Reproduction and the renin-angiotensin system

Neuroscienc¢ and Biobehavioral Reviews, Vol. 19, No. 2, pp. 241-250, 1995 Copyright ©1995 Elsevier Science Ltd Printed in the USA. All rights reserved 0149-7634/95 $9.50 + .00

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Reproduction and the Renin-Angiotensin System W I L L I A M F. G A N O N G

Department of Physiology, Universityof California, San Francisco, CA 94143-0444, USA GANONG, W. F. Reproduction and the renin-angiotensin system. NEUROSCI BIOBEHAV REV 19(2) 241-250, 1995.A unique aspect of the circulating renin-angiotensin system and the many independent tissue renin-angiotensin systems is their interactions at multiple levels with reproduction. These interactions, which have received relatively little attention, include effects of estrogens and possibly androgens on hepatic and renal angiotensinogen mRNA; effects of androgens on the Ren-2 gene and salivary renin in mice; the prorenin surge that occurs with but outlasts the LH surge during the menstrual cycle; the inhibitorj effects of estrogens on thirst and water intake; the tissue renin-angiotensin systems in the brain, the anterior pituitary, and the ovaries and testes, that is, in all the components of the hypothaiamo-pitnitary-gonadal axis; the presence of some components of the renin-angiotensin system in the uterus and the fetoplacentai unit; and the possible relation of renin a~Ld angiotensin to ovulation and fetal well-being. These interactions are described and their significance considered in this Sl~Lortreview.

Renin

Angiotensin

Angiotensinogen

Reproduction

Hypothalamus

Ovaries

Testes

Uterus

INTRODUCTION

CIRCULATING AND TISSUE RENIN ANGIOTENSIN SYSTEMS

I AM pleased to contribute this review to honor Julian Davidson on the occasion of his retirement. Julian was the first student to obtain a PhD in my laboratory. He was bright, innovative, and independent, and had a broad interest in reproduction in males. He :focussed in particular on neuroendocrine control of testicular function via the hypothalamic regulation of pituitary secretion of gonadotropins, and this became the subject of his thesis. In his subsequent career, he continued to explore this subject, along with sexual behavior and human sexual function. He became internationally known for his work in this area. In the meantime, my interest shifted to the renin-angiotensin system, first in relation to the regulation of aldosterone secretion, then to renin secretion in its own right, and finally to the multiple separate ti~;sue renin-anglotensin systems that have been described in the past few years. One intriguing aspect of the circulating and tissue reninangiotensin systems is the striking number of interactions between them and reproduction. Since in a real sense this brings my interest and Davidson's back together, it seems appropriate to make the interactions the subject of this short review honoring him. The goal of the review is to list the interactions, set them in context where l~ossible, and provide references to reviews and individual papers for these wishing to explore them in more detail.

The reactions that produce anglotensin II in the circulating blood depend on 3 circulating proteins: angiotensinogen, renin, and anglotensin-converting enzyme (Fig. 1). Circulating angiotensinogen is a glycoprotein that is produced in the liver and contains 453 amino acid residues. It is the product of a single gone, and is synthesized with a 32amino acid signal sequence that is removed when the nascent protein enters the endoplasmic reticulum. Active renin is a 37 kDa aspartyl protease secreted by the juxtaglomerular cells of the kidneys. The only known function of renin is formation of the dccapeptide angiotensin I by hydrolyzing the bond between amino acid residues l0 and l l at the N terminal end of the anglotensinogen molecule. The juxtaglomerular cells and other tissues also secrete prorenin, the inactive precursor of renin. However, prorenin is not convened to active renin in the circulation, and the only source of active renin in the circulation appears to be the juxtaglomerular cells (99). In some strains of mice, there are 2 renin genes, Ren-1 and Ren-2, but in rats and humans, renin is the product of a single gene. Angiotensin-converting enzyme is a dipeptidyl carboxypeptidase which removes a 2 amino acid fragment from the Cterminal of anglotensin I to form the biologically active octapeptide, angiotensin II. It is an ectoenzyme which in most of the tissues has a short cytoplasmic domain, 1 membrane241

242

GANONG ANGIOTENSINOGEN ] RENIN ~ [

ANGIOTENSIN,

ACE ~ [

~ "=- - Renin inhibitors

~ ~ " - Captopril, other ACE inhibitors

ANGIOTENSINII

~.= PD 123177, others - ~

]

}

- Saralasin, other analogues

" ~

- Losartan (Oup 753), others

FIG. 1. Formation of angiotensin II in circulating blood. The sites at which various inhibitors of the formation of angiotensin II or its actions are also shown. ACE, angiotensin-converting enzyme. Reproduced with permission from (34).

spanning region, and a large extracellular domain which contains 2 active sites (87). This form is known as somatic angiotensin-converting enzyme. In the testes, there is a second smaller form, germinal angiotensin-converting enzyme, which contains only 1 active site and is associated exclusively with spermatozoa (see below). It is worth noting that a variety of acid proteases in addition to renin can form angiotensin I, and angiotensin-converting enzyme can act on a variety of different substrates in addition to angiotensin I. However, the only known precursor of angiotensin I is angiotensinogen. Angiotensin II has a short half life in the circulation. It is metabolized by aminopeptidase and other peptidases to form partially active fragments such as angiotensin 2-8 (AIII) and angiotensin 3-8 (A IV) as well as inactive fragments. There is little evidence that the fragments have special physiological functions, although it has been argued that A IV has a special relation to memory and other aspects of brain function (40). The main actions of circulating angiotensin II are summarized in Table 1. It not only causes constriction of vascular smooth muscle and stimulates aldosterone secretion, but it acts on the brain via the circumventricular organs to produce a variety of effects including stimulation of thirst, increased blood pressure, and increased secretion of arginine vasopressin and ACTH. Two different types of angiotensin II receptors have been described (4,96). AT= receptors mediate most of the known effects of angiotensin II. They are G protein-coupled to phospholipase C, and increase intracellular IP3 and DAG. Two closely related AT~ receptors, AT~A and ATm, have been cloned. AT2 receptors have also been cioned (49,60). They have 7 transmembrane domains and are 32-34o70 identical in sequence to AT1 receptors, but unlike the vast majority of receptors with 7 transmembranes, they do not appear to be coupled to G proteins. They may act by altering intracellular phosphatases (4). However the details of their actions and their exact functions are still unknown. The prominent role of the renin-angiotensin system in human hypertension and heart failure has provided the impetus for rapid development of drugs that inhibit the production of angiotensin II or its effects. These include renin inhibitors such as enalkiren, angiotensin-converting enzyme inhibitors such as captopril and enaiaprilat, and drugs which block angiotensin II receptors. Competitive antagonists such as sara-

lasin, which are modifications of the angiotensin II molecule, block all known angiotensin II receptors (Fig. 1). Recently developed nonpeptide receptor antagonists selectively block ATm or AT2 receptors (96). The best known AT1 blocking drug is losartan. PD123177 and several other drugs block AT 2 receptors. In 1971, Ganten and associates (37) reported evidence that the brain had intrinsic renin activity. In the years since that discovery, evidence has accumulated that a remarkably large number of tissues appear to have their own renin-angiotensin systems which produce angiotensin II for local use. Table 2 is a current list of the tissues in which at least some of the components of the renin-angiotensin system have been found. In most instances, the tissues contain the mRNAs for angiotensinogen and/or renin, and the presence of angiotensin II and angiotensin-converting enzyme immunoreactivity has been demonstrated in many of them. In the context of a relation to reproduction, note that the list includes all the components of the hypothalamic-pituitary-ovarian axis (i.e., the brain, the anterior pituitary, and the ovaries). It also includes the nonpregnant and the pregnant uterus, the placenta, and the testes. There is of course no rule that the cascade of reactions responsible for production of angiotensin II is the same in all the tissues as it is in the circulation. However, at least in some instances, the steps appear to be the same. EFFECTS OF REPRODUCTIVEHORMONESON THE CIRCULATINGRENIN ANGIOTENSINSYSTEM

A ngiotensinogen The secretion of angiotensinogen from the liver is under hormonal control. Release is increased by glucocorticoids, thyroid hormones, cytokines associated with the acute phase response, and estrogens. The overall control of secretion has been reviewed elsewhere (58). There has been debate about whether the estrogen effect is primary or secondary, but there are several reports of stimulation of angiotensinogen secretion by estrogen in vitro (20). An observation that appears to be at odds with the conclusion that estrogen acts directly on the liver is the finding that hypophysectomy blocks the effect of estrogen on circulating angiotensinogen and hepatic angiotensinogen mRNA (41,55). However, estrogen receptors in the liver are dependent on prolactin (8), and the prolactin deficiency produced by hypophysectomy could be responsible. In one experiment (41),

TABLE 1 ACTIONS OF CIRCULATINGANGIOTENSINII Contracts vascular smooth muscle Promotes growth of vascular smooth muscle Stimulates aldosterone secretion Stimulates growth of zona glomerulosa Facilitates noradrenergic transmission in the autonomic nervous system Stimulates prostaglandin synthesis Inhibits renin secretion Acts on the circumventricular organs in the brain to produce: Increased water intake Increased salt intake Increased blood pressure Increased secretion of vasopressin Increased secretion of ACTH

RENIN AND REPRODUCTION TABLE 2 PUTATIVE TISSUE RENIN-ANGIOTENSIN SYSTEMS

Brain Endocrine glands Anterior lobe of pituitary Intermediate lobe of pituitary Adrenal zona glomerulosa Ovaries Testes Pineal Exocrine portion of pancreas Uterus Endometrium Decidua Kidneys Heart Arterial Walls Vascular smooth muscle Endothelium Brown fat Thymus Eye Placenta

prolactin treatment partially restored the estrogen response in hypophysectomized rats. The effect was small, but thyroid hormones and glucocortio3ids also affect plasma anglotensinogen (20,58), and these need to be replaced as well (53). The increase in angiotensinogen secretion produced by estrogens in female rats is low before puberty and increases during sexual maturation in parallel with an increase in the number of estrogen receptors in the fiver (55). Clinically, contraceptive pills containing relatively large amounts of estrogens increase circulating anglotensinogen (20). Since the concentration of anglotensinogen as well as the concentration of renin determines the amount of anglotensin I and anglotensin II formed in the blood (39), the increase in plasma angiotensinogen produces an increase in circulating anglotensin II. The angiotensin II inhibits renin secretion by a direct feedback effect on the juxtaglomeru][ar cells, and circulating angiotensin II falls back to normal levels. However, this compensation is incomplete in some women, and blood pressure is chronically increased ("pill hypertension"). Given the effect of estrogen on angiotensinogen secretion one might expect a higher circulating level of angiotensinogen in the preovulatory and luteal phase of the menstrual cycle, when estrogen secretion is i[ncreased. However, no statistically significant differences have been observed (46). In addition, plasma anglotensinogen concentrations in women are generally comparable to those in men. Therefore, the physiological role of estrogen in the regulation of anglotensinogen secretion remains obscure. Testosterone does not effect plasma anglotensinogen, and may actually inhibit expression of the angiotensinogen gene in the fiver (54). On the other hand, androgens increase angiotensinogen mRNA in the kidneys (25). Renin The Ren-2 gene which is found in some strains of mice appears to have an androgen binding site in its promoter (24,97). The major consequence is that in strains of mice

243 which have this second renin gene, the salivary glands in males contain about 5 times as much renin mRNA and 8 times as much renin as they do in females (100). Castration reduces salivary renin to female levels. The renin content of saliva is high in male mice and it has been argued that in the frequent fights characteristic of male mice, they bite their opponents and thus inject them with renin (79). On the other hand, there is little salivary renin in other species, and in them, androgens normally do not increase PRA (51). Prorenin An interesting relation between the menstrual cycle and the renin-angiotensin system is the mid-cycle increase in plasma prorenin (5,43,83). This surge occurs just after ovulation and lasts 2-3 days (Fig. 2). A similar surge is induced by injection of gonadotropins, and the source of the prorenin is clearly the ovary because the concentration of prorenin is greater in ovarian vein blood than peripheral blood (73,83). However, the significance of the surge is uncertain. Prorenin is not convened to active renin in peripheral blood, and the concentration of active renin in ovarian vein blood is not significantly higher than the concentration in peripheral venous blood (73). Some report a small increase in peripheral plasma active renin in the midluteai phase of the menstrual cycle, but this occurs after the prorenin peak (83), when progesterone is high, and is usually ascribed to stimulation of renal renin secretion caused by progesterone-induced natriuresis and diuresis. Others report that a luteai increase only occurs in women with hypertension (50). It may be that the prorenin increase is merely spillover from intraovarian events orchestrated by the ovarian renin-angiotensin system (see below). Estrogens and Drinking Circulating angiotensin II acts on the subfornical organ to increase water intake in rats and other species. Water intake decreases at the time of estrus in rats, when circulating estrogen is high, and systemic injections of estrogens decrease ad lib and anglotensin II-induced drinking in ovariectomized rats (29,30). To determine the site at which estrogens exerted this inhibitory effect, Jonklaas and Buggy (47,48) injected estradiol benzoate into the cerebral ventricles or implanted crystalfine estradiol benzoate in various parts of the brain. Intraventricular injections and implants in the medial preoptic area but not in other parts of the brain inhibited drinking. Drinking responses to carbachol and hypertonic saline were unaffected. The subfornical organ per se was not tested, but estrogen from the implants in the medial preoptic area could well have diffused to this circumventricular organ. Interestingly, the inhibitory effect of estrogens on drinking was sexually dimorphic; it was not seen in male rats. Furthermore, it was absent in female rats treated with testosterone during the neonatal period, whereas it was present in male rats castrated at birth. THE BRAIN RENIN-ANGIOTENSIN SYSTEM

The brain renin-angiotensin system has been the subject of numerous reviews, and several recent reviews have focussed on its relation to the regulation of LH and prolactin secretion (32-34,81,90). All the components of the renin-anglotensin system are present in the brain. Angiotensin II immunoreactivity is found in neurons, and particularly in their endings. The amount of renin is low, but it generally parallels distribution of angiotensin II. Renin mRNA is also present. Angiotensin-converting

244

GANONG

Active renin ng/ml/hr

I0

'° I 0

I

Prorenin ng/ml/hr

30 20 I0 0 15

Progesterone =o

ng/ml

5

0 3OO FstrodioI 2 0 0

pglml

Ioo 0

40

LH MIUIml

30 20 ~o

1.5 to FSH 5 Ulornl -

0

= ill

i , i ,I

-I0

= , , llJ

-5

.

0 =J

0

-

iI

, i =i

5

Ill

lO

Doys FIG. 2. Changesin prorenin, activerenin and other hormonesthroughout the menstrual cycle in a normal woman. Day zero = LH peak. Reproduced, with permission, from (84a).

enzyme is present, although most of it is in the choroid plexus and circumventricular organs. Angiotensinogen and its mRNA are present in abundant amounts, but most and possibly all of the anglotensinogen is produced in astrocytes (35). Thus, it appears that some sort of shuttle of components is involved in the production of angiotensin II in neurons, and that anglotensinogen is taken up by the neurons, or angiotensin I or II is formed extracellularly and taken up by the neurons with transport to their endings. The astrocytes in the brainstem and diencephalon produce more anglotensinogen than those in the cerebral cortex. Over a number of years, Steele and associates (34,90) have accumulated considerable evidence that in female rats, anglotensin II produced by the brain renin-angiotensin system plays an important excitatory role in the regulation of GnRH secretion. Angiotensin II increases plasma LH when administered intraventricularly during proestrus, and in ovariectomized rats treated with estrogen and progesterone. In the absence of ovarian steroids and in male rats, the response to intraventricular angiotensin II is inhibition of LH secretion, but so is the response to intraventricular norepinephrine, which like anglotensin II stimulates in the presence of ovarian steroids. In our hands, systemic administration of saralasin and enalaprilat

has no effect on LH secretion or ovulation. In normally cycling rats, intraventricular saralasin and enalaprilat inhibit the normal LH surge and block ovulation. The site of action of the angiotensin II is the anterior portion of the hypothalamus, and it acts by releasing GnRH into the portal-hypophysial vessels. Interestingly, the increase in LH secretion produced by intraventricular anglotensin II is blocked not only by intravcntricular losartan but by intraventricular administration of the AT2 blocking drug PD123177 (92). Losartan has a small amount of AT2 blocking activity and PD123177 has a small amount of AT1 blocking activity. However, losartan and the PD compound are equally effective in blocking the LH increase. Therefore, the data suggest a third, as yet uncharacterized anglotensin II receptor may be involved. Another situation has been reported in which there is equal inhibition of an anglotensin II response by ATt and AT2 blocking drugs (10). There is good evidence that the increase in GnRH secretion produced by intraventricular angiotensin II is due to increased release of norepinephrine in the anterior portion of the hypothalamus. Thus, the increase is blOcked by or2 adrenerglc blocking drugs, and it is also blocked if norepinephrine syn-

RENIN AND REPRODUCTION thesis is inhibited by a(~miuistration of the dopamine ~hydroxylase inhibitor DDC (34). The data are consistent with our working hypothesis chat angiotensin II acts presynaptically on ascending nora&'energic neurons to facilitate release of norepinephrine at endings on the GnRH neurons in the preoptic area. This in turn increases secretion of GnRH. It is worth noting that in rats, neither systemic saralasin nor systemic enalaprilat in high doses inhibit LH secretion produced by intraventricular angiotensin II, and neither of these substances cross the blood-brain barrier to any appreciable degree (12). Perhaps this is why treatment with angiotensin-converting enzyme inhibitors falls to interfere with the menstrual cycle (83). On )'.he other hand, losartan does penetrate the brain when administered acutely in intravenous doses of 3 mg/kg or more (3,89). Therefore, we tested the effect of losartan, 1 mg/kg and l0 mg/kg, on the LH surge produced by intraventricuiar angiotensin II in ovariectomized rats treated with estrogen and progesterone. The smaller dose had no significant effect, but the larger dose blocked the LH response (67). Consequently, it seems reasonable to conclude that the blood-brain barrier normally protects the hypothaiamic site at which angiotensin II acts to increase GnRH secretion. The brain renin-angiotensin system also plays a role in the regulation of prolactin secretion. Systemically administered angiotensin II increases prolactin secretion in rats, but intraventricular angiotensin II inhibits prolactin secretion (90). Like the increase in LH, the decrease in prolactin is prevented by both ATL and AT2 blocking drugs administered intraventricularly (92). Intraventri('ular renin generates angiotensin II in the central nervous system, and it increases dopamine turnover in the tuberinfundibular neurons. Recently, we have shown that angiotensin II-containing nerve terminals end in close apposition to dopaminergic cell bodies in the arcuate nuclei, and the AT~ receptors are readily demonstrated in this area (59). Therefore, it seems likely that angiotensin II released from nerve endings in the arcuate nuclei acts on cell bodies of the dopaminergic neurons to increase release of dopamine into the portal vessels. What is the physiological role of this arcuate system? Myers and Steele (62,64,90) found that intraventricular angiotensin II inhibits prolactin secretion in all the rat preparations they tested: intact male rats, intact female rats, untreated ovariectomized rats, and ovariectomized rats treated with estrogen and progesterone. However, intraventricular administration of saralasin or losartan only increased resting prolactin secretion in intact female rats and ovariectomized estrogenprogesterone treated rats. This indicates that there is no tonic inhibition of prolactin secretion by the brain renin-angiotensin system in male rats or female rats in the absence of sex steroids. However, there is a modest degree of this inhibitory "tone" in females in the presence of estrogen and progesterone. Myers and Steele (64) also investigated the role of the brain renin-angiotensin system in the increase in prolactin secretion produced by stre.,ss, and obtained evidence that it was due in part to decreased release of angiotensin II in the hypothalamus. Another possibility is that brain angiotensin II plays a role in the regulation of sexual behavior. There are 2 short reports of effects of central angiotensin II on sexual function in male rats (9,63), but the matter has not been explored in detail. Finally, there is a report that angiotensin II increases the release of prolactin-llke inm~unoreactivity from the brain in vitro (22), but the significance of this finding is unknown.

245 THE ANTERIOR PITUITARY RENIN ANGIOTENSIN SYSTEM

Like the brain renin-angiotensin system, the system in the anterior pituitary has been the subject of several recent reviews (17,18,33,34,gi). All the components of the renin-angiotensin system are present in the anterior pituitarygland, along with the m R N A s for renin and angiotensinogen. In rats, the L H ~-contalning granules in the gonadotropes contain immunoreactive angiotensin II and reuin. Angiotensin-converting enzyme is mainly found in the endothelial ceilsof the sinusoids, but some is also found in gonadotropes. The angiotensin II immunoreactivity probably represents authentic angiotensin II, since it comigrates with authentic angiotensin II on H P L C . It appears to be made in the gonadotropes, since it persists when the gland is organ cultured for 14 days in serum free medium. In our laboratory, angiotensinogen immunoreactivity was found in a different population of cells than the other components of the renin-angiotensin system. These cells did not contain gonadotropins or any other known anterior pituitary hormones (19,36). Sernia and associates (85) also found angiotensinogen in a separate population of cells,but claimed that in addition, gonadotropes contained small amounts of angiotensinogen. This claim needs to be confirmed, and it is unsettled whether the angiotensinogen in the gonadotropes was produced there or taken up by the ceils. In m y view, it seems likelythat most if not all of the angiotensinogen that serves as the substrate for angiotensin II in the gonadotropes reaches them by a paracrine route from the angiotensinogen-rich ceils elsewhere in the gland. It is then taken up by the gonadotropes, or alternativelyangiotensin II is formed extracellularly and taken up by endocytosis into the gonadotropes. The function of the angiotensin II in the gonadotropes is unsettled. One possibility is that it is released with L H and acts in a paracrine fashion on other cellsin the gland. In rats, there are angiot~nsin II receptors on lactotropes and corticotropes (34). Presumably these are the ATIB type, since these are the predominant type in the anterior pituitary (61). Addition of angiotensin II to anterior pituitary cells in vitro produces increases in the secretion of prolactin and A C T H . Therefore, one might expect that exposing the cellsto G n R H would increase prolactin secretion if angiotensin II were released from gonadotropes. Under most circumstances, this does not occur. However, an increase has been reported when the cellsare from male dogs (34). In addition, G n R H releases prolactin in ovariectomized rats treated with estrogen and progesterone (62). These observations suggest that angiotensin II can be released from the gonadotropes, and act in a paracrine fashion in the regulation of prolactin secretion. However, there are marked species differences (16). In addition, we found littledifference in angiotensin II content in male and female rats, and ovariectomy seemed to have littleeffect (unpublished observations). Furthermore, we could not measure angiotensin II in the effluent from pituitariesperifused with a potent G n R H analog that caused marked L H secretion (34). Clearly, more research is needed to settlethe matter. THE OVARIAN RENIN ANGIOTENSIN SYSTEM

All the components of the renin-angiotensin system plus renin mRNA and angiotensinogen mRNA are found in the ovaries (43,83). As noted above, prorenin produced in the ovaries enters the blood. Reuin mRNA and prorenin are found in corpora lutea. Prorenin is also found in thecal cells, and thecal cells have been reported to produce prorenin in

246 culture (23). Angiotensin II is present in corpora lutea and thecal cells (57,68). It also occurs in follicular fluid, along with prorenin and active renin (43,83). It is found in granulosa cells, but only near the time of ovulation (68). Angiotensinogen immunoreactivity is present in granulosa cells and the germinal epithelium covering the ovary (95). Angiotensinconverting enzyme is found in granulosa cells of some but not all follicles, and the converting enzyme-containing follicles also contain angiotensin II receptors (15). The enzyme is also found in corpora lutea, the germinal epithelium, and ovarian blood vessels (15). It is uncertain how the compounds interact to form angiotensin II (35), and there may be species differences, but at least it is clear that all the components are present. Finally, there are AT2 angiotensin receptors on granulosa cells (80). There are reports of both AT~ (76) and AT2 (7) receptors on thecal cells. The function of the ovarian renin-angiotensin system is uncertain. The increased number of angiotensin II receptors in atretic follicles suggests an association with follicular atresia (13). There have been conflicting reports about stimulatory effects of angiotensin II on the production of estrogen and progesterone (83), and Stifling and associates (93) have reported that angiotensin II inhibits LH-stimulated progesterone secretion by bovine luteai cells in vitro. They also found that angiotensin II reduced the amount of mRNA for the cholesterol side-chain cleaving enzyme P-450SCC and increased the mRNA for basic fibroblast growth factor. It may be relevant in terms of normal function of the ovarian renin-angiotensin system that there are 2 reports of patients with prorenin-secreting ovarian tumors (1,2). Both patients had elevated plasma levels of testosterone which returned to normai when the tumor was removed. In addition, renin and angiotensin II immunoreactivity are prominent in the thickened walls of ovarian follicles in the polycystic ovary syndrome (69). Another condition which may be associated with excess activity of the ovarian renin-angiotensin system is the ovarian hyperstimulation syndrome that is sometimes seen in women treated with gonadotropins (66,82).

Relation to Ovulation The possibility that angiotensin II is involved in ovulation has received considerable attention. In 1988, Pelllcer and associates reported that systemically administered saraiasin blocked ovulation in immature rats treated with pregnant mares' serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG), and then proposed "a direct, obligate role for angiotensin II in ovulation" (75). They and others found that systemically administered angiotensin-converting enzyme inhibitors had no effect on ovulation (75,77,83,91), but they argued that the angiotensin II responsible for ovulation was produced by an alternate pathway. The reported blockade with saralasin seemed to be in conflict with a report by Steele and associates. In their 1983 paper reporting that intraventricular saralasin blocked ovulation (91), Steele et ai. noted that control systemic injections of saralasin had no effect on spontaneous ovulation in adult rats. In addition, Daud and associates (14) repeated the experiment of Pellicer et ai. and could not confirm their results. Therefore, it seems unlikely that circulating angiotensin II plays any physiological role in ovulation. On the other hand, there are reports that when rat (78) and rabbit (56,101,102) ovaries are perfused in vitro, angiotensin II facilitates ovulation. This effect may be due to increased production of prostaglandins (102), and could be explained by

GANONG perfusion doses producing higher local concentrations than circulating angiotensin II. The lack of any effect of angiotensin-converting inhibitors on ovulation remains a puzzling finding, particularly in view of the absence of a barrier such as the blood-brain barrier or the blood-testis barrier separating the tissue system from the blood. Obviously, additional research is in order. COMPONENTSOF THE RENINANGIOTENSINSYSTEMIN THE UTERUS AND FETOPLACENTALUNIT The nonpregnant uterus contains renin (27). Some of this is in the myomctrium, but much is in the endometrium (46,86,94). Most of it is prorenin, but active renin is also present (94). Renin mRNA is present in the endometrium but not in the myometrium (86). Angiotensinogen has not been detected (94), and angiotensinogen mRNA is absent, even when the polymerase chain reaction is employed (W. Hsueh, personal communication). However, the active renin in the tissue could generate angiotensin I from angiotensinogen reaching the uterus in the circulating blood. AT~ and AT2 receptors are both found in the uterus (96). The active renin in the uterus does not appear to enter the circulation because circulating active renin falls to undetectable levels after nephrectomy (99), and the function of renin in the nonpregnant uterus is unknown. During pregnancy, the endometrium undergoes chemical changes that convert it to the decidua, and its prorenin and renin mRNA content increase (86,94). Furthermore, deciduai cells produce more total renin in culture than endometriai cells (86). It has been argued that the cells of the chorion also produce renin, but Shaw and associates (86) noted that renin mRNA was present only when the chorion was closely associated with the decidua; decidua-free chorion did not express renin mRNA. The decidua or the chorion is presumably the source of the prorenin which is found in very high concentration in humans in the fluid inside the chorion and, later in pregnancy, the amniotic fluid (45,88). The concentration in these fluids parallels that of hCG, being highest before 8 weeks and lower at 10-12 weeks of pregnancy. The high concentration of prorenin in the fluids that surround the fetus suggests an as yet undefined role for prorenin in embryonic development. Prorenin and active renin concentrations in maternal plasma increase during pregnancy, along with circulating angiotensinogen and angiotensin II (94). It is uncertain whether any of the prorenin and active renin come from the uterus and the fetoplacentai unit, although prorenin from the ovary appears in the circulation in nonpregnant women (see above). In rats, ovarian active renin increases slightly during pregnancy, whereas the percent of total renin that is inactive falls (42,65).

Fetal Complications Although angiotensin-converting enzyme inhibitors have not been reported to have adverse effects on reproductive cycles in nonpregnant women, captopril causes an increase in the incidence of stillbirths in rabbits and sheep (6,28). Their use has also been associated with renal failure in new born humans, and they are contraindicated in pregnancy (44). THE TESTICULARRENIN-ANGIOTENSINSYSTEM The testes contain renin mRNA (21,24), and renin, angiotensin II, and angiotensin-converting enzyme immunoreactivity are found in Leydig cells (70). Angiotensin converting enzyme of the somatic type is present in endothelial cells and

RENIN A N D REPRODUCTION

247

epididymal epithelial cells (87). Angiotensinogen has not been demonstrated in the testes by northern blot analysis (35), but circulating angiotensinogen may be adequate in amount for the Leydig cell renin to form angiotensin I. In any case, angiotensin II is found in Leydig cells. Angiotensin II receptors are also present (18). The function of angiotensin II in the Leydig cells is unsettled. Khanum and Dufau (152) found that angiotensin II inhibits testosterone secretion. Leydig cell renin immunoreactivity is decreased after hypophysectomy and treatment with estrogens, but it is also reduced by treatment with gonadotropins (71). The amount of prorenin in testicular venous blood is greater than in arterial blood, but the amounts of active renin and angiotensinogen are not significantly different (84). The epididymis also contains angiotensin II receptors (38,74,96) and somatic mlgiotensin-converting enzyme (87). Angiotensin II makes the epididymis contract and expel its contents o f fluid and sperm (38). Angiotensin II receptors are also present in the vas deferens, where angiotensin II appears to facilitate noradrenergic transmission (87). However, the relation, if any, of the receptors in the epididymis and vas deferens to the angiotensin II in the Leydig cells is unknown. In mice with one renin gene, the Ren-1 gene is expressed in the coagulating gland (anterior prostate). However, this gene is not expressed in mice with 2 renin genes or in rats (26). Human semen contains prorenin and active renin in greater amounts than in plasma, and vasectomy does not change the renin content, indicating that it comes from the prostate or other sexual accessory glands, not the testes (11,94). The testes are unique in that in adults, they contain an abundant supply of germinal angiotensin-converting enzyme in addition to somatic artgiotensin-converting enzyme (87). This angiotensin-converting enzyme is different from somatic angiotensin-converting enzyme in that it has only 1 active site and is much smaller than somatic angiotensin-converting enzyme (90 kDa vs. 150 kDa). Somatic angiotensin-converting enzyme has 2 active sites (87). At least in humans and marmosets, both forms of angiotensin-converting enzyme are produced from a single gene which has 2 different promoters and produces 2 different mRNAs. The germinal angiotensinconverting enzyme is only expressed in spermatids and spermatozoa, and is mostly found in the membrane of the sperm head, middle piece, and tail. It is also present in the acrosome. Its concentration is decreased by hypophysectomy and main-

tained after hypophysectomy by injection o f pituitary gonadotropins, hCG, or testosterone (98). These procedures have no effect on pulmonary angiotensin-converting enzyme. The function of germinal angiotensin-converting enzyme is unsetfled, but it could play a role in sperm maturation, sperm motility, or the fertilization process. Angiotensin-converting enzyme inhibitors do not appear to affect sperm function, and indeed there is one preliminary report that they actually facilitate fertility (72). The lack of any deliterious effect on reproductive performance in men taking angiotensin-converting enzyme inhibitors could be due to protection of the seminiferous epithelium by the bloodtestes barrier. CONCLUSIONS The preceeding sections of this review document the multiple interactions between reproduction, the circulating reninangiotensin system, and the renin-angiotensin systems in the hypothalamus, anterior pituitary, ovaries, uterus, fetoplacented unit, and testes. As yet, there is no unifying theme or pattern to the interactions, and there is still much to be learned. One possibility is that they relate more to the ubiquitous distribution of peptides than to reproduction per se. In many instances, the same peptide is secreted by neurons in the brain as a neurotransmitter, by neurons in the hypothalamus as a hypophysiotropic hormone, and by typical endocrine cells in other organs as a paracrine and an endocrine chemical mediator (31). Somatostatin is an example; it is secreted by neurons in the spinal cord that mediate sensation, by hypophysiotropic neurons as the growth hormone-inhibiting hormone, by endocrine cells in the pancreas, where it is a paracrine mediator, and by endocrine cells in the gastrointestinal tract, where it is an endocrine as well as a paracrine mediator. Other examples o f peptides with multiple functions are vasoactive intestinai polypeptide (VIP) and opioids, and these both have some relation to reproductive function. However, the components of the renin-angiotensin system have more and closer ties to reproduction than the other peptides, and it seems likely to me that with further research, a common theme will emerge. ACKNOWLEDGEMENTS This review includes research in the author's laboratory supported by USPHS Grant HL29714, NASA Grant NAG 2-779, and The Smokeless Tobacco Research Council.

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