Edited by Eoas BAjusz, Cambridgejfk.hood.edu/Collection/Weisberg Subject Index Files/N Disk/Nichols... · Edited by Eoas BAjusz, Cambridge Anencephaly Geographic Incidence, Etiology

BASEL (Switzerland) S. KARGER Printed in Switzerland

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An Introduction to Clinical Neuroendocrinology

Edited by Eoas BAjusz, Cambridge

Anencephaly Geographic Incidence, Etiology and Hormonal Relations

of the Pituitary and Adrenal Cortex

JOHN NIC HOLS

ran Reprint

S 19 C 67

An Introduction to C

linical Neunxadoctinology, ed. by E

. Baps., pp. 273-295

(S. Karger, B

asel/New

York 1967).

Departm

ent of Pathology and Oncology, U

niversity of Kansas M

edical Center,

Kansas C

ity, Kansas, U

SA

An

encep

haly:

Geograp

hic In

ciden

ce, Etiology, an

d H

ormon

al Relation

s of the

Pituitary and A

drenal Cortex

- Join

; Nicn

ors

Introduction

Anencephaly, so far at least, has not been attributed to horm

onal im

balance. It has, however, recently becom

e apparent that a hormonal

imbalance betw

een the fetus and pregnant mother does arise as a result

of the abnormality. T

here is a paucity of information about horm

onal relations in the anencephalic new

born, because of infrequency of the co

nditio

n an

d sh

ort life sp

an o

f the in

fant. O

nly

a few h

orm

onal

studies exist, but there is a considerable literature about the two m

ain anatom

ic deficiencies, viz., the deficient pituitary and atrophic adrenal glands. T

his chapter will consider a few

of the more im

portant studies and w

ill mention som

e unpublished observations of the author.

Historical

Anencephaly is abundantly described and discussed in early m

edi-cal history. T

his malform

ation enjoys one distinct advantage unique in m

edicine, i.e., it cannot be misdiagnosed 1 T

he 'infant' in Fig. 1 w

as described by LYCOSTHENEM

[30] in 1557. He w

rites:

QV

into Calend. Septem

bris Argentina nobilis A

lfatia 16-1-m

etropolicinfansfcaninei feaus,horrendo>tn5ftrofo,ab quein fuperiori parte, aperto plane capita lato ore, bouinis os culis nan'bus aquainis nam

e eft.

Translation: 'In the m

onth of Septem

ber, it is known an infant of

female sex

was b

orn

in S

trassbourg

, the m

etropolis o

f Alsace, a

INCID

ENCE PER

THO

USA

ND

BIRTH

S

I _. 3

.17

-10

.00

1

.00-3

.18

0.3

2-1

.00

0.00— 0.31

274 N

ustioLs: A

nencephaly: Geographic Incidence, E

tiology, and H

ormonal R

elations of the Pituitary and A

drenal Cone:

275

Figure 1. A

mcepbalic m

onster b

ons in

Alsace d

urin

g reig

n o

f Charles V

. (Courtesy

C

lendening Medical L

ibrary, Historical C

ollection).

horrible monster and w

ith the head for the most part com

pletely open, the m

outh wide, w

ith eyes like an ox, and with nostrils like an eagle.'

MO

RG

AG

NI [37] described three

case

s of an

encep

haly

; he d

id n

ot

comm

ent on the pituitary, but stated that the abdominal viscera w

ere norm

al. ZA

ND

ER

[55] in 1890 firmly established the fact that the adrenal

glands are small in anencephaly.

Geographic Incidence

Despite certainty of diagnosis and the fact that anencephaly is

relatively comm

on among congenital C

NS

malform

ations, most phy-

sicians deliver only very few w

omen of such infants, if any, during a

life time. S

tudents of the problem, therefore, have to obtain their cases

for study from colleagues, hospital records, and governm

ent registries. A

dequacy of statistical data depends obviously upon the curiosity and

Fivers 2. D

istribution of anencephaly in Europe based on births in hospital (A

fter Pan -

nom

, with perm

ission editor J. mem

. Deftc. R

es.).

thoroughness of the medical profession in addition to a governm

ent w

ith an enlightened outlook towards public health. T

he degree of com

pleteness of birth and death certificates of different countries var-ies w

idely. This elim

inates many areas of the w

orld as a source of data for study of anencephaly.

Recent studies show

that the incidence varies widely in different

areas at the same tim

e and in the same area at different tim

es. Thus,

BO

OK

and FRA

CC

AR

O [8] and PE

NR

OSE

[47] analyzing an extensive

literature report that the incidence in Ireland (Belfast [0.67%

] and D

ublin [0.50%]) is three tim

es higher than in Birm

ingham, E

ngland, (0.23 %

) and ten times higher than in M

almo and L

und, Sw

eden (0.063%

), and 50 times higher than in L

yons, France (0.012 %

). In-deed, C

OFFE

Y and JE

ssop [12] find variation among hospitals in D

ub-lin

. Durin

g 1

940-1

949 th

ere appears to

hav

e been

a decrease in

incidence in S

cotland and Birm

ingham. T

hese data concerning the incidence in the B

ritish Isles an Eire are significant, because the social

and Horm

onal Relations of the P

ituitary and Adrenal C

ortex 277

Tobl

Incidence of smeacephaly am

ong infants born in hospital (after PE

NR

OS

E)

276 M

ellow A


tiology,

and economic standards are parallel and the m

edical profession is hom

ogen

ous. It h

as been

furth

er reported

[1] th

at in co

mparab

le N

orth Am

erican populations the incidence in Charleston, S

outh Caro-

lina (0.061 %), is less than one-half that of H

alifax, Canada (0.15 %

), w

hich is 1000 miles north. T

able I from P

EN

RO

SE gives the num

erical ratios for 33 m

edical centers with geographic distribution as show

n in F

ig. 2. Any theory of etiology w

ill have to take into account this rem

arkable distribution as well as the fact that m

ost anencephalic infants are born in w

inter (Decem

ber), having been conceived in early spring. It is w

orthy of note that distribution of hydrocephaly paral-lels that of anencephaly but the sex ratio is about equal for hydroce-phaly w

hile anencephaly affects the female three to five tim

es as often as the m

ale. Despite the staggering effort represented in the foregoing

data, the actual incidence of anencephaly is unknown because m

any such conceptions are aborted, frequently w

ithout knowledge of the

patient. The high incidence of m

alformations in abortions is w

ell know

n.

Etiology

Study of possible transm

ission of the malform

ation is made diffi-

cult; because affected infants do not live to reproductive age. How

ever, there is a 2-3 %

risk of central nervous system m

alformation in subse-

quent children of the same parents having a child w

ith anencephaly. T

his is more than six tim

es the risk in the general population and sug-gests strongly a genetic influence. T

here are some exam

ples of both m

onozygotic twins having the defect, but there are m

ore examples

of one of a pair of monozygotic tw

ins having the defect and the other tw

in being normal. O

bviously such a case is due to other than genetic influence. A

nencephaly has its highest incidence in mothers of blood

type 0. The high ratio of fem

ale to male anencephalics is alm

ost unique am

ong congenital abnormalities although there is a sim

ilar trend in patent ductus arteriosus and congenital dislocated hip. A

nencephaly is th

e on

ly m

alform

ation

with

a hig

h seaso

nal in

ciden

ce. Th

is is especially pronounced in E

urope but not in North A

merica. E

DW

AR

DS

[16] has suggested that the absence of seasonal variation in U

nited S

tates is due to the 'deepfreeze? eliminating seasonal sw

ings in diet I T

his is doubtful but, if so, the change could be detected in birth rate befdre an after W

orld War II. If one considers the fact that gestation

of the anencephalic is usually 2-3 weeks shorter than the usual 9

Area

No.

Anencephalics

Period

births N

o.

Ew

alt,

London

Birm

ingham

Liverpool

Belfast

Dublin

Copenhagen

Malm

o and Lund

Helsinki

Viipuri

Reykjavik

Munchen

Zurich

Paris

Lyon

Napoli

Parm

a T

orino B

arcelona A

thens

North A

morita

Rhode Island

Boston, M

ass. R

ochester, Minn.

London, O

nt.. M

ontreal, Q.P

. C

harleston, S.0

Halifax, N

. S.

Africa

Johannesburg (A).

Pretoria (A

). Johannesburg (E

)r P

retoria (E)'

Ado

Bom

bay S

ingapore H

ong Kong

1938-53 52 693

82 0.156

1940-47 158 307

366 0.229

1923-32 13 964

44 0.3

15

1938-55 30 855

207 0.671

1953-54 12 552

63 0.502

1911-49 167 940

170 0.101

1917-49 105 812

67 0.063

1935-44 17 084

5

0.029 1928-37

11425 34

0.297 1949-55

10 655 5

0.047 1929-41

141 706 117

0.0

83

1921-44

49 539 27

0.054 1945-55

144 611 65

0.045 1945-55

59 406 7

0.012 1943-51

8994 36

0.400 1938-47

8 228 12

0.145 1949-55

7 991 1

0.013 -

12 969 10

0.0

78

1951-55 34978

21 0.060

1936-52 168 654

326 0.194

1930-41 29 024

67 0.231

1944-50 8 716

5 0.057

1945-55 10 834

12 0.111

1950-55 19 839

42 0.211

1946-55 55 156

34 0.061

1946-55 49 704

74 0.150

1951-55 32186

6

0.019 1953-55

4407 1

0.023 1952-53

7 779 6

0.077 1953-55

8 413 8

0.095

1946-55 76 763

58 0.076

1953 8 267

8

0.097 1951-53

32 176 18

0.056

278 M

astics: Anenceplady: G

eographic Incidence, Etiology,

months, then, the environm

ental influence would be acting during

mid-sum

mer. T

aking into account distribution, familial incidence, sea-

sonal incidence, frequency in pairs of twins, and sex ratio, a genetic

factor cannot be invoked with precision.

From studies of C

OFFE

Y and JE

ssoe [11], a strong suggestion of an environm

ental influence is derived. These D

ublin investigators found the m

alformation m

ore comm

on in the lower socio-econom

ic class of patients w

ho have a higher incidence of minor illnesses, such as 'colds'.

Indeed, they found that by eliciting a history and by serological exam-

ination of blood drawn for this purpose in a prospective study, a large

number of m

others of anencephalic infants had Asian influenza in the

early weeks of gestation. T

heir analysis of the incidence following the

1957-58 Asian influenza epidem

ic showed a m

arked increase in rate of anencephaly w

hich coincided with m

aternal illness during the first trim

ester of pregnancy and also in wom

en with positive serological

evidence who had no clinical history of influenza.

Experimental Production

Exencephaly (incom

plete eversion of the brain) has been described as occurring w

ith high frequency in some strains of m

ice and in off-spring of som

e strains of X-irradiated m

ale mice. A

nencephaly is readily induced in offspring of pregnant m

ice and rats by X-irradiation.

Pantothenic acid deficiency induces com

plex cranial abnormalities in-

cluding anencephaly as do vitamin E

and folic acid deficiencies. A

noxia causes anencephaly in mice and birds. E

xcess of CO

, is even m

ore effective. Other chem

ical agents include tryptoflavine, saponin, trypan blue, ricin, salicylates, actinom

ycin, and oral hypoglycemic

agents. Excess of vitam

in A seem

s to be the most reliable m

ethod for production of anencephaly in eats and m

ice. All of these agents seem

to act best about the tim

e of gastrulation, i.e., 8-10 days gestation. The

human em

bryo is said to be most sensitive to X

-iradiation at about 16-18 days of gestion. T

hese experimental m

ethods of producing anencephaly have been tabulated by G

IRO

UD

[21]. Joss [26] has devised an elegant technique for decapitating the head of the rabbit fetus in 'tiara. T

his results in atrophy of the peripheral endocrines but is not quite com

parable to anencephaly in the human. H

UT

CH

INSO

N et a/. [23]

failed to cause peripheral endocrine atrophy by destroying the hypo-physis of the m

onkey fetus in Wen, during the last m

onth of pregnancy.

and Horm

onal Relations of the Pituitary and Adrenal Cortex

279

Parkgrneur

The m

orphogenesis of anencephaly is unsettled. One prom

inent school, usually cited in textbooks of em

bryology, holds that the defect arises from

failure of the anterior neural tube to close. Ordinarily clo-

sure is about the 3-4 mm

stage (3rd week) before subdivision into

forebrain, midbrain, and hindbrain. Y

et anencephalics have well-deve-

loped

eyes an

d cran

ial nerv

es suggestin

g th

e defect arises later.

Another school holds that spinal fluid dynam

ics are upset, from pos-

sible stenosis of the aqueduct, resulting in development of a condition

of internal hydrocephaly with subsequent degeneration of forebrain

and midbrain. If one assum

es absence of brain tissue causes loss of stim

uli for bone development, this w

ould explain the varying stages of vault form

ation found in different anencephalics. R

apid growth and com

plex folding in early formation of the brain

is well-know

n and any interference at this time w

ould have catastro-phic consequences. P

Arnw

[46] recently described several embryos in

w

hich there was asym

metry and overgrow

th of the early formative

roofplate and parts of the fore and midbrain. T

his is frequently seen in aborted specim

ens and is usually ascribed to artifacts and poor fixation, but he is convinced that it is a developm

ental defect which

may give rise to anencephaly. E

longation of the neural tube appears to depend on stretching produced by grow

th of adjacent tissues, espe-cially the notochord. It has also been postulated that anencephaly results from

lack of mechanical tension, because of im

paired growth

of the chordal system. A

nother prominent view

[54] is that developing arteries fro

m th

e carotid

and v

ertebral sy

stems fail to

org

anize

properly, invade the in situ vascular bed of the encephalon, and as-sum

e the pattern destined for adult distribution. Brain form

ation may

be p

artly in

fluen

ced b

y em

bry

onic b

lood v

essels som

ewhat lik

e em

bryonic bone formation is influenced by early vascularization. T

he angiom

atous mass found at term

may b

e the rem

nan

t of earlier

vascular non-organized encephalon.

Alta

/mg

a) The Lesion E

xamination of an anencephalic infant reveals that the scalp and

frontal bones above the supraorbital ridge, the parietal bones, and usually the squam

ous portion of the occipital bone are absent. The

280 N

mnom

: Anencephaly G


foramen m

agnum m

ay be incomplete and the spinal canal partially or

completely open, in such cases the term

iniencephaly may be applied.

The anterior fossa is foreshortened, the sphenoid bone flattened, the cli-

noid processes are frequently absent, and the sella shallow or non-ex-

istent. Cerebral hem

ispheres, basal ganglia, and hypothalamus are ab-

sent. The m

edulla is frequently present in an imperfect form

, and the cerebellum

is usually absent but when present is m

arkedly imperfect.

The bones of the base of the skull are covered w

ith a highly vascular m

eshwork of m

esenchymatous tissue in w

hich are sometim

es found v

aryin

g am

ou

nts o

f cerebral tissu

e, diso

rgan

ized n

euro

nes, g

lia, choroid plexus, and, very rarely, cranial nerve nuclei. T

his mass of

red-purple tissue varies in thickness from a few

millim

eters to a few

centimeters and lies directly on bone, dura being absent. T

he mass is

sometim

es partly covered by hair-bearing squamous epithelium

, but is usually nude w

ith the exposed surface condensed into a relatively acellular collagenous m

embrane. T

his becomes the seat of infection if

the infant lives a few days. F

ragments of cranial nerves m

ay be found in various foram

ina, and if rachischisis is absent, spinal cord is present. R

arely may fragm

ents of cerebral tissue be found in the meninges. T

he eyes bulge forw

ard because of foreshortened orbits giving the cham-

teristic frog-like appearance in wood-cuts of m

edieval illustrators. In about a third of the cases the bony defect extends varying lengths into the spine and in these instances som

e cervical vertebrate may be absent

so the chin lies at the level of the sternum. In such cases, the thoracic

cavity is reduced in size with less space available for the heart and

lungs. Concom

itant lesions include: talipes equinovarus or valgus, spina bifida, cystic kidneys, cystic liver, high palate w

ith frequent cleft, diaphragm

atic hernia, 'imm

ature' lungs with cuboidal cells lining the

alveoli, polycythemia, m

egaloesophagus, hypertrophy of the bladder, deficient A

uerbach and Meissner's plexi, thym

ic hyperplasia, degenera-tion of retinal ganglion cells and hypoplastic epididym

us [56].

b) Pituitary

The anterior pituitary is rarely of norm

al size, and often on cursory exam

ination said to be absent. How

ever, laborious search with serial

sectioning of the sells region will alw

ays reveal at least a few scattered

clumps of anterior pituitary cells [2]. C

ytologic study of these cells by the now

elegant tinctorial techniques for differentiation has not been done. F

igure 3 shows a pituitary w

hich weighed 90 m

g. This is the lar-

gest pituitary known to the author from

a case of anencephaly, yet the

and Horm


ituitary end Adrenal C

ortex 281

Figw

e 3. In this one of mencephaly the pituitary gland at the top consists entirely o

f n

orm

al anterio

r lob

e tissue w

ith v

ascular stasis. It w

eigh

s 90

tug

, bein

g th

e greatest

amount of pituitary tissue in m

encephaly known to the author. A

CT

H assay w

as not done. T

he adrenal beneath shows atrophy characteristic of anencephaly (C

ourtesy Dc. D

AV

ID

JEMCINS).

adrenals show the usual atrophy. M

icroscopic examination (w

ith hem

atoxylin and eosin) showed considerable vascular stasis and w

ell-preserved parenchym

a, not unlike that of a normal new

born. The

posterior lobe is usually absent, but when present is separate from

the anterior lobe. O

f course, the hypophyseal portal system and hypo-

thalamic connections do not exist. F

igure 4 shows a sagittal section of

sphenoid bone from an anencephalic w

ith a histologically 'normal'

anterior pituitary at the base of the crattiopharyngeal canal. Disregard-

ing shrinkage, calculations from m

easurements on the slide indicate

this gland would have w

eighed 56 mg, yet the adrenals in F

igure 5 are atrophic.

282 N

icums: A


tiology,

Figure 4. Note the disc-like pituitary on the pharyngeal surface of the sphenoid bone

imm

ediately beneath the persistent cranio-pharyngeal canal. In the gross it measured 6 m

m

in diameter and 1 j/.-2 m

m in thickness. T

he wedge of free tissue anteriorly is an aberrant

fold of nasal mucosa. M

agnification 13 x (after N

ICN

OL

S et al. w

ith permission of the

Endocrine S

ociety).

Figure 5. Adrenals on left from

a full term norm

al' infant dying two hours after birth w

ith atelectasis (co

mb

ined

weig

ht 7

.2 g

rams). T

hese g

land

s con

i t main

ly o

f fetal som

e. A

drenals on right are from sam

e as pituitary in Figure 4. T

he f sal sons is entirely absent, and the conical tissue present is the rim

of defmitive cortex characteristic of analcephaly

(combined w

eight 0.39 grams) (after 6ficnom

d al. with perm

ission of the Endocrine

Society).

and Horm



ortex 2

83

e) Adrenal G

land T

he adrenal cortex arises at a level between the seventh cervical

and second thoracic nerves from celom

ic mesoderm

contiguous and co

ntin

uo

us w

ith its cau

dal g

on

adal an

lagen

. At ab

ou

t the 8

mm

(crow

n-rump length) stage or 4 w

eeks of gestation a wave of cells

migrates from

each lateral primorclium

to a position adjacent to the

root of the dorsal mesentery. T

his first migration of cells form

s the 'fetal zone' and is im

mediately follow

ed by a second wave w

hich fo

rms th

e 'defin

itive zo

ne'. A

t abo

ut th

e 20

mm

stage p

heo

-chrom

oblast cells begin migrating to invade the cortex and form

the m

edulla; this is complete at about the 10 centim

eter stage. The adrenal

glands of the normal fetus in proportion to other organs are com

par-atively larger about the 4th m

onth of gestation than at any other time

in life. The cortex of the gland at this tim

e is composed of definitive

and fetal zones; the latter predominates and reaches its apex at tim

e of birth. T

he medulla at birth is negligible.

The definitive zone is com

posed of a few layers of sm

all uniform

well-dem

arcated cells having nuclei and cytoplasm that stain prom

i-nently basophilic w

ith hematoxylin and eosin. It is located just beneath

the capsule, and a few m

onths after birth differentiates into the zona glom

erulosa, zona fasciculata, and zona reticularis of the adult. The

fetal zone imm

ediately begins involution at birth and is sometim

es accom

panied by hemorrhage. T

his zone is confined to the human,

monkey [28], and perhaps, the arm

adillo [38]. It composes m

ost of the gland in the new

born, is just beneath, and is much thicker than the

defin

itive zo

ne. T

he cells are larg

e, hav

ing

an in

distin

ct sligh

tly

eosinophilic cytoplasm, and a sm

all nucleus which stains poorly w

ith hem

atoxylin and eosin. T

he definitive and fetal zones of the human w

ere first described in

LL

IOT

and AR

MO

UR

[17] in 1911 s of the n

ence halic wer

•'d

of fetal zone. This observation has been confirm

ed repeatedly in all of the w

orld's literature and exceptions noted by only four authors [20, 34, 52, 22]. A

ll of the cases are not convincing. In an effort to deter-m

ine th

e mag

nitu

de o

f this atro

phy a n

orm

al adren

al weig

hin

g

4.9

g fro

m an

infan

t dy

ing

on

e ho

ur after b

irth w

as cut serially

to yield 1280 sections. E

very fifth section [256] was projected onto

paper at 30 diameters m

agnification. The definitive zone and fetal zone

with m

edulla were traced, cut out and w

eighed as previously described

EG

RII2Y

NO

WS

KI [5

1] in

1

284 N

ictioxs Anencephaly: G


Table II

Weight of a 'norm

al' adrenal from a new

born compared w

ith weights of three adrenals

from cases of term

anencephaly. The proportion of definitive and fetal zones has been

determ

ined

by

pro

jection

of serial sectio

ns an

d th

e mass o

f these zo

nes d

etermin

ed.

It can be seen that the definitive zone undergoes almost as profound atrophy as does the

fetal zone.

'No

rmal'

Adrenals from

three cases of anencephaly adre

nal fro

m A

C

new

born

decrease

decease

decrease

Weight of gland

4.9

gra

ms 2

46

mg

95

% 2

83

mg

94

% 1

24

mg

97

%

portion D

efinitive cortex

of g

land 1

3%

75.7%

actual

87"

54.5%

mass

0.6

4 g

rams 1

86 m

g

portio

n

70%

246 m

g 6

1%

68 m

g 8

9%

Fetal

CO

LL

ea of g

land 8

7%

24.3%

actual

12.7%

45.5%

mass

4.26 grams

59 mg

99%

36 m

g 9

9%

56 m

g 9

9%

[41] from w

hich the ratio of definitive cortex with m

edulla and fetal cortex w

ere calculated. Adrenals from

three cases of anencephaly were

treated in a similar fashion the results of w

hich are shown in T

able II w

here it can be seen that the definitive cortex in anencephaly has a sim

ultaneous and significant degree of atrophy with the fetal cortex,

albeit o

f 'lesser magnitude. T

he function of these zones is the subject of m

uch speculation. T

he fetal zone forms norm

ally up to at least the fifth month of

gestation I36, 42, 3] the time w

hen growth rate for this zone slackens

durin

g th

e course o

f norm

al dev

elopm

ent b

ut su

bseq

uen

tly in

the

anencephalic, it involutes almost com

pletely by term. F

igure 6 shows

adren

als weig

hin

g 7

0 m

g fro

m a 'n

orm

al' fetus o

f five m

on

ths'

gestation'as compared w

ith adrenals weighing 63 m

g from an anence-

phalic fetus of five months' gestation. T

he small adrenal of the anence-

phalic at term, therefore, represents atrophy and not agenesis. F

igure 7 show

s a microscopic section of the atrophic cortex w

ith definitive zone present and fetal zone absent.

and Horm



ortex 285

illenormenio .m

mi I

IHE

IRM

EH

HIM

US

ER

ME

MIM

EM

IRIIM

IIIIII

Figsere 6. A. adrenals from

normal fetus of her m

onths' gutation; weight 0.70 gram

s. B

. adrenals from norm

al term fetus; com

bined weight 9.60 gram

s. C adrenals from

pre-m

ature anencephalic fetus of five months' gestation; w

eight 0.63 grams. D

. adrenals from

=encephalic fetus at term

; weight 0.45 gram

s. (after NIC

HO

LS

with perm

ission Am

er. M

ed. Ass.).

Horm

onal Relations

Absence of fetal zone in the anencephalic has been tacitly assum

ed the result of `absence' (or deficiency) of anterior lobe pituitary tissue (A

CT

H). A

NG

EV

INE

[2] in 1928 demonstrated anterior lobe tissue by

serial sectioning in all of 28 anencephalic fetuses, albeit, in some cases

the amount w

as very small. H

e could not correlate the amount of

pituitary with the degree of atrophy of the adrenal cortex.

The questions of w

hy the fetal zone in the normal infant begins

involution at birth, and why it begins involution after the 5th m

onth of intrauterine life in anencephaly are enigm

as. One school of thought

summ

arized by CH

ES

TE

R Jones [9] suggested that sudden w

ithdrawal

and Horm



ortex 287

286 P

ficnoxs: Anencephalyt G


Fig

NW

7. Section of adrenal cortex from

atrophic adrenals from case of anencephaly in

Figure 5. T

he entire cortex consists of deeply staining cells histologically identical with

those of the definitive cortex of a normal new

born. The inneespace adjacent to the m

edulla is devoid of feral cortex and is com

posed of loose edematous m

esenchyme. H

ematoxylin

and eosin, magnification 130x. (after N

ICH

OL

S el al. w

ith permission of the E

ndocrine Society).

of gonadotrophic hormone at birth, possibly, in part, from

the pla-centa, m

ay be the initiating factor for involution of normal fetal zone.

This w

ould not explain the normal grow

th of this zone until the fifth m

onth and its subsequent atrophy prior to birth in cases of anenceph-aly. C

onstant histological defects have not been noted in placentas of anencephalic infants. W

hether or not atrophy of the fetal zone in anencephaly is due to deficient A

CT

H is open to serious doubt. T

he adrenal cortex of the new

born reacts very sluggishly to exogenous

Figure 8. R

adiograph of skull in a mse of m

icrocephaly at term illustrating sm

all size of vault in com

parison to facial hones. The prom

inent sella contained a 'normal' pituitary

yet the adrenals showed atrophy characteristic of anencephaly (after JANIGAN et al. w

ith

permission of the E

ndocrine Society).

Figaro, 9. Coronal section of brain in a case of m

icrocephaly at term show

ing incomplete

development of gyri, rudim

entary ventricular system, and absence of hypothalam

us. The

pitu

itary in

this case w

as consid

ered n

orm

al, yet th

e adren

al glan

ds sh

ow

ed atro

phy

characteristic o

f anen

cephaly

(after p.m

., et al. with

perm

ission o

f the E

ndocrin

e S

ociety).

288 N

tcnots Anencephaly G


porcine AC

TH

[27], as judged by urinary excretion of hormones,

and injection of exogenous AC

TH

does not impede involution [29]

of the fetal zone. Perhaps it m

ight respond to injection of human

AC

TH

. T

his au

thor [4

3] h

as found A

CT

H p

resent, b

y th

e meth

od o

f N

EL

SO

N and H

ymn [40], in pituitary and/or sella tissue in all of five

cases of anencephaly. The am

ount could not be determined quantitati-

vely because the tissue by histological examination w

as composed in

large and varying part of nonpituitary mesenchym

e, and some tissue

was necessarily. utilized in the'histological preparations. If the fetal

zone is dependant on AC

TH

for its integrity and becomes atrophic in

the anencephalic because of lack of AC

TH

, it would m

ean simultane-

ously that the definitive zone is less dependent on AC

TH

, because atrophy of the definitive zone is not as profound as atrophy of the fetal zone. P

erhaps the plasma A

CT

H levels in anencephalics and

normal infants w

ill be compared and the answ

er forthcoming w

hen bio-assay for A

CT

H becom

es more sensitive. A

lthough AC

TH

has not been determ

ined in the placenta of anencephalics, there is no reason to doubt its presence, and therefore, availability as a stim

ulus if the fetal zone is susceptible.

There is am

ple evidence of at least two kinds of A

CT

H for the

adult human adrenal gland, one a w

eight maintaining factor and the

other a steroid releasing and/or forming factor. T

hese two A

CT

H's

are sometim

es formed in tissue other than pituitary, e.g., lung tum

ors [44]. A

trophy of the fetal zone in anencephaly could be explained by either a) the absence of a 'fetal adrenal A

CT

H' from

the cerebrum

and midbrain w

hich would act directly on the fetal zone (and defini-

tive zone) in the normal fetus, or b) absence of a 'fetal adrenal cortico-

trophin releasing factor' which w

ould stimulate the fetal pituitary to

form a special 'fetal adrenal A

CT

H'. T

hese postulated factors would

no

t be n

eeded

prio

r to th

e 5th

mo

nth

of g

estation

, bu

t wo

uld

be

required subsequently. M

any cases of microcephaly and hydrocephaly show

varying degrees of atrophy of the fetal adrenal cortices usually paralleled w

ith absence of C

NS

tissue and with varying am

ounts of pituitary tissue. F

igure 8 shows the skull, and F

igure 9 shows the brain in tw

o cases of m

icrocephaly where the corpus callosum

and hypothalamus w

ere absent [24]. T

he cerebral tissue was greatly reduced in am

ount yet the pituitary grossly and histologically w

as normal, but the fetal zones

were absent. hvinstances such as these, a dim

inished amount of cere-

and Horm



onn 289

Figure 10. T

his represents the brain in a case of congenital hydrocephaly due to atresia of she aqueduct. T

he cerebral hemispheres and hypothalam

us are, for the most part, reduced

to a thin walled sac. T

wo sm

all islanda of cerebral tissue, a small fragm

ent of cerebellum

and a deformed m

edulla are present. The flattened isolated pituitary and atrophic adrenals

did not react to metapirone (S

U 4885). T

he infant lived 9 days.

bral tissue is present but the hypophyseal portal system is absent.

Figure 10 show

s the 'brain' from a case of hydrocephalus in w

hich the infant lived nine days. T

he cerebral hemispheres are reduced to a sac

with a thickness of 0.5 m

m; the basal ganglion, choroid plexus, and

midline structures are m

arkedly atrophic due to massive internal hydro-

cephalus from atresia of aqueduct of S

ylvius. The isolated anterior

lobe of pituitary is flattened and reduced in mass, w

hile the adrenals show

atrophy characteristic of anencephaly. Posterior lobe tissue is not

present. Plasm

a 17-0HC

S (P

orter-Silber chrom

ogen) determinations

were done in this infant on each of five days, i.e., tw

o days prior to adm

inistration of SU

4885 (Metapirone) in four doses of 100 m

g each by gavage at six hour intervals and for tw

o additional days at w

hich time the infant died. U

rine collection was unreliable. T

he plasma

values were 1.5, 1.7, 1.8, 1.8, and 1.7 m

icrograms per 100 m

l on the five days. T

his lack of response could be due to either a) refractory or inadequate adrenal, b) refractory or inadequate pituitary, or c) both.

290 N

EC

HO

LS: A

nencephaly: Geographic Incidence, Etiology,

FunthO

n of Fetal Zone

Fu

nctio

n o

f the fetal zo

ne fo

rmerly

was en

tirely sp

eculativ

e, how

ever, recently some clues have been obtained. It w

as held, by m

any, that androgenic hormones w

ere formed in this zone, because the

newborn infant excretes large quantities of 17-ketosteroids w

hich decline parallel w

ith involution of the fetal cortex. Considerable

evidence has accumulated indicating that this zone does contain C

„ steroids and can,', in vitro, perform

many biochem

ical steps necessary for production of androgens [4:6, 50]. D

IGE

OR

GE

et al. [14] report an anencephalic w

ith high levels of plasma 17-ketosteroids 12 hours

after birth. NIC

HO

LS et al. [45] reported that plasm

a of 5 newborn

anen

ceph

alic infan

ts had

no

rmal am

ou

nts an

d n

orm

al matern

al-fetus gradient of 17-O

HC

S. T

he 17-ketosteroids in three of these infants w

ere in the normal range and in tw

o of these cases plasma

deh

yd

roiso

-and

rdstero

ne su

lfate was v

ery lo

w, a fin

din

g also

noted by SIM

ME

R et al. [49]. T

his suggests that physiological func-tion of the fetal zone does not necessarily reflect its pharm

acologic capacity.

The m

ost interesting work recently has com

e from the laboratories

of FRA

ND

SEN

and STA

KE

MA

NN

[18, 20] who report patients pregnant

with an anencephalic fetus do not excrete the high estrogen levels

characteristic of pregnancy, but instead excrete a low level characte-

ristic of the non-pregnant wom

an. This has been confirm

ed by Corta

[13] by injecting into spayed imm

ature mice a) adrenal cortex, 13) pla-

centa and c) adrenal and placenta from prem

ature normal fetuses

obtained at therapeutic abortions, it was found that neither adrenal

cortex nor placenta alone caused estrogen effect, but when adrenal and

placenta were injected together, the m

ouse showed estrogen effect.

From

this they concluded the fetal adrenal cortex produces a precursor stero

id fro

m w

hich

the p

lacenta fo

rms th

e hig

h lev

el of estro

gen

characteristic of pregnancy. M

AcD

omm

.13 and Sum

ter [31, 32] with

radioactive material concluded that this precursor is dehydroiso-

androsterone. From

the fact that the definitive zone also undergoes profound involution, in anencephaly it does not seem

justified to conclude that this capacity to form

estrogen precursor is limited to

the fetal zone. It is to be noted that FR

AN

DS

EN

and ST

AK

EM

AN

N

injected 'adrenal Cortex', presum

ably both definitive and fetal zones. T

hey did not separate and inject a) definitive zone, b) fetal zone and c) both definitive and fetal zones nor have they injected adrenals from

and Horm

onal Relations of the Pituitary and

Ad

renal Cortex

291

cases of anencephaly formed m

ainly of definitive zone. The function

of the fetal zone is, therefore, not yet settled. B

ecause the fetal zone of the human adrenal is often confused and

or compared to the a-zone' of the m

ouse adrenal, a few w

ords about the latter is in order. T

his zone develops in the mouse adrenal about

21 days after birth and occupies a position between the zona reticularis

and medulla. In the m

ale it begins involution at about 45 days of age sim

ultaneous with appearance of androgens from

the testicle, and in th

e female it p

ersists for ab

out 2

50 d

ays o

r onset o

f preg

nan

cy,

whichever com

es first. During pregnancy in the m

ouse a small quan-

tity of androgens is produced, as some are produced in aging ovary.

The X

-zone can be maintained indefinitely by castration or m

ade to disap

pear at an

y tim

e by in

jection o

f andro

gen

s and, th

erefore,

obviously is quite different from the fetal zone of the hum

an gland [10].

Other C

lonal:

Gross and m

icroscopic examinations of the other glands in anen-

cephaly reveal no findings comparable in m

agnitude to atrophy of the adrenals and deficiency of the pituitary gland. G

rossly the thyroid gland is norm

al and microscopically it appears, perhaps slightly, m

ore m

ature th

an fro

m a n

orm

al infan

t of co

rrespondin

g ag

e. Pro

tein

bound io

din

e determ

inatio

ns o

n m

aternal an

d co

rd b

lood in

two

cases of anencephaly reveal respectively the following m

aternal: fetal ratios, 9.0 : 10.8 and 11.2 : 10.6 m

icrograms per 100 m

l. The author

knows of no com

parable data, but this suggests fetal thyroid function to be norm

al or hyperactive in cases of anencephaly. In two cases of

anencephaly the maternal F

BI w

as 8 and 13 microgram

s per 100 ml

and the thyroxine binding globulin 32 and 41 microgram

s per 100 ml

respectively. This is about tw

ice the values of the non-pregnant wo-

man and is the sam

e level as found in the wom

an pregnant with a

normal fetus and high estrogen levels. B

ecause these wom

en had low

non-p

regnan

t estrogen

valu

es the p

revalen

t theo

ry th

at PB

I and

thyroxine binding globulin are increased due to the accompanying

high estrogens [15, 53] is open to question. Of course, norm

al appear-ance of the thyroid in anencephaly m

ay be due to long acting thyroid stim

ulating hormone w

hich in the adult, at least, does not arise from

the pituitary. The pancreas and the parathyroid glands grossly and

microscopically appear norm

al. The gonads, both m

ale and female,

and Horm



ortex 2

93

292

Nicitors A


tiology,

Fist. 11. X

ray of anencephalic infant delivered from m

other with polyhydram

nios 5 hours after injection of barium

sulphate into the amniotic sae. It can be seen that the

infant has swallow

ed the barium, thereby elim

inating 'absence of swallow

ing' as cause of m

aternal polyhydnunnios in this case. Coincidentally, there are healing fractures of the

upper left h

um

erus an

d u

pper rig

ht fem

ur ('b

attered ch

ild in nitre!') (W

aanurt an

d

Mum

., unpublish

ed).

appear grossly somew

hat small and histologically slightly im

mature.

Despite apparent low

estrogen values, the vagina appears to be fully as corniced as in norm

al infants born of mothers w

ith characteristic high estrogen levels. T

he author in his five cases has observed the pigm

entation of the vulva and scrotum to be som

ewhat less than

Figure 12. Esophagus, stom

ach, md duodenum

of anencephalic infant in Figure II opened

sho

win

g th

e meg

aloeso

ph

agu

s and

bariu

m in

the sto

mach

(WA

RR

EN

and

/Victim

s, unpublished).

normocephalic infants, suggesting a low

level of MS

H. O

ne char-acteristic finding is a large hyperplastic thym

us. It is unlikely that th

is is due to

'atrophic' ad

renals, b

ecause p

lasma 1

7-0

HC

S an

d

17-ketosteroid values in anencephaly are not below those of the nor-

mal fetus. D

espite the many defects present in the anencephalic the

growth in oder° is not im

paired, except, perhaps a faster growth rate in

the upper extremities [39]. T

he few rare cases w

hich live a week or

so die usually from sepsis, pneum

onia, and atelectasis and not from

endocrine causes.

294 N

tcum

s: An

enap

haly

: Geo

grap

hic In

ciden

a, Etio

log

y,

Effect on the M

other

Anencephaly m

ay have no effect on the mother. H

owever, fre-

quently polyhydramnios is present. In fact, w

hen polyhydramnios is

present, anencephaly or other malform

ation should always be suspec-

ted. Excess am

niotic fluid is presumably due to a) excess form

ation from

the exposed choroid plexus, b) absence of a swallow

ing reflex by the infant, c) im

paired motility of the gut, d) increased urine for-

mation by the kidney and e) decreased fluid absorption by the sm

all crow

ded hypoplastic lungs. In the author's 29 cases, hydramnios w

as present in 18. C

horoid plexus was found in only 5 of these cases.

In 11 cases withot polyhydram

nios, choroid plexus was present in 4,

and in all of these nine cases the choroid plexus was very sm

all in am

ount. Figure 1:1 show

s an X-ray of a new

born anencephalic with

barium sulphate to the stom

ach. The m

other had profound hydram-

nios and barium w

as injected into the amnion five hours before labor.

The fact that the infant sw

allowed the barium

indicates, in this case, that the hydram

dios was not due to absence of sw

allowing despite

megaloesophagus' (F

ig. 12). This is contrary to the report of JE

FF

-C

OA

TE

and Scarr[25] w

ho found that three of four anencephalics did not sw

allow radibpaque m

edia injected into the amniotic cavity. A

t delivery the fourth case w

as a spurious diagnosis. In all the author's cases of anencephaly, m

econium has been found in the sm

all intestine irrespective of w

hether or not the mother had hydram

nios. This sug-

gests that the observed hypoplasia of the intrinsic plexi [7, 35, 48] of the sm

all intestine is not of great physiological importance.

BE

NIR

SC

HIC

E and M

cICA

y [5], in a histochemical study of tw

o cases of anencephaly failed to fm

d antidiuretic substance in the small

amount of posterior lobe pituitary and neural tissue. T

hey hold that this supports the idea that excess am

niotic fluid may arise as a result

of diuresis from nonresorbing kidneys. U

rine outputs in cases of anencephaly w

hich survive for a few days w

ould be worth w

hile on this point but such observations are not in the literature.

It seems that the low

levels of estrogens in wom

en pregnant with

anencephalic fetuses do not have adverse effects on the course of the p

regn

ancy

altho

ug

h m

ost cases o

f anen

ceph

aly h

ave 1

-2 w

eeks

shorter gestation than the normal infant despite M

Arrns' [33] report

that anencephaly is one of the few absolute causes for post m

aturity. T

wenty of the author's cases w

ere 1-2 weeks prem

ature, six were at

term, and three w

ere two w

eeks overdue. Assum

ing the incidence of

and Horm



ortex 295

toxem

ia to b

e 5%

and an

encep

haly

to b

e 0.1

% th

e incid

ence o

f toxem

ia associated with anencephaly should be 0.005%

. The author

does not know of a case. A

few cases of hypopituitarism

and hypo-adrenalcorticalism

have been reported to benefit from pregnancy and

the benefit attributed to fetal pituitary andfor adrenalcortical hor-m

ones from the fetus crossing the placenta and entering the m

aternal circulation. It w

ould be interesting to observe the effect of an anen-cephalic pregnancy w

hen the mother has hypopituitarism

or hypo-adrenakorticalism

. The author know

s of no such case. F

inally a word m

ay be said about intrauterine diagnosis which

should always be m

ade several months prior to labor. W

hen a head is not felt on exam

ination a) the patient is extremely obese, b) there is

an anterior placenta covering the head, c) the fetal head has descended into the pelvis and can be felt from

below, or d

) the patient has an anencephalic, or m

icrocephalic, fetus. The latter condition (d) justifies

confirmation by X

-ray so the patient may be inform

ed and interested personnel alerted to conduct appropriate horm

one studies. In the author's 29 cases, 15 w

ere diagnosed prior to delivery, albeit, five of them

very late pregnancy; 10 presented in labor without prior obstet-

ric attention; and 4 were not detected by the attending physicians during

prenatal care. Indeed, in 3 of the latter cases the position of the occiput had been recorded I I I

Summ

ary

Anencephaly, a condition w

ith absent forebrain and midbrain

structures, occurs in newborn fem

ale infants with three to five tim

es the frequency as in m

ales. It has a unique geographic distribution, occurring in Ireland (0.6%

) fifty times as frequently as in L

yons, F

rance (0.012%). A

genetic mechanism

appears involved but cannot account for all cases; unknow

n diverse environmental factors undoub-

tedly are responsible for a large number of cases. T

he morphogenesis is

uncertain, but several possible mechanism

s exist. The condition m

ay be produced by diverse agents in experim

ental animals.

A m

arked deficiency of anterior pituitary tissue is present but A

CT

H is present in sells tissue, albeit in sm

all amounts. T

he fetal zone of the adrenal cortex develops norm

ally, at least, until the fifth month

of gestation, whereupon it involutes alm

ost completely by tim

e of birth. T

he fetal zone apparently forms a steroid precursor w

hich the placenta converts into estrogenic horm

ones. This fetal zone, being

296 M

emo.: A


tiology,

almost absent in cases of anencephaly and the definitive zone m

arkedly hypoplastic causes the m

other to have a low estrogen level charac-

teristic of th

e non-p

regnan

t wom

an. T

his lo

w lev

el of estro

gen

s apparently has no adverse effects on the course of the pregnancy. T

he most likely cause for the atrophy of both fetal and definitive zones

is absence of a neurohumor form

ed in structures of the fore and mid-

brain which either stim

ulates directly the fetal adrenal or a neuro-hum

or which stim

ulates the pituitary to form a special 'fetal adrenal

AC

TH

'. Anencephaly can and should be diagnosed w

ith precision prior to labor.

The author is indebted to D

r. HE

NR

DC

KU

RSK

, for providing the Polish papers 1511 to M

rs. WA

ND

A W

OR

NE

GC

S for translation, to Mr. A

trium. SH

EPH

ER

D and M

rs. SHE

RR

Y

JOH

NS

ON

for assistance in obtaining the unpublished data. T

he unpublished work

mentioned w

as supported, in part, by U.S. Public H

ealth Service grant AM

02767.

1. A

uras, M.: A

nencephalic births in a northern and a southern comm

unity. Am

er. J. D

is. Child 1

06: 536-544 (1963).

2. A

ttosvoss, D. M

.; Pathologic anatomy of hypophysis and adrenals in anencephaly.

Arch. Path. 26: 50/-518 (1938).

3. BE

DIR

SGSC

E, K

.: Adrenals in anencephaly and hydrocephaly. O

bstet. Gynec., N

.Y.

8: 412-425 (1956).

4. BEDIR

SCH

ICE, K

.; Ehnen, E

. and Fisarto, A

.T. C

oncerning the function of the fetal zone of the hum

an adrenal gland. Endocrinology 58: 598-625 (1956).

5. BEDIR

SGH

ICR

, K. and M

cKee, D

. G.: T

he antidiuretic hormone in fetus and infant.

Obstet. G

ynec., N.Y

. 1: 638-649 (1953).

6. B

locs., E.; B

ER

NISG

HC

A, K

. and RO

SENBER

G, E

.: C,, steroids, 17a hydroxycortico-

sterone and a sodium retaining factor in hum

an fetal adrenal glands. Endocrinology

58: 626-633 (1956).

7. BO

MB

AR

D...A

, M.P.: Studio sal sistem

a nervom intram

urale delPimestino nell'anen.

«fel°. Riv. A

nat. pat. 18: 801-807 (1960). 8.13N

ix, J. A. and Fasccsao, M

.: Research on congenital m

alformations. E

t. 'leo-natal. 5

: 39-52 (1956). 9

. Crnersa J

on

es, I.: Role of the adrenal cortex in reproduction. B

rit. med. B

ull. 11: 156-160 (1955).

10. alarm

s. loom, I. T

he adrenal cortex (University Press, C

ambridge, 1957).

11. CO

FFEY

, V.P. and lessor, W

. J. E.: A

study of 137 cases of anencephaly. Brit. J. prey.

soc. Med. 1

1: 174-380 (1957).

12. CO

FFEE

. V.P. and Jsm

or, W. J.E

.: Maternal influenza and congenital deform

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prospective study. Lancet ii : 935-938 (1959).

13. C

orks, M.G

.: The urinary excretion of oestrogen in four cases of anencephaly and

one case of foetal death from cirrhosis of the liver. J. E

ndocrin. 25: viii-ix (1962).

and Horm

onal Relations of the Pituitary and A

drenal Cortez

297

14. D

iGsoaos, A

.M.; A

RSE

, J.B. and B

ottmoveratt, A

. M.: Plasm

a 17-ketosternids In an sm

encep ludic infant. J. clin. Endnerin. 16: 1281-1282 (1956).

15. D

owutto, J.T

.; FR

EID

A., N

. and loom, S

. H.: E

ffect of diethylatilbesterol on the binding of thrust=

in serum. J. O

lin, Endocrin. 1

6: 1491-1506 (1956).

16. ED

WA

RD

S. 3.14.. The epidem

iology of congenital malform

ations; in: tad Internat. C

onf. Congenital M

alformations (July 1963), pp.297-305 (International M

edical C

ongress Ltd., N

ew Y

ork 1964). 17. E

kuorr, T.R

. and Aattoua, A

.G.: T

he development of the cortex in the hum

an suprarenal gland and its condition In hernicephaly. J. Path. B

ent. 15: 481-488 (1911). 18. Fitstrusztt, V

. A. and ST

AR

EM

AN

N, G

.: The site of production of oestrogenic horm

ones in hum

an pregnancy. Horm

one excretion in pregnancy with anencephalic fetus.

Acts endocrin., K

bh. 38: 383-391 (1961). 19. FIU

ND

SILD

, V.A

. and STA

CM

IAN

D, G

.: The site of production of oestrogenic hor-

mones in hum

an pregnancy. II. Experim

ental investigation on the role of the foetal adrenal. A

ra endocrin., Kbh. 4

3: 184-194 (1963).

20. FRA

ND

SEN

. V.A

. and SPA

...MA

NN

, G.: T

he site of production of oestrogenic hormones

in human pregnancy. III. Further observations on the horm

one excretion in pregnancy w

ith mencephalic foetus. A

= endoetin., K

bh. 47: 265-276 (1964). 21. G

IRO

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Edited by Eoas BAjusz, Cambridgejfk.hood.edu/Collection/Weisberg Subject Index Files/N Disk/Nichols... · Edited by Eoas BAjusz, Cambridge Anencephaly Geographic Incidence, Etiology