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Low-dosage irradiation to the pituitary gland and ovaries in amenorrhea and dysfunctional uterine bleeding
971
REIDENBERG : IRRADIATION IN AMENORRHEA
The incidence of toxemia was not lowered in the patients who restricted both salt and fluids. This is partially at,tributable to a concentration of unfavorable cases in this group. The incidence of toxemia was considerably lowered in the patients who restricted salt and forced fluids. The effectiveness of prophylaxis against toxemia increased as greater weight losses were induced by the dietary regimes. Paradoxically, the gain or loss in extracellular water seemed to bear no relation to the incidence of toxemia: our data are inconclusive on this point. We wish to acknowledge our indebtedness and E. G. Waters for reading the typescript. by Lorene Dickerson, chief dietitian at the The urinary creatinine determinations were Marotta.
to Drs. S. A. Cosgrove, J. F. Norton, The 2 gram salt diet was devised Margaret Hague Maternity Hospital. done by Frances Orsato and Peter
References 1. Arnold, 2. 3. 4. 5. 6. 7. 8. 9. 10.
J. O., and Fay, T.: Surg., Gynec. & Obst. 55: 129,1932. de Alvarez, R. R.: AM. J. OBST. 8; GYNEC. 39: 476, 1940. Chesley, L. C., and Chesley, E. R.: Ibid. 42: 976, 1941. Idem: Ibid. In press. Chesley, L. C.: In press. Quantitative Clinical Chemistry, Peters, J. P., and Van Slyke, D. D.: Methods, Baltimore, 1932, Williams and Wilkins, pp. 602 and 834. Darrow, D. C., and Yannet, H.: J. Clin. Investigation 15: 419, 1936. Harding, V, J., and Van Wyck, H. B.: AK J. OBST. & GYNEC. 24: Strauss, M. B.: Ibid. 38: 199, 1939. McPhail, F. L.: West. J. Surg. 47: 306, 1939.
Vol.
II,
820, 1932.
LOW-DOSAGE IRRADIATION TO THE PITUITARY GLAND AND OVARIES IN AMENORRHEA AND DYSFUNCTIONAL UTERINE BLEEDING” A Long-Term (From
LEON REIDENBERG, the Graduate Hospital
Survey
M.D., PHILADELPHIA, of
the
Uniaersity
of
PA. Pennsylvania)
YSFUNCTIONAL menstrual disorders, with or without associated sterility, are the most difhcult problems encountered by the gynecologist. The patients stop at nothing in their search for a cure. In most instances of dysfunctional menstrual disorders, especially amenorrhea of long duration, endocrine and other forms of therapy fail to produce consistent results. Clinicians have long sought an agent capable of normalizing the menses and of relieving sterility of dysfunctional origin. It seems probable that this long-sought remedial agent has at last been discovered in the form of low-dosage irradiation.
D
*Thesis submitted to the Faculty of the Graduate School of Medicine of the University of Pennsylvania, in partial fulfillment of the requirements for the degree of Master of Science in Medicine. NOTE: The cases herein reported were selected from the private practice of Dr. Charles Maser.
Originally, only the dcstructioe cffwls of ilTi~cli;ltion wcu2 wnsitlt~wtl of t,herapeutic value in the control of d~-si’ut~c~t iollal tlt.ednc l)le~~ling~ incvitahly reslllting ill temporary or lwniiul(~nf srqJ~Jressiorl oi' tlw menstrual function and in steril it,?-. 7%~ 11s~0f notitlcsl,i~nclivc~ &~c’s of rocntgcn rays for thv pi~rposc of rvlicving i~mCllorrh<~:l. tllv ealirlival nntilhcsis of menornrt~~oi~1~1~;1~i~~, was first 1 ricvl c11JriJry 1 II(~ SCYY~II~~ II(v* ade of this c~entnq-.
Historical
Sketch
Ad hricf history of tlic deoclopmcnl of low-tlosagc irradiation as a therapeutic agent is wal~:~nt,ed. Tn 19 10 an11 1911 C%won' ant1 associat.es warned that x-ray es~~osm~s und(~t* 110 1WJ' writ skin cryt~hcma dose stimulate the growth of carcinoma of ihc rttcrrw and incwasc the incidence of metastasis. Their dcdllctions ~ww lat cr I)rovcd to 1)~ errcnlc~ns. HOWCWX, these reports init.iatc(l an PIX of c~sl)c‘rimcnt,a.tioll on the stimulating effects of irradiation on ~~lants ant1 lowr animals. Ht:WPF induced sexual maturity in infnntiln rats with mild irradiation IJ~ I hc ovaries. This was probably tluc to irradiation of the anterior pit.uitary gland which, in small animals, is nnintcntionally bnt, simnltaneonsly c’sposed. Steinach and Kun” indrlccd hyqwrl nt(~mixatiorl o-f the cLlirIC:J pig’s ovaries h,v s-ray treatmrnt. Iki 11salttl FOIY~~obscrvcd only slipht congestion 01 the ovaries of rals t.hat w’w killed shortly after tlw administration of a 10 per writ ~U~XICOILSvrvthcma dose for the ral. The follicular apparatus was nppare~ltly JJot ‘inflnctwcd by the pl’occd.ure. Parke? observed ingrowth of epithelioid bawds of: cells from the pcriphcrg into the stroma of mouse ovaries that wl;fw: intensively j wadi-. al cd; 1he cords eshibitcd a tcndcncb. 1award follicnlar arranwncnt. Epifanio and Cola’ obscrvcd a rnI)id illcw;lsv ill ~J'OWth of yolln~ r;ihl~ils nft,cr low-dosage irradiat,ion of the pifltita~y gland which at ir\Itops!. showed no widencc of cytologic a11 (al*;li-iorl. Clinically, Van dc Vclde’ rcporlr(1 iu lnls the return of ?lol’Jrra~ ovarian fnnction aftrr small doses 01’ x-rays hat1 been applitvl owr tllc 1,~. Hirwh." ovaries. Soon t hcrcaftcr similar I~cwllls \vvrc wportctl Rubin,” Rouyy-,“’ Kaplan," ilHd I )rAiljs iltltl FOJYI.” R;IglIPr ;lllCl S~‘ElO(‘llhof’” ha.vc found no dcgfwcratiyc rhan~:trs in the ovarjcs OUwcnno~~sill)jccted t-o low-dosage irradiat,ion prior to IJwnl-1?-st,erectomy and bilatrl*al salpingo-oophorcctom\, for carcinoma of the 111 crlls. (IJlly OJIC (I[ t;hC ovaries 01’ cacxh paticni was irradiatccl : tlw cwrresponding OKWJ ww prot.ected from the rays by means of propel. sc*rccning for I hc p\U’poSC of histologic comparison. &fore uxeritly, a. 1lnJlLh of iJlvcSti~iltorS dso report,ed 011 ill(! 1 hvmpeatic ralue of low-dosapc irradiat ioll o/' t Ii0 [)itUitilr), gland alit1 o\-arirs in instances of amcnorrhw with 01’ without ;~sso~inlcd sterility i Tahlc 1). A composite rcvicw of thvsc rclwits iJidicxlcs :I restoration 0C menstrual periodicity in 440 of 755 patients thaw trwt t:d with no iJltcrferenc~~ in the fertility in thosct who dcsircd ofislkri 11%. Nevert.heless, most, clinicians ~vgarc 1 it as ii dangerous agent ailtl are loath to employ it for fc:i~ ol' irw~Jar;rhlc tlamag?:c,t,o t,he ovaries. This attitude toward low~-dosa~~~ irratliation is mostly l~sccl upon animal txpcrimeiitation wit Ii tlwt rnvt ivc dosw. The numerolw (*Iin iwl wtwrl s OII to\v-tlosape irradiation 10 the pituitwy gland and ovaries cowr onI>R short period of follow-up, one
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to three years. It is, therefore, of interest to learn what has happened to a representative group of these women and their offspring during a much longer follow-up period. A careful follow-up of 136 women who received low-dosage irradiation to the pituitary gland and ovaries from three to thirteen years ago forms the basis of this presentation. The results indicate that low-dosage irradiation, within the dosage limits employed in these cases, is a most helpful and safe agent in the armaMoreover, the follow-up shows no mentarium of the gynecologist. TABLE
I.
STATISTICS
Note
ON RQENTGEN
:
Improved
cases
TREATMENT
RAY
grouped
OF AL[EP;OILRHEA
as failures
= I
REPORTED BY
)IJRATION OF AMENORRHIU
NO.
GLAND IRRADIATED
AGE OF PATIENTS
NO. OF PATIENTS
-
Thalerl4
i
OF
CURESFOR ONE OR nfoim YEARS
H;;;;;Iy OFFSPRING
(65%)
NO.OF ABORTIONS
2
-
31 (50%)
11
-
25
15 (60%)
-
-
56
40 (72%)
11
1
12
11 (93%)
8
1
13
5 (37%)
-
-
73
23 (31%)
20
6
58
38 (66%)
20
5
74
41 (55%)
26
2
106
62 (59%)
62
40
62
.-
Werner17 Steinhardtls
.tI
mo. yr. 1 mo. to 19 to 45 14 yr. yr.
.-
EaplanlQ ._
-
Drip@
.
.
Tami@
3 to mo. .
.
36
-
RubinQ
19 to Yr. .-
2 to mo.
Rmongyl” . .
Mazer and Goldstein23 Mazer and Spitz24 Mazer and Baerzs
33 -
3
I I
-
Porchownick22
16 to vr.
39
I” -120 mo.
to
35
Y’.
.-
-:
.-
King26
1 to Yr.
6
18 to yr.
36
1 to Y’.
13
18 to Yr.
36
Iito3 vr.
Bogart27 -
Pituitary and ovaries Pituit,ary and ovaries Pituitary and ovaries Pituitary and ovaries Pituitary and I ovaries IPituitary and ovaries Pituitary and ovaries Pituitary and ovaries Pituitary
I I
-
EdeikenlQ
29 single and 33 married women 17 to 36 y”.
Pituitary and ovaries Pituitary and ovaries
I
-
I
Pituitary and ovaries
1- I
____~
10
-3716
10 (100%)
(68%)
20
2-
/_I_
4
0
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OI3S’lWTRICS
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deleterious effect upon the offspring of 54 wor11e11 who have given birth to X0 children. Illu&rative of the harmlessness to 111~ pat icnt and to the puyqny of the first. generation, t’ven of thrcr (~)ursf’s of low-dosage irradiation to the pituitary gland and ovaries, is the following cast record : Mrs. hf. S., aged 24 years, sought~ treatment in DecemheTl 1933, for 1.11~relief of amenorrhea of eight. years’ duration and inablllty to conceivc for two years. Episodes of mcnomdrorrhagia were frequent, from the age of t-wclvc to sixken. Thercnftcr amenorrhea (three cycles per year) ensued for eight >-cars. In the k-0 pears prior to low-dosage irradiation l.reatment, conception did Ilot o(acur. In December, 1933, physical and general lahoratorv csnmination revealed nothing abnormal. liow-dosage irradiation, qivcn ’ in Ikccmbcr, 1933, prompt,lv normalized her menstrual cycles. khc conccivctf in ,Jul>-, 1934, and delivered a normal full-term infant. She mcnstrnatcd regularly until 1937 when the tendency to nmcnorrhca returnctl. Tn November, 1937, ;I second course of s-rays was given nftcr a periocl of amcnorrhca of eight months’ duration. Partial improrcment, was al,tainetl and a Ihird course in March, 1938, regulated her menses to th(> dil.t(l oi‘ this folio-v\-np (May, 3942). During the intrrim she dclivc~rod two ll~~illtll~~ infants. This case record illuskates hot11 t 11tksitt’t’l>- of cve11 t.llmtc (Y)IIIWS pi low-dosage irradiation 1o t hc ovnrics o I’ I hc ~~i~t,iel~t, ant1 the harn~lessncss of the treatment.s upon 1he rhildr(~n 0C the first generation. The hypothetical ol)jection to Ion-dosage irradiation on the basis of it,s possible harmful cffcc4s npon f Ilc swoutl nuil third gcwetdions cannot be rclevant,ly aryictl since 1 his lY~i~l~tliil1il
Modus Operandi of Low-Dosage
Irradiation
Although twenty-seven gears have elapsed since Van de Velde’ suggested low-dosagc irradiation as a therapeutic agent, its modus operandi is still undetermined. Most radiologists maint,ain t.hat roentgen. rays rapidly product: hypcremia, and that. they arc always destructirc. For example, Thalcr,l” Ikqjardins’” and others believe that the beneficial cffccts of low-dosage irradiation in t,lrc treatment. of amenorrhea and dysfunctional iltcrinc blceding result from the destruction of a persistent corpus lutcum 013of an abnormally large Graafian follicle. ‘l’hq do not explain the pticnomenal CSCil[)t' from damage of the remaining essential and more vuhlcrablc elements of the ovaries. Others, on the other hand, apply 111~:icrm “stimulation therapy” to low-dosage irradint,ion because there is clinitdal cvidcncc of funct,ional stimulation of the irratliat~cd glantls witlroul s~~bsec~uenl tlelctcrious effects. While the modus operandi of lo\\.-dossag2.cirradiation rcma.ins controversial, the last,ing restoration of mcnst rual periodicit+- in the majority of women who were thus treat-cd as far back as 1927 points to a stimulative rather than to a destructive effect.
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Techniqueof Low-DosageIrradiation The patients herein reported were treated by several radiologists who employed the technique of RdeikenlG with uniformly good results. The treatment may be described as follows : One hundred and thirty-five kv., 5 ma. at a distance of 40 cm. with 6 mm. of aluminum filtration through an anterior pelvic field of 20 by 20 cm. Depending upon the thickness of the abdominal wall, 50 to 90 r., measured in air, are given three times at intervals of one week. The pituitary gland is treated with the same dosage at the same time through a portal of 3 by 3 cm. just above and posterior to the midpoint of an imaginary line joining the outer canthus of the eye and the external auditory meatus. Partial relief of the amenorrhea by one course of treatment seemingly justifies a second course within three to six months. The harmlessness of a second course is demonstrated by 7 of 16 patients who received a They second course of treatments within the dosage-level recommended. conceived thirteen times, deliverin g 12 healthy offspring and one stillbirth (cause unknown). Of 249 patients thus treated by one gynecologist (C. &I.) during the eleven-year period of 1927 to 1937, inclusive, 136 responded to a questionnaire submitted to them concerning menstrual periodicity, fertility, the number of offspring since treatment and the present physical and mental status of their children.
End-Resultsin OneHundred Thirty-Six Patients Treated With Low-DosageIrradiation The follow-up of 136 patients who received low-dosage irradiation to the pituitary gland and ovaries during the period of 1927 to 1937, inclusive, permits the following classification as to indications and results: 1. Sec,ondary amenorrhea: R’lenstrual intervals of four or more months or years. 2. Primary amenorrhea: Embracing those patients who had never menstruated. 3. Oligome,norrhea: Menstrual intervals of six to thirteen weeks. 4. Hypomenorrhea: Regular menstruation with scanty flow. 5. Merzorrhagia: Prolonged or excessive menstrual flow. 6. Metrorrhagia: Acyclic uterine bleeding.
Selectionof Patients for Low-DosageIrradiation of the Pituitary Gland and Ovaries Only those patients who after a careful history and physical examination showed no evidence of a constitutional debilitating disease, diabetes mellitus, or thyroid malfunction were subjected to this form of treatment. Nearly all of the patients had previously received organotherapy without improvement. In most of the patients with menometrorrhagia, a diagnostic curettage preceded low-dosage irradiation treatment to the pituitary gland and ovaries in order to eliminate the possible presence of intrauterine pathology. A careful pelvic examination eliminated uterine fibroids as the cause of bleeding. Women with premenopausal uterine bleeding were not treated with low-dosage irradiation. In almost all amenorrhea] women subjected to low-dosage irradiation, a
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biologic test was performed to exclude a chanc~c pregnancy, curlews Ihr patient happened t,o have had a. mt~nsi1~181 110~ within I\VO hawks 1rr(‘rcding the instikxtion of treatment.
Effect on Secondary Amenorrhea Fifty-one patients, ranging in apt 1’rom 17 to 35 J-GWS, wrll~~iaillctl of infrequent menstruation for periods ranging from six months lo fifteen years. Seven patients wcrc to1 al lp ;~rnc~norrhcal for 1.w-c~ 01’ mow years; 8 patients W.W totally arnenorrh~;rl rot8 one year; and the w maining 36 patients mcnsi.ruated at intervals of 1’01~ or more moni hs.
The response to lo~dosagc irradi;lt ion Sims i o Lc irlverscbl\- ~)t’opo~+tional to the duration 01’ t.he disordcta, For insi:lncc, only 3 (:U j~(‘l* cent) OF the 8 WOIIl?ll WllO WCl’C t,Ot;llly iIIll~?llOlThl?ill f’O1’ Oll(’ )‘t’;jP 01 longer prior to theral)y ww c*urcd, ~ll~cas 38 (76 per WIII. I 11t’111~ remaining 43 patients \\-ho had had one 1.0 tlil~eo menstrual pctaiotis cllrving the year preceding treatment werr c~7wd. FortJ--six infants n-wc hrn to 25 v,~~n~c~i oi’ Ihc> ;Irrienorrhcill proIll) t,reatcd with low-dosage irradiat,ion. ‘I’~~0 of t Ilc 16 were slillborn front in ;lgC http tIll’c.l! 10 vnrious causes ; 1lie rcmainin, m 44, 110TV J4illlgiIlg tchn Tears, have tkvrlo~~ccl mcnlally iiflcl ~)tl~~Si~illl~to the 1)twlidrd dcgrce.
Effect on Primary
Amenorrhea
Four patients, ranging in ngz’e i’roJll 1X 1(1 ?? !-Wl‘S!, hd lteV(?l’ menstruated. Their avcragc age was 19.X ?-caI’Sand the follow-up period averaged 5.5 years. Three patients llavc~ rcn~ainccl amenorrh(~al, whereas I 1~ fourth began to menstruate spol~t,nnc-,ousl!- two years after trriltmcnf and continued to menstruate llor.tn;ill?- ih~~~~~hoi~f a follolv-up ]Wrictd of
four
~ealTi.
It is evident
from ;I follow-t(l) 01’ 1his small Illullbcr ill’ patitrnls tflrlt primary. amenorrhea, is not likely to r~~spo~~d1o low-dosage irradiation of the pituitary gland i01cl ovaricis. ~2 cwcsisi ir!g Miillcrian Iract defec~t may add to the difficulty in these cases.
Effect on Oligomenorrhea Oligomenorrhea is a milder form of ovarian dysfunction than is frank amenorrhea and, therefore, yields more readily to t,herapy. Thirtyseven -patients, ranging in age from eighteen to thirty-nine years, cumplained of oligomenorrhca for periods xw& 0 from one to sixteen j~~a1.s. Their average age was twcul-y-six years, ant1 I hq- ;lv(Lragcd 5.7 mensl l*uitl cycles per year. Twenty-nine (‘75 per cc~nt) were rcslorcd lo normal menstrual rJ1J.thm during a follow-up period of three to nine ~-cars with an average of 5.2 years for the group; five (14 per cent) were temporarily benefited; 3 (8 per cent,) remained unaffected by t,rcatment.
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Of this group of 37 oligomenorrheal women, 23 complained of sterility. Following low-dosage irradiation of the pituitary gland and ovaries, 17 of these patients conceived and carried to term 23 healthy infants. Additionally, there were 5 pregnancies among those patients who did not complain of sterility. Of the 28 pregnancies, 24 were successfully carried to term; 3 teriinated by abortion; and 1 terminated in a stillbirth of unknown cause. It is interesting to compare the results obtained with low-dosage irradiation in the three types of amenorrhea. The treatment totally failed in primary amenorrhea; it yielded 71 per cent permanent cure in secondary amenorrhea; and ‘i8 per cent cure in oligomenorrhea. Of the 92 patients in the three subgroups of amenorrhea, 65 (71 per cent) were restored to normal menstrual rhythm for a period of from three to t,hirteen years solely by the use of low-dosage irradiation t,herapy.
Effect on Hypomenorrhea Hypomenorrhea, per se, is not disturbing to the patient until sterility, so frequently associated with it, becomes a major problem. Of 7 hypomenorrheal women, 6 sought relief of associated sterility and only one complained of hypomenorrhea primarily. Their ages ranged from twenty to twenty-nine years and their symptoms were present for one to twelve years. Four (57 per cent) of the 7 patients were relieved during a period of four to nine years with an average of 6.3 years for the group; and 3 (43 per cent) remained unaffected by low-dosage irradiation. Only one patient was relieved of her sterility, resulting in two full-term healthy infants and in one abortion.
Effect on Menorrhagia Twenty-seven patients, ranging in age from 14 to 43 years, menstruated cyclically but either excessively or for a prolonged int,erval. The duration of the menorrhagia was from three months to t,en years. Sixteen (59 per cent) were restored to normal menstrual rhythm by low-dosage irradiation during a follow-up period of three to eleven years with an average of 5.6 years for the group; 3 (11 per cent) were benefited temporarily; and the remaining 8 (30 per cent) were unaffected by treatment. Two patients, age 40 and 43, had normal cycles for three years after treatment before typical menopausal symptoms commenced. Two patients became temporarily amenorrhea1 for five and eight months, respectively, after irradiation and then normal rhythm was re-established. It is probable that both of these patients followed the usual clinical course of this type of dysfunction since menorrhagia is often a precursor to amenorrhea. Therefore these two patients are classified as therapeutic failures. Of 4 menorrhagic patients complainin g of sterility, only one was relieved. Seven pregnancies occurred in 5 of the group of 27 patient,s and all were successfully carried t,o t,erm. ,411 7 children developed physically and mentally to their predicted degree.
Effect on Metrorrhagia Ten t,otally t,o four plained
patients, ranging in age from eighteen to thirty-six vears, had acyclic menstrual rhythm for periods ranging from s”ix months years, with an average of 1.2 years for the group. None comof sterility.
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Five (50 per cent) were restored to normal menstrual rhythm during a follow-up period of three to eleven years wit,h an average of 7.2 years for the group; 3 (30 per cent ) were temporarily benefited; and 2 (20 per cent) were unaffected bv irradiation therapy. The his@,, of one patient is unusually int,ere&g and dcscrvcs recording : Niss (1. It.. aged 25 ~YWX, sought relief from scvcrc metrorrhagia in July, 1933, having stained or bled dail\- throughout the preceding Examination (sighteen months despite curettage and organotherapy. LOWrevealed a moderately anemic but otherwise healthy patient. gland was administered in .\ugusi, dosage irradiation of the pituitary 1933, resulting in partial improvement during t,he following four months. In January, 1934, a second ~:oursc of irradiation t,reatments gland and ovaries, resulting in was administered over the pituitary prompt establishment of normal menstrual rhythm which continued UIIinterruptedly during the follow-1~1, ]JOri0d oi‘ three arid one-half ychars.
CONDITION
Xumber
of
pa
tients Average age oi each group Xumber of pe riods per yea] preceding treatment Average duration of symp toms (years) Pure5 of 3 tc 13 years sumber of sue cessful pregnancies -7 Number of abortions Surnber of stillbirths -____-._
A long-term survey of the end-results of low-dosage irradiation of the pituitary gland and ovaries in amenorrhea and in dysfunctional uterine bleeding, with or without sterility, is presented. Of 249 patients treated between 1927 and 1937, inclusive, 136 were followed up for periods rangin, 0’ from three to thirteen years This method of treatment resulted in restoration of normal menstrual function in 71 per cent of 51 amenorrhea1 women; 78 per cent of 37 oligomenorrheal patient,s; 57 per cent of 7 hypomenorrheal women; 59 per cent of 27 menorrhagic women; and 50 per cent of 10 metrorrhagic women.
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Four patients with primary amenorrhea were unaffected by lowdosage irradiation therapy. The percentage of cures for’the group of 136 as a whole was 66. Two patients were temporarily ma$e worse and the remaining 44 were either unaffected or only temporarily improved. The restoration of menstkual function in 57 of the patients with associated sterility materially aided 34 of them in becoming pregnant. Of the 90 pregnancies in 54 women of the group of 136, 80 resulted in full-term healthy offspring; 7 pregnancies terminated during the first trimester; and 3 terminated in stillbirths near term. From this long-term follow-up it appears that preconceptional lowdosage irradiation to the pituita:y gland and ovaries has no deleterious effect upon the generative organs or upon the offspring of the first generation. References Schwarz,
8: 3. 4. 0. f: 8. 9 lb: 11. 12. :1: 15. 16. 17. 18. 19. 20. ii: 23. 2: 22;:
G. : Handbuch der Gesamten Strahlenheilkunde, Biologic, Pathologie und Therapie Vol. II, p. 46, Strahlenklinik und Spezielle Therapeutische Methodik. By numerous collaborators. Edited by Dr. Paul Lazarus.
Cheron: Cited by Schwarz. Hewer, E. E.: J. Physiol. 50: 438, 1916. Arch. f. d. ges. Physiol. (Pfluger’s) 227: 266, 1931. Steinach, E., and Kun, H.: Drips, D. G., and Ford, F. A.: Proc. Staff Meetings of the Mayo Clinic 7: 18, 1932. Parkes, A. S.: Proc. Roy. Sot. Lond., s.B. 100: 172, 1926. Epifanio, G., and Cola, G.: Radiol. m6d. 19: 1338, 1932. Van de Velde: Cited bv Thaler.14 Hirsch. I. S.: Radiolo& 7: 422. 1926. Rubin,’ I. C. : AM. J. &ST. & ~YNFC. 12: 76, 1926. Rangy, A. J.: Ibid. 7: 169, 1924. Kaplan, I. I.: Ibid. 21: 52 and 59, 1931. Drcps, b. G., and Ford, F. A.: J.‘A. M. A. 91: 1358, 1928. Wagner, G. A., and Schoenhof, C.: Strahlentherapie 22: 125, 1926. Thaler, H. : Zentralbl. f. GynLk. 46: 2034, 1922. Desjardins, A. U.: J. A. M. A. 87: 1537, 1926. Edeiken, L. : AM. J. OBST. & GYNEC. 25: 511,1933. Werner, P. : Zentralbl. f. Gynlk. 47: 1260, 1923. Steinhardt, B.: Ztschr. f. Geburtsh. u. Gynlk. 102: 481, 1932. Kaplan, I. I.: New York State J. Med. 38: 626, 1938. Drips, D. G.: Trans. Am. Therapeutic Sot. 33: 108, 1933. Tamis, A. B.: AM. J. OBST. & GYNEC. 32: 845, 1936. Porchownik, J. G., and Wittenburg, W. W.: Roentgen praxis 8: 695, 1936. Mazer, C., and Goldstein, L.: Clinical Endocrinology of the Female, Plnladelphia, 1932, W. B. Saunders Co. Mazer, C., and Spitz, L., Jr.: A&f. J. OBST. & GYNEC. 30: 214, 1935. Mazer, C., and Baer, G.: Ibid. 37: 1015, 1939. King, J. C.: South. M. J. 33: 28, 1940. Bogart, F. B.: Ibid. 32: 708, 1939.
REIDENBERG : IRRADIATION IN AMENORRHEA
The incidence of toxemia was not lowered in the patients who restricted both salt and fluids. This is partially at,tributable to a concentration of unfavorable cases in this group. The incidence of toxemia was considerably lowered in the patients who restricted salt and forced fluids. The effectiveness of prophylaxis against toxemia increased as greater weight losses were induced by the dietary regimes. Paradoxically, the gain or loss in extracellular water seemed to bear no relation to the incidence of toxemia: our data are inconclusive on this point. We wish to acknowledge our indebtedness and E. G. Waters for reading the typescript. by Lorene Dickerson, chief dietitian at the The urinary creatinine determinations were Marotta.
to Drs. S. A. Cosgrove, J. F. Norton, The 2 gram salt diet was devised Margaret Hague Maternity Hospital. done by Frances Orsato and Peter
References 1. Arnold, 2. 3. 4. 5. 6. 7. 8. 9. 10.
J. O., and Fay, T.: Surg., Gynec. & Obst. 55: 129,1932. de Alvarez, R. R.: AM. J. OBST. 8; GYNEC. 39: 476, 1940. Chesley, L. C., and Chesley, E. R.: Ibid. 42: 976, 1941. Idem: Ibid. In press. Chesley, L. C.: In press. Quantitative Clinical Chemistry, Peters, J. P., and Van Slyke, D. D.: Methods, Baltimore, 1932, Williams and Wilkins, pp. 602 and 834. Darrow, D. C., and Yannet, H.: J. Clin. Investigation 15: 419, 1936. Harding, V, J., and Van Wyck, H. B.: AK J. OBST. & GYNEC. 24: Strauss, M. B.: Ibid. 38: 199, 1939. McPhail, F. L.: West. J. Surg. 47: 306, 1939.
Vol.
II,
820, 1932.
LOW-DOSAGE IRRADIATION TO THE PITUITARY GLAND AND OVARIES IN AMENORRHEA AND DYSFUNCTIONAL UTERINE BLEEDING” A Long-Term (From
LEON REIDENBERG, the Graduate Hospital
Survey
M.D., PHILADELPHIA, of
the
Uniaersity
of
PA. Pennsylvania)
YSFUNCTIONAL menstrual disorders, with or without associated sterility, are the most difhcult problems encountered by the gynecologist. The patients stop at nothing in their search for a cure. In most instances of dysfunctional menstrual disorders, especially amenorrhea of long duration, endocrine and other forms of therapy fail to produce consistent results. Clinicians have long sought an agent capable of normalizing the menses and of relieving sterility of dysfunctional origin. It seems probable that this long-sought remedial agent has at last been discovered in the form of low-dosage irradiation.
D
*Thesis submitted to the Faculty of the Graduate School of Medicine of the University of Pennsylvania, in partial fulfillment of the requirements for the degree of Master of Science in Medicine. NOTE: The cases herein reported were selected from the private practice of Dr. Charles Maser.
Originally, only the dcstructioe cffwls of ilTi~cli;ltion wcu2 wnsitlt~wtl of t,herapeutic value in the control of d~-si’ut~c~t iollal tlt.ednc l)le~~ling~ incvitahly reslllting ill temporary or lwniiul(~nf srqJ~Jressiorl oi' tlw menstrual function and in steril it,?-. 7%~ 11s~0f notitlcsl,i~nclivc~ &~c’s of rocntgcn rays for thv pi~rposc of rvlicving i~mCllorrh<~:l. tllv ealirlival nntilhcsis of menornrt~~oi~1~1~;1~i~~, was first 1 ricvl c11JriJry 1 II(~ SCYY~II~~ II(v* ade of this c~entnq-.
Historical
Sketch
Ad hricf history of tlic deoclopmcnl of low-tlosagc irradiation as a therapeutic agent is wal~:~nt,ed. Tn 19 10 an11 1911 C%won' ant1 associat.es warned that x-ray es~~osm~s und(~t* 110 1WJ' writ skin cryt~hcma dose stimulate the growth of carcinoma of ihc rttcrrw and incwasc the incidence of metastasis. Their dcdllctions ~ww lat cr I)rovcd to 1)~ errcnlc~ns. HOWCWX, these reports init.iatc(l an PIX of c~sl)c‘rimcnt,a.tioll on the stimulating effects of irradiation on ~~lants ant1 lowr animals. Ht:WPF induced sexual maturity in infnntiln rats with mild irradiation IJ~ I hc ovaries. This was probably tluc to irradiation of the anterior pit.uitary gland which, in small animals, is nnintcntionally bnt, simnltaneonsly c’sposed. Steinach and Kun” indrlccd hyqwrl nt(~mixatiorl o-f the cLlirIC:J pig’s ovaries h,v s-ray treatmrnt. Iki 11salttl FOIY~~obscrvcd only slipht congestion 01 the ovaries of rals t.hat w’w killed shortly after tlw administration of a 10 per writ ~U~XICOILSvrvthcma dose for the ral. The follicular apparatus was nppare~ltly JJot ‘inflnctwcd by the pl’occd.ure. Parke? observed ingrowth of epithelioid bawds of: cells from the pcriphcrg into the stroma of mouse ovaries that wl;fw: intensively j wadi-. al cd; 1he cords eshibitcd a tcndcncb. 1award follicnlar arranwncnt. Epifanio and Cola’ obscrvcd a rnI)id illcw;lsv ill ~J'OWth of yolln~ r;ihl~ils nft,cr low-dosage irradiat,ion of the pifltita~y gland which at ir\Itops!. showed no widencc of cytologic a11 (al*;li-iorl. Clinically, Van dc Vclde’ rcporlr(1 iu lnls the return of ?lol’Jrra~ ovarian fnnction aftrr small doses 01’ x-rays hat1 been applitvl owr tllc 1,~. Hirwh." ovaries. Soon t hcrcaftcr similar I~cwllls \vvrc wportctl Rubin,” Rouyy-,“’ Kaplan," ilHd I )rAiljs iltltl FOJYI.” R;IglIPr ;lllCl S~‘ElO(‘llhof’” ha.vc found no dcgfwcratiyc rhan~:trs in the ovarjcs OUwcnno~~sill)jccted t-o low-dosage irradiat,ion prior to IJwnl-1?-st,erectomy and bilatrl*al salpingo-oophorcctom\, for carcinoma of the 111 crlls. (IJlly OJIC (I[ t;hC ovaries 01’ cacxh paticni was irradiatccl : tlw cwrresponding OKWJ ww prot.ected from the rays by means of propel. sc*rccning for I hc p\U’poSC of histologic comparison. &fore uxeritly, a. 1lnJlLh of iJlvcSti~iltorS dso report,ed 011 ill(! 1 hvmpeatic ralue of low-dosapc irradiat ioll o/' t Ii0 [)itUitilr), gland alit1 o\-arirs in instances of amcnorrhw with 01’ without ;~sso~inlcd sterility i Tahlc 1). A composite rcvicw of thvsc rclwits iJidicxlcs :I restoration 0C menstrual periodicity in 440 of 755 patients thaw trwt t:d with no iJltcrferenc~~ in the fertility in thosct who dcsircd ofislkri 11%. Nevert.heless, most, clinicians ~vgarc 1 it as ii dangerous agent ailtl are loath to employ it for fc:i~ ol' irw~Jar;rhlc tlamag?:c,t,o t,he ovaries. This attitude toward low~-dosa~~~ irratliation is mostly l~sccl upon animal txpcrimeiitation wit Ii tlwt rnvt ivc dosw. The numerolw (*Iin iwl wtwrl s OII to\v-tlosape irradiation 10 the pituitwy gland and ovaries cowr onI>R short period of follow-up, one
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to three years. It is, therefore, of interest to learn what has happened to a representative group of these women and their offspring during a much longer follow-up period. A careful follow-up of 136 women who received low-dosage irradiation to the pituitary gland and ovaries from three to thirteen years ago forms the basis of this presentation. The results indicate that low-dosage irradiation, within the dosage limits employed in these cases, is a most helpful and safe agent in the armaMoreover, the follow-up shows no mentarium of the gynecologist. TABLE
I.
STATISTICS
Note
ON RQENTGEN
:
Improved
cases
TREATMENT
RAY
grouped
OF AL[EP;OILRHEA
as failures
= I
REPORTED BY
)IJRATION OF AMENORRHIU
NO.
GLAND IRRADIATED
AGE OF PATIENTS
NO. OF PATIENTS
-
Thalerl4
i
OF
CURESFOR ONE OR nfoim YEARS
H;;;;;Iy OFFSPRING
(65%)
NO.OF ABORTIONS
2
-
31 (50%)
11
-
25
15 (60%)
-
-
56
40 (72%)
11
1
12
11 (93%)
8
1
13
5 (37%)
-
-
73
23 (31%)
20
6
58
38 (66%)
20
5
74
41 (55%)
26
2
106
62 (59%)
62
40
62
.-
Werner17 Steinhardtls
.tI
mo. yr. 1 mo. to 19 to 45 14 yr. yr.
.-
EaplanlQ ._
-
Drip@
.
.
Tami@
3 to mo. .
.
36
-
RubinQ
19 to Yr. .-
2 to mo.
Rmongyl” . .
Mazer and Goldstein23 Mazer and Spitz24 Mazer and Baerzs
33 -
3
I I
-
Porchownick22
16 to vr.
39
I” -120 mo.
to
35
Y’.
.-
-:
.-
King26
1 to Yr.
6
18 to yr.
36
1 to Y’.
13
18 to Yr.
36
Iito3 vr.
Bogart27 -
Pituitary and ovaries Pituit,ary and ovaries Pituitary and ovaries Pituitary and ovaries Pituitary and I ovaries IPituitary and ovaries Pituitary and ovaries Pituitary and ovaries Pituitary
I I
-
EdeikenlQ
29 single and 33 married women 17 to 36 y”.
Pituitary and ovaries Pituitary and ovaries
I
-
I
Pituitary and ovaries
1- I
____~
10
-3716
10 (100%)
(68%)
20
2-
/_I_
4
0
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OI3S’lWTRICS
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deleterious effect upon the offspring of 54 wor11e11 who have given birth to X0 children. Illu&rative of the harmlessness to 111~ pat icnt and to the puyqny of the first. generation, t’ven of thrcr (~)ursf’s of low-dosage irradiation to the pituitary gland and ovaries, is the following cast record : Mrs. hf. S., aged 24 years, sought~ treatment in DecemheTl 1933, for 1.11~relief of amenorrhea of eight. years’ duration and inablllty to conceivc for two years. Episodes of mcnomdrorrhagia were frequent, from the age of t-wclvc to sixken. Thercnftcr amenorrhea (three cycles per year) ensued for eight >-cars. In the k-0 pears prior to low-dosage irradiation l.reatment, conception did Ilot o(acur. In December, 1933, physical and general lahoratorv csnmination revealed nothing abnormal. liow-dosage irradiation, qivcn ’ in Ikccmbcr, 1933, prompt,lv normalized her menstrual cycles. khc conccivctf in ,Jul>-, 1934, and delivered a normal full-term infant. She mcnstrnatcd regularly until 1937 when the tendency to nmcnorrhca returnctl. Tn November, 1937, ;I second course of s-rays was given nftcr a periocl of amcnorrhca of eight months’ duration. Partial improrcment, was al,tainetl and a Ihird course in March, 1938, regulated her menses to th(> dil.t(l oi‘ this folio-v\-np (May, 3942). During the intrrim she dclivc~rod two ll~~illtll~~ infants. This case record illuskates hot11 t 11tksitt’t’l>- of cve11 t.llmtc (Y)IIIWS pi low-dosage irradiation 1o t hc ovnrics o I’ I hc ~~i~t,iel~t, ant1 the harn~lessncss of the treatment.s upon 1he rhildr(~n 0C the first generation. The hypothetical ol)jection to Ion-dosage irradiation on the basis of it,s possible harmful cffcc4s npon f Ilc swoutl nuil third gcwetdions cannot be rclevant,ly aryictl since 1 his lY~i~l~tliil1il
Modus Operandi of Low-Dosage
Irradiation
Although twenty-seven gears have elapsed since Van de Velde’ suggested low-dosagc irradiation as a therapeutic agent, its modus operandi is still undetermined. Most radiologists maint,ain t.hat roentgen. rays rapidly product: hypcremia, and that. they arc always destructirc. For example, Thalcr,l” Ikqjardins’” and others believe that the beneficial cffccts of low-dosage irradiation in t,lrc treatment. of amenorrhea and dysfunctional iltcrinc blceding result from the destruction of a persistent corpus lutcum 013of an abnormally large Graafian follicle. ‘l’hq do not explain the pticnomenal CSCil[)t' from damage of the remaining essential and more vuhlcrablc elements of the ovaries. Others, on the other hand, apply 111~:icrm “stimulation therapy” to low-dosage irradint,ion because there is clinitdal cvidcncc of funct,ional stimulation of the irratliat~cd glantls witlroul s~~bsec~uenl tlelctcrious effects. While the modus operandi of lo\\.-dossag2.cirradiation rcma.ins controversial, the last,ing restoration of mcnst rual periodicit+- in the majority of women who were thus treat-cd as far back as 1927 points to a stimulative rather than to a destructive effect.
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Techniqueof Low-DosageIrradiation The patients herein reported were treated by several radiologists who employed the technique of RdeikenlG with uniformly good results. The treatment may be described as follows : One hundred and thirty-five kv., 5 ma. at a distance of 40 cm. with 6 mm. of aluminum filtration through an anterior pelvic field of 20 by 20 cm. Depending upon the thickness of the abdominal wall, 50 to 90 r., measured in air, are given three times at intervals of one week. The pituitary gland is treated with the same dosage at the same time through a portal of 3 by 3 cm. just above and posterior to the midpoint of an imaginary line joining the outer canthus of the eye and the external auditory meatus. Partial relief of the amenorrhea by one course of treatment seemingly justifies a second course within three to six months. The harmlessness of a second course is demonstrated by 7 of 16 patients who received a They second course of treatments within the dosage-level recommended. conceived thirteen times, deliverin g 12 healthy offspring and one stillbirth (cause unknown). Of 249 patients thus treated by one gynecologist (C. &I.) during the eleven-year period of 1927 to 1937, inclusive, 136 responded to a questionnaire submitted to them concerning menstrual periodicity, fertility, the number of offspring since treatment and the present physical and mental status of their children.
End-Resultsin OneHundred Thirty-Six Patients Treated With Low-DosageIrradiation The follow-up of 136 patients who received low-dosage irradiation to the pituitary gland and ovaries during the period of 1927 to 1937, inclusive, permits the following classification as to indications and results: 1. Sec,ondary amenorrhea: R’lenstrual intervals of four or more months or years. 2. Primary amenorrhea: Embracing those patients who had never menstruated. 3. Oligome,norrhea: Menstrual intervals of six to thirteen weeks. 4. Hypomenorrhea: Regular menstruation with scanty flow. 5. Merzorrhagia: Prolonged or excessive menstrual flow. 6. Metrorrhagia: Acyclic uterine bleeding.
Selectionof Patients for Low-DosageIrradiation of the Pituitary Gland and Ovaries Only those patients who after a careful history and physical examination showed no evidence of a constitutional debilitating disease, diabetes mellitus, or thyroid malfunction were subjected to this form of treatment. Nearly all of the patients had previously received organotherapy without improvement. In most of the patients with menometrorrhagia, a diagnostic curettage preceded low-dosage irradiation treatment to the pituitary gland and ovaries in order to eliminate the possible presence of intrauterine pathology. A careful pelvic examination eliminated uterine fibroids as the cause of bleeding. Women with premenopausal uterine bleeding were not treated with low-dosage irradiation. In almost all amenorrhea] women subjected to low-dosage irradiation, a
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biologic test was performed to exclude a chanc~c pregnancy, curlews Ihr patient happened t,o have had a. mt~nsi1~181 110~ within I\VO hawks 1rr(‘rcding the instikxtion of treatment.
Effect on Secondary Amenorrhea Fifty-one patients, ranging in apt 1’rom 17 to 35 J-GWS, wrll~~iaillctl of infrequent menstruation for periods ranging from six months lo fifteen years. Seven patients wcrc to1 al lp ;~rnc~norrhcal for 1.w-c~ 01’ mow years; 8 patients W.W totally arnenorrh~;rl rot8 one year; and the w maining 36 patients mcnsi.ruated at intervals of 1’01~ or more moni hs.
The response to lo~dosagc irradi;lt ion Sims i o Lc irlverscbl\- ~)t’opo~+tional to the duration 01’ t.he disordcta, For insi:lncc, only 3 (:U j~(‘l* cent) OF the 8 WOIIl?ll WllO WCl’C t,Ot;llly iIIll~?llOlThl?ill f’O1’ Oll(’ )‘t’;jP 01 longer prior to theral)y ww c*urcd, ~ll~cas 38 (76 per WIII. I 11t’111~ remaining 43 patients \\-ho had had one 1.0 tlil~eo menstrual pctaiotis cllrving the year preceding treatment werr c~7wd. FortJ--six infants n-wc hrn to 25 v,~~n~c~i oi’ Ihc> ;Irrienorrhcill proIll) t,reatcd with low-dosage irradiat,ion. ‘I’~~0 of t Ilc 16 were slillborn front in ;lgC http tIll’c.l! 10 vnrious causes ; 1lie rcmainin, m 44, 110TV J4illlgiIlg tchn Tears, have tkvrlo~~ccl mcnlally iiflcl ~)tl~~Si~illl~to the 1)twlidrd dcgrce.
Effect on Primary
Amenorrhea
Four patients, ranging in ngz’e i’roJll 1X 1(1 ?? !-Wl‘S!, hd lteV(?l’ menstruated. Their avcragc age was 19.X ?-caI’Sand the follow-up period averaged 5.5 years. Three patients llavc~ rcn~ainccl amenorrh(~al, whereas I 1~ fourth began to menstruate spol~t,nnc-,ousl!- two years after trriltmcnf and continued to menstruate llor.tn;ill?- ih~~~~~hoi~f a follolv-up ]Wrictd of
four
~ealTi.
It is evident
from ;I follow-t(l) 01’ 1his small Illullbcr ill’ patitrnls tflrlt primary. amenorrhea, is not likely to r~~spo~~d1o low-dosage irradiation of the pituitary gland i01cl ovaricis. ~2 cwcsisi ir!g Miillcrian Iract defec~t may add to the difficulty in these cases.
Effect on Oligomenorrhea Oligomenorrhea is a milder form of ovarian dysfunction than is frank amenorrhea and, therefore, yields more readily to t,herapy. Thirtyseven -patients, ranging in age from eighteen to thirty-nine years, cumplained of oligomenorrhca for periods xw& 0 from one to sixteen j~~a1.s. Their average age was twcul-y-six years, ant1 I hq- ;lv(Lragcd 5.7 mensl l*uitl cycles per year. Twenty-nine (‘75 per cc~nt) were rcslorcd lo normal menstrual rJ1J.thm during a follow-up period of three to nine ~-cars with an average of 5.2 years for the group; five (14 per cent) were temporarily benefited; 3 (8 per cent,) remained unaffected by t,rcatment.
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Of this group of 37 oligomenorrheal women, 23 complained of sterility. Following low-dosage irradiation of the pituitary gland and ovaries, 17 of these patients conceived and carried to term 23 healthy infants. Additionally, there were 5 pregnancies among those patients who did not complain of sterility. Of the 28 pregnancies, 24 were successfully carried to term; 3 teriinated by abortion; and 1 terminated in a stillbirth of unknown cause. It is interesting to compare the results obtained with low-dosage irradiation in the three types of amenorrhea. The treatment totally failed in primary amenorrhea; it yielded 71 per cent permanent cure in secondary amenorrhea; and ‘i8 per cent cure in oligomenorrhea. Of the 92 patients in the three subgroups of amenorrhea, 65 (71 per cent) were restored to normal menstrual rhythm for a period of from three to t,hirteen years solely by the use of low-dosage irradiation t,herapy.
Effect on Hypomenorrhea Hypomenorrhea, per se, is not disturbing to the patient until sterility, so frequently associated with it, becomes a major problem. Of 7 hypomenorrheal women, 6 sought relief of associated sterility and only one complained of hypomenorrhea primarily. Their ages ranged from twenty to twenty-nine years and their symptoms were present for one to twelve years. Four (57 per cent) of the 7 patients were relieved during a period of four to nine years with an average of 6.3 years for the group; and 3 (43 per cent) remained unaffected by low-dosage irradiation. Only one patient was relieved of her sterility, resulting in two full-term healthy infants and in one abortion.
Effect on Menorrhagia Twenty-seven patients, ranging in age from 14 to 43 years, menstruated cyclically but either excessively or for a prolonged int,erval. The duration of the menorrhagia was from three months to t,en years. Sixteen (59 per cent) were restored to normal menstrual rhythm by low-dosage irradiation during a follow-up period of three to eleven years with an average of 5.6 years for the group; 3 (11 per cent) were benefited temporarily; and the remaining 8 (30 per cent) were unaffected by treatment. Two patients, age 40 and 43, had normal cycles for three years after treatment before typical menopausal symptoms commenced. Two patients became temporarily amenorrhea1 for five and eight months, respectively, after irradiation and then normal rhythm was re-established. It is probable that both of these patients followed the usual clinical course of this type of dysfunction since menorrhagia is often a precursor to amenorrhea. Therefore these two patients are classified as therapeutic failures. Of 4 menorrhagic patients complainin g of sterility, only one was relieved. Seven pregnancies occurred in 5 of the group of 27 patient,s and all were successfully carried t,o t,erm. ,411 7 children developed physically and mentally to their predicted degree.
Effect on Metrorrhagia Ten t,otally t,o four plained
patients, ranging in age from eighteen to thirty-six vears, had acyclic menstrual rhythm for periods ranging from s”ix months years, with an average of 1.2 years for the group. None comof sterility.
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Five (50 per cent) were restored to normal menstrual rhythm during a follow-up period of three to eleven years wit,h an average of 7.2 years for the group; 3 (30 per cent ) were temporarily benefited; and 2 (20 per cent) were unaffected bv irradiation therapy. The his@,, of one patient is unusually int,ere&g and dcscrvcs recording : Niss (1. It.. aged 25 ~YWX, sought relief from scvcrc metrorrhagia in July, 1933, having stained or bled dail\- throughout the preceding Examination (sighteen months despite curettage and organotherapy. LOWrevealed a moderately anemic but otherwise healthy patient. gland was administered in .\ugusi, dosage irradiation of the pituitary 1933, resulting in partial improvement during t,he following four months. In January, 1934, a second ~:oursc of irradiation t,reatments gland and ovaries, resulting in was administered over the pituitary prompt establishment of normal menstrual rhythm which continued UIIinterruptedly during the follow-1~1, ]JOri0d oi‘ three arid one-half ychars.
CONDITION
Xumber
of
pa
tients Average age oi each group Xumber of pe riods per yea] preceding treatment Average duration of symp toms (years) Pure5 of 3 tc 13 years sumber of sue cessful pregnancies -7 Number of abortions Surnber of stillbirths -____-._
A long-term survey of the end-results of low-dosage irradiation of the pituitary gland and ovaries in amenorrhea and in dysfunctional uterine bleeding, with or without sterility, is presented. Of 249 patients treated between 1927 and 1937, inclusive, 136 were followed up for periods rangin, 0’ from three to thirteen years This method of treatment resulted in restoration of normal menstrual function in 71 per cent of 51 amenorrhea1 women; 78 per cent of 37 oligomenorrheal patient,s; 57 per cent of 7 hypomenorrheal women; 59 per cent of 27 menorrhagic women; and 50 per cent of 10 metrorrhagic women.
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Four patients with primary amenorrhea were unaffected by lowdosage irradiation therapy. The percentage of cures for’the group of 136 as a whole was 66. Two patients were temporarily ma$e worse and the remaining 44 were either unaffected or only temporarily improved. The restoration of menstkual function in 57 of the patients with associated sterility materially aided 34 of them in becoming pregnant. Of the 90 pregnancies in 54 women of the group of 136, 80 resulted in full-term healthy offspring; 7 pregnancies terminated during the first trimester; and 3 terminated in stillbirths near term. From this long-term follow-up it appears that preconceptional lowdosage irradiation to the pituita:y gland and ovaries has no deleterious effect upon the generative organs or upon the offspring of the first generation. References Schwarz,
8: 3. 4. 0. f: 8. 9 lb: 11. 12. :1: 15. 16. 17. 18. 19. 20. ii: 23. 2: 22;:
G. : Handbuch der Gesamten Strahlenheilkunde, Biologic, Pathologie und Therapie Vol. II, p. 46, Strahlenklinik und Spezielle Therapeutische Methodik. By numerous collaborators. Edited by Dr. Paul Lazarus.
Cheron: Cited by Schwarz. Hewer, E. E.: J. Physiol. 50: 438, 1916. Arch. f. d. ges. Physiol. (Pfluger’s) 227: 266, 1931. Steinach, E., and Kun, H.: Drips, D. G., and Ford, F. A.: Proc. Staff Meetings of the Mayo Clinic 7: 18, 1932. Parkes, A. S.: Proc. Roy. Sot. Lond., s.B. 100: 172, 1926. Epifanio, G., and Cola, G.: Radiol. m6d. 19: 1338, 1932. Van de Velde: Cited bv Thaler.14 Hirsch. I. S.: Radiolo& 7: 422. 1926. Rubin,’ I. C. : AM. J. &ST. & ~YNFC. 12: 76, 1926. Rangy, A. J.: Ibid. 7: 169, 1924. Kaplan, I. I.: Ibid. 21: 52 and 59, 1931. Drcps, b. G., and Ford, F. A.: J.‘A. M. A. 91: 1358, 1928. Wagner, G. A., and Schoenhof, C.: Strahlentherapie 22: 125, 1926. Thaler, H. : Zentralbl. f. GynLk. 46: 2034, 1922. Desjardins, A. U.: J. A. M. A. 87: 1537, 1926. Edeiken, L. : AM. J. OBST. & GYNEC. 25: 511,1933. Werner, P. : Zentralbl. f. Gynlk. 47: 1260, 1923. Steinhardt, B.: Ztschr. f. Geburtsh. u. Gynlk. 102: 481, 1932. Kaplan, I. I.: New York State J. Med. 38: 626, 1938. Drips, D. G.: Trans. Am. Therapeutic Sot. 33: 108, 1933. Tamis, A. B.: AM. J. OBST. & GYNEC. 32: 845, 1936. Porchownik, J. G., and Wittenburg, W. W.: Roentgen praxis 8: 695, 1936. Mazer, C., and Goldstein, L.: Clinical Endocrinology of the Female, Plnladelphia, 1932, W. B. Saunders Co. Mazer, C., and Spitz, L., Jr.: A&f. J. OBST. & GYNEC. 30: 214, 1935. Mazer, C., and Baer, G.: Ibid. 37: 1015, 1939. King, J. C.: South. M. J. 33: 28, 1940. Bogart, F. B.: Ibid. 32: 708, 1939.