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Hypothesis: Placental membranes produce prolactin
Molecular and Cellular Endocrinology, 11 (1978) l-6 0 Elsevier/North-Holland Scientific Publishers, Ltd.
REVIEW ARTICLE
HYPOTHESIS:PLACENTALMEMBRANESPRODUCEPROLACTIN David L. HEALY r, Henry G. BURGER ’ and H.K. MULLER 2 1 Medical Research Centre, Prince Henry’s Hospital, Melbourne 3004, and 2 Department of Pathology and Immunology,
Monash University, Clayton 3168, Australia
Received 16 Febri.rary 1978
Orthodox views for the origin of the high concentration of prolactin (PRL) present in amniotic fluid suggest it is derived from maternal or fetal serum. However, the data on which these conclusions are based can also be interpreted to indicate that this hormone may be a product of placental or periplacental tissues. Trophoblast or amnion do not appear to produce PRL, while PRL synthesis by decidua-chorion is suggested from experiments in the rhesus monkey and by in vitro incubation of human tissue. Production of PRL by an extrapituitary cell is not without precedent and would be a simple explanation for high amniotic fluid PRL concentrations. Moreover, decidual-chorionic PRL would be strategically placed to mediate local functions of this hormone such as osmoregulation and myometrjal inhibition. Keywvrds:
prolactin; amniotic fluid; decidua-chorion;
amnion; placenta.
The application of the radioimmunoassay for prolactin (PRL) to a variety of physiological states has revealed high concentrations of PRL in amniotic fluid of the human and rhesus monkey (Hwang et al., 1971). The PRL concentration in human amniotic fluid exceeds the maternal or fetal serum concentration by a factor of lOO-200-fold at mid-gestation (Tyson et al., 1972; Clements et al., 1977) and has been sufficient to allow purification of milligram quantities of this protein (Hwang et al., 1974; Ben-David and Chrambach, 1977). The partitioning of PRL within the amniotic fluid, as opposed to the serum compartment, is unique amongst the protein hormones found in amniotic fluid: PRL, chorionic gonadotrophin, chorionic somatomammotrophin or placental lactogen, growth hormone (GH), somatomedin and glucagon (Tyson et al., 1972; Dawood, 1977; Chochinov et al., 1976). Where is amniotic fluid PRL produced? Most explanations have centred upon how maternal (Josimovich et al., 1974; Schenker et al., 1975) or fetal (Chochinov et al., 1976; Fang and Kim, 1975) pituitary PRL might provide the high concentrations observed in amniotic fluid. We propose that the decidua-chorion is a major source of this hormone.
1
2
D.L. Healy et
al.
LOCAL FUNCTIONS OF AMNIOTIC FLUID PROLACTIN PRL affects water and electrolyte exchange in many species of fish (Ball, 1969) and amphibians (Bern and Nicoll, 1968) where its action is considered important in maintaining sodium homeostasis. The fetal state represents the only circumstance in which the human lives in an aquatic environment. Following the demonstration of high PRL concentrations in amniotic fluid, several studies have examined the possible action of PRL on water and ion fluxes across the fetal membranes. Investigations in vitro show that PRL, at concentrations in the range found in human amniotic fluid, induces fluid to pass from the fetal to the maternal side of guinea-pig (Manku et al., 1975) and human amnion (Leontic and Tyson, 1977). In vivo studies in the rhesus monkey confirm these findings and demonstrate that PRL preserves amniotic fluid water and sodium ion content (Josimovich et al., 1977) in the face of either hyper- or hypotonicity. Clinical studies also indirectly confirm this osmoregulatory function of PRL. Amniotic fluid PRL levels are elevated in some patients with toxaemia of pregnancy or idiopathic fetal growth retardation, two conditions associated with oligohydramnios (Josimovich, 1977). Conversely, PRL values are low in 50% of women with polyhydramnios. Inhibition of uterine motility is a prerequisite to the continuation of pregnancy. The profile of active uterine pressure in human gestation is the inverse of the profile of amniotic fluid PRL concentration throughout pregnancy (Wood, 1972), suggesting that PRL may inhibit myometrial contractility. In vitro studies confirm that this hormone can inhibit uterine muscle activity in the non-pregnant rat (Horrobin et al., 1973) and human (Mugambi et al., 1974). There is also clinical data to support the proposition that PRL may inhibit myometrial action: nearly 50% of women with polyhydramnios, a condition associated with low amniotic fluid PRL values, commence labour before the 37th week of gestation (Yordan and D’Esopo, 1955). Animal studies suggest additional functions for amniotic fluid PRL. Fetal swallowing would bring this hormone into contact with small bowel mucosa where, in the rat (Mainoya, 1975) it has been shown to influence sodium absorption. PRL receptors are reported in the lung of the fetal monkey (Josimovich, 1977) and PRL induces surfactant synthesis in the fetal rabbit lung (Hamosh and Hamosh, 1977). In the human it is possible that amniotic fluid PRL does reach the alveoli of the human fetus via the trachea to aid in surfactant synthesis (Duenhoelter and Pritchard, 1973). Surfactant is first demonstrated in the human lung from about 24 weeks gestation (Dawes, 1968), a time of high amniotic fluid PRL concentrations but relatively low fetal serum values. Another possible function for amniotic fluid PRL is immunosuppression of the maternal response to the fetal allograft. PRL inhibits lymphocyte activity in vitro at concentrations found in amniotic fluid (Karmali et al., 1974). A high level of this hormone at the interface between mother and fetus might facilitate local suppression of maternal cellular immunity.
Placental membranes produce prolactin
MATERNAL PITUITARY
PROLACTIN
One source of high PRL concentrations in amniotic fluid is pituitary PRL from the maternal circulation (Josimovich et al., 1974; Schenker et al., 1975). This conclusion is based upon a correlation between maternal serum PRL values and amniotic fluid PRL concentrations in the rhesus monkey. Additional evidence is the recovery in amniotic fluid of 1% of an injected dose of [‘*‘I]PRL given to the pregnant monkey. Furthermore, the PRL molecules isolated from maternal serum and from amniotic fluid are chemically similar. However, much evidence stands against this view. No other protein hormone of molecular weight 22,000 daltons is known to cross the placental barrier and reach the amniotic fluid concentrations observed with PRL. A statistical association between maternal and amniotic fluid concentrations does not prove a common origin. There is no rise in serum PRL during pregnancy in the rhesus monkey yet the amniotic fluid concentrations are high in that species and increase as gestation proceeds (Friesen et al., 1972). If the maternal pituitary gland is the major source of amniotic fluid PRL, one would expect some decrease in amniotic fluid values after hypophysectomy. This is not the case. In the rhesus monkey the PRL concentration in amniotic fluid remains unchanged after maternal hypophysectomy (Walsh et al., 1977). Moreover, chromatography reveals size heterogeneity of PRL isolated from maternal blood and amniotic fluid (Fang and Kim, 1975), suggesting chemical differences in these molecules.
FETAL PITUITARY
PROLACTIN
A second explanation for the high concentration of amniotic fluid PRL is that the hormone comes from the fetal pituitary, passes through the immature kidney into urine and is then excreted (Chochinov et al., 1976; Fang and Kim, 1975). The profiles of PRL concentrations in fetal serum and amniotic fluid are essential to this explanation. Most reports find peak amniotic fluid PRL concentrations at 14-16 weeks gestation (Tyson et al., 1972; Clements et al., 1977; Friesen et al., 1972; McNeilly et al., 1977) with a subsequent slow fall to term, although other studies have suggested that peak values occur at 24 (Chochinov et al., 1976) or 32 (Fang and Rim, 1975) weeks. Fetal serum PRL levels rise only after 20-24 weeks pregnancy (Clements et al., 1977; Aubert et al., 1975). Chochinov et al. (1976) found that the profile of the amniotic fluid concentrations of PRL, GH and somatomedin was similar with all three hormones showing peak values at 22-26 weeks with decreasing concentrations after this time. This pattern correlated with fetal-renal maturation as assessed by amniotic fluid creatinine estimations. If amniotic fluid PRL concentrations peak at 14-16 weeks as most reports claim (Tyson et al., 1972; Clements et al., 1977; Friesen et al., 1972; McNeilly et al., 1977) rather than 26 weeks gestation, the profile for PRL is clearly different from that of GH and soma-
4
D.L. Healy et al.
tomedin. It is difficult to explain how this difference, between hormones of similar molecular weight, could be produced by maturation of the fetal kidney. Apart from the negative correlation between amniotic fluid and fetal serum PRL concentrations (Clements et al., 1977; Josimovich et al., 1974) other evidence indicates that the fetal pituitary is not the major source of amniotic fluid PRL. Radiolabelled PRL does not reach amniotic fluid after injection into the monkey fetus (Friesen et al., 1972; Josimovich et al., 1974) and there are chromatographic differences between fetal serum and amniotic fluid PRL molecules (Fang and Kim, 1975). If the fetal pituitary is the major source of amniotic fluid PRL, fetal death should result in reduced hormone concentrations. This is not so and, on the contrary, amniotic fluid PRL values are higher in a rhesus monkey carrying a dead fetus than in mothers with living fetuses (Walsh et al., 1977).
HYPOTHESIS We suggest that the major source of amniotic fluid PRL is the decidua-chorion. Local synthesis would best serve the physiological functions of this hormone described above. The profile and magnitude of the amniotic fluid PRL concentrations, when compared with maternal or fetal blood levels, are unique amongst protein hormones. Up to 34% of radiolabelled PRL injected into the amniotic cavity of the rhesus monkey disappeared within 212 min (Josimovich et al., 1974). This implies a moderate hormone turnover. Also consistent with local PRL production is the demonstration in some monkeys of higher PRL concentrations in the uterine vein compared with the maternal peripheral vein (Walsh et al., 1977). Trophoblast produces a number of protein hormones and is an obvious tissue to examine for PRL synthesis. However, placenta does not release PRL into medium upon organ culture (Friesen et al., 1972; Riddick and Kusmik, 1977; Healy et al., submitted for publication) and chorionic villi do not stain with PRL antiserum when examined by immunofluorescence (Healy et al., 1977). Of the other tissues, decidua-chorion and amnion both bind PRL antibody (Healy et al., 1977) but only decidua-chorion appears to be the origin of amniotic fluid PRL since decidua is capable of protein synthesis (Miller, 1973) and more PRL appears in medium after organ culture of decidua-chorion than of amnion (Riddick and Kusmik, 1977; Healy et al., submitted for publication). We have recently reported direct evidence of PRL synthesis by decidua-chorion. Pieces of this tissue were incubated in organ culture without or with puromycin or cycloheximide (Healy et al., submitted for publication). PRL production was markedly decreased in the presence of these inhibitors. A recent report showed that maternal serum PRL values fell 2 h before vaginal delivery, but not caesarean section (Rigg and Yen, 1977). This result was unexpected, being in conflict with known stimuli to pituitary PRL release such as pain, stress and anaesthesia which occur in labour. The decrease was postulated to be due
Placental membranes produce prolactin
5
to rapid changes in the maternal hypothalamus during labour. If decidual-chorionic PRL can reach the maternal circulation, as is suggested by animal experiments (Walsh et al., 1977) this data can be simply explained by reduced PRL release from the decidua-chorion into the maternal circulation during uterine contractions. Synthesis of a pituitary hormone by a normal non-pituitary cell is unique. The cell responsible for PRL production in decidua-chorion is not yet identified and PRL synthesis by this tissue may involve gene modulation or derepression. Precedents exist for such changes in the genome in that ectopic PRL production has been demonstrated by human lung and renal cancers (Turkington, 1971). Although the amount of PRL secreted per unit weight of decidua-chorion may be small compared with the pituitary, its influence may be great due to the large mass of decidua-chorion in human pregnancy and from its strategic location near the amnion, myometrium and fetus. Our hypothesis can be tested by further in vitro studies of the fetal membranes and the decidua. Crucial to such studies would be to determine the optimal conditions for organ culture of decidua-chorion. Experiments investigating the effects of known modulators of pituitary PRL would further amplify the hypothesis. Factors controlling PRL synthesis and secretion by decidua-chorion are unknown at this time, but it is of interest that cortisol, which inhibits pituitary PRL secretion in vitro (Dannies and Tashjian, 1973) is first produced by chorion at 18-20 weeks gestation (Murphy, 1977) the time when peak amniotic fluid PRL values begin to fall. The possibility that cortisol may be a local inhibitor of PRL secretion by decidua-chorion requires examination.
ACKNOWLEDGEMENTS The work was supported by the National Health and Medical Research Council of Australia, with whom D.L. Healy is a Medical Postgraduate Scholar, and the Anti-Cancer Council of Victoria.
REFERENCES Aubert, M.L., Grumbach, M.M. and Kaplan, S.L. (1975) J. Clin. Invest. 56, 155. Ball, J.N. (1969) Gen. Comp. Endocrinol. 2, 10. Ben-David, M. and Chrambach, A. (1977) Endocrinology 101, 250. Bern, H.A. and Nicoll, C.S. (1968) Recent Prog. Horm. Res. 24,681. Chochinov, R.H., Ketupanya, A., Ma&, I.K., Underwood, L.E. and Daughaday, W.H. (1976) J. Clin. Endocrinol. Metab. 42, 983. Clements, J.A., Reyes, FL, Winter, J.S.D. and Faiman, C. (1977) J. Clin. Endocrinol. Metab. 44,408. Dannies, P.S. and Tashjian, A.J. (1973) J. Biol. Chem. 248,6174. Dawes, G.S. (1968) Fetal and Neonatal Physiology (Year Book Medical Publishers Inc., Chicago).
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al.
Dawood, M.Y. (1977) Am. J. Obstet. Gynecol. 128,576. Duenhoelter, J.H. and Pritchard, J.A. (1973) Obstet. Gynecol. 42, 746. Fang, VS. and Kim, M.H. (1975) J. Clin. EndocrinoL Metab. 41, 1030. Friesen, H., Hwang, P., Guyda, H., Tolis, G., Tyson, J. and Myers, R. (1972) In: Proceedings of the Fourth Tenovus Workshop. Eds.: A.R. Boyns and K. Griffiths (Alpha Omega Alpha, Cardiff) p. 64. Hamosh, M. and Hamosh, P. (1977) J. Clin. Invest. 59, 1002. Healy, D.L., Muller, H.K. and Burger, H.G. (1977) Nature (London) 265, 642. Healy, D.L., Kimpton, W.G., Muller, H.K. and Burger, H.G. Submitted for publication. Horrobin, D.F., Lipton, A., Muiruri, K.L., Manku, MS., Bramley, P.S. and Burstyn, P.G. (1973) Experlentia 29, 109. Hwang, P., Guyda, H. and Friesen, H. (1971) Proc. Natl. Acad. Sci. U.S.A. 68, 1962. Hwang, P., Murray, J.B., Jacobs, J.W., Niall, H.D. and Friesen, H. (1974) Biochemistry 13, 2354. Josimovich, J.B. (1977) In: Prolactin and Human Reproduction. Eds.: P.G. Crosignani and C. Robyn (Academic Press, New York) p. 27. Josimovich, J.B., Weiss, G. and Hutchinson, D.L. (1974) Endocrinology 94, 1364. Josimovich, J.B., Merisko, K. and Boccella, L. (1977) Endocrinology 100,564. Josimovich, J.B., Merisko, K., Bocella, L. and Tobon, H. (1977) Endocrinology 100,557. Karmali, R.A., Lauder, I. and Horrobin, D.F. (1974) Lancet 2, 106. Leontic, E.A. and Tyson, J.E. (1977) In: Prolactin and Human Reproduction. Eds.: P.G. Crosignani and C. Robyn (Academic Press, New York) p. 37. Mainoya, J.R. (1975) Endocrinology 96, 1158. Manku, M.S., Mtabaji, J.P. and Horrobin, D.F. (1975) Nature (London) 259, 78. McNeilIy, A.S., Gilmore, D., Jeffery, D., Dobbie, G. and Chard, T. (1977) In: Prolactin and Human Reproduction. Eds.: P.G. Crosignani and C. Robyn (Academic Press, New York) p. 21. Miller, B. (1973) J. Endocrinol. 59, 275. Mugambi, M., Mati, J.K.G., Muriuki, P.G. and Thairu, K. (1974) East Afr. Med. J. 5 1, 392. Murphy, B.E.P. (1977) Nature (London) 266, 179. Riddick, D.H. and Kusmik, W.F. (1977) Am. J. Obstet. Gynecol. 127,187. Rigg, L.A. and Yen, S.S.C. (1977) Am. J. Obstet. Gynecol. 128,215. Schenker, J.G., Ben-David, M. and Polishuk, W.Z. (1975) Am. J. Obstet. Gynecol. 123, 834. Turkington, R.W. (1971) N. Engl. J. Med. 285, 1455. Tyson, J.E., Hwang, P., Guyda, H. and Friesen, H.G. (1972) Am. J. Obstet. Gynecol. 113, 14. Walsh, S.W., Meyer, R.K., Wolf, R.C. and Friesen, H.G. (1977) Endocrinology 100,845. Walsh, S.W., Wolf, R.C., Meyer, R.K., Aubert, M.L. and Friesen, H.G. (1977) Endocrinology 100, 8.51. Wood, C. (1972) In: Human Reproductive Physiology. Ed.: R.P. Shearman (Blackwell, Oxford) p. 324. Yordan, E. and D’Esopo, D.A. (1955) Am. J. Obstet. Gynecol. 70, 266.
REVIEW ARTICLE
HYPOTHESIS:PLACENTALMEMBRANESPRODUCEPROLACTIN David L. HEALY r, Henry G. BURGER ’ and H.K. MULLER 2 1 Medical Research Centre, Prince Henry’s Hospital, Melbourne 3004, and 2 Department of Pathology and Immunology,
Monash University, Clayton 3168, Australia
Received 16 Febri.rary 1978
Orthodox views for the origin of the high concentration of prolactin (PRL) present in amniotic fluid suggest it is derived from maternal or fetal serum. However, the data on which these conclusions are based can also be interpreted to indicate that this hormone may be a product of placental or periplacental tissues. Trophoblast or amnion do not appear to produce PRL, while PRL synthesis by decidua-chorion is suggested from experiments in the rhesus monkey and by in vitro incubation of human tissue. Production of PRL by an extrapituitary cell is not without precedent and would be a simple explanation for high amniotic fluid PRL concentrations. Moreover, decidual-chorionic PRL would be strategically placed to mediate local functions of this hormone such as osmoregulation and myometrjal inhibition. Keywvrds:
prolactin; amniotic fluid; decidua-chorion;
amnion; placenta.
The application of the radioimmunoassay for prolactin (PRL) to a variety of physiological states has revealed high concentrations of PRL in amniotic fluid of the human and rhesus monkey (Hwang et al., 1971). The PRL concentration in human amniotic fluid exceeds the maternal or fetal serum concentration by a factor of lOO-200-fold at mid-gestation (Tyson et al., 1972; Clements et al., 1977) and has been sufficient to allow purification of milligram quantities of this protein (Hwang et al., 1974; Ben-David and Chrambach, 1977). The partitioning of PRL within the amniotic fluid, as opposed to the serum compartment, is unique amongst the protein hormones found in amniotic fluid: PRL, chorionic gonadotrophin, chorionic somatomammotrophin or placental lactogen, growth hormone (GH), somatomedin and glucagon (Tyson et al., 1972; Dawood, 1977; Chochinov et al., 1976). Where is amniotic fluid PRL produced? Most explanations have centred upon how maternal (Josimovich et al., 1974; Schenker et al., 1975) or fetal (Chochinov et al., 1976; Fang and Kim, 1975) pituitary PRL might provide the high concentrations observed in amniotic fluid. We propose that the decidua-chorion is a major source of this hormone.
1
2
D.L. Healy et
al.
LOCAL FUNCTIONS OF AMNIOTIC FLUID PROLACTIN PRL affects water and electrolyte exchange in many species of fish (Ball, 1969) and amphibians (Bern and Nicoll, 1968) where its action is considered important in maintaining sodium homeostasis. The fetal state represents the only circumstance in which the human lives in an aquatic environment. Following the demonstration of high PRL concentrations in amniotic fluid, several studies have examined the possible action of PRL on water and ion fluxes across the fetal membranes. Investigations in vitro show that PRL, at concentrations in the range found in human amniotic fluid, induces fluid to pass from the fetal to the maternal side of guinea-pig (Manku et al., 1975) and human amnion (Leontic and Tyson, 1977). In vivo studies in the rhesus monkey confirm these findings and demonstrate that PRL preserves amniotic fluid water and sodium ion content (Josimovich et al., 1977) in the face of either hyper- or hypotonicity. Clinical studies also indirectly confirm this osmoregulatory function of PRL. Amniotic fluid PRL levels are elevated in some patients with toxaemia of pregnancy or idiopathic fetal growth retardation, two conditions associated with oligohydramnios (Josimovich, 1977). Conversely, PRL values are low in 50% of women with polyhydramnios. Inhibition of uterine motility is a prerequisite to the continuation of pregnancy. The profile of active uterine pressure in human gestation is the inverse of the profile of amniotic fluid PRL concentration throughout pregnancy (Wood, 1972), suggesting that PRL may inhibit myometrial contractility. In vitro studies confirm that this hormone can inhibit uterine muscle activity in the non-pregnant rat (Horrobin et al., 1973) and human (Mugambi et al., 1974). There is also clinical data to support the proposition that PRL may inhibit myometrial action: nearly 50% of women with polyhydramnios, a condition associated with low amniotic fluid PRL values, commence labour before the 37th week of gestation (Yordan and D’Esopo, 1955). Animal studies suggest additional functions for amniotic fluid PRL. Fetal swallowing would bring this hormone into contact with small bowel mucosa where, in the rat (Mainoya, 1975) it has been shown to influence sodium absorption. PRL receptors are reported in the lung of the fetal monkey (Josimovich, 1977) and PRL induces surfactant synthesis in the fetal rabbit lung (Hamosh and Hamosh, 1977). In the human it is possible that amniotic fluid PRL does reach the alveoli of the human fetus via the trachea to aid in surfactant synthesis (Duenhoelter and Pritchard, 1973). Surfactant is first demonstrated in the human lung from about 24 weeks gestation (Dawes, 1968), a time of high amniotic fluid PRL concentrations but relatively low fetal serum values. Another possible function for amniotic fluid PRL is immunosuppression of the maternal response to the fetal allograft. PRL inhibits lymphocyte activity in vitro at concentrations found in amniotic fluid (Karmali et al., 1974). A high level of this hormone at the interface between mother and fetus might facilitate local suppression of maternal cellular immunity.
Placental membranes produce prolactin
MATERNAL PITUITARY
PROLACTIN
One source of high PRL concentrations in amniotic fluid is pituitary PRL from the maternal circulation (Josimovich et al., 1974; Schenker et al., 1975). This conclusion is based upon a correlation between maternal serum PRL values and amniotic fluid PRL concentrations in the rhesus monkey. Additional evidence is the recovery in amniotic fluid of 1% of an injected dose of [‘*‘I]PRL given to the pregnant monkey. Furthermore, the PRL molecules isolated from maternal serum and from amniotic fluid are chemically similar. However, much evidence stands against this view. No other protein hormone of molecular weight 22,000 daltons is known to cross the placental barrier and reach the amniotic fluid concentrations observed with PRL. A statistical association between maternal and amniotic fluid concentrations does not prove a common origin. There is no rise in serum PRL during pregnancy in the rhesus monkey yet the amniotic fluid concentrations are high in that species and increase as gestation proceeds (Friesen et al., 1972). If the maternal pituitary gland is the major source of amniotic fluid PRL, one would expect some decrease in amniotic fluid values after hypophysectomy. This is not the case. In the rhesus monkey the PRL concentration in amniotic fluid remains unchanged after maternal hypophysectomy (Walsh et al., 1977). Moreover, chromatography reveals size heterogeneity of PRL isolated from maternal blood and amniotic fluid (Fang and Kim, 1975), suggesting chemical differences in these molecules.
FETAL PITUITARY
PROLACTIN
A second explanation for the high concentration of amniotic fluid PRL is that the hormone comes from the fetal pituitary, passes through the immature kidney into urine and is then excreted (Chochinov et al., 1976; Fang and Kim, 1975). The profiles of PRL concentrations in fetal serum and amniotic fluid are essential to this explanation. Most reports find peak amniotic fluid PRL concentrations at 14-16 weeks gestation (Tyson et al., 1972; Clements et al., 1977; Friesen et al., 1972; McNeilly et al., 1977) with a subsequent slow fall to term, although other studies have suggested that peak values occur at 24 (Chochinov et al., 1976) or 32 (Fang and Rim, 1975) weeks. Fetal serum PRL levels rise only after 20-24 weeks pregnancy (Clements et al., 1977; Aubert et al., 1975). Chochinov et al. (1976) found that the profile of the amniotic fluid concentrations of PRL, GH and somatomedin was similar with all three hormones showing peak values at 22-26 weeks with decreasing concentrations after this time. This pattern correlated with fetal-renal maturation as assessed by amniotic fluid creatinine estimations. If amniotic fluid PRL concentrations peak at 14-16 weeks as most reports claim (Tyson et al., 1972; Clements et al., 1977; Friesen et al., 1972; McNeilly et al., 1977) rather than 26 weeks gestation, the profile for PRL is clearly different from that of GH and soma-
4
D.L. Healy et al.
tomedin. It is difficult to explain how this difference, between hormones of similar molecular weight, could be produced by maturation of the fetal kidney. Apart from the negative correlation between amniotic fluid and fetal serum PRL concentrations (Clements et al., 1977; Josimovich et al., 1974) other evidence indicates that the fetal pituitary is not the major source of amniotic fluid PRL. Radiolabelled PRL does not reach amniotic fluid after injection into the monkey fetus (Friesen et al., 1972; Josimovich et al., 1974) and there are chromatographic differences between fetal serum and amniotic fluid PRL molecules (Fang and Kim, 1975). If the fetal pituitary is the major source of amniotic fluid PRL, fetal death should result in reduced hormone concentrations. This is not so and, on the contrary, amniotic fluid PRL values are higher in a rhesus monkey carrying a dead fetus than in mothers with living fetuses (Walsh et al., 1977).
HYPOTHESIS We suggest that the major source of amniotic fluid PRL is the decidua-chorion. Local synthesis would best serve the physiological functions of this hormone described above. The profile and magnitude of the amniotic fluid PRL concentrations, when compared with maternal or fetal blood levels, are unique amongst protein hormones. Up to 34% of radiolabelled PRL injected into the amniotic cavity of the rhesus monkey disappeared within 212 min (Josimovich et al., 1974). This implies a moderate hormone turnover. Also consistent with local PRL production is the demonstration in some monkeys of higher PRL concentrations in the uterine vein compared with the maternal peripheral vein (Walsh et al., 1977). Trophoblast produces a number of protein hormones and is an obvious tissue to examine for PRL synthesis. However, placenta does not release PRL into medium upon organ culture (Friesen et al., 1972; Riddick and Kusmik, 1977; Healy et al., submitted for publication) and chorionic villi do not stain with PRL antiserum when examined by immunofluorescence (Healy et al., 1977). Of the other tissues, decidua-chorion and amnion both bind PRL antibody (Healy et al., 1977) but only decidua-chorion appears to be the origin of amniotic fluid PRL since decidua is capable of protein synthesis (Miller, 1973) and more PRL appears in medium after organ culture of decidua-chorion than of amnion (Riddick and Kusmik, 1977; Healy et al., submitted for publication). We have recently reported direct evidence of PRL synthesis by decidua-chorion. Pieces of this tissue were incubated in organ culture without or with puromycin or cycloheximide (Healy et al., submitted for publication). PRL production was markedly decreased in the presence of these inhibitors. A recent report showed that maternal serum PRL values fell 2 h before vaginal delivery, but not caesarean section (Rigg and Yen, 1977). This result was unexpected, being in conflict with known stimuli to pituitary PRL release such as pain, stress and anaesthesia which occur in labour. The decrease was postulated to be due
Placental membranes produce prolactin
5
to rapid changes in the maternal hypothalamus during labour. If decidual-chorionic PRL can reach the maternal circulation, as is suggested by animal experiments (Walsh et al., 1977) this data can be simply explained by reduced PRL release from the decidua-chorion into the maternal circulation during uterine contractions. Synthesis of a pituitary hormone by a normal non-pituitary cell is unique. The cell responsible for PRL production in decidua-chorion is not yet identified and PRL synthesis by this tissue may involve gene modulation or derepression. Precedents exist for such changes in the genome in that ectopic PRL production has been demonstrated by human lung and renal cancers (Turkington, 1971). Although the amount of PRL secreted per unit weight of decidua-chorion may be small compared with the pituitary, its influence may be great due to the large mass of decidua-chorion in human pregnancy and from its strategic location near the amnion, myometrium and fetus. Our hypothesis can be tested by further in vitro studies of the fetal membranes and the decidua. Crucial to such studies would be to determine the optimal conditions for organ culture of decidua-chorion. Experiments investigating the effects of known modulators of pituitary PRL would further amplify the hypothesis. Factors controlling PRL synthesis and secretion by decidua-chorion are unknown at this time, but it is of interest that cortisol, which inhibits pituitary PRL secretion in vitro (Dannies and Tashjian, 1973) is first produced by chorion at 18-20 weeks gestation (Murphy, 1977) the time when peak amniotic fluid PRL values begin to fall. The possibility that cortisol may be a local inhibitor of PRL secretion by decidua-chorion requires examination.
ACKNOWLEDGEMENTS The work was supported by the National Health and Medical Research Council of Australia, with whom D.L. Healy is a Medical Postgraduate Scholar, and the Anti-Cancer Council of Victoria.
REFERENCES Aubert, M.L., Grumbach, M.M. and Kaplan, S.L. (1975) J. Clin. Invest. 56, 155. Ball, J.N. (1969) Gen. Comp. Endocrinol. 2, 10. Ben-David, M. and Chrambach, A. (1977) Endocrinology 101, 250. Bern, H.A. and Nicoll, C.S. (1968) Recent Prog. Horm. Res. 24,681. Chochinov, R.H., Ketupanya, A., Ma&, I.K., Underwood, L.E. and Daughaday, W.H. (1976) J. Clin. Endocrinol. Metab. 42, 983. Clements, J.A., Reyes, FL, Winter, J.S.D. and Faiman, C. (1977) J. Clin. Endocrinol. Metab. 44,408. Dannies, P.S. and Tashjian, A.J. (1973) J. Biol. Chem. 248,6174. Dawes, G.S. (1968) Fetal and Neonatal Physiology (Year Book Medical Publishers Inc., Chicago).
6
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