CLINICAL NUTRITION CASE

HYPOTHALAMIC DYSFUNCTION IN A CASE OF MASSIVE OBESITY

Obesity is a syndrome of excessive fatness which is frequently associated with hyperin- sulinism, hypertriglyceridemia and reduced glucose tolerance. The causes of obesity are multiple and obscure. They are intertwined with neurohumoral and metabolic factors that adjust appetite to energy expenditure. Psy- chological and social factors play a role as does the population and activity of fat cells. The oft-repeated statement that obesity is caused by the ingestion of more calories than are expended in the same time period is factual but is a statement of conditions re- quired for deposition of lipid in adipocytes rather than a statement which elucidates the causes for that deposition.

The idea that endocrine factors play some role in obesity is a long-standing one. Disorders of hypothalamic function have been suspected in human obesity from time to time, but the im- paired growth hormone response to insulin in- duced hypoglycemia has been until recently the only evidence for this.' Kopelman et aL2 have recently investigated the possibility that the hypothalamic pituitary function in massively obese patients might be altered. They have studied prolactin release in people of normal weight and those who were massively obese. Prolactin release in normal subjects is stimu- lated by insulin-induced hypoglycemia and by intravenous thyrotropin releasing hormone (TRH) which acts directly on pituitary cells. These investigators have observed that mas- sively obese women respond differently to these endocrine stimuli than do lean control women of the same age.

Case A 33-year-old obese woman, 5' 4 ' tall and weighing

281 pounds (220 percent of ideal body weight), was ad- mitted to the hospital for endocrinologic tests. She was fed a diet adequate in all essential nutrients and calories to maintain her weight. Tests were performed in the morn- ing after an overnight fast. Plasma growth hormone, pro- lactin and cortisol levels were measured by specific radioimmunoassays. Her basal values were: prolactin 370 m1.U. per liter; growth hormone 2.4 m1.U. per liter and cortisol 506 nmol per liter. The first two values were not significantly different from those obtained from six lean control women 19 to 28 years of age. Her cortisol level was significantly higher (controls: 325 t 59 nmol per liter), She was given an insulin tolerance test (0.1 units per kilogram) which caused her fasting blood glucose of 90 mg per deciliter to fall to 30 mg per deciliter during which she experienced sweatiness and feelings of anxiety. Her release of growth hormone and prolactin in response to this hypoglycemia was much lower than that observed in lean control subjects as shown in Figure 1. Her re- lease of prolactin in response to 200 Fg of thyrotropin releasing hormone was also less than that of lean controls. The release of cortisol by this patient in response to in- sulin hypoglycemia was only 30 percent of that of lean control women. The response of this obese patient to these stimuli was not different from that of ten other massively obese patients subjected to the same tests.

Comment It has been found that the growth hormone

response during intravenous insulin tolerance tests is impaired in obese patients in agreement with other studies3?* In this patient there was no prolactin release in response to insulin hypoglycemia. Direct stimulation of the pituitary with thyrotropic releasing hormone, however, did produce a prolactin response in this obese patient, but it was subnormal. These findings provide direct evidence of an alteration of hypo- thalamic function in massively obese patients.

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500r hypothalamic disorder in some massively obese subjects is etiologic or simply an accom- panying trait. The nocturnal release of prolac- tin and growth hormone is altered in obese subjects and prolonged fasting tends to restore secretion of these hormones to normal.8 Obesity influences prolactin and growth hormone secretion in mice. The pattern of re- sponse depends on type of obesity. In geneti- cally obese (ob/ob) mice, plasma prolactin and growth hormone concentrations are low before the onset of obesity, and in adult ob/ob mice, the prolactin response to the dopamine recep-

'Oo0 c 5 tor an!agonist perphenazine is i m ~ a i r e d . ~ Conversely, mice made obese from gold thioglucose injections show an exaggerated prolactin response to perphenazine which re- turns to normal on weight reduction.

Further studies are needed to determine how aeneral this hypothalamic defect is in obese

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Alterations of adrenocortical function have been reported previously to be a feature of hu- man obesity.5 This patient and others like her showed a defective cortisol response to insulin hypoglycemia. It is interesting that patients with Cushing's disease showed an im- paired growth hormone and cortisol response to insulin-induced hypoglycemia and a reduced nocturnal secretion of prolactin and growth hormone.6

Prolactin is predominantly under the inhibi- tory control of hypothalamic dopaminergic mechanisms. Dopamine itself is probably the prolactin inhibiting f a ~ t o r . ~ There are also stimulatory serotoninergic mechanisms which result in the stimulation of prolactin release. Dopamine agonists such as ergot derivatives and bromocryptine lower plasma prolactin concentrations whereas dopamine antagonists such as reserpine and those drugs that block dopamine receptors such as phenathiazines elevate the plasma level. Estrogen and TRH are direct stimulants to prolactin release by the pituitary.

18 NUTRITION REVIEWSIVOL. 38, NO. 1 I JANUARY 1980

;omen and men. There is no doubt that obes- ity is a syndrome that has diverse roots and metabolic features. Studies such as this one2 constitute an important early step in sorting out the etiology and pathogenesis of its numerous variants. 0

1. W.M. Jordan: Pulmonary Embolism. Lancet 2,

2. P.J. Kopelman, N. White, T.R.E. Pilkington and S.L. Jeffcoate: Impaired Hypothalamic Control of Prolactin Secretion in Massive Obesity. Lancet 1 : 747-749, 1979

3. P. Beck, J.H.T. Koumans, C.A. Winterling, M.F. Stein, W.H. Daughaday and D.M. Kipnis: Studies of Insulin and Growth Hormone Secre- tion in Human Obesity. J. Lab Clin. Med. 64:

4. A.Z. El-Khodary, M.F. Ball, T.M. Krop and J. Ca- nary: Inappropriate Growth Hormone Response to Hypoglycemia in Obesity Irrespective of Body Weight. Clin. Res. 17: 545, 1969

5. D.E. Schteingart, R.I. Gregerman and J.W. Conn: A Comparison of the Characteristics of Increased Adrenocortical Function in Obesity and Cush- ing's Syndrome. Metabolism 12: 404-497, 1963

6. D.T. Krieger, P.J. Howanitz and A.C. Frank: Absence of Nocturnal Elevation of Plasma

1146-1147, 1961

654-667, 1964

Prolactin Concentrations in Cushing’s Dis- ease. J. Endocrinol. Metab. 42: 260-272, 1976

7. R.M. Macleod in Frontiers in Endocrinology, Vol. 4. L. Martini and W.F. Ganong, Editors, pp. 169-194. Raven Press, New York, 1976

8. G. Copinschi, M.H. DeLaet, J.P. Brion, R. Leclercq, M.L. Hermite, C. Robyn, E. Viresoro and E. Vancanter: Simultaneous Study of Cortisol,

Growth Hormone and Prolactin Nyctohemeral Variations in Normal and Obese Subjects. In- fluence of Prolonged Fasting in Obesity. Clin. Endocrinol. 9: 15-26, 1978

9. Y.N. Shha, C.B. Salocks and W.P. Vanderlaan: Control of Prolactin and Growth Hormone Sec- cretion in Mice by Obesity. Endocrinology 99: 881 - 886,1976

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