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February 15, 1985, Vol 253, No. 7 >
ARTICLE | February 15, 1985

Pharmacologic Suppression of the Fetal Adrenal Gland In Utero: Title and subTitle BreakAttempted Prevention of Abnormal External Genital Masculinization in Suspected Congenital Adrenal Hyperplasia FREE

Mark I. Evans, MD; George P. Chrousos, MD; Dean W. Mann, MD; John W. Larsen, Jr, MD; Ira Green, MD; James McCluskey, MB, BS; D. Lynn Loriaux, MD, PhD; John C. Fletcher, PhD; Gregory Koons, MD; James Overpeck, PhD; Joseph D. Schulman, MD
[+] Author Affiliations

Reprint requests to the Genetics and IVF Institute, 3020 Javier Rd, Fairfax, VA 22031 (Dr Schulman).


JAMA. 1985;253(7):1015-1020. doi:10.1001/jama.1985.03350310097034
Text Size: A A A
Published online
Article
References

21-Hydroxylase deficiency results in congenital adrenal hyperplasia and leads to masculinization of the external genitalia of affected females. This complication could be avoided if fetal adrenal gland function were suppressed. A woman with mild 21-hydroxylase deficiency whose previous female child had classic congenital adrenal hyperplasia with masculinization was given dexamethasone beginning at the tenth week of gestation. Maternal estriol and cortisol values indicated rapid and sustained fetal and maternal adrenal gland suppression. At 39 weeks' gestation, the patient was spontaneously delivered of a female neonate with normal external genitalia. Postnatal tests indicated the infant was a single heterozygote for 21-hydroxylase deficiency. This study demonstrates prolonged suppression of the fetal adrenal gland with dexamethasone and suggests it might prevent abnormal masculinization in fetuses with severe congenital adrenal hyperplasia.

(JAMA 1985;253:1015-1020)

REFERENCES

1 +
Recent studies published after the present investigation was under way have shown that dexamethasone suppresses fetal adrenal gland function and fetal growth in pregnant Rhesus monkeys at pharmacologic doses (40 to 160 ÎĽg/kg/day). Doses higher than 160 ÎĽg/kg/day caused fetal death.37,38 Transplacental passage of dexamethasone has also been documented previously in rats39 and in women receiving high doses of dexamethasone in the last trimester of pregnancy for prevention of respiratory distress syndrome.40
2 +
New MI, Dupont B, Pang S, et al:  An update of congenital adrenal hyperplasia . Recent Prog Horm Res 1981;;37:105-181.
3 +
Blankstein J, Faiman C, Reyes FI, et al:  Adult-onset familial adrenal 21-hydroxylase deficiency . Am J Med 1980;;68:441-448.
4 +
Migeon CJ, Rosenwaks Z, Lee PA, et al:  The attenuated form of congenital adrenal hyperplasia as an allelic form of 21-hydroxylase deficiency . J Clin Endocrinol Metabol 1980;;51:647-649.
5 +
Chrousos GP, Loriaux DL, Mann DL, et al:  Late-onset 21-hydroxylase deficiency mimicking idiopathic hirsutism or polycystic ovarian disease: An allelic variant of congenital virilizing adrenal hyperplasia with a milder enzymatic defect . Ann Intern Med 1982;;96:143-148.
6 +
Chrousos GP, Loriaux DL, Mann DL, et al:  Late-onset 21-hydroxylase deficiency in an allelic variant of congenital adrenal hyperplasia characterized by attenuated clinical expression and different HLA haplotype associations . Horm Res 1982;;16:193-200.
7 +
O'Neill GJ, Dupont B, Pollack MS, et al:  Complement C4 allotypes in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: Further evidence for different allelic variants at the 21-hydroxylase locus . Clin Immunol Immunopathol 1982;;23:312-322.
8 +
Villee DB:  Development of endocrine function in the human placenta and fetus: I . N Engl J Med 1969;;281:473-484.
9 +
Villee DB:  Development of endocrine function in the human placenta and fetus: II . N Engl J Med 1969;;281:533-544.
10 +
Pang S, Levine LS, Cederqvist LL, et al:  Amniotic fluid concentrations of Delta 5 and Delta 4 steroids in fetuses with congenital adrenal hyperplasia due to 21-hydroxylase deficiency and anencephalic fetuses . J Clin Endocrinol Metabol 1980;;51:223-229.
11 +
Warsof SL, Larsen JW, Kent SG, et al:  Prenatal diagnosis of congenital adrenal hyperplasia . Obstet Gynecol 1980;;55:751-754.
12 +
Forest MG, Betuel H, Gouillin P, et al:  Prenatal diagnosis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency by steroid analysis in the amniotic fluid of mid-pregnancy: Comparison with HLA typing in 17 pregnancies at risk for CAH . Prenat Diagn 1981;;1:197-207.
13 +
Pollack MS, Levine LS, Pang S, et al:  Prenatal diagnosis of congenital adrenal hyperplasia (21-hydroxylase deficiency) by HLA typing . Lancet 1979;;1:1107-1108.
14 +
Kao M, Voina S, Nichols A, et al:  Parallel radioimmunoassay for plasma cortisol and 11-deoxycortisol . Clin Chem 1975;;21:1644-1647.
15 +
Schiebinger RJ, Albertson BD, Barnes KM, et al:  Developmental changes in rabbit and dog adrenal function: A possible homologue of adrenarche in the dog . Am J Physiol 1981;; 240:694-699.
16 +
Weintraub BD, Rosen SW:  Ectopic production of human chorionic somatomammotrophin by non-trophoblastic cancers . J Clin Endocrinol Metabol 1971;;32:94-101.
17 +
Loriaux DL, Ruder HJ, Knab RD, et al:  Estrone sulfate, estrone, estradiol and estriol plasma levels in human pregnancy . J Clin Endocrinol Metabol 1972;;35:887-891.
18 +
Abraham GE, Buster GE, Lucas LA, et al:  Chromatographic separation of steroid hormones for use in radioimmunoassay . Anal Letters 1972;;5:509-517.
19 +
Abraham GE, Swerdloft R, Tulchinsky D, et al:  Radioimmunoassay of plasma progesterone . J Clin Endocrinol Metabol 1971;;32:619-624.
20 +
Schiebinger R, Chrousos GP, Cutler GB Jr, et al:  The effect of serum prolactin on plasma adrenal androgens and the production and metabolic clearance rate of dehydroepiandrosterone sulfate in normal and hyperprolactinemic subjects . J Clin Endocrinol Metabol , in press.
21 +
Cutler GB Jr, Glenn M, Bush G, et al:  Adrenarche: A survey of rodents, domestic animals and primates . Endocrinology 1978;;103:2112-2118.
22 +
Ruder HJ, Guy RL, Lipsett MB:  Radioimmunoassay for cortisol in plasma and urine . J Clin Endocrinol Metabol 1972;;35:219-224.
23 +
Davis SE, Loriaux DL:  A simple specific assay for estriol in maternal urine . J Clin Endocrinol Metabol 1975;;40:895-900.
24 +
Rodbard D, Hutt DM:  Statistical analysis of radioimmunoassays and immunoradiometric (labeled antibody) assays , in RIA and Related Procedures in Medicine . Vienna, International Atomic Energy Agency, 1974;, pp 165-192.
25 +
Hague N, Thrasher K, Werk EE Jr, et al:  Studies on dexamethasone metabolism in man: Effect of diphenylhydantoin . J Clin Endocrinol Metabol 1972;;34:44-48.
26 +
Mann DL, Abelson L, Henkart P, et al:  Serologic detection of B-lymphocyte antigens , in Kissmeyer-Nielsen F (eds): Histocompatibility Testing . Copenhagen, Munksgaard, 1975;, pp 707-709.
27 +
Amos DB, Pool P:  HLA typing , in Rose S, Friedman R (eds): Manual of Clinical Immunology . Washington DC, American Society for Microbiology, 1976;, pp 297-323.
28 +
Awdeh ZL, Alper CA:  Inherited structural polymorphism of the fourth component of complement (C4) . Proc Natl Acad Sci USA 1980;;77:3576-3580.
29 +
Ghosh AK:  Polymorphism of red cell glyoxalase-1 . Hum Genet 1975;;39:91-95.
30 +
Bongiovanni AM, McFadden AJ:  Steroids during pregnancy and possible fetal consequences . Fertil Steril 1960;;11:181-186.
31 +
Green OC:  Steroid metabolism in the fetus and the newborn infant . Pediatr Clin North Am 1965;;12:615-634.
32 +
Warrell DW, Taylor R:  Outcome for the fetus of mothers receiving prednisolone during pregnancy . Lancet 1968;;1:117-118.
33 +
Kenny FM, Preeyasombat C, Spaudling JS, et al:  Cortisol production rate: IV. Infants born of steroid-treated mothers and of diabetic mothers: Infants with trisomy syndrome and with anencephaly . Pediatrics 1966;;37:960-966.
34 +
Shields JR, Resnik R:  Fetal lung maturation and the antenatal use of glucocorticoids to prevent the respiratory distress syndrome . Obstet Gynecol Surv 1979;;34:343-363.
35 +
Murphy BEP, Clark SJ Donald IR, et al:  Conversion of maternal cortisol to cortisone during placental transfer to the human fetus . Am J Obstet Gynecol 1974;;118:538-541.
36 +
Nolten WE, Lindheimer MD, Rueckert PA, et al:  Diurnal patterns and regulation of cortisol secretion in pregnancy . J Clin Endocrinol Metabol 1980;;51:466-472.
37 +
Fauci AS, Dale DC, Balow JE:  Glucocorticosteroid therapy: Mechanisms of action and clinical considerations . Ann Intern Med 1976;; 84:304-315.
38 +
Walsh SW, Norman RL, Novy MJ:  In utero regulation of rhesus monkey fetal adrenals: Effects of dexamethasone, adrenocorticotropin, thyrotrophin releasing hormone, prolactin, human chorionic gonadotropin and alpha-mealanocyte-stimulating hormone on fetal and maternal plasma steroids . Endocrinology 1979;;104:1805-1813.
39 +
Novy MJ, Walsh SW:  Dexamethasone and estradiol treatment of pregnant rhesus macaques: Effects on gestational length, maternal plasma hormones, and fetal growth . Am J Obstet Gynecol 1983;;145:920-930.
40 +
Funkhouser JD, Peevy KJ, Mockridge PD, et al:  Distribution of dexamethasone between mother and fetus after maternal administration . Pediatr Res 1978;;54:1053-1056.
41 +
Motoyama EK, Orzalesi MM, Kikkawa Y, et al:  Effect of cortisol on the maturation of fetal rabbit lungs . Pediatrics 1971;;48:547-555.
42 +
Wellman KF, Volk BW:  Fine structure changes in the rabbit placenta induced by cortisone . Arch Pathol Lab Med 1972;;94:147-157.
43 +
Kotas RV, Mims LC, Hart LK:  Reversible inhibition of lung cell number after glucocorticoid injection into fetal rabbits to enhance surfactant appearance . Pediatrics 1974;;53:358-361.
44 +
Sanfacon R, Possmayer F, Harding PGR:  Dexamethasone treatment of the guinea pig fetus: Its effects on the incorporation of 3H-thymidine into deoxyribonucleic acid . Am J Obstet Gynecol 1977;;127:745-752.
45 +
Katsumata M, Baker MK, Goldman AS:  An H-2 linked difference in the binding of dexamethasone to murine hepatic cytosol receptor: A possible role of endogenous modifier(s) . Biochem Biophys Acta 1981;;676:245-248.
46 +
McCluskey J, Kay PH, Stuckey M, et al:  MHC 'Supratype' predicting heterozygous 21-hydroxylase deficiency . Lancet 1983;;1:764-765.
47 +
Simoni G, Brambati B, Danesino C, et al:  Efficient direct chromosome analysis and enzyme determinations from chorionic villi samples in the first trimester of pregnancy . Hum Genet 1983;;63:349-357.
48 +
Gosden JR, Mitchell AR, Gosden CM, et al:  Direct vision chorion biopsy and chromosomespecific DNA probes for determination of fetal sex in first-trimester prenatal diagnosis . Lancet 1982;;2:1416-1419.
49 +
Kolata G:  First trimester prenatal diagnosis . Science 1983;;221:1031-1032.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Recent studies published after the present investigation was under way have shown that dexamethasone suppresses fetal adrenal gland function and fetal growth in pregnant Rhesus monkeys at pharmacologic doses (40 to 160 ÎĽg/kg/day). Doses higher than 160 ÎĽg/kg/day caused fetal death.37,38 Transplacental passage of dexamethasone has also been documented previously in rats39 and in women receiving high doses of dexamethasone in the last trimester of pregnancy for prevention of respiratory distress syndrome.40
2 +
New MI, Dupont B, Pang S, et al:  An update of congenital adrenal hyperplasia . Recent Prog Horm Res 1981;;37:105-181.
3 +
Blankstein J, Faiman C, Reyes FI, et al:  Adult-onset familial adrenal 21-hydroxylase deficiency . Am J Med 1980;;68:441-448.
4 +
Migeon CJ, Rosenwaks Z, Lee PA, et al:  The attenuated form of congenital adrenal hyperplasia as an allelic form of 21-hydroxylase deficiency . J Clin Endocrinol Metabol 1980;;51:647-649.
5 +
Chrousos GP, Loriaux DL, Mann DL, et al:  Late-onset 21-hydroxylase deficiency mimicking idiopathic hirsutism or polycystic ovarian disease: An allelic variant of congenital virilizing adrenal hyperplasia with a milder enzymatic defect . Ann Intern Med 1982;;96:143-148.
6 +
Chrousos GP, Loriaux DL, Mann DL, et al:  Late-onset 21-hydroxylase deficiency in an allelic variant of congenital adrenal hyperplasia characterized by attenuated clinical expression and different HLA haplotype associations . Horm Res 1982;;16:193-200.
7 +
O'Neill GJ, Dupont B, Pollack MS, et al:  Complement C4 allotypes in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: Further evidence for different allelic variants at the 21-hydroxylase locus . Clin Immunol Immunopathol 1982;;23:312-322.
8 +
Villee DB:  Development of endocrine function in the human placenta and fetus: I . N Engl J Med 1969;;281:473-484.
9 +
Villee DB:  Development of endocrine function in the human placenta and fetus: II . N Engl J Med 1969;;281:533-544.
10 +
Pang S, Levine LS, Cederqvist LL, et al:  Amniotic fluid concentrations of Delta 5 and Delta 4 steroids in fetuses with congenital adrenal hyperplasia due to 21-hydroxylase deficiency and anencephalic fetuses . J Clin Endocrinol Metabol 1980;;51:223-229.
11 +
Warsof SL, Larsen JW, Kent SG, et al:  Prenatal diagnosis of congenital adrenal hyperplasia . Obstet Gynecol 1980;;55:751-754.
12 +
Forest MG, Betuel H, Gouillin P, et al:  Prenatal diagnosis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency by steroid analysis in the amniotic fluid of mid-pregnancy: Comparison with HLA typing in 17 pregnancies at risk for CAH . Prenat Diagn 1981;;1:197-207.
13 +
Pollack MS, Levine LS, Pang S, et al:  Prenatal diagnosis of congenital adrenal hyperplasia (21-hydroxylase deficiency) by HLA typing . Lancet 1979;;1:1107-1108.
14 +
Kao M, Voina S, Nichols A, et al:  Parallel radioimmunoassay for plasma cortisol and 11-deoxycortisol . Clin Chem 1975;;21:1644-1647.
15 +
Schiebinger RJ, Albertson BD, Barnes KM, et al:  Developmental changes in rabbit and dog adrenal function: A possible homologue of adrenarche in the dog . Am J Physiol 1981;; 240:694-699.
16 +
Weintraub BD, Rosen SW:  Ectopic production of human chorionic somatomammotrophin by non-trophoblastic cancers . J Clin Endocrinol Metabol 1971;;32:94-101.
17 +
Loriaux DL, Ruder HJ, Knab RD, et al:  Estrone sulfate, estrone, estradiol and estriol plasma levels in human pregnancy . J Clin Endocrinol Metabol 1972;;35:887-891.
18 +
Abraham GE, Buster GE, Lucas LA, et al:  Chromatographic separation of steroid hormones for use in radioimmunoassay . Anal Letters 1972;;5:509-517.
19 +
Abraham GE, Swerdloft R, Tulchinsky D, et al:  Radioimmunoassay of plasma progesterone . J Clin Endocrinol Metabol 1971;;32:619-624.
20 +
Schiebinger R, Chrousos GP, Cutler GB Jr, et al:  The effect of serum prolactin on plasma adrenal androgens and the production and metabolic clearance rate of dehydroepiandrosterone sulfate in normal and hyperprolactinemic subjects . J Clin Endocrinol Metabol , in press.
21 +
Cutler GB Jr, Glenn M, Bush G, et al:  Adrenarche: A survey of rodents, domestic animals and primates . Endocrinology 1978;;103:2112-2118.
22 +
Ruder HJ, Guy RL, Lipsett MB:  Radioimmunoassay for cortisol in plasma and urine . J Clin Endocrinol Metabol 1972;;35:219-224.
23 +
Davis SE, Loriaux DL:  A simple specific assay for estriol in maternal urine . J Clin Endocrinol Metabol 1975;;40:895-900.
24 +
Rodbard D, Hutt DM:  Statistical analysis of radioimmunoassays and immunoradiometric (labeled antibody) assays , in RIA and Related Procedures in Medicine . Vienna, International Atomic Energy Agency, 1974;, pp 165-192.
25 +
Hague N, Thrasher K, Werk EE Jr, et al:  Studies on dexamethasone metabolism in man: Effect of diphenylhydantoin . J Clin Endocrinol Metabol 1972;;34:44-48.
26 +
Mann DL, Abelson L, Henkart P, et al:  Serologic detection of B-lymphocyte antigens , in Kissmeyer-Nielsen F (eds): Histocompatibility Testing . Copenhagen, Munksgaard, 1975;, pp 707-709.
27 +
Amos DB, Pool P:  HLA typing , in Rose S, Friedman R (eds): Manual of Clinical Immunology . Washington DC, American Society for Microbiology, 1976;, pp 297-323.
28 +
Awdeh ZL, Alper CA:  Inherited structural polymorphism of the fourth component of complement (C4) . Proc Natl Acad Sci USA 1980;;77:3576-3580.
29 +
Ghosh AK:  Polymorphism of red cell glyoxalase-1 . Hum Genet 1975;;39:91-95.
30 +
Bongiovanni AM, McFadden AJ:  Steroids during pregnancy and possible fetal consequences . Fertil Steril 1960;;11:181-186.
31 +
Green OC:  Steroid metabolism in the fetus and the newborn infant . Pediatr Clin North Am 1965;;12:615-634.
32 +
Warrell DW, Taylor R:  Outcome for the fetus of mothers receiving prednisolone during pregnancy . Lancet 1968;;1:117-118.
33 +
Kenny FM, Preeyasombat C, Spaudling JS, et al:  Cortisol production rate: IV. Infants born of steroid-treated mothers and of diabetic mothers: Infants with trisomy syndrome and with anencephaly . Pediatrics 1966;;37:960-966.
34 +
Shields JR, Resnik R:  Fetal lung maturation and the antenatal use of glucocorticoids to prevent the respiratory distress syndrome . Obstet Gynecol Surv 1979;;34:343-363.
35 +
Murphy BEP, Clark SJ Donald IR, et al:  Conversion of maternal cortisol to cortisone during placental transfer to the human fetus . Am J Obstet Gynecol 1974;;118:538-541.
36 +
Nolten WE, Lindheimer MD, Rueckert PA, et al:  Diurnal patterns and regulation of cortisol secretion in pregnancy . J Clin Endocrinol Metabol 1980;;51:466-472.
37 +
Fauci AS, Dale DC, Balow JE:  Glucocorticosteroid therapy: Mechanisms of action and clinical considerations . Ann Intern Med 1976;; 84:304-315.
38 +
Walsh SW, Norman RL, Novy MJ:  In utero regulation of rhesus monkey fetal adrenals: Effects of dexamethasone, adrenocorticotropin, thyrotrophin releasing hormone, prolactin, human chorionic gonadotropin and alpha-mealanocyte-stimulating hormone on fetal and maternal plasma steroids . Endocrinology 1979;;104:1805-1813.
39 +
Novy MJ, Walsh SW:  Dexamethasone and estradiol treatment of pregnant rhesus macaques: Effects on gestational length, maternal plasma hormones, and fetal growth . Am J Obstet Gynecol 1983;;145:920-930.
40 +
Funkhouser JD, Peevy KJ, Mockridge PD, et al:  Distribution of dexamethasone between mother and fetus after maternal administration . Pediatr Res 1978;;54:1053-1056.
41 +
Motoyama EK, Orzalesi MM, Kikkawa Y, et al:  Effect of cortisol on the maturation of fetal rabbit lungs . Pediatrics 1971;;48:547-555.
42 +
Wellman KF, Volk BW:  Fine structure changes in the rabbit placenta induced by cortisone . Arch Pathol Lab Med 1972;;94:147-157.
43 +
Kotas RV, Mims LC, Hart LK:  Reversible inhibition of lung cell number after glucocorticoid injection into fetal rabbits to enhance surfactant appearance . Pediatrics 1974;;53:358-361.
44 +
Sanfacon R, Possmayer F, Harding PGR:  Dexamethasone treatment of the guinea pig fetus: Its effects on the incorporation of 3H-thymidine into deoxyribonucleic acid . Am J Obstet Gynecol 1977;;127:745-752.
45 +
Katsumata M, Baker MK, Goldman AS:  An H-2 linked difference in the binding of dexamethasone to murine hepatic cytosol receptor: A possible role of endogenous modifier(s) . Biochem Biophys Acta 1981;;676:245-248.
46 +
McCluskey J, Kay PH, Stuckey M, et al:  MHC 'Supratype' predicting heterozygous 21-hydroxylase deficiency . Lancet 1983;;1:764-765.
47 +
Simoni G, Brambati B, Danesino C, et al:  Efficient direct chromosome analysis and enzyme determinations from chorionic villi samples in the first trimester of pregnancy . Hum Genet 1983;;63:349-357.
48 +
Gosden JR, Mitchell AR, Gosden CM, et al:  Direct vision chorion biopsy and chromosomespecific DNA probes for determination of fetal sex in first-trimester prenatal diagnosis . Lancet 1982;;2:1416-1419.
49 +
Kolata G:  First trimester prenatal diagnosis . Science 1983;;221:1031-1032.

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