Highlights from endocrine surgical history.

Endocrine surgery includes excision of diseased or sometimes normal endocrine glands and occasionally the transplantation of endocrine tissues. Male castration was performed for social reasons in prehistoric times, and thyroid operations were described during the twelfth century. Until the end of the nineteenth century most operations were undertaken to relieve the local effects of pathologic enlargement of the thyroid, ovaries, pituitary, and adrenals; and with the development of anesthesia, antisepsis, and effective hemostasis, thyroidectomy for benign, nontoxic goiter was perfected. Thyroid deficiency followed total thyroidectomy, and thyroid replacement therapy was developed. Toxic goiter was sometimes relieved by partial thyroidectomy. After the discovery of hormones early this century, knowledge of endocrinology increased, and many syndromes of hormonal excess were described. Surgeons began to operate to relieve them. Results improved with mastery of surgical technique, especially for operations on the thyroid, parathyroids, and pituitary; with the development of methods for diagnosis of syndromes and the localization of lesions; with teamwork; and with the use of hormones, drugs, and radiotherapy as alternative or additional forms of therapy before, during, and after operation. Notable advances followed adequate resection of thyroid tissue and the use of iodine and antithyroid drugs before operation for toxic goiter. The use of cortisone rendered adrenalectomy safe for the relief of cancer of the breast and prostate and of Cushing's syndrome. For about 40 years increasing numbers of surgeons have specialized in endocrine surgery as a discipline within general surgery, and results of treatment have improved greatly.

The emergence of endocrinology.

Endocrinology was recognized as a new branch of biological science mainly as a result of events which took place between about 1890 and 1905, but ideas and discoveries dating from antiquity contributed to it also. Experiments supporting the concept of internal secretions by the testicles were described by Aristotle (4th c. B.C.) and by Hunter (18th c.) and Berthold (19th c.). In 1855 Bernard described glucose as an internal secretion of the liver and Addison reported the effects of adrenal disease in man. Adrenalectomy was fatal in animals. Goitre was known in antiquity and cretinism had been described by Paracelsus. Myxoedema was reported by Gull in 1873, and Kocher described cachexia strumipriva in 1883. In 1888 cretinism, myxoedema and cachexia strumipriva were attributed to thyroid insufficiency. In the 1890s Gley found that tetany after thyroidectomy was due to removal of the parathyroids. In 1884 Rehn proposed that toxic goitre was due to thyroid excess. In 1889 Brown-Séquard claimed that injections of testicular extract rejuvenated the elderly, and in 1893 he introduced organotherapy. In 1891 Murray treated myxoedema successfully with thyroid extract. In 1893 Oliver and Schäfer found that an adrenal extract raised the blood pressure, and soon adrenaline was extracted from the adrenal medulla. Adrenocortical deficiency was proposed as the cause of Addison's disease, and in 1896 Osler prepared an extract which relieved one patient. Diabetes mellitus, described in the first century, was usually fatal. Thirst and polyuria followed experimental pancreatectomy, and pancreatic lesions were found in some human diabetics. In the 19th century workers in France and Germany found that diabetes resulted from absence of an internal secretion by the islets of Langerhans and, in 1893, Laguesse described the function of the islets as "endocrine". In 1895 Beatson treated advanced breast cancer successfully by oöphorectomy. In 1895 Schäfer commended study of the internal secretions to physiologists. In 1902 Bayliss and Starling discovered secretin, a chemical messenger secreted by the intestinal mucosa. In 1905 Starling proposed the name "hormone" for this class of internal secretions. By then endocrinology had been launched as a new branch of science. The crucial events which led to the recognition of endocrinology as a new branch of biological science took place between about 1890 and 1905. Many ideas and discoveries dating from antiquity and apparently unrelated at first had, however, contributed to it. Most of the organs and tissues that form the endocrine system were recognized over 100 years ago.(ABSTRACT TRUNCATED AT 400 WORDS)

The evolution of transsphenoidal pituitary microsurgery.

Serious interest in pituitary disease started 100 years ago when acromegaly was described (1886, Marie). Transcranial pituitary operations soon followed (1889, Horsley). Transnasal operations (1907, Schloffer) were complicated by cerebrospinal fluid leakage and meningitis. Improvements led to definitive transseptal (1910, Cushing and Hirsch) and transethmoidal (1911, Chiari) decompressing surgery for tumors. The mortality rate fell below 10%, and relief, mainly from local effects, often followed, sometimes for many years. By 1930 Cushing and most U.S. surgeons used a transcranial approach because suprasellar lesions were inaccessible from below, but several European surgeons continued to use transsphenoidal operations when appropriate (Hirsch, Dott, and Nager). By 1950 antibiotics had reduced infection, and cortisone soon rendered total hypophysectomy by all routes safe for tumorous and normal glands. Microsurgical transethmosphenoidal hypophysectomy was introduced by ear, nose, and throat surgeons (1957 or 1958, Gisselsson, Riskaer, Bateman, MacBeth, and James). Neurosurgeons introduced intraoperative radiofluoroscopy (1957, Guiot), air encephalography, televised fluoroscopy, microsurgical transseptal hypophysectomy, and selective anterior hypophysectomy (1965, Hardy). Microadenomectomy for lesions invisible radiologically was introduced in 1968 (Hardy). The operative death rate is now negligible. Computerized tomographic scanning helps locate tumors, but increasingly surgeons now regard endocrinologic diagnosis alone as justification for operation. Early outcome is excellent, especially in experienced hands, and particularly for noninvasive tumors, but later results are forthcoming.

Oral water causes emptying of the human gallbladder through actions of vagal stimuli rather than motilin.

A drink of water was found to cause partial emptying of the human gallbladder in parallel with the release of motilin. The water-induced effect on the gallbladder was abolished by atropine, whereas the release of motilin remained unchanged. Exogenous infusions of porcine motilin aimed at achieving either a physiological or a pharmacological plasma motilin increment were both without effect on gallbladder dynamics as compared with saline infusions. It is concluded that the water-induced gallbladder emptying is vagally dependent. Furthermore, the results suggest that motilin does not cause gallbladder emptying in man.

A model for teaching medical ethics.

The approach to teaching employed in the Dictionary of Medical Ethics (1) provides a model which might be adopted in other media. Most of the 150 authors were medical, but many represented other disciplines, and they wrote for similar professionals and for the general public. Medical ethics is derived from medical science and practice, moral philosophy, sociology, theology, the law and other disciplines, all of which make essential, distinctive and complementary contributions to knowledge and to teaching. Medical practitioners must play the primary role, because they are responsible for clinical ethical decisions, but they need the co-operation and guidance of others. All who are concerned should work towards the development of a general moral consensus among the profession and public, which keeps abreast of scientific and technical advances and to which all are committed.

KIE: An editor of the Dictionary of Medical Ethics draws on his experiences in this capacity to develop a model of how a multidisciplinary perspective can be brought to bear on the teaching of medical ethics. He believes that medical practitioners should play the primary role in the ethical training of physicians, but that teachers should be drawn as well from the ranks of moral philosophers, lawyers, theologians, social scientists, and others. He also advocates the broad involvement of many disciplines and the general public in helping to develop a moral consensus on bioethical issues.

Survival and causes of death after adrenalectomy for Cushing's disease.

A consecutive series of 79 patients with Cushing's disease, treated by bilateral adrenalectomy (subtotal, total initially, or total finally) between 1953 and 1980, were studied to determine the survival and mortality rates and causes of death as long as 28 years after surgery. There were three early postoperative deaths, the last in 1974, caused by coma of unknown cause, severe diarrhea, and pulmonary embolism, respectively. The actuarial survival rates at intervals of 1, 2, 3, 5, 10, 15, and 20 years after surgery were approximately 87%, 83%, 82%, 79%, 72%, 68%, and 62%, respectively. These are significantly less than the rates for the general population (p less than 0.001). There were no differences between the sexes or between the types of operation (p greater than 0.05). The commonest causes of death were cardiac or vascular lesions (11 patients) and the local effects of pituitary tumors (four patients). These long-term results of an established method of treatment provide a standard by which other, especially newer, methods may be compared.

Lymph, pancreatic and gastrointestinal hormones in response to feeding in the conscious pig.

Concentrations of several gastrointestinal hormonal peptides were measured in lymph from the cisterna chyli and in arterial plasma; in healthy, conscious pigs during ingestion of a meal. Lymph concentrations of the pancreatic hormones insulin, glucagon and pancreatic polypeptide were small compared with plasma concentrations, although postprandial increments were significant. In contrast lymph concentrations of gastrin, cholecystokinin, motilin and gastric inhibitory peptide (GIP) from the foregut showed a more marked postprandial rise than the pancreatic hormones. Indeed the total integrated responses of these peptides in lymph reached about 50% of those seen in arterial plasma. It would appear unlikely that the lymphatics constitute an important transport mechanisms for these regulatory peptides. However, lymph concentrations of hormones may reflect levels in interstitial fluid better than plasma and may be of value in assessing putative physiological actions within a target tissue.

Effect of food on porcine gut regulatory peptides in arterial and portal venous blood.

The concentrations of gut regulatory peptides were monitored simultaneously in the portal and arterial circulations of 8 healthy conscious swine in the fasted state and after a standard mixed meal. The sampling was achieved via chronic cannulations of these two vessels. Portal/arterial differences of insulin and glucagon were similar to those previously described, indicating the importance of hepatic extraction of these two hormones. Portal/arterial differences for the gastrointestinal regulatory peptides were relatively small, however, and the liver is unlikely to be of major importance in the metabolism of these peptides.

Plasma histamine in pig: effect of food and pentagastrin.

Histamine may have a role in the physiological control of gastric acid secretion. We aimed to detect histamine release into the circulation during food and pentagastrin. Non-parametric statistical analysis was used. Seven pigs bearing iliac artery, iliac vein and portal vein cannulae were given a standard meal. Blood samples were collected at 10-minutes intervals over a period of 2 hours for histamine assay. There were no significant changes in whole blood and plasma histamine concentrations in the iliac arterial or venous blood. In portal venous blood, no significant changes were observed in whole blood histamine, but there were significant increases in plasma histamine 40 minutes after food (basal median: 149.0; range: 50.3-258.6 pmol ml-1; 40 minutes, median 214.9; range: 64.2-319.6 pmol ml-1). Four pigs were given pentagastrin, 6 micrograms kg-1 h-1 i.v. Iliac and portal venous bloods were collected for histamine assay before and 15 minutes after pentagastrin infusion. There were no significant changes in the whole blood histamine concentration in either iliac or portal venous blood. A small increase, mean 5%, of plasma histamine concentration was detected in the iliac venous blood (basal mean 242.9 +/- 21.7 pmol ml-1; stimulated mean 256.9 +/- 39.1 pmol ml-1). A 20% increase in the portal plasma histamine concentration was observed after pentagastrin (basal mean 240.1 +/- 13.2; stimulated mean 288.4 +/- 18.8 pmol ml-1). Both food and pentagastrin increase plasma histamine concentration in the portal vein. Pentagastrin has a greater effect than food.

Neural regulation of pancreatic polypeptide release.

To clarify the nervous system's role in the regulation of pancreatic polypeptide (PP) release, extrinsic innervation to the in situ pancreas was eliminated in five dogs. Before and 2 weeks after denervation, PP was measured during insulin hypoglycemia and ingestion of a protein meal. Exogenous insulin caused a similar marked hypoglycemia in both control and denervated dogs. Hypoglycemia caused a significant increase in plasma PP in control dogs from a baseline of 42 +/- 8 pg/ml to 86 +/- 18 pg/ml at 20 minutes (P less than 0.01). In denervated dogs plasma PP did not increase with hypoglycemia, and levels were significantly less than in the control animals at 30 and 60 minutes (P less than 0.05). With a protein meal, PP increased in the control animals from 53 +/- 12 to 116 +/- 16 pg/ml at 10 minutes (P less than 0.05), 164 +/- 22 pg/ml at 20 minutes (P less than 0.05), and 193 +/- 20 pg/ml at 60 minutes (P less than 0.01). Denervation markedly blunted this response, and PP increased only from 53 +/- 6 to 64 +/- 4 pg/ml at 10 minutes, to 83 +/- 12 pg/ml at 20 minutes, and to 91 +/- 8 pg/ml at 60 minutes. PP became significantly elevated above baseline in denervated dogs only at 60 minutes (P less than 0.05), and PP was significantly lower than in the control group at 10, 20, and 60 minutes after the meal (P less than 0.05). Immunostaining for insulin, glucagon, somatostatin, and PP showed no difference in the number and distribution of these endocrine cells in predenervation and postdenervation specimens. Adrenergic and cholinergic nerves were seen in all control specimens but, except for a few adrenergic fibers, were not seen in denervated animals. Peptidergic nerves that contained vasoactive intestinal polypeptide (VIP) were seen in all areas of the pancreas before and after denervation. This study confirms that the initial rise in PP with a protein meal is governed by vagal cholinergic pathways. Later postprandial PP secretion is controlled by an interplay between these cholinergic pathways and other uncertain influences such as hormonal or substrate changes. The pancreas has a rich intrinsic peptidergic system of VIP-containing nerves.

An experimental model for simultaneous chronic sampling of portal and systemic blood and gastrointestinal lymph via cannulae in conscious swine.

Surgical techniques are described whereby safe chronic cannulations of the portal vein, the external iliac artery and vein and the cisterna chyli of pigs were performed. The pigs tolerated the operations well and there was a short recovery period. They were unrestrained during the subsequent feeding experiments, when large sequential blood and lymph samples were withdrawn readily. The experimental periods varied from 3 to 46 days (mean : 13.4 days, SE: 2.0). All of 22 arterial cannulae remained patent (mean : 16 days, SE : 2.2), nineteen of 22 portal cannulae (mean : 15 days, SE : 1.8) and eighteen of 22 venous cannulae (mean : 14 days, SE : 1.9). The lymph cannula patency varied from 2 to 7 days, but lymph samples were easily obtained through all but one of them during the third postoperative day.

Peptide histidine isoleucine (PHI). A secretagogue in porcine intestine.

PHI (peptide histidine isoleucine) is a recently identified porcine peptide, present in large quantities in the intestine, which has sequence homologies with VIP, an established intestinal secretagogue, and with secretin, glucagon, and GIP. The effects of PHI on jejunal, ileal, and colonic fluid and electrolyte transport were studied in the pig. PHI appears to be an intestinal secretagogue inducing a reversible net secretion of fluid and electrolytes in jejunum and ileum and less marked effects in the colon.

Pancreatic polypeptide and calcitonin secretion from a pancreatic tumour-clinical improvement after hepatic artery embolization.

We present a case in which plasma pancreatic polypeptide and calcitonin were found to be raised in association with an islet cell tumour of the pancreas and its hepatic metastases. In this patient, no specific endocrine syndrome was found. Therapeutic hepatic artery embolization improved the general health of the patient with no change in plasma pancreatic polypeptide, but a fall in calcitonin.

Interdigestive biliary output in man: relationship to fluctuations in plasma motilin and effect of atropine.

The fasting output of bile into the bowel was investigated in nine healthy volunteers by hepatobiliary scanning. Subjects were studied twice, on each occasion for 2.5 hours. A significant flow of radioactivity from the gall bladder to the duodenum was observed on one or two occasions during each experiment. A 32 +/- 4% mean decrease in counts over the gall bladder was recorded, indicating partial emptying of this organ in the interdigestive state. The output of bile into the bowel was found to be related to fluctuations in fasting plasma motilin levels in that a significant motilin increment (18 +/- 4 pmol/l, p less than 0.005) paralleled the appearance of radioactivity in the duodenum. The onset of gall-bladder emptying regularly preceded the peak in plasma motilin (mean: 25 +/- 2 minutes). Atropine, intravenously, 0.6 mg followed by 0.3 mg, nearly abolished both fasting biliary output and plasma motilin fluctuations. Thus, bile output appears to occur frequently in fasting humans, but our data do not allow any conclusions as to the possible causal relationship between fasting gall-bladder emptying and release of motilin. Cholinergic influences appear to be of importance in the regulation of interdigestive biliary output in man.

Surgical management of the ectopic ACTH syndrome.

Most patients with extra-pituitary ACTH-secreting tumors die from carcinoma, but a few can benefit from operation. Of 96 patients with Cushing's syndrome, 11 probably had such tumors. There were three modes of presentation: (1) three had malignant tumors with visceral metastases initially. One (bronchial carcinoid) died without operation. Two with carcinoma (thyroid medullary and islet-cell) underwent adrenalectomy with remission, but died soon. (2) three had apparently benign tumors initially. One (appendicular carcinoid) underwent appendectomy and one (bronchial carcinoid with hilar node metastases) underwent lobectomy. Both had rapid remissions. The third (pheochromocytoma) died after resection of the tumor. (3) five patients had no obvious tumors and underwent adrenalectomy with remission. In one a benign bronchial carcinoid was removed later. Four others remain well, but without localizing signs of tumor. The main biochemical features in all were hypokalemic alkalosis and very high urinary excretion of free cortisol. Seven of the eight patients without visceral metastases are in remission from one to 15 years after operation.