Dysmenorrhea―Including Clinical and Pharmacological Studies on Benzedrine Sulfate

Dysmenorrhea―Including Clinical and Pharmacological Studies on Benzedrine Sulfate

Baltimore Number THE MEDICAL CLINICS OF NORTH AMERICA Volume 23 March,1939 Number 2 CLINIC OF DRS. J. MASON HUNDLEY, JR., JOHN C. KRANTZ, JR. AND...

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Baltimore Number

THE MEDICAL CLINICS OF

NORTH AMERICA Volume 23

March,1939

Number 2

CLINIC OF DRS. J. MASON HUNDLEY, JR., JOHN C. KRANTZ, JR. AND J. T. HIBBITTS FROM THE DEPARTMENTS OF GYNECOLOGY AND PHARMACOLOGY, UNIVERSITY OF MARYLAND DYSMENORRHEA-INCLUDING CLINICAL AND PHARMACOLOGICAL STUDIES ON BENZEDRINE SULFATE

DYSMENORRHEA, meaning difficult-month-flow or painful menstruation, is one of the most frequent complaints for which patients consult the gynecologist, and in many instances is one of the most baffling to alleviate. As we all know, dysmenorrhea is only a symptom, but from custom and for convenience the subject will be discussed here somewhat as a disease entity. These painful disorders of menstruation may be of a primary or of a secondary type. The former, also known as es~ sential, occurs in patients with no demonstrable pelvic pathology, and the latter, also known as acquired, arises secondarily from definite lesions of the pelvis. Secondary dysmenorrhea, as readily understandable, presents no very difficult problem, for its alleviation can as a rule be brought about by the correction of the primary pelvic pathology. This phase of the subject will be discussed here in somewhat of a cursory fashion so that more space will be available for the consideration of the less well understood primary dysmenorrhea. From a study made by G. Holden of 1000 patients suffering with dysmenorrhea at the Johns Hopkins Hospital, it was found that the causal factor in 41 per cent was retrodisplaceVOL. 23-18

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ments, in 37 per cent pelvic inflammatory disease, in 11 per cent uterine fibroids, and of the remaining 11 per cent endometriosis was an outstanding pathological finding. Dysmenorrhea produced by such pathological conditions is of the dullaching, congestive type, frequently lasting throughout the duration of the flow. However, there may be attacks of spasmodic pain incident to the passage of clots which are concomitant with the frequently existing menorrhagic. The diagnosis of the causal factors in this type of dysmenorrhea is usually simple, although at times may be obscure, thus necessitating special procedures before it can be determined. In patients with chronic salpingitis and adhesions, the most meticulous bimanual examination may elicit no definite lesion; however, by the use of transtubal insufflation, as developed by Rubin, an accurate diagnosis qf obstructive chronic salpingitis may be readily made. If one wishes to determine the exact point of obstruction, frequently desirable in sterility studies, lipiodol injection of the uterus and tubes with subsequent x-ray visualization will accurately portray the lesion. As is well known, the great majority of simple retrodisplacements cause no symptoms, and only those associated with descensus, lacerations of the pelvic floor, and chronic passive congestion of the uterus are provocative of discomfort. These simple displacements have little significance, for they are of frequent occurrence; in fact, whenever the bladder becomes filled with urine, the uterus is pushed backward, and returns to its normal position when the bladder is emptied. In patients with retrodisplacement who have had children, and there exist the above mentioned associated lesions but in mild degree, it is difficult to decide whether an operation is indicated for the relief of the dysmenorrhea which is usually of the. congestive type. In such a condition, the use of a Smith-Hodge pessary is of great value. With relief of symptoms thus produced by the correction of the displacement, one may then perform a suspension of the uterus and the necessary plastic procedures with the assurance that the patient will be cured. Another cause of severe acquired dysmenorrhea is endo-

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metriosis, a condition. produced by the retrograde reflux of menstrual deb.ris which contains viable endometrial cells. These bits of tissue lodge upon the ovaries, in the cul-de-sac and other adjacent organs, and there develop typical endometrial glands with their surrounding stroma. These glands undergo cyclical activity, as does the endometrium of the uterus. The dysmenorrhea produced by this type of pelvic pathology is quite severe and frequently lasts throughout the period. The diagnosis of endometriosis is oftentimes quite difficult. However, it is readily made if the patient is in the childbearing age, has an acquired dysmenorrhea, is sterile, and on pelvic examination bilateral adnexal masses are felt and blue dome cysts are seen in the posterior fornix. It would not be of advantage to discuss here the other etiologic factors which produce secondary dysmenorrhea, for they are easily recognizable and present no definite problem. In summary, this type of dysmenorrhea presents few difficult problems, for its alleviation is quite readily brought about by the appropriate correction of the underlying causa] pathology. PRIMARY OR ESSENTIAL DYSMENORRHEA

This condition, in which no definite demonstrable pelvic pathology can be made out, is the bete-noir of the gynecologist, due primarily to our lack of definite knowledge as to its etiology. Dysmenorrhea of this type, usually beginning with puberty, is as a rule characterized by spasmodic, cramplike pains localized for the most part in the suprapubic region. The pain, which resembles' miniature labor pains, usually begins just prior to the onset of the menstrual flow and in twentyfour to forty-eight hours has nearly disappeared. The patients frequently state that once the flow has become well established th~ severe symptoms quickly abate, and they can again resume their normal activities. There is a wide variation in the degree of dysmenorrhea experienced, some individuals being completely prostrated from the severe discomfort and are confined to bed for one or two days, while others are able to carry on their daily routine, aided by the use of mild sedatives.

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Severe dysmenorrhea is very frequently seen in young, unmarried women who are engaged in occupations which are somewhat of a sedentary nature and who are subjected to considerable nerve strain, for example, school teachers and secretaries. They usually are of a high-strung, nervous temperament, underweight, and of a visceroptotic type with visceral atony and constipation. However, occasionally one encounters severe dysmenorrhea in the robust, athletic type of young women. During the past half century frequent studies on large numbers of normal menstruating women have been conducted, and it is the consensus of opinion that no definite change occurs in the organism during this physiological period.Quoting from N ovak/4 cardiovascular changes during menstruation have been studied by Jessie L. King, the basal metabolism by Katherine Blount, and the excitability of the nervous system by Leta Hollingsworth; all agree that there is no noteworthy change during this period. Dysmenorrhea is frequently spoken of as the "disease of theories" and in spite of a large experimental work done on this subject, as yet no satisfactory explanation has been presented. Several of the outstanding theories of etiology will now be presented. Probably one of the oldest theories to account for primary dysmenorrhea was that of mechanical obstruction, and in this country Marion Sims was strongly of this opinion. His paper , "Nulla Dysmenorrhea Nisi Obstructiva," maintained that "there can be no dysmenorrhea, properly speaking, if the canal of the neck of the uterus be straight and wide enough to permit a free passage of the menstrual blood." Today the obstructive theory has few enthusiastic adherents, in spite of the fact that dilatation of the cervix does cause relief in a certain percentage of patients. Novak some years ago observed in a small series of patients that during the height of the menstrual cramp a probe could be introduced into the cervical canal with no evidence of obstruction. Another theory based primarily on the phenomenon of obstruction is that of Beckwith Whitehouse19 who in 1926 brought forth

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the concept that for reasons not clearly understood, instead of the normal molecular disintegration of the menstrual decidua, the latter may at times separate in macroscopic fragments. It is quite possible that the passage of large fragments of tissue acting as a foreign body would cause dysmenorrhea, but this phenomenon is most likely of infrequent occurrence and would be the etiological factor in only a few instances. Also falling into this group of obstructive dysmenorrheas is hypoplasia of the uterus, and here we have a combination of underdevelopment plus obstruction. The uterus is frequently of the anteflexed, prepuberal type, with a diminished, firm body and an elongated cervix. This uterus infantilis is often associated with hypomenorrhea and oligomenorrhea, and has been looked upon as an expression of decreased ovarian activity. It is possible that in this type of uterus, the thickened premenstrual endometrium might be a factor in producing obstruction to the menstrual flow. It has been estimated that the rate of menstrual discharge in a normal woman is about two thirds of a drop per minute. Therefore, it is difficult to conceive that the obstruction offered by the thickened endometrium and anteflexion could interfere with the egress of such small amounts of blood sufficiently to produce dysmenorrhea. An observation that would also tend to refute the belief that congenital hypoplasia is a frequent etiological factor is that dysmenorrhea does not always arise with the onset of menstruation but may develop at a later period. ENDOCRINE FACTORS

With our increasing knowledge concerning the activity of the ovarian hormones, great interest has been shown in their possible relationship to dysmenorrhea. N ovak and Reynolds in 1932 14 presented their studies on uterine motility in the rabbit. A brief description of their methods and a summary of their work follows. In order to obtain tracings of uterine activity in the unanesthetized rabbit, the following technic was developed. The vagina was divided and the upper end brought out through the abdominal wall and there sutured. Through

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this fistula, a small balloon was introduced into the uterus which was connected with an air-water manometer, and kymographic tracings were then obtained. By this method they were able to show that variation in uterine activity corresponded to the various phases of the sexual cycle. During estrus marked activity was present, while during anestrus the motility was feeble or nearly absent. Castration produced complete quiescence. It was shown that uterine motility was restored in the castrated animal with the use of theelin, as substitutive therapy. In order to study the effect of the corpus luteum on uterine motility, animals in a state of pseudopregnancy were investigated, and as was expected, there was a quiescence of muscular activity observed, due to progestin effect. Animals were then injected with commercial preparations obtained from the urine of pregnant women, and there was a similar inhibition of motility. When the urine of nonpregnant women was injected no effect was noted. From these physiologic studies Novak and Reynolds conclude that the immediate cause of dysmenorrhea is most likely a disturbance of the normal motility factors of the uterine muscle. The estrogenic substance, theelin, as a rule is an excitant, and progestin an inhibitant of uterine motility. The inhibitory influence of progestin on uterine motility is removed a day or two before the menstrual onset and this withdrawal produces dysmenorrhea in some women, possibly those with such predisposing factors as constitutional subnormality or psychoneurosis. In other cases it would seem that there is an actual imbalance between the theelin and progestin, either quantitative or chronological or both. Recently Fluhmann s has investigated the relationship of the ovarian hormones, estrogen and progestin, in regard to their being factors in the production of dysmenorrhea. In this study, the estrogenic content of the blood of 19 women with severe dysmenorrhea was investigated. Of these 19 patients, all were nulliparae except two, and their ages varied from thirteen to thirty-four years of age. In no instance was there any evidence of systemic or pelvic pathology. Eighty-five tests for estrogen

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were carried out, which included at least 3 on each patient at weekly intervals. The mucification test was the one employed, which consists of the injection of untreated blood serum into adult spayed mice, with subsequent study of microscopic sections of the vagina. The hormonal theories of the cause of dysmenorrhea are placed in three groups, those due to a deficiency of estrogen, an excess of estrogen or a deficiency of progestin, and finally, those due to overactivity of progestin; these will be briefly elaborated upon. 1. Deficiency of Estrogen.-As we have already stated, the association of dysmenorrhea with uterine hypoplasia and oligomenorrhea was quite suggestive of decreased ovarian activity. It has also been noted that castration produces degenerative changes in the ganglion of Frankenhauser, which returns to normal under the administration of estrogen. Therefore, it was suggested that dysmenorrhea could be caused by changes in the sympathetic nerve supply of the uterus due to lack of sudfcient estrogenic hormone. Fluhmann has been able to show that the blood of dysmenorrheic women .manifests no decrease of estrogen. He also is of the opinion that hypoplasia of the uterus, as evidence of ovarian deficiency, is present only in a limited number of patients. 2. Excess of Estrogen, or Progestin Deficiency.-According to this theory, dysmenorrhea results from an imbalance between the two hormonal factors regulating uterine motility. The experimental work of Novak and Reynolds, already presented, elaborates the physiological background for this theory; therefore, no further discussion is necessary except to reiterate that the proponents of this theory are of the opinion that increased muscular activity of the uterus is produced by either an increase of estrogen or by a deficiency of progestin. One of the outstanding objections to this theory, which is quite evi_dent, is that with hyperplasia of the endometrium, due to hyperestrinism uninhibited by progestin, the bleeding is nearly always painless. In this study, an increase of estrogen in the blood at the time of menstruation was not found more frequently than in women without dysmenorrhea. However,

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Kotz and Parker, using the Frank-Goldberger test, found a higher level of estrogenic substances in the blood of a large percentage of dysmenorrheic patients. Fluhmann states that the peak of estrogen concentration and uterine contractions occurs at about the time of ovulation, but except for women with "mittelschmerz," dysmenorrheic patients do not have pain at this time. 18 However, although this finding differs from that of Frank and Goldberger, who observed a rise of estrogen in the week preceding menstruation, it is in keeping with numerous studies conducted on the excretion of estrogen in the urine of normal women. Fluhmann also states that the concept of a deficient corpus luteum as a cause of dysmenorrhea is difficult to understand since normally there is always a deficiency of this gland at the time of menstruation. 3. The last theory, based on an excess of progestin as a cause for dysmenorrhea, is supported by Cannon2 who believes that macroscopic fragmentation of the endometrium is due to overactivity of the corpus luteum hormone produced by hyperactivity of the luteinizing hormone of the anterior lobe of the pituitary. In conclusion, it is stated that "there are serious objections to the acceptance of any theories which seek to explain· the cause of primary dysmenorrhea on the basis of a deficiency or excess of either estrogen or progestin. However, it is also important to point out that this conclusion should not discourage attempts to treat dysmenorrhea with these hormones, provided they are used for their definite pharmacological properties and not as substitutive therapy for theoretical insufficiencies." As is readily seen from the foregoing experimental problems, the evaluation of the part played by the endocrines in the production of dysmenorrhea is difficult. It is most likely that they do play an important role, however, in conjunction with many other factors, i.e., constitutional, psychogenic, and neurogenic. Constitutional and psychogenic factors are of paramount importance in the production and perpetuation of dysmenorrhea, and probably the latter plays the greatest role. An anxious mother, who herself has experienced dysmenorrhea,

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may soon inculcate in her daughter great apprehension over this normal physiological· state and, with coddling, the child may soon become a complete invalid for several days each month. "Mens sana in corpore sano" is an excellent concept to be ever borne in mind in the treatment of dysmenorrhea. TREATMENT OF DYSMENORRHEA

The treatment of secondary or acquired dysmenorrhea is as a rule a comparatively simple matter and comprises in the main operative correction of the causal pathology. As Curtis" states, we must not overlook the fact that dysmenorrhea may still persist after a satisfactorily performed abdominal oper. atioa, due to inadequate uterine drainage cau?ed by cervical or uterine obstruction. This latter condition may be relieved by thorough dilatation, preferably using Hegar dilators. The treatment and cure of primary dysmenorrhea are at times a difficult procedure. The evidence of this is shown by the great array of therapeutic agents available, none of which are completely efficacious. However, there are various simple measures which ·frequently give relief and these will be discussed here; later in the text other remedial agents will be presented. During the attack, if severe, certain general procedures are carried out by the patient of her own volition, i.e., hot-water bag to the lower abdomen, evacuation of the bowels, and above all, bed rest. In addition, mild analgesics are of value, such as aspirin and phenacetin, the latter being frequently combined with codeine sulfate in capsule form. Sedatives in the form of phenobarbital and sodium bromide are also of aid in patients with marked nervous systems. This simple medication is frequently all that is needed. At times, oral medication is impossible due to the frequently associated nausea and vomiting, thus necessitating hypodermic therapy. Alcohol and morphine should never be prescribed, due to the hazard of habit formation. When the above mentioned simple measures fail, then others must be instituted. We must realize that the causative factors vary greatly in each patient, and that before any type of treatment is instituted, an accurate

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diagnosis based upon a careful history and physical examination is most essential. Investigation and treatment of subnormal constitutional and psychogenic factors should not be neglected for they are of fundamental importance in producing and perpetuating dysmenorrhea. The patient's anamnesis may elicit incidences which aid in the diagnosis and treatment. For example, the late onset of menstruation with hypomenorrhea and oligomenorrhea bespeaks a hypo-ovarian condition frequently associated with hypoplastic generative organs. The sudden increase in weight with oligomenorrhea is suggestive of a thyroid disturbance. Hertzler speaks of "goitrous dysmenorrhea" attributable to an interstitial thyrotoxicosis. It is a well-known fact that in selected cases the administration of thyroid is beneficial. Others are of the opinion that premenstrual hypoglycemia or a calcium deficiency may be causative factors. Ovarian hormonal therapy has been rather disappointing on the whole. If one selects this type of therapy, the hormone most suitable on a physiological basis is the relaxing one, progestin, commercially known as proluton. Other luteinizing substances such as follutein and antuitrin "S," obtained from the urine of pregnant women, may also be of value. With hypoplasia of the uterus as a causative factor, estrogenic substances may be employed in attempt to normalize this structure, for we know that with a proper balance between the ovarian hormones and the receptor organ, the uterus, a normal menstrual period ensues. Definite increased development of the uterus can be obtained, as shown by Kaufmann,ll who administered enormous doses of progynon to spayed women with atrophic uteri over a long period of time. He was able to demonstrate the increase in size by frequent x-ray examinations of the lipiodol injected uterus. However, such a result with ordinary therapeutic doses can hardly be expected. Nevertheless, Payne and Shelton17 have reported instances of uterine development following treatment with conventional doses of gonadotropic extract derived from the anterior lobe of the pituitary gland. Some gynecologists administer estrogenic substances up to within three to four days of the

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period, and then give the corpus luteum hormone to produce . relaxation of the uterine musculature. One of the great stumbling blocks to the more frequent use of these ovarian hormones is their expensiveness. However, from the rapid advances made in their synthetic production it would seem likely that in the near future they will be available at a much lower cost. The drugs used in treatment have been legion, and it would be impossible in this presentation to even enumerate them all, much less attempt their evaluation. Atropine sulfate, in doses of %20 grain every four hours, has been used with considerable success. This drug has no direct action on the uterus; however, it does decrease its muscular contractions by depressing the parasympathetics. Relief is also at times obtained from belladonna, acting similarly to atropine, its chief alkaloid. The extract of belladonna in suppository form alone or combined with the extract of opium is frequently efficacious. According to the English pharmacologist Dixon/ "there are but few, if any drugs which really inhibit uterine contractions. The opium group slows them down rather by fhe general lethargy produced, as will also the general anesthetics, but never completely. Drugs which relax plain muscle, like the nitrites and papaverine, may have some slight effect. Lutein in sufficient quantity might prove to be sedative." Many gynecologists are of the opinion that the great majority of proprietary medicaments offered to the public, containing vegetable drugs and alcohol, owe their efficacy primarily to the large amount of the latter ingredient ingested. During recent years, various reports have appeared on the relation of allergy to dysmenorrhea. It is thought that this association is prone to occur in asthmatics. Dutta7 reviews the subject and cites reported instances of dysmenoqheic women who were allergic to various foods, pollens, etc., and were relieved by their elimination. In 1931, D. R. Smith reported 12 such cases, 8 of whom were cured completely by withdrawal of the food to which these patients were sensitive. Stimulated by the demonstration of Myerson and Ritvo, that benzedrine sulfate brought about relaxation of the alimen-

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tary tract as evidenced by fluoroscopic examination, we decided to undertake a clinical as well as a pharmacological study of this substance. We wished to observe its effecr in the treatment of dysmenorrhea and also its action on the uterus, in vitro and in vivo; a summary of the preliminary report follows. In the investigation of the effects of benzedrine sulfate in the treatment of dysmenorrhea, 91 girls at work were administered the drug by mouth, several of them returning for subsequent treatment; 186 cases of dysmenorrhea were treated over a period of six months. The subjects were given 10 mg. by mouth and this dose was repeated in four hours if necessary, and only on two occasions were 20 mg. given at a single dose; never more than 20 mg. was given in twenty-four hours. The results were classified as good, fair, and poor. In the first group were those who were completely relieved by the initial 10-mg. dose; the second group comprised those who required a second 10-mg. tablet for the relief of either the continuous or the recurrent pain, whereas the third group included those in whom no result was obtained. Of the 186 cases treated, good results were observed in 114, fair results obtained in 27, and poor results were noted in 4S cases. In 2 of the 4S cases with poor results the patients were considered to have salpingitis; this diagnosis was based on history and symptoms. Pelvic examinations were not permissible. When the drug was effectual, pain was completely relieved in from three-quarters of an hour to two hours. Of the 114 patients that were completely relieved of pain by the first 10 mg. of the drug, 33 reported that varying degrees of psychic stimulation were experienced, work was easier, they worked faster with little effort, and at the end of the day felt no fatigue. Fourteen patients complained of insomnia, but each had taken the last 10 mg. after 6 o'clock in the evening. No insomnia or psychic stimulation was reported in the fair or poor cases. Dryness of the throat was reported in 8 cases, this symptom lasting about four hours after taking the drug. De-

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pression was reported in 4 cases and a mild degree of vertigo in 7. Nausea and vomiting after eating a heavy meal was reported in 4 cases, and drowsiness reported in 6. The action of benzedrine sulfate was then studied on the uterus of the guinea-pig, rabbit, and human, in vitro as well as in vivo. Unpublished reports15 indicate the favorable use of benzedrine sulfate in the treatment of dysmenorrhea. Only one report was observed in the literature of an experimental nature with regard to the action of benzedrine sulfate on the uterus. Boyd1 showed that benzedrine sulfate in concentrations of 0.01 to 0.001 per cent produced prolonged spastic contractions ofOlthe smooth muscle of the rabbit's intestines and the uterus of the guinea-pig, by direct action on the muscle fibers. On the rabbit's uterus he found that previous treatment with atropine sulfate did' not affect the benzedrine action. To establish a physiologic basis for the clinical studies, the following pharmacological tests were carried out. 1. Isolated Uterus.-Virgin Guinea-pig.-Seven typical smooth muscle experiments confirmed Boyd's work on the guinea-pig's uterus as far as spastic contractions are concerned. The guinea-pig's uterus, which is relaxed by epinephrine, is strongly contracted by benzedrine sulfate. The contractions are not increased by previous treatment with cocaine, which indicates that on this test object the activity of the drug is not through the sympathetic nerve endings. Boyd observed that on the rabbit's uterus the action of benzedrine was not affected by atropine, ruling out the parasympathetics, but on the guinea-pig's uterus previous treatment with atropine obliterated the benzedrine response. Epinephrine, however, relaxed the muscle after atropine. On this test object, benzedrine apparently does not act on the muscle cells directly but behaves a,s a parasympathetic drug. Figure 24 shows a typical response of the isolated uterus of the virgin guinea-pig before and after atropine. 2. Isolated Uterus.-Virgin Rabbit.-Although epinephrine relaxes the guinea-pig's uterus, it is well known that it

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Fig. 24.

Fig. 25.

forcibly contracts the rabbit's uterus which in turn is the basis for the Broom-Clark ergot assays. It was deemed of interest

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to test benzedrine on the rabbit's uterus. In two experiments, benzedrine sulfate Ielaxed the rabbit's uterus which is strongly contracted by epinephrine, indicating the parasympathomimetic character of the drug on this test object. A typical response is shown in Fig. 25. 3 . Isolated Human Uteri.-Surviving strips of human uteri studied immediately after hysterectomy were studied as another material for smooth muscle experiments. In 8 experiments, in which only those portions of the uterine wall visibly unaffected by the disease process for which the organ was removed, benzedrine sulfate showed as a rule an increase of tonus in the muscle with a trend toward diminishing the amplitulle, of contractions. A typical response of an organ taken

Fig: 26.

from a colored female (aged eighteen years) is shown in Fig. 26. The tubes and ovaries were markedly infected but uterine musculature was apparently normal. 4. Human Uterus in Situ.-Using essentially the procedure of Kurzrok et alP of inserting a rubber bulb capable of being inflated in the human uterus and measuring the activity of the muscle through its action on a mercury manometer of a kymograph, 7 experiments were performed. Benzedrine sulfate was injected hypodermically (50 mg.) after about fortyfive minutes of normal tracing. The effects on the amplitude of contraction were irregular; in some instances these were increased and in others diminished. The predominant effect was an increase in tonus almost immediately after injection. Figure 27 shows this effect on a colored female, aged forty-five

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years, who had ten pregnancies and was convalescent from the removal of a pedunculated cervical fibroid tumor. Further in vivo experiments will be conducted to determine if there is a variation in reaction during the various phases of the sexual cycle. From this study, it would appear that benzedrine. sulfate is of definite value in the treatment of dysmenorrhea, for 61 . per cent of the patients were relieved by the ingestion of 10 mg. of the drug. Relief was also obtained in an additional 14 per cent by taking a second 10-mg. tablet. The in vitro

Fig. 27.

and in vivo experiments in general show marked increase of uterine tonus with a diminution of uterine contractions. It is possible that this diminution accounts for the relief of the dysmenorrhea. The value of benzedrine sulfate in the treatment of dysmenorrhea is concluded to be due to peripheral action rather than dependent upon its central stimulation. OPERATIVE TREATMENT

As is well known, the physiological cure for primary dysmenorrhea is pregnancy, and even without gestation com-

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ing about, marriage alone may bring alleviation. In the severe, intractable type of. dysmenorrhea, operative interference frequently produces quite pleasing results. The most popular procedure still remains dilatation of the cervix, in spite of the fact that the theory of obstruction, as the etiological factor in the production of dysmenorrhea, has few enthusiastic proponents. In spite of the theory being most likely incorrect, a number of patients receive relief, however, this being mostly of a temporary nature. A curettage is frequently done so as to rule out the existence of a submucous or pedunculated fibroid. Holden statistically reviewed 9S patients who had been treated for dysmenorrhea by dilatation and curettage. He found that 40 per cent were entirely or greatly relieved for at least one year, with a recurrence after a year or more in 7 per cent; 30 per cent obtained no relief, while the remaining 30 per cent had but slight alleviation, if any. Maldevelopment of the uterus was present in 20 patients, only 2S per cent of them being relieved. The late Wm. P. Graves10 stated, "In our own series, in which we have been able to obtain definite reports at least a year after the operation, 60 per cent of the dysmenorrheic patients were relieved or cllred by simple dilatation and curettement. The other 40 per cent were either not relieved at all or only temporarily so." In view of these quoted figures and the experience of many gynecologists, dilatation of the cervix still remains the first operative procedure of choice. In dysmenorrheic patients with hypoplasia of the uterus, the operation of dilatation of the cervix is sometimes combined with the use of the intracervical stem pessary. Such an instrument produces continuous dilatation of the cervix and also stimulates contractions with development of the uterus. This type of pessary, which is not entirely without hazard, is now infrequently used, due to the possibility of ascending infection with the development of endometritis, salpingitis, or even pelvic cellulitis. In earlier days, plastic operations for stenosis of the cervix were frequently performed, but today such a proVOL. 23-19

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·cedure is rare, except for the relief of occlusions resulting from poorly executed operations. In December 1924, Gaston Cotte 3 of Lyons, France, performed, for the first time, resection of the presacral nerve for the relief of obstinate dysmenorrhea. In the next twelve years he completed nearly 300 such operations, and to his personal knowledge there were only 2 failures. During this time, presacral resection has been performed by many surgeons, mostly abroad, and the high percentage of good results obtained attests the value of this procedure. Here, in this country, gynecologists have been rather slow in accepting this operation which they feel should not be performed until other simpler measures have been tried. When associated abdominal or pelvic pathology is present in the patient with essential dysmenorrhea, there is then no reason for hesitancy in performing a laparotomy. The term "presacral" as chosen by Laterjet is anatomIcally incorrect, for this netlike plexus, instead of being a single nerve, is prelumbar in position. The term "superior hypogastric plexus" as suggested by Hovelacque, or prelumbar plexus (Elant) is more accurate. Before describing the operation, a brief anatomical description of the hypogastric plexus would be advantageous. An excellent description of the presacral nerve in relation to its anatomy, physiology, pathology, and surgery is presented by Albert A. Davis of London. 5 The following remarks are quoted from his article appearing in the British Medical Journal. "The presacral nerve is formed above by the confluence of the intermesenteric nerves, long, fine, para-aortic sympathetic trunks arising from the solar plexus and the adjacent lumbar ganglia. This hypogastric plexus rests on the bodies of the fourth and fifth lumbar vertebrae and is an isoscelesshaped structure. From its lower angles, long, narrow nerve bundles run forward and downward, one on each side, forming the hypogastric nerves, or as they are also designated, the inferior hypogastric plexuses. The fibers of these plexuses pass down into the pelvis near the sacral end of the uterosacral

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ligament and then forward over the lateral surface of the rectal ampulla to join the pelvic plexus, more commonly known as the uterovaginal plexus, the cervical ganglion, or the ganglion of Frankenhiiuser. The hypogastric plexus furnishes the main sympathetic nerve root to this pelvic ganglion. The parasympathetic supply to this ganglion is furnished by the nervi 'erigentes which arise from the second to the fourth anterior roots of the sacral nerves, and some additional sympathetic fibers also reach it from the sacral chain. The pelvic plexus is a bilateral, thin sheet of nerve fibers with fascia, measuring about 2 by 3 centimeters, and lies upon the anterolateral aspect of the ampulla of the rectum. All of the pelvic organs are innervated from this pelvic ganglion." In considering the physiology of this nerve, one realizes that there is no unanimity of opinion in regard to its functions. As a comprehensive discussion of this subject would, alone comprise a lengthy treatise, it will .only briefly be here considered. It would seem that the majority of authorities are of the opinion that the hypogastric plexus carries the important pathways of sensation from the internal genital organs to the medullary centers.9 The part played by the sympathetics and parasympathetics in regulating the motor control of the uterus is unknown. As is well recognized, contractile activity of the uterine musculature occurs in the absence of nerve stimulation. This phenomenon has been demonstrated by Rein 16 who showed that spontaneous birth of young rabbits occurred after section of all extrinsic nerves. As to the para sympathetic influence, Fountaine and Hermann 20 cite the observations of Mueller, Brachet, and Gertsmann, who have found that neither the section nor the complete destruction of the sacral part of the spinal cord will prevent childbirth. Of great importance is the observation of 'Cotte, that in 30 pregnancies occurring after presacral resection there was no evidence of altered uterine contractility. The rOle of the sympathetics and parasympathetics in relation to bladder and rectal function will not be discussed. The most favorable results from presacral resection are

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obtained in those whose pain of menstruation is located in regions corresponding to the terminal distribution of this hypogastric plexus. The technic of the operation offers, as a rule, little difficulty to those familiar with pelvic surgery. A paramedian incision begun about 2 to 3 cm. above the umbilicus exposes most advantageously the promontory of the sacrum and gives easy access to the retroperitoneal hypogastric plexus. The posterior parietal peritoneum is incised, care being taken not to injure the ureters or the proximate large vessels. This plexus is encompassed in an isosceles triangle bounded laterally by the common iliac arteries and caudally by the lower lip of the fifth lumbar vertebra. As already stated, the structure is netlike in formation; for this reason, one should exercise care to divide the several nerve bundles if a good result is to be obtained. . Following section of the nerves, the peritoneum is closed with a continuous suture and the operation is completed. We have performed this procedure six times for primary dysmenorrhea, with good results. This operation is also of some value for the relief of intractable pain occasioned by metastasis from a carcinoma of the cervix; it has been perfor~ed by us five times, with only fair results. SUMMARY

1. Secondary dysmenorrhea offers little difficulty, for the etiologic factors can be readily eradicated. 2. Primary dysmenorrhea presents many individualistic problems demanding thorough study before treatment is instituted. 3. A multiplicity of factors, as a 'rule, play a role in its etiology. 4. No panacea has as yet been discovered, although several remedial agents of value are available. S. Constitutional and psychogenic factors are important in producing and perpetuating dysmenorrhea. 6. In our experience, hormonal therapy has not been very satisfactory. 7. Benzedrine sulfate is a valuable adjunct to our therapeutic armamentarium.

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8. Dilatation of the cervix offers a fair percentage of cures. 9. In selected cases, after simpler methods have failed, resection of the hypogastric plexus is of decided value. BmLIOGRAPHY 1. 2. 3. 4. 1938.

Boyd, Eldon M.: Am. J. Med. Sei., 195: 445, 1938. Cannon, D. J.: Jour. Obst. and Gynee. Brit. Emp., 42: 409, 1935. Cotte, Gaston: Am. J. Obst. and Gynee., 33: 1034, 1937. Curtis, H. C.: Textbook of Gyneeology, 3d Ed., W. B. Saunders Co.,

5. Davis, A. Albert: Brit. Med. Jour., Vo!. 2, July 7, 1934. 6. Dixon's Manual of Pharmacology, 8th Ed., London, Edward Arnold and Co., 1936. 7. Dutta, P. C.: J. Obst. and Gynec., Brit. Emp., 42: 409, 1935. 8. Fluhmann, C. F.: Endocrinology, 23: 4, Oct., 1938. 9. Gask, G. E., and Ross, J. P.: Surgery of the Sympathetic System, Wm. Wood and Co., Baltimore, 1934. 10. Graves, Wm. P.: Textbook Gynecology, W. B. Saunders Co. 11. Kaufmann, C.: Jour. Obst. and Gynec., Brit. Emp., 42: 409, 1935. 12. Kurzrok, R., Wiesbader, H., Mulinos, M., and Watson, D. P.: Endocrinology, 21: 335,1937. 13. Myerson, A., and Ritvo: J.A.M.A.,107: 24, 1936. 14. Novak, E., and Reynolds, S. R.: J.A.M.A., 99: 18, Oct. 29, 1932. 15. Personal communication: Smith, Kline and French, 1938. 16. Rein: Soc. de Bio!., 1882. 17. Payne, S. A., and Shelton, E. K.: Endocrinology, 23: 5, Nov., 1938. 18. Wharton, L. R., and Henriksen, ErIe: J.A.M.A., 107: 18, Oct. 31, 1936. 19. Whitehouse, B.: Jour. Obst. and Gynec., Brit. Emp., 42: 309, 1935. 20. Fountaine, R. and Hermann, L. G.: Surg., Gynec. and Obst., 54: 133, 1932.