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The action of papain and bromelain on the uterus
THE ACYl’ION OF PAPAIN AND BBOMELAIN ON THE UTSWS ROBERT G. HUNTER, M.D., GEORGE W. HENRY, M.D., AND W. H. CIVIN, M.D., HONOLULU, HAWAII (From
the Department
.
of Obstetrks-Gynecology and the Department of Radiology, Group, and the Laboratories of Queen’s Hospital)
Medbal
Part III. The Physiologically Incompetent Internal Cervical OS* or habitual R EPEATED lem to the obstetrician
abortion has always been a most distressing proband gynecologist. Defects of the internal cervical OS may play some part in the early abortions, but it is felt that they play a principal role in the loss of pregnancies in the second trimester and later. Many explanations have been given, but there are still numerous patients who lose their pregnancies, although examination had shown each to have a normal fetus and apparently a normal implantation, as evidenced by early sacculation. These patients appear with a widely dilated external cervical OS and bulging membranes, to be followed by the gentle oozing of the fetus and amniotic sac through the cervical canal with loss of the pregnancy. In 1950 Lash and Lash1 described the condition and a method of repair which was further elaborated by Lash2 and his associates in 1953. Palmer and Lacomme3* 4 discussed the problem and offered a method of investigation and repair. In 36 cases of habitual abortion investigated by hysterosalpingography, Palmer5 found : 5 patients with fibroids, 7 with malformations with significant bicornuate uterus, 7 with hypoplasia (4 with discrete bicornuate fundus) and 3 with associated gaping of the isthmus, 2 with hyperanteflexion and hypercontractility, 2 with hypercontractility alone, and 6 with gaping of the isthmus alone. In 6 the findings were normal. He states, “The possible causation (overdilatation), confactors of this gaping of the isthmus are . . . traumatic genital, and functional (nervous) .” The commonest form is usually caused by injury, such as placenta previa, lacerations of delivery, or too enthusiastic curettage. This is easily demonstrated by the method of Riazzi-Palmer,4 or that of Lash and Lash,l or by the use of a revised cannula and cervicosalpingography as demonstrated by Hunter and Henry.6 The single or multiple defects are definitely located and the field of repair can be accurately defined by the latter method. Repair by Lash’s method of imbrication results in marked success in this particular group. Danforth who first objected to the terminology now agrees that it is logical and that the entity does exist. We would like to call this entity the strueturally incompetent 0s. The congenital type, which we have found to be the least common in occurrence, is always associated with primary habitual abortion. None of these *The radlopaque ceutical Corporatfon.
medium used in these studies was Salpix, supplled by the Ortho Pharma875
HUNTER,
876
HENRY,
AND
Am. J. Oh
CIVIN
& Gym. April. 1957
patients have delivered a full-term infant. The gaping of the OS is very similar to that of the functional incompetence. No localized outpouching as of an unhealed injury can be found. We have found another form of incompetency which is not demonstrable by the usual means and apparently is of a different origin. The method of cervicohysterosalpingography was published in 1954 by Hunter and Henry, and the use of the enzymes such as bromelain and papain was demonstrated
Fig.
l.-Normal
uterus
before
and
after
papain.
at that time. These enzymes were used first to remove excessive cervical mucus. Observations following its use demonstrated that pseudo and actual space-occupying lesions could be more positively identified and inflammatory changes of the canal and its glands could be visualized with greater accuracy. The activities of the cervix were observed during these examinations. It soon became apparent that some action other than the simple removal of mucus was taking place. The cervical and uterine shadow was so markedly changed that we were sure that some relaxing effect was obtained. The cervical canal, in particular, was greatly dilated. Fig. 1 shows an example
Volume 73 Number 4
ACTION
OF
PAPAIN
AND
BROMELAIN
ON
877
UTERUS
Relaxation was so marked in some cases that a probable of this enlargement. effect on dysmenorrhea was suspected. These studies have been reported by Hunter, Henry, and Heinicke.’ This relaxation has occurred to varying degrees in practically all of the patients examined, but in this series all but a few patients have retained tha
Fig.
2.-Structurally
Fig.
3.-Structurally
incompetent
internal
incompetent
6:
OS. (From 68, 1955.),
internal
os and
Hunter
a polyp
and
Henry:
of the
Fertil.
cervical
Rc Steril.
canal.
usual contour of the uterocervical shadow. Fig. 2 shows the usual structurally incompetent OS as demonstrated on the primary salpingogram before the use of papain. There is no difficulty in making this diagnosis. It adequately explains this woman’s failure to retain her pregnancies for any length of time.
878
HUNTE&
HENBY,
AND
Am. .I. Obst. & Gym. April, 1957
CIVIN
The next illustration, Fig. 3, is that of a patient who has never delivered a fullterm infant, and, as you see, the cervical canal has a uniform broad caliber throughout its entire length with no evidence of an internal OS. The diameter of the cervical canal is many times greater than that of the normal. This was unchanged by the use of papain and probably was congenital or embryological in its origin. Fig. 4, A, shows an apparently adequate internal cervical OS and a normal uterine shadow. Fig. 4, B, shows the same uterus after irrigation of the cervix with papain. The uterine shadow has enlarged in all directions, and the region of the internal OS is no longer clearly defined. The constriction representing this muscular activity is gone, and the grossly dilated cervical canal merges smoothly into the endometrial cavity. The similarity between this picture and that of the structurally incompetent OS is striking.
A. Fig.
4.-A
and
B.
B.
Physiologically
incompetent
OS before
and
after
papain.
This patient demonstrates what we call a physiologically incompetent internal cervical OS. The canal appears normal on the first cervicohysterosalpingogram. After irrigation with papain, the canal relaxes, its original contour disappears, and it assumes the appearance of a large cylinder. The The change produced by these enzymes cervix dilates in an abnormal way. presumably mimics the dilatation of pregnancy, resulting in incompetency of
Volun1e Number
73 4
ACTION
OF
PAPAIN
AND
BROMELAIN
ON
UTERUS
879
the internal OS. All our patients showing this relaxation of the internal OS with papain have lost three or more pregnancies between 12 and 20 weeks. Once having aborted during the middle trimester, none of them have subsequently carried a pregnancy to term. Whet,her repair of this defect will enable any of them to carry their pregnancies to term remains to be seen. Internal pressure within the amniotic sac produces dilatation and enlargrrnent of the uterus. If the internal OS remains closed, the pressure is applied uniformly to the entire internal surface of the uterus, according to Pascal’s law. In the normal pregnant uterus, the internal OS is tightly closed, and the sac cannot bulge into the cervical canal. If t,he internal OS is open, the pressure of the amniotic fluid pushes the sac into t,he cervical canal. The same pressure which is applied against the lining of the muscular uterus is then applied to the walls of the cervical canal resulting in further dilatat,ion and further bulging of the sac. The muscular force of the continually contracting uterus is transmitted to the cervix and furt,hrr pouching of the sac 0ccu1’s. Eventually t,hese patients arc seen with bulging m~~mbrancs and a patent csternal OS. The pregnancy is soon lost. Five of the patient,s in this series became pregnant again before any type of repair could be effected. They all aborted at, from 15 to 23 weeks with repetition of their former chain of events. Three of these 5 had excessive bleeding and evidence of retained secundines and were brought to dila.tation and curettage. At operation the cervices presented an entirely different picturc from that seen in the average and in the structurally incompetent OS. The cervix was widely dilated, very soft, and appeared as a cuff of tissue about 1 cm. in thickness. This measurement was uniform throughout the cervical circumference and extended into the uterine cavity. There was no ridge at the internal OSas usual. The curette could be passed from the fundus to the external OS without a trace of tissue obstruction. The internal OS had completely disappeared. Three of the patients demonstrating these changes have been operated upon. The repairs have been done by the Lash method. Two of the patients have subsequently become pregnant only t,o repeat the original chain of events. The cervices have been unimproved by the surgical procedures. While the rrpair by this method has served very well for those who demonstrate a strutturally incompetent OS,it is not sufficient re-enforcement for the physiologically incompetent one. Subsequently we have attempted a different type of repair. the results of which will be published at a later date. We are now investigating all patients who have lost pregnancies beyond 12 weeks to determine whether this is a common finding. Ten patients to date, In no all those examined with such a history, have shown t,his phenomenon. case without this history of pregnancy loss beyond 12 weeks has such a change been shown. The ordinary lacerated canal or other variation in no way approaches this broad change. The enzyme-induced dilatation is apparently a specific means of demonstrating the physiologically incompetent OS.
880
IIVNTER,
HENRY,
We wish to express our appreciation preparation of the enzyme solution.
AND
CIVIK
Am.
1. Obst. & Gym April. Is57
to Mrs. Ann Madsen of Queen’s Laboratory
for
References 1. 2. 3. 4. 5.
Lash, A. F., and Lash, S. R.: AM. J. OBST. & GYNEC. 59: 68,195O. Rubovits, F. E., Cooperman, N. R., and Lash, A. F.: AM. J. OBST. & GYNEC. 66: 269,1953. Palmer, R., and Lacomme, M.: Gym%. et. obst. 47: 905, 1948. Palmer, R.: Bruxelles-MB& 30: 409, 1950. Palmer, R.: Trans. Internat. & Fourth Am. Congress on Obst. & Gynec. (supp. vol. AM. J. OBST. & GYNEC.)
6. Hunter, 7. Hunter,
61A:
715,195l.
R. G., and Henry, 0. W.: Fertil. & Steril. 6: 68, 1955. R. G., Henry, G. W., and Heinicke, R. M.: AU. J. OBST. & GYNEC.
73: 867, 1957.
the Department
.
of Obstetrks-Gynecology and the Department of Radiology, Group, and the Laboratories of Queen’s Hospital)
Medbal
Part III. The Physiologically Incompetent Internal Cervical OS* or habitual R EPEATED lem to the obstetrician
abortion has always been a most distressing proband gynecologist. Defects of the internal cervical OS may play some part in the early abortions, but it is felt that they play a principal role in the loss of pregnancies in the second trimester and later. Many explanations have been given, but there are still numerous patients who lose their pregnancies, although examination had shown each to have a normal fetus and apparently a normal implantation, as evidenced by early sacculation. These patients appear with a widely dilated external cervical OS and bulging membranes, to be followed by the gentle oozing of the fetus and amniotic sac through the cervical canal with loss of the pregnancy. In 1950 Lash and Lash1 described the condition and a method of repair which was further elaborated by Lash2 and his associates in 1953. Palmer and Lacomme3* 4 discussed the problem and offered a method of investigation and repair. In 36 cases of habitual abortion investigated by hysterosalpingography, Palmer5 found : 5 patients with fibroids, 7 with malformations with significant bicornuate uterus, 7 with hypoplasia (4 with discrete bicornuate fundus) and 3 with associated gaping of the isthmus, 2 with hyperanteflexion and hypercontractility, 2 with hypercontractility alone, and 6 with gaping of the isthmus alone. In 6 the findings were normal. He states, “The possible causation (overdilatation), confactors of this gaping of the isthmus are . . . traumatic genital, and functional (nervous) .” The commonest form is usually caused by injury, such as placenta previa, lacerations of delivery, or too enthusiastic curettage. This is easily demonstrated by the method of Riazzi-Palmer,4 or that of Lash and Lash,l or by the use of a revised cannula and cervicosalpingography as demonstrated by Hunter and Henry.6 The single or multiple defects are definitely located and the field of repair can be accurately defined by the latter method. Repair by Lash’s method of imbrication results in marked success in this particular group. Danforth who first objected to the terminology now agrees that it is logical and that the entity does exist. We would like to call this entity the strueturally incompetent 0s. The congenital type, which we have found to be the least common in occurrence, is always associated with primary habitual abortion. None of these *The radlopaque ceutical Corporatfon.
medium used in these studies was Salpix, supplled by the Ortho Pharma875
HUNTER,
876
HENRY,
AND
Am. J. Oh
CIVIN
& Gym. April. 1957
patients have delivered a full-term infant. The gaping of the OS is very similar to that of the functional incompetence. No localized outpouching as of an unhealed injury can be found. We have found another form of incompetency which is not demonstrable by the usual means and apparently is of a different origin. The method of cervicohysterosalpingography was published in 1954 by Hunter and Henry, and the use of the enzymes such as bromelain and papain was demonstrated
Fig.
l.-Normal
uterus
before
and
after
papain.
at that time. These enzymes were used first to remove excessive cervical mucus. Observations following its use demonstrated that pseudo and actual space-occupying lesions could be more positively identified and inflammatory changes of the canal and its glands could be visualized with greater accuracy. The activities of the cervix were observed during these examinations. It soon became apparent that some action other than the simple removal of mucus was taking place. The cervical and uterine shadow was so markedly changed that we were sure that some relaxing effect was obtained. The cervical canal, in particular, was greatly dilated. Fig. 1 shows an example
Volume 73 Number 4
ACTION
OF
PAPAIN
AND
BROMELAIN
ON
877
UTERUS
Relaxation was so marked in some cases that a probable of this enlargement. effect on dysmenorrhea was suspected. These studies have been reported by Hunter, Henry, and Heinicke.’ This relaxation has occurred to varying degrees in practically all of the patients examined, but in this series all but a few patients have retained tha
Fig.
2.-Structurally
Fig.
3.-Structurally
incompetent
internal
incompetent
6:
OS. (From 68, 1955.),
internal
os and
Hunter
a polyp
and
Henry:
of the
Fertil.
cervical
Rc Steril.
canal.
usual contour of the uterocervical shadow. Fig. 2 shows the usual structurally incompetent OS as demonstrated on the primary salpingogram before the use of papain. There is no difficulty in making this diagnosis. It adequately explains this woman’s failure to retain her pregnancies for any length of time.
878
HUNTE&
HENBY,
AND
Am. .I. Obst. & Gym. April, 1957
CIVIN
The next illustration, Fig. 3, is that of a patient who has never delivered a fullterm infant, and, as you see, the cervical canal has a uniform broad caliber throughout its entire length with no evidence of an internal OS. The diameter of the cervical canal is many times greater than that of the normal. This was unchanged by the use of papain and probably was congenital or embryological in its origin. Fig. 4, A, shows an apparently adequate internal cervical OS and a normal uterine shadow. Fig. 4, B, shows the same uterus after irrigation of the cervix with papain. The uterine shadow has enlarged in all directions, and the region of the internal OS is no longer clearly defined. The constriction representing this muscular activity is gone, and the grossly dilated cervical canal merges smoothly into the endometrial cavity. The similarity between this picture and that of the structurally incompetent OS is striking.
A. Fig.
4.-A
and
B.
B.
Physiologically
incompetent
OS before
and
after
papain.
This patient demonstrates what we call a physiologically incompetent internal cervical OS. The canal appears normal on the first cervicohysterosalpingogram. After irrigation with papain, the canal relaxes, its original contour disappears, and it assumes the appearance of a large cylinder. The The change produced by these enzymes cervix dilates in an abnormal way. presumably mimics the dilatation of pregnancy, resulting in incompetency of
Volun1e Number
73 4
ACTION
OF
PAPAIN
AND
BROMELAIN
ON
UTERUS
879
the internal OS. All our patients showing this relaxation of the internal OS with papain have lost three or more pregnancies between 12 and 20 weeks. Once having aborted during the middle trimester, none of them have subsequently carried a pregnancy to term. Whet,her repair of this defect will enable any of them to carry their pregnancies to term remains to be seen. Internal pressure within the amniotic sac produces dilatation and enlargrrnent of the uterus. If the internal OS remains closed, the pressure is applied uniformly to the entire internal surface of the uterus, according to Pascal’s law. In the normal pregnant uterus, the internal OS is tightly closed, and the sac cannot bulge into the cervical canal. If t,he internal OS is open, the pressure of the amniotic fluid pushes the sac into t,he cervical canal. The same pressure which is applied against the lining of the muscular uterus is then applied to the walls of the cervical canal resulting in further dilatat,ion and further bulging of the sac. The muscular force of the continually contracting uterus is transmitted to the cervix and furt,hrr pouching of the sac 0ccu1’s. Eventually t,hese patients arc seen with bulging m~~mbrancs and a patent csternal OS. The pregnancy is soon lost. Five of the patient,s in this series became pregnant again before any type of repair could be effected. They all aborted at, from 15 to 23 weeks with repetition of their former chain of events. Three of these 5 had excessive bleeding and evidence of retained secundines and were brought to dila.tation and curettage. At operation the cervices presented an entirely different picturc from that seen in the average and in the structurally incompetent OS. The cervix was widely dilated, very soft, and appeared as a cuff of tissue about 1 cm. in thickness. This measurement was uniform throughout the cervical circumference and extended into the uterine cavity. There was no ridge at the internal OSas usual. The curette could be passed from the fundus to the external OS without a trace of tissue obstruction. The internal OS had completely disappeared. Three of the patients demonstrating these changes have been operated upon. The repairs have been done by the Lash method. Two of the patients have subsequently become pregnant only t,o repeat the original chain of events. The cervices have been unimproved by the surgical procedures. While the rrpair by this method has served very well for those who demonstrate a strutturally incompetent OS,it is not sufficient re-enforcement for the physiologically incompetent one. Subsequently we have attempted a different type of repair. the results of which will be published at a later date. We are now investigating all patients who have lost pregnancies beyond 12 weeks to determine whether this is a common finding. Ten patients to date, In no all those examined with such a history, have shown t,his phenomenon. case without this history of pregnancy loss beyond 12 weeks has such a change been shown. The ordinary lacerated canal or other variation in no way approaches this broad change. The enzyme-induced dilatation is apparently a specific means of demonstrating the physiologically incompetent OS.
880
IIVNTER,
HENRY,
We wish to express our appreciation preparation of the enzyme solution.
AND
CIVIK
Am.
1. Obst. & Gym April. Is57
to Mrs. Ann Madsen of Queen’s Laboratory
for
References 1. 2. 3. 4. 5.
Lash, A. F., and Lash, S. R.: AM. J. OBST. & GYNEC. 59: 68,195O. Rubovits, F. E., Cooperman, N. R., and Lash, A. F.: AM. J. OBST. & GYNEC. 66: 269,1953. Palmer, R., and Lacomme, M.: Gym%. et. obst. 47: 905, 1948. Palmer, R.: Bruxelles-MB& 30: 409, 1950. Palmer, R.: Trans. Internat. & Fourth Am. Congress on Obst. & Gynec. (supp. vol. AM. J. OBST. & GYNEC.)
6. Hunter, 7. Hunter,
61A:
715,195l.
R. G., and Henry, 0. W.: Fertil. & Steril. 6: 68, 1955. R. G., Henry, G. W., and Heinicke, R. M.: AU. J. OBST. & GYNEC.
73: 867, 1957.