hypophysectomized rats by mikesanye

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									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
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                           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
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                                  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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