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The control of menorrhagia by prolactin
THE CONTROL OF MENORRHAGIA BY PROLACTIN':' HElWERT
8.
.'iND
KCPl'ER~IA~,
Jj. Q.
HAIR,
PH.D., PAGL
B.S.,
FRIED,
ArGUtiTA,
}1.I>.,
eLl.
(From. the Departments of Experimental Medimne and Obstetl'ics and Gynecolo.ml. Unirersity of Georgia School of Medicine)
F ALLj the dysfunctions that aee associated with the menstrual (',Vcle of women and which are of discomfort and even hazardous to the health of the patient, menorrhagia presents the most formidable problem to the clinician. Inasmuch as the physiology of uterinr hleeding' is not entirely nnderstood, it is quitr apparent that the physiological eoncept of malfulJetion of the menst.rual eyele is likewise confnsed and misinterpreted. In addition, failnre to reproduC'(' the phenonH'na of ('x('essive uterine bleeding in the C'ommon lahoratory animal haH preventrd adequate t'xperimcntal investigat.ion of this prohlem, and h,1s led to empirical therapeutiC' proeedul'es or radiC'al sllrgieal C1lJ'es. AIt hough many different forms of' therapy havp been suggest.ed, nOlle Iws assnmt'd the position of a pHlla(~ea for the eontrol of exeessive uterine bleeding. In view of the multitude of methods proposed for tlw allnvialion of' functional and pathologi('al uterine bleeding, it is apparent. that not olle has heell uniformly aeeepted as the ideal mode of therapy. In a seareh for a satisfaetory t.herapeutie tool to dam sUl'('es:;:fully the menol'l'hagic iiow, we deeided 10 inwstigate 1he possibilities of thu laetogenic hormone, prolaetill, since it wa:;: shown b~' Ur'cenblatt e1 a1H that hlood from lactating women was a llseful, though ill<'ollvenieni mode of therapy in metropathic menorrhagia. Their l'ationale 1'01' employing this mode of therapy was based UpOll two linrs of thought:
O
1. TIl(' only true period of' physiologic amenorrhea other t.han pl'eglW]H'.V occurs during the interval of lactation. 2. Experimental evidence at that. time had demonst.rated the ant i· gonadal effed of lactog'
228
KUPPERMAN, }'RIED, AND HAIR:
CONTROL OF ME~ORRHAGIA
229
of earlier work H and those of Hall and also present some preliminary data on the effect of prolactin upon the normal menstrual cycle and threatened abortion.
Procedure
Two types of purified prolactin preparations were employed in this investigation.'"' One type of preparation was available as a sterile powder and supplied with a solvent (saline or distilled water) to he added hefore using, while the other preparation was made up in solut~on form. \Ve have found the powdered preparations to he more effectlve in treatment and saline to be the preferred solvent. The lactogenic hormone was administered for various periods of time to 43 women exhibiting organic or functional uterine bleeding. In patients suffering from organic disturbances sueh as fibromyoma, pelvic inflammatory disease, etc., it is to be emphasized that the lact.ogenic medication was purely palliative in action and was not employed with the intention of alleviating the organic disturbance. By controlling the excessive uterine bleeding in these patients, a suitable interval was provided between the cessation of bleeding and preparation of the patient for a more final and complete cure. The doses of prolactin that were employed ranged from 100 to 250 International {~nits per injection and were administered subcutaneously every day, or second day during the abnormal period of bleeding. In several cases \Yhere the menorrhagia had heen of long duration, it was necessary to administer 100 to 200 T.U. of prolactin in daily doses for 4 to 8 days before the bleeding could be checked. When possible, suction curettages were undertaken to determine the condition of the endometrium before and during administration of prolactin. Uterine biopsies were taken for a twofold purpose: 1. To determine the type of endometrium from which bleeding occurred. 2. To ascertain activity of the ovary by noting its physiologic effect upon the endometrium. Operative specimens of the uterus or ovaries, or both, were also obtained and studied, particularly in patients undergoing hysterectomy, for additional evidence Oil the physiologic action of prolactin. In addition to the patients exhibiting abnormal bleeding, three women with normal cycles were treated with daily doses of prolactin to determine the effect of the lactogenic hormone upon 1he length of cycle and endometrial histology. Preliminary data arc also presented on the effect of prolactin in six cases of threatened abortion. Foul' patients ga,'e a history of previous abortion, while two presented a history of earlier uncomplicated pregnancies. These patients were all subjected to all intensive course of prolactin therapy in an attempt to control the untoward symptoms which were associated with cramps and hlceding.
Results The data summarizing the results obtained with prolactin are presented in Table I, where the clinical outcome is classified as follows: (a) Excellent--indicating prompt and complet.e ('ontrol of the uterine ___bleeding. 'Prola~tin prepara tions were generously supplied by Armour Laboratories, E. R. Squibb and Sons, and Winthrop Chemical Co.
230
AMERICAX .TOURNAI, OF OBSTETRICS AXD GYNECOLOGY
(b) Good-referring to those cases where longer therapy was necessary to control bleeding. (c) Fair-those cases in which bleeding was largely suppressed, but never completely inhibited, so that the patient exhibited a prolonged hut mild menstrual flow dnring the administration of prolactin. (d) Poor-indicating no diminution of bleeding following lactogenic treatment. TABU: CHIEF COMPLAINT
Menorrhagia Menorrhagia Menorrhagia Menorrhagia Dysmenorrhea Threatened abortion
r.
Cr,TXICAT, EVFEC:TS OF PnOT.ACTIN
ASSOCIATED WITH
Functional bleeding Uterine fibromyoma Cystic ovaries Chronic pelvic inflammatory disease Menorrhagia Cramps and bleeding --4.- . -
.. --
CJ.lNICAL RESULTS };XO;LT,ENT GOOD
8 8
:1
7
12
5
3 4
5 3
3 0
...- - -.
( NUMBER OF CASES) FAIR POOR
1 1
2
1 2 1
4
2
:I
0
2
3
-. - - -
In the accompanying chart, menorrhagia is listed as bcing associated with other clinical symptoms or entities such as fibromyoma of the uterus, cystic ovaries, chronic pelvic inflammatory disease, etc. In presenting the summary in a chart form, some cases have' been itemized in more than one group due to dual complaints. For example, a patient with fibromyoma might also be subject to dysmenorrhea at onset of the menses which, in turn, might be menorrhagic in nature. Likewise, cystic ovaries or fibromyoma might be present in a menorrhagic patient. The clinical results are evaluated on the basis of the chief complaint and not upon the improvement of the associated conditions. Hence, although 43 patients in all were treated for abnormal bleeding, a great many more notations are included in the chart due to concomitant symptoms. From 'rable I it is apparent that lactogenic hormone is of proved value in controlling excessive uterine bleeding. It was equally effective in controlling menorrhagia, whether functional or organic in origin. Of the 17 women suffering from functional menorrhagia, i.e., menorrhagia associated with no pathologic manifestations, two failed to respond favorably to the hormone therapy. All the patients in this group gave a history of exccssive bleeding for at least one cycle prior to their appearance in the clinic. In fact, a majority of the patients offered thc information that the excessive menstrual periods werc of long duration and the interval between the menstrual flow was obvious only by its brevity. Uterine biopsies taken in this group of patients on the first day of menses exhibited predominately an estrogenic or cystic glandular hyperplastic endometrium, although several cases were observed where menorrhagia was associatcd with a secretory endometrium. Daily injections of 100 IT. of prolactin were administered during the period of uterine bleeding. The clinical success of this mode of therapy was indicated by the cessation of hleeding that occurred in all but two of the 17 patients treated. The severity of bleeding in subsequent cycles depended upon the regimcn that was employed. In those cases where prolactin was injected on the first day of subsequent menses and continued for 2 to 3 days, bleeding was well controlled. Of those patients
KUPPERMA~, FRIED, AND HAIR:
CO~TROL OF MEXORRHAGIA
231
who did not receive further treatment after one successful therapeutic course with prolactin, five had normal cycles and two reverted to their original condition of excessive and prolonged uterine bleeding. Menorrhagia associated with fibromyoma of the uterus responded very satisfactorily to prolactin therapy. These patients were more resistant to treatment than those with functional menorrhagia and required daily doses of 100 to 200 I.U. of prolactin for a period of 4 to 8 days, whereas patients with functional menorrhagia required only 100 LU. per day for 3 to 6 days. All the patients in this group had been suffering with menorrhagia for at least three months and one third of these patients bled almost continually. The clinical results with prolactin were pronounced, although not as favorable as in the patients with functional menorrhagia. Three patients failed to respond satisfactorily to prolactin therapy. As has been mentioned before, prolactin was not administered to these patients for the purpose of causing a regression of the uterine fibromyomas, but was employed so that the patient might be placed in proper physical condition to withstand the necessary surgery. This procedure was resorted to since clinically, many of these patients exhibited a severe secondary anemia as a result of their bouts of excessive uterine bleeding. In no instance in cases of fibromyomas of the uterus does the use of prolactin imply a substitute for surgery. Menorrhagia noted in the presence of cystic follicles in the ovaries likewise required persistent prolactin therapy to control the excessive uterine bleeding. The presence of cystic ovaries was determined by palpation and then confirmed by laparotomy, or was ascertained by surgery alone. In those cases in which prolactin was effective, it was necessary to use daily doses of 100 to 200 LU. of prolactin for periods of 5 to 8 days before bleeding could be controlled. Inasmuch as all the patients in this group were subjeet to pelvic surgery, data on the menstrual periods following therapy is meager'. However, it may be said that three patients who had been successfully treated with one or two courses of prolactin had 2 to 4 normal menstrual periods prior to the time of their operations. ~fenorrhagia when seen with concomitant chronic pelvic inflammatory disease, was aided by prolactin therapy, although we had our greatest percentage of failures in this group of patients. Two patients did not respond to prolactin, and in three, prolactin induced a diminution of bleeding but not complete arrest. However, of the nine patients that responded to prolactin therapy, all but one resumed normal menstrual periods after two or three courses of treatment. This ability of prolactin to exercise curative effects after cessation of therapy is of importance and implies a degree of permanency in the corrective effect of prolactin upon excessive uterine bleeding in certain selected cases. Fourteen patients, although complaining of menorrhagia, also experienced severe dysmenorrhea either during the entire menorrhagic period, or on the first few days of the menstrual flow. Of these women, eight obtained relief from their painful menstruation accompanied by cessation of the abnormal bleeding. Three of the six patients not obtaining relief from dysmenorrhea with prolactin, did receive prompt relief from their menorrhagic syndrome. In the treatment of threatened or habitual abortion, the results observed with prolactin were at times promising and at times disappointing. Six cases in all were treated. All the patients gave a history of previous pregnancies which in four patients were associated with missed or habitual abortion. In three patients, all having previous abortive
232
.. :IU;RICAX
,IOCR.'\AL OF OHS:'E'llUCS A.'\D GYNECOLOGY
inten'uptioll:- ~)r lll'egnaney, the results \,'ere sppetacular. \Vhen first seen, these patients had severe abdominal eJ'amps aCl'ompanied by profuse uterine hIee.'ing. After daily doses of 400 I.e. of prolactin (200 I.e. adlllillistcl'ed:wil~p ])('1' day) fot' :l to 4 tOllsneutive days, abdominal <'ram ps heeame qnies('ent. and bleeding eeased. One patient. with a history of two previous ahortiOlls expl'l'imH'ed an aH~wk similar' to those whieh had precipitated the other abol'tions, but. this time she received a eOlll'se of proladin thNapy. .All threatening symptoms subsided after t his mil: series of injeetiolls, and she del iverl'd a normal infant at term several months Iatm·. ]1\ the other i,yo ('ases of threatened ahortion lhat were suecessfully ('ollil'olled by ])]'oIaetin, it was necessary to administer pl'olaetin dmillg -t to G sli('('es~i\'l' attaeks of severe abdominal ('l'amps and bleeding. hlllllcdiatdy after all intensi ve hut brief <'OUl',,( of prolaetill treatment, the mus('ullll' ('ontnH'tiolls subsided and bleeding was SUPlll'{'sSe(1. III these la1,1 er two eases, OIl(' viahle infant was clelivl'l'pd at terlll to a woman who had lIot he(,11 able to carry her pregllaJH'." to tl;I'm in threc ]JI'(;vious instaw'('s. Prola(,tin had been administered 10 this paticlll at eaeh Olle of sevcral seizllres of threatened abortion and had adeqnn tdy (,ontrolled her rtllverse Rymptoms. The other patient who had responded favorably to prolaet in when sllbjeeted to thl'eatenim.!' seizures finallv dplivel'P(l it viahle 7-lllonth fetus folhwing a shOl'1. l)('~iod of seven' licrinc '('Oldnwtions and bleeding'. This J)j'em}~~ 1ur(' delivery ('ould not be pl'('vcnll'd sill('p till' pa ti('l1t failed to inform llS of her ('orHlition early PllOllgh so tha1 ef'f'(,eti\'(' prolactin treatment eould lw instigated, Prior to this, lIw patient hnrl had four seizures of ('\'amps and hleeding whi('h had heel! ('ompletely ('olltrolll'<1 by prolactin. The tfll'(~e ('ases that did not respond 10 pl'olaet in therapy ahorted during' t I'l'atment. I t. is ('onc'('ivahl(, t hat in these eases some untoward faetoe W;lS in vol yed anu/of' 1he Pf'OliH'till inj('('1 ions wert' started hefore their lllaximal illlluellee ('ould take effect and their fUl'lIH'I' adioll "'as illt,(,l'J'lIpte<1 hy the spontanf'ons abortion. Pl'olaetin whm admillist('I'pd to llormal ry('lic women ill doses of 300 to fiOO 1. C. pel' WPl'k JOT' pl'riods of 7 t () i 0 \n~('ks, did 1Iot have any appl'l'eiable effeel UpOll 1he length of the ('yele, amollut of bleeding or' ronditioll o[ the cndOIlWll'imn. Ftel'ine biopsies taken at various intervals during the period of laetogPll ie titel'ap? mieros('opieally did not show any deviation from 1he normal. Two of the women who had been m(,llsh'u~lting' regularly from a progestational endomPi rium (,ontiuue
KUPPERMAN, I<'RIED, AXD HAIR:
COXTROL 01<' M~;XORRHAGIA
233
successfully controlled the excessive uterine bleeding did not bring about any change in the morphologic appearance of the menstrual endometrium, regardless of its histologic make-up before treatment. Discussion The control of uterine bleeding by lactogenic hormone raises the question of its possible mode of action. Evidence from animal experiments of earlier investigators and also endometrial studies in the human have indicated that prolactin might conceivably have an antigonadal action. This has been demonstrated by the action of prolactin in decreasing gonadal size in fowls 8 and suppressing estrous cycles in rats. U- 12 In the human, endometrial studies 13 - 15 have shown that only a relatively small number of women ovulate during the period of lactation. In addition, those women not ovulating, while exhibiting a proliferative endometrium, show one of an early differentiating type, or one associated with low ovarian activity. In contradistinction to the supposed ovarian negating action of prolactin, recent experimental evidence has shown that the suppressing effect of prolactin upon the estrous cycle of the rat may he ascribed, not to the inhibitory effect of prolactin upon the ovary, but actually to its ability to prolong and maintain the function of the corpus luteum. Administration of lactogenic preparations to adult female rats results in cessation of estrous cycles with the persistence of one crop of active corpora lutea.lO Evans, et al.,'6 showed that the corpora lutea persisting during lactogenic administration arc physiologically active and will induce deciduomata formation in hypophysectomized adult rats, It remained for Astwood 17 to postulate and demonstrate the presence of a third gonadotropic hormone, luteotrophin, which regulates the activity and maintains the function of formed corpora lutca. Since purified lactogenic prcparations are capable of maintaining active corpora lutea ill the rat, the lactogenic hormone has become allied with the luteotrophic hormone of Astwood. In considering which one of these propel'ties, ovarian negating or luteotrophic action attributed to prolactin, is the modus operandi in controlling uterine bleeding, it is difficult to reconcile our results with the ovarian negating action of prolactin. In our study of women with normal cycles and thosc suffering with menorrhagia, massive doses of prolactin did not in any way alter the cyclic manifestations, or cause retrogressive changes to take place in the endometrium. There was no evidence of gonadal inhibition as determined by repeated examinations of the uterine scrapings and operative specimens of the ovaries. On the other hand, it is conceivable that the lactogenie preparations are effective in controlling abnormal uterine bleeding through their luteotrophic properties. It is possible that the administration of these pituitary extracts enhances the production of the corpus luteum hormone or hormones, and provide thereby a proper hormonal balance for the
234
AMERICA X JOcRXAL OF OBSTETRICS AXD GYXECOLOGY
control of menorrhagia. This seems to he the most logical explanation of the satisfactory results in which not only menorrhagia was controlled, but threatened abortion was held in abeyance. Summary
1. Menorrhagia, either fuudional or organic in nature, was favorably influenced by administration of lactogenic preparations extracted from the pituitary gland. :3fenorrhagia associated with uterine fibromyomas, cystic ovaries, or chronic pelvic inflammatory disease was suppressed in the majority of patients by administration of prolactin. Those patients, however, in the latter two categories were more resistant to therapy. Normal cyclic bleeding followed cessation of prolactin therapy in many of the patients receiving one or more courses of treatment. This permalleney or HemipermallelH"y ill the d'fect of prolactin afforded a sufficient interval to enable the patient to undergo a more strenuous regime to correct the underlying cause of the excessive uterine bleeding. 2. Some success was obtained in mitigating dysmenorrhea by prolactin therapy when it was associated with excessive uterine bleeding. ;~. In addition, the signs and symptoms of threatened abortion were alleviated by administering prolactin to 3 of 6 patients giving a history of previous abortive interruptions of pregnancy. 4. Administ.ration of lactogenic preparations to normal eyclic womell did not have an appreciable effect UpOIl nIP length of eyde, menstrual bleeding or morphologic appearallC'() of the (!]lCiometrium. 5. It is suggested that. the effectiveness of Jae10gellie hormone ]n C011trolling uterine hleefling is prohably lillked with its luteotrophic properties. 6. In view of the innocuous effect of prolactin upon the normal menstrual cycle and corrective action in metropathic menorrhagia, we find its use is warranted in the control of excessive uterine bleeding.
References 1. Greenblatt, R. B., 'l'orpin, R, Coopedge, W. W., and Gatewood, 'r. S.: Univ. Ilosp. Bull. V, 1: 11, 1939. 2. Greenblatt, R. B., and Torpin, R.: J. 11. A. Georgia 28: :>42, 1939. :~. Greenblatt, R. R.: .r. Mer!. Assoc. Georgia 29: 481, 1940. 4. Greenblatt, R. B.: Offic~ Endocrinology, 2 ed. Rpringfielrl, Illinois, ]944, Charles C Thomas. 5. Leblond, C. P.: Compt. rend. Soe. de hiol. 124: 1062, ]937. 6. Meitea, .f., and Turner, C. W.: .1. Clin. Endoerinol. 1: !ll8, 1941. 7. Hall, G. J.: J. Clin. Endocrinol, 2: 296, 1942. S. Bates, It. W., Lahr, E. L., and l'!.iddlc, 0.: Am .•r. Physiol. 111: :16], 1935. 9. Dresel, 1.: Science 82: 173, 1935. 10. Lyons, W. It.: Cold Spring Harbor Symp. Quant. BioI. 5: 198, 1937. 11. I.ahr, E. L, and Riddle, 0.: Proc. Soc. Bxper. BioI. & Med. 38: 713, 1938. 12. Nathanson,1. 'r., and Pevold, H. L.: Endocrinology 22: 86,1938. 13. Kurzfoek, R., Lass, P. M., and Smelser, J.: Endocrinology 23: 43, 1938. 14. Griffith, r,. S., and McBride, W. P. L.: J. Michigan M. Soc. 38: 1064, 1939. 15. 'l'opkins, P.: A)1. J. OBST. & GYXEC. 45: 48, ]943. 16. Evans, H. M., Simpson, 1-L E., and Turpeinen, K.: Anat. Ike. (Supplement) 70: 26, 1938. 17. Astwood, E. B.: Endocrinology 28: 30!), 1941.
8.
.'iND
KCPl'ER~IA~,
Jj. Q.
HAIR,
PH.D., PAGL
B.S.,
FRIED,
ArGUtiTA,
}1.I>.,
eLl.
(From. the Departments of Experimental Medimne and Obstetl'ics and Gynecolo.ml. Unirersity of Georgia School of Medicine)
F ALLj the dysfunctions that aee associated with the menstrual (',Vcle of women and which are of discomfort and even hazardous to the health of the patient, menorrhagia presents the most formidable problem to the clinician. Inasmuch as the physiology of uterinr hleeding' is not entirely nnderstood, it is quitr apparent that the physiological eoncept of malfulJetion of the menst.rual eyele is likewise confnsed and misinterpreted. In addition, failnre to reproduC'(' the phenonH'na of ('x('essive uterine bleeding in the C'ommon lahoratory animal haH preventrd adequate t'xperimcntal investigat.ion of this prohlem, and h,1s led to empirical therapeutiC' proeedul'es or radiC'al sllrgieal C1lJ'es. AIt hough many different forms of' therapy havp been suggest.ed, nOlle Iws assnmt'd the position of a pHlla(~ea for the eontrol of exeessive uterine bleeding. In view of the multitude of methods proposed for tlw allnvialion of' functional and pathologi('al uterine bleeding, it is apparent. that not olle has heell uniformly aeeepted as the ideal mode of therapy. In a seareh for a satisfaetory t.herapeutie tool to dam sUl'('es:;:fully the menol'l'hagic iiow, we deeided 10 inwstigate 1he possibilities of thu laetogenic hormone, prolaetill, since it wa:;: shown b~' Ur'cenblatt e1 a1H that hlood from lactating women was a llseful, though ill<'ollvenieni mode of therapy in metropathic menorrhagia. Their l'ationale 1'01' employing this mode of therapy was based UpOll two linrs of thought:
O
1. TIl(' only true period of' physiologic amenorrhea other t.han pl'eglW]H'.V occurs during the interval of lactation. 2. Experimental evidence at that. time had demonst.rated the ant i· gonadal effed of lactog'
228
KUPPERMAN, }'RIED, AND HAIR:
CONTROL OF ME~ORRHAGIA
229
of earlier work H and those of Hall and also present some preliminary data on the effect of prolactin upon the normal menstrual cycle and threatened abortion.
Procedure
Two types of purified prolactin preparations were employed in this investigation.'"' One type of preparation was available as a sterile powder and supplied with a solvent (saline or distilled water) to he added hefore using, while the other preparation was made up in solut~on form. \Ve have found the powdered preparations to he more effectlve in treatment and saline to be the preferred solvent. The lactogenic hormone was administered for various periods of time to 43 women exhibiting organic or functional uterine bleeding. In patients suffering from organic disturbances sueh as fibromyoma, pelvic inflammatory disease, etc., it is to be emphasized that the lact.ogenic medication was purely palliative in action and was not employed with the intention of alleviating the organic disturbance. By controlling the excessive uterine bleeding in these patients, a suitable interval was provided between the cessation of bleeding and preparation of the patient for a more final and complete cure. The doses of prolactin that were employed ranged from 100 to 250 International {~nits per injection and were administered subcutaneously every day, or second day during the abnormal period of bleeding. In several cases \Yhere the menorrhagia had heen of long duration, it was necessary to administer 100 to 200 T.U. of prolactin in daily doses for 4 to 8 days before the bleeding could be checked. When possible, suction curettages were undertaken to determine the condition of the endometrium before and during administration of prolactin. Uterine biopsies were taken for a twofold purpose: 1. To determine the type of endometrium from which bleeding occurred. 2. To ascertain activity of the ovary by noting its physiologic effect upon the endometrium. Operative specimens of the uterus or ovaries, or both, were also obtained and studied, particularly in patients undergoing hysterectomy, for additional evidence Oil the physiologic action of prolactin. In addition to the patients exhibiting abnormal bleeding, three women with normal cycles were treated with daily doses of prolactin to determine the effect of the lactogenic hormone upon 1he length of cycle and endometrial histology. Preliminary data arc also presented on the effect of prolactin in six cases of threatened abortion. Foul' patients ga,'e a history of previous abortion, while two presented a history of earlier uncomplicated pregnancies. These patients were all subjected to all intensive course of prolactin therapy in an attempt to control the untoward symptoms which were associated with cramps and hlceding.
Results The data summarizing the results obtained with prolactin are presented in Table I, where the clinical outcome is classified as follows: (a) Excellent--indicating prompt and complet.e ('ontrol of the uterine ___bleeding. 'Prola~tin prepara tions were generously supplied by Armour Laboratories, E. R. Squibb and Sons, and Winthrop Chemical Co.
230
AMERICAX .TOURNAI, OF OBSTETRICS AXD GYNECOLOGY
(b) Good-referring to those cases where longer therapy was necessary to control bleeding. (c) Fair-those cases in which bleeding was largely suppressed, but never completely inhibited, so that the patient exhibited a prolonged hut mild menstrual flow dnring the administration of prolactin. (d) Poor-indicating no diminution of bleeding following lactogenic treatment. TABU: CHIEF COMPLAINT
Menorrhagia Menorrhagia Menorrhagia Menorrhagia Dysmenorrhea Threatened abortion
r.
Cr,TXICAT, EVFEC:TS OF PnOT.ACTIN
ASSOCIATED WITH
Functional bleeding Uterine fibromyoma Cystic ovaries Chronic pelvic inflammatory disease Menorrhagia Cramps and bleeding --4.- . -
.. --
CJ.lNICAL RESULTS };XO;LT,ENT GOOD
8 8
:1
7
12
5
3 4
5 3
3 0
...- - -.
( NUMBER OF CASES) FAIR POOR
1 1
2
1 2 1
4
2
:I
0
2
3
-. - - -
In the accompanying chart, menorrhagia is listed as bcing associated with other clinical symptoms or entities such as fibromyoma of the uterus, cystic ovaries, chronic pelvic inflammatory disease, etc. In presenting the summary in a chart form, some cases have' been itemized in more than one group due to dual complaints. For example, a patient with fibromyoma might also be subject to dysmenorrhea at onset of the menses which, in turn, might be menorrhagic in nature. Likewise, cystic ovaries or fibromyoma might be present in a menorrhagic patient. The clinical results are evaluated on the basis of the chief complaint and not upon the improvement of the associated conditions. Hence, although 43 patients in all were treated for abnormal bleeding, a great many more notations are included in the chart due to concomitant symptoms. From 'rable I it is apparent that lactogenic hormone is of proved value in controlling excessive uterine bleeding. It was equally effective in controlling menorrhagia, whether functional or organic in origin. Of the 17 women suffering from functional menorrhagia, i.e., menorrhagia associated with no pathologic manifestations, two failed to respond favorably to the hormone therapy. All the patients in this group gave a history of exccssive bleeding for at least one cycle prior to their appearance in the clinic. In fact, a majority of the patients offered thc information that the excessive menstrual periods werc of long duration and the interval between the menstrual flow was obvious only by its brevity. Uterine biopsies taken in this group of patients on the first day of menses exhibited predominately an estrogenic or cystic glandular hyperplastic endometrium, although several cases were observed where menorrhagia was associatcd with a secretory endometrium. Daily injections of 100 IT. of prolactin were administered during the period of uterine bleeding. The clinical success of this mode of therapy was indicated by the cessation of hleeding that occurred in all but two of the 17 patients treated. The severity of bleeding in subsequent cycles depended upon the regimcn that was employed. In those cases where prolactin was injected on the first day of subsequent menses and continued for 2 to 3 days, bleeding was well controlled. Of those patients
KUPPERMA~, FRIED, AND HAIR:
CO~TROL OF MEXORRHAGIA
231
who did not receive further treatment after one successful therapeutic course with prolactin, five had normal cycles and two reverted to their original condition of excessive and prolonged uterine bleeding. Menorrhagia associated with fibromyoma of the uterus responded very satisfactorily to prolactin therapy. These patients were more resistant to treatment than those with functional menorrhagia and required daily doses of 100 to 200 I.U. of prolactin for a period of 4 to 8 days, whereas patients with functional menorrhagia required only 100 LU. per day for 3 to 6 days. All the patients in this group had been suffering with menorrhagia for at least three months and one third of these patients bled almost continually. The clinical results with prolactin were pronounced, although not as favorable as in the patients with functional menorrhagia. Three patients failed to respond satisfactorily to prolactin therapy. As has been mentioned before, prolactin was not administered to these patients for the purpose of causing a regression of the uterine fibromyomas, but was employed so that the patient might be placed in proper physical condition to withstand the necessary surgery. This procedure was resorted to since clinically, many of these patients exhibited a severe secondary anemia as a result of their bouts of excessive uterine bleeding. In no instance in cases of fibromyomas of the uterus does the use of prolactin imply a substitute for surgery. Menorrhagia noted in the presence of cystic follicles in the ovaries likewise required persistent prolactin therapy to control the excessive uterine bleeding. The presence of cystic ovaries was determined by palpation and then confirmed by laparotomy, or was ascertained by surgery alone. In those cases in which prolactin was effective, it was necessary to use daily doses of 100 to 200 LU. of prolactin for periods of 5 to 8 days before bleeding could be controlled. Inasmuch as all the patients in this group were subjeet to pelvic surgery, data on the menstrual periods following therapy is meager'. However, it may be said that three patients who had been successfully treated with one or two courses of prolactin had 2 to 4 normal menstrual periods prior to the time of their operations. ~fenorrhagia when seen with concomitant chronic pelvic inflammatory disease, was aided by prolactin therapy, although we had our greatest percentage of failures in this group of patients. Two patients did not respond to prolactin, and in three, prolactin induced a diminution of bleeding but not complete arrest. However, of the nine patients that responded to prolactin therapy, all but one resumed normal menstrual periods after two or three courses of treatment. This ability of prolactin to exercise curative effects after cessation of therapy is of importance and implies a degree of permanency in the corrective effect of prolactin upon excessive uterine bleeding in certain selected cases. Fourteen patients, although complaining of menorrhagia, also experienced severe dysmenorrhea either during the entire menorrhagic period, or on the first few days of the menstrual flow. Of these women, eight obtained relief from their painful menstruation accompanied by cessation of the abnormal bleeding. Three of the six patients not obtaining relief from dysmenorrhea with prolactin, did receive prompt relief from their menorrhagic syndrome. In the treatment of threatened or habitual abortion, the results observed with prolactin were at times promising and at times disappointing. Six cases in all were treated. All the patients gave a history of previous pregnancies which in four patients were associated with missed or habitual abortion. In three patients, all having previous abortive
232
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,IOCR.'\AL OF OHS:'E'llUCS A.'\D GYNECOLOGY
inten'uptioll:- ~)r lll'egnaney, the results \,'ere sppetacular. \Vhen first seen, these patients had severe abdominal eJ'amps aCl'ompanied by profuse uterine hIee.'ing. After daily doses of 400 I.e. of prolactin (200 I.e. adlllillistcl'ed:wil~p ])('1' day) fot' :l to 4 tOllsneutive days, abdominal <'ram ps heeame qnies('ent. and bleeding eeased. One patient. with a history of two previous ahortiOlls expl'l'imH'ed an aH~wk similar' to those whieh had precipitated the other abol'tions, but. this time she received a eOlll'se of proladin thNapy. .All threatening symptoms subsided after t his mil: series of injeetiolls, and she del iverl'd a normal infant at term several months Iatm·. ]1\ the other i,yo ('ases of threatened ahortion lhat were suecessfully ('ollil'olled by ])]'oIaetin, it was necessary to administer pl'olaetin dmillg -t to G sli('('es~i\'l' attaeks of severe abdominal ('l'amps and bleeding. hlllllcdiatdy after all intensi ve hut brief <'OUl',,( of prolaetill treatment, the mus('ullll' ('ontnH'tiolls subsided and bleeding was SUPlll'{'sSe(1. III these la1,1 er two eases, OIl(' viahle infant was clelivl'l'pd at terlll to a woman who had lIot he(,11 able to carry her pregllaJH'." to tl;I'm in threc ]JI'(;vious instaw'('s. Prola(,tin had been administered 10 this paticlll at eaeh Olle of sevcral seizllres of threatened abortion and had adeqnn tdy (,ontrolled her rtllverse Rymptoms. The other patient who had responded favorably to prolaet in when sllbjeeted to thl'eatenim.!' seizures finallv dplivel'P(l it viahle 7-lllonth fetus folhwing a shOl'1. l)('~iod of seven' licrinc '('Oldnwtions and bleeding'. This J)j'em}~~ 1ur(' delivery ('ould not be pl'('vcnll'd sill('p till' pa ti('l1t failed to inform llS of her ('orHlition early PllOllgh so tha1 ef'f'(,eti\'(' prolactin treatment eould lw instigated, Prior to this, lIw patient hnrl had four seizures of ('\'amps and hleeding whi('h had heel! ('ompletely ('olltrolll'<1 by prolactin. The tfll'(~e ('ases that did not respond 10 pl'olaet in therapy ahorted during' t I'l'atment. I t. is ('onc'('ivahl(, t hat in these eases some untoward faetoe W;lS in vol yed anu/of' 1he Pf'OliH'till inj('('1 ions wert' started hefore their lllaximal illlluellee ('ould take effect and their fUl'lIH'I' adioll "'as illt,(,l'J'lIpte<1 hy the spontanf'ons abortion. Pl'olaetin whm admillist('I'pd to llormal ry('lic women ill doses of 300 to fiOO 1. C. pel' WPl'k JOT' pl'riods of 7 t () i 0 \n~('ks, did 1Iot have any appl'l'eiable effeel UpOll 1he length of the ('yele, amollut of bleeding or' ronditioll o[ the cndOIlWll'imn. Ftel'ine biopsies taken at various intervals during the period of laetogPll ie titel'ap? mieros('opieally did not show any deviation from 1he normal. Two of the women who had been m(,llsh'u~lting' regularly from a progestational endomPi rium (,ontiuue
KUPPERMAN, I<'RIED, AXD HAIR:
COXTROL 01<' M~;XORRHAGIA
233
successfully controlled the excessive uterine bleeding did not bring about any change in the morphologic appearance of the menstrual endometrium, regardless of its histologic make-up before treatment. Discussion The control of uterine bleeding by lactogenic hormone raises the question of its possible mode of action. Evidence from animal experiments of earlier investigators and also endometrial studies in the human have indicated that prolactin might conceivably have an antigonadal action. This has been demonstrated by the action of prolactin in decreasing gonadal size in fowls 8 and suppressing estrous cycles in rats. U- 12 In the human, endometrial studies 13 - 15 have shown that only a relatively small number of women ovulate during the period of lactation. In addition, those women not ovulating, while exhibiting a proliferative endometrium, show one of an early differentiating type, or one associated with low ovarian activity. In contradistinction to the supposed ovarian negating action of prolactin, recent experimental evidence has shown that the suppressing effect of prolactin upon the estrous cycle of the rat may he ascribed, not to the inhibitory effect of prolactin upon the ovary, but actually to its ability to prolong and maintain the function of the corpus luteum. Administration of lactogenic preparations to adult female rats results in cessation of estrous cycles with the persistence of one crop of active corpora lutea.lO Evans, et al.,'6 showed that the corpora lutea persisting during lactogenic administration arc physiologically active and will induce deciduomata formation in hypophysectomized adult rats, It remained for Astwood 17 to postulate and demonstrate the presence of a third gonadotropic hormone, luteotrophin, which regulates the activity and maintains the function of formed corpora lutca. Since purified lactogenic prcparations are capable of maintaining active corpora lutea ill the rat, the lactogenic hormone has become allied with the luteotrophic hormone of Astwood. In considering which one of these propel'ties, ovarian negating or luteotrophic action attributed to prolactin, is the modus operandi in controlling uterine bleeding, it is difficult to reconcile our results with the ovarian negating action of prolactin. In our study of women with normal cycles and thosc suffering with menorrhagia, massive doses of prolactin did not in any way alter the cyclic manifestations, or cause retrogressive changes to take place in the endometrium. There was no evidence of gonadal inhibition as determined by repeated examinations of the uterine scrapings and operative specimens of the ovaries. On the other hand, it is conceivable that the lactogenie preparations are effective in controlling abnormal uterine bleeding through their luteotrophic properties. It is possible that the administration of these pituitary extracts enhances the production of the corpus luteum hormone or hormones, and provide thereby a proper hormonal balance for the
234
AMERICA X JOcRXAL OF OBSTETRICS AXD GYXECOLOGY
control of menorrhagia. This seems to he the most logical explanation of the satisfactory results in which not only menorrhagia was controlled, but threatened abortion was held in abeyance. Summary
1. Menorrhagia, either fuudional or organic in nature, was favorably influenced by administration of lactogenic preparations extracted from the pituitary gland. :3fenorrhagia associated with uterine fibromyomas, cystic ovaries, or chronic pelvic inflammatory disease was suppressed in the majority of patients by administration of prolactin. Those patients, however, in the latter two categories were more resistant to therapy. Normal cyclic bleeding followed cessation of prolactin therapy in many of the patients receiving one or more courses of treatment. This permalleney or HemipermallelH"y ill the d'fect of prolactin afforded a sufficient interval to enable the patient to undergo a more strenuous regime to correct the underlying cause of the excessive uterine bleeding. 2. Some success was obtained in mitigating dysmenorrhea by prolactin therapy when it was associated with excessive uterine bleeding. ;~. In addition, the signs and symptoms of threatened abortion were alleviated by administering prolactin to 3 of 6 patients giving a history of previous abortive interruptions of pregnancy. 4. Administ.ration of lactogenic preparations to normal eyclic womell did not have an appreciable effect UpOIl nIP length of eyde, menstrual bleeding or morphologic appearallC'() of the (!]lCiometrium. 5. It is suggested that. the effectiveness of Jae10gellie hormone ]n C011trolling uterine hleefling is prohably lillked with its luteotrophic properties. 6. In view of the innocuous effect of prolactin upon the normal menstrual cycle and corrective action in metropathic menorrhagia, we find its use is warranted in the control of excessive uterine bleeding.
References 1. Greenblatt, R. B., 'l'orpin, R, Coopedge, W. W., and Gatewood, 'r. S.: Univ. Ilosp. Bull. V, 1: 11, 1939. 2. Greenblatt, R. B., and Torpin, R.: J. 11. A. Georgia 28: :>42, 1939. :~. Greenblatt, R. R.: .r. Mer!. Assoc. Georgia 29: 481, 1940. 4. Greenblatt, R. B.: Offic~ Endocrinology, 2 ed. Rpringfielrl, Illinois, ]944, Charles C Thomas. 5. Leblond, C. P.: Compt. rend. Soe. de hiol. 124: 1062, ]937. 6. Meitea, .f., and Turner, C. W.: .1. Clin. Endoerinol. 1: !ll8, 1941. 7. Hall, G. J.: J. Clin. Endocrinol, 2: 296, 1942. S. Bates, It. W., Lahr, E. L., and l'!.iddlc, 0.: Am .•r. Physiol. 111: :16], 1935. 9. Dresel, 1.: Science 82: 173, 1935. 10. Lyons, W. It.: Cold Spring Harbor Symp. Quant. BioI. 5: 198, 1937. 11. I.ahr, E. L, and Riddle, 0.: Proc. Soc. Bxper. BioI. & Med. 38: 713, 1938. 12. Nathanson,1. 'r., and Pevold, H. L.: Endocrinology 22: 86,1938. 13. Kurzfoek, R., Lass, P. M., and Smelser, J.: Endocrinology 23: 43, 1938. 14. Griffith, r,. S., and McBride, W. P. L.: J. Michigan M. Soc. 38: 1064, 1939. 15. 'l'opkins, P.: A)1. J. OBST. & GYXEC. 45: 48, ]943. 16. Evans, H. M., Simpson, 1-L E., and Turpeinen, K.: Anat. Ike. (Supplement) 70: 26, 1938. 17. Astwood, E. B.: Endocrinology 28: 30!), 1941.