In the 1995 American Thyroid Association (ATA) guidelines, biological and synthetic thyroid hormone preparations containing T4 plus T3 were not recommended out of concern for fluctuating and often elevated serum T3 concentrations (71). In 2014, the ATA recommendations evolved with the recognition that 1) serum T3 levels might not be normalized in all l-thyroxine–treated hypothyroid patients and 2) some patients remain symptomatic while receiving l-thyroxine monotherapy. Titration of l-thyroxine dose to achieve normal TSH concentrations remains a first-line approach, but trials with combination therapy can be considered. In addition, the guidelines recognize that although superiority data are lacking, some patients do experience a clinical response with desiccated thyroid preparations or combination therapy with l-thyroxine plus l-triiodothyronine (1). The therapeutic use of levothyroxine (LT4) arose from observations made in the second half of the nineteenth century that linked the severe physical and cognitive defects of cretinism with an under-developed, or absent, thyroid gland.
When it is remembered that these injections have to be personally administered for the remainder of the patient’s life by the medical attendant, these risks, however slight in regard to a single application they may appear, become immensely magnified when a long series has to be taken into account. Research since 2008 has theorized that more optimal levels of T3 hormone in serum could help thyroid patients with genetic polymorphisms in T4 conversion (DIO1 and DIO2) and thyroid hormone transport (MCT8, MCT10). Several of our blog posts have reviewed articles on these polymorphisms and combination therapies. Since 1989, Hotze Health & Wellness Center has helped over 33,000 patients get their lives back using bioidentical hormones that restore hormones to optimal levels, strengthen immune systems, and increase energy levels.
The evolution of thyroid hormone therapies has been significant over an extended period of time. Thyroid hormone replacement is very useful in the treatment of those with hypothyroidism. All of the most recent guidelines of major endocrine societies recommend levothyroxine mono-therapy for first line use in hypothyroidism. Secondly, the application of the remedy sometimes produces alarming immediate symptoms, such as loss of consciousness and tonic spasm; and remoter effects, such as indurated swellings and abscesses at the seat of injection, have followed the use of even the most carefully prepared extract.
Synthroid, Levothroid, Levoxyl, and other synthetic T4 products entered the market years later without FDA approval, under the mistaken assumption that these products were not new drugs and that their manufacturers were not required to prove their safety or effectiveness. However, in 1997, the FDA ruled that oral levothyroxine sodium products were indeed “new drugs” and that manufacturers who wanted to continue marketing these products must submit a new drug application for approval. This decision was based on a long history of potency and stability problems with these drugs. In fact, between the years 1991 and 1997, there were ten recalls of levothyroxine sodium tablets, involving more than 100 million tablets. These recalls occurred primarily because these products had a lower potency than claimed or had lost their potency before their expiration dates. In some cases, patients required hospitalization due to problems with their thyroid medication.
Compounded slow-release L-T3 varies in its absorption through the gut and will therefore vary in its potency as gut health improves or worsens. Perhaps a dermal patch or subdermal implant could assist patients with T3 dosing in a way that would not suppress fluconazole synthroid the TSH as much as oral dosing does. Gross and Pitt Rivers found in the 1950s that injection vs. oral dosing made a difference in effectiveness (injection being far more effective for both L-T4 and L-T3). The discovery in 1895 of a substance containing high concentrations of iodine within the thyroid gland (“thyroiodine”) was therefore of considerable interest in unifying concepts relating to hypothyroidism and iodine, and the role of the thyroid as an endocrine organ 17.
Within a decade there was a major transition toward l-thyroxine monotherapy as first-line therapy (Appendix Table and Figure) (38). Clinicians noted several differences in the ability of l-thyroxine monotherapy to normalize markers of hypothyroidism at doses that normalized serum TSH (45). For instance, in many l-thyroxine-treated patients with a normal serum TSH, the BMR remained at about 10% less than that of normal controls even after 3 months of therapy (53). At the same time, doses of l-thyroxine that normalize the BMR can suppress serum TSH and cause iatrogenic thyrotoxicosis (28, 45, 46). The clinical significance of this was not fully understood because many patients appeared clinically euthyroid with a BMR between −20% and −10% (36, 37).
Moreover, too high a dose of T3 results in symptoms of hyperthyroidism, complicating the delivery of combination therapy 26. A series of clinical trials from 1970 onwards compared T4 + T3 combination therapy with monotherapy with LT4 in hypothyroid patients, and these studies have established monotherapy with LT4 as the standard of care for managing hypothyroidism for the vast majority of patients 28, 29. A fuller account of the current status of and prospects for LT4 + T3 combination therapy is given in the chapter, “Pharmacodynamic and Therapeutic Actions of Levothyroxine” of this book. With the availability of multiple forms of thyroid hormone replacement, early clinical trials were designed to assess efficacy and dose equivalency among natural thyroid (typically desiccated), synthetic l-thyroxine, and/or l-triiodothyronine.
“In 1891, a young Newcastle doctor, Dr George Murray, injected an extract from a sheep’s thyroid gland into a patient with symptoms of thyroid under-activity. Doctors and clinical researchers from around the world came together in Newcastle to mark 125 years since the discovery of thyroid hormone replacement. There is no suggestion of this in the British Medical Journal’s detailed transcription of the proceedings,1 nor in the exceedingly brief original written minutes of the meeting (an extended account must have been written up at some later point for the BMJ).
Improved outcomes for these subjects following empirical treatment with crude thyroid extracts spurred further research, and isolation, characterisation, and chemical synthesis of LT4 and triiodothyronine (T3) followed in the first half of the twentieth century. Treatment with LT4 + T3 combinations superseded the use of thyroid extracts from the 1960s onwards. The development of reliable and specific assays for thyroid hormones contributed greatly to understanding the importance and function of the thyroid and facilitated individualised treatment.
While Brown-Séquard’s research was of the highest order – he had, for example, proven that the adrenals were essential to life – the sensational nature of these later experiments blinded many to the general principle of replacement therapy that was trying to shine through. The history of hypothyroidism and its management spans the golden age of clinical research, from empirical medical and surgical treatments unencumbered by understanding of thyroid physiology in the nineteenth century to individualised, TSH-guided treatment with LT4 today. Along the way, many clinical and experimental studies, enhancements in technology, and improved LT4 preparations have increased greatly our ability to deliver optimal care for hypothyroidism, based on the therapeutic administration of LT4. Surgery to remove goitre was being performed at this time, for example, to relieve symptoms of compression in the neck, despite a continuing lack of understanding of the function of the thyroid gland 8.
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