The role of human fetal adrenals in steroidogenesis: Effect of adrenocorticosterone on urinary excretion of estrogens in pregnancy

59

THE ROLE EFFECT

OF H U M A N

FETAL ADRENALS

OF A D R E N O C O R T I C 0 S T E R O N E

OF E S T R O G E N S Masao

IN S T E R O I D O G E N E S I S :

ON U R I N A R Y

EXCRETION

IN P R E G N A N C Y

Maeyama,

Tomoyoshi

Nakagawa,

and H i r o z o Department

Tuchida

Matuoka

of O b s t e t r i c s

Nara Medical

Yoko

College,

and

Gynecology

Kashihara~

Japan

Received July 26, 1968 ABSTRACT In ? h e a l t h y w o m e n in late p r e g n a n c y the u r i n a r y e x c r e t i o n of e s t r i o l i n c r e a s e d c o n s i d e r a b l y f o l l o w i n g intramuscular i n ~ e c t i o n of 40 IU a d r e n o c o r t i c o t r o p i n ( A C T H - Z ) . No i n c r e a s e of e s t r i o l a f t e r A C T H a d m i n i s t r a t i o n was found in 4 w o m e n in w h o m i n t r a u t e r i n e fetal d e a t h occunred. T h e r e s u l t s o b t a i n e d c o n f i r m t h o s e f o u n d b y other workers. In 3 w o m e n w i t h p r e g n a n c i e s of twins the u r i n a r y e s t r i o l i n c r e a s e d r e m a r k a b l y a f t e r A C T H administration~ t h o u g h the e x c r e t i o n s of e s t r o n e and e s t r a d i o l did not r i s e to c o m p a r a b l e extents. F o u r w o m e n in 9th and 1 0 t h m o n t h s of p r e g n a n c y ~ e a c h w i t h a live a n e n c e p h a l i c fetus~ showed a l o w level of e s t r i o l in the u r i n e a f t e r A C T H a d m i n i stration. H o w e v e r ~ one case in w h o m the a d r e n a l gland of the a n e n c e p h a l i c f e t u s h a d a t h i n but d i s t i n c t fetal a r e a showed a c e r t a i n i n c r e a s e of u r i n a r y e s t r i o l e x c r e t i o n a f t e r A C T H a d m i n i s t r a tion. T h e s e r e s u l t s i n d i c a t e that the h u m a n fetal ~ d r e n a l p l a y s an i m p o r t a n t r o l e in @ s t r i o l s y n t h e s i s by the f e t o - p l a c e n t a l unit. It h a s estrogens,

been and

shown by m a n y

particulary

a normal

pregnancy.

cephalic

monster(4-?)and/or

occurs(8)no

women

increased

in w h o m

trimester ACTH

administration.

in normal paper

considerably

of g e s t a t i o n

faro-placental

women

The

women

death

no

theory

that

unit

plays

some part

pregnancy

gains

support

reports

the

effect

of A C T H

what

throughout

who h a v e

a live fetal

found.

of ACTH~

and

women

of e s t r i o l

from these

reports.

administration

death

urinary while in the

excretion

Diczfalusy(9)called

in the p r o d u c t i o n

anen-

Moreover,

pregnancy

infusion

occurred

of

steadily

was

in late

increase

excretion

intrauterine

urine

following

fetal

showed

women

in w h o m

in the

in n o r m a l

intrauterine

increase

in p r e g n a n t

of e s t r i o l

that

D~ssler(8)reported estriol

of e s t r i o l

However,

increase

invest i g a t o r s ( l - 3 ) t h a t

first

afte~ the

of e s t r o g e n s The

on u r i n a r y

present excretion

60

S T E R 0 1D S

of estriol

on n o r m a l

and a b n o r m a l

women with twins 9 intrauterine

13:1

pregnancies

including

those

f e t a l d e a t h and a n e n c e p h a l i c

MATERIALS

of

monsters.

AND METHODS

C l i n i c a l m a t e r i a l s . (i) S e v e n h e a l t h y w o m e n at the full term of pregnancy. (2) T h r e e w o m e n w i t h t w i n s in the 9th and 1 0 t h m o n t h s of g e s t a t i o n . (3) Four w o m e n in w h o m i n t r a u t e r i n e f e t a l d e a t h o c c u r r e d in the 8th and 9th m o n t h s of gestation. (4) Four p a t i e n t s in w h o m a n e n c e p h a l i c f e t u s e s were d i a g n o s e d by X - r a y a n d / o r c l i n i c a l e x a m i n a t i o n in the 9 t h and 1 0 t h m o n t h s of g e s t a t i o n . ACTH-test. 40 IU A C T H - Z ( C O R T R O P H I N E - Z ~ N. V. 0 R G A N O N ) w e r e i n j e c t e d i n t r a m u s c u l a r l y into each patient. E s t i m a t i o n of e s t r o g e n s in urine. T w e n t y - f o u r - h o u r u r i n e s p e c i m e n s were c o l l e c t e d b e f o r e and a f t e r A C T H injection. H y d r o l y s i s and e x t r a c t i o n of t h r e e f r a c t i o n s of e s t r o g e n s were p e r f o r m e d by the method of B r o w n ( 9 ) ~ and c o l o r i m e t r i c e s t i m a t i o n was c a r r i e d out by m e a s u r e m e n t of the d e n s i t i e s at 4809 515 and 550 mD u s i n g A l l e n ~ s correction. C o r r e c t i o n for loss d u r i n g the e x t r a c t i o n was m a d e by e s t i m a t i n g the r e c o v e r y of a t r a c e of e s t r i o l - 6 , ? - H ( 0 . 2 Dc, 14.? c u r i e s / m i l l i m o l e , NEW E N G L A N D N U C L E A R CORP.)added to e a c h s a m p l e at the i n i t i a l e x t r a c t i o n step. RESULTS Normal estriol

late p r e g n a n c y : in ? h e a l t h y

intramuscular increases

As s h o w n

pregnant

injection

over the m e a n

in T a b l e

women

increased

of 40 IU ACTH-Z. initial

level(2

were 148 % ( 0 n the day of i n j e c t i o n ) a n d Twin pregnancy: of estriol

In 3 p r e g n a n t

i n c r e a s e d to m o r e

ACTH injection~

and two

The a m o u n t s

so m u c h ( T a b l e

of e s t r o n e

were

intrauterine significantly

after ACTH

T.

following

percentage

showed

the u r i n a r y

N.)and

amount

very high

of

injection)

105 % ( o n the f o l l o w i n g

the i n i t i a l

of

day).

fraction after

levels

of as

53.2 m g / 2 4 h r s ( s u b j e c t 9

and e s t r a d i o l

excreted

did not i n c r e a s e

2).

Pregnancy with intrauterine which

The a v e r a g e

days b e f o r e A C T H

than t w i c e

of the t h r e e

excretion

considerably

w o m e n w i t h twins

m u c h as 67.8 m g / 2 4 h r s ( s u b j e c t , N. K.).

i 9 the u r i n a r y

fetal death:

fetal d e a t h

occurred

In 4 p r e g n a n t the l e v e l s

3).

in

of urinary

low 9 b e i n g 1.0 - 2.8 m g / 2 4 hrs 9 and

injection(Table

women

estriol

did not increa~

Jan. 1969

Pregnancy

with

in 4 w o m e n One

s T ER O I D S

live

with

live

case(subject~

monster

was

anencephalic anencephalic

K. M . ) i n

about

a third

whom

to A C T H - s t i m u l a t i o n

was

On the

glands no

of the

increase

tion.

contrary~

anencephalic

in u r i n a r y

Histological

(subject,

K. M.

K.

U.)had

women

after

that

the

fetal

fetus

hrs.

showed

some

of estriol the

0.?-0.8

adrenal

g showed

ACT}{ a d m i n i s t r a -

cortex

zone,

a so-called

estriol

of the a n e n c e p h a l i c

in w h o m

estriol

showed

mg/24

amount

only

a small

I. and K.

gland

weighed

of

of u r i n a r y

0.6-2.2

of a n o r m a l

three

monsters

Y.)had

were

the a b s o l u t e

other

examination

a n d M.

fetumms(subject,

size

excretion

amount

adrenal

though

the

The

fetuses

the

of the

response low.

fetus:

61

of the f e t u s e s

and that

adult

off,he

type

cortex.

DISCUSSION In the h u m a n adrenal

during

to the w i d t h which this

also

uncertain

it was

the

those

a small

molecular

barrier

from

biological promoted

and

congenital

function

adrenal

the

greatly

weight,

the m a t e r n a l The

controlled

hypoplasia

a significant

is not k n o w n ( l l ) .

urinary after

women.

estriol

ACTH

It

women

to the f e t a l

development

adrenal

Moreover~

that

it is

work

women

in late

These

findings

a hormone

with

the p l a c e n t a l -

side w i t h o u t

any

is most

loss

adrenal

of the fetal

gland

Whether

a different

in n o r m a l

likely

zone~

In the p r e s a n t

of the fetal

function

inner

administration.

seems

of

increase

cells.

shows

s u c h as A C T H 9 can pass

of the

the

in s u d a n o p h i l i c

of p r e g n a n t

by the

in w e i g h t

particulary,

of n o n - p r e g n a n t

that

increase

however,

increase

of D ~ s s l e r ( 8 ) .

activity.

is~

fasciculata~

to that

increased

significant

There

a relative

demonstrated

with

zona

increased

to A C T H

pregnancy agree

of the

whether

response

is no

pregnancy.

showed

indicate

there

of

is p r o b a b l y

hypophysis

frequently

since

seen

in

62

S T E R O I D S

association evidence infants

that

monster

had

women(K. monster

estriol

zone~

whom

distinct

anencephalic no

area~

ACTH

increase

In the

of the

anencephalic

of the

no fetal

was v e r y

of u r i n a r y

present

a certain while

increase the two

anencephalic

zone~

The w o m a n ( M .

monster

some

in a n e n c e p h a l i c

showed

gland

with

ACTH.

is a l s o

administration

adrenal

adrenal

after

zone

adrenal

fetal

the

adult

showed

the

after

whom

estriol

of the

fetal

showed

Y.)in

mmall

whom

the

though

estriol

no

with

after

administration. In two

of t h r e e

50 mg per

result

might

receiving

women

24 h r s ) w e r e

be b e c a u s e

twins

excreted

two

It is v e r y

interesting

the

of u r i n a r y

the

with

rather

large

after than

amount

ACTH

of

estriol(more

administration.

one fetal

adrenal

This

gland

ACTH-stimulation.

levels

intrauterine

fetal

levels

extra-fetal death

U.)in

a so-called

gland

M.)in

fetal

There

secretion(14).

of A C T H

excretion

of u r i n a r y

a little

than

K.

but

monster(12-14).

so-called

to l a c k

a thin~

had

adrenal

of the

woman(K.

I. and

increase

that

lack

the

of u r i n a r y

than

anencephalic

is r e l a t e d

experiment

ACTH

with

13:1

estriol

and

of e s t r i o l

source

or live

death

in the p r e s e n t

monster

in n o n p r e g n a n ~

women.

in p r e g n a n t s

monster

should

and

in p r e g n a n t

anencephalic

of e s t r i o l

anencephalic

found

results

with be

other's

reports

women

having

are m u c h

higher

The

presence

ani~trauterine

investigated

of fetal

in future.

Jan. 1969

ST ER O I D S

63

Table i, Urinary excretion of estriol in 7 noFmal pregnant women in full-term after intramuscular injection of ACTH Urinary estriol mg/24 hrs Days 40 IU Days before ACTH after ACTH ACTH 2

i

i

2

K.S. Primigravida 37 weeks

11.4 10.2 (10.8)

32.7

16.0

14.2

M.F. Primigravida 39 weeks

9.2 11.5 (IQ.~)

31.7

31.5

13.0

A. S. i gravida 39 weeks

11.2 12.8 (12.0)

18.1

26.3

2?.0

T.M. Primigravida 38 weeks

20.6 28.3 (24.4)

41.3

34.8

S. 0. 1 gravida 39 weeks

14.3 20.5 (17.4)

30.6

29.4

T.S. Primigravida 37 weeks

23.2 23,0 (23.1)

37.3

31,1

S. N. Primigravida 39 weeks

8.8 10.4 (9.6)

40,0

32.5

Figures in parenthesis represent bmfore ACTH injeEtion.

13.4

18.1

the mean values two days

64

S T ER O I D S

= 0

13:1

Q}

.,,~ =

='~"

=. ="

='=

~r~

0

O0

gg

g ,-,

:3 ..p Q}

I1)

o

0

~-I

dg

i-'-t

O e',

~-t

0

o~

=

,-4

,,-4

mm~ h

P, .p (.-,

0

o~ o"

=

Mo" 04

04

O,I 4.)

,-4 0 .,,-I

= If) e-

QOO,~

0

Owl

O~

hO~ .p _.-)-,~ 0 4.)

+

p., h

0 = 0 .PI 4-) ID

.,-I h

,.-4 0 O4

O4

= 0

D,-O ,-4

h

4-) t~

Q)

..~ ii

0

04 -I,-4

+ ("~ , - I

=

04 + O~ ,-4

e}~

O0

0

O,I + ,,-I P-I 0

O0 0 .,-I

..'4 0] G) • ~

®

..,-4

®

.~

®

ee

0

Jan. 1969

s T ER O I D S

65

..a = 0

"O

40

,,.-4

~) "~"~ = ,1-1

(.) 0 0

to ® ~ ~40~

W'~

0d

°

,

•

v--4

v--4

v--I

to

0d

MD

00

',,D

0d °

Od"

Od"

v-4

Od

p,..

CO

v-4

v-.4

Od°

O

O

0d"

v-4

00 ¢q"

v-4

tO 4-)

00

•

v--4

40 ,.-4 O .H

0

e" to tD

40 to

• 40

0

40

0 •,-t 40

0

N

=

O~..)

v-4

g~ t'-. .H

v-4 Et

,--4

~D v-4 = ~

0 40 e"

to

40 •

to O

>., :~

~:~

•

.H 4.) t¢

tO q0

.v-4

or..4

.v--t

z"

66

ST ER 0 1D S

13:1

,el 4,~ t~

,-4 "t-

g] .,-I

4o

,n

r' 0

0

0 .,-I

'I~

'ID

"{D

0

0 ,..4

0 ,-I

I ,-I ,-I •,-I

I ,-I ,-I .,-I

I ,-I ,-I .,-I

÷

r-, 0 .,-I 4J 0 0

0

~

~-4 ~.-

0 O'~

CJ (0

O~

o'o" o"

0 .,-I

,-4

CO

oC

o'o" o"

.Z)~ 0,1°O,l*

0 ° O"

O0 0 O"

O"

o"

'I3

..p .,-I

0

(.,-I

,.el 0

Q}

.p

0 4-) (II

4~ 0

0

O~

O 0

O"

0 .,-I ~0

0 0

4-)

4-) (ll

g

g

r" 0

0

0

1,4 0

4J 0 -t-

0 0 tO .,-I 4-) 0

r" 0 ,p

0

0 O0

0 O0

0

0 0

•

0

~0

~-I •

(',nO •,-I rO

•

00.I

•

~--I

•

0

~C)

0

•

O r" 0 4.}

0 0 ae

0 ,I"

CO

°

0

0 0

0 (-, .r.l

¢.-I

IL~

~-I

O"

O"

r~ .,-I Iw

0,1 -t" 0

{_) (XI + 0

O0

0

04 + 0

0

0 .,'4 1.4 4J

.p

(1)

-,.4 4~

C~ 0

Jan. 1969

s T E R O I D S

67

ACKNOWLEDGMENT Authentic steroids were kindly supplied by Teikoku Zoki Pharmaceutical Co., LTD.

I. 2. 3.

REFERENCES Beling, C. G., Acta Endocrinol. Suppl., 79(1963). Frandsen, V. A., The Excretion of 0estriol in Normal Human Pregnancy. Copenhagen: Munksgaard,(1963). Beling, C. G., Advances in Obstetrics and Gynecology, Vol. i, p

88, (1967).

4. Frandsen, V. A. and Stakeman, G., Acta Endocrinol. 38, 383(1961). 5. Frandsen, V. A. and Stakeman~ G, , Acta Endocrinol. 4?, 265(1964). 6. Coyle, M., J. Endocrinol., 25, 8(1962). 7. Michie, A. A., Acta Endocrinml., 51, 535(1966). 8. DMssler, C. D., Acta Endocrinol., 53, 401(1966) 9. Diczfalusy, E., Fed. Proc., 23, 791(1964). i0. Brown, J. B., Biochem. J., 60, 185(1955). ii. Whiteley, H. J. and Stoner, H. B., J. Endocrinol., 14, 325(1957). 12. Tuchiyama, H., Nagasaki Medical, 31, 1062(1956). 13. Tuchmann-Duplessis Par H., Biologica Neonatorum, i, 8(1959). 14. Migeon, C. J., Somatic Stability in The newly Borne, A Ciba Foundation Symposium(J. & A. Churchill LTD), London, P. 215(1961).