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THE DEMONSTRATION OF HORMONES IN TUMORS*

DFAN LEWIS, M.D., AND CHARLES F. GESCHICKTER, M.D.


BALTIMORE, MD.
FRO.M TIIE SURGICkL PATHOLOGICAL LABORATORY, DEPARTMENT OF SURGERY,
THlE JOHNS HOPKINS HOSPITAL AND UTNIVERSITY

THE isolation of the pituitary an(d ovarian hormiones has opiened ul) new
fields of experimental investigation as to the causes ancd processes of normal
andl pathologic growth. The significanice of some of the results of these
investigations is not yet un(lerstood. Herewith is recorded the results of
b)io-assays of the tissue of a number of different tumors. It was thought,
in the beginning of this investigation of the lhormones, that if the tissue
changes associated with cystic disease of the breast and benign tumors were
(lue to the ovarian hormonies, these might, or probably could, be recovere(d
fromin the tissue affected on bio-assay.
The effects of hormonlal stillmulationi in normal development are general-
ized. A group of organs respondls in a correlated mannlier to a given level
of secretioni anld( in a single organi all of the tissues comn)osing it teln(l to
respon(l to the samiie (legree. IThis is qtiite (lifferenit from tumlaor growth
in wliclh a single comiiponent in a localize(d focus of tissue excee(ls in growth
and(I amiiouniit the surirounidinig tissue in the remiaill(ler of the or-ganll. H30owvevel-,
it has been (lemonstr-ate(l by means of bio-assay that suclh a focus of actively
(growing cells may responl selectively ani(l excessively to a biocheill cal stilltulus
of a hormiionie wliclh usually is uniformly distributed in the b)1cvo(l.
Lewis andl Geschickter24 reportedl a localizedl concenitrationi of the ovariani
hiormlone, estrin, in a benign breast tumlor (fibroadenoma) removed at opera-
tion, and(l slhowed that injections of this estrogenic hor-miionie into monkeys pro-
(ltce(l hypertrophy of the breast. Extending this methodl of biochemical study
to other human tunmors, it lhas been shown that hormiionies secreted by the pitui-
tary gland and the ovaries may be recovered in high concenitrationis fromn a
variety of benign ancd maligniant tumors. The miietho(d of assav conisists of
grind1illng up the freshly excised tumor and extracting the finely divided tissues
with suitable solvents. The substances recoveredI bv extraction are then
injected into rats, mice or rabbits ancd the presence andl amounit of the hor-
monies present determined by the effects on the sexual organs of the animals
used for testing. These studies reveal that when high or normal levels of
endocrine secretioni are present in the blood or urine of patients, the tumor
may contain excessive amoulnts of lhormones probably concenitratedI locally
by the growing tissues.
The presence in growing tissues of high concentrations of hormones has
* Aided by a grant from the Aimia Fuller Fund.
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LEWIS AND GESCHICKTER Annalsot Surgery

but recently been demonstrated. Such concentrations had been found only in
the tumors of organs which are normally endocrine in nature (organs which
elaborate the hormone locally) such as the testicle, ovary or placenta. In
the present studies such concentrations have been found in tumors of non-
endocrine organs such as the breast, uterus, and bone.
HORMONE STUDIES OF BREAST TuMORS.-Castration was suggested as
a treatment of carcinoma of the breast in women before the menopause by
Beatson,4 in I896. He thought that castration caused fatty degeneration and
death of the cancer cell. A few striking results were obtained in cancer by
castration, but because of the number of failures and the higher percentage
of cancer of the breast occurring after the menopause, this method of treat-
ment was abandoned. In I919, Loeb26 came to the conclusion that the inci-
dence of spontaneous cancer of the breast
in inbred strains of mice could be re-
duced and ultimately prevented, if castra-
tion was carried out at progressively
early stages in female mice. Loeb raised
the question as to whether the relation of
hormones to the development of cancer
is specific, and whether a hormone in-
fluences the development of cancer only
in those organs to which, under normal
conditions, it has a definite relation. Corn,'
iI927anMury8 in 1928, supplied
experimental evidence demonstrating that
the ovaries and their endocrine secretions
were of primary importance in raising
FIG. I.-Photograph of a girl, aged five, with breasts to the physiologic threshold where
enlargement of the breast and nipple following
susceptibility to mammary carcinoma oc-
the injection of 6,ooo rat units of estrin. The
circles mark the limit of mammary enlarge-
ment. curred in strains of mice susceptible to
cancer of this organ.
A specific relationship between ovarian hormones and cancer of the
breast, however, was not demonstrated until after the isolation of the ovarian
hormone, folliculin or estrin, by Allen and Doisyl and other investigators.
Lacassagne,22 in I932, demonstrated that injections of estrin caused carcinoma
of the breast in male mice which otherwise remained cancer free, although
the females of the same strain were susceptible to cancer of the breast.
Lacassagne,21' 23 in 1934, also found estrin in colostrum secreted from the
breast of a woman with mammary carcinoma.
Virginal Hypertrophy, Gynecomastia and Fibro-Adenowa.-Enlargement
of the breast associated with granulosa cell tumors of the ovary and high
levels of estrin secretion have been repeatedly reported in the literature. Fig.
I illustrates the action of estrin on the breast of a girl, aged five, who had
received injections amounting to 6,ooo rat units of estrin over a period of six
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weeks in the treatment of gonorrheal vaginitis (Fig. i). Apparently the tre-
mendous hypertrophy of the breast observed at puberty (virginal hypertrophy)
in certain women is due to increased secretion of estrin. In the one case in
which we have had an opportunity to make an assay of the blood 25 rat units
of estrin per liter were recovered.
Gynecomastia occurs in 5 per cent of the cases of teratoma testis. Lili-
enthal25 has reported a striking case associated with chorio-epithelioma aris-
ing apparently in a mediastinal teratoma and accompanied by a positive
Aschheim-Zondek test. In addition to the high concentration of the prolan
found in the urine, both Heidrich and Hamberger have reported high con-
centrations of estrin in men suffering from gynecomastia and testicular
tumors. We have demonstrated experimentally that mammary hypertrophy
can be produced in male monkeys either through the direct action of estrin
or indirectly by injections of prolan, the testicles being present. Moreover,
in a case of gynecomastia occurring in a man of 22, we have demonstrated
increased concentrations of estrin in the blood (I0 rat units per liter) in the
absence of any testicular neoplasm. In two other cases of gynecomastia,
uncomplicated by testicular tumors, 200 and 2,500 rat units of estrin per kilo-
gram have been recovered from the excised breast tissue.

TABLE I
BIO-ASSAYS FOR ESTRIN AND GONADOTROPIC SUBSTANCE IN FIBRO-ADENOMA,
GYNECOMASTIA, INTRACANALICULAR MYXOMA, AND FIBROSARCOMA OF BREAST*

Subject Estrin Gonadotropic Substance


(Rat Units per Kilo) (Rat Units per Kilo)

Rat: Control breasts ............. Negative t


Rat: Fibro-adenoma ........ . . . 2,000
Rat: Fibrosarcoma ............... I,000
C. F. I9 Control breast ........... Negative
Menopause Control breast ...... Negative
B. Fibromyxoma .Negativ Negative 6o, ooo
C. Fibromyxoma .200
C. Forro-adenoma. I, 000
L. Fibro-adenoma .200 2,500
J. Fibro-adenoma .6, ooo
D. Fibro-adenoma .12,000
Co. Fibro-adenoma .............. 2,000
Ba. Fibro-adenoma .............. I8,ooo
Ku. Fibro-adenoma .............. 250
M. Gynecomastia ............... 200 Negative
K. Gynecomastia ............... 2,500 Negative
* Tissues fixed in 95 per cent alcohol.
t Not done.
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LEWIS AND GESCHICKTER Annals of Surgery
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The localizedl tumors of the l)reast, suclh as fibro-adenomata, have a


microscopic strtucture similar to that seen in (liffuse virginal hypertrophy.
In the belief that concentrations of estrin would l)e physiologically significant
for the tumor growths we lhave assaye(d suclh tumors removed at operation.
These assays show that the concenitration of estrin may be as high as i8,ooo
rat units per kilograml. Giant fibromyxomiata of the breast have also been
assaye(l. T hese assays niot only showed high concentrations of estrin but also
as many as 6o,ooo -at uniits of golnadotropic substance per kilo (Tables I
an(d 11).
TABLE II
ASSAYS OF BLOOD AND URINE IN VIRGINAL HYPERTROPHY AND GYNECOMASTIA

Diagnosis Estrin Gonadotropic Substance


Rat Units per Liter Rat Units per Liter

Gynecomastia (S) ............... Blood Negative Urine Negative


Gynecomastia (K) ............... Blood-Negative Urine-Negative
Gynecomastia (L) ............... Blood-25 Urine Negative
Gynecomastia (W)* .............. Blood Positive Urine-40, ooo
Infantile hypertrophy (H) ........ Blood Not done Urine Positive
Virginial hypertrophy (LKY) ... Blood-25 Urine-Not done
*Associated with Teratoma Testic
Cystic Disease of the Breast.-In cystic disease of the breast there is an
inicrease in the fibrous elements, and hyperplasia of the duct epithelium witl
dlilatationi of the ducts and cyst formation. Experimentally-cystic changes
miiay be pro(luced in the breast by the injection of estrin and( changes simu-
lating lactation by the use of prolactin (Geschickter and Lewis). 1 It would
seem that in cystic disease the coml)inedl effects of estrin and prolactin stimu-
lation were represented. The assays of the tissue an(l cyst fluid, from the
breast of patients witlh cystic disease, have revealed high concentrations of
both estrin and prolactin (the lactogenic substance of the anterior pituitary)
(Table III).
TABLE III
ASSAYS OF TISSUE AND FLUID FROM PATIENTS WITH CYSTIC DISEASE OF THE BREAST FOR
LACTOGENIC AND ESTROGENIC SUBSTANCES

Specimen Patient Hormone Assayed Bird Units per Liter

Cyst fluid* S. K........ Lactogenic substance 2,000

L. F. Lactogenic substance 720


Bur......... Lactogenic substance 0

Jar.......... Lactogenic substance 250


Car......... Lactogenic substance 100

Gar......... Lactogenic substance 750


N. W. Lactogenic substance 250
Grom....... Lactogenic substance 250
Wei......... Lactogenic substance 400
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TABLE III-Continu?d

Specimen Patient Hormone Assayed Results of Bio-Assay

Rat Units per Liter


Cyst fluidt B. C. Estrogenic substance 6,ooo
Jar... Estrogenic substance 0
Car.. Estrogenic substance 2,000
Gar . . Estrogenic substance 0
N. W ...... Estrogenic substance 0
Joh... Estrogenic substance I,000
Rat Units per Kilogram
Mammary Tissue N. B .. Estrogenic substance 6,ooo
R. C Estrogenic substance I,000
P. D.. . Estrogenic substance 200
I. D....... Estrogenic substance 4,000
Bro Estrogenic substance 0
A. L........ Estrogenic substance 0
Bur ...... Estrogenic substance 0
(Adenosis) D .. Estrogenic substance 200

* Tested by the response in the crops of pigeons (Riddle test).


t Tested by vaginal smear in castrated rats (Allen-Doisy test).
t Fluid was removed from cysts of both breasts of this patient. The milky fluid from the
right breast contained 6,ooo rat units of estrogenic substance per liter. The yellow turbid
fluid from the left breast did not contain any estrogenic substance.

Although the experiments of Loeb and Lacassagne would seem to indi-


cate that estrin may play a r6le in the formation of carcinoma of the breast
in mice, bio-assays for estrin in the tissue of mammary carcinoma removed
from patients have yielded no strikingly positive results. The majority of
cases assayed to date have proved negative (Table IV).
ENDOCRINE STUDIES IN UTERINE MYOMATA.-Myomata of the uterus
and endometrial hyperplasia are associated with ovarian tumors of the
granulosa cell type. In over I25 granulosa cell tumors of the ovary ap-
pearing in the literature, endometrial hyperplasia, thickening of the muscula-
ture or the occurrence of adenomata or adenomyomata have been common
(Stefancsik29). In such cases increased blood levels of estrin and an in-
creased urinary output of the same hormone have been reported. When
estrin has been injected in rabbits it has been noted frequently that the
musculature of the uterine horns has been doubled or trebled in thickness
as a result. Bearing this in mind we have assayed myomata of the uterus
for estrin (Table V). The high concentration (II,OOO rat units per kilo)
of prolan, or a pituitary-like sex horm-one present in some of these tumors,
would seem to indicate that this hormone may play a synergistic role in
stimulating the musculature.
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LEWIS AND GESCHICKTER Annals of Surgery

TABLE IV
BIO-ASSAYS OF ESTRIN, PROGESTIN, AND GONADOTROPIC SUBSTANCE IN CANCER
OF THE BREAST

Patient Age Diagnosis Hormone Assayed Result of Bio-Assay


(Rat Units per Kilo)

M. H ....... 50 Adenocarcinoma Prolan Negative


Estrin Negative
R. L........ 43 Scirrhus Progestin Negative
C. C........ 50 Scirrhus Progestin Negative
Estrin Negative
L. L........ 65 Colloid Estrin Negative
M. L.*.. 37 .....
Scirrhus Estrin Negative
G. K...... 36 Scirrhus Estrin 2,500
Prolan Negative
D. B. 5I Infiltrating duct ca. Estrin Negative
E. S.t...... 32 Grade IV carcinoma Estrin 850
Prolan 7,000
B. B.t ...... 47 Grade IV carcinoma Estrin 850
Prolan Negative
M. C. t. 65 Papillary Estrin Negative
Prolan Negative
CAR. t... 45 Papillary Estrin Negativet
Prolan Negative
C. C .. Papillary Estrin 2,500
M.. Papillary Prolan 6,ooo
*
Virginal hypertrophy with cancer. Blood positive for estrin on seventh day of period.
t Checked by Doctor Morrell.
t Positive for estrin on direct injection of tissue.
TABLE V
BIO-ASSAYS OF ESTRIN AND GONADOTROPIC SUBSTANCE OF MYOMATA
OF THE UTERUS

Patient Estrin
(Rat Units per Kilo) Gonadotropic Substance
(Rat Units per Kilo)

Control normal
Premenstrual uterus.. 3,000
P................ 4,000 4,500
J.. ....... I,000 I1,000
G*............... Negative Negative
T*............... Negative Negative
R................ 6oo Ii,000
D................ 200 *
0o............... 30,000 *
J.... ........... 6oo
B................ 60
O................ 600
B................ 250
K................ Negative
J................ Negative
* Not done.
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Number 4 HORMONES IN TUMORS
STUDIES OF THE OCCURRENCE OF PARATHORMONE IN GIANT CELL
TUMORS.-Erdheim,'2 in I907 called attention to changes in the bones asso-
ciated with parathyroid adenoma. Mandl,27 in I926, conclusively proved the
endocrine basis underlying tumors and cysts found in von Recklinghausen's
disease. He removed a parathyroid adenoma and obtained clinical improve-
ment in a case of multiple osteitis fibrosa cystica. Since this date many con-
tributions (Hunter,20 Ballin and Morse,3 etc.) have emphasized the endocrino-
logical factor in this disease.
While hyperparathyroidism, with an elevation of blood calcium is an
etiological factor in von Recklinghausen's disease, no parathyroid changes nor
increase of blood levels of calcium or parathormone have been found in soli-
tary giant cell tumor or solitary bone cysts. Repeated determinations of
calcium and phosphorus in the blood serum of patients with solitary giant cell
tumors and bone cysts have been made in this clinic and elsewhere. How-
ever, nothing has been found which would indicate a state of hyperpara-
thyroidism.
However, giant cell tumors may occasionally occur in the latter third of
pregnancy. We have seen several instances in the long bones. Epulis
of the alveolar margin, developing during pregnancy, is a well recognized
clinical variety of giant cell tumor. Hamilton18 has demonstrated that the
parathormone output is increased during pregnancy. In several instances of
giant cell tumor occurring in patients between 39 and 6o years of age, the
long bones in the unaffected extremity showed a visible epiphyseal line.
These findings suggest a possible disturbance in bone metabolism as a factor
in the development of solitary giant cell tumor. The possibility that a localized
increase in the concentration of parathormone may occur at the site where
the tumor develops has led us to attempt the bio-assay of solitary giant cell
tumor for parathormone. Two cases treated by preoperative irradiation
gave negative results.
Three additional benign giant cell tumors treated by primary curettement
gave positive bio-assays for parathormone. Dogs weighing approximately
IO kilograms were injected with the equivalent of 4 to 8 grams of tumor
tissue, and showed an increase of i8 to 22 per cent in their blood calcium
I5 hours after the initial injection.
The tumor tissue was extracted in 5 per cent hydrochloric acid in a boil-
ing water bath for 45 minutes (Collip8). The digested material was diluted
with four parts of hot water and subsequently chilled to remove the fat. The
liquid was then raised to a PH 8 to 9 with sodium hydroxide. Five per
cent hydrochloric acid was added slowly until a precipitate occurred (at about
Pi 5.5). The material was then filtered, saving both filtrate and precipitate.
The precipitate was again made alkaline and again precipitated as above.
This process was repeated three times. The hormone was then recovered
from the free filtrate by making the solution acid to congo red and then
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LEWRIS AND GESCHICKTER Annals of Sturgery
October, 1936

saturating witlh sodiumii chloride. The flocculent, active material was then
separated andl dissolved in weak so0ium hydroxide, and the liquid adjusted
to Pi, 4.8. The precipitate was centrifuged and the supernatant liquid was
treated as above. The precipitates were then added together and dissolved
in a weak hydroclhloric acid solution at P,0 3. This active solution was in-
jecte(l into the (log after being netutralize(d just before injection.
Table VI shows the results of assays on parathormone in giant cell
tunmors and in a case of osteolytic sarcoma, occurring three an(I olne-half years
after curettage and( irradiation for benign giant cell tumnor. In addition,
assays for growth hormonie and gonadotropic substance in benign osteo-
chondroma ancd osteogenic sarcoma are recorded.

TABLE VI
BIO-ASSAY OF PARATHORMONE, GROWTH AND GONAI)OTROPIC HORMONE IN BONE TUMORS

Patient Diagnosis Hormone Assayed Restilt Units per Kilo


Dry Weight
J. C. B..... Giant cell tumor Parathormone Negative 0
2-I 5-35 (irradiated)
Monroe... Giant cell tumor Parathormone Negative 0
9-11-35 (irradiated)
Henry ..... Giant cell tumor Parathormone Positive 25, 000
1-21-36
Irwin..... Giant cell tumor Parathormone Positive I4,000
3-11-36
Mentzner. Giant cell tumor Parathormone Positive I4,000
7-29-36
Brown .. Sclerosing osteogenic Growth hormone Positive 65
10-I 1-34 sarcoma (irradliated) Gonadotropic
hormone Positive 4, 500
Ewing .... Osteolytic sarcoma Parathormone Positive 25,000
3-I -36
Harper.... Osteochondroma Growth hormone Negative 0
4-IO-35

CONCLlUSlONS

No conclusions are to be drawni froml the results of these b)io-assavs re-


garding the causal relationslhip between the hormones and tumor formationi.
In certain benign lesions of the breast, suclh as cystic disease and( fibro-
adenomata, these hormiiones may be recovered in a high percentage of cases,
wlhile they are inconstanit, or absent, in carcinoma of the breast. On the otlher
hand, the methods in use for extracting hormones from tissue do Inot lneces-
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Volume 104 HORMONES IN TUMORS
Zsumber 4

sarily yield the total amount of active substance fromii the tissue. It hlas
been shown, particularly in regard to estrogenic substances, that various
methods of extraction will yield differenit quantitative results or a variety of
active fractions. Preliminary hydrolysis of the tissue with hydroclhloric acid
or injectioni of anl emulsioni of freshly ground(I tissue (wNhen nlot too toxic)
may give hiigher values than the routine method of hot alcolholic extraction.
The exact composition of the hormonie, its source and its ultimate fate
in the body, often renmains in doubt after repeated assay of the tissues, bloodI
and urine in a giveni case. \Vhllile the structural formula for the female sex
hormone is known (ketolyd(lroxyestrin anid trihydlroxyestrin), estrogenic ac-
tivity has been deemonstrate(d for a series of condlensed ring compounds of
similar structures wlich are closely relate(d to the sterols and bile acids (Cook,
DLodds and others"). Hence nio conclusioni regarding the chemical identity
of the substance canl be drawn from bio-assay. A varied group of substances
likewise may produce the Asclhheim-Zond(lek2 reaction.
The above assays are merely recorde(l as facts anid any attempt at inter-
l)retationimust await the restults of further investigation. The presence of
these end(locrine sul)stances in new growths woul(l seem, however, to have
significance in the physiology of the growth and to explain more satisfactorily,
than any theory yet adlvanced, why tisstues in a new growth reproduce tlhenm-
seives locally, and(I in metastases.
BIBI-TOGRAPHY
Allen, Fdgar: The Ovarian Follicular Hormonie. Theelin, Animal Reactions, Chapter
X, in Sex and Initernial Secretions. Williams & WN'ilkilns Co., Baltimore, 1932.
-Aschheimii, S., anid Zondek, B.: Schwangerschaftsdiagnlose aus dem Harm (durch Hor-
monniachweis). Klin. Wchnschr., 7, 8, 1928.
:'Ballin, M., and Morse, P. F.: Parathyroidism. Am. Jour. Surg., I2, 403, I931.
4Beatson: Cited by Cahen: Lancet, 2, U. I8, 7, i896.
Bonser, G. M.: The Effect of Oestrone Administration of the Mammary Glands of
Male Mice of Two Strains Differing Greatly in Their Susceptibility to Spontaneous
Mammary Carcinoma. Jour. Path. and Bact., 42, i6i, January, 1936.
"Burrows, H.: A Comparisoni of Changes Induced by Some Pure Oestrogenic Com-
pounds in the Mammae and Testes of Mice. Jour. Path. and Bact., 42, i6i, Janluary,
1936.
Burrows, H.: Pathological Changes Induced in the Mamma by Oestrogenic Com-
pounids. Brit. Jour. Surg., 23, 191, 1935, 1936.
'
Collip, J. B.: The Parathyroid Glands. Phys. Rev., I2, 309, 1932.
'
Cook, J. XV., Dodds, E. C., Hewett, C. L., and Lawson, XV.: The Oestrogenic Activity
of Some Condensed-rinig Compounds in Relation to Their Other Biological Activities.
Proceedings of the Royal Society, II4, 272, 1934.
'Cori, C. F.: The Influence of Ovariectomy on the Spontaneous Occurrence of Mam-
mary Carcinoma in Mice. Jour. Exper. Med., 45, 983, 1927.
"Dodds, E. C.: Hormones and Their Chemical Relations. Lancet, I, 93I, 987, 1048,
May, 1934.
12 Erdheim, J.: Sitzungsber. d. Akad. d. \Viss., Wvien 3 Ab., ii6, 311, 1907.
3Gardner, W. U., Diddle, A. W., Allen, E., and Strong, L. C.: The Effect of Theelin
on the Mammary Rudimenits of Male Mice Differing in Susceptibility to Tumor
Development. Anat. Rec., 6o, 457, 1934.
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LEWIS AND GESCHICKTER Annals of Surgery
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4 Geschickter, C. F., and Lewis, D.: Lactogenic Substance in the Human Breast. Arch.
Surg., 32, 598, I936.
5Girard, A.: La Chimie des Hormones Sexuellen. Bull. Soc. Chim. Biol., 15, 562, I933.
6 Goormaghtigh, M., and Amerlinck, A.: Production de formations adenomatenous
mammaires par des injections prolongies de folliculine. Compt. Rend. Soc. de
Biol., I03, 527, I930.
Hamburger, C.: Studies on Gonadotropic Hormones, Supplementum XVII. Acta
Path. et Microbiol. Scandinav., I933.
1Hamilton, B., Dasef., L., Highman, W. J., and Schwartz, C.: Parathyroid Hormone
in Blood of Pregnant Women. Jour. Clin. Invest., 15, 241, I936.
9 Heidrich, L., Fels, E., and Mathias, E.: Testikulares Chorionepitheliom mit Gyna-
komastie und mit einigen Schwangerschaftsercheinungen. Beitr. z. klin. Chir., i50,
349, I 930.
"') Hunter, D.: Calcium and Phosphorus Metabolism. Lancet, i, 897, 947, 999, I930.
Lacassagne, A., and Nyka: Pathogenesis of Mammary Adenocarcinoma: Folliculin in
the Colostrum. Compt. rend. Soc. de biol., ii6, 844-845, 3934.
Lacassagne, A.: Apparition de cancers de la mamelle chez la souris male, soumise a
des injections de folliculine. Compt. rend. Acad. d. sc., i95, 630, October I0, I932.
23 Lacassagne, A.: Sur la pathogenie de l'adenocarcinome mammaire de la souris. Compt.
rend. Soc. de biol., 115, 937, I934.
21 Lewis, D., and Geschickter, C. F.: Estrin in High Concentrations Yielded by a Fibro-
adenoma of the Breast. J.A.M.A., 103, I2I2, I934.
'3 Lilienthal, H.: Choreoepithelioma with Gynecomastia Diagnosis by Thoracotomy.
Libman Ann., 2, 745, I932.
a Loeb, L.: Internal Secretion as a Factor in the Origin of Tumors: Further Investi-
gation on the Origin of Tumors in Mice. Jour. Med. Research, 40, 477, I919.
27 Mandl, F.: Zentralbl. f. Chir., 53, 260, i926.
2 Murray, W. S.: Ovarian Secretion and Tumor Incidence. Jour. Cancer Research,
12, i8, 3928.
Stefancsik, S.: Beitriige zur Kasuistik der Granulosazellentumoren. Monatschr. f.
Geburts. u. Gynak., 92, 400, I932.
'
Zondek, B.: Hormone des Ovariums und des Hypophysenvorderlappens. Julius
Springer, Vienna, 3935.
DIsCUSSION.-DR. CHARLES CARROLL LUND (Boston, Mass.).-It is note-
worthy to have as busy a surgeon as Doctor Lewis take an interest in chem-
istry and hormones, and I think it has an important bearing on the surgery
of the future.
It might be of interest to know that in the recent general examination at
the Harvard Medical School, the men were given great latitude in the choice
of writing a paper, in a four hour test. They were given three hours of
the four to write on any subject in medicine they wanted to, in which there
had been recent advances. Three-quarters of the class elected some phase
of endocrinology. It is obvious, therefore, that this is one of the fields the
present student is interested in.
Doctor Lewis, wisely, does not draw any conclusions from his observa-
tions. The field is opening up so rapidly that the first thing of importance
is to collect relevant data, and certainly the essayist has made noteworthy
advances in the subjects considered.
There has been considerable discussion concerning these hormones being
important as an etiologic factor of breast cancer. Gardner and Allen in
New Haven, and others, have shown that there are at least three hormones
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Volume 104 HORMONES IN TUMORS
Number 4

important in the development of the breast, the gonadotropic, estrin, and


progestin, and in addition there is the prolactin, which is important in secre-
tion. I think the conservative point of view to take about the animal ex-
periments of Lacassagne and others, at present, is not to attribute to estrin,
or any other hormone, the cause of cancer in male breasts or in breasts of
castrated animals, but simply to consider that if you are going to have cancer
in a breast you have to have breast tissue. On a quantitative basis, roughly,
in the human male and female, you get about as much cancer in the male
breast per gram of tissue as you do in the female breast. So that it may not
be hyperestrinism, or any endocrine deficiency, but simply the number of
cells that are exposed by time to other processes which cause cancer of the
breast.

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