REVIEW ARTICLE

SPECIAL SECTIONS

REVIEW ARTICLE

ADRENOCORTICAL

METABOLISM

OF

THE

FETUS,

INFANT

AND

CHILD

By Lytt I. Ga;dner, M.D.

Department of Pediatrics, State University of New York, Upstate Medical Center, Syracuse, New York

Aided by a grant (G-403.3-C) from the National Institutes of Health, U.S. Public Health Service.

ADDRESS: Upstate Medical Center, 766 Irving Avenue, Syracuse 10, Now York.

897

Ped

VOLUME 17 JUNE 1956 NUMBER 6

T

of adrenocortical steroids in body fluids over the past 2 decades have made possible

an extensive exploration of adrenal func-tion. This review is restricted to adreno-cortical metabolismn in the fetus, infant and

child. No attempt will be made to cover all of this rapidly developing area of

en-deavor. Certain aspects have been treated in other review articles, to which the reader is referred. The reviews by Moore on fetal endocrinobogy,1 Klein on neonatal adrenal physiology,2 Lieberman and Teich3 and Roberts and Szego4 on steroid biochemistry,

Whites and Wettstein and Anner6 on

ad-renal cortical hormones, Ingle on cortisone7 and Gaunt, Renzi and Chart on

aldoster-one8 are especially useful. The books by

Wilkins9 and by Talbot and colleagues#{176}

contain helpful treatments of this area. Due

to the prolific nature of even the review literature, it is necessary to make a rather

arbitrary selection of material.

NEWER METHODOLOGY

Within recent years a number of methods

have been developed for the estimation of

hormones in urine and plasma. Several

techniques for the chirornatographic

separa-tion of the 17-ketosteroids in urine have been descnibed.1113 Of particular value in the diagnosis of vinilizing adrenal tumor

has been the development of colorimetric methods for the estimation of dehydroep-iandrosterone in urine.1416 Some progress

has been made in the estimation of

corti-costeroids in the unine.1719 Techniques for

the measurement of 11-oxygenated neutral

17-ketosteroids, pregnanetriol and

preg-nanediol in the urine of patients with

con-genital adrenal hyperplasia have been die-scribedi.b021

There has been a blossoming of methods for estimating steroids in plasma. Several varieties of techniques are now available for the measurement of corticosteroids2228 and

17-ketosteroids in plasma.2933 It has proven to be very difficult to assay ACTH in hio-logical fluids, but some data are now avail-able.34

FETUS AND NEWBORN

16 22 26 30 2 3 4

-

Month5-Age

898 GARDNER - ADRENOCORTICAL METABOL1S\I

described by Deane (1955).36 Our state of

knowledge of the human fetal adrenal gland

has been reviewed by Moeni (1951), Lan-man (1953)38 and Baar (1954). The cells

forming the fetal adrenal cortex have been

identified in the human embryo as early

as the 10-mm. stage. Shortly thereafter cells

of the adult-type cortex make an appear-ance. At about the 30-mm. stage granula-tions appear in the cells of the fetal cortex which at this time represents nearly all of the adrenal gland. Contemporaneously the

first basophilic cells are differentiated in the fetal hypophysis.

The adult-type adrenal cortical tissue,

which is located at the periphery of the

gland, grows slowly throughout fetal life. At the time of birth the inner fetal cortex represents about 80 per cent of the total

gland. There is some disagreement as to whether the fetal cortex begins to involute just before birth or at the time of birth. In

any case there is rapid involution of the

fetal adrenal zone after birth. By the third week of life there has been a loss of 50 per

cent of the total weight of the gland. In 1951 T#{228}hk#{228}made an extensive study of 311 adrenals of children from birth until 24 months of age.4#{176}In this study the mean

weight of both adrenals at birth was 6.5 gm. This value fell to 3.51 gm. at the age

of 2 to 3 months. Following this there was

a gradual increase of weight to a mean

value of 5.23 gm. at 24 months. The weight

curves of the adrenals in premature infants

did not differ greatly fromn the findings in

full-term infants. The involution of the fetal

zone tissue in full-termii and premature imi-fants is shown graphically in Figure 1.

During the first 3 weeks of life there is rapid disintegration of the fetal cortex

whereas the adult-type cortex proliferates slowly for the first 4 days of life, then

rapidly thereafter. It has been hy1)OthesiZe(i

that the proliferation of adult-type adrenal cortex in the embryo may have been

in-hibited by corticoids, exogenous to the

fetus, so that growth of this adult-type

tis-sue would not begin until the newborn has eliminated these hormones from its cir-culation (see Fig. 2).’ Deane has recently

evaluated the adrenal cortical activity in

newborn rats by histochemical rnethods.0 Her findings indicate an acute shrinkage

of the adrenal cortex after birth in a man-ner reminiscent of the involution of the

human fetal cortex. She interprets this

do-dine in adrenal size in the newborn rat

as a reflection of loss of stimulus arising

from the mother or placenta. Whether this

stimulus referred to is adrenocorticotropin

(ACTH) itself6 or a luteinizing (LH-like)

hormone4’ is still in question. Gemzell and

colleagues42 analyzed human cord blood

for ACTH by the technique of Sayers, Sayers and Woodbury. No ACTH activity

was demonstrated.

There appears to be a relationship

be-tween the central nervous system amid the fetal adrenal cortex. The literature on this

Fir’ cent of gland

occupied

by fetal zone

FIG. 1. Relative size of fetal adrenal zone in full-term and premature infants of

I FASCICULATA ATROPHIC

WITHOUT ACTH SlIM

IIE\7lE\V ARTICLE 899

[ST OGEN CORT OIDS

ANT PITUITARY

LH ACTH

INNER I

ZONE

HYPERPLASTIC

.

,

DUE TO LI-I STIM

‘S ‘S

NO CORTICOIDS

I‘- *NDRoS”1N-3.7-O$ON(

UPGEST*’flONAL CPQS

mO(HYDROLPIACROSTLRON(

FIG. 2. Interrelationships of placenta, fetal

pittii-tary and fetal adrenal as suggested by the

observa-tions of Gardner and \Valton,’ Forbes,4 Bloch et

(1l.,” Migeon et and Klein (‘t (Ii.”

subject has l)een recently evaluated.338

Observations extending over 2 centuries indicate that the condition of anencephaly is associated with fetal adrenal dysgenesis. More recent studies of anencephalics point out a connection between abnormal

devel-opment of the pituitary amid hypoplasia of

the fetal cortex. In this condition the sella turcica was found to be poorly formed.

While some pars anterior tissue could

usu-ally be demonstrated, the pars intermedia and pars nervosa are quite frequently ab-sent. These findings lend support to the hypothesis that the fetal zone is maintained in utero by some trophic substance from

the pituitary and/or hypothalamus. It has beemi suggested that a LH-like hormone is elaborated from the fetal pituitary under stimulation by the estrogens of pregnancy.41

This trophic hormone would serve to

main-tam the fetal cortex until the time of

par-turition. After birth, stimulation of

produc-tion of LH-like hormone by the estrogen

of pregnancy would no longer take place and the fetal adrenal cortex then involutes. Forbes has recently found that the con-centration of biologically measurable

pro-gestational substances in the umbilical

ar-tery is higher than in the umbilical vein.43

This is consistent with the foregoing

hy-pothesis.4’ This author reviews other

evi-dence which favors the fetal adrenal as a

source of progesterone. In this connection it is interesting that Ober and Bernstein routinely found histological evidence of a

progestational response in the endometrium

of autopsied female newborns.44 These

authors also noted that the fetal ovary

could not very well be the source of this progestational response, as in no case did

they observe luteinization of theca or

granubosa cells. Figure 2 shows a schematic representation of some of the proposed

relationships of the fetal hypophysis and fetal adrenal.#{176}

Lanman has discussed the attempts which have been made to assay hormones from fetal adrenal glands.38 Biological

as-says both for androgen and estrogen

yielded no evidence that either group was

especially concentrated in the fetal adrenal. However, Bboch and colleagues have

re-cently reported the finding of andro-stone -3,17-dione in human fetal adrenal

tissue.45 This finding is of great interest, because in-vitro experiments have shown that adrenal tissue is active in the conver-sion of dehydroepiandrosterone to the above

compound.4647 Plasma from the umbilical

cord has been shown to have higher con-centrations of 17-ketosteroids than plasma from maternal blood, measured at the same time.41’48’4#{176} Migeon et al. identified the 2 principal 17-ketosteroids of adult human

plasma to be dehydroepiandrosterone and androsterone.30’ #{176}Analyses of cord plasma

revealed concentrations of these 2 steroids

similar to those found in the nonpregnant adult, whereas data on the mothers’ plasma showed a diminution in the concentration of dehydroepiandnosterone.49 All these data

suggest that some tissue in the fetal

circu-lation is producing 17-ke#{149}tosteroids. Evi-dence is not yet available to indicate whether these 17-ketosteroids are being

0 A highly unsaturated ketonic compound has

just been isolated from the adrenal glands of

newly born infants.”7 This ketone has an Rf only

900 GARDNER - ADRENOCORTICAL METABOLISM

produced by the placenta or by the fetus.

Forbes’ data would indicate that the human fetal adrenal also produces

proges-terone or a substance with very similar

po-tentialities.4 Although the Hooker-Forbes

biological assay for progesterone has been shown to be quite specific for progesterone,

there is still the possibility that the material measured in Forbes’ experiment is a steroid

intermediate in the biosynthesis of com-pound F and/or dehydroepiandrosterone.

The latter 2 steroids are known to have no activity in the Hooker-Forbes test.

There are many aspects of adrenocortical

metabolism of the normal newborn which are reminiscent of untreated congenital adrenal hyperplasia in the older infant. The newborn has a “relative” adrenal

hyper-plasia (in adrenal size),5’ and the “andro-genic” zone of the fetal cortex has long been compared with the histological appearance of the adremial tissue in congenital adrenal hyperplasia; 17-ketosteroids are “high” in

the plasma of newborns and corticoids are

nearly absent;2 the newborn may respond

to ACTH by a sodium diuresis.2 All these findings are also true in congenital adrenal hyperplasia. On the other hand 2 important

differences must be pointed out: The

new-born responds to ACTH stimulation by a rise in the level of corticoids in the serum;

patients with congenital adrenal hyper-plasia usually do not. There is no measur-able ACTH in newborn (cord) blood; there

are measurable (elevated) levels of ACTH in the blood of untreated patients with congenital adrenal hyperplasia. Is there a normal developmental stage in steroidal

pathways of the human fetus and newborn in some ways comparable to the metabolic

error in congenital adrenal hyperplasia? It is conceivable that the newborn’s

immedi-ate inability to elaborate compound F re-fleets a developmental block in synthesis of this compoun1 at the level of progester-one, 17-hydroxyprogesterone or a related

in-termediate, a block which has possible met-abolic advantages for the embryo. The re-cent studies by Migeon and cogu253

indicate that the human embryo does not

elaborate corticoids, yet is bathed in

corti-coids probably furnished by the placenta. The fetal adrenal cortex may not possess a

“mature” chain of enzymatic reactions all the way to compound F, the latter being provided “exogenously,” and in fact could find a certain advantage in permitting one

of the progestationally active intermediates to accumulate just for the duration of fetal life.#{176} Possibly this built-in mechanism serves as a sort of life-jacket in case the

extra-fetal sources of progesterone fail. On the other hand it may be a vestigial biosyn-thetic pathway held over from an earlier phylogenetic day.

Migeon has found in adults that there is

a lag of about 4 hours after ACTH therapy before dehydroepiandrosterone rises in the plasma, and he suggested that this lag

may be the result of an intermediate being produced by the adrenals, which intermedi-ate in turn is transformed into dehydro-epiandrosterone. It is possible in the fetus

that the biosynthesis of

dehydroepiandro-sterone as well as progesterone-like steroids

by the fetal cortex need not take place via

mutually exclusive pathways.5’ 56

A comparative study of 17-ketosteroids in the plasma of full-term versus premature newborn infants has revealed that the

pro-mature tends to have higher concentrations of 17-ketosteroids in the plasma in early life than does the full-term (see Fig. 3). These steroids also persist longer in the plasma of the premature than in the full-term newborn.57 The full-term newborn

normally has values for 17-ketosteroids in

the plasma in the adult range for the first few days of life, after which time they fall precipitously. The premature infant shows a different pattern of 17-ketosteroids in

0 Paradoxically, Zander and Solth found no

“pregnandiolkomplex” in the urine of newborn

in-fants. These authors gave 20 mg. of

progesterone-in-oil intramuscularly to each of 5 newborns on

the first day of life. No “pregnandiolkomplex” was

found in the urine collected from these newborns

for the first 5 days of life. These findings suggest that the newborn (and by inference the fetus) has

CONGENITAL ADRENAL

HYPERPLASI A

A DRE NA

FULL TERM OOPHORX

NEWBORN

FIRST 2 DA

I

I

I

Ftc. 3. Levels of 17-ketosteroid in the plasma of premature and full-term infants

constrasted with values obtained from other individuals.” ‘

I1Iii:VIE\\/ A1ii’I(;LE 901

i L A S M A

I7- S

EN CENT

urine, when investigated by

spectrophoto-metric and chromatographic techniques,

than does the full-term infant.58’ 59 Ulstrom

amid Doeden measured total 17-ketosteroid excretion in urine in full-term and

prema-tune infants for the first 23 months of life.

There was no significant difference in the total urinary excretion of 17-ketosteroids.

When the chromatographic pattern of

17-ketosteroids in urine of full-term and

pro-mature infants was studied, the fraction

contaimiing dehydroepiandrosterone was found to be relatively more prominent in

the m59

Klein has reviewed corticosteroid

metab-olism in the newborn period.2 The

con-centration of corticosteroids in cord serum was found to be like that of normal adults

or higher, whereas there was essentially no measurable corticosteroid in the serum of newborns 2 to 5 days of age (cf. Fig. 2).60

This finding is quite consistent with the

observation by Deane in newborn rats that the secretory activity of the adrenal fascic-ulata is very low for the first 10 days of life. After that time she found

histochemi-cal evidence of increasing activity in the

fasciculata. Genizell has found the concen-tration of corticords in plasma of newborns

born of pnimipanae to be significantly higher than similar measurements mnade on

newborns born of multiparae. Infants

dIe-livered by cesanian section showed very low

values for the concentration of corticords in uml)ihcal cord plasma.6’ Migeon and

col-leagues found that in cases of vaginal

deliv-ery, labor increased the levels of corticoids in maternal plasma over the already

ele-vated values found in pregnant patients at

term.52’ 53 In addition, delivery itself had a

tendency further to raise the level. In cases

of vaginal delivery, the concentrations of conticoids in cord plasma were 1/2 to 1/5

those of the mother, and in elective

cesar-ian sections the relative concentrations of

corticoids in cord plasma were even less When compound F was administered intra

venously to mothers just prior to cesanian

section, it was found that compound F penetrated the placental barrier in constant proportions, suggesting that the concen-tratiomi in maternal plasma was the

deter-mining factor for the concentration of

corticoids in the fetal circulation. When ACTH was given to similar patients, there was an increase of the conticoids in the

902 GARDNER - ADRENOCORTICAL METABOLISM

of corticoids did not change. No evidence of comnpound B was found by paper

chro-matography either in maternal or fetal plas-ma. The data obtained from infusion of corn-pound F data and ACTH therapy are inter-preted by Migeon and colleagues to mean that the fetus itself is producing little if any corticoids at term.53 On the other hand, as previously noted, the fetus seems to be

pro-ducing considerable quantities of 17-keto-steroids at term. The increased concentra-tion of glycogen known to exist in newborn tissues62 probably is a reflection of the

in-creasing concentrations of corticoids in the fetal circulation during the process of

de-livery. It will be recalled that the classical technique for bioassay of corticoids depends

upon glycogen deposition.

When the newborn adrenal cortex is stimulated with ACTH, there is elevation

of values for corticosteroids in the serum.61 Corticosteroids other than compound F

have recently been reported in newborn tmnine and serum by Klein and colleagues. These workers reported the finding of tetrahydro-F and tetrahydro-E in the urine

of newborns, as well as compound F itself.#{176}4 They pooled sera from newborn infants after the injection of ACTH, and found material in serum which occupied the

posi-tion of compound F on chromatograms. Al-though other spots of unknown identity were also found, none of themn had the characteristics of compound B.64 The fore-going findings indicate that the full-term newborn is able to respond readily to

stim-ulation by exogenous ACTH with a rise in

concentration of corticoids in the serum, even though under normal conditions

values for corticoids in the serum are very low during the first days of life.

Lanman has observed that otherwise nor-mal premature infants show a significant rise in the urinary excretion of corticoster-oids (formaldehydogenic) during the first

30 days of life.65 This finding also suggests

that the transitional fetal adrenal tissue is not an important source of corticosteroids,

because this inner region is degenerating

during this period. It supports the concept that the outer zones of the adrenal cortex

are involved in the production of corticos-tenoids (cf. Fig. 2). Measurements of

un-nary excretion of “C-21 steroid” have been

made recently by Zander, who seems to

have demonstrated a sex difference in

ox-cretion pattern.66 These findings do not appear to have beemi confirmed as yet.

The normal, full-term newborn appears

to have a type of adrenocortical metabolism

all its own. Whether it is more or less ado-quate than that of the older individual is a philosophical consideration, but it certainly

is different. Other such differences which

have been described are the relatively high values for the concentration of eosinophils in the blood67 and lack of diurnal variation in sodium and potassium concentration in saliva in the newbonn.hs Both these

rhythms are well-developed in children and

especially in adults.

Little work has been done on the adreno-cortical metabolism of newborns with

dis-ease states. Venning. and colleagues made observations on 2 atelectatic premature

in-fants of diabetic mothers.69 They found that

there was increased urinary excretion of

corticosteroids (glucocorticoids) during the first few days of life. The authors

hypoth-esized that this finding was due to the

stress associated with the atelectasis.

Bj#{246}rklund and Jensen have measured the urinary excretion of 17-ketosteroids of new-born infants of diabetic rnothers.7#{176} They found that these newborns showed higher

urinary excretion of 17-ketosteroids corn-pared with data from newborns of

nondia-betic mothers. This was interpreted as mdi-eating increased adrenocortical function in

the babies of diabetic mothers. Lanman has

studied the urinary excretion of corticoste-roids (formaldehydogenic) by premature in-fants treated with ACTH.71 A group of 5 such infants gave responses similar to what

is found in adults.

HEALTHY OLDER INFANTS AND

CHILDREN

Additional information has now become available concerning the nature of the

17-ketosteroids in urine of older infants and

re-903 REVIEW ARTICLE

ported data, obtained from column

chro-matography, on 17-ketosteroids found in

urine of infants, pre-adolescents amid!

adults. They found a similarity of excre-tion pattern between full-term infants (age 14 days to 10 months) and pro-adolescents. These workers found that adolescents and

normal adults showed a relative increase in the urinary excretion of those

17-keto-steroids thought to be derived from

go-nads. Similar studies in children have also

l)een reported by Do Courcy72 and by Ma-suda and Little or no

17-keto-steroids have been detected in the plasma

of normal, pro-adolescent 30,49

Migeomi found practically no 17-ketosteroids in the plasma at 6 months of age. He found, imi children 8 to 10 years of age, that the level of dehydroepiandrosterone in plasma

was 12 to 20 p.g./100 ml. of plasma and the

level of androsterone, 4 to 10 When

acltiltlio#{248}d is reached the average value for 17-ketosteroids in the plasma has been found to be approximately 60 p.g./100

rnl.46#{176} Studies of corticoids in the plasma of normal older infants and children have

revealed that the concentration of

approxi-rnatelv 11 .tg./100 ml. which is reached in

the first few months of life is maintained! throughout childhood and

ALTERATIONS IN DISEASE IN OLDER

INFANTS AND CHILDREN

Relationship to Diabetes Mellitus

An elegant series of experiments by Mc-Arthur and colleagues has defined the

temporal relationships between the

meta-bolic events in diabetic acidosis and adrenal

cortical 76 These studios were

carried out in dogs made diabetic,

expeni-mentally. Mongrel bitches were adrenalec-tomized and maintained on special diets containing desiccated pancreas substance and on amounts of insulin permitting a moderate glycosuria. The temporal

rela-tionships between adrenal hyperactivity

and other metabolic phenomena were studied during the development of

expeni-niental acidosis caused by the withdrawal of insulin therapy. The development of

eosinopenia and an increased urinary

excre-tion of corticoids were found to be relatively late features of diabetic acidosis which was

brought on by the omission of insulin. There was found to be a close temporal relationship between the above changes in eosinophils and urinary excretion of corti-coids and the following metabolic events:

(a) increased negativity of nitrogen, potas-sium and phosphorous balances; (b) a loss of

potassium in excess of nitrogen, and (c) a decrease in sensitivity to injected insulin. The losses of phosphorus and potassium were not believed to be due to the acidosis

per Se, because had these losses been due

primarily to acidosis, phosphorus as well as

potassium would be expected to be lost in excess of nitrogen. In some of the expeni-ments it was noted that increased lipemia

and ketonemia correlated temporally with the increased adrenal activity. When ACTH was administered to a depancreatized dog deprived of insulin for a relatively short

period there was a premature worsening of the diabetic state. There resulted a series of metabolic changes reminiscent of

dia-betic acidosis resulting from prolonged in-sulin withdrawal.

In a further experiment, an adrenalec-tomized-deparicreatized dog was main-tamed on a fixed dose of adrenal cortical

hormones. When insulin was withdrawn under these conditions a number of the components of pure insulin-deprivation

acidosis were not observed. McArthur and her colleagues conclude that the following

constituents of the insulin-deprivation state

in diabetes mellitus are adrenal-condi-tioned: (a) the increased neutrophil and total leukocyte counts and decreased

eo-sinophil and lymphocyte counts; (b) the increased catabolism of protoplasm; (c) the loss of potassium in excess of nitrogen, and (d) decreased sensitivity to injected insulin.

It would appear that a significant propor-tion of the pathologic physiology of expeni-mental diabetes mellitus is due to the

in-crease in adrenal cortical activity which comes in the train of insulin depriva-tion.75’T

hyperac-904 GARDNER - ADRENOCORTICAL METABOLiSM

tivity which occurs in the normal

nondia-betic organism in response to stress as a

reaction having some value for survival.

If the reaction to stress in the normal

or-ganism serves to protect the organism from

damage, for example, by satisfying an

in-creased need for carbohydrate, then cer-tainly in this respect the increase of

adreno-cortical activity in response to stress in the diabetic individual is inappropriate. This

hyperadrenocortical reaction to stress prob-ably has positive value for survival of the normal organism, but it seems to have

nega-tite value for survival of the diabetic, due

to the particular defect of carbohydrate

metabolism inherent in that condition. The hypenadrenocortical reaction to stress in the

diabetic takes place as though the adrenal cortex were unaware that the host has dia-betes. Possibly this aspect of a vicious circle

in diabetes is in large part responsible for the peculiarly difficult emotional problems of juvenile diabetics. hi these children it is often not possible to know whether the

diabetic state has precipitated an emotional crisis or vice versa.

Recently measurements have been made of the concentrations of corticoids in the

serum of children with diabetes mollitus.

Klein and colleagues77 estimated corticoids

iii the serums of a large series of diabetic children under treatment. Free corticoids

were found to be significantly higher in these serums than similar measurements

made in normal children. In the diabetic

children, the level of corticoids in the serum was found to be directly related to the amount of reducing substances found in the urine, and inversely related to the carbon dioxide content of the serum.

Relationship to Nephrosis

In 1950 Deming and Luetscher observed that children with the nephrotic syndrome excreted excessive amounts of a biologically

measurable sodium-retaining substance;78 this was confirmed by others.79 Luetscher

and Johnson8#{176} devised a chromatographic method for the separation of this potent

sodium-retaining substance from the urine of children with nephrosis. With the

dis-covery and identificatiomi of aldosterone,’

it became possible to identify this

sodium-retaining substance chemically.

Accord-ingly, it has now been established that the

sodium-retaining substance in the urine of

children with the neplirotic syndrome is in

fact 682 Luetscher and

col-leagues have isolated a crystalline steroid

from the unimie of a 10-year-old boy with the

nephrotic syndrome which appears to be identical with aldosterone. The substance

was identical in melting point and infrared

spectrum with authentic aldosterone pro-pared from adrenal cortical extract.82 It is

almost certainly the same sodiurn-retainimig

substance which Luetscher and colleagues found in small amounts in normal human

urine and in increased quantities dunimig sodium depletion or durimig the

accumula-tion of Present evidence

mdi-cates that aldosterone is formed in the

adrenal cortex and passes imito the venous blood. It influences the renal tubules to promote reabsorption of sodium amid the

ox-cretion of potassium. ACTH does not ap-pear to have a very measurable effect on the

urinary excretion of aldosterone, and

pan-hypopituitarism is not accompanied by an

abnormally low urinary excretion of aldo-sterone. After adrenalectorny, aldosterone

disappears from the urine.81 For further details concerning the new knowledge of this important aspect of adrenal physiology, the reader is referred to the reviews by

Gaunt and colleagues.

Congenital Adrenal Hyperplasia

In the spring of 1950, 2 independent re-ports described suppression of urinary

ox-cretion of 17-ketosteroids by cortisone

treat-mont in patients with congemiital adremial

hyperplasia.86 S7 No medical therapy had

been successful prior to these reports of Wilkins and colleagues and of Bartter and

colleagues. The sudden availability of sue-cessful medical treatment of the excessive vinilization which accompanies this syn-(Iromo resulted iii the accuniulation of

con-siderable metabolic data over a relatively

l1EVIEV ARTICLE 905

I1O\’ l)eefl \vorke(l out in somiie (letail, ali(1

flu in#{128}’roii5 workers have reI)Orte(I

observa-tions 011 j)atieIltS IIn(ler niedical

treat-mneiit.

Studies directed toward uncovering the

complex metabolic processes imivolved in this disease state have gone on for several

years. This syndrome is particularly

corn-1)lictted by the fact that one may find!

sev-eral variations on the central theme; there

nmy be patiemits who show only excessive

vinilization; others show both vinilization

and addisonian-like episodes; others show

virilization and hypertension;’ II while still

others show vinilization and hypogly-cemiaT 92 Omie patient has been described

who showed virilization with periodic acute e1)isodes resembling histaniine poisonimig. 1)6

in 1944 Darrow reported a case of con-genital adrenal hyperplasia with addisoniaii

crises, and found that desoxycorticosterone

ha(I to be givemi in disproportionately large

(loses to bring the serum sodium and

potas-sium concentrations to normal. He

sug-gested that the excess production of

andro-gens might have influenced the metabolism

of sodium and potassium.’07 Later Lewis

amid Wilkins gave ACTH to 2 cases of con-#{149}

genital adrenal hyperplasia who were riot known to have any addisonian component

to their disease’#{176}8 The ACTH therapy

re-suIted imi a marked rise in the renal

excne-tion of 17-ketosteroids and only a slight rise in the renal excretion of corticoids. There

was found to I)e no rise in fasting blood

sugar, only a slight fall in the respiratory

(Itlotielit, a polyrnorthonuclear leukocytosis and a moderate to marked increase, rather than decrease, in sodium excretion. These

authors developed the concept of Darnow

a step further and suggested that the secre-tory activity of the adrenal in congenital

adrenal hyperplasia differs qualitatively

from that of other conditions, pointing out the qualitatively different effect of ACTH

oh these patients with respect to the above

findings. Iii the same year Barnett and

McNamara reported electrolyte balance studies on a male infant with congenital

adrenal hyperplasia who showed addison-iaii crises.”9 Their stu(lies indlicated that

the balance of potassium (lid not follow the

classical pattern seen ill adrenalectomy iii

animals amidl in Addisomi’s dilseaSe in human

beings. They found that withdrawal of desoxyconticosterone acetate therapy and

reduction of sodium intake resulted in a

rapid elevation of potassium in the serum. Thus far this appeared not unlike the classi-cal addisoniami I)attern. But when the

bal-ances of potassium were plotted, there was

found a paradoxically increased excretion

of potassium, with markedly negative

extra-and intracellular potassium balances. Treat-merit with desoxycortfcosterone acetate

re-versed these changes. The changes in treat-merit produced no significant changes in

glomerular filtration rate. Barnett and

Mc-Namara concluded that the shifts of

potas-shim observed were mediated through shifts of potassium between intra- and

cx-tracellular fluids rather than l)y renal con-trol of excretiomi. Because treatment with desoxycorticosterone and added sodium

caused retention rather thami loss of potas-sium, added dietary potassium did! not seem

indicated. It was suggested that the para-doxical behavior of potassium in this

syn-drome was related to the excessive produc-tion of androgenic hormones, a conclusion in line with the postulation of Darrow.107 In 1950 Wilkins, Klein and Lewis reported

that the administration of ACTH caused a marked diuresis of sodium in some cases of

congenital adrenal hyperplasia, and in 1 of their cases (a “sodium-loser”) there was a clinical relapse with dehydration and weight 1055.110 It was suggested that the

ab-normal patterns of steroids secreted might

tend actively to promote the loss of sodium. In an experiment similar to the one by

Lewis and Wilkins described

Bartter and colleagues found that the ad-ministration of ACTH to patients with con-genital adrenal hyperplasia resulted in an

increase in urinary excretion of 17-keto-steroids, and in 1 case a rise in nitrogen re-tontion.89 The usual metabolic effects seen after ACTH were not apparent, including a lack of rise of urinary excretion of

pro-906 GARDNER - ADRENOCORTICAL METABOLISM

duction of corticoids by the adrenal cortex,

which in turn gives rise to an increased out-put of ACTH and a resulting increase of adrenal androgens. Jailer and colleagues

also observed in congenital adrenal

hyper-plasia treated with ACTH a failure of the

level of eosinophils in the blood fall, of sodium to be retained and of urinary

excre-tion of corticoids to nise,Hl others have made similar

In 1950 Gardner and colleagues reported data on chromatographic fractionation of the 17-ketosteroids in the urine of a boy

with the sodium-losing variety of congenital adrenal hyperplasia,”3 using the technique of Zygmuntowicz and colleagues.11 These studies revealed thtt in this boy with con-genital adrenal hyperplasia there was an

abnormally high urinary excretion of those 17-ketosteroids which appeared in the frac-tion where androsterone appeared. There

was a relatively low excretion of those 17-ketosteroids which appeared in the

frac-lions where etiocholanolone appeared. It

was concluded that the 17-ketosteroids

ex-creted in the urine by this patient differed qualitatively from those excreted by normal persons. Zygmuntowicz and colleagues

re-ported similar results in 4 female

pseudo-hermaphrodites with congenital adrenal hyperplasia,11 and Bergstrand and

col-leagues made similar chromatographic

find-ings in 3 boys with congenital adrenal

103

The boy studied by Gardner and

col-leagues3 was experimentally treated with oral methyl testosterone for a period of 33

days, resulting in a marked fall of urinary

excretion of 17-ketosteroids (methyl testos-terone is not metabolized itself as a 17-kotosteroid). Previous data had indicated that the administration of methyl

testos-terone served to reduce the urinary excre-tion of 17-ketosteroids by what was be-lieved to be suppression of the trophic hormones affecting the adrenal cortex.188

Thus the response to methyl testosterone therapy in this boy with congenital adrenal

hyperplasia was believed to be mediated

via suppression of ACTH production. It

was postulated that adrenal hyperfiinction

in this syndrome was due to excessive

stimulation from pituitary ACTH.’13 In the same year Miller and Dorfman reported the

isolation of 13 steroid metabolites from the

urine of a patient with virilizing adrenal

hyperplasia.”4 These workers found the 2

most prominent steroids to be

andro-stanediol-32-113-one-17 and

pregnanetriol-3; 17, 20 (also cf. Kepler and Mason115).

When it was found in 1950 that cortisone

would suppress the excessive adrenal ac-tivity in congenital adrenal

it immediately became possible to

investi-gate the changes which take place when the cause of the syndrome was “turned

off.” Studies were made of the urinary

excretion of 17-ketosteroids and of Allen’s sulfuric acid chromogens16 in a number of

cases of vmnilizing adrenal hyperplasia.

De-hydroepiandrosterone, desoxycorticosterone

and several other steroids may give a char-acteristic spectral peak at 600 m. in the sulfuric acid chromogen technique of Allen

and colleagues.15 When quantitative studies were made of urinary excretion of

17-keto-steroids and Allen’s chrornogens in virilizing adrenal hyperplasia,16 it was observed that

.there was a reduction in urinary excretion

of both these groups of steroids on cortisone

treatment. Before treatment, there was no

disproportionate increase in the excretion of the Allen chromogens as compared with 17-ketosteroids save in 2 cases studied. Two patients with vinilizing adrenal hyperplasia and hypertension exhibited spectral curves

for products of the Allen reaction with peaks at 600 mi.. When the 2 patients were

treated with cortisone, both the

hyperten-sion and the peaks at 600 mi.. were

dimin-ished. The configuration of the spectral

curves from patients with virilizing adrenal

hyperplasia without hypertension was not

modified by cortisone thenapy.16 In the case

of children with the sodium-losing variety of the disease, it was found that less therapy with desoxycorticosterone and so-diuin chloride was necessary after suppres-sion of adrenal overactivity by cortisone.93

Luetscher has reported that the urinary excretion of aldosterone is normal in

NORM AL

CONGEN ADRENAL

HYPERPLASIA

(NA LOSING)

BALANCE

EXCESSIVE

NA LOSS

REVIEW ARTICLE 907

n

STEROID STEROID

MADE WORSE BY ACTH

THERAPY

FIG. 4. l)iagramnlatic concept of the steroidal defect in tile sodium-losing

typo of congenital adrenal hyperplasia.

that somiiething is actively promoting the

excretion of sodium (see Fig. 4) (also cf. data of Grumbach,105 p. 102).#{176}

Estrogens in the urine, measured

fluori-metrically, have been found to be elevated

in congenital adrenal 688, 117

Studies revealed that cortisone therapy

re-duced the urinary excretion of these

fluoni-metrically and biologically measured

com-pounds as well as the h18

Wilkins and colleagues postulated that the decrease of excessive secretion of estrogen

and androgen from the adrenal by cortisone therapy released the normal

pituitary-ovarian mechanism, thus permitting femini-zation of pseudohermaphnodites.91 Migeon has investigated the estrogens in the urine

of patients with congenital adrenal hyper-plasia l)y countercurrent distribution . 19

There was found to be an almost constant ratio between the 3 fluorogonic fractions in the urine of normal individuals and

pa-tients with congenital adrenal hyperplasia.

He found that only 30 per cent of the total

fluorescomice could be accounted for by the fractions representing estrono, estradiol-17& and estriol. Gastineau and colleagues

studied the urinary excretion of estrogens,

a Prader et al. have recently measured urinary

aldosterone excretion in infants with the

sodium-losing syndrome and obtained normal or slightly

increased values. An older child with

spontane-OIlS regression of excessive sodium-loss was found

to have enormously increased urinary aldosterone

excretion. This finding of compensatory

overpro-duction of akiosterone would appear to explain

the clinical remission of sodium-loss soon in older

patients with this syndrome.

measured biologically, in a male with con-genital adrenal hypenplasia.98 These

work-ers found that cortisone therapy nearly

completely suppressed estrogenic activity in the urine, a more striking fall than the

decrease of biologically measured estrogens reported by Migeon and Gardner.’18 How-ever, the bioassay test animal differed, the former workers using the immature rat and the latter using the immature mouse.

Wilkins has described 2 male siblings

who showed sexual precocity at the age of

8 years.105 These boys had maturation of

the testes with spermatogenesis and were

thought to represent constitutional sexual

precocity. However, the 17-ketosteroids and pregnanetniol which were found to be ele-vated in the urine responded to cortisone

therapy. It was found that these boys did

not show the increased urinary excretion of

estrogens believed to be typical of congeni-tal adrenal hyperplasia, which probably

ac-counts for the spermatogenesis observed in these cases.

In 1952 Kelley and colleagues reported

analyses made by Nelson of corticoids in

the plasma of untreated patients with con-genital adrenal hyperplasia.12#{176} The

concen-trations of corticoids were quite low. Kelley

and colleagues also reported that the

ad-ministration of ACTH to such patients

failed to induce a significant increase in

the concentration of corticoids in the

122 This strongly suggested that

the adrenal cortex in this condition is

in-capable of producing optimal amounts of

908 GARDNER - ADRENOCORTICAL METABOLISM

by Sydnor and colleagues, who found

amounts of ACTH in the blood! of untreated

children with congenital adrenal hyper-plasia greater than in normal children.121 123

These workers reported that they could not find detectable quantities of ACTH in the

blood of afebnile children without endo-cnine disease. ACTH could be detected in the 1)100(1 of untreated, but not of

cortisone-treated, children with congenital adrenal

hvperplasia. All these findings gave firm

support to the original hypothesis of Bartter

amid! colleagues.87’ 89

With the development of chemical

tech-niques for the estimation of neutral

17-ketosteroids in peripheral plasma,2’ it be-came possible to obtain data on this aspect

of congenital adrenal hyperplasia.124 It was found that children with congenital adrenal hyperplasia had levels of 17-ketosteroid in the plasma generally higher than normal

adults, and in somiie cases in the range found for vmnilizimig adrenal tumors.124 When corti-sone was administered to a child with congenital adrenal hyperplasia, there was a fall of the concentrations of 17-ketosteroids

in the plasma to low or unmneasurable

values (see Fig. 5).

Plasma clearaiice values for neutral 17-ketosteroicis have been calculated,’2 amid

the value for the adult male approximates

25 nil ./min./ I.7Siii. . In untreated cae

of congenital adrenal liyperplasia plasma

clearances as high as 110 ml./min./l.7:3rn.2

have been reported. The latter value closely

aI)proxirnates the normal adult value for

glomerular filtration rate.

In 1947 Kepler and Mason isolated

pregnane-32, 17, 20-trio! from the urine

of 3 cases of congenital adrenal

hyper-plasia, and suggested that the examination of the urine for this substance might be of value in the diagnosis of adrenal hvper-plasia.1’5 This steroid had been found pro-viously in the urine of such patients by

Broster andi Vines and also by Butler and Marrian. In 1954 Bongiovanni amid Clayton reported a spectropliotometric method for

estimation of pregnanetriol in urine,2’

which was applied to the investigation of

i)atiemits with congenital adrenal hvper-plasia.129 127 Bongiovanni ali(l colleagues

-NORMAL CHILD _UNTREATEDCONGENITAL ADRF’1AL HYPERPLASIATREATED

LM POPHYSIS

AH

I7-POCOIDS

)JLASMA4

URINEH

/J

Li

H

Li

i

LJ

H

H

VIRILIZING

ADENAL TUMOR

CUSHINGS SYNDROME

NON-NEOPLASTIC NEOPLASTIC

1_i

0

U

LI

Li ?

0

Li

J

Li

0

Li

H

FIG. 5. ilyperadrenocorticism in childhood: Diagramatic comparison of values for

REVIEW ARTICLE 909

found that pregnanetriol was regularly

1)reselit iii the urine of patients with

con-genital adrenal liypenplasia, and, like the urinary excretion of 17-ketosteroids, was suppressed when cortisone was given. In

such I)atiemits if ACTH or

17-hydroxypro-gesterone was given, pregnanetniol

reap-peared in the urine. The presence of preg-nanetriol imi the urine was found! to aid in the diagnosis of congenital adrenal

hyper-I)laSia if the urinary 17-ketosteroids were

low. In light of the sttmdies made,

Bongio-Tanni and colleagues postulated that the

pregnanetriol excreted in the urine in

con-genital adrenal hyperplasia probably repro-sents a nietabolite of

17-liydroxyprogester-OflC. This would represent a defect in the

biosynthesis of compound F in this

syn-drome. These authors concluded that this

defect imi biosynthesis was not complete in all patients with this disease.

To explain the defect in steroidal

syn-thesis in this syndrome, Dorfman has sug-gested that there is a deficiency of an

en-zynie which hydroxylates the steroid nu-cleus at the C-21 position.128’ 129 Such an

hypothesis would fit in with the findings of low levels of corticoids in the plasma and

high urinary excretion of pregnanetniol.

However Eberlein and Bomigiovanni have foumid that individuals with congenital

adrenal hyperplasia excrete the same amount of C-21-hydroxylated steroids as do normal individuals.’3” ‘“ This would argue against the hypothesis of C-21-hydroxylase deficiency. The same workers have studied

a single patient with the hypertensive

van-ant of congenital adrenal hyperplasia.131 132

The extraction of large quantities of urine

showed no C-il-oxygenated steroids. The major C-21 metabolite in urine was

tetra-hydro-S (the li-desoxy analog of compound F). There were also considerable amounts of totraliydro-Q, which is the reduced

de-rivative of desoxycorticosterone. It was

sug-gested that the latter was responsible for

the hypertension. After treatment with rela-tively small amounts of cortisone, both the

tetrahydro-S and tetrahydro-Q compounds disappeared from the urine, and the blood

pressure became miormal. These findings

were also interpreted to indicate that the human adrenal cortex may synthesize do-soxycorticosterone under certain conditions.

It would thus appear that the nature of the enzymatic defect varies in the different clinical forms of congenital adrenal

hyper-plasia. Variations on this rather complicated

theme may come about as a result of meta-bolic blocks at any of several sites affected

by these enzymes and their cofactors (cf.

further discussions by Bongiovanni and Eberlei&84 and by Jailer amid colleagues’85).

Prader and Maassen have made a special

survey of 19 patients with congenital

adrenal hyperplasia with respect to body growth, osseous and dental development, and levels of calcium, inorganic phos-phorus and alkaline phosphatase in the

serum.’33 They fcund that ossification cen-tens and bone diameter are more advanced than bone length in the untreated case. At

an average age of 10 years it was found that epiphyses close and growth ceases. At

this point ossification centers and bone

diameters are similar to those of the normal adult, whereas height-age (hence bone

length) is as of 12 years. The dental

devel-opment in these cases was found not to be accelerated. The values for inorganic phos-phortis and alkaline phosphatase in the

serum were found to decrease at 10 years

of age to the normal adult value. Ordinarily this decrease does not take place until adolescence in the normal individual. There

was no change in values for calcium in the

serum.

Although most workers are impressed

with the tendency of congenital adrenal hyperplasia to occur in siblings, few

ado-quate genetic studies have been made. Knudson reviewed the data from 34

af-fected families in 1951, and came to the conclusion (which had been expressed

pro-viously) that the disease is a recessive

trait.134 A review of the literature on th2s

subject was made in 1952 by Bentinck and colleagues.135 Childs and colleagues have recently studied a group of 56 affected

910 GARDNER - ADRENOCORTICAL METABOLISM

minimal incidence of this disease to be 1 in 65,000 of the general population. It was

calculated that the gene frequency for the population was 1 in 250. No abnormalities were noted when the maternal ages, birth weights and birth ranks were considered.

These authors found that their data were consistent with a recessive mode of inher-itance. The previously reported increased incidence of this disease in the female was found by Childs and colleagues to be due to bias in the identification of cases. They

believe that this is due to the facilitation of diagnosis in the female during infancy. When 18 sibships were examined, each

containing a patient with the salt-losing defect, all other affected siblings also had this form of the disease. This was also true for the hypertensive form of the disease. Thus it was suggested that a system of

multiple alleles might be involved. A search

was made for minor manifestations of the disease in parents, assuming them to be

heterozygotes. This was done by giving the parents 60 to 80 I. U. of ACTH gel. Urinary excretion of pregnanediol, pregnanetniol and 17-ketosteroids was measured before

and after ACTH. No significant difference was found in the increments of urinary

ex-cretion of steroids between controls and the

parent group.

The psychiatric aspects of congenital adrenal hyperplasia have proven to be

in-tensely interesting and important beyond the boundaries of this syndrome per se. Hampson and Money have made

observa-lions on 60 hermaphroditic patients, among

whom were 39 cases of pseudohermaphro-ditism due to congenital adrenal

hyper-37138 They studied a total of 51

cases of congenital adrenal hyperplasia, both male and female. Hampson found that the external morphology of the genitalia

agreed with assigned sex in over half the 60 hermaphroditic individuals she studied. Of the 22 who lived with a contradiction between external morphology of the

gen-italia and assigned sex, 21 had a gender role and erotic practices wholly consistent with their assigned sex and mode of

rear-ing. Early reconstructive surgery of the

genitalia appeared to be beneficial. The evi-dence at hand indicated that clitoral am-putation in childhood or later did not prove detrimental to erotic responsiveness or

capacity for orgasm. Physical precocity,

such as occurs in hyperadronocortical chil-dren, did not seem to present any special problems of sexual misconduct. Money

in-vestigated the same group of patients with psychological techniques.18 He found that the psychological maturity of children with precocity and hyperadrenocorticism

resem-bled that of children of their own chrono-logical age. In some instances a

combina-lion of high IQ with the precocious body build permitted acceleration of psychologi-cal development, if environmental

condi-tions favored this.

From these studios it is apparent that the assigned sex of a child is the best indicator

of what is to be that child’s gender role

for the rest of his or her life. Often the assignment of a child’s sex is (lone by par-ents on family physician on the basis of the external morphology of the genitalia. It was

found that the histological structure of the gonads, the cytology of sex chromosomes or the sex hormonal pattern of the individual were most unreliable in prognostication of

the person’s gender role. Hampson and Money recommended that in assigning a sex to a newborn hermaphrodite,

regard-less of the etiology, primary consideration should be given to the external morphology of the genitalia, not to chromosomes,

go-nads or hormones. The clear warning which has emerged from these studies is the fact that imposed change of sex in childhood imposes an extreme psychological hazard.

Changes of sex made within the first year of life have proven to be successful;

changes made after 2% years should

gen-erally be avoided.

In a recent study made in Zurich, Z#{252}blin

has similarly reported that in childremi with hypenadrenocorticism the measurable

as-pects of intelligence did not parallel the

accelerated somatic 19 He also

REVIEW ARTICLE 911

that the assigned sex appeared to condition

the future gender role.

Virilizing Adrenal Tumor

The recent modifications by Patterson, Allen and Jensen of the Dirscherl-Zilliken

chemical technique for

dehydroepiandro-sterone have greatly facilitated the

diagno-sis of virilizing adrenal tumor (for review

of these methods see references 16 and 140). Prior to this development the

17-ketoster-oids in the urine had to be fractionated

by digitonin precipitation into alpha and beta fractions, an effective but tedious pro-coduro.” Shortly after it was observed that

cortisone therapy could suppress the

un-nary excretion of 17-ketosteroids in

viniliz-ing adrenal hyperplasia, it was also

dis-covered that cortisone could not

sup-press the urinary excretion of

17-ketoster-oids in cases of virilizing adrenal

tu-mnor’41’ 140, 16, 142-144 This has been a useful

finding, and has helped in differential

diag-nosis between congenital adrenal hyper-plasia and vinilizing adrenal tumor.

Wilkins has reviewed the literature to

1947 concerning adrenal tumors in children

12 years of age and younger.145’9 At this time there had been recorded 70 children

who had developed adrenal tumors

(Cush-ing’s type on virihizing type) before the age

of 12 years. Metastases occurred in 30 of

these cases. Of the 70 cases, 53 were girls

and 17 were boys. In the female group there were 22 with symptoms suggestive of Cushimig’s syndrome, while in the male

group there were only 2 who showed such

findings, and 1 patient who showed gyneco-mastia. The latter case, reported by

Wi!-kins,145 showed regression of breast en-langement after operative removal of the

adrenal tumor. It is apparently the only such case of its kind.

Sobel and colleagues have reviewed the

literature to 1953 concerning neoplasms of

the adrenal cortex in childhood.”4 These

authors found 30 reported instances of Gushing’s syndrome with adrenal tumors and 55 cases of vinilizing adrenal tumors

l)et\Veeii the ages of 3 months and 10 years.

Wilkins and Ravitch report a curious, and

apparently unique, case of a 2%-year-old child who was found to have vinilism and!

signs of Gushing’s syndrome.”6

Roentgeno-grams revealed a large calcified mass in the right upper quadrant of the liven.

When operated, an adnenocortical tumor

was found buried in the right lobe of the

liver, and receiving its circulation entirely

from the liver. Most of the night lobe of the liver had to be removed to get the tumor out. There was no right adrenal in the normal position. After operation there was

a fall in urinary excretion of 17-ketosteroids to normal values and regression of the vinilization and manifestations of Gushing’s

syndrome.

Lloyd and colleagues have reported

studies made on a 7-year-old girl with vinilizing adrenal tumor.”7 In addition to greatly increased urinary excretion of 17-ketosteroids there was also an increased

(twofold) excretion of formaldehydogenic steroids in the urine. In spite of the latter finding, there was no evidence of the signs

of Gushing’s syndrome. When the tumor was removed, it was extracted and assayed for biologically-active androgen and for 17-ketosteroids. Neither was found. Paper

chromatography of extracts of both urine and tumor demonstrated a substance which moved in the position of compound F.”7

A study of the estrogens in the urine,

measured chemically and biologically, in cases of vinilizing adrenal tumor in children

revealed that these steroids were excreted

in increased The

administra-tion of cortisone did not decrease the ex-cretion of estrogens, a point in contrast to the findings in patients with congenital

adrenal hyperplasia. Operative removal of the adrenal neoplasm in question resulted

in a sharp drop in the urinary excretion of estrogens. In 1 boy with a vinilizing adrenal tumor there was a greater than twofold transitory rise in fluonimetrically measured

estrogens in the urine when cortisone was given. This increase in urinary excretion of

estrogens (by bio-assay as well) was

912 (;ARDNER - ADRENOCORTICAL METABOLISM

aclnuinistratiomi of cortisone, and! must

repre-sent some as yet not understood effect of

cortisomie on the steroidal metabolism of the

tumor. Cortisone had no effect on the

un-nary excretion of estrogens of a normal

individual.

Hirschmann and Hirschmann have car-ned on a series of isolations of steroids in

the urine of a boy with an adnenocortical tumon.’48’52 They have identified a number of crystalline steroids from his urine (see titles of references cited). They suggest that 16 oxygenated steroids of the C-21 series

may be derived from substances formed in the adrenal cortex. The full relevance of

these findings to the abnormal steroidal pathways of ad!renocortical tumors is not yet aj)parent.

Syndrome of Female External Genitalia, Male Gonads and Chromosomes,

Adrenocortical Hyperplasia and Addisonian Electrolyte

Disturbance

Prader and Gurtner have described this

remarkable syndrome very 15:1

These authors made extensive studies of 1

such case which came to autopsy, and they were able to find 4 other similar cases in the

literature since 1928; 2 adults and 2

chil-dren. The external genitalia were female in appearance. The testes were histologically miorma! in the infants, and in the adults the testes resembled cryptorchidism, being

lo-cated either in the abdomen or in the

in-guinal canal. Sex chromatin studies re-vealed a male chromosomal pattern. The infant described by Praden and Gurtner

died at the age of 6 weeks from an addisonian crisis. Autopsy revealed very

greatly enlarged adrenal glands (17.5 gm.).

Multinuclear giant cells with large

crystal-line inclusions were observed in the histo-logic preparations of the adrenal. Extracts

of the hyperplastic adrenal gland were tested by bio-assay for estrogen and

andro-gen with negative results. Urinary concen-tration of 17-ketosteroids was 0.2 mg./100

ml. It was hypothesized that an abnormal

adrenocortical hormone was being pro-duced. There (lid! not appear to be an

over-production of either androgen or estrogen.

Relationship to Rheumatic Fever

Kelley and colleagues have published a

number of papers describing their investi-gations of adrenal function in patients with

rheumatic fever.’54 11 The details of these studies have been reviewed recently by Kelley.’62 These authors report that

clur-ing the first week of rheumatic activity the values for corticoids in the plasma were approximately twice normal. During the second week of rheumatic activity the mean

values for corticoids in the pltsmiia did not

differ significantly from the control group. however, children who had had active

rheu-m’natic fever for at least 2 weeks had

con-sistently low values. In patients with

mac-tive rheum’natic fever amxl Svdenhamii’s

chorea, \alues for corticoids in the plasma

were significantly lower than the comitrol

group. It was foumid that the rate of disap-pearance of free hvdrocortisone from the

circulation in patients with rheumatic fever

was slower than nornial. This was a sur-prising finding, as the low levels of corti-coids in the plasma might have been

postu-hated to be due to an increased peripheral utilization.

When the blood concentration of ACTH

was estimated in patients in the first week

of rheumatic fever, no measural)le ACTH

was found. The technique used does tiot

normally detect ACTH imi the blood of

con-trol children either. During the second week of illness concentrations of ACTFI in the plasma ‘ere negularl elevated, as

they were in the cases of well-established

rheumatic fever, and iii chorea. The no-sponse to a test (lose of 25 I. U. of ACTH given intramuscularly was nieasured hi con-trol childiren and in childremi with rheumatic fever: The mean increase of corticoids in

the plasma 2 hours after ACTI-I injection was no different in children with rheumatic

fever than in controls.

The data were interpreted by Kelley and

REVIEW AR’!’ICLE 913

rhetiniatic fever has rclaticc rather than

(ibSolilfe a(lnenal insufficiency. No evidence

as yet appears to be available to indicate whether the described changes in adrenal

function occur prior to or because of the

rheuniatic fever. These authors believe that

these abnormalities in pituitary-adrenal

function in rheumatic fever provide a physiological rationale for hormone therapy.

Details of their views on therapy have

been published recently in this journal)#{176}

The urinary excretion of 17-ketostenoids

in rheumatic fever has recently been

in-vestigated by Lubschez.”’

Failure of Circulation and Toxemia

in Acute Infection

The patient with meningococcemia,

pe-techiae and vascular collapse continues to

haunt the clinician. Our state of knowledge

of this syiidrome is still highly

unsatisfac-tory, SO that the physician must put behind!

liini the conflicting pathogenetic possibili-ties and come to some personal decision

about what therapy to use. The proponents

of the “generalized vascular injury” theory

can point convincingly to widespread

pe-techial lesions in vital centers of the brain,

spinal cord, etc., in many of those patients

who die. On the other hand there is just

enough evi(!ence from eosinophil counts

and from a few scattered determinations of corticoids in the plasma to suggest that at least some of these cases suffer primarily

from organic damage to hormone-producing

areas of the adrenal cortex and/or hypo. physis, and possibly may be saved by proper therapy with adrenal steroids. Klein has reported very high levels of corticoids

in the plasma in cases of meningococcemia

and meningococcus meningitis, the lowest value being 17 .g./106 ml. in a case of

meningococcus meningitis with vascular

collapse.b63 Kelley has also reported high values for corticoids in the plasma imi a

variety of acute bacterial and viral

infec-tions, the mean value for 18 such patients

I)eimig 32 .g./106 ml. (controls, 12 g./100 mI.).”2 Kelley stated that ho found 1

ex-ception, that 1)0mg a 2-month-old child

with clinical and autopsy evidence of

cir-culatory failure and toxemia who had a concentration of corticoids in the plasma

at death of only 2 g./100 ml. These straws

in the wind cannot be ignored, and the need is great for the accumulation of addi-tional data of this sort.

Figure 6 shows a conceptual scheme of what may be the response in corticoids of

the plasmnia to stress in infection. It should be noted that in the patient without

pe-techiae, the adrenal cortex an(l/or pituitary react sharply, and a sustained increase of conticoids in the plasma results, in response to the stress of acute infection. This normal response to stress, as was mentioned in

con-nection with the previous section on dia-betes mellitus, would seem to possess SOriiC

value for survival of the organism. Hence in the patient with normal adrenals and pituitary, subjected to the stress of acute infections, the “normal” values for

corti-coids in the plasma are seen to be over 30 p.g./100 ml. Values less than this would

have to be considered as abnormally low under these conditions. It is therefore pos-sible, once sufficient data are available,

that Klein’s value of 17 ig./100 ml. in a patient with meningococcus meningitis will be considered as ominously low (even though the value is actually higher than the mean for uninfected, unstressed

mdi-viduals).

In the management of patients in whom circulatory failure and toxemia are thought to be impending, it would seem worthwhile to pay especially close attention to

peniph-eral circulation, blood pressure and total eosinophil count. If methods for the deter-mination of sodium and potassium on

capil-lary blood (serum) are available, these values should be followed closely.

Corti-coids in the plasma should be estimated where possible. In the event of the devel-opment of cyanosis, diminution of peniph-eral circulation or sudden rise in total

STRESS OF INFECTION

--NORMAL LEVE

STRESSED

UNSTRESSED

() II CABI)NER - Al)B1’NO( X’)lI’[’ICAL M ETAB( )IJS\1

FL ASMA

COR I ICCflD S

)G I 00 ML

-

:ORGANIC DAMAGE ADR[NAL’ - PITU:TP5)

,

CNORMAL ADRENAL - PTUITARY)

I’lL. 6. i8PIC of level of corticoids in the plasma to tilE’ stress of acute severe infections. ‘Ilic

trails-verse dotted line depicts an inadequate rise of cortiCOi(lS during an infection such as nlcluiIlgOEOcccfllia.

serum, adrenal steroid therapy should!

cer-tainly be given. In general, aqueous adrenal

extract and cortisomie or hydnocortisone are

used imi therapy. There is now available at

least 1 commercial preparation of a

water-soluble hydrocortisomie derivative which

may readily be given intravenously,

hydro-cortisone hemisuccinate (Solu-Gortof 1

Up-john).

Permissive Role of Adrenal Corticoids in Stress

The previous discussion of the stress

reaction in severe acute bacterial infections

suggests a brief consideration of what has i)een called the permuissive role of adrenal corticoids in stress. Inglelhi4 and EngeP65

have reviewed the experimental evidence

supporting the concept that during stress

the adrenal corticoids play a supporting role, but are not necessarily the exciting

cause of many of the metabolic responses

to stress. Ingle”4 studied the metabolic re-sponses of rats following fracture of the hind legs. The results of these experiments

indicated that the metabolic responses to

fractures required the presence of adrenal

cortical hormones for support, but all these

responses were not caused specifically b the increase in secretiomi of the

adremio-cortical hiormiiones. He postulated that the end results of hormone action are

deter-mined by the extent of “need” for the

hor-mono as related to the quantity of hormone available. Thus a quantity of hormiione, which exceeds “need” amid causes hvper-adrenocorticism immider restimig conditions,

may barely meet the increased “need” dur-ing severe stress, amid under the latter

con-dition fails to cause signs of

hvperadreno-corticism. The implications of these findings

for the syndrome of circulatory failure and

toxemia and the colicept prtrlYe(l iii

Figure 6 are obvious.

One may compare the supporting role of

the adrenal corticoids in situatiomis of stress

to the role of vacuum’n tubes imi amplifying radio signals. A weak signal can be

01)-tamed in the headphones of a crystal set

without any amplification. However the proper amplifier tubes can increase this sigmial so as to activate the largest

loud-speaker. The original exciting signal,