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or desiccated thyroid in physiologic dosage. XVI
Hydrocortisone and/or Desiccated Thyroid in Physiologic Dosage. XVI. Therapy of Obesity with Starvation and Desiccated Thyroid B y G.
SABEH,J.
V. BONESSI, M. E. SARVER, C. MOSES AND T. S. DANOWSKI
Twelve obese adults were starved with water as desired for 2 weeks. Desiccated thyroid was administered to 7 of these subjects in dosages increased by 1 grain daily to a total of 15 or 16 grains per day. Therapy with desiccated thyroid during the starvation regimen cancelled and reduced, respectively, the usual decrease in NPN and in serum CO2 observed during starvation alone. Also such treatment with thyroid regularly raised the serum PBI and usually increased the BMR. Electrocardiographic changes consisted of tachycardia in some but not all patients treated with thyroid and occasional S-T and T wave depression during starvation with and without this hormone. The administration of desiccated thyroid in increasing dosages during treatment of obesity by total starvation increased the mean weight loss by 38 per cent above that recorded with starvation alone, viz. from 9.3 to 13.0 Kg. in 2 weeks. Potassium losses from cells were about 14 per cent higher during the second week of starvation and thyroid administration. The addition of
desiccated thyroid to the starvation regimen did not increase the proportion of the body weight losses attributable to loss of protein. Thus, negative balance of protein accounted for 8.4 per cent of the weight loss in those treated by starvation and 8.3 per cent in those treated by starvation and thyroid administration. Hence, the bulk of the weight loss during starvation and thyroid therapy stemmed, as it did during starvation alone, from losses of body fat and/or body water. Thyroid feeding during total starvation with water had no effect on the usual decrease in extracellular fluid volume observed with starvation alone but external losses of sodium and of chloride were slightly greater during the combined regimen. The combined regimen was well tolerated but it must be emphasized that this is a preliminary report of studies in selected hospitalized patients in good health. The program is not recommended for outpatient or universal trial without regard to age, cardiovascular status, etc.
N P R E V I O U S S T U D I E S from this laboratory we have defined the parameters of biochemical and endocrine changes to be expected during the administration of desiccated thyroid to healthy adults and patients in increasing dosage? "aS T h e lack of u n t o w a r d effects of such dosages in controlled hospitalized patients and in prisoners has led us to undertake a limited number of carefully supervised trials of large dosages of desiccated thyroid in obese subjects undergoing total starvation.
I
From the Section of Endocrinology and Metabolhvn of the Department of Medicine, University of Pittsburgh, and the Medical Center and Shadyside Hospitals, Pittsburgh, Pennsylvania. Aided by grants from the John A. Hartford Foundation, Inc., the Western Pennsylvania Chapter of the Arthritis and Rheumatism Foundation, the Muscular Dystrophy Associations of America, Inc., the Medical Research Foundation of Pennsylvania, lnc,, the Commonwealth of Pennsylvania, the Department of Health, Education and Welfare, and Armour Pharmaceutical Co. Received for publication Jan. 4, 1965. 603 ~[ETABOLISM,VOL. 14, No, 5 (MAY), 1965
604
SABEH ET AL.
The studies herein reported indicate that the administration of desiccated thyroid in increasing dosages during total caloric restriction in obese subjects did not have any significant untoward effects and enhanced the rate of weight loss. Balances of nitrogen, electrolytes and extracellular water during 2 weeks of such therapy point to the probable sources of this additional weight IOSS. PtlOCEDURE Twelve adults, 10 females and 2 males, 17 to 55 years of age, with obesity associated at times with obvious endocrinopathy (table 1) were hospitalized for 14 days of total starvation. Prior to admission each patient was evaluated by measurements of blood and serum solutes, serum PBI, thyroidal uptake of I lal, oral glucose tolerance (1.75 Gm./Kg), ereatinine clearance, and urinary 17-ketosteroids, Porter-Silber chromogens, ii-desoxycortisol metabolites, gonadotropins, and pressor materials (aortic strip assay) by methods in use in this and in other laboratories.5,1~-22 When indicated, responses of the above urinary steroids to exogenous ACTH and to dexamethasone, were also determined. During the starvation water, tea or coffee without sugar was permitted as desired. Seven of the 12 patients were given desiccated thyroid, beginning with 3 grains on the first day of total starvation and increasing by 1 grain each day to a maximum of 15 to 16 grains at the end of 2 weeks. The following data obtained prior to and during the 2 weeks of starvation are available: (1) Daily body weight; pulse rate at 4 hour intervals while awake; (2) daily measurements of fluid intake and urine output; (3) weekly BMR and ECG records; (4) analyses of blood for sugar and NPN and of serum for Na, CO2, C1, K, Ca, inorganic phosphorus, total protein, albumin, globulin, protein bound iodine, uric acid, alkaline phosphatase, and total and alpha and beta lipoprotein cholesterol and triglycerides;4,5,e3e7 (5) calculations at weekly intervals of external balances of nitrogen (macro Kjeldahl determination), Na, C1, and K based on intake in tea or coffee and excretion in urine pooled at weekly intervals; the electrolytes and nitrogen in the desiccated thyroid were ignored in the balance calculations since the quantities were smalh 0.035 mEq. Na; 0.019 mEq, K; 0.025 mEq. C1; and 10.8 mg. N per 5 grain tablet; no stools were passed after the second or third day; and (6) partitions of external balances into extracellular and cellular fractions; the extraeellular balances of water and electrolytes were based on the changes in chloride space as estimated from the balances and serum concentrations of this electrolyte.2S RESULTS
Patient Reactions The regimen was well tolerated. H u n g e r was present only during the initial 24 to 48 hours. Gccasional patients experienced nausea and retching. Weakness, fatigue, muscle cramps, light headedness, and generalized pain were reported by some but these were not debilitating and lasted just a day or two. Only 2 patients manifested severe generalized aching (M. R. and A. K. ). Save for tachyeardia (pulse rates between 90 to 120 per minute) in 4 of the 7 patients, hyperkinetic behavior, nervousness, sweating, palpitation and other symptoms or signs of thyroid hormone excesses were conspicuous by their absence in those patients treated with desiccated thyroid.
BMR and ECG Recvrds Total starvation with thyroid therapy was accompanied b y an increase in the BMR of 15 to 37 per cent (in absolute terms) in 4 of 6 patients, whereas comparable starvation without thyroid was associated with a BMR lise in only 1 of 5 patients (table 1).
OBESITY, STARVATION AND DESICCATED THYROID
605
Table I.--Starvation Without and With Desiccated Thyroid in Therapy of Obesity Body W e i g h t (lbs.)
Patient
Age
Sex
M. L . G .
45
F
A.H. B.K.
40 55
F F
M. L . M .
47
F
M.R.
47
F
R.A. R.C. D. F. C. i t . A, K. J.P. L.Y.
37 23 22 31 25 24 17
F F F F F M M
Diagnoses O t h e r T h a n Obesity Myxederaa ( t r e a t e d ) ; diabetes m e l l i t u s Recurrent hyperthyroidism; diabetes melEtus Hypothyroidism; diabetes m e l l i t u s Diabetes m e l l i t u s Polycystic o v a r i e s Polycystic o v a r i e s
Polycystic o v a r i e s Diabetes m e l l i t u s Gynecomastia
Thyroid Rx (grains/d)
B M R (%)
Starvation
Starvation
0
295.8
270.2
~6
--8
0 0
184.2 180
166 160.2
~-1 -~13
--1 q-4
0
189.5
173.2
~5
6
196
172.2
-~ 9
--4
167.5 182.2 233.2 334 194 299.2 283
146 157,2 203 302 171 264.5 250
--21
-[-16
--4 -~6 -~-1
q-1 ~-21 ~27
--16
~3
3-15" 3-15 3-16 3-16 3-16 3-16 3-16
Starvation
Starvation
+17
* B e g i n n i n g w i t h 3 g r a i n s on the f i r s t day of t o t a l s t a r v a t : o n a n d incre~Mng by I g r a i n daily t o a t e t a l of 15 t o 16 g r a i n s on day 14.
Save for sinus tachycardia in 4 of 7 patients treated with thyroid and minor S-T and T wave depression in several patients in both groups, the electrocardiograms remained within normal limits (table 2).
Bload and Serum Solutes Starvation for 2 weeks without thyroid therapy was associated with the well-recognized decrease in fasting levels of blood sugar and NPN, the fall in the serum COe and lipids, and the increase in serum uric acid (table 3) .29 30
The inclusion o[ desiccated thyroid in increasing dosages in the starvation regimen raised the serum PBI, cancelled the hypoazotemic trends observed with starvation alone and reduced the serum CO2 decrease. These differences in the responses to the 2 regimens were statistically significant. The apparent cancellation of the hypoglycemic trend, the accentuation of the decrease in the total serum cholesterol and triglycerides, and the decrease, in the serum chloride during thyroid therapy were not statistically significant.
Urine Findings In both groups of patients (starvation alone and starvation with thyroid) acetone appeared in the urine on the second or third day and persisted throughout the remainder of the 9, weeks. The mean weekly water intake and urine volumes were greater in the patients who did not receive thyroid (table 4). External Balances of Nitrogen and Electrolytes Without and With Thyroid Therapy Nitrogen losses during the first week of starvation without and with desiccated thyroid administration averaged 63.7 and 79.6 Gin., respectively (table
606
SABEI-I E T A L .
Table 2.--ECG Changes during Total Starvation of Obese Subiects
Without and With Thyroid Therapy ECG F i n d i n g s Patient
Age
Sex
Thyroid T h e r a p y (grains/d)
M. L . G . A.H. M. L . M . M.R.
45 40 47 47
F F F F
0 0 0 0
R.A. R.C. D.F. C.H. A.K. J.P. L.Y.
37 23 22 31 25 24 17
F F F F F M M
3-15" 3-15 3-16 3-16 3-16 3-16 3-16
l~retherapy
p 1 week
p 2 weeks
S.B.
T$ S-T Abn. S-T Abn.
S.A., Q-T~ S-T Abn.,'Q-T t
T$
S.Wo
S.A. S.A.
T% Tt
S.T., P.V.C. S.T., T t less
S.T. T~, S.T., T t
S-T Abn. S.T., T t less, T a r L inverted
*Beginning with 3 grains on the first day of total starvation and increasing by 1 grain daily to a total of 15 to 16 grains per day. Code: S.T. ~ sinus tachycardia, S.B. = sinus bradycardia, S.A. ~ sinus arrhythmia. P.V.C. = premature ven~icular contraction. S-T Abn. = S-T abnormality. T$ = nonspecific flattening or depression of T wave. TI" ~ peaked T wave. Q-T1' = interval prolonged. TAr L ~ T wave inversion in leads A, V, and L.
4). The difference between the 2 groups was greater during the second week: those who were starved without thyroid therapy lost 56.8 Gin. of nitrogen, while those patients on the combined treatment had a mean nitrogen loss of 89.5 Gm. during the second week. On the average, therefore, administration of desiccated thyroid during 2 weeks of starvation increased the negative balance of nitrogen by about 40 per cent. Potassium losses were comparable during the first week of starvation without and with thyroid: 298.5 and 299.3 mEq., respectively. During the second week the loss of potassium was slightly greater in those receiving thyroid: 185.3 versus 168.2 mEq. (table 4). The potassium:nitrogen (K:N) ratios averaged 4.7 and 3.0 in the first and second weeks in the subjects who were only starved. These were somewhat lower, 3.8 and 2.1, during the same periods in the patients who were given desiccated thyroid during total starvation. The negative balances of sodium and chloride during the first week of total starvation with thyroid administration were greater than those recorded on starvation alone. The sodittm loss was 192.0 mEq. with thyroid and 166.4 without thyroid; the chloride balances during the same period were -298.9 and -235.1 mEq. with and without thyroid administration, respectively. During the second week, both groups lost much less chloride and sodium but further comparison is not possible because 3 of the patients not treated with desiccated thyroid received sodium chloride on the fourteenth day. Estimates o[ Extracellular and Cell Balances The decreases in the extracellular volume at the end of the first and second
OBESITY, STARVATION
607
AND DESICCATED THYROID
Table 3.--Changes in Blood and Serum Solutes during 14 Days of Total Starvation
Without or With Increasing Dosages oI Desiccated Thyroid S t a r v a t i o n only p 2 weeks
S t a r v a t i o n -/- T h y r o i d * p 2 weeks
Blood sugar (rag. 7o) --13.75 (4) +11.5 (7) BloodNPN (mg.%) --6.2 (5) +2.5~ (7) SerumNa (mEq./L.) +2.4 (5) +1.9 (7) Serum K (mEq./L.) --0.4 (5) --0.4 (7) Sermn CI (mEq./L.) +0.1 (5) --4.0 (7) Serum CO2 (mEq,/L,) --7,4 (5) --0.6~ (7) Serum Ca (rag. %) --0.02 (3) --0.07 (7) Serumphos (rag.%) --0.04 (4) +0.3 (6) Serum totalprotein (Gin. %) +0.16 (4) --0.16 (7) Serum albumin (Gm. %) +0.16 (4) +0.01 (7) Serum globulin (Gin. %) --0.01 (4) --0.17 (7) Serum PBI +0.7" (3) +7.7 (7) Serum alkaline phosphatase (K-A units) --0.2 (2) +1.5 (6) Serum uric acid (rag. %) +4.4 (1) +4.7 (7) Serum total lipoprotein cholesterol (mg. ~) --35.0 (4) -75.3 (5) Serum alpha lipoprotein cholesterol (mg. %) -24.0 (4) -16.2 (5) Serum beta lipoprotein cholesterol (mg. %) - 14.8 (4) -49.8 (5) Serum total ]ipoprotein triglyeerides (rag, %) --55.3 (4) --104.9 (5) Sermn alpha lipoprotein triglyeerides (mg. %) --11.8 (4) -9.2 (5) Sermn beta lipoprotein triglyeerides (mg. %) --41.8 (4) -46.8 (5) *At the end of 2 weeks the patients were taking 15 or 16 grains of desiccated thyroid daily. ~Only these differences are statistically significant. weeks were virtually identical in both groups, but in each case the losses were much greater during the first week. The changes in extraeellular and intraeelhdar sodium were quite comparable in the 2 groups of subjects. Thus, both groups lost approximately 300 mEq. of sodium from the extracellular space during the first week. Slightly more than a third of this represented transfers into the cells. During the second week the balances of extraeellular and cell sodium were much lower and of the same order of magnitude in the 2 groups. Losses of extraeellular potassium were about the same in the 2 groups. This was also true of the losses of cell potassium during the first week. However, during the second week the negative balances of cell potassium were about 14 per cent greater in the patients who received thyroid during starvation. The K:N ratio was greater than 3.0 during the first week in both groups indicating losses in excess of those occurring with protein breakdown. T h e lower K:N ratios during the second week point to losses with protein degradation as the chief and probably the only source.
Weight Loss Without and With Desiccated Thyroid Therapy Starvation alone resulted in a mean weight loss of 9.3 Kg, or 20.5 pounds (table 4) in 2 weeks, consisting of 6.1 Kg. during the first 7 days and 3.2 during days 8 through 14. The addition of desiccated thyroid to the treatment
608
S A B E H E T AL.
Table 4.--Sumraary of Balance Data Starvation Only (5 pts.) Week 1 (Mean values)
Water Intake (L.) Output ( L. )
9.15 7.88
External Balances Nitrogen (g) Potassium (mEq.) K: N ratio (mEq.:g) Sodium ( mEq. ) Chloride (mEq.)
--63.7 --298.5 4.7 -- 166.4 -235.1
Extracellular Balances Water Sodium (mEq.) Potassium (mEq.)
-2.33 --294.9 -- 11.4
Cell Balances Sodium (n~Eq.) Potassimn (mEq.)
+128,6 --287.2
A Body Weight (Kg.)
Week 2 (Mean values)
9.22 6.17 --56.8 --168.2 3.0 +28.4 -- ] 6.8 -0.22 -4.2 --6.5 +32.6 --161.7
-6.12
-3.21
Starvation + Thyroid (7 pts,) Week 1 (Mean values)
6,42 5.57 --79.6 --299.3 3.8 -- 192.0 --298,9 --2.38 --309.6 - 14.3 +117,6 --235,0 -8.24
Week 2 (Mean values)
8.18 5.05 -89.5 --185.3 2.1 + 1.9 -43.2 -0.37 -17.3 -- 1.0 +19.2 -184.3 -4.79
regimen increased the mean loss to a total of 13.0 Kg. or 28.7 pounds in 2 weeks. DISCUSSION
With Respect to Body Weight Changes In this comparison of 2 small groups of obese patients treated by total starvation, the administration of desiccated thyroid in daily dosages increased progressively from 3 to about 16 grains was accompanied b y a 38 per cent greater weight loss. The nitrogen data permit calculations of the role of protein catabolism in the weight loss. Thus, with the weight loss averaging 20.5 pounds in 2 weeks of total starvation without thyroid, 753.1 Gm. or 1.7 pounds of protein were catabolized (1 Gm. nitrogen = 6.25 Gm. of protein). During comparable starvation with desiccated thyroid the total weight loss averaged 28.7 pounds and 1057 Gin. or 2,3 pounds of protein were catabolized. In the former instance protein loss contributed 8.3 per cent of the total weight loss and 8.4 per cent in the latter. Hence, it is clear that the increased weight loss observed with thyroid feeding did not result solely or even largely from protein loss. Since glycogen stores were exhausted b y the second or third day, the remainder of this increment must have come from decreases in body fluids, body lipids, or both. Our data do not permit a choice between these alternatives, since balances of cell water cannot be calculated. The external exchanges of water and the balances of extraeetlular water provide no clues which help decide whether the additional weight loss during thyroid
OBESITY, STARVATIONAND DESICCATEDTHYROID
609
f e e d i n g resulted f r o m an additional deficit of cell w a t e r or f r o m c o m b u s t i o n of lipid stores.
With Respect to Serum Findings T h e failure to observe d u r i n g starvation and t h y r o i d administration crease in the blood N P N p r e s u m a b l y reflects the greater nitrogen load ing f r o m protein catabolism. T h e lesser d e g r e e of acidosis r e c o r d e d t h y r o i d was a d d e d to the starvation r e g i m e n m a y m e r e l y reflect the chloremia w h i c h can develop in spontaneous thyrotoxicosis. 4~ a n d m a y h a v e o c c u l t e d in o u r studies as a trend.
a deresultwhen hypowhich
With Respect to Safety of the Regimen O u r findings are p r e s e n t e d as a p r e l i m i n a r y report of a clinical investigation a n d obviously c a n n o t be taken as a r e c o m m e n d a t i o n for casual administration of large dosages of desiccated t h y r o i d to patients with obesity or a n y o t h e r condition. T h e y do indicate, however, that t h e r e m a y well be a span of t h y r o i d d o s a g e s o m e w h e r e b e t w e e n the usual m a i n t e n a n c e quantities of 2 or 3 grains a n d a m o u n t s w h i c h p r o d u c e h a z a r d o u s thyrotoxicosis w h i c h can be administered w i t h relative i m p u n i t y to selected subjects. REFERENCES
1. Danowski, T. S., and Moses, C.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. I. Introduction to studies of hypolipemic and other effects including relationships to the aging process. Metabolism 11:648, 1962. 2. Moses, C., Jablonski, J. R., Sunder, J. H., Greenman, J. H., and Danowski, T. S.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. II. Hypolipemic effects. Metabolism 11:653, 1962. 3. Danowski, T. S., Moses, C., and Heineman, A. C., Jr.: Hydrocortisone and/ or desiccated thyroid in physiologic dosage. III. Effects on urinary steroids, pressor amines and gonadotropins. Metabolism 11:665, 1962. 4. , -, and Mateer, F. M.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. IV. Serum protein-bound iodine and other thyroid ho'rmone indices. Metabolism 11:679, 1962. 5 . - - , and - - : Hydrocortisone and/or desiccated thyroid in physiologic dosage. V. Serum solutes and electrolytes. Metabolism 11:689, 1962.
6. --, - - , and Mateer, F. M.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. VI. Effects on glucose tolerance and insulin tolerance. Metabolism 11:699, 1962. 7. --, - - , Borecky, D. C., Balash, W. R . , Bonessi, J. V., and Gilberti, M. V.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. VII. Pituitary-adrenocortieal and thyroidal function. Metabolism 11:705, 1962. 8. - - , Tinsman, C. A., and Moses, C.: HydTocortisone and/or desiccated thyroid in physiologic dosage. VIII. Lipid and body fluid patterns in North American Negro and white prisoners. Metabolism 12:117, 1963. 9. Moses, C., and Danowski, T, S.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. IX. Comparable hypolipemic effects of desiccated thyroid in Negroes and whites. Metabolism 12:126, 1963. 10. Danowski, T. S., Sarver, M. E., D'Ambrosia, R. D., and Moses, C.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. X. Effects of thyroid hormone excesses on clinical status and thyroid indices. Me-
610 tabolism 13:702, 1964. 11. Moses, C., Sunder, J. H., Vester, J. W., and Danowski, T. S.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. XI. Effects of thyroid hormone excesses on lipids and other blood and serum solutes. Metabolism 13:717, 1964. 12. Danowski, T. S., Rodnan, G. P., Sarver, M. E., and Moses, C.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. XII. Effects of thyroid hormone excesses on urinary solutes and steroids. Metabolism 13:729, 1964. 1 3 . - - , Bonessi, J. V., Sarver, M. E., and Moses, C.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. XIII. Carbohydrate metabolism during large dosage thyroid (Proloid) therapy. Metabolism 13: 739, 1964. 1 4 . - - , Heineman, A. C., Jr., Bonessi, J. V., and Moses, C.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. XIV. Effects of thyroid hormone excesses on pressor activity and epinephrine responses. Metabolism 13:747, 1964. 1 5 . - - , Vester, J. W., Sabeh, G., Sullivan, W. A., and Sarver, M. E.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. XV. Thyroid therapy, serum CPK, and other indices in muscular dystrophy. Metabolism 13:1393, 1964. 1 6 . - - , Johnston, S. Y., and Greenman, J. H.: Alterations in serum iodine fractions induced by the administration of inorganic iodide in massive dosage. J. Clin. Endocrinol. 10:519, 1950. 17. Peters, J. H.: The determination of ereatinine and creatine in blood and urine with the photoelectric colorimeter. J. Biol. Chem. 146:179, 1942. 18. Holtorff, A. F., and Koch, F. C.: The colorimetric estimation of 17-ketosteroids and their application to urine extracts. J. Biol. Chem. 135:377, 1940. 19. Porter, C. C., and Silber, R. H.: Quantitative color reaction for cortisone and related 17, 21-dihydroxy-29ketosteroids. J. Biol. Chem. 185:201, 1950.
SABEH ET AL.
20. Henke, W. J., Doe, R. P., and Jacobson, M. E.: A test of pituitary reserve utilizing intravenous SU 4885, with a new method for extraction of 11desoxysteroids. J. Clin. Endocrinol. 20:1527, 1960. 21. Albert, A.: Human urinary gonado~,-opin. Rec. Progr. Hormone Res. 12:227, 1956. 22. Heineman, A. C., Jr., and Danowski, T. S.: Potentiation and stabilization of aortic strip pressor assay by plasma and hydrocortisone: routine use in the diagnosis of pheochromocytoma. Am. J. Med. Sci. 239:167, 1960. 23. Crowley, L. V.: Automated determination of uric acid by a carbonate method. Clin. Res. 10:85, 1962. 24. Powell, M. E. A., and Smith, M. J. H.: The determination of serum acid and alkaline phosphatase activity with 4aminoantipyrine (A. A. P.) J. Clin. Path. 7:245, 1954. 25. Green, A. A., Lewis, L. A., and Page, I. H.: A method for the ultracentrifugal analysis of a and fl-lipoproteins. Fed. Proc. 10:191, 1951. 26. Sperry, W. M., and Webb, M.: A revision of the Sehoenheimer-Sperry method for cholesterol determination. J. Biol. Chem. 187:97, 1950. 27. Van Handel, E., and Zilversmit, D. B.: Micromethod for the direct determination of serum ta'iglycerides, j. Lab. Clin. Med. 50:152, 1957. 28. Elkinton, J. R., and Danowski, T. S.: The Body Fluids; Basic Physiology and Practical Therapeutics. Baltimore, Williams & Wilkins Co., 1955, pp. 569-578. 29. Duncan, G. G., Jenson, W. K., Cristofori, F. C., and Schless, G. L.: Intermittent fasts in the correction and control of intractable obesity. Am. J. Med. Sci. 245:515, 1963. 30. Bakulev, A. N., and Kolesnikova, R. S.: Starvation treatment (fasting): preliminary report. Klin. Med. 40:14, 1962. 31. Drenick, E. J., Swendseid, M. E., Blahd, W. H., and Tuttle, S. G.: Prolonged starvation as treatment for severe obesity. J. A. M. A. 187:100, 1964. 32. Murphy, R., and Shipman, K. H.: Hy-
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peruricemia during total fasting: renal factors. Arch. Int. Med. 112:954, 1962. Unger, R. H., Eisentraut, A. M., and Madison, L. L.: The effects of total starvation upon the levels of circulating glucagon and insulin in man. J. Clin. Invest. 42:1031, 1963. Duncan, G. G., Jenson, W. K., Fraser, R. I., and Cristofori, F. C.: Correction and control of intractable obesity: practicable application of intermittent periods of total fasting. J. A. M. A. 181:309, 1962. Van Riet, H. G., Schwarz, F., and Der Kinderen, P. J.: Metabolic observations during the treatment of obese patients by periods of total starvation. Metabolism 13:291, 1964. Cristofori, F. C., and Duncan, G. G.: Uric acid excretion in obese subjects
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during periods of total fasting. Metabolism 13:303, 1964. Beck, P., Koumans, J. H. T., Winterling, C. A., Stein, M. F., Daughaday, W. H., and Kipnis, D. M.: Hormonal and metabolic changes during total starvation in obese subjects. J. Lab. Clin. Med. 62:857, 1963. Wulff, J., and Madison, L.: The role of the liver and peripheral tissues in reduced glucose tolerance of prolonged starvation. Clin. Res. 12:283, 1964. Lecocq, F. R., and McPhaul, J. J.: The effects of starvation, high fat diets and ketone infusions on uric acid balance. Clin. Res. 12:274, 1964. DeCourt, J.: Le role du corps thyroidc dans la r6gulation de la chlor6mie. Ann. reed. 44:133, 1938.
George Sabeh, M.D., former Fellow in Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa. 1ames V. Bonessi, M.D., former Fellow in Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa. Margaret E. Sarver, M.D., former Fellow in Endocrinology and Metabolism, Department of Medicine, University af Pittsburgh School of Medicine, Pittsburgh, Pa. Campbell Moses, M.D., Associate Professor of Medicine and Director of Addison H. Gibson Laboratory, University of Pittsburgh School of Medicine, Pittsburgh, Pa. Thaddeus S. Danowski, M.D., Professor of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
SABEH,J.
V. BONESSI, M. E. SARVER, C. MOSES AND T. S. DANOWSKI
Twelve obese adults were starved with water as desired for 2 weeks. Desiccated thyroid was administered to 7 of these subjects in dosages increased by 1 grain daily to a total of 15 or 16 grains per day. Therapy with desiccated thyroid during the starvation regimen cancelled and reduced, respectively, the usual decrease in NPN and in serum CO2 observed during starvation alone. Also such treatment with thyroid regularly raised the serum PBI and usually increased the BMR. Electrocardiographic changes consisted of tachycardia in some but not all patients treated with thyroid and occasional S-T and T wave depression during starvation with and without this hormone. The administration of desiccated thyroid in increasing dosages during treatment of obesity by total starvation increased the mean weight loss by 38 per cent above that recorded with starvation alone, viz. from 9.3 to 13.0 Kg. in 2 weeks. Potassium losses from cells were about 14 per cent higher during the second week of starvation and thyroid administration. The addition of
desiccated thyroid to the starvation regimen did not increase the proportion of the body weight losses attributable to loss of protein. Thus, negative balance of protein accounted for 8.4 per cent of the weight loss in those treated by starvation and 8.3 per cent in those treated by starvation and thyroid administration. Hence, the bulk of the weight loss during starvation and thyroid therapy stemmed, as it did during starvation alone, from losses of body fat and/or body water. Thyroid feeding during total starvation with water had no effect on the usual decrease in extracellular fluid volume observed with starvation alone but external losses of sodium and of chloride were slightly greater during the combined regimen. The combined regimen was well tolerated but it must be emphasized that this is a preliminary report of studies in selected hospitalized patients in good health. The program is not recommended for outpatient or universal trial without regard to age, cardiovascular status, etc.
N P R E V I O U S S T U D I E S from this laboratory we have defined the parameters of biochemical and endocrine changes to be expected during the administration of desiccated thyroid to healthy adults and patients in increasing dosage? "aS T h e lack of u n t o w a r d effects of such dosages in controlled hospitalized patients and in prisoners has led us to undertake a limited number of carefully supervised trials of large dosages of desiccated thyroid in obese subjects undergoing total starvation.
I
From the Section of Endocrinology and Metabolhvn of the Department of Medicine, University of Pittsburgh, and the Medical Center and Shadyside Hospitals, Pittsburgh, Pennsylvania. Aided by grants from the John A. Hartford Foundation, Inc., the Western Pennsylvania Chapter of the Arthritis and Rheumatism Foundation, the Muscular Dystrophy Associations of America, Inc., the Medical Research Foundation of Pennsylvania, lnc,, the Commonwealth of Pennsylvania, the Department of Health, Education and Welfare, and Armour Pharmaceutical Co. Received for publication Jan. 4, 1965. 603 ~[ETABOLISM,VOL. 14, No, 5 (MAY), 1965
604
SABEH ET AL.
The studies herein reported indicate that the administration of desiccated thyroid in increasing dosages during total caloric restriction in obese subjects did not have any significant untoward effects and enhanced the rate of weight loss. Balances of nitrogen, electrolytes and extracellular water during 2 weeks of such therapy point to the probable sources of this additional weight IOSS. PtlOCEDURE Twelve adults, 10 females and 2 males, 17 to 55 years of age, with obesity associated at times with obvious endocrinopathy (table 1) were hospitalized for 14 days of total starvation. Prior to admission each patient was evaluated by measurements of blood and serum solutes, serum PBI, thyroidal uptake of I lal, oral glucose tolerance (1.75 Gm./Kg), ereatinine clearance, and urinary 17-ketosteroids, Porter-Silber chromogens, ii-desoxycortisol metabolites, gonadotropins, and pressor materials (aortic strip assay) by methods in use in this and in other laboratories.5,1~-22 When indicated, responses of the above urinary steroids to exogenous ACTH and to dexamethasone, were also determined. During the starvation water, tea or coffee without sugar was permitted as desired. Seven of the 12 patients were given desiccated thyroid, beginning with 3 grains on the first day of total starvation and increasing by 1 grain each day to a maximum of 15 to 16 grains at the end of 2 weeks. The following data obtained prior to and during the 2 weeks of starvation are available: (1) Daily body weight; pulse rate at 4 hour intervals while awake; (2) daily measurements of fluid intake and urine output; (3) weekly BMR and ECG records; (4) analyses of blood for sugar and NPN and of serum for Na, CO2, C1, K, Ca, inorganic phosphorus, total protein, albumin, globulin, protein bound iodine, uric acid, alkaline phosphatase, and total and alpha and beta lipoprotein cholesterol and triglycerides;4,5,e3e7 (5) calculations at weekly intervals of external balances of nitrogen (macro Kjeldahl determination), Na, C1, and K based on intake in tea or coffee and excretion in urine pooled at weekly intervals; the electrolytes and nitrogen in the desiccated thyroid were ignored in the balance calculations since the quantities were smalh 0.035 mEq. Na; 0.019 mEq, K; 0.025 mEq. C1; and 10.8 mg. N per 5 grain tablet; no stools were passed after the second or third day; and (6) partitions of external balances into extracellular and cellular fractions; the extraeellular balances of water and electrolytes were based on the changes in chloride space as estimated from the balances and serum concentrations of this electrolyte.2S RESULTS
Patient Reactions The regimen was well tolerated. H u n g e r was present only during the initial 24 to 48 hours. Gccasional patients experienced nausea and retching. Weakness, fatigue, muscle cramps, light headedness, and generalized pain were reported by some but these were not debilitating and lasted just a day or two. Only 2 patients manifested severe generalized aching (M. R. and A. K. ). Save for tachyeardia (pulse rates between 90 to 120 per minute) in 4 of the 7 patients, hyperkinetic behavior, nervousness, sweating, palpitation and other symptoms or signs of thyroid hormone excesses were conspicuous by their absence in those patients treated with desiccated thyroid.
BMR and ECG Recvrds Total starvation with thyroid therapy was accompanied b y an increase in the BMR of 15 to 37 per cent (in absolute terms) in 4 of 6 patients, whereas comparable starvation without thyroid was associated with a BMR lise in only 1 of 5 patients (table 1).
OBESITY, STARVATION AND DESICCATED THYROID
605
Table I.--Starvation Without and With Desiccated Thyroid in Therapy of Obesity Body W e i g h t (lbs.)
Patient
Age
Sex
M. L . G .
45
F
A.H. B.K.
40 55
F F
M. L . M .
47
F
M.R.
47
F
R.A. R.C. D. F. C. i t . A, K. J.P. L.Y.
37 23 22 31 25 24 17
F F F F F M M
Diagnoses O t h e r T h a n Obesity Myxederaa ( t r e a t e d ) ; diabetes m e l l i t u s Recurrent hyperthyroidism; diabetes melEtus Hypothyroidism; diabetes m e l l i t u s Diabetes m e l l i t u s Polycystic o v a r i e s Polycystic o v a r i e s
Polycystic o v a r i e s Diabetes m e l l i t u s Gynecomastia
Thyroid Rx (grains/d)
B M R (%)
Starvation
Starvation
0
295.8
270.2
~6
--8
0 0
184.2 180
166 160.2
~-1 -~13
--1 q-4
0
189.5
173.2
~5
6
196
172.2
-~ 9
--4
167.5 182.2 233.2 334 194 299.2 283
146 157,2 203 302 171 264.5 250
--21
-[-16
--4 -~6 -~-1
q-1 ~-21 ~27
--16
~3
3-15" 3-15 3-16 3-16 3-16 3-16 3-16
Starvation
Starvation
+17
* B e g i n n i n g w i t h 3 g r a i n s on the f i r s t day of t o t a l s t a r v a t : o n a n d incre~Mng by I g r a i n daily t o a t e t a l of 15 t o 16 g r a i n s on day 14.
Save for sinus tachycardia in 4 of 7 patients treated with thyroid and minor S-T and T wave depression in several patients in both groups, the electrocardiograms remained within normal limits (table 2).
Bload and Serum Solutes Starvation for 2 weeks without thyroid therapy was associated with the well-recognized decrease in fasting levels of blood sugar and NPN, the fall in the serum COe and lipids, and the increase in serum uric acid (table 3) .29 30
The inclusion o[ desiccated thyroid in increasing dosages in the starvation regimen raised the serum PBI, cancelled the hypoazotemic trends observed with starvation alone and reduced the serum CO2 decrease. These differences in the responses to the 2 regimens were statistically significant. The apparent cancellation of the hypoglycemic trend, the accentuation of the decrease in the total serum cholesterol and triglycerides, and the decrease, in the serum chloride during thyroid therapy were not statistically significant.
Urine Findings In both groups of patients (starvation alone and starvation with thyroid) acetone appeared in the urine on the second or third day and persisted throughout the remainder of the 9, weeks. The mean weekly water intake and urine volumes were greater in the patients who did not receive thyroid (table 4). External Balances of Nitrogen and Electrolytes Without and With Thyroid Therapy Nitrogen losses during the first week of starvation without and with desiccated thyroid administration averaged 63.7 and 79.6 Gin., respectively (table
606
SABEI-I E T A L .
Table 2.--ECG Changes during Total Starvation of Obese Subiects
Without and With Thyroid Therapy ECG F i n d i n g s Patient
Age
Sex
Thyroid T h e r a p y (grains/d)
M. L . G . A.H. M. L . M . M.R.
45 40 47 47
F F F F
0 0 0 0
R.A. R.C. D.F. C.H. A.K. J.P. L.Y.
37 23 22 31 25 24 17
F F F F F M M
3-15" 3-15 3-16 3-16 3-16 3-16 3-16
l~retherapy
p 1 week
p 2 weeks
S.B.
T$ S-T Abn. S-T Abn.
S.A., Q-T~ S-T Abn.,'Q-T t
T$
S.Wo
S.A. S.A.
T% Tt
S.T., P.V.C. S.T., T t less
S.T. T~, S.T., T t
S-T Abn. S.T., T t less, T a r L inverted
*Beginning with 3 grains on the first day of total starvation and increasing by 1 grain daily to a total of 15 to 16 grains per day. Code: S.T. ~ sinus tachycardia, S.B. = sinus bradycardia, S.A. ~ sinus arrhythmia. P.V.C. = premature ven~icular contraction. S-T Abn. = S-T abnormality. T$ = nonspecific flattening or depression of T wave. TI" ~ peaked T wave. Q-T1' = interval prolonged. TAr L ~ T wave inversion in leads A, V, and L.
4). The difference between the 2 groups was greater during the second week: those who were starved without thyroid therapy lost 56.8 Gin. of nitrogen, while those patients on the combined treatment had a mean nitrogen loss of 89.5 Gm. during the second week. On the average, therefore, administration of desiccated thyroid during 2 weeks of starvation increased the negative balance of nitrogen by about 40 per cent. Potassium losses were comparable during the first week of starvation without and with thyroid: 298.5 and 299.3 mEq., respectively. During the second week the loss of potassium was slightly greater in those receiving thyroid: 185.3 versus 168.2 mEq. (table 4). The potassium:nitrogen (K:N) ratios averaged 4.7 and 3.0 in the first and second weeks in the subjects who were only starved. These were somewhat lower, 3.8 and 2.1, during the same periods in the patients who were given desiccated thyroid during total starvation. The negative balances of sodium and chloride during the first week of total starvation with thyroid administration were greater than those recorded on starvation alone. The sodittm loss was 192.0 mEq. with thyroid and 166.4 without thyroid; the chloride balances during the same period were -298.9 and -235.1 mEq. with and without thyroid administration, respectively. During the second week, both groups lost much less chloride and sodium but further comparison is not possible because 3 of the patients not treated with desiccated thyroid received sodium chloride on the fourteenth day. Estimates o[ Extracellular and Cell Balances The decreases in the extracellular volume at the end of the first and second
OBESITY, STARVATION
607
AND DESICCATED THYROID
Table 3.--Changes in Blood and Serum Solutes during 14 Days of Total Starvation
Without or With Increasing Dosages oI Desiccated Thyroid S t a r v a t i o n only p 2 weeks
S t a r v a t i o n -/- T h y r o i d * p 2 weeks
Blood sugar (rag. 7o) --13.75 (4) +11.5 (7) BloodNPN (mg.%) --6.2 (5) +2.5~ (7) SerumNa (mEq./L.) +2.4 (5) +1.9 (7) Serum K (mEq./L.) --0.4 (5) --0.4 (7) Sermn CI (mEq./L.) +0.1 (5) --4.0 (7) Serum CO2 (mEq,/L,) --7,4 (5) --0.6~ (7) Serum Ca (rag. %) --0.02 (3) --0.07 (7) Serumphos (rag.%) --0.04 (4) +0.3 (6) Serum totalprotein (Gin. %) +0.16 (4) --0.16 (7) Serum albumin (Gm. %) +0.16 (4) +0.01 (7) Serum globulin (Gin. %) --0.01 (4) --0.17 (7) Serum PBI +0.7" (3) +7.7 (7) Serum alkaline phosphatase (K-A units) --0.2 (2) +1.5 (6) Serum uric acid (rag. %) +4.4 (1) +4.7 (7) Serum total lipoprotein cholesterol (mg. ~) --35.0 (4) -75.3 (5) Serum alpha lipoprotein cholesterol (mg. %) -24.0 (4) -16.2 (5) Serum beta lipoprotein cholesterol (mg. %) - 14.8 (4) -49.8 (5) Serum total ]ipoprotein triglyeerides (rag, %) --55.3 (4) --104.9 (5) Sermn alpha lipoprotein triglyeerides (mg. %) --11.8 (4) -9.2 (5) Sermn beta lipoprotein triglyeerides (mg. %) --41.8 (4) -46.8 (5) *At the end of 2 weeks the patients were taking 15 or 16 grains of desiccated thyroid daily. ~Only these differences are statistically significant. weeks were virtually identical in both groups, but in each case the losses were much greater during the first week. The changes in extraeellular and intraeelhdar sodium were quite comparable in the 2 groups of subjects. Thus, both groups lost approximately 300 mEq. of sodium from the extracellular space during the first week. Slightly more than a third of this represented transfers into the cells. During the second week the balances of extraeellular and cell sodium were much lower and of the same order of magnitude in the 2 groups. Losses of extraeellular potassium were about the same in the 2 groups. This was also true of the losses of cell potassium during the first week. However, during the second week the negative balances of cell potassium were about 14 per cent greater in the patients who received thyroid during starvation. The K:N ratio was greater than 3.0 during the first week in both groups indicating losses in excess of those occurring with protein breakdown. T h e lower K:N ratios during the second week point to losses with protein degradation as the chief and probably the only source.
Weight Loss Without and With Desiccated Thyroid Therapy Starvation alone resulted in a mean weight loss of 9.3 Kg, or 20.5 pounds (table 4) in 2 weeks, consisting of 6.1 Kg. during the first 7 days and 3.2 during days 8 through 14. The addition of desiccated thyroid to the treatment
608
S A B E H E T AL.
Table 4.--Sumraary of Balance Data Starvation Only (5 pts.) Week 1 (Mean values)
Water Intake (L.) Output ( L. )
9.15 7.88
External Balances Nitrogen (g) Potassium (mEq.) K: N ratio (mEq.:g) Sodium ( mEq. ) Chloride (mEq.)
--63.7 --298.5 4.7 -- 166.4 -235.1
Extracellular Balances Water Sodium (mEq.) Potassium (mEq.)
-2.33 --294.9 -- 11.4
Cell Balances Sodium (n~Eq.) Potassimn (mEq.)
+128,6 --287.2
A Body Weight (Kg.)
Week 2 (Mean values)
9.22 6.17 --56.8 --168.2 3.0 +28.4 -- ] 6.8 -0.22 -4.2 --6.5 +32.6 --161.7
-6.12
-3.21
Starvation + Thyroid (7 pts,) Week 1 (Mean values)
6,42 5.57 --79.6 --299.3 3.8 -- 192.0 --298,9 --2.38 --309.6 - 14.3 +117,6 --235,0 -8.24
Week 2 (Mean values)
8.18 5.05 -89.5 --185.3 2.1 + 1.9 -43.2 -0.37 -17.3 -- 1.0 +19.2 -184.3 -4.79
regimen increased the mean loss to a total of 13.0 Kg. or 28.7 pounds in 2 weeks. DISCUSSION
With Respect to Body Weight Changes In this comparison of 2 small groups of obese patients treated by total starvation, the administration of desiccated thyroid in daily dosages increased progressively from 3 to about 16 grains was accompanied b y a 38 per cent greater weight loss. The nitrogen data permit calculations of the role of protein catabolism in the weight loss. Thus, with the weight loss averaging 20.5 pounds in 2 weeks of total starvation without thyroid, 753.1 Gm. or 1.7 pounds of protein were catabolized (1 Gm. nitrogen = 6.25 Gm. of protein). During comparable starvation with desiccated thyroid the total weight loss averaged 28.7 pounds and 1057 Gin. or 2,3 pounds of protein were catabolized. In the former instance protein loss contributed 8.3 per cent of the total weight loss and 8.4 per cent in the latter. Hence, it is clear that the increased weight loss observed with thyroid feeding did not result solely or even largely from protein loss. Since glycogen stores were exhausted b y the second or third day, the remainder of this increment must have come from decreases in body fluids, body lipids, or both. Our data do not permit a choice between these alternatives, since balances of cell water cannot be calculated. The external exchanges of water and the balances of extraeetlular water provide no clues which help decide whether the additional weight loss during thyroid
OBESITY, STARVATIONAND DESICCATEDTHYROID
609
f e e d i n g resulted f r o m an additional deficit of cell w a t e r or f r o m c o m b u s t i o n of lipid stores.
With Respect to Serum Findings T h e failure to observe d u r i n g starvation and t h y r o i d administration crease in the blood N P N p r e s u m a b l y reflects the greater nitrogen load ing f r o m protein catabolism. T h e lesser d e g r e e of acidosis r e c o r d e d t h y r o i d was a d d e d to the starvation r e g i m e n m a y m e r e l y reflect the chloremia w h i c h can develop in spontaneous thyrotoxicosis. 4~ a n d m a y h a v e o c c u l t e d in o u r studies as a trend.
a deresultwhen hypowhich
With Respect to Safety of the Regimen O u r findings are p r e s e n t e d as a p r e l i m i n a r y report of a clinical investigation a n d obviously c a n n o t be taken as a r e c o m m e n d a t i o n for casual administration of large dosages of desiccated t h y r o i d to patients with obesity or a n y o t h e r condition. T h e y do indicate, however, that t h e r e m a y well be a span of t h y r o i d d o s a g e s o m e w h e r e b e t w e e n the usual m a i n t e n a n c e quantities of 2 or 3 grains a n d a m o u n t s w h i c h p r o d u c e h a z a r d o u s thyrotoxicosis w h i c h can be administered w i t h relative i m p u n i t y to selected subjects. REFERENCES
1. Danowski, T. S., and Moses, C.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. I. Introduction to studies of hypolipemic and other effects including relationships to the aging process. Metabolism 11:648, 1962. 2. Moses, C., Jablonski, J. R., Sunder, J. H., Greenman, J. H., and Danowski, T. S.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. II. Hypolipemic effects. Metabolism 11:653, 1962. 3. Danowski, T. S., Moses, C., and Heineman, A. C., Jr.: Hydrocortisone and/ or desiccated thyroid in physiologic dosage. III. Effects on urinary steroids, pressor amines and gonadotropins. Metabolism 11:665, 1962. 4. , -, and Mateer, F. M.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. IV. Serum protein-bound iodine and other thyroid ho'rmone indices. Metabolism 11:679, 1962. 5 . - - , and - - : Hydrocortisone and/or desiccated thyroid in physiologic dosage. V. Serum solutes and electrolytes. Metabolism 11:689, 1962.
6. --, - - , and Mateer, F. M.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. VI. Effects on glucose tolerance and insulin tolerance. Metabolism 11:699, 1962. 7. --, - - , Borecky, D. C., Balash, W. R . , Bonessi, J. V., and Gilberti, M. V.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. VII. Pituitary-adrenocortieal and thyroidal function. Metabolism 11:705, 1962. 8. - - , Tinsman, C. A., and Moses, C.: HydTocortisone and/or desiccated thyroid in physiologic dosage. VIII. Lipid and body fluid patterns in North American Negro and white prisoners. Metabolism 12:117, 1963. 9. Moses, C., and Danowski, T, S.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. IX. Comparable hypolipemic effects of desiccated thyroid in Negroes and whites. Metabolism 12:126, 1963. 10. Danowski, T. S., Sarver, M. E., D'Ambrosia, R. D., and Moses, C.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. X. Effects of thyroid hormone excesses on clinical status and thyroid indices. Me-
610 tabolism 13:702, 1964. 11. Moses, C., Sunder, J. H., Vester, J. W., and Danowski, T. S.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. XI. Effects of thyroid hormone excesses on lipids and other blood and serum solutes. Metabolism 13:717, 1964. 12. Danowski, T. S., Rodnan, G. P., Sarver, M. E., and Moses, C.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. XII. Effects of thyroid hormone excesses on urinary solutes and steroids. Metabolism 13:729, 1964. 1 3 . - - , Bonessi, J. V., Sarver, M. E., and Moses, C.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. XIII. Carbohydrate metabolism during large dosage thyroid (Proloid) therapy. Metabolism 13: 739, 1964. 1 4 . - - , Heineman, A. C., Jr., Bonessi, J. V., and Moses, C.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. XIV. Effects of thyroid hormone excesses on pressor activity and epinephrine responses. Metabolism 13:747, 1964. 1 5 . - - , Vester, J. W., Sabeh, G., Sullivan, W. A., and Sarver, M. E.: Hydrocortisone and/or desiccated thyroid in physiologic dosage. XV. Thyroid therapy, serum CPK, and other indices in muscular dystrophy. Metabolism 13:1393, 1964. 1 6 . - - , Johnston, S. Y., and Greenman, J. H.: Alterations in serum iodine fractions induced by the administration of inorganic iodide in massive dosage. J. Clin. Endocrinol. 10:519, 1950. 17. Peters, J. H.: The determination of ereatinine and creatine in blood and urine with the photoelectric colorimeter. J. Biol. Chem. 146:179, 1942. 18. Holtorff, A. F., and Koch, F. C.: The colorimetric estimation of 17-ketosteroids and their application to urine extracts. J. Biol. Chem. 135:377, 1940. 19. Porter, C. C., and Silber, R. H.: Quantitative color reaction for cortisone and related 17, 21-dihydroxy-29ketosteroids. J. Biol. Chem. 185:201, 1950.
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George Sabeh, M.D., former Fellow in Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa. 1ames V. Bonessi, M.D., former Fellow in Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa. Margaret E. Sarver, M.D., former Fellow in Endocrinology and Metabolism, Department of Medicine, University af Pittsburgh School of Medicine, Pittsburgh, Pa. Campbell Moses, M.D., Associate Professor of Medicine and Director of Addison H. Gibson Laboratory, University of Pittsburgh School of Medicine, Pittsburgh, Pa. Thaddeus S. Danowski, M.D., Professor of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa.