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OCR for page 211
E= ME R~CN ~ Em: away
Jo M. 13ann~
Icon
The grow and ~velc~: of ache ovarian follicle entails a final
process of call r—licati~ arm differ~iatic~n churl Whim the Infer of
marl arms lining the follicle may increase by several logs arm daughter
alas eve With a Sniffers ~~ of horn rancors arx]
st~id~enic enzymes (retrim in Richards, 1980~. Purim this process
ma~raticmaleven~cs=~e several folli~1ar~-~a granola
am come - mast be mused. Purim the r - motive life of news
these ells are cI—rly strait deco the pity signals of the
r~pr~ive Cycle. E~ver, few follicles are able ~ row to we
signals and Mach an arable state. :En minion, a ax~sic3erable body of data
SLIMS that initial stages of folli~,lar grouch begm before the Cyclic
hy~mic~pi - Entity f~c~k Manic are establish art that the
initiation of folli=~1ar grew entire to scare extent Hegira periods in
Thick pyclic~1 gana~r~n secretion is in ran not
(Ri~, 1980~.
_ ~ ~ = ~ ~ - =_ ~ ~ _~ ~
Awe pysiologica1 facts r~i~ marian Physiologists to idols
illtramarian control systems ran term authorize or paracrine Anion,
lc~ before ~ Am; were ~velc~ and polarized. The definition of
we ~i~ has earl as me of the mint tics ~ Ovarian arm
In the last Clyde. In rat years, refine in vitro systems arx] Swear
appeal; to identify arx] characterize sum ~i~ have ally an
unpr~ rate of data activation. It is near generally agreed that
paracrine ~i~ are critical to follicle development an] ~]ecci=~, but
c3efiniti~re proof of this hypes reman elusive.
To care to grips win this amount of information it has been rosary to
limit the ~ of this Alien. Tic ~ to air con r~r~ area -
paracrine and autocrine Mongol of samtic cells of Me Ovarian follicle by
~tr~ arm gnash factors - have bee ~hasiz~, arm air own data have
been use1 as exiles for nary fits pro. D;-~=i~ of Ante
mz~turatia~ wit be left to irxlivi~nals at this ~ ;ium ~ o have been more
directly involved in defining these mechanisms. For a survey of paracrine
mechanisms in the corpus luteum, the reader is referred to another recent
review (KhanrDawcod and Dawcod, 1986~. In reviewing paracrine nechariscs in
folli=~1ar cell function several classes of regulators have been identified.
These are distinguished ~ part by then' biochemical nature and in part by the
strategies amply n Air elucidation.
2'1 -
OCR for page 212
, Ovarian ~i~
It was `~= in Me 1940's that Cambrian sten~ids wan strong Midair
for ovarian regulatory prirx:~les (P~arz, 1940; Simian et al, 1941~. this
his Is canfin~ arm refine by a rower of critical In viva
e~peri~nts perform in he 1970's (Golderiberg et al, 1972a,b arm 1973;
Fret et al 1975; Peso et al, 1978~. -these studies, ungirt varietal-=
c~inatic~s of ~ins, art, ~tr~ and slid antacid
immature a~/or ~ys~ized rats ~~~ a rib for
follia~ar <3evelc~ and~cr - In action; In general,
a~r~ were found to be inhibitory or attic. he effects of
tr~ an gears cull r—licatial In viva Are particularly impressive
and these c~;ervatiaY; 1~ to ~ e~ro1utia~ of Me -tatted rat new which
has Jaw provided biological malaria for Mantles sties of granule at
function In villa. In addition, ~tr~ ~ found ~ interact
synergistically with Mains in pm folli=~lar cell
diff~ntiatic~n, with Ill r~r irruption Selkirk as a convenient and widely
shied end point (See Richards, 1980~.
Are or 1~= sin~tan~sly, the obligatory Aeration of {H~t
at bilks In p~idi~ serrate for FSH~t
grid outran synthesis was defined (Pelvic far Dorrir~ 1977; Byan
1979~. C~11ecti~rely these c~vatians pelvic the frank for Current
i~ir~ ~ the induration of steroid bills and action, In the Ovarian
follicle.
^m rent c~vatic=; have peril a mx~ pore detailed picture of
the action of steroids an follicle ~11 faction. EN action, In
particular, has been investigated ~ Hirable Am. Data on estrogen
rectors ark their r~ulaticn In Cat ovarian ells ~ particularly adamant
arm has led ~ a p~;ive ~ for these birdie sites as an Nor cent
regulatory 1~'= for had interaction (Richards, 1975~. Aver, a recent
ientia~s effort to - 1 ineate ~tn~ rectors ~ Mar Ovarian Ails
fail to disclose sum sty why i~r~ai~1 tennis; 1Hi~d-Petito
et al, 1988~. These studies;, alar' th the failure to ~~ the
m~t~enic action of ~tr~ In yivo In several species other than the Cat
(Kim arm ~1d, 1987) may inclicate significant differer~es ~ the nature
arx] ir~ta~ of Ate effects an He Ovary of variants As.
He stogie; perform ~ by laboratory and else by J*~a~es Veldt;
are typical of Variants Al By several groups whim have pir~poir~
03 action of ~tr~ cm the client s~id~ic pathway ~ Ovarian
ells. ~;esh~ies, Nurtured porcine gran~106acelis, rev~leda
ted irAibitozy action of ~tradiol (E2) (Veldts and Eland,
1980) which smears to be Aviated at the 3~roid d~ydr~ step
(Veldinlis, et al 1986,a) and whit is followed by a brisk stipulatory acticu1
Of ~m ~ E~in bits (Veldht,;~ and ~d, 1980; Veldt
et al, 1981). Ibe latter effects are ti _ t, inhibited by
anti~tz~, andinvol~rebi~sofs~idog~icenzyD~, ~ole~ero1
~ ~~ _
OCR for page 213
aid ~~a:Lr~ cleavage ~x~r~*s ~ particular Oreld~s arx] me, 1980,
Trellis et al 1981, 1982a,b; Staff et al 1983; 1985). In amidic, a
Cal Grease In spate foxy to ~ side ~ camp sip ~
generated by agrarian In patters of lip~r~ein utilization (pelvis et
al, 1982b, 19847. EffectE; of ~ In this stun are parti=~1ary
~ ~ the pow of Strains (Veldts et al 1981; 1982a;b). :Cn
the Maine system this intmactia, BERM to Mar p~inantly, if net
allusively at a Ices distal to Me ger~ral:ian of cAMP: it has been
infusible far us to ~ an effect of ~ art bum or F5H~b
chap levels (Spicer ark Hand, 1988,b) and E' significantly is the
effects of chap anal~; (Veldtmis et al, 1981~. In no - t z~s, Air
sties ~ the porcine grams of system agree well with data ~~—
stipulatory effects of E2 an terms in rat graraIl~ cello: shim
were ~ at the sane tine in atoner laboratories (Fitful et al, 1984~.
In a~itic:'n, ~= resets camp the sties of Richards arx] of who
have Straw i~rtarTt stipulatory i~ractic~ns of g0ad~r~ins ark
~ at Me level of Ibid proteins ark of f~tic~al plated
kinase activity (Rata~h arx] Richards, 1985~. Awe latter results suggest a
plausible ir~ra~lular manic By whim the ~i~ic-actic~ns of
might be ;. Wile the initial germ print leadir~ to these
Strom effects has net been det~i~, the Ire distal effects are ran
w~l ~ ~;iderable de - I.
Are went shies; ~ Char laboratory have fc=~ an the
cat~=l~trc~, an irrtriguir~ cleric of chucks which mav fur~tion to
~1 - ~^ =~ ,~ em; =+ ~ a, _~ ~_: - ~ - an: ~~ ~¢ _~ ,~
"Lucas: ashy ~1 u~ ~ ~ Al ~ al ~ Woo bale AL ~~ ~uc~ens. Me activity of
~tr~2~y1~-~ (E-2 ~ the enzyne responsible for Overtire E to
cat ~ olestrogens, is as high or higher in ~ e pa ~ ulatory porcine follicle
than in other extrahepatic tissues; importantly, the activity of E-2-M
dramatically enhanced An the walls of large well-differentia~c~ ovarian
follicles, in the mPmbrana granulnFa in particular, with levels 10-100 fold
lower measured in immature follicles and corpora lutea (Hammond et al, 1986~.
A physiologist function for the brief surge of catecholestroqan biosynthesis
in the preavula~cory follicle has been suited By air sties of the actions
of ca~lestr~ens con Turk porcine granule Owls. These studies have
shun Bat the cat~olestr~s, in the presence of FUJI, have pi
Ale to that of E2 in stipulating pro~ne ~etion; hover,
their ~ of actia, ~ ite di~tir~b - the two claims- of steroids are
signific~y a`3di~cive at dimly effective ~tra~cicms and the actions
of ca~lestn~ens are rut inhibited By anti estr~Fns, Bile those of E2
are Copier am ~xl, 1987~. Further the cat~lestr~Fns have
minatory effects cm AMP levels arx] ~rgic rectors which Writ be
mimic ~ the parents est~ (spider ark HI, 1988a,b). Incus the
stage is set for an; - tidal autocrine/paracrine Cysts in the pr~vulatory
follicle by chick lamlly so catec~ol~ mild function, all
with ~ to; - lify the stipulatory acticns of ~r~ins al a lock
level.
Al~h space does not permit a Sails review, both alarm arx]
Heir also have cI—rly Titrated ream and actions can ovarian
(reprised ~ HA et al, 1984~.
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OCR for page 214
Ih sunny, Aids of several claim- can be r~l as established
paraded armor a~crire radiators of cwarian furls by He criteria
Aim can be fitly applied in Die field. }A the bigness and
antis of these ~ are w~t~ In ~iderable ~tail. In general,
me ~`kvl of Base Em—can be in~ra~ced into a Went and plausible
~t of Vary E~siolc~y dung me rq~tive ~e. War.
· ~ __ ~ ~ a · _ _
~nc AL 1 - ~~ Ron to be resolved Knin the bib al
Rices of ~ and ~tr~ and their relative i~rtar~e ~ vivo. on
cre hand, ~ skids serve as a Ned for ~ levy of ~ii~ whim
to be aliens Ernie many of me ovarian Eyes
He secticms. on 03 our hand, the anus of p~ister~t Ir~i~
point At st ~ on, difficulties in ~ trapolati*~ fink ~ in vitro to ~ e
complex milieu of the ovary ~ Viva.
The Role of Ovarian Grcw~h Factors
As d;-rn-Cc~ above, gFxiYk~bro pins and gonadal studies have unambiguous
stipulatory effects on follicular growth and granule== cull replication in
viva. However, at least in cur hands, these hormones lack significant
mitogenic actions when added to cultured granulate calls in viler (Hammond and
English, 1987). In contrast, peptide growth factor,; have been keen to exert
pi ~tcgenic effects an ventured granule cells for at least a ~de.
~us, Air In beret, and that of of, in the Ovarian Growth factor was
stimulated in part By the speculation fat such factors might provide the
His by whip pib';tary and g~1 hinges regulated Ovarian ce11
r—1ication. In the years which have folded, immortal actions of Growth
factors =~ ~adiffermiciatia~ of Ovarian cells have ^~ beeline augment. In
the E~r~s whip follow, He eviderxx snip palatine effaces of
Oral growth factor fairies—the insul~like growth factors (IGFs), the
epid~mal growth factor (~-~/tra=;formir~ growth factor -a pa family,
the TO - eta fairy, and the fibrc~last growth factom (add;) are retrim.
For each of He flies He minim criteria of Utica n folli=~lar cells
and Em ~ the ovarian follicle have beg Am. Her, it has ret yet
been pcessible to page Cat ardor of Pose p~ptide; are obligatory nE,diatom of
follicalar grca~h. Perfuse of Air awn card it and ~ airs- of the
amount of evidence available, the IGFs are considered ~ greatest detail.
Ir~;uli~like ~ Fencers. The IGFs (exultation factors, satire
were originally disxx~w~ned and named And on their insulin-like effects and
on their presumed role as the circulating mediators of growth hormone action
a~ cartilage Levied ill I)ll~ay, 1984~. E~v~, it he also He clear
that IGF~ are synthesized widely in peril tic and recent interest In
the field has Realized their role as lom1 mediators of tissue gram and
differ~ii~tion {U~d et al., 1986~. King the organs for which an
auto or paracrine Fannie of the IGFs has been Cat—, the cat
~ their effects In the ovary may be the Nat ca~r~bensi~re and
persuasive.
- 214
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OCR for page 215
Sina3 air original A~ripticn of the effects of rat ISF-II (MSA) on the
level of orn~thi~ ~1~ ~ porcine grad ells ~elc~hu;~
Hi, 1979), are Man 50 pipers have been public ~nL~ the action
of the I~ ~ the ad. filly, an Chic review Is ignoble
In the Averment Apace. Briefly stated, it ad: Cat these pepti~= have a
Amatory action art every edging whim has On did. these
Cremate readily into the general areas of gr~-related actions arx] effects
on differentiated function. the first area include stipulatory effects of
the I0Fs ox ornithir~ Bylaws (Veldbu;-= ark Ed, 1979), cell remeet
Are (Savian et al., 1981; Ed et al., 1983), thymidine
in~rporati~ into 1~ (Baranao arm }I, 1984; }A arm English, 1987) ,
glad a~cidatim (fir and Subarea, 1988), and stipulation of
olysa~ride Venetian (~3a~hi et al., 1986c).
In Haitian ~ these Greed F~, ir~;ul~ arm the IGEs have
been fang to errand cliff~iated furx~ic~n of both theta As (Barbieri et
al., 1986; Bra arx] ~field, 1988) arm Gould ~Is. With gram
Ails, me IGFs or insulin seen to be essential for optimal effects of AH on
IH receptor ir~tic:~n (Mash) et al., 198Sc), ger~rati~ of cyclic Ad (Ada~hi
et al., 198Eib) and for FIJI antic on sternid~enesis (I~ranao arx] Hand,
1984, 198fib; ~3adhi et al., 198Sb). Se; specific points in the sten~ici~
genie pathway am Chad by Ids including i~alizatioa' arm pressing of
ex~xls ^)l~terl:~1 (Veldht];~ et at., 1987), the sit clangs ~
(Veldhuis et al., 1986b) , arm ar~atase (Ada~hi et al., 1985a; I~voren et al.,
1985; Veldts et al., 1985~. Ad con the magnitude of the effects
;, it ~1d Bar that the clifferentiative influence; of the IGFs on
folli~1ar cells are at let as important as then' m~tc~enic actions. In
Batik, the relative inportar~e of the gr~ch-relat~ and
c~iffer~iative effects of ~ I0Fs ~ an the level of Greta
cliff~tiati~ am the influx of Aver hordes and grad factors
~ et al., 1988b): ~ the presence of AH and In the milieu of the
pr~vulatory follicle, IGFs prance sterai~;is; in the presence of other
growth factom m~togenes~s p~irmtes.
For Be actions of the IGFs to be mediated in an autccrine or p~crine
fashion, it was redry for them to be present anchor secreted ~ the
marian follicle. this Chic has ~n a particular inb~b of air
I^ - ratory, and Cal' s ~ ies have Rae Gently been confir ~ d and extended Or ot~ r
groups. Fegardin3 ovarian IGF levels in viva, our studies have indicated that
I) IGFs and IGF binding prcte ~ were -~-~ y reasuc able ~ porcine folli~,lar
fluid OKam~on] et al., 1982; 1983), 2) IGF-II-like ma1~les and IGF-~-like
in~Lncactivity were both present piamnond et al., 1985, Mcrdschein et al
1988c), 3) the ococantrations of the IGFs were sufficient to tunic the actions
of Be Patti - ; in folli=~lar Be so (~d et al., 1983,1985),
4) me oonc~rati~ of T~ in folli~1ar fluid imposed Purim folli~1ar
Gnat (~d et al., 1985, disdain et al 1988c), ark 5) the
concentration of IGF-] in follim3lar flog was Creased for grins
(~xl et al., 1988a), ark grad homage (Bryan et al., 1988) . Related
dad n ovarian I=-I levels in the rat ark Weir stimulation by growth
horde have bed develc~ through organ ex~ctic~ by Da~roren ark ~ueh
- 215 -
OCR for page 216
(1986). In Portia,, high ticks of I~-II have }on famd in }Oman
follic-,lar fluid, harm et al., 1986).
Elided Urns he station of IGFs By Ovarian ~1 Is and its
Hannibal r~ulati~ has ban plaids ore directly ~ cultured grar~lc~
cells of porcine and Ban species. Our data with porcine cells s—lest hat
IGF secretion ~ Staid urger senm~free a~i~cia~ for at lost 10 days In
culture (A et al., 1985), and that inactive IGF-I paired
Over IG]?-II~s~ein et al, 1988c). lee secretion of im~nx~reactive IG]?-I
Cold be Shard by AH, estradiol, Is, growth Laurie (Lou and ~d,
1987a,b), and ,hI_~- ~~ ~ ~d, 1988). ~ i, ~fo~
growth factor~eta airs to inhibit IGF secretion in vitro except at very
lcx~~ntratic=; p~mand~d, 1988c;M0sdm~net al, 1988a).
Our data with folliallar fluid, rightly collected by analysis of ovarian
Ned levels, Ant At I~-I and II am both synthesized In the porcine
ovary ~= et al 1988; And et al unpublished). Ihis situation may
differ Frau that ~ the hen ~ assays for Be aseptic and their A;
At that the dminant Ovarian IGF Is I0F-II (R~ and Li, 1987;
Va~tila~nen and Miller, 1987). In fist, hybridization data fmn Ovarian
extracts (gnat et al., 1987a; Arty et al., 1987) sagest that IGF-I is
Be dominant, if AL the exclusive, Ovarian IGF in the rat. Be diversity of
expression of th—;e peptide; ~ to= Ovary ~ ~C:i~X is intriguing and
scx~hat Al.
Be evil reviewed above Air s;~1tanea~s section arx! action
of IGFs ~ the follicle sorely sits a rule for IS In folli~1ar grouch
ark desrelc~nt. Hover, it zag; ~aller~ir~ to prove that they are
c~ligatory n~;ators In thee pros. St~ies with ~clonal antibodies
to the I=s have putrid an ~;ticxlal approach. In air porcine granule
~11 culture system (HINDU arrt HA 1987b), go hogan, E2 arid
Perkins interact syr~istically to stimulate IGF-I and pz~te~
secretion. Rent studies have An that the effects of these hoDnes on
steraid~enes" can be ~tantially diminish by a n~l~al antibody to
IGF-I fin et al, 1988b). obese data constitute a direct
tration of an autocrine action of IGF in vitro. Related studies,
ir~icati~ an inhibitory effect of the ISF-T antibody can the sten~i~enic
actions of folly fluid] have also An the illporta~e of IGFs ~ the
stipulatory milieu of Be preavulatory follicle fin et al, 1988b).
these data are consistent with a role for IGF in folli~1ar devel~nt in
vivo ark cystic the mat direct evic3erx~e available for a critical Hale for
l
IGFs as 1~l amplifiers of the effect; of pih~ita~ ark gonac~al hormones. TO
air kr~l~ge, sum ions= here rot been USA for the cipher Arm
factors.
H-~ and ELF- PeptideE;. As reviewEx1 by ethers (greets ark
Z~i, 1986; Cohen, 1987) , the primary stroke of ED ~ as well as Pat of
its rotor, hoe been Leon for sag the. Bile many ells ~ Be bog
~ to this peptide, the nature ark sage of the As ligate for
these actions Is unclean Stable levels of ~pr~;orn~were fag
in ~illary gland, kinky, Awry gland, As, small i~;tine,
- 216
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OCR for page 217
pit~;tary, lured ppleen, b~' arxt Ovary ~ order of d~asir~ ~a~
~1 et al., 1985). ~ Critics to pepsin similar t;o salivary ~F, relay
peptic have been ~zed tory the use of radior~xptor assays for
Em. Ire must windy shxli.3d of these is 3= alma. This factor has been
fat Gainly In trar~fo~ ~11 my;, but Patti—: him alar to be
similar ham been fat ~ platelets (Assoian et al., 1984), pituitary
(s~ar et al., 1986), and Emery epithelium (Val~rerius et al., 1987) .
As filed ~~ - J. I~F alla Is to be ~ Fr-~—like provide ~ the ovary.
The Masonic actions of Em c' varian ~Is, first ~at"1 by
r~n.cz et al. (1977a) In bovine grarnOosa ~Is, have mew been In
granul=;a cells of c*her species arx] In a variety of =~ ~itions,
(~ncz arm Bial~ki, 1979, F~i~t et al., 1986; Hat and
Erotic, 1987~. ~ brash to me cot' stipulatory actions of =t an ~1l
~plicatico, me actions of ELF on differ~ia~ function are Ire complex
and generally inhibitory. Severn1 gram have demonstrated a r - Dative effect
cn Men genetic by grammar calls (~ et al., 1981; Knot arx] C~tt,
1983a) arx] ~ FSH-ir*~ ~ rectors ~s~= and Sc~a~rg, 1981; it
a=] Ott, 1983b). As arIticipat~, Arable results were adhie~red with
'~-alpha (~3a~hi am] Rennin, 1986) whim birds to tile sane rotor. me
multiple inhibitory effects of Em an FSH action ~ me possibility of
a gimbal antacid of F5H effects. ~ever, Be- can erhance FI;H birxti~ to
pig granulosa ~11s (My et al., 1987), arm me data or1 ELF effects and
~F/DiH interactions An me priests bi~thetic pathway have bed quite
var;~hie. Ibe latter results are at least partially at for by
cx~znita~ stipulation of peters metabolism to 20—ydr~p~ter~e
and sti~:tatic~n of averts preen bills at me sidereal cleavage
reaction arm the 3 - Rid d~y~na~ step (Jones et al., 1982~.
me data rubric above Dede EGF-like peptic; attractive mr~idat~ as
intraovarian regulatory ~1 es. Ihis poesibili~r has been further
sup~r~ by red shies In several laboratories indicating Ad- or
-alpha like activity In Me Ovary. Using a radiator Ably which
realizes both Em- and 1~ alpha, we detected ~ysiologi~1ly significant
levels of -like activity in porcine folli~llar fluid (Hd;u et al., 1987~.
me ~wrtra~cio'= In folli~lar fluid wed ~canbially higher than those In
porcine plum and higher in fluid f`~ "nail man fmn pr~vulatory
follicles. Are Ray, these studies have bed ED r other groups
do have In that TGF aplha is secret" by Rod ~ cells (Skinner et
al 1988) and localized to ~ Owls 18s~_i~1ly (~1~ et al,
1988~. Collectively, these data DElke it Try ~ ly lilmly that EX~-like
pumpkin-= will be assigned an autocrine or paracrine function ~ ovarian
physiology. We postulate that their dot inant effects will be exerted in cnF11
follicles where they should act to promote ~11 replication and restrain
differentiation. However, an understanding of the true significance of these
pqpkiAFc will ~ more detailed studies of their nature and regulation.
l~nsformir~ Growth Factors beta was initially defined as a peptide
whim, in (~xljUrXItiOll off EXJF or ~~ a, allied reversible transformation
of normal rat kidney Ills to anchorage irk growth (Spore et al.,
1986). S~ral analyses have In a s~cia1 duke of seye
- 217
OCR for page 218
l~y been l - ~a, irhibins, activins arm Mullerian irhibitir~
tang, 1987). Toyota Is new In to be p= t in, or
s~ by, a rower of reseal as ~1 as nonplastic cell types and is
print in al in platelets (Assoian et al., 1984). Ite action of this
factor is bi~tial, faci~i~cati~ grog in ~ ~11 go; ark ,~llb~
cities, but inhibiting growth ~ our ci~ (lies et al., 1984;
Alerts et al., 1985).
As purified preparation; of Taffeta beg available, its effects con cat
granary Ills Ire ever; Ire or 1~ si~ltar~sly by several
laboratories (A`3ashi and Pesni~k, 1986; get et al., 1986; Yips et al.,
1986; Susan ark go, 1987). In the adulate, these studies
a sti~la~ry action of 'yucca An AH acetic, reflect ~ an Age in
espy secretion (Mash) ark Resrlick, 1986; Yir~ et al., 1986), IT }or
activity (Kit, et al., 1986; rag and Sag, 1987), are] pr~t~e
bi~yr~is (Dysan and Sag, 1987). Ire recently, a stipulatory
infraction of Qua ~ FSH con INA Rests by rat granule cells has
also been Strafed (Dorri~ et al, 1988~. While the stipulatory
actions of Thea can rat gram owls seem clan', the work of ~t et
al. (1987) has mien that tom effects dam critically an the ~ntration
of the grub factor and of FSH. At high FI;H ~xr*rati~ a d~3ent
irhibitoryacti~of TGr~etz~was Scam. In a~rporuine grayly cell
culture system, ~ whim z~licatic~, thymidine incorporation, IGF secretion,
arm Eli _ t pr~t~e suction Here storied, an inhibitory
effect of 1~ was fat on all the parroters ermine Rein and
}go, 1988; Rein et al., 1988a). Me effects of '~-beta in this
system were particularly caviar= when the particle was Cabined with
stipulatory ~tratic~ns of or ~ (offs ~ to thymidil~e ir~rE=n~tion. ark
IGF-I satiny or with FSH (with rears to pr~e #accretion). Our
ruts are In aghast with the grub inhibitory effects of ~ - em on
bovine Granule Delis (Skinned et al., 1987) as well as with the inhibitory
effects of TGF—eta an grub ark differ~iatic~n of abler retrial arxi
nonplastic ~11 types; (grief ~ go; et al., 1984) ir~c1~i~
Article Ells (cotta and Baird, 1986~. In go, TGF - eta has bun
fat to have paint hat variable effects on bath replication art
diff~tdilt~ fur~ticn of Adrian grar~losa ells. It ~r; that the action
of this peptize will depend critically cm the sties ard,/or the preserve or
absence of other speculators of grate call faction. This ~ reflective,
An the Ace herd, of the ~1 trim biE~eia1 nature of T~a's action
~ n3~s ~11 types; art, cm the Aver, of the duplex Iranian of
- ~ltip1e facts Aids are irrvolv" in cFrarian cellular dial.
six i~rtar~ of these actions of TG[ - eta i'; ~or" by rent data
fray several "arm; ir~icatir~ probable s~reti~ of ]~ - pica ~ the ovary.
skier et al. (1987) have Rated the gig of in am
reactive Area by Future bovine are Nat theca Ems. In Ratio,
the MA for Strata has bun fa=1 in the chary by I~rynd}c and Rhee (1987)
are ~rnar~z et al. (1987b). Alto the details of the secretion of
Rota by ovarian Ells r'= to be worm At, this Gram factor can
probably be r~r~ as an important autocrirx3/paracrine influence in the
Ovary A the buts of present dam.
218
OCR for page 219
Fibr~last Ah Factor. Me ~ of Im was ~ ~ the
Botanic activity of pi - Italy Tracts ark partially purified pituitary
handle pr~ratic~ns. Since these original st~ies He peptize has been
purified to hey fmll a ~ of hiss, including We ovary, and its
Binary 6tr~re analyzed (retrim by Bird et al., 1986; Wick et
al., 1986b). Be OF peptic= have patent gr~r~ti~ activities an many
cams of Hal origin, are the my - enic action of me Few on
Lial cells, Implying angi~enic activity, has attract particular
a~ic~n. this action may be of Rare ~ me develc~ of ~ ovarian
follicle as sell as the corms 1~.
shortly after purified preparatic~ns of F0F ~ available, the Halide
fang to be m~tog~ic for granulosa cells f~ Ovine (~ar~icz et
al., 1977a), rabbit, porcine, An, are guide pig follicles (~ar~icz
and Biale~ki, 1979). Ells free corpora lutes also retained sensitivity to
OF but not ~ (~ar~icz et al., 1977b). In addition, [~t shorts the
Garth of luteal filial calls ((~ar~icz et al., 1986a). Effects of
E~ ~ diff~tiated fur~tion and s~ic~;is by ovarian cells have net
been stied as Thematically, but the available data Hats that the net
effects are generally inhibitory (Savior and ~ar~icz, 1980, Baird et
al., 1986, Hi et al, 1988).
me fist clef' Cation of [ - In the Calvary was by ~ar~icz et
al. (1985) who purified an attic factor Mom bovine corms luteum that
had binning, biological, arm Hex homology to pituitary For. Ore
meetly, Neufeld et al. (1987) have also An that bovine granulosa Ells
prime a basic E~ similar to that fm~pit~uit~ ~ Tare
el~tz~hore~cic arm reactor bit activity. Related data have been
pulpy Birded al. (1986) whc) extracted an [~-likepeptide fin
rr~luteiniz~ rat ovary. the r~aticmship of He well characterized
liar species to atoner peroxides which EYK~= me or Ore of the
pry of Em rum; a subject of active Elation. A hepari~birdi~
Al mit~angiogenic factor, d~ated tar Claris et al. (1984),
aE~ar~y has scare similarities to ~ ~ edict Tuition (M&kr~s,
E~1 Fornication). In Action, other facto=; rem grant
cell~iti~l Odium love ar~iogenic activity (Ken;, 1986~. With the
i~E~t ~ specific receptor and Whys for Me EGFs, a Ire dint
Parish of Me factors to ] - ~d be fo~irg.
In spry, ovarian growth factors have been intently investigated an
reagent year';. Be data available irxlicat~ that ~rera1 Ha; of gram
factors are Rested, active, arm probably Important ~ the ovarian
follicle. Eta Hurt the IGFs ~ mart complete, arm our level of
~i.rq of me role these phi - ; rivals Cat achieve for steroids.
With Rae to the IGFs, the Rim picture Hats an Ovarian
an~lificati~ An interfaced with pituitary arm goal horns at several
levels whim ~c! erharx~e the ~velc~nt of follicles sell for
ovulation. coca Nordic the secretion arm action of our Growth factors Is
I^~c at, but it Is actuating rapidly. A ~~ Hub picture of the
p~siolc~i~1 i~ortarx~e of He peptides ~ ld be Fusible shortly.
- 2Ig
OCR for page 220
Our ~ Prides
, _ _, , _ be Ovarian Follicle
men I first reprised this an for a sy~6ium ~ 1980 (and, 1981),
thinking In be field was dominated by a lumber of factors, identified in
folli~llar fluid or ovarian e~ccracts and fined In tenrd; of In vitro
bits whim were assured to reflect paracrine relati~hip6 In me ovary
cx~yte ma~ratic~n ir~ibitortt, ~luteinizati~ inhibitors, ttl~Tteinization
~imdatort', ~cz - in birding ir~ibitors, arm Gr~H-like suntan (~c
Adonis and S—al, 1982). At the Tim, these factors berm ~E;iderable
city ham a, the as~ion that they ~ unique ovarian Riptides
which, when EA~rifi", w ~ d allow safe and specific a ~ roac ~ ; to f ~ iffier
regulation. Particularly frum this historian perspective, progress ~ the
definition of these factors has been disappointing. Although the
phenomenclogi~1 and conceptual framework of these observations has persisted
(ace reviews by Tbnetta and deZeriga, Tsafriri and Pomerantz, and Khan-Dawcod
and Dawc ad, in Franchlmcnt, 1986) none of the peptizes themselves has been
purified sufficiently to permit structural analys ~ or definition of mechanism
of action. In the He of sew coca, it seems Educible that sum effects
may be redated for other, mare rightly defined paracrine regulator=, acting
indivisibly or in concert. In particular, we found that most of the
stipulatory activity, for granule ~1l steruidc~enes" in folli~llar fluid
Frau preavulatory follicles, previa~sly termed "~xteinization stimulator"
(l~witz-Rigby am Rightly, 1983), could be neutralize By a mor~oclona1 arrtib~
t:o IGF-I. Apices of severe of the other grew factors described ate
overlap the inhibitory effects ascribed to variants follit-,lar factors on
somatic cells of the follicles, and the Offs and EGF also have well described
effects on oocyte maturation (Dekel and 5heriz~y, 1985, Feng et al, 1988~. Of
the follicular factors, ~ data is most abundant concerning a GnRH-like
pepkide identified and partially purified by Behrman and oolleagues (Aten et
al, 1986), and a broad spectrum inhibitor of steroidbgenes ~ named Follicular
Regulatory Fepkide by deZeriga and colleagues (reviewed ~ Tboetta and
diZerega, 1986). Both of these factors appear to represent discrete entities;
however, their biochemical nature and similarity or diccim;larity to other
proteins previously identified in the gonad or elsewhere remains to be
determined. The cu~bersoca bioassays for apparently unique ovarian peekides
may ~ Retinue to hamper purification efforts. However, it would be unfortunate
if such efforts were totally suspended, since they set l offer the best change
to isolate peptides unique to the gonad and useful for regulation of gonad
function. As proved to be the CAMP for inhibin, these difficult purifications
should be technically forcible when cl~-ccical bi^~=C^y prooedure6 are
reinforced with modern fractionation and mal ~ alar techniques.
A.,
~ ore recent years, l~66 at Me clefiniticm of peptide radiators In
the gcmad has pro with pros and techniques quite different than
ewhi~urx3erlay these initial efforts. The tacit a~bic~n of most
Parr studies Is Mat peptide radiators id~ifiec] arm purified f~ other
organs are pro and inpor~cant in the Ovary. Ire utilizatic~n of
i~i~1 and ~1~1 ar probes for sum previously identified pepti - =
has maw Foible a~nJatic~n of information cn goal E~i~X at a lance
previously infusible. Variants of this strategy led to identification of
many of the ovarian growth factors described previously. Aversely, surveys
- 220
-
OCR for page 221
of other ti~PC for go gene pc~t6, e.g. irhib=, indicated the
F~i~ for a Max broker physiological hale than initially ~
(punier et al, 1988). Finally, sup techniques have ~ possible a Dare
rapid Edit of the relaticm of gimbal Stir to relate gene
fPmi 1 ies of considerable interest to ovarian physiologists. As again
exemplified By Me ir~ibirVactiv~n field, ~ of Eve woo urban at Me
initiaticn of Hose sh~ies (Ying, 1988~. Other global peptic identified
by these strategies include transferrin, fibm~tin, ar~iatensm lI,
Stile Y. Fiord patio, vasc~ressm, growth lxn~3 relying hormone
and Ear Amps factor. It Is inedible to Graze the sta~of-~art
Zaire eat of Muse regulatory Scam Am. Sam of He topics have
been ~ ire our remet review that may be helpful ~ Bring areas
~ apply develop hue —.~ et al., 1984; Hs~, 1986; Rosetta and
—7:^riga, 1986; ~afr~i are F~antz, 1986; Smith and Fiery, 1988,
Syrups, 1988~.
Sugary of Current Efforts and Fire Ares
It will be clear fzan the forgoing rev)"' that the aut~rine/paracrine
influerx~; which impinge can ovarian sells are axY;i~rably more n ~ s and
~ t certainly as important as the classic endocrine feedback loops. On the
other hands the endocrine, autocrine' and paracrine relationships involved in
ovarian development have reached a level of complexity that currently defies
comprehensive analysis, and the true situation is urdkLb*eCly substantially
more complex. While continuing the descriptive phase, concerned principally
Pith identification and characterization of new regulatory mechanisms in the
ovary, we also need to integrate this information into pysiologir~1
coo structs, to establish criteria for judging which of the putative regulatory
systems are most important, and to begin to develop new investigative
strategies which may ultimately lead to phar~oologi~1 control of such
Units
.
by general Dent the minis criteria for Avis
paracrine/aut~ine regulatory systems is loam solution err] local action of
putative regulatory principles. these criteria have Ben met for the
principles considered In this redries with the e ~ tion of Are of the more
recently discovered peptizes mentioned in the previous paragraph. However,
considerably more detailed information about the mechanisms involved In the
synthesis and action of effect or molecules ~~ needed for most of the
paracrine systems. Of many topics deserving of mention, two are particularly
intriguing to me: 1) the ?n~1tiplicity of mRNHk species an4/or large pepkide
Arm; for several ovarian factors ~ Desist with biotic arx3/or
pot - ranslatia~al r~ati~ whim Alla be Dime Pacific art hormone
rearm; 2) the biochemical Manic whim govern the interplay between
z - licati~ arm differentiation of ovarian cells represents a critical topic
for further ~ y. A =ivatia, of pret ~ s may be Are fruitful a Breach
~ this area. Next, it seems essential to understand the manner in which the
secretion and action of these local regulators is inberfared with the hormonal
signals of the reproductive cycle and coordinate] with developmental changes
in the several clarion compartments. These issues have been best addressed
with regard to steroids and the IGFs. Increasingly refined Nell culture
· ~ ~( ~ _
OCR for page 223
~,,3
I a~wledge the helpful its of leer. J.S. disc - In arm devat"
service of Mrs. icy Muir, i. Saga Clan, is. saga ~ aced
- . ME Of Em.
223 -
OCR for page 224
Lily Ci~
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hor~i~ ar~atase activity of ablaze rat grmn~lc~ Owls.
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Sanatcrr - uric sy~izes Pith folliclff~;n',Qatir~ hormone In the
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- 233
Representative terms from entire chapter:
ovarian follicle
