European Journal of Obstetrics & Gynecology and Reproductive
Biology, 38 (1990) 145-150
145
Elsevier EUROBS 01046
The effect of chronic oral methadone treatment on monkey chorionic gonadotropin, estradiol, dehydroepiandrosterone sulfate, progesterone, prolactin and cortisol levels during pregnancy in the cynomoigus monkey ( Macaca fascicularis) P.R. Hein, J.S.J.O. SchatorjC, H.J.A.A.M. Frencken, M.F.G. Segers and C.M.G. Thomas Department
of Obstetrics and Gynecology, University Hospital Nijmegen, Nijmegen,
The Netherlands
Accepted for publication 13 March 1990
The effect of chronic methadone treatment upon the serum levels of Estradiol (E,), Progesterone (P), Prolactin (Prl), monkey chorionic gonadotropin (mCG), dehydroepiandrosterone sulfate (DHEAS) and Cortisol (C) in pregnant Cynomolgus monkeys (Macuca fuscicularis) is described in comparison with the hormone levels in a control group. Only DHEAS was significantly decreased in late pregnancy in the methadone group. From these data it can not be concluded that methadone treatment compromises (feto)placental function. The observed intra-uterine growth retardation in the methadone treated group might be a result of a direct influence of methadone upon growth. Serum level; Methadone; Estradiol; Dehydroepiandrosterone dotropin; Pregnancy; Cynomolgus monkey
A generally accepted way to manage drug addiction during pregnancy in the human is the methadone maintenance treatment program. The opinion of several investigators is that there are no more complications of pregnancy than in an average obstetric population [l]. This agree-
Correspondence: P.R. Hein, M.D., Ph.D., Department of Obstetrics and Gynecology, St. Radboud Hospital, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
0028-2243/90/$03.50
sulfate; Progesterone:
Prolactin; Cortisol; Monkey chorionic gona-
ment, however, does not exist for the incidence of low birthweight babies in methadone users. Some investigators report normal birthweight [2,3] whereas others report an impaired growth [1,4-121. An explanation for these different data could be that in drug addicts other factors than methadone alone may be responsible, such as, for example, inadequate prenatal care, smoking, malnutrition, vitamin deficiency or the use of other drugs. In order to exclude these possibilities we decided to investigate the influence of methadone treatment under standardized conditions upon
0 1990 Elsevier Science Publishers B.V. (Biomedical Division)
146
several aspects of pregnancy. This was done in a prospective study, supported by the Dutch ‘Praeventiefonds’ in Cynomolgus monkeys (Macucu fusciculuris), nonhuman primates with reproductive characteristics which are similar to those of the human [13-151. In a previous article we described the influence of methadone upon the birthweight in the Cynomolgus monkey (Mucucu fmciculuris) [16]. Although the duration of pregnancy did not differ between a control- and a methadone-treatment group, the birthweight was significantly lower in methadone-treated monkeys.. To investigate whether this was a result of impaired placental- or fetoplacental function, we compared in the present study the monkey chorionic gonadotropin (mCG), Estradiol (E2), and Progesterone (P) levels in peripheral serum throughout pregnancy in methadone-treated monkeys and in a control group. Since estrogen precursors originate from both fetal and maternal adrenals, we also measured serum levels of dehydroepiandrosterone sulfate (DHEAS) and Cortisol (C). Moreover, the serum levels of prolactin (Prl) were determined. Materials and Methods The study was conducted in 16 pregnancies in 6 Cynomolgus monkeys ( Mucucu fusciculuris ) : 3 monkeys (10 pregnancies) were on methadone medication (40 mg/day) and 3 monkeys (6 pregnancies) served as controls. Methadone treatment, housing, feeding, breeding and diagnosing of pregnancy have been described previously [16]. Blood samples (3-4 ml) were drawn twice a week between 8 and 10 a.m. from the bra&al or cubital vein without anaesthesia, since our monkeys are trained to present their arms through the bars of the cage to the technician who then draws blood from a vein without difficulty. Blood sampling was initiated prior to conception. Per pregnancy we obtained 48 samples. The blood samples were left to clot overnight at 4’C. Then they were centrifuged at 1200 X g for 20 min. The serum was separated and stored at -20°C until mCG, E,, DHEAS, P, Prl and C concentrations
were measured in all samples by radioimmunoassay (RIA). The RIA systems used for the determination of E, and P and for DHEAS and C have been published previously [17,18] as well as those for Prl and mCG [19]. Statistical methods used for comparison of control and methadone pregnancies were the nonparametric Mann-Whitney U test. Per monkey we calculated per hormone the mean values in three periods: Period I: blood samples 1-16. Period II: blood samples 17-32. Period III: blood samples 33-48. This was done for E,, DHEAS, P, Prl, C. For mCG we only investigated whether during the mCG peak there was a significant difference between the control and methadone value of samples 5, 6 and 7. Results Figs. 1, 2, 3 and 4 illustrate the mean serum levels (f SEM) of circulating mCG, estradiol, DHEAS and progesterone, respectively, from the beginning of pregnancy until delivery in 6 control pregnancies and 10 methadone pregnancies. Patems of serum mCG, E,, DHEAS, P, Prl and C in normal pregnancy have been described before
1191.
Fig. 1. Concentrations of mCG (mean* SE) in peripheral serum of 10 pregnant Cynomolgus monkeys on methadone medication (40 mg/day) from beginning of pregnancy until parturition. The shaded area and the dotted line represent the meanf SE in 6 pregnant control monkeys (blood sampling twice a week).
147
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Fig. 2. Concentrations of estradiol (mean f SE) in peripheral serum of 10 pregnant Cynomolgus monkeys on methadone medication (40 mg/day) from beginning of pregnancy until parturition. The shaded area and the dotted line represent the mean+ SE in 6 pregnant control monkeys (blood sampling twice a week).
twice a week).
In both groups serum mCG levels followed the same patem (Fig. 1). The mCG peak in the methadone group was higher than in the control group, although not significantly. Serum estradiol levels. In both groups the serum estradiol followed the same patem (Fig. 2). Except in the beginning of pregnancy, the levels in the methadone group were lower than in the control group, although not significantly so. Serum DHEAS levels. Serum DHEAS levels in the control group and in the methadone group showed the same pattern (Fig. 3). Serum
mCG
Fig. 4. Concentrations of progesterone (mean f SE) in peripheral serum of 10 pregnant Cynomolgus monkeys on methadone medication (40 mg/day) from beginning of pregnancy until parturition. The shaded area and the dotted line represent the mean+ SE in 6 pregnant control monkeys (blood sampling
levels.
In early and midpregnancy the differences between the control group and methadone group were not statistically significant. In late pregnancy, however, there was a statistically significant difference. (P = 0.02). Serum progesterone levels. Fig. 4 illustrates the progesterone levels in early, mid and late gestation. Serum progesterone levels followed the same pattern for both groups. In the methadone group the progesterone levels were higher than in the control group. However, the values in the control group and in the methadone group were not statistically significantly different.
L
20
55
90
125
160
Fig. 3. Concentrations of DHEAS (mean f SE) in peripheral serum of 10 pregnant Cynomolgus monkeys on methadone medication (40 mg/day) from beginning of pregnancy until parturition. The shaded area and the dotted line represent the mean+ SE in 6 pregnant control monkeys (blood sampling twice a week).
Fig. 5. Concentrations of cortisol (mean+SE) in peripheral serum of 10 pregnant Cynomolgus monkeys on methadone medication (40 mg/day) from beginning of pregnancy until parturition. The shaded area and the dotted line represent the meanf SE in 6 pregnant control monkeys (blood sampling twice a week).
148
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‘,_
;it,
Fig. 6. Concentrations of prolactin (mean* SE) in peripheral serum of 10 pregnant Cynomolgus monkeys on methadone medication (40 mg/day) from beginning of pregnancy until parturition. The shaded area and the dotted line represent the meanf SE in 6 pregnant control monkeys (blood sampling twice a week).
Serum cortisol levels. The patem and levels of serum cortisol were not different in both groups (Fig. 5). Serum prolactin levels. In early and midpregnancy prolactin was higher in the methadone group than in the control group, although not significantly, whereas in late pregnancy prolactin was higher in the control group, although not significantly so (Fig. 6).
Discussion In a previous article [16] we described decreased birthweights in methadone-treated monkeys. If the intrauterine growth retardation (IUGR) of the monkeys on methadone maintenance was only a result of impaired placental function, one might perhaps expect the mCG, E, and P levels to be decreased as compared to those of the control group. However, this was not the case. Of course one could wonder whether the here described hormones reflect placental or fetoplacental function. In humans (without methadone use) test properties of urinary estriol and total estrogen measurements for prediction of low birthweight are as follows: sensitivity varies between 14 and 868, specificity ranges from 63 to 94%. The test properties of the plasma and serum assays are comparable to those of urinary assays [20]. For
~
Cynomolgus monkeys these data are not available. For human chorionic gonadotrophin, DHEAS, progesterone and cortisol to our knowledge no 2 x 2 tables are available with regard to their clinical value as predictor of intrauterine growth retardation and again to our knowledge these data are not available for Cynomolgus monkeys either. Considering DHEAS and C levels, we found (exactly as Facchinetti et al. [21] did in pregnant women) a discrepancy between the levels of both adrenal hormones: cortisol did not change whereas DHEAS significantly decreased under methadone treatment. We have no explanation for this discrepancy. We do not agree with the conclusion of Facchinetti et al. that this points to an isolated effect of methadone upon the fetal adrenal (and not the maternal adrenal), since DHEAS in the maternal circulation originates almost entirely from the maternal adrenal, whereas only negligible amounts of DHEAS can be transferred from the fetal to the maternal circulation [22]. From our data it can not be concluded that the fetal adrenal is influenced in a negative way. This is also unlikely since the E, levels are not decreased in the methadone treated group. Steroids of fetal adrenal origin (mainly DHEAS), are considered to provide approx. 50% of the precursors for E, production, whereas approx. 40% is provided by maternal DHEAS [22]. Since maternal DHEAS is significantly decreased, whereas E, is not decreased, it is probable that the fetal adrenal functions very well, so that it may even compensate for the decreased supply of maternal DHEAS, so that E, levels do not fall. With regard to prolactin, the following can be said: prolactin is considered by some as a stress hormone [23]. In our study there was no difference in prolactin levels between the two groups of monkeys. From our data one could conclude that the lower birthweights in the methadone group [16] can not be attributed to impaired placental function and/or maternal stress. Since there were no differences in food or vitamin intake between the two groups nor differences in other variables, the explanation for the IUGR in the methadone group might perhaps be that methadone itself has a direct influence upon
149
birthweight, as has been suggested for small laboratory animals such as rats [24,25]. How this influence is exerted is a matter of speculation. As we have described in a previous article [16], methadone 40 mg/day is a very high dose, corresponding with lo-13 mg/kg per day, leading to plasma levels exceeding those attained in patients in human maintenance programs. To our knowledge no evaluations have been made to determine the direct effects of methadone levels of this magnitude on fetal growth using in vitro systems or during the early postnatal interval. Anyway, intra-uterine growth retqrdation is not a result of a negative influence upon release of growth hormone, since morphinomimetics increase this release in mammalian species [26]. Acknowledgements
The expert technical assistance and animal care by Diane Haverkate, Rob van den Berg and Albert Peters are gratefully acknowledged. This work was supported by the Dutch ‘Praeventiefonds’, grant No. 28-723. References 1 Blinick G, Wallach RC, Jerez E et al. Drug addiction in pregnancy and the neonate. Am J Obstet Gynecol 1976;125:135-142. 2 Rementeria JL, Lotongkum L. The fetus of the drug-addicted woman: conception, fetal wastage and complications. In: Rementeria JL, ed. Drug abuse in pregnancy and neonatal effects. Saint Louis: The CV Mosby Company, 1977;3-18. 3 Strauss ME, Andresko M, Stryker JC et al. Methadone maintenance during pregnancy: pregnancy, birth and neonate characteristics. Am J Obstet Gynecol 1974:120: 895-900. 4 Chasnoff IJ, Hatcher R, Bums WJ. Polydrug- and methadone-addicted newborns: a continuum of impairment? Pediatrics 1982;70:210-213. 5 Connaughton JF, Reeser D, Schut J et al. Perinatal addiction:outcome and management, Am J Obstet Gynecol 1977;129:679-686. 6 Dinges DF, Davis MM, Glass P. Fetal exposure to narcotics: neonatal sleep as a measure of nervous system disturbance. Science 1980;209:619-621. 7 Lifschitz MH, Wilson GS, O’Brian Smith E et al. Fetal and post-natal growth of children born to narcotic-dependent women, J Pediatr 1983;102:686-691.
8 Lifschitz MH, Wilson GS, G’Brian Smith E et al. Factors affecting head growth and intellectual function in children of drug addicts. Pediatrics 1985;75:269-274. 9 Newman RG, Bashkow S, Calko D. Results of 313 consecutive live births of infants delivered to patients in the New York City methadone maintenance treatment program. Am J Obstet Gynecol 1975;121:233-237. 10 Pelosi MA, Frattarola M, Apuzzio J et al. Pregnancy complicated by heroin addiction. Obstet Gynecol 1975;45:512515. 11 Stimmel B, Adamsons K. Narcotic dependency in pregnancy: methadone maintenance compared to use of street drugs. J Am Med Assoc 1976;235:1121-1124. 12 Wilson GS, Desmond MM, Wair RB. Follow-up of methadone-treated and untreated narcotic-dependent women and their infants: health, developmental, and social implications. J Pediatr 1981;98:716-722. 13 Hodgen GD, Stauffer RL, Barber DL et al. Serum estradiol and progesterone during pregnancy and the status of the corpus luteum at delivery in cynomolgus monkeys (Macaca jascicularis). Steroids 1977;30:295-301. 14 Morris M, Stevens SW, Adams MR. Plasma oxytocin during pregnancy and lactation in the Cynomolgus monkey. Biol Reprod 1980;23:782-787. 15 Shaikh AA, Naqvi RH, Shaikh SA. Concentrations of 17boestradiol and progesterone in the peripheral plasma of the cynomolgus monkey (Macaca fascicularis) in relation to the length of the menstrual cycle and its component phases. J Endocrinol 1978;79:1-7. 16 Hein PR. Schatorjt JSJO, Frencken HJAAM. The effect of chronic methadone treatment on intra-uterine growth of the Cynomolgus monkey (Macaca fascicularis ). Eur J Obstet Gynecol Reprod Biol 1988;27:81-85. 17 Helmond FA, Simons PA, Hein PR. The effects of progesterone on estrogen-induced luteinizing hormone and follicle-stimulating hormone release in the female rhesus monkey. Endocrinology 1980;107:478-485. 18 Reijnders FJL. The influence of 17o-hydroxyprogesterone caproate on early pregnancy. Ph.D. Thesis, University of Nijmegen, Nijmegen. The Netherlands, 1985. 19 Hein PR. Schatorjt JSJO, Frencken HJAAM et al. Serum hormone levels in pregnant cynomolgus monkeys. J Med Primatol 1989;18:133-142. 20 Alexander S, Stanwell-Smith R, Buekens P, et al. Biochemical assessment of fetal well-being. In: Chalmers I. Enkin M, Keirse MJNC, eds. Effective care in pregnancy and childbirth. Vol 1. Oxford: Oxford University Press, 1989;455-476. 21 Facchinetti F, Comitini G. Petraglia A et al. Reduced estriol and dehydroepiandrosterone sulphate plasma levels in methadone-addicted pregnant women. Eur J Obstet Gynecol Reprod Biol 1986;23:67-73. 22 Tulchinsky D. Adrenal Androgens in Pregnancy. In: Genazzani AR, Thijssen JHH, Siiteri PK. eds. Adrenal Androgens. New York: Raven Press, 1980;189-198. 23 Horrobin DF. Effects of metabolic and environmental stimuli on prolactin secretion. In: Horrobin DF, ed. Pro-
150 lactin: physiology and clinical significance. Lancester: Medical and Technical Publishing Co, 1973;23. 24 Field T, McNelly A, Sadava D. Effect of maternal methadone addiction in offspring in rats. Arch Int Pharmacodyn 1977;228:300-303. 25 Seidler FJ, Whitmore WL, Slotkin TA. Delays in growth and biochemical development of rat brain caused by maternal methadone administration: are the alterations in syn-
aptogenesis and cellular maturation independent of reduced maternal food intake? Dev Neurosci 1982;5:13-18. 26 Krulich L, Koenig JI, Conway S et al. Opioid kappa receptors and the secretion of prolactin (PRL) and growth hormone (GH) in the rat. I. Effects of opioid kappa receptor agonist bremazocine and U-50,488 on secretion of PRL and GH: comparison with morphine. Neuroendocrinology 1986;42:75-81.
Biology, 38 (1990) 145-150
145
Elsevier EUROBS 01046
The effect of chronic oral methadone treatment on monkey chorionic gonadotropin, estradiol, dehydroepiandrosterone sulfate, progesterone, prolactin and cortisol levels during pregnancy in the cynomoigus monkey ( Macaca fascicularis) P.R. Hein, J.S.J.O. SchatorjC, H.J.A.A.M. Frencken, M.F.G. Segers and C.M.G. Thomas Department
of Obstetrics and Gynecology, University Hospital Nijmegen, Nijmegen,
The Netherlands
Accepted for publication 13 March 1990
The effect of chronic methadone treatment upon the serum levels of Estradiol (E,), Progesterone (P), Prolactin (Prl), monkey chorionic gonadotropin (mCG), dehydroepiandrosterone sulfate (DHEAS) and Cortisol (C) in pregnant Cynomolgus monkeys (Macuca fuscicularis) is described in comparison with the hormone levels in a control group. Only DHEAS was significantly decreased in late pregnancy in the methadone group. From these data it can not be concluded that methadone treatment compromises (feto)placental function. The observed intra-uterine growth retardation in the methadone treated group might be a result of a direct influence of methadone upon growth. Serum level; Methadone; Estradiol; Dehydroepiandrosterone dotropin; Pregnancy; Cynomolgus monkey
A generally accepted way to manage drug addiction during pregnancy in the human is the methadone maintenance treatment program. The opinion of several investigators is that there are no more complications of pregnancy than in an average obstetric population [l]. This agree-
Correspondence: P.R. Hein, M.D., Ph.D., Department of Obstetrics and Gynecology, St. Radboud Hospital, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
0028-2243/90/$03.50
sulfate; Progesterone:
Prolactin; Cortisol; Monkey chorionic gona-
ment, however, does not exist for the incidence of low birthweight babies in methadone users. Some investigators report normal birthweight [2,3] whereas others report an impaired growth [1,4-121. An explanation for these different data could be that in drug addicts other factors than methadone alone may be responsible, such as, for example, inadequate prenatal care, smoking, malnutrition, vitamin deficiency or the use of other drugs. In order to exclude these possibilities we decided to investigate the influence of methadone treatment under standardized conditions upon
0 1990 Elsevier Science Publishers B.V. (Biomedical Division)
146
several aspects of pregnancy. This was done in a prospective study, supported by the Dutch ‘Praeventiefonds’ in Cynomolgus monkeys (Macucu fusciculuris), nonhuman primates with reproductive characteristics which are similar to those of the human [13-151. In a previous article we described the influence of methadone upon the birthweight in the Cynomolgus monkey (Mucucu fmciculuris) [16]. Although the duration of pregnancy did not differ between a control- and a methadone-treatment group, the birthweight was significantly lower in methadone-treated monkeys.. To investigate whether this was a result of impaired placental- or fetoplacental function, we compared in the present study the monkey chorionic gonadotropin (mCG), Estradiol (E2), and Progesterone (P) levels in peripheral serum throughout pregnancy in methadone-treated monkeys and in a control group. Since estrogen precursors originate from both fetal and maternal adrenals, we also measured serum levels of dehydroepiandrosterone sulfate (DHEAS) and Cortisol (C). Moreover, the serum levels of prolactin (Prl) were determined. Materials and Methods The study was conducted in 16 pregnancies in 6 Cynomolgus monkeys ( Mucucu fusciculuris ) : 3 monkeys (10 pregnancies) were on methadone medication (40 mg/day) and 3 monkeys (6 pregnancies) served as controls. Methadone treatment, housing, feeding, breeding and diagnosing of pregnancy have been described previously [16]. Blood samples (3-4 ml) were drawn twice a week between 8 and 10 a.m. from the bra&al or cubital vein without anaesthesia, since our monkeys are trained to present their arms through the bars of the cage to the technician who then draws blood from a vein without difficulty. Blood sampling was initiated prior to conception. Per pregnancy we obtained 48 samples. The blood samples were left to clot overnight at 4’C. Then they were centrifuged at 1200 X g for 20 min. The serum was separated and stored at -20°C until mCG, E,, DHEAS, P, Prl and C concentrations
were measured in all samples by radioimmunoassay (RIA). The RIA systems used for the determination of E, and P and for DHEAS and C have been published previously [17,18] as well as those for Prl and mCG [19]. Statistical methods used for comparison of control and methadone pregnancies were the nonparametric Mann-Whitney U test. Per monkey we calculated per hormone the mean values in three periods: Period I: blood samples 1-16. Period II: blood samples 17-32. Period III: blood samples 33-48. This was done for E,, DHEAS, P, Prl, C. For mCG we only investigated whether during the mCG peak there was a significant difference between the control and methadone value of samples 5, 6 and 7. Results Figs. 1, 2, 3 and 4 illustrate the mean serum levels (f SEM) of circulating mCG, estradiol, DHEAS and progesterone, respectively, from the beginning of pregnancy until delivery in 6 control pregnancies and 10 methadone pregnancies. Patems of serum mCG, E,, DHEAS, P, Prl and C in normal pregnancy have been described before
1191.
Fig. 1. Concentrations of mCG (mean* SE) in peripheral serum of 10 pregnant Cynomolgus monkeys on methadone medication (40 mg/day) from beginning of pregnancy until parturition. The shaded area and the dotted line represent the meanf SE in 6 pregnant control monkeys (blood sampling twice a week).
147
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20-
o-
O-
Fig. 2. Concentrations of estradiol (mean f SE) in peripheral serum of 10 pregnant Cynomolgus monkeys on methadone medication (40 mg/day) from beginning of pregnancy until parturition. The shaded area and the dotted line represent the mean+ SE in 6 pregnant control monkeys (blood sampling twice a week).
twice a week).
In both groups serum mCG levels followed the same patem (Fig. 1). The mCG peak in the methadone group was higher than in the control group, although not significantly. Serum estradiol levels. In both groups the serum estradiol followed the same patem (Fig. 2). Except in the beginning of pregnancy, the levels in the methadone group were lower than in the control group, although not significantly so. Serum DHEAS levels. Serum DHEAS levels in the control group and in the methadone group showed the same pattern (Fig. 3). Serum
mCG
Fig. 4. Concentrations of progesterone (mean f SE) in peripheral serum of 10 pregnant Cynomolgus monkeys on methadone medication (40 mg/day) from beginning of pregnancy until parturition. The shaded area and the dotted line represent the mean+ SE in 6 pregnant control monkeys (blood sampling
levels.
In early and midpregnancy the differences between the control group and methadone group were not statistically significant. In late pregnancy, however, there was a statistically significant difference. (P = 0.02). Serum progesterone levels. Fig. 4 illustrates the progesterone levels in early, mid and late gestation. Serum progesterone levels followed the same pattern for both groups. In the methadone group the progesterone levels were higher than in the control group. However, the values in the control group and in the methadone group were not statistically significantly different.
L
20
55
90
125
160
Fig. 3. Concentrations of DHEAS (mean f SE) in peripheral serum of 10 pregnant Cynomolgus monkeys on methadone medication (40 mg/day) from beginning of pregnancy until parturition. The shaded area and the dotted line represent the mean+ SE in 6 pregnant control monkeys (blood sampling twice a week).
Fig. 5. Concentrations of cortisol (mean+SE) in peripheral serum of 10 pregnant Cynomolgus monkeys on methadone medication (40 mg/day) from beginning of pregnancy until parturition. The shaded area and the dotted line represent the meanf SE in 6 pregnant control monkeys (blood sampling twice a week).
148
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*oooo-
‘,_
;it,
Fig. 6. Concentrations of prolactin (mean* SE) in peripheral serum of 10 pregnant Cynomolgus monkeys on methadone medication (40 mg/day) from beginning of pregnancy until parturition. The shaded area and the dotted line represent the meanf SE in 6 pregnant control monkeys (blood sampling twice a week).
Serum cortisol levels. The patem and levels of serum cortisol were not different in both groups (Fig. 5). Serum prolactin levels. In early and midpregnancy prolactin was higher in the methadone group than in the control group, although not significantly, whereas in late pregnancy prolactin was higher in the control group, although not significantly so (Fig. 6).
Discussion In a previous article [16] we described decreased birthweights in methadone-treated monkeys. If the intrauterine growth retardation (IUGR) of the monkeys on methadone maintenance was only a result of impaired placental function, one might perhaps expect the mCG, E, and P levels to be decreased as compared to those of the control group. However, this was not the case. Of course one could wonder whether the here described hormones reflect placental or fetoplacental function. In humans (without methadone use) test properties of urinary estriol and total estrogen measurements for prediction of low birthweight are as follows: sensitivity varies between 14 and 868, specificity ranges from 63 to 94%. The test properties of the plasma and serum assays are comparable to those of urinary assays [20]. For
~
Cynomolgus monkeys these data are not available. For human chorionic gonadotrophin, DHEAS, progesterone and cortisol to our knowledge no 2 x 2 tables are available with regard to their clinical value as predictor of intrauterine growth retardation and again to our knowledge these data are not available for Cynomolgus monkeys either. Considering DHEAS and C levels, we found (exactly as Facchinetti et al. [21] did in pregnant women) a discrepancy between the levels of both adrenal hormones: cortisol did not change whereas DHEAS significantly decreased under methadone treatment. We have no explanation for this discrepancy. We do not agree with the conclusion of Facchinetti et al. that this points to an isolated effect of methadone upon the fetal adrenal (and not the maternal adrenal), since DHEAS in the maternal circulation originates almost entirely from the maternal adrenal, whereas only negligible amounts of DHEAS can be transferred from the fetal to the maternal circulation [22]. From our data it can not be concluded that the fetal adrenal is influenced in a negative way. This is also unlikely since the E, levels are not decreased in the methadone treated group. Steroids of fetal adrenal origin (mainly DHEAS), are considered to provide approx. 50% of the precursors for E, production, whereas approx. 40% is provided by maternal DHEAS [22]. Since maternal DHEAS is significantly decreased, whereas E, is not decreased, it is probable that the fetal adrenal functions very well, so that it may even compensate for the decreased supply of maternal DHEAS, so that E, levels do not fall. With regard to prolactin, the following can be said: prolactin is considered by some as a stress hormone [23]. In our study there was no difference in prolactin levels between the two groups of monkeys. From our data one could conclude that the lower birthweights in the methadone group [16] can not be attributed to impaired placental function and/or maternal stress. Since there were no differences in food or vitamin intake between the two groups nor differences in other variables, the explanation for the IUGR in the methadone group might perhaps be that methadone itself has a direct influence upon
149
birthweight, as has been suggested for small laboratory animals such as rats [24,25]. How this influence is exerted is a matter of speculation. As we have described in a previous article [16], methadone 40 mg/day is a very high dose, corresponding with lo-13 mg/kg per day, leading to plasma levels exceeding those attained in patients in human maintenance programs. To our knowledge no evaluations have been made to determine the direct effects of methadone levels of this magnitude on fetal growth using in vitro systems or during the early postnatal interval. Anyway, intra-uterine growth retqrdation is not a result of a negative influence upon release of growth hormone, since morphinomimetics increase this release in mammalian species [26]. Acknowledgements
The expert technical assistance and animal care by Diane Haverkate, Rob van den Berg and Albert Peters are gratefully acknowledged. This work was supported by the Dutch ‘Praeventiefonds’, grant No. 28-723. References 1 Blinick G, Wallach RC, Jerez E et al. Drug addiction in pregnancy and the neonate. Am J Obstet Gynecol 1976;125:135-142. 2 Rementeria JL, Lotongkum L. The fetus of the drug-addicted woman: conception, fetal wastage and complications. In: Rementeria JL, ed. Drug abuse in pregnancy and neonatal effects. Saint Louis: The CV Mosby Company, 1977;3-18. 3 Strauss ME, Andresko M, Stryker JC et al. Methadone maintenance during pregnancy: pregnancy, birth and neonate characteristics. Am J Obstet Gynecol 1974:120: 895-900. 4 Chasnoff IJ, Hatcher R, Bums WJ. Polydrug- and methadone-addicted newborns: a continuum of impairment? Pediatrics 1982;70:210-213. 5 Connaughton JF, Reeser D, Schut J et al. Perinatal addiction:outcome and management, Am J Obstet Gynecol 1977;129:679-686. 6 Dinges DF, Davis MM, Glass P. Fetal exposure to narcotics: neonatal sleep as a measure of nervous system disturbance. Science 1980;209:619-621. 7 Lifschitz MH, Wilson GS, O’Brian Smith E et al. Fetal and post-natal growth of children born to narcotic-dependent women, J Pediatr 1983;102:686-691.
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