EUROP. J. OBSTET. GYNEC. REPROD. BIOL., 1976, 6/4,157-164.
EXCERPTA MEDICA
Experimental aspects of corpus luteum function B.T. Donovan Department
of Physiology, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, United Kingdom
In surveying current research on the corpus hrteun it becomes very clear that some of the greatest steps forward have come from studies on the formation of this organ. At one time, follicular rupture, the maturation and extrusion of the oocyte, and the luteinization of the granulosal cell layer inside the follicle all appeared to be parts of a sequential process. Now it emerges that these processes are individual in character and that separate actions of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) can be recognized.
Oocyte
of Tsafriri and Channing (1975) who have shown with porcine tissue that the follicle wall, or granulosal cells, or follicular fluid, inhibits meiosis. Cultured porcine oocytes underwent meiosis, whereas oocytes still enclosed in follicles did not. In this investigation, seventy to eighty per cent of oocytes cultured alone showed meiosis, but this percentage fell when the oocytes were cultured with granulosal tissue. Physical contact between the follicle wall and the oocyte was not necessary for the inhibitory influence upon meiosis to become manifest, while thecal tissue was ineffective. The nature of the inhibitory signal acting within the follicle remains obscure. It does not appear to be steroidal, for inhibition of progesterone synthesis by cyanoketone or aminoglutethimide did not alter oocyte maturation in the enclosed state, while follicular fluid from which estrogen and progesterone and other steroids had been removed by extraction with charcoal still inhibited ovum maturation (Tsafriri and Channing, 1975). The block to continued meiosis can be overcome fairly readily, for oocytes can be induced to mature by a variety of agents, such as FSH, LH, prostaglandin E2 (PGEa) prostaglandm Fzo, (PGF& and cyclic adenosine monophosphate (AMP) (Lindner, Tsafriri, Lieberman, Zor, Koch, Bauminger and Barnea, 1974; Neal and Baker, 1975).
maturation
It is well known that the nucleus or germinal vesicle of the oocyte is at the dictyate, or diffuse diplotene stage. Normally, exposure of the oocyte to a raised blood concentration of gonadotropin, as at the ovulatory surge, causes completion of the first reduction division and separation of the first polar body. Meiosis is resumed and proceeds to the metaphase of the second meiotic division unless fertilization occurs, when meiosis is completed, with the extrusion of the second polar body. These events represent oocyte maturation, and have been re-examined by Vermeiden and Zeilmaker (1974) who found that less gonadotropin was required for oocyte maturation than for corpus luteum formation. However, it has long been known that after removal from the ovarian follicle oocytes can mature in the absence of gonadotropin so that some constituent or product of the follicle would seem to inhibit oocyte maturation. This old concept is substantiated by the modern in vitro work
The oocyte
and luteinization
Five years ago El Fouly, Cook, Nekola and Nalbandov (1970) reaffirmed that the oocyte in its turn, may produce a factor inhibiting luteinization of the 157
158
granulosal cells, for removal of eggs from the follicles of rabbits or pigs led to luteinization of the ovectomized follicles. Luteinization produced in this way was slow to set in, but the significance of the effect is underlined by the fact that loss of follicular fluid alone did not cause luteinization, so the luteinization seems to be due to loss of the oocyte. Since luteinization of unruptured follicles is a common accompaniment of ovulation, the inhibitory influence of the oocyte can be over-ridden relatively easily. On the other hand, ovulation without luteinization of the evacuated follicles apparently never has been observed. Other observations attest to the anti-luteinization property of the oocyte. Nekola and Nalbandov (1971) found that oocytes in rat granulosal cell cultures maintained the closely neighboring cells in the granulosal state, while a luteal-like transformation occurred at a distance. Parallelism between the vitality of the oocyte and luteinization of whole rat folliclesin organ culture has also been observed (Stoklosowa and Nalbandov, 1972). When, on days 2 or 3 of culture, oocytes show signs, of degeneration, signs of luteinization appear in the thecal layer and in the granulosal cell layers furthest from the ovum. Production of the inhibitory material by the oocyte can be blocked by gonadotropin. Jones and Nalbandov (1972) found that the injection of nanogram amounts of FSH or LH into single rabbit ovarian follicles caused ovulation. With a subovulatory dose of gonadotropin, luteinization in the presence of the oocyte occurred so that it may be presumed that the process in the oocyte suspending meiosis at the dictyate stage is also responsible for the production of the inhibitory factor. As meiosis continues the inhibitory influence is lost. A somewhat similar influence of the oocyte in inhibiting cell growth in rat granulosal cell cultures has been observed by Bernard (1975), who found that pig follicular fluid inhibited cell growth. Removal of estrogen from the follicular fluid by incubation with dextran-coated charcoal did not interfere with the inhibition. An intriguing finding in this study was that progesterone secretion occurred in all cultures and was enhanced in the presence of estradiol. There was a divergence between the usual morphological signs of luteinization (increase in cell size, appearance of granules and lipid droplets in the cytoplasm, and the appearance of large and prominent nucleoli), and the
B. T. Donovan: Corpus luteum function
stimulation of progesterone secretion by estrogen, for the development of the morphological signs of luteinization was inhibited by follicular fluid. Normally the morphological signs of luteinization and progesterone secretion develop in parallel, although Lindner et al. (1974) reported that the ovectomy of rat follicles in culture did not lead to the expected rise in progesterone secretion over the ensuing 18-24 h. Progesterone secretion developed in response to LH and gives rise to the suggestion that in culture the inhibitor of luteinization may not be flushed away after ovectomy and so remains effective. Luteinization of granulosal cells collected from the ovaries of many species has commonly been observed in vitro, although it is necessary that the cells be collected from preovulatory follicles. Channing (1973, 1974) has argued persuasively that prior exposure of the cells to LH is necessary, or that FSH and LH must be present in the culture, so that a receptor for LH may be induced in the granulosal cells. Under these circumstances luteinization is accompanied by progesterone secretion and the secretion of this steroid is enhanced by LH, through the mediation of cyclic AMP. The entire molecule of LH is required, for the alpha or beta subunits are ineffective in this respect, while luteinization can also be induced by the prostaglandins, with prostaglandins of the F series being less effective than those of the E range. It appears that the granulosal cells from large follicles contain more cyclic AMP than those from small or medium bodies. When LH is added to granulosal cells the ability of cells from large follicles to synthesize cyclic AMP is much greater than those from small, even though the individual cell size is the same. This apparent increase in sensitivity also may simply reflect prior exposure to LH, for the follicular fluid of large porcine ovarian follicles has a higher concentration of this gonadotropin than that collected from small follicles, although the concentration remains below that of serum. Interestingly, the stimulation of cyclic AMP production in granulosal cells by LH can be inhibited by follicular fluid.
Ovulation Alongside the acquisition of a greater insight into the processes accompanying luteinization, more is
B.T. Donovan: Corpus luteurn function
159
acin was effective. On this basis, it is no longer surprising that ovulation itself can be blocked by the inhibitors of prostaglandin synthesis, indomethacin and aspirin, or, indeed, by the intra follicular injection of an antiserum to prostaglandin Fzcu. It is significant that oocyte maturation and follicular luteinization continue undisturbed after the blockade of oocyte extrusion with indomethacin.
being learned about the involvement of steroids and prostaglandins in the induction of ovulation. In rats, for example, treatment with cyanoketone, an inhibitor of 3/3-hydroxysteroid dehydrogenase, blocks the ovulation expected after the injection of LH (Lipner and Greey, 1971). Aminoglutethimide, an inhibitor of 20ar-hydroxycholesterol dehydrogenase is also effective and these observations imply that progesterone is involved in the ovulatory mechanism - as also is indicated by the finding that the elongation or distensibility of strips of follicle wall in vitro is increased upon exposure to LH, cyclic AMP or progesterone and that the action of LH and cyclic AMP is blocked by cyanoketone (Lipner, 1973). There is now substantial evidence for the involvement of prostaglandins in ovulation, The concentrations of prostaglandins E and F in rabbit or pig follicles or rat ovaries increase as ovulation approaches and follows the rise in plasma gonadotropin (Yang, Marsh and Le Maire, 1973; Armstrong, Moon and Zamecnik, 1974; Bauminger and Lindner, 1975; Bauminger, Lieberman and Lindner, 1975; Ainsworth, Baker and Armstrong, 1975). The blockade of steroid synthesis in cultured follicles with aminoglutethimide did not block the rise in prostaglandin, but indometh-
DAYS
The corpus luteum
With the formation of the corpus luteum after follicular rupture, new considerations arise which center around the mode of control of luteal function, and the operative factors which give rise to the characteristic life span of the corpus luteum of a particular species. In recent years the realization of the existence of a luteolytic influence on the part of the uterus has considerably clarified matters and the relative importance of the hypophysis and uterus in controlling luteal function has come to be evaluated. Thus, in the guinea pig the uterine influence appears to be dominant in the control of the corpus luteum. In women the life of the corpus luteum appears to be predeter-
WEEKS
Fig. 1. The changing concentration of progesterone in the plasma nancy induced by injection of LH(dottcd bars), or pseudopregnancy Donovan, 1976)
of ferrets during pregnancy (striped bars), during pseudopreginduced by coitus (open bars). (from the data of Blatchley and
160
mined, unless degeneration is halted by the chorionic gonadotropin produced after conception, while in the ferret pituitary hormone is essential for luteal activity, although the mechanism governing this aspect of hypophysial function awaits analysis. There is a remarkable parallelism between the pattern of progesterone secretion of the pregnant and the pseudopregnant ferret, whether pseudopregnancy be induced by coitus or by gonadotropin injection (Fig. 1; Blatchley and Donovan, 1976). A fall in the plasma progesterone concentration sets in after the third week in both pregnant and pseudopregnant animals, yet delivery does not take place for a further three weeks. Besides indicating that the placenta is not a significant source of progestin in this species, these findings well illustrate the operation of a timing factor in the control of hypophysial activity and luteal function, which, in a way as yet unknown, begins to depress the plasma level of progestin between the third and fourth week of pregnancy or pseudopregnancy.
Estrogen and the corpus luteum
There is a curious paradox in the effect of estrogen on luteal function. It has long been known that estrogen acts directly upon the corpus luteum of the rabbit to sustain luteal function. This observation has been reaffirmed recently by the effects of estradiol upon ectopic corpora lutea (Miller and Keyes, 1975) and the finding that the destruction of ovarian follicles by X-irradiation causes luteal regression (Keyes and Nalbandov, 1968). In the work of Bernard (1975) and the earlier studies of others in a variety of species, estrogen directly stimulated progesterone production by corpora lutea. It is also relevant that estrogen is secreted by corpora lutea, for MacDonald, Armstrong and Greep (1966) showed that the ovaries of hypophysectomized rats could be stimulated by LH to produce estrogen and that estrogen secretion did not occur in the absence of luteal bodies. In primates, by contrast, estrogen appears to be directly luteolytic, for estrogen implanted into corpus-luteum bearing ovaries, but not elsewhere, in women caused premature menstruation (Hoffman, 1960). Estrogen has been shown to be luteolytic in monkeys (Karsch, Krey, Weick, Dierschke and Kno-
B. T. Donovan: Corpus luteum function
bil, 1973) and women (Hoffman, 1960; Gore, Caldwell and Speroff, 1973), and it is significant that the estrone and estradiol content of the monkey corpus luteum rises considerably as that of progesterone falls during the late luteal phase (Butler, Hotchkiss and Knobil, 1975). Of the luteotropic and luteolytic actions of estrogen, the luteolytic effect could, perhaps, be more readily explained, for estradiol inhibits the activity of the 3fl-hydroxysteroid dehydrogenase necessary for the conversion of pregnenolone to progesterone in human and ovine tissue in vitro (Depp, Cox, Pion, Conrad and Heinrichs, 1973; Akbar, Stormshak and Lee, 1972) as well as in rat ovaries (Goldman, 1968). What, therefore, is the basis of the luteotrophic action?
Uterus and corpus luteum
There is now very good evidence that the luteolytic agent produced by the uterus is prostaglandin Fzcu (Pharriss, Tillson and Erickson, 1972; Goldberg and Ramwell, 1975). The injection of PGFa& has resulted in luteolysis in a variety of species, while this prostaglandin is released from the uterus and can be detected in uterine venous blood, in the sheep (Bland, Horton and Poyser, 1971), guinea pig (Blatchley, ‘Donovan, Horton and Poyser, 1972), pig (Gleeson, Thorbum and Cox, 1974) and cow (Nancarrow, Buckmaster, Charnley, Cox, Cumming, Cummins, Drinan, Findlay, Goding, Restall, Schneider and Thorburn, 1972). Treatment with antibodies to PGFZa has been shown to extend luteal life and lead to a considerable increase in the length of the estrous cycle in sheep (Scaramuzzi, Baird, Wheeler and Land, 1973) and in guinea pigs (Horton and Poyser, 1974; Poyser and Horton, 1975; Hildebrandt-Stark, Marcus, Yoshinaga, Behrman and Greep, 1975) and, appropriately, receptors for PGFZa have been found in ovine (Powell, Hammarstrom and Samuelsson, 1974a), bovine, and human corpora lutea (Powell, Hammarstrom, Samuelsson and Sjoberg, 1974b). The latter observation is of particular interest in view of the minimal influence of the human uterus upon luteal function, even though there is a rise in the amount of PGFzo, in the endometrium during the luteal phase of the menstrual cycle (Downie, Poyser
B. T. Donovan:
Corpus luteum function
and Wunderlich, 1974). This elevation is sustained up to menstruation, when a rise in PGE, is also seen. Despite the fact that the intrauterine administration of PGFzcv to women does not cause luteal regression Korda, Shutt, Smith and Shearman, (Lyneham, 1975), the human corpus luteum could produce sufficient PGFza for its own downfall, as may be implied by the presence of PGFzo, receptors. It would be surprising if the human corpus luteum were not sensitive to prostaglandin, for it seems to be accepted that PGF2, is luteolytic in the monkey (Kirton, Pharris and Forbes, 1970; Auletta, Speroff and Caldwell, 1973). The direct injection of the prostaglandin into human corpora lutea has depressed progesterone secretion (Korda, Shutt, Smith, Shearman and Lyneham, 1975). In those species in which uterine prostaglandin is luteolytic there must be some means of curtailing the production of the agent, or of antagonizing its action in the event of conception. Both processes seem to be employed, for the uterus of the pregnant guinea pig on day 15 produces very much less than the amount of PCF2, synthesized by the nonpregnant organ (Maule Walker and Poyser, 1974). There is also less PGF2, in the utero-ovarian venous blood of the pregnant than in that of the nonpregnant animal (Blatchley, Maule Walker and Poyser, 1975). The plasma concentration of progesterone is also higher in the pregnant animal, so reflecting a greater degree of luteal activity. Unfortunately, it is not yet possible to make wide generalizations, for in sheep PGFzo, is higher in the uterus of pregnant females on day 13 than in nonpregnant ewes (Wilson, Butcher and Inskeep, 1972). There is good evidence that the conceptus produces a luteotrophin to counter the luteolytic effect of prostaglandin, for luteal enlargement occurs in instances of ectopic pregnancy (Bland and Donovan, 1969) and, in species with a bicornuate uterus, bilateral luteal enlargement occurs in cases of unilateral pregnancy (Deanesly, 1967; Oxenreider and Day, 1967). The mode of action of prostaglandin upon the corpus luteum has been, and is, the subject of intensive investigation (Pharriss et al., 1972; Goldberg and Ramwell, 1975). Luteal function might be affected through a change in gonadotropin secretion brought about by an action of prostaglandin upon the brain or hypophysis, although the localized effects of the
161
prostaglandins upon the genital tract make this unlikely. The vasoconstrictor properties of PGE?, have often prompted the suggestion of an action of the lipid upon the ovarian vasculature. Pharriss and Wyngarden (1969) argued that luteolysis followed constriction of the ovarian vein, but a net change in blood flow has not been proven, for the evidence is conflicting (Goldberg and Ramwell, 1975). Alternatively, PGF*, could alter or redistribute blood flow within the ovary (Janson, Albrecht and Ahre’n, 1975), but it is very difficult to determine whether any changes observed are primary in character or follow secondarily from metabolic changes. A fall in overall blood flow through the ovary could also arise from a fall in blood pressure. The most attractive possibility at the present time is that PGFza antagonizes the action of gonadotropin on the ovary (Behrman, Yoshinaga and Greep, 1971b), although this view is largely based on studies made on the rat. Accordingly, the fall in progesterone secretion by rat luteal bodies caused by PGFzo, can be corrected by providing LH. Progesterone secretion from the corpora lutea of hypophysectomized rats is maintained by prolactin, but the synthesis is depressed by PGFzo, (Behrman, MacDonald and Greep, 1971a). This prostaglandin is also effective in reducing the progesterone output of corpora lutea in organ culture (C)‘Grady, Kohorn, Glass, Caldwell, Brock and Speroff, 1972), although progesterone synthesis is often favored (Pharriss et al., 1972) a finding which excludes the sole involvement of vasoactive processes. With cultured rat corpora lutea, PGF2, not only inhibited progesterone synthesis from labelled acetate but also inhibited protein synthesis. Initially, Behrman et al. (1971b) argued that prostaglandin Fza inhibited the conversion of cholesteryl ester to free cholesterol for progesterone synthesis. The cholesteryl esterase needed for this purpose would be activated by cyclic AMP, and Henderson and McNatty (1975) believe that PGF2, interferes with the generation of cyclic AMP. In their view, luteal regression arises from the gradual dissociation of LH from its specific membrane receptors in the luteal cell which promotes a conformational change within the plasma membrane to facilitate the uptake of PGF2,. As PGFzo, becomes bound to the plasma membrane of the luteal cell so the activation of adenylate cyclase by LH becomes inhibited and
B. T. Donovan:
162
cellular cyclic AMP falls, with a consequent decline in progesterone synthesis. Final morphological regression of the corpora lutea could ensue from the subsequent release of larger amounts of PGFZa which cause lysosomal activation through further changes in the plasma membrane. This is an attractive concept but requires substantiation before it becomes applicable to species other than the rat. Prostaglandin-induced luteolysis is viewed as an irreversible process, but this is an oversimplification. Further, LH is not a universal requirement for luteal function. Nevertheless, the theory is amenable to test in a wide variety of situations. Efforts to account for the development and decline of luteal activity too often presume that the corpus luteum is an homogenous structure. Yet it proves to be remarkably complicated (Guraya, 1971) particularly in the interaction of the derivatives of granulosal and thecal cells in producing steroids. For the human corpus luteum, Savard (1973) has pointed out that all the enzymes needed for the production of progesterone, testosterone and estradiol are present in all three ovarian compartments (follicle, stroma and corpus luteum). “How then does each tissue elaborate its own distinctive hormonal product under normal physiological conditions?” Seen in this way, it is not surprising that a full understanding of the life cycle of the corpus luteum remains a distant goal.
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Bauminger, S., Lieberman, M.E. and Lindner, H.R. (1975): Steroid-independent effect of gonadotropins on prostaglandin synthesis in rat graafian follicles in vitro. Prostag-
Corpus luteum function
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Bauminger, S. and Lindner, H.R. (1975): Periovulatory changes in ovarian prostaglandin formation and their hormonal control in the rat. Prostaglandins, 9, 737-751, Behrman, H.R., MacDonald, G.J. and Greep, R.O. (1971a): Regulation of ovarian cholesterol esters: Evidence for the enzymatic sites of prostaglandin-induced loss of corpus luteum function. Lipids, 6, 791-796. Behrman, H.R., Yoshinaga, K. and Greep, R. (1971b): Extraluteal effects of prostaglanains. Ann. N.Y. Acad. Sci., 180,426-433.
Bernard, J. (1975): Effect of follicular fluid and oestradiol on the luteinization of rat granulosa cells in vitro. J. Reprod. Fertil., 43, 453-460.
Bland, K.P. and Donovan, B.T. (1969): Control of luteal function during early pregnancy in the guinea-pig. J. Reprod. Fertil., 20, 491-501.
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Blatchley, F.R., Maule Walker, F.M. and Poyser, N.L. (1975): Utero-ovarian venous plasma levels of prostaglandin F,, progesterone and oestradiol in non-pregnant and early pregnant guinea-pigs. J. Endocr., 64, 12P. Butler, W.R., Hotchkiss, J. and Knobil, E. (1975): Functional luteolysis in the rhesus monkey: Ovarian estrogen and progesterone during the luteal phase of the menstrual cycle. Endocrinology, 96, 1509-1512. Channing, C.P. (1973): Factors involved in luteinization in vitro. In: Endocrinology, pp. 914-919. ICS 273, Excerpta Medica, Amsterdam. Channing, C.P. (1974): The use of granulosa cell cultures and short-term incubations in the assay for gonadotropins. In: Gonadotropins and Gonadal Function, pp. 185-198. Editor: N.R. Moudgal. Academic Press, New York. Deanesly, R. (1967): Normal growth and persistence of corpora lutea in both ovaries in the unilaterally pregnant guinea-pig. J. Reprod. Fertil., 14, 5 19-521. Depp, R., Cox, D.W., Pion, R.J., Conrad, S.H. and Heimichs, W.L. (1973): Inhibition of the pregnenolone As-@hydroxysteroid dehydrogenase-Ass4 isomerase systems of human placenta and corpus luteum of pregnancy. Gynec. Invest., 4, 106-120.
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163 Lipner, H. (1973): Mechanism of mammalian ovulation. In: Handbook of Physiology, Section 7, Volume II, Female Reproductive System, Part I, pp. 409-437. Editor: R.O. Greep. American Physiological Society. Lipner, H. and Greep, R.O. (1971): Inhibition of steroidogenesis at various sites in the biosynthetic pathway in relation to induced ovulation. Endocrinology>, 88, 6022 607. Lyneham, R.C., Korda, A.R., Shutt, D.A., Smith, I.D. and Shearman, R.P. (1975): The effect of intrauterine prostaglandin Fao on corpus luteum function in the human. Prostaglandins, 9, 431-442. MacDonald, G.J., Armstrong, D.T. and Greep, R.O. (1966): Stimulation of estrogen secretion from normal rat corpora lutea by luteinizing hormone. Endocrinology, 79, 289~293. Maule Walker, F.M. and Poyser, N.L. (1974): Production of prostaglandins by the early pregnant guinea-pig uterus in vitro. J. Endocr., 61, 2655271. Miller, J.B. and Keyes, P.L. (1975): Progesterone synthesis in developing rabbit corpora lutea in the absence of follicular estrogens. Endocrinology, 97, 83-90. Nancarrow, C.D., Buckmaster, J., Charnley, W., Cox, R.I., Gumming, I.A. Cummins, L., Drinan, J.P., Findlay, J.K., Goding, J.R., RestaB, B.J. Schneider, W. and Thorburn, G.D. (1972): Hormonal changes around oestrus in the cow. J. Reprod. Fertil., 32, 320-321. Neal, P. and Baker, T.G. (1975): Response of mouse Graafian follicles in organ culture to varying doses of follicle-stimulating hormone and luteinizing hormone. J. Endocr., 65, 27-32. Nekola, M.V. and Nalbandov, A.V. (1971): Morphological changes of rat follicular cells as influenced by oocytes. Biol. Reprod., 4, 154-160. O’Grady, J.P., Kohorn, EL, Glass, R.H., Caldwell, B.V., Brock, W.A. and Speroff, L. (1972): Inhibition of progesterone synthesis in vitro by prostaglandin Fao. J. Reprod. Fertil., 30, 153-156. Oxenreider, S.L. and Day, B.N. (1967): Regression of corpora lutea in unilaterally pregnant guinea-pigs. J. Endocr., 38, 279-289. Pharriss, B.B., Tillson, S.A. and Erickson, R.R. (1972): Prostaglandins in luteal function. Recent Progr. Hormone Res., 28, 51-73. Pharriss, B.B. and Wyngarden, L.J. (1969): The effect of prostaglandin F20 on the progestogen content of ovaries from pseudopregnant rats. Proc. Sot. exp. Biol. Med., 130,92-94. Powell, W.S., Hammarstrom, S. and Samuelsson, B. (1974a): Prostaglandin FZo! receptor in ovine corpora lutea. Europ. J. Biochem, 41, 103-107. Powell, W.S., Hammarstrom, S., Samuelsson, B. and Sjoberg, B. (1974b): Prostaglandin Fao receptor in human corpora lutea. Lancet, I, 1120. Poyser, N.L. and Horton, E.W. (1975): Plasma progesterone levels in guinea pigs actively immunized against prostaglandin Fao, hysterectomized or treated with intra-uterine indomethacin. J. Endocr., 6 7, 81-88.
164 Savard, K. (1973): The biochemistry of the corpus luteum. Biol. Reprod., 8, 183-202. Scaramuzzi, R.J., Baird, D.T., Wheeler, A.G. and Land, R.B. (1973): The oestrous cycle of the ewe following active immunization against prostaglandin Fzd. Acta endocr. (Kbh.), Suppl. 177, 3 18. Stoklosowa, S. and Nalbandov, A.V. (1972): Luteinization and steroidogenic activity of rat ovarian follicles cultured in vitro. Endocrinology, 91, 25-32. Tsafriri, A. and Channing, C.P. (1975): An inhibitory influence of granulosa cells and follicular fluid upon porcine meiosis in vitro. Endocrinology, 96, 922-927.
B. T. Donovan: Corpus luteum function
Vermeiden, J.P.W. and Zeilmaker, G.H. (1974): Relationship between maturation division, ovulation and luteinization in the female rat. Endocrinology, 95, 341-35 1. Wilson, L., Butcher, R.L. and Inskeep, E.K. (1972): Prostaglandin Fsor in the uterus of ewes during early pregnancy. Prostaglandins, I, 479-482. Yang, N.S.T., Marsh, J.M. and Le Maire, W.J. (1973): Prostaglandin changes induced by ovulatory stimuli in rabbit Graatian follicles. The effect of indomethacin. Prostaglandins, 4, 395-404.
EXCERPTA MEDICA
Experimental aspects of corpus luteum function B.T. Donovan Department
of Physiology, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, United Kingdom
In surveying current research on the corpus hrteun it becomes very clear that some of the greatest steps forward have come from studies on the formation of this organ. At one time, follicular rupture, the maturation and extrusion of the oocyte, and the luteinization of the granulosal cell layer inside the follicle all appeared to be parts of a sequential process. Now it emerges that these processes are individual in character and that separate actions of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) can be recognized.
Oocyte
of Tsafriri and Channing (1975) who have shown with porcine tissue that the follicle wall, or granulosal cells, or follicular fluid, inhibits meiosis. Cultured porcine oocytes underwent meiosis, whereas oocytes still enclosed in follicles did not. In this investigation, seventy to eighty per cent of oocytes cultured alone showed meiosis, but this percentage fell when the oocytes were cultured with granulosal tissue. Physical contact between the follicle wall and the oocyte was not necessary for the inhibitory influence upon meiosis to become manifest, while thecal tissue was ineffective. The nature of the inhibitory signal acting within the follicle remains obscure. It does not appear to be steroidal, for inhibition of progesterone synthesis by cyanoketone or aminoglutethimide did not alter oocyte maturation in the enclosed state, while follicular fluid from which estrogen and progesterone and other steroids had been removed by extraction with charcoal still inhibited ovum maturation (Tsafriri and Channing, 1975). The block to continued meiosis can be overcome fairly readily, for oocytes can be induced to mature by a variety of agents, such as FSH, LH, prostaglandin E2 (PGEa) prostaglandm Fzo, (PGF& and cyclic adenosine monophosphate (AMP) (Lindner, Tsafriri, Lieberman, Zor, Koch, Bauminger and Barnea, 1974; Neal and Baker, 1975).
maturation
It is well known that the nucleus or germinal vesicle of the oocyte is at the dictyate, or diffuse diplotene stage. Normally, exposure of the oocyte to a raised blood concentration of gonadotropin, as at the ovulatory surge, causes completion of the first reduction division and separation of the first polar body. Meiosis is resumed and proceeds to the metaphase of the second meiotic division unless fertilization occurs, when meiosis is completed, with the extrusion of the second polar body. These events represent oocyte maturation, and have been re-examined by Vermeiden and Zeilmaker (1974) who found that less gonadotropin was required for oocyte maturation than for corpus luteum formation. However, it has long been known that after removal from the ovarian follicle oocytes can mature in the absence of gonadotropin so that some constituent or product of the follicle would seem to inhibit oocyte maturation. This old concept is substantiated by the modern in vitro work
The oocyte
and luteinization
Five years ago El Fouly, Cook, Nekola and Nalbandov (1970) reaffirmed that the oocyte in its turn, may produce a factor inhibiting luteinization of the 157
158
granulosal cells, for removal of eggs from the follicles of rabbits or pigs led to luteinization of the ovectomized follicles. Luteinization produced in this way was slow to set in, but the significance of the effect is underlined by the fact that loss of follicular fluid alone did not cause luteinization, so the luteinization seems to be due to loss of the oocyte. Since luteinization of unruptured follicles is a common accompaniment of ovulation, the inhibitory influence of the oocyte can be over-ridden relatively easily. On the other hand, ovulation without luteinization of the evacuated follicles apparently never has been observed. Other observations attest to the anti-luteinization property of the oocyte. Nekola and Nalbandov (1971) found that oocytes in rat granulosal cell cultures maintained the closely neighboring cells in the granulosal state, while a luteal-like transformation occurred at a distance. Parallelism between the vitality of the oocyte and luteinization of whole rat folliclesin organ culture has also been observed (Stoklosowa and Nalbandov, 1972). When, on days 2 or 3 of culture, oocytes show signs, of degeneration, signs of luteinization appear in the thecal layer and in the granulosal cell layers furthest from the ovum. Production of the inhibitory material by the oocyte can be blocked by gonadotropin. Jones and Nalbandov (1972) found that the injection of nanogram amounts of FSH or LH into single rabbit ovarian follicles caused ovulation. With a subovulatory dose of gonadotropin, luteinization in the presence of the oocyte occurred so that it may be presumed that the process in the oocyte suspending meiosis at the dictyate stage is also responsible for the production of the inhibitory factor. As meiosis continues the inhibitory influence is lost. A somewhat similar influence of the oocyte in inhibiting cell growth in rat granulosal cell cultures has been observed by Bernard (1975), who found that pig follicular fluid inhibited cell growth. Removal of estrogen from the follicular fluid by incubation with dextran-coated charcoal did not interfere with the inhibition. An intriguing finding in this study was that progesterone secretion occurred in all cultures and was enhanced in the presence of estradiol. There was a divergence between the usual morphological signs of luteinization (increase in cell size, appearance of granules and lipid droplets in the cytoplasm, and the appearance of large and prominent nucleoli), and the
B. T. Donovan: Corpus luteum function
stimulation of progesterone secretion by estrogen, for the development of the morphological signs of luteinization was inhibited by follicular fluid. Normally the morphological signs of luteinization and progesterone secretion develop in parallel, although Lindner et al. (1974) reported that the ovectomy of rat follicles in culture did not lead to the expected rise in progesterone secretion over the ensuing 18-24 h. Progesterone secretion developed in response to LH and gives rise to the suggestion that in culture the inhibitor of luteinization may not be flushed away after ovectomy and so remains effective. Luteinization of granulosal cells collected from the ovaries of many species has commonly been observed in vitro, although it is necessary that the cells be collected from preovulatory follicles. Channing (1973, 1974) has argued persuasively that prior exposure of the cells to LH is necessary, or that FSH and LH must be present in the culture, so that a receptor for LH may be induced in the granulosal cells. Under these circumstances luteinization is accompanied by progesterone secretion and the secretion of this steroid is enhanced by LH, through the mediation of cyclic AMP. The entire molecule of LH is required, for the alpha or beta subunits are ineffective in this respect, while luteinization can also be induced by the prostaglandins, with prostaglandins of the F series being less effective than those of the E range. It appears that the granulosal cells from large follicles contain more cyclic AMP than those from small or medium bodies. When LH is added to granulosal cells the ability of cells from large follicles to synthesize cyclic AMP is much greater than those from small, even though the individual cell size is the same. This apparent increase in sensitivity also may simply reflect prior exposure to LH, for the follicular fluid of large porcine ovarian follicles has a higher concentration of this gonadotropin than that collected from small follicles, although the concentration remains below that of serum. Interestingly, the stimulation of cyclic AMP production in granulosal cells by LH can be inhibited by follicular fluid.
Ovulation Alongside the acquisition of a greater insight into the processes accompanying luteinization, more is
B.T. Donovan: Corpus luteurn function
159
acin was effective. On this basis, it is no longer surprising that ovulation itself can be blocked by the inhibitors of prostaglandin synthesis, indomethacin and aspirin, or, indeed, by the intra follicular injection of an antiserum to prostaglandin Fzcu. It is significant that oocyte maturation and follicular luteinization continue undisturbed after the blockade of oocyte extrusion with indomethacin.
being learned about the involvement of steroids and prostaglandins in the induction of ovulation. In rats, for example, treatment with cyanoketone, an inhibitor of 3/3-hydroxysteroid dehydrogenase, blocks the ovulation expected after the injection of LH (Lipner and Greey, 1971). Aminoglutethimide, an inhibitor of 20ar-hydroxycholesterol dehydrogenase is also effective and these observations imply that progesterone is involved in the ovulatory mechanism - as also is indicated by the finding that the elongation or distensibility of strips of follicle wall in vitro is increased upon exposure to LH, cyclic AMP or progesterone and that the action of LH and cyclic AMP is blocked by cyanoketone (Lipner, 1973). There is now substantial evidence for the involvement of prostaglandins in ovulation, The concentrations of prostaglandins E and F in rabbit or pig follicles or rat ovaries increase as ovulation approaches and follows the rise in plasma gonadotropin (Yang, Marsh and Le Maire, 1973; Armstrong, Moon and Zamecnik, 1974; Bauminger and Lindner, 1975; Bauminger, Lieberman and Lindner, 1975; Ainsworth, Baker and Armstrong, 1975). The blockade of steroid synthesis in cultured follicles with aminoglutethimide did not block the rise in prostaglandin, but indometh-
DAYS
The corpus luteum
With the formation of the corpus luteum after follicular rupture, new considerations arise which center around the mode of control of luteal function, and the operative factors which give rise to the characteristic life span of the corpus luteum of a particular species. In recent years the realization of the existence of a luteolytic influence on the part of the uterus has considerably clarified matters and the relative importance of the hypophysis and uterus in controlling luteal function has come to be evaluated. Thus, in the guinea pig the uterine influence appears to be dominant in the control of the corpus luteum. In women the life of the corpus luteum appears to be predeter-
WEEKS
Fig. 1. The changing concentration of progesterone in the plasma nancy induced by injection of LH(dottcd bars), or pseudopregnancy Donovan, 1976)
of ferrets during pregnancy (striped bars), during pseudopreginduced by coitus (open bars). (from the data of Blatchley and
160
mined, unless degeneration is halted by the chorionic gonadotropin produced after conception, while in the ferret pituitary hormone is essential for luteal activity, although the mechanism governing this aspect of hypophysial function awaits analysis. There is a remarkable parallelism between the pattern of progesterone secretion of the pregnant and the pseudopregnant ferret, whether pseudopregnancy be induced by coitus or by gonadotropin injection (Fig. 1; Blatchley and Donovan, 1976). A fall in the plasma progesterone concentration sets in after the third week in both pregnant and pseudopregnant animals, yet delivery does not take place for a further three weeks. Besides indicating that the placenta is not a significant source of progestin in this species, these findings well illustrate the operation of a timing factor in the control of hypophysial activity and luteal function, which, in a way as yet unknown, begins to depress the plasma level of progestin between the third and fourth week of pregnancy or pseudopregnancy.
Estrogen and the corpus luteum
There is a curious paradox in the effect of estrogen on luteal function. It has long been known that estrogen acts directly upon the corpus luteum of the rabbit to sustain luteal function. This observation has been reaffirmed recently by the effects of estradiol upon ectopic corpora lutea (Miller and Keyes, 1975) and the finding that the destruction of ovarian follicles by X-irradiation causes luteal regression (Keyes and Nalbandov, 1968). In the work of Bernard (1975) and the earlier studies of others in a variety of species, estrogen directly stimulated progesterone production by corpora lutea. It is also relevant that estrogen is secreted by corpora lutea, for MacDonald, Armstrong and Greep (1966) showed that the ovaries of hypophysectomized rats could be stimulated by LH to produce estrogen and that estrogen secretion did not occur in the absence of luteal bodies. In primates, by contrast, estrogen appears to be directly luteolytic, for estrogen implanted into corpus-luteum bearing ovaries, but not elsewhere, in women caused premature menstruation (Hoffman, 1960). Estrogen has been shown to be luteolytic in monkeys (Karsch, Krey, Weick, Dierschke and Kno-
B. T. Donovan: Corpus luteum function
bil, 1973) and women (Hoffman, 1960; Gore, Caldwell and Speroff, 1973), and it is significant that the estrone and estradiol content of the monkey corpus luteum rises considerably as that of progesterone falls during the late luteal phase (Butler, Hotchkiss and Knobil, 1975). Of the luteotropic and luteolytic actions of estrogen, the luteolytic effect could, perhaps, be more readily explained, for estradiol inhibits the activity of the 3fl-hydroxysteroid dehydrogenase necessary for the conversion of pregnenolone to progesterone in human and ovine tissue in vitro (Depp, Cox, Pion, Conrad and Heinrichs, 1973; Akbar, Stormshak and Lee, 1972) as well as in rat ovaries (Goldman, 1968). What, therefore, is the basis of the luteotrophic action?
Uterus and corpus luteum
There is now very good evidence that the luteolytic agent produced by the uterus is prostaglandin Fzcu (Pharriss, Tillson and Erickson, 1972; Goldberg and Ramwell, 1975). The injection of PGFa& has resulted in luteolysis in a variety of species, while this prostaglandin is released from the uterus and can be detected in uterine venous blood, in the sheep (Bland, Horton and Poyser, 1971), guinea pig (Blatchley, ‘Donovan, Horton and Poyser, 1972), pig (Gleeson, Thorbum and Cox, 1974) and cow (Nancarrow, Buckmaster, Charnley, Cox, Cumming, Cummins, Drinan, Findlay, Goding, Restall, Schneider and Thorburn, 1972). Treatment with antibodies to PGFZa has been shown to extend luteal life and lead to a considerable increase in the length of the estrous cycle in sheep (Scaramuzzi, Baird, Wheeler and Land, 1973) and in guinea pigs (Horton and Poyser, 1974; Poyser and Horton, 1975; Hildebrandt-Stark, Marcus, Yoshinaga, Behrman and Greep, 1975) and, appropriately, receptors for PGFZa have been found in ovine (Powell, Hammarstrom and Samuelsson, 1974a), bovine, and human corpora lutea (Powell, Hammarstrom, Samuelsson and Sjoberg, 1974b). The latter observation is of particular interest in view of the minimal influence of the human uterus upon luteal function, even though there is a rise in the amount of PGFzo, in the endometrium during the luteal phase of the menstrual cycle (Downie, Poyser
B. T. Donovan:
Corpus luteum function
and Wunderlich, 1974). This elevation is sustained up to menstruation, when a rise in PGE, is also seen. Despite the fact that the intrauterine administration of PGFzcv to women does not cause luteal regression Korda, Shutt, Smith and Shearman, (Lyneham, 1975), the human corpus luteum could produce sufficient PGFza for its own downfall, as may be implied by the presence of PGFzo, receptors. It would be surprising if the human corpus luteum were not sensitive to prostaglandin, for it seems to be accepted that PGF2, is luteolytic in the monkey (Kirton, Pharris and Forbes, 1970; Auletta, Speroff and Caldwell, 1973). The direct injection of the prostaglandin into human corpora lutea has depressed progesterone secretion (Korda, Shutt, Smith, Shearman and Lyneham, 1975). In those species in which uterine prostaglandin is luteolytic there must be some means of curtailing the production of the agent, or of antagonizing its action in the event of conception. Both processes seem to be employed, for the uterus of the pregnant guinea pig on day 15 produces very much less than the amount of PCF2, synthesized by the nonpregnant organ (Maule Walker and Poyser, 1974). There is also less PGF2, in the utero-ovarian venous blood of the pregnant than in that of the nonpregnant animal (Blatchley, Maule Walker and Poyser, 1975). The plasma concentration of progesterone is also higher in the pregnant animal, so reflecting a greater degree of luteal activity. Unfortunately, it is not yet possible to make wide generalizations, for in sheep PGFzo, is higher in the uterus of pregnant females on day 13 than in nonpregnant ewes (Wilson, Butcher and Inskeep, 1972). There is good evidence that the conceptus produces a luteotrophin to counter the luteolytic effect of prostaglandin, for luteal enlargement occurs in instances of ectopic pregnancy (Bland and Donovan, 1969) and, in species with a bicornuate uterus, bilateral luteal enlargement occurs in cases of unilateral pregnancy (Deanesly, 1967; Oxenreider and Day, 1967). The mode of action of prostaglandin upon the corpus luteum has been, and is, the subject of intensive investigation (Pharriss et al., 1972; Goldberg and Ramwell, 1975). Luteal function might be affected through a change in gonadotropin secretion brought about by an action of prostaglandin upon the brain or hypophysis, although the localized effects of the
161
prostaglandins upon the genital tract make this unlikely. The vasoconstrictor properties of PGE?, have often prompted the suggestion of an action of the lipid upon the ovarian vasculature. Pharriss and Wyngarden (1969) argued that luteolysis followed constriction of the ovarian vein, but a net change in blood flow has not been proven, for the evidence is conflicting (Goldberg and Ramwell, 1975). Alternatively, PGF*, could alter or redistribute blood flow within the ovary (Janson, Albrecht and Ahre’n, 1975), but it is very difficult to determine whether any changes observed are primary in character or follow secondarily from metabolic changes. A fall in overall blood flow through the ovary could also arise from a fall in blood pressure. The most attractive possibility at the present time is that PGFza antagonizes the action of gonadotropin on the ovary (Behrman, Yoshinaga and Greep, 1971b), although this view is largely based on studies made on the rat. Accordingly, the fall in progesterone secretion by rat luteal bodies caused by PGFzo, can be corrected by providing LH. Progesterone secretion from the corpora lutea of hypophysectomized rats is maintained by prolactin, but the synthesis is depressed by PGFzo, (Behrman, MacDonald and Greep, 1971a). This prostaglandin is also effective in reducing the progesterone output of corpora lutea in organ culture (C)‘Grady, Kohorn, Glass, Caldwell, Brock and Speroff, 1972), although progesterone synthesis is often favored (Pharriss et al., 1972) a finding which excludes the sole involvement of vasoactive processes. With cultured rat corpora lutea, PGF2, not only inhibited progesterone synthesis from labelled acetate but also inhibited protein synthesis. Initially, Behrman et al. (1971b) argued that prostaglandin Fza inhibited the conversion of cholesteryl ester to free cholesterol for progesterone synthesis. The cholesteryl esterase needed for this purpose would be activated by cyclic AMP, and Henderson and McNatty (1975) believe that PGF2, interferes with the generation of cyclic AMP. In their view, luteal regression arises from the gradual dissociation of LH from its specific membrane receptors in the luteal cell which promotes a conformational change within the plasma membrane to facilitate the uptake of PGF2,. As PGFzo, becomes bound to the plasma membrane of the luteal cell so the activation of adenylate cyclase by LH becomes inhibited and
B. T. Donovan:
162
cellular cyclic AMP falls, with a consequent decline in progesterone synthesis. Final morphological regression of the corpora lutea could ensue from the subsequent release of larger amounts of PGFZa which cause lysosomal activation through further changes in the plasma membrane. This is an attractive concept but requires substantiation before it becomes applicable to species other than the rat. Prostaglandin-induced luteolysis is viewed as an irreversible process, but this is an oversimplification. Further, LH is not a universal requirement for luteal function. Nevertheless, the theory is amenable to test in a wide variety of situations. Efforts to account for the development and decline of luteal activity too often presume that the corpus luteum is an homogenous structure. Yet it proves to be remarkably complicated (Guraya, 1971) particularly in the interaction of the derivatives of granulosal and thecal cells in producing steroids. For the human corpus luteum, Savard (1973) has pointed out that all the enzymes needed for the production of progesterone, testosterone and estradiol are present in all three ovarian compartments (follicle, stroma and corpus luteum). “How then does each tissue elaborate its own distinctive hormonal product under normal physiological conditions?” Seen in this way, it is not surprising that a full understanding of the life cycle of the corpus luteum remains a distant goal.
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Bauminger, S., Lieberman, M.E. and Lindner, H.R. (1975): Steroid-independent effect of gonadotropins on prostaglandin synthesis in rat graafian follicles in vitro. Prostag-
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Bauminger, S. and Lindner, H.R. (1975): Periovulatory changes in ovarian prostaglandin formation and their hormonal control in the rat. Prostaglandins, 9, 737-751, Behrman, H.R., MacDonald, G.J. and Greep, R.O. (1971a): Regulation of ovarian cholesterol esters: Evidence for the enzymatic sites of prostaglandin-induced loss of corpus luteum function. Lipids, 6, 791-796. Behrman, H.R., Yoshinaga, K. and Greep, R. (1971b): Extraluteal effects of prostaglanains. Ann. N.Y. Acad. Sci., 180,426-433.
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