- Email: [email protected]
ASSESSING THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS
215
(1.7 cm, p < 0.025), and placental weight (136 g, p < 0.02) in those patients with high initial SD ratio. For the 12 women with extreme initial SD ratio, aspirin therapy did not result in a significantly different pregnancy outcome, suggesting that in these cases the
placental lesion and fetal effect were too far advanced to reverse. Maternal ingestion of aspirin affects the maternal and fetal circulation.4 We have demonstrated that the pathology of placental insufficiency that is identified by doppler study of the flow velocity waveform in the umbilical artery is present in the fetal umbilical placental circulation.2 Sometimes there is associated vascular disease in the maternal uteroplacental circulation.3 Our results support the hypothesis that the benefits of aspirin result from its actions in the fetal circulation. Studies of flow velocity waveforms from branches of the maternal uterine artery in the placental bed were normal in our patients. We do not advocate the widespread use of aspirin in all pregnancies in which the fetus might be considered at risk on the basis of obstetrical history or associated maternal disease. Our study demonstrated fetal benefit when umbilical placental insufficiency was defined early by doppler flow study. Accordingly aspirin treatment is better reserved for these cases.
Fetal Welfare Laboratory, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia
BRIAN TRUDINGER COLLEEN-M. COOK ROSEMARY THOMPSON WARWICK GILES ANITA CONNELLY
Trudinger BJ, Cook C-M, Thompson RS, Giles WB, Connelly A. Low dose aspirin therapy improves fetal weight in umbilical placental insufficiency. Am J Obstet Gynecol (in press). 2. Giles WB, Trudinger BJ, Baird P. Fetal umbilical artery flow velocity waveforms and placental resistance: Pathological correlation. Br J Obstet Gynecol 1985; 92: 31-38. 3. Trudinger BJ, Giles WB, Cook CM. Flow velocity waveforms in the maternal uteroplacental and fetal umbilical placental circulation. Am J Obstet Gynecol 1985; 1.
152: 155-63. 4. Ylikorkala O, Makila U, Kaapa P, Vinikka L. Maternal ingestion of acetylsalicylic acid inhibits fetal and neonatal prostacyclin and thromboxane in humans. Am J Obstet Gynecol 1986; 155: 345-48.
POLYCYSTIC OVARIAN SYNDROME TREATED BY LASER THROUGH THE LAPAROSCOPE
SIR,-Bilateral ovarian wedge resection is still widely accepted in the management of the polycystic ovary syndrome (PCO).l Treatment by ovarian electrocautery through the laparoscope has been reported by Gjonnaess.2 This method reduces the risk of adhesions, the main complication of wedge resection. Lasers have the advantages over electrocautery of a reduced area of damage and haemostasis during sharp dissection. Furthermore, tissue regeneration is greater after laser treatment than after electrocautery.3 Because the placebo effect of surgical procedures in PCO remains unresolved4 we evaluated laparoscopic laser treatment in two groups of patients with PCO, one being studied by laparoscopy for diagnosis only (group A) and the other scheduled to receive laser treatment at laparoscopy (group B). All the patients had an LH/FSH ratio of 2 or more with macroscopic confirmation of enlarged sclerocystic ovaries. The study was not, therefore, randomised. Patients were told of the possibility of normal menstrual cycles and pregnancy arising after the procedure and the women in group B were informed about the ovarian excision procedure. We used
an
neodymium (Nd:YAG) laser with
a
flexible
fibre,
introduced through a third endoscopic puncture. Bilateral incision of the ovary was carried out for a distance of around 5 mm on the opposite of the mesovarium. In each ovary the laser incisions were done three, four, or five times to a length of 5-1 mm and a depth of 4 mm. Before the procedure clomiphene failure had been recorded in all patients, and testosterone, androstendione, and dehydroepiandrosterone were raised in most of them. All women had hirsutism and oligomenorrhoea. Spontaneous menstrual bleeding occurred 2-10 days after the procedure in all patients in group B. In group A menstruation occurred in only 2 cases, both 12 days after laparoscopy. No follicular maturation could be demonstrated in group A by daily monitoring of LH and oestradiol whereas in group B 5 patients ovulated spontaneously, and in 3 cases ovulation could be achieved
by clomiphene 2 months after the laser treatment. In these 3 cases LH and androgen levels were raised again after one cycle with an established ovulation. In the remaining 5 patients, the menstrual cycle was monitored for 2 months by endocrinological testing (LH, oestradiol), after that, basal body temperature was recorded. We now have follow-up data over about 6 months. All 5 patients now have a biphasic basal body temperature record, although none have yet become pregnant. In group A, despite the 2 cases of menstrual bleeding, ovulation could not be documented by basal body temperature measurement. These results confirm that endoscopic wedge resection is clinically relevant and does not act merely as a placebo. The incision of polycystic ovaries seems to be a new application for this kind of laser. First Department for Gynaecology and Obstetrics, University of Vienna, 1090 Vienna, Austria
J. HUBER J. HOSMANN J. SPONA
EY, Rock JA, Guzick D, Wentz AC, Jones GS, Jones HW Jr. Fertility following bilateral ovarian wedge resection: a critical analysis of 90 consecutive cases of the polycystic ovary syndrome. Fertil Steril 1981; 36: 320-25 2. Gjonnaess H. Polycystic ovarian syndrome treated by ovanan electrocautry through the laparoscope. Fertil Steril 1984; 41: 20-25. 3. Goldzieher J, Green JA. The polycystic ovary: Clinical and histologic features. J Clin 1. Adashi
Endocrinol Metab 1962; 22: 325-38. 4. Shearman RP, ed. Clinical reproductive Livingstone, 1985.
endocrinology. Edinburgh: Churchill
ASSESSING THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS SiR,—Dr Stewart and colleagues (May 28, p 1208) propose the of the short ’Synacthen’ (synthetic corticotropin) test rather than the insulin tolerance test for the assessment of hypothalamopituitary-adrenal function in patients with hypothalamo-pituitary disease but not in patients who have been treated with a glucocorticoid. I cannot agree that the insulin tolerance test should be used routinely for those who have received glucocorticoid use
therapy. Stewart and colleagues did not in fact study patients on glucocorticoid therapy. They excluded patients with Cushing’s syndrome, those taking glucocorticoids, and those within 15 days of an acute pituitary insult. Thus their recommendation is based on the work of others. However, other reports do not support this exclusion. In general, the maximum response of the plasma cortisol level to corticotropin corresponds to the maximum plasma cortisol level observed during the induction of general anaesthesia and surgery in patients who have received glucocorticoid therapy.l-4 This occurs after a rapid intravenous injection of synthetic corticotropin with measurement of the plasma cortisol level 30 min2 or 60 min1 after the injection, or after a 6 h infusion of COrtlCOtropln.3’4 Thus a normal preoperative response to corticotropin is unlikely to be followed by impaired secretion of cortisol during anaesthesia and surgery in glucocorticoid-treated patients. It is true that patients have occasionally been reported in whom the response to corticotropin is normal but the response to insulin-induced hypoglycaemia or metyrapone is abnormal. 5,6 However, these studies did not systematically compare their findings with the response to a physiological stress such as the induction of general anaesthesia and surgery. (In one instance where this was done, a patient had normal corticotropin and cortisol responses to the stress of a vasovagal attack, but failed to respond to subsequent hypoglycaemia.6) Without such information, the comparison between a corticotropin test and an insulin tolerance or metyrapone test is difficult to interpret. It is possible, for example, that the hypoglycaemic stimulus was not adequate in the insulin tolerance test since normally there is variation between subjects in the plasma cortisol response to hypoglycaemia.7 It is also possible that the insulin tolerance or metytrapone test is too sensitive, rather than that the corticotropin test is insufficiently sensitive. Thus systematic studies consistently demonstrate the value of a corticotropin test in the assessment of hypothalamo-pituitaryadrenal function in patients who have been treated with glucocorticoids. As Stewart et al argue, for patients with hypothalamo-pituitary disorders the short synthetic cortcotropin
216 is practical, reliable, and preferable to the "lengthy, uncomfortable, and potentially dangerous insulin tolerance test".
test
The short
synthetic corticotropin test should be used for the initial assessment of the hypothalamo-pituitary-adrenal axis in patients on gluccorticoid therapy. Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA 1.
LLOYD AXELROD
Jasani MK, Freeman PA, Boyle JA, Reid AM, Diver MJ, Buchanan WW. Studies of the rise in plasma 11 -hydroxycorticosteroids (11-OHCS) in corticosteroid-treated patients with rheumatoid arthritis during surgery: correlations with the functional integrity of the hypothalarnic-pituitary-adrenal axis. Quart J Med 1968; 37:
407-21. 2. Kehlet H, Binder C. Value of
3.
4. 5. 6.
7.
an ACTH test m assessing hypothalamic-pituitaryadrenocortical function in glucocorticoid-treated patients. Br Med J 1973; ii: 147-49. Marks LJ, Donovan MJ, Duncan FJ, Karger R. Adrenocortical response to surgical operations m patients treated with corticosteroids or corticotropin pnor to surgery. J Clin Endocrinol Metab 1959; 19: 1458-70. Sampson PA, Winstone NF, Brooke BN. Adrenal function in surgical patients after steroid therapy. Lancet 1962; ii: 322-25. Cunningham SK, Moore A, McKenna TJ. Normal cortisol response to corticotropin m patients with secondary adrenal failure. Arch Intern Med 1983; 143: 2276-279. Harrison BDW, Rees LH, Cayton RM, Nabarro JDN. Recovery of hypothalamopituitary-adrenal function in asthmatics whose oral steroids have been stopped or reduced. Clin Endocr 1982; 17: 109-18. Streeten DHP, Anderson GH Jr, Dalakos TG, et al. Normal and abnormal function of the hypothalamic-pituitary-adrenocortical system in man. Endocr Rev 1984; 5: 371-94.
DISSOLUTION OF CALCIFIED GALLBLADDER STONES BY TREATMENT WITH METHYL-HEXYL ETHER AND UREA-EDTA
SiR,—We have successfully treated 2 patients with calcified gallbladder stones by alternating perfusion with methylhexyl ether (MHE) and urea-EDTA (UEDTA) solutions. Both patients had a high calcium content in their stones, as identified by computed tomography (CT). The first patient was male, aged 59, and had a single stone with a diameter of 2cm. The stone was disaggregated within 72 h after the start of dissolution therapy with a percutaneously introduced pigtail catheter. The second patient, a 74-year-old woman, had recurrent biliary colic. Ultrasound showed multiple gallstones, the largest being 5 mm in diameter. These stones had not been detected by conventional intravenous cholangiography. CT showed an even distribution of calcium compounds throughout the stones. After ultrasoundguided, percutaneous transhepatic insertion of a 5 F pigtail catheter into the gallbladder, she was treated for 48 h. After the introduction of the catheter the bile was aspirated and replaced by the same volume of 75% MHE or buffered UEDTA, pH 9-5 (prepared by H. Baumgaertel and Dr Falk, GMBH, Freiburg, West Germany). MHE remained,in the gallbladder for 5 min, UEDTA for 10 min. Enzymatic determination showed that cholesterol in the ether phases varied between 200 and 1800 mg/dl. Calcium in the UEDTA portions was between 8 and 16 mg/dl in the aspirate. Treatment was continued until abdominal ultrasound demonstrated complete stone dissolution. Gallbladder stones can be treated by surgery, systemic dissolution with bile acids,’ extracorporeal shock wave,2or local litholysis with methyl tertiary butyl ether.3 Non-surgical methods are restricted to pure cholesterol stones, because only the fatty compound can be dissolved. This is the first report of successful treatment of calcium-containing pigment stones in the gallbladder by the combination of a fat solubiliser (MHE) and a calcium chelator (UEDTA). W. SWOBODNIK H. BAUMGAERTEL P. JANOWITZ Department of Gastroenterology and Nutrition, S. FUCHS University Clinic Ulm, H. DITSCHUNEIT D 7900 Ulrn, West Germany Danziger RG, Hofmann RF, Schonfield LJ. Dissolution of cholesterol gallstones by chenodeoxycholic acid. N Engl J Med 1972; 286: 1-8 2. Sackmann M, Delius M, Sauerbruch T, Hall J, et al Shock-wave lithotripsy of gallbladder stones. the first 175 patients. N Engl JMed 1988, 318: 393-97. 3. Allen MJ, Borody TJ, Bugliosi TF, May GR, La Russo NF, Thistle JL Rapid dissolution of gallstones by methyl tertiary-butyl ether N Engl J Med 1985, 312: 1.
217-20.
INTRANASAL GLUCAGON FOR HYPOGLYCAEMIA
SiR,—The secretion of glucagon is triggered when the blood glucose falls below 3-67 (SD 0’ 11) mmol/1,1 and in non-diabetics the magnitude of the glucagon response is directly related to the degree of hypoglycaemia.2 Some insulin-dependent diabetics have defective glucagon and other counterregulatory hormonal response to hypoglycaemia.3-5 The study on intranasal glucagon in hypoglycaemia by Dr Freychet and colleagues (June 18, p 1364) was not placebo controlled, so it is difficult to say how much the exogenous glucagon contributed to the restoration of euglycaemia. Comparison with glucagon levels found in studies of hypoglycaemia without exogenous glucagon is not truly valid. Glucagon is secreted by the A cells of the pancreas and reaches the liver via the portal veins before it reaches the peripheral circulation. Glucagon is mainly degraded by the liver so peripheral blood levels are low. Freychet et al did not study counterregulatory hormonal responses but refer to work by Bolli et al5 showing that after untreated insulin-induced hypoglycaemia there is a transient suppression of glucose production lasting at least an hour, despite counterregulatory hormone secretion. Glucagon too is a counterregulatory hormone and, whether exogenous or endogenous, it acts to reverse hypoglycaemia by increasing glucose production. Adrenaline, noradrenaline, and glucagon form the vanguard of the counterregulatory response, followed by cortisol and growth hormone. Sacca et al6 have reported that the initial reversal of insulin-induced hypoglycaemia is due to synergistic interaction among the counterregulatory hormones even before each individual hormone increases significantly. In this study the one patient who did not respond to intranasal glucagon had the highest serum glucagon of those in whom this hormone
measured. This diabetic may have had defective of other hormones, underlining the importance interaction among the hormones to trigger hepatic was
counterregulation of
glycogenolysis. Since glucagon stimulates insulin secretion it should not be used to treat hypoglycaemia induced by oral sulphonylureas Nor is it effective in alcohol-induced hypoglycaemia.7 Exogenous glucagon has a half life of about 10 min, making necessary immediate oral glucose or repeat doses of glucagon to prevent hypoglycaemic relapse. King’s College Hospital Medical School, Dulwich Hospital (North Wing), London SE22 8DF
J.
D. ARNOLD
SD, Cryer PE. Glycaemic thresholds for activation of glucose counter regulatory systems are higher than the thresholds for symptoms J Clin Invest 1987; 79: 777-82. Gale EAM, Bennett IA, Macdonald JJ, et al The physiological effects of insulin-induced hypoglycaemia in man: Responses at differing levels of blood glucose. Clin Sci 1983; 65: 263-71. Amiel SA, Tamborlane WV, DeFronzo RA, Sherwin RS. Intensive insulin therapy reduces counter regulatory hormonal responses to hypoglycaemia in patients with Type I diabetes. Ann Intern Med 1985; 103: 184-90. Amiel SA, Tamborlane WV, Simonson DC, Sherwin RS. Defective glucose counter regulation after strict glycaemic control of insulin dependent diabetes mellitus N Engl J Med 1987; 316: 1376-83. Bolli GB, Dimitriadis GD, Pehling GB, et al. Abnormal glucose counter regulation after subcutaneous insulin in insulin-dependent diabetes. N Engl J Med 1984, 310:
1. Schwarz NS, Clutter WE, Shah
2.
3.
4.
5.
1706-11. L, Sherwin R, Hendler R, Felig P. Influence of continuous physiologic hyperinsulinemia on glucose kinetics and counterregulatory hormones in normal and diabetic humans. J Clin Invest 1979; 63: 849-57. 7. Marks V, Rose FC Hypoglycaemia, 2nd ed. Oxford: Blackwell Scientific Publications, 1981: 475. 6. Sacca
SIR,-Dr Freychet and colleagues discuss the administration of intranasal glucagon in comparison with the traditional remedies of oral sugar for conscious hypoglycaemic patients or the injection of glucagon when consciousness is impaired. A recovery time of about 15 min is cited following the administration of oral sugar. This response time is very variable, depending upon the length and depth of the hypoglycaemia. Parents of children with diabetes are often supplied with injectable glucagon for hypoglycaemic crises but in many instances, because of a natural panic reaction, they attempt to administer oral sugar whatever the state of consciousness, and the glucagon pack remains a formidable obstacle. A 40% glucose gel in
(1.7 cm, p < 0.025), and placental weight (136 g, p < 0.02) in those patients with high initial SD ratio. For the 12 women with extreme initial SD ratio, aspirin therapy did not result in a significantly different pregnancy outcome, suggesting that in these cases the
placental lesion and fetal effect were too far advanced to reverse. Maternal ingestion of aspirin affects the maternal and fetal circulation.4 We have demonstrated that the pathology of placental insufficiency that is identified by doppler study of the flow velocity waveform in the umbilical artery is present in the fetal umbilical placental circulation.2 Sometimes there is associated vascular disease in the maternal uteroplacental circulation.3 Our results support the hypothesis that the benefits of aspirin result from its actions in the fetal circulation. Studies of flow velocity waveforms from branches of the maternal uterine artery in the placental bed were normal in our patients. We do not advocate the widespread use of aspirin in all pregnancies in which the fetus might be considered at risk on the basis of obstetrical history or associated maternal disease. Our study demonstrated fetal benefit when umbilical placental insufficiency was defined early by doppler flow study. Accordingly aspirin treatment is better reserved for these cases.
Fetal Welfare Laboratory, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia
BRIAN TRUDINGER COLLEEN-M. COOK ROSEMARY THOMPSON WARWICK GILES ANITA CONNELLY
Trudinger BJ, Cook C-M, Thompson RS, Giles WB, Connelly A. Low dose aspirin therapy improves fetal weight in umbilical placental insufficiency. Am J Obstet Gynecol (in press). 2. Giles WB, Trudinger BJ, Baird P. Fetal umbilical artery flow velocity waveforms and placental resistance: Pathological correlation. Br J Obstet Gynecol 1985; 92: 31-38. 3. Trudinger BJ, Giles WB, Cook CM. Flow velocity waveforms in the maternal uteroplacental and fetal umbilical placental circulation. Am J Obstet Gynecol 1985; 1.
152: 155-63. 4. Ylikorkala O, Makila U, Kaapa P, Vinikka L. Maternal ingestion of acetylsalicylic acid inhibits fetal and neonatal prostacyclin and thromboxane in humans. Am J Obstet Gynecol 1986; 155: 345-48.
POLYCYSTIC OVARIAN SYNDROME TREATED BY LASER THROUGH THE LAPAROSCOPE
SIR,-Bilateral ovarian wedge resection is still widely accepted in the management of the polycystic ovary syndrome (PCO).l Treatment by ovarian electrocautery through the laparoscope has been reported by Gjonnaess.2 This method reduces the risk of adhesions, the main complication of wedge resection. Lasers have the advantages over electrocautery of a reduced area of damage and haemostasis during sharp dissection. Furthermore, tissue regeneration is greater after laser treatment than after electrocautery.3 Because the placebo effect of surgical procedures in PCO remains unresolved4 we evaluated laparoscopic laser treatment in two groups of patients with PCO, one being studied by laparoscopy for diagnosis only (group A) and the other scheduled to receive laser treatment at laparoscopy (group B). All the patients had an LH/FSH ratio of 2 or more with macroscopic confirmation of enlarged sclerocystic ovaries. The study was not, therefore, randomised. Patients were told of the possibility of normal menstrual cycles and pregnancy arising after the procedure and the women in group B were informed about the ovarian excision procedure. We used
an
neodymium (Nd:YAG) laser with
a
flexible
fibre,
introduced through a third endoscopic puncture. Bilateral incision of the ovary was carried out for a distance of around 5 mm on the opposite of the mesovarium. In each ovary the laser incisions were done three, four, or five times to a length of 5-1 mm and a depth of 4 mm. Before the procedure clomiphene failure had been recorded in all patients, and testosterone, androstendione, and dehydroepiandrosterone were raised in most of them. All women had hirsutism and oligomenorrhoea. Spontaneous menstrual bleeding occurred 2-10 days after the procedure in all patients in group B. In group A menstruation occurred in only 2 cases, both 12 days after laparoscopy. No follicular maturation could be demonstrated in group A by daily monitoring of LH and oestradiol whereas in group B 5 patients ovulated spontaneously, and in 3 cases ovulation could be achieved
by clomiphene 2 months after the laser treatment. In these 3 cases LH and androgen levels were raised again after one cycle with an established ovulation. In the remaining 5 patients, the menstrual cycle was monitored for 2 months by endocrinological testing (LH, oestradiol), after that, basal body temperature was recorded. We now have follow-up data over about 6 months. All 5 patients now have a biphasic basal body temperature record, although none have yet become pregnant. In group A, despite the 2 cases of menstrual bleeding, ovulation could not be documented by basal body temperature measurement. These results confirm that endoscopic wedge resection is clinically relevant and does not act merely as a placebo. The incision of polycystic ovaries seems to be a new application for this kind of laser. First Department for Gynaecology and Obstetrics, University of Vienna, 1090 Vienna, Austria
J. HUBER J. HOSMANN J. SPONA
EY, Rock JA, Guzick D, Wentz AC, Jones GS, Jones HW Jr. Fertility following bilateral ovarian wedge resection: a critical analysis of 90 consecutive cases of the polycystic ovary syndrome. Fertil Steril 1981; 36: 320-25 2. Gjonnaess H. Polycystic ovarian syndrome treated by ovanan electrocautry through the laparoscope. Fertil Steril 1984; 41: 20-25. 3. Goldzieher J, Green JA. The polycystic ovary: Clinical and histologic features. J Clin 1. Adashi
Endocrinol Metab 1962; 22: 325-38. 4. Shearman RP, ed. Clinical reproductive Livingstone, 1985.
endocrinology. Edinburgh: Churchill
ASSESSING THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS SiR,—Dr Stewart and colleagues (May 28, p 1208) propose the of the short ’Synacthen’ (synthetic corticotropin) test rather than the insulin tolerance test for the assessment of hypothalamopituitary-adrenal function in patients with hypothalamo-pituitary disease but not in patients who have been treated with a glucocorticoid. I cannot agree that the insulin tolerance test should be used routinely for those who have received glucocorticoid use
therapy. Stewart and colleagues did not in fact study patients on glucocorticoid therapy. They excluded patients with Cushing’s syndrome, those taking glucocorticoids, and those within 15 days of an acute pituitary insult. Thus their recommendation is based on the work of others. However, other reports do not support this exclusion. In general, the maximum response of the plasma cortisol level to corticotropin corresponds to the maximum plasma cortisol level observed during the induction of general anaesthesia and surgery in patients who have received glucocorticoid therapy.l-4 This occurs after a rapid intravenous injection of synthetic corticotropin with measurement of the plasma cortisol level 30 min2 or 60 min1 after the injection, or after a 6 h infusion of COrtlCOtropln.3’4 Thus a normal preoperative response to corticotropin is unlikely to be followed by impaired secretion of cortisol during anaesthesia and surgery in glucocorticoid-treated patients. It is true that patients have occasionally been reported in whom the response to corticotropin is normal but the response to insulin-induced hypoglycaemia or metyrapone is abnormal. 5,6 However, these studies did not systematically compare their findings with the response to a physiological stress such as the induction of general anaesthesia and surgery. (In one instance where this was done, a patient had normal corticotropin and cortisol responses to the stress of a vasovagal attack, but failed to respond to subsequent hypoglycaemia.6) Without such information, the comparison between a corticotropin test and an insulin tolerance or metyrapone test is difficult to interpret. It is possible, for example, that the hypoglycaemic stimulus was not adequate in the insulin tolerance test since normally there is variation between subjects in the plasma cortisol response to hypoglycaemia.7 It is also possible that the insulin tolerance or metytrapone test is too sensitive, rather than that the corticotropin test is insufficiently sensitive. Thus systematic studies consistently demonstrate the value of a corticotropin test in the assessment of hypothalamo-pituitaryadrenal function in patients who have been treated with glucocorticoids. As Stewart et al argue, for patients with hypothalamo-pituitary disorders the short synthetic cortcotropin
216 is practical, reliable, and preferable to the "lengthy, uncomfortable, and potentially dangerous insulin tolerance test".
test
The short
synthetic corticotropin test should be used for the initial assessment of the hypothalamo-pituitary-adrenal axis in patients on gluccorticoid therapy. Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA 1.
LLOYD AXELROD
Jasani MK, Freeman PA, Boyle JA, Reid AM, Diver MJ, Buchanan WW. Studies of the rise in plasma 11 -hydroxycorticosteroids (11-OHCS) in corticosteroid-treated patients with rheumatoid arthritis during surgery: correlations with the functional integrity of the hypothalarnic-pituitary-adrenal axis. Quart J Med 1968; 37:
407-21. 2. Kehlet H, Binder C. Value of
3.
4. 5. 6.
7.
an ACTH test m assessing hypothalamic-pituitaryadrenocortical function in glucocorticoid-treated patients. Br Med J 1973; ii: 147-49. Marks LJ, Donovan MJ, Duncan FJ, Karger R. Adrenocortical response to surgical operations m patients treated with corticosteroids or corticotropin pnor to surgery. J Clin Endocrinol Metab 1959; 19: 1458-70. Sampson PA, Winstone NF, Brooke BN. Adrenal function in surgical patients after steroid therapy. Lancet 1962; ii: 322-25. Cunningham SK, Moore A, McKenna TJ. Normal cortisol response to corticotropin m patients with secondary adrenal failure. Arch Intern Med 1983; 143: 2276-279. Harrison BDW, Rees LH, Cayton RM, Nabarro JDN. Recovery of hypothalamopituitary-adrenal function in asthmatics whose oral steroids have been stopped or reduced. Clin Endocr 1982; 17: 109-18. Streeten DHP, Anderson GH Jr, Dalakos TG, et al. Normal and abnormal function of the hypothalamic-pituitary-adrenocortical system in man. Endocr Rev 1984; 5: 371-94.
DISSOLUTION OF CALCIFIED GALLBLADDER STONES BY TREATMENT WITH METHYL-HEXYL ETHER AND UREA-EDTA
SiR,—We have successfully treated 2 patients with calcified gallbladder stones by alternating perfusion with methylhexyl ether (MHE) and urea-EDTA (UEDTA) solutions. Both patients had a high calcium content in their stones, as identified by computed tomography (CT). The first patient was male, aged 59, and had a single stone with a diameter of 2cm. The stone was disaggregated within 72 h after the start of dissolution therapy with a percutaneously introduced pigtail catheter. The second patient, a 74-year-old woman, had recurrent biliary colic. Ultrasound showed multiple gallstones, the largest being 5 mm in diameter. These stones had not been detected by conventional intravenous cholangiography. CT showed an even distribution of calcium compounds throughout the stones. After ultrasoundguided, percutaneous transhepatic insertion of a 5 F pigtail catheter into the gallbladder, she was treated for 48 h. After the introduction of the catheter the bile was aspirated and replaced by the same volume of 75% MHE or buffered UEDTA, pH 9-5 (prepared by H. Baumgaertel and Dr Falk, GMBH, Freiburg, West Germany). MHE remained,in the gallbladder for 5 min, UEDTA for 10 min. Enzymatic determination showed that cholesterol in the ether phases varied between 200 and 1800 mg/dl. Calcium in the UEDTA portions was between 8 and 16 mg/dl in the aspirate. Treatment was continued until abdominal ultrasound demonstrated complete stone dissolution. Gallbladder stones can be treated by surgery, systemic dissolution with bile acids,’ extracorporeal shock wave,2or local litholysis with methyl tertiary butyl ether.3 Non-surgical methods are restricted to pure cholesterol stones, because only the fatty compound can be dissolved. This is the first report of successful treatment of calcium-containing pigment stones in the gallbladder by the combination of a fat solubiliser (MHE) and a calcium chelator (UEDTA). W. SWOBODNIK H. BAUMGAERTEL P. JANOWITZ Department of Gastroenterology and Nutrition, S. FUCHS University Clinic Ulm, H. DITSCHUNEIT D 7900 Ulrn, West Germany Danziger RG, Hofmann RF, Schonfield LJ. Dissolution of cholesterol gallstones by chenodeoxycholic acid. N Engl J Med 1972; 286: 1-8 2. Sackmann M, Delius M, Sauerbruch T, Hall J, et al Shock-wave lithotripsy of gallbladder stones. the first 175 patients. N Engl JMed 1988, 318: 393-97. 3. Allen MJ, Borody TJ, Bugliosi TF, May GR, La Russo NF, Thistle JL Rapid dissolution of gallstones by methyl tertiary-butyl ether N Engl J Med 1985, 312: 1.
217-20.
INTRANASAL GLUCAGON FOR HYPOGLYCAEMIA
SiR,—The secretion of glucagon is triggered when the blood glucose falls below 3-67 (SD 0’ 11) mmol/1,1 and in non-diabetics the magnitude of the glucagon response is directly related to the degree of hypoglycaemia.2 Some insulin-dependent diabetics have defective glucagon and other counterregulatory hormonal response to hypoglycaemia.3-5 The study on intranasal glucagon in hypoglycaemia by Dr Freychet and colleagues (June 18, p 1364) was not placebo controlled, so it is difficult to say how much the exogenous glucagon contributed to the restoration of euglycaemia. Comparison with glucagon levels found in studies of hypoglycaemia without exogenous glucagon is not truly valid. Glucagon is secreted by the A cells of the pancreas and reaches the liver via the portal veins before it reaches the peripheral circulation. Glucagon is mainly degraded by the liver so peripheral blood levels are low. Freychet et al did not study counterregulatory hormonal responses but refer to work by Bolli et al5 showing that after untreated insulin-induced hypoglycaemia there is a transient suppression of glucose production lasting at least an hour, despite counterregulatory hormone secretion. Glucagon too is a counterregulatory hormone and, whether exogenous or endogenous, it acts to reverse hypoglycaemia by increasing glucose production. Adrenaline, noradrenaline, and glucagon form the vanguard of the counterregulatory response, followed by cortisol and growth hormone. Sacca et al6 have reported that the initial reversal of insulin-induced hypoglycaemia is due to synergistic interaction among the counterregulatory hormones even before each individual hormone increases significantly. In this study the one patient who did not respond to intranasal glucagon had the highest serum glucagon of those in whom this hormone
measured. This diabetic may have had defective of other hormones, underlining the importance interaction among the hormones to trigger hepatic was
counterregulation of
glycogenolysis. Since glucagon stimulates insulin secretion it should not be used to treat hypoglycaemia induced by oral sulphonylureas Nor is it effective in alcohol-induced hypoglycaemia.7 Exogenous glucagon has a half life of about 10 min, making necessary immediate oral glucose or repeat doses of glucagon to prevent hypoglycaemic relapse. King’s College Hospital Medical School, Dulwich Hospital (North Wing), London SE22 8DF
J.
D. ARNOLD
SD, Cryer PE. Glycaemic thresholds for activation of glucose counter regulatory systems are higher than the thresholds for symptoms J Clin Invest 1987; 79: 777-82. Gale EAM, Bennett IA, Macdonald JJ, et al The physiological effects of insulin-induced hypoglycaemia in man: Responses at differing levels of blood glucose. Clin Sci 1983; 65: 263-71. Amiel SA, Tamborlane WV, DeFronzo RA, Sherwin RS. Intensive insulin therapy reduces counter regulatory hormonal responses to hypoglycaemia in patients with Type I diabetes. Ann Intern Med 1985; 103: 184-90. Amiel SA, Tamborlane WV, Simonson DC, Sherwin RS. Defective glucose counter regulation after strict glycaemic control of insulin dependent diabetes mellitus N Engl J Med 1987; 316: 1376-83. Bolli GB, Dimitriadis GD, Pehling GB, et al. Abnormal glucose counter regulation after subcutaneous insulin in insulin-dependent diabetes. N Engl J Med 1984, 310:
1. Schwarz NS, Clutter WE, Shah
2.
3.
4.
5.
1706-11. L, Sherwin R, Hendler R, Felig P. Influence of continuous physiologic hyperinsulinemia on glucose kinetics and counterregulatory hormones in normal and diabetic humans. J Clin Invest 1979; 63: 849-57. 7. Marks V, Rose FC Hypoglycaemia, 2nd ed. Oxford: Blackwell Scientific Publications, 1981: 475. 6. Sacca
SIR,-Dr Freychet and colleagues discuss the administration of intranasal glucagon in comparison with the traditional remedies of oral sugar for conscious hypoglycaemic patients or the injection of glucagon when consciousness is impaired. A recovery time of about 15 min is cited following the administration of oral sugar. This response time is very variable, depending upon the length and depth of the hypoglycaemia. Parents of children with diabetes are often supplied with injectable glucagon for hypoglycaemic crises but in many instances, because of a natural panic reaction, they attempt to administer oral sugar whatever the state of consciousness, and the glucagon pack remains a formidable obstacle. A 40% glucose gel in