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Plasma renin activity and plasma aldosterone during the normal menstrual cycle
Plasma renin activity and plasma aldosterone during the normal menstrual cycle ANDREW
M.
HISAYOSHI ,JOHN
MICHELAKIS,
PH.D..
YOSHIDA. C.
DORMOIS.
M.D.
M.D. h1.D.
Six twrmal uompI1 iovr/’ ,sfudied u&r ml,tabolic balanw conditions dwing rhr menatrucll cyclr. Plasmct wnin ac.tiz@y (PRA) artd plasma aldosterorw UIQIYPstimatPd throughout thP cycle uudrr .stalldurdiwd, uniform co~~ditior~c zlfifh sunsitiz~e radioinlmunoassa~s. Thrrv is C; linear increuw in PRA and plasma aldosterone during thr lutval phav qj’thc cycle prokkd ovulation occurs. If ovulatiorl,fails. no rise is seen in either parameter. Thw (I
junctioning chn n
corpus Iutwm seems to be essential for Ihe prodwtion
C RI NARY aldosterone secretion and excretion increase in the luteal phase of the menstrual cycle.‘-” As more information became available concerning the controlling factors governing aldosterone production, it was demonstrated that plasma renin activity (PRA) also increased in the luteal phase.4 Difficulty existed, however, in drawing a direct relationship between PRA and aldosteronc in plasma because of the technical difficulty in measuring repeated aldosteronc levels from the same patient. Reported herein are the results of studies of the renin-aldosterone system employing a sensitive radioimmunoassay to estimate plasma aldosterone in the normal menstrual ( yclc.
Methods Six young female vol-lnteers (ages 19 to 22). free of known gynecologic problems or history of excessive weight gain with menses, were studied in the Clinical Research Center. A defined metabolic diet ot 100 mEq. of sodium was given daily throughout the
any
of the.re hormonal
study. Daily 24 hour urine collections for electrolytes. creatinine. and volume were made. TO assess ovulation, daily basal body temperatures were determined in all subjects during the study and urinary pregnanediol excretion was measured. The subjects slept in the research unit three times per week and on the subsequent morning, while the) were still supine, blood was taken for PRA and plasma aldosterone. The samples were collected in ( hilled tubes containing EDTA. immediately placed in ice. md the plasma separated as soon as possible following centrifugation in the cold. The frozen plasma was stored at -X0 (:. until analyzed. Plasma renin activity was estimated by radioinmunoassay of angiotensin I with the results expressed as millimicrograms of angiotensin I per 100 ml. of plasma per three hours incubation. Plasma aldosterone was estimated with a radioimmunoassay developed by Mayes and associates,” modified in that dichloromethane used for the extraction of aldosterone from plasma was washed with 0.1 N NaOH solution instead of a silica gel column: it is expressed as millimicrograms per 100 ml. of plasma. Urinal-! pregnanediol was measured by the Bioscience I.ahoratory. Urinary sodium, potassium. and creatinine were determined b) AutoAnalvzer methods.
Results cycles. Fig. 1 is representative 01’ the five instances of ovulatory cycles and the temporal changes in PRA and plasma aldosterone. In the upper portion of each graph the urinary excretion of pregnanediol is Ovulatory
Ph;?rmaco&y Program, and Medirirw, Michigan Mithigun 48823.
Departments of Pharmacolog? State Uni~wsity, East Lansing.
Volume Number
I23 7
Plasma renin and aldosterone during menstrual cycle
m
I,
, I Fig.
5
1 IO
1. Ovulatory
15 cycle
20
25
of L. R.,
19 years
I
old.
shown which demonstrates a two- to four-fold increase in the latter part of the cycle. Coinciding with this increase in pregnanediol, PRA and aldosterone both increased. In three instances the PRA reached its maximum prior to the rise in aldosterone. In the other two cases the PRA and aldosterone peaked at the same time. In these five subjects, the mean value of PRA determination in the follicular phase was 168 ? 30 (SD.) and that of the luteal phase was 296 ? 52 (S.D.) mpg per 100 ml. of plasma. The mean values of plasma aldosterone in the follicular and luteal phases were 6.6 C 1.9 (SD.) and 11.8 ? 3.0 (S.D.) m/*t: per 100 ml. of plasma, respectively. In all cases, at or near the time of menstruation the PRA and aldosterone had returned to baseline or follicular-phase levels. Anovulatory cycle. One subject (Fig. 2) failed to ovulate as defined by basal body temperature measurements and by a lack of pregnanediol increase in the latter half of the cycle. As can be seen in Fig. 2, no change in PRA or aldosterone occurred.
Comment Multiple hormonal events occur related to the normal menstrual cycle. In this study attention was directed toward the renin-aldosterone system. In 1962 Reich6 demonstrated that there was an increased urinary aldosterone excretion during the luteal phase of the menstrual cycle. As the methodology developed to study the controlling influences of aldosterone production, Brown and associates4 demonstrated a rise in PRA during the luteal phase. Further support for the hypothesis that the increase in renin leads to the increase in aldosterone production was shown by Sundsfjord and
l-i-l
300
% ~
200
8 ;
100
z a (L P
,
I
dw
725
5
IO
Fig. 2. Anovulatory
15
cycle
20 of I.. A.,
25
dQY
20 years
old.
Aakvaag,? employing a radioimmunoassay for angiotensin II which showed a correlation between the plasma level of angiotensin II and urinary aldosterone excretion. Furthermore, Gray and associates3 showed that the secretion rate as well as the excretion rate of aldosterone was increased. More recently, Katz and Romfh* demonstrated a linear relationship between PRA and plasma aldosterone during the luteal phase. The study clearly shows a close temporal and directional relationship between an increase in PRA during the luteal phase and increased levels of plasma aldosterone. Employing a sensitive radioimmunoassay for aldosterone, frequent determinations of plasma aldosterone requiring only small amounts of plasma were possible. Thus, these findings show that (1) the increase in renin activity either precedes or coincides with the increased aldosterone and (2) on the basis of one anovulatory cycle if no ovulation occurs the observed changes in renin and aldosterone do not occur. The factor or factors leading to these changes remain unclear. On the bases of previous observations and those demonstrated here, however. support is given to the thesis that a functioning corpus luteum is required for the observed changes in renin and aldosterone. Specifically, Sundsfjord and AakvaagY have shown that during the luteal phase if no increase in plasma progesterone occurs indicative of luteal failure, no rise in PRA and urinary aldosterone occurs. Thus, it seems likely that there is a relationship between progesterone or some related product of the corpus luteum and the increase in PRA and plasma aldosterone during the luteal phase of the normal human menstrual cycle.
726
Michelakis,
Yoshida,
and Dormois
REFERENCES
1. Venning. E. H.. Primrose, T., C:aligaris, L. C. S.. and Dyrenfurth. I.: Aldosterone excretion in pregnancy-. J. Clin. Endocrinol. Metab. 17: 473, 1957. 2. Layne, D. S., Meyer, C. J., Vaishwanal-, P. S., and Pincus. G.: Secretion and metabolism of cortisol and aldosterone in normal and in steriod treated patients. J. Clin Endocrinol. Metab. 22: 107, 1962. 3. Gray, M. J., Strausfeld, S., Watanabe, M., Sims, E. A. H., and Solomon, S.: Aldosterone secretion rate in the normal menstrual cycle. J, Clin. Endocrinol. Metab. 28: 1269. 1968. 4. Brown, J. J., Davis, D. I... Lever. A. F.. and Roberson, J. 1. S.: Variations in plasma renin during the menstrual cycle, Br. Med. J. 2: 1114, 1969. 5. Mayes, D., Furuyama. S.. Kern. D. C., and Nugent, (1. B.: A
Note to authors:
Change
in reference
6.
7.
8.
9.
radioirnmulloas~~~ for plasma aldostet-one, J, (;lin. Endocrinol. Metab. 30: 682, 1970. Reich. M.: The variations in urinary aldosterone levels of noI-ma1 females during their menstrual cycle. AUG. Ann. Med. 11: 41. 1962. Sundsfjord, J. A.. and Aakvaag. il.: Plasma ang~otcnsin II and aldosterone excretion during the menstrual cycle. Acta Endocrinol. 64: 4.52. 1970. Katz. F. H.. and Romfb. P.: Plasma aldosterolle and renin activity during the menstrual cycle. J. (Xn. E:ndocrinol. Metab. 34: 819, 1972. Sundsfjord, ,J. A.. and Aakvaag. A.: Plasma rcnin activity, plasma renin substrate. and urinary aldosteronc excretion in the menstrual cycle in relation to the concentration ot progesterone and estrogen in the plasma, Acta Endocrinol. 71:
51Y,
lY7’L.
style
The Editors and AMERICAN JOURNAL.
Publisher have agreed to add the article title to references in the OF CksrETRIc:s AND GYNF.COLOC,Y. Referencts will now conform to the Cumulntcd Z&x MC& U, vk., name of author. title of article, name of period-
style of the ical, volume. page. and year. Authors are always encouraged to limit references to sixteen for the following JO&AL sections: Obstetrics, Gynecology. and Fetus, Placenta. and Newborn. I
M.
HISAYOSHI ,JOHN
MICHELAKIS,
PH.D..
YOSHIDA. C.
DORMOIS.
M.D.
M.D. h1.D.
Six twrmal uompI1 iovr/’ ,sfudied u&r ml,tabolic balanw conditions dwing rhr menatrucll cyclr. Plasmct wnin ac.tiz@y (PRA) artd plasma aldosterorw UIQIYPstimatPd throughout thP cycle uudrr .stalldurdiwd, uniform co~~ditior~c zlfifh sunsitiz~e radioinlmunoassa~s. Thrrv is C; linear increuw in PRA and plasma aldosterone during thr lutval phav qj’thc cycle prokkd ovulation occurs. If ovulatiorl,fails. no rise is seen in either parameter. Thw (I
junctioning chn n
corpus Iutwm seems to be essential for Ihe prodwtion
C RI NARY aldosterone secretion and excretion increase in the luteal phase of the menstrual cycle.‘-” As more information became available concerning the controlling factors governing aldosterone production, it was demonstrated that plasma renin activity (PRA) also increased in the luteal phase.4 Difficulty existed, however, in drawing a direct relationship between PRA and aldosteronc in plasma because of the technical difficulty in measuring repeated aldosteronc levels from the same patient. Reported herein are the results of studies of the renin-aldosterone system employing a sensitive radioimmunoassay to estimate plasma aldosterone in the normal menstrual ( yclc.
Methods Six young female vol-lnteers (ages 19 to 22). free of known gynecologic problems or history of excessive weight gain with menses, were studied in the Clinical Research Center. A defined metabolic diet ot 100 mEq. of sodium was given daily throughout the
any
of the.re hormonal
study. Daily 24 hour urine collections for electrolytes. creatinine. and volume were made. TO assess ovulation, daily basal body temperatures were determined in all subjects during the study and urinary pregnanediol excretion was measured. The subjects slept in the research unit three times per week and on the subsequent morning, while the) were still supine, blood was taken for PRA and plasma aldosterone. The samples were collected in ( hilled tubes containing EDTA. immediately placed in ice. md the plasma separated as soon as possible following centrifugation in the cold. The frozen plasma was stored at -X0 (:. until analyzed. Plasma renin activity was estimated by radioinmunoassay of angiotensin I with the results expressed as millimicrograms of angiotensin I per 100 ml. of plasma per three hours incubation. Plasma aldosterone was estimated with a radioimmunoassay developed by Mayes and associates,” modified in that dichloromethane used for the extraction of aldosterone from plasma was washed with 0.1 N NaOH solution instead of a silica gel column: it is expressed as millimicrograms per 100 ml. of plasma. Urinal-! pregnanediol was measured by the Bioscience I.ahoratory. Urinary sodium, potassium. and creatinine were determined b) AutoAnalvzer methods.
Results cycles. Fig. 1 is representative 01’ the five instances of ovulatory cycles and the temporal changes in PRA and plasma aldosterone. In the upper portion of each graph the urinary excretion of pregnanediol is Ovulatory
Ph;?rmaco&y Program, and Medirirw, Michigan Mithigun 48823.
Departments of Pharmacolog? State Uni~wsity, East Lansing.
Volume Number
I23 7
Plasma renin and aldosterone during menstrual cycle
m
I,
, I Fig.
5
1 IO
1. Ovulatory
15 cycle
20
25
of L. R.,
19 years
I
old.
shown which demonstrates a two- to four-fold increase in the latter part of the cycle. Coinciding with this increase in pregnanediol, PRA and aldosterone both increased. In three instances the PRA reached its maximum prior to the rise in aldosterone. In the other two cases the PRA and aldosterone peaked at the same time. In these five subjects, the mean value of PRA determination in the follicular phase was 168 ? 30 (SD.) and that of the luteal phase was 296 ? 52 (S.D.) mpg per 100 ml. of plasma. The mean values of plasma aldosterone in the follicular and luteal phases were 6.6 C 1.9 (SD.) and 11.8 ? 3.0 (S.D.) m/*t: per 100 ml. of plasma, respectively. In all cases, at or near the time of menstruation the PRA and aldosterone had returned to baseline or follicular-phase levels. Anovulatory cycle. One subject (Fig. 2) failed to ovulate as defined by basal body temperature measurements and by a lack of pregnanediol increase in the latter half of the cycle. As can be seen in Fig. 2, no change in PRA or aldosterone occurred.
Comment Multiple hormonal events occur related to the normal menstrual cycle. In this study attention was directed toward the renin-aldosterone system. In 1962 Reich6 demonstrated that there was an increased urinary aldosterone excretion during the luteal phase of the menstrual cycle. As the methodology developed to study the controlling influences of aldosterone production, Brown and associates4 demonstrated a rise in PRA during the luteal phase. Further support for the hypothesis that the increase in renin leads to the increase in aldosterone production was shown by Sundsfjord and
l-i-l
300
% ~
200
8 ;
100
z a (L P
,
I
dw
725
5
IO
Fig. 2. Anovulatory
15
cycle
20 of I.. A.,
25
dQY
20 years
old.
Aakvaag,? employing a radioimmunoassay for angiotensin II which showed a correlation between the plasma level of angiotensin II and urinary aldosterone excretion. Furthermore, Gray and associates3 showed that the secretion rate as well as the excretion rate of aldosterone was increased. More recently, Katz and Romfh* demonstrated a linear relationship between PRA and plasma aldosterone during the luteal phase. The study clearly shows a close temporal and directional relationship between an increase in PRA during the luteal phase and increased levels of plasma aldosterone. Employing a sensitive radioimmunoassay for aldosterone, frequent determinations of plasma aldosterone requiring only small amounts of plasma were possible. Thus, these findings show that (1) the increase in renin activity either precedes or coincides with the increased aldosterone and (2) on the basis of one anovulatory cycle if no ovulation occurs the observed changes in renin and aldosterone do not occur. The factor or factors leading to these changes remain unclear. On the bases of previous observations and those demonstrated here, however. support is given to the thesis that a functioning corpus luteum is required for the observed changes in renin and aldosterone. Specifically, Sundsfjord and AakvaagY have shown that during the luteal phase if no increase in plasma progesterone occurs indicative of luteal failure, no rise in PRA and urinary aldosterone occurs. Thus, it seems likely that there is a relationship between progesterone or some related product of the corpus luteum and the increase in PRA and plasma aldosterone during the luteal phase of the normal human menstrual cycle.
726
Michelakis,
Yoshida,
and Dormois
REFERENCES
1. Venning. E. H.. Primrose, T., C:aligaris, L. C. S.. and Dyrenfurth. I.: Aldosterone excretion in pregnancy-. J. Clin. Endocrinol. Metab. 17: 473, 1957. 2. Layne, D. S., Meyer, C. J., Vaishwanal-, P. S., and Pincus. G.: Secretion and metabolism of cortisol and aldosterone in normal and in steriod treated patients. J. Clin Endocrinol. Metab. 22: 107, 1962. 3. Gray, M. J., Strausfeld, S., Watanabe, M., Sims, E. A. H., and Solomon, S.: Aldosterone secretion rate in the normal menstrual cycle. J, Clin. Endocrinol. Metab. 28: 1269. 1968. 4. Brown, J. J., Davis, D. I... Lever. A. F.. and Roberson, J. 1. S.: Variations in plasma renin during the menstrual cycle, Br. Med. J. 2: 1114, 1969. 5. Mayes, D., Furuyama. S.. Kern. D. C., and Nugent, (1. B.: A
Note to authors:
Change
in reference
6.
7.
8.
9.
radioirnmulloas~~~ for plasma aldostet-one, J, (;lin. Endocrinol. Metab. 30: 682, 1970. Reich. M.: The variations in urinary aldosterone levels of noI-ma1 females during their menstrual cycle. AUG. Ann. Med. 11: 41. 1962. Sundsfjord, J. A.. and Aakvaag. il.: Plasma ang~otcnsin II and aldosterone excretion during the menstrual cycle. Acta Endocrinol. 64: 4.52. 1970. Katz. F. H.. and Romfb. P.: Plasma aldosterolle and renin activity during the menstrual cycle. J. (Xn. E:ndocrinol. Metab. 34: 819, 1972. Sundsfjord, ,J. A.. and Aakvaag. A.: Plasma rcnin activity, plasma renin substrate. and urinary aldosteronc excretion in the menstrual cycle in relation to the concentration ot progesterone and estrogen in the plasma, Acta Endocrinol. 71:
51Y,
lY7’L.
style
The Editors and AMERICAN JOURNAL.
Publisher have agreed to add the article title to references in the OF CksrETRIc:s AND GYNF.COLOC,Y. Referencts will now conform to the Cumulntcd Z&x MC& U, vk., name of author. title of article, name of period-
style of the ical, volume. page. and year. Authors are always encouraged to limit references to sixteen for the following JO&AL sections: Obstetrics, Gynecology. and Fetus, Placenta. and Newborn. I