To understand what is happening, it should be clear that five matters have to be considered in planning replacement therapy:

1. Dose

2. Vehicle

3. Conversion T4 - T3

4. Receptor resistance or deficiency

5. Adrenal insufficiency

1. Dose. This has to be infinitely variable. It starts low and will be increased progressively and incrementally, until full response is obtained. Neither doctor nor patient should be satisfied with 60% response, or 80%. 100% is the target. The patient will be asked to monitor her response to treatment. This is satisfactorily done by three simple exercises.

a. Basal Temperature, this is the temperature (10 mins axillary, or 3 mins in mouth) immediately on waking. It is low in hypo-metabolic states, but will rise, albeit slowly, in response to treatment, (as reported elsewhere this is valuable diagnostically). A sudden rise may indicate, all things being equal, the start of overdose.

b. Basal Pulse. This may be taken at the same time as temperature; overdose will result in a rise of the resting pulse. 80 bpm will usually signify overdose.

c. "Feel good factor". It is possible to ask the patient to make a subjective assessment, say, one out of ten, on the same days as temperature or pulse. Since improvement in thyroid replacement may be quite slow, placebo effect does not occur; if the patient feels better, then she is better.

Considerations will be given to actual dosage shortly.

2. Vehicle. There are three options to choose from.

a. Thyroxin (T4)

b. Tertroxin (T3)

c. Dried, natural thyroid U.S.P

a. In this country (Great Britain), Thyroxin (marketed usually as Eitroxin—Synthroid in the US), is almost invariably used. Of the naturally occurring thyroid hormones it is the most plentiful. The thyroid hormone in the natural state is made up of around 80% Thyroxine (T4), 15% Triiodothyronine (Tertroxin T3—Cytomel in the US), and 5% Diiodothyronine (T2),Mono idothyronine (T1), and Thyronine (T0).

Thyroxine has a half-life of 8 days and works fairly well for the more simple, uncomplicated, early, not too severe, hypothyroid patient. But note should be made that this is not how thyroid hormone is naturally produced. There is a body of opinion, sympathetically supported by the writer, that if natural thyroid is not to be used, then at least T4 should be combined with T3 for a more satisfactory and more logical replacement.

b. Triiodothyronine – (T3) Tertroxin or Cytomel. This is quite considerably more potent than T4, four or five times so, but unlike T4, the half life of T3 is about 8 hours.

c. Dried Natural Thyroid. Used from about 1900, desiccated thyroid fell into disfavour in Great Britain and availability ceased in 1985. The synthetic Thyroxine (T4) was considered to be a better, purer preparation. Though, of course, it is purer in that it does not contain the other thyronines. However, this may be its weakness and ignores the fact that thyroid replacement need not be exact. The amount required varies from day to day, even hourly, and this dynamic variation may be compensated for by the patient’s own thyroid - which although deficient, may still be taking some of the load. Natural thyroid is widely used in USA, as Natural Thyroid U.S.P., but in the UK has to be specifically imported. It almost invariably works better than the synthetic T4, and is generally preferred by the patient. About half of the patients in the writer’s practice are maintained on this preparation. (obtained from Gold Line Laboratories, Fort Lauderdale; or Armour thyroid, from The Barnes Foundation, Trumbull, Connecticut).

3. Conversion. Thyroxine (T4) has a low biologic activity and is transported linked to a binding globulin in a non-active state. The removal of one of the four Iodine atoms from the Thyronine molecule converts it to the biologically most active Triiodothyronine (T3) - available as Tertroxin (Cytomel in the US). This is achieved by the (largely liver produced), 5’deiodinase enzyme. In this form, it will be passed, via receptors, into the cell, where passage of protein and sugars across cell membranes is encouraged, and mitochrondrial activity stimulated. It is now clear that prolonged and/or severe hypothyroidism may be associated with partial failure of the 5’deiodinase enzyme. Although suspected, this situation may be diagnosed in default when failure of response in thyroid replacement occurs. The effect of Thyroxine (T4) in this situation is to cause an overload of unused T4 due to conversion failure. This will cause some symptoms of thyroid excess, high pulse, tremor, headache for example, while the hypothyroid symptoms remain (It is of remark that on occasions, high T4 levels in this situation have resulted in inappropriate hypothyroid medication, or thyroid ablation). Thyroid function tests will show high Free T4 and low TSH; resulting in thyroid supplementation actually being withdrawn by the physician.

Management, where this problem is believed to be present, consists in discontinuing some or all T4 and substituting with T3, preferably in divided doses. Since poor conversion may be associated with a raised sex hormone binding globulin (SHBG) and high levels of exogenous oestrogen, re-appraisal of any HRT may need to be considered. Ensuring correct levels of vitamins A & B, Iron and Magnesium (as above), is also mandatory.

4. Receptor resistance or deficiency:

Resistance to the passage of T3 via the receptors has been seen in a number of cases. Why this occurs is not clear, but long periods of thyroid dysfunction are associated. The replacement dose of the chosen thyroid hormone has to be much larger than usual, which may cause some heart searching. Deficiency results from a protracted low thyroid state; prolonged low levels de-sensitizes the receptors. This will improve with time, and treatment of any Adrenal insufficiency present.