METHYL TESTOSTERONE IN PREMATURE INFANTS

METHYL TESTOSTERONE IN PREMATURE INFANTS BY URSULA JAMES and B. L. COLES Frm the General Lying-In and Annie McCall Hspitals, Lndn (RECE:IVED FOR PUBLICATiN crber 18. 195 1) It is an established fact that teststerne cmpunds cause a reductin in urinary nitrgen excretin which affects mainly the urea fractin. The faecal nitrgen excretin remains unaltered, leading t a nitrgen retentin in the tissues. The haemglbin, plasma prtein, nn-prtein nitrgen and urea cncentratins in the bld are unchanged. The urinary sdium, chlride, ptassium and phsphrus are reduced. The net result is a gain in weight due t water retained by the eectrlytes and prtein. The gain exceeds any pssible increase accunted fr by enlargement f genital tissue and represents tru smatic grwth. After teststerne is discntinued there is a rapid lss f water, sdium and chlride frm the bdy, ptassium and phsphrus are slwly excreted, but nitrgen rmains in the tissues fr sme weeks. Similar results have been bserved in eunuchids and in nrmal cntrls f bth sexes (Kenyn, Knwltn and Sandifrd, 1944; Kenyn, Knwltn, Sandifrd, Kch and Ltwin, 194). This prperty f teststerne t prmte nitrgen retentin suggests a pssible use in the treatment f premature infants t prmte a mre rapid weight gain. Several reprts f its use in this cnnexin have been published in the American literature. Sheltn and Varden (1946) treated 15 premature infants with birth weights f less than 1,92 g. (4 lb.) with methyl teststerne (2 5 mg. 12-hurly fr three t seven weeks). Their initial weight lsses were reprted t be minimal and subsequent weight gain and vigur were initiated early. N undesirable side-effects were nted. In further papers (Sheltn, Varden and Mark, 1947; Sheltn and Mark, 1948) 74 prematures were divided int three grups. Twenty were used as cntrls, 3 received methyl teststerne, 5 mg. daily in prpylene glycl, and 24 were given 4 mg. f teststerne prpinate daily by intramuscular injectin. Treatment was started at 12 hurs and cntinued fr three weeks. The cases were further sub-divided accrding t birth weight, 1,-1,5 g. and 1,5-2, g. Of thse with the lwer birth weights the cntrls tk an average f 14-7 days t regain their birth weight, thse receiving methyl teststerne averaged nine 265 days, and thse receiving teststerne prpinate 7 5 days. Of the cases with birth weights f 1,5-2, g., the cntrls tk an average f I I 9 days t regain their birth weight, thse n methyl teststerne 7 8 days and thse n teststerne prpinate 9 8 days. The treated cases als reached the weight f 2,5 g. significantly earlier than the cntrls. Fur sets f twins were als investigated. In three sets the larger twin acted as cntrl and the smaller twin received teststerne. In all fur sets the treated twin was the first t reach bth birth weight and 2,5 g. N difference between the tw cmpunds used was nted apart frm the greater accuracy f dsage pssible with the intramuscular teststerne prpinate, and n side effects were seen. Tittle (1949) reprted 18 premature infants with birth weights ranging frm 3 lb. t 4 lb. 13 z. These were given 2 5 mg. teststerne 12-hurly frm 24 hurs until 5 lb. was reached. These cases were cmpared with infants brn during the previus year f cmparable birth weight. The treated cases shwed a 45 % decrease in the number f days taken t regain their birth weight and a 32% advantage in reaching 5 lb. Hardy and Wilkins (1949), hwever, fund that 26 infants given 2 5 mg. f methyl teststerne 12-hurly starting between the seventh and tenth day and cntinuing fr fur weeks shwed n significant advantage ver 26 cntrl cases with a similar feeding regime. Tw f these cases develped mderate enlargement f the penis and several females had transient enlargement f the clitris. Seitchik and Agerty (195) treated 27 premature infants with birth weights f 1-3 t 2-3 kg. with 2-5 mg. f methyl teststerne 12-hurly and cmpared them with 3 cntrls. The percentage f nitrgen retained was slightly higher in the treated cases, but there was n marked difference in the time taken t regain birth weight, t reach 2 5 kg., r in the percentage f birth weight attained during the perid f study in the tw grups. Reilly and Earle (1951) fund n difference between the prgress f 25 premature infants given 5 mg. methyl teststerne in prpylene glycl daily and 25 cntrl prematures. Therapy started between the furth and eighteenth days

266 ARCHIVES OF DISEASE IN CHILDHOOD (average tenth day) and was cntinued fr an daily by muth. This was cntinued until the average f 24 days. infant was diwharged, r fr 28 days in cases where prlnged hspital treatment was required. These cases were cmpared with premature infants brn in the same unit in 194849, and subject t the same feeding methds. Hspial Y (Annie McCail Maternity Hspital). Cases were divided int similar weight grups and The Present Investigtin Th present investigatin, which lasted fr ne year, was undertaken t determine (1) if methyl teststerne had any effect n the rate f weight gain in premature infants, and (2) if the effect f methyl teststerne was enhanced by simultaneus high prtein feeding. The investigatin was cnducted at tw maternity hspitals and the cases were divided as fllws: Hspital X (Genlm Lying-In Hspitl). All infants were divided int three grups accrding t birth weight. Grup (1) birth weight 4 lb. 8 z.- 5 lb. 8 z.; Grup (2) birth weight 3 lb. 8 z.-4 lb. 7 z.; Grup (3) birth weight under 3 lb. 8 z. Alternate cases were further subdivided int Grups A and B. Grup A received 'casinal', 1 g. per lb. f birth weight per day, frm the third r furth day accrding t when feeding began. Grup B received 'casinal' as in Grup A tgether with methyl teststerne (Ciba) 5 mg. 2-5 2-251 2-4-7s; I CONTROL GROUP A (-Casinal ) X GROUP B: Casslaf ) (+ Meth teststerne) O 4-Sb - 55lb X 1 L'. X i. a X.. ibṙ : - X P1 - t... X 3.- O"i a-. FIG. 1. t. further subdivided int Grups C and D. Grup C acted as cntrls. Grup D received methyl teststerne, 5 mg. by muth, daily frm the first r secnd day. The teststerne was given during the stay in hspital r fr 28 days as in Hspital X. At bth hspitals the feeding regime was the same. Breast milk was fed whenever pssible. Where this was nt pssible half cream Cw and Gate made up t 2 calries per unce was used. Seven calries per pund f birth weight were given n the first day f feeding, and this was increased in multiples f seven calries up t 5 calries per pund n the seventh day. Further increases ver 5 calries per pund were made when tlerated. Breast feeding was initiated early in sme cases, in thers varius frms f hand feeding were emplyed as indicated by the vigur f the infant. N subcutaneus fluid was given in any case. In all cases except 1 in Grups 2 and 3 feeding I was started n the first r secnd day X, f life. In the ther 1 feeding X began n the third day. Vitamins S A and D were added n the tenth day and vitamin C n the furteenth- The criteria f prgress adpted were the number f days taken t regain birth weight, and the weight gain ver and abve birth weight at the age f 1 mnth. At Hspital X the minimum number f days f treatment was six days (ne case), the maximum 28 days, and the average 15 days. At Hspital Y the minimum number f days in which teststerne was given was 1, the maximum 28 and the average 17 6. AU cases at this hspital were started n feeds n the first r secnd day f life. Results The days taken t regain birth weight in Grups 1 and 2 at bth hspitals are shwn in Tables 1 and 2. The average time taken fr treated cases t regain birth weight was slightly lnger than in the cntrls,

W METHYL TESTOSTERONE IN PREMATURE INFANTS 267 but the differences are nt cnclusive. s 2-5 x The number f Grup 2 cases seen CONTROL at Hspital Y are t small t draw GROUP A(+ Csinl) X any cnclusins and n Grup 3 2-25 GROUP B (+Casinal) cases were seen at this hspital. (+ Meth teststerne) The Grup 3 cases at Hspital X 2- were all Grup B and the results are 31bh8z--41b 7z X given in Table 3. The tw Grup A 1-75 cases bth died during the first frtnight, ne frm cngenital heart t1 5 x disease and ne frm brnchpneumnia, and they are therefre &m( X X '. t14j S!1-25 Ṡ S X excluded frm this series. @ Figs. I and 2 shw the weights f. X S cntrl and treated cases at Hspital x x X X x X pltted at varius ages. N @ 5 significnt difference between the -75 I tw is apparent. Fig. 3 shws xx- similar scatter fr bth Grup 1 and -5 6'L g 4 X O 2 cases frm Hspital Y. X 6'V Table 4 shws the gain ver birth -25 weight attained at 1 mnth f age at -OS--- a X X O Hspital X. Nt all the rginal - qf cases returned fr fllw-up at this X #X ' xe 2 I age, s that the numbers cmpared X4 I X '4J are less than thse treated in the -- :;- 6 Thspital. zi Results fr cases frm Hspital Y 8 are given in Table 5. :2 in 2 f e._ 1 2 3 4 5 6 The average weight gain in all WEEKS treated cases is slightly lwer than in FiG. 2. the cntrls in all weight grups. TAXI I Table 3 shws the gain abve birth weight f DAYS TAi TO REGAIN BartH WEGHr AT HsprrAL X Grup 3 cases at 1 mnth f age, and where pssible Grup 1 Grup 2 at 2 and 3 mnths. N marked difference between Cntrl A B Cntrl A B cntrl and treated cases is demnstrated. N. f Cases 37 2 14 1 6 7 Thrughut the investigatin a careful watch was kept fr side-effects. The nly ne nted was Minimum days t regain birth weight 8 7 8 8 1 a transient enlargement f the clitris in tw cases at Maximum days Hspital Y. N edema was seen in any case t regain birth weight 17 19 2 13 21 21 fllwing the administratin f methyl teststerne with r withut 'casinal'. Average days t regain birth weight 1 8 11-7 13 3 1-5 14-1 14-2 TABLE 2 DAYS TAKEN TO REGAIN BARTH WEIGHT AT HsTpAL Y Grup 1 Grup 2 Grup C Grup D Grup C Grup D N. f Cases 12 8 3 2 Minimum days t regain birth weight 5 5 12 Maximum days t regain birth weight 16 17 14 15 Averag days t regainbirthweight 8-8 9-1 8 15-5 Disac In agreement with ther bservers, we fund n adverse effects f the use f methyl teststerne, and the substance appears safe fr administratin t premature infants in the dsage emplyed. Since teststerne is knwn t accelerate epiphyseal unin Sheltn and Mark (1948) radigraphed the lng bnes f all infants during treatment and again at the end f ne year, but n radilgical differences were bserved between cntrl and treated cases. Kenyn, Knwltn and Sandifrd

268S TAN_ 3 WEw.HT GAJm F GtuP 3 CAS AT HspiTAL X ARCHIVES OF DISEASE IN CHILDHOOD TAULr 4 WExu-HT GAIM AT I MNTH F AGE AT HsP!TAL X Days t Regain Weight Gain Birth Birth Weight Weight I mnth 2 mnths 3 mnths lb. z lb. z lb. z. lb. z Cntrl 2 7 23 3 2 2 8 Cntrl 3 6 14 1 1 14 3 8 Treated 3 6 14 15 2 3 - Treated 3 1 2 6 Treated 2 1 25 14 1 3 4 C Grup I Grup 2 Cntrl A B Cntrl A B N. f Cases 15 15 11 9 6 7 lb. z lb. z lb. z lb. z. lb. z lb. z Maximum weight gain 2 3 1 15 1 1 1 6 1 1 1 6 Minimum weight gain 8 1 7 1 8 5 Average weight gain 1 4i 1 31 13i 1 1 1 13X (1944) state that epiphyseal clsure is nt readily grwth. N investigatins t demnstrate increased induced and that prlnged and ht eavy dsage is nitrgen retentin were made in this series, but necessary t prduce it. the dsage f methyl teststerne was the same as As n edema was seen in cases fllwing the in cases where this had been shwn (Seitchik and administratin f teststerne, it appears that the Agerty, 195) s that it was unlikely that inadequate nitrgen retentin induced by this! substance des dsage was respnsible fr ur failure t btain nt lead t water retentin in the firm f clinical weight gain.- Seitchik and Agerty, hwever, edema. If water retentin is resjx)nsible fr any questin whether adequately nurished prematures gain in weight it must be utilized fc)r true smatic respnd t the theretical grwth stimulatin f teststerne, and are supprted by Beattie (persnal cmmunicatin) -%.CONTROL C wn tuna mat aaiurs my respnea TREATED 'D (+Meth testst by weight increase and marked nitrgen retentin where previus 1V 1-3-5 lb. - 5-5 lb axx x x x x a @ FIG. 3. physilgical stresses, i.e. infectins, trauma, etc., were a prminent feature. Nrmal adult cntrls failed t shw any appreciable results when treated with teststerne. Sheltn and Varden (1946) and Tittle (1949) started teststerne during the first 24 hurs and claimed significant results, whereas Hardy and Wilkins (1949) began treatment n the seventh t tenth day and were unable t shw that it accelerated grwth. Our cases at Hspital Y started teststerne n the first r secnd day and thse at Hspital X n the third r furth day. We feel that it is unlikely that a delay f 24 t 48 hurs in starting therapy has made a significant difference t ur results. The duratin f treatment in this series was less than in ther reprted cases, but nce an infant was sufficiently established t leave hspital there seemed little pint in cntinuing teststerne, and we felt that the uncertainties f dsage inherent in dmiciliary administratin wuld

METHYL TESTOSTERONE IN PREMATURE INFANTS 269 furth day. Twenty-fur received the same dse f i casinal ' tgether with 5 mg. methyl teststerne Grup I Grup 2 daily by muth. These were cmpared with 49 cntrls frm the previus year. Twenty-five premature infants frm anther hspital were divided int tw grups, 1 receiving 5 mg. methyl teststerne frm the first r secnd day, and 15 were cntrls. AU grups were further subdivided accrding t birth weight. N significant difference in the time taken t regain birth weight r the amunt f weight gained ver birth weight at 1 mnth was nted between the treated cases and the cntrls in any weight grup. TALE 5 WEIGHT GAIN AT I MONTH OF AGE AT HsprrAL Y Cntrl Treated Cntrl Treated N. f Cases 6 6 3 2 lb. z. lb. z. lb. z OZ. Maximum weight gain.. 2 2 2 8 2 14 Minimum weight gain.. 1 14 13 6 Average weight gain I. 1 1 II 1 8 1 have made further treatment valueless frm the pint f view f a cntrlled investigatin. We were anxius t ascertain if the additin f prtein t standard feeds wuld in any way enhance the actin f teststerne and the grup f cases receiving ' casinal ' alne was included in rder t prve that high prtein feeding itself was nt respnsible fr any accelerated weight gain. Cnsideratin f the results frm the tw hspitals makes it plain that the simultaneus administratin f prtein and teststerne has n advantage. This is nt in accrdance with the wrk f Earle (1951) wh nted appreciable difference in weight gain and shrter hspital stay in 13 premature negr infants wh were given methyl teststerne, 5 mg. daily tgether with 1-15 ml. plasma rally a day, until they reached the weight f 2,722 g. These were cmpared with a cntrl series receiving similar rutine treatment and feeding. Fifty premature infants were divided int tw grups. Twenty-six received 'casinal', 1 g. per lb. birth weight daily, starting n the third r N side-effects were nticed as a result f treatment apart frm transient enlargement f the clitris in tw cases. We think it unlikely that the nrmal adequately nurished premature infant respnds t the grwth stimulus f teststerne, and in ur pinin this hrmne is f n value in the rearing f healthy premature babies. We wish t thank the resident medical fficers and the nursing staff f the hspitals cncemed fr their unfailing c-peratin thrughut the investigatin. We als wish t thank Prfessr Jhn Beattie fr his helpful criticism. REFERENCES Beattie, J. (1951). Persnal cmmunicatin. Earle, A. M. (195). J. Pediat., 36, 87. Hardy, J. and Wilrins, L. (1949). Ibid., 34. 439. Kenyn, A. T., Knwltn. K. and Sandifrd, I. (1944). Ann. intern. Med-, 23, 632. -,-,,Kch, F. C. and Lt-in, G. (194). Endinlgv, 26, 26. Reilly, W. A. and Earle, A. M. (1951). Amer. J. Dis. Child., 32, 323. Seitchik, J. N. and Agerty, H. A. (195). Pediatrics, 5, 2. Sheltn, E. K. and Mark, J. S. (1948). Calif. Med., 69, 339. and Varden, A. E. (1946). J. din. EAdcr.. 6, 812. and Mark, J. S. (1947). Ibid., 7, 78. Tittle. G. A. (1949). Tex. St. J. Med., 45, 563.