THYROID FUNCTION IN THE PRETERM FETUS

(1)

(Received January 16; revision accepted for publication March 20, 1970.)

Supported by U. S. Public Health Service Grant HD-04270 from the National Institute of Child Health and Human Development.

ADDRESS: (D.A.F.) Harbor General Hospital, 100 West Carson Street, Torrance, California 90509.

PEDIATRICs, Vol. 46, No. 2 August 1970

208

THYROID

FUNCTION

IN THE

PRETERM

FETUS

Delbert A. Fisher, M.D., Calvin J. Hobel, M.D., Romulo Garza, B.S., and

Claire A. Pierce

From the Department of Pediatrics and Obstetrics and Gynecology, Harbor General Hospital,

Torrance, California, and the University of California Los Angeles, School of Medicine

ABSTRACT. Measurements of serum total

thyrox-ine (T4), free thyroxine (FT4), and/or

immunore-active thyrotropin (TSH) were conducted on 14

pairs of maternal and cord blood specimens

ob-tained at the time of elective therapeutic abortion

of 11- to 18-week pregnancies and on 21 paired

maternal and fetal cord blood specimens collected at the time of spontaneous, premature delivery of 22- to 34-week pregnancies. T4 concentrations were elevated in all maternal samples to levels character-istic of pregnancy; mean values were similar at 11

to 18 and at 22 to 34 weeks and did not differ

from the mean level reported previously at term.

Mean maternal TSH concentrations also were

simi-lar at 11 to 18 weeks, 22 to 34 weeks, and at term. The mean FT4 concentration in maternal serum be-tween 11 and 18 weeks was significantly higher than the level reported previously at term. Fetal

serum T4 and FT4 concentrations were low

be-tween 11 and 18 weeks and increased progressively

between 22 weeks and term. Fetal serum TSH

con-centrations were low between 11 and 18 weeks of

pregnancy but seemed to increase abruptly betsveen 18 and 22 weeks to levels characteristic of term infants.

These data suggest that the maternal

concen-tration of FT4 is higher early in pregnancy than at term, perhaps because of the higher blood levels of human chorionic thyrotropin in early pregnancy. They also indicate autonomous function of the fetal hypothalamic-pituitary control system as early as 12 weeks’ gestation. The abrupt increase in fetal serum TSH between 18 and 22 weeks suggests rapid maturation of the fetal hypothalainic-pitui-tary unit during this period. The subsequent pro-gressive increase in fetal FT4 concentration indi-cates an increasing thyroidal response to the TSH stimulus. Pediatrics, 46:208, 1970, FETAL THYROID

FUNCTION, THYROID HORMONE, TSH, FREE THYROX-INE.

B

Y 10 to 14 weeks’ gestation, the human

fetal thyroid gland is capable of

con-centrating iodine and synthesizing thyroxine

(T4).’ Moreover, thyrotropin (TSH) is

present in the fetal pituitary and serum at

this time.24 Since T4 synthesis by the fetal

thyroid has been shown in animals to be

TSH-dependent5 and since it has been

de-termined by indirect studies in a number of

animal species that TSH does not cross the

placental barrier,7 these data suggest that

central nervous system stimulation of

thy-roid function may occur near the end of the

first trimester. Davis and Forbes8 have

re-ported a goiter in the aborted 5-month fetus

of a thiouracil-treated mother, suggesting

that negative feedback control of TSH

se-cretion is operative at midgestation. The

ob-servation that fetal serum free thyroxine

(FT4) and TSH concentrations exceed

ma-ternal values at term9’1#{176}supports the view

that the fetal pituitary-thyroid control

sys-tem functions autonomously at a high level

near term. While these observations

indi-cate the presence of an intact fetal

hypo-thalamic-pituitary-thyroid control system

during the second and third trimesters,

de-tails of the relationships between fetal T4,

FT4, and TSH during this time remain

ob-scure.

The present study was conducted to

ex-plore these relationships and to assess

maturation of the fetal

hypothalamic-pituitary control system between 11 and 34

weeks of gestation.

METHODS AND PROCEDURES

Serum T4 was measured by the method

of Murphy and Jachan. Dialyzable or FL

(2)

Crown-rump length (mm). §Weight (gin).

magnesium precipitation method of Sterling

and Brenner.’2 All T4 1125 was predialyzed

as suggested by Schussler and Plager.13

Serum was diluted 1 : 10 for assay; percent dialyzable 1’4 1125 was corrected for dilution,

using a correction factor derived by

corn-paring measurements of replicate diluted

and undiluted aliquots of a single pooled

serum. All paired maternal and fetal T4 and

FT4 determinations were run in a single

assay in duplicate. Coefficient of variation

for each of these assays was less than 5%.

TSH was measured using the method of Odell and coworkers.14 The intra-assay

co-efficient of variation of this assay was 2.5%;

inter-assay coefficient of variation was 22%.

Excess human chorionic gonadotropin

(HCG) was added to each assay tube to

prevent HCG or luteinizing hormone (LH)

cross-reaction.9 Highly purified human

chorionic thyrotropin (HCT) reacts with

the present antiserum, but 2,000 times more

HCT (by weight) is required to produce

the same response as a given weight of

human pituitary TSH.9

Paired maternal and cord blood samples were obtained from 14 women and their

re-spective fetuses at the time of elective

abor-lion performed for psychiatric indications; estimated gestational age varied in these

in-stances from 11 to 18 weeks. Amniotic fluid

samples were obtained by puncture before

uterotomy. In addition, paired maternal and cord blood specimens were obtained at the time of spontaneous, premature

deliv-ery of 21 pregnancies estimated to be 22 to

TABLE I

SERUM THYII0xINE AND TSH CONCENTRATIONS IN PAIRED MATERNAL AND

FETAL BLOOD SAMPLLS FROM - TO 34-WEEK PREGNANCIES

Gesla-Sub- taLionol.

ject Age Size (zak)

Maternd Serum

T4 FT4 TSII

(1L/lOO (pU/me

f1 \ (mig/1OO

/o)

Fetal Serum

-14 FT4 TS!I

(g/1OO

UI \ (mpg/ffX k/c)

Zab OO(CR)

Was 2OO(CR)

Jam 05(CR) Car 4 5(CR)

Har 4 68O

Cas 26 (A)879* (B)9O7 And 27 992

Lan 27 1,O0O Gri 27 1,O0O Vin 28 1,106 McB 28 1,162 Woo 30 l,260 Spu 30 1,361k

Bic 32 1,588k

Ser ‘32 1,588k

Wyn 32 1,700

Joh 33 1,818

Net 33 1,900

Tyl 34 1,956

Vii 34 ‘2,041

Rob 34 2,126

14.0 .OO .8 7.0

11. .OQf2 .5 8.3

12.3 .0S .8 3.8

8.9 .0S .0 4.0

9.9 .O4 2.4 3.3

10.5 .026 2.7 7.5

- - <2.0

15.7 .024 3.8 3.0

9.7 .022 2.1 3.8

13.6 .023 3.1 2.3 13.8 .022 3.0 <2.0 13.1 .022 2.9 2.4

- - - 2.5

11.7 .024 2.8 5.0

- - - 3.3

15.9 .023 3.7 4.3

12.1 .023 2.8 ‘3.5

11.3 .028 ‘3.1 2.4

- - - 3.0

- - - 3.5

12.0 .022 2.6 3.0

4.Z .0.59 .5 6.6

5.0 .035 1.7 13.0

8.7 .035 3.0 1.&

3.3 .043 1.4 9.5

.7 .051 1.4 7.8

5.2 .032 1.7 18.0

8.1 .038 3.0 20.0

- - 2.4

- - - 9.3

9.1 .029 2.6 11.3

7.8 .040 3.1 8.3

8.6 .036 3.1 6.5

8.3 .036 3.0 7.5

- - - 10.0

11.5 .028 3.2 7.1

-

- 8.8

8.4 .042 3.5 5.4

7.3 .035 2.5 7.5

7.9 .028 2.2 5.2

- - - 17.5

- - - 10.3

9.4 .020 1.9 6.3

(3)

Gesta-Sub- tional ject Age (wk) Crown-rump length (mm)

Hol 11 68

Cox* Ft (A)75 (B)81) T4 (pg/100 ml) .lmniotic Fluidt TS!I (/.Lf7mi) May Par Fab Den Tay Hen Mu Bag Mae Mar Bur Pme* 13 100 13 14 110 14 11’2 14 115 14 115 14 HO 15 135 16 140 16 145 17 155 18 (A)160 (B)160

-

---

--

8.4

-

<‘2.() ‘to

9.5 16.6 .024 .0’2’t ‘2.3 3.7 9.6 6.8

---‘2.1 3.0 -.088 .068

-1.8 ‘2.0 ‘2.7 4.0 <‘2.0) ‘to ‘2.0 ‘to

13.0 .0-28 3.6 <‘2.0 -

-

<‘2.0 ‘2.0

-

--

---

3.0

--

- --

‘2.5

--

-

---

4.0

-

3.0 1.0

14.4 .0’t0 ‘2.9 3.3 ‘2.6 .093 ‘2.4 ‘2.5 ‘2.0

8.5 .0-24 ‘2.0 ‘2.5 3.5 .068 ‘2.4 ‘2.0) ‘2.0

18.1 .023 4.’2 1.5 ‘2.’t .095 ‘2.1 <1.3 1.5

9.0) .029 ‘2.6 3.2 ‘2.1 .075 it; ‘2.0 1.5

--

- 4.5 -

-

‘2.3 ‘2.0

16.8 .024 4.0 6.0 1.9 .054 1.0 <‘2.8 ‘2.8

9.9 .018 1.8 <‘2.0 ‘2.0 .076 1.5 ‘2.3 ‘2.0

13.0 .0)20 ‘2.6 <‘2.0 3.9

-

- ‘2.2

-TABLE II

THYROXINE ANI) TSI-I CONCENTRATIONS IN l’AIRED MATERNAL ANI) F’ETAI.

B1ooD SAMPLES FROM 11- TO 18-WEEK PIEGNANCIES

Maternal Serum FT4

T4 TSI!

(Mg/lOO nil) (1zU/nil)

(mig/lOO 7)41)

* Indicates twins.

t All values undetectable at the levels indicated.

Fetal Serum

FT4 TSI!

(pU/mi) (mpg/100

nil)

34 weeks’ gestation. There were three sets of

twins so that a total of 38 fetal specimens

were obtained. In all cases, except one, the

fetus was alive at the time of birth; in that

one instance

(

Table I

)

the fetus died

during labor. Estimates of gestational age

were based on crown rump length and/or

fetal weight.15’” TSH concentration was

measured in all blood and amniotic fluid

samples. Total and FT4 concentrations were

measured in the sera of 9 of the 14 abortion

samples and in 16 of the 21 paired samples

obtained at the time of premature delivery.

RESULTS

The estimated gestational age, crown

rump length or body weight, and serum

T4, FT4, and TSH concentration data in

blood and amniotic fluid of the 11 to 18

week fetuses obtained by elective abortion

are summarized in Table II. These data in

the 22 to 34 veek fetuses resulting from

spontaneous, premature labor are collated

in Table I.

The combined fetal data are summarized

graphically, with previously reported data

from term pregnancies, in Figures 1 to 3:

total serum T4 concentration is plotted

versus gestational age in Figure 1, serum

FT4 concentration versus gestational age in

Figure 2, and serum TSH concentration

versus gestational age in Figure 3. Finally,

the maternal and fetal data are summarized

for 11- to 18-week, 22- to 34-week, and

38-to 40-week pregnancies in Table III and

Figure 4.

The maternal serum total T.1

concentra-tion is elevated to levels characteristic of

pregnancy in all instances. Individual values

vary from 8.5 to 18.1 p.g/100 ml (Tables I

and II). The mean concentration between

11 and 18 weeks (12.9 ± 1.1 g/100 ml)#{176}

(4)

ARTICLES 211

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9,

w

‘2 ‘ ‘ 2’4

GESTATIONAL AGE (WEEKS)

Fic. 1. Fetal serum total thyroxine concentration (T4 g/100 ml) plotted versus gestational age (in weeks). The data for term infants are from an

earlier publication.9

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10

2 6 20 24 28 32 3638

to

GESTATIONAL AGE (WEEKS) 40

FIG. 2. Fetal serum free thyroxine concentration

(FT4 mtg/100 ml) plotted versus gestational age

(in weeks). The data for term infants are from an earlier publication.’

20 4os.rad vo/us

L* not deteclad a

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2 0

2 6 20 28 32

GESTATIONAL AGE (WEEKS)

36 38

to 40

is similar to that between 22 and 34 weeks

(

12.2 ± 0.51 .g/100 ml) and neither mean

value differs significantly from the mean

concentration previously reported at term

(

11.5 ± 0.56 tg/109 ml, Table III and

Fig. 4).

The maternal serum concentrations of

TSH vary from undetectable levels to a

value of 9.6 .&U/ml (Tables I and II);

nor-mal euthyroid adult levels vary from

un-detectable levels to 10 U/ml. The mean

concentration between 11 and 18 weeks

(4.2 ± 0.68 tU/ml) is similar to that

be-tween 22 to 34 weeks (3.8 ± 0.38 tU/ml)

and that (4.3 ± 0.4 tU/ml) previously

re-ported at term (Table III and Fig. 4).

The concentrations of FT4 in maternal

serum vary from 1.8 to 4.0 mpg/100 ml

(Tables I and II). The mean values at 11 to

18 weeks (2.97 ± 0.27 mg/ 100 ml) and at

22 to 34 weeks (2.82 ± 0.12 mpg/100 ml)

are similar. Ho ever, that previously

re-ported at term (2.30 ± 0.13 mpg/100 ml)

seems significantly lower (p values 0.04 and

<0.01, respectively, Table III and Fig. 4).

T4 is present in all fetal sera tested

(Tables I and II and Fig. 1) although the

concentrations are low in the 11- to 18-week

fetuses (1.9 to 3.9 tg/100 ml). The mean

level increases progressively to term: 2.6 ±

0.24 at 11 to 18 weeks; 7.2 ± 0.61 at 22 to

34 weeks; 11.2 ± 0.43 g/100 ml

(pre-viously reported9) at term. All values differ

statistically (at the p <0.001 level, Table

III and Fig. 4).

A similar progressive increment in serum

FT4 concentration is observed with

increas-ing gestational age (Tables I and II and

Fig. 2). Although the percent dialyzable

T4 is high in the 11- to 18-week fetuses

(.054 to .095%, mean .077%), the FT4

con-Fic. 3. Fetal serum im.munoreactive thyrotropin concentration (TSH, tU/ml) plotted versus gesta-tional age (in weeks). The data for term infants

(5)

TABLE III

SUMMARY OF MATERNAL AND FETAL SERUM THYROXINE (T4), FREE THYROXINE (FT4), AND TSH

CONCENTRATION DATA BETWEEN 11-WEEK GESTATION AND TERM*

Period of

Gesta-tion

T4 (pg/i00 ml)

Maternal FT4 (mpg/lOt) ml)

TM! (pU/mi)

74 (pg/lOU ml)

Fetal FT4

(mpg/lOO ml) TS!I (pU/ml)

(wk)

11-18 12.9±1.1(10) ‘2.97±0.27(10) 4.2±0.68(14) 2.6±0.24(9) 1.85±0.17(8) ‘2.4±0.14(16) 22-34 12.2±0.51(16) 2.82±0.12(16) 3.8±0.38(21) 7.2±0.61(16) 2.49±0.17(16) 9.6±0.93(22)

38-40f 11.5±0.56(17) 2.30±0.13(17) 4.3±0.40(16) 11.2±0.43(17) 2.90±0.10(17) 8.9±0.93(16)

* Numbers in parentheses indicate iiumbcr of samples. f Data from Fisher, et al.9

centration is low; the mean value

(

1.85 ±

0.17 mg/100 ml) is significantly less (p

0.01

)

than that in the 22- to 34-week fetuses

(2.49 ± 0.17 mp.g/100 ml). The latter value

differs from that reported earlier for term

infants (2.90 ± 0.10 m.g/100 ml) at the

p = 0.04 level of significance (Table III

and Fig. 4).

Finally, serum TSH concentrations in the

11- to 18-week fetuses vary from

undetect-able levels to 4 iU/ml (Table II and Fig.

3) ; the mean concentration is 2.4

(

± 0.14)

tU/ml (Table III) . The TSH

concentra-lions in fetal blood between 22 and 34

weeks’ gestation vary from 2.4 to 20 .U/ml

(Table I and Fig. 3); the mean value

(9.6 ± 0.93 tU/ml) is similar to that

pre-viously reported for the term fetus (8.9

± 0.93 p.U/ml) and significantly higher

(p <0.001) than the value at 11 to 18

weeks (Table III and Fig. 4). TSH was not

detected in the thirteen 11- to 16-week

amniotic fluid samples tested (Table II).

DISCUSSION

The present data indicate a low level of

thyroid function in the 11- to 18-week

human fetus. The low total serum T4

con-centration (2.6 ± 0.24 tg/100 ml, Table

III) is in agreement with data of Osorio

and Myant’7 and Greenberg and

col-f The mean was calculated using the “less than” values recorded in Table II. These values repre-sent the lower limit of assay sensitivity.

8 and presumably is due to a low

maximal binding capacity of serum T4

bind-ing globulin.1718 The proportion of

dialyz-able T4 is high in these samples (mean,

0.77%; Table II

)

but is not sufficient to

corn-pensate for the low total T4 level; thus, the

absolute FT4 concentration also is low

(

1.85 ± 0.17 m.g/100 ml, Table III ). Since

T4 does not cross the placental barrier early

in pregnancy,1#{176} this T4 presumably is

de-rived from the fetal thyroid.

Serum TSH also is detectable at low

levels in fetuses of 11- to 18-weeks’ gestation

(

Tables II and III and Fig. 3), an

observa-tion in agreement with that of other

investi-gators.3’18 Although the possibility cannot

be excluded that this TSH is derived

trans-placentally from maternal blood, the change

in direction of the maternal to fetal concen-tration gradient for TSH at about 20 weeks

(from M > F, to F > M; Fig. 3 and 4)

and the animal data suggesting that TSH

does not cross the placenta5 would argue

against this view. Maternal serum appears

to contain relatively high concentrations of

HCT early in gestation2#{176} and it also is

pos-sible that some of this material is being

secreted directly into the fetal circulation or

being transferred across the placenta from

maternal to fetal blood. However, we have

shown that the cross reactivity of HCT in

the present immunoassay is much less than

that of pituitary TSH (1/2,000 by weight

(6)

Lii

*0

>-.

ARTICLES 213

and unlikely HCT concentrations would be

required in fetal blood to account for the

apparent 2.5 to 4 tU/ml quantities of TSH

observed in some of these early fetuses.

Thus, the present data suggest that fetal

pituitary control of thyroid function must

exist as early as 12 weeks’ gestation.

How-ever, the control system is immature since

the serum TSH levels are low in spite of

low T4 and FT4 concentrations.

An abrupt increase in fetal serum TSH

concentration is observed between 18 and

22 weeks (from levels below 5 U/ml to

values in the 5 to 20 p.U/ml range, Fig. 3).

The mean concentration increases from a

level of 2.4 ± 0.14 ,.U/ml at 11 to 18 weeks

to 9.6 ± 0.93 p.U/ml between 22 and 34

weeks and is maintained at this level until

term (Table III and Fig. 4). The 22- to

34-week fetuses were delivered vaginally

rather than via uterotomy as was the case

for the 11- to 18-week fetuses; the higher

serum TSH concentrations in the former

group are not accountable, however, on this

basis. We have shown earlier that cord

blood TSH levels are similar at term

whether the fetus is delivered vaginally or

by cesarean section.

It is possible that some, or all, of the

pre-maturely born (22- to 34-week) infants

were not representative of a healthy

popu-lation and that the dramatic shift in serum

TSH concentration in this group may be

the result of environmental factors.

How-ever, earlier studies suggesting a parallel

in-crease in thyroidal radioiodine uptake by

the fetal thyroid at about 22 weeks2’ and

the high fetal serum TSH levels in the term

newborn infant (Fig. 3 and 4) would

sug-gest that the observed increase in fetal

se-rum TSH concentration at about 22 weeks

is a significant physiological phenomenon.

Data of Evans and colleagues2l regarding

thyroidal radioiodine concentration in the

fetal thyroid after maternal radioiodine

in-jection are summarized in Table IV and

in-dicate that the fetal thyroid begins to

con-centrate iodine at about 13 weeks. Between

13 and 21 weeks the concentration of

ra-dioiodine averages about 1.5%/gm

thy-roid. At 22 weeks an abrupt increase to a

mean concentration of 4.6%/gm seems to

occur. There are no reliable uptake data

be-tween this period and term when the

new-born 24-hour uptake after direct injection

into the infant averages about 50% of the

dose per gram thyroid.22 This value,

cor-rected for the difference in radlioiodine

dis-tribution volume for comparison with fetal

values (about 21 liters maternal volume

plus the fetal volume of 1.6 liters after

ma-ternal injection versus 1.6 liters after

injec-tion into the newborn) amounts to 3.8%!

gm thyroid (Table IV). Thus, radioiodine

uptake, like serum TSH concentration,

seems to increase abruptly at about 22

weeks and thereafter tends to plateau at

3o

0 cr0 >-0

4

2

l0

8 6 4

2 4.

12’ 10’

8 6 4,

2

11-18 22-34 TEIM

WEEKS

FIG. 4. Mean (± SEM) total thyroxine (T4, ig/10O ml), free thyroxine (FT4, m&g/100 ml) and

thyro-tropin (TSH, tU/ml) concentrations from paired

maternal and fetal serum specimens plotted for

three periods of gestation: 11 to 18 weeks, 22 to 34 weeks, and 38 to 40 weeks. The 38- to 40-week

(7)

TABLE IV

RADIOLODINE UPTAKE BYFETAL Tiittoiu

Z’umber Fetuses

or Newborn infants

Fetal Age (irk)

Mean . Thyroid

.

Ueight

(ing)

Mean

.

Thyroid

J131 Conceit-. tration (%/gm)

0

3 8-12

-11 13-15 21 1.6

5 17-21 109 1.4

5 22 203 4.6

17* 38-40 1430t 3.8

Data from Evans, et a!.21 unless otherwise indicated.

9 Data from Fisher and Oddie.22 Values corrected for smaller iodide space of newborn.

t Data from Palmer, et aL”

high levels to term. Although this abrupt

in-crease in iodide uptake by the fetal thyroid

at 22 weeks could reflect abrupt maturation

of the iodide pump, the close correlation

with the apparent increase in fetal serum

TSH concentration suggests that these

events may be related. Such a relationship

argues against the possibility that the

in-crease in serum TSH represents

compensa-tion for reduced tissue TSH responsiveness;

in this case, no increase in thyroid gland

function would be expected. Therefore, it

seems likely that the increase in fetal serum

TSH concentration represents an increased secretion rate.

The progressive increase in total serum

T4 between 12 and 40 weeks

(

Fig. 1

)

is, in

part, due to a progressive increase in serum

T4-binding globulin (TBG)

concentra-tion,17’18”3 but the concomitant increase in

F’T4 concentration (Fig. 2 and 4) indicates

that T4 secretion is increasing more rapidly

than binding protein concentrations so that

a progressive saturation of protein binding

sites occurs. These data are in agreement

with those of Perry and co-workers23 who

observed a progressive increase in cord

blood T4 concentration with increasing

weight and gestational age in premature

infants without significant increase in T4

binding prealbumin or TBG binding

capaci-ties. This progressive saturation of fetal

serum T4 binding proteins could be due to

an increasing maternal to fetal transfer of

maternal T4 or to an increasing rate of fetal

T4 secretion. The facts that the mean fetal serum FT4 exceeds the maternal level at

term (Table III and Fig. 4), and that there

is no evidence of progressive suppression

of fetal serum TSH

(

Fig. 4), would not be

compatible with placental transfer of

ma-ternal hormone and would indicate that

fe-tal T, secretion is increasmg progressively

in response to fetal TSH stimulation. In

sup-port of this conclusion, Dussault and

Fisher24 have shown that radiothyroxine

does not cross the sheep placenta during the

last trimester and that fetal thyroxine

turn-over at this time approximates 40 i.g/kg/ day,

exceeding the maternal turnover rate about

eight times.

The increasing serum FT4 concentration

cannot be explained on the basis of

se-cretion of human chorionic thyrotropin

since secretion of this hormone, like human

chorionic gonadotropin, is maximal early in

pregnancy and decreases near

term.2#{176}How-ever, secretion of HCT might explain the relatively high free thyroxine concentration

in maternal serum at 11 to 18 weeks

(

Table

III, Fig. 4) . This observation has not previ-ously been reported.

SPECULATION

The present observations suggest that the

fetal hypothalamic-pituitary TSH control

system begins to mature between 18 and 22

weeks. The abrupt increase in the serum

TSH/FT4 ratio which occurs at this time

might be explained in several ways :

(

1

)

an

increase in hypothalamic thyrotropin

re-leasing factor

(

TRF) secretion,

(

2

)

in-creased pituitary TRF responsiveness, or

(3) decreased hypothalamic and/or

pitu-itary sensitivity to thyroid hormone

feed-back. Preliminary data25 suggesting an

abrupt increase in fetal pituitary TSH

con-tent between 18 and 22 weeks would

in-dicate that the increase in serum TSH

concentration (and probably secretion) is

associated with an increased rate of

(8)

ARTICLES 215

turn, an increased rate of TRF secretion or

augmentation of TRF responsiveness. Data

of Levina4 indicating a marked increase in

fetal pituitary FSH and LH content between

20 and 23 weeks, although not excluding an

increased pituitary response to releasing

factor as an explanation, favors the

alterna-tive possibility of maturation of the

hypo-thalamic neuroendocrine transducer system

controlling pituitary hormone synthesis and

release. Should this prove to be the case,

this intra-uterine hypothalamic maturation

might be likened to amphibian

metamor-phosis involving, as it does, histologic and

functional maturation of the hypothalamus

and median eminence and a progressive

in-crease in thyroxine secretion rate.2#{176}

SUMMARY

Total and free thyroxine

(

T.9 and VF4)

and thyrotropin

(

TSH

)

concentrations have

been measured in human fetal blood and

paired maternal blood specimens between

11 and 34 weeks’ gestation. Fourteen cord

blood specimens from 11- to 18-week

fe-tuses were obtained at the time of elective

abortion conducted for psychiatric

indica-tions. Twenty-one cord blood specimens

were obtained from 22- to 34-week fetuses

at the time of spontaneous, premature labor

and vaginal delivery. Maternal serum T4

concentrations were elevated to levels

char-acteristic of pregnancy; mean 11- to

18-week, 22- to 34-week, and (previously

re-ported) term values were similar. Maternal

serum TSH concentrations were similar to

values in euthyroid, nonpregnant subjects;

mean 11- to 18-week, 22- to 34-week and

(previously reported) term values were

similar. The maternal serum FT4

concentra-tion was significantly higher (p <0.01)

be-tween 11 and 18 weeks than (previously

re-ported) at term.

Fetal serum T4 and FT4 concentrations

were low between 11 and 18 weeks and

in-creased progressively between 22 weeks and

term. Fetal serum TSH concentrations also

were low between 11 and 18 weeks [2.4 ±

0.14 (SEM) U/ml] but seemed to increase

abruptly between 18 and 22 weeks to levels

characteristic of term infants [mean 8.9 ±

0.93 (SEM

)

U/ml]. These data indicate

autonomous function of the fetal

hypotha-lamic-pituitary control system as early as 11

to 14 weeks’ gestation and suggest rapid

maturation of the system between 18 and 22

weeks.

The increasing fetal serum FT4

concen-tration between 22 weeks and term

inch-cates an increasing thyroidal response to the fetal TSH stimulus.

REFERENCES

1. Shepard, T. H.: Onset of function in the

hu-man fetal thyroid: Biochemical and radioau-tographic studies from organ culture. J. Clin.

Endocr., 27:954, 1967.

2. Gitlin, D., and Biassucci, A. : Ontogenesis of immunoreactive growth hormone, follicle stimulating hormone, thyroid stimulating hormone, hiteinizing hormone, chorionic prolactin, and chorionic gonadotropin in the

human conceptus. J. Clin. Endocr., 29:926,

1969.

3. Costa, A., Cottino, M., Dellapiane, M.,

Fer-raris, C. M., Lenart, L., Magro, C., Patrito,

C., and Zoppetti, C. : Thyroid function and

thyrotropin activity in mother and fetus. in

Cassano, C., and Andreoli, M., ed. : Current

Topics in Hormone Research. New York:

Academic Press, pp. 738-748, 1965.

4. Levina, S. E.: Endocrine features in develop-ment of human hypothalamus, hypophysis, and placenta. Gen. Comp. Endocr., 11:151,

1968.

5. Jost, A.: Anterior pituitary function in foetal life. in Harris, G. W., and Donovan, B. T.,

ed. : The Pituitary Gland, Vol. II. London: Butterworths, pp. 299-323, 1966.

6. Knobil, E., and Josimovich, J. B.: Placental transfer of thyrotropic hormone, thyroxine, triiodothyronine, and insulin in the rat. Ann.

N.Y. Acad. Sci., 75:895, 1958.

7. Sobel, E. H., Hamburgh, M., and Koblin, R.:

Development of the fetal thyroid in rats:

Evidence for placental transfer of thyroxine. Amer.

J.

Dis. Child., 100:709, 1960.

8. Davis, L., and Forbes, W.: Effect of

antithy-roid drugs on the fetus. Lancet, 2:740, 1945. 9. Fisher, D. A., Odell, W. D., Hobel, C. J., and

Garza, R.: Thyroid function in the term

fe-tus. PsmIATmcs, 44:526, 1969.

10. Robin, N. I., Refetoff, S., Fang, V., and

Selen-kow, H. A.: Parameters of thyroid function

in maternal and cord serum at term

preg-nancy. J. Clin. Endocr., 29:1276, 1969.

(9)

deter-press.

mination of thyroxine by competitive pro-tein-binding analysis employing an anion-exchange resin and radiothyroxine. j. Lab. Clin. Med., 66:161, 1965.

12. Sterling, K., and Brenner, M. A. : Free thyrox-me in human serum: Simplified measure-ment with the aid of magnesium precipita-tion. J. Clin. Invest., 45: 153, 1966.

13. Schussler, C. C., and Plager, J. E.: Effect of preliminary purification of 131J thyroxine on the determination of free thyroxine in senirn. J. Clin. Endocr., 27:242, 1967.

14. Odell, W. D., Vanslager, L., and Bates, R. W.: Radioimmunoassay of human thyrotropin. in Radioisotopes in Medicine: in Vitro Studies. AEC Symposium Series, 13:185, 1968.

15. Shepard, T. H.: Growth and development of

the human embryo and fetus. In Gardner, L. I.,ed: Endocrine and Genetic Diseases of Childhood. Philadelphia: W. B. Saunders, pp. 1-6, 1969.

16. Lubchenco, L. 0., Hansman, C., and Boyd, E.: Intrauterine growth in length and head cir-cumference as estimated from live births at gestational ages from 26 to 42 weeks.

Pam-ATBICS, 37:403, 1966.

17. Osorio, C., and Myant, N. B.: The binding of thyroxine by human foetal serum. Clin. Sci., 23:277, 1962.

18. Greenberg, A. H., Czernichow, P., Reba, R. C., Tyson, J., and Blizzard, R. M.: Oh-servations on the maturation of thyroid func-tion in early fetal life. J. Clin. Invest., in

19. Myant, N. B. : Passage of thyroxine and trim-dothyronine from mother to fetus in

preg-nant women. Clin. Sci., 17:75, 1958.

20. Hennen, G., Pierce, j. C., and Freychet, P.: Human chorionic thyrotropin : Further char-acterization and study of its secretion dur-ing pregnancy. j. Clin. Endocr., 29:581, 1969.

21. Evans, T. C., Kretzschmar, R. M., Hodges, R. D., and Song, C. W. : Radioiodine uptake studies of the human fetal thyroid. j. Nod. Med., 8:157, 1967.

22. Fisher, D. A., and Oddie, T. H.: Neonatal thy-roidal hyperactivity. Amer. J. Dis. Child., 107:574, 1964.

23. Perry, R. E., Hodgnsan, J. E., and Starr, P.: Maternal, cord and serial venous blood pro-tein-bound iodine, thyroid-binding globulin, thyroid-binding albumin and prealbumin values in premature infants. PEDIAT1uC5, 35:

759, 1965.

24. Dussault, J., and Fisher, D. A.: Thyroxine se-cretion in the fetal sheep. (Abst. 110) Pro-gram of the Endocrine Society Meeting, June 10-12, 1970.

25. Fisher, D. A., Hobel, C. J., and Pierce, C.: Un-published data.

26. Etkin, W.: Metamorphosis. In Moore, J. A.,

ed.: Physiology of the Amphibian. New York: Academic Press, pp. 427-468, 1966. 27. Palmer, W. W., Leland, J. P., and Cutman,

A. B.: The microdetermination of thyroxine

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1970;46;208

Pediatrics

Delbert A. Fisher, Calvin J. Hobel, Romulo Garza and Claire A. Pierce