Fetal and Postnatal Development of the Adrenal Glands in ...

INTRODUCTION

The adrenal cortex of the fetal rhesus

macaque contains a wide inner zone of large

cells in reticular arrangement called, by analogyto its human couterpart, the fetal zone (Hill,

1930, 1933; Lanman, 1957). In human infants,

this zone, which constitutes 80% of the cortex

at term, has been reported to involute rapidly

occur in the adrenal glands of rhesus macaques

(Lanman, 1957) and marmosets (Benirschke

and Richart, 1964). In the rhesus fetus, the pro-

cess was believed to be under way even before

birth.

However, in the course of routine micro-

scopic examination of adrenal glands of rhesus

infants that came to autopsy for a variety of

reasons, we failed to find a collapsed inner zone

but did see an apparent persistence of at least

some of the fetal zone well into postnatal life.

BIOLOGY OF REPRODUCTION 25, 1079-1089 (1981)

1079

Fetal and Postnatal Development of the Adrenal Glands

in Macaca mulatta’

WILBUR P. McNULTY,2 MILES J. NOVY and SCOTT W. WALSH

Laboratory of Pathology and Division of Perinatal Physiology,

Oregon Regional Primate Research Center,

Beaverton, Oregon 97006

ABSTRACT

The inner four-fifths of the fetal and newborn adrenal cortex in Macaca mulatta morpholo-

gically resembles the human adrenal fetal zone. The human adrenal fetal zone is thought to under-go a dramatic collapse in the early postpartum period, whereas the inner zone of the rhesus fetal

adrenal is slowly remodeled into definitive cortex. This remodeling is accompanied by a loss ofone-third of the weight of the adrenals in the first 2 weeks postpartum and then by weight con-stancy for 6 months, after which growth is resumed. Near parturition, groups of small cells withlittle cytoplasm appear in the outermost rhesus fetal zone. In the early postpartum period, thesegroups coalesce into a “dense band” beneath the giomerubosa. This band is found progressively

nearer the medulla during the early months of postnatal life, and the zona fasciculata appeaxsperipheral to it. The cortical cells central to this band retain their fetal pattern; remnants of thefetal zone are still visible adjacent to the medulla 6 months after birth.

Fetal hypophysectomy (decapitation) at midgestation or chronic administration of dexameth-

asone to the mother for several weeks during the third trimester caused hypoplasia of the fetalzone and precocious formation of a dense band and a zona fasciculata. Continuous infusion ofACTH into two fetuses resulted in hypertrophy of the fetal zone. Fetal adrenal weights wereincreased by ACTH (943 and 1149 mg, compared with 298 ± 27 mg for controls), but they weredecreased by fetal decapitation or dexamethasone (46 ± 4 mg and 87 ± 13 mg, respectively). Thus,there is concordance between the histologically assessed magnitude of the fetal zone and thepreviously shown extent of fetal production of dehydroepiandrosterone sulfate and andros-

tenedione, which are substrates for estrogen biosynthesis by the placenta.These data indicate that 1) the fetal zone is present until birth in M. mulatta, and it disappears

slowly after birth, with no massive necrosis; and 2) the maintenance of fetal conformation of theadrenal glands depends on a functioning fetal pituitary gland. Normal evolution from a fetal toadult anatomical structure may be the consequence of a decreased circulating level of ACTH or achanging mode of response of the inner-zone cells to the trophic hormone.

after birth, with necrosis and hemorrhage

(Thomas, 1911; Lewis and Pappenheimer,

1916; Benner, 1940), and the weight of the

glands falls to about two-thirds that at birth

(Scammon, 1926;Benner, 1940). The peripheral

cortex (including but not limited to the zona

gbomerulosa) does not take part in the involu-

tion, but rather grows and generates the defini-

tive adult cortex.

A similar involution has been reported to

Accepted August 24, 1981.Received June 16, 1981.‘Publication No. 1177 of the Oregon Regional

Primate Research Center. Supported by grants

RR-00163 and HD-06159 from NIH and 1-363from the March of Dimes Birth Defects Foundation.Presented in preliminary form at the 1st ORPRCSymposium on Primate Reproductive Biology,Beaverton, OR, May 9, 1981.

2Reprint requests: Dr. W. P. McNulty, OregonRegional Primate Research Center, 505 N.W. 185th

Ave., Beaverton, OR 97006.

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FIG. 1. Adrenal glands of infant rhesus macaque. Note plane of section in left gland.

1080 McNULTY ET AL.

We therefore systematically investigated the

evolution of the fetal zone in healthy monkeys,

both during fetal life and during the first few

months after birth.

MATERIALS AND METHODS

We examined histologically the adrenal glands ofnormal rhesus (Macaca mulatta) fetuses of knowngestational age delivered live by cesarean section andof normal infants killed for collection of tissues. Theglands were removed immediately after death, weighed,and immersed in cold buffered (pH 7) fixative con-taining 1% glutaraldehyde and 4% formaldehyde.After 1 h, a single block 2 mm thick was cut from theleft gland in a plane extending from the antero-

medial apex to the center of the renal depression (Fig.

1). This plane was chosen to give the most nearlyradial orientation of the cortical zones for estimation

of their relative widths. After 24 to 48 h in the samefixative, the block was embedded in glycol methacry-late, and 2 �m sections were stained with hematoxylin,methylene blue, and basic fuchsin.

The adrenal weights of rhesus fetuses of known

gestational age obtained by cesarean section and ofinfants of known birth age that had been spontaneouslydelivered at term were retrieved from the autopsy files

of the Oregon Primate Center. Only fetuses andinfants considered normal after perusal of the clinicalrecords of both mother and infant were included in

the analysis.

Fetal rhesus adrenal glands were also obtainedfrom 15 fetuses in which we produced anencephaly

experimentally by decapitation between Day 73 andDay 82 of gestation (term is Day 167). The fetuseswere delivered between Day 140 and Day 151 to

ensure recovery of a live fetus. Experimental anen-cephaly was accomplished through removal of the,

fetal head along a plane formed by the occipitocervicaland mandibulomaxillary junctures. The surgicalprocedures have been described in detail elsewhere(Novy et al., 1977).

To test the effects of inhibiting secretion ofendogenous fetal ACTH on adrenal gland structureand weight, we treated eight pregnant rhesus macaqueswith dexamethasone (0.25-1.0 mg i.m. twice daily;

Decadron, Merck Sharp and Dohme, Inc., Montreal,Canada) from gestation Day 130 until delivery or

cesarean section between Day 169 and Day 181 ofgestation (i.e., gestation was prolonged; see Results).

Saline-injected controls delivered on Day 167 ± 2.To test the effects of augmented levels of ACTH,

we continuously infused a corticotropin solution (1lU/h; Acthar, Armour Pharmaceutical Co., Chicago,

IL) for 19 days into one fetus and for 8 days into

another fetus (Days 128 to 157 and 135 to 144,respectively). The experimental procedures for chronic

catheterization and use of fetal monitoring deviceshave been described in detail elsewhere (Walsh et al.,

1979).

Normal Growth

RESU LTS

The weights of adrenal glands in fetuses and

in monkeys in the first year after birth are

shown in Fig. 2. The glands grow rapidly during

the latter half of gestation, and then decrease inweight by about one-third in the first 2 weeks

postpartum. After this decrease, they remain

approximately the same size for 6 months, then

double in weight by the end of the next 6

months.

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ADRENAL DEVELOPMENT IN THE RHESUS MACAQUE 1081

800 - - ‘600

700 #{149} ‘700

600 ‘tOO

.E

‘500

400 #{149}

#{149}#{149}:#{149}#{149}.#{149} 0

.�30O #{149}#{149}.l 0 ‘200.. .. ,. 0

C) .. � . 0200 . . #{149}#{149}S,. ‘200

#{149}#{149} �&#{149}� � 0 0

ioo S ‘100

�‘ibo’;�o’�o’Gestotional Age. Days Postnatal Age. Days

FIG. 2. Combined weights of adrenal glands of rhesus fetuses and infants. Symbols: ., routine autopsies;0, autopsies, this study; and #{149},combined weight estimated from weight of left gland removed surgically (leftadrenal/both 0.555 ± 0.010).

TABLE 1. Microscopic examination of left adrenal glands.

Infantand sex Age (days)a Source

Adrenal weight (g)

Right Left Both

101 34M 161 + 0 Autopsy 0.125 0.204 0.3299519F 172+ 0 Autopsy 0.224 0.246 0.470

9496F 169 + 1 Autopsy 0.201 0.245 0.446

10140M9321M9399M9497M

173 + 1167+ 3169+ 6166 + 14

AutopsyBiopsyBiopsyBiopsy

0.197 0.2360.1830.1510.153

0.43 30333b0�275b0�278b

9785M P + 14 Autopsy 0.065 0.089 0.1549786M P + 20 Autopsy 0.087 0.080 0.1679470M9402M9487M9589M

163+ 21163 + 21

168+ 28159+ 45

BiopsyBiopsyBiopsyBiopsy

.. -

0.187

0.1960.134

...0�340b0356b

0244b9756M 165 + 45 Autopsy 0.081 0.095 0.176

11037M 160+ 59 Autopsy 0.094 0.122 0.2169590M 167 + 90 Autopsy 0.126 0.167 0.293

11OIOM 162+ 90 Autopsy 0.134 0.183 0.31711029F 176+ 120 Autopsy 0.133 0.199 0.33211013M 162+ 149 Autopsy 0.125 0.147 0.27210936F 157+ 180 Autopsy 0.139 0.158 0.297

aGestational age + postpartumagein days.

bCalculated from left/both: n 13, mean = 0.55 5, SD = 0.036, SEM = 0.010.

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#{149} 85+0 ,,-,� 157+0

1082 McNULTY ET AL.

FIG. 3A-H. Adrenal cortices of rhesus fetuses and infants at indicated ages (gestational age plus birth age).The fetuses were delivered by cesarean section. Abbreviations: DC, definitive cortex; ZG, zona glomerulosa;

ZF, zona fasciculata; DB, dense band; FZ, fetal zone; and M, medulla. All panels are at the same magnification.

The ages of fetuses and infants, the left

adrenals of which were examined microscop-

ically, are shown in Table 1, and the histological

appearances of selected specimens are shown in

Fig. 3.

At a conceptual age of 45 days, the adrenal

gland was a homogenous unstructured mass of

large cells with abundant reticulated cytoplasm,

arranged in nests with intervening vascular

spaces. At the periphery was a densely packed

narrow band of small cells with little cytoplasm.

The neural cells destined to become the medulla

had not yet invaded the cortex.

By Day 65, the cortex had assumed the

structural pattern that persisted throughout

fetal life. A peripheral band of small cells, 5 to

10 cells thick, lay just beneath the capsule.

Central to this were large cells with reticulated

cytoplasm; these were closely packed just

beneath the peripheral band and separated into

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FIG. 4. Rhesus macaque adrenal fetal zone, immediately adjacent to the medulla, at indicated ages (gesta-tional age plus birth age). All panels are at the same magnification.

anastomosing cords by sinuous vascular channels

toward the center.

On Day 85 (Fig. 3A), the pattern was much

the same, and the subcapsular band of small

cells showed an indistinct glomerular pattern.

Although the gland continued to increase in

size, the qualitative appearance of the zonesand their relative thicknesses did not change by

Day 126 or 145 (Fig. 3B).

However, on Day 157 (Fig. 3C), 10 days

before expected delivery, the outer fetal zone

showed irregularly distributed groups of cellswith reduced volumes of cytoplasm. These

small cells constituted a broad band lyingbetween the glomerulosa and the inner fetal

zone, 1 day after term vaginal delivery on Day

169 (Fig. 3D).

Twenty days after birth (Fig. 3E), the cells

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1084 McNULTY ET AL.

in the outer part of this new zone grew larger,

acquired lightly vacuolated cytoplasm, and

became arranged in columns. A zone of closelypacked cells with dark compact nuclei and

scant cytoplasm (“dense band”) now separated

this recognizable zona fasciculata from the fetal

zone, which, though reduced in width and more

densely packed, showed no necrotic or involu-

tional changes.

By Day 45 postnatum (Fig. 3F), the defini-

tive zona fasciculata was relatively broader and

its cells were larger and more vacuolated. The

dense band was now located approximately

midway between the glomerulosa and medulla.

The only change seen in older glands - 60, 90

(Fig 3G), 120, 150, and 180 days old - was

progressive displacement of the dense band

toward the medulla. In the oldest gland ex-

amined (180 days; Fig. 3H), this band, together

with a thin rim of fetal zone, occupied the

inner quarter of the cortex.

Although there was no necrosis in the fetal

cortex, the cells in this zone did change in

appearance around the time of parturition

(Fig. 4). On Day 145 of gestation, they were

small and round and had few cytoplasmicvacuoles. The vascular sinusoids were widely

open. On Day 157, the cells were larger, poly-

gonal, and more closely packed, and the cyto-plasm was moderately vacuolated. One day

after term delivery, vacuolation was much more

TABLE 2. Adrenal weights of decapitated fetuses.

intense. Then on Day 20 postpartum, the cells

were smaller and much less vacuolated.

At no time in the first 6 months postpartum

were mitotic figures seen either at the periphery

of the zona fasciculata or at the junction of the

zona fasciculata and the dense band, and

neither regressive changes nor necrotic areas

were seen at either the inner or outer borders of

the dense band. Rather, a smooth transition

with intermediate forms was present between

the dense band and the zona fasciculata and

between the dense band and the remnant fetal

zone.

Experimentally Altered Growth

The adrenal glands of rhesus fetuses decapi-

tated on Day 75 of gestation and obtained by

cesarean section on Day 145 (Novy et al.,

1977) were small (20% of normal weight, Table

2) and had only a narrow fetal zone with small

cells (Fig. 5A). Surprisingly, the dense band,

which first appears in the outermost fetal zone

at or soon after birth in intact infants, was

clearly present in the midcortex 22 days before

normal term (Day 167).

Nearly identical effects on fetal adrenal

weight and histological appearance followed

administration of 0.25 to 1.0 mg of dexameth-

asone twice daily to pregnant rhesus females,

beginning on gestational Day 130 (Table 3).

These females were allowed to deliver vaginally,

Infantand sex

Body

weightGestationalage (days)

Adrenal weight (g)

Right Left Botha

6287F 164 151 0.021 0.018 0.039

6425F 150 150 0.018 0.025 0.043

6434F 192 150 0.029 0.033 0.062

6601F 161 148 0.021 0.035 0.0566691M 141 142 0.025 0.022 0047

6768F 153 150 0.010 0.026 0.036

6797M 219 145 0.015 0.016 0.031

6956M 199 140 0.012 0.013 0.025

7036M 177 141 0.020 0.016 0.0367035M 190 143 0.018 0.035 0.053

7057F 170 146 0.036 0.033 0.069

7064M 199 145 0.019 0.021 0.0407722F 210 148 0.025 0.021 0.0467878M 260 145 0.039 0.040 0.079

8114F 135 147 0.022 0.013 0.035

= 15, mean = 0.046, SD = 0.015, SEM = 0.004, compared with controls (data not shown) (Days 143 to

151): n = 23, mean = 0.235, SD 0.074,SEMO.026. Ratio of experimental to control means: 0.046/0.235

0.196.

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145+p �

#{149}- :.,

157+2


172+1

FIG. 5. Effects on rhesus macaque fetal adrenal gland of A) hypophysectomy (decapitation) on Day 75 ofgestation; B) daily administration of dexamethasone to the mother, Days 130 to 172 of gestation; and C) infu-sion of ACTH into the fetus, Days 128 to 157 of gestation. Note the reduction in magnification for C). Abbrevi-

ations: DC, definitive cortex; ZG, zona glomerulosa; ZF, zona fasciculata; DB, dense band; FZ, fetal zone; andM, medulla.

or the pregnancies were terminated by cesarean

section on Day 180. Gestation was significantly

longer than normal (Novy et al., 1980), and the

adrenal glands were 30% of the value expected

at term (Table 3). (The weights of adrenals for

equivalently long control pregnancies were not

available.) The fetal zones were narrow, and the

cells were small, but the glomerulosa, the

fasciculata, and a midcortical dense band were

present (Fig. 5B).

On the other hand, the adrenals of two

fetuses that received exogenous ACTH by

continuous infusion between Day 128 and Day

157, and between Day 135 and Day 144, were

very large, about 4 times the expected weight.

Both the thickness of the fetal zones and the

size of the cells in that zone were markedly

increased. The number of nuclei per unit

area (counted in strips from medulla to capsule

and averaged over the full cortical thickness)

was one-fifth the number in a control gland;

therefore, the ACTH did not cause an increase

in the number of cortical cells. Furthermore,

the zona glomerulosa, which can normally be

recognized as early as Day 65, was not discerni-

ble; the fetal-zone pattern extended uniformly

to the capsule (Fig. 5C).

DISCUSSION

During the first weeks of postnatal life, the

rhesus adrenals decrease in weight, as they have

been reported to do in human babies. Although

the human adrenal fetal zone is commonly

believed to suffer a rapid collapse with necrosis

and hemorrhage, no such dramatic event occurs

in macaque glands. Instead, the rhesus fetal

zone undergoes a gradual remodeling to adult

conformation over a period of months, or

perhaps longer.

This remodeling is characterized first by the

appearance of a band of small cells with little

cytoplasm in the outer fetal zone, at or shortly

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1086 McNULTY ET AL.

an = 8, mean = 0.087, SD = 0.037, SEM = 0.013, compared with controls (data not shown) (155-164 days):

n = 18, mean = 0.286, SD = 0.068, SEM = 0.016. Ratio of experimental to control means: 0.087/0.286 = 0.304.

before parturition. As the infant ages, this

“dense band” is found progressively closer to

the medulla. As the band appears to move

centrally, mature zona fasciculata becomes

recognizable outside it, while a shrinking fetal

zone persists inside it. These remaining cells of

the fetal zone are smaller and have less vacuo-

lated cytoplasm than fetal-zone cells at birth,

but they are not dying. At 6 months (the oldest

age studied), a central rim of fetal zone is still

present. The ultimate fate of the dense band is

not known. We speculate that it may be the

precursor of the zona reticularis but have no

supporting evidence.

The mode of generation of the zona fascicu-

lata is not clear. Since mitotic figures were not

seen either in or at the borders of this zone, and

the outer dense band contained cells morpho-

logically intermediate between cells of the zona

fasciculata and the dense band, we speculate

that the definitive cortex is progressively

generated by transformation of cells preexisting

in the dense band. Autoradiographic and

ultrastructural studies are needed to support

this notion.

The fate of the human fetal zone may be less

certain than has commonly been believed.

Sucheston and Cannon (1968) did not see

involution of the human fetal adrenal cortex

with hemorrhage and cell loss, but rather a slow

regression of the fetal zone throughout the first

year. During this time, they saw little mitosis or

signs of cell death, and suggested that the final

structure of the adrenal cortex is slowly achievedby proliferation of the definitive cortex and a

transformational process whereby fetal zone

cells mature into the zona fasciculata. Their

report is, of course, at variance with what is

commonly believed about the fate of the

human adrenal fetal zone. Since promptly

obtained postmortem specimens of adrenals

from healthy human infants are rarely available,

we suggest that disease-associated and post-

mortem changes in the human fetal adrenal

cortex may have been misconstrued as a physio-

logic process, and that the true fate of the

normal human fetal zone is transformation, not

disappearance.

The transformation of fetal cortex to adult

cortex in the rhesus macaque must be regulated

at least in part by pituitary factors. When the

fetal pituitary is either surgically removed or its

release of trophic factors is suppressed by dcx-

amethasone, the cortex stops growing and

undergoes a precocious histological maturation,

a caricature of that seen in normal postnatal life

(Figs. 5A,B). We infer that, during fetal life,

pituitary agents both stimulate the growth of

the fetal zone and inhibit maturation of that

zone to adult conformation.

One of these pituitary agents must be ACTH

because pharmacologic doses ofACTH continu-

ously infused into the fetus cause a pronounced

increase in fetal adrenal cell size and conversion

even of the subcapsular cells of the zona gb-merulosa into cells morphobogically similar to

those in the fetal zone proper (Fig. 5C). How-ever, the observation that continued exposure

to a high level of ACTH in vivo causes morpho-

logical “hyperfetalization” of the fetal cortex

(at the light microscopic level) does not neces-

sarily mean that the altered cells show exag-

TABLE 3. Effects of dexamethasone trealment on gestational length, fetal weight, and adrenal weight.

Infantand sex

Dose(mg bid)

Gestationalage (days)

Mode ofdelivery

BodyStatus

Bodyweight

Ad renal weigh t (g)

Right Left Botha

8686F 1.00 180 Cesarean Dead 374 ... . -. ...

8799M 0.50 180 Cesarean Dead 303 0.034 0.051 0.085886SF 0.50 181 Cesarean Dead 379 ... . -. . -.

92MM 0.25 168 Vaginal Alive 480 0.029 0.03 3 0.062

9317M 0.25 179 Cesarean Alive 422 0.047 0.057 0.1049403M 0.25 172 Vaginal Alive 380 0.027 0.029 0.0569492M 0.25 180 Cesarean Alive 454 0.063 0.086 0.149

9498M 0.25 173 Vaginal Alive 380 0.034 0.038 0.0729514F 0.25 177 Vaginal Alive 391 0.020 0.023 0.0439549M 1.00 169 Vaginal Dead 410 0.059 0.067 0.126

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gerated physiological characteristics of the fetal

zone.

The trigger for the initiation of maturation

in the macaque fetal cortex remains unknown.

The following hypotheses have been proposed:

1) Decreasing sensitivity of the fetal cortical

cells to ACTH: 2) declining release of ACTH by

the late-fetal and infant pituitary; 3) withdrawal

of placental adrenotropic factors or ACTH-

related peptides from the fetal pituitary; 4)

withdrawal of factors inhibiting cortical matu-

ration.

Decreasing Sensitivity to ACTH

The bulk of data on primates and other

animals points to a gradual increase in the

responsiveness of the fetal adrenal gland to

ACTH rather than a decrease late in gestation

(Challis and Manning, 1978; Magyar et al.,

1980). But for the most part, investigators have

measured cortisol’ secretion in response to

ACTH, and their data are not directly applicable

to the function of the fetal zone per se, the

major site of DHEA and DHEAS production.

There is preliminary evidence that adrenal

glands of newborn rhesus infants produce less

DHEAS in response to ACTH with advancing

age (Ser#{243}n-Ferr#{233}et al., 1980).

Decline in Circulating ACTH

In the human fetus, ACTH values decline

with advancing gestation, and an additional fall

has been observed in the neonate (Winters et

al., 1974). The plasma level declines during the

first few hours of life, and values equivalent to

those found in older children are present at the

end of the first week of newborn life (Cacciari

et al., 1975). The diminution of plasma ACTH

postnatally may be related to a reduction in the

metabolic clearance rate of cortisol associated

with the change from an intrauterine to an

extrauterine environment (Jaffe et al., 1979).

Whether a similar pattern in fetal and newborn

ACTU levels occurs in rhesus fetuses and

newborns is not yet known. Our observations

that removal or suppression of the pituitary in

late fetal life is accompanied by loss of fetal-

zone characteristics and that pharmacolo-

gic doses of ACTH accentuate them are con-

sistent with the idea that the fetal zone is

ACTH-dependent.

Withdrawal of Placental A drenotropic

Factors or ACTH-R elated Fetal

Pituitary Factors

A placental origin for a putative hormone

trophic for the fetal zone (such as chorionic

gonadotropin) seems unlikely since atrophy of

the fetal zone occurs with pituitary ablation in

the face of normal placental function in utero

(Novy et al., 1977). However, several pituitary

hormones other than ACTH have been suggested

as regulators of fetal adrenal growth and

secretion, namely, prolactin (Winters et al.,

1975) and the ACTH-related peptides

a-melanocyte-stimulating hormone (a-MSH)

and corticotropin-like intermediate lobe peptide

(CLIP) (Silman et al., 1976). In fact, in the

rhesus macaque, as in the human, these peptides

predominate in the pituitary during fetal

life and nearly disappear in adulthood (Silman

et aL, 1978). However, chronic infusion of

ACTH into rhesus fetuses in utero increases

fetal plasma levels of DHEAS, androstenedione,

estrone, estradiol, and cortisol, as well as

maternal plasma levels of estrone and estradiol

(Walsh et al., 1980); infusion of human

chorionic gonadotropin, a-MSH, or prolactin

between Day 125 and Day 143 of gestation had

no such effects (Walsh et al., 1979). Still, it is

possible that one or another of the second

group of hormones is stimulatory at a specific

gestational age or acts synergistically with

ACTH. Korotnik et al. (1980) reported that

luteinizing hormone (LH) or a hormone released

in response to gonadotropin releasing hormone

(GnRH) stimulated DHEAS secretion in the

neonatal rhesus macaque.

Withdrawal of Factors Inhibiting

Cortical Maturation

Because studies on adrenal responses to

ACTH in various species, including M. mulatta,

have shown discrepancies between in vivo and

in vitro results, the presence in the fetal blood

of factors that inhibit the maturation of the

fetal adrenal glands has been postulated (Jaffe

et al., 1979). There is limited evidence that

factors from the placenta [progesterone,

estrogens (Bboch and Benirschke, 1962; Villee,

1972), or unidentified agents (Voutilainen and

Kahn, 1980)] inhibit 3f3-hydroxysteroid dehy-

drogenase �4-M isomerase. According to this

hypothesis, inhibition of this enzyme facili-

tates production of f.�5 -3j3-hydroxysteroids

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1088 McNULTY ET AL.

(DHEA and DHEAS) in utero and promotes the

development of the fetal zone and disappearance

of the placental influence after birth permits

maturation. But both in vivo and in vitro data

clearly indicate that macaque fetal adrenal

glands have the biosynthetic capacity for

progesterone and androstenedione production

and thus for an active 313-hydroxysteroid

dehydrogenase system in utero (Gorwill et al.,

1971; Kittinger and Beamer, 1971;Walsh etal.,

1979). Furthermore, in anencephalic human

fetuses and in hypophysectomized rhesus

fetuses (Novy et al., 1977), an apparently

normal placenta and normal fetal levels of

estrogen and progesterone (Kenny et al., 1973)

do not support a normal adrenal fetal zone. The

apparent contradiction between our morpho-

logic finding that chronic in vivo administration

of ACTU to rhesus fetuses caused hypertrophy

of the fetal zone, and the finding of Sirnonian

and Gill (1981) that ACTH stimulation in vitro

induced biochemical characteristics of definitive

zone cells in cultural human fetal zone cells,

can be explained by the presence of an

unidentified factor that modulates in vivo the

action of ACTH on fetal zone cells. Jones and

Roebuck (1980) reported that high-molecular-

weight forms of sheep ACTH inhibited ACTH-

stimulated contisol secretion in isolated adrenal

cells from one sheep fetus and one rhesus

infant. Our morphological data, which show a

precocious maturation in connection with

pituitary ablation or dexamethasone suppres-

sion, are consistent with the withdrawal of

hypophyseal inhibitory factors.

ACKNOWLEDGMENTS

We thank Verna Russell and Helrny Hawash fortheir excellent technical assistance.

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Brenner, M. C. (1940). Studies on the involution ofthe fetal cortex of the adrenal glands. Am. J.Pathol. 16, 787-798.

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