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The treatment of sterility with “small dose” x-ray therapy
852
AMERICAN
*JOURNAL OF OBSTETRICS AND GYNECOLOGY
Reich, using ergonovine intravenously during the second stage of labot found, in a series of 154 cases, retained placenta in four instances (3.85 per cent) which necessitated manual removal. Tritsch and Behm similarly report an incidence of 3.47 per cent of retained placenta in a series of 115 cases. COXCLIJYIOSS I L
1. The intravenous use of basergen at the end of the second stage of labor shortens the duration of the third stage. 2. With the exception of about I.5 per cent of the patients treated, this procedure does not brin g about any appreciable decrease in the volume of blood loss in the third stage. 3. Contraction of the lower uterine segment necessitating manual extraction of the placenta is definitely increased after intravenous basergen administered at t,he end of the second stage. REFERENCES 1. Tritsch, 2. Adair,
J. IS., and Behm, K. H.: Anf. Davis, Kharasch, and Legault:
1935. 3. Reich, 4. Davin,
J. OBST. & GYNEC. 34: 676, 1937. AM. J. OBST. & GYNEC. 30: 466 and 740,
A. M.: AM. J. OBST. & GYNEC. 37: 224, 1939. E. J., and Morris, T. N.: Med. Ann. District
of Columbia
9: 1, 1940.
..
2398 SACRAMENTO STREET
THE
TREATMENT
MILTOK
FRIEDMAN,
T
OF STERILITY WITH X-RAY THERAPY M.D.,New
YORK, N.Y., NEWARK, N. J.
“SMALL
DOSE”
AND RITA FINKLER,
M.D.
HE treatment of functional menstrual disorders and sterility by irradiation of the ovaries and pituitary gland with small doses of roentgen rays (so-called x-ray stimulation) has been described by many. In 1939, Kaplan,’ and Mazer and Baer’ analyzed fifty-two articles on the subject and described their own extensive experiences. From these reports, they concluded that small-dose irradiation appears to be of distinct, therapeutic value in the treatment of irregular menses,amenorrhea, and sterility. In the face of this evidence, it is surprising to find that this type of therapy is not attempted with greater frequency. Some of the reasons for this are: the belief that x-rays are not effectual in restoring an endocrine imbalance; that many of the reported successesare chiefly coincidental ; and the fear of damage to the offspring.3-9 The following case of sterility is therefore presented againlo and brought up to date because of the comprehensive clinical and laboratory
FRIEDMAN
AND
FINKLER
:
TREATMENT
OF
evidence of the nature of the endocrine imbalance, apparently repeated successful responses following therapy. REPORT
STERILITY
853
and because of the small dose x-ray
OF A CASE
Mrs. E. P., white, aged 26 years, first sought medical attention on May 21, 1935, because of menstrual irregularities of thirteen years’ duration and sterility of six years’ duration. Her menses began at the age of thirteen, were generally scant, and averaged six to eight periods a year. Since her marriage, six years prior, there were four episodes of amenorrhea lasting six to seven months each. Occasionally there had been a hemorrhage lasting about one week, and, for the past eight weeks, there had been continuous staining (see Fig. 1). Previous treatment for her sterility had been unsuccessful. Physical examination revealed an obese patient weighing 215 pounds with a fat distribution suggestive of pituitary deficiency (girdle obesity, apronlike abdomen, narrow ankles and wrists, scant pubic and axillary hair). Examination of the pelvic organs revealed a slightly enlarged right ovary. Rubin and Hiihner tests were normal. The husband’s Roentgenographic examination spermatic fluid was found to be normal. of the skull revealed a normal sella tureiea. The patient was given the following hormone therapy in 1935 without benefit : oral medication with anterior pituitary extract (5 gr. emplets) ; thyroid extract (0.25 gr.) 3 times daily for one month; intramuscular injections of A.P.L. (anterior pituitary-like hormone) (2 C.C. each) twice weekly for one month; three courses of injections of prephysin given in December, 1935, January, and February, 1936, each course consisting of 1 C.C. daily for ten days; the last course was followed by 3 injections of progynon-B (2,000 R. U. each) in one week; and in March, 1936, the patient received 3 hi-weekly injections of A.P.L. (2 C.C. each). In spite of this treatment, the menses remained irregular (see Fig. 1). A comprehensive endocrine study was conducted. Four endometrial biopsies were taken on March 30, April 6, May 29, and June 4, 1936. The first one, taken on March 30, showed only moderate luteinization, but, the one taken the following week, instead of showing more advanced luteinization, showed a proliferative phase. The third biopsy was deferred for three weeks in order to study the same phase in a succeeding menstrual period. It was taken on May 29, and showed very slight luteinization. Once again the following biopsy showed only a proliferative endometrium. Thus the endocrine imbalance consisted in part of an incomplete or abortive luteinization process. At four consecutive intervals of about one week (May 12, 19, 28, and June 4, 1936)) bio-assays of twenty-four-hour specimens of urine, taken during the middle of a two-month period of amenorrhea, failed to reveal any prolan or estrin, except for 13 rat units of estrin in the last specimen (see Fig. 1). Two of the aforementioned endometrial biopsies were taken on the same day as the last two bio-assays. It was decided to administer small dose x-ray therapy. Four x-ray treatments were given from June 25 to July 5, 1936, delivering in four treatments a total dose of 80 roentgens (measured with back scattering) to the pituitary gland and 80 roentgens to each ovary. One month later, the patient began to menstruate regularly once a
854
AMERICAN
JOlJRSAI,
OF
OBSTETRICS
AND
GYNECOLOGY
month for the first time in her life. After the third regular menstrual period, it was decided to determine whet,her the restored monthly bleeding was accompanied 1)~ normal cyclical endometrial changes. Consequently, on the day preceding the fourth expected period (CM. 29, 1935) 1 a premenstrual endometrial biopsy was taken. In the microscopic examination of this endometrium, Dr. William Antopol found “endomctrium in lytcin phase with an early embryo. ” A detailed study of &is embryo IQ- Scipiades” at the depart.mtnt of JIFMAMJJASON~ h.t. ....! 1.
1935 _.
193 7-
193 8
_-______._-____- --- -_..__---.__-.-. PREC-NANCY
chi -----
_. I
0’ ,’ eeee..t
193 9
child
__ ___.___--.-.__ -____-__1____ _-.___.____._______-_--.
194 0 L
PREC.
LACTATION
Fig. l.-Monthly menstrual chart, illustrating clinical course over a period Of six The solid blocks represent menstrual flow; the broken line represents the years. 1935 : Menometrorrhagia alternating with amenofnormal level of menstrual flow. rhea: H.T., hormone therapy. 1936: H.T. hormone therapy, associated with a severe biopsies which showed incomplete luteinization : Bti., hemorrhage ; E, endometrial bio-assays of prolan and estrin in the urine (see text) : X-ra.?/, small dose r-ray therapy ; E~&rvo, accidentally removed by suction curettage (see text). 1937 : Normal child born in December. 1933: Regular normal menses. 1939: Amenorrhea cW.raCtermed by absence of lutein effect as shown by four weekly endometrial biopsies (El : X-UZ~, small dose x-ray therapy. 1940: Normat child born in June.
FRIEDMAN
AND
FINKLER
:
TREATMENT
OF
STERILITY
855
embryology, Carnegie Institution of Washington, revealed “that, among the young human embryos already recorded in the literature, this specimen falls between the Kleinhans and the V. Mollendorf ‘Sch. ’ Thus it occupies the third or at the most the fourth place, with its degree of trophoblastic differentiation and its estimated age of 11 to 12 days.” Thus three months after x-ray therapy, the patient became pregnant for the first time in her life. In spite of this accidental abortion the patient continued to menstruate regularly. No further treatment was given. Finally, in April, 1937, nine months after the small dose x-ray therapy, she became pregnant, again. During. the first two months of this pregnancy, the patient had pelvic discomfort and occasional spotting. She was given injections of progestin (Proluton) and calcium and wheat germ oil for one month, because of threatened abortion, due possibly to lutein deficiency. She was finally delivered at ful1 term of a normal female child in December, 1937. The patient nursed the baby for five months, although supplementary feedings were given. Menstrual bleeding returned four months after delivery. It was normal and regular except for a missed period in July, 1938. Following her menstrual period in October, 1938, there was a period of amenorrhea of eight months’ duration. During this time t,wo Friedman tests were negative for pregnancy. Another series of four consecutive weekly endometrial suction biopsies were taken on April 20 and 27, May 4 and 11, 1939. All of these showed the endometrium to be in proliferative phase. There was no evidence of any lutein activity. Thus the ovarian failure had returned in a more severe form and was now characterized by amenorrhea and absent luteinization. Two days after the last endometrial biopsy, a second course of small dose x-ray therapy was given. From May 13, 1939, to May 19, 1939, a total dose of 80 r. (measured with scattering) was delivered in four treatments to each ovary and to the pituitary gland. There was no menstrual period in June, but there were normal periods commencing July 3, and Aug. 9, 1939. She then became pregnant. There was no menstrual period in September. There were two positive Friedman tests on October 5 and 10, 1939. On Oct. 24,1939, the patient developed pelvic cramps and spotting. A diagnosis was made of threatened abort,ion, which could be interpreted as another manifestation of deficient progestin activity. She was therefore given fourteen injections of 5 mg. of proluton each, three times a week. After the second injection, the pelvic pains and spotting disappeared. Thereafter, although symptom-free, she was given 2 mg. of proluton twice weekly for four months. The pregnancy proceeded uneventfully and on June 8, 1940, the patient was delivered of a normal male child. She nursed this child for nine months. There was no menstrual period during this time, and for six months thereafter, up to September, 1941. DISCUSSION
This case strongly suggests that small dose x-ray therapy can favorably affect sterility due to ovarian deficiency. In 1935, the patient’s sterility was accompanied by irregular menses, possible estrogen deficiency (as evidenced by bio-assays), and faulty luteinization (as evi-
856
AMERICAN
JOURNAL
OF
OBSTETRICS
AND
GYNECOLOGY
dented by endometrial biopsies ) . The first course of’ small dose x-ray therapy was followed by normal menses and two pregnancies within nine months. The first pregnancy was accidentally interrupted hy a prcmenstrual endometrial biopsy which removed a t,wclve to fourteen day old embryo, which proved to be the third or at most t,he fourth earliest embryo in the history of medicine. The monthly cyclical bleeding was not thereby disturbed. The scrond pregnancy resulted in the delivery of a normal child at full term. In 1939, four years later, the rlinical picture of ovarian deficiency ret.urned in a more severe form, as cvidented by amenorrhea and absent Iuteinization. A second course of small dose x-ray therapy was followed by restoration of normal menses and a third pregnancy with delivery of a normal child. This case further illustrates the fact that the successful response to therapy of an endocrine imbalance, when viewed over a period of many years may be only temporary. The organism, after responding favorably for a time, may revert, to the original deficiency picture. In the above case this was not unexpected, because the endocrine deficiency was profound, as indicated by irregular menses ever since puberty, hypopituitary type of obesity, six-year duration of sterility, and faulty luteinization. The possibility that the favorable result might have been coincidental is to a great extent eliminated because of the prompt response to each course of x-ray therapy. The original designation of this type of therapy as “x-ray stimulation” has been discarded in favor of the noncommittal “small dose x-ray therapy. ” It has not yet been established that small doses of x-rays will actually stimulate the ovaries. It is possible that this t,ype of therapy can destroy some inhibitory factor. Mart& and Kroning12 have shown that small amounts of roent,gen irradiation (5 to 50 r. at the surface) can so damage the follicle apparatus of rats and mice as to produce appreciable variations from normal of the estrus cycle. Evidence of the possible existence of an inhibitory factor in the ovary, which could be neutralized by the irradiation is seen in the work of Stein and Cohen,13 and RobinsonI who have successfully treated amenorrhea and sterility by removal of the cystic portions of both ovaries; and by one of us (M. F.) who has successfully treated several cases of dysmenorrhea and painful breast hyperplasia by unilateral roentgen irradiation of one cystic ovary with inhibitory doses of roentgen rays. The evidence concerning possible damage to the unfertilized ovum with resultant injury to the offspring has been based chiefly on the effect of x-rays on the fruit fly (Drosophila melwwgnste-r) ,3-i. I5 and to a lesser extent the mouse and guinea pig.8 The frequency with which difficulties are encountered in attemptin g to transpose the results of animal experiments to human beings is well known. This species difference to
FRIEDMAN
AND
FINKLRR
:
TREATMENT
OF
STERILITE’
857
which many biologic phenomena are subject is also observed in the field of radiation genetics. Even should the human germ cells eventually be shown to be capable of producing mutation forms as a result of sublethal radiation damage, the statistical probability of a previously irradiated ovum ever resulting in a monstrosity, following fertilization, is so small as not to constitute a hazard. The majority of sterile women who respond successfully to smalldose irradiation usually menstruate for a varying number of months before conceiving. Thus, the ovum which eventually becomes fertilized may very likely have been quiescent and inactive within a primordial follicle during the actual exposure to radiation, and in this state, it would be relatively radioresistant at that particular time. Therefore, in view of the fac,t that the inevitability of germ plasm damage to the hz~rytan OVUI~I from small-dose irradiation has not yet been demonstrated, one ought not at this time deny this effective type of treatment to a woman who ardently desires a child. The possible theoretical dangers should be explained to t.he patient and t.he final decision left to her. CONCLUSIONS
1. Roentgen rays administered to the ovaries and pituitary gland in small doses are capable of correcting an ovarian dysfunction of a deficiency type accompanied by sterility. 2. A case is reported wherein two separate episodes of ovarian deficiency with sterility in the same patient were each successfully treated with roentgen rays. 3. Though a review of the experimental evidence based on lower animals suggests the possibility of harmful effects to the germ cells of small doses of radiation, there is as yet no evidence and small likelihood that small-dose x-ray therapy constitutes a real hazard to the human ovum. REFERENCES 1. Kaplan, Ira I.: Am. J. Roentgenol. 42: 731, 1939. 2. Mazer, C., and Baer, G.: AK J. OBST. & GYNEC. 37: 1015, 1939. 3. Darlington, C. D.: Recent Advances in Cytology, Philadelphia, 1937, P. Blakiston’s Son $ Co. 4. Westing, 9. W.: New York State J. Med. 40: 1139, 1940. 5. Whiting, P. W.: Am. J. Roentgenol. 43: 271, 1940. 6. Demerec, M.: Radiology 30: 212, 1938. Radiology 36: 145, 1941. 7. Pickhan, A.: 8. Snell, George D.: Radiology 36: 189, 1941. 9. Lorenz, Ii. P., and Henshaw, P. 8.: Radiology 36: 471, 1941. 10. Finkler, Rita, and Friedman, Milton: Endocrinology 22: 104, 1938. 11. Scipiades, E.: Contrib. Embryol. No. 163. Washington, D. C., p. 95, 1938. 12. Martius, H., and Kroning, F.: Med. Welt. 12: 947, 1938. 13. Stein, Irving F., and Cohen, Melvin R.: AM. J. OBST. & GYNEC. 38: 465, 1939. 14. Robinson, M. R.: AK J. OBST. & GYNEC. 30: 18, 1935. 15. Muller, H. J.: Effects of Roentgen Rays Upon the Hereditary Material. Science of Radiology, Springfield, 1933, Charles C Thomas. 153 EAST
72
STREET
AMERICAN
*JOURNAL OF OBSTETRICS AND GYNECOLOGY
Reich, using ergonovine intravenously during the second stage of labot found, in a series of 154 cases, retained placenta in four instances (3.85 per cent) which necessitated manual removal. Tritsch and Behm similarly report an incidence of 3.47 per cent of retained placenta in a series of 115 cases. COXCLIJYIOSS I L
1. The intravenous use of basergen at the end of the second stage of labor shortens the duration of the third stage. 2. With the exception of about I.5 per cent of the patients treated, this procedure does not brin g about any appreciable decrease in the volume of blood loss in the third stage. 3. Contraction of the lower uterine segment necessitating manual extraction of the placenta is definitely increased after intravenous basergen administered at t,he end of the second stage. REFERENCES 1. Tritsch, 2. Adair,
J. IS., and Behm, K. H.: Anf. Davis, Kharasch, and Legault:
1935. 3. Reich, 4. Davin,
J. OBST. & GYNEC. 34: 676, 1937. AM. J. OBST. & GYNEC. 30: 466 and 740,
A. M.: AM. J. OBST. & GYNEC. 37: 224, 1939. E. J., and Morris, T. N.: Med. Ann. District
of Columbia
9: 1, 1940.
..
2398 SACRAMENTO STREET
THE
TREATMENT
MILTOK
FRIEDMAN,
T
OF STERILITY WITH X-RAY THERAPY M.D.,New
YORK, N.Y., NEWARK, N. J.
“SMALL
DOSE”
AND RITA FINKLER,
M.D.
HE treatment of functional menstrual disorders and sterility by irradiation of the ovaries and pituitary gland with small doses of roentgen rays (so-called x-ray stimulation) has been described by many. In 1939, Kaplan,’ and Mazer and Baer’ analyzed fifty-two articles on the subject and described their own extensive experiences. From these reports, they concluded that small-dose irradiation appears to be of distinct, therapeutic value in the treatment of irregular menses,amenorrhea, and sterility. In the face of this evidence, it is surprising to find that this type of therapy is not attempted with greater frequency. Some of the reasons for this are: the belief that x-rays are not effectual in restoring an endocrine imbalance; that many of the reported successesare chiefly coincidental ; and the fear of damage to the offspring.3-9 The following case of sterility is therefore presented againlo and brought up to date because of the comprehensive clinical and laboratory
FRIEDMAN
AND
FINKLER
:
TREATMENT
OF
evidence of the nature of the endocrine imbalance, apparently repeated successful responses following therapy. REPORT
STERILITY
853
and because of the small dose x-ray
OF A CASE
Mrs. E. P., white, aged 26 years, first sought medical attention on May 21, 1935, because of menstrual irregularities of thirteen years’ duration and sterility of six years’ duration. Her menses began at the age of thirteen, were generally scant, and averaged six to eight periods a year. Since her marriage, six years prior, there were four episodes of amenorrhea lasting six to seven months each. Occasionally there had been a hemorrhage lasting about one week, and, for the past eight weeks, there had been continuous staining (see Fig. 1). Previous treatment for her sterility had been unsuccessful. Physical examination revealed an obese patient weighing 215 pounds with a fat distribution suggestive of pituitary deficiency (girdle obesity, apronlike abdomen, narrow ankles and wrists, scant pubic and axillary hair). Examination of the pelvic organs revealed a slightly enlarged right ovary. Rubin and Hiihner tests were normal. The husband’s Roentgenographic examination spermatic fluid was found to be normal. of the skull revealed a normal sella tureiea. The patient was given the following hormone therapy in 1935 without benefit : oral medication with anterior pituitary extract (5 gr. emplets) ; thyroid extract (0.25 gr.) 3 times daily for one month; intramuscular injections of A.P.L. (anterior pituitary-like hormone) (2 C.C. each) twice weekly for one month; three courses of injections of prephysin given in December, 1935, January, and February, 1936, each course consisting of 1 C.C. daily for ten days; the last course was followed by 3 injections of progynon-B (2,000 R. U. each) in one week; and in March, 1936, the patient received 3 hi-weekly injections of A.P.L. (2 C.C. each). In spite of this treatment, the menses remained irregular (see Fig. 1). A comprehensive endocrine study was conducted. Four endometrial biopsies were taken on March 30, April 6, May 29, and June 4, 1936. The first one, taken on March 30, showed only moderate luteinization, but, the one taken the following week, instead of showing more advanced luteinization, showed a proliferative phase. The third biopsy was deferred for three weeks in order to study the same phase in a succeeding menstrual period. It was taken on May 29, and showed very slight luteinization. Once again the following biopsy showed only a proliferative endometrium. Thus the endocrine imbalance consisted in part of an incomplete or abortive luteinization process. At four consecutive intervals of about one week (May 12, 19, 28, and June 4, 1936)) bio-assays of twenty-four-hour specimens of urine, taken during the middle of a two-month period of amenorrhea, failed to reveal any prolan or estrin, except for 13 rat units of estrin in the last specimen (see Fig. 1). Two of the aforementioned endometrial biopsies were taken on the same day as the last two bio-assays. It was decided to administer small dose x-ray therapy. Four x-ray treatments were given from June 25 to July 5, 1936, delivering in four treatments a total dose of 80 roentgens (measured with back scattering) to the pituitary gland and 80 roentgens to each ovary. One month later, the patient began to menstruate regularly once a
854
AMERICAN
JOlJRSAI,
OF
OBSTETRICS
AND
GYNECOLOGY
month for the first time in her life. After the third regular menstrual period, it was decided to determine whet,her the restored monthly bleeding was accompanied 1)~ normal cyclical endometrial changes. Consequently, on the day preceding the fourth expected period (CM. 29, 1935) 1 a premenstrual endometrial biopsy was taken. In the microscopic examination of this endometrium, Dr. William Antopol found “endomctrium in lytcin phase with an early embryo. ” A detailed study of &is embryo IQ- Scipiades” at the depart.mtnt of JIFMAMJJASON~ h.t. ....! 1.
1935 _.
193 7-
193 8
_-______._-____- --- -_..__---.__-.-. PREC-NANCY
chi -----
_. I
0’ ,’ eeee..t
193 9
child
__ ___.___--.-.__ -____-__1____ _-.___.____._______-_--.
194 0 L
PREC.
LACTATION
Fig. l.-Monthly menstrual chart, illustrating clinical course over a period Of six The solid blocks represent menstrual flow; the broken line represents the years. 1935 : Menometrorrhagia alternating with amenofnormal level of menstrual flow. rhea: H.T., hormone therapy. 1936: H.T. hormone therapy, associated with a severe biopsies which showed incomplete luteinization : Bti., hemorrhage ; E, endometrial bio-assays of prolan and estrin in the urine (see text) : X-ra.?/, small dose r-ray therapy ; E~&rvo, accidentally removed by suction curettage (see text). 1937 : Normal child born in December. 1933: Regular normal menses. 1939: Amenorrhea cW.raCtermed by absence of lutein effect as shown by four weekly endometrial biopsies (El : X-UZ~, small dose x-ray therapy. 1940: Normat child born in June.
FRIEDMAN
AND
FINKLER
:
TREATMENT
OF
STERILITY
855
embryology, Carnegie Institution of Washington, revealed “that, among the young human embryos already recorded in the literature, this specimen falls between the Kleinhans and the V. Mollendorf ‘Sch. ’ Thus it occupies the third or at the most the fourth place, with its degree of trophoblastic differentiation and its estimated age of 11 to 12 days.” Thus three months after x-ray therapy, the patient became pregnant for the first time in her life. In spite of this accidental abortion the patient continued to menstruate regularly. No further treatment was given. Finally, in April, 1937, nine months after the small dose x-ray therapy, she became pregnant, again. During. the first two months of this pregnancy, the patient had pelvic discomfort and occasional spotting. She was given injections of progestin (Proluton) and calcium and wheat germ oil for one month, because of threatened abortion, due possibly to lutein deficiency. She was finally delivered at ful1 term of a normal female child in December, 1937. The patient nursed the baby for five months, although supplementary feedings were given. Menstrual bleeding returned four months after delivery. It was normal and regular except for a missed period in July, 1938. Following her menstrual period in October, 1938, there was a period of amenorrhea of eight months’ duration. During this time t,wo Friedman tests were negative for pregnancy. Another series of four consecutive weekly endometrial suction biopsies were taken on April 20 and 27, May 4 and 11, 1939. All of these showed the endometrium to be in proliferative phase. There was no evidence of any lutein activity. Thus the ovarian failure had returned in a more severe form and was now characterized by amenorrhea and absent luteinization. Two days after the last endometrial biopsy, a second course of small dose x-ray therapy was given. From May 13, 1939, to May 19, 1939, a total dose of 80 r. (measured with scattering) was delivered in four treatments to each ovary and to the pituitary gland. There was no menstrual period in June, but there were normal periods commencing July 3, and Aug. 9, 1939. She then became pregnant. There was no menstrual period in September. There were two positive Friedman tests on October 5 and 10, 1939. On Oct. 24,1939, the patient developed pelvic cramps and spotting. A diagnosis was made of threatened abort,ion, which could be interpreted as another manifestation of deficient progestin activity. She was therefore given fourteen injections of 5 mg. of proluton each, three times a week. After the second injection, the pelvic pains and spotting disappeared. Thereafter, although symptom-free, she was given 2 mg. of proluton twice weekly for four months. The pregnancy proceeded uneventfully and on June 8, 1940, the patient was delivered of a normal male child. She nursed this child for nine months. There was no menstrual period during this time, and for six months thereafter, up to September, 1941. DISCUSSION
This case strongly suggests that small dose x-ray therapy can favorably affect sterility due to ovarian deficiency. In 1935, the patient’s sterility was accompanied by irregular menses, possible estrogen deficiency (as evidenced by bio-assays), and faulty luteinization (as evi-
856
AMERICAN
JOURNAL
OF
OBSTETRICS
AND
GYNECOLOGY
dented by endometrial biopsies ) . The first course of’ small dose x-ray therapy was followed by normal menses and two pregnancies within nine months. The first pregnancy was accidentally interrupted hy a prcmenstrual endometrial biopsy which removed a t,wclve to fourteen day old embryo, which proved to be the third or at most t,he fourth earliest embryo in the history of medicine. The monthly cyclical bleeding was not thereby disturbed. The scrond pregnancy resulted in the delivery of a normal child at full term. In 1939, four years later, the rlinical picture of ovarian deficiency ret.urned in a more severe form, as cvidented by amenorrhea and absent Iuteinization. A second course of small dose x-ray therapy was followed by restoration of normal menses and a third pregnancy with delivery of a normal child. This case further illustrates the fact that the successful response to therapy of an endocrine imbalance, when viewed over a period of many years may be only temporary. The organism, after responding favorably for a time, may revert, to the original deficiency picture. In the above case this was not unexpected, because the endocrine deficiency was profound, as indicated by irregular menses ever since puberty, hypopituitary type of obesity, six-year duration of sterility, and faulty luteinization. The possibility that the favorable result might have been coincidental is to a great extent eliminated because of the prompt response to each course of x-ray therapy. The original designation of this type of therapy as “x-ray stimulation” has been discarded in favor of the noncommittal “small dose x-ray therapy. ” It has not yet been established that small doses of x-rays will actually stimulate the ovaries. It is possible that this t,ype of therapy can destroy some inhibitory factor. Mart& and Kroning12 have shown that small amounts of roent,gen irradiation (5 to 50 r. at the surface) can so damage the follicle apparatus of rats and mice as to produce appreciable variations from normal of the estrus cycle. Evidence of the possible existence of an inhibitory factor in the ovary, which could be neutralized by the irradiation is seen in the work of Stein and Cohen,13 and RobinsonI who have successfully treated amenorrhea and sterility by removal of the cystic portions of both ovaries; and by one of us (M. F.) who has successfully treated several cases of dysmenorrhea and painful breast hyperplasia by unilateral roentgen irradiation of one cystic ovary with inhibitory doses of roentgen rays. The evidence concerning possible damage to the unfertilized ovum with resultant injury to the offspring has been based chiefly on the effect of x-rays on the fruit fly (Drosophila melwwgnste-r) ,3-i. I5 and to a lesser extent the mouse and guinea pig.8 The frequency with which difficulties are encountered in attemptin g to transpose the results of animal experiments to human beings is well known. This species difference to
FRIEDMAN
AND
FINKLRR
:
TREATMENT
OF
STERILITE’
857
which many biologic phenomena are subject is also observed in the field of radiation genetics. Even should the human germ cells eventually be shown to be capable of producing mutation forms as a result of sublethal radiation damage, the statistical probability of a previously irradiated ovum ever resulting in a monstrosity, following fertilization, is so small as not to constitute a hazard. The majority of sterile women who respond successfully to smalldose irradiation usually menstruate for a varying number of months before conceiving. Thus, the ovum which eventually becomes fertilized may very likely have been quiescent and inactive within a primordial follicle during the actual exposure to radiation, and in this state, it would be relatively radioresistant at that particular time. Therefore, in view of the fac,t that the inevitability of germ plasm damage to the hz~rytan OVUI~I from small-dose irradiation has not yet been demonstrated, one ought not at this time deny this effective type of treatment to a woman who ardently desires a child. The possible theoretical dangers should be explained to t.he patient and t.he final decision left to her. CONCLUSIONS
1. Roentgen rays administered to the ovaries and pituitary gland in small doses are capable of correcting an ovarian dysfunction of a deficiency type accompanied by sterility. 2. A case is reported wherein two separate episodes of ovarian deficiency with sterility in the same patient were each successfully treated with roentgen rays. 3. Though a review of the experimental evidence based on lower animals suggests the possibility of harmful effects to the germ cells of small doses of radiation, there is as yet no evidence and small likelihood that small-dose x-ray therapy constitutes a real hazard to the human ovum. REFERENCES 1. Kaplan, Ira I.: Am. J. Roentgenol. 42: 731, 1939. 2. Mazer, C., and Baer, G.: AK J. OBST. & GYNEC. 37: 1015, 1939. 3. Darlington, C. D.: Recent Advances in Cytology, Philadelphia, 1937, P. Blakiston’s Son $ Co. 4. Westing, 9. W.: New York State J. Med. 40: 1139, 1940. 5. Whiting, P. W.: Am. J. Roentgenol. 43: 271, 1940. 6. Demerec, M.: Radiology 30: 212, 1938. Radiology 36: 145, 1941. 7. Pickhan, A.: 8. Snell, George D.: Radiology 36: 189, 1941. 9. Lorenz, Ii. P., and Henshaw, P. 8.: Radiology 36: 471, 1941. 10. Finkler, Rita, and Friedman, Milton: Endocrinology 22: 104, 1938. 11. Scipiades, E.: Contrib. Embryol. No. 163. Washington, D. C., p. 95, 1938. 12. Martius, H., and Kroning, F.: Med. Welt. 12: 947, 1938. 13. Stein, Irving F., and Cohen, Melvin R.: AM. J. OBST. & GYNEC. 38: 465, 1939. 14. Robinson, M. R.: AK J. OBST. & GYNEC. 30: 18, 1935. 15. Muller, H. J.: Effects of Roentgen Rays Upon the Hereditary Material. Science of Radiology, Springfield, 1933, Charles C Thomas. 153 EAST
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