Prostaglandins in Reproductive Processes

Symposium on Prostaglandins

Prostaglandins in Reproductive Processes Burton V. Caldwell, Ph.D.,* and Harold R. Behrman, Ph.D. t

From the initial description of the biological effects of prostaglandins on uterine muscle throughout the long history of scientific development and clinical applications, it has been clear that prostaglandins play a major role in the regulation of the reproductive processes. In large measure, the rediscovery of prostaglandins late in the 1960' s stemmed directly from the potential for these compounds as a means for terminating pregnancy at any stage, including the induction of labor at term. Much of the early scientific investigation centered on the actions of the arachidonic acid metabolites on the functions of the ovary, hypothalamus and pituitary, uterus and other organs of the reproductive tract. The purpose of this article is to delineate our present understanding of the importance of prostaglandins as regulators and mediators of the processes which assure the reproductive competence of the human species. Also, we will discuss the agents which are currently being utilized to modulate prostaglandin levels in controlling clinical entities such as dysmenorrhea.

Role of Prostaglandins in the Female Reproductive System The evidence that prostaglandins affect pituitary gonadotrophin secretion in submammalian species is quite firm l -3 and suggests that they stimulate release of gonadotrophin by acting at the level of the hypothalamus; however, much of the evidence comes from in vitro studies showing trophic hormone release from pituitary cells in culture. Use of prostaglandin synthesis inhibitors have demonstrated that a reduction in serum LH secretion can be accomplished4 and administration of prostaglandin into the ventricle of the brain (rat) mimics the intravenous effect of prostaglandins on stimulation of gonadotrophin secretion." It is also known that median eminence tissue contains significant amounts of prostaglandins and that stimulation with norepinepherine and dopamine induces the release of LHRH and prostaglandins, an effect blocked by prostaglandin synthesis inhibitors (PGSI). No definitive reports have appeared which would substantiate that the prosta*Associate Professor, Yale University School of Medicine, Yale-:\Iew Haven Hospital, New Haven, Connecticut fProfessor, Yale University School of Medicine, New Haven, Connecticut

Medical Clinics of North America - Vol. 6.5, No. 4, July 1981

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glandins are involved in the regulation of gonadotrophin secretion in the human.

Ovulation and Prostaglandins The fact that nonsteroidal anti-inflammatory agents blocked ovulation in several species 6 , 7, S suggested that prostaglandins were involved in the ovarian follicular rupture process. The investigators have concentrated on the events leading to follicular maturation and rupture and it is now substantiated that prostaglandin formation is increased during the process of follicular maturation and that the process of ovulation is dependent upon luteinizing hormone (LH) stimulating prostaglandin production in the developing follicle. The induction of ovulation by LH is mediated by prostaglandins and cyclic nucleotides, and prostaglandins may also mediate the stimulatory effects of LH on "ovulatory enzymes" such as protease or collagenases. 9 , 10 Prostaglandins may actually be responsible for initiating the contractal response in the follicular wall l2 which is now known to contain contractile elements such as myosin and actin. Plasminogen activator or some other protease appears to be intrinsically involved in follicular rupture and it is evident that secretion of this protein is associated wih the LH-induced rise in follicular prostaglandin biosynthesis although these two events may not be interdependent. l l Figure 1 shows a possible mechanism for the role of prostaglandins in follicular rupture.

Corpus Luteum Function In the subprimate mammalian species , PGF 20< acts as a hormone to regulate ovarian periodicity,13 Many investigators have clearly established that uterine production ofPGF 20< acting directly on the corpus luteum induces luteal regression and the cessation of progesterone production. In the human, however, no clear evidence has been presented to suggest that prostaglandins have a similar role. Whereas hysterectomy in the subprimate mammalian species clearly causes an elongation of corpus luteum function, in the human female this procedure has no effect on the duration of corpus luteum life span. Also, nonsteroidal anti-inflammatory drugs, while prolonging luteal function in the subprimates, do not alter the course of progesterone secretion in normally ovulating women. In very high doses, prostaglandin administration to monkeys l4. 15, 16, 17 and in the human can induce changes in ovarian steroidogenesis, including decreasing progesterone production. The doses required for demonstrating this effect are clearly nonphysiologic; however, direct injection ofPGF 20< into human corpus luteum does induce progesterone withdrawal and the early onset of menses. IS These findings suggest that endogenous ovarian prostaglandins or some other luteolytic agent may be required for luteal regression in the human since no other clear explanation for the regulation of the functional life span of the corpus luteum can be found. Human luteal tissue is certainly capable of producing prostaglandins in vitro l9 however, attempts to correlate increased PGF 20< levels in the corpus luteum and luteal regression in the late luteal phase have not been successfu1. 20 This information has been clearly established for the rat, however, it is still speculative when applied to the human species. It is well known that the newly formed corpus luteum of many species is refractory to the luteolytic action ofPGF 20<21 and this observation appears also

REPRODUCTIVE PROCESSES

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Figure 1. Prostaglandin-Gonadotropic Hormone Interactions in Follicular Rupture. Gonadotropins have been shown to increase prostaglandin synthesis in a time-dependent manner by a mechanism which appears to be due to induction of prostaglandin synthetase. Since gonadotropins also increase plasminogen activator secretion from .granulosa cells the presumed proteocollagenolytic digestion of the follicular wall (stigma) may be due to an interdependent action between prostaglandins and plasminogen activator secretion in gonadotropin-controlled follicular rupture.

to extend to the human corpus luteum. Henderson and McNaty 22 have suggested that peF 2,. receptors in the newly formed corpUS luteum may in some way be masked by LH receptors and they suggest that a gradual dissociation of LH and its receptor may increase the susceptibility of the corpus luteum to peF 2,.. An alternate hypothesis suggests that the susceptibility of the human corpus luteum to peF 2,. may be dependent on ovarian norepinephrine levels which increase during the luteal phase. 23 These authors have also suggested that the vascular innervation of the human ovary would allow transport locally of the uterine luteolysin. Other evidence suggesting that prostaglandins may play a role in regulation of the corpus luteum comes from studies showing that estrogen-induced luteolysis in the monkey and the human can be effectively blocked by the simultaneous administration of nonsteroidal anti-inflammatory agents, suggesting that estrogen may be acting by way of stimulating corpus luteum prostaglandin

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production or action. 24 . 20 Figure 2 shows our current model for the action of prostaglandins on the luteal cell.

Production of Prostaglandin by the Uterus Since Pickles described the smooth muscle stimulation properties of prostaglandins and their increased levels in menstrual Huid,26 many workers have found the striking association of elevated levels of prostaglandins in the menstrual fluid of patients with dysmenorrhea, or painful menses. It is known that uterine prostaglandin biosynthesis occurs mainly in the endometrium 27 and a number of studies have shown that the ability of the uterus to produce prostaglandins varies according to the reproductive state of the animal. In the human, levels of prostaglandins in the endometrium vary during the menstrual cycle and it has been shown that PGF 2",levels increase during the latter part of the luteal phase. It has also been reported that endometrial prostaglandin biosynthesis is elevated in females with intrauterine devices which may partially explain the antifertility eiTect of the IUD.28 Estrogen and progesterone play important roles in the modulation of uterine prostaglandin biosynthesis with estrogen seemingly being involved in the stimulation of their synthesis while progesterone seems to modulate not only the amount but also the PGE to PGF ratio. It is possible that estrogens require a progesterone primed uterus for their action. The level of activity may be at the acylhydrolase or on prostaglandin synthestase. 29 Specifically estrogens may act by stimulating the induction of phospholipase At. triglyceride lipase or cholesterol estrase, all of which would increase the flow of substrates into the arachidonic acid cascade (see Fig. 2).

Dysmenorrhea A large number of investigators have recently centered on the possibility that the pathogenesis of dysmenorrhea is related to abnormal prostaglandin production andlor action. The syndrome described as dysmenorrhea includes a variety of signs and symptoms which mayor may not be secondary to altered prostaglandin production. Among those symptoms which are considered most bothersome to patients aside from the severe cramping associated with menses, are abdominal bloating, breast tenderness, mood changes, headache, edema, and frequently excessive menstmal flow. The disorder seems to be most pronounced in women who ovulate as opposed to those who do not have normal corpus luteum function. Attempts to control the disorder in the past with a variety of pharmacologic agents have been met largely with incomplete success. This disorder is an extremely important one economically because it is the major cause of work loss by the female population in this country. The most frequently employed agents in the management of this disease include aspirin and its combination with codeine as well as more potent anelgesic agents in severe cases. Although these will frequently have a positive dTect upon the pain syndromes, there is generally little influence on the other symptoms associated with the disorder. Although the intensity of pain is difficult to measure objectively, in many women the severity of the cramping may approach that which occurs during delivery. When it became clear that prostaglandin syntheseis inhibitors could effectively block uterine muscle contraction in a variety of states, including the slowing of contraction patterns at or near term, many investigators

931

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secreted Figure 2. Direction Action of Pros tag land ins on the Luteal Cell. Prostaglandin (PG)F," directly blocks LH-stimulatcd cyclic AMP accumulation and progesterone secretion in isolated luteal cells. This action ofPGF," appears to be receptor mediated. Th,c site ofPGF," action may be at the level of "coupling" between the LH receptor and adenylate cyclase or on modification of substrate levels of ATP. As a consequence either intracellular or extracellular PGF2 " may block LH-dependentprocesses in the luteal cell, resulting in loss of corpus luteum function.

performed studies to determine their efficacy in the treatment of dysmenorrhea. As of the present writing, the nonsteroidal anti-inflammatory agents (NSAID) are the commonly accepted drugs of choice for treating dysmenorrhea syndromes. There is a broad range of literature confirming their advantagcs. 3D • :13 The studies which provided the basis for their use demonstrated that the menstrual effluent of women with dysmenorrhea had significantly elevated levels of prostaglandins andlor their metabolites. It was also demonstrated that the use of the NSAID's significantly reduced this level. It has been noted in some of these studies that not only is there less dysmenorrhea, but also the amount of menstrual flow is also decreased, as well as associated signs and symptoms of the disorder. The recommendations for the treatment of dysmcnorrhea are to initiate therapy with NSAID as soon as, or preferably before, the onset of menstrual symptoms. When the agents are begun before the cramping has started, they

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appear to be much more efficacious. This presents a minor problem in women who are attempting to become pregnant because it frequently means that they would be taking a fairly potent therapeutic drug at a time when there is some uncertainty as to whether or not they are in a fertile cycle. The risks of given these drugs at this vulnerable stage of an early pregnancy have not been clearly established. The wisest course is to await the first overt symptom of menstrual flow in those patients in whom a contraceptive technique is not being employed. The drug is usually necessary for only the first 2 to 3 days of the menstrual cycle and is most efficacious when the signs and symptoms appear at the onset of the menstrual flow. When pain occurs later, day 2 to 4, of menstrual flow, then the possibility of endometriosis as the causative condition must be entertained. Although it has been stated that the use of NSAID helps to differentiate primary dysmenorrhea from endometriosis, at this writing that distinction cannot be clearly documented. It is generally felt that NSAID are not efficacious in the pain associated with endometriosis, although several investigators have in controlled studies concluded that the NSAID may also be of benefit in achievement of pain associated with this disorder. It has also been suggested that the endometrial inflammatory response associated with interperitoneal endometriosis may be secondary to the release of prostaglandins from the ectopic sites within the abdominal cavity. It is not possible to clearly elucidate the pathophysiology of dysmenorrhea; nor is it possible at this time to satisfactorily evaluate whether an endocrine imbalance may cause abnormal prostaglandin production. We would not like to speculate further than to state our agreement with the view that prostaglandins may be involved in the symptomology associated with severe dysmenorrhea.

Pregnancy Prostaglandins are clearly involved in parturition and much evidence suggests that many of the physiologic changes in the uterus that occur during pregnancy may be related to prostaglandin action. It is known that administration of prostaglandins can induce labor at any time during the pregnancY.34 This effect has been utilized for termination of pregnancy in any trimester but is currently the method of choice for inducing a therapeutic abortion in the second trimester. It is also known that administration of nonsteroidal antiinflammatory agents result in the prolongation of gestation, an observation which has led to the trial of NSAI's in the treatment of premature labor. The efficacy of these agents and the potential side-effects of their action on the ductus arteriosus 35 does not permit the recommendation for their use in this condition currently. However, this therapeutic strategy is presently under study in many clinical trials. There appears to be an important relationship between the sensitivity of the uterus to prostaglandins and the level of progesterone in the circulation and perhaps in the myometrial cell itself. In the human, during the last 24 hours before delivery, the sensitivity of the myometrium is increased, owing mainly to a decline in placental progesterone production. It has been suggested that withdrawal of placental progesterone (either by vasoconstriction, ischemia, or direct effects of prostaglandins on the placenta) leads to an unopposed action of prostaglandins on the induction of cyclic uterine contractions. Prostaglandins, of course, are not the only hormonal regulators of

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parturition, and they may be mediators of the action of oxytocin since inhibition of their synthesis leads to a marked diminution of the stimulating effects of oxytocin on uterine contraction. The possible relationship between these agents in the control of parturition is shown in Figure 3. Prostaglandins may also be involved in the regulation of uterine blood flow which is greatly increased in pregnancy. During pregnancy there is also a consistant decrease in the reactivity of the uterine vaculature to vasoconstrictor hormones and adrenergic nerve stimulation. There is also a significant increase in the amount of prostaglandin production; however, the site of uteroplacental synthesis of prostaglandin has not been determined. Many workers have attempted to implicate prostaglandin deficiency in toxemia of pregnancy. Although the theory is attractive in that it could

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Figure 3. Role of Pros tag land ins in the Uterus. The endometrium appears to be a major source of prostaglandins and prostaglandin production is increased by both estrogen and oxytocin in the uterus. A direct action of prostaglandins on the uterine musculature is to stimulate contraction. This action of prostaglandins may be receptor mediated and appears to involve an increase in available calcium concentration which activates the actin-myosin contractile process.

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potentially explain many of the altered signs in the pathophysiology of toxemia, no clear-cut evidence has been reported that establishes that the prostaglandins are directly responsible for this devastating condition. The action of prostaglandins in the stimulation of uterine conh'action may be mediated through alterations of myometrial cell calcium flux. The data showing that prostaglandins inhibit the ATP-dependent sequestration of calcium by sarcoplasmic recticulum 34 suggest that the increase in intracellular free calcium may be responsible for the increase in myometrial contractility. The possibility that progesterone may play a role in modulating this calcium flux.or in the stabilization of phospholipase A 2 10cated in the fetal membranes has been suggested as an explanation for the apparent inhibitory action of progesterone both on the onset oflabor and the sen sitivity of the myometrium to prostaglandins.

Induction of Labor at Tenn Although the oxytocic effect of prostaglandins has been long known, and many workers have studied the possible use of intravenous or intravaginal prostaglandins for the induction of labor at term, at the present time these agents are not utilized for this purpose to any great extent. The main problem appcars to be that the degree of myometrial contractility is more difficult to control with prostaglandins than it is with other available agents such as oxytocin. Uterine hyperstimulation has been observed more frequently with intravenous prostaglandins than with oxytocin. There are also side-effects on the gastrointestinal tract, such as nausea, vomiting and diarrhea as well as frequent hypothermia which limit their efficacy and safety.36

Prostaglandins in the Male The original discovery of prostaglandins in seminal fluid suggested to many that they may play an important part in the regulation of male fertility. Although many studies have been conducted and several have suggested that some male infertility may be associated with low concentrations of prostaglandins,37 at the present time there is no clear consensus as to whether or liot prostaglandin levels in the seminal fluid are in any way related to sperm activity. Replacing the decreased amounts of prostaglandins in seminal fluid with exogenous prostaglandins does not appear to re-establish infertility in oligospermic men with decreased prostaglandin production. Other studies have shown that penetration of cervical mucus and muscular contraction of all the component parts of the reproductive tracfl7 may be facilitated by the addition of prostaglandins resulting in greater sperm migration from the vagina through the uterine cavity and to the fallopian tubes. This may explain why the seminal fluid contains the highest level of prostaglandins in the male body. However, no studies have been reported that demonstrate important effects of NSAID's on sperm function or seminal fluid.

CONCLUSION Although we have learned a great deal in the last 15 years about the possible role of prostaglandins and their regulation of reproductive processes, much remains to be elucidated. At the present time, we can state with some

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assurance that prostaglandins may he involved at multiple levels of fertility regulation. They are certainly an important part of the follkular rupture proeess, seemingly very important in the control of corpus luteum function (at least in subprimate species), they are the most active stimulators of uterine muscle contractility, and they may also be important in the eontrol of fallopian tube motility. Prostaglandins may be important regulators of the onset of labor, and their reaction on the uterine muscle may be an important determinant of parturition in addition to their effects in the brain.

REFERENCES 1. Behrman. H. R: Prostaglandins in hypothalamo-pituitary and ovarian function. Ann. Rev. Physio!., 41;68.5,1979. 2. Drollin, J., and Labrie, F., Specificity of the stimulatory eHeet of prostaglandins on hormone release in rat anterior pituitary cells in clllhue. Prostaglandins, 11 :355, 1976. 3. Labrie, F., Pelletier, C., Borgeat, P., et al.: Mode of action ofhypothalalllic regulatory hormones in the adenohypophysis. In ~lartini, L., and Ganong, W. G., eels.: Frontiers in Neuroendocrinology. ;-';ew York, Raven Press, 1976, pp. 63-93. 4. Linder, H. R., Zor, U., Ball1ninger, S., et al.: The use of prostaglandin synthetase inhibitors in analysing the role of prostaglandins in reproductive physiology. I" Rohinson, L Vane, J. R., eds: Prostaglandin Synthesis Inhibitors: Their Eflects of Physiological Function and Pathological States. New Yrok, Raven Press, 1974. pp. 271-2il7. 5. Ojeda, S. R, Naor, Z., and Negro-Vilar, A.: The role of prostaglandins in the control of gonadotropin and prolactin secretion (review). Prostaglandins Med., 5:249, 1979. 6. O'Crady, J. P., Caldwell, B. V., Auletta, E. J., et al.: The effects of an inhibitor ofprostaglamlin synthesis (indomethacin) on ovulation, pregnancy and pseudopregnancy in the rabbit. Prostaglandins, 1 :97, 1972. 7. Orczyk, G., and Behrman, H. R: Ovulation blockade by aspirin or indomethacin: In Vivo cvidence for a role of prostaglandins in gonadotropin secretion. Prostaglandins, 1 :3, 1972. 8. Armstrong, D. T., Grinwich, D. L., Moon, Y. S., et al.: Inhibition of ovulation in rabbits by intrafollicular injection of indomethacin and prostaglandin F antiserum. Life Sci., 14;129, 1974. 9. Marsh, J. M., Yang, N. S. T., and LeMaire, W. J.: Prostaglandin synthesis in rabbit graafian follicles in vitro: EHec! of luteinizing hormone and cyclic-AMP. Prostaglandins, 7;269, 1974. 10. Beers, W. H., Strickland, S., and Reich, E.: Ovarian plasminogen activator: Relationships to ovulation and hormone regulation. Cell, 6;3il7, 1975. 11. Strickland, S., and Beers, W. H.: Studies on the role of plasminogen activator in ovulation. J. Bio!. Chem., 251 :5694, 1976. 12. Zor, U., ancl Lamprecht, S. A.: Mechanism of prostaglandin action in endocdne glands. In Litwach, G.: Biochemical Actions of Hormones. New York, Academic Press, 1977, Vo!. 4, pp. 85--133. 13. Horton, E. W., and Poyster, N. L.: Uterine luteolytic hormone: A physiological role tor prostaglandin F 2a • Physio!. Rev., 56:595,1976. 14. Wentz, A. C., and Jones, C. S.: Transient luteolytic effect of PGF," in the human. Ob stet. Cyneco!., 42; 172, 197.3. 15. Speroff, L., Caldwell, B. V., Brock, W. A., et al.: Hormone levels during prostaglandin F," inti.lsions for therapeutic abortion. J. Clin. Endocr. Metab., 34(3}:531, 1972. 16. Turksoy, N. R., and Safaii, H. S.: immediate effect of prostaglandin F 2" during the luteal phase of the menstrual cycle. Ferti!' Steri!', 26:634, 1975. 17. Lehmann, F., Peters, F., Breckwoldt, M., et al.: Plasma progesterone levels during infusion of prostaglandins F '" in the human. Prostaglandins, 1 ;269, 1972. 18. KOl'da, A. R., Shutt, D. A., Smith, 1. D., et al.: Assessment of possible luteolytic etfect of intra-ovarian injection of prostaglandin F '" in the human. Prostaglandins, 9:443, 1975. 19. Challis, J. R G., Calder, A. A., Dilley, S., et a!.: Production of prostaglandins E and F" by corpora luteal, corpora alhicantes and stroma from the human ovary. J. Endocrino!., 68:401, 1976. 20. Swanston, 1. A., MeNatty, K. P., and Baird, D. T.: Concentration of prostaglandin F," and steroids in the human eorpns luteum. J. Endocrino!., 73;115, 1977. 21. Behnnan, H. R., Luborsky-Moore, J. L., Pang, C. Y., et a!.: Mechanisms of PGF," action in functionalluteolysis.ln Channing, C. P., Marsh, J., Sadler, W. A., eds.: Ovarian Follicular and Corpora Luteum Function. New York, Plenum, 1979, pp. 557-575.

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22. Hendersoll, K. M., and McNatty, K. P.: A possible interrelationship between gonadotrophin stin1ulation and prostaglandin F:1O: inhibition of steroidogenesis by granulosa-luteal cells in vitro. J. EndocrinoJ., 73:71, 1977. 23. Hamberger, L., Nilsson, L., Denne/'lfs, B., et al.: Cydic-A~lP formation of isolated human corpora lutea in response to hCG-interference by PGF". Prostaglandins, 17 :61.5, 1979. 24. Caldwell, B. V., Auletta, F. J., and Speroff, L.: Prostaglandins in the control of ovulation, corpus luteum function and parturition. J. Reprod. Med., 10:133, 1973. 25. Auletta, F. J., Caldwell, B. V., and Speroft', L.: Estrogell-induced lutealysis in the rhesus monkey: Reversal with indomethacin. Prostaglandins, 11 :745, 1976. 26. Pickles, U. H., Hall, W. J., Best, F. A., et al.: Prostaglandins in endometrium and menstrual Huid horn normal and dysmenorrheic subjects. Br. J. Obstet. Gynaecol., 72:185,1965. 27. Lundstrom V., and Grccn, K.: Endogenous levels of prostaglandin F " and its main metabolites in plasma and endometrium of normal and dysmenorrheic women. Am . .T. Ob stet. Gynecol., 130:690, 1978. 28. WiIlman, E. A., Collins, W. P., and Clayton, S. G.: Studies in the involvement of prostaglandins in uterine symptomatology and pathology. Br. J. Ohstet. Gynaecol., 83:337, 1976. 29. Ham, E. A., Cirillo, V. J., Zanetti, M. E., et al.: Estrogen-directed synthesis of specific prostaglandins in uterus. Proc. Natl. Acad. Sci. USA, 72: 1420, 1975. 30. Lundstrom, V.: Treatment of primary dysmenorrhea with prostaglandin synthetase inhibitors a promising therapeutic alternative. Acta Ob stet. Gynaec. Scand., 57:421, 1978. 31. Halbert, D. R., Demers, L. M., Fontana, J., et a!.: Prostaglandin levels in endometrial jet wash specimens in patients with dysmenorrhea before and after indomethacin therapy. Prostaglandins, 10: 1047, 1975. 32. Csapo, A. I., Pulkkinen, M. 0., and Henzl, M. R: The effect of naproxen sodium on the intrauterine pressure and menstrual pain of dysmenorrheic patients. Prostaglandins, 13: 193, 1977. 33. Larkin, R M., Van Orden, D. K, Poulson, A. M., et al.: Dysmenorrhea: Treatment with an Antiprostaglandin. Ob stet. Gynec., 54;456,1979. 34. Thorburn, G. D., and Challis, J. It G.: Endocrine control of parturition. Physiol. Rev., 59:863, 1979. 35. Olley, P. M., Coceani, F., and Howe, R D.: Role of prostaglandin Eland E, in the management of neonatal heart disease. In Coceani, F., and Olley, P. M., eds.: Advances in Prostaglandin and Thromboxane Hesearch. New York, Raven Press, 1978, vo!. 4, p345. 36. \Vorld Health Organization Task Force on Use of Prostaglandins: Comparison of intraamniotic prostaglandin F 2a and hypertonic saline /"r induction of second-trimester ahortion. Br. ,',led. J., 1: 1373, 1976. 37. Schlegel, W., Hotermund, S., Fiirher, G., et al.: The inHuence of prostaglandins on sperm motility. Prostaglandins, 21 :87. Yale University School of ,',ledicine 333 Cedar Street i'\ew Haven, Connecticut 06.510