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SUGGESTIONS FOR AN APPROACH TO THE MANAGEMENT OF THYROID DEFICIENCY

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SUGGESTIONS FOR AN APPROACH TO THE MANAGEMENT OF THYROID DEFICIENCY

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SUGGESTIONS FOR AN APPROACH TO THE MANAGEMENT OF THYROID DEFICIENCY

by Dr Barry J Durrant-Peatfield
M.B., B.S., LR.C.P., M.RCS.
Approved Civil Aviation Medical Examiner.

THE CLINIC (United Kingdom)
86 Foxley Lane Purley
SURREY CR2 3EE
Telephone - 020 8660 0905

The clinical syndrome of thyroid deficiency is very much more common than is generally realized; Barnes, in several publications, drew attention to this in the last two decades, as has the present writer more recently. One reason for this, is a tendency to think of hypothyroidism and myxoedema as one of the same thing, when this is quite wrong. Myxoedema, as doctors were taught in medical school, is the end result of a progressive disease process resulting in more or less total absence of thyroid hormone; whose symptoms and signs are no doubt perfectly familiar. But this state of deficiency has to start somewhere, winding down over a variable period to the terminal state of myxoedema. Symptoms and signs will naturally vary according to the extent of the level of deficiency reached. Clearly, a 10% loss may have little to show for it; whereas a 25% loss may have several very definite symptoms and signs; and a 40% loss even more so. Furthermore, patients show very individual response to any given level of dysfunction; while one may complain of excessive fatigue and weight gain, another may be more troubled by depression and menstrual problems.

That the diagnosis is all too frequently missed, is an inevitable result of this fundamental misunderstanding, and is commonly the result of an incomplete clinical appraisal in favor of the standard thyroid function tests. These tests are the real problem in diagnostic failure since there are inherent problems in interpreting blood levels of thyroxine and/or thyroid stimulating hormone (TSH) when blood levels may differ widely from tissue blood levels. Since the diagnosis may very properly, and easily, be made clinically, unreliable blood levels should NOT take precedence over clinical judgment.

Equally unsatisfactory is the acceptance by doctors and patients alike of poor response to thyroid replacement.

The present writer has been constantly alarmed and dismayed by hypothyroid patients who for years, all too often, have been obliged to accept a much less than satisfactory amelioration of their illness, being taught to expect no more than some improvement. It is perfectly possible that complete and long lasting remission should be obtained, and neither doctor nor patient should accept anything less. Further, the response should be monitored, not just by the doctor, but by the patients themselves. Since there often is a dynamic situation, the patients should be educated and taught to monitor themselves, making their own adjustments to dosage. In this connection, frequent monitoring by blood tests may be quite misleading and unhelpful. Surely it must be more satisfactory for the physician to ask the patients how they feel; and guide the informed patient in establishing the right dosage levels of replacement therapy.

One of the most taxing problems in diagnosis is the multiplicity of symptoms, which need not be rehearsed here. It is all too easy to pigeonhole the polysymptomatic patient as one of the heart sink variety, and much too often, for example, inappropriately prescribe anti-depressants. Thyroid deficiency may cause all sorts of major and minor symptoms and their very frequency should raise an index of suspicion for thyroid deficiency. The simple Basal Temperature Test, (see below), wrongly derided by many authorities, can provide valuable clinical backup. Finally, there is nothing wrong with a thoughtfully planned trial of treatment with an informed and cooperative patient.

Hypothyroidism is due either to:

A. Deficiency of thyroid hormone production;
B. Failure of thyroid hormone to reach the tissues.

Both may operate together in varying degrees.

Deficiency of hormone production is due to:

1. Environmental toxins/deficiencies
2. Genetic thyroid failure
3. Thyroid failure secondary to pituitary insufficiency
4. Thyroid surgery
5. Treatment of previous over-activity
6. Major surgery
7. Tonsillectomy
8. Major trauma
9. Glandular fever

Failure of hormone to reach the tissues results from:

1. Receptor resistance, or failure
2. Dysfunction of T4-T3 conversion
3. Adrenal insufficiency

Dealing in turn with the therapeutic management of these problems, we may turn first to (A)Thyroid hormone production failure. This will be due to:

1. Environmental toxins and deficiency
   
   a)Toxins
   
   -A number of chemical agents tend to interfere with the manufacture of thyroid hormone. -Notables among these are:
   -Poly chlorinated Biphenyls (Paints and wood preservatives)
   -Resorcinol (Millet)
   -Phthylate Esters (Plastics)
   -Thiouracil (Cabbages, Turnips, Cassava.)
   -Anthracin
   -Bromoform
   -Cyanides (Barbiturates)
   -Fluorides
   -Thiocyanates (Smoking)
   -Caffeine
   -Aspirin
   -Lithium
   -Amiodarones
   
   The elimination of these from the diet may be desirable, if not always practical.
   
   b) Nutritional Deficiencies
   
   
   (i) Iodine. Endemically absent in certain inland areas e.g. (Peak District, UK)
   (ii)Minerals, in particular:
   
   

   Selenium
   Iron
   Magnesium
   Zinc

   
   (iii) Vitamins.
   
   

   Vit A - Conversion of Carotene to Vit A is inhibited by low thyroid states, and may cause yellow pigmentation.
   It controls uptake of Iodine into the thyroid gland. Deficiency also reduces TSH
   
   Vit B Riboflavin, Niacin, Pyridoxine play a role in thyroid hormone manufacture.
   
   Vit C & Vit E - Deficiency has been shown to cause hyperplasia at cellular level in the thyroid.
   Clearly, part of the management of hypothyroidism requires some dietary advice;
   the provision of iron and vitamins and other minerals is simple and obvious.
   ---
2. Genetic Thyroid Failure.
   This will have become apparent soon after birth; but may not be obvious cretinism. A sickly child, with poor weight gain, frequent infections, lethargy, or oddly enough, hyperkinesia, and is a candidate for genetic poor thyroid function. Thyroid replacement is mandatory as early as possible.
   ---
3. Pituitary Failure.
   This is a more common problem than is recognized, and apart from its specific clinical features, it may be a cause of secondary hypothyroidism. The pituitary may have a genetic deficiency, when it will have been probably recognized early. Not uncommon is Sheehan’s Syndrome, resulting from major trauma from accidents or surgery. Adenomas of the pituitary may cause pressure atrophy and / or abnormal hormone outputs. But the pituitary may be involved in the general multiple deficiency state, and more specifically in low thyroid states. This partial failure in hypothyroidism may well be a cause of low TSH, so that a vicious spiral may slip into being. The danger of a low or normal TSH in this situation being misinterpreted when thyroid function tests are carried out is quite clear. In this situation, correction of the thyroid state will bring benefits to the pituitary; and may explain why some patients on thyroid replacement therapy begin to need lesser doses as time passes. Correction of the thyroid deficiency is clearly necessary; but adrenal insufficiency, considered in more detail later, as a consequence of lowered ACTH output, may require cortisone and Dehydroepiandrosterone (DHEA) in addition.
   ---
4. Thyroid Surgery.
   This is undertaken as a treatment for pathology of the thyroid itself, or as a treatment for over-activity, discussed below. Thyroid cysts, adenomas or carcinomas are necessarily removed by surgery; and it is sometimes necessary to remove goiters where the size is causing respiratory or oesophageal embarrassment. Hashimoto’s disease may come into this category.
   Replacement by thyroid hormone is an obvious consequence.
   ---
5. Treatment of previous thyroid over-activity, by surgery or I131 ablation (radioiodine/red.)
   Grave’s disease is widely treated, where medical methods are deemed unsatisfactory, by partial thyroidectomy, or Radioactive Iodine ablation. This is often unsatisfactory, since it is very difficult to get it right. Either too much is removed or destroyed; (in which case replacement therapy is a permanent necessity) or too little, and it may have to be done again.
   For such patients, replacement therapy is an obvious no-option requirement.
   ---
6. Major Surgery.
   Most particularly in this context comes cholecystectomy and hysterectomy. Many doctors are aware that women may suffer weight gain and loss of well being after this surgery; and this will be found to be due to early loss of thyroid function. Replacement therapy is required.
   ---
7. Tonsillectomy.
   Quite why in adults, tonsillectomy may result in slow running down of thyroid function is not clear, but may be the result of interruption of the blood supply. The present writer has noted a number of cases of young adults misdiagnosed as M.E sufferers in this situation. Replacement therapy provides a most satisfactory return to normal.
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8. Major Trauma.
   Major road traffic accidents, and surgical accidents are known to precipitate thyroid and/or pituitary insufficiency. In this category have been noted the major psychic trauma of certain life events. Replacement indicated, with regard given to pituitary/adrenal function.
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9. Glandular Fever.
   This is an often met with cause of failure of the thyroid/adrenal axis. Evidence has pointed to pituitary damage causing secondary hypothyroidism, but progressive loss of thyroid-producing cells within the thyroid has been noted. In either event, replacement is required. Discussion of failure of uptake at tissue level may be conveniently dealt with in the section below on therapeutic options. Consideration should now be given to the aims of replacement therapy.

The overall purpose is to restore metabolism to normal, so as to eliminate all hypothyroid symptoms, and to secure a sense of normal well being. This implies that thyroid hormone levels in each and every cell are nominal; that all the exchange reactions are taking place, as they should be. Sadly, this ideal is at least as often as not, simply not reached, often by a long way. Residual tiredness, lack of drive, or depression is frequently admitted to. Menstrual dysfunction may remain a feature. Skin problems, fluid retention, digestive problems, or arthralgia may remain in some degree. Many patients will continue to complain of weight gain, or great difficulty in losing it, and receive scant sympathy.

In this situation, the physician may estimate thyroid function by Free Thyroxine Index (Free T4), or Thyroid Stimulating Hormone (TSH) and be confronted by normal readings. It is the present writer’s view that these estimations may be seriously flawed, and their value fundamentally limited. The most popular, at the moment, is the TSH. This may be much affected by poor pituitary function itself due to hypothyroidism; it may be low or normal, rather than raised. The Free T4 test is subject to several errors. Poor tissue uptake is probably the most telling. If the actual use by the tissues is reduced by poor conversion of T4 to T3 (see below) and/or receptor block, then high or normal Free T4 blood tests will result. Haemoconcentration may be an additional factor.

There can be no substitute for proper clinical appraisal. If the patient sounds and looks hypothyroid, then probably that is the problem, irrespective of pathological testing.

The net result very much too often in clinical practice is to under-dose. To provide full remission of symptoms, the level in the tissues of thyroid hormone should be as high as possible, short of too much. (The patient/doctor monitoring to achieve this is described later). The situation is worsened by a tightly held misapprehension in many quarters that there are grave risks associated with overdose. These are largely apocryphal and must be corrected. Probably most widely held, is that thyroid overdose is bad for the heart. The risk is there if coronary artery insufficiency, previous M.l or incipient failure already compromises the heart; the risk of over working a damaged heart is obviously undesirable. The healthy heart will not be damaged by minor degrees of overdose, whether by accident or design; and is rarely much affected even by high levels of thyroid hormone, as in Grave’s Disease.

Another anxiety is osteoporosis. There is a risk in sustained overdose, and untreated hypothyroidism, but this is still not certain. There is NO risk of osteoporosis in thyroid supplementation in correct, physiological doses obviously; and in any inadvertent minor overdose is rapidly detected by monitoring, and therefore of no consequence either.

Suppression of the thyroid gland as a result of treatment is another frequently expressed anxiety. There is a sensitive negative feedback operating through the hypothalamus and the pituitary Overdose will suppress the thyroid; but this will come back to normal at once when the dose is adjusted. Not treating a patient with an under-active thyroid for tear of promoting further depression is quite unrealistic.

Vague fears that thyroid is like "speed"; that any deliberate or accidental overrunning of the metabolism will result in early "burn out"; have been expressed. All that can be said is that is simply not true.

The correct management of thyroid replacement requires a flexible approach; full explanation to the patient, and monitoring, relying as much on the patient’s assessment as the physician’s own clinical impression. One may often be obliged to deal with partial response to replacement therapy, with failure to respond to an increase of dose; and more wrongly, some symptoms of overdose on small levels of treatment. These will include raised pulse rate, tremor, breathlessness, headaches. Sometimes an encouraging response levels off and drops back.

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 T4 - T3. 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.
   ---
5. Adrenal insufficiency.
   This might be more properly described as low adrenal reserve. Since hypothyroidism adversely affects every cell, every tissue, and every gland in the body it is clear that the endocrine system as a whole will be also similarly affected. The adrenals will be subject firstly to lowered efficiency resulting from a lowered vitality primary to hypothyroidism, and secondarily, to reduced ACTH stimulation from the pituitary. As a result, in general, patients with a protracted and/or severe hypothyroid state will have some degree of adrenal insufficiency. A significant level of this will be suspected in these situations:
   
   
   a. Longstanding and severe hypothyroidism.
   b. Episodes of extreme exhaustion, or collapse.
   c. Bad response to minor illness.
   d. Multiple allergies.
   e. Digestive problems – alternate diarrhea and constipation
   f. Flatulence
   g. Weight loss
   h. Increasing arthralgia (fibromyalgia) and morning stiffness.
   i. Pallor, yellow pigmentation (due to poorly metabolized carotene)
   j. Fainting, dizziness

These patients often present with dark rings under their eyes, looking quite ill. Blood pressure is low, with a positive Raglan’s sign. (Pressure fails to rise on standing). These symptoms and signs, it will be appreciated, are those of the early phases of Addison’s Disease.

A single estimation of blood Cortisol is usually unhelpful, but De-hydroepiandrosterone sulphate (DHEA), the main hormone output from the adrenals, will be found to be low. Depressed levels in the endocrine system as a whole are likely to be found. The low adrenal reserve means patients are more or less well, until challenged by the stress of illness or life events--even the thyroid replacement therapy itself initially. And this partial failure will affect adversely T4-T3 conversion and the integrity of the thyroid receptors.

It is essential to manage this insufficiency where present, or where suspected. Remarkably, patients with symptoms, signs and blood pathology of low thyroid, may improve completely on management and correction of the adrenal problems alone; as conversion and receptor efficiency improves, the thyroid hormone circulating - partly unused - is brought into play.

Adrenal insufficiency is dealt with by the provision of the two hormones most likely to be lacking; Cortisonehydrocortisone, and DHEA. (as pointed out above, low DHEA may be used to infer low cortisone output). The treatment therefore, is the exhibition of, ideally, Hydrocortisone. This should be given in divided doses initially of 5mg qds; after a week, 10 mg qds may be used. This remains a physiological dose, not challenging or suppressing the adrenal function, but supplementing it. In these doses all of the usual anxieties associated with cortisone do not apply, since restoration of normality is being aimed at.

This may need to be explained to patients long subject to media-induced fears of the horrors of corticosteroids (Their physicians may share these anxieties, unnecessarily). Dr McCormack Jeffries’ papers on the subject are most worthy of study. DHEA has reached prominence in recent times as a hormone of multiple, and magic properties. Certain it is that the adrenals secrete more DHEA than anything else, and the amount is inversely proportional to age. It is metabolized to oestrogen and/or testosterone, but also has been shown to play a role in reducing obesity; in reducing atherosclerosis and cholesterol; it inhibits the glucose -6-dehydrogenase enzyme in cancer; it improves immune response, and, possibly, acts as a neural facilitator. In physiological doses, there seems to be no problem in its long-term use. If levels are demonstrably low, it is reasonable to provide replacement therapy.


Treatment Protocol

1. General consideration. Correction of Nutritional deficiencies, and elimination of environmental challenges and toxins, has been noted above.
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2. Simple, early hypothyroidism. Readily available tablets of Levothyroxine 50mg may be used. Initial dose is low (in the elderly as low as 25mg daily) and will usually start at 50mg daily. This may be increased 25mg daily every two or three weeks. The ceiling is reached at the judgement of the physician with feedback from the patient. It is unusual to go higher than 300mg.
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3. Moderate hypothyroidism. If the synthetic products are to be used, many patients will benefit if, when a dose of 100mg or more levothyroxine is used, Tertroxin (T3) is added. 10mg for each 100mg of T4 is to be preferred. The dose may be increased incrementally at the physician (and patient’s) discretion.
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   If natural thyroid is to be used, a start may be made with 1/2 grain (30 mg). (Commensurate with its 100 years of use by the medical profession, natural thyroid is still measured in grains). Dosage is increased by 1/2 gr. every two weeks; usually by six weeks the dose will level off. Improvement on any given dose continues for weeks and weeks, and the temptation, scenting victory, to increase the dose too soon, should be resisted. (One grain equivalent 60mg of natural thyroid is equivalent to 38mg T4 and 9mg T3). The definitive dose may remain unchanged for months or years, but the patients should be allowed to make small adjustments themselves, depending on activity, ambient temperature, for example.
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4. Severe hypothyroidism. As indicated above, simple replacement is unlikely to be sufficient. Receptor block and adrenal insufficiency require adrenal support; preferably initiated a week before thyroid supplementation is started. A satisfactory protocol is to, start with 5mg hydrocortisone qds, and after a week, double the dose. Alternatively Prednisolone 2.5 mg (or the enteric-coated Deltacortril) may be used, doubling after a week. Clinical judgment, based on the patient’s condition being normal - perhaps after about three months - will enable the dose then to be halved, and then discontinued. It will be a matter of clinical judgment and preference to use T4 and T3, or natural thyroid.

Some patients already on levothyroxine (T4), but far from well, have to be considered separately. If the condition is really quite severe, and increasing thyroxine makes matters worse, it should be stopped for a short while and cortisone prescribed. The sudden improvement in thyroid uptake brought about by the cortisone may actually result in overdose symptoms if exogenous thyroid is continued. The treatment of choice is to restart thyroid hormone, using instead T3, after a 7 day interim period; 10 mg for a few days, then 20 mg and so on. After the improvement is seen to be full, and sustained, natural thyroid can be reintroduced. The general improvement may, secondarily, improve endogenous thyroid production, which can result in the overall exogenous dose being reduced.

As regards DHEA, its significance in the management of adrenal insufficiency is unsure, but where low levels have been found, it seems proper and logical to restore them to normality. In women 25mg daily, and men 50mg daily sometimes produces significant benefit. In this practice, its use has always been an advantage.

The management of hypothyroidism in children requires fine clinical judgement; but one quarter to one half of the adult dose seems to be a satisfactory starting point. Reliance on blood testing should be modified by clinical appraisal of the child and his parents’ observations. The diagnosis is often missed in children; and should be considered in any child often ill. The basal temperature test may prove a helpful pointer.

Thyroid insufficiency may have a number of different causes and its symptoms may masquerade as a number of different illnesses. It should always be considered in patients with prolonged ill health, and the diagnosis rely on history and examination. The reliance of the profession on the pathological tests in favor of thoughtful appraisal is to be deplored. The treatment is inexpensive and low tech, requiring a few simple guidelines and a listening approach by the physician. Rarely is consultant advice necessary; the family physician is well able to initiate and monitor the treatment even in quite severe cases. The rewards are invariable; with no fuss, and with delight, the patients always get better. This common condition is one of few where simple measures can transform patients’ lives.

References:

1. The Unsuspected Illness. Barnes. Harper and Row. 1976
2. Jackson. A.S. Hypothyroidism. J.A.M.A. 165:121:1957
3. B. Durrant-Peatfield. Aspects Of A Common Missed Diagnosis. Journal Of Nutrition And Environmental Medicine. 6: 4: Dec 1996
4. ORD W.M, On Myxoedema, a term proposed to be applied to an essential condition in the critinoid infection observed in middle aged women. Transactions Of The Medical - Chirurgical Society Of London 57:6(~611877
5. E. Hertoghe. Treatment Of Myxoedema International Clinic Week. New York 4: 14:1915
6. The Fallacy Of Thyroid Function Tests. The Riddle Of Heart Attacks. Barnes & Barnes 1976. ROBINSON PRESS. ISSN 0-913730-27-0
7. Interindividual Differences in The Pituitary-Thyroid Axis Influence The Interpretation Of Thyroid Function Tests. Clinial endo crinology . 39:101-107:1993
8. Staub et aI. Spectrum Of SubClinical And Overt Hypothyroidism. American Journal Of Medicine 92: June 1992 pp 631
9. Barnes. Temperature v Basal Metabolism. Journal Of American Medical Association. 119:1072,1942
10. Klause Wenzel. Osteoporosis. Lancet 340 15. 8. 92 pp 435-6
11. Franhyn et al. Long-term Thyroxine treatment and bone mineral density. Lancet 340 4.7.92
12. Jeffries. W.M. Safe Uses Of Cortisone. Charles C. Thomas. 1981
13. Klinefelter et al. Single Dose Prednisone Therapy. J.A.M.A. 241 No 25 22.6.79
14. Barnes. Etiology And Treatment Of Lowered Resistance To U.R.I.s Federation Proceedings 12 No I March 1953