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718
Involvement of Prostaglandins in the Female Reproductive Cycle
NORMAN L. POYSER
Department of Pharmacology, University of Edinburgh, 1 George Square,
Edinburgh EH8 9JZ, Scotland, U.K.
Many female mammals exhibit cyclical sexual activity. Fig. 1 shows the general
relationship between oestradiol, lutropin (luteinizing hormone) and progesterone in the
peripheral plasma during the cycle. Within the last 6 years, it has become apparent that
prostaglandins are involved in the processes that regulate this cyclical pattern.
Lutropin secretion
Orczyk & Behrman (1972) reported experiments in rats that indicated that prostaglandins, acting centrally, may have a role in regulating lutropin secretion from the
pituitary. They found that systemically administered indomethacin [I-(Cchlorobenzoyl)-5-methoxy-2-methylindol-3-ylacetic
acid] blocked ovulation, and this blockade
could be overcome by administering lutropin. Later it was found that the injection
of prostaglandin-synthesis inhibitors (eicosa-5,8,11,14-tetraynoicacid or indomethacin)
into the third ventricle of ovariectomized rats decreased plasma lutropin concentrations
(Ojeda et al., 1975). Tsafriri et al. (1973) reported that the systemic injection of
prostaglandin E2 increased plasma lutropin concentrations in Nembutal-blocked
pro-oestrus rats. Spies & Norman (1973) similarly reported that prostaglandin El
increased plasma lutropin concentrations in Nembutal-blocked rats after administration
into the third ventricle.
Harms et al. (1974) demonstrated that prostaglandin E, was more potent in
releasing lutropin in ovariectomized rats when given into the third ventricle than when
given intravenously. Furthermore, prostaglandin ELwas more potent than prostaglandin
E l , with prostaglandins F,. and F1. being inactive. Prostaglandin EL did not cause
Oestradiol Lutropin
Progesterone
z
/
' '.
\
I
!'.
\
"
Time
Fig. 1. Relationship between oestradiol, lutropin hormone and progesterone during the
female reproductive cycle
1978
575th MEETING, GLASGOW
719
lutropin release in ovariectomized rats if injected directly into the pituitary, though it
did have a small effect if the animals were initially primed with oestradiol. These
experiments indicate that prostaglandin E2 primarily acts centrally to induce lutropin
release. Later it was shown that centrally administered prostaglandin Ez into adult male
rats causes the release of luliberin (lutropin-releasing hormone) into the hypophysial
portal blood vessels (Eskay et al., 1975). Furthermore, prostaglandin Ez infused directly
into these portal blood vessels did not cause lutropin release from the pituitary. These
results suggest that prostaglandin E2 stimulates release of lutropin by acting at the
hypothalamus to enhance the release of luliberin, and has little direct effect on the
pituitary. These suggestions are supported by the finding that antiserum to luliberin
administered to rats prevents prostaglandin E,-induced lutropin release (Chobsieng
et a[., 1975; Drouin et al., 1976).
By giving implants of prostaglandin E2,Ojeda et al. (1977) found that prostaglandin
E2 can act at the arcuate-nucleus-median-eminence region, and the pre-optic area of
anterior-antrum portion of the anterior-hypothalamic area within the hypothalamus,
to cause lutropin release. These areas supposedly are the regions that contain luliberin.
Prostaglandin E,-induced release of lutropin by intra-ventricular injection is not
prevented by prior treatment with drugs that block adrenergic, dopaminergic,
serotinergic or cholinergic receptors (Harms et al., 1976). These results suggest that
prostaglandin E2 is not acting transsynaptically, but probably directly stimulates the
luliberin neuron to cause luliberin release into the hypophysial portal blood vessels.
Furthermore, phentolamine-blocked ovulation in rats can be overcome by the central
administration of prostaglandins E2 or El (Linton et al., 1977).
All these results suggest that prostaglandin E, produced centrally in the rat may act
within the hypothalamus to control luliberin release, which in turn regulates lutropin
release from the pituitary. However, prostaglandin Ez production by the rat brain in
relation to lutropin release has still to be measured. Also, surprisingly, it has not been
reported, to my knowledge, that indomethacin given systemically or into the third
ventricle inhibits the ovulatory lutropin surge that occurs between pro-oestrus and
oestrus. More experiments are needed to establish a role for prostaglandin E2 in lutropin
secretion in the rat. Prostaglandin E2 will also stimulate follitropin (follicle-stimulating
hormone) and prolactin secretion, but to a lesser extent than its effect on lutropin release
(Harms et a / . , 1974; Sato et al., 1974; Eskay et al., 1975).
Concerning other species, indomethacin will block oestradiol-induced release of
lutropin in anoestrous sheep (Carlson e t a / . , 1974). Systemic prostaglandin F,. increases
plasma lutropin concentrations in ‘cycling’ sheep (Carlson et a/., 1973). Since luliberin
will induce lutropin secretion during indomethacin blockade, it is concluded that
prostaglandin F2. is acting again on the hypothalamus (Roberts et al., 1976). In addition,
oestradiol-induced release of lutropin in sheep is associated with increased prostaglandin
F,. release from the brain (Roberts etal., 1976). These results suggest that prostaglandin
F2,, produced ,within the brain and acting on the hypothalamus, is associated with
lutropin release in sheep.
Indomethacin will also prevent oestradiol-induced release of lutropin during the
follicular phase in the rhesus monkey. Conversely, prostaglandins E2 and F,, enhance
lutropin release in the monkey when administered towards the end of the cycle
(Carlson et al., 1977a). In women, intravenous prostaglandin F,. administered in the
mid-late luteal phase of the menstrual cycle caused a transient increase in lutropin
(Hillier et al., 1973). It is possible therefore that, in primates, brain prostaglandins are
involved in lutropin release. However, administration of prostaglandin Fzuto normal
men did not provoke lutropin release (Coudert & Faiman, 1973;Craig, 1975). Returning
to non-primates, intracarotid administration of prostaglandin Fz, released lutropin
in non-receptive, pseudopregnant, and oestrogen-pretreated, oestrous rabbits. Prostaglandin E2had a similar action, but was much less potent (Carlson et a[.,19776). It is
apparent from all these data, that prostaglandins EZor Fz,,depending upon species, is a
potent stimulant to lutropin release by acting centrally to cause the liberation of luliberin
into the hypophysial portal blood vessels. Furthermore, the evidence suggests that
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BIOCHEMICAL SOCIETY TRANSACTIONS
prostaglandins produced in the brain may form a n essential link in the release of lutropin
induced by oestradiol.
Ovulation
The lutropin surge once released acts on the ovary t o cause ovulation. This process
is blocked by indomethacin pre-treatment in the rat (Armstrong & Grinwich, 1972;
Tsafriri et al., 1972), rabbit (Grinwich et a/., 1972; O’Grady et al., 1972) and monkey
(Wallach et al., 19750). This blockade by indomethacin can be overcome by administering prostaglandin Ez t o the rat (Tsafriri et al., 1972), or prostaglandin F,, t o the rabbit
(Diaz-Infante et al., 1974) and monkey (Wallach et al., 19756).
Prostaglandins E and F concentrations in the rat ovary increase before ovulation
(Armstrong & Zamecnik, 1975; Bauminger & Lindner, 1975). This increase is prevented
in the Nembutal-blocked rat, but restored after lutropin treatment. In addition, this
increase in ovarian prostaglandin concentrations is prevented by treating normal cyclic
rats with anti-(P-lutropin) serum (Bauminger & Lindner, 1975). It has also been demonstrated in normal, cyclic rats that prostaglandins E and F concentrations within
the Graafian follicles increase before ovulation (LeMaire e i al., 1975). Similarly in rabbits
the amounts of prostaglandins F and E in the graafian follicles increase after a n ovulatory
dose of human chorionic gonadotropin or lutropin, and after mating (LeMaire et al.,
1973; Yang e t a / . , 1973; Armstrong et al., 1974). This increase in both prostaglandins is
limited to those follicles that actually ovulate (Yang et a / . , 1974). These increases in
follicular prostaglandin concentrations are prevented by pre-treating the rabbits with
indomethacin (Yang et al., 1973). In addition, ovulation in rabbits is blocked after the
intrafollicular injection of indomethacin or anti-(prostaglandin F,,) serum (Armstrong
et al., 1974).
Limited studies have been performed on other species. In guinea-pigs, ovarian
prostaglandins F and E concentrations increase before ovulation (Sharma et a/., 1976).
In women, the concentration of prostaglandin Fzuin fluid taken from a pre-ovulatory
follicle was higher than in fluid taken from less mature follicles (see Edwards, 1973).
Similarly, Swanston et a/. (1977) found that the concentration of prostaglandin Fza
in human corpora lutea immediately after ovulation was significantly higher than in
corpora lutea examined later during the luteal phase, indicating that follicular prostaglandin F,, concentrations were probably high at the time of ovulation.
All these studies performed on several species suggest that prostaglandins E, and/or
Fz. are involved in the process of ovulation induced by lutropin. However, it is not clear
which cells within the ovary actually produce the prostaglandins in response t o the
lutropin stimulus.
Progesterone secretion
The lutropin surge from the anterior pituitary also causes luteinization of the follicle
(with the formation of a corpus luteum) and the secretion of progesterone. Experiments
performed in rats and rabbits indicate that indomethacin administered subcutaneously
or directly into the follicle, although preventing the increase in follicular prostaglandin
concentrations and ovulation, does not prevent luteinization of the follicle and progesterone secretion (Armstrong & Grinwich, 1972; Grinwich et a / . , 1972; O’Grady
et al., 1972; Armstrong et a / . , 1976; Phi et a/., 1977). These observations indicate that
prostaglandins are not involved in luteinization and progesterone secretion induced by
lutropin.
Progesterone output from a functional corpus luteum is maintained for several days
during the reproductive cycle. The corpus luteum then regresses, progesterone output
falls and the cycle is terminated. There is much evidence that in several non-primate
mammalian species, prostaglandin Fza released from the uterus acts on the ovary in a
local manner to cause this cessation of corpus luteum function (see Horton & Poyser,
1976). The physiological stimulus for uterine prostaglandin F1. production is probably
1978
575th MEETING, GLASGOW
72 1
oestradiol acting on the progesterone-primed uterus. The large oestrogen surge
responsible for lutropin release occurs after progesterone has fallen. However, oestradiol
concentrations begin to slowly increase several days before this large peak, and this
smaller output may be sufficient t o cause prostaglandin F,. release from the uterus.
It is important for progesterone output from the ovary t o fall since high progesterone
concentrations would prevent lutropin release from the anterior pituitary in response to
oestradiol.
In some species therefore, like the sheep and guinea pig, prostaglandin F,, released
from the uterus is important in regulating cycle length. I n other species, like the rat,
a functional corpus luteum is not formed during the oestrous cycle and therefore
prostaglandin F2. from the uterus is not involved in controlling cycle length. However, it
is probably important in the rat in controlling the length of pseudopregnancy, since
functional corpora lutea are formed during this period. It probably has a similar role
in the pseudopregnant rabbit. In primates, where a functional corpus luteum is formed
during the cycle, uterine prostaglandin FZadoes not cause luteal regression, and some
other mechanism is involved in controlling menstrual-cycle length.
Conclusion
It is apparent that prostaglandins produced by the brain, ovary and, in some species,
the uterus are involved in maintaining normal cyclical activity in the female. Many of the
studies have been performed on a limited number of species, and further studies o n more
mammalian species are needed for this conclusion t o be applied generally. For example,
it is known that lutropin will stimulate the production of prostaglandin F,, by bovine
follicular tissue in uitro (Shemesh & Hansel, 1975), but these studies need extending
t o the situation in viuo before it is possible to conclude that ovarian prostaglandins are
involved in ovulation in the cow. Also, it is unclear in those species studied so far whether
it is universally prostaglandins E, or F,, involved in lutropin secretion and ovulation.
Maybe the prostaglandin involved is species specific, and may therefore differ among
species. Finally, the studies so far have been limited t o examining the roles of prostaglandins E2and F,.. With the discovery of the thromboxanes and prostacyclin, further
possibilities exist of which prostaglandin is involved in these reproductive processes.
Consequently, further study with the ‘newer’ prostaglandins would also appear necessary in those species that have received examination so far.
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Armstrong, D. T. & Zamecnik, J. (1975) Mol. Cell. Endocrinol. 2, 125-131
Armstrong, D. T., Grinwich, D. L., Moon, Y. S. & Zamecnik, J. (1974) Life Sci. 14, 129-140
Armstrong, D. T., Dorrington, J. H. & Robinson, J. (1976) Can. J. Biochem. 54, 796-802
Bauminger, S. & Lindner, H. R. (1975) Prostaglandins 9, 737-751
Carlson, J. C., Barcikowski, B. & McCracken, J. A. (1973) J . Reprod. Fert. 34, 357-362
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Prostaglandins and Opioids
H A R R Y 0. J. COLLIER
Miles Laboratories Ltd., Stoke Poges, Slough, Berks. SL2 4 L Y, U.K.
SpeciJic opioid actions
The pharmacological actions of opioids are of two general types: specific and nonspecific. The specific actions are those blocked by the opioid receptor antagonist, naloxone, and therefore arise as consequences of the interaction of opioid molecule with
its receptor on a neuron. The non-specific actions are not blocked by naloxone, which
may itself exert the same action. In this paper I a m concerned only with the interactions
between prostaglandins and the specific actions of opioids.
The specific actions of opioids occur a t two different rates, one measurable in
minutes and the other in days. The faster are the acute, or direct actions, of which
analgesia and constipation are examples. The slower actions are the subacute, o r
reactive, expressed as tolerance and dependence. The reactive largely represent the
development of a tendency of the nervous system t o oppose the acute actions of a n
opioid t o which it is repeatedly or continuously exposed (Himmelsbach, 1943). F o r
example, withdrawal of morphine from dependent animals results in hyperalgesia and
diarrhoea.
I n several biological preparations a n antagonism has been observed between E
prostaglandins and both the direct and reactive specific actions of opioids. The present
paper summarizes what we know of this antagonism and discusses its mechanisms and
implications.
Antagonism of prostaglandin El as an acute specific action of opioids
Small intestine. Jaques (1965) reported that analgesic drugs of both the morphine
and aspirin groups inhibit the contraction of the longitudinal muscle of the isolated
guinea-pig ileum, elicited by arachidonic acid. Later, Jaques (1969) reported that
the opioid, but not the antiphlogistic drugs antagonized the shortening of the ileum
1978