William Jefferies, M.D., professor emeritus of internal medicine at the University of Virginia.
below are key points pulled from Jeffries book. Of course, there is much more in the book,
SAFE USES OF CORTISOL by William McK. Jeffries 3rd Edition
Chapter 1-Background
The first chapter discusses the history of our knowledge of cortisone and cortisol. In 1929, Dr. Hench figured out that rheumatoid arthritis disappeared because of a normal adrenocortical response after surgery, pregnancy and other situations. They didn’t multi-dose then, and used much larger amounts than needed. We now know that smaller dosages of cortisone or cortisol are effective and may take ten to 14 days to produce impressive improvement in arthritis. Because they used such large doses of cortisol in treatment, side effects occurred, and the presumption was made that any dosage of any glucocorticoid would have potentially hazardous and undesirable effects. “For over thirty years, physicians have been indoctrinated with this concept.”
Chapter 2
1) It is not generally realized that the dangerous side effects of glucocorticoid therapy occur only with certain dosages and not with others. That there is a tremendous difference between the effects of small “physiologic” dosages and those of larger “pharmacologic” dosages (larger than 40mg) has not been emphasized. 11 When applied to hormone actions, a “physiologic” dosage implies one that promotes normal function, whereas a “pharmacologic” dosage is one in excess of normal requirements and hence, one that might alter normal function. 12
2) Physiologic studies indicate that the average daily production of cortisol by human adrenals under basal conditions is approximately 15-20 mg, but this dosage will not maintain a totally adrenalectomized patient. 35-40 mg daily is necessary to inhibit endogenous adrenal steroid production to zero, and this dosage will satisfactorily maintain an adrenalectomized patient with a minimum of supplementary sodium-retaining steroid. Taken by mouth, even in divided doses, cortisone acetate or cortisol is only approx. 60% as efficient as when the hormone is naturally produced by the adrenals or released directly into the blood. 13 (the last statement makes you wonder about doing cortisol sublingually! Janie)
3) It has been demonstrated that when subjects with intact adrenals receive less than full replacement dosages of cortisol, endogenous adrenal function is suppressed only sufficiently to achieve a normal glucocorticoid level. For example, subjects receiving 20 mg (5 mg. four times) daily of cortisol have their endogenous adrenal steroid production decreased by approx. 60%, and subjects receiving 10 mg. (2.5 mg. four times) daily have their adrenal steroid production decreased by approx. 30%. The residual functioning tissue is adequate for apparently normal responses to stresses such as respiratory or gastrointestinal infections or even major surgery, but because their hypothalamus-pituitary-adrenal (HPA) response to stress might be impaired, and because of recent evidence that at least some autoimmune disorders are associated with a defective HPA response to stress, it seems advisable to supplement their cortisol dosages at times of any increased stress and especially at times of surgery or similar severe stress as in patients with more severe adrenocortical deficiency. 14
Subreplacement dosages also avoid the complete suppression of endogenous adrenal androgen production that probably causes a higher incidence in women than in men of undesirable side effects such as osteoporosis when larger dosages are taken for long periods. Many patients who need subreplacement dosages have low adrenal reserve, so the administration of such dosages actually improves the adrenals’ ability to respond to stress in these cases. 14
4) The schedule of administering cortisol every eight hours or four times daily is followed because of evidence that normal blood levels and some metabolic effects of a single dose of cortisol do not last longer than 8 hours. For practical purposes, dividing the total daily dosage into four parts taken before each meal and at bedtime has two advantages. It is easier for a patient to remember to take a medication at these times than at other times, and the ingestion of food tends to counteract the development of acid indigestion from the cortisol. For the bedtime dose, patients are instructed to drink milk or take an antacid with the medication. 15-16 (from Janie–In Wilson’s book, Adrenal Fatigue 21st Century, he recommends the following: 12 mg. first thing in the morning, then 5 mgs at noon, then 2 mgs at 3 pm, and finally 1 mg at 6 pm. That better follows the normal rhythm.)
5) Why should most physicians be unaware of the safety of small physiologic dosages?
1. There has been no promotion of physiologic dosages by pharmaceutical companies.
2. There has been little, if any, discrimination between the effects of physiologic vs. pharmacologic dosages.
3. There is a tendency to confuse cortisone and cortisol with there more potent derivatives, such as prednisone, prednisolone, dex, etc. 18-19
Chapter 3- The Significance of Normal Adrenocortical Function
6) Four known types of steroids of the cortex are: glucocorticoid, mineralocorticoid (aldosterone), androgen, and estrogen, (plus an unknown probable other).,
Glucocorticoid has one of its chief actions stimulation of the formation of glucose from non-carbohydrate sources such as amino acids from protein, a process known as gluconeogenesis. This is a vital effect in the maintenance of normal levels of blood glucose when food intake is irregular, since low blood sugar is incompatible with normal function of the brain, muscles or other tissues. 25-26
7) It has been recognized for many years that patients with adrenal insufficiency not only are more susceptible to low levels of serum sodium, with resulting hypotension and shock, but are also more susceptible to pathologic sodium retention from excessive amounts of salt or of sodium-retaining steroids, such as aldosterone, desoxycorticosterone, or 9-alpha-fluorohydrocortisone, suggesting that the adrenals might produce a substance that protects against sodium retention. 27
Two hormones produced normally by the ovaries, progesterone and 17-hydrozyprogesterone, have been demonstrated to have natriuretic properties (from Janie: causing salt to be eliminated from the body through urine, lowering blood pressure) and they are known intermediary steroids in adrenal cortices in the pathway of production of cortisol, occurring in excess in certain types of congenital adrenal hyperplasia, but the possibility that they might aid in normal water balance has apparently not been investigated. 27
9) A person who sleeps from 11 pm to 7 am has a maximum level of cortisol in his or her blood at approx. 8 am, then it gradually decreases through the day and evening, reaching a low point at approx. 1 am, following which it increases progressively during sleep to reach it’s max again at 8 am. The peak daily level of plasma-cortisol in a normal individual is usually between 20 and 30 mcg and the lowest level is between 5 and 10 mcg. 28
10) The production of cortisol is primarily regulated by the production of ACTH/corticotrophin by the pituitary, which is in turn controlled by the production of corticotrophin-releasing factor (CRF) by the hypothalamus. The production of DHEA seems to be only partly regulated by ACTH, but its
control is less well understood.
11) A patient with untreated mild adrenal insufficiency or low adrenal reserve may function reasonable well when environmental conditions are optimum but tends to tire more easily, and if strenuous physical exercise is undertaken or a meal skipped, hypoglycemic symptoms may develop. If an infection such as a common cold develops, symptoms tend to be more severe and last longer than in a person with normal adrenocortical reserve. These undesirable developments may be prevented by administration of suitable, safe, physiologic dosages of cortisol. It has also been demonstrated that normal adrenocortical function is essential for optimum ability to withstand infections, numerous studies having indicated that either too little or too much glucocorticoid can impair resistance to infection, whereas an optimum level of cortisol enhances resistance to infection. 29
12) It is suggested that adrenal production of glucocorticoids is related to body size and fat composition. 31
Chapter 4 – GENERALLY ACCEPTED USES OF PHYSIOLOGIC DOSAGES
13) Adrenal insufficiency can be manifested by hyperpigmentation of the skin, weakness, fatigue, anorexia, and susceptibility to collapse and shock with exposure to stress. Adrenal insufficiency resulting from an autoimmune phenomenon have become more common diagnoses. 33
14) When cortisone and ACTH became available for human use in 1948, these hormones first attracted worldwide attention by their dramatic beneficial effects on patients with rheumatoid arthritis. The dosages employed were large, however and produced catastrophic side effects….33
15) Meanwhile, experience with the use of small, safe, physiologic dosages of cortisol in patients with ovarian dysfunction and infertility revealed that patients with associated allergies, chronic fatigue or autoimmune disorders also reported improvement in these conditions while taking the steroid, without experiencing any undesirable side effects. These results were published in a leading medical journal, but the reputation of glucocorticoids had become so bad that they received little attention. 34
16) Hence, the diagnosis and treatment of mild adrenocortical deficiency, a condition that is rarely mentioned in medical textbooks, has become important for all practicing physicians to recognize. It may be primary, resulting from inadequate production of cortisol by the adrenals and sometimes termed “low adrenal reserve”, or it may be secondary to inadequate stimulation of the adrenals by ACTH from the pituitary or by corticotrophin releasing factor (CRF) from the hypothalamus. Another possible cause of symptoms of cortisol deficiency is a defect in the cellular receptors (i.e. cellular resistance) for cortisol causing associated normal or elevated levels of plasma cortisol. 34
17) Recent reports have presented evidence that patients with rheumatoid arthritis and several other autoimmune disorders have abnormal responses of the HPA axes to stress, so the possibility that the development of these disorders might be related to defective HPA responses seems likely. This would explain the beneficial effects of small, physiologic dosages of cortisol that have been observed in some of these patients and support the advisability of testing the integrity of this axis and the use of therapeutic trials with safe, physiologic dosages of cortisol in patients with these disorders. 35
18 } It is preferable to have these tests run in the morning after the patient has had adequate sleep and has not taken for a sufficient interval of time any glucocorticoid or other medication that might affect adrenal function or blood levels of cortisol, but helpful information can be obtained by running them at any time of day. A more sensitive low dose Cortrosyn test (what we call the STIM test—Janie) has been suggested for the diagnosis of mild adrenal deficiency, but because therapeutic trials are usually justified, even in patients with apparently normal tests, sometimes it is preferable to delay further testing until a therapeutic trial has been made, especially if it might avoid otherwise unnecessary hospitalization. 36
19) It is important to be aware that test results that fall within the “normal range” do not rule out the possibility that a patient might have mild adrenal deficiency since the normal range was probably obtained from a group of people who did not have classical Addison’s disease or hypopituitarism or any other known physical disorder and is rather broad. Hence, it might include persons with chronic allergies or other conditions that may be associated with mild adrenal deficiency. Furthermore, as previously mentioned, mild adrenal deficiency can occur secondary to inadequate stimulation by ACTH from the pituitary or by CRF from the hypothalamus. These patients have low normal baseline blood cortisol levels that respond normally to Cortrosyn, but still improve with physiologic dosage of cortisol. Hence, results of Cortrosyn tests within the normal range do not exclude the possibility that patients might benefit from cortisol therapy, so a therapeutic trial might still be justified. 36
20) The baseline cortisol test is an example of the impossibility of having strict end points in designating normal ranges of hormone levels, especially for a dynamic hormone such as cortisol, whose levels may fluctuate from minute to minute depending upon the degree of stress in addition to diurnal variation. Hence, patients with adrenal insufficiency may have plasma cortisol levels within low normal range, especially in the afternoon and evening, and patients with hyperadrenalism may have plasma cortisol levels within upper normal range in the morning. It is there possible that milder degrees of low adrenal reserve may not be detected unless Cortrosyn tests are performed in the morning at a time when baseline cortisol levels are maximum. Furthermore, patients vary in the susceptibility to various degrees of stress, including the stress of having injections and blood tests, so these factors must be considered in interpreting the results of tests. Hence, a diagnosis of mild adrenocortical deficiency should depend primarily on the clinical picture and therapeutic trials are often justified even when the results of tests fall within the normal range. 37
21) It should be emphasized that a “normal” baseline plasma cortisol and response to Cortrosyn does not rule out the possibility that a patient might improve with a physiologic dosage of cortisol, so for patient with disorders that suggest the possibility of mild adrenal deficiency, therapeutic trials with a small, subreplacement dosage of cortisol might still be helpful. 38
22) Because spontaneous adrenal insufficiency results from progressive destruction of adrenal tissue, symptoms appear when the process reaches the point where remaining adrenal tissue is insufficient to maintain normal well-being. This may require destruction of over 90% of the glandular tissue, but the remnant is capable of some function, so replacement dosages of cortisol in chronic adrenal insufficiency are usually less than the 35-40 mg daily that are required for the totally adrenalectomized patients. Most patients can be maintained on between 20 and 30 mgs. daily in divided doses. Although some patients may feel well on less than 20 mg. daily, it seems preferable to give at least this much cortisol, even to patients with low adrenal reserve, because it takes the strain off of the residual adrenal tissue and provides for more functional reserve in times of stress. Under some circumstances, it appears to provide an opportunity for residual tissue to regenerate. A few patients with low reserve have demonstrated evidence of recovery of reserve after months of even years of such treatment, but most seem to require some replacement for the remainder of their lives. 39
23) Widely recommended is 2/3rds of the daily dosage before breakfast and 1/3 after supper, but patients have preferred four divided doses. This is not surprising in view of the evidence that the half-life of cortisol in the blood is only 100 minutes, and some metabolic effects of even large doses do not last longer than 8 hours. Four divided doses produce more energy and less fatigue. 39-40
24) Although a lower dosage at supper time is logical and seems to diminish a tendency to insomnia that occurs in some patients, a lower dosage at bedtime is not always desirable because with normal diurnal variation the plasma cortisol level rises during sleep to reach a peak shortly after awakening in the morning. It also results in a need to get up and void once or twice during the night. 41
25) Patients with chronic adrenocortical deficiency can usually be well maintained with cortisol, 5 or 7.5 mg orally before each meal and at bedtime. 41
26) Package inserts for cortisol still do not mention the differences between physiologic and pharmacologic dosages and effects, implying that any of the many alarming side-effects that are listed may occur. 42-43
27) When a patient with adrenal insufficiency encounters stress, additional cortisol is necessary to maintain normal health and sense of well-being. 41 Higher dosages of cortisol are required to maintain a physiologic state that would produce hypercortisolism with it’s well-known undesirable effects in the unstressed states. The increased secretion of adrenal hormones serves to meet an increased need during stress and trends to maintain homeostasis rather than to disturb it. The increased secretion does not cause a state of hypercorticism such as develops when the titer of these hormones is increased artificially in the absence of need. Hence, a patient with adrenal insufficiency under stress may require dosages of cortisol to maintain a physiologic state that would produce hypercortisolism with its well-known undesirable effects in the unstressed state. 44-45
28) Patients with adrenal insufficiency should be cautioned to carry ID cards stating their diagnosis, treatment, etc.
29) In some respects, patients taking cortisol seem to be healthier than many persons without adrenal insufficiency in that they often appear to have more energy, less fatigue, and a greater resistance to at least some types of infection. 46
MILD ADRENOCORTICAL DEFICIENCY
30) As mentioned previously, mild adrenocortical deficiency, either primary (low adrenal reserve) or secondary to inadequate stimulation by the pituitary or the hypothalamus is another clinical disorder in which physiologic dosages of cortisol have a rational roles in therapy. Low adrenal reserve is characterized by a subnormal response to ACTH with baseline plasma cortisol level within normal range. Because of their residual adrenocortical function, patients with this disorder can sometimes omit the bedtime dose of cortisol. Mild secondary adrenocortical deficiency is characterized by a baseline plasma cortisol level either low or in the low normal range, but with a normal response to Cortrosyn stimulation. 54
31) “Thirty-six years ago, I reported the beneficial effects of physiologic dosages of cortisone acetate or cortisol on two patients with rheumatoid arthritis, with evidence that patients with rheumatoid arthritis seemed to have lower excretion of dehydroepiandrosterone in their urine and, hence, might have a mild abnormality of steroid metabolism. A review of the literature fails to reveal any attempts by others to confirm these observations or even any comment on them. The benefit of low dosage glucocorticoid therapy in menopausal arthritis is exemplified in Case 6 in Chapter 4, and patients with other nonspecific types of arthritis have reported impressive improvement in arthritic symptoms when this treatment was administered for associated problems.” (Five detailed case histories follow) 90
32) Because of the onset and aggravation of rheumatoid arthritis after periods of increased stress, it is probably important not only to increase the dosage of cortisol commensurate with the degree of increased stress, but also, as soon as optimum benefit is obtained, to taper the dosage to maintenance levels as quickly as possible without causing a return of symptoms. 100
Chapter 7 – ALLERGIC DISORDER
33) Patients with seasonal allergies may benefit from taking small, physiologic dosages of cortisol in the spring or autumn, with temporary increases depending upon the severity of symptoms. 110
34) Patients who were receiving physiologic dosages of cortisol began to report that they seemed to get fewer colds than other members of their families, often escaping completely when everyone else in the family had been ill. 128
35) A possible explanation of the contrasting effects of physiologic vs. pharmacologic dosage of glucocorticoids upon resistance to respiratory infections might be as follows: Normally the body maintains levels of cortisol and immune globulins sufficient to protect against average daily exposure to infection. The lowering of resistance that follows various stresses such as excessive fatigue, lack of sleep, or emotional upset is accompanied by a relative deficiency of cortisol that causes malaise and anorexia, and evidence of infection develops. When the person is able to produce sufficient antibodies and other components of the immune response, the infection subsides and symptoms clear. The mobilization of at least some of the components of the immune response may depend upon the presence of adequate cortisol, since adrenally insufficient subjects are not able to produce a normal immune response. Hence, administration of physiologic dosages of cortisol may help to prevent the lowering of resistance that enables an infection to start or, after an infection has started, may assist the immune response and enable the person to recover more quickly. If, however, an excessive amount of glucocorticoid is present before an infection develops, the immune response may be blocked or misdirected, allowing infections to develop and progress abnormally. It is temping to speculate that the apparent beneficial effect of vitamin C in the common cold may be mediated at least in part through the adrenals, since the highest concentration of ascorbic acid in the body occurs in the adrenal cortex.
VIRAL INFECTIONS
36) Patients with acute influenza were treated in the same manner in which patients with chronic adrenal insufficiency were treated when they developed acute infections. Cortisol, 20 mg. by mouth four times daily before meals and at bedtime, was started. Patients were instructed to continue this dosage until they felt well, then decrease to 10 mg. four times daily for two days, then 5 mgs.four times daily for two days, then stopped. Clinical responses were striking. Within 24 hours, all patients felt much better, and within 48 hours symptoms such as fever, malaise, and generalized aching had completely subsided, and they felt quite well. The initial dosage of cortisol was decreased after 48 hours and discontinued after six days of therapy. No relapse or complications occurred. 136
37) For many years, it has been recognized that the clinical symptoms of acute malaise, anorexia, fever, weakness, exhaustion, and generalized aching that occur with any acute severe infection, but especially with influenza, are similar to the symptoms of acute adrenal insufficiency. 138 The possibility that a relative deficiency of adrenal response might be present in the incipient phase of any infectious disease should therefore be further investigated. 139
38) We now know that influenza viruses attack the human body by decreasing the production of adrenocorticotropic hormones (ACTH), thereby decreasing the production of cortisol, the only hormone that is absolutely essential for life, so treatment with physiologic dosages of cortisol is a safe and beneficial therapy for patients with influenza, regardless of its type. 143
Safe Uses of Cortisol | Stop The Thyroid Madness
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