H. G. Dörr

Circadian Rhythm of Salivary Cortisol, 17α-Hydroxyprogesterone, and Progesterone in Healthy Children

Very few reference intervals for salivary steroids in children have been established to date (1). Even the manufacturers of salivary steroid assays do not provide sufficient reference data for their products. This lack of information is surprising because the measurement of salivary steroids has been accepted as being noninvasive and stress-free (2)(3). In particular, psychiatric and neuro-endocrinologic experiments are frequently designed with saliva as the medium of choice for steroid analysis (4)(5)(6). A large variety of stressors can rapidly affect the adrenal cortex, causing increased adrenal steroid concentrations. For example, hypoglycemia (7) or physical exercise (8) are potent physiologic stressors, whereas fear (9), feelings of inferiority (10)(11), or experiences at school (12)(13) can affect the adrenal cortex activity as psychologic stressors. The taking of blood can also influence adrenal steroid concentrations in children; saliva collection, however, is almost stress-free (14). The use of saliva for steroid analysis in children is therefore an excellent alternative to blood. The aim of our study was to establish age-dependent reference values for salivary cortisol, 17α-hydroxyprogesterone (17OHP), and progesterone in a large cohort of healthy children. The availability of such reference intervals will improve the applicability of saliva analysis as a diagnostic tool in pediatric endocrinology. We collected 252 saliva profiles from healthy children and adolescents (125 boys; age range, 4 days to 15 years; 127 girls; age range, 6 days to 13 years) with normal body length/height and weight. None of the girls had developed a regular menstrual cycle. The parents of the children gave informed consent. Saliva was collected either with the Salivette®, using polyester swabs (Sarstedt), from children >1 year of age or with modified medical pacifiers (Buttner-Frank; see Fig. 1⇓ in the Data Supplement that accompanies the …

Endocrine disorders in septo-optic dysplasia (De Morsier syndrome) — evaluation and follow up of 18 patients

Septo-optic dysplasia (SOD) is characterized by hypoplasia of the optic nerve, various types of forebrain defects and hormonal deficiencies. We have studied the clinical and endocrinological characteristics of 18 such patients retrospectively to: (1) better define the endocrine abnormalities in children with SOD; and (2) to find approaches for the interdisciplinary long-term care of children with SOD. The children were seen at the Childrens Hospital of the University of Munich from 1976 to 1992 (8 boys, 10 girls; age at initial presentation: 1 day–13 years of age, mean 1.9 years). Unilateral hypoplasia of the optic nerve was found in 7 cases, bilateral hypoplasia in 11. Sonographic, CCT or MRI yielded the following results: 4 of the patients had a cavum septum pellucidum, 3 patients had hypoplasia of the cerebellum, 1 aplasia of the corpus callosum and 1 aplasia of the fornix. An empty sella with or without an ectopic pituitary was seen in 4 cases. Height standard deviation score (SDS) at time of diagnosis was −4.0 to +0.4, mean −2.92. Endocrine deficiencies were present in all 11 patients who had undergone endocrinological investigations. Seven patients suffered from isolated growth hormone (GH) deficiency or multiple hypopituitarism. One had diabetes insipidus centralis, 2 had hypogonadotropic hypogonadism, 1 had hypothyroidism and 2 adrenal insufficiency. Hypothalamic testing was performed only in a subset of patients: in 5 of 11 children tested a thyrotropin releasing hormone (TRH test), in two out of nine a gonadotropin releasing hormone (GnRH) test, and in three out of six GH releasing hormone (GHRH) test yielded abnormal results. High prolactin levels were measured in two out of five patients.ConclusionSOD is characterized by optic nerve hypoplasia and a variety of endocrine deficiencies. In addition, forebrain malformations are present in most SOD patients. Hormonal disorders are present in some SOD patients which may be of hypothalamic origin and need to be investigated systematically.

Spontaneous Nocturnal Leptin Secretion in Children with Myelomeningocele and Growth Hormone Deficiency

Objective: To examine the spontaneous leptin secretion in patients with myelomeningocele (MMC) and growth hormone deficiency (GHD). Methods: Serum leptin levels were studied in 10 prepubertal MMC patients with GHD (CA 6.2 ± 0.5 years), 10 patients with idiopathic GHD (IGHD; CA 7.6 ± 0.7 years) and 12 children with normal variant short stature (NVSS; CA 7.6 ± 0.5 years). Mean BMI (kg/m2) values of the groups did not differ significantly. Nocturnal leptin levels were analyzed over 10 h (blood samples every 20 min) and measured by specific radioimmunoassay. Results: Mean leptin concentrations did not correlate with BMI in MMC patients. Nocturnal leptin secretion of MMC patients was significantly different to those of children with IGHD and NVSS. Morning leptin levels did not decline as observed in both other groups. Conclusion: Since all groups were matched for BMI values, we suggest a hypothalamic dysregulation of leptin secretion in MMC patients.

Relationship between salivary progesterone, 17-hydroxyprogesterone, and cortisol levels throughout the normal menstrual cycle of healthy postmenarcheal girls

OBJECTIVE To determine the usefulness of salivary P and 17 alpha-hydroxyprogesterone (17-OHP) for the assessment of ovarian function. In addition, salivary cortisol (F) levels were measured to assess the role of the adrenal cortex throughout the menstrual cycle. DESIGN Prospective study. SETTING Outpatients in hospital for children and adolescents. PATIENT(S) Thirty young women with regular menstrual cycles. INTERVENTION(S) Saliva collection in the early morning from day 1 of menstrual bleeding until next menses. MAIN OUTCOME MEASURE(S) Salivary P, 17-OHP, and F measured by RIAs. RESULT(S) During days 1-12 of the follicular phase, P and 17-OHP levels remained unchanged (P: 9-29.3 pg/mL; 17-OHP: 8-31 pg/mL). Thereafter, P increased exponentially from day 13 onward, reaching a plateau (mean +/- SEM, 70.1 +/- 9.0 pg/mL) between day 16 and 20, followed by a constant decrease until end of the cycle. The 17-OHP levels increased between day 14 and 17 (maximum: 45.8 +/- 4.5 pg/mL), decreasing rapidly thereafter. The F levels remained unchanged (follicular: 7.5 +/- 1.1 ng/mL; luteal 7.2 +/- 1.1 ng/mL). There was a significant correlation between P and 17-OHP (r(2) = 0.43; P<.001). When calculating ratios of P/F and 17-OHP/F, linear regression yielded a much stronger correlation (r(2) = 0.74; P<.001), although F did not show any correlation to P or 17-OHP. CONCLUSION(S) Changes in salivary 17-OHP levels throughout the menstrual cycle reflect ovarian but not adrenal function.

Changes in the Concentrations of Dehydroepiandrosterone Sulfate and Estriol in Maternal Plasma during Pregnancy: A Longitudinal Study in Healthy Women throughout Gestation and at Term

In a longitudinal study, the changes in plasma concentrations of dehydroepiandrosterone sulfate (DHAS) and total estriol (E3) were followed in 10 normal pregnant women throughout gestation at 8-10, 14-17, 21-24, 28-32, and 38 weeks as well as at the time of admission to the delivery room. The mean plasma concentration of DHAS decreased from 325 +/- 38.2 micrograms/dl in early gestation to minimum levels of 120 +/- 15.9 micrograms/dl at week 38. At delivery there was a 2-fold increase in plasma DHAS (205.3 +/- 17.7 micrograms/dl). The mean total E3 plasma concentration increased from 6.53 +/- 2.5 ng/ml at week 8-10 to 198.6 +/- 30.3 ng/ml prior to delivery. The decrease in the DHAS plasma levels is caused by the elevated metabolic clearance rate throughout pregnancy. The increasing E3 plasma levels are caused by increasing steroid production by the fetoplacental unit and reflect fetal well-being. The peak levels of DHAS and E3 as well as of other steroids of adrenal or placental origin at admission to the delivery room reflect increased maternal and fetal stress with the onset of labor. These longitudinal reference data determined by modern radioimmunoassay methodology are helpful for the prenatal diagnosis of congenital disorders with insufficient or absent fetoplacental function, and in the control of suppression of the fetal pituitary-adrenal axis during dexamethasone treatment in pregnancies with a female fetus affected with congenital adrenal hyperplasia.

Analysis of an interstitial deletion in a patient with Kallmann syndrome, X-linked ichthyosis and mental retardation.

Contiguous gene syndromes are an interesting clinical phenomenon, resulting from interstitial or terminal deletions of several adjacent genes. The phenotype results in a combination of two or more monogenic disorders and relates clinical findings to corresponding genotypes. We present the case of a male patient with Kallmann syndrome (KS), X‐linked ichthyosis (XLI) and X‐linked mental retardation (MRX). He was referred at the age of 15.4 years for delayed puberty and obesity. He had a previous history of pyloric stenosis, bilateral orchidopexy and surgical correction of a pes equinovarus adductus. On physical examination, generalised ichthyosis and hypoplastic external genitalia were found. KS was evident with hypogonadotropic hypogonadism, hyposmia and a hypoplastic anlage of the olfactory tract in magnetic resonance imaging. Lipoprotein electrophoresis, and lack of steroid sulfatase and arylsulfatase‐C activity in leucocytes confirmed XLI. DNA investigation established an interstitial deletion in Xp22.3 involving the Kallmann (KAL) gene, the steroid sulfatase (STS) gene and a putative mental retardation locus (MRX). The novel MRX locus maps to a 1‐Mb region between DXS1060 and GS1.

No Correlation between Androgen Receptor CAG and GGN Repeat Length and the Degree of Genital Virilization in Females with 21-Hydroxylase Deficiency

CONTEXT In 21-hydroxylase (CYP21A2) deficiency (21OHD), the level of in vitro enzymatic function allows for classification of mutation groups (null, A, B, C) and prediction of disease severity. However, genital virilization in affected females correlates only weakly with CYP21A2 mutation groups, suggesting the influence of genetic modifiers. OBJECTIVE The objective of the study was to investigate the influence of the polymorphic CAG and GGn repeats of the androgen receptor (AR) gene on the degree of genital virilization in 21OHD females. DESIGN AND PATIENTS Design of the study was the determination of CYP21A2 genotype, degree of genital virilization (Prader stage), and X-weighted biallelic mean of AR CAG and GGn repeat length in 205 females with 21OHD. OUTCOME MEASUREMENTS Correlation of AR CAG and GGn repeat lengths with Prader stages using nested stepwise logistic regression analysis was measured. RESULTS CYP21A2 mutation groups null and A showed significantly higher levels of genital virilization than groups B and C (P < 0.01). However, Prader stages varied considerably within mutation groups: null, Prader I-V (median IV); A, Prader I-V (median IV); B, Prader I-V (median III); C, 0-III (median I). Mean GGn repeat length of patients was not significantly associated with Prader stages, classified as low (0-I), intermediate (II-III), or severe (IV-V) (odds ratio per repeat: 0.98, 95% confidence interval 0.71-1.35). In contrast, patients with Prader 0-I showed a trend toward longer CAG repeats without reaching statistical significance (P = 0.07, odds ratio per repeat: 0.82, 95% confidence interval 0.65-1.02). CONCLUSION Neither CAG nor GGn repeat lengths are statistically significant modifiers of genital virilization in females with 21OHD.

Prenatal Diagnosis of Congenital Adrenal Hypoplasia

Congenital adrenal hypoplasia is a rare disorder and one of the possible causes of low maternal plasma and/or urine estriol during pregnancy. We studied 2 cases pre- and postnatally. Dehydroepiandrosteronesulfate (DHAS) and estriol (E3) studied longitudinally in maternal plasma were at or below the lower limit of the normal range. Prior to substitution treatment, an ACTH test revealed low plasma levels of aldosterone, cortisol and all their precursors, with no rise after ACTH. ACTH plasma levels were elevated. It is possible to detect congenital adrenal hypoplasia prenatally in families at risk by repeated measurements of DHAS and estriol in maternal plasma during pregnancy.

Chromosome 5q subtelomeric deletion syndrome

The pure 3.5 Mb subtelomeric deletion syndrome is very rare but causes a recognizable phenotype characterized by prenatal lymphedema with increased nuchal translucency, pronounced muscular hypotonia in infancy, borderline intelligence, postnatal short stature with delayed bone age due to growth hormone deficiency, and multiple minor anomalies including mildly bell‐shaped chest, minor congenital heart defects, and a distinct facial gestalt. Terminal deletions including the adjacent ∼2 Mb NSD1‐locus show a compound phenotype with overlap to Sotos syndrome. Larger terminal deletions including also chromosomal bands 5q35.1 and 5q35.2 cause a more severe phenotype with normal body length, significant congenital heart defect, microcephaly, profound developmental retardation or early death due to respiratory failure. Heart defects in the latter are explained by haploinsufficiency of the NKX2.5 gene at 5q35.1. The deletion breakpoint of the 3.5 Mb subtelomeric microdeletion maps to a low copy repeat which is identical to the distal copy of two highly similar regions flanking the recurrent interstitial NSD1 microdeletion. As meiotic mispairing between these low copy repeats seem to be much more likely than a terminal aberration, these neighborhood may prevent occurrence of the subtelomeric deletion syndrome, which could explain the rareness of the latter.

Value of direct measurement of active renin concentrations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

In congenital adrenal hyperplasia (CAR) due to 21-hydroxylase deficiency, measurement of plasma renin activity (PRA) has been the method of choice in diagnosing salt loss and in monitoring adequacy of mineralocorticoid replacement therapy. Due to methodological problems in PRA determinations, direct immunoradiometric assays for the measurement of active renin concentration have been developed. We measured PRA and active renin concentrations simultaneously in 39 patients with CAH (30 salt-wasting, 9 simple virilizing) to evaluate the potential role of this new method in the management of this disease. PRA was determined with an enzymatic assay (sample volume: 2 × 1000 μl plasma), active renin concentration with a direct immunoradiometric assay (sample volume: 2 × 200 μl plasma or serum). We found a highly significant correlation between active renin and PRA in our patients (P < 0.001), as previously shown in healthy subjects. Active renin was as reliable as PRA to assess the quality of mineralocorticoid replacement.