Indian Journal of Experimental Biology Vol. 4 1, July 2003, pp. 669-68 1

Local regulatory factors in regulation of ovarian function: Role of prorenin-renin-angiotensin-system

Barbel Brull swig-Sp ickenheier* & A mal K M ukhopadhyay

Insti tute for Hormone and Fertil i ty Research at the Un iversit y of Hamburg: CIM . Falkennied 88. 2025 1, Hamburg, Germany

During reproductive l ife in the fe male, there is a cont inuous !low of growth , malli rati on and demise of ovarian folli cles. unless pregnancy occurs. A lthough ovari an functi on is primaril y controlled by the hypothal amus-pi tuitary-ax is, there is 11 0

doubt that a horillona lmicroenvironillent specific for each individual fo lli cle is es tabl ished , that finall y determines whether a foll icle ovulates and beeomcs a corpus luteulll or undergocs atresia. In thi s rcspeet, autocrinc and paracrinc ractors that act alone or modu late gonadotropins action arc of paramount imporl ance. In this arl icle, we wan t to introducc the ovarian prorenin -renin -angiotensin-system (PRAS) and summari ze what is ac tu all y known about i ts involvement in ovari an phys iol­ogy and pathology.

Key words: A ngiotensinogen, A ngiotensin rcccptors. Ovarian functi on. Prorcnin-ren in -angiotcnsin-system. Rcgu lation of ovari an functi on

In the cyc ling ovary, a number of follicles starts growing but onl y a limited number fin ally ovul ates whereas the majority undergoes atresia . Gonadotrop ic hormones are, no doubt , the major regul ators of follicul ar growth , ovulation and formation of the corpus luteum. In the last few years, however, the ro le of locally generated fac tors, like e.g. growth factors, cy tokines and steroids as modul ators of gonadotropic actions has gained increas ing attenti on. It has become more and more ev ident that these factors generate a unique microenvironment that determines the fate of any individ ual follicl e. This rev iew aims to introduce the ovarian prorenin-renin-angiotensin-system (PRAS) as an important member of thi s ever growing li st of intraovari an regul atory factors. After presentati on of the individual components of the PRAS and their ex pression and regulation in ovarian structures in diffe rent species, we will give an outlook on what is currentl y known about its functi on III ova ri an physiology and pathology.

Prorenin-renin-angiotensin-system The prorenin-renin-angiotensin-system (PRAS) is a

complex enzy me-hormone cascade, primarily known to be responsible for the regulation of blood pressure,

*Correspondcnce: Dr. Barbel B runsw ig-Spickenheier Tel.: + 49-40-47 196602 Fax: + 49-40-47 196648 E-Mai l: Brunsw ig@ IHF.de

water and electrolyte homeostas is. But apart fron' these cardi ovasc ular effec ts, locally ac ting PR AS car be fo und in numerous organs of the body, inc lud in ~

brain and endocrine glands, like heart, adrenal, testis uterus, placenta, and ovary, and take part in the loca regulati on of spec ific organ functi ons l

.? The components of the PR AS are schemati ca ll y shown ir Fig. 1. The glycoprotein renin , whi ch was firs isolated from the kidney by Tigerstedt and Berg mar in 18988 is the rate-limiting enzy me in thi s cascade Its gene has been cloned from several species including human, rat, mouse and sheep9.13. The aspartyl protease renin is sy nthesized as preproreni r whi ch is rapidly converted to prorenin , the

. II" 1415 Th ' . enzy matl ca y In acti ve precursor '. IS protell1 car either be stored within the cell s, secreted into th( circulation or converted intracellul arly to renin by ; cleavage of a 43 amino ac id fragment from the amine tenninus '5 .

t6 There is still an ongo ing debatc abou the enzy me that may be responsible for the conversion of prorenin to renin . Strong candidates an cathepsin B and members of the ti ssue kallikreir famil y, mainl y kallikrein mK 13 17

•1Y

, but the ex istence of a spec ific prorenin convert ing enzyme has als( been di scussed. Whereas pl asma pro renin ma) ori ginate from di verse tissues, the juxtaglomerul os; ce ll s of the kidney are the excl usi ve source 0

circul atory renin 2o. Following thc release of the renil

into the circul ati on, it cleaves the decapeptidc angiotensin I CAl ) from the N-tenninus of its unique

670 INDIAN J EX P BIOl. JULY 2003

PCE Angiotcnsinogcn

?I'--R-~n-i-n--'~ ~ 1f----II~I!.llmIM~M~ilil •• I Prorcnin

Angiotensi n I

ACE

Angiotensin II

~-~'~., : .. !..~!"!'\. ~~':-

A n·AQtagonist · , "

Physiological R~sponscs

Fig. 1- Prorenin-renin-angiotensin system

substrate, the hepatic urg lobul i n angiotensinogen21 -24.

Interspecies differences exist in the peptide bond cleaved by renin . Whereas human ren in cleaves a leucine-valine bond, other mammalian renins cleave a leucine- leucine bond25. During the passage of the blood through the lungs, two C-terminal amino ac ids are removed fro m AI by the endotheli al angiotensin converting enzyme (ACE). The generated angiotensin II (A ll ) can furthermore be metabolized by non­specific am inopeptidases to yield biologica lly st ill active angiotensins (e.g. angiotensin III , angiotensin 1-7) and non-acti ve fragme nts.

The best stud ied act ive principle of the PRAS is the octapeptide All, wh ich is in volved in the regu lat ion of blood pressure, fluid vo lume homeostas is, hormone secret ion , cell growth and 11 eu ronal acti vit/ 6

.2

<J .

Angiotensin II exerts its actions by binding to an tagoni sts and acti vating at least two di ffe rent specific receptor subtypes , termed AT I and AT2. This classification was fi rst based on the use of pharmacological receptor antagoni sts. AT I ac ti on is :lIltagonized by substances, like losartan and AT2 acti on is antagonized by substances like PD 1233 1930

.

33 . It appears that most of the above mentioned All actions are med iated by the AT I receptor. Although the genes for both receptor subtypes have already been cloned from several species more than a decade

34·42 kId b h h . I . I ago , our ' now e ge a out t e p YS lo oglca roles played by the AT2 receptor as signal transd uction

mechani sms in volved is still in its infanc/3.44 . Both

receptor subtypes belong to the seven-transmembrane G-protein coupled receptor superfamily, however they share minimal sequence ho rno logl5

.46. There appears to be general consensus that A T2 medi ates anti growth and proapoptotic effects and counteracts AT 1- and growth factor mediated cell prol i feratio n43.44A7.58. Whereas AT I receptors can be detected almost ubiquitously, AT2 receptors are highly ex pressed i feta l ti ssues, declin ing SOO I1 after birrh 59

.6o

. In the ad ult , AT2 expression is confined to some ti ssues, including adrenal, uteru s, bra in , heart, kidney and

5'1.61·70 F I T2 . I d . ovary . -urt 1ermore A IS u. regu ate In vasc ular injury and wound healing, after myocardi al infarcti on and heart fa ilure71.75

. Thi s highly specifi c expression pattern supports the assumption that AT2 plays a role in developmental processes and in ti ssue reorganization .

Expression of PRAS in ovary

Allgiotensinogen

Angiotens inogen has been detected in human and porcine follicular fluid in concentrati ons comparable t I . 76· 78 D . I ' I o p as ma concentratI ons . ue to Its 11g 1 molecul ar weight, local production wi thin the ovary itself appears reasonable. Indeed, express ion of angiotensin.ogen gene has been demonstrated within whole ovari an homogenates of several spec ies,

BRUNSWIG -SPICKENH EIER & MUKHOPADHYA Y : REGULATION OF OVARIAN FUNCTION 67 1

. I d' d h 7\1· 81 I . h IIlC U IIlg rat, mouse an uman , eavlllg t e questi on of its ce llular ori gin unanswered . There is on ly one report on cellular distribution of angiotensinogen in normall y cycling rats. Immunohistochcmical staining for angiotensinogen seems to be limited to fo lli cular fluid, to antral and cumulus granu losa cells of maturing follicl es and to a lesser extent to granul osa ce ll s in fo llicles undergoi ng atresia. No staining could be detected in primary fo lli cles whereas in corpora lutea. occasional stain ing

x' -was observed -.

Proren in-Rellin In the earl y 1970s, first studi es showing an increase

in pl asma renin in women during the luteal phase of the menstrual cyc le were publi shed. At thi s time, it was not taken into considerati on that this renin could be originating from the ovary, but an increased natriuresis as .. :1 consequence of an increase in gestagens a:-- we ll as an increase in angiotensinogen due to higher es tradiol production were di scussedRJ

.x4

.

Only Michelaki s el 0[85 suspected a coherence between plasma renin and ovulation, and claimed that a funct ional corpus luteum had to be present , however they did not continue with these studies. Ten years later, this research topi c was taken up again by Sea ley and coworkers who unequi vocall y demonstrated a ti ght correlat ion between plasma prorenin ac tiv ity and the concentrations of gonadotropic hormone in blood. There are significant increases in plasma prorcnin shortl y (8 -1 6 hI') after the ovu latory LH peak in women, undergoing trea tment w ith gonadotropic hormones d uri ng I V F sti mul atory protocol and in

I 86·8 \1 Th 'k ' II I' . I ear y pregnancy . e stn IIlg para e Ism III t le ri se of LH concentration and prorcnin led to speculation, that the ovary was thc source of prorcnin and that synthesis and secreti on of this enzy me were under gonadotropic contro l. These speculations were soon corroborated by a number of observation s, as di scussed below,

Prorenin , renin , ang iotensinogen, A l and A ll were reported to be present in human fol li cul ar fiuid 76,90.'J I, Whereas folli cular fluid concentration of ac ti ve renin was sim ilar to that found in pl asma, follicular fluid prorenin concentration was approx imate ly 12 times higher than that of plasma. Prorenin levcls in the ovari an venous eflluent are twofold higher than levels in peripheral bloocln . In ovarian hyperstimulated women, the plasma prorenin concentration positi ve ly correlated w ith the number of folli cles93 , Plasma prorenin levels during pregnancy remained

abnormall y low in a woman with primary ovarian failure, in whom pregnancy was estab li shed by the induct ion of an artifi cial cyc le and in vi tro fertili zation of a donated oocyte fert ili zed with the sperm of her husband94

, The postovulatory increase in plasma prorenin still persists 111 a bilaterall y nephrectomi zed woman95

.

The source of these ovarian prorenin and renin act iviti es in the human is the theca, as demonstrated by immunohistochemistry and cell culture

. 96·98 I II d expenments ; granu osa ce s 0 not secrete prorenin. Thi s appears also to be true for other primates. In situ hybridi zation loca li zed renin mRNA in cynomolgus and rhesus monkeys primarily to the theca interna and theca lutein cells\l~ .

Up to now, most informati on on the ex press ion of ovarian prorenin and renin comes from studies performed in primates, A ll other mammals exam ined so far likewise express prorenin and renin in the ovary , though to a di fferent ex tentlOO.IlH Li ke in pri mates, theca ce ll s are the source of 1'0 11 icular prorenin and renin activit ies in the cow and the

bb ' 100 IDS Th f" d ' ra It . . e source 0 ovanan renin an prorenlll in the rat is still controvers ial. There are some report s in which exclusive localization in luteal ti ssue has been publ ished; in other studi es theca ce ll s appear to be the predominant site of originI 06.I09. Probab ly due to limited ava ilability of theca cell cu ltures. little is known about the hormonal regulati on of the ovari an PRAS. In vitro as well as in vi vo stimulation by the gonadotropic hormones FSH or LH leads to all increase of ovarian prorenin producti on in the rat , rabbit and COWI OS. IIO,III . Although gonadotropic

hormones are no doubt the most important stimulators of the ovarian PRAS, synthesis and release or prorenin and renin are subject to a complex regulat ion by growth fac tors and cy tok ine, . Whereas granulosa cell condit ioned medium and factors like tumor necros is factor-a, epidermal growth factor and fibroblast grow th factor are inhibitors or L11 -stimulated prorenin release by bov ine theca ce l ls. transforming growth fac tor-~ acts as a

. I ' II " 113 A ' d ,. . stlmu ator -, ' . paracnne an autocnne Interaction between theca and granu losa cell s therefore may modulate the ex tent of prorenin production in any i ndi vidual 1'011 icle.

Whereas in human, bov ine and porcine folli cul ar fluid , only prorenin and not renin can be detected lllO, in theca cell homogenates both prorenin and renin can be found in a ratio of I : 1111. The qucsti on wh ich enzy me is respons ible for prorenin conversion to

672 INDIAN J EXP BIOL, JULY 2003

ren in within these cel ls has not been answered yet. Interes tingly, presence of prorenin converting enzy me has been demonstrated in rat and mouse ovari es, but there are still many uncertainti es concerning the cellul ar distri bution of speci fic isoforms throughout the cyc le I14 .11.'.

Angiolcnsin convening ellzyme

Since AI is not biologically ac ti ve, loca l production of All from Al by thc action o r ACE is one prerequisite for phys iologica l function s of the PR AS withi n the ovary. ACE was detected in human ova ri an homogenates and in fo lli cular fluid where it comprises 60% of the plas ma concentration IIC,-I I'} Human ovari an ex press ion of ACE increases with the age of the patient and correlates with the progesterone, however not with the es trad iol content or the follicular flu id 11 7. II K. In bovi ne ovari an follicular fluid , on the contrary , no correlation of ACE acti vity with steroid levels, the stage of the es trous cyc le or the onset of pregnancy could be dctecteclI 211. 121. The cellular ori gin of ACE in the ovary sti II remai ns a mailer of debate. Some detailed studi es performed in the rat locali zed ACE to blood vesse ls, to the germinal epithelium surrounding corpora lutea and to granulosa cell s of most developing and atreti c foll icles . ACE levels in preov ul atory follicles , on the other hand , appear to be very low or even absent ,n.m. In the cow, express ion of mRNA for ACE was found in theca interna of mature follicles, in early corpora lutea and endotheli al cells from developing corpora lutea, but not in granulosa ce ll s of mature follicles. The subseq uent immunohi stochemica l analysis re vea led th at onl y the endotheli al ce ll s in the blood capill aries stained fo r the ACE protein '24 . The observati ons th at ACE ac tivity is locali zed in endotheli al ce ll s of ovari an blood vessels are in accorda nce with data obtained by Schauser el al. and Hayashi el al.1 25 .1 26 who also demonstrated that microvasc ul ar endotheli al cells from deve loping bovine corpora lutea possess the capacity to convert AI to All , indicating that these ce ll s have ACE-like acti vity.

Angiotensin

Follicular fluid angiotensin immunoreactivity in the hu man significantly exceeds the corresponding I . 90 P7 A" . P asma concen trati on . -. ngJOtensln concentrati on

positi vely correlates with the prorenin concent ration within the ovary and is especially high in women who

underwe nt gonadotrop ic stimul at ion of the ova ry iii the course of IY F treatment7(,· 11l9.m. Local syn thesis and release of All has been demonstrated in terti ary fo lli cles and freshl y formed corpora lute' from sows and cows by the use of an impl anted mi crod ialys is system. The loca ti on of the dialys is system all ows the conclusion that theca layers and corpus luteum tissue are the origin of ova rian All. There appears to be a relationsh ip to other v soac ti ve peptides. For exa mpl e, add iti on of atrial natriuretic peptide to the microdial ys is system lead to an increase in th e release of All , whereas endothelin- l did not show any e tTed 2

'i. The peptide was released ep isod ica ll y and the release was hi ghest in the peri ov ul atory periocl l ~o The theca layer of the periovul atory fo llicle and the ea rl y to midlutea l corpora ILttea are characte ri zed by a

d I Il l-Ill S· ACE . . h pronounce vasc u ature ' " . Ince act ivity as been demonstrated in the vascul ar endotheli al cel ls, these ce ll s may be the pl ace where local conversion of

pc, Al to All may take place - .

Angiotensin receptors

Studies on di stribution and possible phys iological signifi cance of All receptors in folli cul ar and lu teal ce ll s ad another leve l of complex ity to the understanding of PRAS in the ovary. Interpretation of the publi shed data is rendered d iffi cult by considerab le differences in , nimal species studied and the developmental stage of the folli cle. Most of the studi es performed so far are based on li gand binding techniques and the use of pharmacological receptor agoni sts and antagonists. Although cloning or both All recept.or SUbtypes has been accompli shed nea rly a decade ago, there are on ly limited studies demonstrating the expression of All receptor genes within the ovarian structures. Binding of labeled All to ovarian cells has been demonstrated in the rat, bovine, porcine, rhesus monkey and In the rabbit61.I02.122. 134-137. Generall y, in most species exami ned so far, these receptors appear to be predominantly of the PD 1393 19-sens iti ve AT2 s ub[ype61 . ' ~R-'42 , but a predominance of ATI receptors has also been documented as exempl ified in the

. 1-11144 Wh h h . II porcine ovary " . et er uman ovari an ce s ex press All receptors is not clear yet. Whereas Rainey el al. 14S

, could neither detect AlI binding to human luteini zed granul osa cells nor an effect of AIl on steroidogenes is and second messenger generati on in these ce ll s, Johnson e l 0 1.140 described a regul atory role of All on progesterone producti on in human

BRUNSWIG-SPICKEN HEIER & MUKHOPADHYAY: REGULATIO OF OVARI A FU NCTION 673

cultured granulosa cell s, which was attributed to AT2 receptor. Li ke thi s example on data obtained in the human, studi es on other speci es are also fraught with di screpancies. U sing radioreceptor assay, All binding was limited to theca cell s in the bov ine, however mRNA expressi on of ATl and AT2 was recentl y shown in luteal ce ll s and in microvascular endothelial ce ll s of the corpus luteum61.1~6 In the rabbit, although AT I receptors were detected on granulosa and theca ce ll s of preovulatory folli cles lJ7, inducti on of ovulation and oocyte maturation, as we ll as hCG­induced prostaglandin synthesis were blocked by PO 1 393 19 "9 . 1~ 7 . In contrast to bovine and rabbit ovari es, where AT2 receptors are expressed predominantl y in theca layer in the rat, the AT2 receptor subtype appears to be limited to granul osa ce ll s in the rat , as d d I . . h b ·d· . 14R E . emonstrate )y In Situ y n Izallon . xpress lOn of these receptors in the rat has been shown to be dependent on the stage o f the estrus cyc le, the highest

. b . b d d· d· 114 liS express IOn elllg 0 serve unng lestrus ·· .. . Apparently , there is a strong correlation between the express ion of A T2 receptors and the onse t o f atresia. Binding of All is the highest in granul osa ce ll s from

. t· II · I 14X·1 si d . . I I d . I atretic 0 IC es . an IS negal! ve y corre ate \.v l\l

the level of express ion of FSH receptorsl4lJ. Like prorenin, these receptors are al so subjec t to hormonal regul ation . Treatment of rat granulosa cell s w ith FSH downregulates All binding sites '52 , whereas in vi vo treatment of rats w ith eCG increases ovari an A T2 expressionl51 . In contras t, the number of AT2 on bov ine theca ce ll s is increased by LH in a cAMP­dependent mechanism61. The inlluence of A ll on AT2 receptor density in a cell is rather controversial ; in one study, All has been reported to downregulate its own receptors 150, whereas in another study , AT2 express ion is upregul ated fo llow ing treatment o f granulosa ce ll s with A1I 152 . Another enigma that has not yet been sol ved is the obse rvati on, that rat lute~1I

ce ll s respond to treatment w ith All w ith an increase of intrace llular calciulll , although receptors for Air have not been clearl y demonstrated in these ce lls 15:1.

Physiology During reproducti ve life in the female, a

continuous cyc le o f growth , maturati on and atresia of folli cles occurs, whi ch is only interrupted by pregnancy . From hundreds of folli cles, whi ch start grow ing, onl y a limited number finall y ov ulates and di f ferentiates into a corpus luteum, whereas most folli cles undergo atres ia. A lthough gonadotropi c hormones are we ll known as major players in thi s

scenario, there is no doubt that the fate of an individual folli cle is highly dependent on its unique hormonal microenvironment th at is generated by the ovary itse lf. In thi s respect, autocrine and paracrine factors, like the PRAS, which either ac t alone or modu late gonadotropic action s are of considerable import ance.

A fter the ex istence of an intraovari an PR A S became evident, the sc ientifi c community has made effort s to elucidate its poss ible functi on in reproduction . There are, however, still a number of limitations. Experimental studi es to evaluate a ro le for angiotensin in the regulation of ovarian functi on are gener:111 y based on two di fferent approaches. Either ovarian homogenates or ovari an ce lls ill viTro were directly subjected to treatment with angiotensin andlor its respective receptor antagonists, or angiotensin II generati on in whole ovari es was disturbed by pharmaco logica lly blocking ACE activity. Defining a physio logical role for the PRA S in ovari an functi on is furthermore limited by a relati ve ly small number of studi es that has been carri ed out so far and by considerabl e differences in experimental conditions employed. e. g. in vivo vs ill viTro studies, use of different animals, cell s and ce ll culture models. Taken together, from these reports it may be concluded that a modulatory effecl of A ll on steroidogenes is, prostaglandin production, oocy te maturati on and ovulation may bear some relevance for foil icle se lec tion and atres ia.

An giotensin II appears to be in volved in the process of ovulation , as demonstrated by ill vil ro perfusion experiments performed in rabbit ovaries. Additi on of A ll to the perfusate stimulates ovul ation and oocyte maturation even in the absence of gonadotropic hormones. The ovulatory effect of A ll however, is less pronounced than the ovulatory effec t o f hCG I54.155. The ovulatory influence of All appears

to be mediated by AT2 receptor, since it was tota lly blocked by simultaneous addition of saralasin, an All antagoni st and by PO 1233 19, a spec ific AT2 receptor

b . 119 147 WI I · I su type antagonist · ·. l ereas t 1e stllnu atory cffec t of A ll on ovulation may at least in part be mediated by the producti on of pros taglandins, A II ­induced oocyte maturati on is independent of prosta-

I I· d · I ';6 Fl · . g a III In pro UClIon . . ~ url1ermo re, an Interac ti on between IGF-I and 1\11 in oocy te maturation and ov ulation has been proposed 157

An other spec ies in whi ch the influence of All on ov ulation has been studi ed so far is the rat. Earl y data

674 IND IAN J EXP BIOL. JULY 2003

showing that intraperitoneal inj ec ti on of saralasin into immalu /·c PMSG-treated rats reduced the number of ova released after a si ngle dose of heG and suggest ing a facilitatory role of All on ov ulati on were questioned by Duud et al. who cou ld not confirm these results experimentally' 5X.16(). Subseq uently. a role for All in the process of ov ulati on in the rat was corroborated by Peterson el (I /. who demonstrated a significant dose-dependent reduction in the number of ova after an addition of saralas in to the medium which was used to perfuse ovari es from PMSG-treated . llil J . I I· I bb· Immatu re rats . ust as In t le case o · tle ra It , the role of All in the process of ovulation appears LO be associa ted with ovarian prostaglandin sy nthes is. Intercstingly, thi s effect however appears not to be se lecti vc ly regulated via the AT2 receptor subtype, since the ac tion of saralasin could not be mimicked by the addition of PO 123 319 to the perfusion medium l62 .

Since All is a well-know n st imulator of adrenal ·d . 161164 .. sterol ogenesl s .. , attempts were made to dettne a

possible role for All in ovarian steroidogenesis. The data obtained however are rather controversial ; whether or not All affects ovarian steroidogc nes is appears to be hi ghly dependent on thc spec ies of ani ma ls used and experimental cond itions. Whereas All inhibits the gonadot rop in -st imulated progesterone production by means of a reduction of 3~-HSD mRNA and enzyme in porcine granulosa cell s, it has no effect on progesterone production in rat granulosa

II 1(,).1(,6 I I I R . 1 145 Id ce s . n t le lUman, alney el (I. , cou not show any effect fo llowi ng treatment of granu losa cells with All . whereas Johnson el al.146

, demonstrated a modu lato ry effect of All on ovarian stero idogenesis that was however, strictly dependent on experimental conditi ons. During a 2 day culture period , All inhibited progesterone production , but after culturing the ce ll s fo r 4 days with All , a st imulatory effect of rhe peptide on progesterone production was noted . ]n the rabbit , AU increased the heG-stimulated androgen production by theca cells. At the same time, it decreased aromatization of androstend ione to es tradi ol in the granul osa cell . This modulatory intlueilce on steroidogenesis could lead to a shift in the fo ili cu lar fluid androgen/estrogen ratio toward a more and rogenic milieu, indicating that All may possib ly participate in ca usi ng follicular atres ia l67. A similar sh ift to a more androgeni c milieu following treatment with All has also been observed in the hamster ovaryl 6S. In bovine theca cells, addition of Ali to the ce ll culture medium influenced neither

basal nor gonadotropin -st imulated steroidogenes is 169. An in vo lvement of the ova ri an PRA.S in the deve­

lopme nr of follicular atres ia appears to be an attractive hypothesis. In the rat, granulosa ce ll s from atretic ce ll s preferentially express All binding .. t .149.1511.152 ] th II A I I d· h Sl es . n ese ce s, me lates t e progression of fo lli cle atresia by coun teract ing FSH actions, such as expression of lutein izing hormone receptor con tent and prevention of DNA fragmentationl ) l.

In the bovine fo lli cular fluid. prore nin express ion negati vely correlates with the estradio l/proges terone

. IOIl. 17() TI· . , ratIo . lIS rat io represents a marker lor lile developmental stage of an indi vidua l follicle. An estrad iol/progesterone ratio > 1.0 is characterist ic for a healthy , preovulatory follicle , whereas an estrad iol/rat io < 0.1 can be taken as d marker for

. 171 Th . . . d d· d . . atresia . at prorenln IS In ee Increase In atretic follicles was furthermore corroborated by morphological data lol .

The fact that paracrine factors like FGF-2, TGF-cx. TGF-~ and TNF-cx modulate the express ion of theca ce ll PRAS may represent a .l ink to the developmental stage of an indi vidual follicle l/2 . In health y, preovulatory foil icles the biochemically acti ve gra nulosa cells may sy nthes ize and secrete factors like FGF-2 and TNF-cx, which ac t on theca ce ll s to keep the PRAS suppressed and thereby prevent transi ti on to atresia. This suppress ive effect may furthermore be substanti ated by theca-ce ll derived TGF-cx which inhibits prorenin production and acts as a mitogen for gran ulosa cells.

The onset of atresia is characteri zed by a rapid degeneration of gran ulosa cells accompanied by a hypertrophy of theca cells l7J

. In thi s case, the inhibitory intluence of granulosa cell-de ri ved factors on prorenin production is <Htenuated . This proatretic effect is furthermore supported by theca cell deri ved TGF-~ which on the one hand is antagoni stic to granulosa cell growth and on the other hand Illay act in an autocrine manner to sy nergist ically enhance LH­stimul ated prorenin production . The resulting increase in prorenin may finally lead to follicle demise.

The reg ressive action of the PRAS may not onl y be limited to the follicle, but may also be seen in the corpus luteum. In a microdialysis system applied to bovine ovaries, All was show n to increase prostaglandin F2a secret ion from the corpus iuteum I2

-1 .

Furthermore intraluteal injection of angiotens in II togeth er with a subluteolyti c concentration of prosta­glandin F2r1 leads to a pl·ematurt> inducti on of

-.,..

BRUNSWIG-SPICKENHEIER & MUKHOPADHYAY: REGULATION OF OVARIAN FUNCTION 675

luteolys is and the onset of estrus, supporting the notion that All may be directl y in volved in the progress of luteal regression l74.

Recent studies performed by in vivo perfusion of bovine ovaries have added further ev idence for the complex ity of the PRAS in ovarian fun ction . PRAS appears not onl y to be a modulator of follicular and luteal function but also influences ovarian microvasculature endothelial cell s 110.175.176. These authors propose that the PRAS within the ovary not onl y consists of the classical renin-angiotensin pathway, but may bc tight ly associated with the regulation of endothelin and atrial natriuret ic peptide.

Pathology Data on the ex i s t e n l" ~ of an intraovarian PRAS

stimulated research LO elucidate its possible role in the aeti opathogenesis of a variety of disturbances of ovarian function, like ovari an tumors, polycysti c ovarian syndrome (PCO) and ovarian hyperstimula­tion sy ndrome (OHSS ).

Ovarian HSS is a serious iatrogenic di sorder that complicates the use of follicle-stimulating agents in ass isted reproduction programs. Since OHSS may be accompanied by altered ovarian capill ary permeability and increased interstiti al fluid accumulation, the assumption is appea ling that the ovarian PRAS like other vasoactive substances could be in vo lved in the developmen t of this disturbance I77.J78

. Although so me studi es demonstrate a direct correlation betwee n plasma and follicular fluid prorenin activity and the severity of OHSS , its pathogenes is and the possible ro le of the PRAS therein is still elusive J77· 179. 180.

The use of prorenin measurement in the aspirated fo lli cular fluid as a predicti ve indicator for the outcome of in vitro fe rtili zati on was studi ed by three groups. The number of pati ents examined however is still too small to yield stati stically significant data. Whereas Paulson el ai.

97 did not find a correlati on between oocyte maturity and ovarian prorenin production , ltskovitz er 0 /.

18 1 and Cornwalli s el a/. 182,

suggested that the measurement of follicular fluid prorenin relates to ovum viability and could therefore be of pred icti ve use in IYF progra mmes. Another approach to use the PRAS as an indicator for pregnancy outcome in IYF programs was performed by Heill1l er el O/.IR3 , Wil O measured All concentrations in follicular fluid and stated that a hi gh All concentrati on correlated with a poor pregnancy outco me, whereas women with a low All concen­tJ'a tion in the follicu lar fluid had a better chance to become r rcg nant.

Patients with PCO di sease are characteri zed by a significantly hi gher pl asma prorenin than normal controls. There appears to be a strong positive correlation of plas ma prorenin with androgen level, leading to the assumption that there is a connection between expression of the ovarian PR AS and h . 1 . 18-1 185 I . I h ' yperanurogenlsm ' . nteresllng y, t e Immuno-histochemical loca li zati on of renin and angiotensin in follicles from PCO differs from follicles in normal ovari es. Whereas in normal deve loping follicles, staining for renin and angiotensin is restricted to the theca layer, large cystic fo lli cles of PCO show staining both in theca and granulosa ce ll sl ~6

In sumlllary, although there are some strong hints pointing to an involvement of the ovarian PRAS in the etiology of diseases like PCO and OHSS, more research is necessary to definitely establi sh its role therein . The idea to employ follicular tluid prorenin and/or All concentration as a predictive indicator for the outcome of lYF still needs much more data to ga in attractivity.

Coda Ovarian cells are characterized by their rapid

cyclical change of growth , differentiation and regression, which can hard ly be found in any other organ of the adult organism. To prevent di sturbances that might result in uncontrolled growth or unwanted regress ion, all aspects of ovari an functi on must be controlled rigorously. Data rev iewed in thi s essay suggest that the PRAS may be added to the growing li st of intraova ri an regul atory factors in volved in the generation of a microenvironment th at guar~l.I1tees

normal follicular and lutea l deve lopment. Allhough limitations due to experimental variations and species variability prevent a clear and uniform pi cture about its role in ovarian physiology from emerging, there are strong indicati ons that the PRAS may be associated with the developmental stage of indi vidual follicl es and the corpus luteum. A special emphasis should be lai d on the observa tion th at the PRAS appears mainl y to be associated with the regress ion of ovarian cell and that thi s regressive acti ons appear to be medi ated by AT2 receptor subtypes, whi ch have been shown [ 0 exert pro-apoptotic and antigrowth effects in other ce ll systems. Since there are onl y few cells in the adu lt organi sm that ex press thi s All receptor subtype, ovari an expression Illay turn ou t to

be of so me interest for a potenti al pharmaceu tical intervention . Before however seri ously taking thi s into considerat ion, a better understanding of its role in ovarian physiology and pathology is required.

676 I DI AN J EXP BIOL. JULY 2003

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