The Effects of Stilbestrol upon Lactation

THE EFFECTS OF

A. R.

ABARBANEI",

STII~BE~TROL

l:PON LACTATION*

M.D., AND M. ,J. nooD:PRIEND, M.D., F.AJ'.S., NEw YoRK, N.Y.

(From thP Department of 0/Jstetrics and (!ynec•olo(ly of the

Jlorri.~ani.n

J[ospitr!ll

HB ph,Ysiologie processes involved h1 lac·tation arc essentiall:r endoerine in nature. The development of the lobnle-ah-eolar ,-,ystem proreeds undel' the> i.nfiuenre of the oval'ian hormone'l. t The initiation of ladation depends upon the anterior lobe of the pituitar:'. for h:-rwphysertom~· during late pregnaney will prevent milk RC'rretion post partum. 2 'rhe anterior hypophysis also iR <•ssential !'or the maintemtn('(' of establiRhed lartation, for th0 removal of th(' anterior lob0 during this timf' will result in a rapid c·essation of milk seerc·tion.'l While the initiation of ]a(·tation appears to be under pur(•l:- hormonal influenrP. the maintrnam•e of established lactation requires n neurog<'nie factor in arldition to the hormonal one. This is the reflex stimulation of tlw ant(•riol' pituitar~- hy tlw act of suekling for the further serretion of milk. Clearl~-, then, tlw process of lac·tation f(\solns itself into two fmHlamf>ntal m(•ehanisms: first, the initiation of lac·tation by hormonal factors, and second, the maintenance of c·stahlished lactation h:v hoth hormonal and neurogenic agencies. The 0\'id(•1we i~ both 0xperimmtal and f'linic·al,3 The· initiation of lactation post part urn has heen explained by Nelson in the following manner :1 The presence of unusually large amounts of t'strogen during the latter part of pregnanry inhihits the secretion am1 action of the lactogenic prineiple (s) of pitnitan·. With parturition, the level of the eireulating ovarian hormoneR drops pr·N•ipitousl~·: the inhibiting infiuenres are thus r()movcd, laetogenic hormone is f-H~eretPd. and laetation oeeurs. As ex}Jerimental proof of this, Nelson offered tlw following data: Injections of large dosps of estrogen into the gnim·a pig :-lOon aft<>r parturition would hold milk se(·rt>t.ion in ahe.vance dnl'in~ the injeetion period. Lactation, however. ·would oeeur within two da.vs aft(•r eessation of treatment, or if laetogenie hormone were administc•t·r·d simultmwousl~' with the estrogen. On ihP other hand, the do:4ag1• nf t'stt'ogen conld be so inereaRed that even Iat·g-r dos(·s of the ladogulie hormone would be ineffeetual. Inhibition of lactation by large doses of various estrogens in the <·xperimental animal has been claimed by several workers. Their cvidPnf't' has been eited as confirming the estrogm1 inhibition theory. Crit i<·al analy:,;is of the results bringR to light sen~ral serious objec•tions and dis('repancies. In the first place, most of the l'eports dealing with tlw rat and the mouse showed that a good man~' of the litten; were reared. lmt wen~ stunted in growth. Young Tats and mjce otre parti.eularly sen;.;itiw to estrogens, whieh adversely affeet body growth, 4 upon whkh, in tlll'll,

T

* Pn·s••nt.,d, in part, by Dr. A. R. Abarbanel at the Section •.m Obstetrics and (Jynr;-

e0lo~Y.

N<>w York Academy of 'Medicine, February 37, 1B40.

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AMERICAK JOUR\fAI.- OF OBSTETRICS AKD GYNECOLOGY

body weight depends. Sinee estrogens are readily secreted in tlw milk, the evidence in these animals may not be accepted as conclusive proof of inhibition of lactation. Second. estrogens arc known to affect the composition of the milk, increasing the amount of fat and nonfatty solids. 6 Whether these very immature animal'! are capable of digesting an altered milk is problematical. Moreover, the mothers were found to have lost considerable weight, indicating an additional systemic response in the maternal organism that was detrimental to her well being. 7 On the other hand, large amounts of estrogen injected over a period of six days were found to be without effect upon the amount or duration of secretion in the lactating rabbiU Others have reported a reduction, but not suppression, of lactation with large doses of estrogen in the rat/• 9 • 10 goat, 11 and cow. 6 • 12 The hypothesis advanced by Nelson also fails to explain the wellknown fact that lactation may continue through successive pregnancies in several species including the rat, rabbit, goat, and the human being. In man especially, increasingly larger amounts of estrogen are produced during pregnancy. In the cow and the rabbit, lactation occurs some twenty and six days, respectively, before parturition. All in all, the experimental evidence for the inhibition and suppression of lactation by estrogens is far from decisive. The evidence has recently been critically reviewed by Turner. 3 In spite of the rather inconclusive experimental data, many clinical reports have appeared, claiming hormonal inhibition and suppression of lactation in the human being. The estrogens (estradiol benzoate, estrone, and lately stilbestrol) have been used in varying dosage. Sawizki,~s using 200 to 800 I.U. of estrone plus 100 R.U. of chorionic gonado· tropin, reported successful inhibition of lactation in the human being. Others, finding this dosage far too small, have recommended 30,000 to 50,000 I.B.U. (international benzoate units) of estradiol benzoate as a daily or total dosage over a period of one to :five days.H-17 In a detailed study of the question of dosage, Mayor1s found that not only was 1,000 I.U. of estrone (0.1 mg.) irumfficient, but even 10,000 I.B.U. of estradiol benzoate (1 mg.) administered daily for six to eight days was not enough. Using 250,000 I.B.U. of estradiol benzoate (25 mg.) in oil as a single injection on the first day post partum, he found that of 14 patients so treated, 4 (29 per cent) had no filling, 8 (57 per cent) filled without pain between the fifth and seventh days, while 2 (14 per cent) became fully engorged on the eighth and twelfth days post partum, respectively. Lehman,19 using a single injection of 100,000 to 150,000 I.B.U. of estradiol benzoate (10 to 15 mg.) the first day postpartum, reported that in a serios of 75 cases, 32 per cent had no engorgement, 59 per cent had some secretion or painless filling, while 9 per cent became engorged. For the suppression of established lactation, he found that a single dose of 20 mg. of estradiol benzoate (200,000 I.B.U.) was necessary to yield results in 88 per cent of his series.

'l'he dosage recommended for stilbestrol, the orally active and highly potent synthetic estrogen,* has also been quite variable, ranging from 6 to 80 mg. 20-22 Careful analysis of the clinical reports reveals certain inadequacies as a result of which the claims for hormonal inhibition and suppression *One milligram of stilbestrol is approximately equivalent to 2.5 mg. of estrone or 25,000 I.U. One milligram of estradiol benzoate equals 10,000 I.B.U.

ABARBAKEL AND GOODFRIEND: EFJ<'ECT OF STILBES'I'ROL ON LACTATION

10BH

of lactation in the human being may not be properly evaluated. In the first place, the baby was removed from the breast simultaneously ·with the administration of the hormone. It is a well-known fact, however, hacked up by abundant experimental and clinical evidence, that the maintenance of lactation is dependent upon the nervous stimulus of :·melding, or its equivalent. Furthermore, practically no differentiation seems to have been made between the onset of lactation and painful engorgement of the breasts. The,;e are two distinct phenomena that are not synonymous at all. Painful engorgement is caused by lymphatic and vascular stasis, not hy distentio~ of the ducts by milk. 23 Berause of the inconclusive experimental and clinical data, the following studies were carried out in order to clarify the effects of estrogens upon lactation in the human being. The estrogen chosen was stilbestrol since it retains most of its potency on oral administration while the latter route requires a minimum of nursing care. PROCEDURES AND RF:SUUrS

Three hundred and fifteen parturient women were studied. These were divided into several groups. A control group was chosen of 50 apparently healthy mothers who had had normal spontaneous deliveries of normal active babies. Each gave a history of having adequately nursed their previous babies for at least three months. The daily amount of mother's milk was computed from weighing the baby before and after each feeding. The babies were allowed to nurse for twenty minutes five times a day, at four-hour intervals. As the babies did not go to breast at 2 A.M., each received a dilute formula of three onnres at this time. In this manner, the average normal amount of breast milk obtained by the baby in five daily feedings was found to total from 8 to 14 ounees daily. A daily individual variation was found in practically evet')' patient, ranging from one to as much as six ounces. Interesting, too, is the almost universal drop in the amount of milk obtained on the seventh, ~eighth, or ninth post-partum day (Fig. 1). At first it was felt that this was due to the fact that the male babies were circumcised on the seventh or eighth day. But as it occurred with female babies, too, the only common denominator that could be discovered was that the mothers w<>re allowed to be up for the first time on either one of these days. It was found that approximately one-third of the babies were above birth weight, one-third somewhat below birth weight, while the remain-· ing one-third had just about regained their original hirth weight by tlw tenth post-partum day. Four ~~:roups of patients were ,rhosen to amlwer the following questions: 1. Will the eAtrogen, Ati!be~trol, inhibit the onsel of la.etation in the nursing human being"l ~. Will stilbestrol suppress established lactation in the nur~ing human Leing? :1. How useful is stilbestrol in preventing or relieving painful engorgement nr the breast in the non-nursing mothed -L Will stilbestrol prevent painful engorg·ement in the nursing pr·imiprnous mother~

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A11ERICAX JOURNAL OF OBSTETRICS AND GYNECOLOGY

1. In onlet to obsen·e the pfft'rt of a group of 2G mothers awl lJahies wet'<'

upon the initiation of ladation, in th<• same manner a~ the <·•mtrol~.

~tilhe~trol

(']Jo~Pn

Beginning soon after parturition, varying doHage,_ of stilh;;strol, ranging from ;)0 to ] ,000 mg., WE'J'E' are allowed tu nur~(' aH usual. Brit>fi_v sunmuu·ir,etl, it >YaK fountl that tlw onset of laetation on tlie tli ird or fourth day po~t partn:n wa~ nnt

It was nott•tl, ltowt•ver, ~'"peeially wlwn tlw 1laily awragP normal rang-P of 8 to 1+ onU<·e, tlnily until two to six da.vH after thP :;tillwstrol hail bt><'JJ Htopperl (Fig. 1). Even with 1,000 mg. ( 1 Gm.), the see ret ion of milk wac; not l'omplPtPly inhihitcll. ln the latter patient, lactation ditl not hecome fully E·stahlish\'<1 until ~ix •lays after the last rlose of stilbestrol, that i~. on the RixtePntil •lay po~t partum. inhibit~11.

I --· l

------

STILilOIIS'l'liOL !0 'l'IST .:>'rBIDI

J!. 0

_E

u

....!Q_

B

_8

•c s

___§_ _4

_2

10

Fig. 1.-The curve of the amount of milk secretion in the control nursing mother compared with that obtained when 500 mg. of stilbestrol was administered orally over the course of four days, beginning soon after parturition. Although the normal onset of lactation was not inhibited, the appearance of the normal average amount of milk secretion was definitely delayed until five days after the last dose of stilbestrol.

From these data, then, it may be said tlu•t the est-rogen, sti.lbestrol, U'ill not inhibit the onset of laotat-ion ·in the nursing human being. It will, howe~cr, delay the apzu;amnre of the normal at:emge a.mo'unt of m-ilk Sf'Cretion. Lactation will bf adequately established soon after stilbestrol is discontin-ued, provided the: baby conti·nut·s to nurse. 2. The effeet of stilbestrol upon est.abli~lwd lactation in the nursing hun1an being was studied next. Twenty-five mothers were chosen in the same manner as the eontrol group of 50. The habies were allowed to nurse as usual. The te~t group receive•! varying dosages of stilbeRtrol ranging from 50 to 500 mg. ovrr a period of two to four t.lays after laetation hacl heen !Hlequately established for twenty-four to seventy-two hours. A minimum of St>VPll awl one-half ounces of mother 'A milk by the fourth clay was accepted as normal. In brief, the results obtained demonstrated no apparent suppression of lactation as judgeJ by the bahy 's daily weight

.\BARBA::\EL AND GOODFRIEXD: EFFECT OF f'TILDERTROL ON l .ACTATIOX

1041

a~ WPll ag th<• mnount. of milk secretion daily Cl'~ig. 2). Carpful fWr was then df'tf'rmined.. On,. hun,Jret! Hml ~ixty-five patient~ fnrmnt wPn' iii) easp,; in the gronp wlwrp the imlieation for not nursing was prest>nt at th;: tim<" of •lPlivery. A ~imila t group of 65 patients who were not treatP< foun<· rlPgrPe of painful engorgement was Yery mild, if il Ol'I'Urt't>t1 at all, awl 1l1r amount of lal'tation, if any, I[Uite slight and tmn~itory.)

_M_ 0 11'

•

~

c

~

li!

.-!.

s

__.!_ 4 2 DAWl

AJI>UIIT OF

II)1'H2R 'S

J1II.K

10

Fig, 2.-Failure of 50() mg. of

to affect established laetation in the nur:;:inghuman being.

stilbe~trol

After preliminary triaiR with varying dosages ranging from ]0 to 100 mg. OYer two to ten days, it was found that the most consistent results were obtained with the following schedule. Five milligrams of Rtilbestrol wrre givf'n twice the •lay of deliwry and then onre a day for three or four days. In multiparas, who gave a history of having lactated well before, the same tlo8age >va.s continued for five or !-'ix days. The total dosage, therefore, rangere administered freely; in some, they were actually for,·e<.l. A loose, not tight, uplift hinder was used whPre indieatea. Results were tabulated as excellent if no engorgmnent occ.urret1, either <'arly or late. The result was classified as good if somf' mild transitory heavines~ or slight filling up of the breasts oceurred which could be readily reli;ved merely hy using an adequate loo:;re uplift breast him1er. The outeome was terme'ult could be termed exeellent even though in 14 >
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AMERICAN JOUR~AL OF OBSTETRICS AKD GYNECOLOGY

pressed for several days. In 31 cases, or 47.7 per c,ent, the result was termed good. Of these 31 patients mild, transitory heaviness of the breasts was noted on the second to fourth day in 9 cases. In the other 22 patients, some slight fullness or heaviness of the breasts, associate(1 with a transitory waterv-chalky secretion in most of them, was noted anywhere from the fifth to the fo;uteenth day post partum. The only complaint, if any, wa~ a mild tran~ient heaviness or achiness which was adequately relieved with a prop('!' loose uplift breast binder. In 9 patients, or 13.8 per cent, the results were classifieu as poor. Analysis of these cases reveals that in 2 of them the pain oeeurred only in the axillary breast tissut>. In another the breasts filled up spontaneously and became painfully engorged on the eighth post-partum day. This patient admitted stripping her nipples becausP of a slight watery sec.retion. In 3 others, it was observed that the 1Jreast binder had been made so tight that when filling oecnrred, it went on to painful engorgement of the breasts associated with lumpiness at the region where the binder had cut across the breast. Simple adjustment of the billller frequently gave markerl relief. It is interesting to observe that one of these patients expressed a desire to nurse her baby on the eighth post-partum day. Her breasts, which had remained soft and asymptomatic, were pumped four times and a total of 2 ounces were secured in twenty-four hours. In seventy-two hours, however, her baby was receiving 12 ounces daily from the breast. On the basis of this case, a small series of patients have been treated in the following manner: If, at delivery, an indkation is present for the mother not to nurse for the first few days post partum, such as an upper respiratory infection, the mother receives 15 mg. of stilbestrol daily for three to six days. The baby is permitted to suckle when the mother is again well. Lactation soon becomes adequate. In the control gmup of 65 patients who did not reeeive hormonal therapy, severe painful engorgement of the breasts occurred in 31, or 47.7 per cent. Mild engorge· ment, enough to make the patient complain of fullness or heaviness with occasional secretion of milk, was noted in 29 cases, or 44.6 per c.ent. Here again a loo.~e uplift breast binder was usually sufficient to give adequate relief. In 5 cases, or 7.7 per cent, the patient remained symptomless. Analysis of these data reveals that about 50 per cent of the eontrol group complained of painfully engorged breasts. With stilbestrol therapy, only 13.8 per cent, or 1 in 7, suffered. In short, the use of stilbestrol had prevented painful engorgement in more than 70 per cent of the patients that would have suffered from it. There were 35 patients in whom established lactation had to be interrupted for various indications. Stilbestrol was only a\lministered to those patients who had been lactating well up to the time interruption was deemed necessary. If a patient, for example, had fissured nipples because the baby had been suckling mightily on a poorly lactating breast, she was not given hormonal therapy unless actual painful engorgement occurred. Fluids were administered freely; in fact, in many cases they were actually foreed. Each received a loose uplift breast binder. Since most of these patients would have been relieved in two or three days on symptomatic therapy, our criterion of a successful result necessarily had to be a strict one. Accordingly, only if praetically complete relief was secured within twenty-four hours, was the therapeutic result deemed successful. The following schedule of dosage was evolved after several preliminary trials. On instituting therapy, 25 mg. of stilbestrol were given at once. The next day two doses of 5 mg. each were followed by 5 rug. daily for three days. 'rotal dosage, therefore, was 50 mg. Of this group of 35, the results in 30, or 85.7 per cent, were considered as successful. Of the 5 failures, 2 can be ascribed to inadequate dosage. Although the breasts continued to feel lumpy for one or two more days, no pain was noted. In many, secretion was still present anywhere from two days to three weeks later. rn 6, a late secondary, slight, painless filling of the breasts, transitory in character, was recorded. ConseqtWJnUy, when aU these results are carefully reviewed, it ·i.s fo-wnd toot stil· bestrol ~' Vndeea, a r·ather useful therapeutio agent both in preventing and reliem.ng painful engorgement of the breasts in the non·nursing mother.

ABARBANEL AND GOODPRIEND: EE'FECT OF S'l'ILBEt'lTROL ON LACTATION

104B

4. '!'he usefulness of stilbestrol in preventing pain;ful engorgement in the nur:;ing primiparous mother was then determined, since painful engorgement of the breasts is especially common in this group. Accordingly, 50 primiparas were divir rent, who~e breasts filled painlessly. The onset of normal laetation wa~ not affe('terl at all. Fmm these results it is readi-ly seen tha,t sHlbe8trol is t'ery etfecti1;e in preve~,fin,{! painful en[!orgemen.t of the breaHts ,in the musinp prim.iparou.~ mother, wh.iJe not intN[Prin.rt noticeably u·ith lactation. DISCUSSIO!'

Adequate comprehension of the fundamental endocrine physiology of the secretion of milk by the mammary gland necessitates a clear differentiation of the phenomena of the initiation of lactation, the maintenance of established lactation, and the dinical syndrome of painful engorgement of the breasts. Only when this is done may the many Heemingly contradictory reports, experimental and clinical, be interpreted correctly. The initiation of lactation appears to be, basically, hormonal in nature, involving formative stimuli from the ovarian hormones and functional stimuli by lactogenic principles of the anterior lobe of the pituitary. The role played by other endocrine glands, especiall;.' the thyroid and adrenal, appears to be secondary, involving water balance as well as nutritional and metabolic factors. It is conceivable, then, that the onset of lactation in the human being might be inhibited by preventing the r·hange in hormonal balance that occurs with parturition. The only substance which yielded any suggestive results was the estrogen stilbestrol. Although the actual onset of lactation at the usual time was not inhibited by stilbestrol, the appearance of the average normal amount of milk secretion was materially delayed when large doses were given soon after delivery (Fig. 1). Reece and Turner reported similar results with estrogens in the rat. 10 That the onset of lactation might have been completely inhibited if a still larger dosage of stilbestrol had been administered soon after parturition must be considered. On the other hand, similar experiments using 250 mg. of testosterone propionate, 500 mg. of methyl testosterone, 100 mg. of progesterone, and 500 mg. of pregneninolone failed to demonstrate any delay in the appearance of the onset of the average normal amount of milk secretion in the nursing human heing. 24 Most reports have postulated that estrogens inhibit the production of the lactogenic principle(s) of the anterior pituitary and thus inhibit lactation. Turner, 3 however, feels that inhibition of lactation, when it occurs, involves either a direct action upon the epithelium of thP mammary gland, or possibly an inhibition of the release of lactogenie hormone from the pituitary, for hi"' group found that treatment with estrogens would markedly raise the lactogenic content of the rat's

1044

AM:ERICAX JOPRNAL o:f' OBSTETRIC;;; AND GY:-.!ECOLOOY

pituitary. 2 " The former premise seems to be the correc-t one, for Reece,Z'' using colchicine, has shown that inje<'tions of estrogen in the rat would bring about an extensive proliferation of the glandular cells of the breasts, as shown by the increased mitotic count. Since a cell that is proliferating cannot very well seeretr at the same time, it is assumed that the action of estrogens is a direct one upon the glandular epithelium. Folley and Kon 7 had a similar idea, when they stated that the ability of a substance to inhibit laetation sef'med to parallel the proliferating effect of that substance upon the mammarr glands. The hypothesis outlined above seems to explain the effect of large doses o:f stilbestrol upon the onset of lactation in the nursing human being. The proliferating effect of stilbestrol upon the mammary gland is the same as that of ('strone. 2 ' The apparent cause for the redueed amount of milk secretion during administration of this estrogen becomes discernible (Fig. 1). Since estrogens raise the lactogenic content of the pituitary, whose release seems to be stimulated by the act of suckling/ 8 it now becomes clear why, soon after the administration of estrogen is stopped, the amount of milk secretion rapidly becomes normal in the nursing human being." The maintenance of laetation involves both hormonal and neurogenic factors. It is a well-known elinical and experimental fact that the secretion of milk will soon cease if suckling, or its equivalent, is stopped. Once lactation is adequately established, relatively massive doses of stilbestrol proved quite ineffectual in suppressing milk secretion in the nursing human being (Fig. 2). Similar negative results have been obtained with 500 mg. of testosterone propionate, 550 mg. of methyl testosterone, 100 mg. of progesterone and 500 mg. of pregneninolone. 24 The exact mechanism by which the nervous stimulation of nursing maintains lactation is still not clear on the basis of our present knowledge.3 Suckling appears to be a powerful reflex stimulus for the release of lactogenic hormone from the pituitary, thus maintaining lactation. 2 ~ The centrifugal arm of this reflex directly involves the nerves leading to the spinal cord, for denervation of all the exposed breasts by a spinal cord lesion leads to rapid cessation of milk secretion even if the young continue to nurse. 29 The centripetal arm of this reflex is hormonal, for denervated or transplanted mammary glands ·will continued to lactate provided a normal breast of that animal is stimulated to secrete by suckling. 30 'l'he act of nursing, then, seems to be a much more powerful stimulus for the secretion of milk by the glandular epithelium of the breast than 500 mg. of stilbestrol is a stimulus for proliferation of this same epithelium. This explains why established lactation may be maintained in several species, incluillng man, through successive pregnancies. *Recently, Folley, ·watson and Bottomley (J. Physiol. 98: 15, 1940) reported that they were able to stimulate the appearance of lactation in 2 virgin goats by combining local application of stilbestrol with mechanical massage of the mammary gland. Somewhat similar observations were noted in these studies in a patient whose breasts had never tilled, much less lactated, after four previous full-term pregnancies. She received 50 mg. of stilbestrol during the first two post-partum days. The baby was put to breast. On the fourth day, her breasts became engorged for the :first time in her life. Milk secretion soon a.ppeared, but proved to be inadequate, totalling 2 to 3 ounces daily. This evidence, however, is only suggestive, being far from conclusive.

ABARBANEIJ AND f',.OODFRIEKD: EFFECT OF STILBESTROL 0::\ f,ACTATIO::\

10-ff)

Painful engorgement of the breast is caused by lymphatic and venous stasis, not by distention of the ducts with milk. 23 Unfortunately, moRt of the clinical reports on the effect of estrogens upon lactation in the human being have confused painful engorgement with the onset of lactation, using these terms intcrC'hangeabl:v. These are two distin<•t and separate phenomena. By what means painful engorgement is prPnmted or relieved by the various sexual hormones cannot be explained on our present-day knowledge. That it is not by inhibition of lactation is obvious from the fact that lactation may proceed normally as in the nursing primiparous mothers treated with stilbestrol. ~\ similar finding has been reported with testosterone propionate. 31 The delayed filling of the breasts and seeretion therefrom that was noted in some of the ~non-nursing group ma~· be explained in the follow~ ing manner : The administration of estrogen brought about an increased laetogcn content of the pituitary. ;\fter the Htilbestrol was stopped, th<> lactogf'nic hormone was now frre to art upon a hrNtst alrt>ad~, suitahl~· prf'pared by the previous pregnaner. An illustrative case is that of the mother who received f.ltilbestrol after the hahy was removed from the breast because of fissured nipples. Six days later her breasts began to fill up again. A second course of stilbestrol was given. Seven days later h<'r breasts again filh•d up and ran over with milklike secretion. The results obtained with stilbestrol oralJ~· in preventing painful engorgement of the breasts in the nonnursing mother are quite similar to thosP reported with 10 to 25 mg. of estradiol bE'nzoate given intramuscularly in oi1. 18 • 19 With stilbestrol, the result was termed excellent in :38.G per cent as compared to 29 per cent'R and 32 per cenflH when estradiol henzoate was used. With the latter estrogen failures oeeur1wl in 14 per centl 8 and 9 per cent/ 9 while with stilbestrol 13.8 per c•t>nt failed to respond. The advantages, then, lie with stilbestrol for two reasons: First, it is active orally, requiring a minimum of nursing e::n·e. Reeond, the cost of stilbestrol is extremely little <'Ompared to that of the natural estrogen. The only disadvantage of the estrogens, it sec•ms, is the late secondary filling that so frequently occurs. This may be obviated to a great extent by using an adequate nplift breast hiuder that is loose, not tight. A second course .of stilbt>strol is rarel?, if ('\'<'1', neN•ssary. COMMENT

Stilbestrol has been reported to have so-called "toxic" effects in the nonpregnant individuaJ.3 2 Two puerperal patients were given 1500 mg. (1.5 Om.) during the course of ten and twelve days, respectiYely. Complete blood chemistries, urine examinations, blood counts, et<'., before. during, and after the administration of this enormous dose failed to reYeal any ''toxic" effects. One patient felt slightly dizzy for ahout thirty minutes after a dose of 50 mg. Pre-eclamptic and eclamptie patients with uric acid values between 7 and 9 were given as mueh as 150 mg. of stilbestrol in the space of twenty-four hours for inducing labor with no untoward effects. Presumably the pregnant and puerperal patient can metabolize stilbestrol more efficiently than the nonpregnant one.

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AMERICAN JOl:R~AL OF OBSTETRICS AXD GYJ'\l<~COLOG\' SL':MMARY

The synthetic estrogen, stilbestrol, when administered orally soon after parturition in dosages up to 1,000 mg. did not inhibit the actual onset of lactation in the nursing human being. The appearance of the average normal amount of milk secretion, however, was delayed until as many as five or six days after the last dose of stilbestrol. No effect at all was noted upon established lactation in the nursing human being with 50 to 500 mg. of stilbestrol administered orally in divided doses over a period of one to four days. In the prevention of painful engorgement of the breast in 65 nonnursing full-term mothers, 25 to 40 mg. of stilbestrol orally in divided doses failed to yield a satisfactory result in but 9, or 13.8 per cent. On the other hand, in a control group of 65 similar cases, 31, or 47.7 per cent, suffered from painful engorgement of the breasts. In 35 cases where adequate established lactation had to be interrupted, 50 mg. of stilbestrol orally in divided doses provided satisfactory relief for painful engorgement within twenty-four hours in 30, or 85.7 per cent. Of 25 primiparous nursing mothers given 5 mg. of stilbestrol daily for the first three post-partum days, practically painless and asymptomatic filling of the breasts occurred in 21, or 84 per cent. In the control group, however, only 5, or 20 per cent, had painless filling of the breasts. The pregnant and puerperal patieut was found to be unusually tolerant of huge doses of stilbestrol. The authors gratefully acknowledge the sincere interest of Dr. Harry Aranow during the course of these studies. In addition, the splendid cooperation of the Misses Andes, White, and :VIills of the nursing staff of the Obstetrical Division was deeply appreciated. The stilbestrol used in this study was kindly supplied by Dr. J. A. 1\1orrel! of E. R. Squibb & Sons.

REFERENCES

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