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Low oxytocin secretion in diabetes insipidus associated with normal labor
Low oxytocin secretion in diabetes insipidus associated with normal labor EDGARD
COBO,
MATILDE
DE
EDUARDO Cali,
M.D. BERNAL,
GAITAN,
M.D. M.D.
Colombia
A 35-year-old woman with diabetes insipidus of 23 years’ duration was studied by recording uterine and milk-ejecting activities. Observed mammary gland hypersensitivity to exogenous oxytocin suggests that this woman had low levels of endogenous oxytocin but was able to function normally because of end-organ adaptation and hyperreactivity to oxytocin. Despite this, normal labor occurred. Uterine activity was in the low normal range, but the uterus was not hyperreactive to exogenous oxytocin. This suggests that other factors were producing a normal labor in this patient.
o F diabetes insipidus EFFECT (DI) on oxytocin secretion is still not clearly known. Limitations in methods of measuring oxytocin, lack of knowledge about its physiologic role, and absence of conspicuous clinical manifestations have made this question difficult to answer. The coexistence of DI and pregnancy is uncommon; there are about 60 cases reported in the literature. Reports dealt mostly with clinical symptoms, vasopressin requirements, clinical course of labor, and variations of the condition during pregnancy and lactation.1-8 Milk ejection, one of the unique physiologic processes associated with pregnancy, is known to depend on oxytocin release. Thus, the coexistence of pregnancy and DI pro-
vides a hitherto unutilized opportunity to ask the following question: Does the oxytocin-controlled milk ejection of a patient with DI suggest a low production of oxytocin? In a previous report, we have suggested that normal labor is not initiated and controlled only by oxytocin release.Q* lo This leads us to ask another question about the patient with DI: If endogenous oxytocin indeed seems low in the DI patient, does the uterine activity and its response to exogenous oxytocin suggest uterine control during labor by some other means? The use of appropriate, innocuous, and sensitive technique of detecting changes in intrauterine12 and intramammary pressurel’ in human beings has permitted us to try to answer the above-mentioned questions. This paper describes the results obtained in a patient with DI by recording uterine milkejecting, and antidiuretic activities during 3 lactational periods and 2 spontaneous labors.
THE
From the Unit of Physiology of Reproduction, Section of Endocrinology, Facultad de Medicina. This study was supported in part Grant GA-MNS 6463 from the Rockefeller Foundation. Received
for
publication
April
by the
7, 1972.
Case
Accepted for publication July 12, 1972. Reprint requests: Dr. E. Cobo, Laboratorio de Fisiologia de la Reproduction, Departamento de Obstetricia and Ginecologia, Apartados Aereo 2188, Cali, Colombia.
repoti
The patient, a 35-year-old Caucasian woman (gravida 9, para 6, abortions 3), was first seen in the Endocrine Section at the University Hospital in September, 1959, because of lower back
861
862
Cobo,
de
Bernal,
and
NORMAL +18 _
December 1, 197: Am. J. Obstet. (:ynewl
Gaitan
D.I.
NORMAL -
t
48
700
t
D.I. *.
-
700
'$
-
t-t
:
f
t-1
[ul osm mCS.m/Kg L--.
w-CC,&.
9-d
b-***.* 0
3
30min NICOTINE, NORMAL
lmg.
I.V.
I TILTING I
D.I.
NORMAL
D.I.
Fig. 1. Antidiuretic activity after different stimuli in a normal woman and in the patient with DI. In the upper left a normal response to exogenous ADH (Pitressin) was observed in both cases, demonstrating a normal renal handling of water. Hypertonic saline, nicotine, and tilting Failed to induce antidiuresis in the DI patient, demonstrating a slightly impaired ADH secretion.
pain, malaise, fever, and hematuria. She had this problem intermittently during the previous 6 months. The patient also complained of marked-pblydipsia and polyuria since the age of 12 years, which she claims began immediately after head trauma with loss of consciousness. In 1959, different tests were carried out in order to explore neurohypophyseal function. After nicotine, acetylcholine, and hypertonic saline administration, the urine remained hypotonic. The same results were obtained by dehydration and tilting. In addition, 15 mu. of Pitressin” constantly produced hypertonic urine, demonstrating a normal tubular handling of water. On the above-mentioned basis, the diagnosis of complete
diabetes insipidus was established. Fig. 1 summarizes some of the diagnostic tests performed on this patient. Spontaneous term labor occurred in all of her pregnancies. The fourth labor resulted in a dead fetus and was complicated by severe intra-amniotic infection. One of the 3 abortions was a hydatidiform mole. Two different labors (1964 and 1966) were studied in our laboratory by simultaneous recording of uterine, milk-ejecting, *Parke,
Davis
& Co.,
Detroit,
Michigan.
and antidiuretic activities. During early lactation (3 to 8 days post partum), milk-ejecting and antidiuretic activities were studied again. Methods Milk-ejecting ing mary
one
activity
polyethylene duct
according
was
studied
catheter to
into the
by the
method
placmamde-
scribed by Sica-Blanc0 and associates.11 Records of milk-ejecting activity were obtained over a 0 to 25 mm. Hg scale at a paper speed of 1 cm. per minute. The area under the curves representing mammary contractions was measured with a compensating polar planimeter and expressed in square millimeters. Uterine activity was studied by continuously recording amniotic fluid pressure.12 Under local anesthesia and with a rigorous aseptic technique, a transabdominal puncture of the amniotic cavity was performed, and a thin polyvinyl catheter filled with water was introduced. This catheter was connected to a pressure transducer coupled to an amplifier system and a recording gal-
Low
vanometer as previously described.13 Pressure was recorded over a 0 to 100 mm. Hg scale, and the paper speed was again 1 cm. per minute. The area under uterine contractions was expressed in square millimeters per minute. For the study of antidiuretic activity, a constant water load (20 ml. per kilogram of body weight) was given intravenously throughout the whole first recorded labor as 5 per cent dextrose in water starting after one hour of uterine and mammary gland recordings. The infusion rate was changed after each urine sample collection to compensate for the rate of urinary flow; in this way, a constant water load was maintained. In the second recorded labor, no water overload was given. In all the studies, urine was collected with a three-way Foley catheter, and samples were taken at 15 to 60 minute intervals. Prior to taking each sample complete emptying of the bladder was assured by introduction of 100 to 150 C.C. of air and by suprapubic manual compression. Serum samples were obtained before and during overhydration. Osmolality and creatinine concentration in blood and urine were measured and expressed in milliosmols per kilogram of solution and milligrams per cent, respectively. Creatinine, osmolal, and free water clearances were calculated13 and expressed in milliliters per minute. Antidiuretic activity was assumed to exist when urine was hyperosmolal to plasma, with a low free water clearance (Cnzo) in absence of sustained variations in glomerular filtration rate (GFR) solute excretion (Cosm) during and/or water diuresis. Synthetic oxytocin” was administered in single intravenous injections in order to determine both uterine and mammary gland sensitivity to this hormone. Uterine response was tested by administering a dose of 50 mu., and mammary gland responses were tested with doses of 1, 2, 5, and 10 mu. Both target organ responses were compared with the values obtained in normal subjects.14 “Syntocinon,
supplied
by Sandoz,
S. A.
oxytocin
in diabetes
insipidus
863
Fig. 2. Milk ejection evoked by different stimuli in a patient with DI. Top, Instrumental dilatation of one mammary duct induces one mammary contraction, which was matched to 1 mu. of oxytocin. Bottom, Baby’s suckling evokes a normally shaped mammary response. The amount of oxytocin required to equal this response was 11.5 mu. of oxytocin, the lowest we have used in this kind of experiment.
Results Milk-ejecting activity. During the 3 different postpartum periods in which we recorded mammary gland activity, the responses obtained were similar. Responses to stimuli capable of releasing oxytocin, such as instrumental mammary duct dilatationI and baby’s suckling, were similar to responses obtained in normal subjects (Fig. 2). The area under mammary contractions evoked by suckling was in the limits of 1,200 mm.’ in the 3 times we recorded it, a figure similar to control values (Fig. 3, left). The administration of different single doses of exogenous oxytocin resulted in the highest rcsponse we have recorded (Fig. 4). Low doses such as 2 mu. produced 2 mammary contractions, a finding usually observed as a response to 10 to 20 mu. This high sensitivity of the mammary myoepithelium may have maintained normal milk ejection despite low endogenous oxytocin levels. This suggested the idea of calibrating myoepi-
864
Cobo,
de
Bernal,
MILK-EJECTING ACTIVITY 3000
and
December I, 19i2 Am. J. Obstet. Gynrcol.
Gaitan
MATCHING OOSE OF OXVTOCIN
- 200
wm
0
2000
- 150
0 0
-
00” 00 00 00 0
AREA mm*
% 00
1.000 -
8
- 100
-
DOSE mll
50
0%
-0
0‘
Fig. 3. Absolute values of milk-ejecting activity (left) and estimated amount of oxytocin (right) by baby’s suckling in normal women (circles) and in the patient with DI (filled circles). Note the very low amounts of oxytocin required to equal normal milk-ejection activity.
‘0°/ MILK-EJECTING ACTIVITY
nun2
OXVTOCIN i7”
Fig. 4. Dose-effect relationship during lactation obtained in 16 normal women (0) compared with the DI patient (0). The dotted area represents the range of normal responses. The effect produced by exogenous oxytocin in the DI patient is the highest we have observed in more than 100 recordings.
thelial response to exogenous oxytocin blood levels. We reasoned that the exogenous dose which produced activities milk-ejection equal to normal could serve as an estimate of the endogenous release which is actually controlling the patient’s myoepithelium. The results of these experiments are displayed in Figs. 2 and 3. We estimate that the patient released 15 mu. of oxytocin, while similar experiments with control subjects suggest
a much higher release, ranging from 40 to 180 mu. Labor. Spontaneous uterine activity showed a closely similar pattern in the 2 labors recorded. Fig. 5 shows parts of an original record of amniotic fluid pressure obtained during labor. It can be observed that during the advanced first stage of labor, when cervical dilatation was 8 cm., a normal contraction intensity (about 30 mm. Hg) and a low contraction frequency (2 in 10 minutes) were found. During the second stage of labor, uterine activity increased in a normal fashion. Comparison between mean values
of uterine
activity
obtained
in
normal
labors and those obtained in our patient with DI, showed that the latter fell into the low normal range (Fig. 6). The similarity persists even when the patient is compared only to women of the same parity. Thus, uterine activity during labor in the DI patient can be considered normal. In the 2 labors which we recorded, the duration
was
tion
progressed
about
6 hours. as
in
The normal
cervical subjects,
dilataand
the neonates were clinically normal. Finally, no differences were observed in the uterine contraction pattern when labor occurred under water overload. Uterine responses to a single dose of 50 mu. of oxytocin administered at the beginning of labor to the patient with DI were similar to those obtained in normal women (Fig. 7). Comment DI constitutes a “natural” experiment characterized by a deficiency of antidiuretic hormone (ADH) production. Since some similarities between ADH and oxytocin have been stressed, it seems to be important to explore oxytocin production when the disease is associated with pregnancy and lactation. The estimation of the amount of oxytocin released by infant suckling, obtained by matching the induced milk-ejecting activity produced by the stimulus with known amounts of exogenous oxytocin, demonstrates a release of about 15 mu., which is defynitely low. Normal women released from 3
Volume Number
114 7
Low
Fig.
5. Recording
of uterine
activity
during
labor
oxytocin
in diabetes
in a patient
with
“TERlNE DURING
RESPONSE PRELABOR
insipidus
865
DI.
TO OXYTOCtN AND LABOR
SPONTANEOUS
INDUCED
UTERINE ACTlYlTY
m&min
UTERlNE ACTWTY
m&m!”
Fig. 6. Mean values for uterine activity in 22 normal women (circles) compared with values obtained in the 2 different labors recorded in the patient DI with (triangles). The dotted area
represents the range of normal
values.
to 12 times more oxytocin during baby’s suckling. This fact suggests the existence of a neurohypophyseal insufficiency comprising both oxytocin and ADH production in our patient with DI. Despite a low oxytocin release, neither abnormal uterine action nor uterine hyperreactivity to exogenous oxytocin was recorded in our patient. Moreover, the clinical evolution of labors as well as the health of the newborn infants were strictly normal. This observation suggests that factors other than oxytocin appeared to mediate
Fig. 7. Uterine response to a single of oxytocin during prelabor and
dose (50 mu.) labor in term
normal pregnant women (0) compared with that of the patient with DI (0). The increases of uterine activity induced in the DI patient fall responses.
by 50 mu. of oxytocin into the range of normal
labor in this patient. This finding is in agreement with the previous suggestion that other biologically occurring substances and mechanisms besides oxytocin are responsible for uterine activation during human labor.gy lo Results obtained in animals in which DI was experimentally produced are controversial, some of them reporting different degrees
866
Cobo,
de
Bernal,
and
December 1, 1972 .4m. J. Obstet. Gynecol.
Gaitan
of impairment of labor.16, I7 Nevertheless, among reports* of DI in pregnant women, one patient has been observed to have proIonged labors and uterine inertia. No other such difficulties reported case+ ti indicate were encountered. Moreover, normal uterine activity and progress of cervical dilatation were observed in a patient with Dl’*; in the above-mentioned patient, the ability to release oxyticin was also found to be much
REFERENCES
A.: Br. Med. J. 2: 769, 1947. A. C., and Robbins, J.: J. Clin. Endocrinol. 7: 753, 1947.
1. Maraiion, 2. Carter, 3. 4. 5. 6. 7. 8. 9. 10.
Eglin, J, M., Jr., and Jessiman, A. G.: J. Clin. Endocrinol. 19: 369, 1959. Warren, J. Cl., and Jernstrom, R. S.: A&r. J. OBSTET. GYNECOL. 81: 1036, 1961. Coggins, C. H., and Leaf, A.: Am. J. Med. 42: 807, 1967. Stephens, 0. C., and Hayes, 0. J.: Obstet. Gynecol. 31: 79, 1968. Pica, I., and Greenblatt, R. B.: Fertil. Steril. 20: 384, 1969. Whalley, P. J., Roberts, A. D., and Pritchard, J. A.: J. Lab. Clin. Med. 58: 867, 1961. Cobo, E.: J. Appl. Physiol. 24: 317, 1968. Cobo, E.: de Bernal, M., Quintero, C. A., and Cuadrado, E.: AM. J. OBSTET. GYNECOI.. 101:
11.
479,
1968.
Sica-Blanco,
Cabot,
Y.,
H.
M.,
Mendez-Bauer,
and
C.,
Sala,
Caldeyro-Barcia,
M., R.:
lower than that in normal women.‘s~ I9 Finally, it must be stressed that milk ejection occurred in our patient by an increase of the myoepithehal cells’ sensitivity to oxytocin, in a way resembling a compensatory response of the target organ. Therefore, it must be concluded that milk ejection as well as uterine contractions during labor may occur in the presence of a low production of neurohypophyseal hormones.
Arch. Uruguayos GineroI. Obstet. 17: 6X. 1959. 12. Alvarez, H., and Caldeyro-Barcia, R.: Surg. Gynecol. Obstet. 91: 1, 1950. 13. Cobo, E., Gait+ E., Mizrachi, M., and Strada, G.: AM. J. OBSTET. G~NECOI.. 91: 905, 1965. 14. Cobo, E., and Quintero, C. .4.: AILI. J. OBSTET. GYNECOL. 105: 877. 1969. 15. Cobo, E., de Bernal, M., Gaitan, E., and Quintero, C. A.: AM. J. OBSTET. GYNECOI.. 97: 519. 1967. 16. Dey, F.’ L., Fisher, C., and Ranson, S. W.: Arx. J. OBSTET. GYNECOL. 42: 459, 1941. 17. Fisher, C., Magoun, H. W.. and Ranson. S. W.: AM. J. OBSTET. GYNECOL. 36: I, 1938. 18. Fielitz, C. A., Cabot, H. J., Brovetto, J., and Coch, J. A.; IV Congr. Uruguayo de Ginecotocologia 2: 614, 1964. 19. Branda, L. A., Fielitz, C. .4.. and Rota. R.: Ann. Meet. R. COB. Physicians Surg. Can. Jan., 1970.
COBO,
MATILDE
DE
EDUARDO Cali,
M.D. BERNAL,
GAITAN,
M.D. M.D.
Colombia
A 35-year-old woman with diabetes insipidus of 23 years’ duration was studied by recording uterine and milk-ejecting activities. Observed mammary gland hypersensitivity to exogenous oxytocin suggests that this woman had low levels of endogenous oxytocin but was able to function normally because of end-organ adaptation and hyperreactivity to oxytocin. Despite this, normal labor occurred. Uterine activity was in the low normal range, but the uterus was not hyperreactive to exogenous oxytocin. This suggests that other factors were producing a normal labor in this patient.
o F diabetes insipidus EFFECT (DI) on oxytocin secretion is still not clearly known. Limitations in methods of measuring oxytocin, lack of knowledge about its physiologic role, and absence of conspicuous clinical manifestations have made this question difficult to answer. The coexistence of DI and pregnancy is uncommon; there are about 60 cases reported in the literature. Reports dealt mostly with clinical symptoms, vasopressin requirements, clinical course of labor, and variations of the condition during pregnancy and lactation.1-8 Milk ejection, one of the unique physiologic processes associated with pregnancy, is known to depend on oxytocin release. Thus, the coexistence of pregnancy and DI pro-
vides a hitherto unutilized opportunity to ask the following question: Does the oxytocin-controlled milk ejection of a patient with DI suggest a low production of oxytocin? In a previous report, we have suggested that normal labor is not initiated and controlled only by oxytocin release.Q* lo This leads us to ask another question about the patient with DI: If endogenous oxytocin indeed seems low in the DI patient, does the uterine activity and its response to exogenous oxytocin suggest uterine control during labor by some other means? The use of appropriate, innocuous, and sensitive technique of detecting changes in intrauterine12 and intramammary pressurel’ in human beings has permitted us to try to answer the above-mentioned questions. This paper describes the results obtained in a patient with DI by recording uterine milkejecting, and antidiuretic activities during 3 lactational periods and 2 spontaneous labors.
THE
From the Unit of Physiology of Reproduction, Section of Endocrinology, Facultad de Medicina. This study was supported in part Grant GA-MNS 6463 from the Rockefeller Foundation. Received
for
publication
April
by the
7, 1972.
Case
Accepted for publication July 12, 1972. Reprint requests: Dr. E. Cobo, Laboratorio de Fisiologia de la Reproduction, Departamento de Obstetricia and Ginecologia, Apartados Aereo 2188, Cali, Colombia.
repoti
The patient, a 35-year-old Caucasian woman (gravida 9, para 6, abortions 3), was first seen in the Endocrine Section at the University Hospital in September, 1959, because of lower back
861
862
Cobo,
de
Bernal,
and
NORMAL +18 _
December 1, 197: Am. J. Obstet. (:ynewl
Gaitan
D.I.
NORMAL -
t
48
700
t
D.I. *.
-
700
'$
-
t-t
:
f
t-1
[ul osm mCS.m/Kg L--.
w-CC,&.
9-d
b-***.* 0
3
30min NICOTINE, NORMAL
lmg.
I.V.
I TILTING I
D.I.
NORMAL
D.I.
Fig. 1. Antidiuretic activity after different stimuli in a normal woman and in the patient with DI. In the upper left a normal response to exogenous ADH (Pitressin) was observed in both cases, demonstrating a normal renal handling of water. Hypertonic saline, nicotine, and tilting Failed to induce antidiuresis in the DI patient, demonstrating a slightly impaired ADH secretion.
pain, malaise, fever, and hematuria. She had this problem intermittently during the previous 6 months. The patient also complained of marked-pblydipsia and polyuria since the age of 12 years, which she claims began immediately after head trauma with loss of consciousness. In 1959, different tests were carried out in order to explore neurohypophyseal function. After nicotine, acetylcholine, and hypertonic saline administration, the urine remained hypotonic. The same results were obtained by dehydration and tilting. In addition, 15 mu. of Pitressin” constantly produced hypertonic urine, demonstrating a normal tubular handling of water. On the above-mentioned basis, the diagnosis of complete
diabetes insipidus was established. Fig. 1 summarizes some of the diagnostic tests performed on this patient. Spontaneous term labor occurred in all of her pregnancies. The fourth labor resulted in a dead fetus and was complicated by severe intra-amniotic infection. One of the 3 abortions was a hydatidiform mole. Two different labors (1964 and 1966) were studied in our laboratory by simultaneous recording of uterine, milk-ejecting, *Parke,
Davis
& Co.,
Detroit,
Michigan.
and antidiuretic activities. During early lactation (3 to 8 days post partum), milk-ejecting and antidiuretic activities were studied again. Methods Milk-ejecting ing mary
one
activity
polyethylene duct
according
was
studied
catheter to
into the
by the
method
placmamde-
scribed by Sica-Blanc0 and associates.11 Records of milk-ejecting activity were obtained over a 0 to 25 mm. Hg scale at a paper speed of 1 cm. per minute. The area under the curves representing mammary contractions was measured with a compensating polar planimeter and expressed in square millimeters. Uterine activity was studied by continuously recording amniotic fluid pressure.12 Under local anesthesia and with a rigorous aseptic technique, a transabdominal puncture of the amniotic cavity was performed, and a thin polyvinyl catheter filled with water was introduced. This catheter was connected to a pressure transducer coupled to an amplifier system and a recording gal-
Low
vanometer as previously described.13 Pressure was recorded over a 0 to 100 mm. Hg scale, and the paper speed was again 1 cm. per minute. The area under uterine contractions was expressed in square millimeters per minute. For the study of antidiuretic activity, a constant water load (20 ml. per kilogram of body weight) was given intravenously throughout the whole first recorded labor as 5 per cent dextrose in water starting after one hour of uterine and mammary gland recordings. The infusion rate was changed after each urine sample collection to compensate for the rate of urinary flow; in this way, a constant water load was maintained. In the second recorded labor, no water overload was given. In all the studies, urine was collected with a three-way Foley catheter, and samples were taken at 15 to 60 minute intervals. Prior to taking each sample complete emptying of the bladder was assured by introduction of 100 to 150 C.C. of air and by suprapubic manual compression. Serum samples were obtained before and during overhydration. Osmolality and creatinine concentration in blood and urine were measured and expressed in milliosmols per kilogram of solution and milligrams per cent, respectively. Creatinine, osmolal, and free water clearances were calculated13 and expressed in milliliters per minute. Antidiuretic activity was assumed to exist when urine was hyperosmolal to plasma, with a low free water clearance (Cnzo) in absence of sustained variations in glomerular filtration rate (GFR) solute excretion (Cosm) during and/or water diuresis. Synthetic oxytocin” was administered in single intravenous injections in order to determine both uterine and mammary gland sensitivity to this hormone. Uterine response was tested by administering a dose of 50 mu., and mammary gland responses were tested with doses of 1, 2, 5, and 10 mu. Both target organ responses were compared with the values obtained in normal subjects.14 “Syntocinon,
supplied
by Sandoz,
S. A.
oxytocin
in diabetes
insipidus
863
Fig. 2. Milk ejection evoked by different stimuli in a patient with DI. Top, Instrumental dilatation of one mammary duct induces one mammary contraction, which was matched to 1 mu. of oxytocin. Bottom, Baby’s suckling evokes a normally shaped mammary response. The amount of oxytocin required to equal this response was 11.5 mu. of oxytocin, the lowest we have used in this kind of experiment.
Results Milk-ejecting activity. During the 3 different postpartum periods in which we recorded mammary gland activity, the responses obtained were similar. Responses to stimuli capable of releasing oxytocin, such as instrumental mammary duct dilatationI and baby’s suckling, were similar to responses obtained in normal subjects (Fig. 2). The area under mammary contractions evoked by suckling was in the limits of 1,200 mm.’ in the 3 times we recorded it, a figure similar to control values (Fig. 3, left). The administration of different single doses of exogenous oxytocin resulted in the highest rcsponse we have recorded (Fig. 4). Low doses such as 2 mu. produced 2 mammary contractions, a finding usually observed as a response to 10 to 20 mu. This high sensitivity of the mammary myoepithelium may have maintained normal milk ejection despite low endogenous oxytocin levels. This suggested the idea of calibrating myoepi-
864
Cobo,
de
Bernal,
MILK-EJECTING ACTIVITY 3000
and
December I, 19i2 Am. J. Obstet. Gynrcol.
Gaitan
MATCHING OOSE OF OXVTOCIN
- 200
wm
0
2000
- 150
0 0
-
00” 00 00 00 0
AREA mm*
% 00
1.000 -
8
- 100
-
DOSE mll
50
0%
-0
0‘
Fig. 3. Absolute values of milk-ejecting activity (left) and estimated amount of oxytocin (right) by baby’s suckling in normal women (circles) and in the patient with DI (filled circles). Note the very low amounts of oxytocin required to equal normal milk-ejection activity.
‘0°/ MILK-EJECTING ACTIVITY
nun2
OXVTOCIN i7”
Fig. 4. Dose-effect relationship during lactation obtained in 16 normal women (0) compared with the DI patient (0). The dotted area represents the range of normal responses. The effect produced by exogenous oxytocin in the DI patient is the highest we have observed in more than 100 recordings.
thelial response to exogenous oxytocin blood levels. We reasoned that the exogenous dose which produced activities milk-ejection equal to normal could serve as an estimate of the endogenous release which is actually controlling the patient’s myoepithelium. The results of these experiments are displayed in Figs. 2 and 3. We estimate that the patient released 15 mu. of oxytocin, while similar experiments with control subjects suggest
a much higher release, ranging from 40 to 180 mu. Labor. Spontaneous uterine activity showed a closely similar pattern in the 2 labors recorded. Fig. 5 shows parts of an original record of amniotic fluid pressure obtained during labor. It can be observed that during the advanced first stage of labor, when cervical dilatation was 8 cm., a normal contraction intensity (about 30 mm. Hg) and a low contraction frequency (2 in 10 minutes) were found. During the second stage of labor, uterine activity increased in a normal fashion. Comparison between mean values
of uterine
activity
obtained
in
normal
labors and those obtained in our patient with DI, showed that the latter fell into the low normal range (Fig. 6). The similarity persists even when the patient is compared only to women of the same parity. Thus, uterine activity during labor in the DI patient can be considered normal. In the 2 labors which we recorded, the duration
was
tion
progressed
about
6 hours. as
in
The normal
cervical subjects,
dilataand
the neonates were clinically normal. Finally, no differences were observed in the uterine contraction pattern when labor occurred under water overload. Uterine responses to a single dose of 50 mu. of oxytocin administered at the beginning of labor to the patient with DI were similar to those obtained in normal women (Fig. 7). Comment DI constitutes a “natural” experiment characterized by a deficiency of antidiuretic hormone (ADH) production. Since some similarities between ADH and oxytocin have been stressed, it seems to be important to explore oxytocin production when the disease is associated with pregnancy and lactation. The estimation of the amount of oxytocin released by infant suckling, obtained by matching the induced milk-ejecting activity produced by the stimulus with known amounts of exogenous oxytocin, demonstrates a release of about 15 mu., which is defynitely low. Normal women released from 3
Volume Number
114 7
Low
Fig.
5. Recording
of uterine
activity
during
labor
oxytocin
in diabetes
in a patient
with
“TERlNE DURING
RESPONSE PRELABOR
insipidus
865
DI.
TO OXYTOCtN AND LABOR
SPONTANEOUS
INDUCED
UTERINE ACTlYlTY
m&min
UTERlNE ACTWTY
m&m!”
Fig. 6. Mean values for uterine activity in 22 normal women (circles) compared with values obtained in the 2 different labors recorded in the patient DI with (triangles). The dotted area
represents the range of normal
values.
to 12 times more oxytocin during baby’s suckling. This fact suggests the existence of a neurohypophyseal insufficiency comprising both oxytocin and ADH production in our patient with DI. Despite a low oxytocin release, neither abnormal uterine action nor uterine hyperreactivity to exogenous oxytocin was recorded in our patient. Moreover, the clinical evolution of labors as well as the health of the newborn infants were strictly normal. This observation suggests that factors other than oxytocin appeared to mediate
Fig. 7. Uterine response to a single of oxytocin during prelabor and
dose (50 mu.) labor in term
normal pregnant women (0) compared with that of the patient with DI (0). The increases of uterine activity induced in the DI patient fall responses.
by 50 mu. of oxytocin into the range of normal
labor in this patient. This finding is in agreement with the previous suggestion that other biologically occurring substances and mechanisms besides oxytocin are responsible for uterine activation during human labor.gy lo Results obtained in animals in which DI was experimentally produced are controversial, some of them reporting different degrees
866
Cobo,
de
Bernal,
and
December 1, 1972 .4m. J. Obstet. Gynecol.
Gaitan
of impairment of labor.16, I7 Nevertheless, among reports* of DI in pregnant women, one patient has been observed to have proIonged labors and uterine inertia. No other such difficulties reported case+ ti indicate were encountered. Moreover, normal uterine activity and progress of cervical dilatation were observed in a patient with Dl’*; in the above-mentioned patient, the ability to release oxyticin was also found to be much
REFERENCES
A.: Br. Med. J. 2: 769, 1947. A. C., and Robbins, J.: J. Clin. Endocrinol. 7: 753, 1947.
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