Use of Low-Dosage Irradiation in the Treatment of Infertile Women with Ovarian Dysfunction

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1 Use of Low-Dosage Irradiation in the Treatment of Infertile Women with Ovarian Dysfunction Sheldon Payne, M.D. Two YEARS AGO we summarized our results in the diagnosis and treatment of endocrine disorders in infertility.u Of 600 consecutive private patients investigated for infertility major factors were found in both partners in 41 per cent, impaired fertility exclusively in the wife in 33 per cent, and in 26 per cent the husband alone was found to be at fault. The majority of our patients had previously been extensively studied by other physicians without result and were referred to us because of the suspected endocrine factor. Because of our specialized interest, tubal or vas occlusions, infections, tumors, etc., are encountered less frequently than is generally reported. Psychogenic factors are common but often difficult to evaluate. In reviewing the treatment of 154 women with functional infertility, 27 ( 17.5 per cent) became pregnant following instrumentation, diet, vitamin supplements, thyroid regulation and/ or estrin priming. When gonadotropic therapy (pregnant mare's serum or pregnant mare's serum plus chorionic gonadotropin) was added to the above routine, of 112 women 37 ( 33 per cent) more conceived. Of the 90 "failures" by all previous methods-the majority young and with amenorrhea of from several months to several years-were selected for a trial with low-dosage irradiation therapy. Eleven ( 43.5 per cent) promptly conceived and 8 delivered viable normal babies. Although roentgen-ray therapy in these 23 women was employed as a last resort in what had previously been considered failures the percentage of success was far greater than could be attributed to any other management. Also, the women that conceived following general measures, thyroid, estrin, Presented at the Eighth Annual Meeting of the American Society for the Study of Sterility, Chicago, Illinois, June 8,

2 Vol. 3, No. 6, 1952] LOW-DOSAGE IRRADIATION 501 gonadotropin, etc., for the most part had minor derangements of function compared to the several women with long-standing amenorrheas who responded to radiation therapy. The treatment of menstrual disturbances and sterility by irradiation was gaining considerable popul~rity in the decade 1930 to 1940 and there are many reports-all favorable-by such pioneers as Kaplan, Edeiken, Mazer, Rock, and others. About that time hormone treatment came into vogue and with the promising reports of the stimulating effects of various endocrine preparations on laboratory animals the clinical investigations were mostly limited to this field. Ultimately, however, the clinical results of hormone therapy fell short of the expectations and experienced clinicians such as Rubin, Drips, Finkler, Rakoff, and others again turned to a more general employment of irradiation therapy. No untoward effects of low-dosage irradiation of ovaries and/or pituitary have been reported except an occasional mention of transient amenorrhea or premature menopause in women whose ovarian function had previously been considered very poor. Babies and grandchildren of irradiated mothers have all been normal within the usual expectancy. 7 The fear that mutations and congenital mahormations may occur in future generations has been paramount particularly as a result of the reports of Muller's experiments with the fruit fly. This fear of altering the genes of future generations has kept gynecologists from a more general application of irradiation therapy. Chantraine discusses the relative numbers of roentgen-ray and spontaneous mutations in humans and believes it is absurd to apply mutation rates of Drosophila to humans. In his experience the genetic changes associated with the medical application of roentgen-radiation are no more frequent than those caused by numerous other circumstances of modern life. Kaplan 7 presented to this Society a classical dissertation concerning the effects of roentgen irradiation on germ plasm in relation to infertility. He concludes that irradiation when properly given for this purpose is harmful neither to the mother nor to the offspring and that it has proved a valuable therapeutic procedure for the treatment of amenorrhea and sterility. METHODS We have employed low-dosage roentgen-ray to the ovaries and pituitary or to the pituitary alone in the treatment of 49 infertile women during the period from July, 1947, to January, 1952, where we had the opportunity of studying both marriage partners over a period of several months and years.

3 502 PAYNE [Fertility & Sterility Initial investigations in each instance included the minimal procedures recommended by the Society 16 for evaluation of the barren marriage and in each couple the major factor in failure to reproduce was considered ovarian dysfunction. The husband's sperm analyses were done at frequent intervals and were considered adequate except for Case 13 whose husband was azoospermic; here donor inseminations were employed. Occasionally where observations were extended over several months or years a husband has shown transient impairment of spermatogenesis which occurs at times with acute infections. Investigations of the wives all included routine blood and urine studies, basal metabolic rates, estimations of the serum cholesterol, 4-hour glucose tolerance tests, and the icteric index. Protein bound iodine determinations were done if there was a question of thyroid imba,lance. Vaginal smears were made at each visit. The initial endometrial biopsy specimens were taken two or three days before menstruation or during the first twelve hours of uterine bleeding. Subsequent specimens were usually obtained during the first twelve hours of flowing. All patients kept basal body temperature charts. Hormone assays for urinary gonadotropins, estrogens, and 17-ketosteroids were done in selected cases but were not used routinely because of the expense involved and the frequently variable results. In our experience the endometrial biopsy is the most reliable index of ovarian function and is particularly valuable for assaying progestin activity. Also if basal body temperature graphs are properly kept, there is a very close relationship between ovarian function and the endometrial biopsy pattern. All 49 women had normally functioning tubes as determined by hysterosalpingography although 2 women had histories of previous bilateral ovarian surgery. Postcoital tests of cervical secretions in all instances* showed satisfactory sperm survival. Forty-seven couples were observed and treated for 3 months or more before irradiation was given and 33 women had been under our observation from 6 months to 13~ years. During this preliminary period diets, vitamin supplements, thyroid regulation where indicated and cyclic estrin therapy for those with hypoplastic uteri and long-standing amenorrhea had frequently been employed but without success in establishing regular spontaneous bleeding or regular ovulatory menstrual cycles. Cyclic estrin (stilbestrol) sufficient to develop the hypoplastic uterus or to produce at least one period of estrin withdrawal bleeding was administered ~ See exception Case 13.

4 Vol. 3, No. 6, 1952] LOW-DOSAGE IRRADIATION 503 to all women with amenorrhea. The response to irradiation treatment appears to be better when genital development is more normal. By establishing uterine bleeding first and starting the roentgen-ray treatment soon after the flow, and by prohibiting intercourse during the course of roentgen treatments, we feel reasonably certain we are not likely to radiate an unsuspected early pregnancy. Irradiation treatments were given* in series according to the technic of Kaplan, usually beginning the third or fourth day of uterine bleeding and at 5- to 7-day intervals for three treatments. If the pituitary and ovaries were both treated, therapy was given to both areas at the same sitting. Treatments to the ovaries each consisted of 75 r. and to the pituitary r. so that each patient received a total of 225 r. in the series of three treatments to the ovaries ( 0) and r. in the series of three treatments to the pituitary ( P). RESULTS Table 1 summarizes the results of irradiation treatment of 23 infertile women with fairly normal, cyclic uterine bleeding but with impaired ovarian function as indicated by abnormal basal body temperature graphs ( BBT) and/ or endometrial biopsies ( EB). Seventeen had atrophic or proliferative types of endometrium and the basal body temperature curve ( BBT) was flat or biphasic with a gradual rise. Five had gradually rising biphasic curves and the endometrial biopsies ( EB) showed but little secretory effect. Case # 11 showed a normal secretory type of endometrium but the BBT was considered abnormal. Sixteen of this group ( 70 per cent) showed definite improvement in BBT and/ or EB following treatment and 8 ( 35 per cent) became pregnant. Four have delivered at term and 1 of these is again pregnant at 5 months. Two women aborted first pregnancies and are now pregnant at the third and seventh months, and 2 are pregnant for the first time at 1 and 5 months. Table 2 illustrates a comparable study of the irradiation of 17 infertile women, one (age 23 years) with primary amenorrhea and 16 with secondary amenorrhea of from 3 months to 13 years duration. The case ( #25) with primary amenorrhea failed to respond to two series of treatments. Ten women (59 per cent) showed improvement in BBT and EB and 7 ( 41 per *The author is indebted to Dr. M. L. Pindell, Radiologist, Beverly Hills, California, for administering the roentgen-ray therapy to these patients.

5 TABLE 1. Irradiation Treatment of 23 Infertile Women Cause of Infertility Anovulation or Impaired Corpus Luteum Function Basal Menarche Uterine body Endo- Endocrine Married Infertile Irradiation age bleeding temp. me trial Patient status Age (yr.) (yr.) 0 bservation treatment (yr.) type curves* biopsiest Pregnancies (1) G.B. Pit. -ovarian May d q 28d G.R. A Nov. Same 1st & 2nd G.R. P.S. then B s. May 1952 (2) E.B. Pit.-ovarian Oct d scanty F. p (small q 2-5 mo. uterus) July d q 35d 1st&2ndB S. p 3rd G.R. P.S. 4th F. p Jan d at 8 wk. B. April 1952 (3) M.B. Ovarian 25 3)/z 2)/z March dq28-35d G.R. p June Same 1st G.R. P.S. 2nd B PregnantLMPtJuly Abortion 2nd mo. Sept. & Oct. B s Pregnant LMP Oct. May 1952 (Pregnancy at 7 mo.) (4) L.C. Pit.-ovarian 28 5)/z 3 Oct d q 5-10 wk. G.R. p Aug dq28-31d B s PregnantLMPNov. May 1952 delivered at term 6d Nov. & Dec. B Pregnant LMP Dec. (Pregnancy at 5 mo.)

6 (5) K.C. Pit.-ovarian 21 Aug d q 28d (dysmenorrhea) p Aug. 17'2 June dscanty G.R. P.S. Pregnant LMP Aug q 28d Abortion 3rd mo. 2d scanty 1st G.R. Jan.&Feb nd B Pregnant LMP Feb. May 1952 (Pregnancy at 3 mo.) (6) M.H. Pit.-ovarian March dq 26-32d G.R. P.S. (dysmenorrhea) Sept. 3-4d scanty B. s. q 25-27d April1952 (7) B.K. Pit.-ovarian March lrreg. & in- F -G.R. p freq. alternatingwith metrorrhagia March dq4-6wk. G.R. P.S. (Adopted Pregnant LMP June newborn Delivered June at term. Baby: 1950) Congenital pyloric April obstruction 1951 * BBT curves: Basal body temperature graphs; F: Flat; GR: Biphasic with gradual rise; B: Normal biphasic. t Endometrial biopsies-a: Atrophic; P: Proliferative; PS: Poor secretory (poor p~ogestational); S: Normal secretory (Normal progestational). t LMP: Last menstrual period.

7 TABLE 1. (Continued) Cause of Infertility Anovulation or Impaired Corpus Luteum Function Basal Menarche Uterine body Endo- Endocrine Married Infertile Irradiation age bleeding temp. me trial Patient status Age (yr.) (yr.) 0 bservation treatment (yr.) type curves biopsies Pregnancies (8) M. Pit.-ovarian )12 April dq27-28d G.R. P.S. Lem. Sept. Same 2 cycles B s theng.r. P.S. Pregnant LMP Dec. Delivered at term (9) M. Pit.-ovarian June dq26-28d G.R. p Les. Feb Same G.R. p July 1950 (10) D.L. Ovarian 34 4)12 2)12 July d q 28d F. A (rt. oophorectomy Oct. P Amenorrhea F and left Sept d q F except A oophoro d one cycle cystectomy Dec. B 1948) Oct uterus small (11) S.Mc. Pit.-ovarian )12 Jan dq26-28d G.R. July Same G.R. s. s. Child 4 yr. of age. May 1952 (12) T.M. Ovarian Oct d q 1948, aborted at 35-42d G.R. P. 2 mo. Feb. 1951, aborted at 6 wk. Aug d q 35d 2nd&3rd P.S. B theng.r. March 1952

8 (13) E.M. Pit.-ovarian 22 3!;2 3!;2 July dq6-8wk. F A (donor Oct. 3-4d q 25-1st G.R. insem.) (Insem. 27d then B. s. Nov Jan., Feb., April, May Pregnant LMP Apr. 1952) (Pregnancy 1 mo.) (14) N.R. Pit.-ovarian Oct dscanty F. A. Child 7!;2 yr. old q 1-3 mo. (March 2 abortions 5 yr ago adopted 1 abortion 3 yr. newborn) ago March 1950 Amenorrhea F. Menopausal May 1950 (15) R.R. Menopausal Jan dq24-26d G.R. P. Jan Same 4 cyclesb P.S. theng.r. P.S. Sept (16) H.R. Pit.-ovarian, Y2 3 Feb !;2d scanty G.R. P.S aborted at anxiety q28-30d 2!;2 mo. state May premature 6 Y2 mo. (living) 1944 stillborn at 7!;2 mo. Sept dq28-30d 4 cycles B s. theng.r. P.S. Pregnant LMP Dec (Pregnancy 5 mo.)

9 TABLE 1. (Concluded) Cause of Infertility Anovulation or Impaired Corpus Luteum Function Basal Menarche Uterine body Endo- Endocrine Married Infertile Irradiation age bleeding temp. metria/ Patient status Age (yr.) (yr.) Observation treatment (yr.) type curves biopsies Pregnancies (17) N.R. Pit.-ovarian March d q 28d F-G.R. P stillborn (term) 1941 term birth (living child) abortions Aug. 3dq26-31d G.R. P.S. Dec (18) I.S. Pit.-ovarian March d q 27d G.R. P.S. (small July 1950 Same G.R. P.S. uterus) Jan P Same G.R. P. March 1952 (19) E.Sm. Pit.-ovarian April dq26-27d G.R. P. Oct. Same G.R. P.S. March 1950 (20) E.Sp. Ovarian Nov d scanty G.R. A induced q 28d abortion Breasts Jan Same 1st B. P.S. engorged 2ndG.R. Polypoid G.R. P.S. May 1952

10 (21) u.s. Pit.-ovarian Oct d q F. A d March dq28-30d B. s. Pregnant LMP June July d q 6-7 wk. (22) L.W. Pit.-ovarian Aug mo. F. P. amen orrhea alternating with metrorrhagia Aug. 2-3dscanty F. P. q 28-45d Oct d q F. P d June 1951 (23) L.Y. Pit.-ovarian July dscanty G.R. P.S. q 36-38d Jan dq26-30d 4 cycles B. P.S. then G.R. P. :!# May 1951 Delivered at term

11 510 PAYNE [Fertility & Sterility cent) of the 17 treated became pregnant. In all there were 11 pregnancies; 4 having been pregnant twice, 1 delivered twice, 1 aborted and then delivered at term, 1 delivered at term then aborted, and 1 is now pregnant for the second time. There have been 7 term births and 1 patient is pregnant for the first time at 3 months. In Table 3 one woman with polycystic ovaries showed satisfactory improvement in BBT and EB for 5 months following irradiation but failed to conceive. Three women with pituitary exhaustion following childbirth failed to respond to the first series of irradiation. However, following a second series of treatment, Case #43 improved, became pregnant during the fourth cycle, and delivered at term. Table 4 summarizes the treatment of 5 infertile women with the benign adrenogenital syndrome. Four ( 80 per cent) showed improvement in BBT and EB and 3 ( 60 per cent) conceived. The highest incidence of miscarriage (50 per cent) occurs in this group. Case #47, after each series of treatments, became pregnant but miscarried at the fourth and at the fifth month, and amenorrhea followed each pregnancy. Case #49, who conceived during the same cycle that she received irradiation treament, miscarried a "blighted ovum" at 4 months and without further treatment subsequently carried and delivered 2 normal pregnancies at term. No definite change in hirsutism was observed in any of this group. Summary Thirty-two ( 65 per cent) of 49 women treated by pituitary and ovarian irradiation demonstrated improvement in basal body temperature curves and endometrial biopsy patterns. Nineteen patients conceived. There were 29 pregnancies: 15 full term, 7 miscarriages, and 7 patients now pregnant. The incidence of abortion and miscarriage was 24 per cent. DISCUSSION There were very few untoward effects of roentgen-ray therapy. Occasionally the month following tr.aatments there was mention of premenstrual pelvic discomfort, breast fu'llness, and increased nipple sensitivity. Case #20 was troubled with abdominal "soreness" for two or three weeks following therapy. Treatment seemed to precipitate amenorrhea in Cases # 10, #14, and #27, although with further irradiation, Case #10 returned to cyclic bleeding.

12 TABLE 2. Irradiation Treatment of 17 Infertile Women Cause of Infertility Ovarian Dysfunction with Amenorrhea Three or More Months Basal Menarche Uterine body Endo- Endocrine Married Infertile Irradiation age bleeding temp. metria! Patient status Age (yr.) (yr.) Observation treatment (yr.) type curves biopsies Pregnancies (24) D.B. Pit.-ovarian 26 1}-2 1}-2 March Amenorrhea F. P. 2 yrs. July F. May 1952 (25) C.B. Ovarian 23 Aug Never F. A. (primary Dec. hypogonad) }-2 Aug Amenorrhea F. P. Better Jan Amenorrhea F. P. developed uterus, vagina, etc. May 1952 (26) J.B. Pit.-ovarian 18 Nov Amenorrhea A. 3}-2 yr. Jan. Single mense (afterpms) 6 June 1948 Sd q 28d B. s. Pregnant LMP Jan Delivered at term. March d q 28d Pregnant LMP Oct (Pregnancy at 5 mo.)

13 TABLE 2. (Continued) Cause of Infertility Ovarian Dysfunction with Amenorrhea Three or More Months Basal Menarche Uterine body Endo- Endocrine Married Infertile Irradiation age bleeding temp. metria/ Patient status Age (yr.) (yr.) Observation treatment (yr.) type curves biopsies Pregnancies (27) N.B. Ovarian 23,3 3 Nov Amenorrhea F. A. 5mo. (Bilateral Feb P 3-4d scanty 1st G.R. P. oophor- q 23-27d then F. P. ocystectomy Jan Amenorrhea F. A. Nov. 1948) May 1952 (28) G.E. Pit.-ovarian Nov Amenorrhea F. P. 5 mo. May d q 26-28d G.R. P.S. July 1950 (29) B.Gr. Ovarian 24 Oct Amenorrhea A. (small 10 mo. uterus) Feb F. 2 March d scanty B. s. Pregnant LMP July q 4-6 wk. D&C Sept. Aborted 2 mo. (blighted ovum) 5-6d Oct. & B. s. PregnantLMPNov. Nov. Delivered at term. Feb Amenorrhea 5 mo.

14 (30) J.H. Pit.-ovarian Sept Amenorrhea F. A. 3mo. Jan d heavy q 2 cyclesb s d then grad- theng.r. P.S. ually scanty April1951 (31) C.H. Pit.-ovarian Sept Amenorrhea A. (small 10 yrs. uterus) June 1949 Amenorrhea F. Nov. Amenorrhea F. April1950 (32) P.H. Pit.-ovarian March d q F. P. 3-4 mo. June 5d q 2-3 F. P. mo. Dec. 5d at 29d G.R. P.S. then 2 mo. Feb (33) N.K. Pit.-ovarian 16 Feb Irreg. & A. (small infreq. uterus) Amenorrhea 7mo. March 172 Dec Amenorrhea F Dec. 1951

15 TABLE 2. (Concluded) Cause of Infertility Ovarian Dysfunction with Amenorrhea Three or More Months Basal Menarche Uterine body Endo- Endocrine Married Infertile Irradiation age bleeding temp. me trial Patient status Age (yr.) (yr.) Observation treatment (yr.) type curves biopsies Pregnancies (34) A.K. Menopausal Nov Regular up to past yr. F. A. Child 9 yr. old Amenorrhea 4mo. Jan P 3d scanty q 19-27d G.R. P.S. Feb (35) E.K. Pit.-ovarian 17 April Irreg. & P. infreq. Amenorrhea 7 mo. Oct. 1Y2 April 1950 G.R. Pregnant LMP Apr Delivered at term. (36) M.L. Pit.-ovarian 29 2Y2 1Y2 June d q 30-45d Amenorrhea F. P. 3mo. Sept. 5d q 25-30d 2 cycles B s. theng.r. P.S. March 1952 (37) S.Mic. Pit.-ovarian May d scanty (small q 25-35d uterus) Amenorrhea 6 mo. Sept. D&C P. Oct. 4d q 30d B. s. PregnantLMPNov. Delivered 42 wk. May d q 23-24d PregnantLMP Aug Delivered at 41 wk.

16 (38) S.Miy Pit.-ovarian 27 1)..2 1)..2 Oct Sd scanty q 1-6 mo. G.R. P. Amenorrhea 3mo. Dec. 2-3d q B. s. Pregnant LMP Feb d May 1952 (Pregnancyat3mo.) (39) A.T. Pit.-ovarian Nov Sd q 30-31d F. A. Amenorrhea 9mo. July d q 29-31d G.R. P.S. Sept. Same G.R. P.S. Pregnant LMP Feb Delivered at term. 11 May d scanty q 26-29d G.R. P.S. Sept. Same G.R. P.S. Pregnant LMP May Aborted at 3 mo. Feb Same G.R. P.S. (40) H.W. Pit.-ovarian Dec Sd q G.R. P Spont. aboranxiety 1-3 mo. tion. state Amenorrhea (small 6 mo. uterus) (Diaphragm July d q 26d B. s. contraception Pregnant LMP May Aug to Delivered Feb. 1951) at term.

17 TABLE 3. Irradiation Treatment of 4 Infertile Women Cause of Infertility Polycystic Ovaries (Stein-Leventhal Syndrome) (Case 41) and Pituitary Injury or Exhaustion at Delivery (Sheean's Disease) (Cases 42-44) Ba.sal Menarche Uterine body Endo- Married Infertile Irradiation age bleeding temp. metria! Patient Age (yr.) (yr.) 0 bservation treatment (yr.) type curves biopsies Pregnancies (41) J.S )1 July d q 6-12 G.R. A. wk. Oct. Same 5 cycles B s. theng.r. P.S. April1952 (42) R.D )1 May d q 6 wk. Since childbirth Amenorrhea F. P. Child 2)1 yr. old. Jan Amenorrhea F. P. April1952

18 (43) C.D June d q month Child 3~ yr. old. Since childbirth 2d scanty q 3-5 mo. Amenorrhea 5 mo. F. A. Jan Amenorrhea F. P. June 5d q 25-31d 1st 2 G.R. P.S. Dec rd & 4th B 4-5d q month Pregnant LMP Aug. Delivered at term. (44) N.E. 26 4~ 3~ April d q 25-35d Child 3~ yr. old. Since childbirth Amenorrhea F. A. Oct. Amenorrhea F. P. April 1952

19 TABLE 4. Irradiation Treatment of 5 Infertile Women Cause of Infertility Benign Adrenogenital Syndrome Basal 24-hr. Menarche Uterine body Endo- urine Married Infertile Irradiation age bleeding temp. metria[ 17-keto Patient Age (yr.) (yr.) Observation treatment (yr.) type curves biopsies (mgm.) Pregnancies (45) M.C. 28 5).1 5).1 July d q 28d G.R. P.S Dec. Same G.R. P.S. Jan (46) V.D. 31 Feb d q 1-12 mo Oct. Irreg. & 1946 infreq. F. P April d scanty B. s. q 30d Feb (47) B.G Feb Irreg. q 3-9 mo. F. A. Amenorrhea 7 mo. March 1952 Sept. 6d at 2nd mo. B. P.S. Pregnant LMP Nov. miscarried at 4 mo. (? blighted ovum) q 5-7 wk. 3 cycles Amenorrhea 5 mo. March d q 5-6 B. P.S. Pregnant LMP Aug. wk. miscarried at 5 mo. (normal fetus).

20 (48) P.M Jan Amenorrhea F. A mo. alternating with metrorrhagia May d q 6-8 1st F. Breasts wk. then G.R. P. engorged Dec. P 3d scanty at 45d 1st B P.S. thenf-g.r. Pregnant LMP May Delivered at April1952 term. (Nursing) (49) P.M. 24 Jan d scanty q 30d F. P Jan. Same Aug d q 30d B. Pregnant LMP Aug. miscarried at 4 mo. "Blighted ovum." March to May d q G.R. P.S. Pregnant LMP May 27-29d 1949 Delivered at term. May 1950 to May 1951 Same G.R Pregnant LMP May Delivered at term. Feb. 1952

21 TABLE 5. Results of Low-Dosage Irradiation of 49 Infertile Women with Endocrine Dysfunction Anovulation or impaired corpus luteum function Amenorrhea (1 primary 16 secondary 3 mo.-13yr.) Polycystic ovaries Pituitary exhaustion or damage following delivery Benign adrenogenital syndrome Total Total number cases treated Number improved BBT and EB * Percentage improvement BBT and EB * Number women pregnant 8.., I Percentage pregnant Total number pregnancies Term births 4 7 Number presently pregnant 5 2 Number abortions and miscarriages 2 2 Percentage abortions and miscarriages so 24 *BBT-Basal body temperature graphs. EB-Endometrial biopsies.

22 Vol. 3, No. 6, 1952] LOW-DOSAGE IRRADIATION 521 Not infrequently patients volunteered that they felt much better after treatments. The mental outlook and energy improved and menstruation generally was more normal. Those with scanty infrequent menstruation flowed more regularly and more copiously, while the 3 women with metrorrhagia flowed less heavily. Those with dysmenorrhea usually reported freedom from discomfort. Only 2 of 6 women 35 or more years of age developed appreciable benefit from irradiation treatment. Although Case # 15 ( 44 years) showed improved function and Case #34 resumed cyclic uterine bleeding, both failed to conceive. Two young women (Cases #10 and #27) with approaching menopause, following ovarian surgery, failed to respond to irradiation therapy. There were no pregnancies in this menopausal group. All but one case ( #34) received roentgen-ray treatments to the pituitary and ovaries. of the women showed variations in the glucose tolerance, basal metabolic rate, serum cholesterol, or the protein-bound iodine which could be attributed to the irradiation therapy. Vaginal smears were useful in determining estrogenic function and correlated well with the clinical observations, basal temperatures, and endometrial biopsies. Most gynecologists agree that low-dosage irradiation is effective but there is much conjecture concerning the mechanism of its action. Some believe the effect is entirely psychosomatic. In probing the attitude of many of our patients toward their roentgen-ray treatments we find that the majority accept the procedure more with an added feeling of frustration rather than with any expectancy or anticipation. Although we attempt to maintain a level of optimism, it is doubtful if many of the successes can be attributed to the psychogenic factor alone. Drips examined the ovaries of rats following low-dosage irradiation and noticed considerable congestion. With this congestion she theorizes there may be increased hormone elaboration. Hartman and Smith reported a study of 13 nonovulatory rhesus monkeys treated with a single dose of r. to the pituitary. There was no increase in ovarian size in 11 animals and in only 1 case did the animal ovulate. Rock expressed the theory that roentgen therapy destroys one or more follicles that have matured, but which have failed to rupture and progress through a normal corpus luteum phase. He feels that irradiation destroys these mature follicles and allows a new crop of follicles to develop. Clinically, he found no difference in patients whose pituitary and ovaries were irradiated from those whose ovaries were treated alone. He concluded that treatment to the pitui-

23 522 PAYNE [Fertility & Sterility tary is of no value. All of his later cases received irradiation of the ovaries alone. The wide variety of responses observed in the treatment of the 49 women presented here leads us to believe the action may be quite variable and complex. Case #35, with long-standing menstrual irregularity and amenorrhea, became pregnant the month she took roentgen-ray therapy, whereas Case # 11, the most nearly normal of the 49 women presented, failed to respond. Case #26, with years of amenorrhea, was apparently cured after one series of treatments, whereas several women such as Case #47 received only transient benefit. In the majority of the responsive women the maximum effect occurred within a few weeks, but there were a few (such as Case #43) who obtained increasing benefit over a period of several months from a single series of treatments. Five women received a series of treatments to the pituitary alone and 4 of these also were given a series of treatments to the pituitary and ovaries. Case # 10, with fairly regular cyclic bleeding, developed amenorrhea after pituitary irradiation but resumed bleeding again after another series of therapy to both the pituitary and the ovaries. Case #27, with amenorrhea, began cyclic bleeding following treatment to the pituitary alone but ceased to menstruate after combined therapy to both pituitary and ovaries. Case #48, having previously received treatment to both pituitary and ovaries, seemed to derive additional benefit from subsequent pituitary treatments alone and ultimately became pregnant. Menopausal Case #34 resumed cyclic bleeding for more than a year following treatment to the pituitary alone. While most clinicians now favor treatment directed to the ovaries alone, pituitary irradiation may be effective. Because of these variable results and the fact that new technics may be forthcoming, we prefer still to consider the pituitary as well as the ovary when irradiation therapy is employed. The high incidence of abortion and miscarriage, 24 per cent of 29 pregnancies, in this group will be the subject of a future paper. During early pregnancies basal temperature records were kept and the patients examined by vaginal smears and vulval luminescence at least every two weeks. Many of the pregnant women exhibited hormonal deficiencies and were given supportive therapy with estrogens and/ or progesterone. Several of these women carried to term. In many instances where abortion or miscarriage occurred, the products of conception were examined by pathologists and

24 Vol. 3, No. 6, 1952] LOW-DOSAGE IRRADIATION 523 many proved to be defective. However, the incidence of defective babies in our infertility group is no higher than is generally observed. One baby born with a pyloric obstruction required operation at 5 days of age, but is now healthy and robust at 14 months of age. This mother failed to conceive until 27 months following the irradiation therapy and is included in the group only because some might feel that irradiation was a factor in the defective offspring. We do not feel that this is the case. CONCLUSIONS Mter the time-honored approach to the problems of infertility have failed, irradiation therapy to the ovaries and pituitary offers the infertile woman with ovarian dysfunction the greatest hope for offspring. REFERENCES 1. CHANTRAINE, H. Roentgen Blatter 5:1, DRIPS, D. G. Am. ]. Obst. & Gynec. 55:789, EnEIKEN, L. Am. ]. Obst. & Gynec. 25:511, FINKLER, R. Am.]. Obst. & Gynec. 58:559, HARTMAN, C. A., and SMITH, C. Proc. Soc. Exper. Biol. & Med. 39:390, KAPLAN, I. I. Am.]. Obst. & Gynec. 21:52, KAPLAN, I. I. Fertil. & Steril.1:123, MAZER, C., and ANDRUSSIER, I. Am.]. Obst. & Gynec. 22:46, MAZER, C., and GREENBURG, R. Am.]. Obst. & Gynec. 46:648, MuLLER, H. J. Science 66:84, PAYNE, S., and TYLER, E. T. Exhibit: Endocrine Factors in Fertility. A.M.A. Convention, RAKOFF, A. E. Fertil. & Steril.1:504, RocK, J., BARTLETT, M. K., GouLD, A. G., and RuTHERFORD, R. N. Surg., Gynec. & Obst. 70:903, RuBIN, I. C. Am. ]. Obst. & Gynec. 12:76, RuBIN, I. C. New York State]. Med. 46:2621, Soc. for the Study of Sterility Fertil. & Steril. 2:1, DISCUSSION DR. S. LEON IsRAEL, Philadelphia, Pa.: The opportunity of opening the discussion is greatly appreciated. The results attained by means of low dosage irradiation in Dr. Payne's series of infertile women are in consonance with the clinical reports published during the past 25 years and they speak for themselves. The essayist has quite properly pointed out that the reluctance of most gynecologists to employ low dosage irradiation is based, in the main, upon two objections: ( 1) the fact that its precise histologic and physiologic effect is unknown; and ( 2) fear of injury to the germ plasm. Theories of the mode of action of small roentgen doses remain, despite various opinions based upon experiments, widely divergent and contradictory. Overt anxiety concerning the genic effects of pre-

25 524 PAYNE [Fertility & Sterility conceptional low dosage irradiation stems from two sources: confusion with the proved fact that postconceptional irradiation is harmful to the embryo, and the speculative applicability to man of the increased mutation-frequency induced experimentally in plants and animals. Two major differences must, however, be noted between the experimental observations and the possible effects in man: the comparatively excessive dosage of roentgen rays employed experimentally to study the genetic effects, and the necessity of irradiating the whole body of most of the experimental animals, a type of irradiation which is followed by a complicated series of interrelated functional changes. While I agree with Dr. Payne that the dangers of low dosage irradiation have been overemphasized and that the widespread attitude of alarm should be discarded, I do believe that two hazards exist in its clinical usage. First, there is a direct linear relation of radiation dosage to genetic disasters in animals and, since we do not know the upper limit of safety in man, the low dosage must be carefully maintained. Second, the incidence and severity of fetal damage by roentgen rays are proportionate to both the dosage of irradiation and the immaturity of the exposed embryo. The recent report of the birth of a normal child following the unknowing use of low dosage irradiation to the ovaries after the inception of pregnancy is not sufficiently reassuring to warrant freedom from fear of the effects of such irradiation on a developing embryo. I wish to underscore and re-emphasize Dr. Payne's precautionary admonition that low dosage irradiation should never be instituted during a period of amenorrhea, irrespective of the patient's history of prior barrenness, without definite knowledge regarding the absence of pregnancy. My use of low dosage irradiation is limited to patients with secondary amenorrhea between the ages of 20 and 35 years because the clinical end-point in such patients is more exact than that in regularly menstruating women. Accordingly, I adhere to the wise advice of Dr. Payne to begin roentgen-ray therapy after either an induced or a spontaneous menstrual period, and to have the patient assiduously avoid conception during the brief period of treatment. The favorable response of amenorrheal women selected in this way appears, as Dr. Payne states, undisputed. DR. CHARLES L. BuxTON, New York City: It has been a great pleasure to hear Dr. Payne's paper and Dr. Israel's interesting discussion. I think that there is little doubt in anybody's mind now that irradiation of the ovaries has a definite effect on ovarian function. As has been expressed both by Dr. Payne and Dr. Israel, the mechanism of this effect is apparently unknown. I was delighted that neither of these gentlemen used the word "stimulating" in connection with irradiation of the ovary. Radio-physicists tell us that irradiation destroys and does not stimulate activity or growth. The question that bothers us all, of course, and which both Drs. Payne and Israel mentioned, is whether or not there is a possibility of producing any chromosomal mutations by irradiation of the gonads which may result in fetal monstrosities in later generations. Experimental investigations with mammals on the probability of specific irradiaton causing chromosomal mutations resulting in monstrosities in subsequent generations have been carried out. Abnormalities occur, not in the first, but in subsequent generations. Therefore, the fact that monstrosities occur in the first generation is not of particular signifi-

26 Vol. 3, No. 6, 1952] LOW-DOSAGE IRRADIATION 525 cance, as Dr. Payne and Dr. Israel both said. On the other hand, I do think the problem of whether or not low dosage irradiation is going to produce sufficient chromosomal mutations to result in abnormalities in subsequent generations does not rest with us as gynecologists, but with geneticists. I must disagree with Dr. Israel when he speaks of terrific and excessive doses given to mice and rats in the laboratory compared with those administered to humans with the usually-accepted technic. Actually, only the accepted amount of irradiation can be given to a sinall animal, because in order to have subsequent genesis it must be a sub-sterilizing dose and, therefore, cannot be a large one. The fact was mentioned that the whole body was irradiated. I cannot see why total body irradiation would produce a greater effect on the individual chromosome in the ovum of the animal than localized irradiation. Expecting that this problem would come up, I brought along a few notes prepared by a geneticist, Dr. Roberts Rugh, Associate Professor of Radiology, Columbia University. I would like to read a few brief comments taken from the genetic literature. These are not my ideas. The genetic literature has been fairly carefully reviewed by Dr. Rugh, these notes having been taken from 75 or 80 references on the effects of ionizing irradiation. "Ionizing radiations are the most effective form of activation which brings about hereditary changes, no matter how small the dose. The effects of radiations on genetic material are cumulative. Most effects are harmful and therefore undesirable. A total dose of 50 r. doubles the rate of the spontaneously-appearing mutations in the animal. The effect is long delayed and is never seen in the first generation. It will, however, eventually cause a genetic death. It is conceivable that any exposure to ionizing radiations of the gonads carries some hazard. If 20,000 people are exposed so that their gonads receive 150 r. x-rays, 1,000 will eventually die a genetic death and several thousand will be maimed. For each 100 r. to which the human sperm are exposed, 10 per cent of the subsequently fertilized eggs will die in utero and 0.5 per cent of the live-born children will show structural abnormalities, and many of them will prove to be sterile or semisterile as adults." DR. SoPIITA J. KLEEGMAN, New York City: I have had 1 case of an anencephalic monster in which there was no pregnancy at the time of administration of the x-rays. I have also had 1 case of spontaneous abortion, the woman subsequently becoming pregnant and delivering a normal baby. The patient who had the anencephalic monster became pregnant after no treatment. I advise my patients not to allow themselves to become pregnant until they have had two ovulatory cycles. Most of them begin to menstruate immediately after treatment. Yesterday, Dr. Jones reported 3 pregnancies after cortisone; 2 of these aborted. Both of these patients became pregnant immediately after the first ovulation. The rest became pregnant after the third ovulation. I would like to ask Dr. Payne, Dr. Israel, and Dr. Buxton whether any time is required to prepare the ovum. DR. SHELDON PAYNE, closing: I want to thank you all for your fine discussions and suggestions. This subject is very controversial, and there are many varied

27 526 PAYNE [Fertility & Sterility opinions concerning the effects of irradiation. We are all agreed that roentgen rays are a potent therapeutic medium and should only be employed when their limitations and dangers have been carefully considered. In answer to Dr. Kleegman's question, I think that when you have the opportunity to study the tables you will note that in some women the effects of x-rays seem immediate, and in others they are delayed; in some patients the effects seem transitory, and in others, permanent. There may be danger of irradiating an early pregnancy and we were careful to avoid that. However, some of our women became pregnant the same month x-ray treatments were given. In all instances intercourse was avoided until after the x-ray series had been completed. Also, in those who became pregnant, basal temperature records in all cases showed ovulation occurring after the last x-ray treatments had been given. Although the number of these pregnancies was small, in our series there was no increase in the incidence of abortion and miscarriage in this group. Atomic medicine is making rapid strides. With the many studies now in progress, our knowledge of irradiation therapy should be much more thoroughly elucidated within the next few years.