- Email: [email protected]
The effect of intravenous estrogens on uterine motility
The effect of intravenous estrogens on uterine motility JOHN V. KELLY, M.D. Los Angeles, California
T H E first report that estrogen was necessary for uterine motility was published in 1925." Since that time considerable experimental work has been done to assess the role of estrogen in the regulation of myometrial activity. These studies have revealed that uterine contractions disappear when animals are castrated and reappear when estrogen is administered. 18 The same findings have been demonstrated in humans. 16 • 22 • ~ 3 Thus, there seems to be convincing evidence that this hormone plays a major role in the control of myometrial function. Estrogen probably governs uterine muscle function by regulating both the accumulation of its contractile proteins and the activities of the energy-supplying phosphates. 1 The characteristics of uterine contractions in women with "normal" ovarian function have been rather extensively documented. 7 • 14 • 17 • 22 In fact, a characteristic pattern called the "A wave" pattern has been ascribed to the effects of endogenous estrogen. 6 The question of whether the human uterus which is under the custody of endogenous estrogen (from ovaries or placenta) would respond to exogenous estrogen has been the subject of numerous studies over the past three decades. 18 Unfortunately, the results from these experiments have been conflicting and inconsistent. One reason for these discrepancies may be that none of these investigations were designed to include
three requisites which are now considered to be essential in any in vivo study of the effects of drugs on the dynamics of human myometrium: 1. A tokometric technique ~hould be employed to record the uterine contractions during the study period. 2. The drug under evaluation should be administered under control conditions utilizing placebos, double-blind arrangements, or similar tools of objectivity. 3. The substance under investigation should be given by the intravenous route; in this way the obvious disadvantages of unknown rates of drug absorption and metabolism are minimized. In the hope that an objective approach might provide an answer to the question of whether exogenous estrogen would influence functioning myometrium, we undertook such a study.
Material and technique Thirty-three nonpregnant women with no evidence of organic pelvic disease were selected for study. Seven patients were studied in the follicular phase, 9 in the luteal phase, and 5 in the menstrual phase of their cycles; 12 women were investigated during the early postpartum period. Uterine contractions were recorded by the intrauterine carbon-transducer method developed by Karlson. 9 The transducer probe was inserted into the uterine cavity without cervical dilatation or anesthesia. The spontaneous motility pattern characteristic of the functional state of the uterus was observed
From the Department of Obstetrics and Gynecology, UCLA Medical Center.
1207
B'
A'
ll
A
k
I
PR£,... ..,.,.- .
,""-
Ru-11- ().,
z
II
PosT- flm.t Il:Ar Z
~·----
-·~
...__.1....
Fig. I. A, A' , Postpartum D ay 2; Premarin, 40 mg. intravenously. B, B' , C ycle Day 7; Prema rin, 60 mg. intravenously.
I(
PREMAR • +OIIJ
~
""-
Jl
If---J. "''" :-----t\
rv
:;
:: ~
~
~
.? ~
~
;..,t::
?~
>
.:z-
(1)
;;><;:
0 00
Volume 82 1'\umhcr 6
for a period of at least 30 minutes. Then an intravenous infusion of 5 per cent glucose in water was started to act as a vehicle for drug injection through its tubing, thus avoiding the disadvantage of repeated dermal puncture. The solution of 5 per cent glucose in water has been shown to have no effect on uterine activity. 19 Initially, two or three injections of saline were performed through the infusion tubing as controls. Subsequently, conjugated equine estrogens in the form of Premarin* were injected in dosages ranging from 20 to 200 mg. Each injection was given over a period of 20 to 60 seconds. Recordings were continued for periods of approximately 4 hours. Results
In none of the 33 patients studied was there observed any change in the uterine contraction patterns following administration of the estrogens (Fig. 1). The same was true of saline. This lack of observed effect on uterine dynamics was consistent regardless of the functional state of the uterus, the time of the cycle, or the dosage of estrogens employed. No side effects were noted in any of the women studied. Comment
The present study has demonstrated that myometrium which is governed by endogenous estrogen does not respond to exogenous estrogens administered in this fashion. More precisely, in patients with "normal" ovarian function, there was no observed effect on motility of the nonpregnant human uteri over the 4 hour period of recording when estrogens were administered by vein in the specified dosages. It is of interest that this finding of lack of response of the nonpregnant uterus to exogenous estrogens is quite consistent with the ultimate conclusions of similar studies carried out in pregnant patients. In 1953 Jeffcoate and his associates20 reported that treatment of pregnant patients with estrogen re-
Effect of estrogens on uterine motility
1209
suited in increased uterine contractions. As a result, these authors recommended the use of estrogen to promote evacuation of the uterus in cases of missed abortions. During the next decade this oxytocic potential of estrogen was observed to be inconsistent by several investigators. 2 ' 4 ' 12 • 15 In 1950, Jeffcoate himself became suspicious of the uterine-stimulating effect of estrogen8 and in 1955 his colleagues published a retraction of their original contention. 13 This change of opinion resulted when careful study revealed estrogen to be no more effective for inducing labor than an inert substance. Previously, Karnaky 10 had asserted that intrauterine injection of estrogen actually relaxed a contracted pregnant utems; also Rowe-Dutton and his group 21 had demonstrated tokometrically that estrogen was ineffective for stimulating uterine evacuation in cases of missed abortion. Thus, the thesis that exogenous estrogen increases the activity of the pregnant uterus seems to have been disproved although it is still occasionally recommended in the literature. 3 In conclusion, we have presented evidence that the functioning nonpregnant uterus is refractory to estrogen therapy by vein. Speculation as to the reasons for this patriotic allegiance of the myometrium to the estrogens of its gonadal supervisors is indeed tempting. Philosophical discussion, however, should probably be limited to academic ruminations. To wit, there may be a latent period longer than our 4 hour study period before the injected estrogens exert their influence. More likely, when this steroid is given by the intravenous route, it may be deactivated so rapidly by the liver that the uterine muscle has little opportunity to be affected.U Until future studies provide answers to such possibilities, it may be asserted that intravenous estrogens have neither a stimulatory nor an inhibitory influence on the contracting muscle of a nonpregnant uterus. Summary
*Supplied by Ayerst Laboratories. New York 16, New York.
1. The role of estrogen in uterine muscle function is briefly reviewed.
1210 Kelly
2. Tokometric studies of 33 healthy nonpregnant women were carried out employing an intrauterine carbon transducer. 3. There was no observed change in the uterine contractility patterns of these pa-
REFERENCES
1. Csapo, A.: Am. J. Physiol. 162: 406, 1950. 2. Daels, J.: Schweiz. med. Wchnschr. 71: 1249, 1941. 3. Eastman, N.: A.:r.t. J. OnsT. & GYNEC. 76: 1362, 1958. 4. Effkemann, G.: Zentralbl. Gynak. 65: 338, 1941. 5. Frank, R. T., Bonham, C. D., and Gustavson, R. G.: Am. ]. Physiol. 74: 395, 1925. 6. Garrett, W. J.: J. Physiol. 132: 533, 1956. 7. Henry, J. S., Browne, J. S., and Venning, E. H.: AM. J. 0BST. & GYNEC. 60: 471, 1950. 8. Jeffcoate, T. N. A.: Proc. Roy. Soc. Med. 43: 734, 1950. 9. Karlson, S.: Acta obst. et gynec. s~andinav. 24: suppl. 4, 1944. 10. Karnaky, K. J.: AM. J. On sT. & GYNEC. 53: 312, 1947. 11. Kelly, J. V.: Obst. & Gynec. 17: 149, 1961. 12. Kurzrok, L.: AM. J. 0BST. & GYNEC. 56: 796, 1948. 13. Martin, R. H., and Menzies, D. N.: J. Obst. & Gynaec. Brit. Emp. 62: 256, 1955.
Am.
J.
December, 1961 Obst. & Gynec.
tit"nts after they were given estrogens intravenously. 4. The impotence of exogenous estrogens on myometrium in both its pregnant and nonpregnant states is discus~ed.
14. Moir, J. C.: Edinburgh M. J. 41: 93, 1934. 15. Murphy, D. P.: Surg. Gynec. & Obst. 77: 433, 1943. 16. Posse, N.: Acta obst. et gynec. scandinav. 38: ............ _,
110
::.u pp1. ..Jo,
1nt:o ~
;JJO.
17. Posse, N., and Kelly, J. V.: Obst. & Gynec. 8: 531, 1956. 18. Reynolds, S. R. M.: Physiology of the Uterus, New York, 1949, Paul B. Hoeber, Inc., pp. 76·86. 19. Reynolds, S. R. M., Harris, J. S., and Kaiser, I. H.: Clinical Measurement of Uterine Forces in Pregnancy and Labor, Springfield, Ill., 1954, Charles C Thomas, Publisher, p. 207. 20. Robinson, A. L., Datnow, M. M., and Jeffcoate, T. N. A.: ilrit. M. J. 1: 749, 1935. 21. Rowe-Dutton, G., Lubin, S., Reynolds, S. R. M., and Waltman, R.: AM. J. 0BST. & GYNEC. 63: 650, 1952. 22. Wilson, L., and Kurzrok, R.: Endocrinology 23: 79, 1938. 23. Wittenbeck, R.: Arch. Gynak. 142: 446, 1930.
T H E first report that estrogen was necessary for uterine motility was published in 1925." Since that time considerable experimental work has been done to assess the role of estrogen in the regulation of myometrial activity. These studies have revealed that uterine contractions disappear when animals are castrated and reappear when estrogen is administered. 18 The same findings have been demonstrated in humans. 16 • 22 • ~ 3 Thus, there seems to be convincing evidence that this hormone plays a major role in the control of myometrial function. Estrogen probably governs uterine muscle function by regulating both the accumulation of its contractile proteins and the activities of the energy-supplying phosphates. 1 The characteristics of uterine contractions in women with "normal" ovarian function have been rather extensively documented. 7 • 14 • 17 • 22 In fact, a characteristic pattern called the "A wave" pattern has been ascribed to the effects of endogenous estrogen. 6 The question of whether the human uterus which is under the custody of endogenous estrogen (from ovaries or placenta) would respond to exogenous estrogen has been the subject of numerous studies over the past three decades. 18 Unfortunately, the results from these experiments have been conflicting and inconsistent. One reason for these discrepancies may be that none of these investigations were designed to include
three requisites which are now considered to be essential in any in vivo study of the effects of drugs on the dynamics of human myometrium: 1. A tokometric technique ~hould be employed to record the uterine contractions during the study period. 2. The drug under evaluation should be administered under control conditions utilizing placebos, double-blind arrangements, or similar tools of objectivity. 3. The substance under investigation should be given by the intravenous route; in this way the obvious disadvantages of unknown rates of drug absorption and metabolism are minimized. In the hope that an objective approach might provide an answer to the question of whether exogenous estrogen would influence functioning myometrium, we undertook such a study.
Material and technique Thirty-three nonpregnant women with no evidence of organic pelvic disease were selected for study. Seven patients were studied in the follicular phase, 9 in the luteal phase, and 5 in the menstrual phase of their cycles; 12 women were investigated during the early postpartum period. Uterine contractions were recorded by the intrauterine carbon-transducer method developed by Karlson. 9 The transducer probe was inserted into the uterine cavity without cervical dilatation or anesthesia. The spontaneous motility pattern characteristic of the functional state of the uterus was observed
From the Department of Obstetrics and Gynecology, UCLA Medical Center.
1207
B'
A'
ll
A
k
I
PR£,... ..,.,.- .
,""-
Ru-11- ().,
z
II
PosT- flm.t Il:Ar Z
~·----
-·~
...__.1....
Fig. I. A, A' , Postpartum D ay 2; Premarin, 40 mg. intravenously. B, B' , C ycle Day 7; Prema rin, 60 mg. intravenously.
I(
PREMAR • +OIIJ
~
""-
Jl
If---J. "''" :-----t\
rv
:;
:: ~
~
~
.? ~
~
;..,t::
?~
>
.:z-
(1)
;;><;:
0 00
Volume 82 1'\umhcr 6
for a period of at least 30 minutes. Then an intravenous infusion of 5 per cent glucose in water was started to act as a vehicle for drug injection through its tubing, thus avoiding the disadvantage of repeated dermal puncture. The solution of 5 per cent glucose in water has been shown to have no effect on uterine activity. 19 Initially, two or three injections of saline were performed through the infusion tubing as controls. Subsequently, conjugated equine estrogens in the form of Premarin* were injected in dosages ranging from 20 to 200 mg. Each injection was given over a period of 20 to 60 seconds. Recordings were continued for periods of approximately 4 hours. Results
In none of the 33 patients studied was there observed any change in the uterine contraction patterns following administration of the estrogens (Fig. 1). The same was true of saline. This lack of observed effect on uterine dynamics was consistent regardless of the functional state of the uterus, the time of the cycle, or the dosage of estrogens employed. No side effects were noted in any of the women studied. Comment
The present study has demonstrated that myometrium which is governed by endogenous estrogen does not respond to exogenous estrogens administered in this fashion. More precisely, in patients with "normal" ovarian function, there was no observed effect on motility of the nonpregnant human uteri over the 4 hour period of recording when estrogens were administered by vein in the specified dosages. It is of interest that this finding of lack of response of the nonpregnant uterus to exogenous estrogens is quite consistent with the ultimate conclusions of similar studies carried out in pregnant patients. In 1953 Jeffcoate and his associates20 reported that treatment of pregnant patients with estrogen re-
Effect of estrogens on uterine motility
1209
suited in increased uterine contractions. As a result, these authors recommended the use of estrogen to promote evacuation of the uterus in cases of missed abortions. During the next decade this oxytocic potential of estrogen was observed to be inconsistent by several investigators. 2 ' 4 ' 12 • 15 In 1950, Jeffcoate himself became suspicious of the uterine-stimulating effect of estrogen8 and in 1955 his colleagues published a retraction of their original contention. 13 This change of opinion resulted when careful study revealed estrogen to be no more effective for inducing labor than an inert substance. Previously, Karnaky 10 had asserted that intrauterine injection of estrogen actually relaxed a contracted pregnant utems; also Rowe-Dutton and his group 21 had demonstrated tokometrically that estrogen was ineffective for stimulating uterine evacuation in cases of missed abortion. Thus, the thesis that exogenous estrogen increases the activity of the pregnant uterus seems to have been disproved although it is still occasionally recommended in the literature. 3 In conclusion, we have presented evidence that the functioning nonpregnant uterus is refractory to estrogen therapy by vein. Speculation as to the reasons for this patriotic allegiance of the myometrium to the estrogens of its gonadal supervisors is indeed tempting. Philosophical discussion, however, should probably be limited to academic ruminations. To wit, there may be a latent period longer than our 4 hour study period before the injected estrogens exert their influence. More likely, when this steroid is given by the intravenous route, it may be deactivated so rapidly by the liver that the uterine muscle has little opportunity to be affected.U Until future studies provide answers to such possibilities, it may be asserted that intravenous estrogens have neither a stimulatory nor an inhibitory influence on the contracting muscle of a nonpregnant uterus. Summary
*Supplied by Ayerst Laboratories. New York 16, New York.
1. The role of estrogen in uterine muscle function is briefly reviewed.
1210 Kelly
2. Tokometric studies of 33 healthy nonpregnant women were carried out employing an intrauterine carbon transducer. 3. There was no observed change in the uterine contractility patterns of these pa-
REFERENCES
1. Csapo, A.: Am. J. Physiol. 162: 406, 1950. 2. Daels, J.: Schweiz. med. Wchnschr. 71: 1249, 1941. 3. Eastman, N.: A.:r.t. J. OnsT. & GYNEC. 76: 1362, 1958. 4. Effkemann, G.: Zentralbl. Gynak. 65: 338, 1941. 5. Frank, R. T., Bonham, C. D., and Gustavson, R. G.: Am. ]. Physiol. 74: 395, 1925. 6. Garrett, W. J.: J. Physiol. 132: 533, 1956. 7. Henry, J. S., Browne, J. S., and Venning, E. H.: AM. J. 0BST. & GYNEC. 60: 471, 1950. 8. Jeffcoate, T. N. A.: Proc. Roy. Soc. Med. 43: 734, 1950. 9. Karlson, S.: Acta obst. et gynec. s~andinav. 24: suppl. 4, 1944. 10. Karnaky, K. J.: AM. J. On sT. & GYNEC. 53: 312, 1947. 11. Kelly, J. V.: Obst. & Gynec. 17: 149, 1961. 12. Kurzrok, L.: AM. J. 0BST. & GYNEC. 56: 796, 1948. 13. Martin, R. H., and Menzies, D. N.: J. Obst. & Gynaec. Brit. Emp. 62: 256, 1955.
Am.
J.
December, 1961 Obst. & Gynec.
tit"nts after they were given estrogens intravenously. 4. The impotence of exogenous estrogens on myometrium in both its pregnant and nonpregnant states is discus~ed.
14. Moir, J. C.: Edinburgh M. J. 41: 93, 1934. 15. Murphy, D. P.: Surg. Gynec. & Obst. 77: 433, 1943. 16. Posse, N.: Acta obst. et gynec. scandinav. 38: ............ _,
110
::.u pp1. ..Jo,
1nt:o ~
;JJO.
17. Posse, N., and Kelly, J. V.: Obst. & Gynec. 8: 531, 1956. 18. Reynolds, S. R. M.: Physiology of the Uterus, New York, 1949, Paul B. Hoeber, Inc., pp. 76·86. 19. Reynolds, S. R. M., Harris, J. S., and Kaiser, I. H.: Clinical Measurement of Uterine Forces in Pregnancy and Labor, Springfield, Ill., 1954, Charles C Thomas, Publisher, p. 207. 20. Robinson, A. L., Datnow, M. M., and Jeffcoate, T. N. A.: ilrit. M. J. 1: 749, 1935. 21. Rowe-Dutton, G., Lubin, S., Reynolds, S. R. M., and Waltman, R.: AM. J. 0BST. & GYNEC. 63: 650, 1952. 22. Wilson, L., and Kurzrok, R.: Endocrinology 23: 79, 1938. 23. Wittenbeck, R.: Arch. Gynak. 142: 446, 1930.