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Prenatal Treatment of Congenital Adrenal Hyperplasia: A Commentary
Meyer-Bahlburg HFL, Gruen RS, New MI, et al.: 1996. Gender change from female to male in classical congenital adrenal hyperplasia. Horm Behavior 30:319–332. Migeon CJ: 1990. Comments about the need for prenatal treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metal 70:836–837. Miller WL: 1994. Genetics, diagnosis, and management of 21-hydroxylase deficiency. J Clin Endocrinol Metab 78:241–246. Miller WL, Morel Y: 1989. Molecular genetics of 21-hydroxylase deficiency. Annu Rev Genet 23:371–393. Miyakawa I, Ikeda I, Maeyama M: 1974. Transport of ACTH across human placenta. J Clin Endocrinol Metab 39:440–442. Morel Y, Miller WL: 1991. Clinical and molecular genetics of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Adv Hum Genet 20:1–68. Morel Y, Andre J, Uring-Lambert B, et al.: 1989. Rearrangements and point mutations of P450c21 genes are distinguished by five restriction endonuclease haplotypes identified by a new probing strategy in 57 families with congenital adrenal hyperplasia. J Clin Invest 83:527–536. Mulaikal RM, Migeon CJ, Rock JA: 1987. Fertility rates in female patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. New Engl J Med 316:178–182.
Osamura RY: 1977. Functional prenatal development of anencephalic and normal anterior pituitary glands. Acta Pathol Jpn 27:495–509. Pang SY, Clark A: 1990. Newborn screening, prenatal diagnosis, and prenatal treatment of congenital adrenal hyperplasia due to 21hydroxylase deficiency. Trends Endocrinol Metab 1:300–307. Pang S, Clark AT, Freeman LC, et al.: 1992. Maternal side-effects of prenatal dexamethasone therapy for fetal congenital adrenal hyperplasia. J Clin Endocrinol Metab 75:249–253. Rhoades GG, Jackson LG, Schlesselman SE, et al.: 1989. The safety and efficacy of chorionic villus sampling for early prenatal diagnosis of cytogenetic abnormalities. New Engl J Med 320:609–617. Seckl JR, Miller WL: 1997. How safe is longterm prenatal glucocorticoid treatment? J Am Med Assoc 277:1077–1079. Speiser PW, New MI: 1994. Prenatal diagnosis and management of congenital adrenal hyperplasia. Clin Perinatol 21:631–645. Speiser PW, Dupont J, Zhu D, et al.: 1992. Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21hydroxylase deficiency. J Clin Invest 90:584–595. Tapanainen J, Kellokumpu-Lehtinen P, Pelliniemi L, Huhtaniemi I: 1981. Age-related changes in endogenous steroids of human fetal testis during early and midpregnancy. J Clin Endocrinol Metab 52:98–102.
Prenatal Treatment of Congenital Adrenal Hyperplasia: A Commentary E. Martin Ritzén
Girls with severe forms of congenital adrenal hyperplasia (CAH) are virilized at birth, sometimes to such a degree that the sex of the newborn child is uncertain. Therefore, when it was first shown that treatment of the fetus (through medication of the mother) with dexamethasone could prevent or reduce the virilization so that the female sex was indisputable and no feminizing surgery was needed, it was highly acclaimed by both parents and doctors. E.M. Ritzén is at the Department of Woman and Child Health, Karolinska Institute, S-171 76 Stockholm, Sweden.
TEM Vol. 9, No. 7, 1998
Parents who previously did not dare to risk a second pregnancy because of the fear of having another virilized daughter would now do so. Later, words of caution were voiced that exposure of the fetus to higher than normal levels of glucocorticoids might be hazardous to the child and give long-term adverse effects. This issue of Trends in Endocrinology and Metabolism brings up this controversy for discussion, by presenting two seemingly opposing opinions on this new treatment modality: one (Forest et al.) is written by the investigators who reported the first successfully treated case. Since that time, these authors and
Trautman PD, Meyer-Bahlburg HFL, Postelnek J, New MI: 1995. Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children: results of a pilot study. Psychoneuroendocrinology 20:439–449. Tusie-Luna MT, Traktman P, White PC: 1990. Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus. J Biol Chem 265:20916–20922. Wedell A, Thilén A, Ritzén EM, Stengler B, Luthman H: 1994. Mutational spectrum of the steroid 21-hydroxylase gene in Sweden: implications for genetic diagnosis and association with disease manifestation. J Clin Endocrinol Metab 78:1145–1152. Whincup PH, Cook D, Papacosta O, Walker M: 1995. Birth weight and blood pressure: cross-sectional and longitudinal relations in childhood. Br Med J 311:773–776. White PC, Vitek B, Dupont B, New MI: 1988. Characterization of frequent deletions causing steorid 21-hydroxylase deficiency. Proc Natl Acad Sci USA 85:4436. White PC, Mune T, Agarwal AK: 1997. 11β-hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid excess. Endocr Rev 18:135–156. Zucker KJ, Bradley SJ, Oliver G, et al.: 1996. Psychosexual development of women with congenital adrenal hyperplasia. Horm Behavior 30:300–318.
others have collected data on a large number of treated cases. The other article is written by a concerned scientist (Miller) who is worried that this treatment, although admittedly successful in reducing or preventing virilization, might later prove to have long-term sequelae for the child. Both papers deal with the same basic set of data, but these data are viewed through different colored glasses: Forest and colleagues point out all the beneficial effects of treatment and stress that few observations of adverse events have so far been noted in the treated children, while Miller lists all the concerns about the possible effects in later life (childhood or adulthood) of exposure of the fetus to excess glucocorticoids. The basis for this concern is mainly derived from animal experiments. Both authors agree that the treatment is effective in reducing or preventing virilization of the genitalia of affected female fetuses. Theoretically, treatment
© 1998, Elsevier Science Ltd, 1043-2760/98/$19.00. PII: S1043-2760(98)00073-3
293
should also abolish any androgen priming of the brain in a male direction. The relief from the need for sometimes repeated feminizing surgery and from the psychological trauma for the parents in having a virilized daughter (which might secondarily influence their way of treating the child) at present outweigh the possible (unknown) future adverse effects on the child. The ethical problem comes when male or unaffected female fetuses are treated during early gestation – they have no benefit from the treatment, but will be equally exposed to potential problems. This is currently unavoidable, because prenatal diagnosis (sex determination and mutation analysis of DNA from biopsies of chorionic villi) cannot be done until the tenth week of pregnancy, but treatment must start at the sixth to seventh week to be effective. Siblings of a child with CAH run a one in four risk of being affected by the same disease. However, CAH causes no apparent problems for a male fetus; therefore, it is only one out of eight fetuses that will benefit from treatment. Conversely, seven out of eight mothers and fetuses are treated unnecessarily. What could be the possible side effects for these fetuses/children, and how do the two articles about this issue deal with them? •
Possible Adverse Effects
Risk for Abortion After Tissue Sampling Both Forest (1997) and Mercado et al. (1995) report that 9–10% of treated pregnancies ended in unprovoked abortion. This is similar to the overall risk for pregnancies in general, but it is probably higher than that expected after the tenth week of pregnancy. Intrauterine Growth It is well known that excess glucocorticoids cause impaired growth during childhood. However, this does not seem to be the case in utero. In the two large collections of weights and lengths at birth of babies treated prenatally, either short-term (from the sixth to the twelth week of gestation) or full-term (Forest 1997, Mercado et al. 1995), totalling more than 400 cases, there was no
294
difference in weight or length between treated and untreated newborns. This was confirmed in a recent case-control study of 44 treated pregnancies in Sweden (Lajic et al. 1997 and 1998). Miller, however, points out that when treating pregnant rats with similar doses (20 µg kg−1) of dexamethasone, birth weight is reduced by 14% and, in adulthood, blood pressure is elevated. He links this observation with the recently much publicized observation (reviewed by Barker 1997) that being small at birth is a strong risk factor for cardiovascular disease and diabetes later in life. However, because the dexamethasone treatment of human fetuses at the doses used does not seem to cause intrauterine growth retardation, this linkage might not be warranted. Postnatal Growth This is not dealt with in the present articles. Mercado et al. (1995) and Forest et al. (1997) reported it to be ‘normal’, and the case-control study by Lajic et al. (1997 and 1998) confirmed this, when whole groups were compared. Two of the six affected girls reported by Lajic et al. had initial failure to thrive (which might be ascribed to concurrent disease), but later recovered. Effects on the Fetal Brain The results of animal experiments with prenatal treatment of pregnant females with large doses of dexamethasone give reasons for concern: in both rats and monkeys, prenatal dexamethasone treatment reduced the size of the hippocampus, which also contained fewer neurons than normal. In a follow-up study of children at risk of having CAH who had been treated with dexamethasone during pregnancy, Trautman et al. (1995) found a tendency towards increased withdrawal and shyness, compared with controls. In the series of Lajic et al. (1997 and 1998), one child out of 36 treated short-term was born with hydrocephalus and agenesis of the corpus callosum. This might be coincidental. Controlled prospective studies including large numbers of children will be needed to determine the true incidence of side effects.
Maternal Side Effects In the large patient groups described by Forest et al. (1997) and Mercado et al. (1995), reported transient maternal side effects included striae, excessive weight gain, hypertension, pre-eclampsia and diabetes in a few cases. In the casecontrol study by Lajic et al. (1997 and 1998), the treated mothers reported significantly more mood fluctuations, early pregnancy ‘swollenness’ and weight gain than controls. Only the increased weight gain could be documented by objective measurements. Obviously, the maternal reports vary in different populations. •
How Important are these Possible Adverse Effects?
Both Forest et al. and Miller conclude that more long-term (many years) follow-up studies are needed. However, Miller expresses more concerns, and lists several criteria that should be met by such a rigorous study. I have no reservations as to his demands for good prospective controlled studies: they should fulfil the usual rules in clinical studies, such as approval by a local ethics committee and oral and written patient/parent information with all relevant data known today. However, it does not seem appropriate to mention growth retardation of the fetus as possible side effects, in light of the normal birth weight and length noted to date. Also, the reasoning behind warning about adult hypertension seems too weak to be relevant at the present state of knowledge. The follow-up studies of treated children done so far are retrospective, and generally lack proper controls. Miller correctly argues that prenatal treatment with dexamethasone should only be done as part of a prospective clinical study. CAH is a rare disease, and prenatal treatment will be ever rarer. Therefore, national or even international study protocols should be worked out, so that groups big enough to meet statistical power calculations can be collected. Only those centres should be involved that can provide genotyping (including gene sequencing, if necessary) of the index cases and rapid mutation analysis of placenta biopsies, to TEM Vol. 9, No. 7, 1998
avoid unnecessarily long treatment of male or unaffected female fetuses. Long-term follow-up (until adulthood) of somatic and psychological development is mandatory, as suggested by Miller. Proper control groups, both healthy individuals and preferably patients with another chronic illness, should be followed in parallel. •
Conclusions
It is very satisfying to be able to offer prenatal diagnosis and treatment in utero to prevent malformations of the newborn girl. So far, the benefits of treatment of affected girls have outweighed the discomforts of the mother. Further studies are needed to exclude late adverse effects on the fetus and child. Future research should focus on reducing the ‘unnecessary’ treatment of seven out of eight mothers and fetuses.
Many questions remain unanswered: are the doses of dexamethasone used at present optimal? Should the dose be varied during different periods of the gestation? Could the overproduction of androgens be reduced by other means? What is the mechanism of action of dexamethasone during the first trimester, when the fetal hypothalamus–pituitary–adrenal axis might not be functional? Treatment should be performed in conjunction with prospective controlled studies, which include careful follow-up of all treated children for many years.
References Barker DJP: 1997. The fetal origins of coronary heart disease. Acta Paediatr 84 (suppl 422):78–82.
Forest MG: 1997. Prenatal diagnosis, treatment, and outcome in infants with congenital adrenal hyperplasia. Curr Opin Endocrinol Diab 4:209–217. Lajic S, Bui TH, Holst M, Ritzén EM, Wedell A: 1997. Prenatal diagnosis and treatment of adrenogenital syndrome prevents virilization of female fetuses [abst]. Läkartidningen 94:4781–4786. Lajic S, Wedell A, Bui TH, Ritzén EM, Holst M: 1998. Long-term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia. J Clin Endocrinol Metab (in press) Mercado AB, Wilson RC, Cheng KC, Wei JQ, New MI: 1995. Prenatal treatment and diagnosis of congenital adrenal hyperplasia owing to steroid 21-hydroxylase deficiency. J Clin Endocrinol Metab 80:2014–2020. Trautman PD, Meyer-Bahlburg HFL, Postelnek J, New MI: 1995. Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children: results of a pilot study. Psychoneuroendocrinology 20:439–449.
Coming soon in TEM Current Concepts of the Mechanisms of Menstruation: A Normal Process of Tissue Destruction by L.A. Salamonsen Corticotropin Releasing Hormone and the Stress Response by G. Aguilera Role of Phoshatidylinositol-transfer Proteins (PITPs) in Intracellular Signalling by C. Wiedemann and S. Cockcroft Molecular Mechanisms of Androgen Action by R.A. Hiipakka and S. Liao Prostate Specific Antigen – Its Usefulness in Clinical Medicine by E. Diamandis Lispro Insulin: Benefits and Limitations by D.S. Schade, M.R. Burge and A.G. Rassam
TEM Vol. 9, No. 7, 1998
295
Osamura RY: 1977. Functional prenatal development of anencephalic and normal anterior pituitary glands. Acta Pathol Jpn 27:495–509. Pang SY, Clark A: 1990. Newborn screening, prenatal diagnosis, and prenatal treatment of congenital adrenal hyperplasia due to 21hydroxylase deficiency. Trends Endocrinol Metab 1:300–307. Pang S, Clark AT, Freeman LC, et al.: 1992. Maternal side-effects of prenatal dexamethasone therapy for fetal congenital adrenal hyperplasia. J Clin Endocrinol Metab 75:249–253. Rhoades GG, Jackson LG, Schlesselman SE, et al.: 1989. The safety and efficacy of chorionic villus sampling for early prenatal diagnosis of cytogenetic abnormalities. New Engl J Med 320:609–617. Seckl JR, Miller WL: 1997. How safe is longterm prenatal glucocorticoid treatment? J Am Med Assoc 277:1077–1079. Speiser PW, New MI: 1994. Prenatal diagnosis and management of congenital adrenal hyperplasia. Clin Perinatol 21:631–645. Speiser PW, Dupont J, Zhu D, et al.: 1992. Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21hydroxylase deficiency. J Clin Invest 90:584–595. Tapanainen J, Kellokumpu-Lehtinen P, Pelliniemi L, Huhtaniemi I: 1981. Age-related changes in endogenous steroids of human fetal testis during early and midpregnancy. J Clin Endocrinol Metab 52:98–102.
Prenatal Treatment of Congenital Adrenal Hyperplasia: A Commentary E. Martin Ritzén
Girls with severe forms of congenital adrenal hyperplasia (CAH) are virilized at birth, sometimes to such a degree that the sex of the newborn child is uncertain. Therefore, when it was first shown that treatment of the fetus (through medication of the mother) with dexamethasone could prevent or reduce the virilization so that the female sex was indisputable and no feminizing surgery was needed, it was highly acclaimed by both parents and doctors. E.M. Ritzén is at the Department of Woman and Child Health, Karolinska Institute, S-171 76 Stockholm, Sweden.
TEM Vol. 9, No. 7, 1998
Parents who previously did not dare to risk a second pregnancy because of the fear of having another virilized daughter would now do so. Later, words of caution were voiced that exposure of the fetus to higher than normal levels of glucocorticoids might be hazardous to the child and give long-term adverse effects. This issue of Trends in Endocrinology and Metabolism brings up this controversy for discussion, by presenting two seemingly opposing opinions on this new treatment modality: one (Forest et al.) is written by the investigators who reported the first successfully treated case. Since that time, these authors and
Trautman PD, Meyer-Bahlburg HFL, Postelnek J, New MI: 1995. Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children: results of a pilot study. Psychoneuroendocrinology 20:439–449. Tusie-Luna MT, Traktman P, White PC: 1990. Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus. J Biol Chem 265:20916–20922. Wedell A, Thilén A, Ritzén EM, Stengler B, Luthman H: 1994. Mutational spectrum of the steroid 21-hydroxylase gene in Sweden: implications for genetic diagnosis and association with disease manifestation. J Clin Endocrinol Metab 78:1145–1152. Whincup PH, Cook D, Papacosta O, Walker M: 1995. Birth weight and blood pressure: cross-sectional and longitudinal relations in childhood. Br Med J 311:773–776. White PC, Vitek B, Dupont B, New MI: 1988. Characterization of frequent deletions causing steorid 21-hydroxylase deficiency. Proc Natl Acad Sci USA 85:4436. White PC, Mune T, Agarwal AK: 1997. 11β-hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid excess. Endocr Rev 18:135–156. Zucker KJ, Bradley SJ, Oliver G, et al.: 1996. Psychosexual development of women with congenital adrenal hyperplasia. Horm Behavior 30:300–318.
others have collected data on a large number of treated cases. The other article is written by a concerned scientist (Miller) who is worried that this treatment, although admittedly successful in reducing or preventing virilization, might later prove to have long-term sequelae for the child. Both papers deal with the same basic set of data, but these data are viewed through different colored glasses: Forest and colleagues point out all the beneficial effects of treatment and stress that few observations of adverse events have so far been noted in the treated children, while Miller lists all the concerns about the possible effects in later life (childhood or adulthood) of exposure of the fetus to excess glucocorticoids. The basis for this concern is mainly derived from animal experiments. Both authors agree that the treatment is effective in reducing or preventing virilization of the genitalia of affected female fetuses. Theoretically, treatment
© 1998, Elsevier Science Ltd, 1043-2760/98/$19.00. PII: S1043-2760(98)00073-3
293
should also abolish any androgen priming of the brain in a male direction. The relief from the need for sometimes repeated feminizing surgery and from the psychological trauma for the parents in having a virilized daughter (which might secondarily influence their way of treating the child) at present outweigh the possible (unknown) future adverse effects on the child. The ethical problem comes when male or unaffected female fetuses are treated during early gestation – they have no benefit from the treatment, but will be equally exposed to potential problems. This is currently unavoidable, because prenatal diagnosis (sex determination and mutation analysis of DNA from biopsies of chorionic villi) cannot be done until the tenth week of pregnancy, but treatment must start at the sixth to seventh week to be effective. Siblings of a child with CAH run a one in four risk of being affected by the same disease. However, CAH causes no apparent problems for a male fetus; therefore, it is only one out of eight fetuses that will benefit from treatment. Conversely, seven out of eight mothers and fetuses are treated unnecessarily. What could be the possible side effects for these fetuses/children, and how do the two articles about this issue deal with them? •
Possible Adverse Effects
Risk for Abortion After Tissue Sampling Both Forest (1997) and Mercado et al. (1995) report that 9–10% of treated pregnancies ended in unprovoked abortion. This is similar to the overall risk for pregnancies in general, but it is probably higher than that expected after the tenth week of pregnancy. Intrauterine Growth It is well known that excess glucocorticoids cause impaired growth during childhood. However, this does not seem to be the case in utero. In the two large collections of weights and lengths at birth of babies treated prenatally, either short-term (from the sixth to the twelth week of gestation) or full-term (Forest 1997, Mercado et al. 1995), totalling more than 400 cases, there was no
294
difference in weight or length between treated and untreated newborns. This was confirmed in a recent case-control study of 44 treated pregnancies in Sweden (Lajic et al. 1997 and 1998). Miller, however, points out that when treating pregnant rats with similar doses (20 µg kg−1) of dexamethasone, birth weight is reduced by 14% and, in adulthood, blood pressure is elevated. He links this observation with the recently much publicized observation (reviewed by Barker 1997) that being small at birth is a strong risk factor for cardiovascular disease and diabetes later in life. However, because the dexamethasone treatment of human fetuses at the doses used does not seem to cause intrauterine growth retardation, this linkage might not be warranted. Postnatal Growth This is not dealt with in the present articles. Mercado et al. (1995) and Forest et al. (1997) reported it to be ‘normal’, and the case-control study by Lajic et al. (1997 and 1998) confirmed this, when whole groups were compared. Two of the six affected girls reported by Lajic et al. had initial failure to thrive (which might be ascribed to concurrent disease), but later recovered. Effects on the Fetal Brain The results of animal experiments with prenatal treatment of pregnant females with large doses of dexamethasone give reasons for concern: in both rats and monkeys, prenatal dexamethasone treatment reduced the size of the hippocampus, which also contained fewer neurons than normal. In a follow-up study of children at risk of having CAH who had been treated with dexamethasone during pregnancy, Trautman et al. (1995) found a tendency towards increased withdrawal and shyness, compared with controls. In the series of Lajic et al. (1997 and 1998), one child out of 36 treated short-term was born with hydrocephalus and agenesis of the corpus callosum. This might be coincidental. Controlled prospective studies including large numbers of children will be needed to determine the true incidence of side effects.
Maternal Side Effects In the large patient groups described by Forest et al. (1997) and Mercado et al. (1995), reported transient maternal side effects included striae, excessive weight gain, hypertension, pre-eclampsia and diabetes in a few cases. In the casecontrol study by Lajic et al. (1997 and 1998), the treated mothers reported significantly more mood fluctuations, early pregnancy ‘swollenness’ and weight gain than controls. Only the increased weight gain could be documented by objective measurements. Obviously, the maternal reports vary in different populations. •
How Important are these Possible Adverse Effects?
Both Forest et al. and Miller conclude that more long-term (many years) follow-up studies are needed. However, Miller expresses more concerns, and lists several criteria that should be met by such a rigorous study. I have no reservations as to his demands for good prospective controlled studies: they should fulfil the usual rules in clinical studies, such as approval by a local ethics committee and oral and written patient/parent information with all relevant data known today. However, it does not seem appropriate to mention growth retardation of the fetus as possible side effects, in light of the normal birth weight and length noted to date. Also, the reasoning behind warning about adult hypertension seems too weak to be relevant at the present state of knowledge. The follow-up studies of treated children done so far are retrospective, and generally lack proper controls. Miller correctly argues that prenatal treatment with dexamethasone should only be done as part of a prospective clinical study. CAH is a rare disease, and prenatal treatment will be ever rarer. Therefore, national or even international study protocols should be worked out, so that groups big enough to meet statistical power calculations can be collected. Only those centres should be involved that can provide genotyping (including gene sequencing, if necessary) of the index cases and rapid mutation analysis of placenta biopsies, to TEM Vol. 9, No. 7, 1998
avoid unnecessarily long treatment of male or unaffected female fetuses. Long-term follow-up (until adulthood) of somatic and psychological development is mandatory, as suggested by Miller. Proper control groups, both healthy individuals and preferably patients with another chronic illness, should be followed in parallel. •
Conclusions
It is very satisfying to be able to offer prenatal diagnosis and treatment in utero to prevent malformations of the newborn girl. So far, the benefits of treatment of affected girls have outweighed the discomforts of the mother. Further studies are needed to exclude late adverse effects on the fetus and child. Future research should focus on reducing the ‘unnecessary’ treatment of seven out of eight mothers and fetuses.
Many questions remain unanswered: are the doses of dexamethasone used at present optimal? Should the dose be varied during different periods of the gestation? Could the overproduction of androgens be reduced by other means? What is the mechanism of action of dexamethasone during the first trimester, when the fetal hypothalamus–pituitary–adrenal axis might not be functional? Treatment should be performed in conjunction with prospective controlled studies, which include careful follow-up of all treated children for many years.
References Barker DJP: 1997. The fetal origins of coronary heart disease. Acta Paediatr 84 (suppl 422):78–82.
Forest MG: 1997. Prenatal diagnosis, treatment, and outcome in infants with congenital adrenal hyperplasia. Curr Opin Endocrinol Diab 4:209–217. Lajic S, Bui TH, Holst M, Ritzén EM, Wedell A: 1997. Prenatal diagnosis and treatment of adrenogenital syndrome prevents virilization of female fetuses [abst]. Läkartidningen 94:4781–4786. Lajic S, Wedell A, Bui TH, Ritzén EM, Holst M: 1998. Long-term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia. J Clin Endocrinol Metab (in press) Mercado AB, Wilson RC, Cheng KC, Wei JQ, New MI: 1995. Prenatal treatment and diagnosis of congenital adrenal hyperplasia owing to steroid 21-hydroxylase deficiency. J Clin Endocrinol Metab 80:2014–2020. Trautman PD, Meyer-Bahlburg HFL, Postelnek J, New MI: 1995. Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children: results of a pilot study. Psychoneuroendocrinology 20:439–449.
Coming soon in TEM Current Concepts of the Mechanisms of Menstruation: A Normal Process of Tissue Destruction by L.A. Salamonsen Corticotropin Releasing Hormone and the Stress Response by G. Aguilera Role of Phoshatidylinositol-transfer Proteins (PITPs) in Intracellular Signalling by C. Wiedemann and S. Cockcroft Molecular Mechanisms of Androgen Action by R.A. Hiipakka and S. Liao Prostate Specific Antigen – Its Usefulness in Clinical Medicine by E. Diamandis Lispro Insulin: Benefits and Limitations by D.S. Schade, M.R. Burge and A.G. Rassam
TEM Vol. 9, No. 7, 1998
295