Hormonal Changes Following Low-Dosage Irradiation of Pituitary and Ovaries in Anovulatory Women

Transcription

1 Hormonal Changes Following Low-Dosage Irradiation of Pituitary and Ovaries in Anovulatory Women Further Studies A. E. Rakoff, M.D. Tms PRESENTATION is a second progress report in a long-term study of the effects of low-dosage irradiation directed to the pituitary, the ovaries, or both, of women with persistent anovulatory infertility who failed to respond to other methods of treatment. The purpose of this investigation was not only to evaluate the clinical results in a standardized group of patients, but to follow more precisely the effect of treatment on the pituitary and ovary by hormonal assays and other pertinent studies relating to endocrine function before, during, and for at least six months following irradiation therapy. From such studies it was hoped that some informative data would be obtained concerning the following specific problems: 1. Does low-dosage irradiation actually stimulate the endocrine function of the pituitary or the ovary in women with prolonged anovulation? Is the endocrine function of either of these glands inhibited in some patients? 2. In either case are the results primarily due to irradiation of the pituitary, the ovaries, or both? 3. What are the endocrine changes and the sequence in which these effects appear? How are they mediated? From the Department of Obstetrics and Gynecology, and the Division of Endocrine and Cancer Research, Jefferson Medical College and Hospital, Philadelphia, Pa. Presented at the First World Congress on Fertility and Sterility, New York City, May 27,

2 264 RAKOFF [Fertility & Sterility 4. Are these effects obtained in patients with diminished gonadotropic activity, or those with a primary ovarian deficiency, or both? 5. How soon is the endocrine function of the pituitary-ovarian mechanism influenced by irradiation, and how long does the effect continue? The pertinent literature relating to these questions have been reviewed in our first report,6 together with preliminary observations on some of these phases gathered from a study of the first 12 patients. SELECTION OF PATIENTS Only those patients were accepted for this type of treatment who were under our direct supervision for at least two years because uf anovulatory infertility, and in whom appropriate investigation revealed no additional significant factors in the patient or her husband to account for the infertility. The diagnosis of an anovulatory state was established by endometrial biopsies, basal temperature charts and hormonal studies. All of these patients had failed to respond adequately to other methods of treatment, such as repeated courses of various hormonal therapies, thyroid if indicated, vitamins and dietary measures for nutritional disturbances, or sedation and superficial psychotherapy for nervous and emotional factors. As a rule only patients under the age of 35 years were considered acceptable for low-dosage irradiation therapy. Two exceptions were made for special reasons, one in a 37-year-old woman with an adrenogenital syndrome and another in a 41-year-old woman with a gonadotropic deficiency. METHODS OF STUDY All patients were given a rest period from all treatment for at least a month before starting a preliminary observation period of another month. During the latter cycle, hormonal bio-assays were made at weekly intervals on a twenty-four hour urine specimen for gonadotropins* and estrogenst; pregnandiol determinationst were made in some instances, usually in cycles in which an endometrial biopsy was not taken. 17-Ketosteroids were fol- * Gonadotropins were determined by a modification of the mouse uterine weight method4 on an alcohol precipitate of the urine. t A partially purified steroid extract of the hydrolyzed urine was assayed on castrated mice by a modification of the Allen-Doisy method. t Pregnandiol was determined on urinary extracts by the colorimetric method of Sommerville et al. 17-Ketosteroids were determined on a partially purified carbon tetrachloride extract of the hydrolyzed urine using the Zimmerman reaction.lo

3 Vol. 4, No. 4, 1953] LOW-DOSAGE IRRADIATION 265 lowed in selected cases. Vaginal cytologyl! smears for estrogen effect were taken once weekly. Endometrial biopsies~, which had been taken at intervals during the previous two years, were repeated before therapy. The basal temperature charts were continued. Hormonal assays were repeated at weekly intervals during the first four weeks after irradiation therapy was started and were then taken at approximately monthly intervals for six months, except when pregnancy occurred sooner. Vaginal smears were made frequently, and endometrial biopsies were repeated in some of the patients. Basal temperature charts were kept continuously. METHODS OF TREATMENT** To the first group of 20 patients low-dosage irradiation was given to the pituitary and ovaries in three divided doses, at weekly intervals, following the technic of Kaplan. To a second group of 20 patients the same dosage of ovarian irradiation was given, but no treatment was given to the pituitary. These patients were instructed to avoid becoming pregnant during the course of irradiation therapy. In a third group of patients which is now under investigation pituitary irradiation alone has been used, with none to the ovaries. Since only 5 patients in this group have completed their therapy and their full observation period has not been completed, the results have not been included in this report. RESULTS AND COMMENT The occurrence of pregnancy is of course, the most convincing evidence of the return of normal ovarian function. On the other hand, ovulation on one or more occasions may occur without resulting conception. In other instances there may be improvement in follicular activity without ovulation or luteinization. For these reasons a battery of appropriate studies gives far more complete evidence of changes in hormonal activity of the ovary and pituitary than is afforded by the clinical manifestations alone, such II A rapid vagina1 smear technic described by Rakof 7 was employed. 1f Endometria] biopsies were fixed in absolute alcohol and stained with hematoxylin and Best's carmine to demonstrate glycogen. **The author is indebted to Dr. Theodore P. Eberhardt and Dr. J. G. Teplick for administering therapy to these patients.

4 266 RAKOFF [Fertility & Sterility as the occurrence of pregnancy, and changes in the menstrual cycle. In the same way worsening of the function. of the ovary may be suspected on the basis of a change in menstrual function or the appearance of "menopausal" symptoms, but can be more accurately established by objective studies of ovarian function. TABLE 1. Low-Dosage Irradiation to Pituitary and Ovaries, and to Ovaries Alone Comparison of Results Pituitary and Ovaries Ovaries alone No. % No. % Number of patients Improved Estrogenic function Corpus luteum function Became pregnant No change 7 6 Made worse 1 3 It will be noted from Table 1 that some degree of improvement occurred in 12 ( 60 per cent) of the 20 patients who received irradiation to the pituitary and ovaries and in 11 (55 per cent) of the 20 patients in whom the ovaries alone were irradiated. In each of these 23 patients there was an improvement in estrogenic function as indicated by significantly increased amounts of estrogens in the urine and improvement in the vaginal smears. In the first group, 9 ( 45 per cent) of the women also showed good corpus luteum function and 7 ( 35 per cent) became pregnant. The corpus luteum activity was reflected in basal temperature charts, endometrial biopsies, or pregnandiol excretion. In almost every instance in this group there was a concomitant improvement in menstrual function, particularly in the patients who had oligomenorrhea or secondary amenorrhea. As we have previously emphasized, 6 basal temperature charts were reliable indicators of improvement in those patients who showed corpus luteum activity, but of course did not reflect the improvement in the several patients who had only increased follicular activity. Of the second group who received only ovarian irradiation, 8 ( 40 per cent) of the women showed corpus luteum function and 7 ( 35 per cent) became pregnant. No significant changes occurred in 7 of the patients in Group I and 6 of the patients in Group II.

5 Vol. 4, No. 4, 1953] LOW-DOSAGE IRRADIATION 267 It is thus apparent that ovarian irradiation was followed by favorable results quite comparable to combined pituitary and ovarian irradiation, both in the number of resulting pregnancies and objective improvement in hormonal pattern. Similar favorable effects evaluated by endometrial biopsy had been reported by Rock and his associates. One patient who received irradiation to the pituitary and ovaries was made worse and 3 who received irradiation to the ovaries alone showed unfavorable effects. One of these was a woman, aged 41, who should perhaps be omitted from statistical evaluation because of her age. Since the number of cases involved is so small, it is doubtful that any significance can be attached to the differences in untoward results in these two groups, particularly if the latter case is omitted. These 4 cases are discussed separately below. It is of interest to compare the results of treatment of irradiation therapy in relationship to the endocrine status of the patients (Table 2). It will be TABLE 2. Comparison of Results in Correlation to Endocrine Status Number of patients Improved Estrogenic function Corpus luteum function Became pregnant No change Made worse Gonadotropic deficiency No. % Primary ovarian deficiency No. % noted that there were 32 patients who had a gonadotropic deficiency with secondary ovarian hypofunction, whereas 8 patients had a primary ovarian deficiency characterized by diminished estrogens and high gonadotropins. It is apparent at once that the patients with a gonadotropic deficiency had a far better response than the smaller group with a primary ovarian deficiency, improvement occurring in 21 ( 66 per cent) of the former and in 2 ( 25 per cent) of the latter. It is to be noted that one of the 2 patients in the second group who showed improvement also developed good corpus luteum function and became pregnant. Seventeen (53 per cent) of the patients in the first group had improvement in both estrogenic and corpus luteum function and 13 ( 41 per cent) of these became pregnant. Of the 4

6 268 RAKOFF [Fertility & Sterility patients who became worse after therapy, 3 occurred among the 32 patients with a gonadotropic deficiency and l in the 8 patients with a primary ovarian deficiency. The effectiveness of the low-dosage irradiation to the pituitary and ovaries in patients who had either a pituitary gonadotropic deficiency or a primary ovarian deficiency was previously noted by Drips, and by Mazer and Israel. One patient with an adrenogenital syndrome and gonadotropic deficiency showed improvement in follicular function after each of 2 courses of x-ray therapy; the results in this case have been discussed previously. 6 In our initial report, 6 dealing with the first 12 patients treated with lowdosage irradiation to the pituitary and ovaries, it was noted that a favorable response was indicated by an increase in estrogen promptly after the irradiation therapy. Almost always this has occurred within four weeks after treatment was completed, and occasionally was seen even before the third dose had been given. Conceptions occurred from two weeks to five months after completing treatment, most often in the second cycle. We have continued to observe that in the patients with gonadotropic deficiencies the rise in estrogens is far more clear-cut and more marked than the rise in gonadotropins and usually precedes the latter. It would appear that the ovaries become more responsive to even the minimal amounts of gonadotropic hormone present. There is a mbsequent rise in gonadotropic hormone in many cases, which perhaps may be secondary to the improved estrogen function of the ovary. This point of view now seems even more likely since precisely the same hormonal patterns were noted in the patients who had ovarian irradiation alone. In light of these observations together with the comparable clinical results, it seems that it is the irradiation to the ovary which is primarily responsible for the beneficial effect and that pituitary irradiation may be omitted. To establish with greater certainty that pituitary irradiation does not exert a stimulatory or inhibiting effect on the gonadotropic hormones with a secondary influence on the ovary, it is necessary to treat and study a similar group of patients after pituitary irradiation alone. As indicated above, observations on such a group are now under way and will be reported. If the results in this group are not favorable after a six-month period, these patients will be encouraged to complete their therapy with ovarian irradiation. In the 2 patients with a primary ovarian deficiency in whom improvement

7 Vol. 4, No. 4, 1953] LOW-DOSAGE IRRADIATION 269 occurred, there was a simultaneous fall of the gonadotropins and a rise in the estrogens. Since one of these patients received irradiation therapy to the ovary alone it would seem again that the initial effect was one of increased responsiveness on the part of the ovaries, with prompt suppression of pituitary gonadotropin function, rather than an inhibiting effect of the pituitary irradiation on the gonadotropins. In both of these patients the favorable effects occurred within 4 weeks following the completion of therapy. Of the 10 patients who showed improvement but did not become pregnant, the beneficial effects diminished or disappeared in 6 patients in from three to six months. Four patients continued to show improvement in menstrual pattern and estrogen secretion beyond the six-month observation period. Untoward Results The unfavorable effects of x-ray therapy which occurred in 4 of the 40 patients are summarized in Table 3. It is of interest that 3 of these patients Patient, Age, X-ray therapy A. G., 29 Ovary and pituitary M. H., 34 Ovary B. W., 30 Ovary J. M., Ovary 41 TABLE 3. Endocrine status Gonadotropins and estrogens diminished; oligomenorrhea Gonadotropins and estrogens diminished; menses q. 3-8 wks.; cystic hyperplasia of endometrium Gonadotropins excessive; estrogens slightly diminished; polymenorrhea Gonadotropins d i - minished; estrogens slightly diminished, menses q days Untoward Results Clinical change Amenorrhea and hot flashes for 5 months Severe dysfunctional bleeding and hot flashes for 3 months Secondary amenorrhea; mild Hashes for 3 months Secondary amenorrhea; mild Hashes for > 6 months Hormonal change Gonadotropins e x - cessive; estrogens diminished Gonadotropins e x - cessive; estrogens diminished Gonadotropins e x - cessive; estrogens diminished Gonadotropins elevated; estrogens diminished

8 270 RAKOFF [Fertility & Sterility had a gonadotropic deficiency and only one had a primary ovarian deficiency. Although the group is too small for quantitative evaluation, it is clearly evident that women with failure of ovulation secondary to the gonadotropic deficiency can experience an unfavorable action on the ovaries to even the small dosage of irradiation empl~yed. The fact that the unfavorable action is mediated through the ovary is indicated by the prompt fall in estrogens and the simultaneous rise of the gonadotropins to excessively high levels (96 to more than 192 m.u.j24 hours). Fortunately, the unfavorable effects wore off in 3 of 4 patients within the six-month observation period. None of them later showed an improvement beyond their pre-treatment' stage. It is of interest that one of these patients ( M.H.) developed almost continuous uterine bleeding as well as hot flashes for a three-month period, rather than amenorrhea as occurred in the others who reacted unfavorably. The fourth patient developed an amenorrhea which has persisted for more than six months together with vasomotor symptoms. In this woman, aged 41, low-dosage irradiation therapy was suggested despite her age because of the intense desire to try every method of therapy for primary infertility, after failure to respond to long-continued treatment with other means. Her cycle had been only slightly irregular and gonadotropins were diminished. This case again shows that diminished gonadotropins offers no assurance that an untoward effect may not occur, even though the chances for a favorable result seems greater than in those with a primary ovarian deficiency. SUMMARY 1. In this second progress report the effects of low-dosage irradiation were studied in 40 women with long-standing anovulatory infertility which had been resistant to other forms of treatment. Twenty patients received treatment to the pituitary ovaries, and 20 received ovarian irradiation alone. Hormone assays were made before, during and for six months following treatment. Endometrial biopsies, vaginal smears, and basal temperature charts were also evaluated. 2. The clinical and laboratory results in both groups were comparable, improvement in ovarian function occurring in 60 per cent of the first group and 55 per cent of the second group, with pregnancy resulting in 35 per cent of each group.

9 Vol. 4, No. 4, 1953] LOW-DOSAGE IRRADIATION The hormonal studies suggest that low-dosage irradiation increases the sensitivity of the ovaries to the gonadotropic hormones. 4. Patients with a gonadotropic deficiency are more likely to improve following low-dosage irradiation than are those with a primary ovarian deficiency. Improvement occurred in 21 of 32 patients of the former group with 13 becoming pregnant, while in the latter group only 2 of 8 improved, and 1 became pregnant. 5. Untoward results occurred in 4 patients, three with a gonadotropic deficiency, and one with a primary ovarian deficiency. These effects were temporary in 3 patients and permanent in 1 older patient, age The effects of irradiation, both favorable and unfavorable, were generally evident within four weeks after treatment. REFERENCES 1. ALLEN, E., and DmsY, E. A. ].A.M.A. 81:819, DRIPS, DELLA, G. Am. ]. Obst. & Gynec. 55:789, KAPLAN, I. I. Am. ]. Roentgenol. 59:370, KLINEFELTER, H. F., JR., REIFENSTEIN, E. C., JR., and ALBRIGHT, F. ]. Clin. Endocrinol. 2:615, MAZER, C., and IsRAEL, S. L. Diagnosis and Treatment of Menstrual Disorders and Sterility (ed. 2). New York, Roeber, RAKoFF, A. E. Fertil. & Steril. 1:504, RAKOFF, A. E. In Meigs and Sturgis (eds.). Progress in Gynecology. Grune and Stratton, 1950, vol RocK, J., BARTLETT, M. K., GAULD, A. G., and RUTHERFORD, R.N. Surg., Gynec. & Obst. 70:903, SoMMERVILLE, I. F., GousH, N., and MARRIAN, G. F. ]. Endocrinol. 5:247, ZIMMERMAN, W. Ztschr. f. physiol. Chem. 288:257, 1935.