June 1935] June 1935] HENDERSON: ANTERIOR PITUITARY-LIKE HORMONE HENDERSON: ANTERiOR PITUITARY-LIKE HORMONE 615 THE TREATMENT OF MENORRHAGIA AND METRORRHAGIA BY ANTERIOR PITIJITARY-LIKE HORMONE* BY D. NELSON HENDERSON, Toronto FAVOURABItE results in the treatment of produce gonadotropic effects of follicle matura- irregular and profuse uterine bleeding by tion and formation of corpus luteum even in the use of anterior pituitary-like hormone have hypophysectomized rats. been reported by A. D. Campbell,' E. Novak2 It is due to the luteinizing power of the and A. Gabrielianz.3 This paper is concerned anterior pituitary-like hormone that it has been with the treatment of a series of 39 patients recommended for the treatment of bleeding due suffering from menorrhagia and metrorrhagia to endocrine unbalance. In endometrial hyper- due to endocrine unbalance. plasia characterized by excessive uterine bleed- The anterior pituitary-like hormone found in ing with occasional periods of amenorrhuca pregnancy urine, placenta and blood, is a Schroeder has noted the absence of the corpus gonadotropic hormone resembling the anterior luteum in the ovary. The absence of the pituitary gonadotropic hormone, but differing corpus luteum is undoubtedly a very constant from it in some ways. The anterior pituitary finding, although Novak has failed to confirm hormone produces maturation of the follicles it and our experience points to the occasional and formation of the corpus luteum in the occurrence of the lutein body in this type of hypophysectomized rat; the anterior pituitary- menorrhagia. Endometrial hyperplasia, how- like hormone fails to do so. It further differs ever, is not a constant finding in all cases of from the anterior pituitary hormone in that it functional menorrhagia. In our experience the fails to affect the development of the immature characteristic microscopic picture of endo. avian testes. It differs also in its effect on the metrial hyperplasia is probably not obtained in immature rat ovary in that it rarely produces more than a third of these cases. In the ab- increase in weight of the ovary beyond 70 mg., sence of hyperplasia no characteristic changes whereas the anterior pituitary hormone causes can be noted on one microscopic examination of a weight increase two or three times as the endometrium in these functional cases of great.4' menorrhagia. It would seem reasonable to While these differences are noted, the re- suppose, however, that repeated examinations semblance between these two hormones is great, of the endometrium at various stages of the and it is still a possibility that they may be cycle in the same patient might demonstrate identical. The gonadotropic pituitary hormone constant variations from the normal endo- appears to be composed of two fractions, as metrial cyclic phase. Such investigation, how- suggested by Zondek, A-the follicle-stimulat- ever, is quite impractical, necessitating re- ing hormone and B-the luteinizing hormone; peated curettages in one patient. the anterior pituitary-like hormone from pla- A good working hypothesis for the physio- centa is more comparable to the luteinizing logy of menstruation, taking into consideration fraction, while the hormone obtained from the various hormone factors combined with a menopausal urine and the urine of castrates correlation of the endometrial phase and the resembles more the follicle-stimulating frac- stage of follicle and lutein development in the tion.5 It is interesting to note that the anterior ovary, may be summarized as follows. The pituitary-like hormone when combined with the post-menstrual phase of the normal menstrual hormone obtained from menopausal urine will cycle, associated with the developing follicle and regeneration and development of the endo- * Read before the Section of Obstetrics and Gynaeco metrium, is under the control of the folliele- logy, Academy of Medicine, Toronto, April 11, 1935. From the Department of Obstetrics and Gynaecology, stimulating hormone A. The premenstrual University of Toronto. hyperplasia of the endometrium associated wTith 616 616 THE CANADIAN IVIEDICAL ASSOCIATION JOURNAL THE CANADIAN MEDICAL [June 1935 1935 the developing corpus luteumn is unider the in- lacerated it was taken as a contraindication for flueniee of the luteinizing hormone B. It may the use of the hormone. be assumed that the maintenanee of a regular The anterior pituitary-like hormone used in normal menstrual cycle of maturation and de- this clinical investigation was prepared by the velopment of the follicle, ovulation and forma- method recommended by Collip.* It was ad- tioIi of the corpus luteum depends on a delicate ministered hypodermically and should be relationship and balance between the tw o frac- injected slowly and intramuseularly. The tions A and B of the goinadotropic pituitary treatment was started regardless of the men- hormone. strual phase and continued till a full course was At the present time the diagniosis of endo- administered with no cessation during menstru- crine unbalance as a cause of disturbed ation. The medication was given in 1 e.e. doses menstrual function is frequeintly a negative oine. for seven consecutive days, and then three days Until the dysfunction can be definitely stated a week until eighteen to twenty-two doses had as ovarian or pituitary in origin, and a prac- been given. This is the procedure recom- tical biological or chemical method devised to mended by Campbell. Variations in the number estimate the amount of gonadotropic hormone of injections were tried, hoping that equally in the blood or urine, the use of female sex satisfactory results might be obtained by fewer hormone therapy will be limited and the full doses, but this was not the case. The injections value of such therapy not obtained. were not follow ed by any general systemic In this series the diagnosis of endocrine un- reaction except in one case in which an urti- Ibalance was made by ruling out systemic caria developed. The local reaction varied from disease afecting pituitary or ovary, hypo- or slight local soreness without evident reaction to hyper-thyroidism, and pathological lesions of rather marked local tenderness and superficial uterus, tubes and ovaries. If satisfactory re- erythema. It was observed that the local re- sults are to be obtained by the administration action was much more intense following the of anterior pituitary-like hormone it is essential first four or five injections than after sub- that the presence of tubo-ovarian inflammatory sequent ones. The majority of patients suffered disease, niew growth and disturbed pelvic only slight local tenderness. mechanies l)e diagnosed. This neeessitates an For the purpose of presenting the results of accurate menstrual history anid ain exacting this investigation the cases were divided into pelvic examination. If doubt exists in regard five groups: Group I, those with normal men- to the existence of carcinoma of the cervix or strual cycle and excessive flow; Group II, uterus, an examination under ami,tsthesia with those wsith shortened menstrual cycle and ex- cervical biopsy and curettage should be per- cessive flow; Group III, those with completely formed. Moderate, diffuse enilargement of the iriregular eyele and excessive or normal flow; uterus with chanige to globular shape is a ( roup IV, those with continuous bleeding; frequent finding in menorrhagia and in itself Group V, those with cyclic intermenstrual or cannot be taken as a contraiiidication to the premeniistruial spotting. uise of hormone therapy. Patienits sufferinig It was with difficulty that an even greater from uterine bleeding after the meniopause were niumber of groupings wNere avoided, as despite not treated due to the high ineidence of car- the relatively small number of patients treated cinoma in this type of case. All patients had great variations occurred in the type of menor- blood pressure readings withini normal limits, rhagia and the menstrual cycle. Thus in Group and a high percentage had basal metabolism I are ineluded patients with minor variations of estimations done. Two patients treated had cycle up to six days, and in Group II are positive Wassermann reactions but no other included some cases of metrorrhagia. The re- evidence of syphilis. The only other treatment sults of treatment of the Group T type of case given during the trial of the anterior pituitary- are shown in Table I. In this group of fifteen like hormone consisted in the administration patients the menorrhagia varied from moderate of ferrum redactum for an<Tmia and cauteriza- tion of the cervix in mild cases of exo- * A sterile standardized solution of the hormone cervicitis. If the cervix was badly eroded and containing 100 biological day units per each cubic centimetre. Junec1935] JHENDMRSON: ANTERIOR PITUITARY-LIKE HORMONE 617 TABLE I. NORMAL MENSTRUAL CYCLE WITH EXCESSIVE FLOW. Duration of Period of No. symptoms observation after A.P.L. Results and sucbsequent history H.B. 12 mhonths 3 months Normal flow. B.W. 9 months 12 months Normal flow. E.P. 9 months 14 months Normal flow. E.H. 2 years 1 year Normal flow. A. 6 months 9 months Normal flow. L. 2 years . 3 months Normal flow. P.W. 1 year 4 months Normal flow. M.H. 2 years 1 year Normai flow. F.F. 14 months 1 year Normal flow but periods still prolonged. M.E. 2 years 1 year 2Normal flow of variable duration. C.M. 2 months 1 year Normal flow. Relapse at end of year. Dilatation and curettage done. Endometrial hyperplasia diagnosed. J.F. 3 months 8 months Normal flow. Relapse after 3 months, controlled by further treatment. S. 6 years 2 years Normal flow. Recurrence after appendectomy, relieved by further treatment. A.S. 9 months 14 months Normal flow. Pregnancy occurred after 3 normal menstrual periods. M.H. 2 years 1 year Normal flow. One year before treatment had dilatation, curettage and 6ophorectomy, without relief. SUMMARY No. of cases Normal flow Normal flow and duration Failures Relapses 15 15 13 0 3 to severe necessitating resting in bed during rhagia. In one the menorrhagia returned one part of each menstruation. The duration of the year after treatment. This patient was curetted flow in most cases was increased one to four days. and a diagnosis of endometrial hyperplasia Two patients had had previous operations to made. The second patient had a relapse after relieve the menorrhagia, with either temporary or three months, which was controlled by six more no relief. All patients in this group had a return doses of the hormone; the third had a recur- to a normal amount of flow, but in two the rence after an appendectomy. Ten doses were duration of menstruation was variable or pro- repeated with a satisfactory result. One pa- longed. Three had a recurrence of the menor- tient became pregnant after three normal TABLE 11. SHORTENED) MENSTRUAL CYCLE WITH EXCESSIVE FLOW Duration of Period of No. symptoms observation after A.P.L. Results and subsequent history Z.S. 6 months 15 months Normal flow and interval. R. 6 months 5 months Normal flow and interval. J.P. 12 months 7 months Normal flow and interval. R.S. 2 years 2 months Normal flow and interval. A.G. 1 year 1 year Normal flow and interval. O.H. 4 months 3 months Normal flow and interval. V.W. 2 years 1 year Normal flow and interval. Y.D. 10 months 4 months Normal flow interval unchanged. Dt.M. 9 months 1 year Normal flow variable interval. L.P. 3 years 6 months Normal flow variable interval. C.T. 2 years 1 year Lessened flow, irregular. Operation revealed small myoma. I.S. 2 years Failure. Operation revealed bilateral salpingitis. T. 6 months 1 year Failure. Examination now reveals a fibroid in anterior wall of uterus. D.M. 2 years 5 months Normal flow interval unchanged. SUMMARY No. of cases Normal f low Normal flow and cycle Failures 14 11 7 3 one case of salpingitis two cases of myomata 618 618 THE CANADIAN MEDICAL AssoCIATION JOURNAL [June 19035 menstrual periods. The results of treatment of hyperplasia had a return to normal menstrua- the fourteen patients in Group II are shown in tion for one year, when a relapse occurred; the Table II. Eleven patients had a complete second patient receiving benefits has had two return to normal flow, and seven a return to menstrual periods without excessive flowsr. both normal flow and cycle, leaving four pa- The results of treatment of four patients tients with shortened or variable cycle. One suffering from continuous bleeding are shown patient had only a moderate decrease in flow in Table IV. One patient had been operated on and at operation a small intramural myoma for chronic pelvic inflammation causing metror- was revealed. Two patients showed no change rhagia, at which time.bilateral salpingectomy in menorrhagia or cycle. At operation un- and right 5ophorectomy wvere done. Following suspected salpingitis was found in one and a operation, bleeding, varying from slight to myoma in the other. severe,continued for three months, when treat- Table III shows the results of treatment of ment started. The bleeding was tempo- was the four patients in Group III. All these pa- rarily increased and then stopped, to be tients had had previous operations or had followed by normal menstruation. Two pa- received x-ray or radium treatment with only tients wiere suffering from menorrhagia at partial or temporary relief of symptoms. Two puberty; both were relieved, but one has had were not benefited by the anterior pituitary- two relapses, one of which was controlled by like hormone. One patient with endometrial further hormone treatment. This patient is TABLE III. COMPLETELY IRREGULAR CYCLE WITH EXCESSIVE OR PROLONGED FLOW. Duration of No. symptoms Previous treatment Flow Reesults Subsequent history S.S. 13 years Higlh voltage x-ray Moderate but prolonged No change B. 4 years 100 nig. of radium. High voltage x-ray Excessive No change Submucous myoma M.M. 2 years Dilatation and curet- Excessive Noriimal flow. tage. Right oophorec- Normal interval Relapse at end of year tomy. Endometrial liyperplasia diagnosed S. 12 years Dilatation and curet- tage. (300 mg-lours radium; higlh voltage Excessive Normal flow Only observed for 3 x-ray and cycle months SUM1MARY No. of cases Return to niormal menstruation Failure Relapse 4 2 2 1-treated in another city by operation TABLE IV. CONTINuOUs BLEEDING Duration of No. symptoms Previous treatment Flow Results and subsequent history D.S. 3 montlhs Salpingectomy. Normal flow and interval for over Right 6ophorectomy Variable one year F.T. 29 days (puberty) Excessive Normal flow and interval for over one year 1.W. 2 years (puberty) Slight spotting Failure. Dilatation and curettage re- sulted in 3 months' amenorrhoia L'.P. 3 months (puberty) Moderate to Normal flow and interval. Relapse at excessive 4 months. A.P.L. repeated. Nor- mal for 8 months; relapse again SUMMARY ,No. of cases Return to normal menstruation Failure Relapse 4 3 1 1-under treatment at present June 1935] June 1935] HENDERSON: ANTERIOR PITUI'TARY-LIKE HORMONE HENDERSON: ANTERIOR PITUITARY-LIKE HORMONE 619 now receiving more treatment. The last case ment show that of the 39 patients receiving in this group is a peculiar one. With the onset treatment 31 obtained relief from the menor- of puberty, two years ago, slight spotting began rhagia and 25 of these had a complete return and continued one or two days each week with to a normal menstrual cycle; 8 showed no ap- no other evidence of menstruation. No improve- parent effect from treatment; 3 were proved ment took place after anterior pituitary-like to have small myomata; and 1, pelvic inflam- hormone treatment. Curettage was performed mation, leaving 4 cases in which the anterior and resulted in three months' amenorrhoea, pituitary-like hormone was completely unsuc- after which the almost daily bleeding recurred. cessful and no cause for the menorrhagia and This patient is still under observation. metrorrhagia was determined. TABLE V. CYCLIC INTERMENSTRUAL AND PREMENSTRUAL SPOTTING Duration of Period of observation No. symptoms Previtos operations after A.P.L. Result A. 7 months No change l,.G. 14 months Dilatation, curettage and 2 years 3 months,cure; relapse. More myomectomy for small myomata A.P.L. 4 month cure; relapse again SUMMARY OF RESULTS Number Normal flow Group of cases Normal flow and cycle Failures Relapses I 15 15 13 0 3-two relieved by further treatment II 14 11 7 3-one case of salpingitis; 0 two cases of myomata III 4 2 2 2-one case of myoma 1-treated surgically IV 4 3 3 1 1-Under treatment V 2 0 0 2 0 Total 39 31 25 8 5 Group I-Normal menstrual cycle with excessive flow. Group II-Shortened menstrual cycle with exces- sive flow. Group III-Completely irregular cyle with excessive or prolonged flow. Group IV-Continuous bleeding. Group V-Cyclic intermenstrual and premenstrual spotting. Table V shows the results of treatment of COMMENT two patients suffering from cyclic inter- The anterior pituitary-like hormone is par- menstrual and premenstrual spotting. One ticularly valuable in treating menorrhagia and patient had previously received temporary re- metrorrhagia due to endocrine unbalance in lief from curettage. The anterior pituitary- young women where hysterectomy or the pro- like hormone had no apparent effect in this duction of an artificial menopause by x-ray or case. The second patient in this group com- radium is very undesirable. In the group of plained of sterility and premenstrual spotting cases reported only 9 patients were over forty starting ten days before each menstruation. years of age. She had been previously operated upon, when The immediate effect of treatment if the myomectomy was performed for multiple small patient is menstruating when treatment is be- subserous myomata. Two courses of anterior gun or menstruation occurs soon after is a pituitary-like hormone were given, each of temporary increase in the bleeding. Dysmen- which was followed by three months' relief orrhaea, when present, was slightly aggravated from premenstrual spotting. This patient prob- by the anterior pituitary-like hormone. ably has small submucous myomata. As this The moderate menorrhagia developing after supposition has not been confirmed by opera- pregnancy encountered in young patients was tion, this case is classified as a failure. very responsive to treatment. Many of the A general summary of the results of treat- patients in this series complained of dizziness 620 THE CANADIAN MEDICAL ASSOCIATION JOURNAL [June 19353 which was very frequently relieved early in the menorrhagia and metrorrhagia due to endocrine course of treatment before any improvement in unbalance. the anaemia had occurred. Many patients 2. Successful results from this form of volunteered the information that their general therapy can only be obtained in the absence of sense of well-being was markedly improved. pathological lesions in the genital tract. It has been suggested by Greenhill,7 Frank8 Moderate diffuse enlargement of the uterus is and Wolff9 that the use of the female sex frequently encountered in functional bleeding hormones may do irreparable harm to the pa- and is not a contraindication to hormone tient. In regard to the anterior pituitary-like therapy. hormone a theoretical possibility would be the 3. Harmful effects from the administration excessive formation of corpora lutea. This of anterior pituitary-like hormone are con- condition is a frequent finding in hydatidiform sidered unlikely, and are outweighed by the mole, where huge amounts of gonadotropic excellent therapeutic results. hormone are produced. Such huge quantities 4. Improvement in the patient's general certainly would not be given therapeutically, sense of well-being after treatment is noted, and even if such excessive luteinization did and frequent relief of dizziness, when asso- occur from therapeutic doses, once the ad- ciated with menorrhagia, is observed. ninistration of the hormone is discontinued, retrogressive changes should occur in the 5. More exacting methods of diagnosis of corpora lutea as they do in hydatidiform mole pituitary and ovarian dysfunction are necessary when it is expelled. The real danger in the use before the full value of anterior pituitary-like of anterior pituitary-like hormone is the hormone therapy will be realized. possibility that it will be used indiscriminately I wish to express my thanks to Professor W. B. Hendry for making it possible to carry out this investi- for the treatment of menorrhagia and metror- gation; also to Drs. W. G. Cosbie, W. A. Scott and H. B. rhagia without proper examination to rule out Van Wyck for permission to include their private cases in this series. The preparation of the anterior pituitary- malignant disease. It cannot be too strongly like hormone used in this investigation was a stand- emphasized that all patients suffering from ardized solution known as " A.P.L. " It was supplied menorrhagia or metrorrhagia should have the by the manufacturers, Ayerst, McKenna and Harrison. cervixn carefully inspected, and if there is any REFERENCES doubt of the possible existence of carcinoma of 1. CAMPBELL, A. D.: Further studies on anterior pituitary- like hormone with special reference to irregular uterine cervix or endometrium section of the cervix bleeding, Canad. M. Ass. J., 1932, 27: 352. 2. NovAx, E.: Observations on gyneecological aspects of endo- and curettage should be performed. crinology, Brit. M. J., 1933, 2: 553. 3. GABPRIELIANZ, A.: Treatment of functional uterine bleeding with extract of placenta, Am.. J. Obs. & Gyn., 1934, 28: CONCLUSIONS 262. 4. EVANS, H. McL.: Clinical manifestations of dysfunction of Thirty-nine cases of menorrhagia and met- anterior pituitary, J. Am. M. Ass., 1935, 104: 464. rorrhagia, presumably due to endocrine un- 5. COLLIP, J. B.: Interrelationships among urinary, pituitary and placental gonadotropic factors, J. Am. 1U. Ass., 1935, balance, have been treated by anterior 104: 556. 6. CoLLiP, J. B., THOMSON, D. L., MCPHAIL, M. K. AND pituitary-like hormone; 31 were relieved of the WILLIAMSON, J. E.: Can&d. M. Ass. J., 1931, 24: 203. 7. GREENHILL, J. P.: Year Book of Obstetrics & Gyniecology, menorrhagia and 25 had a complete return to 1933, p. 507; 1934, p. 564. normal menstruation. Of the 8 patients who 8. FRANK, R. T., GOLDBERRER, M. A. AND SPIELMAN, F.: Present endocrine diagnosis and therapy, J. Amn. M. Ass., failed to respond to treatment 4 were proved 1934, 103: 393. 9. WoLFF, F.: Schwere Erbschiidigung der weissen Maus durch to have local pelvic lesions sufficient to cause Hormzufuhr, Ztsel)r. f. Geburtsh. der Gynak., 1934, 108: 246. the complaint. From an analysis of these results 10. OoLLip, J. B., SwLLYE, H., ANDERSON, E. M. AND THOMSON, it is concluded: D. 1L: Production of aestrus: relationship between active principles of placenta and pregnancy blood and urine 1. The anterior pituitary-like hormone is a and those of anterior pituitary, J. Am. M. Ass., 1933, -101: 1553. valuable therapeutic agent for the treatment of CloLap, J. B.: Trans. of Congress of American Physicians and Surgeons, Fifteenth Session, 1933, p. 47.
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