003 1 -399X/93/3405-0h42$03.00/0 PEDIATRIC RESEARCH Copyright fc) 1993 International Pediatric Research Foundation. Inc.

Dopamine Inhibits Growth Hormone and Secretion in the Human Newborn

FRANCIS I>I; ZEGHER. GREET VAN IIEN BERGIIE, HUGO DEVLIEGER. EPIIREhl EGGERMONT. AND JOHANNES D. VELDFIUIS

ABSTRACT. is frequently used in neonatal Circulating levels of GH and prolactin PRL have long been intensive care for its vasopressor, renal vasodilating, and known to be strikingly elevated in the newborn (1-3). Recently, cardiac inotropic properties. The effect of i.v. dopaminc deconvolution analysis of GH and PRL profiles revealed that infusion on nconatal pituitary hormone sccrction is cur- the nconatal hypersomatotropism is characterized by high-am- rently unknown. \Ve observed strikingly low serum conccn- plitudc and high-frequency pulsatile secretion of GH without a [rations of growth hormone (GII) and prolactin (PRI,) prolonged GH half-life. whereas hyperprolactincmia appears to during a therapeutic, standardized, isovolumctric, partial be due to GH-independent, continuous PRL release (4). exchange transfusion (blood sampling every 20 min for 6 Here, we provide evidence suggcstingthat dopaminc is a potent h) in two polycythemic neonates rcquiring intensive thcr- inhibitor of neonatal GH and PRL hypersecretion. apy, including continuous dopamine infusion. In addition, the secretion of GEI and PRL was studied in three nconatcs SUBJECTS AND METIIODS with symptomatic polycythemia (gestational age 34-38 ~vk; birth weight 21 10-2530 g; postnatal age 10-30 h) during This report consists of two parts. one with GH and PRL a partial exchange transfusion, including an intervening profiles obtained in polycythemic newborns and one with paired dopamine infusion (8 pg/kg/min i.v. for 2 h). The GI1 and GH and PRL evaluations in nonpolycythemic neonates. The PRL profiles were evaluated by deconvolution analysis. serum GH and PRL profiles were obtained in a total of seven Initially, the three newborns exhibited high-amplitude, newborns. Thcse infants were admitted because of premature pulsatile GI1 secretion and continuously elevated PRI. birth. low birth weight, suboptimal cardiovascular condition. release. During the dopamine infusion, GI1 secretion was and/or respiratory distress. All infants were polycythemic, the virtually abolished and I'RL release was reduced by at median venous hematocrit being 0.7 (range 0.65-0.73). The least 50%. Dopaminc withdrawal was associated with a decision to perform a therapeutic partial exchange transfusion rebound release of GI1 and PRL. Finally, scrum GI1 and was made in each case by the attending neonatologist. Arterial PRL concentrations were studied in nine nonpolgcgthcmic blood samples were obtained every 20 min for 6 h during a newborns (gestational age 31-40 wk; birth weight 1680- standardized, isovolumctric, partial exchange transfusion. as prc- 4000 g; postnatal age 2-28 d) at the end of a prolonged viously described (5). dopamine infusion (3-5 pg/kg/min i.v. for 2-27 d). Within The serum concentrations of GH were measured by RIA. 2 h after dopamine withdrawal. GI1 and I'RI, levels in- using a polyclonal antibody (6): the intraassay coefficient of creased a median 3-fold and 10-fold respectively. Thcse variation was 5.89'0 at 35 pg/L. The serum concentrations of data concord to indicate that dopamine is a potent inhibitor PRL were measured by immunoradiomctric assay using the of GI1 and PRI. secretion in the human newborn. (Pediatr PRL-IRMA kit (Medgcnix. Flcurus, Belgium). having an intraas- Res 34: 642-645, 1993) say coefficient of variation of 6.4% at 27 pg/L. All samples of each infant were assessed in the same assay run. Abbreviations The sequential GH and PRL concentrations of each infant were evaluated by multiple-parameter deconvolution analysis, a GI I, growth hormone technique examining the possibility of pulsatile hornione secre- PRL, prolactin tion, taking into account both the secretory episodes and the metabolic clearance of the investigated hormone (7). The profile part of this report consists of two sets of studies. First. the GH and PRL profiles from two newborns receiving Intravenous infusion of the catecholamine dopamine is rec- intensive care including positive pressure ventilation and dopa- ommendcd as the treatment of choice for cardiovascular support mine infusion (8 ~g/kg/min)were analyzed in comparison with of the newborn. As a result, dopamine administration has be- the profiles of two newborns not requiring intensive care. The come common practice in neonatal intensive care. However, latter infants were matched for gestational age. birth bvcight. dopamine is also a widely distributed neurotransmitter and, in postnatal age, hematocrit (~37;difference). and gender (male). addition, may act as a hormone on the hypothalamic-pituitary In second set of studies, GH and PRL profiles axis. ~t present, the effect of exogenous dopamine on the secre- obtained during a therapeutic partial exchange transfusion in tory dynamics of the neonatal gland have not three newborns with symptomatic polycythcmia (gestational age been evaluated. 34-38 wk: birth weight 21 10-2530 g: postnatal age 10-30 h: hcmatocrit 0.67-0.73). These infants received additional dopa- Received Fehruary 1. 1993: accepted hlay 28. 1993. Correspondence and reprint requests: Francis de Zeghcr, h1.D.. 1'h.D.. Depart- mine support (8 pg/kg/min for 2 h, dissolved in I mL of isotonic ment of Pediatrics, University Hospital Gasthuisberg. 3000 Leuven. Rclgium. saline) halfway through the partial exchange transfusion. in Supported by a research grant from Kahi Pharmacia, Stockholm. Sweden. accord with the clinical protocol that was used in our neonatal 642 DOPAMINE EFFECT ON rUEONATAL Gf-I AND I'RL 643 intensive care unit at the time of these studies. During the piirtial 0 36 reeks exchange transfusion, all infants remained euglyccmic and had '"1 253Ogrnm21 .l7 houn DOPAMINE a normal percutaneous oxygen saturation. During the interven- ing dopamine infusion, the heart ratc was increased maximally by 20% compared with the heart ratc beforc and aftcr dopaminc administration. The second part of this report concerns nine nonpolycythemic PRL newborns (gestational age 3 1-40 wk: birth weight 1680-4000 g: postnatal age 2-28 d) who had bccn admitted either for intensive care after cardiovascular surgery (t1= 5) or because of respiratory distress related to prematurity (tl = 4). These infants had bccn receiving a prolonged dopamine infusion (median duration 3 d, range 2-27 d; dose 3-5 pglkglmin at least for 24 h beforc withdrawal). GH and PRL concentrations were measured in serum obtained through an arterial catheter immediately beforc and 100-120 min after dopamine withdrawal. Statistical comparisons were made by Mann-Whitney U test. Approval for these studies and for the use of blood that would otherwise have bcen discarded was granted by the Ethical Com- Fig. 2. Serum GH and PRL concentration profiles from t\vo new- mittee of the Medical School, University of Leuven. borns with polycythcmia during an isovolumetric partial eschange trans- fusion and an intermittent dopamine infusion (.sl~~itk~pclcirc,m). The gesta- tional age (wk). birth weight (g). and postnatal age (h) are indicated. SI RESULTS conversion: ng/niL = pg/L. The two examined newborns receiving intensivc care. includ- ing continuous dopamine infusion, were found to have dramat- 3). The secrction of PRL was calculated to be decreased by 50% ically decreased levels of GH and PRL compared with their or more during the dopamine infusion and to be reinstated soon matched controls (Fig. I). Deconvolution analysis of these pro- thereafter. files indicated that the pulsatile sccretion of GH in the intensivc In the nine newborns studied at the end of a prolonged care patients was decreased in burst amplitude but not in burst dopaminc infusion, serum GH concentrations rose (p= 0.02) frequency or burst duration (4). The PRL secrction rates in the from a median 6 pg/L (range 5- 19 pg/L) to 17 pg/L (range 9- preterm and term infant receiving intensive care were calculated 53 pg/L) within 2 h after dopamine withdrawal, whereas PRL to be respectively one third and one tenth that in the controls. levels increased (p = 0.002) from a median 5 pg/L (range <3- In the three newborns receiving an intervening dopamine 39 pg/L) to 54 pg/L (range 12- 134 pg/L). infusion, the latter was accompanied by a striking decrease in the serum concentrations of GH and PRL, whereas dopamine DISCUSSION withdrawal was associated with a rapid normalization or tran- Strikingly low serum concentrations of GH and PRL were sient overshoot of GH and PRL levels (Fig. 2). Dcconvolution found in newborns receiving intensive care, including continuous analysis of these three GH and PRL profiles revealed that the dopamine infusion. Perinatal stress conditions are usually asso- secretion of GH was virtually abolished during the dopamine ciated with excessively elevated GH and PRL levels (8, 9). infusion and was rcestablishcd after dopaminc withdrawal (Fig. Thcreforc, the intensive treatment rather than the clinical con- dition itself was thought to induce the low GH and PRL lcvels 11H1- 40 WCCL< found in thcse infants. The GH and PRL results from the three 3250 crams 61 .67 houn infants rcceiving an intervening dopamine infusion and from the 1511- nine infants at withdrawal of prolonged dopamine administra- tion uniformly point toward dopamine as one of the causative factors within the intensive care setting. Together, thcse obscr- vations provide direct and consistent evidence suggesting that dopaminc is a potent inhibitor of neonatal GH and PRL hypcrsc- cretion. Our results support the concept that functional dopaminc receptors are present in the hypothalamo-pituitary axes govern- ing GH and PRL sccretion in the human newborn. Although 34 UCCLI 31 uech? 1600 grim$ I7lOgrams the concentration of dopamine in the human fetal hypothalamus 6 - I2 houn 8 - I4 houn exceeds that in the adult (lo), our data suggest that the dopamine receptors linked to the somatotropic or lactotropic axis are not maximally activated by endogenous dopamine secrction. It is plausible that the infused dopamine exerts its principal action on GH and PRL release directly at the pituitary level. Dopamine has bccn demonstrated to inhibit pituitary GH and PRL release in virro, through specific membrane-bound dopaminc receptors of the D2 subtype (I I). Moreover, human newborns receiving dopamine exhibit a blunted PRL response to exogenous thyro- tropin releasing hormone (C. Vanhole, F. dc Zegher, H. Devlie- Fig. 1. Serum GII and PRL concentration profiles from two term ger, ct (I/., unpublished observations). (lop ppc1tlc~1.s)and two pretcrm (1o~c.c.rpcltli~k) male newborns with poly- It is noteworthy that the inhibitory responses of the newborn cythemia during an isovolumctric partial exchange transfusion. The low presenting with physiologic hypcrsecretion of GH and PRL and flattened profiles (ri,ylrr I)NII(,/.S)arc from infants receiving intensive parallel the inhibitory responses ofGH and PRL to dopaminergic care including dopamine infusion: thc profiles in the /c:/i I)NII~,/.Yare from agents in acromegalic adults with pathologic hypersonlatotrop- control infants. matched for gestational age (wk). birth weight (g), and ism and hyperprolactinemin (12). Howcvcr, our findings rcgard- postnatal age (h). SI conversion: ng/mL = fig/L. ing suppression of neonatal GH secrction by dopaminc contrast 111: ZEGHER /:'T :1L

400- mass12 h Growth Hormone Prolactin (ngfml) / 300-

DOPAMINE DOPAMINE

Fig. 3. Results of dcconvolution analysis of GF1 and PRL secretion by three newborns with polycythemia during a 6-h isovolumctric partial exchange transfusion and an intermittent dopamine infusion of 2 h. The amount of pulsatile GH secretion (ldi pctticl) and the secretory rate of I'RL (ri,qlli prrtlc'l) before, during. and after the dopamine infusion are indicated. The results of each infant arc interconnected. SI conversion: ng/mL = MIL. sharply with the stimulatory GH response to levodopa and/or REFERENCES dopamine in healthy children and adults (13, 14). These discrep- I. Cornblath M. Porker ML. Rcisncr SI1. Forbes AE. Daughaday Wl1 1965 ancies in neuroregulation may be related to multiple factors. Secretion and metabolism of growth hormone in premature and full tern1 including age-dependent differences in the number and efficacy infants. J Clin Endocrinol Metab 25:209-2 18 of pituitary dopamine receptors and in the regulation of hy- 2. Guydn l1J. 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Announcement 12th International Convocation on Immunology The 12th International Convocation on Immunology, "Transfusion Immunology in Medicine," will be presented by the Ernest Witebsky Center for Immunology from May 14-18, 1994, in Buffalo, NY. Topics will include removal of infectious agents, testing for infectious agents, allotypes, immunological effects on blood transfusion, components and alternatives, and transfusion strategies. Open poster sessions will be offered. CME credit available. For Jirrtllcr it~/i)rrl~cition,contract Dr. R. K. Cunningham, Director, 269 Sherman Hall. SUNY at Buffalo, 3435 Main St., Buffalo, NY 14214-3078, (7 16) 829-2848, Fax (7 16) 829-2158.