afternoon.
Compounded T3, in a slow-release format, is preferred, because it does not produce a “spike and crash” phenomenon [4] and symptom relief persists throughout the day.

Treatment protocol [4] – Titrating the dose of T3:
The prescription begins with 5 µg of triiodothyronine (T3), taken at, or close to, 4 AM, so as to mimic the diurnal rhythm of thyroid hormone release.
Serum T3 is estimated weekly*, increasing the dose of T3 by 5 µg each week until an FT3 of 5.0-6.2 pmol/L is attained. When a serum T3 level of 5 pmol /L, to 6.2 pmol/L has been reached, the prescription is renewed without change *.
If a T3 test result of >6.2 pmol/L is reported, the dose is reduced.
Serum rT3 is repeated, as part of the thyroid profile, 2 weeks after the maximum dose is attained, so as to confirm normalization of the T3/rT3 ratio.

So as to avoid recurrence of IH, it is best to maintain serum FT3 between 5.0 and 6.2 pmol/L: a brief perusal of Cameron Sutherland’s T3/rT3 ratio table.
Fluctuating stress may render cortisol production and resulting effects on intracellular T3 concentration variable, therefore the patient’s symptomatology, FT3 and T3/rT3 are reviewed every 3 months for a year and thereafter, yearly.

Discontinuation of therapy:
Occasionally, stress can be completely eliminated, in which case IH may go into remission. When this happens, it may be reasonable to discontinue T3 treatment. However a relapse to intracellular hypothyroidism is likely, if stress recurs.

  • Caveat:
    The T3/rT3 ratio shows whether the abnormality of thyroid hormone metabolism needs to be corrected.
    However T3/rT3 is not a “target”, in terms of calculating the dosage of slow-release T3 for the individual patient: the serum T3 level is better.
  • The dosage of slow-release T3 is increased until the serum T3 is between 5.0 and 6.2 pmol/L (see below).
    However the patient’s symptoms are more important than blood test results: for “perfect” physical and psychological function, some individuals need a T3 serum level at, or slightly over, the accepted upper limit.
  • Intracellular hypothyroidism is of particular importance in pregnancy: for a pregnant woman, IH is no different than true hypothyroidism, excepting that it is not recognized and is therefore not treated, much to the detriment of the fetus, who is liable to all the effects of maternal hypothyroidism, including cognitive deficits, ADD, ADHD, dyslexia, autism and schizophrenia [17].

*The half-life of T4 is 6 or 7 days, so we repeat the thyroid profile 6 weeks after prescribing thyroxine, to ensure testing at a “steady-state” of T4 serum concentration. T3’s half-life is 22 hours [16], so the T3 can be checked at 7 days post-Rx. **The half-life of oral Liothyronine varies with the individual’s thyroid function status and with the method of calculation, so it is variously reported by different investigators.
Perhaps the best estimate to date is that provided by Jacqueline Jonklaas et al [7] in 2015; but in terms of comparison with the half-life of T4, a factor of 1:6 is appropriate.


[1] Thyroid Hormone Transport into Cellular Tissue, by Kent Holtorf, Holtorf Medical Group (HMG), Journal of Restorative Medicine 3(1):53-68, April 2014, DOI:10.14200/jrm.2014.3.0104

[2] Erika T. Schwartz, MD, Kent Holtorf, MD, Hormones in Wellness and Disease Prevention: Common Practices, Current State of the Evidence, and Questions for the Future. Prim Care Clin Office Pract 35 (2008) 669–705

[3] Peripheral Thyroid Hormone Conversion and Its Impact on TSH and Metabolic Activity, Kent Holtorf, MD, Journal of Restorative Medicine 2014; 3: page 30, 2014, DOI 10.14200/jrm.2014.3.0103

[4] Gervais A. Harry, “T3 and intracellular hypothyroidism”, 2022.

[5] “Cortisol”, by G. A. Harry,

[6] Myocardial Induction of Type 3 Deiodinase in Dilated Cardiomyopathy (experimental, Mice), Ari J. Wassner,1Rebecca H. Jugo,1David M. Dorfman,2Robert F. Padera,2Michelle A. Maynard,1Ann M. Zavacki,3Patrick Y. Jay,4 and Stephen A. Huang1 . Thyroid. 2017 May 1; 27(5): 732–737. Published online 2017 May 1. doi: 10.1089/thy.2016.0570PMCID: PMC5421592PMID: 28314380

[7] Hypothyroidism-induced reversible dilated cardiomyopathy, by P Rastogi, A Dua, S Attri, and H Sharma, J Postgrad Med. 2018 Jul-Sep; 64(3): 177–179. doi: 10.4103/jpgm.JPGM_154_17

[8] Euthyroid Sick Syndrome in Patients With COVID-19, by Runmei Zou,1,† Chenfang Wu,2,† Siye Zhang,2 Guyi Wang,2 Quan Zhang,3 Bo Yu,2 Ying Wu,2 Haiyun Dong,2 Guobao Wu,2 Shangjie Wu,4 and Yanjun Zhong2,*

Front Endocrinol (Lausanne). 2020; 11: 566439. Published online 2020 Oct 7. doi: 10.3389/fendo.2020.566439

[9] Higher Prevalence of “Low T3 Syndrome” in Patients With Chronic Fatigue Syndrome: A Case–Control Study.
By Begoña Ruiz-Núñez,1,2,* Rabab Tarasse,1 Emar F. Vogelaar,3 D. A. Janneke Dijck-Brouwer,1 and Frits A. J. Muskiet1
Front Endocrinol (Lausanne). 2018; 9: 97. Published online 2018 Mar 20. doi: 10.3389/fendo.2018.00097 PMCID: PMC5869352 PMID: 29615976

[10] Hoffman’s syndrome – A rare facet of hypothyroid myopathy, by Swayamsidha Mangaraj and Ganeswar Sethy, Neurosci Rural Pract. 2014 Oct-Dec; 5(4): 447–448. doi: 10.4103/0976-3147.140025PMCID: PMC4173264PMID: 25288869

[11] “Stiff person syndrome” –

[12] Amyotrophic lateral sclerosis (ALS) and the endocrine system: Are there any further ties to be explored? , By Alexios-Fotos A Mentis, Anastasia M Boujea and George P Chrousos, in “Aging Brain”, Volume 1, 2021, 100024

[13] Biography of a Doctor, by G. A. Harry, Https://

[14] The evidence for a narrower thyrotropin reference range is compelling. By Leonard Wartofsky 1 Richard A Dickey, J Clin Endocrinol Metab, 2005 Sep; 90(9):5483-8PMID: 16148345 DOI: 10.1210/jc.2005-0455 .

[15]  &nbsp;

[16] Jonklaas J, Burman KD, Wang H, Latham KR. Single-dose T3 administration: kinetics and effects on biochemical and physiological parameters. Ther Drug Monit. 2015 Feb;37(1):110-8. doi: 10.1097/FTD.0000000000000113. PMID: 24977379; PMCID: PMC5167556.

 (17) Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: a Danish nationwide cohort study, by
S L Andersen  1 P LaurbergC S WuJ Olsen,
PMID: 24605987, DOI: 10.1111/1471-0528.12681

[18] Clinical Endocrin., Volume81, Issue5, Review, November 2014, Pages 633-641: Defending plasma T3 is a biological priority Sherine M. Abdalla, Antonio C. Bianco: 05 July 2014

Published by Dr. Gervais Harry

I am a Toronto-trained Urologist. I practiced in downtown Toronto, from 1977 to 1997, when I went to Saudi Arabia as chief of Urology at the Armed Forces (teaching) hospital in Tabuk. Returning to Toronto in Y2000, I switched to family practice. In 2007, began to prescribe Hormone Restoration Therapy and in 2012, I became a member of the American Academy of Antiaging Medicine [A4M]. I successfully wrote the A4M's written examination in December, 2013 and In May, 2016 I passed the oral examination, for accreditation as a BHRT consultant. In 2014 I began BHRT practice in Collingwood, Ontario and in January, 2017, joined the Stone Tree Naturopathic Clinic. Now I am 82 and have retired, but it seems wasteful to jettison my learning and experience: the medical establishment knows nothing of BHRT / Functonal medicine and I feel obliged to offer my knowledge in the interest of those who are willing to think outside the box. MY QUALIFICATIONS: MB, BS, (from UWI), 1964. LMCC 1969. FRCSC (Urology), 1974. ECFMG 1984. Florida license 1998 [inactive], ABAARM Certification [A4M], 2016. I am a Member of CSAMM [the Canadian Society for Aging and Metabolic Medicine], the OMA&CMA, SUSO, CUA, RCP&S/C. PRACTICE TO DATE: Consultation in Functional Medicine, including assessment of Chronic Fatigue Syndrome, Fibromyalgia, Andropause, Menopause, Teenage and Postpartum Depression/Panic Attacks, Thyroid Hormone malfunction, Infertility, Sexual Dysfunction and “the Undiagnosable”. ALL ARE WELCOME to read, comment or question!

%d bloggers like this: