Commentary on Classics of Obesity 4. Hypothalamic Obesity George A. Bray

The fourth Classic in (3-esity comprises three papers, each dealing with obesity and hypothalamic or pituitary disease. The published versions are transla- tions of a paper by Bernard Mohr (1809-1848) entitled, “Hypertrophy of the Hypophysis Cerebri and its Pressure on the Ventral Brain Surface, particularly on the Optic Tract and Chiasm of the Left Hemisphere,” a paper by Joseph Francois Felix Babinski (1857-1932) entitled, “Tumor of the Pituitary Body without Acromegaly and with the Arrest of the Genital Organs,” and a translation by Hilda Bruch of the paper by Alfred Frohlich (1871-1953) entitled, “A Case of Tumor of the Hypophysis without Acromegaly.” The earliest of these three cases was published in 1840 by Mohr (1 8) and is sometimes credited as the initial description of the pitu- itary tumor as the cause of obesity. Although there was an association between the pituitary tumor in an over- weight individual, a cause and effect relationship was not suggested by the author nor was there any evidence of a temporal relationship between the pituitary disease and the patient’s weight gain. A second paper by Rayer (20) has also been identified as a paper relating pituitary tumors and obesity. On reading this paper, there is no identification of obesity among the cases with pituitary tumors. It is thus more appropriate to accord recogni- tion for the association between a pituitary tumor and obesity to the two papers by Frohlich (12) and Babinski (2).

With the advent of frequent autopsy examination at the beginning of the 19th century, many reports of dis- eases involving the pituitary and hypothalamus began to appear (17). These can be grouped into several cate- gories (6), including inflammatory lesions, hemorrhagic lesions, cysts, and a variety of tumors.

Recognition that a disorder of the pituitary could produce generalized systematic symptoms goes to Pierre Marie (16) for his description of acromegaly in 1886. From the Dept. of Medicine, LSU School of Medicine and Pennington Biomedical Research Center, Baton Rouge, LA. Copyright 81993. NAASO.

The paper by Marie includes two cases with complete clinical descriptions of acromegaly. This paper aroused considerable clinical interest, and was translated into English by the new Sydenham Society in 1891. An ear- lier description of acromegaly by Saucerotte in 1772 (21) was only subsequently recognized as a case of acromegaly by Marie.

The description of pituitary tumor and obesity in the publication by Frohlich has attracted much attention. Frohlich’s name was subsequently given to the syn- drome “Adiposo-Genital Syndrome” by Bartels (4) and was extrapolated as a description for obese children with delayed gonadal development, whether or not there was a hypothalamic tumor. Reference to this syndrome, whether associated with evidence of an hypothalamic or pituitary tumor or other central nervous system disease, persisted for more than 50 years. It may be instructive to examine the original case described by Frohlich and its subsequent follow-up.

The patient of Frohlich was a 12-year-old boy com- plaining of severe headaches (7,12). These headaches were associated with vomiting, but no other complaints. In 1901, two years following the first evaluation, the boy, now age 15, returned to the clinic with a number of serious complaints. The patient, who originally had been slim, had been rapidly gaining weight. Beginning in January 1901 his eyesight began to diminish on the left. Six months later the headaches recurred and increased in severity. The boy became easily tired and vomited repeatedly, most commonly after meals. His visual acu- ity declined until he was blind in the left eye. His height was 1.45 meters and his weight 54 kg for a body mass index of 25.7, well above the normal limits for a 15- year-old boy. The largest accumulation of fat was in the subcutaneous tissues of the trunk particularly on the abdomen and in the neighborhood of the genitals. The testes were small and axillary hair was absent. Based on these findings, Frohlich made the diagnosis of a neo- plasm of the pituitary gland. Following the report by

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Frohlich the patient continued to be followed in their clinic. In 1907 an x-ray of the skull was obtained and showed destruction of the dorsum sellae, with preserva- tion of the anterior clinoid process (4). Examination of the eyes showed atrophy of the optic disc and further weight gain to 65.2 kg for an immature boy of average height. Parenthetically it was only in 1895 that Rontgen had originally reported the discovery of x-rays.

In 1907 a craniotomy was performed with drainage of a hazelnut size cyst containing several spoonfuls of fluid resembling old blood (25). Histology revealed an abnormality of the pituitary in a precancerous stage. Following surgery the patient improved and reproduc- tive function developed. The last report on this patient, in 1913 (5). showed that improvement had persisted but the patient maintained his infantile habitus.

In reaching his diagnosis, Frohlich used several fea- tures of the case. First, the patient had headaches and vomiting which slowly progressed and suggested a slowly expanding process located at the base of the skull. Because of the decreased vision, he reasoned that the lesion was in the region of the optic chiasm. Since the left eye was involved more than the right, he assumed there was a neoplasm in the region of the pitu- itary. In reviewing the older literature, Frohlich noted that several authors had commented on the presence of adiposity with effeminante appearance as a coexisting symptom. None of these earlier authors, however, had recognized the diagnostic importance of these associat- ed symptoms nor their potential causal relationship. Only with the syndrome of acromegaly described in 1886 by Marie (16) had the connection been made between pituitary enlargement and the development of disease.

In contrast with the case by Frohlich, the case by Babinski is shorter in length and there is little in the way of discussion of the literature. The patient was a 17- year-old girl who had been observed for 10 years and was the basis for a doctoral thesis by Onanoff (19). The 17-year-old girl of Babinski, like the patient of Frohlich, had complained of headaches for several years which had increased in intensity. Her vision was diminished. On examination, Babinski was struck by the excess adi- pose tissue on her body and the infantile nature of her genital organs. Babinski’s paper contained the autopsy examination showing a tumor of the sella turcica adher- ing to the pituitary body and engulfing the tuber cinereum. As Babinski noted, this case was interesting from two perspectives. The first was the absence of acromegaly and gigantism in the presence of a large pituitary tumor. The second was the coexistence of the pituitary lesion and infantilism with an arrest in the development of genital organs. As Babinski noted, “the idea of a cause and effect relationship between the

tumor of the body of the pituitary and infantilism is very acceptable.” Because Babinski’s patient was obese and his focus was on the impaired gonadal development, this would lead me to believe that Frohlich deserves the pri- mary credit for recognizing the relationship between a tumor of the hypophysis and obesity.

Immediately after recognition by Frohlich of the relation of a tumor at the base of the brain and obesity, the question of whether it was a tumor of the pituitary or a tumor outside the pituitary became the subject of debate. In 1904 bdheim (10) took issue with Frohlich’s conclusion that it was a pituitary tumor. In a long and detailed paper, Erdheim concluded that a tumor of the pituitary was less likely to be the cause of obesity than a superaseller or hypothalamic tumor. Reviewing a series of autopsies, he demonstrated that only tumors of the pituitary which grow beyond the sella turcica are associ- ated with obesity. Moreover, he noted, tumors limited to the pituitary did not produce adiposity. Finally, tumors of the pituitary stalk originating in or near the pituitary but without the involvement of the pituitary, could pro- duce obesity. On the basis of this evidence Erdheim argued that the syndrome of adiposity was caused by tumors outside the pituitary impinging on the base of the brain. In her discussion of the role of tumors of the pituitary versus the hypothalamus as cause of this syn- drome, Bruch says, “For a long time it seemed that the conflicting theories (pituitary versus hypothalamus) could be reconciled by the assumption that an intimate anatomic and physiologic connection existed between the hypophysis and the surrounding nerve centers. Recent anatomic investigations (26), she says, “have shown this concept to be false. There are no veins of any consequence passing from the infundibular stem to the hypothalamic region or vice versa” (7,12). Unfortunately the studies Bruch relied on to reach this conclusion were inaccurate (26). The existence of an hypothalamic pituitary-portal system was eventually proven by Harris (14).

The syndrome of obesity and delayed development of the reproductive organs was reproduced experimen- tally by Crowe, et al. in 1910 (8). In their review, Fulton and Bailey suggest that, “it is doubtful whether the hypophysis plays an essential role in the production of hypersomnia adiposity and genital dystrophy ... (13):’ A clear cut experimental demonstration that the infantilism of this syndrome was a result of pituitary damage was furnished by the experiments of Evans and Long in 1921 (11) and by PE Smith in 1927 (22). After it became clear by 1927 that the destruction of the pitu- itary produced atrophy of the thyroid, adrenal, and gonads, but not obesity, Hetherington and Ranson (15) showed that lesions of the ventromedial hypothalamus uniformly produced obesity. Subsequently lesions of the

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lateral hypothalamus were shown to produce anorexia and weight loss (1) and led to the dual center hypothesis for explaination of hunger and satiety (23).

More recently it has been shown that a lesion in either the ventromedial hypothalamus or paraventricular nucleus will produce obesity. These two syndromes of hypothalamic obesity differ in a number of respects. Damage to the paraventricular nucleus produces hyper- phagia which is essential for development of the syn- drome. When food intake is maintained at normal levels following a lesion in the paraventricular nucleus, obesi- ty does not occur. In contrast, a lesion in the ventrome- dial nucleus produces an imbalance between the sympa- thetic and parasympathetic limbs of the autonomic ner- vous system. This results in increased levels of insulin and decreased thermogenesis by the sympathetic ner- vous system. There is also a reduction in growth hor- mone secretion and a reduction in physical activity in association with damage to the ventromedial nucleus. Thus current work nearly a century after the classic description by Frohlich (12) and Babinski (2) suggests that there are two distinctive syndromes in hypothalamic obesity: 1) A hyperphagic syndrome due to increased food intake and 2) A metabolic syndrome with altered balance between the sympathetic and parasympathetic components of the autonomic nervous system .

Alfred Frohlich (1871-1953), author of the most important of these three papers, was born in Vienna where he received his MD degree in 1895. Following graduation, he joined the Department of Medicine under the direction of Dr. Nothnagel and worked in experi- mental pathology and in the neurology clinic. It was during his stay in Sherington’s Lab in Liverpool, England, that Frohlich met Harvey Cushing. Frohlich’s first academic appointment with tenure was in the Department of Pharmacology and Toxicology in Vienna. He was subsequently appointed a full professor and served in that position from 1919-1939. He Came to the US in 1939, a victim of the German-Austrian Anschluss. He continued his pharmacologic studies as a member of the May Institute of Medical Research at the Jewish Hospital in Cincinnati, OH. Frohlich’s work touched almost all areas of vertebrate and invertebrate

uate thesis, published in 1885, was on multiple sclero- sis. At age 30 he became chief assistant to Professor Charcot at Hopital Salpetriere and shortly after became Mtdecin aux Hepitaux. He was an editor of the Revue Neurologique and a founder of the Soci t t t de Neurologie de Paris (24).

Information on Bernard Mohr (1809-1848) is scant compared with that on Frtihlich and Babinsiki. Bernard Mohr graduated from Medical school in Wiirtzburg. In 1833 he published his doctoral thesis.

References 1. Anand BK, Brobeck JR. Hypothalamic control of food

intake in rats and cats. Yale J Biol Med 1951;24123-146. 2. Babinski JFF. Tumeur du corps pituitaire sans acromk-

galie et avec m e t de dkveloppement des organes gknitaux. Rev Neurol 1900;8:531-533.

3. Bailey P, Bremer F. Experimental diabetes insipidus.

4. Bartels M. Ueber Plattengeschwulste der Hypophysenge- gend (des Infundubulums), Ztschr. f. Augenh. 1906;16:

Arch Int 1921;28:773-803.

407438,530-560. 5. Biedl A. Innere Sekretion: Ihre physiologischen Grund-

lagenund ihre Bedeutung fur die Pathologie. 2nd ed. Berlin: Urban & Schwarzenberg; 1913.

study of the pathology of the hypophysis cerebri. J Path & Bacteriol 1893; 1:359-383.

7. Bruch H. The Frohlich Syndrome: Report of the original case. Am J Dis Child 1939; 58: 1281-1289.

8. Ctowe SJ, Cushing H, Homans J. Experimental hypo- physectomy. Johns Hopk Hosp Bull 1910;21: 127-169.

9. Editorial on Alfred Frohlich. J Am Med Asso. 1969;

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11. Evans HM, Long JA. ’Ihe effect of the anterior lobe administered inhaperitoneally upon growth, maturity and oestrus cycles of the rat. Anat Rec 1921;21:62-63.

12. Frohlich A. Ein Fall von Tumor der Hypophysis cerebri- ohne Akromegalie, Wien klin Rundschau 1901;15: 883-886,906-908.

13. Fulton JF, Bailey P. Tumors in the Region of the Third Ventricle: The Diagnosis and Relation to Pathological Sleep. J Nerv & Ment Dis 1929; 69: 1-25, 145-164,261- 777 L , I .

pathology (9).

born in Paris of Polish parents. Under the influence of the famous Charcot he became a neurologist and was appointed to the Hopital de la PitiC in 1890 where he became a senior neurologist in 1914. He is best for his description of the plantar reflex which bears his name. Babinski was a prolific writer, publishing in

ogy, psychiatry, and medical editing. His first Scientific contribution in 1882 concerned typhoid fever. His grad-

14. Harris GW. Neural Control of the Pituitary Gland.

15. Hetherington AW, Ranson SW. Hypothalamic lesions

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besondere auf die Sehnerven, das Chiasma derselben und den linkseitigen Himschenkel. Wschr ges Heilk 1840; 6:565-571.

19. Onanoff. Sur un cas d'epithelioma. These de Paris 1892. 20. Rayer PFO. Observations sur les maladies de l'appendice

sus-spheno'idal (glande pituitaire) du Cerveau. Arch GBn MM 1823;3:350-367.

d'un h o m e Og6 de 39 ans. MClanges de chirurgie 1801: 21. Saucerotte N. Accroissement singulier en grosseur des 0 s

407-41 1. 22. Smith PE: The disabilities caused by hypophysectomy

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23. Stellar E. The Physiology of Motivation. Psycho1 Rev

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neuer Fall von Hypophysisoperation bei Degeneratio adi- posogenitalis. Wien klin Wchnschr 1908;21:1115.

Hypophysis and Hypothalamus to Vital Dyes, with a Study of the Hypophyseal Vascular Supply. Am J Anat 1936;58:421-472

25. von Eiselsberg A. , von Frankl-Hochwart L. Ein

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