8th Postgraduate Course for Training in Reproductive Medicine and Reproductive Biology

Renin and aldosterone in human reproduction

M.B. Vallotton
Division of Endocrinology, Department of Medicine
University Cantonal Hospital, 1211 Geneva 14, Switzerland

INTRODUCTION

The need during pregnancy to supply oxygen and nutrients to the fetoplacental unit and to counterbalance the effects exerted by the new gonadotropic and sex hormone blood levels requires profound adjustments of all the hormones involved in the regulation of blood volume and hydro-electrolytic homeostasis, and thereby blood pressure.

CARDIOVASCULAR AND RENAL ADJUSTMENTS DURING PREGNANCY (5-7)

The state of pregnancy is normally accompanied by a global gain of 500 to 900 mmol NaCl which are distributed between the maternal side and the fetoplacental unit. As a consequence of this saline retention, a regular and progressive increase of plasma volume occurs from the early weeks of gestation, reaching a maximum toward delivery. At the same time, but following a different pattern of progression, glomerular filtration increases very rapidly at the very onset of gestation to reach a maximum around the 10th week and is maintained thereafter to term. The increment of glomerular filtration can be as much as 50%, bringing the total load of filtered sodium to 30,000 mmol per 24 h (an increment of 5,000 to 10,000 mmol). This represents an enormous quantity of supplemental filtered sodium when compared to the maintained urinary excretion of some 100 to 200 mmol NaCl. It results from these phenomenons that the pregnant women are especially sensitive to factors interfering with renal sodium reabsorption. Pregnant women are prone easily to develop edema in case of excessive sodium intake or tubular reabsorption, or on the contrary, to develop hypovolemia in case of excessive uncompensated renal excretion of sodium. Perturbation of this fine-tuning of the hemodynamic and endocrine homeostasis leads to preeclampsia (15). Table 1 shows the renal factors favoring or opposing sodium excretion in pregnant women. In parallel, and in spite of saline retention, the blood pressure of pregnant women diminishes normally during the first trimester to become stabilized at values some 20 mmHg lower than when in the non-pregnant state. Commonly, a certain degree of tachycardia at rest is observed. From the changes in these observable cardiovascular parameters, a reduced total peripheral resistance can be inferred.

TABLE 1. Renal factors influencing sodium excretion in pregnancy.

Increased NaCl excretion	Decreased NaCl excretion
Increased glomerular filtration	Increased filtration fraction
Decreased plasma albumin concentration	Increased post-glomerular oncotic pressure
Decreased vascular resistance	Increased ureteral pressure
.	Increased vena cava compression

As a consequence of increased renal blood flow, a decrease in plasma levels of creatinine, urea, and above all uric acid (-20%) is normally observed, so that new criteria of normalcy, particularly for the latter, should be applied throughout pregnancy. A normal pregnancy value of uric acid of 4 mg/dl (238 mmol/l) increases to 5 mg/dl (297 mmol/l) in mild preeclampsia and >6 mg/dl (>357 mmol/l) in severe preeclampsia (12).

HORMONAL ADJUSTMENTS THROUGHOUT PREGNANCY

In view of the profound modification of the renal and cardiovascular systems to satisfy the need of the fetoplacental unit, it is not surprising that important adjustments of plasma levels of hormones involved in the water and electrolytes homeostasis occur. Actually, some of these changes may be the cause and others the consequence of the new hormonal environment and of the circulatory modification resulting from pregnancy with the new important role played by the placenta. Table 2 displays a list of hormones facilitating or opposing renal sodium reabsorption.

TABLE 2. Hormonal factors influencing sodium excretion in pregnancy.

Augmentation	Diminution
Progesterone	Plasma Aldosterone
Antidiuretic hormone	Plasma Renin-Angiotensin II
Atrial natriuretic hormone	Thromboxane A2
Prostacyclin	Estrogens
.	Cortisol

THE RENIN-ANGIOTENSIN SYSTEM (3-4,26)

The changes observed in plasma level or activity of the various components of the renin-angiotensin system are quite complex as they involve non-regulated changes of renin substrate, regulated changes of prorenin and renin synthesis, secretion from the maternal and the fetal kidney as well as from the placenta, and, finally, changes in the effect of angiotensin II on its target cells.

Angiotensinogen or renin substrate (10,30-34)

Angiotensinogen is constitutively synthesized by the liver; as other plasma proteins, however, its synthesis is up-regulated by estrogens. In pregnant women, or women taking estrogen-containing preparations, the plasma level of angiotensinogen increases approximately 3 to 5-fold. As the plasma concentration of angiotensinogen in the non-pregnant state is close to the numerical value of the Km of renin, it ensues that plasma renin activity can at most double when the angiotensinogen level increases under the effect of estrogen.

Renin synthesis, release and resulting plasma renin activity (2,10,14,30-34)

Plasma concentration of active renin increases slightly early in the first trimester to reach a plateau (five-fold basal value) at the 20th week of gestation which is then maintained throughout pregnancy. On the maternal side, the parallel but more important increase of plasma renin activity is a consequence of the increased renin substrate concentration (see above). A contribution of the placenta is conceivable. A low level of active renin has been proposed as a good marker of extrauterine pregnancy. By contrast, on the fetal side, the much increased level of plasma renin activity appears to be almost entirely due to increased renin synthesis and release, with no contribution from changes in the substrate level.

Prorenin (18,19,25,34)

This inactive precursor of active renin deserves special mention as it appears to be generated not only by the kidney but also from extra-renal sources notably the female reproductive tract and the placenta. Prorenin is normally partly constitutively synthesized and secreted by the juxta-glomerular cells of the kidney, but some 10% originates from ovarian tissue and can be recovered from follicular fluid (9,15). Prorenin but not active renin increases in the plasma transiently, but markedly (about 2-fold) during the LH surge at the time of ovulation, and in response to hCG to induce ovulation. After conception, it increases about 8 to 10-fold in parallel with plasma hCG. It can be recovered from ovarian follicular fluid. Ovarian prorenin might be involved in the pathogenicity of ovarian hyperstimulation syndrome as, in this circumstance, very high values of total renin, renin activity and aldosterone, unsuppressed by fluid overload, have been reported. The level of prorenin in follicular fluid could have a prognostic value as a marker for the chance of survival of transplanted eggs. Not only prorenin, but also angiotensin II and III, with their renin-like activity, have been recovered from gonadotropin-stimulated and unstimulated follicular fluid. At term pregnancy, inactive renin has been localized by the immunofluorescent technique in trophoblasts of the human chorion laeve.

Angiotensin II (10, 32,33)

This terminal active peptide of the renin-converting enzyme cascade increases in consequence of the rise of renin activity or of active renin. Yet the pressor action of angiotensin II is blunted: the mean effective pressor dose of angiotensin II is approximately 3 to 4-fold higher during normal pregnancy, but is again reduced early before the onset of preeclampsia. The increase of prostacyclin (PGI2), a vasorelaxing arachidonic acid product, during normal pregnancy and the decrease of these values along with an increase of thromboxane A2 (and/or the ratio TXA2/PGI2) is considered the most likely explanation for the changes of pressor activity of angiotensin II during pregnancy and preeclampsia (see below).

Prorenin, active renin, angiotensin converting enzyme and angiotensin II have been observed in the chorion, except for angiotensin II, whose concentration per gram tissue was highest in the placenta (13). In that study, no difference was observed between placenta and fetal membranes whether they were obtained from normal or from preeclamptic pregnancies.

Angiotensin II receptors

Changes in the number of angiotensin II binding sites (11) may also account for the changes of pressor activity of angiotensin II during pregnancy and preeclampsia. There is a good correlation between the pressor response to angiotensin II and the binding of angiotensin II to platelets during pregnancy, and the increase of both parameters in pregnancy-induced hypertension (1).

Two different classes of angiotensin II receptors, designated AT1 and AT2 have been pharmacologially identified and subsequently their genes have been cloned and their amino acids sequence determined. AT1 is the classical receptor mediating all the known biological responses to angiotensin II through a well characterized transmembrane signalling system. Much less i known about the AT2 subtype, whose biological role and the secondary messenger mediating it are still uncertain. There are suggestion that it might play a role in fetal life as a modulator of the action of growth factor during embryogenesis. The regional distribution of these two receptor subtypes is markedly different. Whereas AT1 is widespread distributed throughout the cardiovascular system, the adrenals, the CNS, and the liver, the AT2 is present only in the adrenals, the uterus and the coronary endothelial cells. In nonpregnant human uterus AT2 sites predominate and their density is considerably augmented by estrogen, an effect blunted by progestogens. They are found only at very low concentration in sex-steroid-deprived uterus of post-menopausal women (21). By contrast, during ovine or human pregnancy AT1 receptors subtypes are relatively more abundant.

Cortisol

The peripheral modulation of cortisol action by the "cortisol-cortisone shuttle" is of utmost importance in clinical medicine (28). It explains the variety of syndromes of apparent mineralocorticoid excess (AME) due to mutation of the gene encoding 11b-hydroxysteroid dehydrogenase (11b-HSD) or to inhibition of the isoform 11b-HSD2 of the enzyme responsible for the conversion of cortisol to cortisone. The isoform 11b-HSD1 of this enzyme has a low affinity dehydrogenase and acts essentially as an oxo-reductase converting cortisone to cortisol. Deficiency of this isoform has been observed in women with a phenotype of polycystic ovary-like syndrome (29), but no anomaly in the interconversion of cortisol to cortisone could be found in a large series of women with hirsutism and oligomenorrhea (29).

Cortisol has been found to act directly in human granulosa-lutein cells to inhibit the LH-induced steroidogenesis. In these cultures, the 11b-HSD was high and its inhibition by carbenoxolone potentiated the action of cortisol. The cells from 5/14 patients undergoing oocyte collection for in vitro fertilization and embryo transfer lacked detectable 11b-HSD and exhibited an increased sensitivity to the inhibitory action of cortisol (22). The same authors made recently the interesting observation of an inverse relation between the activity of 11b-HSD in cultured granulosa-lutein cells and the outcome of in vitro fertilization-embryo transfer. The authors propose this biochemical test for the selection of the oocyte (23).

Aldosterone (10,31-34)

Plasma aldosterone concentration increases early and progressively during pregnancy, reaching a level around 40 ng/dl (1.1 nmol/l) at the 16th week of gestation with a further rise to 60 ng/dl (1.7 nmol/l) after the 32nd week. Urinary aldosterone increases steadily up to the last week of gestation. This increase partly results from increased renin activity and partly counteracts the opposing effect of increased progesterone which experts an antialdosterone effect. From these findings, one may assume that no changes of angiotensin II binding sites occur on the zona glomerulosa cells of the adrenal cortex, contrary to what has been observed in platelets and inferred to occur in vascular smooth muscle cells.

Atrial natriuretic hormone

Plasma ANP concentration increases significantly during the third trimester of uncomplicated pregnancy with a further rise 72 h postpartum. A further elevation of ANP plasma concentration antedating the elevation of blood pressure has been reported in preeclampsia (17,20).

Endothelin

Endothelin-1 (ET1) is an extremely potent vasoconstrictor released by the endothelial cells and mainly acts locally. It might also be involved in steroidogenesis. Increased levels have been found in patients with preeclampsia and could play a role in its pathogeny by aggravating fetal hypoxia through its vasoconstrictor effect on the placental vascular bed.

Prostanoids (8,35)

The products of the arachidonic acid cascade play an important role in the local regulation of vascular tone and renal function. Prostanoids of the E2 and I2 (prostacyclin) series are vasorelaxing and natriuretic, while thromboxane A2 (TXA2) has opposing effects. Most studies have reported a decrease of PGI2 in preeclampsia along with an increase of TXA2. Accordingly, pregnancy-induced hypertension appears to be secondary not only to an excess of vasoconstrictor agents but also to a deficit of vasorelaxing compounds. Hence the proposition to prevent the occurrence of preeclampsia in predisposed women by low dose aspirin (24).

CONCLUSION

The state of pregnancy, with the new hormonal environment resulting from hormonal secretion of the placenta and the need to satisfy the vascularization of the fetoplacental unit, requires dramatic changes of the cardiovascular and renal systems. This is achieved through adaptation of maternal hormonal systems. Up-regulation of numerous vasoconstrictors as well as vasodilators is observed very early and throughout pregnancy. Imbalance in favor of the first category appears to account for the occurrence of pregnancy-induced hypertension, but pathological placental and/or renal vascular modifications can also be contributory, accounting for increased total peripheral resistance and decreased placental and renal perfusion. Recently, a predominant role has been attributed to an increased ratio of TXA2/PGI2 in the pathogeny of preeclampsia, explaining loss of normal resistance to the pressor effects of elevated angiotensin II level normally observed in uncomplicated pregnancy.

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