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TUMOUR OF THE PITUITARY INDUCED WITH FOLLICULAR HORMONE
776 two adenomata were observed in the anterior lobe of the same rat (Fig. III., and Fig. IV. on Plate). All showed multiple mammary milk cysts (Fig. VII.);
the litter cages ; the colony consists of some 6000 animals, and breeding is conducted without segregation of families ; it is therefore improbable that all those which developed pituitary tumours, for instance, were of one litter or otherwise closely related. It is therefore unlikely that hereditary factors could have played an important part in producing the changes described. The incidence of
FIG. IIL-blacroscopic picture of a large pituitary tumour in an cestrin-treated rat.
while an
other
breast
changes
observed
included
adenofibroma, whose scirrhous tissue invaded the
spaces between the fibres of the
pectoral muscle VIII. on Plate). The adrenals were enlarged in five cases, and in one of these a cystic adenoma of the cortex was found on the left side (Fig. IX.); in the rat which received cestrin treatment up to the day when it was killed, however, cortical atrophy, haemorrhages, and cysts were evident. Five male rats, two of which were castrated during the experiment, received similar daily injections of cestrone for periods up to 344 days. As in a previous experiment,2 the testes, penis, seminal vesicles, and prostate showed marked atrophy, but metaplasia and keratinisation were not observed. The pituitaries were enlarged in all cases, and in two (one normal, (Fig.
FIG. IX.-Cystic adenoma in the adrenal cortex of treated rat.
spontaneous colony.
tumours
of
an
oestrin-
any kind is very low in this
This work was made possible by the generous support of Sir Charles Lindsay of Montreal. We are also indebted to Dr. A. Girard of Paris for supplying the cestrone ; to Miss J. E. Williamson for technical assistance; and to Dr. J. S. L. Browne for preparing the progesterone, REFERENCES
Selye, H., Thomson, D. L., and Collip, J. B. : Nature, 1933, cxxxv., 65. 2. McEuen, C. S. : Amer. Jour. Cancer (in press). 3. Cramer, W., and Horning, E. S.: THE LANCET, Feb. 1st, 1936, p. 247. 4. Selye, H., Collip, J. B., and Thomson, D. L.: Proc. Soc. Exp. Biol. and Med., 1935, xxxii., 1377. 1.
TUMOUR OF THE PITUITARY INDUCED WITH FOLLICULAR HORMONE BY Prof. BERNHARD ZONDEK
(From the Gynœcological and Obstetrical Department of the Rothschild-Hadassah Hospital, Jerusalem)
FIG. VII.-Milk
cysts
in the mammary gland of treated rat.
an
oestrin-
castrate) cavernous adenomata were discovered in the anterior lobe. The animals selected for these experiments were taken at random from stock cages containing 20-50 rats each, which in turn are filled haphazard from one
As I reported a short while ago in THE LANCET,1 the function of the anterior pituitary gland may be inhibited by administering large doses of cestrin over a long period of time. Both the growth hormone of the anterior lobe and the gonadotropic hormones are put out of action by the follicular hormone, so that experimental animals (rats) show inhibition of growth and atrophy of the gonads. In this way dwarfed animals with atrophic genitals are produced. I intended to describe in later reports the effect on other endocrine glands and on the anterior lobe of the pituitary itself. Meanwhile an article by W. Cramer and E. S. Horning2 appeared four weeks
777
after my paper. The authors investigated the carcinogenic effect of cestrin by painting the skin of mice twice weekly with a 0-01 per cent. oestrin solution (a-folliculin) in chloroform. They studied the pituitary in twelve mice, which were treated over a prolonged period. Only one gland was normal to the naked eye; eight were macroscopically enlarged without an alteration in the general shape and without- gross pathological lesions in the gland; and three were definite adenomatous tumours-nodular, round, deeply congested, and haemorrhagic. In one case
the tumour extended
over
the
optic
nerves
and
compressed them, producing degenerative changes; the authors described the tumour
as a
haemorrhagic
adenoma of the anterior lobe. They believe that they have experimentally produced the syndrome of a disease known in man as Simmonds’s disease (cachexia hypophysipriva).
chromophobe
EFFECT OF (ESTBIN ON THE PITUITARY
In the following I wish to report, as I mentioned in my last paper, my findings in the pituitary of animals whose growth was inhibited by the administration of follicular hormone. TABLE I
Weight of
the
Pituitary and Body-weight in (a)
(b)
Nlale Rats
CONTROL ANIMALS
are macroscopically unaltered. Table I. shows that while the weight of the pituitaries in male controls varies from 7-0 to 13.6 mg., with an average of 9-7 mg., those of male rats after folliculin treatment lasting from 14-19 weeks weigh from 9-0 to 41-6 mg., with an average of 26 mg. Comparing each animal with its individual control (Table I.) there was in every case an enlargement of the pituitary, the increase in its weight varying from 29 to 395 per cent. The body-weight therefore decreases by an average of about 30 per cent., the pituitary enlarges by an average of 170 per cent. The results in female rats are quite different, though they also display stunting of the body growth. After treatment for 15 weeks-5000 M.U. (mouse units) of folliculin twice weekly-the body-weight of the treated animal is 33 per cent. less than that of the controls. However, there are no marked the pituitary. differences in the weight of The pituitaries of the controls weigh 10-9 mg. on an average, the pituitaries of the treated animals 12 mg. The period of treatment lasted in male and female animals 16 weeks on an average. These experiments show that the functional inhibition of the anterior lobe of the pituitary-i.e., the production of stunted growth and atrophic genitals-appears equally in male and female animals, but that the reaction of the pituitary itself differs in the two sexes. The growth of the anterior lobe itself
EXPERIMENTAL ANIMALS
Brain of control rat (R 233), showing normal pituitary. Right: (R. 228). Tumour of the pituitary, after receiving 280,000 M.U. dimenformon.
Left:
Whereas the gonads (ovaries and testes) of the animals undergo complete atrophy, the pituitary is enlarged. It is interesting to note, however, that an increase in the weight of the pituitary-i.e., of the anterior lobe-was not found in all animals. There is also a characteristic difference between the sexes. After prolonged treatment with follicular hormone,the pituitary of male rats shows enlargement in all cases, while the pituitaries of the females * I am indebted to the Organon (Oss) for kindly supplying large amounts of Folliculin Menformon and Dimenformon.
cannot be held responsible for the defect in pituitary function because the growth hormone and the gonadotropic hormones are also diminished in females whose pituitaries are not enlarged. It is not the enlargement of the pituitary and the formation of a tumour which causes the syndrome of hypopituitarismas is claimed by Cramer and Horning-because, if it did, the hormone would not inhibit the function of the pituitary in female animals. Why the male pituitary reacts by enlargement while the female pituitary does not do so cannot be explained. It may be mentioned that Collip3 and Evanswere able to produce considerable enlargement of the anterior lobe of the pituitary in female animals, but not in males, by prolonged treatment
778
respectively with prolan from pregnancy urine and with gonadotropic hormone from the blood of a pregnant mare. Here, too, the pituitaries of rats react differently, according to their sex, but in a reverse way from my experiments. Enlargement of the anterior lobe in the female is caused by giving gonadotropic hormone, whereas in the male animal it is the follicular hormone that produces enlargement. EXPERIMENTAL PITUITARY TUMOUR IN A FEMALE RAT
Only in one experiment have I observed a considerable reaction of the anterior lobe of the pituitary in a female animal (R 228). Treatment commenced at an age of four weeks and at a weight of 35 g. The rat was given 5000 M.U. twice M.U. of folliculin in all. In the 28th 280,000 weekly, TABLE II The Action
of
(Estrin
on
the Pituitary in Female Rabbits
follicular hormone over a prolonged period. Immature female rabbits received 10,000-50,000 M.U. folliculin menformon or dimenformon, usually twice weekly. Table II. shows an average weight for the pituitaries of the treated animals of 16-9 mg.; the same average weight was found in the control animals. After a
longer showed similar
(12 weeks, K 268) the pituitary slight enlargement (24 mg.); pituitaries of weight, however, are also to be found
treatment
in control animals. As we see, there is no marked influence on the size of the pituitary of the female rabbit after a prolonged treatment with follicular hormone. Whether or not this is also the case in the male animal is now being investigated.
occasionally
SUMMARY
1. Administration of follicular hormone over a inhibits the anterior lobe of the pituitary so that the growth hormone and the gonadotropic hormone are not active. Dwarfed animals with hypoplastic genitals result. 2. The dysfunctioning pituitaries of such rats are enlarged and their weight may amount to four times the normal. This increase occurs in male rats only. 3. However, a very large tumour of the pituitary, produced in a female rat, was 20 times the normal size of the gland. This tumour produced signs of pressure on the brain and optic nerve. 4. The pituitaries of female rabbits do not enlarge after prolonged periods of folliculin administration. Whether or not this is the case in male animals is
long period
now
being
studied. REFERENCES
1. Zondek, B. : THE LANCET, Jan. 4th, 1936, p. 10. 2. Cramer, W., and Horning, E. S. : Ibid., Feb. 1st, 1936,
week of treatment certain reactions pointing to cerebral disturbances were found in the animal. The rat turned and rolled only towards the right, ptosis of the right eye was present, the head was turned to the right, and the equilibrium of the animal was disturbed. It was therefore killed. On removal of the brain a very large tumour with a smooth surface was found in place of the pituitary (see Figure). It had a yellowish-green and in places dark red colour, and was the size and shape of a bean ; the anterior and posterior lobe could not be identified as such. The optic nerves were invisible, being completely covered by the tumour, and the chiasma could only just be seen. The tumour weighed 250 mg., while the pituitary of the control animal was only 12 mg., an increase of over twenty times. On dissection the tumour was found to be very soft and crumbly ; it was not possible to separate it completely from the nervi optici, because the tumour tissue had almost united with the nerves. I cannot yet make an exact statement regarding its histology, but I have sent it for examination to Prof. Erdheim of Vienna, who has an expert knowledge of the anatomy of the pituitary. I have myself examined a small piece of the tumour and I was impressed by multiple areas of
hsemorrhage. It is
to state why in this case the of a female animal reacted by forming a tumour, while the growth of female pituitaries generally remained uninfluenced by the cestrogenic hormones. The treatment however of the animal in which the tumour was found was continued ten weeks longer than in other female animals, and it is possible that the duration of the treatment is an essential factor.
impossible
pituitary
REACTION OF THE PITUITARY IN RABBITS
After I had found that the pituitaries of rats vary in their reaction according to sex, I examined the reactions of other rodents to the application of
p. 247. Collip, J. B., Selye, H., Thompson, D. L., and Williamson, J. E. : Proc. Soc. Exp. Biol. and Med., 1933, xxx., 590; Virchows Arch. f. path. Anat., 1933, xxiii., 290. 4. Evans, H. M., Simpson, M. E., and Williams, M. M.: Univ. California Publ. Anat., 1934, i., 161. 3.
Clinical and Laboratory Notes NINETEEN MONTHS’ HUNGER-STRIKE BY H. BASIL
ROSAIR, L.R.C.S. Irel., D.T.M.
MAJOR, I.M.D. ; SUPERINTENDENT AND MEDICAL OFFICER, CENTRAL PRISON, BAREILLY, UNITED PROVINCES, INDIA
Convict Munshi Khan resorted to hunger-strike on His weight was then approxi-
May 18th, 1934. mately 130lb.
Regular forcible feeding was begun on July 2nd, but before that date he had been forcibly fed on eight or ten occasions. On July 2nd his weight was 95 lb. and there were definite signs of weakness and exhaustion; from that time until Oct. 15th it ranged between 91 and 96 lb. By December it had dropped to 85-the lowest recorded during his nineteen months’ hunger-strike. Between December, 1934, and January, 1936, his weight varied between 85 and 105 lb., the increase or decrease being mainly dependent on the quality and quantity of liquid food given. Hunger pangs were confined to the first seven days of the fast. Nausea was an unpleasant symptom from time to time, but usually it was easy to check with a little bicarbonate of soda in barley water. The mind was always very active-if anything more alert than normal. Forcible feeding through the nose by means of a soft rubber tube was the only form of feeding resorted to. I was fortunate in that the prisoner after the first ten days or so of forcible feeding offered little or no obstruc-
the litter cages ; the colony consists of some 6000 animals, and breeding is conducted without segregation of families ; it is therefore improbable that all those which developed pituitary tumours, for instance, were of one litter or otherwise closely related. It is therefore unlikely that hereditary factors could have played an important part in producing the changes described. The incidence of
FIG. IIL-blacroscopic picture of a large pituitary tumour in an cestrin-treated rat.
while an
other
breast
changes
observed
included
adenofibroma, whose scirrhous tissue invaded the
spaces between the fibres of the
pectoral muscle VIII. on Plate). The adrenals were enlarged in five cases, and in one of these a cystic adenoma of the cortex was found on the left side (Fig. IX.); in the rat which received cestrin treatment up to the day when it was killed, however, cortical atrophy, haemorrhages, and cysts were evident. Five male rats, two of which were castrated during the experiment, received similar daily injections of cestrone for periods up to 344 days. As in a previous experiment,2 the testes, penis, seminal vesicles, and prostate showed marked atrophy, but metaplasia and keratinisation were not observed. The pituitaries were enlarged in all cases, and in two (one normal, (Fig.
FIG. IX.-Cystic adenoma in the adrenal cortex of treated rat.
spontaneous colony.
tumours
of
an
oestrin-
any kind is very low in this
This work was made possible by the generous support of Sir Charles Lindsay of Montreal. We are also indebted to Dr. A. Girard of Paris for supplying the cestrone ; to Miss J. E. Williamson for technical assistance; and to Dr. J. S. L. Browne for preparing the progesterone, REFERENCES
Selye, H., Thomson, D. L., and Collip, J. B. : Nature, 1933, cxxxv., 65. 2. McEuen, C. S. : Amer. Jour. Cancer (in press). 3. Cramer, W., and Horning, E. S.: THE LANCET, Feb. 1st, 1936, p. 247. 4. Selye, H., Collip, J. B., and Thomson, D. L.: Proc. Soc. Exp. Biol. and Med., 1935, xxxii., 1377. 1.
TUMOUR OF THE PITUITARY INDUCED WITH FOLLICULAR HORMONE BY Prof. BERNHARD ZONDEK
(From the Gynœcological and Obstetrical Department of the Rothschild-Hadassah Hospital, Jerusalem)
FIG. VII.-Milk
cysts
in the mammary gland of treated rat.
an
oestrin-
castrate) cavernous adenomata were discovered in the anterior lobe. The animals selected for these experiments were taken at random from stock cages containing 20-50 rats each, which in turn are filled haphazard from one
As I reported a short while ago in THE LANCET,1 the function of the anterior pituitary gland may be inhibited by administering large doses of cestrin over a long period of time. Both the growth hormone of the anterior lobe and the gonadotropic hormones are put out of action by the follicular hormone, so that experimental animals (rats) show inhibition of growth and atrophy of the gonads. In this way dwarfed animals with atrophic genitals are produced. I intended to describe in later reports the effect on other endocrine glands and on the anterior lobe of the pituitary itself. Meanwhile an article by W. Cramer and E. S. Horning2 appeared four weeks
777
after my paper. The authors investigated the carcinogenic effect of cestrin by painting the skin of mice twice weekly with a 0-01 per cent. oestrin solution (a-folliculin) in chloroform. They studied the pituitary in twelve mice, which were treated over a prolonged period. Only one gland was normal to the naked eye; eight were macroscopically enlarged without an alteration in the general shape and without- gross pathological lesions in the gland; and three were definite adenomatous tumours-nodular, round, deeply congested, and haemorrhagic. In one case
the tumour extended
over
the
optic
nerves
and
compressed them, producing degenerative changes; the authors described the tumour
as a
haemorrhagic
adenoma of the anterior lobe. They believe that they have experimentally produced the syndrome of a disease known in man as Simmonds’s disease (cachexia hypophysipriva).
chromophobe
EFFECT OF (ESTBIN ON THE PITUITARY
In the following I wish to report, as I mentioned in my last paper, my findings in the pituitary of animals whose growth was inhibited by the administration of follicular hormone. TABLE I
Weight of
the
Pituitary and Body-weight in (a)
(b)
Nlale Rats
CONTROL ANIMALS
are macroscopically unaltered. Table I. shows that while the weight of the pituitaries in male controls varies from 7-0 to 13.6 mg., with an average of 9-7 mg., those of male rats after folliculin treatment lasting from 14-19 weeks weigh from 9-0 to 41-6 mg., with an average of 26 mg. Comparing each animal with its individual control (Table I.) there was in every case an enlargement of the pituitary, the increase in its weight varying from 29 to 395 per cent. The body-weight therefore decreases by an average of about 30 per cent., the pituitary enlarges by an average of 170 per cent. The results in female rats are quite different, though they also display stunting of the body growth. After treatment for 15 weeks-5000 M.U. (mouse units) of folliculin twice weekly-the body-weight of the treated animal is 33 per cent. less than that of the controls. However, there are no marked the pituitary. differences in the weight of The pituitaries of the controls weigh 10-9 mg. on an average, the pituitaries of the treated animals 12 mg. The period of treatment lasted in male and female animals 16 weeks on an average. These experiments show that the functional inhibition of the anterior lobe of the pituitary-i.e., the production of stunted growth and atrophic genitals-appears equally in male and female animals, but that the reaction of the pituitary itself differs in the two sexes. The growth of the anterior lobe itself
EXPERIMENTAL ANIMALS
Brain of control rat (R 233), showing normal pituitary. Right: (R. 228). Tumour of the pituitary, after receiving 280,000 M.U. dimenformon.
Left:
Whereas the gonads (ovaries and testes) of the animals undergo complete atrophy, the pituitary is enlarged. It is interesting to note, however, that an increase in the weight of the pituitary-i.e., of the anterior lobe-was not found in all animals. There is also a characteristic difference between the sexes. After prolonged treatment with follicular hormone,the pituitary of male rats shows enlargement in all cases, while the pituitaries of the females * I am indebted to the Organon (Oss) for kindly supplying large amounts of Folliculin Menformon and Dimenformon.
cannot be held responsible for the defect in pituitary function because the growth hormone and the gonadotropic hormones are also diminished in females whose pituitaries are not enlarged. It is not the enlargement of the pituitary and the formation of a tumour which causes the syndrome of hypopituitarismas is claimed by Cramer and Horning-because, if it did, the hormone would not inhibit the function of the pituitary in female animals. Why the male pituitary reacts by enlargement while the female pituitary does not do so cannot be explained. It may be mentioned that Collip3 and Evanswere able to produce considerable enlargement of the anterior lobe of the pituitary in female animals, but not in males, by prolonged treatment
778
respectively with prolan from pregnancy urine and with gonadotropic hormone from the blood of a pregnant mare. Here, too, the pituitaries of rats react differently, according to their sex, but in a reverse way from my experiments. Enlargement of the anterior lobe in the female is caused by giving gonadotropic hormone, whereas in the male animal it is the follicular hormone that produces enlargement. EXPERIMENTAL PITUITARY TUMOUR IN A FEMALE RAT
Only in one experiment have I observed a considerable reaction of the anterior lobe of the pituitary in a female animal (R 228). Treatment commenced at an age of four weeks and at a weight of 35 g. The rat was given 5000 M.U. twice M.U. of folliculin in all. In the 28th 280,000 weekly, TABLE II The Action
of
(Estrin
on
the Pituitary in Female Rabbits
follicular hormone over a prolonged period. Immature female rabbits received 10,000-50,000 M.U. folliculin menformon or dimenformon, usually twice weekly. Table II. shows an average weight for the pituitaries of the treated animals of 16-9 mg.; the same average weight was found in the control animals. After a
longer showed similar
(12 weeks, K 268) the pituitary slight enlargement (24 mg.); pituitaries of weight, however, are also to be found
treatment
in control animals. As we see, there is no marked influence on the size of the pituitary of the female rabbit after a prolonged treatment with follicular hormone. Whether or not this is also the case in the male animal is now being investigated.
occasionally
SUMMARY
1. Administration of follicular hormone over a inhibits the anterior lobe of the pituitary so that the growth hormone and the gonadotropic hormone are not active. Dwarfed animals with hypoplastic genitals result. 2. The dysfunctioning pituitaries of such rats are enlarged and their weight may amount to four times the normal. This increase occurs in male rats only. 3. However, a very large tumour of the pituitary, produced in a female rat, was 20 times the normal size of the gland. This tumour produced signs of pressure on the brain and optic nerve. 4. The pituitaries of female rabbits do not enlarge after prolonged periods of folliculin administration. Whether or not this is the case in male animals is
long period
now
being
studied. REFERENCES
1. Zondek, B. : THE LANCET, Jan. 4th, 1936, p. 10. 2. Cramer, W., and Horning, E. S. : Ibid., Feb. 1st, 1936,
week of treatment certain reactions pointing to cerebral disturbances were found in the animal. The rat turned and rolled only towards the right, ptosis of the right eye was present, the head was turned to the right, and the equilibrium of the animal was disturbed. It was therefore killed. On removal of the brain a very large tumour with a smooth surface was found in place of the pituitary (see Figure). It had a yellowish-green and in places dark red colour, and was the size and shape of a bean ; the anterior and posterior lobe could not be identified as such. The optic nerves were invisible, being completely covered by the tumour, and the chiasma could only just be seen. The tumour weighed 250 mg., while the pituitary of the control animal was only 12 mg., an increase of over twenty times. On dissection the tumour was found to be very soft and crumbly ; it was not possible to separate it completely from the nervi optici, because the tumour tissue had almost united with the nerves. I cannot yet make an exact statement regarding its histology, but I have sent it for examination to Prof. Erdheim of Vienna, who has an expert knowledge of the anatomy of the pituitary. I have myself examined a small piece of the tumour and I was impressed by multiple areas of
hsemorrhage. It is
to state why in this case the of a female animal reacted by forming a tumour, while the growth of female pituitaries generally remained uninfluenced by the cestrogenic hormones. The treatment however of the animal in which the tumour was found was continued ten weeks longer than in other female animals, and it is possible that the duration of the treatment is an essential factor.
impossible
pituitary
REACTION OF THE PITUITARY IN RABBITS
After I had found that the pituitaries of rats vary in their reaction according to sex, I examined the reactions of other rodents to the application of
p. 247. Collip, J. B., Selye, H., Thompson, D. L., and Williamson, J. E. : Proc. Soc. Exp. Biol. and Med., 1933, xxx., 590; Virchows Arch. f. path. Anat., 1933, xxiii., 290. 4. Evans, H. M., Simpson, M. E., and Williams, M. M.: Univ. California Publ. Anat., 1934, i., 161. 3.
Clinical and Laboratory Notes NINETEEN MONTHS’ HUNGER-STRIKE BY H. BASIL
ROSAIR, L.R.C.S. Irel., D.T.M.
MAJOR, I.M.D. ; SUPERINTENDENT AND MEDICAL OFFICER, CENTRAL PRISON, BAREILLY, UNITED PROVINCES, INDIA
Convict Munshi Khan resorted to hunger-strike on His weight was then approxi-
May 18th, 1934. mately 130lb.
Regular forcible feeding was begun on July 2nd, but before that date he had been forcibly fed on eight or ten occasions. On July 2nd his weight was 95 lb. and there were definite signs of weakness and exhaustion; from that time until Oct. 15th it ranged between 91 and 96 lb. By December it had dropped to 85-the lowest recorded during his nineteen months’ hunger-strike. Between December, 1934, and January, 1936, his weight varied between 85 and 105 lb., the increase or decrease being mainly dependent on the quality and quantity of liquid food given. Hunger pangs were confined to the first seven days of the fast. Nausea was an unpleasant symptom from time to time, but usually it was easy to check with a little bicarbonate of soda in barley water. The mind was always very active-if anything more alert than normal. Forcible feeding through the nose by means of a soft rubber tube was the only form of feeding resorted to. I was fortunate in that the prisoner after the first ten days or so of forcible feeding offered little or no obstruc-