More Proof and Reasoning that T4 Monotherapy Results in Inadequate Conversion
More Proof and Reasoning that T4 Monotherapy Results in Inadequate Conversion
Written by Neal Rouzier, MD
A 45 y/o female with persistent symptoms of fatigue, low energy, depression, presents for evaluation of her thyroid hormone therapy. She is referred by her friend who insists she consult with me due to her dissatisfaction with her current therapy. Her PMD insists that her symptoms are not related to her thyroid function as her TSH is always normal, indicating that her symptoms are related to something else. She is frustrated that SSRIs, and antidepressants do not make her feel better. She continues to gain weight and feel lousy no matter what she does. She reports that her thyroid tests are always perfect, and her doctors do not have an explanation. Initial lab results demonstrate normal TSH and Free T4 levels, but a Free T3 is low at 1.8. She is excited but also upset at finally finding an answer to her symptoms and frustration.
If she wishes to continue to see her endocrinologist, I advise her not to discuss her current therapy and benefits in order to avoid confrontation. She questions why I would recommend this as her doctors should know what it was that made her feel better.
In the last course, Treating T3 Deficiency: The Evidence You Need (Part 2), we summarized that the use of thyroxine (T4) alone resulted in a lowering or suppression of Free T3, which is the opposite of what we would expect logically. This then accounts for the explanation as to why thyroxine monotherapy does not improve symptoms of hypothyroidism or metabolic parameters in a majority of patients, particularly in older individuals. This also accounts for worsening of symptoms instead of improvement of symptoms as would be expected. The expected improvement in hypothyroid symptoms, along with the expected improvement in physiologic Free T3 levels when TSH levels are normalized by thyroxine monotherapy, has been held with much conviction. Unfortunately, multiple studies prove this religiously held belief to be false. Yes, conversion of T4 to T3 does take place adequately in some individuals, but not in most as can be seen from the studies presented. And adequate conversion to optimal levels of Free T3 thereby resulting in resolution of symptoms and metabolic defects occurs very rarely, thereby requiring addition of T3 to adequately improve psychologic, metabolic, signs and symptoms of thyroid dysfunction. Multiple studies now document this inadequate conversion with the resultant lack of symptom improvement. Nevertheless, the endocrine world rejects this as their 14 or so flawed studies demonstrated that addition of 5ug of T3 to T4 thyroxine did nothing as far as improving symptoms.
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Dr. Pepper and T3 and T4
Despite claims by some authors that the above issues/problems/persistent thyroid hypofunction symptoms are not related to thyroid at all but rather to some other metabolic problem (yet no other illness has been discovered that accounts for these abnormalities), no other therapy results in improvement in these parameters other than thyroid administration.
A landmark study published by Dr. Pepper in the “Journal of Endocrinology,” demonstrates that adequate doses of T3 along with T4 will result in resolution of thyroid hypofunction symptoms and metabolic abnormalities, whereas no other treatment modality is successful in this regard. Despite resistance by some endocrinologists and thyroid organizations, this study by Dr. Pepper and his retrospective review of past studies, demonstrate the success of using combination T4 &T3 (desiccated thyroid extract or DTE). In patients treated with thyroxine monotherapy, 80% of patients preferred DTE over T4 monotherapy when switched from T4 monotherapy to DTE. Despite the dozen flawed studies using subtherapeutic doses of T3 demonstrating no benefit of adding T3 to T4, subsequent studies utilizing adequate T3 doses do demonstrate therapeutic efficacy compared to T4 monotherapy. Dr. Pepper also demonstrated that DTE resulted in better patient satisfaction and symptom improvement over the combination of T4 & T3 used separately. DTE, which contains T1, T2 T3, and T4, results in better symptom resolution and patient satisfaction than does T4 & T3 administered individually.
Unfortunately, most studies demonstrate a side effect of weight loss. (Sorry for my sarcasm).
Use of T4 Monotherapy Lowers Free T3 Instead of Increasing
Further review of additional literature in Treating T3 Deficiency: The Evidence You Need (Part 3), demonstrates the proof and reasoning for all of the foregoing. A paper published in PLoS ONE provides further documentation that T4 monotherapy results in inadequate conversion of T4 into T3. Furthermore, this paper proves that use of T4 monotherapy lowers Free T3 instead of increasing it as would be expected. There are multiple reasons sited for this observation. Athyreotic patients treated with high dose T4 monotherapy failed to restore pre-surgery Free T3 levels, despite high dose T4 doses that suppress TSH levels and increase FT4 to supraphysiologic levels. This explains patient complaints of hypothyroid symptoms and increased weight gain after thyroid removal as well as patient dissatisfaction with thyroxine treatment. Athyreotic patients’ complaints are frequently ignored because their TSH is “normal.” The low Free T3 levels are also frequently ignored despite symptomology related to low Free T3 levels.
“Yes, but your TSH is normal and therefore your symptoms are not related to your thyroid.”
How many times have I heard that from patients, referring to conversations with their PMD?
Unfortunately, it has been stated that the ratio of T4 to T3 should be replaced in a 14/1 ratio. However, therapeutically this ratio does not result in symptom improvement, yet it is the ratio utilized in many studies that are destined and designed to fail. The ratio of 4/1 found in DTE works perfectly well. This ratio also results in improvement in metabolic and lipid parameters not seen with T4 monotherapy, or in studies replacing T3 with low doses of 5ug. Nevertheless, the endocrine society still quotes the plethora of studies demonstrating no benefit when T3 is added to T4. However, a paper published in Endocrine Reviews criticizes those studies as being flawed due to their consistent use of low dose T3 replacement. Studies using a higher ratio of T3, or those utilizing DTE, prove beneficial. Furthermore, these studies demonstrate very low levels of Free T3 after thyroidectomy despite high TSH suppressive doses of T4 replacement. The bias against the use of DTE or additional T3 is impressive despite multiple studies demonstrating benefit.
Studies that T4 Monotherapy Doesn’t Work
Finally, this week, AACE released a statement recommending that combination T4/T3 therapy should be considered as an alternative to patients that do not improve on T4 alone. The endocrine academy finally had to succumb to the pressure of all the studies demonstrating the benefit of adding T3 and the lack of benefit of T4 monotherapy. Continuing to ignore the scientific literature was not in their best interest. The final study reviewed in Endocrine Opinion explains why patients treated with T4 monotherapy suppress T3 levels and that also do not result in symptom improvement. And not until an adequate dose of T3 is administered will symptoms improve as well as patient satisfaction scores.
Next month, in Treating T3 Deficiency: The Evidence You Need (Part 4), we’ll review all the studies proving that T4 monotherapy does not work and the conclusion that patients don’t need to take thyroid because their symptoms do not improve on T4 monotherapy.