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Levothyroxine: from sheep thyroid injections to synthetic formulations

Jenny Bryan takes a look at the colourful and interesting history of levothryoxine sodium, and the ongoing debate over combination treatment versus monotherapy

By Jenny Bryan

Jenny Bryan takes a look at the colourful and interesting history of levothryoxine sodium, and the ongoing debate over combination treatment versus monotherapy

Every day, about one million people in the UK take the thyroid hormone levothyroxine sodium (L-T4), but few are aware of controversies that have surrounded the treatment of hypothyroidism for over a century.

From the first injections of sheep thyroid in 1891 to the academic rivalry surrounding the identification of thyroxine (T4), and the ongoing debate over the advantages of combining L-T4 with liothyronine (L-T3), boosting a sluggish thyroid has never been straightforward.

“Ninety-five per cent of people on thyroxine probably fluctuate between an underactive and an overactive thyroid without even noticing. But about 5 per cent are unhappy with their symptom control even when we achieve apparent biochemical perfection. They continue to feel tired and jaded and put on weight, and we don’t yet know how best to help them,” explains Mark Vanderpump, consultant endocrinologist the Royal Free London NHS Foundation Trust.

In 2007, the British Thyroid Association advised that levothyroxine alone was the only evidence-based treatment for hypothyroidism,1 and a year later the Royal College of Physicians confirmed this advice, recommending that combination L-T4 and L-T3 therapy should be reserved for use by accredited endocrinologists for individual patients.2

In 2012, the European Thyroid Association (ETA) lent its weight to the view that L-T4 monotherapy remains the standard treatment for hypothyroidism, but spelt out which groups of patients might be considered for experimental combination treatment by endocrinologists.3

From abattoir to clinic

When a young 19th century English physician, George Murray, first suggested injecting patients with myxoedema (severe hypothyroidism) with extract of sheep thyroid he received little support from the medical establishment.4 But the beneficial effects he achieved with sheep thyroid in a 46-year-old woman in 18915 aroused considerable interest, even when the third and fourth patients he treated died of heart failure.4 Fortunately, the first patient survived nearly 30 years and continued to use sheep thyroid extract, initially by injection and later orally.4

As use of animal thyroid gland became more widespread, chemists set about extracting the vital ingredient responsible for overcoming symptoms of hypothyroidism. The first success went to US chemist Edward Kendall, who succeeded in isolating 7g of thyroxine from some 3,000kg of pig thyroid gland in 1914.6,7

This was no mean feat, as those who have struggled to extract a biological substance from animal tissue as part of their undergraduate training will agree. Kendall isolated thyroxine, although it was British chemist Charles Harington who synthesised the hormone and corrected Kendall’s description of its chemical structure and formula a decade later.8,9

Harington also recognised that, although thyroxine occurred naturally as a racemic mixture of the levo and dextro forms of the chemical, it was the levo form that had greater physiological activity.8,10 A commercial product was launched by Glaxo in 1949.4

Synthetic versus “natural”

Although synthetic forms of levothyroxine have been available since the 1950s,1 there is continued public demand for porcine thyroxine as a more “natural” product than the synthetic version.

“Synthetic levothyroxine is exactly the same as human thyroxine and has the obvious advantage that you don’t need to go to an abattoir to get it. But no randomised controlled trials were done to compare the effectiveness of the two products before patients were switched to synthetic treatment, and some patients feel that their symptoms are better controlled with pig thyroid hormone preparations,” says Dr Vanderpump.

He explains that the introduction of more accurate tests for serum thyroid stimulating hormone (TSH), the pituitary hormone that controls T4 and tri-iodothyronine (T3) production from the thyroid have meant that patients tend to be prescribed lower doses of levothyroxine than in earlier decades.

“Previously, the serum TSH assay wasn’t very sensitive at the lower end of the range and, if people felt tired and unwell, they tended to take higher doses of levothyroxine, which made them marginally hyperthyroid but helped them feel better.

However, in recent years, there have been concerns about atrial fibrillation and bone loss, particularly in postmenopausal women, if thyroid hormone levels are too high. That, coupled with the more accurate serum TSH assays, means that patients may be on lower levothyroxine doses, more closely matched to their serum TSH, T4 and T3 levels, and some aren’t happy with the way they feel,” he says.

Another factor that may contribute to treatment dissatisfaction in some patients could be related to the non-physiological way in which thyroid function is supplemented by levothyroxine. Dr Vanderpump explains that the healthy thyroid produces mainly T4 and much smaller amounts of the physiologically more active, T3.

Most of the body’s needs for T3 are provided by conversion of T4 to T3, but about 20 per cent of the body’s T3 comes direct from the thyroid. In contrast, people with hypothyroidism are treated with T4 alone, so all of their T3 is produced as a result of conversion from T4.

“It has been suggested that one reason why some people are not happy with levothyroxine treatment is that they are not getting their supply of T3 in a physiological way, as all of it is coming from the conversion from T4,” says Dr Vanderpump.

However, as he points out, the balance of T4 and T3 that patients get from porcine therapy is far from physiological. Pig thyroid produces T4 and T3 in a ratio of 4:1, compared with the ratio of 14:1 in human thyroid.

Combination vs monotherapy

Setting aside the issue of the “unnatural” ratio of thyroid hormones in pig tissue, would patients be better off with potentially more physiological combination treatment with synthetic human L-T4 and L-T3 than with L-T4 monotherapy?

In developing its 2013 guidelines, the ETA reviewed data on 1,355 patients in 13 randomised controlled trials of L-T4+L-T3 versus L-T4 monotherapy.3 Study design, duration of treatment and dose ratio of T4 to T3 were variable. In studies that considered quality of life, cognition, mood and symptoms, combination therapy was no better than monotherapy in nine out of 12 studies, but better in three.3

Data were analysed from six trials in which patients were asked to state a preference for treatment, and 48 per cent preferred combination treatment, 27 per cent preferred monotherapy and the rest expressed no preference.

The ETA concluded that there was insufficient evidence to show that combination treatment is more effective than monotherapy.3 Having considered the factors that have been linked to persistent symptoms in the presence of adequate biochemical control of hypothyroidism, the ETA recommended that endocrinologists should reassure patients about their condition and support them in coming to terms with a chronic disease requiring life-long medication.

In addition, autoimmune disease associated with thyroid autoimmunity should be ruled out. If symptoms still persist for six months or more, endocrinologists may consider combination treatment on an experimental basis.3 When combination treatment is considered appropriate, the ETA suggests that treatment should be started in a L-T4/L-T3 dose ratio between 13:1 and 20:1 by weight, and that L-T3 should be divided in two doses (one before breakfast and the largest one at bedtime).

Future research

As we approach the centenary of Kendall’s great achievement in isolating thyroxine, the ETA and others are calling for further research to understand why a small but unhappy proportion of people with hypothyroidism continue to get symptoms even when their serum TSH is in the laboratory reference range.

Studies have been proposed to identify the optimal L-T4/L-T3 dose ratio that can bring patients closest to the serum ratios found in healthy individuals, together with research aimed at targeting combination treatment to those who need it most — possibly those with certain genetic polymorphisms.

A patient petition currently before the Scottish Parliament looks set to raise awareness about the plight of those who do not feel their symptoms are adequately addressed by current treatment.11 It calls for improvements in diagnosis and treatment, including greater availability of L-T3 and natural dessicated thyroid.11

Meanwhile, Quality and Outcomes Framework thyroid targets in England encourage regular monitoring of patients with hypothyroidism, and Dr Vanderpump suggests this may demonstrate greater fluctuations in thyroid levels than previously realised, accompanied by a tendency for micromanagement of levothyroxine dosing in primary care, whether or not this is indicated by a patient’s presenting symptoms.

As Dr Vanderpump points out, in the modern world, people have high and sometimes unrealistic expectations about how energetic they should feel, but that does not mean that tiredness and depression should be ignored.

“Levothyroxine is the most perfect hormone replacement that has yet been devised for endocrine conditions, but there are undoubtedly people who fall outside the current treatment model. Animal-derived products that contain T4 and T3 are not physiological and are not the answer in the longer term, but we do need to find ways to ensure that all our patients with hypothyroidism feel the full benefits of replacement therapy.”

References

  1. British Thyroid Association. Armour Thyroid (USP) and combined thyroxine/tri-iodothyronine as Thyroid Hormone, November 2007. Available at: www.british-thyroid-association.org (accessed 10 July 2013).
  2. Royal College of Physicians. The diagnosis and management of primary hypothyroidism, November 2008. Available at: http://www.british-thyroid-association.org (accessed 10 July 2013).
  3. Wiersinga WM, Duntas L, Fadeyev V et al. 2012 ETA Guidelines: The use of L-T4 +L-T3 in the treatment of hypothyroidism. European Thyroid Journal 2012;1:55–71.
  4. Slater S. The discovery of thyroid replacement therapy. Available at: www.jameslindlibrary.org (accessed 10 July 2013).
  5. Murray GR. Note on the treatment of myxoedema by hypodermic injections of an extract of the thyroid gland of a sheep. BMJ 1891;2:796–7.
  6. Simoni RD, Hill RL, Vaughan M. The isolation of thyroxine and cortisone: the work of Edward C. Kendall. Available at: www.jbc.org (accessed 10 July 2013).
  7. Kendall EC. Landmark article, June 19, 1915. The isolation in crystalline form of the compound containing iodine, which occurs in the thyroid. Its chemical nature and physiologic activity. JAMA 1983;250:2045–6.
  8. Chemburkar SR, Deming KC, Reddy RE. Chemistry of thyroxine: an historical perspective and recent progress on its synthesis. Tetrahedron 2010;66:1955–62.
  9. Harington CR, Barger G. Chemistry of Thyroxine: constitution and synthesis of thyroxine. Biochemical Journal 1927;21:169–83.
  10. Harington CR. Resolution of dl-thyroxine. Biochemical Journal 1928;22:1429–35.
  11. The Scottish Parliament. PEO 1463. Effective thyroid and adrenal testing, diagnosis and treatment. Available at: www.scottish.parliament.uk (accessed 10 July 2013).

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2013.11123454

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