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Inhibition of menstrual uterine motility during water diuresis
Inhibition of menstrual uterine motility during water diuresis EDGARD
COBO,
RODRIGO MARY Cali,
M.D.
CIFUENTES, DE
M.D.,
VILLAMIZAR,
PH.D.
B.Sc.
Colombia
Induced water diuresis blocks the central release of antidiuretic hormone (ADH) which is, in turn, supposed to play a role in the high uterine activity recorded during human menstruation, In order to further explore this possibility, uterine and antidiuretic activities were studied during water diuresis in 27 normal menstruating women, prior to the insertion of an intrauterine device. Shortly after the initiation of the water overload, simultaneous inhibitlon of both uterine and antidiuretic activities was obtained. Furthermore, the administration of ADH by intravenous infusion reestablished the uterine motility to normal values while the administration of oxytocin did not. It is suggested that ADH has a direct role in the control of uterine activity during human menstruation. (AM. J. OBS~T. GYNECOL. 132: 313, 1978.)
DURING menstruation uterine motility is extremely high. The pattern observed is different from any other recorded during both the proliferative and secretory phases of the menstrual cycIe, during pregnancy and labor, or even during the puerperium when the uterus carries out a function comparable to that during menstruation, mainly the expulsion of blood, clots, and intrauterine debris. Menstrual uterine motility has been reported to have a “labor-like” pattern.‘* ’ However, during menstruation, it is common to observe contractions with intensities above 100 mm. Hg, frequencies higher than ten per ten minutes, and prolonged periods of hypertonicity, none of which occurs during normal labor. These differences in the behavior of the same smooth muscle suggest that menstrual myometrial function is under different hormonal regulatory influences and/or that there is a change in its reactivity to certain circulating hormones.
From the Department of Obstetrics and Gynecology, Section of Reproductive Physiology, Division of Health scipnces, Universidad de1 Valk.
Subjects and methods
S@orted in part by the Latin American Program for Research in Human Reproduction (PLAMIRH} ‘Grant X6.38.1.75. Received for
publication September 16, 1977.
Revised January
I6, 1978.
Accepted March
7, 1978.
Reprint requxstr: Dr. Edgard Cobo, Department of Obstetrics and Gynecologr, Section of Reproductive Physiology, Division of Health S&laces, Universidad Valle, Cali, Colombia, South America. 0002s9378/78/190313+08$00.80/0
0
1978
The
C. V. Moshy
de1
Co.
There is no agreement concerning the hormones involved in the regulation of menstrual motility. The ovarian steroids are said to play a role by their withdrawal effect which interrupts the block exerted during the previous phases of the cycle.3* 4 The hormones of the adrenergic system5 and the prostaglandin9 can also stimulate the nongravid uterus to levels of contractility recorded during menstruation. Some previous reports4* 7-s, i2, i3 suggest that antidiuretic hormone (ADH), a hormone which is known to regulate water balance and to maintain the plasma osmotic pressure, can also act as an oxytocic agent integrated in the control of uterine action. Surprisingly, the administration of water overload, a more simple and specific way to block ADH release, has not been studied. This paper deals with the measurement, in menstruating women, of the uterine and antidiuretic activities before, during, and after experimental water diuresis.
Twenty-seven normal women requesting insertion of an intrauterine device (IUD) were selected from the Outpatient Clinic of the University Hospital and volunteered for the induction of water diuresis and the experimental procedure. All had regular menstrual cycles, had not taken contraceptive pills during the previous cycle, and clinically had no abnormalities in the genital tract. Recordings of uterine contractility were performed between Days 1 and 3 of the cycle, within the three hours preceding insertion of the IUD. 313
314
Cobo,
Cifuentes,
and De Villamizar
WATER
LOAD
Fig. 1. Effect of water overload on uterine motility during menstruation in three selected cases. Large arrows indicate the initiation of water overload. Numbers in the intrauterine pressure recordings indicate the magnitude of the water overload 15 minutes later. Notice the short time elapsed between initiation and the appearance of the inhibitory effect on the uterus. Observe how different amounts of’water overload (6.4 to 17.0 ml. per kilogram) produce an equally marked depression in uterine contractility. Aseptically, a sponge-tipped, open polyethylene catheter (Clay-Adams PE-60) was inserted into the uterine cavity14 without using forceps to immobilize the cervix. The other end was connected to a pressure transducer (Sanborn 267-A) coupled to an electronic multichannel amplifier system and a recording galvanometer (Sanborn, Poli-Viso 150). Uterine contractility was recorded on a O-50 to O-100 mm. Hg scale, depending on the contraction intensity and the final values converted to the O-100 mm. Hg scale. A uterine contraction was defined as any pressure rise equal to or greater than 5 mm. Hg. The intensity, frequency, and tonus of the uterine contractions were measured for periods of 15 minutes. Total uterine activity was calculated by means of a measurement comparable to the uterine “work”rS by adding the contraction intensities for each 15 minute period. Immediately after the insertion of the uterine catheter, an indwelling Foley catheter was introduced into
the bladder and urine samples were collected every 15 minutes. Before each sample was taken, 100 to 150 ml. of air were introduced to assure adequate emptying at the bladder. After 30 minutes of recording uterine contractility, a water overload of about 20 ml. of water per kilogram of body weight was initiated by giving 5 per cent dextrose in water intravenously plus tap water by mouth. A constant state of positive water balance was maintained by administration of additional water to equal the rate of urine flow. In 15 of 27 subjects the water overload was discontinued after one hour in order to study the disappearance of its effects on both uterine and antidiuretic activities. Adequate serum samples were obtained prior to hydration and at the peak of water diuresis. Blood and urine creatinine concentrations were measured by the Jaffe reaction.” Total solute concentration in urine and serum was quantitated by osmometry (Advanced Instruments Osmometer 64-31) and expressed in ntil-
Volume Number
132 3
Inhibition of menstrual uterine motility
315
5 min
Fig. 2. Effect
of water overload and recovery of uterine contractility. The three panels are sequential fragments of a single recording. A deep inhibition of the menstrual uterine contractility occurs and becomes stable within 20 minutes after initiation of the water overload and begins to recover approximately 60 minutes after its interruption.
liosmoles per kilogram of water. Urinary output was carefully measured every 15 minutes. Based on these data, endogenous creatinine clearance (Ccr), osmolat clearance (Cosm), and free water clearance (CH20) were calculated and expressed in milliliters per minute. When urinary osmolality (Uosm) rose above that of serum and CHzO values became negative, it was considered evidence of antidiuretic activity. An ADH effect was assumed with these findings when, simultaneously, no significant changes were observed in the glomerular filtration rate (Ccr) and/or in the solute excretion (Cosm). Likewise, when as a result of water diuresis the urinary osmolality values fell below those of serum and the CHzO became markedly positive, this was considered evidence of inhibition of ADH activity. The control values were those obtained in all observations made before water overload was initiated. The mean values and the standard error of the mean (S.E.M.) were calculated for all the variables studied.
Student’s t test was used to evaluate the statistical significance of the variations observed between the control values and those obtained during water diuresis.
Results Spontaneous uterine and antidiuretic activities. Each subject presented individual characteristics in the uterine contractility pattern, due mainly to variations in uterine tonus. In nine of 27 subjects hypertonicity was observed ranging from 22 to 58 mm. Hg and lasting from 30 to 66 minutes. Accordingly, most periods of stable nonhypertonic uterine activity were considered controls. Mean uterine tonus was 11.7 t 1.8 mm. Hg. The mean contraction intensity was 39.9 f 3.6 mm. Hg and the mean frequency was 12.4 t 2.4 contractions in 15 minutes; uterine work ranged between 86.2 and 966.4 mm. Hg and the mean value was 404.1 + 43.1 mm. Hg. Spontaneous antidiuretic activity was high. The av-
316
Cobo,
Cifuentes,
and De VilIamitar
in
All of the differences uterine work during
were
smtistical]y
control
observed from the period of
significant.
The
water
inhibition
v&~s diuresis
of
uterine
became evident 5 to 15 minutes after the iniriation of water overload (Figs. 1 and 2), but there were wide individual variations in the time required to attain
activity
maximal
inhibition
(8 to 76.5
minutes)
with
a tnean
c)t
28.5 + 3.2 minutes. As anticipated, water overload led to a progressive inhibition of antidiuretic activity, as indicated by the gradual changes in CHzO and Uosm which varied in time,
Fig. 3. Percentage
variation in uterine “work” and urinary osmolality during and after water diuresis. The upper panel shows the water balance which increases to a steady level at about 20 ml. of water per kilogram of body weight. This positive balance decreases to slightly negative values after discontinuation of the water overload. In the lower left panel it is possible to observe how the percentage decrease in uterine “work” (Uw) parallels urinary osmolality (Uosm). T50% (small arrou!, is the same (15 minutes) for both values. The recovery (tight panel) is not parallel, with the uterine “work” showing a shorter T50% (35 minutes) than osmolality (56 minutes). erage
urinary
output
was
2.2
2 0.5
ml.
per
minute.
and urinary osmolality were 290.3 & 1.6 and 577.8 t 50.9 mOsm. per kilogram, re-
Mean
spectively,
values
for
the
serum
latter
clearly
hyperosmolal
to
serum.
The mean values of the clearances studied were 1.2 It: 0.5 ml. per millimeter for CH20, 73.5 C 5.4 ml. per minute for Ccr, and 3.9 2 0.6 ml. per minute for Cosm. The effect of water overload on uterine and antidiuretic activities. Water overload led to a marked decrease in uterine motility in 24 of 27 patients studied and to a moderate decrease in the three remaining patients. In seven subjects this inhibition was complete (Fig. 1). There was a proportional decrease in the intensity and frequency of uterine contractions, while no significant changes were observed in uterine tonus. Therefore, the results presented refer only to the analysis of uterine work which integrates the intensity and frequency of contraction in a given 15 minute period. Mean values of uterine work before water overload were 404.1 +- 43.1 mm. Hg. These values decreased exponentially during the time of water overload to 248.5 * 34.7 mm. Hg after 15 minutes and to 110.8 ? 20.2 mm. Hg after 90 minutes.
like
uterine
work.
After
1.5 minutes,
the
mean
urinary osmolality values decreased to 395.9 + 51.6 mOsm. per kilogram and continued to fall. becoming hypoosmolal, and reached an average of 81.7 ? 9.9 mOsm. per kilogram after 90 minutes. There was also a fairly wide individual variation in the time required to produce urinary hypoosmolality after wat.er overloa.d, with a range of 15 to 60 minutes and a mean of 30.6 served
*
2.7 in
minutes. CH,O
Also, with
a similar
a mean
of
variation -0.8
2 0.7
was
ob-
ml.
per
minute after 15 minutes, increasing to 18.8 h 1.1 ml. per minute after 90 minutes. After the first 15 minutes the variations in Uosm and CH,O became significantly different from mean control
values.
There
was
no
significant
variation
in the
creatinine clearance during the period of water diuresis, which ranged from 81.6 2 5.8 to 71.8 % 5.6 ml. per minute. Cosm increased during water diuresis and differences from control values in urine samples taken 30. 45, 60, and 75 minutes after initiation of water overload were statistically significant. Disappearance of water overload effects. After interruption of water overload, the recovery of uterine contractility was slower than its inhibition (Fig. 2). After one hour, more than half of the subjects had not regained control levels. The mean value of uterine work after 45 minutes was 217.5 +- 47.0 mm. Hg, which is significantly less than the previous control (P < 0.01). After 60 minutes, the mean value was 244.0 -t 50.5 which was no longer significantly different (P > 0.5). and it increased to 290.7 * 53.3 mm. E-Ig 75 minutes later. The time required for uterine work to reach stable values similar to preoverload controls varied between 15 and 102 minutes with a mean of 43.9 r 8.1 minutes. The recovery of antidiuretic activity was also prolonged. Urinary output continued to be high for one hour after interruption of water overload. Urinary osmolality increased but did not reach control levels in one hour; after 75 minutes, the mean value was 413.0 4 64.1 mOsm. per kilogram, significantly different from the control (P < 0.1). CHzO values showed
Volume Number
132 3
Inhibition of menstrual uterine motility
317
Fig. 4. Effect of synthetic arginine-vasopressin on uterine contractility depressed by water overload. The administration of A-vasopressin (1 mu. per minute) during the stable phase of uterine contractility depression caused by water overload produces an activation of uterine motility which is similar to that observed before water diuresis. similar changes and their mean remained positive for 60 minutes, becoming negative only after 75 minutes (-0.7 ? 0.6 ml. per minute). During this recovery period no significant changes were observed in the osmolal clearance and in the glomerular filtration rate. The recovery of antidiuretic inhibition, measured by the time elapsed before urine became hypoosmolar, varied between 30 and 105 minutes with a mean of 77.1 2 13.9 minutes. Comparison of uterine and antidiuretic effects. Because of the wide disparity of the data obtained and the individua1 variations of the uterine and antidiuretic effects of water overload, it was decided to normalize these data and analyze them in terms of percentage deviations from mean values before overload. The percentage of decrease in uterine work and urinary osmolality during water overload is shown on the left side of Fig. 3 and on the right, their increase after its interruption. The decreasing curves for the two variables are aimost paraIM. The time required to reach a level of 50 per cent below the control (T50%) was 15 minutes for both variables. By contrast, the recovery curves after interruption of overload are quite differ-
ent for reaches molality, T50% uterine
both variables (Fig. 3, right side). Uterine work control levels much sooner than urinary oswhich remains low for another hour. The required for recovery was 35 minutes for work and 56 minutes for urinary osmolality.
Comment Although the hormones that control menstrual contractility have not been precisely identified, the following evidence suggests that ADH plays an important role since: (a) During menstruation the uterus is highly sensitive to this hormone,7”g; (b) if nausea and vomiting are induced during different phases of the menstrual cycle there is, at the same time, an increase in uterine activity and antidiuresiP; and (c) during menstruation, the administration of ethanol, which is a central inhibitor of ADH release and also acts directly upon the myometrium, produces a marked inhibition of uterine evidence of contractility. 4* I* Our results give additional the participation of ADH in the control of menstrual uterine contractility. Water overload, sufficient to block ADH liberation and induce water diuresis, results in a marked inhibition of uterine motility which occurs si-
318
Cob,
Cifuentes, and De Villamirar
ta
Fig. 5. Effect of synthetic oxytocin on uterine contractility depressed by water overload. Oxytocin (1 mu. per minute) does not produce an activation of uterine motility comparable to that achieved by A-vasopressin (Fig. 4). Moreover, the pattern of oxytocin-induced uterine motility is different from that observed before water diuresis.
muhaneousiy with the inhibition of antidiuretic activity, as evidenced by the fall of urinary osmolality (Fig. 3) and the rise in urinary output and free water clearance’@ with no changes in the glomerular filtration rate estimated by endogenous creatinine clearance. During water diuresis there was an increase of solute excretion in the second and up to the fifth urine sample. This elevation was dependent upon urinary osmolality which decreases to its lowest values only 75 to 95 minutes after the initiation of water overload, whereas urinary output increased to 20 ml. per minute 30 minutes before. The inhibition of uterine work occurred pari passu with the lowering of urinary osmolahty (Fig. 3, left) following exponential type curves in which the T50% is the same for both variables, reaching maximum inhibition 75 minutes after initiation of water overload. These observations are consistent with the following results obtained in human beings by direct measurements of ADH levels: (a) As water diuresis appears, ADH concentrations decrease gradually, reaching the lowest plasma and tissue levels at the peak in
water diuresis,20
(b) T50% for the disappearance ofenADH during water diuresis is between 12 and 19 minutes.z0, ‘I and (c) near-zero plasma levels for ADH were measured 70 to 120 minutes’after initiation of water overload. Therefore, these remarkable coincidences led us to interpret our results as suggesting that the inhibition of uterine contractihty is due to a gradual decrease of the plasma ADH concentration resulting from the central blocking of ADH release during water diuresis. Fig. 3, right side, shows that recovery of uterine contractility and urinary osmolality after water overload is slower than the inhibition, with T50% values of 35 minutes and 56 minutes, respectively. This observation agrees with others2’* 22 that the antidiuretic effect of vasopressin correlates with the previous level of body hydration, being stronger when there is d&y&&on and inhibited when there is water excess. It must be noted that the recovery of uterine activity (35 n+wtes) dogenous
is faster
plasma
than
that
of antidiuretic
activity
(55
m&~ttrs).
A possible explanation for this can be found in the fact that water diuresis is associated with a decrease m the
.me 1.42 .n ber 3
inhibition
osmolality of the interstitial fluid in the renal medulla.‘“* 22 Since in order to reestablish renal concentration capacity it is necessary to have not only adequate levels of ADH but also an elevated medullary osmotic gradient, it is likely that the recovery of urinary osmolality and water transport is limited by the low medullary osmolality present during water diuresis. At present we are studying the response of the menstruating uterus to the administration of oxytocin and ADH and to the endogenous liberation of ADH induced by external stimuli. We have been able to reproduce the spontaneous pattern of uterine activity prior to water diuresis by the intravenous administration of ADH (Fig. 4). On the other hand, oxytocin administration produces little or no effect (Fig. 5). These results are additional evidence that vasopressin is involved in the control of the menstrual uterus. To show that the response to water overload is different, depending upon the function the uterus is performing. we have compared these results with our previous studiesi3s 24 on uterine contractility during pregnancy and labor under water diuresis. Fig. 6 shows that water overload inhibits only the menstrual uterus but does not modify the activity of the term pregnant uterus and does not inhibit its increased contractility during labor. Such marked differences during water diuresis suggest that there is a relationship between ADH and the other regulating hormones of myometrial activity, depending on the phases of the uterus. As we have discussed elsewhere,24 increasing uterine activity during labor occurs simultaneously with a high antidiuretic activity, even when experimental water overload is equal to that used during pregnancy or menstruation, suggesting that ADH release is so high that it does not allow water diuresis to occur
REFERENCES
1. Hendricks, C. H.: Inherent motility patterns and response characteristics of the nonpregnant human uterus, AM. J. OBSTET.
GYNECOL.
96: 824,
1966.
2. Cibils, L. A.: Contractility of the nonpregnant uterus, Obstet. Gynecol. 30: 441, 1967. 3. Knaus. H. H.: Eine neue method zun Bestimmung des Ovulationstermines, 4. Coutinho, E. M.:
Zentrabl. Hormonal
Gynaekol. 53: 2 193, 1929. effects of the non-pregnalit
human uterus, Prog. Endocrinol.
184: 945, 1968.
5. Garret, W. J.: The effects of adrenaline and noradrenaline on the intact nonpregnant uterus, Br. J. Obstet. Gynaecol. 62: 876, 1955. 6. Karim, S. M. M.: Physiological role of prostaglandins in the control of parturition and menstruation, J. Reprod. Fertil. (Suppl.) 16: 105, 1972. 7. Joelsson, I., Sundberg, A. I., and Sanberg, F.: The in viva effect of oxytocin and vasopressin on the non pregnant human uterus, Br. J. Obstet. Gynaecol. 73: 832, 1966. 8. Embrey, M. P., and Moir, Ch.: A comparison of the
of menstrual
I
WATER
uterine
motility
319
OVERLOAD
UTERINE ACTIVITY (Irf
1
Fig. 6. Uterine effect of water overload during menstruation, term pregnancy, and labor. For explanation see text.
and that its oxytocic action is probably synergistic with that of other hormones involved in the control of labor. The results presented clearly support the hypothesis that ADH contributes to the high motility of the uterus during menstruation. However, further studies are necessary to induce the endogenous release of ADH under water diuresis and, finally, to measure plasma ADH during menstruation before and after the inhibition of uterine motility by water overload.
oxytocic effects of synthetic vasopressin and oxytocin, Br. J. Obstet. Gynaecol. 74: 648, 1967. 9. Coutinho, E. M.: The effects of vasopressin and oxytocin on the genital tract of women, Proceedings of the Sixth World Congress on Fertility and Sterility, Tel Aviv, 1970, The Israel Academy of Sciences and Humanities, p. 182. 10. Fuchs, A. R., and Wagner, G.: Quantitative aspects of release ofoxytocin by suckling in unanaesthetized rabbits, Acta Endocrinol. 44: 581, 1963. 11. Cobo, E., and Quintero, C. A.: Milk-ejecting and antidiuretic activities under neurohypophyseal inhibition with alcohol and water overload, AM. J. OBSTET. GYNECOL. 105: 877, 1969. 12. Fuchs, A. R., Coutinho, E. M., Xavier, R., Bates, P. E., and Fuchs, F.: Effect of ethanol on the activity of the nonpregnant human uterus and its reactivity to neurohypophyseal hormones, AM. J. OBSTET. GYNECOL. 101: 997, 1968. ‘13. Coutinho, E. M., Adeodato Filho, J., Xavier, R., Fuchs, A. R., and Fuchs, F.: Effect of ethanol on the response of the
320
14.
15.
16.
17.
18.
19.
Cobo,
Cifuentes,
and De Villamizar
non-pregnant human uterus to oxytocin and vasopressin. Br. J. Obstet. Gynaecol. 77: 164, 1976. Bengtsson, L. Ph.: The sponge-tipped catheter-modification of the open end catheter for recording of myometrial activity in viva, J. Reprod. Fertil. 16: 115. 1968. Cibils, L. A.: Efecto de la rotura de las membranas en el pax-to inducido con oxitocina, 20. Congr. Uruguay0 Obstet. Ginecol. 2: 3 16, 1957. Bonsnes, R. W., and Taussky, H. H.: The calorimetric determination of creatinine by the Jaffe reaction, J. Biol. Chem. 158: 581, 1945. Alvarez, H., and Caldeyro-Barcia, R.: Fisiopatologia de la contraccidn uterina y sus aplicaciones en la clinica, 20. Congr. Latinoamericano Obstet. Ginecol. 1: 5, 1954. Coutinho, E. M.: Oxytocic and antidiuretic effects of nausea in women, AM. J. OBSTET. GYNECOL. 105: 127, 1969. Levinsky, N. G., Davidson, D. G., and Berliner, R. W.:
Copyright
Effects of reduced glomerular filtration on urine concentration in the presence of antidiuretic hormone, J. Clin. Invest. 38: 730, 1959. 20. Czaczkes, J. W., Kleeman, C. R., and Koening, M.: Physiological studies of antidiuretic hormone bv its direct measuyement in human plasma. J. Clin. Invest. 43: 162. 1964. 21. Lauson, H. D.: The problem of estimating the rate at secretion of antidiuretic hormone in man, Am. J. Med. 11: 135, 1951. 22. Epstein, F. H., Kleeman, Cl. R., and Hendrikx, A.: The influence of bodily hydration on the renal concentrating process, J. Clin. Invest. 36: 629, 1957. 23. Cobo, E., Gait&n, E., Mizrachi, M., and Strada, G.: Neurohypophyseal hormone release in the human. I. Experimental study during pregnancy, AM, J. OBSTET. GYNECOL. 91: 905, 1965. 24. Cobo, E.: Uterine and milk-ejecting activities during human labor, J. Appl. Physiol. 24: 317, 1968.
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COBO,
RODRIGO MARY Cali,
M.D.
CIFUENTES, DE
M.D.,
VILLAMIZAR,
PH.D.
B.Sc.
Colombia
Induced water diuresis blocks the central release of antidiuretic hormone (ADH) which is, in turn, supposed to play a role in the high uterine activity recorded during human menstruation, In order to further explore this possibility, uterine and antidiuretic activities were studied during water diuresis in 27 normal menstruating women, prior to the insertion of an intrauterine device. Shortly after the initiation of the water overload, simultaneous inhibitlon of both uterine and antidiuretic activities was obtained. Furthermore, the administration of ADH by intravenous infusion reestablished the uterine motility to normal values while the administration of oxytocin did not. It is suggested that ADH has a direct role in the control of uterine activity during human menstruation. (AM. J. OBS~T. GYNECOL. 132: 313, 1978.)
DURING menstruation uterine motility is extremely high. The pattern observed is different from any other recorded during both the proliferative and secretory phases of the menstrual cycIe, during pregnancy and labor, or even during the puerperium when the uterus carries out a function comparable to that during menstruation, mainly the expulsion of blood, clots, and intrauterine debris. Menstrual uterine motility has been reported to have a “labor-like” pattern.‘* ’ However, during menstruation, it is common to observe contractions with intensities above 100 mm. Hg, frequencies higher than ten per ten minutes, and prolonged periods of hypertonicity, none of which occurs during normal labor. These differences in the behavior of the same smooth muscle suggest that menstrual myometrial function is under different hormonal regulatory influences and/or that there is a change in its reactivity to certain circulating hormones.
From the Department of Obstetrics and Gynecology, Section of Reproductive Physiology, Division of Health scipnces, Universidad de1 Valk.
Subjects and methods
S@orted in part by the Latin American Program for Research in Human Reproduction (PLAMIRH} ‘Grant X6.38.1.75. Received for
publication September 16, 1977.
Revised January
I6, 1978.
Accepted March
7, 1978.
Reprint requxstr: Dr. Edgard Cobo, Department of Obstetrics and Gynecologr, Section of Reproductive Physiology, Division of Health S&laces, Universidad Valle, Cali, Colombia, South America. 0002s9378/78/190313+08$00.80/0
0
1978
The
C. V. Moshy
de1
Co.
There is no agreement concerning the hormones involved in the regulation of menstrual motility. The ovarian steroids are said to play a role by their withdrawal effect which interrupts the block exerted during the previous phases of the cycle.3* 4 The hormones of the adrenergic system5 and the prostaglandin9 can also stimulate the nongravid uterus to levels of contractility recorded during menstruation. Some previous reports4* 7-s, i2, i3 suggest that antidiuretic hormone (ADH), a hormone which is known to regulate water balance and to maintain the plasma osmotic pressure, can also act as an oxytocic agent integrated in the control of uterine action. Surprisingly, the administration of water overload, a more simple and specific way to block ADH release, has not been studied. This paper deals with the measurement, in menstruating women, of the uterine and antidiuretic activities before, during, and after experimental water diuresis.
Twenty-seven normal women requesting insertion of an intrauterine device (IUD) were selected from the Outpatient Clinic of the University Hospital and volunteered for the induction of water diuresis and the experimental procedure. All had regular menstrual cycles, had not taken contraceptive pills during the previous cycle, and clinically had no abnormalities in the genital tract. Recordings of uterine contractility were performed between Days 1 and 3 of the cycle, within the three hours preceding insertion of the IUD. 313
314
Cobo,
Cifuentes,
and De Villamizar
WATER
LOAD
Fig. 1. Effect of water overload on uterine motility during menstruation in three selected cases. Large arrows indicate the initiation of water overload. Numbers in the intrauterine pressure recordings indicate the magnitude of the water overload 15 minutes later. Notice the short time elapsed between initiation and the appearance of the inhibitory effect on the uterus. Observe how different amounts of’water overload (6.4 to 17.0 ml. per kilogram) produce an equally marked depression in uterine contractility. Aseptically, a sponge-tipped, open polyethylene catheter (Clay-Adams PE-60) was inserted into the uterine cavity14 without using forceps to immobilize the cervix. The other end was connected to a pressure transducer (Sanborn 267-A) coupled to an electronic multichannel amplifier system and a recording galvanometer (Sanborn, Poli-Viso 150). Uterine contractility was recorded on a O-50 to O-100 mm. Hg scale, depending on the contraction intensity and the final values converted to the O-100 mm. Hg scale. A uterine contraction was defined as any pressure rise equal to or greater than 5 mm. Hg. The intensity, frequency, and tonus of the uterine contractions were measured for periods of 15 minutes. Total uterine activity was calculated by means of a measurement comparable to the uterine “work”rS by adding the contraction intensities for each 15 minute period. Immediately after the insertion of the uterine catheter, an indwelling Foley catheter was introduced into
the bladder and urine samples were collected every 15 minutes. Before each sample was taken, 100 to 150 ml. of air were introduced to assure adequate emptying at the bladder. After 30 minutes of recording uterine contractility, a water overload of about 20 ml. of water per kilogram of body weight was initiated by giving 5 per cent dextrose in water intravenously plus tap water by mouth. A constant state of positive water balance was maintained by administration of additional water to equal the rate of urine flow. In 15 of 27 subjects the water overload was discontinued after one hour in order to study the disappearance of its effects on both uterine and antidiuretic activities. Adequate serum samples were obtained prior to hydration and at the peak of water diuresis. Blood and urine creatinine concentrations were measured by the Jaffe reaction.” Total solute concentration in urine and serum was quantitated by osmometry (Advanced Instruments Osmometer 64-31) and expressed in ntil-
Volume Number
132 3
Inhibition of menstrual uterine motility
315
5 min
Fig. 2. Effect
of water overload and recovery of uterine contractility. The three panels are sequential fragments of a single recording. A deep inhibition of the menstrual uterine contractility occurs and becomes stable within 20 minutes after initiation of the water overload and begins to recover approximately 60 minutes after its interruption.
liosmoles per kilogram of water. Urinary output was carefully measured every 15 minutes. Based on these data, endogenous creatinine clearance (Ccr), osmolat clearance (Cosm), and free water clearance (CH20) were calculated and expressed in milliliters per minute. When urinary osmolality (Uosm) rose above that of serum and CHzO values became negative, it was considered evidence of antidiuretic activity. An ADH effect was assumed with these findings when, simultaneously, no significant changes were observed in the glomerular filtration rate (Ccr) and/or in the solute excretion (Cosm). Likewise, when as a result of water diuresis the urinary osmolality values fell below those of serum and the CHzO became markedly positive, this was considered evidence of inhibition of ADH activity. The control values were those obtained in all observations made before water overload was initiated. The mean values and the standard error of the mean (S.E.M.) were calculated for all the variables studied.
Student’s t test was used to evaluate the statistical significance of the variations observed between the control values and those obtained during water diuresis.
Results Spontaneous uterine and antidiuretic activities. Each subject presented individual characteristics in the uterine contractility pattern, due mainly to variations in uterine tonus. In nine of 27 subjects hypertonicity was observed ranging from 22 to 58 mm. Hg and lasting from 30 to 66 minutes. Accordingly, most periods of stable nonhypertonic uterine activity were considered controls. Mean uterine tonus was 11.7 t 1.8 mm. Hg. The mean contraction intensity was 39.9 f 3.6 mm. Hg and the mean frequency was 12.4 t 2.4 contractions in 15 minutes; uterine work ranged between 86.2 and 966.4 mm. Hg and the mean value was 404.1 + 43.1 mm. Hg. Spontaneous antidiuretic activity was high. The av-
316
Cobo,
Cifuentes,
and De VilIamitar
in
All of the differences uterine work during
were
smtistical]y
control
observed from the period of
significant.
The
water
inhibition
v&~s diuresis
of
uterine
became evident 5 to 15 minutes after the iniriation of water overload (Figs. 1 and 2), but there were wide individual variations in the time required to attain
activity
maximal
inhibition
(8 to 76.5
minutes)
with
a tnean
c)t
28.5 + 3.2 minutes. As anticipated, water overload led to a progressive inhibition of antidiuretic activity, as indicated by the gradual changes in CHzO and Uosm which varied in time,
Fig. 3. Percentage
variation in uterine “work” and urinary osmolality during and after water diuresis. The upper panel shows the water balance which increases to a steady level at about 20 ml. of water per kilogram of body weight. This positive balance decreases to slightly negative values after discontinuation of the water overload. In the lower left panel it is possible to observe how the percentage decrease in uterine “work” (Uw) parallels urinary osmolality (Uosm). T50% (small arrou!, is the same (15 minutes) for both values. The recovery (tight panel) is not parallel, with the uterine “work” showing a shorter T50% (35 minutes) than osmolality (56 minutes). erage
urinary
output
was
2.2
2 0.5
ml.
per
minute.
and urinary osmolality were 290.3 & 1.6 and 577.8 t 50.9 mOsm. per kilogram, re-
Mean
spectively,
values
for
the
serum
latter
clearly
hyperosmolal
to
serum.
The mean values of the clearances studied were 1.2 It: 0.5 ml. per millimeter for CH20, 73.5 C 5.4 ml. per minute for Ccr, and 3.9 2 0.6 ml. per minute for Cosm. The effect of water overload on uterine and antidiuretic activities. Water overload led to a marked decrease in uterine motility in 24 of 27 patients studied and to a moderate decrease in the three remaining patients. In seven subjects this inhibition was complete (Fig. 1). There was a proportional decrease in the intensity and frequency of uterine contractions, while no significant changes were observed in uterine tonus. Therefore, the results presented refer only to the analysis of uterine work which integrates the intensity and frequency of contraction in a given 15 minute period. Mean values of uterine work before water overload were 404.1 +- 43.1 mm. Hg. These values decreased exponentially during the time of water overload to 248.5 * 34.7 mm. Hg after 15 minutes and to 110.8 ? 20.2 mm. Hg after 90 minutes.
like
uterine
work.
After
1.5 minutes,
the
mean
urinary osmolality values decreased to 395.9 + 51.6 mOsm. per kilogram and continued to fall. becoming hypoosmolal, and reached an average of 81.7 ? 9.9 mOsm. per kilogram after 90 minutes. There was also a fairly wide individual variation in the time required to produce urinary hypoosmolality after wat.er overloa.d, with a range of 15 to 60 minutes and a mean of 30.6 served
*
2.7 in
minutes. CH,O
Also, with
a similar
a mean
of
variation -0.8
2 0.7
was
ob-
ml.
per
minute after 15 minutes, increasing to 18.8 h 1.1 ml. per minute after 90 minutes. After the first 15 minutes the variations in Uosm and CH,O became significantly different from mean control
values.
There
was
no
significant
variation
in the
creatinine clearance during the period of water diuresis, which ranged from 81.6 2 5.8 to 71.8 % 5.6 ml. per minute. Cosm increased during water diuresis and differences from control values in urine samples taken 30. 45, 60, and 75 minutes after initiation of water overload were statistically significant. Disappearance of water overload effects. After interruption of water overload, the recovery of uterine contractility was slower than its inhibition (Fig. 2). After one hour, more than half of the subjects had not regained control levels. The mean value of uterine work after 45 minutes was 217.5 +- 47.0 mm. Hg, which is significantly less than the previous control (P < 0.01). After 60 minutes, the mean value was 244.0 -t 50.5 which was no longer significantly different (P > 0.5). and it increased to 290.7 * 53.3 mm. E-Ig 75 minutes later. The time required for uterine work to reach stable values similar to preoverload controls varied between 15 and 102 minutes with a mean of 43.9 r 8.1 minutes. The recovery of antidiuretic activity was also prolonged. Urinary output continued to be high for one hour after interruption of water overload. Urinary osmolality increased but did not reach control levels in one hour; after 75 minutes, the mean value was 413.0 4 64.1 mOsm. per kilogram, significantly different from the control (P < 0.1). CHzO values showed
Volume Number
132 3
Inhibition of menstrual uterine motility
317
Fig. 4. Effect of synthetic arginine-vasopressin on uterine contractility depressed by water overload. The administration of A-vasopressin (1 mu. per minute) during the stable phase of uterine contractility depression caused by water overload produces an activation of uterine motility which is similar to that observed before water diuresis. similar changes and their mean remained positive for 60 minutes, becoming negative only after 75 minutes (-0.7 ? 0.6 ml. per minute). During this recovery period no significant changes were observed in the osmolal clearance and in the glomerular filtration rate. The recovery of antidiuretic inhibition, measured by the time elapsed before urine became hypoosmolar, varied between 30 and 105 minutes with a mean of 77.1 2 13.9 minutes. Comparison of uterine and antidiuretic effects. Because of the wide disparity of the data obtained and the individua1 variations of the uterine and antidiuretic effects of water overload, it was decided to normalize these data and analyze them in terms of percentage deviations from mean values before overload. The percentage of decrease in uterine work and urinary osmolality during water overload is shown on the left side of Fig. 3 and on the right, their increase after its interruption. The decreasing curves for the two variables are aimost paraIM. The time required to reach a level of 50 per cent below the control (T50%) was 15 minutes for both variables. By contrast, the recovery curves after interruption of overload are quite differ-
ent for reaches molality, T50% uterine
both variables (Fig. 3, right side). Uterine work control levels much sooner than urinary oswhich remains low for another hour. The required for recovery was 35 minutes for work and 56 minutes for urinary osmolality.
Comment Although the hormones that control menstrual contractility have not been precisely identified, the following evidence suggests that ADH plays an important role since: (a) During menstruation the uterus is highly sensitive to this hormone,7”g; (b) if nausea and vomiting are induced during different phases of the menstrual cycle there is, at the same time, an increase in uterine activity and antidiuresiP; and (c) during menstruation, the administration of ethanol, which is a central inhibitor of ADH release and also acts directly upon the myometrium, produces a marked inhibition of uterine evidence of contractility. 4* I* Our results give additional the participation of ADH in the control of menstrual uterine contractility. Water overload, sufficient to block ADH liberation and induce water diuresis, results in a marked inhibition of uterine motility which occurs si-
318
Cob,
Cifuentes, and De Villamirar
ta
Fig. 5. Effect of synthetic oxytocin on uterine contractility depressed by water overload. Oxytocin (1 mu. per minute) does not produce an activation of uterine motility comparable to that achieved by A-vasopressin (Fig. 4). Moreover, the pattern of oxytocin-induced uterine motility is different from that observed before water diuresis.
muhaneousiy with the inhibition of antidiuretic activity, as evidenced by the fall of urinary osmolality (Fig. 3) and the rise in urinary output and free water clearance’@ with no changes in the glomerular filtration rate estimated by endogenous creatinine clearance. During water diuresis there was an increase of solute excretion in the second and up to the fifth urine sample. This elevation was dependent upon urinary osmolality which decreases to its lowest values only 75 to 95 minutes after the initiation of water overload, whereas urinary output increased to 20 ml. per minute 30 minutes before. The inhibition of uterine work occurred pari passu with the lowering of urinary osmolahty (Fig. 3, left) following exponential type curves in which the T50% is the same for both variables, reaching maximum inhibition 75 minutes after initiation of water overload. These observations are consistent with the following results obtained in human beings by direct measurements of ADH levels: (a) As water diuresis appears, ADH concentrations decrease gradually, reaching the lowest plasma and tissue levels at the peak in
water diuresis,20
(b) T50% for the disappearance ofenADH during water diuresis is between 12 and 19 minutes.z0, ‘I and (c) near-zero plasma levels for ADH were measured 70 to 120 minutes’after initiation of water overload. Therefore, these remarkable coincidences led us to interpret our results as suggesting that the inhibition of uterine contractihty is due to a gradual decrease of the plasma ADH concentration resulting from the central blocking of ADH release during water diuresis. Fig. 3, right side, shows that recovery of uterine contractility and urinary osmolality after water overload is slower than the inhibition, with T50% values of 35 minutes and 56 minutes, respectively. This observation agrees with others2’* 22 that the antidiuretic effect of vasopressin correlates with the previous level of body hydration, being stronger when there is d&y&&on and inhibited when there is water excess. It must be noted that the recovery of uterine activity (35 n+wtes) dogenous
is faster
plasma
than
that
of antidiuretic
activity
(55
m&~ttrs).
A possible explanation for this can be found in the fact that water diuresis is associated with a decrease m the
.me 1.42 .n ber 3
inhibition
osmolality of the interstitial fluid in the renal medulla.‘“* 22 Since in order to reestablish renal concentration capacity it is necessary to have not only adequate levels of ADH but also an elevated medullary osmotic gradient, it is likely that the recovery of urinary osmolality and water transport is limited by the low medullary osmolality present during water diuresis. At present we are studying the response of the menstruating uterus to the administration of oxytocin and ADH and to the endogenous liberation of ADH induced by external stimuli. We have been able to reproduce the spontaneous pattern of uterine activity prior to water diuresis by the intravenous administration of ADH (Fig. 4). On the other hand, oxytocin administration produces little or no effect (Fig. 5). These results are additional evidence that vasopressin is involved in the control of the menstrual uterus. To show that the response to water overload is different, depending upon the function the uterus is performing. we have compared these results with our previous studiesi3s 24 on uterine contractility during pregnancy and labor under water diuresis. Fig. 6 shows that water overload inhibits only the menstrual uterus but does not modify the activity of the term pregnant uterus and does not inhibit its increased contractility during labor. Such marked differences during water diuresis suggest that there is a relationship between ADH and the other regulating hormones of myometrial activity, depending on the phases of the uterus. As we have discussed elsewhere,24 increasing uterine activity during labor occurs simultaneously with a high antidiuretic activity, even when experimental water overload is equal to that used during pregnancy or menstruation, suggesting that ADH release is so high that it does not allow water diuresis to occur
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2. Cibils, L. A.: Contractility of the nonpregnant uterus, Obstet. Gynecol. 30: 441, 1967. 3. Knaus. H. H.: Eine neue method zun Bestimmung des Ovulationstermines, 4. Coutinho, E. M.:
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I
WATER
uterine
motility
319
OVERLOAD
UTERINE ACTIVITY (Irf
1
Fig. 6. Uterine effect of water overload during menstruation, term pregnancy, and labor. For explanation see text.
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Copyright
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