The History and Future of Treatment of Hypothyroidism

Maintenance doses of l-thyroxine ranged from 200 to 500 mcg/d before the institution of the TSH assay and then became typically closer to 100 to 150 mcg/d (Appendix Table). Implementation of the TSH radioimmunoassay also provided a means to diagnose much milder, or even subclinical, cases of hypothyroidism that may have been undiagnosed with earlier, less sensitive, diagnostic methods (47). L-Thyroxine was the first synthetic molecule used to treat hypothyroidism (23) and was shown to be efficacious as monotherapy for myxedema (24). Around that time, serum protein-bound iodine (PBI) emerged as a diagnostic test and therapeutic marker; serum PBI quantitation was the only valid way to biochemically assess thyroid hormone status (25). This tool was limited in terms of treatment monitoring because the effect on serum PBI varied by agent (26).

Figure. Events influencing the evolution of treatment trends in hypothyroidism.

• Unfortunately, the solution to this complex problem is not as simple as reverting to combination therapy; the more than a dozen clinical trials on the subject have not shown benefit of superiority and preference for combination therapy, as previously reviewed (1, 3, 70).
• The scale was calibrated so that a normal BMR reference range would be around 0%, whereas athyreotic individuals could have a BMR of about −40% (21).
• 1 provides a timeline of key events along this journey, and these important advances are described below.
• Elsewhere, thyroidectomy in animals was shown to produce symptoms reminiscent of myxoedema, providing further strength to the association of athyroid status with “sporadic cretinism” 10.
• This was partly due to limitations of chemically synthesised LT4, which was produced as an acid and had limited bioavailability before the synthesis of a sodium salt of in 1949 21.

Novel findings highlight the molecular mechanisms underlying the inability of l-thyroxine monotherapy to universally normalize measures of thyroid hormone signaling (8, 9), and new evidence may lay the foundation for a role of personalized medicine (10). Understanding the historical rationale for the trend toward l-thyroxine monotherapy allows us to identify scientific and clinical targets for future trials. SYNTHROID® (levothyroxine sodium) tablets, for oral use is a prescription, man-made thyroid hormone that is used to treat a condition called hypothyroidism in adults and synthroid meals children, including infants. SYNTHROID should not be used to treat noncancerous growths or enlargement of the thyroid in patients with normal iodine levels, or in cases of temporary hypothyroidism caused by inflammation of the thyroid gland (thyroiditis). Major diagnostic and therapeutic advancements in the early 20th century dramatically changed the prognosis of hypothyroidism from a highly morbid condition to one that could be successfully managed with safe, effective therapies.

Animal-derived thyroid hormone

These advancements dictated treatment trends that have led to the adoption of l-thyroxine monotherapy, administered at doses to normalize serum thyroid-stimulating hormone (TSH), as the contemporary standard of care (Figure). Most patients do well with this approach, which both normalizes serum TSH levels and leads to symptomatic remission (1). A clinical trial investigating symptoms found that patients receiving l-thyroxine monotherapy, even with a normal TSH, displayed substantial impairment in psychological well-being compared with controls of similar age and sex (3). Because some hypothesized that this phenomenon came about only after adoption of l-thyroxine monotherapy, a study assessed combination therapy with l-thyroxine and l-triiodothyronine. Remarkably, the latter study showed that psychological measures improve in patients receiving combination therapy until serum TSH level is normal (6).

Resolution of these clinical issues will influence the future management of hypothyroidism, including the therapeutic use of LT4. Because your body needs a precise number of thyroid hormone, it’s important to takeSynthroid the right way every day, just as your doctor prescribes. Your doctor will use a TSH, or thyroid stimulating hormone, test to determine whether you have hypothyroidism. It is our deepest desire to help you obtain and maintain health and wellness naturally so that you may enjoy a better quality of life, pure and simple. But Murray, contrary to general understanding, was not the first to try subcutaneous injections of thyroid extract in myxoedema. Through a series of efforts with physicians, especially endocrinologists, Synthroid’s owners were able to maintain the perception for forty-six years that Synthroid was uniquely effective.

Years of Levothyroxine

Since the 1800s, animal-derived thyroid hormone was first extracted from the thyroid glands of sheep, and later, from pigs. It does this by creating thyroid hormones that are then circulated through the bloodstream to different parts of the body. Holistic, functional medicine doctors in Houston, Texas specializing in bioidentical hormones, hypothyroidism, adrenal fatigue, menopause, perimenopause, low testosterone, allergies and LDI treatment, candida, detoxification, nutritional deficiencies, longevity and aesthetics. At Hotze Health & Wellness Center, our doctors are changing the way women and men are treated through the use of bioidentical hormones.

In another study comparing l-thyroxine monotherapy versus desiccated thyroid, in which both groups had a normal TSH, many patients preferred desiccated thyroid and lost weight (60). Unfortunately, the solution to this complex problem is not as simple as reverting to combination therapy; the more than a dozen clinical trials on the subject have not shown benefit of superiority and preference for combination therapy, as previously reviewed (1, 3, 70). It took considerable time for synthesised LT4 to become the mainstay of treatment for hypothyroidism, however. Indeed, the use of products based on thyroid extracts did not decline markedly until the latter part of the 1960s, due to difficulties with reproducibility of their biological action and limited storage life 2, 22. Desiccated thyroid products are available for therapeutic use to this day, despite the currently high regulatory standards for manufacture of LT4 tablets, which ensure reproducibility of day-to-day dosing (see below). Such preparations have persisted, despite lack of convincing objective evidence of superior efficacy in controlling hypothyroid symptoms 23.

• In some cases, patients required hospitalization due to problems with their thyroid medication.
• Doctors and clinical researchers from around the world came together in Newcastle to mark 125 years since the discovery of thyroid hormone replacement.
• Gross and Pitt rivers found that L-T3 was 5 times as more potent than L-Thyroxine at inhibiting the release of TSH from the pituitary gland.
• Such preparations have persisted, despite lack of convincing objective evidence of superior efficacy in controlling hypothyroid symptoms 23.

For example, l-triiodothyronine corrected BMR without much increase in serum PBI, l-thyroxine increased serum PBI sometimes to above normal, and combination l-thyroxine and l-triiodothyronine and desiccated thyroid had the advantage of normalizing serum PBI (27). In addition to BMR and serum PBI, other surrogates for treatment response included cholesterol levels, symptoms, and deep tendon reflexes, but their lack of sensitivity was always recognized (28). In the opening chapter of this book, we consider the history of the therapeutic use of levothyroxine (LT4). Recognition of the therapeutic value of LT4 emerged from experience gained from, essentially, empirical administration by physicians of crude thyroid extracts to people with advanced sequelae of hypothyroidism 1–4. These clinical experiments arose from early studies of people we would today describe as having severe congenital hypothyroidism.

He recognized what he considered as an ‘overdose’ when his patient developed a tachycardia and pyrexia, and provided a nice graph relating dose to pulse and temperature. Because of these serious blinders and limitations, these studies unsuprisingly end up with comparative results that show no net benefit over LT4 monotherapy. Thyroxine (T4) was isolated from pig thyroids in the early 1900s, but it was not in a form that was very useful in therapy until 1949, when a synthetic Levothyroxine (L-Thyroxine) medication was commercially launched by Glaxo.

Additional references were identified in the course of review of the literature identified. One wonders what Murray and Bettencourt and their colleagues would have made of these nuances in treatment which have arisen since it became possible to assay serum thyroid-stimulating hormone levels in 1965 and with ever-increasing sensitivity since then. In Murray’s day – he died in 1939 – the diagnosis of thyroid deficiency was made on purely clinical grounds and very mild cases will have been missed. All these developments since those days merit a more detailed account than lies within the scope of this series of papers. However, because the potency and speed of L-T3’s actions on the body are far greater than for DTE and L-T4, more hyperthyroid side-effects have been reported for L-T3 over the years.

One contemporary study showed that removal of the entire thyroid led to the development of symptoms resembling those of “sporadic cretinism”, and this observation led the author to restrict future surgeries to partial resection of the thyroid, with better outcomes 9. Elsewhere, thyroidectomy in animals was shown to produce symptoms reminiscent of myxoedema, providing further strength to the association of athyroid status with “sporadic cretinism” 10. These extreme cases were the first demonstrations of the pathophysiological importance of the thyroid gland to healthy development although not based on any understanding of the function of the thyroid. Other experiments conducted at this time noted that thyroidectomy was lethal to dogs, but that the health of the animals could be preserved temporarily by grafting the thyroid elsewhere in the animals’ bodies 11. Even so, it was assumed that the function of the thyroid was allied to detoxification of the blood, rather than to an independent and specific endocrine function 3.