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5-1-1936

Anterior pituitary hormones and their modus operandi

G. Alexander Young
University of Nebraska Medical Center

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Young, G. Alexander, "Anterior pituitary hormones and their modus operandi" (1936). MD Theses. 477.
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 THE ANTERIOR PITUITARY HORMONES AND THEIR

MODUS OPERANDI

by

G. Alexander Young~ Jr.

University of Nebraska

College of :Medioine

1936

1-
A. Communieans .\nterior~ ... ,;Infundibulum
, ... ....·<./Diaphahgma Sellae
Sinus Intercavernosus Anterio,r ,
... ......
"-
/~' / Sinus interc').uernosus
" "', ,/ /Pars Anterior
... "-
Sinus Sphenoidali s_ " ...,... />Pars Intermedia
/ -Pars Posterior
Fossa Hypophysis_-.. __ -..~-- /~:"Pia
--- ...
//-'
,.. ...
~
~ - Arachnoid
Crani o-pharyngeus . - -- - -- - - - - -

____ -~Du.ra

-,,·A. vertebra.lis
Pharyngeal hypophysi s --- - - - - - - - -0
---Roof of nha.rynx

Margin of na.s.g,l septum--- --- ---- - - - Eustachian tube

FIG. I

A. Choroidea --- -- -- -- ---- ---·III Ventricle

Pia--~- ---- -~-:-~:~ ___-:.-=--_-~=~- 1--'~.l.4rR=~=-._-_-------OPtic ohiasma
ArachnOld -- ________ ~____________ -----------A. Communicans -post.
Dura- - ------------------ ---- .. --~-_~-----~--::. --- -- ----Dia-phragma Sellae
N. Oculomotorius .. ----~-=------- ---------.Pars Anterior
N. Trochlearis,.----- ---------Pars In'termedia.
N. Abducens----------------. -----Pa.rs Posterior
R. lcandibularis -ant.--'-------- - -----A. Carotis interna
R. Mandibul9.ris -inf.------_ .' ,inus cavernosus

- - -Sphenoid bone

~-:- _____ Pharynx

FIG. I I

FIG. I Diagr9.m ghowin~ the rel~tions of the human

hypophysis in median sagittal sectionl Dura-
Pi9. - Arachnoid.

FIG. II Diagram of the transverse section of the

human hypophysis~ Dura - Pia - Arachnoid.
 The objeot of this thesis is to disouss the hormones
of anterior pituitary from the standpoint of their history,
their present reoognized funotions, and to emphasize the
modern oonoepts as to the modus operandi of these trophio
substanoes. In writing this paper I have attmapted to
oite the earlier fundimental works and the more reoent re-
oognized artioles so as to present the topio as offered
up until 1936.
As to its gross morphalogy and relations, ftthe
hypophysis is a small body weighing in the adult males and
nulliparae about 65 oe.ntigra.ms • It is oval in shape, being
about one oentimeter long, one to one and one half oenti-
meters broad, and one half to one oenttmeter thiok. During
pregnanoy it inoreases greatly in size, ohiefly in lateral
and vertioal direotions. Addiso.n and Adams (3) have shown
that the we ight of hypophys is is greater ih.fema les t han in
males, this holding true only for women having borne ohildren -
the enlargement being limited primarily to anterior lobe.
Rasmussen has shown a definite inorease in weight of gland
proportional to the height of the individual - and also a
deorease in weight of the g land with age. The general re-
lations ot the hypophysis to the struotures at the base of
the skull, are illustrated in Figs. land 2. It is attaohed
above the hypothalmus ~ the infundibular stalk and is lodged
in the sella turoioa of the sphe.noid bone. It will be seen
 2

from the diagrams (Figs. 1 and 2) that the infundibular

pro!ess, as it enters the sella turoioa, is olosely sur-
rounded by the diaphragma sellae, whioh is formed by a
fold ot the dura mater. The dura mater oontinues ventrally
and lines the entire sella turoioa, being olosely adherent
to the bone. The relations of the a.raohnoid are variable.
It i8 usually refleoted from the intundibulum to the dia-
phragms. sellae, but it oooasionally extends further ventrally
and partially enoloses the hypophysis as it lies in the sella.
The two lobes can easily be distinguished in the gross speoimen.
The anterior lobe is large and firmer in oonsistenoy and part-
ially enoloses the posterior lobe in a hilus-like depression
in its oaudal surfaoe. On seotion it beoomes quite apparent
that the two lobes are quite different in oolor, for the
anterior lobe has usually a reddish tint, owing to its
relatively high vasoularity, while the posterior lobe is
usually greeiish-yellow,depending on the amount of pigment
oontained. On olose examination of the anterior lobe, it
is possible to define the limits of the pars intermedia,
whioh is a thin epithelial layer between the anterior lobe
proper, in front, and the posterior lobe behind. The pars
intertuberalis, whioh is so distinot in lower forms, is only
represented in man by an inoonspiouous prolongation of the
tissue of the anterior lobe along the infundibulum in the
direotion of the tuber cineroum, henoe the term tuberalis." (18)
 The blood supply of the hypophysis springs from two
souroes, from the internal carotids as they are passing
through the cavernous sinus, and from the twenty-five small
arteries from the cirole of Willis. (86) The internal
oarotids give off delicate branohes whioh run to the anterior
lobe. The posterior lobe is supplied by the Cirole of Willis
as is the infundibulum and, aocording to the general view
now, there is adequate anastomosis between the tWo supplies.
The important point relati va to the blood supply is the
greater vasoularity of the anterior lobe.
Dandy, 1913, by use of intravitam methylene blue
demonstrated numerous nerve fibers derived from the carotid
sympathetio plexus and passing along the arterial supply into
the gland where most of the fibers pas sed into the pars ant-
erior but a single fiber separated from the others and passed
down within the hypophyseal oleft where its branohes spread
out on the surface of the pars inte~edia. Fibers going to
the posterior lobe were remarkably few in number oompared to
those of the anterior lobe. At that time Dandy made note of
oolor differenoes in the anterior and posterior lobes whioh
may now be interpreted as due to the unmyelinated fibers so
numerous in the former. (41)
The embryology, taken briefly, shows that the anterior
lobe is developed from an eotode~al puoh, oalled the pouoh
of Rathke, whioh grows upward under the brain from the stomodeal
 4

api thelium. At about the fourth week Rathke t s pouoh aomes

into oontaot with the inf'undibular prooess, whioh is a do~

growth from the floor of the third ventriole, and whioh ulti-
mately forms the posterior lobe. (75)
The anterior pituitary body is a oompaot of oellular
elaments of three reoognizable sorts - divided by histolo-
gists on the basis of their staining re~otions, into two
prinoiple types. One, those with a nongranular oytoplasm
and two* those with a oytoplasm that is distinotly granular.
Those of the fonner type are known as the ohromophobe type,
those of the latter as ohomophile. The latter oonsists of
two types, the aoidophile and basophile, more oorreotly
termed the alpha and beta cells. Whether these oells are
fixed in oharaoter or repres-ent different stages in the
same cell is a matter of dispute. Remy Collin (26) a
reoent advooate of the unitarian view believes that the
no~granular oell represents the primitive stage ot an
element whioh in the process of ripening aoquires a gran-
ular oytoplasm thai; is primarily aoidophilio but whioh
may in turn beoome basophilio. Whe.n the ripened granular
oytoplasm comes to be disonarged* little is lett but the
nuoleus and membran__ of the oell whioh may then either
degenerate or renew tm oyole. The work of Severinghaus,
as interpreted by Cushing (43) seems to disprove the
thoug~t. of basophilic oells being further development ot
 5

the eosinophile as he has shown that a study of the golgi

apparatus of the two ohamaphile oells indioates a differenoe
that may be traoed baok to the mother oell. Rasmussen has
shown that the average frequency of the three oells in the
adult male to be: ohronophobes 52 percent, oells with alpha
granules 37 peroent, and oells with beta granules 11 peroent.
The only known oonditions whioh affects their frequency are
pregnanoy oausing inorease in alpha oells, and rutting season
which causes increase in beta oells. The granules of alpha
oells are oourse while those of beta a quite fine. A few fat
globules oan be demonstrated in the pars anterior and these
appear to inorease with age. Mitochondria have been demon-
strated by Bailey and Oowdry. The oonneotive tissue for.ms
a loose network throughout the pars anterior, the fenestra-
tions of ~ioh are smallest in the posterior superior part
of the anterior lobe. The oonneotive tissue is composed of
oollagen fibers with numerous retioulin fibers attached to
them. At times the retioulin fibers orOBS from one band of
collagen to another oausing fibrosis of the individual alveoli.
The number of oells in such a fibrosed alveolus is greatly
reduoed or may beoome absent. Suoh a prooess may prooeed
to produoe a fibrosis of anterior lobe oalled Simmonds
disease. (90) Oushing summarizes the anatomioal phases
very well; ttindeed, its extraordinarily well proteoted
position, its presenoe in all vertebrates and persistanoe
 6

through life, its remarkably disposed and aboundant blood

supply, would of themselves be enough to stamp the hypophysis,
an organ of vital importance. It (41)
Our present day oo.noept of endoorine therapy is to

supply to the individual suffering from endoorine insuffi-

cienoy, the dessioated gland in question or a potent oon-
oentrated extract of the same. The premature thought, as
expressed by Paraoelsus was that a person suffering from
heart disease should be fed with the same organ "heart oures
heart; spleen~ spleen; lung, lung. (8) A olose analogy to

sympathetic magio of the homeopathic type as desoribed by

Frazer in the Golden Bough oan be seen in Paraoelsus' It yellow
bird of jaundioe." This primB.tive apotherapy was for a time
buried beneath a prevalent theory that oonoootions made up
of many heterogeneous and often repulsive ingredients would
give results in direot proportion to the number and the
odoriferous properties of the oonstituents. To aooomplish
this everything from exoreta to skunk seoretion was used. (65)
This filth pharmooopoeia as it was later kn~n, was permanent-
ly disoredited by the satirioal writing of William Heberden.
in 1745.
As already pointed out Galen'S and Vesatius' oon-

oeptions were that pituitary gland was an organ whioh

seoreted a substanoe known as pituita, whioh then entered
the nose am -was from this organ disoharged. Brillant and
 7

studious men aooepted this for fifteen oe.nturies. Exouses are

numerous enough suoh as the laok of human material, instru-
ments that were not suitable to disseotion, the neoessity or
better the tendenoy to try and make one's findings ooinoide
with prevalent belief's on the subjeot, the laok of mioro-
soopic teohnique and others far too numerous to mention. How-
ever the prbnary reason for this misconception is brought out
by Cushing who tells us that under oertain oonditions of
disease there is suoh a drainage. This drainage is due to
an adenomatous tumor of the body. (41) ttFrom the time of
Galen and Vesaliu8 until the middle of the seventeenth
oentury, knowledge of the pituitary gland and its functions,
made little or no headway, the anatomists of this period
following direotly in the line ot existing beliefs or oasually-
perhaps Wisely - avoiding the subjeot.· Even as late as 1631,
in the lPtegrum Morbor~, Robert Flood explained the etiology
of ooryza on the prinoiple of the siphon aotion between the
ventrioles and the nose. Could he have known that the hypo-
physis is present in all vertebrates, and that in the low
order of amphioxus a canal lined by ciliated epithelium
affords a oommunication between the buoca1 and cerebral
oavities, he would have had something more than tradition
with which to substantiate his beliefs." (39) In 1665, we
find new oonoepts as to pituitary funotion. The first man
to cast a doubt on the prevailing theories was Schneider.
 8

In his ~~ber ~ O~seOribifo~i (1665). he denied the

existanoe of any demonstrable oommunioation between the

nose and the pituitary. However, he as well as Vieussens
and Willis. anatomists of , this e~a. could not quite oorre-
late their findings with the nfaots It of spontaneous oerebro-
spinal rhinorrhea so dogmatically dictated to them by their
learned instruotors. The question came up then what oould
aocount for the rhinorrhea; influenoe and for.mulations of
Galen still persisted. It was Riohard Lower who in his
remarkable work "Dissentati,o ~ O.r.ie;ine Catarrh~, 1672, was
able exper~entally to disprove the Galenic dootrine. His
basic conclusion for this topic is nFor whatever serum is
separated into the ventricles of the brain and tissues out
of them through the infundibulum to the glandula pituitana
distills not upon the palate, but is poured again into the
blood and mixed with it. (41) After this work by Lower the
trend of anatomieal theory was towards tl» funotion of the
pituitary being to secrete the oerebrospinal fluid. It is
interesting to note here that Sylviu8, a oontemporary of
VesaHuB, held this belief. That the importanoe or any
inkling of the importance, of the pituitary was not suspeoted
by the greater majority of t he anatomists is· illustrated in

the following paragraph from the anatomy of Thomas Gibson,

published in l6S8. "In those ereatues that have the glandula
pituita large, (as in oalves f~r instance ) the ~ro oa.rotid
 9

arteries, meeting about tm sella of the wedge - like bone,

presently divide themselves into small twigs, which being
interwoven ---make on each side a notable plexus, called the
Rete meriable... So that in these oreatures the gland seems
to be of the s~e use to the Rete meriable, as the glandual
pinealis 1s to the choroid plexus, vise to separate a serous
matter from the arterial blood. But in man, (aooording to
the best anatomists) this Rete is usually wanting; so that •••
the glandual pituita is of less use in him than in other
oreatures that have the Rete. (39) I.n 1664, Willis, who is
known to the student of today for his disseotion and naming
of the ciroulation at the base of the brain - set out to
finally olear up the vascular supply ot the pituitary_ Willis
began to untangle the knot by desoribing the vasoular oircle
surrounding the pituitary_ Through these disseotions he was
no longer able to aooept the Galenic doctrine, and enoouraged
by the work of "'Sohneider, he made quite a remarkable con-
clusion. "The ramifications of the oarotids into a reticu-
lated plexus shows ••• that the blood ••• before it is let into
the oerebellum takes some pa.rt of the superfluous serum of the
pituitary gland and instils another part into the various
shoots to be led baok toward the heart." This statement is
aptly oommented upon by Cushing who reters to it as the
ttkernal of the modern oonception of internal secretion, but
the idea was stillborn." (42) The foregoing summarizes the
 10

trends d~ring the seventeenth oentury. In the eighteenth

century the advancement was slow, but it showed some advanoe-
ment nevertheless. The writers all along up to this period -
as already stated - had shown a marked liking for the including
of Ithumors lt in their disoussions of disease. This phase of
their ideas oan easily be seen as a forerunner.of the hormone
theories of today. Now oame the new theory whioh was to
influence the pituitary - this theory caming out as all
theories do - based on speoulative hypotheses whioh may be
proven or disproven only after innumerable researohes. This
theory was that brought forth in Morgagne t s tt~ sedibus It (176l)
in which he focused the etiology of disease upon the solid
organs. Th~s: mmediately was supplEmlented by Theophile De
Bordeaus ideas concerning the fmportance of the body fluids.
Bordeaus reputation today is based on his doctrine that not
only each gland, but eaoh organ of the body is the workshop
of specific substanoes or seoretions whioh pasa into the
blood, and that upon these seoretions the physiologioal
integration of the body as a whole depends. This dootrine
is oontained in his Itanalyse medioina~ du sa~. tt (18)
Evidenoe of' the adva.noe in the knowledge of' the pituitary
gland in the eighteenth 0 entury oan be seen in the faot that
Soemmerling, in 1776, f'irst applied the ourrent name hypophysis
oerebri, to this organ. Onoe again one may well quote from
works of' current anatomical volumes, James Drake in 1750 in
 11

his anatomy book. "At the bottom of this oavity (third ventri-
ole), just below the ooalition of the Optio Nerves, lies the
infundibulum, which seems to be nothing else but a passage
continued from this third ventriole to the glandula pitui-
taria, between the medullary parts of the brain, and lined
with the Pia Mater; and therefore not properly to be looked
upon as a vessel, but as an outlet for serosities; through
this g1a.ndula pituita, to which it is oo.ntinued, there seems
no proper drain for them, however, it may have been esteemed
hitherto. Underneath the infundibulum in that sinus of the
skull wnich is oalled sella equina or turoioa, upon the Os
Cr1basum, is situated the glandula pituita, so called from
its supposed offioe ofreoeiving and discharging the serous
humors evaouated by the ventrioles of the brain. But though
the use of the part as of divers others about the brin does
not plainly and distinotly appear to me, yet I oannot admit
of this use, both because it is against the offioe of a gland
to reoeive humors already seoreted whioh a vessel of a more
stmple struoture might more readily and easily perform;
beoause it is the peouliar office of glands to separate
humors before unseareted, which two uses tmply a direot
repugnanoe not to be reoonoiled, but besides the struoture
of this gland whioh is fimer than any other of the body
makes it absurd to think that it should, like a sponge, suok
up humors, not only in contravention to its avm use as a
 12

gland but likewise in violenoe to its own struoture whioh

is more oanpaot than that of other glands, espeoially of
those of the braih. I do therefore tmagine it does, as
other glands, serve to secrete sane humor or other, though
to what purpose is not so apparent. This gland is very small
in human bodies, but in brutes muoh larger, whioh differenoe
may at some time" <r other, suggest to a man of happy sagaoity
something that conoerns the true use of it. It is covered
with two ooats from the meninges of the brain. It (48) The
nineteenth centuny starts out with a decade of great oon-
fusion in regards to the pituitary and the other endoorines.
Grea t steps were made by men who seamed only endowed wi th
intuition and not with persuasive powers. In 1801 the Frenoh
physiologist Legallois, put forth his beliefs oonoerning blood
thus "vtt (Venous blood), "Aft (Arterial blood), I'Stt (Secretion.)
When A and S are ohemioally know, A being oonstant, V will
be ktiown, or, when A and V are knwo.n S will be known. The
V is always variable. (18)
As further evidenoe of the confusion present in the
ear we find that in 1842 Magendie in his ttReoherohes .!.!!. Ie
Liquid!, Cep.~.l_o - ~e.hedi~!.tt leaves the impression that the
hypophysis may represent a sort of lymph gland interposed in
the fluid pathway. In this work he remarked (p_ 22)·1 Uts
aut~ur anoiens, tels que Brumer (Brunner?). Littre, Haller,
out sans doute observed quelque ohose d t analogue (i.e. a
 13

pituitary tumor ) 1arsqu ' e1s out dit que, L. Hydrooepha1e est
sourvent causes par 1a glande pituitaire.~ (39) Only sevan
years later 1849, A. A. Bertha1d is said to have transplanted
the testes of a fowl to anotmr part of its body and still
kept the sexual functions in taot. This phenomenon he
inferred was due to ttthe productive relation of the testes,
i.e., to its effect upon the blood and thenoe, through the
corresponding effeot of such blood upon the entire organism. It
(lS) This work, though it exerted no direct effect upon the
pituitary, brought the use of the terms "blood vessel glands lt
or "blood glands" by the more advanced physiologist of the
time. A further significant observation c~e from Italy when
Vergo, in 1864, gave the post mortem findings in a case in
which the sella turcica was enlarged together with an en1arge~

ment of tl'e hypophysis (20). Bernard in 1849, after doing

work on other ductless glands, discovered that a puncture in
the region of the fourth ventricle produced a temporary
glycosuria. Although Brown Sequard was doing notable work
at this p!lriod references to him will be postpo.ned until
the period when he published his theories of internal secre-
tion. However, the modern period starts with the work of
Marie in 1886 - acromegaly - a work which he did not direotly
associate this disease with the hypophysis, the features of
acromegaly were hitherto known - along with gigantism - and
were known to be associated with hypophyseal tumifaction.
 14

Menkowski in 1887 followed Marie with a definite direoting of

this disorder to the hypophysis. From this stage until the
present time the referenoes to the hypophysis are too numerous
and varied to relate but briefly, but briefly, but before doing
,so - it will be interesting to set down Brown-Sequardts theory
of internal secretions published in 1893. nAll the tissues,

in our View, are modifiers of the blood by means of an internal

seoretion taken fram them by the venous blood. From this we
are forced to the conclusion, that, if suboutaneous injeotions
of the liquids drawn from these tissues are ihjected, then we
inject some of the venous blood supplying these parts ••• We
admit that each tissue and more generally eaoh oell of an
organism seorets on its own aooount certain produots or
ferments, which through this medium influence all other cells
of the body. a definite solidarity, thus being established
among all cells through a mechanism other than the nervous

system... All the tissues, glands or organs, have this a

specifio internal seoretion and so give to the blood some-
thing more than waste produots of metabolism. The internal
secretions whether by direot favorable influence or whether
through the iindranoes of deleterious prooesses, seam to be
of great utility in maintaining the organism in its normal
s~~es." (IS) As far as theory goes nothing haa been added
up to the present time. One of the earliest methods of
experiment was that of thyroideotomy; Ragawitsch and 8tada
 15

,.1889, made many experiments and :1:0 und a co.llstant hypertrophy

of the hypophysis. Another physiologioal approaoh to the
study of the pituitary was that made by injecting pituitary
extraot. Oliver Sohafer (1895) found the notioeable result,
the rapid and sustained pulse that followed Howell (1898)
disagrees saying that the glandular hypophyses are negative.
He plaoes the ohange upon the Va.gus. (20) Now at this period.
many men were oalling attention to tumors of the glands asso-
ciated with optio atrophy, amenorrhoea, infanti~, a.diposity
and diabetes inSipidus. Among these Were Peohkranz (1889),
Frohlioh (1901), Muller (1905), Bressand (1907). With this
great number of artioles conoerning the hypophysis, operative
prooedure was considered and along with this the question went -
was the pituitary neoessary to life? Viotor Horsley (1886)
first attempted experimental hypophyseal ablation; all but
two animals died, these lived 1e ss than a year. Dastio (1889)
Gley (1891), Gemelli (1908), and Pa.ulesoo (1907-1908) all
confirmed the belief that the hypophysis 'W8.sneoessary to
life, the last two operators using the buooal and temporal
routes respeotively, Cushing with others at this time also
believed in its essentiality. Removal and replaoement effects
have been studied by many giving results confirmatory of
todays ideas of funotion. (50) Earlier unsucoessful attempts
were made to extirpate this gland, but, sinoe the prooedure
nullified the results, it was up to Paulesoo (89) to do the
 16

researoh by means of a teohnique of his awn. 'He found that

the loss of the pituitary leads to a typioal death. Paules 00
oontention received support fran Sohafer (1909). Lemon, (1909 g,
Biedl (1910), and numerous others. The question, however, was
not unan~ous. (20)

Reoognized Functions of the Prehypophseal

Hormones

There is now oonsiderable evidenoe that the anterior

pituitary lobe elaborates a number of distinot endoorine
oompounds Whioh, (1) oontrol growth; (2) oontrol the gonads;
(3) oontrol the thyroid; (4) oontrol the parathyroid; (5)
oontrol the islets of langerhans; (6) oontrol adrenal oortex;
(7) oontrol the seoretion of milk; and (8) control fat meta-
bolism. It is obvious since there are only three types of
oells, one or more of these must have a multiplivity of

function; moreover, no other funotion oan be ascribed to

the chromopJ1lale cells other than their being preoursors
of the others. There is some evidenoe that the alpha oells
fW'nish growth prinoiple and that the beta oells elaborate
prinoiples oontrolling the gonads. (25)

Thyrotrophio

The early work i.ndioating the relationship of the

p'ituitary to the hypophysis oame from the following experi-
-
 17

menta. Rogowi taoh noted that a.n enlargement of the anterior

lobe followed thyroideotomy. Gudernotsoh notioed that pre-
oooious metamorphosis eould be induoed in tadpoles by thyroid
feedings. (69) Smith later proved that the thyroid is de-
pendent on the stimulating aotion of the pituitary_ It has
bean ShOll'ln that removal of pituitary gland oauses either
reduotion in development or atrophy of the thyroid (Adler,
1914; Alle.n 1916; Smith 1916; Foster and Smith 1926; Smith

1927; Riohter and Weslaoki 1930). Several of these observers

noted a deoreased metabolio rate and Foster and Smith (1926)

and also Riohter and Wislaoki (1930) noted that the ohange
oan be prevented by injeotion of an anterior lobe extraot. (32)
Moreover, the addition of anterior pituitary extraot into the
fluid in whioh Axaloths are kept initiates a metamorphosis
whioh is preoeded by hyperplasia of the thyroid gland. (96)

Loeb ~d Aron (13), in 1929, independantly discovered that

injeotions of anterior pituitary extraot in guinea pigs
produoed in the thyroid gland a histologioal pioture very
similar to Graves disease. In 1930, ATon, repeating this

work reports that there was a great hypertroppy of the

parenohyma of the gland assooiated with liquifaotion and
final disappearanoe of the oolloid; if the injeotions be
disoontinued the thyroid returns to original state. (46)
Further evidenoe of the direot aotion of thyrotropio hypo-
physeal hor.mone upon the thyroid is gained through Paal
 18

who established a three fold inorease of oxidation in thyroid

f~agments swimming in a fluid to whioh thyrotropio hormone
was added in Warburg Ch~bers. (53) The more reoent workers
have stressed that injeotions of the thyrotropio hormone
has o.nly a temporary stimulating effeet upon the thyroid
gland and that retrog~essive ohanges aotually take plaoe
in spite of oontinued injeotions of the hornl0ne. Biasotti
and Mazzoooo (73) report that anterior lobe extraot aotually
cause a £8011 in blood iodine in thyroideotomized dogs. Others
have noted tmt the B.M.R. reaohed a peak in ten days then
returned to normal. Collip showed that after the fi£th}
week of treatment the B.M..R. was 29 and the ga.and showed
the same histologioal findings as the hypophyeotomized ani111al.
The reason for these aprarently oontrodiotory results is
postulated as being due to an antithyrotropio substanee. (27)
Guinea pigs injeoted with thyrotropio hormone of the
anterior lobe over long periods of ttme show a period of
thyroid st:bnulation and produotiop of oharaoteristio ohanges
in ovary (oessation of growth of follicles), this followed
after four to six weeks by a period of regression. After a
refraotory period the gland shows o.nly a very transitory
period of stimulation followed by a more rapid development
of the refraotory state. (83)
Collip and Anderson have shown that the blood serum
of resistant antmala does not exert a direot neutralizing
 19

effect upon the hor.mone; however, they have demonstrated

that the injeotion of suah serum introduoes into the injeoted
animal reaotions, the nature of whiah are unknown, whioh some-
how oontraots the effect of the hormone for a period. (77)
Clinioally, pituitary insuffioienoies shOW' a tendenoy for
basal rate to be low and oonversely aoromegalias show a
tendenoy for higher B. M. R'a (3S) These results and
observations of a neoessity seleoted, are all in agreement
with the view that a prinoiple of the anterior pituitary
oontrols the output of the thyroid pr,inoiple. What is
known of this hormone and its modus operandi will be taken
up later.

Adre.natropio Prinoiple

Evans has shown that oertain pituitary extraots

prevent or restore degenerative ohanges in the adrenal

cortex of hypophyseotomized animals, partioularly in the
zone fasoiaulata and zona retioularis. Suoh injeotions
produoed an inorease in oell oytoplasm and partial reoovery
of lipoid granules. (56) Further he has shown that hypo-
pituitary states show an atrophy of the adrenals. Unilateral
adrenaleotomy usually is followed by hypertrophy of remaining
adrenals - but this is not so if the hypophysis is extir-
pated. (29) Converselyadrenaleotomy leads to marked ohanges
in the anterior lobe. Collip believes he has isolated a
 20

relatively pure adrenatropio hormone by further refining the

thyrotropio hormone. (28) Severinghaus finds the possibili~J

of oontrol of adrenal oortex by anterior pituitary intriguing,

but points out that it ~aves unanswered the question of in-
oomplete oompensatory hypertrophy of remaining oortioal tissue
after inoomplete adrenaleotomy, when the hypophysis is left
intaot. Very reoently A.C. Crooke and Dorothy S .. Russell
have shown that in Addison's disease there is a oonspiouous
pauoity of basophilio oells and a series of abnormal transi-
tional basophilio oells. (35)

Gonadatropio Prinoiple

The early evide.noes of the presenoe of a gonad stimu-

lating substanoe in the anterior pituitary o~e through the
fundimental disooveries of Smith in 1925 (107) and those of
Zondek and Asohheim shortly afterwards whioh showed that the
ovaries a.nd testicles remained dor.m.a.nt unless stimulated by
a secretion of the anterior hypophysis. They also pointed
out that the gonadotropio substanoe aotivated the gonads
of both sexes alike. (64) Early experiments with oomplaints
of pituitary under the skin showed a produotion of a preoooious
sexuality in lm.m.ature rats. (55) The weights of these ovaries
are distinotly greater than those of controls of same age or
even of the oontrols that have reaohed maturity. This in-
oreased weight being due to the formation of an inoreased
 21

number of follioles. Reoently authors have been inolined to

oonsider the presenoe of two go.nadotropio hormones of the
anterior pituitary namely Prolan A and Prolan B. The aoouraoy
of this interpretation has not yet been deoided. Allen summer-
izes the situation thus, "Beoause of the ease with whioh ovar~

ies of rats and mice may be luteinized by various extraots ot

gland or urine, most investigators have followed the lead ot
Zodek and Asohheim and have spoken of two distinot aotive
prinoiples. The idea of duality of gonadakinetio taotors is
not too oonvenoing when it is oonsidered that quantitative
and temporal relationships vary the response. Sinoe it appears
that the best folliole stimulating extraot tested to date will
produoe lutein tissue in the rodent with oo.ntinued injeotions,
the physiologioal ~cate ot the reoeptor organ rather than the
_ture ot the aotive principle aocounts for the dual response. 1t
(5) Many believe that Prolan A and Bare difterent stages of
aotivity ot a simple prinoiple. (22) A gonadatropio substanoe
tound in pregnanoy urine, though thought to be of ohorionio
origin may be trom anterior hypophysis. Although in hydatidi-
form males and chorion epitheliomas this substanoe remains
until growth is removed, same instanoes of persistanoe atter
operation indioate hypophyseal origin. (55) Gonadotropio
substanoe found in blood or urine of ovarieotomized or meno-
pausal women is different than that found in pregnanoy. The
former has a f611iole stimulating aotion on normal and hypo-
 22

physeotomized an~als while the latter does not. The former

seems to have an almost pure gameto-kinetio aotion, whereas
the latter seems to st~ulate the interstitial oells of the
testes and ovary. (108) In early years little or not gonad-

atropio hormone oan be found in blood or urine. The amount

exoreted in urine of prepubertal persons in twenty-four
hours is less than 2.4 to 3.7 rat units. In adults, the
hormone is found in blood and urine in greater quantities,
being greatest (25 rat units) nine days after the onset of
the preoeeding period, ~rowing less both before and after
this date. (13) In the menopause the gonadatropio hormone
may reaoh the high level of 500 rat units in the blood as
oompared with the 25 rat units of the oyolio fe.m~lew. In
underfunotion of the ovaries the gonadatropio prinoiple is
greatly d~inished. In artifioial menopause the substanoe

is markedly inoreased. (64)

Laotogenio Prinoiple

Riddle (96) obtained, by isoeleotrio preoipitation

of an aoid extraot of the anterior pituitary, a fraotion
whioh stimulates development of the crop gland in the male,
female or oastrate pigeons. Orude extraots of the anterior
pituitary have been shown to produoe oopius laotation in
virgin and dry goats (52) and in virgin heifers and in normal
bitches. (81) Withdrawal of the pituitary hormone at any tim e
 23

during lactation oauses an immediate oessation of laotation.

(115) Smith believes that prolaotin oauses onset and oontin-
uatio,n of the seoretory phase, but the essentiality of the
pituitary galaotoyogue he doubted beoause of the presenoe of
phasio seoretaion present in hypophyseotomized an:iJna.1s. (lOS)
Allen and others in reoent work upon rhesus monkeys ooncluded
that oomplete sexual maturity and oomplete moX'phaloyioal
development of the glands was neoessary to obtain a positive
glaotin or prolaotin reaotio~, mature antmals responding
positively, immature antmals negatively. (9) Prolaotin
also seams to have a marked oalorigenio action whioh unlike
the thyrotropio hormone does not aot through the thyroid but
aots in a manner now praotioally unknown. The synergistio
aotion in the 0 oonsumption that is greater than the sum of
their separate aotio,ns. (95) Riddle et aI, suggests through
experiment that a growth hormone may not exist but rather
that it is a oombination of the laotogenio and thyrotropio
hormone. (95)
Further disoussio,n of this substanoe will be taken
up under its modus aperandi.

Parathyrotropio Hormone

The presenoe of a parathyrotropio substanoe in the

anterior pituitary is not aooepted by all writers as proven.
Severinghaus terms the evidenoe rather meager. (:106)
 24

Houssay and Sammartino were able to show atrophio or de-

generative lesions following the extirpation of the pitui-
tary in the majority of dogs. The frequenoy and intens ity
of these ohanges were, however, inoreased byassooiated
panoreateotomy. Smith, through a parathyrotropio substanoe
that b:J has isolated showed that the substanoe induoes
hypertrophy but that oontinuous injeotions do not maintain
this state. (lOa) Injeotion of anterior pituitary extraot
into male rats produoes a hypertropny of the parathyroids
due to inorease of ohief oel1s. (71) Reoently through the
assooiation of parathyroid adenomas with pituitary sub-
stanoe the belief in a parathyrotropio substanoe has been
strengthelited. Patients with a hyperplasia ot parathyroids
have been found to excrete in their urine a substanoe caus-
ing hyperplasia of parathyroids of normal rabbits. (32)

Growth

Evans and his oo-workers, showed, in a '?8eries

of publioations oo.mmenoing in 1921 that injeotions of
po~ent pituitary extraots into rats produoed gigantism.
(54) Earlier experiments had shown that an immediate
oessation of growth followed hypophyseotomy - later and
more exaot work along this line showed that there was not
a oentimeter of growth in long bones after a oomplete
abolation. (53)
 25

Experiments with mioe have shown that the growth

prinoiple produoes correotly proportional growth of the whole
body. as judged by the relati~ weights of the chief organs,
and the peroe.ntage dry weight, fat oontent, ash oontent and
phosphate and oalcium content of the ash. (67) Clinically
it is not impossible that all the forms at dwartism and in-
fantilism are due to inadequate pituitary tunotion parti-
cularly the Frohlioh, Lorain-Levi and Lruwrenoe Moon - Biedl
types. (55) (88) Acromegaly and gigantism are found as
opposite types of pituitary dysfunctio.n to those just stated.
Aoromegaly has partioular interest in that various animals
show distortion of entirely different struotures showing a
laok of that identioal substanoe to whioh hanl0nious growth
is due. (53) The work on growth hormone, being one of the
first recognized is voluminous, but at the present time its
existance as a separate substanoe is doubtful. If is now
suggested that growth promotion is not the result of a
separate hormone. but rather the oonsequence of several other
materials - that is the hormones so tar disoussed. (104)

Incompletely Defined Pituitary Funotion

Of the inoompletely defined pituitary funotion so

grouped at the present time, the diabetogenio substanoe
seems to oarry the most evidenoe for its existanoe. The
possibility of this pituitary function was first suggested
 26

by Houssay and Gieling and their respective co-workers.(67)

(72) (73) Houssay and Magenta# in 1924# showed that hypo-
physeotomized dogs were hypersensitive to insulin. From this
start further work was done on hypophyseotomized animals
with the following aonolusions. (1) Development of hypo-
glyoemia leading to oonvulsions or death; (2) Inoreased
sensitivity to insulin and (3) that in panareateatomized
dogs the diabetes was lessened. Attaoking the problem from
another approaoh pituitary extraots were injected into normal
animals with the following results: (1),a glycosuria develop-
ed assooiated with de~reased sugar toleranoe and hypoglyoemia,
(2),to produoe the previous results injeotions for several
days were neoessary, and (3),that fat metabolism seem
affeoted along with the difficulties in carbohydrate metabo-
lism. (55) The symptoms of panoreatio diabetes were greatly
ameliorated when the hypophysis was removed fram totally
panoreateotomized days. Fasting blood sugar level in these
ani:m.als rliUlged around 100 mgm. ,; 100 00. - following feeding#
'Values up to 300 mgm. peroent are oommon; There is a glyoo-
suria present but the amount of sugar lost is small.
Ketonuria is at a minimum. When these animals are given
anterior lobe extracts the blood sugar level is raised,
glyoosuria is inoreased and there is a return to Ketonuria.
Suggesting that the deoreased sugar toleranoe may be due to
tuber oinerum. injury or perhaps a chiasmal lesion; we may
 27

oonolude that the general aotion of pituitary extraots is one

of an antiinsulin charaoter. (31) The finding that the anter-

ior lobe extraots develop in the animal and aoteonemia sug-
gests a Ketogenio Prinoiple. (31-55) Many authors have sug-
gested and demonstrated a hyperplasia of the isles of Langer-
hans after administration of extracts of t he anterior lobe.
(108) These two points of view are hard to reoonoile but
perhaps the ideas of "master gland" or dynamio balanoe add
same to its interpretation. Clinioally it has been seen
that obesity is assooiated with both Frohlioh:l:s and ChsU~g 'a

syndromes. Raab~ (92)~ at first oonoluded that pituitrin

promoted the absorption and destruotion of oiroulating fat
by the liver through a nervous pathway starting at tuber
oinerum and running through the oervioal oord and abdominal
splenohinsas to the liver. Recently (93) he has Bome to the
oonolusion that there is a speoial prinoiple of the anterior
pituitary involved. Anselmino and Hoffman (12) and 1mgistris
had previously made suoh oleJ.ms oalling the substanoe oraphys i n -
there is same e videnoe that suoh a prinoiple is exoreted in the

urine.

Mode of Aotions of Hor.mones

The glands of internal secretion are through at the

present to seorete substanoes into the blood stream that have
regulating action on distant tissues. As a group these sub-
 28

stanoes are oalled Autoooids of which there are two types

the Hormones or stimulating substanoes and the ohalones or
inhibitory substanoe. (30) Thomsen suggests that theroeti-
oally there are three possibilities as to the meohanisms of
antagonism and synergism shown by the hormones: (1). tlmne
might be a direot ohemical reaction, that is, they might
ohemically oanoel out each other or perhaps the resultant
aotion might be the result of subtraction; (2), two or
more of the substanoes might aot on the s&me responsive
tissue produoing opposite or inoompatible reaotio.ns - here
the relationship is more of a ratiO; and (3), one hormone
may act upon the endocrine source of some other hormone -
in this manner it might inhibit its aotivity - and hence

decrease the rate of secretion. This possible mode of

~otion may be direct or indireot through the mediation of
the nervous system or perhaps same third endoorine gland
whose role has gone unnotioed. (115) Reoently the term
antihormone has beoome very prominent in the literature and
though I believe, at the present time most authors believe
this substance or phenomenon merely a simple ~unologiaal

response to a foreign protein I shall present the arguments

for the existanoe of an antihormone. Collip states his
theory of inverse response and antihormones as follows:
u (1), Responsiveness of individual to administered
hormone varies inversely with the hormone oontent or pro-
 - ------- <

29

duotion of the subjeots own gland.

(2), For eaoh hormone there is an opposite, an antag-
onistic or antihormone substanoe.
(3), The absolute rumount of a hormone and its respeot~ve

antagonist determines the degree of stability of the subjeot

as far as this one ~rtioular endocrine funotion is ooncerned.
(27)tt

Oollip states that the aotive prinoiple in an antiserum

produoed as a result of long oontinued daily injeotions of
an extraot may be regarded quite rightly as a possible
antibody reaotion to the administered extract or antigen.
This author prefers, however. to think of it as an inorease
of the antagonistic prinoiples whioh are normal to the
blood. Further enoouragement to this belief has been added
by the faot that in certain human patients antithyrotropio
and antimaturity substanoes have been found - these patients
had not been treated previously but there had ooourred
spontaneously a hormone imbalance due to the predominenoe
of the respeotive antisubstance. The antihormones of
Oollip seem to differ from the substanoe diiodotyrosine
which Abelin (1) has found. to antagonize thyroxine and alao
the Kateohin of Blum (24) as the antihormones do not prevent
a rise in B•. M. R. when injeoted with thyroxine as do the
latter two. (27) Further evidenoe of 'the possibility of an
antihonnone oomes from Baohman (16) who working on the anti -
 30

A. P. L. serum has shown that the antihormone effect does not

parallel the antibody content. Rats have been made resistant
to the maturity hormone of rat pituitary by oontinued 1m-
pls.ntations of rat pituitary. Further evidence comes from tm
work of Black (22) who has shown that rats made resistant to
the ketogenic prinoiple by a long period of daily injections
of an extraot from ox anterior lobes have been shown to be

equally resistant to the ketogenio extract made from sheep

or pig anterior lobes. Collip (27) has fouhd that there is a
spontaneous ooourrence in the Serum of oertain individuals of
a substance oapable of inhibiting an anterior lobe prino1.ple.
The site or production of these antihormones_ if they really
exist, is not known. The work of Collip and Anderson (29)
seams to show that the target gland does not play an essential
role in the produotion of the antagonistic hormone. Riddle
(98) has reoently shown that purified prolaction is definitely
antagonistio to the gonad, and that prolaotin has a definite
inhibitory effect in the rat on the action of a;::maturity
extract. Perhaps inhibiting or antognistic effects of this
type are of the same order as the antihormone effeots. Collip
sums up the situation at the present time "In view of the
faot that a somewhat extensive searoh for evldenoe of the
existanoe of antihormones to oestrin~ to parathyroid hor-
mone, and to insulin has failed as yet to demonstrate suoh,
 31

it is possible that the antihormone theory should be applied

only to trophio prinoiples. (27) It must be born in mind
also that a resistant state to a oertain hormone may be due
to a purely looal oondition and not neoessarily to the
preae.noe in abnormal amounts of an antihormone or of a speoifio
antagonistio substanoe_ Thus it is now welJ established that
the ovaries of the very young animals are more responsive to
the anterior lobe maturity hormone. Certain hypoglandular
as well as hyperglanduIar ~ states may be due to deoreased
or inoreased responsiveness respeotively of the gland oon-
oerned to the speoifio trophio prinoiple normally influeno-
ing it. The history and funotions of the various anterior
lobe hormo.nes and their effeots has been dealt with briefly but
fairly oomprehensively as far as present day beliefs direot us •
It is now my intention to briefly sketoh the more popular
theories of interrelationship and operating methods of these
trophio hormones along with wlat is know of their ohemioal
oomposition and preparation.

ThyrQtropio

The thyrotropio hormone las little known of its

ohemioal properties. It is apJ:El.rently protein in oharaoter
readily destroyed by heat and alkaline solution. (29) Pro-
bably the purest preparation yet avialable is that of ~\nderson

and Collip.(lO) They oommenoe with the filtr"ate and washings

 32

fran the caloium phosphate preoipitate formed during the

preparation of the growth prinoiple. These are repeatedly
preoipitated with ammonium sUlphate and the precipitate
dissolved in aloohol or aoetone, until fanally a pure white
protein-like substanoe is obtained. This may oontain
tissues of the adrenotropio prinoiple but the growth prinoi-
pIe is absent. The modus operandi of the thyrotropio
prinoiple is at the present only partly understood. The
theories and suggestions leave suoh a maze that I shall
only attempt an enumeration of the more reoent and popular.
It has already been shown in this paper that inoreased and
lobe aotivity oauses an inoreased response in the throid
and, that after a period of st~lation a latent period is
reaohed. Collip explains this phenomenon by antihormone
produotion. Friedgood (66) in a reoent artiole has pointed
out tha.t there is oylio oharaoter in the departure of the
thyroid gland from normal and tifl. t after a maximum ohs.nge
a spou$aneous remission ooours, and that this remission pro-
gresses in spite of the oontinued presenoe of the stimulus.
Severinghaus (102) puts this interpretation on Friedgood's
work ~This ooncept of oyolio response by the thyroid is
helpful in explaini!lg many phenomena, suoh as the temporary
effeot of using the thyrotropio extraots thus far available.
But it is diffioult to reoonoile the oyolio oonoept with the
well knO'Wll essential oonstancy of the basal metabolism in
 33

man and animals. It may mean that the thyrotropic substanoe

is not the normal stimulant to the thyroid seolusion~ but it is
only a superimposed oontrol for oertain emergencies. It Along
this line of thought i8 the work of A. Sturm and W. Schoning
(113) who disoovered that the ovariea~ adrenala, pancreas, eto.,
opntain oonsiderable amounts of thyrotropio substanoes~ greatly
in excess of the "hormone deposits" in the hypophysis whioh
up to the present time was considered to be the only site of
production of these principles. This led to the question of
whether the thyrotropio hormone is speoifio to the hypo-
phySiS, a questio.n best answered by their assuming that the
hypophysis is the site of transformation of oertain ohemioal
impulse1f whioh, departing from endoorine glands with a def-
inite tendency to direotion (thyrotropio, gonadatropio ..
adrenotropio, eto. ) are conveye~ to the hypophysis. The
relation of the thyrotropio prinoiple to thyroid metabolism
is pointed out by Loeser (SO) who stateS that it even con-
trols the taking up of iodine by the thyroid. Unler the
stimulation of thyrotropio substanoe deorease in the iodine
oontent of the gland is paralleled by deorease in thyroxine
content (62) furthermore the aotive iodine fraotion of the
blood is increased. (68)
Houssay and Artundo have proved that the anterior lobe
exerts its influenoe in the B. M. R. through the thyrOid, for
they find that hypophyseotomy lowers the B. M.R., but sub-
sequent removal of thyroid lowers it still farther,
. .
while af'IBr
initial thyroidectomy removal of pituitary does not affeot
basal rate. (74) The relationship of oyanide to the thyra-
tropic prinoiple is put forward in Marinets (82) hypothesis
that oyanide inhibits tissue oxidation. Amongst other tissues
the hypothalamio oenters are effected. These stimulate the
anterior pituitary so that disoharge of its thyrotropio
faotor is increased, and the thyroid subsequently exhibits
hyperplasia. At the same time the sympathetio system is
stimulated, either direotly or through the pituitary and a
hypothal.m~c oenter, and thereby the pupilla-dilator and
Muller's musoles are affected and exoptha1mus results. It
has been shown by a number of investigators that the thyra-
tropic piinoiple produces exopthalmus in both normal and
thyroideotomized guinea pigs indioating that exophthalmos
is not dependent on a nor.mal or an abnormal thyroid seere-
tioh. (112) (79) Quite reoently Blum has announoed his
theory regarding "Kateohins" whioh he designates as in-
hibitory substanoes adjusted to the hormone, this substanoe
has a definite anti-thyrotropic action and is deoreased in
Graves disease. Blum believes this substance is formed in
the liver. (24)

Adrenotropio

As stated previously, it has been seen that in experi-

 35

mental giant animals adrenal lesions may oocur, and further

that in pituitary basophilism there may be adrenal oortex
involvement. The olose resemblance betwee.n syndromes of
pituitary basophilism and adrenal cortex in itself suggests
a 0 lose interrelationship. Anselmino and Hoffmann (11) (27)
have shown that the prinoiple oan be separated by ultra
filtration (through eight peroent, aoetio aoid callodion)
fram the gonadatropio, thyrotropic, parathyrotropio
growth, laotogenic and fat metabolism principles. It is
present in the aoid ultra filtrate, which only contains
in addition the diabetogenic principle. This substance
is ~ter soluable, but insoluble in lipOid solvents. It is
preCipitated from aqueous solution ~r exoess of alcohol or
acetone. It's properties suggest a relatively small molecule.
Collip (29), by testing extraots from the alooholio mother
liquor from whioh most ot the thyrotropio principle has
been removed found that they had excellent adrenotropic
aotivitye Fram a 75 percent acetone soluable fraction
he obtained on concentrating in the aqueous phase at a pH
5 to 6 a fine flacoulent preoipitate, which was removed,
extraoted with dilute a.mm.onia, and the ammonia removed fram
the extraot by vaouu:m;:distillation. The reSidue, tested on
hypophysectomized rats, had no thyrotropio ac~ivity, but
restored the atrophied adrenal cortex to normal in daily
doses of a quarter of a milligram. Collip considers this
 36

as pure a prepar$tion of any pituitary prinoiple as he has

been able to obtain. The mode of operating of the adreno-
tropio hormone is still in the oonjeoturing stage~ it is
known that hypophyeotamy oauses atrophy and anterior lobe~

adrenotropio injections oause hypertrophy. Likewise it has

been shown that the relationship is reoiprooal and that
oellular ohanges take plaoe in the anterior lobe in adrenal
oortex disease. That this adrenotropio hor:mone may have an
effeot upon other struotures than the oortex is suggested
by the faot that removal of either the adrenal cortex or

pituitary oauses atrophy of the gonads. This is repaired

by pituitary injeotions in the absenoe of the adrenals, but
is not by adrenal oortex injeotion in the absenoe of the
pituitary. (103) Perhaos this explains the reoent linking
of the adrenals to a role in Cushing's syndrome. Further
than this the authors fail to go on interrelationship of
the adrenotropio hor.mone.
Gonadotropio

Various methods for oonoentrating the gonadotropio

prinoiple has been desoribed. They involve either extraotion
with aoid or alkali or aqueous pyridine or aqueous butanol.
No marked oonoentration seams to have been effeoted as yet ..
The prinoiple is soluable in water, aoid and alkali, and is
moderately resistent to heat, although boiling purified pre-
parations in slightly aoid solution destroys it. It does not
 31

dialyae and is probably protein in oharacter. Zondek and

Asohheim (120) believed from their earlier work that there
were two gonadotropio hor.mones, one oontrolling and stimulat-
ing ripening of the ovarian fa11io1e8 ani aedius, a.nd the other -
the so-oalled luteinizing prinoip1e - stimulating the ohange
of follioles into corpus lutea. This belief has reoently
gained support by the study of the relative effects of pit-
uitaries of different speoies of animals as it is stated that

in the different speoies the relative amounts of the sub-

stanoes vary. (18) (10) Fenald and Hisaw (59) olaim to
have effeoted a partial separation. They extraoted des-
sioated sheep pituitary powder with aqueous pyridine, and
treated the extraot with water, obtaining two fraotions.
One, soluable in water was very aotive in stimulating growth
of follioles in the ovaries of immature rats and rabbits,
but relatively inactive in inducing luteinization. The less
soluable fraotion was practioally inaotive for the first effect,
but produoed luteinization. Before stating the more reoent
oonoepts as to the meohanism of the gonadotropio hor.mones it
might be well to cite some oonolusions reaohed by Smith (1)
in his ohapter in Allen's sex and internal seoretions. The
following will be partial quotations from his work. ~Evans

and Simpso.n (1929) reported that in rats the pituitary of

the adult male is about three and one half times as potent
as that of the female. Since the anterior lobe il1 the male
 38

is smaller than in the f'emale., it is evide.nt that the

pote.noy is still greater per tissue unit. The age of'
animals in f'oetal or early post-foetal development at whioh
the pituitary eontent of' gonad stimulating hormone beoomes
Buff'ioiently great to be deoteotable by llftplanting into
immature rats or mioe or by injeotion into rabbits has been
reported by a number of' investigaters, Smi'l:;h and Engle (1927)
found this hormone present in rata five days of age. That
this hormone., though present same time before birth, is not
present in early foetal life in suffioient quantities to be
deotable by the Mouse test is shown from the stUdies of
Smith and Dorlztaoh (192e) on pig foetus. The gonad stimu-
latlng prinoiple of the pituitary is also prese.nt in animals
post aotive selltUal life_ A oorrelation of the oontent of
the gonad stimulating hormone of the anterior pituitary with
the stage in the oestrus oyole, has been reported. Smith and
Engle (1929) having noted in earlier work that pituH;aries of
female guinea pigs varied greatly in their oontent of gonad
stimulating hormone, suspeoted that this might be due to
stage of' the oyole at whioh the pituitaries were r~10ved_

They f'ound that gland from guinea pigs in oestrus of'te.n

gave no response when implanted i.nto white mioe, while those

at mid dioestrus gave good responses •. Wolfe (1931) in a
similar study with the glands of the sow seoured more uni-
form and extensive data. Using the ovalation test in rabbits
 39

he reported that the capacity to produoe ovulation was

greatest during pre-oestrus~ was diminished during the
heat period~ and was lowest at the suooeeding lutein phase.
These experiments oonvinoingly sh~« a periodioity in the
sex hormone oontent of the pituitary oorrelated with the
oyole. Although the parabioses experiaments of Kallas
(1929) show an inorease in the liberation of the gonado-
tropio hormone into the body fluids of oastrated rats
assooiated with the inoreased pituitary oontent of this
horm.one~ ne::vertheless~ the faot must be kept in mind that
a liberation of the pituitary sex hormone parralleling
the hormonal oontent of this g land has .not been demo.nstra ted
under all oonditions. It is the amount of hormone liberated
into the oiroul~tion by the pituitary~ not that whioh is
oontained in the gland~ Whioh is funotionally signifioant.
The anterior pituitarywDDks direotly upon the

gonads as shown b' the ineffeotiveness of implants in

go.nadeotomized animals. The oontradiotory evidenoe upon
the alleged antagonism betwee.n the male and female gonads
has been explained by the work upon the hypophysis. Lip-
schutz and Krause (1923) showed that the amount of gonadal
tissue present was important in the fate of the transplant.
Visualizing that the apparent depressant aation of one gonad
upon the other was not an aoutal depression but a pituitary
defioienoy phenomenon - Engle (1929) showed that the degree
 40

of growth of an ovarian graft into the other sex, if equally

vasoularized, was dependant upon the amount of available

anterior lobe hormone. With the growth of gonads of both

sexes in the same animal st:bnulated by pituitary implants

the effeots oharae-teristio of eaoh sex developed. tt

As was pointed out by Smith in the previous quo-

tation the gonads exert an:iinhibitory effeot upon the

seoretion of the gonadotropio prinoipla. Nelso.!l (87)

through experimental work conoludes this suppressing

aotion is upon the seoretory phase of the anterior lobe

basophilis. In the male the hypophysis is less easily

influenoed by gonad hormone, so that apparently it is

never suppressed to the extent that the male reproduotive

funotions exhibit oyolio oharacteristios. The explanation

of this suppression of' anterior lobe aotivity some authors

ha ve sought to prove the existanoe of asexual oenter gi v-

ing impulses to the hypophysis and the ovaries. Zond~li:::

(121) believes that a oentral regula tion of' the sexual

funotion is pOSsible but ~ thinks it has not been proved.

The theory has in paDt been based on axperimentalw ork with

rats and in faot it has been assumed to explain the .negative

prolan finding in pregnanoy. The rise in the estrin level

in pregnanoy is supposed to bring about, by way of the

oerebral sexual oemer, an interruption in the seoretio.n of

the anterior lobe, i.d. oessation of prolan produotion.

 41

This theory will not be proved, Zondel thinks. until a

suppression of ovarian activity can be demonstrated by
sbutting off a definite brain area. Prolan A or the follicle
stimulating hormone has been found to be more potent when
given with the luteinizing hormone or again when given with
the pregnancy urine hormone. It appears therefore that
developme.nt in the evaries may take place as fellows t
(1) The felliole stimulati.ng hormone produces

primary follioles.
(2) The luteinizing hormone then acts upon the
primary fellioles developing antra.
(3) The folliole stir!lulating hormone then Mts upon
the antra containing fo.llioles to produce maoroscopio fo.llioles

and (4) The luteinizing hormone oan again aot to produce

oorpa lutea. (so)

It has been known that ohronio administratio.n of

gonadotropio extracts from the pituitary or from pregaanoy

urine leads to the for.mation of substanoes inhibiting their
aotion, and that a passive, resistanoe to both of these sub-
stanoes may be produced by administration of serum obtained

fr~n animals ohronioally injeoted with these gonadotropic

substanoes. (15) eollip would interpret this as an anti-
hormone reao'bion, however, the follO"V'ling experiment in-
dioates an other interpretation. Litter mate famale mioe
were united by parabios is at thirty days. Atter fifty days
 42

hypophyaeotamy was done on the right member, then after

maturity had been reaohed the left mamber was oastrated.
The results of this experiment showed that the hypophyseo-
tomized rat did not get enough hormone to maintain body
weight, thyroid, adrenals and ovaries at normal levels.
Castration of the normal fama1e produoes enough folliole
stimulating hormone that the hypophyseotomized animal goes
into oonstant oestrus, the ovaries being obviously over
stimulated. However, not enough oestrin aooumulates to
prevent complete atrophy of the seoondary sex oharacteristics
in the castrate whioh is evidence that muoh oestrin leaves
the blood. This oondition persists indefinitely shOWing no
loss of sensitivity in the follicle stimulating hormone.
Henoe these authors conolude that prolonged stimulation with
gonadotropic hormone of heteroge.neous origin is an immunity
reaotion to a foreign protein. (49)

(1) lactogenic
The lactoge.nic principle has bee.n obtained by
Riddle. (9S) By isoeliotrio preoipitation of an aoid extraot
of anterior pituitary tissue, a fraotion whioh stimulates
develapment of the crop gland in male, female, or castrate
pigeons. The laotogenic hormone is apparently ohief1y of
importa.noe in the initiation of seoretion after the breast
has been prepared during pregnanoy by the ovarian hormones
 43

or those plaoental produots whioh replace or simulate them.

Experimental work with this substance is rather soarce as it
has shown itself to be ra~her polyvalent oausing ohanges in
both adrenals and gonads. The aooepted mode of opperationn~

expressed is that suokling seams to stimulate the seoretion

of prolaotin through a nenvous pathway not yet disoovered.
Hypophyseotomy or withdrawal of pituitary hormone at any time
during laotation oause an ~ediate oessation of the flow. (76)

Growth Hormone

The growth honnone, although one of the first anterior

lobe extraots to be isol~ted, has now shown a tendency to join
the group of indefinitely defined pituitary funotions.- Evans
purest preparation of the growth prinoipla (65) is made by
extraoting pituitary tissue with alkali, preoipitating the
extract with aoetone (the ppt. whioh also oontains the
gonadotropio hormone) and extraotion with 95 to 98 peroent
aoedia aoid, whioh destroys the gonadotropio but does not
affeot the growth prinoiple. Aoetone is added to the
extract i.n presence of quinine sulphate, and the growth
principle is thrown down, oompletely freed of gonadotropio
prinoiple. Collip (33) extraots anterior pituitary with
alkali, acidifies, and filters. Ammonia is added to the
fil trate to a one peroent oonoentration, and than oalcium
ohloride and s odium phosphate to give a suspension of caloium
phosphate, which oarries down the active prinoiple. It is
 44

extraoted with very dilute alkali, the pH adjusted to 65,

ammonia added to alkaline, and the material oonoentrated
in vaouo to p H 7.5 to 8. A sanii-orystaline material
separates. This represents between O.! and 0.2 peroent of
the original material. This produot has no effect upon
the thyroid or on basal metabolism. Sometimes an effeot
on the adrenal. is observed. It has no effeot upon the

gonads but does seem to oontain a traoe of prolaotin.

As to the mode of operation of the growth hormone if
suoh is its idenity the opinions of the authors vary oon-
siderably. Severinghaus (104) makes the following statement.
ttIt is 11M being suggested that the growth promotio.n is
not the result of a separate hormone, but rather the oombined
oonsequenoe of "B8Veral other materials (those previously dis-
cussed in this thesis). Active extraots whioh promote the
rate of skeletal and visceral growth of humans and an:1mals
are now in use. These mixtures may also oontain s orne other
biologio materials whioh have been demonstrated to produoe
growth (glutathione ?). They are knvron to be mixtures with
some of the above mentioned fraotions present. Thera are
evidenoes of distinot effect on nitrogen metaboliam with
the use of suoh pituitary solutions. The varying piotures
of gigantism, aoromegaly, and dwarfism as we)..l as the
different types of infantilism may oocur as oonsequenoes of
varying disturbanoes of this one gland, with slight relative

1,--
 45

ohange in one or more of the faotors enumerated."

Evans, Penoharz, and Simpson (57) found that
purified preportions ot the growth ho~one differed from
the oruder extraots previously used in their inability to
maintain the growth of hypophyseotomized animals after about
thirty to forty days. This may be aooounted for by assuming
that the crude alkaline extraots oontain materials other than
the growth hormone which are essential to survival in the
absenoe of the anterior lobe. The theory of anti hormones
suggested by Collip and his oollaboratoes thus beoomes super-
fluous here. Suoh a theory, moreover, is inoonsistent with
the faot that the crude extraots do not lose their effioacy,
and also that only animals deprvied fo the hypophysis become
refraotory. It might be well to note that at the present time
there are only two such extraots marketed. The Squibb extraot
is of the more oomprehensive type, the Parke-Davis extraot,

more highly fraotionated one. This may influenoe the choioe

of an extraot in a given:ease.
There is no evidenoe that the growth hormone aots
direotly upon wide spread tissues b~ body that it stimulates
to inorease. It is possible that growth is due to stimulation
to over-funotion of one of the other endoorine glands for
example the thymus. Asher (14) obtains £rom the thymus a
sbustanoe thymooresin whioh stimulates the growth of rats.
__ ~ L _

46

Others have noticed disproportionate hyperplasia of the

thymus in dwarf rats when treated with the hypophyseal
growth hormone preparations. The exaot meohanism if the
growth hormone is not known but aaignifioant beginning is
made by an analysis of its effeots. (1) There is a deoreased
nitrogen output indioating that nitrogen is retained to build
up new tissues. (2) There is an inorease ~n water intake.
this is followed by polyuria whioh is a purely physiologioal
effeot. (3) There is found to be an increase in the respiratory
and ventilation rate. (4) There is an inorease in heat produo-
tion which is due to an inoreased oxidation of fat. (53) Further
studies of Lee and Shatter (98) showed that treated animals d~

not possess the oharaoteristio age ohanges that normal rats

present (i.e. a decrease in the proportion of water. nitrogen,

fat tree dry tissue and ash and an inorease in the per-
oentages of ~at.)

In oonoluding this paper I wish to point out some

reoent ideas relative to the hormones of the anterior pit-

uitary and stress some findinglF<already made. It has been
made apparent in this paper that none of the trophio sub-
stanoe of the pre-hypophysis have had their ohemioal seoret
disolosed. This situation is quite in oontrast to the
hormones of the other endoorine glands; in these glands
rather exaot knowledge is available as to their ohemioal
 47

struoture. (45, 46, 47) Mention is made of this situatio.n

as it aids in making tenable the very interesting hypothesis
of Arthur Jores'who points out that it is not reasonable
to suppose that the oells of the hypophyses are oapable of
produoing fifteen different 8ubstanoes, espeoially sinoe
they are oells already differentiated, with funotion in

a oertain direotion laid down. Theoretiaally, the most

reasonable explanation leading out of this diffioulty is
to assume that the hypophyseal oells form oertain basio
substances -out of whioh the separate hormones are later
developed. Perhaps some of the extraoting prooesses used
to separate the various trophio hormones only serve to
aotivate a mother substanoe. Likewise, this mother sub-
stanoe might be aotivated outside the pituitary or it may
be aotivated through nervous stimulation in the hypophyses.
Another point along this 11.ne of thought is the olose re-
lationship of the vitamins with the hormones. This re-
lationshipis only evidenoed, as far as the anterior
lobe is eoneerned, by the finding of greater unit oon-
oentrations of the vitamins (0 partieularly) within the'
gla.nd.. In other hormones (oestrogenio) a s imilari ty of

ohemioal struoture and the ehamioal struoture of the

vitamine has been shown - both having a phenanthrene base.
Earlier authors termed the hypophysis the "mas'cer
 48

gland" suggesting that this gland was the prime mover,

and that all other endoorine ortans dependent in some

way upon it. Present information, such as the absolute

.neoessity of adrenal oortex for life, the isles of Sever-
inghaulJ and the::.manner in whioh thyroidectomy and gonad-
ectomy influenoe the hypophysis, offers suffioiant grounds
for denying the independant mastery by the one gland.
Prof. E. J. Witzeman suggests that the hypophysis may still

be '-master": - he likens the gland to an exeoutive who

gives direotion and ooordination to the whole. "The mutual

interdependenoe of the employer and employee is not viola-
ted by oonaidaring one the master of the situation. tt Just
where the anterior lobe fits in with the reoentwork being
done on the hormonal relationship to oaroinama is not
known. Cramer has shown that the oaroinogenio oestrogenio

substanoe when rubbed on the skin of sane mioe produoes

a cancer; in these same mioe ohanges in the anterior lobe
are quite marked.
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