Distribution and Biological Effects of Prostaglandins by hse16929

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									     DISTRIBUTION AND BIOLOGICAL EFFECTS OF PROSTAGLANDINS

                                     J. W. LAUDERDALE


                                 J Anim Sci 1974. 38:22-30.




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                DISTRIBUTION AND BIOLOGICAL EFFECTS
                         OF PROSTAGLANDINS
                                        J. W. LAUDERDALE
    The Agricultural Laboratories, The Upjohn Company, Kalamazoo, Michigan 49001

                  Summary                                cular, and bronchial systems briefly, but to
                                                         review literature relative to reproduction in
    ROSTAGLANDINS occur in nearly all                    more depth. Most of the information pre-
    mammalian tissues. With the possible ex-             sented has been gleaned from reviews either
ception of PGA’s, prostaglandins appear to               prepared by or published by other researchers
act locally rather than as classical circulating         working at the Upjohn Company.
hormones. Biologic activity is related primar-
ily to alteration of smooth muscle contractility
and modulation of hormonal activity. Relative               Distribution and Chemical Nature
to parturition, prostaglandins, especially           Prostaglandins were detected first in semi-
PGE’s and PGF’s, have been shown to 1) in-        nal fluid of rams, but were thought to be de-
crease at time of parturition in amniotic fluid,  rived from the prostate, hence, the name
maternal placenta, myometrium, and blood;         prostaglandin. Chemically, the primary pros-
2) stimulate myometrial activity; and 3) to       taglandins are unsaturated hydroxy-acids with
induce either abortion or parturition. Relative   a five-membered ring in a 20-carbon skeleton.
to luteolytic effects, prostaglandins, especially Trivial names are by letter and number. Pros-
PGFZol,   have been shown to 1) increase in the   taglandins of the 1 and 2 series have one and
uterus and blood to levels similar to exogenous   two double bonds, respectively. The E-pros-
levels required for eliciting luteolysis; 2) be   taglandins have an oxygen at carbon 9 while
capable of crossing from the uterine vein to      the F-prostaglandins have an alpha-hydroxyl.
the ovarian artery (sheep) ; 3) be related to     The A-prostaglandins are dehydrated deriva-
IUD induced luteal regression (sheep) , and       tives of the E’s in which there is a double bond
4) be capable of regressing the corpus luteum     between carbons 10 and 11. There are over a
of most mammalian species studied to date.        dozen others, with minor variations in double
Prostaglandins have been reported to result in    bonds and hydroxyls.
release of LH, prolactin, growth hormones,           Hundreds of prostaglandin analogs and de-
ACTH, and oxytocin. Data suggest prosta-          rivatives have been reported, from which
 glandins, especially PGE’s and PGF’s, may be     could come “second generation” prostagland-
involved in the processes of ovulation and        ins. Many of these have interesting biological
 gamete transport.                                actions, and promising early clinical studies
                                                  have been reported for the 15 [SI-methyl ana-
                 Introduction                     logs of PGE2 and PGFw. These particular
                                                  analogs are interesting because they are not
   Objective of this presentation will be to substrates for prostaglandin 15-hydroxy de-
present a general review of distribution and hydrogenase, which is responsible for one of
biological effects of prostaglandins. The gen- the important routes of metabolism of natural
eralness is dependent on the quantity of litera- prostaglandins. As oxytocics, these analogs
ture available for review.                        are from 10 to a hundred times more active
   To illustrate the latter, an analogy between than the corresponding natural compound.
“population explosion” and “literature explo-        The word “ubiquitous” has been utilized
sion” seems appropriate, since this is a sym- extensively in papers describing prostagland-
posium on reproduction. The number of pros- ins. This adjective seems appropriate m c e
taglandin papers published during 1960 prostaglandins have been detected in, or re-
through 1961 was five, in 1965 58, during 1966 leased from, lung, thymus, brain, spinal cord,
through 1970 1,200 or about .66 per day, and kidney, iris, umbilical cord, decidua, fat, ad-
about two per day currently.                      renals, ovaries, stomach, intestines, nerves,
   The more specific objective will be to review menstrual fluid, amniotic fluid, seminal
literature relative to renal, gastric, cardiovas- plasma, blood, skeletal muscle, cardiac muscle,
                                                    22




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                     BIOLOGICAL EFFECTS O F PROSTAGLANDINS                                           23
salivary glands, thyroid, pancreas and uterus             In general, both alteration of smooth muscle
 (Bergstrom, Carlson and Weeks, 1968). There           contractility and modulation of hormonal ac-
appears to be a good possibility that most, if         tivity were detected following prostaglandin
not all, mammalian tissues contain, or are             administration. Although, prostaglandins are
capable of synthesizing, some prostaglandins.          synthesized locally, over 90% of infused pros-
Concentrations of prostaglandins have been             taglandins have been shown to be inactivated
on the order of magnitude of 1 ug/g of wet             with one pass through the lungs, except for
tissue. The notable exception is seminal               PGA’s (Bergstrom et al., 1968). These data
plasma with concentrations of 100 pg/ml                suggest that prostaglandins act locally as mod-
 (Bergstrom et al., 1968).                             ulators rather than as classical circulating
   Assumptions may not be correct that tissue          hormones. The adenyl cyclase cyclic AMP
levels of prostaglandins reflect biologic activ-       system appears to be involved in action of
ity. A. Wakeling (personal communication)              prostaglandins as modulators and is receiving
demonstrated that if tissues were not rapidly          much research scrutiny at the present time
removed from the body and either quick                 (Hinman, 1972). Since prostaglandins are so
frozen or immediately placed into solutions            rapidly metabolized and removed, circulating
containing inhibitors of prostaglandin synthe-         blood levels probably have minimal associa-
sis, the prostaglandin levels in excised tissues       tion with psysiologic effects occurring in a par-
would not reflect prostaglandin! levels in the         ticular organ.
body, i.e*, prostaglandins were rapidly synthe-           Prostaglandins are found in different tis-
sized or released by manipulation of tissues.          sues, therefore, a brief review seems appro-
Also, detection of prostaglandins is dependent         priate of effects on systems other than the
on the assay system employed. Data reported            reproductive system. This information is pre-
in most of the older prostaglandin literature          sented to demonstrate that prostaglandins
was based on bioassay methods, the end point           have varied effects. The generalness may be
being smooth muscle contraction. Since many            misleading since there exist species differences
substances will cause smooth muscle contrac-           for some specific effects, especially if different
tion, specificity of prostaglandin bioassays           routs of administration are used.
should be of concern. Newer assays such as                Cardiovascular. PGE and PGA have been
radioimmunoassay and gas chromatography in             shown to be potent blood pressure lowering
conjunction with mass spectrometry have been           compounds, whereas PGF’s produce a rise in
employed to meaure levels of endogenous as             blood pressure (Oesterling, Morozowich and
well as exogenously administered prostagland-          Roseman, 1972).
ins, but radioimmunoassay has received tbe                Kidney and Ureter. In general, PGE1, PGE2
most use. Since radioimmunoassays                      and PGAl increase blood flow, induce natriure-
specificity, the use of radioimmun                     sis and water diuresis, and redistribute blood
quantitation of prostaglandins should be pre-          flow from the cortex to the medulla. They an-
ceded by rigorous validation and adherence             tagonize the action of vasopressin, but in-
 to established principles of radioimmunoassay.        cre3se ureter and bladder motility (Oester-
                                                       ling, et al., 1972).
             Biological Activity                          Gastroinrtestinal. PGE1, PGE2 and PGAl in-
                                                       hibited gastric secretion (Robert et al., 1967),
   Data utilized to describe biologic activity         but increased stomach and intestinal motility,
has been derived from studies both on changes          and may induce vomiting and diarrhea (Oes-
in endogenous levels of prostaglandins in con-         terling et al., 1972).
junction with physiologic event and on physio-            Respiratory. PGEl and PGE2 induced
logic response following administration of ex-         bronchodialation, whereas PGF2a induced
ogenous prostaglandins. As biologic roles of           bronchoconstriction (Oesterling et al., 1972).
prostaglandins are considered, we should re-              C N S + Peripheral Nerves. PGEl and PGEz
call that release of prostaglandins in associa-        were released simultaneously with norepine-
tion with physiologic function suggests a              phrine but acted in a negative feedback way
cause and effect association, but this associa-        to inhibit further norepinephrine release. Var-
tion may be incidental. I n addition, much of          ious prostaglandins have been shown to induce
the data to be discussed has been based on             stupor, catatonia, or excitement (Oesterling et
effects observed following exogenously admin-          al., 1972).
istered prostaglandins ; therefore, only indirect         Differences in biological activity among
conclusions may be made from these data.               different prostaglandins must be emphasized.




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24                                         LAUDERDALE
To generalize, the primary E- and Fa-prosta-           tissues incubated in vitro synthesized prosta-
glandins are powerful smooth-muscle stimu-             glandins from natural precursors (Nugteren
lants, while the PGA’s are relatively inactive         et al., 1966, quoted by Bergstrom et al., 1968).
 in this respect; the primary PGE’s and PGA’s          Prostaglandins stimulated contractions of iso-
have a similar depressor action on all species         lated myometrial strips (Bygdemann, 1964).
 studied, yet PGF2a is pressor in dogs, rats,              Presence of prostaglandins E2 and Faa in
 monkeys, and man, but paradoxically, depres-          amniotic fluid and blood during labor plus
 sor in cats and rabbits.                              their known action of stimulating in vitro
    This brief review of effects of prostagland-       myometrial strip contraction led to the hy-
 ins on systems other than the reproductive            pothesis that prostaglandins played a physio-
 system was presented in an attempt to make            logic role in parturition.
 us more aware of the varied but numerous                  PGEa (0.5 ug/min.) and PGFza (5 ug/
 effects prostaglandins are capable of elicting.       min.), administered by continuous intraven-
 In my opinion, this makes results obtained            ous infusion, stimulated the uterus a t term
 from studies based on exogenously adminis-            to contract in a manner similar to the contrac-
tered prostaglandins more difficult to inter-          tions recorded during normal spontaneous
pret, especially if attempts are made both to          labor, and resulted in induction of labor
establish cause and effect relationships and to         (Karim, 1972). Additional studies have util-
extrapolate from results of exogenous treat-           ized intraamniotic administration of prosta-
 ment to normal physiology.                            glandins. Single doses of either 50 to 100 pg
    Reproductive System. To me, the fact is            PGE2 or 500 to 1,000 micrograms. PGFza
 interesting that in 1935 the coining of the           injected intraamniotically stimulated uterine
 names “prostaglandin” by von Euler and                activity and resulted in induction of labor
“progesterone” by Allen, Corner, Butenandt             (Karim, 1972). In addition, IV infusion of
and Slotta appeared on the same page in                either 5 pg/min. of PGEB or 50 pg/min.
Klinische Wochenschrift. Following that pub-           PGFaa during either of the first two trimesters
lication, research efforts, as measured by pub-        of pregnancy produced uterine contractions
lications, increased rapidly during the 1940’s         similar in frequency and amplitude to those
and continued until now for progesterone,              occurring during spontaneous abortion and
whereas prostaglandins did not achieve such            resulted in abortion (Karim and Filshie, 1970
a rapid publication rate or interest level until       a, b). Other doses and routes of administra-
the mid 1960’s. Thus, 35 years after sharing           tion have also been shown to be effective for
a common page in a journal, these two com-             inducing abortion in women. Also, both PGEz
pounds are again closely associated, but this         and PGFza induced abortion in Rhesus mon-
time biologically, with prostaglandins being          keys (Kirton, Pharriss and Forbes, 1970).
demonstrated to result in luteal regression           The relative potencies and total dose required
and pregnancy termination.                            to initiate myometrial contractions were simi-
   Effects on Pregnancy. Karim (1966) re-             lar between the monkey (Kirton et al., 1970)
ported presence of prostaglandins in human            and human (Karim, 1968; Karim and Filshie,
amniotic fluid, but Karim and Devlin (1967)            1970a).
reported prostaglandin content in amniotic                Another piece of circumstantial evidence
fluid increased a t time of either parturition or     that implicates prostaglandin association with
abortion in women. At term, after spontaneous         parturition is that ethyl alcohol reduces or
rupture of the fetal membranes, uncontami-            inhibits both spontaneous uterine activity of
nated fluid contained PGEl (1 ng/ml), PGEz            pregnant women and prostaglandin induced
 (0.5 ng/ml), PGFla (140 ng/ml) and PGFw               uterine activity of pregnant women, but does
(30 ng/ml) (Beazley, 1971). PGFm was de-               not alter oxytocin induced uterine activity
tected in maternal venous blood obtained               (Karim and Sharma, 1971), suggesting the
either at the time of spontaneous abortion             prostaglandin effects on the uterus were not
(Karim and Hillier, 1970) or a t full term             due to oxytocin.
labor (Karim and Devlin, 1967) and the con-               In sheep, Prostaglandins El, Ea, and Fla
centration increased with progression of labor        were not detected in myometrium, maternal or
(Karim, 1968). Decidua obtained from                  fetal cotyledons or blood prior to initiation of
women in labor contained prostaglandins El,           labor, PGFaa was not detected in uterine ven-
Ez, Fla, Faa in concentrations about 10
           and                                        ous blood prior to labor, but it was detected
to 30 times greater than amniotic fluid con-          in uterine vein plasma during dexamethasone
centrations (Karim, 1972) ; also, endometrial         induced labor in nine of 10 ewes a t a mean




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                         BIOLOGICAL EFFECTS OF PROSTAGLANDINS                                                        25
                          TABLE 1. EFFECT OF PGFz, ON PREGNA-NT CATTLE
   Staee of                                                             Percent cows aborting after PGFa by day
                                                                         I
                                                                                            -             - -
   gestitiotjon        PGFI, dose
    (Days)              WG)"             No. of cows                     4          7         14        21         35
   40 to 7 0              45, 150             14
                                               6
                                                                       100         ..         ..
                                                                                              ..
                                                                                                         ..
                                                                                                         ..
                                                                                                                    ..
                                                                                                                    ..
   80 to 120                45                                          50        100-
                           15~30               6                        17         33         50        50         50
                            1, 5               6                         0          0          0         0          0
  157 to 165            15, 30, 45            20                        25         60         60        60         65
  164 to 179                90                12                         0          0          8        42         42
  217 to 2 4              50, 150             21                         5          5          5        19         29
    aSingle administration of PGFn,-tham salt subcutaneously. Dose-response on the same line was comparable for the doses
shown.

concentration of 18 ng/ml (Liggins and                         dale, 1972), was less effective in inducing
Grieves, 1971). Dexamethasone induced par-                     abortion when administered after 120 but be-
turition resulted in significantly elevated levels             fore 250 days of gestation (table l ) , but was
of PGFza in maternal cotyledons and myo-                       effective in inducing parturition (table 2 ) .
metrium, but this increase was detected about                     These data, obtained from various species
24 hr. prior to onset of induced labor (Liggins                utilizing many different routes of administra-
and Grieves, 1971). The increase in maternal                   tion and dose levels, demonstrated that: 1)
cotyledon levels of PGFza was not blocked by                   levels of prostaglandins increased at time of
exogenously administered progesterone, even                    parturition in amniotic fluid, maternal coty-
though the progesterone suppressed uterine                     ledons and myometrium, and blood, 2 ) prosta-
activity (Liggins and Grieves, 1971). Thus,                    glandins stimulated myometrial activity and
prostaglandins were associated with parturi-                   3 ) prostaglandins induced either abortion or
tion in the ewe.                                               parturition. Thus, prostaglandins have been
   Uterine activity was unchanged by PGF2,                     demonstrated to be associated with termina-
infusion even though jugular plasma levels of                  tion of pregnancy. However, the specific cause-
PGFza were 50 ng/ml during the infusion                        effect relationships between prostaglandins
(Liggins et al., 1972). In addition, Oakes et                  and either parturition or abortion have not
al. (1973) reported for the ewe that intraven-                 been described completely.
ous doses of up to 10 pg/kg of either PGFza                       Since prostaglandins have been shown to
or PGE2 administered to the dam or up to                       have both luteolytic and oxytocic properties,
100 pg/kg PGF2, administered to the fetus
                                                               role(s) of prostaglandins in parturition or
had no effect on either uterine tone or ma-
ternal cardiovascular functions or on fetal                    abortion may relate to both luteolytic and
vascular pressures and cardiac output. Al-                     oxytocic activities. I suggest that for those
though these data suggested that sheep were                    species in which a functional CL is essential
insensitive to prostaglandins, PGFza adminis-                  for maintenance of pregnancy, the primary
tered to ewes (either I M or IV) 7 days prior                  action may be luteolytic, but oxytocic activity
to expected parturition induced parturition on                 may also be involved. For those species in
an average of about 3 days after injection                     which a functional CL is not essential for
 (Harmon and Slyter, 1973).                                    pregnancy maintenance, the primary actions
   Additional studies in the cow demonstrated                  may be oxytocic, i.e., disruption of the fetal-
PGFZ, was effective in inducing abortion dur-                  maternal placental unit. For these latter spe-
ing the first 120 days of gestation (Lauder-                   cies the lytic action of prostaglandins also

                  TABLE 2 EFFECT OF PGFn, INDUCTION OF PARTURITION IN CATTLE
                         .

                                                          Days of gestation                               PGF- to
                                                                                                           calving
                                               Injected                        Calved                  interval (days)
    PGFz,                                 /

 dose (mg)a          No. of cows        Mean         Fafge             Mean         Rkge             Mean        Range
15,30,45,90    30                        267.9       263-276           271.0       2662277              3.0'       %
                                                                                                                   1
         w-- 3
           - -                           263.3       260-267           278.3       269-287             15.6        2-26
    aSingle administration of PGFz,-tham salt subcutaneously. Dose-response on the same line was comparable for the doses
shown.




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26                                         LAUDERDALE
might contribute to reducing serum proges-             inducing luteolysis in the sheep ovary-in-the-
terone levels through CL regression.                   neck model (Carlson et al., 1972).
    Luteolytic Effects. PGFZ, levels increased            Although prostaglandins have been shown
about fourfold between early stages and day-           to be luteolytic, a paradox appears to exist
 14 of the estrous cycle in both endometrium           relative to luteotropic activities of prosta-
 (Wilson et al., 1972b) and uterine venous             glandins. PGFz, has been shown to be luteo-
 blood of sheep (Bland, Horton and Poyser,             lytic in vivo, but various investigators have
 1971; McCracken, Baird and Goding, 1971;              reported increased progestin biosynthesis of
 Coudert et al., 1972; Thorburn et al., 1972).         rat, mouse, rabbit, cow, rhesus monkey, and
 PGFzo! levels in the uterine venous blood at          human ovarian tissue incubated with PGFz,.
 the time of luteal regression were elevated           However, for at least the rat (Wilks, Forbes
  (McCracken et al., 1971; McCracken et al.,           and Norland, 1973) and probably the rabbit
 1972) to levels similar to those which resulted        (Bedwani and Horton, 1971; O’Grady et al.,
 in CL regression when infused into the ad-            197210), subsequent work demonstrated that
 jacent uterine vein, but not when infused sys-        prostaglandins are unlikely to be involved in
 temically (Goding et al., 1972a; Thorburn and         progesterone biosynthesis. However, for the
 Nichol, 1971) during the luteal phase of the          bovine, Hansel, Concannon and Lukaszewska
 estrous cycle of sheep. Also, PGFnorinfused di-        (1973) have demonstrated :several prosta-
 rectly into the ovine ovary resulted in luteo-        glandins to be capable of enhancing proges-
 lysis (McCracken, Glen . and Scaramuzzi,              togen biosynthesis in vitro.
 1970), and labeled PGFza’(3H) infused into            of luteolytic activity in vi
 the uterine vein adjacent to the ovarian artery       activity in vitro exists for
 was detected in the ovarian artery, suggesting        ported in the literature are unequivocable that
.a local transfer mechanism between the uter-          PGFn, is luteolytic for domestic animals such
 ine horn and adjacent ovary (McCracken et             as the bovine (Rowson, Tervlt and Brand,
 al., 1971; McCracken et al., 1 9 7 2 ~ ) . These       1972; Lauderdale, 1972; Louis, Hafs and
 data, in addition to other data reviewed bv           Sequin, 1973; Liehr, M-arion and Olson, 1972;
 Goding et al. ( 1 9 7 2 ~ ) ~
                            Inskeep (1973), and        Inskeep, 1973), ovine (Barrett et al., 1971;
 McCracken (1973) led to the assumption                Thorburn and Nichol, 1971, McCracken et
 that PGFZ, is “the luteolysin” in the sheep           a?., 1971, 1972; Goding et al., 1972a, b, c ) ,
 (Goding et al., 1972b, c). Paradoxically, en-         and mare (Douglas and Ginther, 1972; No-
 dometrial levels of PGFz, are greater in the                 Hafs and Oxender, 1973).
 pregnant than non-pregnant ewe (Wilson et                  ituitary Tropic Hormone Release. Labh-
 al., 1972).                                           setwar (1970) first reported an increase in
    Additional circumstantial evidence for uter-       pjtuitary LH content of pregnant rats follow-
 ine luteolytic agents being prostaglandins was                       ty doses of PGFz,, and he sub-
 reported by Spilman and Duby (1972) using                            orted that PGFz, stimulated an
 the sheep carrying an intrauterine device             increase in serum levels of LH. Both indo-
  (IUD) as a model. To review effects of IUD’s,        methacin and aspirin, inhibitors of prosta-
 Hawk (1968) reported an IUD prevents nor-             glandin synthesis, blocked ovulation, but this
 mal clPvPlnDment of the CL, the effect is uni-”       could be overcome by administering either LH
 lateral (Ginther, Pope and Casida, 1966), and.                            f :PGE1 and PGFz, (Orczyk
 an IUD increases endometrial PGFz, levels                                 72); ovulation blocked by
  (Wilson et al., 197213). Spilman and Dnbv            barbiturates could be restored by exogenous
  (1972) reported: 1) PGF was increased both           PGEz in adult rats (Tasafrini et al., 1972).
 in the endometrium at the site of the IUD and         PGFz, and other prostaglandins have been
 in the uterine vein plasma, but 2) the in-            reported to result in release of prolactin in the
 creases in PGF were abolished by indometb-            pregnant rat (Vermouth and Deis, 1972) and
 acin, an inhibitor of prostaglandin synthesis,        the cow (Hafs et al., 1973), ACTH In the rat
 3) CL were inhibited by an IUD, but 4) the             (Hedge, 1972), growth hormone in human
 inhibition oj CL by the IUD was blocked by             (It0 et al., 1971) and cow (Hafs, 1974) and
 indomethacin. These data indicate, insofar as         oxytocin in human (Gillespie, Brummer and
 indomethacin is specific for prostaglandin syn-       Chard, 1972). These data demonstrate that
 thesis inhibition, that the luteolytic agent pro-     pituitary hormones can be released following
 duced by the sheep uterus carrying an IUD             prostaglandin administration.
 was prostaglandin. Another prostaglandin                 Ovulation. Le Maire et al. (1973) reported
  (PGFl,) has been shown to be capable of              increases in PGF and PGE of 60- and 15-fold




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                     BIOLOGICAL EFFECTS OF PROSTAGLANDINS                                                 27
between follicles from estrous rabbits and fol-        These data suggest prostaglandins may alter
licles harvested 9 hr. after 100 IU of HCG.            oviduct motility resulting in altered gamete
The ratio of PGEIPGF was 4.4 and 1.1 for               transport.
follicles from estrous rabbits and follicles har-
vested 9 hr. after HCG, respectively (Le                                Literature Cited
Maire et al., 1973). Administration of indo-           Armstrong, D. T. and D. L. Grinwich. 1972. Blockade
methacin prior to LH inhibited the ovulatory             of spontaneous and LH-induced ovulation in rats
process in the rabbit (Grinwich, Kennedy and             by indomethacin an inhibitor of prostaglandin bio-
Armstrong, 1972; O’Grady et aZ., 1972a) and              synthesis. Prostaglandins. 1:21.
                                                       Barrett, S., M. A. deBlockey, J. M. Brown, I. A.
indomethacin inhibited coitus induced ovula-             Cumming, J. R. Goding, B. J. Mole and J. M.
tion in the rabbit (O’Grady et al., 1972a).              Obst. 1971. Initiation of the oestrous cycle in the
Also, indomethacin or aspirin blocked ovula-             ewe by infusions of PGF, to the autotransplanted
tion in PMS treated rats (Orczyk and Behr-               ovary. J. Reprod. Fertil. 24: 136 (Abstr.).
                                                       Beazley, J. M. 1971. Prostaglandins in human repro-
man, 1972; Armstrong and Grinwich, 1972).                duction. Brit. J. Hosp. Med. 5:535.
Labhsetwar (1971, 1972) reported that preg-            Bedwani, J. R. and E. W. Horton. 1971. Interaction
nancy terminating doses of PGFz, induced                 between prostaglandins and gonadotrophins in the
not only abortion but ovulation in rats, ham-            rabbit ovary. Brit. J. Pharmacol. 43:794.
                                                       Bergstrom, S., L. A. Carlson and J. R. Weeks. 1968.
sters, and mice. These data suggest prosta-              The Prostaglandins: A family of biologically active
glandins may be involved in the process of               lipids. Pharm. Rev. 2O:l.
ovulation.                                             Bland, K. P., E. W. Horton and N. L. Poyser. 1971.
    Gamete Transport. The suggestion that                Levels of prostaglandin F, in the uterine venous
seminal fluid prostaglandins might facilitate            blood of sheep during the oestrous cycle. Life Sci-
                                                         ences 10:509.
sperm transport in the female (Eliasson, 1959)         Bygdemann, M. 1964. The effect of different pros-
was followed by reports that low PGE concen-             taglandins on the human myometrium in vitro.
tration in semen was associated with lowered             Acta. Physiol. Scand. 63: (Suppl. 242) 1.
fertility (Hawkins and Labrum, 1961; Bygde-            Bygdemann, M. 1969. Prostaglandins in human semi-
                                                         nal fluid and their correlation to fertility. Int. J.
man, 1969; Horton and Thompson, 1964).                   Fertil. 14:228.
Mandl (1972) reported addition of PGEl to              Carlson, J. C., A. E. Rugg, M. E. Glew, B. Barce-
semen at the time of AI in rabbits facilitated           kowski and J. A. McCracken. 1972. Luteolytic
sperm transport, but Chang, Hunt and Polge               properties of prostaglan@n FI, in sheep. Biol.
                                                         Reprod. 7: 109 (Abstr.).
 (1972) reported increased fertilization rates         Chang, M. C., D. M. Hunt and C. Polge. 1972a. Ef-
with PGEI and PGEz but not with PGFz,.                   fects of prostaglandins (PG’s) on sperm and egg
However, Spilman, Finn and Norland (1973)                transportation in the rabbit. Adv. Biosci. 9:805.
reported a significant increase in fertilization       Chang, M. C. and D. M. Hunt. 1972. Effect of pros-
                                                                          on
                                                         taglandin FzOr the early pregnancy of rabbits.
rate of rabbits treated with PGFZ, but not               Nature 236: 120.
when treated with PGEl or PGE2 if oviducts             Coudert, S. P., G. D. Phillips, M. Palmer and C. Fai-
were ligated 2.5 to 3.0 hr. after AI. If ovi-            man. 1972. Prostaglandin F concentration in the
 ducts were not ligated, there was no effect of          peripheral blood of the ewe during the estrous
                                                         cycle. Prostaglandins 2:501.
prostaglandins on fertilization rates. These           Douglas, R. H. and 0. J. Ginther. 1972. Effect of
 data suggest rate of sperm transport could be            prostaglandin Fs, on length of diestrus in mares.
 altered by prostaglandins.                              Prostaglandins 2 :265.
    PGEz inhibited ova transport in rats (Nut-         Eliasson, R. 1959. Studies on prostaglandin. Occur-
                                                          rences, formation and biological actions. Acta.
 ting and Cammarata, 1969) but PGFza (ham-                Physiol. Scand. 46: (Suppl. 158) 1.
 ster, Labhsetwar, 1972) and PGEz (ham-                Ellinger, J. V. and K. T. Kirton. 1974. Ovum trans-
 ster and rabbit, Nutting 1969) had no effect            port in rabbits injected with prostaglandin El and
 on ovum transport. Chang and Hunt (1972)                F2,. Biol. Reprod. (In press).
 reported PGFz, injected 24 hr. after insemi-          Gillespie, A., Brummer and T. Chard. 1972. Oxytocin
                                                         release by infused prostaglandin. Brit. Med. J. 1:
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                                                       Goding, J. R., D. T. Baird, I. A. Cumming and J. A.
 ovum transport through rabbit oviduct.                  McCracken. 1972. The functional assessment of
    Bergstrom et al. (1968) reported prosta-             autotransplanted endocrine glands. Acta. Endocrinol.
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                                                          Chamley, and I. A. Cumming. 1972b. Prostaglandin
 have shown that PGFm stimulates but PGE1                 Fz, “the” luteolytic hormone in the ewe. J. Reprod.
 inhibits oviduct motility in vivo in the rabbit.        Fertil. 28: 146 (Abstr.),




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28                                           LAUDERDALE
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  Brown, M. D. Cain, J. C. Cerini, M. E. D. Cerini,        nant rats. A possible explanation of the luteolytic
  J. K. Findlay, J. D. O’Shea, and D. H. Pemberton.        effect. J. Reprod. Fertil. 23:155.
  1 9 7 2 ~ .Prostaglandin F2, “the” luteolysin in the   Labhsetwar, A. P. 1971. Luteolysis and ovulation in-
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  bits with indomethacin an inhibitor of prosta-           rats. J. Endocrinol. 53:201.
  glandin biosynthesis. Prostaglandins 1:89.             Lauderdale, J. W. 1972. Effects of PGF?,-Tham on
Hafs, H. D., T.M. Louis, P. A. Noden and W. D.             pregnancy and estrous cycle of cattle. J. Anim. Sci.
  Oxender. 1974. Control of the estrous cycle in           35:246 (Abstr.).
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Harman, E. L. and A. L. Slyter. 1973. Planned par-         Anim. Sci. 35:247 (Abstr.).
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  prostaglandin levels in fifty patients attending a       one, oestradiol-l7p and prostaglandin F?, in the
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Karim, S. M. M. and J. Devlin. 1967. Prostaglandin       Nutting, E. F. 1969. Antifertility activity of prosta-
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Karim, S. M. M. and G. M. Filshie. 1970b. Use of         Oakes, G., M. Mofid, C. R. Brinkman I11 and N. S.
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                                               DISCUSSION                                                     29
Orczyk, G. P. and H. Behrman. 1972. Ovulation             Thorburn, G.D., R. I. Cox, W. B. Currie, B. J. Rest-
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  secretion. Prostaglandins 1:s.                            the ewe during the oestrous cycle. J. Endocrinol.
Robert, A., J. E. Nezamis and J. P. Phillips. 1967.         53:325.
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  h e r . J. Dig. Dis. 12:1073.                             of ovine corpus luteum after infusion of prosta-
Rowson, L. E. A., R. Tervit and A. Brand. 1972. The         glandin Fz., into ovarian artery and uterine vein.
  use of prostaglandin for synchronization of oestrus       J. Endocrinol. 513783.
  in cattle. J. Reprod. Fertil. 29:145 (Abstr.).          Vermouth, N. T. and R. P. Deis. 1972. Prolactin re-
Spilman, C. H. and R. T. Duby. 1972. Prostaglandin          lease induced by prostaglandin Fz., in pregnant rats.
  mediated luteolytic effect of an intrauterine device      Nature, New Biol. 238:248.
  in sheep. Prostaglandins 2: 159.                        Wilks, J. W., K. K. Forbes and J. F. Norland. 1973.
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                                                          Wilson, L. Jr., R. L Butcher and E. K. Inskeep.
Spilman, C. H. and M. J. K. Harper. 1972. Effects                                  P!
                                                             1972a. Prostaglandin F . in the uterus of ewes dur-
  of prostaglandins on oviduct motility in conscious        ing pregnancy. Prostaglandins 1:479.
  rabbits. Proc. SOC.Study Reprod. 5th Meeting.           Wilson, L , Jr., R. J. Cenedella, R. L Butcher and
                                                                    .                             .
Tasafrini, A., H. R. Lmdner, U. Zor and S. A. Lamp-         E. K. Inskeep. 1972b. Levels of prostaglandins in
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                                             DISCUSSION
Question: Fred Stmmshak, Oregon State:                       off to base line. Now if one gives super-
  From your presentation it appears that the                 ovulated ewes a single injection of PGFZa,
 IUD is capable of increasing the synthesis                  we see the same thing if you sequentially
 of uterine prostaglandin which in t u n inter-              remove the corpora lutea. One hour after
  feres with the formation of the corpus lu-                 PGFZa, the progesterone concentration of
 teum. Would you care to comment about                       corpora lutea is considerably decreased.
 the apparent inability of an injection of                   Two hours after there’s a tremendous in-
 prostaglandin early in the cycle to alter the               crease in progesterone and 3 hours another
  formation of the CL?                                       drop off. This may well be what they are
                                                             measuring in the in vitro experiments. I t
J. W . Luuderdale: Data have been reported                   could be that you get this initial increase
   that prostaglandins can alter the enzyme                  and that’s simply what we’re measuring in
  patterns in the CL. I wonder if the differ-                vitro. Now you mentioned the enzyme sys-
   ence in response between the early stage of                tem. We’ve found that the increase in pro-
   the cycle and the later stage of the cycle is             gesterone a t 2 hours post PGFza is accom-
  related to the presence or absence of this                 panied by a rapid increase in a specific
  enzyme system. Your question is also re-                   messenger RNA. And this may well be cod-
  lated to whether or not the CL has an in-                  ing for some of the enzyme changes that
  herent predefined life span. PG’s may be                   you mentioned Behrman has shown.
  another tool that can be used to study this.
Question: Colin Kaltenbach, Wyoming:                      J . W . Lauderdale: Thank you. Those are cer-
                                                              tainly pertinent data to the paradox of in
  I might be able to shed a little light in this              vivo luteolytic versus irt vitro luteotropic
 area, Jim. First of all, you mentioned the
 paradox between in vitro and in vivo work                    activities of prostaglandins.
  and we think we can explain this. If you go             Question: Jose) Zolman, Michigan State:
 back and look at McCracken’s original                      I would have a question regarding mechan-
  data, you’ll notice in his transplants where             ism of action of prostaglandins. You men-
 he’s infusing PGFzo that first of all you                  tioned that the action of prostaglandins is
  see a slight increase in progesterone and                mediated through the cyclic AMP system.
  then the decrease. We found this to be the                My question is do you have any informa-
 same in transplants if one infuses PGFzo.                  tion about the involvement of cyclic GMP?
  At the end of about the first hour there’s a
  decrease in progesterone secretion rate fol-            J . W . Lauderdale: No, I do not. This is com-
  lowed bv a fall off and it eventuallv t d s                 pletely out of my field of competence. Hin-




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30                                        LAUDERDALE
   man has a recent review (Annu. Rev. Bio-           Neal First: Yes, in response to the prosta-
   chem. 41:161, 1972) of the papers relative           glandin.
   to prostaglandins and cyclic AMP. Also,
    there is a recent paper in prostaglandins         J . W . Lauderdale: To my knowledge the data
    that gives quite a detailed, schematic di-            have not been reported. . If my interpreta-
   agram of proposed relationships between                tion of data presented by Labhsetwar (J.
   prostaglandins and cellular systems.                   Reprod. Fertil. 23: 155, 1970; J. Endo-
                                                          crinol. 53:201, 1972) is correct, that PG’s
Question: Neal First, Wisconsin:                          may act directly on the hypothalamic-pitui-
   Jim, I’m concerned about the LH release                tary axis, then I would speculate that
   you just presented and I have two questions            neither the uterus nor ovaries are essential,
   pertinent to this that maybe you can answer            depending on the animal model.
    for me. One of these is if you hysterectomize                                               ~




                                                             I would like to make one parting’com-
    a female does this same LH release pattern            ment. To reiterate, I hope that those of us
    occur? You may have to pick the species to            who are working with prostaglandins are
    do this in. Secondly, if you ovariectomize a          cognizant of, and accept, the fact that pros-
    female do you also get this same LH re-               taglandins administered to animals are ca-
    lease?                                                pable of elicting responses other than re-
J . W . Lauderdale: In response to the prosta-            gression of the corpus luteum or changing
    glandin ?                                             myometrial contractility.




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