Journal ArticleIn the present studies, the content and the in vitro production of prolactin by decidua as well as the concentrations of prolactin in amniotic fluid, maternal and fetal serum in normal term pregnancies, induced abortions at various gestational ages, and in pregnancies complicated by diabetes mellitus, preeclampsia, chronic hypertension, and polyhydramnios were measured. Maternal and fetal prolactin levels varied considerably throughout gestation, but at term did not differ significantly between normal and abnormal pregnancies. Prolactin levels in amniotic fluid as well as decidual prolactin content and production were significantly lower only in pregnancies complicated by either hypertension or polyhydramnios. In both normal and abnormal pregnancies, decidual prolactin production correlated strongly with amniotic fluid concentrations. The present data suggest that 1) maternal and fetal prolactin levels do not differ significantly between normal and abnormal pregnancies, 2) the decidua is the principal source of amniotic fluid prolactin, and 3) the significantly lower levels of prolactin in amniotic fluid of pregnancies complicated by hypertension or polyhydramnios are probably due to adverse effects of these conditions on the synthesis and release of prolactin by decidua

Luciano, Anthony A.

Varner, Michael W.

English

The University of Utah: J. Willard Marriott Digital Library

Decidual, Amniotic Fluid, Maternal and Fetal Prolactin in Normal and Abnormal Pregnancies ANTHONY A. LUCIANO, MD, AND MICHAEL W. VARNER, MD In the present studies, the content and the in vitro produc-tion of prolactin by decidua as well as the concentrations of prolactin in amniotic fluid, maternal and fetal serum in normal term pregnancies, induced abortions at various ges-tational ages, and in pregnancies complicated by diabetes mellitus, preeclampsia, chronic hypertension, and polyhy-dramnios were measured. Maternal and fetal prolactin lev-els varied considerably throughout gestation, but at term did not differ significantly between normal and abnormal preg-nancies. Prolactin levels in amniotic fluid as well as decidu-al prolactin content and production were significantly lower only in pregnancies complicated by either hypertension or polyhydramnios. In both normal and abnormal pregnancies, decidual prolactin production correlated strongly with am-niotic fluid concentrations. The present data suggest that 1) maternal and fetal prolactin levels do not differ significantly between normal and abnormal pregnancies, 2) the decidua is the principal source of amniotic fluid prolactin, and 3) the significantly lower levels of prolactin in amniotic fluid of pregnancies complicated by hypertension or polyhydram-nios are probably due to adverse effects of these conditions on the synthesis and release of prolactin by decidua. (Obstet Gynecol 63:384, 1984) During normal human pregnancy, the prolactin levels in amniotic fluid and maternal and fetal serum reach the highest physiologic concentrations, with amniotic fluid levels being the greatest by far. 1-3 Although the biologic significance of this is not yet known, abnormal amniotic fluid prolactin concentrations have been reported to be associated with some pathological situa-tions in which amniotic fluid volumes and fetal hydra-tion are affected. 4,5 In addition, pregnancies complicat-ed by hypertension have been reported by some authors to have abnormal maternal and fetal prolactin levels6 ,7 while others have reported similar prolactin From the Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and MaternaltFetal Medicine, The Univer-sity of Iowa, Iowa City, Iowa. Supported in part by the Biomedical Research Support Grant RR05372 from the Division of Research Facilities and Resources, National Institutes of Health, Bethesda, Maryland. 384 0029-7844/84/$3.00 levels between normal and hypertensive pregnan-cies. 8 ,9 The sources of the circulating maternal and fetal prolactin are believed to be their respective pituitary glands, whereas the major source of prolactin in amni-otic fluid is believed to be the decidua that lines the pregnant uterus. 1(}'-12 A positive correlation between decidual prolactin and the concentrations of prolactin in amniotic fluid has recently been described in normal pregnancies,12 but in abnormal pregnancies no infor-mation is available regarding decidual prolactin secre-tion and its relation to amniotic fluid prolactin levels. Because of the previously mentioned controversies and the lack of information regarding decidual prolac-tin in pathological pregnancies, the authors have mea-sured the concentration of prolactin in amniotic fluid, maternal and fetal serum, and determined the prolac-tin content and the in vitro production of prolactin by decidua in both normal pregnancies and pregnancies complicated by preeclampsia, diabetes mellitus, chron-ic hypertension, and polyhydramnios, Materials and Methods Appropriate informed consent, as approved by the Human Subject Review Committee of the University of Iowa College of Medicine, was obtained from all partic-ipants of this study, which included 20 women under-going first-trimeter suction abortion (six to 16 weeks' gestation), 30 women undergoing second-trimester sa-line abortion (17 to 21 weeks' gestation), 30 women with normal, uncomplicated pregnancies, and ten women each with preeclampsia, insulin-dependent diabetes mellitus, chronic hypertension, and polyhy-dramnios. All diabetic patients were under the care of one of the authors (MWV), who controlled blood glucose strictly with two injections of insulin per day to achieve fasting blood levels between 70 and 110 mg/lOO ml and postprandial levels between 80 and 130 mg/100 ml. All hypertensive patients had been diag-nosed and treated for essential hypertension before pregnancy. Although the majority of them had been Obstetrics & Gynecology j I I I I i I l 1 J U an-~tal ary mi-the een :tin mal for-cre-els. sies Ilac-:tea-uid, llac-:t by lcies ron-the tyof rtic-der-~eks' r sa-men ten dent yhy-re of Ilood ay to 110 1130 diag-efore been 250 200 Serum 150 Prolactin (ng/ml) 100 50 o N= 20 !:16 NP PRE OM HYP PH 30 30 10 10 10 10 17-20 >36 Weeks 01 Pregnancy Figure 1. Mean (± SEM) maternal serum prolactin concentrations during the first and second trimesters of pregnancy. and in normal and abnormal pregnancies at term. Term: NP = normal; PRE = preeclampsia; DM = diabetes mellitus; HYP = chronic hypertension; PH = polyhydramnios. on antihypertensive medication before and sometimes during pregnancy, only three of these patients were on antihypertensive medication at the time of admission into the labor and delivery unit. One patient was taking a-methyldopa, 2 g/day, and the other two patients were taking a-methyldopa, 1 g/day and hy-drochlorothiazide, 50 mg/day. The diagnosis of poly-hydramniOS, with amniotic fluid volumes estimated at greater than 2000 ml, was made clinically in all patients with excessive uterine enlargement associated with difficulty in palpating fetal parts. Seven of these pa-tients underwent ultrasonographic studies that con-firmed the clinical diagnOSis, and three patients under-went amniocentesis during the latter part of the third trimester with removal of excess amniotic fluid to relieve maternal discomfort. Four of the patients with polyhydramnios also had insulin-dependent diabetes mellitus, but they were not included in the group of patients with diabetes mellitus. No other causes for polyhydramnios were evident in the other patients. The preeclampsia was mild to severe in these pa-. tients, and all were treated with intravenous magne-sium sulfate from 12 to 36 hours before delivery. Except for abortions, only pregnancies of greater than 36 weeks' gestation with normal infants were included in the study to avoid differences that might have been attributed to fetal maturity or fetal abnormalities. Sampies of maternal peripheral blood, fetal cord blood, amniotic fluid, and decidual explants were obtained during the immediate peripartum period. The serum and amniotic fluid samples were frozen and : stored until assayed for prolactin in the same batch to avoid interassay variability. Decidual content and pro-duction of prolactin were measured before and after 24-hour incubation of 300-mg samples of freshly ob-. VOL. 63, NO.3, MARCH 1984 tained explants of decidua dissected from the maternal surface of the chorion immediately after delivery of the placenta. 13 Prolactin concentrations were measured by speCific radioimmunoassay based on the technique of Sinha et al,14 and the mean intraassay variability was 7.5%. The statistical analyses of results were per-formed by the Student t test and linear regression analyses. Results Figure 1 shows maternal serum prolactin levels throughout pregnancy and at term in normal and abnormal pregnancies. As reported, 1-3 maternal serum prolactin concentrations increase progressively throughout gestation, reaching the highest levels after the 36th week of pregnancy. At term, although mater-nal prolactin levels varied considerably from patient to patient, they did not differ significantly between nor-mal and abnormal pregnancies. Similarly, fetal prolac-tin levels from normal pregnancies did not differ from abnormal pregnancies at term. Figure 2 shows the mean prolactin concentrations in amniotic fluid throughout gestation in normal pregnancies, and after 36 weeks of abnormal pregnancies. Amniotic fluid prolactin levels were highest between 17 and 20 weeks' gestation (P < .01). After 36 weeks' gestation, they declined to levels similar to those obtained during the first trimester. At term, the amni-otic fluid prolactin levels in pregnancies complicated by chronic hypertension or polyhydramnios were sig-nificantly lower than normal pregnancies or pregnan-cies complicated by either diabetes mellitus or pre-eclampsia (P < .01). Figure 3 shows decidual prolactin content and pro-duction from normal and abnormal term pregnancies. 3500 * 3000 2500 Amniotic 2000 Fluid Prolactin 1500 (ng/ml) 1000 500 NP PRE 0 N= 10 !O16 30 30 10 17-20 >36 Weeks 01 Pregnancy Figure 2. Mean (± SEM) prolactin concentrations in amniotic fluid during the first and second trimesters of pregnancy. and in normal and abnormal pregnancies at term. 'Significantly different from normal pregnancies (p < .01 by Student t test). Abbreviations as in Figure 1. Luciano and Varner Prolactin in Human Gestation 385 ,.' \,i ii :.1· i: i 1 ,I I I As with amniotic fluid prolactin levels, decidual pro-lactin content and production in pregnancies compli-cated by either chronic hypertension or polyhydram-nios were significantly lower than normal pregnancies and pregnancies complicated by diabetes mellitus or preeclampsia (P <:: .01). Because the initial content of prolactin in decidua seemed to parallel the amount of prolactin produced after 24 hours' incubation, correlation analyses were carried out between initial prolactin content and pro-duction after 24-hour incubation. Significant correla-tions were found between the initial tissue content of prolactin and its production in both normal (r = .559, P < .001) and abnormal pregnancies (r = .499, P = .00104). This suggests that the capacity of the decidua to produce prolactin in vitro can be predicted from its initial content. To further test the hypothesis that the decidua is a major source of amniotic fluid prolactin, regression analyses were carried out between the amount of prolactin produced by the decidua after 24-hour incu-bation in vitro and prolactin concentrations in the amniotic fluid of normal and abnormal pregnancies. These correlations were highly significant, as shown in Figures 4 and 5, further supporting the hypothesis that the decidua is the major source of prolactin in amniotic fluid. Discussion Besides preparing the breast for lactation, the biologic roles of the high levels of prolactin in human pregnan-cy remain speculative. Because prolactin has been reported to antagonize the pressor effects of angioten-sin and norepinephrine in laboratory animals,15.16 it 600 500 400 * Prolaclin Levels 300 ng/O.lgm Tissue 200 100 N= • 10 • 10 0 NP PRE OM HYP PH Status 01 Pregnancy Figure 3. Mean (= SEM) prolactin content (black columns) and production (white columns) by decidua in normal and abnormal pregnancies at term. 'Significantly different from normal pregnancies (P < .01 by Student t test). Abbreviations as in Figure 1. 386 Luciano and Varner Prolactin in Human Gestation 3500 3000 2500 AF PRL 2000 (ng/ml) 1500 10oo? ' 00 500L---~L---~----~----~----~---200 300 400 500 600 OP PRL (ng/O.lmg) 700 Figure 4. Correlation of decidual production of prolactin (DP PRL) in vitro and amniotic fluid prolactin (AF PRL) concentrations in normal pregnancies. r = .711; P < .001. has been postulated that the high levels of prolactin during pregnancy may be protective against the devel-opment of hypertension, and that gestational hyper-tension may develop in patients with decreased prolac-tin levels. 17 Although Yuen et al6 reported decreased maternal plasma prolactin levels in pregnant women with either preeclampsia or chronic hypertension, no difference in maternal prolactin levels between normal and hypertensive pregnant women or pregnancies complicated by diabetes mellitus or polyhydramnios have been found in this and other studies.8,9 There-fore it seems that maternal prolactin levels in preg-nancy are not helpful in the evaluation of pathological pregnancies. Fetal prolactin may be important in fetal lung matu-ration during the latter part of pregnancy.7-18 In the present study, cord prolactin levels did not differ between normal and abnormal pregnancies. Grosso et 3000 2500 2000 AF PRL 1500 (ng/ml) 1000 500 o· O~--~----~----~----~--~---200 300 400 500 600 700 OP PRL (ng/O.lmg) Figure 5. Correlation of decidual production of prolactin (DP pr,L) in vitro and amniotic fluid prolactin (AF PRL) concentrations in abnormal pregnancies. r = .480; P = .002. Obstetrics & Gynecology 'RL) s in ctin vel-per-,lac-Ised nen , nQ 'mal lcies nios lere-'reg-gical latu-l the liffer so et .. o P PRL) ions in ecology ae reported that cord prolactin levels in infants of preeclamptic and hypertensive women were higher than in infants of normotensive women delivered between 30 and 39 weeks of gestation, but the differ-ences were insignificant at later gestational ages. The failure to find any differences in cord prolactin levels between normal and abnormal pregnancies after 36 weeks' gestation may be due to the relatively small number of patients in each of the abnormal groups or to the fact that the present study included only full-term pregnancies with completely normal infants, thus avoiding differences that might be attributed to prema-turity and/or fetal anomalies. In agreement with previous reports,I-3 the amniotic fluid prolactin levels in these studies were several times higher than either maternal or fetal levels, with the highest concentrations occurring at midgestation. Although amniotic fluid prolactin levels from patients with diabetes mellitus or preeclampsia did not differ from those in patients with normal pregnancies at term, patients with chronic hypertension or polyhy-dramnios had amniotic fluid prolactin concentrations significantly lower than normal. Similar findings have been reported by Freisen et a14 and Josimovich5 in small numbers of patients with polyhydramnios, and by Yuen et a16 in patients with chronic hypertension. The decreased amniotic fluid prolactin levels in pa-tients with polyhydramnios could be attributed to either a dilutional effect or to a decreased transfer of prolactin from either maternal or fetal serum. But the present findings that decidual prolactin content and production are similarly reduced in pregnancies com-plicated by either chronic hypertension or polyhy-dramnios suggest that the underlying dysfunction lies with the decidua. The report by Rosenberg et al l2 of a high correlation between decidua prolactin content and production with amniotic fluid prolactin concen-trations observed in the present studies in both normal and abnormal pregnancies strongly support the con-clusion that the decidua is the most important source of prolactin in amniotic fluid. Therefore, the decreased prolactin production by decidua is most likely respon-sible for the decreased levels of amniotic fluid prolactin observed in pregnancies complicated by polyhydram-nios or chronic hypertension. What causes the decidua from these pregnancies to produce less prolactin is not known. It is possible that in chronic hypertension the vascular supply to the endometrium may be dimin-ished, causing the decidua to be less productive. The reaSOn similar changes were not observed in pre-eclamptic women may be related to the duration of the vascular compromise, which is much longer in chronic hypertension than in preeclamptic patients. Prolactin VOL. 63, NO.3, MARCH 1984 production by decidua of pregnancies complicated by polyhydramnios may be adversely affected by either the increased intrauterine pressure or the excessive stretching of the decidua by the greatly enlarged uterus. However, these are merely speculations and need to be further evaluated. In conclusion, the authors' findings revealed that: 1) maternal and fetal prolactin levels, although varying considerably throughout gestation, do not differ signif-icantly between normal and abnormal pregnancies; 2) amniotic fluid prolactin levels correlate with decidua prolactin content and secretion in both normal and abnormal pregnancies, and differ from normal only in those pregnancies complicated by chronic hyperten-sion and polyhydramnios; and 3) the strong correla-tions of decidua prolactin production with amniotic fluid prolactin concentrations in both normal and ab-normal pregnancies further support the concept that the decidua is the principal source of amniotic fluid prolactin. References 1. Jaffe RB, Yen BH, Kaye WR, et al: Physiological pathologic profiles of circulatory human prolactin. Am J Obstet Gynecol 111:157, 1973 2. Tyson JE, Hwang P, Guyda H, et al: Studies of prolactin secretion in human pregnancy. Am J Obstet Gynecol 113:14, 1972 3. Fang YS, Kim MH: Study of maternal, fetal and amniotic human prolactin at term. J Clin Endocrinol Metab 41:1030, 1975 4. Friesen H, Hwang P, Guyda H, et al: Prolactin and Carcinogene-sis. Edited by AR Boynes, K Griffiths. Cardiff, Wales, Alpha Omega Publishing, 1972, pp 64-80 5. Josimovich JB: The role of pituitary prolactin in fetal and amniotic fluid water and salt balance. Prolactin and Human Reproduction. Edited by PG Crosignani, C Robyn. London, Academic, 1977, pp 27-36 6. Yuen BH, Cannon W, Woolley S, et al: Maternal plasma and amniotic fluid prolactin levels in normal and hypertensive preg-nancy. Br J Obstet Gynaecol 85:293, 1978 7. Grosso DS, MacDonald CP, Thomasson JE, et al: Relationship of newborn serum prolactin levels to the respiratory disease syn-drome and maternal hypertension. Am J Obstet Gynecol137:569, 1980 8. Ranta T, Stenman UH, Unnerus HA, et al: Maternal plasma prolactin levels in pre-~c1ampsia. Obstet Gynecol 55:428, 1980 9. Sadovsky E, Weinstein D, Menashe BD, et al: Serum prolactin in normal and pathologic pregnancy. Obstet GynecoI50:559, 1977 10. Riddick DH, Luciano AA, Kusmik WF, et al: De novo synthesis of prolactin by human decidua. Life Sci 23:1913, 1978 11. Golander A, Hurleg T, Barrett J, et al: Prolactin synthesis by human chorion-decidu'al tissue: A possible source of prolactin in the amniotic fluid. Science 202:311, 1978 12. Rosenberg SM, Maslar lA, Riddick DH: Decidual production of prolactin in late gestation: Further evidence for a decidual source of amniotic fluid prolactin. Am J Obstet Gynecol 138:681, 1980 13. Luciano AA, Maslar lA, Kusmik WF, et al: Stimulatory activity of Luciano and Varner Prolactin in Human Gestation 387 III"I":'-r:"'===--------I , I I~ ~ +~ "il! ',~ ,'~ '/ 1 'I 1~ a~ 1 .w ~.; .? '~: serum on prolactin production by human decidua. Am J Obstet Gynecol 138:665, 1980 14. Sinha YN, Selby FW, Lewis UJ, et al: A homologous radio-immunoassay for human prolactin. J Clin Endocrinol Metab 36:509, 1973 15. Bryant EE, Douglas BH, Ashburn AD: Circulatory changes fol-lowing prolactin administration. Am J Obstet Gynecol 115:53, 1973 16. Mati JKG, Mugambi M, Odipo WS, et al: Prolactin and hyperten-sion. Am J Obstet Gynecol 127:616, 1977 17. Horrobin DF: Prolactin. Annual Research Reviews, Boston, Eden Press, 1976 18. Hauth Jc, Parker RC, MacDonald pc, et al: A role of fetal prolactin in lung maturation. Am J Obstet Gynecol 51:81, 1978 388 Luciano and Varner Prolactin in Human Gestation Address reprint requests to: Anthony A Luciano, MD Division of Reproductive Endocrinology Department of Obstetrics and Gynecology Tufts-New England Medical Center 171 Harrison Avenue Boston, MA 02111 Submitted for publication January 4, 1983. Revised July 11, 1983. Accepted for publication July 15, 1983. Copyright © 1984 by The American College of Obstetricians and Gynecologists. Obstetrics & Gynecology 

Decidual, amniotic fluid, maternal and fetal prolactin in normal and abnormal pregnancies.

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Decidual, amniotic fluid, maternal and fetal prolactin in normal and abnormal pregnancies.

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