Anterior Pituitary Body and Its Relation to the Reproductive Function

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5-1-1934

Anterior pituitary body and its relation to the reproductive function

Harold A. McConahay University of Nebraska Medical Center

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Recommended Citation McConahay, Harold A., "Anterior pituitary body and its relation to the reproductive function" (1934). MD Theses. 337. https://digitalcommons.unmc.edu/mdtheses/337

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iLPRIL 1934 (a) ~. ~'Iypophys is t Antal' lor lobe (fema le )

B. Genital Hormones C. Ijrowth Horn:ones D. Synergistic Hormone

.3 • Thyra i d r; land

}'. (Iva la t ion::::orr:nne

G. Luteinization Hormone

E. (lvary

I. 3uprarenal Glands

J. ~raafian Follicles

.K. J 0 rp us :L tl t e um

L. ::Jornif iea t ion r. Hormone "A!1

II. iOl'MOne tlBIf

0. ttlC if iea t ion

P. Vaginal l'uensa

1. Inhibitory ~ormone

(b) INTRODUCTION The outline of this work follows in secuential order the functional phases of the female mammalian organism--puberty, menstruation, pregnancy, lactation and menopause. These physiologic phases are lnainly governed by the development, and later decline of ovarian function, which is in turn, controlled by fluctuations in function of the anterior pituitary lobe, and other related glands of internal secretion. This monograph is a survey of the literature the purpose of which i5 to correlate the evidence wbicb leads to our present concept of the anterior pituitary body, and its relation to the reproductive function in female animals. The clinical apDlication of our present knowledre is limited and has led to many conflicting results. However, judging from the rapid advancement in the past, we are safe in predicting a very fruitful future especially with endocrine therapy.

I c~10se this sub je c t to fa.:m i letr ize elf Witll a sctb,jGct excee d i1121 'l fac ina t 1 arlfJ ealing, and, one whiJh ie rapidly ".. ~' ~ becomin? pnpular both in the early Taco itioD of CLinical syn- drOEBS as well ~s vnrable t reapeutic results.

~~naocrillology is in its LnffHwy '~lIld is in ti1.€ experimental sta ~ypical clinical cases relative tn this particular sub-

ject were Gnt available, consequently laborat0ry anirals and experirental resetlts (U;:,VCJ been s tit:.1teci.

(c .) His to I" i ca 1 .... lO .... '" •• '" •• " •• " ...... '" • " " " .. " ...... '" •• 1 ii.na torny .. " .• " •• " • " •• " " • " ••• " •• " • " " " " ..... " " " " " .... 2 Puberty •...... •.....•..•....•..••... 4 ,- ImI.l1anta t ion J;xperiments. " " " ••• " • " ... " " " • " " " ., ••• 0 Feeding Experiments ...... 10

Hy'pophysectomy. "'" •• """"."" ... "" .. """ •• ,, •• ,,",, .. " .... 12

Cas tll:a tee" • " " " " " " " ..... " ., . " ... " " " '" ..... " ., ... " " " " " . " " • " 13

'1: he Sex Hormones •...•...•..•.....•.....•...•... 17

cheim-~ondek Test ...... •...... •...... •.• 20

Pr~egna.ncy C.hunges""""""""" .. " .. """"" .. """".,,,, ..... ,, 22

L~.lcta t ion. " " " " . " " ... " • " " ..... " .. " .... " " " " .. " " " • " " "" ,,26 l:~enOl,)~::ll1Se" •• " • " ...... " " " " " " .. " " " " " .. " ... " " " " .. " " ... 28 i..50nc 1 us ion" " " " .. " " .. " " .• " " .. " " • " • " .. " " • " " ...... " ..... 29

Bi bl iogr~apflY" . " " " " " ..... " " • " .. " " " ...... " " .... " " .. .- .. • 3C'

( d) 3:ISTORICAL

Our earliest conception of trle function of the pi tui tary

gland came from Galen. ~is idea wes that it acted as a filter

for the sedimented waste nroducts of the brain and that these passed out through the infundibulum as a "pituita" or slime from the nose. As late as 1631 Robert Flood explained the etiology of coryza on the principle of a siphon action between the ven tricles and the nose. In Thomas Gibson's anatomy (lS88) it is inferred that in animals such as calves, who have a large pit ui tary \,li th rich arterial supTlly the gland seems to have the same relationship to the arterial plexus as the pineal body has to the choroid plexus; its purpose is to separate serous fluid f'rOT., t he lymph. Very little progress was made in the study of the pituitary body until Pierre Marie (1866) (98) made the discovery that acromegaly was associated with tumors of the gland. This bril l iant observation was confirmed by rankous}~i (1887) and T!lany other investigations since. It turned a new page in the history of hypouhyseal ~hysiology. To be sure acromegaly and gigantism were recognized as clinical entities knOWT to be associated with hypophyseal tume faction. (Pierre Marie (98) and !,:inkouski (41), but Pechkranz (1899), Frolich (1901), Axenfeld (1903), :'uller (1905) (108) and others were calling attention to existence of tumors of the gland or its neighborhood associated with combinations of optic atronhy, amenocrhea, infantilism, adiposity, and often, diabetes insipious. A relationshIp betweeL the hypophysis, and genitalia 2 was, consequently, inferred, but not understood •. As early as 1898 following the work of Howell (86) special attention was given to individual lobes of the gland. Much ex- - perimentationhas been done since to determine the effects of extirpation of the whole gland or :part of the gland, feeding the se-r;arate lobes together atd separately and the administration of extracts of the various lobes individually and collectively •. Prior to the work of Paulesco (1907) (113) a Roumanian investigators , the generally accepted opinion was that the pituitary body was a vestigial structure and of no consequence to the organism.. Total extir9ation of the hypophysis of experimental dogs resulted in their death. Thus, he concluded that the nituitary gland is "essential to life~ Crowe (25), C~shing (27) and ~~omans (1910) (85) reDorted the compl ete removal of the anterior lobe alone resulted in a characteristic train of syru- ntoms termed, tl Ca chexia-pl1Yilopl1yeopri va," resul t lng in death of the animals, therefore confirming Paulesco's (113) observations.

Before proceeding with the main issues of t~is paper it will be necessary to briefly review the a~atomy and histology of the pituitary g19nd. It is an ovoid shaped mass about the size of a pea; situated within the sella tutcica at the base of the brain just behind the optic chiasm. rpon sagittal section the gland is seen to consist of an anter10r and a posterior nortion. The anterior lobe or pars anterior is larger and has a - ,slaLQular structure. Embryologically it does not belong to tbe brain but is developed from a ~ouch in the oriffiitive oral cavity. It is without B duct, as it is one of the glands of internal secretion. Histologically tbe glard is composed of three parts: (1) the largi anterior epithelial lobe, pars anterior; (2) a much s!Iialler Dars nervous or infundIbular, pars posterior, aLd;

( (3) the pars intermedla. The ectoderm of the mouth (Rathkes pouch) origir:ates the anterior lobe which soon becomes a glandular structure. An outgrowth from the floor of the infundibular pouch of the telmencephalon, the mid-brain, develops the posterior lobe. The posterior lobe consists of two parts: (1) the neu roglia cells and fibers with ependymal cells and; (2) the pars intermedia composed of epi thelicll cells from a diverticulum of buccal epithelia, the posterior pharynx and is ectodermal in origin. The anterior lobe contains cells which are clear in hold, in their protoplasm v0rying amounts of granules, which stain deeply. It contains three kinds of cells: (1) the "haupt

zellen," (2) eosinophiles, (3) baso-philes. Erdheim and stumme (51) call the eisino::hiles or acido]?:tliles and basoLJhiles or cyanophiles because their proto-plasITl intersely takes the staJ ns, the chromophiles, while the "Hauptzellen" they call chronrphobes because their protoplasm is difficult to stain. Rasmussen (115) by means of reconstruction of cross sections of many glands, determined the relative number of these cells. He found ttat the chroTliophobe cells make up the largest percen tage (52%), the eosffiophiles occurred in 37% and the basophiles 11%.] In advanced age the chromophiles were unchanged. The eosinophi les are located in greater number In the anterior '.or tion of this lobe near the margins of the alvoeli. The ohromo phobes and basophiles are Jocated in the center of the columns and are present in large numbers in the ,osterior part and near

the stalk of the infundib~pl. 4

The im~ortance of these cells in the secretion of the hy pophysis, and their relationship to the general metabolism of the orf8Lisru. has been 11he subject of much spececlation and experimentation"during the past decade. W. P. Covell (24) has shown th9t the growth in weight of the anterior hypophysis during embryonic and early fetal periods is very rapid. The hypophysis and its lobes grows in weight similar to the increased weight of such vital structures as eyeball and mid-brain. The hypophysis of the full term fetus, consists mostly of pars anterior, roughly 78% (2% pars interr:ledia, 20% pars nervosa.) The generative glands of the embryo is under the influence of the maternal pituitary and the eer characteristics are develop ed up to an infantile state which is complete at birth (Benjamin.). Evans (1928) (44) and Smith (1929) (125) found by experimentation on -pig fetuses that the growth hormone appears earlier than the sex hormone. The anterior lobe of the hypophysis of infants does not function as yet. The inter,na1 secretion of the inffHl tile sex gland is dormant, the sexual chAracters do not develop to matur:i ty. Now comes the n grel:1 t intermission" (Benjamin) (ll). The meaning of this internission can be understood if one considers th~t the infantile body is not equal to or capable of a sudden sexual precocity. During the prepuberal period the internal secretion of the anterior lobe is being utilized for general growth. (24) After the organism has been developed and stren€thened, the l'ltuitary aSSUIlles its actlvatir:g functions. The incretions of the sex glands become lively and the sex characters ra~idly grow to maturity. With the advent of puberty and corresuonding fa11jng off in the rate of growth, quantities 5 of the anterior hormone are set free for the proffiotion of ovarian development. The ovaries increase in size under pituitary

(~ -<0.,. stimulus (Engle) (32). It begins to secrete the oestrin-procuc- ing hormone which is responsible for the onset of -puberty. This state of maturity lasts with individual variations up to sene sence. Then the decline sets iL., the pituitary grows inactive, the iL.cretions of the generative glands cease, the entire endocrine system suffers through this cessation, the sex glands retrogress, thus causing the state of maturity to disappear. This sequence of events shows the importance of the pituitary in the mechanism of the development and establishes a "biological law of puberty." The old concept regarding the hormones responsible for the

onset of puberty, as showr~ by Mazer and Hoffman (102) and many

others, was that they ~ere derived from the Graafian follicle and its successor tbe corpus luteum. The old puberty gland trJeory of Steinach (11) attemnts to correlate the seat of the hormone

production in the i~ter£titial cells of the ovary and testes which he claimed induced puberty and maintained sexual activity. These views were violently disproven by the mocern concepts established by the rigid and fruitful experjmentetion of Smith (123, 124, 125, 126, 127, 128) Smith & Engle (12G, 130) and Ascheim and

Zondek~ (150, 151, 152) and many other investigators. 6

IMPLANTATION EXPERIMENTS Faa (109) as early as 1900 suggested that the periodic changes in the ovary de~end upon some force extern&l to and distinct from the ovary. He found that the ovary of the immature animal grafted into an ovariectomized adult soon attained the state of maturity. T~e association of these findings with the clinical observations of Marie (1889) (98), Frolich and Cushing (27) clearly pointed to the anterior pituitary lobe as the origin of the cyclic ovarian changes. The complete dependence of the ovary upon hormonal influence of the hypophysis was not realized however, until the independent and almost epoch making discoveries of Smith and Engle, and Zondek and !scheim was effected. The in dependent work of these JiJllericar and German investigators publish ed almost sim~ltaneously, represent one of the most brilliant advances 1n our knowledge of sex 'Physiology. Previous to 1921 many attempts to obtain a promotion of growth and the stimUlation of the ovaries of laboratory animals v:'ith various '"!reparations of the anterior lobe, and although one or two successful results were obtained the evidence on the whole was not conclusive. Klinger (89), Hofstetter (48), Clairmont (19) attempted with negative results, the transplantation of the fresh living gland. Smith (125) in 1~26 used daily traLsplants of the anterior lobe with attempt to overcome the effect of hypophy sectomy on white rats. He found that not only was he able to restore an alma st normal g-'owth ra te, but i12 aedl tioll there was partial renair of the injury to sex glands. Smith (123), Smith and Engle (129) extended the study of anterior pituitary trans nlar:tation, using immature, Jemale rats for recinients of 7 transplants from full grown males or female rats and mice and were able to promote sexual precocity in them by only four daily treatments. A whole fresh anterior lobe was implanted intra muscularly into the recipients. There W::1S establishment of, with striking rapidity, the virginal canal, aO uterine hyperemia, oestral "accummulation of fluid, a formation of large follicles ana copora lutea. At autopsy the sex organs showed tremendous hypertrophy the ovaries gave evidence of ovulation and many ova were found within the Fallopian tube. The changes that took place within these precociously mature females corresponds to those normally occurrjng at sexual maturity. Ascheim and Zondek (150) working independently and simul taneously with the above Buthors"also by a series of classical ex:periments upon young whi te mice, succeeded in producir:.g sexual precocity by similar transplantations of anterjor lobe tissue. They found that Lot only the glands obtEdned from iImnature and senile an:i.mals was effective, but those from human subjects ane cattle as well. They used transplantations of thyroid, testes, pineal, thymus, adrenal cortex and medulla, aLd poster'or nituitary body with no effect in bringing ovarian function into action. Only anterior lobe of pituitary gland was shown to ·'roduce effect. They conclude: "If an infant ile mouse of six to eight grams weight receives an implantation of a small "i,iece of fresh anterior lobe from man and animal then after 8 to 100 hours the mouse is in state of oestrus. By tbe implantation the active principle, 1. e., the hormone of the anterior lobe is given to the mouse. The hormone of the anterior ana only t!':is- sets iIi action the latent ovarian function and thereby brings the infantile mouse to sexualc,,~turi ty." These outstanding 8

works of Smith and Engle and Zondek and Ascheim have received abundant confirwation from numerous sources: Biedl (12) Ehrhardt (42), Lipschultz (95), Brouha and Simmonet (17), and others. These works show that a substance is elaborated by the anterior lobe 1'lhich stimulates the formstion of corpora lutea in ovaries of normal, mature and immature animals. Male anterior lobes are as effective as fenale ones: thus Zondek (150) implanted glands from a cow and a bull, from a man and a woman, and from a woman four years after climacteric, the glands being obtained shortly after death. In all these CBses

a ~ositive result was obtained, oestrus occurring in mice together with enlargement of the uterus and ovaries. Evans and Long (1921) (49) and Evans (1924) (43) reported remarkable results on the reproductive system of mice and rats by intraperitoneal injections of properly prepared extracts of the anterjor lobe of beef pituitaries. The results consisted chiefly of an inhibition of ovulation, and stimUlation of the luteal tissue of the ovaries, so that many corpora lutea were formed. These observations may have been the starting point of the newer knowledge of the subject, but are different from the classical stUdies of Smith and Engle and Ascheim and Zondek Oi8- cussed above. Slonaker (1927) (122) questioned the criterion by Which Smith and Engle based their conclusions of sexual precocity-- establishment of vaginal canal, uterine hyperemia, oestral accummulation of fluid, and formation of large follicles or

cornore lutea--as an inade~uate sign saying, rSmith apparently did not try the crucial test of sexual mGturity by mating the 9 animals." He overlooked the fact that'it had been clearly shown by Smith and Engle (1922) that mice mated as early as the 20th day of life after two daily transplants. Ovulation also occurred at time of copulation. Furthermore, Engle (35) reports that of

63 inlillature rE~ts when implanted with anterior :pituitary gland exhibit a ruptured vaginal plate three or four days after first treatment, thirty-seven of the sixty-three mated during the first oestrus, thirty of the thirty-seven were killed and found that ovulation had occurred in eleven. Succeedi.ng oestrus occurred at a significantly later date than the first oestrus for norn:al mice, and also first pregnancy. He thinks that it is possible that induction of oestrus delays the appe;;lrance of normal cycle. Daily injections of extracts of gland into female rats causec't the immediate cessation of the ri"ormal oestrus cycle, the cycle remainir:g in abeyance during the perlod of inje.ction. Examinations of the ovaries found them to be filled with sub stantial corpora lutes. Long and Evans (49) concluded that these extracts were rot only toxic to developing ova, but also had stimulating effects on the growth of luteal tissue. This ob servation was substantiated by Teel (136) and also Bellerby (1928) (10).

Implantations of anterior ~ituitary gland into sdult mice and rat causes an increased weight of both ovaries. Smith and ICngle (129) state that the adul t ovaries of rat may be doubled in weight by only six or eight transplants. This increased weight of ovaries is caused by the develo:pment of large number of follicles followed by su:per-ovulation in young and adult, by the excess number of cornors lutea which are formed a.fter ovulation. 10 Hoffman (82) in studying the effects of hypophyseal im p'.antations upon the ovaries of old sexually degenerated mice,

concludes that the imnlants not only are c~:;:p6ble of initiating ovarian function in immature mice but in old meno-pausal mice. Ole non-oestral mice when once stimulated can be kept sexually

active for considerable time ''I!ithout fur:,ther~stimulat10n. These implants maJ' act by mobilizing the latent residual hormone of the senile ovary. In one experimental animal ovulation was restored and succeeded by the €ravid state. Allan (2) in attempt to extend these experiments on to "pr:mates made small subcutaneous im"laLts of fresh pituitary lobes into flank of immature monkeys (Macacus rhesus). A total of four implants of two day intervals was made. In seven days the treatment there was a morbid development secondary sexual ch8.ract eristics and considerable growth in the genital tract and mammary glands. The oV8.ries were markedly enlarged arl.d contaj ned many follicules filled with liquor folliculi. He interprets the marked effects on sexual characteristics and growth of genital tract and mammary gland, as being apparently secondary to the marked ovarian development, noted by Smith and 'i£ngle (129) anterior lobe implants have no effect upon castrated animals.

In vie~ of the results of transplantation f~eding experiments were begun by ~ulzen (148, 149) and Goetsch (1913-14) )72). The former gave the fresh while the latter fed the dried gland to young animals. The results were entirely contradictory, for whereas, Wulzen found 5 retardation in growth of the young fowls, Goetsch showed tha' the feeding of anterior lobe to young rats resulted in the development of the sexual glands, as Viell as a stimUlation to body growth. This latter investigator also re,orted that the ovary of the ~ituitary fed rats contained a large number of corpora lutes. Marimus (1919) (100) reported 11 somewhat similar results. This work of Goetsch (72) has not been corroborated by other investigators. Schaeffer (1912) and more recent work by Long and Evans, Frank (65, 67), Sisson and Broyle (121) have shown that oral administration has no effect on date of maturity in rats. Clark (20) maintained that he was able to stimulate the ovaries in hens, as evidenced by increased egg-laying by feeding fresh anterior pituitary glands. 12

HYPOPHYSECTotlfY By pjtultary ablation an opposite response of the sex anparatus results before sexual maturIty. The comnlete establish ment of the vaginal canal is ~elayed and the genital system remains undersized. Total hypo~:hysectomy in the rat (Smi th- (27) (123) causes an immediate cessation .. of the oestra.l cycle, which is reestabl lshed vvhen repla cement therapy is inst i tuted. The ovaries in these hypophysectomized animals show no large follicles ir: the various st':'J.ges of development (Smith and Engle --27 (129).

Cushing (27) and his c:~-workers recognized the coridi tion produced in full grown animals, was identical with the patholbg ical condition dystrophia adiposo genitalia, in addition to the a~iposity t~ere was marked atrophy of the uterus, and whilst follicles disappeered from the ovaries there was persistence of the interstitial tissue. Furthermore, rtial removal carried out in young animals resulted in persistent infantile condition of reproductive organs. Similar results have been reported b~ Oschner (5) Bredl (9) Dott (30), and Bell (12). The destruction of the pituitary gland by injections of chemical substances, also resulted in marked disturbances in the reproduc:ive system (Smith) (126), Walker and Gaeser) (140), Fraeukel) (68) and Ford) (53), after x-radiation of ~ituitary:region in rabbits report hypoplasia of genitalia. Smith (126) has succeeded in restorine the normal condition of degenerated se~ual organs of hypophysectomized rats by grBft~ng into them portions of the gland. The results of these investigators not only prove the en docrine nature of the anterior lobe of pituitary, but also show the development and activity of the re~roductive system to be dependent upon secretions. CASTRATES Fischera (1905 quoted from Bell) {9} observed in various mammal that the hypophysis increased in volume and weight after castration. According to the same author an increase of the eosinophile cells both in number and size takes plaee in castrsted cocks and certain castrated mal"Jfllals (rabbits, guinea pigs, buffalo) Tandler and Grosz (1908). Kolde (1912) found that total extirpation of ovaries produced hypertrophy of the pituitary, the increase being due to the increase in eosi~ophile cells and a new type of vacuolated "signet rings," cells which they called "castration-cells." Van Wagenen' (1925)(139) pointed out that the 11castration- cells" were basophilic elements. In 1927 Addison and others described findings of anterior pituitary in castrate cats. The change;, consisted largely of an increased number of large basophile cells and also in appearance of the "castration-cells", me~tioned above •. Engle (32) related the increased gonad--stimulating potency of the castrates ~ituitary body to presence of the basophile "castratIon-cells", being "led to suspect that it is the basophile cells which elaborate the gonad-stImulating fact·or in the castrates". Engle also made clear that not only those basophilic cells increased in number after castration, but they also show enlargement and vacuolization of basophil granules, presumably due to storage of hormones. Englebach (4l) states t:lat there are two histologic changes of the anterior pituitary which occur following castration, namely, (1) the appearance of the "cells of castration" and (2) a relative increase in the number of eos:1.rlophiles. He states 14

that these "c:ells of castration" are enormous cells two or three times the size of an eosinophile, basophile or chromophile. The l1rotoolasm sta:1ns distructly pink or neutral with eosin and rnethy-

lene blue. Evans (43) believes they are baso~hiles probably derived from the chromophiles as tlleir relationship to the sexual function would indicate their source. The investigations of LehmaL (94) on the pituitary body of castrate animals show that the normal histological picture of the gland can. be restored by injection of the follicular hormone.

It has therefore been conclusively shown by Van ~agenen (1925), ELgle (1929) (33) Evans and Simpson (44) that the pituitary sex hormones are derived from the baso~hilic cells. In addition they have shown that the anterior lobes of castrsted animals are more :potent in producing premature maturity than similar lobes from normal animals. Also Fluhman (60) has shown that following total extirpatIon of the ovaries in women there is a large amount of anterior pituitary hormone in the blood which is readily demonstrable by the Ascheim-Zondek test. The gonad hormones, of either sex exert a depressing effect unon the hy-ool)hysis which results in a diminished emount of the sex-- stimulating factor available to the orgar>ism (Moore and Price) Consistent with this observation Engle (1929) (33) and Evans and Simpson (1929) (46) demonstrate that the removal of the gonads--testes or ovaries--lead to a greater sex-stimulating capacity of the hy~ophysis. The depressing effect of the gonads secretion, only incompletely sho'wn by the normal animal, becomes apparent when the gonads are removed. Fluhman (1929) (60) finds in women two months t8 sixteen years after ovariectomy, as \,:el1 as women at the menopause. Meyers, Lenard, Irisal";', ('30) (104) 15

injected normal female rats with oestrin for thirty days and the hy-pophyses of these injf:cted females We;-e fer inferior in their abili ty to stimulate gonads than the hypophyses of' their untreated controls. The prolonged administration of follicular fluid can produce histologic changes in the anterior pituitary lobe of guinea pig, {as manifested by hyperem.ia and increase in acidophilic cells (V. Bisceglie) (62). Kunde (92) stated that oestrin inject ed in a dog resulted in lessening the size of anterior lobe of hynophysis with ciminution in the amount of cytoplasm in chromo 'Phobe cells. Ovaries from immature female r ts have been grafted into normal aeul t and castra ted male ra 1,s. (Engle) (33). These grafts will grow in either the normal or the castrated male, if vascularization is establtshed. There is not sufficient gonadal- stimulating factor from the anterior lobe of the host to cause a high degree of follicular development in these grafted ovaries. However, additional stimulus has been given by daily honeo-trans plantations of the fresh anterior lobe. (Engle) (38).

It lJtH3 10 phy of' tile romfl lnLIe?" oV!::ilywill oee ill' in ra ts 2:l rabbits t'ifter one ovary nus been removed.

Jansen & Boon (26) fa taat 11 tao tubes of' oae ovury is tioa off, b~t taB ovury left at. ~'~lU (jt:le~c ova.

ot~er fro~ ?r~winp behond a certain size or produc over a ceI'- taLn average narnber of ova iAn' ovu.lu ti0n.

Lipschultz (95) in his f'f Cf"1(}>::., ~c,n t follicle n:..rrrber which 16

is supported by u at deal of 00nvi icing s rimental evi nce ctor icn causes follicular growth and cOFpensatiolJ. hypertrophy is to be so,.t fran 80,'"13 extra-

·f O" ...... tao anterior pituitary lobe on t development und ro t io;). of

J.O is t (lEo so u.rce of t ctar responsible for follicultiT vel0pmcnt und therefore the determining factor for compensatory hypertrophy oft he 0 vay y oft unilateral or subtotal ovariectomy. 17

THE SEX HORMONES From the foregoing it is shown that the anterior hypophysis has no effect on the vaginal tract or utsrus in ovariectimized animals. Moreover, the ovari.an hormone when injected into normal animals does not produce any effect u·on the ovaries, but apparent- 1y only acts upon the uterus and vagina. Lipschultz (1927) (95) suggested an extra-gonadal factor which he thinks responsible for

initiation of the ovarian activity. Since t~e work of Smith and Engle and Ascheim and Zondek he concludes that the anterior

pituitary tissue ~roduces the X-factor. This same X-factor was responsible for the development of hetero-sexual ovarian grafts. Kraul (91) referred to the anterior pituitary gland as the

ttregulator. n Z::mdek and Ascheim (150) made the following conclus- ion "the anterior lobe hormone is the motor of sexual function. The anterior 1.obe hormone is primary, the ovarian the secondary. The anterior lobe hormone brings the follicular apparatus into actton, fires off follicle-ripening hormone and mobilizes the secondary ovarian hormone in the follicular cells. This thep acts, in a snecific 7ay in the uterus and vagina". , Evans and Simpson (45, 46, 47) attribute the alterations produced in the ovary by anterior pituitary lobe to two hormones. These are first, a "groy{th hormone" which is closely related to the eosinophile cells of the pars anterior and a !!gonad-stimulat-

ing!! hormone corresponding to the baso~hilic cells. They state that these two '1ormones are antagonistic to one another and can

be completely Dullifjec by simultaneous adnd nistration. Bellerby (lO) also believed that there are two anterior

- nituitary hormones, namely, an "estrous-~roducing" and an

"estrous-Inhi bi ting hormone, It while Lscheim goes" still farther 18 and attrIbutes three hormones to the antertor hY"Pophysis. (1)

the growth hormone (2) the luteinizing hormone and (3) the ovulation hormone. Wiesner and Crew (143) substantiate Ascheims findings. Phillip Smith of New York, who has done some most convincing work upon hormones of the hy')ophysis, is inclined to think that there is only one pituitary sex hormone, and that the cytological and harmonic effect upon the ovarian follicle are merely a continuation of the action of one active principle. The effect of the ovulatIon hormone is the rupturing of the ovarian follicle and liberation of the ovum at maturity. The luteinization, hormone causes the hyperplasia of the lutein cells of the persistent Graafian fo,llicle dur Ing gravidity. In addition there is probably a reverse action of the follicle upon pituitary gland (Moore) (lOG). There is a potent active principle of the ovary which produces inhibition upon the hypophysis. This is important in so far'that it would contra-indicate the use of gonad hormones as a means of stimulating either ovarian or test jcular function. The injection of ovariaL preparation for gonadal anomalies due primarily to ~ituitary disorders would'tend to increase instead of diminish them •

.!.'hat trlere are two gonad.-stimlllhtinfl: hormones produced by trw antelior hypophytlis is the coemon opinio;1 01. the majolity of investigators. ~he extraction and se ration of these, however is another problem. dome: investigators have succee d in sepeH'at ing tnesB factors. ~vans and Long (49) state ~if alcohol is add- ed so thut the concentration is bro~ght to 50% ana the precipitated pr'o ',,19 in Cell ~;r ifu.ge d of tl"H'l i:;1 u.pra.rlu tan t fluid inC:! Lwe oVtlb tory fac tor but .clOt R'Iowth prorotina factor. Ii line extracts ~ontain the 19 growth promoting factor and prod.Qce gigantism." A sir::ilar method has been :r'eported by v(~ld Hisaw and Lenard(5?;}

As c ne im anc1 Zondek (151) have i80 1a te d a R:O.na d -8 t i1:1 la t Lng hormone extracts from t u.rLae of oregnont v,'(lmen. These extracts have ti'le combined physio10,gical properties of follicle- stirrulation and luteiniZing factors which they term "prolan".

The,Y' have also prepared factors said to have separa te properties iIH:l.ividualll and call these "prolan.An antl "prolan BIf. "Prolan

An, follicle ripening or estrus producing substance ~otivates the

oval'iall follicle to production of "estrinfl, which in tern in- d o.ces pro 1 ifera t ion phase of end.o!Y:6 tr il:m:, f1Pro l~:dl BfT is luter'niz- lug prlnciplewhich transforn-·s the granul4'B :and theca cells into lutein cells and therefore motivates progestin (lutein) to cnange - . . prolifer~tive stage of tt16 enctometI'ltUL to a secretory one.

(Pre-r:el1str'l.l.al or .pI"e-gestional stage) 'rhe cner,ic iCientlty of prolan A & B is not understood. It is possible t t we are dea1- ing with different isomers of the same molecule. Prolan B is doubly i~portant because it is the basis for the Ascheim-Zondek

test and second because it is be in~ use d t '.".''''.~ eutically with favorable results.

Tne lute iuiz Lng' nonnone cS.nne tact on the imFa t are ovary. i:he irrrnattlI'e or infantileovary Clwt. be stirc'ulated to follicul;;u' activity by thegOrlfld-stiLl1httin,Q: horn"one br:,iore a characteristic

"mulbery" ovary can be produced.

Hence the' gover'uori :1"'018 of the i)ituitar;! over the oVt.l.ry is charac terized by a dLlal i ty consona n t wi tn t dna 1 i ty of the pitLlitary and ovarian hormones (Novak}(lll) 20

('\ll.the basis of' the resLi_lts obtained from implantation of tne anterior pittJ_itary gland. Ascheim and Zondek Ut;ive ev- oived a test fo]:' tr.e horH'one 'irhich prnD:ises to be of cOl1sider- able clifli0al iFlportance.2he substance to be exarined is in

jected iaot an irmicatur'e !WUSe and in a positive test evidence of estrus (vaginal sE:ear, nypertrophic u.tel"Us) is obser'ved in abolZtt one hundred tlOU1?S. from the ti,':e 01' tile first injection.

:rhe anir'ial is then sacrificed anfi serial secti"ns of tne ovar'ies a} e calefull';:l exar:ined. Accord Lag to ",i.sche im (5) t :re are t(U'ee fC:orpnological cha s in the infantile ovury under the

influence ot hypo:hys(':)al h01It0L1El. ',,",he iLmatLu'0 neuse oVi.3.ry contains only primordial follicles and s~all Graafian follicles wit(lout cavities .rhe fll'st C'~l.Ul1ge .Ls 2'rnwth of the follicle lead.i to rupture a:ld discnarge of the ova into the tllbes,

whicIl tn'e visible to the nEl.k",d eye as C::rI1IlOtic apots, finally atretic cOI'pora ltA.tea are formed in the ovary by lllteintization of ta€! :t'011icles 1,"{hleb ar<:'; not fully iN3.tu.red.

~he criterion upon which tais test is interpreted is as follows:

A.P.II.. 1. U.... £ltelioI' pituita:cy react;io{j oGe)-rhe presence of ripening Graafian fOLlicle or of recent corpora lutes.

A.P.R.II. (Anterior pituitary reactir~ two)-Tne finding of tfBlutpuakte!f sI:iall redd.isl1 pi£1point ,g:ros8l~y' visible in tne o va, 1 i e s Co I' e p J' e s e il t follicles. A.P.R.III. (antelior pituitary reaction three}-Tne app- eurance 01' 111tein cell trU:iS yp,ation iLl foLLicles and the

..." fO:r:'Llii t iOIl 0 J. cor'pOl'a lu. tea oco- urre d. a WI t OVUL renains ir-pr i;30ne::'1 (pBe uClo -corpora 1 utea, corpora lutea atretica)

The find.i!l,q' of any on.e of these ch~l.;.1ges is considered a positive reaction for a'::lterior pituitary substance, but it is of interest to note taat the first reaction compares to that rest:tltifJ,g l-rnr:c; tne imphHltatioas of fresh anterior pi tui tary gland s \lbs tance, whereas the third reac t ion was obtained by Evu.ns & Long (49) with their alkaline extract of bovine glands.

'1::18se three n10.rphological cnaages are available as an

presence of anterior hypophyseal hormone and thllS have rede possible to is to the organ- isr~.. It was by PearlS of tnis test t'wt ZOndel{ isolutecl the anterior lobe hor~oae extract, "prolan". 22

The effects of tne gonads on the pituitary gland during pregnancy has been 1'lr,teO. s inoe Jom.te' ('1t398) described. a r:i.yper- trophy a.ad hyperplas ia of t he pars uflter ior, the pars pos ter ior rer:aining unaltered. :~rdhe irf< and ;stumme (1909) (51) observed tIle anterior pituita.ries of pregnant women 8no_ showed that the hypertrophy is accompanied. by histolo.f':ied c!!anges ana called a t ten tion to pecilliar ce 11s -Schwangerschsftsze llen- -no tieing that they differ from the basopflile and eos inophil cells, and , s ugges t~ha t they arise flioIT'. the cnief or Chrorfopho be cells.

(ReserVe cells of Adaison)(l) These cells nave no demonstrable

ISranllles (}~vans) (43) • Cus Cling (27} reportt::G similar opnyseal finclinB:s in pregnant dogs, cuts rabbits; Kolda in tnes. pigs, Lehr;;an(192l)(94) Ln pregaant Y"ats.

'.l'he hyperphasia of thesencells 0::' pN:"gnancy" is sufficient to

calise an enlurgeren to:;. the hypophys is during pregm:mey

(Englebaeh)(41) Cninei with their appearance there is a

In a ition to the increase of "pre Dey cells", the cyto- intly aeidopnilie (Srdheim &

Stwnr:e)(51). :rhe pitLl.itary chan;;8 of pl'egnancy tH3 compared to tae normal are no'i',' interpretetl '3S a hyperplas ia of eosinophiles the addition of t speciallized !'cells o.t' pregnancy" (inglebactd

(41). Little reference is made in the literature relative to taeiT origin. Kraus (90) considers tnem a type of eosinophile. 2he recent develnpments of the fa.etion of Doth the chromophobes and basophiles clefinitely relate ther to chromopnobe. It is probable that they are a type of basophil cell, directly ijevelop- ed from the chromophobes. 23

?regnal1cy-tyoe pituitary bodies may be produced in normal femu le mice thro J.gh 111_ te it:J.izu t ion 0 I thG OVill ies -by means of continuolls anterior lobe irrplantation. (Hotereu. &; Charypei)(75)

The ovary is an essential intermediary aaeut as indicated by the fact trlat similar pititl.tar"y implallts in castrateS 8.£limals were inei':l:'ective in. iudtwirlg egl1c;i1'lcy chl:illges (Teel)(l36)

The hypertrophy of the anter-ior pituitiiry lobe during pr'egnarwy is poss ibly Cl, dir'ect effect of t ovarian follicle hormone, wnien is present in 13bundance in blood du:r-irL2' course of gestation.

e d in non-pregl1an t cas tra te d non-cas tra tect feI'::ales by injection of placental extracts (Berblinqer)(13) In this connsct- ion tIle e ets of irr:plan tions ai" the anterior' pituitary .gland in pregnancy is important. The trt~atr:.eats invariabl;I{produce an oboJtion (Ehrr.JJ.I'dt & iViesbader) «l:2) expeciall;/ if I'!ivem (illl'ing

s ta t iO£1.

Daily transplants of t~8 fl'es~ anterior lobe to mice and rats in first triY'ester of pr'egnancy prc':vetlts implanations of ova OJ lel:id to obo!tiorl, if' treatlTeI1t is begun d.tlril1g t; mid- tr ster of the period of gestaLion resorption or e ulsion of ye t us taKes phtce. Pre gnuncy is inter-r ape 0. less 0 ften when treatment is bef.'uTi in the last trimoster of plegnElncy. (Engle &

rL('d)(39) :::he r~onaa_-stilrulatiIl": horT"'one 01 tiT) anterior pit uitary introduced by the fresh transplbnts results in the prod-

D.oti011 of a h:rge nurtiber of oVl:llian follicles. L:;vans &: ::liFps0u)

(48) U:nale)(34). ~,:he ovarian horl'r>[w tflUS P:l:'od.uced cao.ses a pyolifeI'a1ii0Yl c:f the u.terine r-ucosa bri.rl&"inQ abrl\H a (;0 itit"")l1 24

S il'; llar to t il<.l t C f nOJ'r!iz.il oes trttS .;?.regnancy seer:s to be Inoom- patib1e with this conditin~. rl{cs (112) llerby (10) suggests two possibilities for t me a ~la Jl~S.E1. x'e s 1?011S i b 1 fj f~o r upse t t il1Q' pregnancy Vi' i th fa 11 ic ultH" ho LL'One • l'i'1ey are inc 1 ine a to re d the 121r ul:ur:ber of rc'so.rpti ions ace urriug us due to an tnaibition or over-rul of the action of the COI'PUS llil.teue" aad alsc the local disturbance of uterus consequent upon an eff-

Different autno!'s hLive e haBised t!lHt the co:rpus luteurr· is a ~land with an internal secretion. which causes by its hormone action. the cyclical uterine changes of ~ens truation and the c s whicn the uterus under~oes in ncy. rraenke1 (68)

_t to ;;:; 81H1 int: Tabbit if t

0veuted, in~~n by c~uterizotion of ndL:Llar f u.n-

is thtnc: is nn llic1e

If" 0 Y1 t ;Ie 0 t lic:r tU::t th sax ,gland

i8 efH:3 on fu.netioning but in- deed puts O~~ ~ore rior~0ae ( a),With prolan, Asuheirr (150) vvas nital cycle. The follicle is FE:de to r!.~~;L1re unct to rtlpture .I'he 1ibera teet ova

igrate thro h the tubes into the uterus. Zcndek succeeded ia

rti1izatio~ of suoh ova 25

£klrlCYWUb pl'odu.ced in 2;U:l i ntile rat

Ilpl.'Cli:dll! taey wens also able to indl.W6 follicle rutulcltion '.,

era t ion of ova even hl ~hus to annihilate the

neral accepted law of ovarian do Bey. By means of prolan in senile animals t quiescent ovarian Bctivity can be restored with rythcic return of the estrus.

I.a f~ 1) 1s increases in si~e and wei~ht (pars anterior) at toe e ney tne n uptzellen~ cells are in~

ber taKe the sGcond place. tor' delivtH'Y these "pre$!naricy cells!!

decrease at end of second r after delivery tne eosinnpailes

dl.l.ring pregnancy.~'i:le n tiEB atrophy, how-

bel'S t .. ~an in pr' ViotlS one (.H:n~lebach) (,11). It; is elaimed that

s~illed histologists can dia2tlOSe a fnr~er pre fley fi' the pit- 26

Irrplanta~ion of t~e anterior hypop 1 su.bstance into senile male rats C!SlllseS a definite irwrease in sexual Lctivity .:l:1d in-

creased wei t of the access0ry or as nf reprodllction (Evans &

Simpson) (43) . During recent ne on

lacta t iOil F:ecr1iiLtlisrf'. Since the rnarr:ary aland nOlT'ully undergoes enlarge1'1C nt and his to lo€>'ica 1 change ;n'e to to tne sE':cret ion of rilk dllIing pn~gnancy only t;nc eallse of tnis nodificaLioll has seemed to lie in some e ct exel'ted by onE:· or another of the

tnreenevv structuI'f", which a,)pear iXl tria pl:egna.nt 8.Ilir:1al, nULely

tne fetus lban 10(5)(83) t~e plfJ.ceflta &nd the corplls luteum of

station (Boiun 1911)(15) of the conjecture and expermentation have

nas t::1hown Lna t implan ta t ion of t he an tel lor hypop-

hysis sU"bstance into senile nile rats cause a definite increase in sex activity a increase in wei t of ac~essnry 0 ns of l'eprcd- action. Implants or extructs of the anterior nypophysis substance

cause markeG hypertrop £"12)1(1 Ln the :ru t when ovary

is present but t yare inca ble of doia~ So after ovariectomy

?arkes (1929)(112) in un in~enius application of the dis-

covery of ;};vans sllOwed tW.it aL{aline ex:;racts of t

leba of pOp:lyS is ind lwe in rale anirals lutieai%ution of

Graaf4an follicle u~d also CUUcie PGrsiste~ce of pre-existent

COJ:'poI'a lll:tea. Evans & dimpson (43) states that the corpora lutea is not responsible for tne sti~ulus of erplas ia. ]:):m:rrar l

hyp~rplasia is notorio~sly easy to produce in rabbits, but much

IT'cre diffeclllt to pn)vok:e in Hits (67). EvanS & SlmpSO!l injected 27

spayed vi~gia ruts wit~ al~~liaeextract8 of eI anterior hypop- gla.ads of castrates did no~ respond.

Corner (23) tested the effe~t of his lutemn horrrone "prog9st- in" on the rnarmlaryhypel'plas ia with tile spayed aId t10\, -IJI'egnant fer:,ale rabbits witil xu)gative results. nn the atriel' Ylij,I10 he sec-

active hyperplasia on injection of an extract of sneep's ;'lypophysis in virginal spayed animals. rhe prese nce of ovary did not increase or alter t he ex ten t of the reaction produ.ced. He cOIlcltldes ttlat the extracts of S(leep /:ypop-

is produ(;e cnange in the n:ar::rnary ~land of rabbits receEblin~ :lyS '.,., ,_,I those occu.rring in pregnancy and leading to secretion of milk.

The effect doesn't depend on ovaries for it can be produced in au- iF.Et is spayed at beginnin;: of thE' expe!' irr:ent . very 1 D:e ly (he add-

ini 1 il.e nce of Cfoestrinff (ovarian follicle nOlrone) ail(\ thus be br0llgb.t into full pubert&l condition at ti~e of spaying and beginn of inje c t ion. 28

•

In all species at u certiftin age l,ne cyclical phe.c~nr:er1a gradually becoInGs less E;aJ:'iCed eventually cease, whether this cessation is due to exhaustion of the follicles or whether another mecnanisrn comes iflto play, f1

rales by i~plantation of anterior lobe pituitary ira uts spea~r:s for a ];'o1'e corr:plicated mechanism than l~erely cessation of function due to exhaustion of follicles. l"luhman (60+ and r;olo.stein (101) have Sl10WLl that tIle unter'ior lobe aSi;:;tllnes increased function with the advent of the menopause. It is liOt Lll0Wll delinitely, however, wh iCIl type o:t' hypopnysea1 cell is respons ible for t rlS excess pro- duct ion of t i1orrrioIH3 in n1enopausal women. 29

Therefore it is seen t~at the existence of a definite r'ellJtiOilShil) between t::ce anterior pitu.itary

tion ~f tl-H9 gland. produ.ce profou.nd c.:hanges cd' t ovary, the transplantation of t; fresh gLt t U1'0

castn:i tion

of tne anterior l0be and an in-

ofGile t ient. I:l:ypopnyse ctomy I'es ul ts in till U SI'opny of tile

le t st for tae anterior pitai ry hor~one,

'iN'lich is of valu.e l11 t d, ia gnos is 0 f ear ldt~ gnancy, been developed. ~ore-~oing reports leads one ~o bolieve t t an active prepulatioJl v/i11 in tiFe be .available a dications for its lJ.se u.nderstood.

Undoubtedly a 7reat deal t rerains obscured, but the ars lead one to anti-

pa tilo1o of Cfli' feniale sex glands f:t.tln of the interrelationship \ of certain other endocrine gldnds. 30

1. A.. ddison 'f. A. A co11ectiou 01: published. writings The new Sydenham 30ciety, London. 1868.

2. allen. ;:£:. Precocious sexual o.evelo::nrlent fZ'ot1 titlterior nypophyseal implants in mO!llceys ..'l.llut. hac. 39: 315-321, August 25, 28

3. Allen and Wiles. Role of pituitary in pregnancy and partuition, hypopnysectomy. J. Physiol. 75: 23-78. ]Fay 32.

4. Armour Daud Van Do 1e ~. B. Innibition of oestrus by excracts of anterior lobe. J. Phar~acal and ~xparF:ental. 2herap. 47: 269-28('- }Tar. 3fL

5 •.El.scheim S. gar1y diagnosis of p:ceg.nancy, Chorie-epith- elioma ct hyditidiionn mole by asc im ;Gondek test. :Arn. J. (',bst. & Gynec: 19 :3~j5. :frar. 30

6. l'..schner B. Il1flu.ence of pit ai tury on fema 10 sex orga.ns. J. A. r. A. 84:238. Jan. 17, 35

7. Asdell 3.~. illffects of pituitary extracts in adva~ced lac ta t ion. Am. J. :? hys io 1. 1 0 (" 137 -40 l'~ar. 33

8. deck H. G. Junction of antenior Inbe us ascertained by . fed} experiments OLI man. Hull. UnL Mary- land 3c11001 ICed. 13:185-199, April 29.

9. Bell W. B. :ne sex complex. ;,.;,uarter. J. i:!lXper. Physiol. 11:77,1917

10. Bel1erby C. J. Relation of anterior lobe to reproduct ive orguns, Lancet 1:1168-1169, June 9, 28

11. Befljardn ':1. :0'ituitar·y extracts on G;onad funct.lon, re sutls of latest researches of 3teinach and Kun vie rna, r. J. (':; Flee. 128:227-29, ,3ept. 5,28.

12. Biedl :~. Internal secl'etlen. j':Se:t'll.l1 ,;:; iHen: Urban u Jchwarze.uberg, IJ10 4th. 3d. 192;~.

rllllger w. ? i t ui tary- -golla da.l re la t io 118 nip. verha l1dl D. v_tsch. th. Gesell;:;ch, 17:184, 1914

14. 3err.7 2L 0. HypopittJ.itarisr 't!ith spocial ref~ere::1Ge to its sexual Planii'estatinns. UatlU.da.:rl.Ji. 22:354- 357. P.:ar. 30.

15. i30llcl J. J. 30me poiats in uterine & ovul'ifinphys io 10 t 10 in rabbits. Br it. :e (1. Jo urn' 2 :U;l 19'-'1 31

16. ~rigbee, ~irrond ~ 0r CG. Anterior Pituitary hormones. j:~ndocrino1ogy 15: 41, 1931

17. Brouhu & SiMnonet. Jondilil.erations Sllr 1e detern,inisme all eycle oestral chez 1es nlr.~r,iferen Proc. 2nd. Int'l Congress for Sex Research, London, 1930

18. Burch J. C. Williams Vi/. T. Wolfe J. M. & Cunningham R. S. Hypophysea1-OVal"ian relationship, qllantita tiVf] studies 'tiith reference to hyperplasia of endometruim. J. A. V. A. 97:l859-61,Dec.31

19. C1airn10tlt ;:;:. Deseuses of antelior pituita:ry body. arch. ~. K1in. Chir., 89:596, 1909

20. Clark lB. P. Effect of pitliitary substance on egg Pl'oduc tion of clomestic fowl. J. Biol. Chem.,22 485, 192[)

21. Collip J. B. 1ely H. & I'hompson. (jonad-stimillating 1101' rr:ones in ~ypophysectM:lixed UlllT::sls. Na till's, Loncton 131: 56, Jan. 33.

22. Corey J. L. fetal early postnatal responses of rat aonada to injections. Paysio1. 2001.3:379,391

23. Cornel' /'}. W. Hnrmonal enntrol of 1acta tiOIl i3.:ndocrinology xcv:43,1930 Am. J. Physiol. 95:143. l"~t.1930

24. Cove 11 W. P. Growth 0 i' l:1UJ':lan prena tal hypopays is and hypophyseal fossa, A.mer. J0urn. Anat. 38:379-422. Jan. 27.

25. Crowe~. 1he pitllitary bedy and its disorders. Ball. JO.hIl Iio)lci11S desp. : ~v. B . .saunders Co.,1922

26. Cu.si1ing H. Pituital'Y gland a::" now kn0wn, Lancet 2:899- 906 ("Ict 31, 1925

27. Cashing H. The pituitary body and its disorders, clinical states produced by disorders of hypophysis cerebri. J. B. Lippinoott Co. Philedelpnia,1912

28. D 'Ac ierno 1'. Ho le of 0 vay ian and ante} ior pit u.i tary horrrones in sexual Hud reproCluctive cycle. J. !l. Soc. N. J(H'cey 29:394-398, I"ay 32

29. Dodds E. C. and Dickins H. A note nn water soluble ovarian ;lO.ir;;One. Lancet, 1182 June 4, 1927.

30. D0tt N. M. A considerati('u of' the hypopil,/seul adenoma Brit. Jou.rn. of' :3u.rg. 13:314, 1925. 31. Jvery F. C. Chronic effects of anterior pituitary sex hormonE en weights of body, ovaries, uterus, pituitary flil(l adrenal glands, 3ndocrL101ogy 17:64-72

32. 3ngle E. T. le of anterior pituitary in compensatory OVarhitl hypertrophy. d,nat. Hec. 37:275-286, Jan. 25, 1928

33. Engle .21.£. Pituitary-gonadal mecl1uniem and neterosexual ovarian 9'rafts. ":ir'. JOllrn.Anut. 44:121-139, July 129':

34. Jngle .Go T. (lvarian r~esp()nses, diffenJrlOe elL:itcd b,'l tI'satr:en.t with ::.trine j:ron~ p t vmmen tand by freshly implanted anterior lobe. J.A.M.A. 93:276-277, July '29

35. I~ngle l~. T.Pituitary-gonad.al relationship and problem of precocious sexu.a1 mat'U..rity • .::.ind,ocrinology 15:405-420, sept. '31

36 • ..:ilngle E.T. Action of extracts of' an't!.erioI: pituitary and of rn:cgnancy urine on tewtes of ir:ma tUl'e rats and r:;onkeys. Endocrinology 16:506-512, 3ept. 1 32

37. illng1elL T. The effects of daily transplants of f;~n.·terior lobe from honad.ectornizeQ. rats on imr'(uture test animals .Am. J. Physiol 88:101, 1929

38. Engle E. T. Gonad stimulating florr"one of antelioI' pituitary /;;1 "he terpsexual oval ial'l grafts, ?roc. So c. Exper.Biol & l,red. 25:83

39. ]ngle l~. T. & Jifel'T<1od C. Effect of daily tran8plants of an terior lobe on co::.trse of pregnancy in ra t and. mOllse. An:;. J. Physiol. 85~b18-26, July 128

40. Eng1eoHch 'N. Endocrine factors related to the genital dev el0pn~ent . Am. J. 3urg. 19:72-75 Jan. 13i3

41. l~ngle bach {i. Endocrine r'edicine, Spr ield Ill., Balti- r:ore lCaryland, :Jnas. Thomas Vol. T 1932

42. Ehrhardt K. Affect of a inistration of anten lor lobe on growth und activity of genitals. ~unchen lied. Wchnsehr 75:785-86, 128

43. ;.~vanB E. t.. Hormones of anterior hypophysis Am. J. Physiol 98 = 511-546, ('ct. '31

44. 3}va:as ll. 1.'. & Jimpsorl l'F. E. "~,r:lt\Ot~()nim:: oi";rro'wth u sex horn:0{15S of anterior b.ypophysL~;. J·.A.}'.A. 91:1337-38, Nov. 3, '28 33

45. L~vaxl H.• r. & S impsoIl r. E. Sex differe nee in hormone con tent of anterior hypophys is of rat • 'lorn. J. PhysioL 89:~)'75-378, July 129

46. Ideb • 371-374 July '27

47. Ideb pp~ 381-387 July '27

48. i:~vaI1S & Simpson H. E. Different effects secured from iutraper i tonea1 as contras ted. with s ubc utanen us adrr;inistra tion of anterior hyt.,;>opl1ysea1 hormones. Anat. Rec. 45:215, 1930

49. Evans & Long. The effect of the anterior lobe administered introperitonea11y, llpon growth matu.rity, and oestrus cycles of rats, also effects of feeding. Anat. Hoc. 21:62, 1927

50. Evans H. 1-. Harvey lectures, ::?hiladelphia, 1923-1924, J. P. Lippincott & Co., PP. 212-215.

51. Erdhe im and S t u.mD:e . tl Uber (lie Schwangershc -aftsverandeI'l.lng der Hypophyse. Be i tr. L. p<1th. Ana t., 1909, 46 t L

52. Fancher J. K • .lnterior lobe hy-perpituitarism 3ndocrinology 16:611-616, Nov. Dec. '32

53. F1 evo1d H. £iisaw ]'. Lenard .3. D. Gonad-stiniulCiting and luter nizing tlormone oj:' anteri('I' lobe of hypophysis. Am. J: 1?hysic1 97:291-301. IV-ay'31

54. }?'1uhman O. J.p.. nterior pito.itary hOl'rnone in bV'od duri.ng pregnancy . .Prelir;inary report. J.A..:M.A. 92: 1744-48, l~ay 25. '29

55. J!1 111hman C. ]'. Interrelation of anterior hypophysis and ovar ies, review of recent 11teratu.re, £1..fI1. J. 01st. & Gynec. 18:738-47, Nov. 1929

60. ]11 uhn:an C. F. Anterior' pituitary hormone in blood of VloIUJn with ovarian difficiency. J.A.V.A. 93:672-674 zi.u.g. ;31, '29

61. ,Bl1 uhman C. ]'. Hyperplas ia of endome tr ilmi and. hormone of an terior rlYPophysis anet ovaries, Surge Gynec. & opst. 52:1051-1068, June 131

62. }' luhrr}i;nl C. F. Interre la t ionsh!p of an ter' ior hypophys is and ovaries, fu.rtrH:lr advance, Am. J. Opst. & Gynec. 22:803-815. Nov. 131

63~ }l'ord :ft'. A. Radiatioll of pituitary Ln functional ovaria:t:1 dis orders. Radiology 16:936-41. June '31

64. Frank Q. T. Inf111ence of pituitary extracts OIl genital tract. Journ. ArneI'. 1:Ted. Assa. 73:1764-1765, 1919 35

65. Jj'rank li.::. lleview of progress in endocrinology of inter est to gynerologists and obstetricians. J\.m. J. 01st. and Gynec. 20:215-220. A~g '30

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70. Gardner 11., dill & dmit.h J. ]ffects feedin.p- anterior oit aitary extracts to children. LGn6et 2:2l9-2~2. Jll1y 126

72. Goetsch E. The inf111ence of pituitary feeding u.iJon growth and sexllal devel0pment. An iSXp. stD.dy. Bull. John Jopkins Hosp. 27:29, 1916

73. :.:rateriev N. 0. helation of pregnancy cell in pituitaI·:1 of rats to reprodLwtivo cycle. Anat. Rec. 54:343-53 132

74. rlartman C. l"tlrror ".1. Geiling 3. 3tudies of ovulative eff ect of hypophysectomy on forr:lation of corpus lut ellIn. J.l)hysiol. 70:38-44.ilug. '30

75. r tel' i e v H. O. D~ C1:1a:1' yp e r . Occurrence of pregxlancy cj!lls ill rnice followi continuO~8 anterior lobe admin istra t ion ,'"na t. c. 51:85-101. Nov. 25 '31

76. deape ~i. OVl;_latinn nG. de neraLio ~ (jf the ova in the rab bit. ?rec. Roy. Soc. 76:260-267. 1925

77. deHldersonr{. H. ;3e:xual dysftlnctiO~l in ac1er10ma of pituitary body. Endocrinology 15:111, 1931

78. Hills M. :Parkes ..:'1.. S. Helation between anterior pituitary body a gonads, f2lctors concerned in format,ion of corpus lute urn. Proc. Roy. Soc. sE. London. 107:30-49. sept. '30

79 .~Ulls 'IV. Ii., :1?ar~kes d. d. ~ction of ovnlation-producing s Ulbs tance nf u.rine of pregnan(!y on hypophysectomized. rabbits. J. Phys iol. 71 :40-46. Jan' 31

80. Hills W. R., Parkes A. S. Induction of ovulation in hypop hysectomized rabbits by adrrinistrati()n of an~erLor lobe extract. J. }?h;rsiol. 71:36-39. Jan.lel

82. Hefirran J. Effect of pituitary irr:plantati0n llpon senile (ivax" ies of mice. Am. J. nbs t. & Gyne c. 22: 201-238 ,,,,"ug. r 31

81. HofbaUer J. Ntiology of hyperplasia of er-ldometrium Sllrg.

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84. i:iops~atter R. Pituital'Y tllmors (;;; relation to genital sys tem. 11onatschr. F'. Geburtsch. tl Gynah. 49: 387, 1919

85 • .iiorr2~i{lS J ..2ituitary secretions. BulL John Hopkins Hasp. 1910, 21. 127

86. Howe 1 VI. H. Glandular therapy, phys io logy of pit ui tary gland. J.A.M.A. 83:1684-1685 Nov. 22, '24

87. Johns "N. O'lt[ulverny J. Potts S. & Laui2'flton l'.I. Studies of anterior lo'be pitllital"Y body, Am. J. Physiol 80: 100 -106. l:a1'. '27 88. Klaften :3;. 2itllitary LJ.meIlorl'hea, 110natscha :J!l. Geblltsh. U. gy.nak 74:38-51. Jllly '26 0ost. J.AJ;:M.A. 87:1250. ('lct. '26

89. Klinger H., .Burch J., & Cllnninglwm Hole of' placc:nta in maintenance of hypophyseal activity during pre- grJ.anc:.l' Surg. Gyhec. &; ('lost. 56:137-148. teb. '33

90. Kraus ·,V. H. Action of pitllitary extract up pregnant uter us of rabbit. J. Physiol. 61:383-87. Jan. '26

91. Krau.l ..:. }few observation on action of anter"iOl' pit"uitary. Am. J. Obst. & t}ynec. 21:301-399, rJ0V. '31

92. Kunde 140 '''"ustavason H. & Caritwl1 ~L The effoct of estrin ad~inistration on the reproductive system. Am. J. Physi01. 96:677,1931

93. Larson E. Eerp-ern ('\" Earber D., ]' is bel:' N. Influence of anterior lobe extract on sex glands and growth. '&ndocrinology 13:63-72. Jan '29

94. Lehmann F. Zu.s ]lraB.'e dea o.ia,gnostrscnen Vereve:rtbarke it des 3cheiden abstrukes. Zentrlbl. F. Gynak, :45, 647, 1921

95. ~ipschu.tz A. The internal secretions of the sex ~l&nds. Willia~s ~ Willes Co., Baltimore 1924.

96. Locke C. E. Jr. Present statns of our knowled,ge Ohio ::3tate Ked. Journ. 24:37-43 Jan '28

97. Loeo~. Specificity in action of anterior pituitary of differe.G,t rnamrna Is on sex or ns and thyvo id gl ands of imrHJ:.tll.re female gllinea pigs. 38

98. rarie -2irre. study of pitu,itary tlJ.r:-ors Rec. de Y'-edParis 1886. 6, 297

99. rlackan. jj'. G.? i tui tary dysfllnction. J'. cli.nic I~ - A.m 7: 1789-1804. May 24

100. ~arinus ~.J. Effects of feeding anterior pituitary gland. Ll.m. J. Physio1. 49:2;38, ,1919

101 Mazer Chas., Goldstein. CLinical endoc}'inolOR:.1 of the fe male. W. B. 3aunders Co. Philedelphia & London. 69, 1932

102. 1;!azer C. & Hoffnian Pituitary hOY'nione in urine of pregnant wo rr;e:n. ,... m. J. ('Ibs t. & fl.yne c. 18: 48 -53. J13.1.1 124

103. l;!euker 3. H. Studie's of female &(,enital h.1poplasea J.iLli:-.A. 95:468, 1930

104. l:eyersK., Lenar~d. 3., & Hisaw]'. ":i:ffects of' oestrin on nad s t irr;ula t ing power of hypophys is. 3xp. Bio1. & 11ec1. 27:702, 1930

105. 1,~oore O. R., Price D. Reciprocal influence betwe fl R"onads ',.; hJPop'nysis ,A.m. J. A,nat. b2:13-71 llar.'i32

106. L:oore C. R., Price D. .:::Jffect of fresh pituitary honeo-im plants and ~onad-stimlllatin~ sabstances from human pregnant u.rine or reprodu.ctive tract of male rat. Am. J. Physio1 99:197 Dec. '31

107. rorss H. H. Hecent stuflies on the 1'01(:) of hypophyseal and OV:t;lr ian hormone in puys io logy of reproduct ive . Yale J. BioI. Mad. 3:;:597-410, :May '31

108. }Jul1er 1". :~ndocri{le studies. utsch. Arch 1.1'. KILn. ]'iced. 1892-93, 51,335

109. ,Munch. J. C. Activity of extracts of anterior a"lo posterior lobes. Delaware :Hate J't. J. 3:75-79

110. Hovalt E. Endocrine factors in ]';'ens truation and menstrllal disorders with special reference to problems of n:enstrll.al b1eedir..l.;!Z and menstrual puin. ilm. J. Obst. & ~ynec. 24~319-329 Sept. '32

111. l~ovak 3. Recent adva(wes in ph:jisi(1lo~y of renst1'ctation, role of anterior nituitary in sex cycle. J.A.V.A. 94:833-39.' Nov. 22, t30

112. Parkes '::... ,3. :r r~e internal se cre t ion of :;he ovary. London. Proc. Hoy. Soc. B. crv, 189.

113. ?aulesco l~. C. Physi0logy of allterior hypophysis.?aris viget Precas, 1908 39

114. Perki~s J. Clinical study rif deficient ant~rior pituitary fG.Clctioning in V!CIrien. Boston I/. & S. J. 19l~ 973-77. Nov. '24

115. RasTrilsson 3easonul changes it'} wood, chuck ( ITJota ronex). ,im. J. c"mat. 22:475-575. 1930

116. IUdd.le n. & Jlerrion P. Eole oj' ~ilnterior pituitary in hast ening sexua 1 ma t llI' i t,Y in l'tn,,- d (Jves • At';. Jo l.1rn. PhysiAl. 87:110-123, Nov. '28

117. Revoltella f}. Functional relations betweHHl hOI'rrones of an terior lobe and genitals. Olin. Obst. 33:593, Oct. '31

118. Silly IL, Gollip J., Thompson I. Effects of anterior pitlli tary upon pregnancy and lactation. Proc. Soc. Exper. Bioi. &; },'ed. 30:589-590. J:!'eb '33

119. veringhare ~:l... E. Effects of castration in fSuinea pi;! upon sex-mi8,tlll'inp: poteucy of anterior pitu.ital'Y'- Am. J. Physio1 101:309-315 July '32

120. Siddall i'~. C. A suggested test for pregna[wy J.A.J't.A. 90: 380. Feb. 128

121. Sisson & Brayl. '.1'he influence of the ~;i:nterior lobe of hypop hysis u.pon development of albino rut. The Bull. John Hopkins Hosp. 32: 22 t 1921

122. Slonaker J. R. effects of' tne follicular horrcone 0':1 old alglno I-ats. Am. Journ Physio1 81:325-335., 1927

12;'3. drJith P. E. Indu.ct ir,:n of pre coc io us sexua 1 rr·a t ur i ty by pit uitary homeo-tra:isplo.nts, Am. J. Physiol. 80:114- 125, f"ar. i 27 t June ' 27

124. 3mi tt.1 Comparative sensitivity of reprodu.ctive tract of hypophysectomized and ovariectomized rats to foll icular hormone. Am. Journ. Physio1 99:349'!"356, Jan. '32

125. Smith P. E. Htlste!lin~ devel011lY:ent of female genital system by daily homeo plastic pituitary transplants. I'roc. 30c. Expel'. & Med. 24:131-132, 1926

126. Smith P. 3. ,(hf" d.isabilities caused by hypo-physectomy &: re pair. ~.A.~.A. 88, 158-161 1927

127. Smitn I?~. ,J~blatio'l and transplantation of the hypophysis in the rat, Annt. Rec. 32:221, 1926

128. Std th P. E. '2'he response of nypophysectomized tad-poles to the intraperitoneal injection of hypophyseal extracts Anat. Rec. 25~ 150, 1923. 40

129. Srd~h P. J.!. & EnB'le ~. T. Precocious sexual matu.rity in P10 use -fo 11ovrinJ2' pit ui thI'Y transplants. Ana t. , T~'""J.. .. v. c 35 • f1,J92 t J.~"a-..L.'!\f~':;' 27

130 Smith P. Z. & Engle B:. T. ExperimelltCil evidence regard ing the role of the anterior pituitary in dev elopment Bnd regulation of the genital system. Am. J •.A.nat. 40:59, 218, 1927 131. Smith P. E. & White W. E. Effect of anterior pituitary lobe on ovula tion and corpus IlltelllI: forma tion 1861-1863, Dec. 19, '31

132. Spaul 3. A. l1ction of anterior lobe extract. J. Expel'. Biol. 7:49-87, Jan. 30

133. Spencer J. Gustavason R. eL, De Armour Jr. 2ituitary ovaI'ian relationshiu. ::>rec. Soc. 3x-per. Bi61. $I" 1,,'.. .:1 Ir.z.8.hnn r'J(~l u..; ""'"-\;] \L. , v. t...! - , " ~j "

134. ~andler J. & Groz S. Ueber den Saisondimorjhismus dea ffiEwlivurfhodens. ArCll. ~? Entiorr:eck., Ed.33. 297-302, 1911.

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136. I'eel d. 11. ,]ffects of injecting anterior' hypophyseal fluid on course of gestation in rats. Am. Journ. Physiol. '19:170-183. Dec. '26

138. Ve jciarsiti V. TUFor of pituitary in pregnancy. nbst. J. A. M. ~. 85: 1847, Dec 5, 1925.

137. ';:v.rner H. H. Anterior pituitu.ry glliind. J. Oklahoma M.A. 25:232, Jan '32

139. Van WUR.'enen!1. ilistolofrical chanR,'es in the rat hypophysis following degeneration'-of the rr"inal epitl1el ium. dnat. Rec. 29:398, 1925

140. Via lke!' & Ciaeser ~~ff(~cts of anteriol~ hypophysis upon oVll.la tion. Am. Joarn. Physiol. 74:249, 1925

141. ~Nade N. 8. Doisy]. A •.;ffects of crystallitle theelin & theelol and extracts of li'iaor fo11icu.le 0i1 rcale rats. Proc. Soc.:~xper. Biol t;:; :FFelt. 28:714, 1931

142. Whi te IV. E. & Lenard ~3. S. ('va I' ian response to pro 1an and anterior pitu.itury extracts in hypophysectomized rabbits, with particu.lar reference to ovulation. Am. J. Physio1104:44, 133 41

143. WieSller B. P., Crew 'Fi. c!... :;he J;wnado-tl:'ooic action of the Eiuterior 1()be~0f pituitary. Proc. roy. 30c. ~din. 50:79, 1929, '30

144. Winton .if. E. Uorrc:al function of pituitary a1a~'1d. rted. dcience 9:355-59, Feb '24 146. Wolfe J. r. Effects of castration on capacity of hypop- is to induce ovulation. AF. J. Anat. 150: 351-357. July '32

147. ',Volfe &; Gleve land. .Pregnancy change in anter lor hypop [lYS is of albino rat. dilat. Ree. 56:33-40. April. '33

I 148. Nu1zen. lation of pituitary body to growth. Arn. J. 1'11ysiol 34:127, 1914.

149 .Viulzen. morpho logy histology of a certain structLJ.!'e c,.'tLle c te d with 1'S inter~edia of ox pituitary b('ldy. t. c. 8:403, 1914 1bO Zondek B. Avarian and anterior pituitary secretions. A test fnr preg~1.aney. Klin. Nschurshi. 7:83,1928 151. Zondek B. finterior pituitary body particularly its relation to reproduction function and influence on other endocrine glands. _-:l.m. J. Obst. & Gynec. 24: 836-843

152. Zondek B., c 1m ,:3. 0vtllation in pregnancy brolJ_ght about by anterior pituitary hormone, ~ndokrinol. 1:10. 1928. Abst. Physio1 0bst. 13:664.