DISTRIBUTION AND BIOLOGICAL EFFECTS OF PROSTAGLANDINS J. W. LAUDERDALE J Anim Sci 1974. 38:22-30. The online version of this article, along with updated information and services, is located on the World Wide Web at: http://jas.fass.org www.asas.org Downloaded from jas.fass.org by on April 4, 2010. 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 Downloaded from jas.fass.org by on April 4, 2010. 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. Downloaded from jas.fass.org by on April 4, 2010. 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 Downloaded from jas.fass.org by on April 4, 2010. 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. Downloaded from jas.fass.org by on April 4, 2010. 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 Downloaded from jas.fass.org by on April 4, 2010. 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: nation resulted in elimination of ova from the 543. oviducts and uteri of rabbits. Subsequent Ginther, 0 J., A. L. Pope and L. E. Casida. 1966. . studies (Ellinger and Kirton, 1974) demon- Local effect of an intrauterine plastic coil on the strated both PGEl and PGFZar accelerated corpus luteum of the ewe. J. Anim. Sci. 25:472. 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. glandins altered oviduct smooth muscle con- Suppl. 158: 169. tractility and Spilman and Harper (1972) Goding, J. R., M. D. Cain. J. Cerini, M. Cerini, W. A. 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.), Downloaded from jas.fass.org by on April 4, 2010. 28 LAUDERDALE Goding, J. R., I. A. Cumming, W. A. Chamley, J. M. on pituitary luteinizing hormone content of preg- 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- mammal? Gynec. Invest. 2:73. duced by prostaglandin Fz, in the hamster. Nature Grinwich, D. L., T. G. Kennedy and D. T. Arm- 230:528. strong. 1972. Dissociation of ovulatory and ste- Labhsetwar, A. P. 1972. Effects of prostaglandin F?, rooidogenic actions of luteinizing hormone in rab- on some reproductive processes of hamsters and 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.). cattle and horses with prostaglandin FW 11th Bi- LeMaire, W. J., N. S. T. Yang, H. H. Behrman and ennial Symposium on Anim. Reprod. J. Anim Sci. J. M. Marsh. 1973. Preovulatory changes in the 38: (Suppl. 1) 10. concentration of Drostadandins in rabbit nraafian D Hansel, W., P. W. Concannon and J. H. Lukaszewska. follicles. Prostaglahim >:367. 1973. Corpora lutea of the large domestic animals. Liehr, R. A., G. B. Marion and H. H. Olson. 1972. Biol. Reprod. 8:222. Effects of prostaglandin on cattle estrous cycles. J. Harman, E. L. and A. L. Slyter. 1973. Planned par- Anim. Sci. 35:247 (Abstr.). turition. Sheep Field Day Bull. Anim. Sci. Series Liggins, G. C. and S. A. Grieves. 1971. Possible role 73-8, South Dakota State Univ., Brookings. for prostaglandin F2, in parturition in sheep. Na- Hawk, H. W. 1968. Effect of intra-uterine devices on ture, London 232 :629. corpus luteum function. J. Anim. Sci. 27: 119. Liggins, G. C., S. A. Grieves, J. Z. Kendall and B. S. Hawkins, D. F. and A. H. Labrum. 1961. Semen Knox. 1972. The physiological roles of progester- prostaglandin levels in fifty patients attending a one, oestradiol-l7p and prostaglandin F?, in the fertility clinic. J. Reprod. Fertil. 2 : l . control of ovine parturition. J. Reprod. Fertil., Hedge, G. A. 1972. The effect of prostaglandins on Suppl. 16:85. ACTH secretion. Endocrinol. 91:925. Louis, T. M., H. D. Hafs and B. E. Sequin. 1973. Hinman, J. W. 1972. Prostaglandins. Annu. Rev. Progesterone, LH, estrus, and ovulation after pros- Biochem. 41: 161. taglandin Fz, in heifers. Proc. SOC.Exp. Biol. Med. Horton, E. W. and C. J. Thompson. 1964. Thin-layer 143: 152. chromatography and bioassay of prostaglandins in Mandl, J. P. 1972. The effect of prostaglandin & on extracts of semen and tissues of the male reproduc- rabbit sperm transport in vivo. J. Reprod. Fertil. tive tract. Brit. J. Pharmacol. Chemother. 22: 183. 31:263. Inskeep, E. K. 1973. Potential uses of prostaglandins McCracken, J. A. 1973. Comment. Prostaglandins 3: in control of reproductive cycles of domestic ani- 696. mals. J. Anim. Sci. 36:1149. McCracken, J. A., D. T. Baird and J. R. Goding. Ito, H., G. Momose, T. Katayama, H. Takogishi, L. 1971. Factors affecting the secretion of steroids by Ito, H. Nakajima, and Y. Takei. 1971. Effect of the transplanted ovary in the sheep. Recent. Prog. prostaglandin on the secretion of human growth Hormone Res. 27:537. hormone. J. Clin. Endocrinol. Metab. 32:857. McCracken, J. A., J. C. Carlson, M. E. Glew, J. R. Karim, S. M. M. 1966. Identification of prostaglandins Goding, D. T. Baird, K. Green and B. Samuelsson. in human amniotic fluid. J. Obstet. Gynaecol. Brit. 1972. Prostaglandin F2, identified as a luteolytic Commonw. 73 :903. hormone in the sheep. Nature New Biol. 238:129. Karim, S. M. M. 1968. Appearance of prostaglandin McCracken, J. A., M. E. Glew and R. J. Scaramuzzi. FP, in human blood during labour. Brit. Med. J. 4: 1970. Corpus luteum regression induced by prosta- 618. glandin Fw. J. Clin. Endocrinol. Metab. 30544. Karim, S. M. M. 1972. Physiological role of prosta- Noden, P. A., H. D. Hafs and W. D. Oxender. 1973. glandins in the control of parturition and menstru- Progesterone, estrus and ovulation after prosta- ation. J. Reprod. Fertil., Suppl. 16:105. glandin F2, in horses. Fed. Proc. 32:229. Karim, S. M. M. and J. Devlin. 1967. Prostaglandin Nutting, E. F. 1969. Antifertility activity of prosta- content of amniotic fluid during pregnancy and glandin E in hamsters, rabbits, and rats. Proc. SOC. 2 labour. J. Obstet. Gynaecol. Brit. Commonw. 74: Study Reprod. 2nd Meet. p. 1. 230. Karim, S. M. M. and G. M. Filshie. 1970a. Thera- Nutting, E. F. and P. S. Cammarata. 1969. Effects of peutic abortion using prostaglandin F?,. Lancet. prostaglandins on fertility in female rats. Nature 1:157. 222:287. Karim, S. M. M. and G. M. Filshie. 1970b. Use of Oakes, G., M. Mofid, C. R. Brinkman I11 and N. S. prostaglandin Ez for therapeutic abortion. Brit. Assali. 1973. Insensitivity of the sheep to prosta- Med. J. 3:198. glandins. Proc. SOC.Exp. Biol. Med. 142: 194. Karim, S. M. M. and K. Hillier. 1970. Prostaglandins Oesterling, T. O., W. Morozowich and T. J. Roseman. and spontaneous abortion. J. Obstet. Gynaecol. 1972. Prostaglandins. J. Pharm. Sci. 61: 1861. Brit. Commonw. 77:837. O’Grady, J. P., B. V. Caldwell, F. J. Auletta and L. Karim, S. M. M. and S. D. Sharma. 1971. The effect Speroff. 1972a. The effects of an inhibitor of prosta- of ethyl alcohol on prostaglandins E? and Fza m- glandin synthesis (indomethacin) on ovulation, duced uterine activity in pregnant women. J. pregnancy and pseudopregnancy in the rabbit. Obstet. Gynaecol. Brit. Commonw. 78:251. Prostaglandins 1:97. Kirton, K. T., B. B. Pharriss and A. D. Forbes. 1970. O’Grady, J. P., E. I. Kohorn, R. H. Glass, B. V. Cald- Some effects of prostaglandins E2 and F?, on the well, W. A. Brock, and L. Speroff. 1972b. Inhibition pregnant rhesus monkey. Biol. Reprod. 3: 163. of progesterone synthesis i vitro by prostaglandin n Labhsetwar, A. P. 1970. Effects of prostaglandin Fza F2*.J. Reprod. Fertil. 30:153. Downloaded from jas.fass.org by on April 4, 2010. DISCUSSION 29 Orczyk, G. P. and H. Behrman. 1972. Ovulation Thorburn, G.D., R. I. Cox, W. B. Currie, B. J. Rest- blockade by aspirin or indomethacin: In vivo evi- all and W. Schneider. 1972. Prostaglandin F con- dence for a role of prostaglandin in gonadotrophin centration in the utero-ovarian venous plasma of secretion. Prostaglandins 1:s. the ewe during the oestrous cycle. J. Endocrinol. Robert, A., J. E. Nezamis and J. P. Phillips. 1967. 53:325. Inhibition of gastric secretion by prostaglandins. Thorburn, G. D. and D. H. Nichol. 1971. Regression 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. Spilman, C. H., A. E. Finn and J. F. Norland. 1973. Prostaglandins and in vitro ovarian progestin bio- Effect of prostaglandins on sperm transport and synthesis. Prostaglandins 3 :427. fertilization in the rabbit. Prostaglandins 4:57. . 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 recht. 1972. Physiological role of prostaglandins in the uterine endometrium during the ovine estrous the induction of ovulation. Prostaglandins 2: 1. cycle. J. Anim. Sci. 34:93. 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- Downloaded from jas.fass.org by on April 4, 2010. 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. Downloaded from jas.fass.org by on April 4, 2010.
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