POSTGRADUATE SECTION Scot. med, J.

, 1971, 16: 183

RENIN, ANGIOTENSIN AND ALDOSTERONE IN HUMAN PREGNANCY

AND THE MENSTRUAL CYCLE

J. I. S. Robertson, R. J. Weir, G. O. Dilsterdieck, R. Fraser and M. Tree

M.R.C. Blood Pressure Unit, Western Infirmary, Glasgow

Summary. Aldosterone secretion is frequently, although not invariably, increased

above the normal non-pregnant range in normal pregnancy. Substantial increases in
plasma aldosterone concentration have also been demonstrated as early as the
sixteenth week. In pregnancy, aldosterone secretion rate responds in the usual
way to changes in sodium intake.
Plasma renin concentration is frequently, but not invariably, raised above the
normal non-pregnant range. Plasma renin-substrate is consistently raised in
pregnancy. Plasma angiotensin II has also been shown usually to be raised in a
series of pregnant women.
A significant positive correlation has been shown between the maternal plasma
aldosterone concentration and the product of the concurrent plasma renin and
renin-substrate concentrations. This suggests that the increased plasma aldo-
sterone in pregnancy is the consequence of an increase in circulating angiotensin
II, which in turn is related to the level of both renin and its substrate in
maternal blood. For these reasons, estimations of renin activity in pregnancy
are of dubious value.
The increased renin, angiotensin and aldosterone concentrations may represent
a tendency to maternal sodium depletion, probably mainly a consequence of
the increased glomerular filtration rate. It is possible that the nausea and other
symptoms of early pregnancy may be a consequence of this tendency to sodium
depletion, with its attendant hormonal changes. In 'pre-eclampsia', renin and
aldosterone values are generally slightly lower than in normal pregnancy. Human
chorion can apparently synthesize renin independently of the kidney. The physio-
logical significance of this remains at present obscure, but it seems unlikely
that this source contributes much, if at all, to the often elevated maternal plasma
renin.
Plasma renin, renin-activity and angiotensin II concentrations, and aldosterone
secretion are increased in the luteal phase of the menstrual cycle.

was discovered as a pressor More recently, the discovery that renin,

R EN IN
substance present in extracts of the renal
cortex (Tigerstedt &Bergman, 1898; Picker-
ing & Prinzmetal, 1938). For many years the
pressor action of the enzyme renin, and of its
active product, the peptide angiotensin, domi-
nated thoughts in this field, and the renin-
angiotensin system was widely regarded as
being largely, if not solely, responsible for the
maintenance of normal blood pressure, and
for the pathogenesis of renal hypertension.
via angiotensin, could stimulate aldosterone
production (Gross, 1958, 1960; Genest et al.,
1960; Laragh et al., 1960; Bartter et al., 1961;
Carpenter et al., 1961; Mulrow & Ganong,
1961; Fraser et al., 1965) has considerably
enlarged concepts of the possible physiolog-
ical functions of the system, although the
extent to which renin and, angiotensin are
normally responsible for regulating aldoster-
one secretion is still a matter of controversy.

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Robertson, Weir, Diisterdieck, Fraser and Tree
In this context, pregnancy is of considerable
interest, since it is now clear that during
pregnancy very large increases in renin and
aldosterone may occur normally, in the
absence of blood pressure elevation.
This review will be restricted to studies in
man. While there is little doubt that modifi-
cations of the renin-angiotensin system do
occur in pregnancy in other mammalian
species such as the cat (Stakemann, 1960),
rabbit (Gross et al., 1964; Bing & Faarup,
1966; Ferris et ai., 1967), sheep (Ferris et al.,
1969) and dog (Robb et ai., 1970); to date the
most extensive investigations have been in
humans. Moreover, marked differences in the
response of renin, angiotensin and aldo-
sterone in pregnancy exist between species,
and the relevance of much of the animal work
to man is questionable.
Aldosterone
The increases in the secretion rate and
plasma concentration of aldosterone which
occur in normal human pregnancy are of
considerable interest for a variety of reasons,
not least their magnitude. The values some-
times achieved are the highest known in
any normal physiological situation, and
indeed may equal or exceed those found in
many pathological circumstances in man.
Aldosterone excretion. An increase in the
urinary excretion of aldosterone metabolites
in normal pregnancy has been reported by
several groups, and has been taken to
indicate increased aldosterone production
(Martin & Mills, 1956; Venning & Dyren-
furth 1956; Nowaczynski et al., 1957;
Wolff et ai., 1958). However, the pattern of
aldosterone metabolites excreted in the urine
is altered in pregnancy as compared with the
non-pregnant state (Jones et ai., 1959; Tait &
Little, 1968) and the increase in the excretion
of the metabolites measured may not repre-
sent a proportionate increase in aldosterone
secretion (vide infra).
Aldosterone secretion. Measurements of
aldosterone secretion rate in normal human
pregnancy have been made by Jones et at.
(1959), Wiele et at. (1960), Watanabe et al.
(1963) and Bayard et al. (1970).
Jones et at. (1959) studied 6 women
between 32 and 38 weeks of pregnancy, on an
184
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unrestricted diet and ambulant. The aldo-
sterone secretion rate ranged from 248 to
1100,ag. per day, compared with a range of
72 to 315 ug. per day in 6 normal non-
pregnant subjects, the highest pregnancy
value thus being about ,3 times the highest
normal non-pregnant value. The more limited
investigation of Wiele et al. (1960) was in
general agreement with these findings.
Watanabe et al. (1963) found a similar nor-
mal non-pregnant aldosterone secretion rate
(85 to 216 ug. per day). In one woman at 15
weeks gestation the aldosterone secretion rate
was 387 ,ag. per day, while in later pregnancy
values up to 2912 ug. per day were obtained,
the secretion rate showing some tendency to
increase with advancing gestation. The
highest value was about 14 times the upper
limit of the normal non-pregnant range. This
study also demonstrated that aldosterone sec-
retion rate in pregnancy responded normally to
variations in dietary sodium intake, in-
creasing, often markedly, with sodium re-
striction and decreasing with sodium loading.
Somewhat at variance was the more
recent observation by Bayard et al. (1970) in
which aldosterone secretion rates in late
pregnancy (38 to 40 weeks) were found to be
a good deal lower (range 16 to 79,ag. per day).
Bayard et al. (1970) tentatively suggested that
the explanation may be that their subjects
were studied after 10 hours recumbency,
whereas the earlier investigations were in
ambulant subjects. However Sims (1964)
reported that 4 to 7 days recumbency in 5
normal pregnant subjects did not reduce
aldosterone secretion.
Plasma aldosterone concentration. Peri-
pheral venous plasma aldosterone concen-
tration was measured by Weir et al. (1970a)
(Fig. 1) in a group of normal pregnant
women at 16, 28, 34 and 38 weeks gestation.
The women were on unrestricted diet, the
blood samples being taken between 09.00
and 10.00 hours after an overnight fast, and
after they had lain supine for 30 minutes.
Plasma aldosterone was markedly increased
in all the women, some of the highest values
occurring at 16 weeks. The over-all range was
60 to 393 mzg. per 100 ml., compared with a
normal non-pregnant upper limit of 18 m,ag.
per 100 mi. Three women with very high
 Renin, Angiotensin and Aldosterone in Human Pregnancy and the Menstrual Cycle
PLASMA ALDOSTERONE
rnjJ.9/100ml
400 •
300
Fig. 1. Peripheral venous plasma aldosterone concentrations at 4 stages of preg-
nancy in 5 normal women (Weir et at., 1970a).
levels at 16 weeks showed a marked fall to
38 weeks, and 2 showed a slight rise to 38
weeks. Although the mean plasma aldosterone
concentration decreased from 16 to 34 weeks,
the change was not statistically significant.
In another series reported by Weir et al.
(1970a), a rather lower overall range of 7 to
130 mzsg. per 100 ml. was found, 6 of the 22
results falling within the normal non-pregnant
range.
The only other study of plasma aldosterone
concentration of which we are aware is that
of Bayard et al. (1970). This was mainly of
late pregnancy (38 to 40 weeks), although one
value was reported for a woman at 20 weeks
gestation. As with the aldosterone secretion
rate measurements reported in the same
paper, the increases in plasma aldosterone
concentration were very slight. Again, the
authors suggest that the explanation may lie in
the fact that these subjects had been recum-
bent for 10 hours before the investigation was
carried out.
It is noteworthy that in none of these 3
studies of plasma aldosterone concentration
in normal pregnancy is there evidence of an
increase with advancing gestation. In view of
the general agreement that the metabolic
clearance rate of aldosterone is unchanged in
pregnancy (vide infra), the plasma findings
seem therefore at variance with the secretion
rate studies of Watanabe et al. (1963).
Aldosterone metabolism. Jones et al. (1959)
reported higher excretion of aldosterone
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j j
28 34
GESTATION in WEEKS
released by mild acid treatment of urine
(presumed to be aldosterone l8-glucuronide)
from pregnant as compared with non-
pregnant subjects and suggested that this was
partially due to increased conversion of
secreted aldosterone to this metabolite.
Watanabe et al. (1963) were unable to
confirm this finding, but reinvestigation by
Tait and Little (1968) confirmed the earlier
findings of Jones et al. (1959). Tait and Little
(1968) suggested that there is a decrease in
splanchnic clearance and an increase in
extrasplanchnic clearance of aldosterone in
pregnancy. The over-all metabolic clearance
rate of aldosterone in pregnancy appears not
to be significantly different from that in non-
pregnant subjects (Tait et al., 1962; Tait &
Little, 1968; Bayard et al., 1970).
Factors possibly responsible for the stimu-
lation of aldosterone secretion in pregnancy.
These include alterations in the Na/K ratio of
plasma, potassium loading, ACTH, HPS
and the renin/angiotensin system.
Altered Na/K ratio of plasma. Weir et al.
(1971) observed only minor changes in plasma
Na and K during normal pregnancy, and
these bore no statistical relationship to plasma
aldosterone concentration measured concur-
rently, thus indicating that this is an unlikely
explanation of the increased aldosterone sec-
retion in human pregnancy.
Potassium loading. Total exchangeable
potassium is increased in normal pregnancy,
but the amount of potassium per kg. body
18S
Robertson, Weir, Diisterdieck, Fraser and Tree
weight is less than in non-pregnant females
(MacGillivray & Buchanan, 1958; MacGilli-
vray, 1961). Since there is no clear increase
in plasma potassium concentration in normal
pregnancy (vide supra), this seems an im-
probable mechanism of the increase in
aldosterone.
ACTH. The evidence in favour of stimu-
lation of aldosterone secretion by ACTH is
conflicting (see Fraser et al., 1969). It is also
uncertain whether ACTH output is increased
in normal pregnancy (see Hytten & Leitch,
1964; Forsham, 1967). Weir et al. (197Ia)
found a marked dissociation between plasma
aldosterone and cortisol concentrations
measured concurrently in pregnancy. This
also indicates that the increases in aldosterone
are not the result of stimulation by ACTH.
Human placental somatomammotrophin
(HPS). This peptide, of placental origin, was
previously known as placental lactogen
(HPL). A preliminary study by Melby et al.
(1966) showed that the intravenous admini-
stration of HPS stimulated aldosterone
secretion in normal non-pregnant females and
in males. If confirmed, this observation
would indicate that the increased aldosterone
secretion of pregnancy might at least in part
be due to HPS.
Renin/angiotensin. Increases in the plasma
concentration both of the enzyme renin and
of its active product, the peptide angiotensin,
have been demonstrated in normal pregnancy.
The possibility that this system may be
responsible for the stimulation of aldo-
sterone production is considered in detail
later.
Renin and angiotensin
Outline of the system. Renin is an enzyme
of renal origin, which is present normally
in plasma and reacts with a substrate in the
alpha-Zglobulin fraction of'plasma to form the
peptide angiotensin. An inactive decapeptide,
angiotensin I, is first formed; this is converted
to the active octapeptide, angiotensin II, in the
circulation.
Separate measurements of the enzyme
renin, of its substrate and of angiotensin II
have all been made in maternal peripheral
blood during normal pregnancy, and the
results are considered in the following
le6
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sections. Another estimation which has been
widely employed, so-called 'renin-activity',
also merits discussion.
Renin activity. A variety of techniques have
been employed for the estimation of renin
activity in plasma samples. These have in
common, usually, the destruction or in-
activation of angiotensinases. The plasma
sample is then incubated for a fixed period
(often 3 hours) and the formed angiotensin
estimated at the end of this time. The quan-
tity of angiotensin produced under these
circumstances is a measure of the renin
activity. It should be noted that renin activity
so calculated is subject to at least two
variables-the concentrations of renin and of
its substrate in the plasma specimen. Any
activators or inhibitors which might remain
will also influence the result. Moreover, a
number of methods which have been so used
do not estimate losses of renin or substrate
during the angiotensinase inactivation pro-
cedures. While estimation of renin activity has
proved useful in diagnostic clinical work in
situations where substrate concentration does
not change greatly, it is not easy to interpret
results in conditions where large changes in
substrate concentration occur, of which
pregnancy is an example. Using different
methods, renin activity has variously been
found to be not significantly different from
the normal non-pregnant range (Maebashi
et al., 1964); variably, but significantly in-
creased (Gordon et al., 1969); and consist-
ently above the normal non-pregnant range
(Fasciolo et al., 1964). Boonshaft et al. (1968)
showed that serum renin activity in pregnancy
increased in response to dietary sodium restric-
tion and also on assuming the upright posture.
In the opinion of the present authors,
measurements of plasma renin activity are,
for the stated reasons, difficult to interpret in
pregnancy. Such estimations will not be
considered further in this paper.
Plasma renin concentration. Renin con-
centration in peripheral venous plasma has
been found to be increased, sometimes
markedly, in many, but not all normal preg-
nant women (Brown et al., 1963, 1966d;
Helmer & Judson, 1967; Weir et al., 1971a)
(Fig. 2). The highest mean levels have been
reported in the first trimester and consider-
 Renin, Angiotensin and Aldosterone in Human Pregnancy and the Menstrual Cycle

PLASMA RENIN
UNITS/L

190
1•

100

80

60

40

20
1non-
Normal
pregnant
J range
i I I
18 26 34 38

GESTAtiON in WEEKS

Fig. 2. Serial measurements of plasma renin concentration in a group of women

during normal pregnancy.
~---~- ~-- -~- ~-~ ~-------

RENIN SUBSTRATE
(mol•• x 10- 6 }
5·0

3·0

•
1·01--.,.~

•
""" _
• Upper limit Normal Nan -Pregnant Range

L.M.P. 6 12 IB 24 30 36
GESTATION (WEEKS)

Fig. 3. Plasma renin-substrate concentrations in normal pregnancy. Lines connect

serial samples from the same women. Dotted line connects with pre-pregnancy
value in one subject.
able elevation has been noted as early as the
fifth week after the last menstrual period
(Brown et al., 1966d). In some women, how-
ever, plasma renin concentration may remain
within the normal non-pregnant range
throughout pregnancy :(Weir et al., 1971a)
(Fig. 2). '
As will be discussed later, it seems possible
that the increases in plasma renin concen-
tration in pregnancy are in some way related
to a tendency to sodium depletion, but the
precise way in which this would lead to an
increase in renin is uncertain. Changes in the
tension of afferent glomerular arterioles (see
Tobian, 1964) or in the sodium content or
osmolality of the fluid bathing the macula
densa cells (see Brown et al., 1964a, 1966b)
have been suggested, but remain unproved.
It is noteworthy that in the study of Weir
et al. (l971a), no relationship was found
between the plasma renin concentration and
the concurrent plasma volume or haematocrit,
both of which have been suggested as possible
stimuli to renin release and hence to a rise in
plasma renin concentration (Brown et al.,
1966c; Nielson & Meller, 1968). Stimulation
of renin secretion secondary to arterio-venous
shunting of blood in the placenta (Mulrow,
1964) or pressure on the renal arteries by the
gravid uterus (Forsham, 1967) have also been
postulated, but seem unlikely to be operative
as early as the fifth week of pregnancy, when
a marked increase in renin has already been
noted (Brown et al., 1966d). Maternal plasma
protein concentration, osmolality and sodium
concentration were also found not to be

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Robertson, Weir, Diisterdieck, Fraser and Tree

100 volunteers. A marked increase in plasma

• renin-substrate occurred in those receiving
90 • the oestrogen, while there was no change in
those taking the progestagen.
80 • Angiotensin in blood and plasma. Few
70 measurements have so far been reported.
• Massani et ai. (1967), employing a chemical
••
Plasma 60 extraction procedure combined with bioassay
Angiotensin n which did not distinguish between angioten-
pg/ml 50 •• sinsIand II, found a range of 124 to 290pg. per

I
ml. of whole arterial blood during the third
40 ••
• trimester, compared with an upper limit of 193

N~~I
30 pg. per ml. in normal non-pregnant women. It
is likely that for technical reasons, these figures
20 Non-pregnant over-estimate the level of angiotensin II.
Range
We have recently applied the radio-
10 immuno-assay technique of Dtisterdieck and
o McElwee (1970; 1971) to this situation.
Peripheral venous blood samples were taken
Fig. 4. Plasma angiotensin II estimations during the
first trimester in a group of normal pregnant women. from normal women in the first trimester of
pregnancy. Some of these were receiving a
correlated with concurrent measurements of normal unrestricted diet, others a diet of
plasma renin (Weir et al., 1971a). known composition with the sodium content
Plasma renin-substrate concentration. In- fixed at a point between 115 and 140 mEq.
creases in plasma renin-substrate have been and the potassium between 40 and 65 mEq.
found consistently in normal human pregnan- daily. All the subjects had lain recumbent for
cy (Helmer & Judson, 1963, 1967; Pickens et 15 minutes before the blood samples were
al., 1965; Gould et al., 1966; Weir et al., taken. The early results are shown in Figure 4.
1970a). Compared with a normal non-pregnant Only 4 of 16 estimations lay within the non-
upper limit of roughly 1 x 10- 6 mols, levels in pregnant range, while the highest value
pregnancy may range from 1.0 to 5.0 X 10- 6 (97 pg.rml.) was almost 3 times the non-
mols. In individual women, plasma renin subs- pregnant upper limit.
trate concentration app ears to remain fairly There is at present insufficient evidence to
constant during pregnancy (Weir et al., 1970a) decide whether or not these increases in plasma
(Fig. 3). angiotensin II are the product simply of the
Helmer & Griffith (1952) found that the raised plasma renin and renin-substrate con-
administration of oestrogens to rats caused centrations of pregnancy, or whether addition-
an increase in plasma renin-substrate, and a al factors need to be considered.
rise in maternal plasma renin-substrate in Angiotensinases. Various peptidases present
pregnancy could well have a similar basis. in blood are capable of inactivating circul-
The administration of combined oestrogen/ ating angiotensin, and are therefore known
progestagen oral contraceptives also causes a as 'angiotensinases'. The term does not imply
rise in renin substrate (Helmer & Judson, 1967; necessarily a specific action on angiotensin.
Newton et al., 1968; Skinner et al., 1969; Weir Since variations in angiotensinase activity
et al., 1970b) and this is almost certainly due might affect the survival, and hence the
to the oestrogen component (Helmer & Judson, concentration, of angiotensin in blood,
1967; Newton et al., 1968). In a recent report, numerous measurements of angiotensinase
Weir et al. (1971b) described the results of activity have been made in blood during
administering separately the oestrogen and normal pregnancy and 'pre-eclampsia'. Klaus
progestagen components (mestranol and and Biron (1964) were unable to demonstrate
ethynodiol diacetate respectively) of an oral a change in angiotensinase activity in normal
contraceptive (Ovulen-50) to 2 groups of pregnancy plasma, although Berger and

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 Renin, Angiotensin and Aldosterone in Human Pregnancy and the Menstrual Cycle
Langhans (1967) reported an increase in mean
activity from about the sixth month. The
studies in pre-eclampsia are discussed later.
The renin/angiotensin system as a possible
stimulus to aldosterone secretion in pregnancy.
Considerable circumstantial evidence sup-
ports the concept that, in man, the renin-
angiotensin system is an important regulator
of aldosterone secretion (see Brown et al.,
1968; Fraser et al., 1969) although it remains
to be shown that the concentrations of renin
or angiotensin in plasma are within a range
capable of affecting aldosterone secretion
(Brown et al., 1967, 1968). In many clinical
situations changes in plasma renin concen-
tration appear to govern the renin-renin
substrate reaction, and positive correlations
between renin and aldosterone concentrations
are demonstrable (Fraser et al., 1969).
However, no such relationship can be seen
in pregnancy where individual concurrent
plasma renin and plasma aldosterone concen-
trations have been found to be quite unrelated
(Weir et al., 1970a). Moreover, no relation-
ship between plasma renin substrate and
plasma aldosterone concentrations has been
shown (Weir et al., 1970a).
The increases in plasma renin substrate oc-
curring in pregnancy are within a range which
theoretically could influence the amount of
angiotensin formed by a given concentration
of the enzyme renin (Helmer, 1964; Brown
et al., 1966b; Helmer & Judson, 1967;
Skinner et al., 1969). Thus angiotensin II and
aldosterone concentrations are more likely
to be related to the product of renin and renin-
substrate concentrations in plasma than to
either individually. Relevant data concerning
angiotensin are not available but Weir et al.,
(1970a) have found in pregnancy a significant
positive correlation between the product of
plasma renin and renin-substrate concen-
trations and the concurrent plasma aldo-
sterone level. This supports the notion that
in pregnancy, changes in both renin and
renin-substrate are important in governing
the quantity of angiotensin formed and hence
the aldosterone production, although the
evidence is at present inconclusive. The
addition of plasma angiotensin II measure-
ments to such studies should help to clarify
the situation.
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Possible reasons for activation of the renin-
angiotensin-aldosterone system in pregnancy
Increases in circulating renin, angiotensin
and aldosterone constitute a normal response
to sodium deprivation or depletion, and their
occurrence in pregnancy suggests a similar
basis.
Studies in late pregnancy have shown
retention of sodium in quantities similar to
those required by the foetus and placenta
and by the increased extracellular fluid, with
no evidence of maternal sodium depletion
(MacGillivray & Buchanan, 1958; Plentl &
Gray, 1959; MacGillivray, 1961). However,
there appear to be no data on sodium balance
in the first weeks of pregnancy, and it is
possible that in these first weeks of gestation
maternal sodium depletion could occur, re-
quiring marked increases in circulating aldo-
sterone in order to restore and maintain
sodium balance. Although diversion of
sodium to the foeto-placental unit could affect
the maternal sodium balance in later preg-
nancy, it seems unlikely that it would be
sufficient to deplete the mother in the first
weeks of gestation.
A marked increase in glomerular fil-
tration rate has been shown to occur by the
12th week of gestation and to remain high
throughout pregnancy (Sims & Krantz, 1958).
This would result in an increased sodium
excretion and consequent maternal depletion
unless tubular sodium reabsorption increased
in parallel. It is possible that the increased
circulating aldosterone concentration pro-
motes this sodium reabsorption, although
in later pregnancy no correlation was found
between aldosterone secretion rate and
glomerular filtration rate (Watanabe et al.,
1963).
Other factors may complicate the situation,
especially in later pregnancy. Progesterone
inhibits the action of aldosterone on renal
tubules (Landau & Lugibihl, 1958, 1961),
and increases the urinary excretion of
sodium when given to non-pregnant women
in doses comparable to the rate of secretion
in normal pregnancy (Landau et al., 1955,
1957). In normal pregnant women the
administration of progesterone has been
shown to stimulate aldosterone secretion
(Laidlaw et al., 1962), and a correlation
189
Robertson, Weir, Diisterdieck, Fraser and Tree

between urinary pregnanediol excretion and ations of taste; a peculiar metallic taste
aldosterone secretion has been shown (Jones sometimes mistaken for thirst, but not
et al., 1959). Drucker et al., (1963) adminis- relieved by drinking water; muscular cramps;
tered large quantities of aldosterone intra- and mental and physical lassitude. More
venously to 2 women with adrenocortical recently it has been found that sodium
insufficiency before and after delivery. Negli- depletion is associated with increased plasma
gible effects on electrolyte excretion were concentrations of renin, angiotensin and
observed in late pregnancy, whereas after aldosterone (see Brown et al., 1966b). It is
delivery the normal sodium-retaining effect uncertain to what extent the symptoms of
of aldosterone was restored. The insensitivity sodium chloride deficiency are due to sodium
to aldosterone in pregnancy was interpreted chloride lack as such, or alternatively to the
as being due probably to the antagonistic associated hormonal changes. For example,
effect of progesterone on aldosterone. angiotensin has been shown to cause poly-
Moreover, it is possible that other steroids dipsia in rats (Fitzsimons & Simons, 1968)
which are increased in pregnancy might have and the associated rise in circulating angio-
a natriuretic effect. For example, a transient tensin has been suggested as a possible cause
natriuresis and an increase in aldosterone of the intense thirst which sometimes accom-
secretion rate have also been demonstrated panies severe renal failure in man (Brown
during the administration of oestriol and et al., 1969).
oestradiol to non-pregnant subjects (Katz & The similarities to the biochemical features
Kappas, 1967). and symptoms of early pregnancy seem to
However, in attempting to relate these be sufficiently striking to merit further
events to changes in renin and aldosterone examination. As has been seen, pregnancy is a
it should be borne in mind that progesterone situation where there are adequate causes for
and oestrogens have been shown to increase a marked tendency to sodium depletion.
slowly in early pregnancy, with a progressive Moreover, several biochemical features of
rise to term (Short & Eton, 1959; Greig et al., sodium depletion are present from early
1962; Yannone et al., 1968; Brown, 1956; pregnancy, namely, increases in plasma renin,
Klopper & Billewicz, 1963; Samaan et al., angiotensin II and aldosterone. Finally, many
1969) and they would therefore be expected of the known symptoms of severe sodium de-
to have a greater effect on sodium balance, pletion (nausea; aberrations of taste; a metallic
renin and angiotensin in late rather than sensation in the mouth unrelieved by drinking;
early pregnancy. thirst; cramps; mental and physical tiredness),
The reason for the increase in aldosterone, are so common in pregnancy, especially in the
especially in early pregnancy, remains there- early weeks, as to be dismissed often without
fore unexplained, but it seems possible that comment. It is quite likely that by the time
it is required to conserve sodium for the needs most women are examined in early pregnancy
of the mother and foetus in the face of the (usually at the end of the first trimester),
raised glomerular filtration rate and the their tendency to sodium depletion is well-
natriuretic action of progesterone and poss- compensated and they are in normal sodium
ibly other steroids. While the raised glomer- balance, albeit at the expense of an increase
ular filtration rate seems likely to be the in circulating renin, angiotensin and aldo-
dominant effect in early pregnancy, this will sterone.
become more obscured later with an increase It would certainly appear to be worth
in the importance of other factors. testing as rigorously as possible the hypo-
thesis that the nausea and other symptoms of
Sodium depletion and the nausea and other early pregnancy are due to a tendency to
symptoms of early pregnancy; a hypothesis sodium depletion.
McCance (1936) gave a detailed account of
the symptoms experienced by normal subjects Renin, renin-substrate, angiotensin, angio-
during severe experimental sodium depletion. tensinase and aldosterone in 'pre-eclampsia'
Prominent features included nausea; aberr- Definitions of what is called variously 'pre-

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 Renin, Angiotensin and Aldosterone in Human Pregnancy and the Menstrual Cycle

eclampsia', 'specific hypertensive disease of

pregnancy, 'pregnancy hypertension' differ,
sometimes quite widely, from one centre to
••
another. In few, if any, of the reported series
in which estimations of different components
1000 •
I
of the renin-angiotensin-aldosterone system
have been reported have adequate control •
subjects been studied in parallel. The follow- •••
ing remarks are therefore to be regarded
rather as indicating trends than as definitive •I
statements. •
It can be said at the outset that in 'pre- •••
eclampsia', the concentrations of renin, renin-
substrate and angiotensin in peripheral blood •••
• •
are generally not strikingly different from nor- ••
•
mal pregnancy, although there is a consistent
tendency for the mean plasma renin concen-
tration to be slightly reduced, while remaining
••
..••
•••
••
••
~.
•
well above the non-pregnant mean. •
••• •••••
•••
Renin. Brown et al. (1965, 1966a) found ••• •••
•••••••• ••••
••
the mean plasma renin concentration in a ••••••••
••••••
group of women hypertensive in the third ••••
trimester of pregnancy, and with proteinuria, •••••
to be slightly, but significantly, lower than •
in a control group of normal women at the
same stage of pregnancy. A similar trend was
noted by Bonar et al. (1966) in American
negro women with severe pregnancy hyper- I
tension. Non-pregnant Pregnant Amniotic
Fluid
In marked contrast, Brown et ai. (1966a)
noted that the mean plasma renin concen- Fig. 5. Comparison of renin levels in amniotic
tration in seven women in whom hypertension fluid with those in peripheral venous blood of pregnant
and non-pregnant normal women (Log. ordinate
was a complication of rhesus iso-immuniz- scale) (Brown et al., 1964b).
ation or hydatidiform mole was considerably --------- ...• --~

above the value for normal pregnancy.
Angiotensin. Massani et al. (1967) found
no significant reduction in angiotensin blood
level in a small series of women with preg-
nancy toxaemia.
Angiotensinase. 'Angiotensinase' activity
found in peripheral blood in pre-eclampsia
has varied widely (Page, 1947; Hickler et al.,
1963; Landesman et ai., 1963). It seems pos-
sible that these variations represent technical
aberrations as much as genuine in vivo
physiological differences. Berger and Langhans
(1967) found increased plasma angiotensinase
in pre-eclampsia compared to normal preg-
nancy of similar duration, and discussed the
possible diagnostic importance of this finding.
Pressor effect of infused angiotensin.
The pressor response to infused angio-
tensin, which would be expected to vary
inversely with the prevailing angiotensin
blood level (see Brown et al., 1966b), is
reduced in normal pregnancy as compared
with the non-pregnant state, but is relatively
enhanced in pre-eclampsia (Abdul-Karim &
Assali, 1961; Chesley, 1966; Talledo, 1966;
Talledo et al., 1968).
Renin substrate. To date, only a few
measurements of circulating renin-substrate
have been reported in pregnancy hyper-
tension; these have fallen usually within the
normal pregnancy range (Helmer & Judson,
1967; Weir & Tree, unpublished).
Aldosterone. Aldosterone measurements
have been in general agreement with the
results obtained for renin, although in several
series the numbers have been too small for

191

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Robertson, Weir, Diisterdieck, Fraser and Tree

worthwhile statistical analysis. Thus, aldo-
sterone excretion (Martin & Mills, 1956;
Venning et al., 1957; Rinsler & Rigby, 1957;
Kumar et al., 1959), secretion (Wiele et al.,
1960; Sims et al., 1964) and plasma concen-
tration (Weir et al., 1971a) have all been, on
average, lower in pre-eclampsia than in
normal pregnancy.
Uterine, placental, amniotic fluid and foetal
renin in man; foetal aldosterone
In the human, high concentrations of renin,
or an enzyme closely resembling it, have
been found in amniotic fluid (Brown et al.,
1964b; Skinner et al., 1968) (Fig. 5) and in
chorion, amnion, decidua, placenta and
myometrium (Skinner et al., 1968). Uterine
renin increases during pregnancy (Geelhoed
et al., 1970). Considerably less renin is detect-
able in human uterine muscle than seems to
be present in that of certain other mammals,
such as the rabbit (Skinner et al., 1968; Ferris
et al., 1967; Ryan, 1970).Symonds et at. (1968)
as a result of tissue culture studies, concluded
that in man, the intra-uterine renin was
mainly of chorionic origin from where there
was ready access to amniotic fluid.
Brown et al. (1964b) found generally
slightly higher concentrations of renin in
umbilical vein plasma than in maternal
peripheral venous plasma at term. In a
similar study Skinner et at. (1968) found no
significant difference between the plasma
renin concentrations at these two sites.
Although not certain, it seems likely that
the high level of renin in the maternal blood
derives from the maternal kidneys rather than
the uterus or its contents. Skinner et at. (1968)
have postulated that it would be difficult
for the human chorion to contribute to the
maternal circulation through the thick deci-
dual layer. Moreover, elevated levels of renin
may persist in the maternal peripheral blood
for as long as 48 hours after delivery (Brown
et al., 1966d), whereas the half-life of endo-
genous renin, at any rate in the anephric
subject, is of the order of 120 minutes
(Brown et al., 1969).
The function of intrauterine renin remains
uncertain; possibly it may be concerned with
the regulation of sodium and fluid transfer
to the foetus. The rudimentary counter-
current vascular system of the human
placenta resembles, in some respects, the more
elaborate arrangements in the kidney (see
Kriz & Lever, 1969); it is at least possible on
present evidence that in both situations renin,
via angiotensin, controls the velocity of blood
flow, and hence the efficiency of exchange, in
these systems.
Bayard et at. (1970)infused radioactively lab-
elled aldosterone intravenously into mothers
before delivery, subsequently detected the lab-
elled steroid in foetal blood, and thus demon-
strated the ability of aldosterone to cross
the placenta. They also concluded that since
the specific activity of aldosterone was less
in foetal than in maternal blood, foetal
secretion of aldosterone before birth was
demonstrated. This, however, is dependent
upon the certainty of equilibration having
been reached during infusion, and requires
confirmation.

•Plasma
Anglotensln'II 30

: r:
pg/ml

rs
Day of Cycle

Fig. 6. Changes in plasma angiotensin II in one normal subject during the

menstrual cycle. The height of the peak level seen in this woman at 23 days should
be noted, since the upper limit of normal with this method (Diisterdieck &
McElwee, 1971) is usually regarded as 35 pg. per ml. The elevated angiotensin
occurring in the luteal phase must be taken into account in making angiotensin
measurements for diagnostic purposes.

192

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 Renin, Angiotensin and Aldosterone in Human Pregnancy and the Menstrual Cycle
Aldosterone, renin and angiotensin in the
menstrual cycle
Aldosterone excretion (Reich, 1962; Nowa-
czynski et al., 1962; Sundsfjord & Aakvaag,
1970) and secretion rate (Gray et al., 1968)
are consistently elevated in the luteal phase of
the menstrual cycle. There isalso general agree-
ment that plasma renin concentration (Brown
et al., 1964c; Skinner et al., 1969), plasma
renin activity (Winer, 1965),and plasma angio-
tensin II (Sundsfjord & Aakvaag, 1970; Diist-
erdieck & McElwee, 1971) (Fig. 6) are eleva-
ted in the luteal phase. The evidence is there-
fore strongly suggestive that the increase in
aldosterone secretion is brought about, at
least partly, by increases in renin and angio-
tensin.
Most workers have considered that an
increase in aldosterone production in the
second half of the cycle is needed to counter-
act the natriuretic effect of the increased
plasma progesterone (Woolever, 1963). The
possibility that changes in the pattern of
oestrogen production might contribute are
also considered by Gray et al., (1968). It is
noteworthy that oestrogens may affect the
renin/angiotensin system directly by causing
increases in the concentration of renin-
substrate (vide supra), although Skinner et al.,
(1969) could detect no change in plasma
renin-substrate level during the menstrual
cycle.
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