Alternative Treatment Considerations in Anorexia Nervosa

R. Wheatland

The Endocrine Research Project, Santa Cruz, CA, USA
Originally published in the journal Medical Hypotheses, 2002;59(6):710-5

Correspondence to: Rand Wheatland, The Endocrine Research Project,
574 Sims Rd., Santa Cruz, CA 95060, USA.
E-mail: rwheatla@query.com

See also the 2005 article, Chronic ACTH Autoantibodies are a Significant Pathological Factor in the Disruption of the Hypothalamic-pituitary-adrenal axis in Chronic Fatigue Syndrome, Anorexia Nervosa and Major Depression

Summary Endocrinological factors underlying the etiology of anorexia nervosa are relevant to its treatment. It appears that sufferers of anorexia nervosa perform their weight-limiting behaviors in an attempt to compensate for adrenocortical insufficiency. Hypoglycemia stimulates the secretion of cortisol. In response to severe malnutrition, blood cortisol levels also rise due to increased cortisol half-life and a decrease in its metabolic clearance rate. If an adrenocortical-insufficient individual goes on a severe diet, one effect will be a significant increase in their blood cortisol levels, which will alleviate their adrenocortical insufficiency and its symptoms. This response is a powerful positive reinforcement for continuing their weight-limiting behaviors. Sufferers of anorexia nervosa commonly exhibit two other behaviors that can raise their cortisol levels: excessive exercise and self injury. Treatment of the underlying adrenocortical insufficiency with cortisol supplements has been shown to be effective in five previously published cases of diagnosed anorexia nervosa. (Med Hypotheses 2002;59(6):710-5)

The eating disorder anorexia nervosa is a serious and pervasive condition. The disorder can cause severe illness and has a high mortality rate (1). It is estimated that anorexia nervosa affects about 0.5% of young women in Europe and North America (2). Anorexia nervosa is defined primarily as a person being at least 15% underweight voluntarily (3). Weight gain is limited by restriction of food consumption and excessive exercise (Restricting type) and/or self-induced purging (Binge-Eating/Purging Type).

Anorexia nervosa is universally treated as a psychiatric disturbance because the disorder appears to be a compulsive behavior in reaction to a socially influenced self image. However, since evidence indicates that anorexia nervosa has an endocrinological basis, treatment with hormone supplements should prove beneficial.

A prominent endocrine feature of individuals diagnosed with anorexia nervosa is that their blood cortisol levels are significantly higher than the cortisol levels of controls (4). It appears that these high cortisol levels result from the behaviors typically expressed in anorexia nervosa: severe dieting, excessive exercise, purging and self-injury. These behaviors may be an attempt to compensate for an underlying endocrine disorder: adrenocortical insufficiency that includes a deficiency of cortisol (see Table 1 for some pertinent details about adrenocortical insufficiency).

Proposed Etiology

The following is a plausible mechanism for the etiology of anorexia nervosa. It is well known that hypoglycemia stimulates the secretion of cortisol. Blood cortisol levels will also rise due to increased cortisol half-life, as in response to fasting (6), and a decrease in its metabolic clearance rate, as seen during protein-calorie malnutrition (7). If an adrenocortical-insufficient individual goes on a severe diet, one effect will be a significant increase in their blood cortisol levels. The increased cortisol level will alleviate the adrenocortical insufficiency and its symptoms. This response is a powerful positive reinforcement for the individual to continue their weight-limiting behaviors.

This etiological hypothesis is consistent with the fact that more women than men suffer from anorexia nervosa, and that women are more likely to be adolescents when they first develop the disorder. Young women endure significant social pressures to appear thin. Therefore, they are more likely to go on the severe diets that begin the cortisol self compensation. That dieting is a major risk factor for anorexia nervosa (2,8) is also consistent with this hypothesis.

Other Cortisol-Raising Behaviors

Sufferers of anorexia nervosa commonly exhibit two other behaviors that can raise their blood cortisol levels: excessive exercise (9) and self injury (10). Since intense exercise can increase cortisol levels (11), sufferers of anorexia nervosa may engage in excessive exercise in an attempt to correct an underlying adrenocortical insufficiency.

Self injury is another behavior that may be employed by sufferers of anorexia nervosa to compensate for an underlying adrenocortical insufficiency, as in Rajathurai et al's report of a 16-year-old girl who regularly cut herself (12). She had a 4-year history of self mutilation, gouging "pieces of skin from her arms and legs every night before falling asleep." "Fairly intensive counselling of the family" had little effect. While on holiday, she required hospitalization for "nausea, vomiting, dizziness, and tiredness." She was diagnosed with Addison's disease. Within one week of beginning treatment with hydrocortisone, she stopped her self mutilation. Her demeanor improved, her social ineptitude disappeared and she became more confident and independent. The underlying disease was not evident under conventional diagnostic criteria until her cortisol deficiency became severe on holiday and typical Addisonian symptoms appeared.

Apparently, since cortisol is secreted by the adrenal glands in response to physical injury, until her holiday, this girl was able to avoid severe adrenocortical insufficiency by cutting herself. The self injury coexistent with anorexia nervosa may serve the same purpose.

Successful Treatment With Cortisol Supplements

If the underlying cause of anorexia nervosa is adrenocortical insufficiency, then subreplacement doses of cortisol, in the form of hydrocortisone, would be an appropriate treatment. A literature search found three published cases of individuals diagnosed with anorexia nervosa that were treated with hydrocortisone.

Tobin and Morris (13) reported the case of a 20-year-old "man with a long history of obsessional traits and food fads" that "presented with anorexia, vomiting and marked weight loss." He was diagnosed with anorexia nervosa and left the hospital. "He was readmitted one month later, severely cachectic and with biochemical abnormalities consistent with advanced Addison's disease." "He responded dramatically, both mentally and physically, to" hydrocortisone and fludrocortisone, a mineralcorticoid supplement.

Adams et al (14) reported the case of an emaciated 18-year-old woman who "had nausea, vomiting, weight loss, and a diagnosis of anorexia nervosa." "Subsequent fever, disorientation, and confusion led to the discovery of Addison's disease, which responded well to" hydrocortisone.

Blaustein et al (15) reported the case of a 12-year-old female presenting with an "inability to eat, vomiting, weight loss of 2.5 kg, and severe weakness over several months. She had been diagnosed as a case of anorexia nervosa." "The patient was treated with hydrocortisone and fludrocortisone, with dramatic resolution of all her symptoms. One month after discharge from the hospital, she had gained 3.2 kg."

The cortisol supplement therapy was successful in all three cases. The patients' symptoms abated and their diets returned to normal. Tobin and Morris (13) suggested that it is likely that the patient's "onset of Addison's disease precipitated the psychological and somatic manifestations of anorexia nervosa." Adams et al (14) concluded that their patient had been misdiagnosed with anorexia nervosa, when the patient actually had Addison's disease. Similarly, Blaustein et al (15) concluded, "We report this patient to emphasize key elements in the medical history and physical examination that helped to exclude an eating disorder. This case exemplifies the importance of differentiating anorexia nervosa from Addison's disease." Adams et al and Blaustein et al dismissed the diagnosis of anorexia nervosa for their patients because the patients were not obsessed with their weight or body shape. It has been suggested that weight phobia should not be a requirement for a diagnosis of anorexia nervosa (16). In any event, these two patients had an eating disorder that had enough consistency with anorexia nervosa that they had been previously diagnosed as suffering from anorexia nervosa. In all three cases the eating disorder not only coexisted with their adrenocortical insufficiency, but may be seen as a symptom of their adrenocortical insufficiency.

The Adams et al paper lists a number of similarities between anorexia nervosa and Addison's disease: nausea, vomiting, weight loss, abdominal pain, cold intolerance, hypothermia, orthostatic hypotension, electrocardiographic and electroencephalographic features, and several laboratory findings. They point out only a few differences. If anorexia nervosa sufferers are adrenocortical insufficient and use self-compensating behaviors to modify their biochemistry, this would explain the differences in their clinical and biochemical status from patients with uncompensated Addison's disease. To see anorexia nervosa and adrenocortical insufficiency as two unrelated dysfunctions is analogous to believing that someone with diabetes mellitus is not diabetic since they have stabilized their glucose levels by making major modifications to their diet.

Low Doses More Effective Than High Doses

Other reports have documented that treatment with cortisone and ACTH (adrenocorticotropic hormone) can relieve the symptoms and improve the condition of patients suffering from anorexia nervosa (17,18). In 1951, Greenblatt et al (18) reported the effectiveness of treating anorexia nervosa using ACTH and cortisone at different dosages (see Table 2). Lower doses were effective, higher doses were ineffective. In the use of oral cortisone, the subphysiological dose of 25 mg daily was effective, whereas the supraphysiological daily dose of 50 mg induced depression. Even though excellent results were achieved with injected cortisone and ACTH at low supraphysiological doses, lower doses may have worked even better. In achieving hormonal balance through hormone supplements, too much can be just as ineffective as none at all.

It may seem anti-intuitive to give cortisol to individuals whose blood cortisol levels are already higher than normal. But the effect of cortisol replacement therapy will be to satisfy the patient's cortisol requirement, which will reduce the patient's perceived need to maintain a near-starving state. When untreated, the patient would begin to feel bad soon after eating too much because their blood cortisol levels would start to fall. Cortisol supplements enable these sufferers to satisfy their hunger pains without the associated drop in cortisol levels.

Relative Adrenocortical Insufficiency

In individuals with marginal adrenocortical production, acute stress can increase their cortisol requirements beyond their adrenocortical capacity, a condition described as relative adrenocortical insufficiency. Symptoms of adrenocortical insufficiency will then appear or increase in severity: fatigue, tiredness, weakness, mental depression, anorexia, weight loss, dizziness, orthostatic hypotension, nausea, vomiting, muscle and joint pain, nervousness, irritability, headaches, inability to concentrate, fears and apprehensions, confusion, poor memory, feelings of frustration, dry skin, scanty perspiration, low basal metabolic rate, constipation or diarrhea, and others (19,20). It is reported that anorexia nervosa episodes are frequently preceded by traumatic or stressful events (21). Sufferers of anorexia nervosa may enter a state of relative adrenocortical insufficiency during these periods, which may, in turn, decrease their appetite, making it easier for them to initiate a severe diet.

Personality Changes

Adrenocortical insufficient individuals commonly display marked personality changes as their condition worsens (22). One of the characteristic behaviors is seclusiveness, also described as social withdrawal. The purpose of this isolation can be explained as an attempt to avoid the stress associated with social interactions, just as people with heart problems avoid the stress of climbing stairs. In anorexia nervosa, severe dieting, excessive exercise, purging and self injury would just be additional behaviors employed to compensate for a dysfunctional endocrine system.

Psychological Disturbances

It is understandable that sufferers of anorexia nervosa demonstrate psychological disturbances. Many organic diseases precipitate an adverse psychological reaction (23). Disease, by definition, negatively impacts the normal functions of someone's life, which can create psychological distress. Endocrine disorders exert a particularly strong influence on a person's psychological well being because their effects are systemic and usually alter the metabolism of the brain.

Food and Body Image Obsessions

Since anorexia nervosa frequently begins with a behavioral act (dieting) that is commonly associated with a poor body image, it is reasonable that body image figures so prominently in the psychology of someone that must make such a considerable effort to continue dieting. Food and body image become obsessional because constant hunger pains are a continual reminder of them.

Biochemical Measurements

Examining hormone concentrations in sufferers of anorexia nervosa for levels consistent with adrenocortical insufficiency would not be productive because, for example, the cortisol concentrations in those sufferers who are successfully self compensating would be higher than the reference range. In sufferers who are inadequately self compensating, the cortisol levels may be within the reference range. Similarly, ACTH levels and corticotropin stimulation tests may yield uninterpretable results.

Bulimia Nervosa

The eating disorder bulimia nervosa, associated with anorexia nervosa, is likely to have a similar endocrine etiology. High blood cortisol levels are also found in individuals suffering from bulimia nervosa (24). Bulimia nervosa is probably another behavioral method for counteracting adrenocortical insufficiency, much the same as anorexia nervosa's Binge-Eating/Purging type, but without the extreme weight loss.

Summary

The food restriction behavior of sufferers of anorexia nervosa increases their blood cortisol levels, just as cortisol levels increase in healthy subjects on starvation or near-starvation diets. Sufferers of anorexia nervosa also commonly engage in two other behaviors that can increase blood cortisol levels: excessive exercise and self injury. If anorexia nervosa sufferers have an underlying adrenocortical insufficiency, the increased cortisol levels resulting from these behaviors will relieve their adrenocortical insufficiency and its symptoms. This relief is a powerful motivation for someone to continue these behaviors.

If patients with anorexia nervosa are given cortisol supplements, they will no longer need to employ these behaviors to relieve their symptoms. Anorexia nervosa sufferers should not be excluded from a diagnosis of adrenocortical insufficiency just because they fall into a behavioral/biochemical cycle that appears to be self destructive. Treatment with subreplacement doses of cortisol, in the form of hydrocortisone, will be found to be effective at relieving their behavioral, psychological and physical problems within a very short time (2 days to 2 weeks).

References

(1) Zipfel S, Lowe B, Reas DL, Deter HC, Herzog W. Long-term prognosis in anorexia nervosa: lessons from a 21-year follow-up study. Lancet 2000 Feb 26;355(9205):721-2. [Abstract]
(2) Hsu LK. Epidemiology of the eating disorders. Psychiatr Clin North Am 1996 Dec;19(4):681-700. [Abstract]
(3) American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th Edn. Washington, DC: American Psychiatric Association; 1994. Diagnostic criteria for 307.1.
(4) Ferrari E, Fraschini F, Brambilla F. Hormonal circadian rhythms in eating disorders. Biol Psychiatry 1990 May 1;27(9):1007-20. [Abstract]
(5) Jefferies WM. Safe uses of cortisol, 2nd Edn. Springfield, IL: Charles C. Thomas; 1996.
(6) Fichter MM, Pirke KM, Holsboer F. Weight loss causes neuroendocrine disturbances: experimental study in healthy starving subjects. Psychiatry Res 1986 Jan;17(1):61-72. [Abstract]
(7) Smith SR, Bledsoe T, Chhetri MK. Cortisol metabolism and the pituitary-adrenal axis in adults with protein-calorie malnutrition. J Clin Endocrinol Metab 1975 Jan;40(1):43-52.
(8) Patton GC, Selzer R, Coffey C, Carlin JB, Wolfe R. Onset of adolescent eating disorders: population based cohort study over 3 years. BMJ 1999 Mar 20;318(7186):765-8. [Abstract] [Free Full Text]
(9) Davis C, Katzman DK, Kaptein S, et al. The prevalence of high-level exercise in the eating disorders: etiological implications. Compr Psychiatry 1997 Nov-Dec;38(6):321-6. [Abstract]
(10) Vanderlinden J, Vandereycken W. In: Trauma, dissociation, and impulse dyscontrol in eating disorders. Bristol, PA: Brunner/Mazel, 1997: 48-55.
(11) Kuoppasalmi K, Näveri H, Härkönen M, Adlercreutz H. Plasma cortisol, androstenedione, testosterone and luteinizing hormone in running exercise of different intensities. Scand J Clin Lab Invest 1980 Sep;40(5):403-9. [Abstract]
(12) Rajathurai A, Chazan BI, Jeans JE. Self mutilation as a feature of Addison's disease. Br Med J (Clin Res Ed) 1983 Oct 8;287(6398):1027.
(13) Tobin MV, Morris AI. Addison's disease presenting as anorexia nervosa in a young man. Postgrad Med J 1988 Dec;64(758):953-5. [Abstract] [Free Full Text]
(14) Adams R, Hinkebein MK, McQuillen M, Sutherland S, El Asyouty S, Lippmann S. Prompt differentiation of Addison's disease from anorexia nervosa during weight loss and vomiting. South Med J 1998 Feb;91(2):208-11. [Abstract] [Free Full Text]
(15) Blaustein SA, Golden NH, Shenker IR. Addison's disease mimicking anorexia nervosa. Clin Pediatr (Phila) 1998 Oct;37(10):631-2.
(16) Hsu LK, Lee S. Is weight phobia always necessary for a diagnosis of anorexia nervosa? Am J Psychiatry 1993 Oct;150(10):1466-71. [Abstract]
(17) Thorn GW, Forsham PH, Frawley TF, et al. The clinical usefulness of ACTH and cortisone. N Engl J Med 1950 May 18;242(20):783-93.
(18) Greenblatt RB, Barfield WE, Clark SL. The use of ACTH and cortisone in the treatment of anorexia nervosa. J Med Assoc GA 1951;40:299-301.
(19) Oelkers W. Adrenal insufficiency. N Engl J Med 1996 Oct 17;335(16):1206-12.
(20) Tintera JW. The hypoadrenocortical state and its management. N Y State J Med 1955 July 1;55(13):1869-76.
(21) Beumont PJ, Abraham SF, Argall WJ, George GC, Glaun DE. The onset of anorexia nervosa. Aust N Z J Psychiatry 1978 Sep;12(3):145-9. [Abstract]
(22) Cleghorn RA. Adrenal cortical insufficiency: psychological and neurological observations. CMAJ 1951 Nov;65:449-54.
(23) Koranyi EK, Potoczny WM. Physical illnesses underlying psychiatric symptoms. Psychother Psychosom 1992;58(3-4):155-60. [Abstract]
(24) Mortola JF, Rasmussen DD, Yen SS. Alterations of the adrenocorticotropin-cortisol axis in normal weight bulimic women: evidence for a central mechanism. J Clin Endocrinol Metab 1989 Mar;68(3):517-22. [Abstract]

Table 1 Adrenocortical Insufficiency

An insufficiency of one or more hormones produced by the adrenal cortex
Frequently described as adrenal insufficiency or low adrenal reserve
Severe primary adrenocortical insufficiency is known as Addison's disease
Rapid deterioration resulting from adrenocortical insufficiency is known as an Addisonian or adrenal crisis

Adrenal Glands
Pyramidal structures atop the kidneys
Composed of two tissues which produce two classes of hormones
The outer tissue (adrenal cortex)surrounds an inner medullary component (adrenal medulla)

Major Adrenal Cortex Hormones
DHEA (dehydroepiandrosterone)
---Prohormone, precursor to testosterone, estradiol, etc.
Aldosterone
---Mineralcorticoid, regulates blood sodium and potassium levels
Cortisol
---Glucocorticoid, promotes glucose production
---Helps maintain normal vascular tone
---Affects the heart rate, digestion, breathing, skin, etc.
---Necessary for responding to many long-term stressors:
------injuries, traumas, infections, starvation, and strenuous or prolonged exertion
---Usually one of the hormones deficient in adrenocortical insufficiency

Causes of Adrenocortical Insufficiency
Today, commonly due to autoimmune disease of the adrenal glands
Before the 1950's, the most common cause was adrenal atrophy as a result of tubercular infection
Many other causes: systemic fungal infections, adrenal toxins, pituitary dysfunction, etc.

Treatment of Adrenocortical Insufficiency
Administration of subreplacement doses of cortisol
---Cortisone acetate or hydrocortisone (20 to 30 mg per day)
Daily dosage needs to be increased in times of stress or illness
Taking cortisol four times a day is found to best duplicate the body's normal production (5)
Synthetic analogs prescribed by some physicians have unclear advantages
Some forms of adrenocortical insufficiency require a supplement of mineralcorticoid

Table 2 Results of different dosing regimens from The Use of ACTH and Cortisone in the treatment of Anorexia Nervosa, Greenblatt et al (18)^a

a Reprinted by permission of the Medical Association of Georgia's Journal

b It must be noted that these dosages cannot be absolutely compared to contemporary dosages since these compounds may have had different absorption and strength characteristics relative to contemporary preparations.

c Greenblatt et al's treatment of case 5 is not included in this table because it involved administration of numerous hormones, vitamins and interventions. Even though there was a positive outcome, it cannot be attributed to any one treatment.

d ACTH (adrenocorticotropic hormone) stimulates the adrenal cortex to produce and secrete cortisol.

e Cortisone is converted to cortisol in the body.