Endocrine Changes in Anorexia Nervosa

Symposium on The Brain and The Endocrine System

Endocrine Changes in Anorexia Nervosa Robert M. Boyar, M.D. *

Primary anorexia nervosa is a disorder of unknown etiology that is characterized by weight loss, amenorrhea, and disturbed ideation concerning body image and food. Patients with this disorder are almost exclusively young adolescent girls who often can relate a significant life stress antedating the onset of secondary amenorrhea and weight loss. This report will describe the results of endocrine studies in a group of patients with primary anorexia nervosa.

Cortisol Secretion and Steroid Metabolism The results of studies of the 24 hour cortisol secretory pattern showed preservation of the normal circadian rhythm; however, the plasma cortisollevel failed to fall to the near undetectable concentrations between 2300 and 0200 hours as it does in normal controls (Fig. 1). In addition, the plasma cortisol level remained elevated during the late afternoon and early evening as a result of a decrease in the metabolic clearance rate and prolongation of the half-life of this steroid. These findings account for the apparent loss of the "diurnal" rhythm reported previously when only A.M. and P.M. samples were obtained (Fig. 1). Studies of cortisol metabolism and kinetics in patients with anorexia nervosa showed significant prolongation of the half-life of disappearance (78 compared with 60 minutes in normal controls and a decrease in the metabolic clearance rate) (Table 1). These two abnormalities resulted in a significant increase in the 24 hour mean plasma cortisol concentration. The normal cortisol production rates in these patients with anorexia nervosa showed definitively that the elevated plasma cortisol levels were not the result of an increase In the cortisol secretory rate. The measurement of the tetrahydrocortisol : tetrahydrocortisone ratio in patients with anorexia nervosa showed a significant increase in the 11-hydroxylated metabolite (tetrahydrocortisol). In addition, the measurement of the androsterone : etiocholanolone ratio showed a marked decrease in the 5a-reduced metabolite (androsterone). Both these abnor"Associate Professor, University of Texas Health Science Center at Dallas; Attending Physician, Parkland Memorial Hospital, Dallas, Texas Medical Clinics of North America-Vo!. 62, No. 2, March 1978

297

298

ROBERT

M. BOYAR

IAg/looml 25

20 15 10

5

o )lQ/looml 25 20 15 10

0300

0700

1100

CLOCK TIME

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1900

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Figure 1. The 24-hour cortisol secretory patterns derived from 20-minute'interval plasma sampling in 2 patients with anorexia nervosa.

malities have been reported in patients with hypothyroidism. It was for this reason that thyroid function was carefully assessed in these patients. The results of the thyroid studies showed that patients with anorexia nervosa had a significant lowering of their plasma Ta level with a preservation of low normal T4 and TSH concentrations (Table 2). This constellation of thyroid function tests is characteristic of the "low Ta syndrome." These thyroid function test abnormalities are found in patients with disorders that are characterized by cachexia, starvation and various catabolic states. Since the major source of Ta is probably the liver, it is not surprising that diminished deiodination ofT4 to Ta is associated with illnesses characterized by hepatic dysfunction. Since the enzymes concerned with the oxidation of cortisol to cortisone and the reduction of testosterone to androsterone (ll-hydroxysteroid dehydrogenase and 5a-reductase) are primarily hepatic, it is not surprising that these steroid abnormalities are found in patients with significant malnutrition. The administration ofT 3 to patients with anorexia nervosa is associated with a return of these steroid parameters to or toward normal (Table 3). This would suggest but not prove that the low Ta concentrations are causally related to the "hypothyroid" steroid metabolic patterns. Gonadotropin Secretion in Anorexia Nervosa In 1974, studies from our laboratory showed that the 24 hour LH secretory patterns in patients with anorexia nervosa were inappropriate for their chronologic age. These studies suggested that body composition in some way exerted an effect on the pattern of LH secretion. Some of our patients with anorexia nervosa showed prepubertal patterns of LH secretion (Fig. 2), while others showed more mature patterns that are charac-

40.5 38.6 31.1 26.5 23.8 37.1 33.5 35.1 24.1 30.0

1 2 3 4 5 6 7 8 9 18.8 ± 3.4 19.9 ± 3.5 (15 - 20) NSt

4.9 ± 0.97 (3.9 - 6.8) P < 0.01

11 17 20

21 22 20 18 22 18

CBGt

8.9 ± 2.9

11.7 5.7 10.8 7.8 8.5 8.7 13.7 3.7 9.5 8.6

(p,G/DL)

(F)

60 ± 7.0 (54 - 73) P < 0.01

78 ± 15.4

64 80 57 86 88 61 110 76 79 74

T% (MIN)

359 ± 83.7 (262 - 495) P < 0.001

177 ± 55.5

190 278 199 138 146 190 94 260 139 132

MCR (LITERS/DAY)

19.5 ± 4.0 (14.4 - 25.5) NS

19.4 ± 5.2

16.5 31.5 20.0 15.6 22.1 19.0 16.0 12.8 24.7 16.1

CPR (MGlDAY)

44.1 ± 13.8 (30- 64) P < 0.05

63.8 ± 9.2

73.0 60.0 50.4

75

61

(/loGlDAY)

URINARY CORTISOL

0.65 ± 0.15 (0.4 - 0.85) P < 0.01

1.2 ± 0.4

1.9 1.1 0.6 1.0 0.9 0.7 1.5 1.4 1.2 1.5

THF/THE

*(F) denotes 24-hour mean cortisol. CBG, cortisol-binding globulin; t%, half-life of plasma cortisol; MCR, metabolic clearance rate; CPR, cortisol production rate, THF/THE, tetrahydrocortisol/tetrahydrocortisone ratio. tExpressed as cortisol-binding capacity in /log/dl. tNot Significant

Mean ± SD Normal Controls: Mean ± SD (range) Significance (patients vs. normal controls

10

FROM IDEAL WEIGHT

% DIFFEBENCE

CASE NO.

Table 1. Cortisol Production and Metabolism*

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Table 2. Plasma Concentrations ofTriiodothyronine (T 3), Total Thyroxine (T J, Thyrotropin (TSH), and Free Thyroxine (fT J CASE

(NGiDL)

T4

TSH

NO.

T3

(/-tGiDL)

(/-tUiML)

(NGiDL)

1 2 3 4 5 6 7 8 9 10

62 80 46 36 46 50 36 54 60 57

6.8 3.8 4.6 5.1 5.4 5.4 4.5 4.5 5.1 5.5

1.3 5.0 0.9 1.3 1.8 1.3 0.8 2.0 3.3 3.5

1.9

2.7 1.8

Mean ± SD Normal mean ± SD Significance

52.7 ± 13.2 137.8 ± 24.1 P < 0.001

5.1 ± 0.8 6.9±1.7 P < 0.02

2.1 ± 1.4 1.6 ± 1.0 NS*

1.9 ± 0.5 (7)t 1.6 ± 0.4(4) NS

fT4

2.6 1.6 1.5 1.7

*N ot Significant tNo. of observations

teristic of mid-late pubertal subjects (Fig. 3). In patients who developed anorexia nervosa prior to menarche, there was an "arrest" of the LH secretion program at an early developmental stage. Studies of the 24 hour LH secretory pattern in patients in remission showed a maturation to an LH secretory pattern consistent with normal postmenarchal women (L e., episodic LH release during sleep and waking periods). Recently, we had the opportunity to study patients with the bulimic form of anorexia nervosa. These patients were generally older than the patients with typical anorexia nervosa and had a history ofthe disease for at least 6 years. Their body weights were 3 to 13 per cent below ideal body weight, but they achieved this at the price of alternating periods of food gorging and self-induced vomiting. Evaluation of the 24 hour LH and FSH secretory patterns in these patients showed significant augmentation of LH secretion occurring synchronously with sleep. In 2 of the 4 patients, FSH secretion was also increased during sleep. These secretory patterns were consistent with normal mid-late premenarchal girls and suggested that mild degrees of weight loss result in abnormal gonadotropin secretory patterns. Further studies will be required to ascertain whether the gonadotropin abnormality is related to the abnormal diet, psychiatric disturbance, or mild degree of weight loss. Estrogen Metabolism in Anorexia Nervosa Studies of estrogen metabolism in patients with anorexia nervosa showed a marked derangement in the ratio of catecholestrogens to estrioL The metabolism of estrone can proceed via two alternative metabolic routes. Firstly, estrone can be 16-hydroxylated to 16-hydroxyestrone, which is rapidly oxidized to estrioL The alternative metabolic route is to the catecholestrogen, 2-hydroxyestrone. In patients with anorexia ner-

301

ENDOCRINE CHANGES IN ANOREXIA NERVOSA

Table 3. The Metabolites of Estradiol as Per Cent of Urinary Glucuronides AGE

ESTRONE

19 22 23 17 21 17 16 Mean ± SD

7.8 22.2 12.9 10.9 14.2 16.1 16.5 14.4 4.5

17 15 26 13 16 13 19 18 Mean ± SD

14.8 17.1 18.4 22.4 1l.6 14.9 16.8 1l.6 15 3.7

CONTROL SUBJECTS 10.7 4.3 7.4 10.5 5.6 10.6 3.8 5.2 7.3 3.0

37.8 37.1 15.6 24.2 33.3 6.5 88 15.5 22.4 12.6

27 28 14 21 Mean ± SD

23.0 22.5 8.8 8.0 15.6 8.3

OBESE SUBJECTS 9.0 16.4 8.4 6.2 10 l.7

20.0 26.2 3l.0 36.0 28.3 6.8

ESTRADIOL

ESTRIOL

ANOREXIA NERVOSA SUBJECTS 5.9 12.6 8.4 1l.8 3.3 8.4 3.6 6.1 4.6 12.2 7.4 17.4 8.2 19.9 5.9" 12.6" 2.1 4.8

2-HYDROXYESTRONE

32.7 22.9 18.9 28.6 35.9 24.8 20.1 26.3*" 6.4 6.3 12.1 14.1 8.2 7.4 10.6 2l.0 14.6 1l.8 4.8 8.3 4.1 5.5 l.4 4.8"*'" 2.9

"Significantly lower than obese p < 0.1 ""Significantly higher than control or obese p < .01 "**Significantly lower than control p == .02

vosa, there was a marked increase in the metabolic conversion of estradiol to 2-hydroxyestrone with a compensatory decrease in estriol. Similar studies in age-matched obese girls showed a marked increase in the transformation of estradiol to estriol and a decrease in 2-hydroxyestrone formation. These findings suggest that weight loss and its attendant effect on body composition can result in significant alterations in the metabolism of biologically active estrogens. Additiopal studies will be required to determine if these changes are related to changes in body fat or to hepatic dysfunction. The possibility exists that this alteration in the metabolism of estradiol in anorexia nervosa is causally related to the "arrest" or "regression" of the LH secretory "program" in these patients. In an attempt to answer this question, preliminary studies in our laboratory showed that the intravenous administration of2-hydroxyestrone caused a

302

ROBERT

M. BOYAR

ANOREXIA NERVOSA

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1000

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Figure 2. The 24-hour LH secretory pattern in a 21 year old girl with anorexia nervosa compared to a normal pre-pubertal girl.

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Figure 3. The 24-hour LH secretory patterns in 4 girls with anorexia nervosa. The patterns are similar to those observed in normal pubertal girls.

ENDOCRINE CHANGES IN ANOREXIA NERVOSA

303

significant decrease in the pulsatile secretion of LH. These data raise the possibility that 2-hydroxyestrone may be the chemical mediator or signal from the periphery that regulates the maturational state of the LH secretory "program." Further studies will be required to determine if this hypothesis is in fact correct. The finding that the gonadotropin, steroid, and thyroid abnormalities all return to normal after normalization of body weight in this disorder, suggests that these abnormalities are the result of the malnutrition and are not due to a primary hypothalamic disturbance. The reason for the preponderance of females with this disorder raises the intriguing question of what determines their susceptibility. In addition, the onset of this disorder during puberty suggests that an hormonal trigger may activate an early developmental or constitutional susceptibility. The very frequent occurrence of a stressful experience preceding the amenorrhea and weight loss suggests an important psychological component in the initiation of this disorder in the susceptible, female adolescent. The factors that are responsible for this susceptibility remain to be determined.

REFERENCES 1. Boyar, R. M .• Hellman, L., Roffwarg, H. J., et al.: Cortisol secretion and metabolism in anorexia nervosa. New Eng. J. Med., 296:190, 1977. 2. Boyar, R. M., Katz, J., Finkelstein, J. W., etal.: Anorexia nervosa; Immaturity of the 24-hour leuteinizing hormone secretory pattern. New Eng. J. Med., 291 :861, 1974. 3. Bradlow, H., Boyar, R. M., O'Connor, J., et al.: Hypothyroid-like alterations in testosterone metabolism in anorexia nervosa. J. Clin. Endocrinol. Metab., 43 :571, 1976. 4. Fishman, J., Boyar, R. M., and Hellman, L.: Influence of body weight on estradiol metabolism in young women. J. Clin. Endocrinol. Metabl., 41 :989, 1975. 5. Miyai, K., Yamamoto, T., Azukizawa, M., et al: Serum thyroid hormones and thyrotropin in anorexia nervosa. J. Clin. Endocrinol. Metab., 40:334, 1975. University of Texas Health Science Center 5323 Harry Hines Boulevard Dallas, Texas 75235