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Prolactin and the renin-aldosterone axis in human pregnancy
Prolactin and the renin-aldosterone axis in human pregnancy BASIL HO YUEN, F.R.C.S.(C.) GERALD W. KORN, F.R.C.S.(C.) Vancouver, British Columbia, Canada !n view of observations suggesting an osmo~egu!ator-1 rote for prolactin (PAL) and the centra! rofe of the renin-aldosterone system in the regulation of pressure-volume homeostasis, this study was undertaken to determine whether acute drug-induced alterations in circulating PAL had any effect on mean arterial blood pressure (MAP), serum osmolality, and the renin-aldosterone response during early pregnancy. Bromocriptine suppressed mean baseline PAL by 83% (p > 0.05), whereas chlorpromazine increased it more than twofold (p < 0.05) during a 180-minute study period. MAP, mean serum osmolality, plasma renin activity, and aldosterone concentrations were hot significantly different from mean baseline values after the administration of either drug. These data suggest that, during early pregnancy, the renin-aldosterone axis is independent of PAL and resistant to the beta-adrenergic agonist effect of chlorpromaz;ne. (AM. J. OBSTET. GYNECOL. 138:738, 1980.)
PROLACTIN (PRL) may be involved in 'the control of fluid exchange across the amniotic membrane.L 2 Estradiol and testosterone affect specific PRL binding in the kidneys and adrenal glands, thus suggesting that gonadal steroids participate in the PRL osmoregulatory system in the rat. 3 PRL receptors are present in the ependyma of the rat choroid plexus, thus suggesting involvement of PRL in the composition of cerebrospinal fluid. 4 Disordered secretion of PRL has also been described in disturbances of fluid and electrolyte metabolism associated with ovulation, 5 • 6 hypertensive disorders of pregnancy/ and congestive heart failure. 8 In view of these observations and the central role of the renin-aldosterone system in the regulation of pressure-volume homeostasis, this study was undertaken to determine whether acute drug-induced alterations in circulating PRL had any effects on arterial blood pressure, serum osmolality, and the renin-aldosterone response during pregnancy. From the Gynaecologic Endocrine Laboratory and the Department of Obstetrics an,d Gynaecology, University of British Columbia. This study was supported by a grant awarded to Dr. Ho Yuen by The British Columbia Heart Foundation. Received for publication April 24, 1980. Revisedjuly 15, 1980. Accepted August 4, 1980. Reprint requests: Dr. B. Ho Yuen, Department of Obstetrics and Gynaecology, Willow Pavilion, First Floor, Vancouver General Hospital, Vancouver, British Columbia, Canada V5Z 1M9.
738
Material and methods The five women receiving bromocriptine (5 mg orally) had a mean age of 21.4 years (range, 19 to 23 years) and mean gestational age of 13 weeks (range, 9.5 to 18.5 weeks). The five women receiving chlorpromazine (50 mg intramuscularly) had a mean age of 20.4 years (range, 19 to 23 years) and mean gestational age of 12.7 weeks (range, 9.5 to 17.7 weeks). All subjects who were later to have therapeutic abortions gave informed consent, were free of dietary restrictions, were not receiving medications, and were free of physical signs of disease. All studies were conducted in hospital, commencing between 0700 and 0900 hours, with the subjects in the supine position and having received nothing by mouth from midnight until completion of the study. The drugs were administered by the routes stated earlier, immediately after the second zero time sampie was obtained through an indweiiing cannuia placed in an antecubital vein. Zero time data were a mean of two sampies obtained 15 minutes apart. Plasma renin activity (PRA) was assayed by the technique of Haber and associates 9 (Dr. G. E. Wilkins, St. Paul's Hospital, Vancouver, British Columbia, Canada), and aldosterone was measured by radioimmunoassay (London Biochemical Reference Laboratory, London, Ontario, Canada). PRL was measured by radioimmunoassay, and the PRL data were previously reported. 10 Mean arterial blood pressure (MAP) = systolic BP + (diastolic BP X 2) mm Hg. Serum os3 molality was measured by the Division of Clinical 0002-9378/80/230738+03$00,30/0
©
1980 The C V, Mosby Co.
PAL and renin-aldosterone axis
Volume 138 ~umber 7. Pan I
Chemistry, Department of Pathology, Vancouver General Hospital. Data were analyzed by one-way analysis of variance for overall statistical significance, and the mean from each sampling interval was compared to that of the baseline, with the use of Dunnett's test as described by Winer. 11 Results
The results are shown in Fig. 1. After bromocriptine, mean baseline PRL concentrations declined from 60 ± 24 (SEM) ng/ml to 10 ± 3 ng/ml, 17% of baseline. This difference was not significant (p > 0.05). After chlorpromazine, mean PRL was 53± 10 ng/ml, increasing significantly (p < 0.05) between 60 and 120 minutes, with peak values of 124 ± 16 ng/ml at 90 minutes. No significant differences in mean arterial blood pressure, PRA. aldosterone, and serum osmolality were observed after the administration of either bromocriptine or chlorpromazine.
ng ml
739
Plasma Prolactin
160 120
80
40 0 mm Hg
Mean Artenal Pressure
80 76 72
68 64 ng / ml hr
Plasma Ren1n Activ1ty
8 Comment
During early human pregnancy, marked drug-induced alterations in maternal PRL concentrations failed to alter MAP, serum osmolality, or the reninaldosterone system over a 3-hour study interval. In contrast to the nonpregnant state, 12 chlorpromazine failed to significantly affect the renin-aldosterone axis during early pregnancy. The mean level of PRA (but not of aldosterone) was higher after chlorpromazine; at 180 minutes. it was 65% above baseline, but this was statistically not significant. The ability of chlorpromazine to stimulate increases in circulating PRA and aldosterone in nonpregnant subjects has been attributed to the beta-adrenergic agonist effect of this phenothiazine. 12 • 11 • 15 although other possibilities, including stimulation of PRA by a centrally mediated drug effect on the autonomic nervous system or directly via the adrenal medulla, have not been excluded. 12 In our experiments, twofold to fivefold higher doses of the drug were given intramuscularly, as compared to the doses administered intravenously by Robertson and Michelakis 12 in nonpregnant subjects. The effect of differing routes of administration of chlorpromazine on the results obtained in these studies is not known, and may be of little significance because the clinical effect by either route is immediate, with high levels detected in the blood at 1 hour and maintained for 12 hours after an intramuscular injection of doses that we employed in these experiments. 15 The secretion of aldosterone from the adrenal glomerulosa appears to be under maximal tonic dopaminergic inhibition, via mechanisms independent of the renin-angiotensin system. 13 Bromocriptine is a
6
:llitij
ng / dL
Plasma Aldosterone
:t I u uI
mOsm / kg Water
[liuU ~ illlli
Serum Osmolal1ty
:l tlWJ
0 30 60 90120 180
Minutes Bromocriptine 5 mg PO
0 30 60 90120180
M1nutes Chlorpromazine 50 mg IM
Fig. 1. Plasma prolactin, mean arterial blood pressure, plasma renin activity, plasma aldosterone, and serum osmolality in women receiving bromocriptine (n = 5) and chlorpromazine (n = 5) in doses and routes of administration as nmed. Except for prolactin at 60, 90, and 120 minutes after chlorpromazine (p < 0.05), no significant differences were observed in all other values after either drug.
specific dopaminergic agonist which lowered mean maternal plasma PRL levels to 17% of baseline. However. because of wide variation and a limited number of samples, this suppression was statisticallv not significant. Nevertheless, the drug achieved a reduction in mean PRL levels of 83%, without significantlv affecting
740
Ho Yuen and Korn Arn
MAP, mean serum osmolality, PRA. and aldosterone. This is also compatible with the belief that the maximal tonic dopaminergic inhibition of aldosterone secretion. which is thought to occur in the nonpregnant state, t:l persists during early pregnancy. Our results, taken together with the findings reviewed, suggest that, under the conditions of our experiments performed in early pregnancy, the renin-aldosterone axis is both independent of PRL and resistant to beta-adrenoreceptor stimulation. Augmented urinary excretion of epinephrine and norepinephrine, 16 unaccompanied by increased circulating levels of PRA, angiotensin, and aldosterone 17 in pregnancy-induced hypertension, further suggests that
lkn·mbn I, I ~IHO Obstet. C1 nee nl.
J.
this apparent insensitivity of the renin-aldosterone axis persists during these clinical disorders of late pregnancy. These data, however, do not exclude a longterm effect of altered PRL secretion on the parameter' which we studit..'d, especially when 'it..'X steroid concentrations in plasma are known to be augmented. We wish to thank Miss Wendy Cannon, B.Sc., for expert technical assistance, Miss Suzanne Woolley, R.N., for assistance in data analysis and the clinical aspects of the project, and Mr. A. Nalecz, Sandoz Company, Montreal, Quebec, Canada, f(ll' supplies of bromocriptine.
REFERENCES I. Vizsolyi, E., and Perks, A.M.: Can.J. Zoo!. 52::17 I, 1974. 2. ~fanku, M.D., Matabaji, J. P., and Horrobin, D. F.: Na~
ture 258:78, 1975. :l. Marshall, S., Kledzik, G. S., Galato, M., Campbell, G. A .. and Meites, J.: Steroids 27:187, 1976. 4. Walsh, R. J., Posner, B. 1., and Kopriwa, B. M.: Science 201:1041, 1978. 5. Ho Yu~?n, B., McComb, P., Sy, L., Lewis,]., and Cannon. W.: AM. J. 0BSTET. GYNECOL. 133:316, 1979. 6. Halbreich, U., Ben-David, M., Assael, M., and Bornstein, R.: Lancet 2:654, 1976. 7. Ho Yuen, B., Cannon, W., Woolley, S., and Charles, E.: Br. J. Obstet. Gynaecol. 85:293, 1978. 8. Curtarelli, G., and Ferrari, C.: Thorax 34:328, 1979. 9. Haber, E., Koerner, T., Page, LB., Kliman, B., and Purnode, A.: J. Clin. Endocrinol. Metab. 29:1349, 1969. 10. Ho Yuen, B., Cannon, W., Lewis,]., Sy, L., and Woolley, S.: AM. J. 0BSTET. GY:\ECOL. 136:286, 1980.
II. Winer, B. J .: In Statistical Principles in Experimental De· sign, New York, 1962, McGraw-Hill Book Co., Inc., p. 89. 12. Robertson, D., and Michelakis, A.M.: J. Clin. Endocrinol. Metab.41:1166,1975. 13. Carey, D. M., Thorner, M. 0., and Oru, E. M.:]. Clin. Invest. 63:727, 1979. 14. Webster, R. A.: Br. J. PharmacaL 25:566, 1965. 15. Meyers, F. H.,Jawetz, E., and Goldfein, A.: In Review of Medical Pharmacology, ed. 2. Los Altos, 1970, Lang Medical Publications, chap. 25. 16. Zuspan, F. P.:]. Reprod. Med. 23:143, 1979. 17. Weir, R. J.. Doig, A., Fraser, R., Morton, J .J .. Parboosingh, J., Robertson, J., and Wilson, A.: In Lindheimer, M. D., Katz, A. 1., and Zuspan, F. P., editors: Hypertension in Pregnancy, New York. 1976,.John Wilev & Sons, Inc., p. 251.
PROLACTIN (PRL) may be involved in 'the control of fluid exchange across the amniotic membrane.L 2 Estradiol and testosterone affect specific PRL binding in the kidneys and adrenal glands, thus suggesting that gonadal steroids participate in the PRL osmoregulatory system in the rat. 3 PRL receptors are present in the ependyma of the rat choroid plexus, thus suggesting involvement of PRL in the composition of cerebrospinal fluid. 4 Disordered secretion of PRL has also been described in disturbances of fluid and electrolyte metabolism associated with ovulation, 5 • 6 hypertensive disorders of pregnancy/ and congestive heart failure. 8 In view of these observations and the central role of the renin-aldosterone system in the regulation of pressure-volume homeostasis, this study was undertaken to determine whether acute drug-induced alterations in circulating PRL had any effects on arterial blood pressure, serum osmolality, and the renin-aldosterone response during pregnancy. From the Gynaecologic Endocrine Laboratory and the Department of Obstetrics an,d Gynaecology, University of British Columbia. This study was supported by a grant awarded to Dr. Ho Yuen by The British Columbia Heart Foundation. Received for publication April 24, 1980. Revisedjuly 15, 1980. Accepted August 4, 1980. Reprint requests: Dr. B. Ho Yuen, Department of Obstetrics and Gynaecology, Willow Pavilion, First Floor, Vancouver General Hospital, Vancouver, British Columbia, Canada V5Z 1M9.
738
Material and methods The five women receiving bromocriptine (5 mg orally) had a mean age of 21.4 years (range, 19 to 23 years) and mean gestational age of 13 weeks (range, 9.5 to 18.5 weeks). The five women receiving chlorpromazine (50 mg intramuscularly) had a mean age of 20.4 years (range, 19 to 23 years) and mean gestational age of 12.7 weeks (range, 9.5 to 17.7 weeks). All subjects who were later to have therapeutic abortions gave informed consent, were free of dietary restrictions, were not receiving medications, and were free of physical signs of disease. All studies were conducted in hospital, commencing between 0700 and 0900 hours, with the subjects in the supine position and having received nothing by mouth from midnight until completion of the study. The drugs were administered by the routes stated earlier, immediately after the second zero time sampie was obtained through an indweiiing cannuia placed in an antecubital vein. Zero time data were a mean of two sampies obtained 15 minutes apart. Plasma renin activity (PRA) was assayed by the technique of Haber and associates 9 (Dr. G. E. Wilkins, St. Paul's Hospital, Vancouver, British Columbia, Canada), and aldosterone was measured by radioimmunoassay (London Biochemical Reference Laboratory, London, Ontario, Canada). PRL was measured by radioimmunoassay, and the PRL data were previously reported. 10 Mean arterial blood pressure (MAP) = systolic BP + (diastolic BP X 2) mm Hg. Serum os3 molality was measured by the Division of Clinical 0002-9378/80/230738+03$00,30/0
©
1980 The C V, Mosby Co.
PAL and renin-aldosterone axis
Volume 138 ~umber 7. Pan I
Chemistry, Department of Pathology, Vancouver General Hospital. Data were analyzed by one-way analysis of variance for overall statistical significance, and the mean from each sampling interval was compared to that of the baseline, with the use of Dunnett's test as described by Winer. 11 Results
The results are shown in Fig. 1. After bromocriptine, mean baseline PRL concentrations declined from 60 ± 24 (SEM) ng/ml to 10 ± 3 ng/ml, 17% of baseline. This difference was not significant (p > 0.05). After chlorpromazine, mean PRL was 53± 10 ng/ml, increasing significantly (p < 0.05) between 60 and 120 minutes, with peak values of 124 ± 16 ng/ml at 90 minutes. No significant differences in mean arterial blood pressure, PRA. aldosterone, and serum osmolality were observed after the administration of either bromocriptine or chlorpromazine.
ng ml
739
Plasma Prolactin
160 120
80
40 0 mm Hg
Mean Artenal Pressure
80 76 72
68 64 ng / ml hr
Plasma Ren1n Activ1ty
8 Comment
During early human pregnancy, marked drug-induced alterations in maternal PRL concentrations failed to alter MAP, serum osmolality, or the reninaldosterone system over a 3-hour study interval. In contrast to the nonpregnant state, 12 chlorpromazine failed to significantly affect the renin-aldosterone axis during early pregnancy. The mean level of PRA (but not of aldosterone) was higher after chlorpromazine; at 180 minutes. it was 65% above baseline, but this was statistically not significant. The ability of chlorpromazine to stimulate increases in circulating PRA and aldosterone in nonpregnant subjects has been attributed to the beta-adrenergic agonist effect of this phenothiazine. 12 • 11 • 15 although other possibilities, including stimulation of PRA by a centrally mediated drug effect on the autonomic nervous system or directly via the adrenal medulla, have not been excluded. 12 In our experiments, twofold to fivefold higher doses of the drug were given intramuscularly, as compared to the doses administered intravenously by Robertson and Michelakis 12 in nonpregnant subjects. The effect of differing routes of administration of chlorpromazine on the results obtained in these studies is not known, and may be of little significance because the clinical effect by either route is immediate, with high levels detected in the blood at 1 hour and maintained for 12 hours after an intramuscular injection of doses that we employed in these experiments. 15 The secretion of aldosterone from the adrenal glomerulosa appears to be under maximal tonic dopaminergic inhibition, via mechanisms independent of the renin-angiotensin system. 13 Bromocriptine is a
6
:llitij
ng / dL
Plasma Aldosterone
:t I u uI
mOsm / kg Water
[liuU ~ illlli
Serum Osmolal1ty
:l tlWJ
0 30 60 90120 180
Minutes Bromocriptine 5 mg PO
0 30 60 90120180
M1nutes Chlorpromazine 50 mg IM
Fig. 1. Plasma prolactin, mean arterial blood pressure, plasma renin activity, plasma aldosterone, and serum osmolality in women receiving bromocriptine (n = 5) and chlorpromazine (n = 5) in doses and routes of administration as nmed. Except for prolactin at 60, 90, and 120 minutes after chlorpromazine (p < 0.05), no significant differences were observed in all other values after either drug.
specific dopaminergic agonist which lowered mean maternal plasma PRL levels to 17% of baseline. However. because of wide variation and a limited number of samples, this suppression was statisticallv not significant. Nevertheless, the drug achieved a reduction in mean PRL levels of 83%, without significantlv affecting
740
Ho Yuen and Korn Arn
MAP, mean serum osmolality, PRA. and aldosterone. This is also compatible with the belief that the maximal tonic dopaminergic inhibition of aldosterone secretion. which is thought to occur in the nonpregnant state, t:l persists during early pregnancy. Our results, taken together with the findings reviewed, suggest that, under the conditions of our experiments performed in early pregnancy, the renin-aldosterone axis is both independent of PRL and resistant to beta-adrenoreceptor stimulation. Augmented urinary excretion of epinephrine and norepinephrine, 16 unaccompanied by increased circulating levels of PRA, angiotensin, and aldosterone 17 in pregnancy-induced hypertension, further suggests that
lkn·mbn I, I ~IHO Obstet. C1 nee nl.
J.
this apparent insensitivity of the renin-aldosterone axis persists during these clinical disorders of late pregnancy. These data, however, do not exclude a longterm effect of altered PRL secretion on the parameter' which we studit..'d, especially when 'it..'X steroid concentrations in plasma are known to be augmented. We wish to thank Miss Wendy Cannon, B.Sc., for expert technical assistance, Miss Suzanne Woolley, R.N., for assistance in data analysis and the clinical aspects of the project, and Mr. A. Nalecz, Sandoz Company, Montreal, Quebec, Canada, f(ll' supplies of bromocriptine.
REFERENCES I. Vizsolyi, E., and Perks, A.M.: Can.J. Zoo!. 52::17 I, 1974. 2. ~fanku, M.D., Matabaji, J. P., and Horrobin, D. F.: Na~
ture 258:78, 1975. :l. Marshall, S., Kledzik, G. S., Galato, M., Campbell, G. A .. and Meites, J.: Steroids 27:187, 1976. 4. Walsh, R. J., Posner, B. 1., and Kopriwa, B. M.: Science 201:1041, 1978. 5. Ho Yu~?n, B., McComb, P., Sy, L., Lewis,]., and Cannon. W.: AM. J. 0BSTET. GYNECOL. 133:316, 1979. 6. Halbreich, U., Ben-David, M., Assael, M., and Bornstein, R.: Lancet 2:654, 1976. 7. Ho Yuen, B., Cannon, W., Woolley, S., and Charles, E.: Br. J. Obstet. Gynaecol. 85:293, 1978. 8. Curtarelli, G., and Ferrari, C.: Thorax 34:328, 1979. 9. Haber, E., Koerner, T., Page, LB., Kliman, B., and Purnode, A.: J. Clin. Endocrinol. Metab. 29:1349, 1969. 10. Ho Yuen, B., Cannon, W., Lewis,]., Sy, L., and Woolley, S.: AM. J. 0BSTET. GY:\ECOL. 136:286, 1980.
II. Winer, B. J .: In Statistical Principles in Experimental De· sign, New York, 1962, McGraw-Hill Book Co., Inc., p. 89. 12. Robertson, D., and Michelakis, A.M.: J. Clin. Endocrinol. Metab.41:1166,1975. 13. Carey, D. M., Thorner, M. 0., and Oru, E. M.:]. Clin. Invest. 63:727, 1979. 14. Webster, R. A.: Br. J. PharmacaL 25:566, 1965. 15. Meyers, F. H.,Jawetz, E., and Goldfein, A.: In Review of Medical Pharmacology, ed. 2. Los Altos, 1970, Lang Medical Publications, chap. 25. 16. Zuspan, F. P.:]. Reprod. Med. 23:143, 1979. 17. Weir, R. J.. Doig, A., Fraser, R., Morton, J .J .. Parboosingh, J., Robertson, J., and Wilson, A.: In Lindheimer, M. D., Katz, A. 1., and Zuspan, F. P., editors: Hypertension in Pregnancy, New York. 1976,.John Wilev & Sons, Inc., p. 251.