Post on 11-Mar-2021
BASEL (Switzerland) S. KARGER Printed in Switzerland
NEW YORK
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e unpublished observations of the author.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
nencephaly: Geographic Incidence, E
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
eographic Incidence, Etiology,
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
onal Relations of the P
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
nencephaly: Geographic Incidence, E
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
onal Relations of the P
ituitary and Adrenal C
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
eographic Incidence, Etiology,
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
onal Relations of the P
ituitary and Adrenal C
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
onal Relations of the P
ituitary and Adrenal C
ortex 287
286 P
ficnoxs: Anencephalyt G
eographic Incidence, Etiology,
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
eographic Incidence, Etiology,
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
onal Relations of the P
ituitary and Adrenal C
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
onal Relations of the P
ituitary and Adrenal C
ortex 2
93
292
Nicitors A
nencephaly: Geographic Incidence, E
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
onal Relations of the P
ituitary and Adrenal C
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
nencephaly: Geographic Incidence, E
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-
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an fetal adrenal glands. Endocrinology
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7. BO
MB
AR
D...A
, M.P.: Studio sal sistem
a nervom intram
urale delPimestino nell'anen.
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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
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1: 174-380 (1957).
12. CO
FFEE
. V.P. and Jsm
or, W. J.E
.: Maternal influenza and congenital deform
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orks, M.G
.: The urinary excretion of oestrogen in four cases of anencephaly and
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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
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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-
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