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Methyl testosterone in the treatment ofpremature infants
METHYL TESTOSTERONE IN THE TREATMENT OF PREMATURE INFANTS J A N E T HARDY,
M.D.,
AND L A W S O N W I L K I N S ,
M.D.
B ALTI]YIORE, M D .
A
PRELIMINARY report by Shelton and Varden 1 suggested that the administration of testosterone preparations to premature infants was of value in decreasing the expected mortality rate of infants weighing less than 2,000 Gin. at birth and that, by promoting a more satisfactory weight curve, it decreased the period of hospitalization necessary for each infant. A subsequent more complete report 2 tends to confirm these impressions. No untoward effects of the drug were noted by the authors. It is generally accepted that the administration of methyl testosterone to an individual brings about an increase in nitrogen retention, protein anabolism, and tissue growth. 3 Therefore, it seems reasonable to hope that the administration of this substance to premature infants might be of value in promoting growth as measured by gain in body weight. An effort to determine if testosterone is of practical value in this respect was made between May and November of 1947 in the Nursery Unit for Premature Infants in the Harriet Lane Home, The Johns Hopkins Hospital. Alternate premature infants were given methyl testosterone by mouth twice daily, 2.5 rag. emulsified in 5 c.c. of sterile water and given by medicine dropper or gavage tube immediately before feeding. In all except two patients the treatment was begun on the seventh to tenth day of life. In patient A (Chart 1) it was begun at 11 weeks and in patient H at 6 weeks. The medication was continued for four weeks. In most instances it was withdrawn abruptly, but in some the dose was reduced to 2.5 rag. daily for an additional three days and then discontinued. The infants receiving methyl testosterone and those serving as controls were all handled according to the standard nursery regime. Feedings consisted of half-skimmed milk with 10 per cent added carbohydrate, having a caloric value of one calorie per cubic centimeter of formula. After the tenth day of life 120 to 130 calories per kilogram of body weight were fed daily. Supplementary vitamins A, C, and D were started on the fifth or sixth day of life. In all, twenty-six infants, varying from approximately 900 to 1,900 Gin. at birth, were given methyl testosterone as described above. Their response to therapy as measured by computing the average daily weight gain for the total period of hospitalization (including the period of initial weight loss) was compared with that of the control, untreated group. The results of this comparison may be seen in Table I. In order that a graphic representation might be made, a group of infants of varying birth weight was chosen from the testosterone-
F r o m the D e p a r t m e n t of Pediatrics, J o h n s I-topkins U n i v e r s i t y School of lViedicine, and t h e H a r r i e t L a n e H o m e of the J o h n s H o p k i n s Hospital. 439
440
THE
JOURNAL
OF P E D I A T R I C S
treated group and paired off with an untreated infant of the same sex and race, of approximately the same birth weight. The selection was done by. an individual who had no knowledge of the clinical course of the infants in either group. In addition, six infants weighing between 850 and 1,370 Gin. at birth were each given 4 rag. testosterone proprionate in oil intramuscularly, on the first day of life and every third day thereafter. All six died between the second and tenth days of life and are not included in this study.
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C h a r t 1.--V~eight curves os premature infants recei.ving methyl testosterone 2.5 rag. twice daily given during the period marked by broken ]ine; 2.5 rag. ,once daily during the period ]c~l~.rked by dotted lille, N o therEtpy during period m a r k e d by solid line,
HARDY AND W I L K I N S :
METHYL TESTOSTERONE FOR PRE~CLATURE INFANTS
44]
TABLE I 2.5 1v[G. METI=[YL TESTOSTEI~ONE TWICE DAILY (AVERAGE DAILY
BIRTH WEIGI~T
(G2r 800- 990 1,000-1,199 1,200-1,399 1,400-1,599 1,600-1,799 1,800-1,999 2,000-2,]99 Totals
NO.
CONTROL (AVERAGE DAILY
GAIN IN GYL) 15.5 16.3 15.7 17.4 17.9 21.7 15.1 17.0
26
NO.
GAIN IN G~{.) ]5.6 ]7.3 17.6 16.5 19.5 20.6
26
18.2
GMS, 3200 3~00l 3000
2900 28001
6 LB$.
4 LB5.
I
2
3
4
5
O
7
B
9 I0 WEEKS
II
12
13
14
15
16
17
18
t9
C h a r t 2 . - - W e i g h t curves of p r e m a t u r e i n f a n t s r a i s e d on s a m e g e n e r a l r e g i m e a s those in C h a r t 1 but g i v e n no testosterone.
442
THE
JOURNAL
OF PEDIATRICS
RESULTS
As may be seen by comparison of the graphic charts, there is no significant difference in the weight curves of the infants treated with methyl testosterone and those who did not receive the drug. Furthermore, as shown in Table I, the average daily weight gain of 17 Gin. made by the infants treated with testosterone is not significantly different from an average daily weight gain of 18.2 Gin. in the control group. The only child in whom any dramatic effect was observed was patient I~I (Chart I), who did not receive the drug until he was 10 weeks of age. This was a twin who had failed to gain at the expected rate. He gained rapidly during the period of treatment but continued to do so after the drug was withdrawn. No untoward effects of the medication were noted. Two of the male infants showed moderate enlargement of the penis, which has persisted. Several of the girls showed transient enlargement of the clitoris. It is of interest that in very few instances was weight loss observed at the termination of the testosterone therapy, whereas in older patients having increased protein anabolism with testosterone, a transient loss of weight and nitrogen usually occurs on its withdrawal. This suggests that the drug had had no marked effect in increasing nitrogen retention. CONCLUSION
In the clinical experiment described above, no benefit was observed from the use of methyl testosterone in the treatment of premature infants. REFERENCES ]. Shelton, E. K., and Varden~ A. E.: The Use of Methyl Testosterone in the Treatment of Premature Infants, J. Clin. Endocrinol. 6: 812, 1946. 2. Shelton, E. I~., Yarden, A. E.~ arid Mark, J. S.: Experimental Use of Testosterone Compounds in Premature Infants, J. Clia. Endocrino]. 7" 709, ]947. 3. I~enyoi% A. T.~ I~nowlton~ I<., and Sandlford~ I.: The Anabolic Effects of the Androgens and Somatic Growth in IVian~ Ann. Int. Med. 20: 632, ]944.
M.D.,
AND L A W S O N W I L K I N S ,
M.D.
B ALTI]YIORE, M D .
A
PRELIMINARY report by Shelton and Varden 1 suggested that the administration of testosterone preparations to premature infants was of value in decreasing the expected mortality rate of infants weighing less than 2,000 Gin. at birth and that, by promoting a more satisfactory weight curve, it decreased the period of hospitalization necessary for each infant. A subsequent more complete report 2 tends to confirm these impressions. No untoward effects of the drug were noted by the authors. It is generally accepted that the administration of methyl testosterone to an individual brings about an increase in nitrogen retention, protein anabolism, and tissue growth. 3 Therefore, it seems reasonable to hope that the administration of this substance to premature infants might be of value in promoting growth as measured by gain in body weight. An effort to determine if testosterone is of practical value in this respect was made between May and November of 1947 in the Nursery Unit for Premature Infants in the Harriet Lane Home, The Johns Hopkins Hospital. Alternate premature infants were given methyl testosterone by mouth twice daily, 2.5 rag. emulsified in 5 c.c. of sterile water and given by medicine dropper or gavage tube immediately before feeding. In all except two patients the treatment was begun on the seventh to tenth day of life. In patient A (Chart 1) it was begun at 11 weeks and in patient H at 6 weeks. The medication was continued for four weeks. In most instances it was withdrawn abruptly, but in some the dose was reduced to 2.5 rag. daily for an additional three days and then discontinued. The infants receiving methyl testosterone and those serving as controls were all handled according to the standard nursery regime. Feedings consisted of half-skimmed milk with 10 per cent added carbohydrate, having a caloric value of one calorie per cubic centimeter of formula. After the tenth day of life 120 to 130 calories per kilogram of body weight were fed daily. Supplementary vitamins A, C, and D were started on the fifth or sixth day of life. In all, twenty-six infants, varying from approximately 900 to 1,900 Gin. at birth, were given methyl testosterone as described above. Their response to therapy as measured by computing the average daily weight gain for the total period of hospitalization (including the period of initial weight loss) was compared with that of the control, untreated group. The results of this comparison may be seen in Table I. In order that a graphic representation might be made, a group of infants of varying birth weight was chosen from the testosterone-
F r o m the D e p a r t m e n t of Pediatrics, J o h n s I-topkins U n i v e r s i t y School of lViedicine, and t h e H a r r i e t L a n e H o m e of the J o h n s H o p k i n s Hospital. 439
440
THE
JOURNAL
OF P E D I A T R I C S
treated group and paired off with an untreated infant of the same sex and race, of approximately the same birth weight. The selection was done by. an individual who had no knowledge of the clinical course of the infants in either group. In addition, six infants weighing between 850 and 1,370 Gin. at birth were each given 4 rag. testosterone proprionate in oil intramuscularly, on the first day of life and every third day thereafter. All six died between the second and tenth days of life and are not included in this study.
GMS. 32OO 3100
.~ ;.."
3000
/ //
2900"
/
2800" 6 LBS2700"
/ / iii1o
ooo.
/
2400-
,,
ii :
5 LBS'2300"
~ /
e2o~c
/
~. ~ " ~ / f t l ;
~ / "
/////
210C
///" t-J"
4 LBS.
y
,7ool
/,t ,
"~/'
/'!
.y///
,,v]/
,,,/
:..:
, ,
,,
\< ,,
./
,,2"/
.,,:,"
~
,I/
,ooo
1500~ l 0 3--LB5.1400 130C
/
t~!fi$' j / " , ~ ~ ( ~ / / ///It ~/ .;
/J 711 i1*1 iii/I
L ~ .~
120C
t/
I100 L~ \ . .-., ,ooo~
i/
i/
/
/
/'
/ ,. / ." t i /" i ~-/ // J
/ t I I I /pl
,/ /,
/
', /
so~
v2~
3
4
5
g
"~
8 w WEEKS
iO
I'1
I";)
1:3
I;r
15
i6
I~t
C h a r t 1.--V~eight curves os premature infants recei.ving methyl testosterone 2.5 rag. twice daily given during the period marked by broken ]ine; 2.5 rag. ,once daily during the period ]c~l~.rked by dotted lille, N o therEtpy during period m a r k e d by solid line,
HARDY AND W I L K I N S :
METHYL TESTOSTERONE FOR PRE~CLATURE INFANTS
44]
TABLE I 2.5 1v[G. METI=[YL TESTOSTEI~ONE TWICE DAILY (AVERAGE DAILY
BIRTH WEIGI~T
(G2r 800- 990 1,000-1,199 1,200-1,399 1,400-1,599 1,600-1,799 1,800-1,999 2,000-2,]99 Totals
NO.
CONTROL (AVERAGE DAILY
GAIN IN GYL) 15.5 16.3 15.7 17.4 17.9 21.7 15.1 17.0
26
NO.
GAIN IN G~{.) ]5.6 ]7.3 17.6 16.5 19.5 20.6
26
18.2
GMS, 3200 3~00l 3000
2900 28001
6 LB$.
4 LB5.
I
2
3
4
5
O
7
B
9 I0 WEEKS
II
12
13
14
15
16
17
18
t9
C h a r t 2 . - - W e i g h t curves of p r e m a t u r e i n f a n t s r a i s e d on s a m e g e n e r a l r e g i m e a s those in C h a r t 1 but g i v e n no testosterone.
442
THE
JOURNAL
OF PEDIATRICS
RESULTS
As may be seen by comparison of the graphic charts, there is no significant difference in the weight curves of the infants treated with methyl testosterone and those who did not receive the drug. Furthermore, as shown in Table I, the average daily weight gain of 17 Gin. made by the infants treated with testosterone is not significantly different from an average daily weight gain of 18.2 Gin. in the control group. The only child in whom any dramatic effect was observed was patient I~I (Chart I), who did not receive the drug until he was 10 weeks of age. This was a twin who had failed to gain at the expected rate. He gained rapidly during the period of treatment but continued to do so after the drug was withdrawn. No untoward effects of the medication were noted. Two of the male infants showed moderate enlargement of the penis, which has persisted. Several of the girls showed transient enlargement of the clitoris. It is of interest that in very few instances was weight loss observed at the termination of the testosterone therapy, whereas in older patients having increased protein anabolism with testosterone, a transient loss of weight and nitrogen usually occurs on its withdrawal. This suggests that the drug had had no marked effect in increasing nitrogen retention. CONCLUSION
In the clinical experiment described above, no benefit was observed from the use of methyl testosterone in the treatment of premature infants. REFERENCES ]. Shelton, E. K., and Varden~ A. E.: The Use of Methyl Testosterone in the Treatment of Premature Infants, J. Clin. Endocrinol. 6: 812, 1946. 2. Shelton, E. I~., Yarden, A. E.~ arid Mark, J. S.: Experimental Use of Testosterone Compounds in Premature Infants, J. Clia. Endocrino]. 7" 709, ]947. 3. I~enyoi% A. T.~ I~nowlton~ I<., and Sandlford~ I.: The Anabolic Effects of the Androgens and Somatic Growth in IVian~ Ann. Int. Med. 20: 632, ]944.