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EXPERIMENTAL HEXADIMETHRINE NECROSIS OF ANTERIOR PITUITARY
31 October
Saturday EXPERIMENTAL HEXADIMETHRINE NECROSIS OF ANTERIOR PITUITARY K. KOVÁCS M.D.
Szeged
CROSBY RESEARCH FELLOW IN ENDOCRINE PATHOLOGY
M.D.
R. CARROLL N.U.I., M.R.C.P.I., D.C.P.
LECTURER IN PATHOLOGY
E. TAPP Lpool
M.B.
LECTURER IN PATHOLOGY
DEPARTMENT OF
PATHOLOGY,
UNIVERSITY OF LIVERPOOL
NECROSIS of the anterior pituitary can be caused by a great variety of local interventions, such as destruction of the pituitary stalk or implantation of isotopes; but there have been no convincing reports that the lesion can be produced experimentally in any other way, such as by the injection of substances into remote parts of the body. We describe here the production of massive ischsemic necrosis of the anterior lobe of the pituitary as a result of the intravenous administration of hexadimethrine bromide
(’ Polybrene ’,
Abbott),
polymeric
quaternary ammonium salt. The necrosis is confined to the anterior lobe, and there are no changes in the posterior lobe, the pars intermedia, or the stalk. a
Previous Attempts to Produce Pituitary Necrosis Some workers have claimed that they could cause anterior-pituitary necrosis in laboratory animals by subjecting them to conditions which have been held responsible for postpartum necrosis of the anterior pituitary in women.
Nassar et al. (1950) reported that 15 rats which had been bled severely did not show any pituitary necrosis, but that 21 rats which had been bled and given ergotoxine, and 21 rats which had been given ergotoxine without being bled, all had pituitary necrosis. One pituitary gland in the last group was said to have been totally destroyed. The rats were killed at various times from six hours to twenty-six days after the procedure: hence many of the lesions should have shown fully developed necrotic changes and others should have been in the healing stage. Yet the three illustrations in the paper by Nassar et al. merely show hyperchromatism of some of the nuclei, and do not provide histological proof of pituitary necrosis. This work was published as a preliminary report but no further account has appeared. The findings have not been confirmed by other workers Orcoyen and Cano (1954) injected chorionic gonadotrophin into 19 pregnant mice and 5 non-pregnant mice, and compared the pituitary glands with those of 7 control mice. They killed some of-the mice immediately and the others at intervals of a month and two months. Foci of necrosis were reported in the anterior lobe, and the incidence was proportional to the dose of chorionic gonadotrophin and particularly to the number of foetuses. The three illustrations are not convincing, and there has been no confirmation of this work. .
7366
1964
Franco (1956) studied the effect of massive bleeding in 27 pregnant rats, 12 male rats, and 9 pregnant guineapigs. Nearly all the rats were killed at one day, three days, or thirty-eight days later. Small groups of cells in the anterior lobe were reported to be necrosed in 1 pregnant rat, 1 male rat, and 1 pregnant guineapig which had been bled, and also in 2 out of 26 control male rats which had not been bled. The histological illustrations are not convincing, and the experiments cannot be accepted as proving that blood-loss gave rise to pituitary necrosis. Updike and Corey (1964) have been unable to produce any changes in the pituitaries of pregnant rats or dogs by bleeding or by artificial separation of the placenta. Neither could they produce pituitary lesions by the intravenous injection of amniotic fluid. One of us (K. K.) has made numerous attempts to produce anterior-pituitary necrosis with injection of posterior pituitary lobe (’Pituitrin’), histamine, serotonin, nicotine, noradrenaline, and ergot, using healthy animals and also animals which had been given oestrogens or progesterone. The experiments were uniformly unsuccessful. In addition, many unsuccessful attempts have been made in this department to produce pituitary necrosis by bleeding animals very severely at the time
of delivery. Toxic Effects of Hexadimethrine
Preston (1952) and Preston and Parker (1953) reported that hexadimethrine neutralised the anticoagulant effect of heparin in vivo and in vitro, and Preston et al. (1956) introduced the substance for clinical use as an antiheparin agent. Weiss et al. (1958) found that in man, among other effects, it brought on respiratory disturbances, flushing, and temporary hypotension. Egerton and Robinson (1961) showed that in dogs hexadimethrine caused transient prolongation of the clotting-time, pulmonary vasoconstriction, and systemic hypotension, as well as a granular agglutination of red blood-corpuscles in vitro. Kimura et al. (1959a and b, 1962) observed that the drug disrupted mast-cells, and mentioned that high doses produced infarcts of the liver and nephrocalcinosis occasionally in animals. Selye et al. (1963), in a detailed study of the necrosis and calcification in the intermediate zone of the kidney, recorded that hexadimethrine produced liver lesions and necrosis of the zona fasciculata and zona reticularis of the adrenal. Its action on the anterior pituitary has not been described by previous workers. Method The experiments were performed on female rats of the Wistar strain, weighing between 150 g. and 250 g. Under light ether anxsthesia, hexadimethrine bromide in 1 % aqueous solution was injected into a tail-vein in doses of 01 to 1-0 ml. (i.e., 1 to 10 mg. of the drug). The rats died or were killed at times varying from a few hours up to seven days after the injection, and the pituitary and hypothalamus were examined microscopically. In addition to the female rats, the experiments were repeated on a group of 5 male rats; the results were the same.
A
dose of 10 mg. intravenously was usually fatal few hours. A dose of 5 mg. immediately gave rise to
single
within
a
920 PITUITARY NECROSIS AFTER VARIOUS INTRAVENOUS DOSES OF
HEXADIMETHRINE
affected less than a third of the lobe; large lesions destroyed nearly all the anterior lobe (figs. 1 and 2) but always left a thin layer of surviving parenchyma under the capsule and rather bigger surviving patches in front of the interlobar groove. Repeated doses of 5 mg. produced large foci of necrosis in 4 of the animals but no lesions in the pituitary in the other 4. The explanation of this discrepancy is not yet clear.
Histological Changes with wheezing. The rats recovered from the acute effects in half an hour to an hour, but became listless and apathetic; most of them died within the next five days. Two doses of 5 mg., given with an interval of an hour, produced severe symptoms; half the animals died within three hours, and the remainder died within two days. Doses of 3 mg. or less caused no symptoms or deaths at the time of injection, and the rats were apparently well at two days; all the rats given these small doses of 3 mg. or less were killed for examination then, and therefore no opinion can be expressed as to the likelihood of late deaths. Results
respiratory difficulty
The foci of necrosis have the histological appearances and course of development characteristic of infarcts
The incidence of necrosis and its extent were related to the dose. The accompanying table shows that doses of 3 mg. or less produced no pituitary necrosis, but that this occurred in about half the rats which had received 5 mg. Fig. 3-Junction of live-margin once or twice. Many experiments were carried out in 2 days. (x 200.) which other substances were given or various operations were performed to influence the effects of hexadimethrine. About a quarter of these rats showed pituitary necrosis. The total of 37 rats with necrosis of the pituitary form the basis of the present histological report. Necrosis is classed in the table as small, medium, and large, on the basis of visual impressions only and not on accurate measurements; but the classification represents a general trend. Small lesions were usually single and
zone
and
Fig. 4-Early healing of infarct,
partial-survival
at 5
zone, at
days. ( x 80.)
(Sheehan and Davis 1958). The larger foci show the ordinary zonal structure, except that a polymorph zone is usually absent, and thus the peripheral dead zone is not
Fig. I-Sagittal section: normal posterior lobe and pars intermedia above cleft, necrotic anterior lobe below cleft; at 2 days. ( x 16.)
delineated from the central dead area. Since the anterior lobe is small, particularly in its anteroposterior diameter, the main central mass undergoes changes which are more those of a peripheral dead zone than those of a true central dead area. The partial-survival zone and live-margin zone are well defined. The moderate-size lesions consist essentially of a small patch of peripheral dead zone surrounded by a partialsurvival zone and live-margin zone. The small lesions are little more than foci of partial survival zone enclosed in
live-margin zone. Course of Development The first stage of extensive necrosis is seen at about six hours. All the sinusoids throughout the anterior lobe are distended by red blood-corpuscles, some of which have escaped into the neighbouring interstitial tissue. The parenchyma is oedematous and its cells are loosened from each other. Most of the nuclei of the parenchyma cells are apparently normal, but some are small and rather Fig. 2-Nuclei still visible in central part of necrosis but lysed in partial-survival zone, at 2 days. ( x 34.)
dark. Thrombi are not seen at this time. At twenty-four hours the necrosis is very obvious. In the central mass all the cells show pyknosis and rhexis of
921 nuclei and pallor of the cytoplasm; the red bloodcorpuscles have disappeared; a few polymorphs are present. The partial-survival zone shows karyolysis of the parenchyma cells but survival of endothelial nuclei, and Uie red blood-corpuscles stain normally. Some of the sinusoids are occluded by thrombi. Occasional polymorphs are invading across the zone. The live-margin zone shows normal parenchyma, but its sinusoids are distended by red corpuscles which, judged by the usual findings in infarction, may be taken as indicating that the blood in the sinusoids is in stasis. At two days the nuclei of the central parts of the necrosis are breaking up and beginning to disappear, sometimes leaving clumps of haematoxyphil material. The partial-survival zone has a few endothelial nuclei and invading polymorphs; the parenchymal nuclei have
disappeared, but the red corpuscles remain (fig. 3). At about four to five days the infarct begins to shrink and to be replaced by loose fibrillary tissue containing very numerous endothelial nuclei (fig. 4). These changes are still progressing at seven days; further stages have not yet been studied. The small infarcts pursue essentially the same course, but the changes occur more rapidly. The necrosis resembles very closely that in postpartum necrosis of the anterior pituitary in patients as described by Sheehan (1937) and Sheehan and Stanfield (1961). There are only minor histological differences which are peculiar to the rat, such as the formation of the clumps of haematoxyphil material. Discussion
The experimental production of ischaemic necrosis of the anterior pituitary by means of hexadimethrine is of importance in several ways. The lesion is certainly an infarction. From previous studies on experimental infarction in various organs, and from observations on pituitary necrosis in women, the pituitary necrosis in the present experiments may reasonably be attributed to a temporary occlusive vasospasm in the blood-supply to the anterior lobe. The thrombosis of occasional small sinusoids in the outer part of the infarct is adequately explained as a secondary change, due to an attempted reflow into the dead vessels here. The site of the primary arrest is presumably further back in the vascular supply; work is at present in progress to ascertain the exact site, nature, and duration of this local vascular disturbance. The necrosis is morphologically remarkably similar to that which is sometimes found in women at delivery, in diabetes mellitus, and in certain other clinical conditions. The experimental lesion may provide a clue to the general factors which initiate the local vascular disturbance in man.
One common method of producing experimental necrosis of the anterior lobe is destruction of the stalk, either by electrocautery or by operation. But this interrupts the nerve-fibres in the stalk and leads to severe atrophy of the posterior lobe, which complicates the study of anterior hypopituitarism. Moreover, experimental methods that depend on destruction of the stalk inevitably produce structural disruption of the portal blood-vessels to the anterior lobe. Though these vessels can regenerate subsequently, the transfer of release factors from the hypothalamus to the pituitary must certainly be impaired for a long time or arrested. In the present experiments the integrity of the stalk was maintained. Unfortunately, hexadimethrine produces not only
but also lesions in various other organs, and some of these other lesions can be fatal in a few days. Thus the acute functional disturbances of the pituitary cannot yet be studied satisfactorily, and there is little immediate prospect of producing chronic hypopituitarism. This problem, however, does not appear insoluble.
pituitary necrosis
Summary Intravenous administration of hexadimethrine bromide produced ischaemic necrosis of the anterior lobe of the pituitary, without lesions in the pars intermedia or in the posterior lobe. to rats
We wish to thank Prof. H. L. Sheehan for his constant encourageand advice during the work and for help in the preparation of the paper. One of us (K. K.) held a Crosby Research Fund fellowship. ment
REFERENCES
Egerton, W. S., Robinson, C. L. N. (1961) Lancet, ii, 635. Franco, A. G. (1956) D.C.M.-C. thesis, University of Bahia, Brazil. Kimura, E. T., Young, P. R., Stein, R. J., Richards, R. K. (1959a) Toxicol. appl. Pharmacol. 1, 185. Ebert, D. M. (1959b) ibid. p. 560. Barlow, G. H. (1962) Proc. Soc. exp. Biol., N.Y. 111, 37. Nassar, G., Djanian, A., Shanklin, W. (1950) Amer. J. Obstet. Gynec. 60, 140. Orcoyen, J. G., Cano, A. (1954) Rev. ibér. Endocr. 1, 753. Preston, F. W. (1952) J. Lab. clin. Med. 40, 927. Parker, R. P. (1953) Arch. Surg. 66, 545. Hohf, R., Trippel, O. (1956) Quart. Bull. Northw. Univ. med. Sch., 30, 138. Selye, H., Gabbiani, G., Tuchweber, B. (1963) Med. exp., Basle, 8, 74. Sheehan, H. L. (1937) J. Path. Bact. 45, 189. Davis, J. C. (1958) ibid. 76, 569. Stanfield, J. P. (1961) Acta endocr., Copenhagen, 37, 479. Updike, G. B., Corey, E. L. (1964) Amer. J. Obstet. Gynec. 90, 25. Weiss, W. A., Gilman, J. S., Catenacci, A. J., Osterberg, A. E. (1958) J. Amer. med. Ass. 166, 603. -
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EXPERIMENTAL HEXADIMETHRINE NECROSIS OF ZONA GLOMERULOSA AND INNER LAYERS OF ADRENAL CORTEX M.D.
R. CARROLL N.U.I., M.R.C.P.I., D.C.P.
LECTURER IN PATHOLOGY
K. KOVÁCS M.D.
Szeged
CROSBY RESEARCH FELLOW IN ENDOCRINE PATHOLOGY
E. TAPP Lpool
M.B.
LECTURER IN PATHOLOGY
DEPARTMENT OF
PATHOLOGY,
UNIVERSITY OF LIVERPOOL
To our knowledge there is no published account of a substance that can cause necrosis of the zona glomerulosa of the adrenal cortex. In studying the action of hexadimethrine bromide (’ Polybrene ’, Abbott) on the pituitary gland of the rat, we observed incidentally that there was almost always necrosis of the zona glomerulosa, and that in addition the zona fasciculata and zona reticularis became necrotic in a considerable number of rats. Selye et al. (1963), in describing the pathological effects of the drug, remarked on this necrosis of the inner zones but said that there were no lesions of the zona glomerulosa. Results
The details of the experiments and the general findings are similar to those already described (Kovacs et al. 1964). Doses of 1 to 10 mg. of hexadimethrine were injected intravenously. In 45 of the rats the hexadimethrine was administered alone, but various procedures were applied at the same time to a further 111 rats in attempts to influence the pathological changes in other organs. These latter experiments will be reported elsewhere ; some of these procedures seem to have reduced and others to have increased the severity of the damage to the adrenal.
Saturday EXPERIMENTAL HEXADIMETHRINE NECROSIS OF ANTERIOR PITUITARY K. KOVÁCS M.D.
Szeged
CROSBY RESEARCH FELLOW IN ENDOCRINE PATHOLOGY
M.D.
R. CARROLL N.U.I., M.R.C.P.I., D.C.P.
LECTURER IN PATHOLOGY
E. TAPP Lpool
M.B.
LECTURER IN PATHOLOGY
DEPARTMENT OF
PATHOLOGY,
UNIVERSITY OF LIVERPOOL
NECROSIS of the anterior pituitary can be caused by a great variety of local interventions, such as destruction of the pituitary stalk or implantation of isotopes; but there have been no convincing reports that the lesion can be produced experimentally in any other way, such as by the injection of substances into remote parts of the body. We describe here the production of massive ischsemic necrosis of the anterior lobe of the pituitary as a result of the intravenous administration of hexadimethrine bromide
(’ Polybrene ’,
Abbott),
polymeric
quaternary ammonium salt. The necrosis is confined to the anterior lobe, and there are no changes in the posterior lobe, the pars intermedia, or the stalk. a
Previous Attempts to Produce Pituitary Necrosis Some workers have claimed that they could cause anterior-pituitary necrosis in laboratory animals by subjecting them to conditions which have been held responsible for postpartum necrosis of the anterior pituitary in women.
Nassar et al. (1950) reported that 15 rats which had been bled severely did not show any pituitary necrosis, but that 21 rats which had been bled and given ergotoxine, and 21 rats which had been given ergotoxine without being bled, all had pituitary necrosis. One pituitary gland in the last group was said to have been totally destroyed. The rats were killed at various times from six hours to twenty-six days after the procedure: hence many of the lesions should have shown fully developed necrotic changes and others should have been in the healing stage. Yet the three illustrations in the paper by Nassar et al. merely show hyperchromatism of some of the nuclei, and do not provide histological proof of pituitary necrosis. This work was published as a preliminary report but no further account has appeared. The findings have not been confirmed by other workers Orcoyen and Cano (1954) injected chorionic gonadotrophin into 19 pregnant mice and 5 non-pregnant mice, and compared the pituitary glands with those of 7 control mice. They killed some of-the mice immediately and the others at intervals of a month and two months. Foci of necrosis were reported in the anterior lobe, and the incidence was proportional to the dose of chorionic gonadotrophin and particularly to the number of foetuses. The three illustrations are not convincing, and there has been no confirmation of this work. .
7366
1964
Franco (1956) studied the effect of massive bleeding in 27 pregnant rats, 12 male rats, and 9 pregnant guineapigs. Nearly all the rats were killed at one day, three days, or thirty-eight days later. Small groups of cells in the anterior lobe were reported to be necrosed in 1 pregnant rat, 1 male rat, and 1 pregnant guineapig which had been bled, and also in 2 out of 26 control male rats which had not been bled. The histological illustrations are not convincing, and the experiments cannot be accepted as proving that blood-loss gave rise to pituitary necrosis. Updike and Corey (1964) have been unable to produce any changes in the pituitaries of pregnant rats or dogs by bleeding or by artificial separation of the placenta. Neither could they produce pituitary lesions by the intravenous injection of amniotic fluid. One of us (K. K.) has made numerous attempts to produce anterior-pituitary necrosis with injection of posterior pituitary lobe (’Pituitrin’), histamine, serotonin, nicotine, noradrenaline, and ergot, using healthy animals and also animals which had been given oestrogens or progesterone. The experiments were uniformly unsuccessful. In addition, many unsuccessful attempts have been made in this department to produce pituitary necrosis by bleeding animals very severely at the time
of delivery. Toxic Effects of Hexadimethrine
Preston (1952) and Preston and Parker (1953) reported that hexadimethrine neutralised the anticoagulant effect of heparin in vivo and in vitro, and Preston et al. (1956) introduced the substance for clinical use as an antiheparin agent. Weiss et al. (1958) found that in man, among other effects, it brought on respiratory disturbances, flushing, and temporary hypotension. Egerton and Robinson (1961) showed that in dogs hexadimethrine caused transient prolongation of the clotting-time, pulmonary vasoconstriction, and systemic hypotension, as well as a granular agglutination of red blood-corpuscles in vitro. Kimura et al. (1959a and b, 1962) observed that the drug disrupted mast-cells, and mentioned that high doses produced infarcts of the liver and nephrocalcinosis occasionally in animals. Selye et al. (1963), in a detailed study of the necrosis and calcification in the intermediate zone of the kidney, recorded that hexadimethrine produced liver lesions and necrosis of the zona fasciculata and zona reticularis of the adrenal. Its action on the anterior pituitary has not been described by previous workers. Method The experiments were performed on female rats of the Wistar strain, weighing between 150 g. and 250 g. Under light ether anxsthesia, hexadimethrine bromide in 1 % aqueous solution was injected into a tail-vein in doses of 01 to 1-0 ml. (i.e., 1 to 10 mg. of the drug). The rats died or were killed at times varying from a few hours up to seven days after the injection, and the pituitary and hypothalamus were examined microscopically. In addition to the female rats, the experiments were repeated on a group of 5 male rats; the results were the same.
A
dose of 10 mg. intravenously was usually fatal few hours. A dose of 5 mg. immediately gave rise to
single
within
a
920 PITUITARY NECROSIS AFTER VARIOUS INTRAVENOUS DOSES OF
HEXADIMETHRINE
affected less than a third of the lobe; large lesions destroyed nearly all the anterior lobe (figs. 1 and 2) but always left a thin layer of surviving parenchyma under the capsule and rather bigger surviving patches in front of the interlobar groove. Repeated doses of 5 mg. produced large foci of necrosis in 4 of the animals but no lesions in the pituitary in the other 4. The explanation of this discrepancy is not yet clear.
Histological Changes with wheezing. The rats recovered from the acute effects in half an hour to an hour, but became listless and apathetic; most of them died within the next five days. Two doses of 5 mg., given with an interval of an hour, produced severe symptoms; half the animals died within three hours, and the remainder died within two days. Doses of 3 mg. or less caused no symptoms or deaths at the time of injection, and the rats were apparently well at two days; all the rats given these small doses of 3 mg. or less were killed for examination then, and therefore no opinion can be expressed as to the likelihood of late deaths. Results
respiratory difficulty
The foci of necrosis have the histological appearances and course of development characteristic of infarcts
The incidence of necrosis and its extent were related to the dose. The accompanying table shows that doses of 3 mg. or less produced no pituitary necrosis, but that this occurred in about half the rats which had received 5 mg. Fig. 3-Junction of live-margin once or twice. Many experiments were carried out in 2 days. (x 200.) which other substances were given or various operations were performed to influence the effects of hexadimethrine. About a quarter of these rats showed pituitary necrosis. The total of 37 rats with necrosis of the pituitary form the basis of the present histological report. Necrosis is classed in the table as small, medium, and large, on the basis of visual impressions only and not on accurate measurements; but the classification represents a general trend. Small lesions were usually single and
zone
and
Fig. 4-Early healing of infarct,
partial-survival
at 5
zone, at
days. ( x 80.)
(Sheehan and Davis 1958). The larger foci show the ordinary zonal structure, except that a polymorph zone is usually absent, and thus the peripheral dead zone is not
Fig. I-Sagittal section: normal posterior lobe and pars intermedia above cleft, necrotic anterior lobe below cleft; at 2 days. ( x 16.)
delineated from the central dead area. Since the anterior lobe is small, particularly in its anteroposterior diameter, the main central mass undergoes changes which are more those of a peripheral dead zone than those of a true central dead area. The partial-survival zone and live-margin zone are well defined. The moderate-size lesions consist essentially of a small patch of peripheral dead zone surrounded by a partialsurvival zone and live-margin zone. The small lesions are little more than foci of partial survival zone enclosed in
live-margin zone. Course of Development The first stage of extensive necrosis is seen at about six hours. All the sinusoids throughout the anterior lobe are distended by red blood-corpuscles, some of which have escaped into the neighbouring interstitial tissue. The parenchyma is oedematous and its cells are loosened from each other. Most of the nuclei of the parenchyma cells are apparently normal, but some are small and rather Fig. 2-Nuclei still visible in central part of necrosis but lysed in partial-survival zone, at 2 days. ( x 34.)
dark. Thrombi are not seen at this time. At twenty-four hours the necrosis is very obvious. In the central mass all the cells show pyknosis and rhexis of
921 nuclei and pallor of the cytoplasm; the red bloodcorpuscles have disappeared; a few polymorphs are present. The partial-survival zone shows karyolysis of the parenchyma cells but survival of endothelial nuclei, and Uie red blood-corpuscles stain normally. Some of the sinusoids are occluded by thrombi. Occasional polymorphs are invading across the zone. The live-margin zone shows normal parenchyma, but its sinusoids are distended by red corpuscles which, judged by the usual findings in infarction, may be taken as indicating that the blood in the sinusoids is in stasis. At two days the nuclei of the central parts of the necrosis are breaking up and beginning to disappear, sometimes leaving clumps of haematoxyphil material. The partial-survival zone has a few endothelial nuclei and invading polymorphs; the parenchymal nuclei have
disappeared, but the red corpuscles remain (fig. 3). At about four to five days the infarct begins to shrink and to be replaced by loose fibrillary tissue containing very numerous endothelial nuclei (fig. 4). These changes are still progressing at seven days; further stages have not yet been studied. The small infarcts pursue essentially the same course, but the changes occur more rapidly. The necrosis resembles very closely that in postpartum necrosis of the anterior pituitary in patients as described by Sheehan (1937) and Sheehan and Stanfield (1961). There are only minor histological differences which are peculiar to the rat, such as the formation of the clumps of haematoxyphil material. Discussion
The experimental production of ischaemic necrosis of the anterior pituitary by means of hexadimethrine is of importance in several ways. The lesion is certainly an infarction. From previous studies on experimental infarction in various organs, and from observations on pituitary necrosis in women, the pituitary necrosis in the present experiments may reasonably be attributed to a temporary occlusive vasospasm in the blood-supply to the anterior lobe. The thrombosis of occasional small sinusoids in the outer part of the infarct is adequately explained as a secondary change, due to an attempted reflow into the dead vessels here. The site of the primary arrest is presumably further back in the vascular supply; work is at present in progress to ascertain the exact site, nature, and duration of this local vascular disturbance. The necrosis is morphologically remarkably similar to that which is sometimes found in women at delivery, in diabetes mellitus, and in certain other clinical conditions. The experimental lesion may provide a clue to the general factors which initiate the local vascular disturbance in man.
One common method of producing experimental necrosis of the anterior lobe is destruction of the stalk, either by electrocautery or by operation. But this interrupts the nerve-fibres in the stalk and leads to severe atrophy of the posterior lobe, which complicates the study of anterior hypopituitarism. Moreover, experimental methods that depend on destruction of the stalk inevitably produce structural disruption of the portal blood-vessels to the anterior lobe. Though these vessels can regenerate subsequently, the transfer of release factors from the hypothalamus to the pituitary must certainly be impaired for a long time or arrested. In the present experiments the integrity of the stalk was maintained. Unfortunately, hexadimethrine produces not only
but also lesions in various other organs, and some of these other lesions can be fatal in a few days. Thus the acute functional disturbances of the pituitary cannot yet be studied satisfactorily, and there is little immediate prospect of producing chronic hypopituitarism. This problem, however, does not appear insoluble.
pituitary necrosis
Summary Intravenous administration of hexadimethrine bromide produced ischaemic necrosis of the anterior lobe of the pituitary, without lesions in the pars intermedia or in the posterior lobe. to rats
We wish to thank Prof. H. L. Sheehan for his constant encourageand advice during the work and for help in the preparation of the paper. One of us (K. K.) held a Crosby Research Fund fellowship. ment
REFERENCES
Egerton, W. S., Robinson, C. L. N. (1961) Lancet, ii, 635. Franco, A. G. (1956) D.C.M.-C. thesis, University of Bahia, Brazil. Kimura, E. T., Young, P. R., Stein, R. J., Richards, R. K. (1959a) Toxicol. appl. Pharmacol. 1, 185. Ebert, D. M. (1959b) ibid. p. 560. Barlow, G. H. (1962) Proc. Soc. exp. Biol., N.Y. 111, 37. Nassar, G., Djanian, A., Shanklin, W. (1950) Amer. J. Obstet. Gynec. 60, 140. Orcoyen, J. G., Cano, A. (1954) Rev. ibér. Endocr. 1, 753. Preston, F. W. (1952) J. Lab. clin. Med. 40, 927. Parker, R. P. (1953) Arch. Surg. 66, 545. Hohf, R., Trippel, O. (1956) Quart. Bull. Northw. Univ. med. Sch., 30, 138. Selye, H., Gabbiani, G., Tuchweber, B. (1963) Med. exp., Basle, 8, 74. Sheehan, H. L. (1937) J. Path. Bact. 45, 189. Davis, J. C. (1958) ibid. 76, 569. Stanfield, J. P. (1961) Acta endocr., Copenhagen, 37, 479. Updike, G. B., Corey, E. L. (1964) Amer. J. Obstet. Gynec. 90, 25. Weiss, W. A., Gilman, J. S., Catenacci, A. J., Osterberg, A. E. (1958) J. Amer. med. Ass. 166, 603. -
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EXPERIMENTAL HEXADIMETHRINE NECROSIS OF ZONA GLOMERULOSA AND INNER LAYERS OF ADRENAL CORTEX M.D.
R. CARROLL N.U.I., M.R.C.P.I., D.C.P.
LECTURER IN PATHOLOGY
K. KOVÁCS M.D.
Szeged
CROSBY RESEARCH FELLOW IN ENDOCRINE PATHOLOGY
E. TAPP Lpool
M.B.
LECTURER IN PATHOLOGY
DEPARTMENT OF
PATHOLOGY,
UNIVERSITY OF LIVERPOOL
To our knowledge there is no published account of a substance that can cause necrosis of the zona glomerulosa of the adrenal cortex. In studying the action of hexadimethrine bromide (’ Polybrene ’, Abbott) on the pituitary gland of the rat, we observed incidentally that there was almost always necrosis of the zona glomerulosa, and that in addition the zona fasciculata and zona reticularis became necrotic in a considerable number of rats. Selye et al. (1963), in describing the pathological effects of the drug, remarked on this necrosis of the inner zones but said that there were no lesions of the zona glomerulosa. Results
The details of the experiments and the general findings are similar to those already described (Kovacs et al. 1964). Doses of 1 to 10 mg. of hexadimethrine were injected intravenously. In 45 of the rats the hexadimethrine was administered alone, but various procedures were applied at the same time to a further 111 rats in attempts to influence the pathological changes in other organs. These latter experiments will be reported elsewhere ; some of these procedures seem to have reduced and others to have increased the severity of the damage to the adrenal.