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Ten patients with anorchia were treated with testosterone undecanoate (40 or 80mg/d) starting at the mean age of 11.5 years (range: 10 - 14 years). The effect on Tanner stage development, growth velocity and weight gain are presented. Therapy was started with 40mg 3x/week (n= 4), 40mg 7x/week (n=6), and was increased to 80mg 7x/week (n=9). Therapy was continued for 23.7 months (range: 14 - 40 months). Stretched penile length before therapy was x = 3.35cm (range: 2.5 - 4cm), at the end of therapy 6.25cm on average (range: 5 - 8cm). Pubic hair Tanner stage 2 (PH2) was achieved after 6.7 months (range: 4 - 14 months) PH3 after 20 months (range: 12 - 29 months). Growth velocity increased to 6.7cm/year (range: 3 - 9cm/year) in the first year of treatment, concomitant weight gain was 7.2kg (range: 5.2 - 10kg). No side effects of treatment were observed. We conclude that oral testosterone undecanoate therapy starting at the age of 11 years with 40mg/d for one year and 80mg/d for a second year is simple, safe and effective and provides for a gentle induction of puberty in anorchid boys.

In 18 families at risk for the HLA-linked, 21-hydroxylase deficient form of autosomal recessive congenital adrenal hyperplasia (CAH), prenatal diagnosis (PD) was performed using two methods: (1) HLA-A,B,C typing and in the latter 11 cases also DR typing of cultured amniotic fluid cells (AFC) using the standard microcytotoxicity assay, and (2) measurement of second trimester amniotic fluid 17-hydroxyprogesterone (17-OHP) concentration using gel chromatography and radioimmunoassay. The accuracy of the prenatal predictions was confirmed by postnatal HLA typing of umbilical cord blood lymphocytes and by clinical evaluation. In 16/18 families, both HLA typing of AFC and 17-OHP measurements proved informative for PD. The predictions of both methods were concordant in 14/16 families (88 per cent). In ten of these families, a normal fetus was predicted, and in four, an affected fetus; all pregnancies were carried to term and all predictions were confirmed postnatally. In 2/16 cases (12 per cent), however, the predictions were discordant: the prenatal HLA typing indicated an affected fetus, whereas the 17-OHP values predicted a normal fetus. Both pregnancies were continued and two healthy boys were delivered. The discordance proved to be due to a 'missed' HLA antigen in one case and to serologically cross-reactive HLA antigens in the second. Finally, in 2/18 cases, prenatal assessment of fetal genotype had to rely on HLA typing alone as 17-OHP measurement was not performed in one family and in the second family the 17-OHP values obtained were not informative due to inadvertent continuation of hormone therapy to the date of amniocentesis. In both cases, the HLA typing data accurately predicted a normal fetus. In conclusion, a combination of HLA typing of cultured AFC and 17-OHP measurements of amniotic fluid permits accurate prenatal diagnosis of CAH in most cases (88 per cent). In addition, the supplementary use of HLA-DR typing of AFC as presented here for the first time proved helpful in families with HLA-A,B homozygosity due to parental sharing of antigens and can be informative for identifying HLA-B/21-OH recombinant haplotypes.

The increase of plasma cortisol (F), androstenedione (A), 17α-hydroxyprogesterone (17-OH-P) and testosterone (T) was measured after iv administration of ACTH in heterozygotes for CAH and in controls under two different conditions: Test 1: ACTH stimulation was performed without any particular preparation. Test 2: 1.5 mg of dexamethasone (dex.) was given the evening before the ACTH stimulation. Plasma F, A, 17-OH-P and T were measured by specific radioimmunoassays (RIA). Following ACTH stimulation, the increase of 17-OH-P was significantly higher in CAH-heterozygotes than in controls in both tests (P < 0.0005). Heterozygotes were characterized by a 17-OH-P increase after ACTH stimulation exceeding the +2 sd limit of the 17-OH-P increase found in controls. The detection of female heterozygotes was considerably improved by the administration of dex. before testing (test 2). In males, however, a better identification of heterozygotes was obtained without previous administration of dex. (test 1). By these tests, 100% of female (test 2) and 79% of male (test 1) CAH heterozygotes could be correctly identified. There were no significant differences in the levels of F, A and T between heterozygotes and controls except for decreased T levels in test 1 (2P < 0.01) in most male heterozygotes after ACTH stimulation.

Summary: Blood volume, plasma volume and red cell mass, red cell parameters, reticulocytes, serum iron, and total iron binding capacity were investigated. Fifty-nine growth-retarded children were studied: 27 children with idiopathic short stature (ISS) and 32 children with isolated growth hormone deficiency (GHD). Fifteen of the CHD patients were studied before treatment and again 3–6 months after onset of treatment with growth hormone, 3 GHD patients only before and 14 only during treatment. Blood volume, plasma volume, and red cell mass were significantly (P < 0.005) decreased by 15% in the untreated GHD patients and were normal in the children studied during treatment with growth hormone compared with the values in ISS patients. In the 15 GHD patients studied before and during treatment, blood volume, plasma volume, and red cell mass increased by 17% to normal values (P < 0.0005) on treatment with growth hormone. No significant differences were demonstrable between values related to actual body weight and to corrected weight for height. Hematocrit, mean corpuscular volume, and reticulocytes remained unchanged. Serum iron and total iron binding capacity were normal before treatment. Serum iron increased and total iron binding capacity decreased significantly during growth hormone substitution. In a pair of twins with Russell-Silver dwarfism and GHD, growth hormone increased blood volume, plasma volume, and red cell mass as in the other GHD patients. In another pair of twins with Russell-Silver dwarfism without GHD, growth the hormone was without effect on blood volume. Speculation: Our results of decreased blood volume and red cell mass in children with isolated GHD and the increase of blood volume and red cell mass during growth hormone treatment provide direct evidence that growth hormone is stimulating erythropoiesis. The less pronounced decrease of blood volume and red cell mass in our patients compared with the literature data obtained on panhypopituitary and hypophyseetomized subjects may indicate that growth hormone, thyroxin, and other hormones act synergistically on erythropoiesis. In children with panhypopituitarism or isolated GHD, blood volume, plasma volume, and red cell mass were found to be decreased by approximately 30% below normal (28, 30). Therefore, Shahidi and coworkers (30) recommended checking of blood volume in order to distinguish between dwarfism due to panhypopituitarism or GHD and idiopathic short stature. Their reports, however, include only one patient with isolved GUD (28), or do not differentiate between children with isolated GHD and panhypopituitarism (30). The effect of growth hormone on blood volume in isolated GHD has not yet been studied.

The patient, diagnosed as a case of testicular feminisation in infancy, was examined at the age of 15 years because of severe symptoms of virilising puberty with poor breast development. Plasma steroid analyses revealed a 10-fold elevated androstenedione concentration (A: 1562 ng/100 ml). Testosterone (T: 266 ng/100 ml) was in the male pubertal range. Thus the A/T-ratio was far above normal. The oestrone/oestradiol ratio was also elevated (Oe1/Oe2: 10.2/2.2 ng/100 ml). A, T, Oe1 and Oe2 could not be suppressed by dexamethasone, but reacted promptly to fluoxymesterone (A: 781 ng/100 ml). hCG caused a further increase of the A/T-ratio (2220/246 ng/100 ml); ACTH did not alter the A-concentration. These findings together with simular investigations after gonadectomy suggest that the failure to convert A to T and Oe1 to Oe2 is essentially located in the testes. In vitro incubations of testicular tissue showed reduced 17-ketosteroid reductase activity in tissue slices and in the subcellular fractions microsomes and cytosole. This form of male pseudohermaphroditism can easily be detected already in infancy, if steroid analyses and stimulation tests are performed. In case of female sex assignment patients should be submitted to early orchidectomy in order to avoid virilisation in puberty.

Beschreibung eines Jungen mit Pseudohermaphroditismus maskulinus, mit normalem mannlichen Karyotyp, welcher bei der Geburt als Madchen angesehen worden war. Mit 12 Jahren Auftreten einer hochgradigen Gynakomastie. Steroiduntersuchungen wurden mit Radiogaschromatographie und mit radioimmunologischen Methoden durchgefuhrt.

In search for a biochemical marker to differentiate between adrenocortical carcinoma (AC) and adenoma (AA), plasma levels of the following steroids were studied preoperatively and postoperatively: 11-deoxycorticosterone (DOC), corticosterone (B), 11-deoxycortisol (S), and cortisol (F). Levels were measured by Sephadex LH-20 chromatography and specific radioimmunoassays. The subjects included eight children ages 2 years, 5 months to 9 years, 10 months. There were three girls and 5 boys with pseudoprecocious puberty due to adrenocortical tumors (histologically, four were AC and four, AA). The preoperative showed that DOC and S levels were elevated in all patients, F levels were elevated in four of eight children when compared with age-matched controls, whereas B was normal. Postoperatively, all levels returned to normal. The ratios of B/DOC and F/S as an index of adrenal 11 beta-hydroxylase activity were calculated. The preoperative ratios of B/DOC were markedly decreased in all patients with AC compared to controls (7.7,4.1,5.9,1.9 versus 23.5, median), but normal in three of four patients with AA (16.2, 29.6, 16.1). The F/S ratios were significantly lower in AC and AA when compared with controls. The data indicate a deficiency in 11 beta-hydroxylation in cases of adrenocortical tumors. Despite a still limited number of patients, the decreased B/DOC ratios may possibly indicate malignancy and could be helpful in distinguishing by biochemical means between benign and malignant adrenocortical tumors.

Extract: Plasma concentrations of estrone and estradiol were determined by radioimmuno-assay of cord blood from 17 neonates and of venous blood of 15 neonates, 61 boys and 69 girls of all developmental stages, 27 healthy women, 20 healthy men, and 89 male and female adolescents with different disorders of sexual development. In cord blood both estrone and estradiol averaged 15,000 pg/ml. Blood drawn from neonates shortly after birth showed levels between 300 and 500 pg/ml. These levels fell to 5–15 pg/ml within a few days after birth, which is the normal range for both sexes up to 7 years. Before puberty, estrone rises earlier in girls than in boys. The increase of estradiol follows the onset of puberty. Boys reach adult levels in stage IV, whereas girls in stage V still have lower estrogen levels than mature women. We did not find higher levels in 29 adolescents with gynecomastia than in normal adolescents at the same stage of puberty. We observed abnormally high estrogens in children with congenital adrenal hyperplasia, but, in spite of some very high levels, we did not observe premature thelarche or gynecomastia in children with this disease. Six females and 10 males with panhypopituitarism, aged from 10 to 19 years, revealed low values within the infantile range. Six boys between 5 and 14 years who suffered from anorchia had very low levels of estrogen, especially estradiol (which was nearly undetectable). In contrast to patients with functioning testicle tissue, the patients with anorchia did not show any increase of estrogens after stimulation with human chorionic gonadotropin. Abnormally low levels were found in females with Turner's syndrome, but only in those with 45, XO karyotype. Patients with 45, XO/46, XX, or 46, XXp– karyotype had high levels of estrogen which corresponded to clinical signs of advanced puberty. Speculation: As demonstrated by our results, the radioimmunologic method enables us to measure the low estrogen levels which are found in children. This will permit a more intensive examination of the pituitary-gonadal and pituitary-adrenal interrelation in the future.

Plasma testosterone was investigated by gas-liquid chromatography with an electron capture detector in a cross-sectional study in childhood and during puberty in 214 boys. The testosterone values were correlated with sexual characteristics such as axillary hair, pubic hair, testicular size and bone age. In 22 individuals during puberty a longitudinal study was started, indicating a very steep increase of plasma testosterone between 40 and 240 ng/100 ml. This stage is mostly passed through very rapidly within 10 months. Plasma testosterone, growth velocity and weight gain were correlated in two boys during puberty. The peak of growth spurt occurs between 50 and 170 ng of plasma testosterone.

Butenandt, O., Bidlingmaier, F. and Knorr, D. (Department of Paediatrics, University of Munich, Germany). Effect of different human growth hormone preparations on nitrogen retention in hypopituitary children. Acta Paediatr Scand, 63: 549, 1974.—The biologic activity of three different preparations of human growth hormone (HGH) obtained with the methods of Raben, Reisfeld and Roos respectively were compared in nitrogen retention tests in 18 patients with hypopituitarism and in 17 children with familial shortness of stature. HGH Raben produced a mean nitrogen retention of 30.9% in 11 hypopituitary patients and no retention in the control group, HGH Reisfeld was followed by a retention of 19.7% in the 9 hypopituitary patients and an elevated excretion of 12% in the control group, and HGH Roos evoked a retention of 33.2% only in the 9 hypopituitary children. HGH Reisfeld had a lesser response in consecutive tests with different HGH preparations in the same patients than the other two HGH preparations. The dilution curve of HGH Reisfeld obtained with a double antibody radio immunoassay did not parallel a dilution curve of a reference hormone from the National Institute of Health whereas the other two preparations had identical dilution curves. It is concluded that the method of extraction alters the biologic activity of the hormone as well as the physico-chemical properties.

Plasma levels of aldosterone, corticosterone, 11-deoxycorticosterone, progesterone, 17-hydroxyprogesterone, 11-deoxycortisol, cortisol, and cortisone were measured simultaneously by a micromethod of multisteroid analysis in eight vaginally delivered premature infants (PI) of 33-36 wk gestation with uneventful peri- and postnatal course. Mean concentrations (ng/ml) in umbilical arterial and in peripheral venous or capillary plasma sampled longitudinally at age 2 h to 7 days were compared with the same kind of data obtained from a group of 12 term infants (TI) who served as controls. Mean aldosterone was two to five times higher in PI than in TI (umbilical artery, 2 h to 7 days; p less than 0.05), whereas 11-deoxycorticosterone was lower in PI from 2 h (p less than 0.01) until 7 days (NS). Corticosterone was significantly higher in PI than TI at 6 and 24 h after birth, whereas cortisol was slightly lower (NS) in PI in umbilical artery and 2 h after birth, but higher (p less than 0.02) at 6 h, showing less variation in PI than in TI. 17-Hydroxyprogesterone levels in PI were two to three times higher (p less than 0.02) during 6 h until 7 days after birth. The data suggest that PI are able to maintain high aldosterone levels in the early neonatal period. Higher levels of the active glucocorticoids (cortisol and corticosterone) seen after delivery point to a more stressful extrauterine adaptation of PI. Furthermore, the data demonstrate that the adrenal cortex is fully functioning in premature infants (33-36 wk gestation) as well as in term infants.

We applied the ACTH-stimulation test developed in our laboratory for the detection of heterozygous carriers of the 21-hydroxylase deficiency gene to patients suffering from hirsutism (n=89), premature pubarche (n=75), early puberty (n=37), and precocious puberty (n=22). While, in the general population, this test is positive in less than 2%, we found in 33% of hirsute patients, in 41% of patients with premature pubarche, and in 33% of patients with early puberty a hormonal response similar to the one seen in heterozygous carriers for the 21-hydroxylase defect. In contrast, only 18% of patients with precocious puberty responded abnormally. Thus we speculate that, at least in some patients with hirsutism, premature pubarche, and early puberty, heterozygosity for the 21-hydroxylase defect plays a major role in the pathogenesis of these disorders.

The pharmacodynamics of plasma testosterone (T) and androstenedione (A) levels were studied in ten hypogonadal boys after oral administration of testosterone undecanoate (TU). Plasma T and A levels were measured by specific radio-immunoassays. Six hours after a single dose of 120 mg TU, there was a significant increase (P < 0.005) in plasma T and A with a median T peak level of 940 ng/100 ml. Furthermore, twelve agonadal boys treated with a mean dose of 60 mg TU/day were examined over a period of 18–24 months. During this therapy, plasma T and A levels were significantly higher than before (P < 0.005), whereas plasma levels of LH and FSH did not decrease significantly. With the exception of one anorchic boy, all patients showed signs of sexual maturation, such as growth of pubic and axillary hair, and steady development of bone age during oral TU treatment.

Congenital adrenal hyperplasia (CAH) is a disorder of Cortisol and aldosterone biosynthesis that mostly results from a 21-hydroxylase enzyme deficiency [1]. There is an incidence of about 1: 7000 to 1: 10 000 in central Europe [2–4]. It is characterized by increased plasma levels of 17-hydroxyprogesterone and elevated adrenal androgens, causing virilization.

Corticosteroids (CS) are known to be essential for fetal organ maturation and seem to play an important role in both the initiation of parturition and the postnatal adaptation of the human neonate. Pharmacologically, CS are widely used for enhancing fetal lung maturation prior to premature delivery. However, knowledge of endogenous CS and precursor levels throughout fetal and perinatal life and their response to exogenous CS is limited. Therefore, using automated liquid column chromatography plus specific radioimmunoassays, unconjugated aldosterone (Aldo), corticosterone (B), 11-deoxycorticosterone (DOC), progesterone (P), 17-hydroxyprogesterone (17-OHP), 11-deoxycortisol (S), cortisol (F) and cortisone (E) were simultaneously followed in 70 amniotic fluid (AF) control samples throughout pregnancy, and in cord and neonatal plasma longitudinally during the first week of life. From 14 to 38 weeks, AF levels of all measured steroids except E rose by 2 to 12-fold on the average (allP

Influence of the Mode of Delivery on Umbilical and Postnatal Plasma Levels of 7 Corticosteroids in the Newborn

Urinary estrone (E1) and estradiol (E2) glucuronide and sulfate were determined separately by RIA in 44 newborn and young infants (26 boys, 18 girls). In 7 cases the estrogen excretion was followed up over one month. The conjugates were hydrolyzed enzymatically; the estrogens were purified and separated by Sephadex LH 20 chromatography. During the first month, children excreted more sulphated than glucuronized estrogens with a ratio of 8:2, but within the first year, this ratio was reversed to 3:7. In both sexes E1 + E2 excretion was 10 times higher during the first 2 months than at the end of the first year. Boys showed a sharp decline during the third month of life; girls, however, did not reach low values until the sixth month. While the E2/E1 ratio in boys was one, girls showed predominance of E2-excretion with a mean ratio of 2.5:1 during the first 6 months of life.

Increased mortality with long-term E infusions in intensive care patients has been reported and evidence is accumulating that E causes reversible adrenocortical suppression with decreased serum cortisol levels. A direct inhibition of adrenal steroidogenesis has been suggested, but so far data on the mechanism of this action are lacking. A 6 1/2 year old boy with convulsions due to encephalitis was treated with constant E infusions (1 - 2 mg/kg/h). Prior to E administration, adrenocortical function was normal as tested by an ACTH-test. 5 days after institution of therapy and 14 days after discontinuation, plasma levels of 11-deoxycorticosterone (DOC), corticosterone (B), 11-deoxycortisol (S) and cortisol (F) were measured by RIAs after Sephadex LH-20 chromatography. During E therapy DOC and S levels were highly elevated, while B was in the lower normal range and F was markedly decreased. Likewise the ratios of B/DOC and F/S, which reflect adrenocortical 11 β-hydroxylase activity, were extremely decreased (B/DOC:0.06 vs 27 in controls; F/S:0.009 vs 230 in controls). After discontinuation of therapy, the absolute values as well as the ratios returned to normal. These results show, that E is a potent inhibitor of adrenal 11 β-hydroxylation.Increased precaution seems to be necessary when this drug is used in patients who are under considerable amount of stress.

In order to obtain an improved differentiation between heterozygotes and normals, the increase of 17-OHP in plasma of CAH parents (n=30) and of controls (n=31) was measured after ACTH (Synacthen) stimulation i.v. at 60' under standardised basal conditions. The ACTH stimulation was performed after suppression of the adrenal cortex with 1.5 mg dexamethasone (Dex.) given the previous evening. Females were tested between days 3 and 8 of the menstrual cycle. Plasma 17-OHP was measured by a specific RIA. The mean increase of 17-OHP was significantly higher in heterozygotes than in normals (p=0.0005). In the control group, 100% of the males and 89% of the females showed an increase below 200 ng/d1. Assuming an increase of 200 ng/d1 as the dividing line for the differentiation, 54% of the CAH fathers and 100% of the CAH mothers were found to be heterozygotes. Because of the unsatisfactory differentiation of CAH fathers, we now carry out our former test without Dex. administration in males. However, for the detection of female heterozygotes, the test described here is a marked improvement.

In our first studies we found elevated plasma levels of ANP and its second messenger cGMP in newborns and in children with cardiac diseases. Despite these high levels there is no effect on the water and electrolyte excretion. The lacking response to ANP in these patients may be explained by an enhanced release of other volume regulating hormones. To prove this hypothesis we measured plasma and urinary levels of ANP and cGMP as well as urinary excretion of aldosterone (Aldo) and vasopressin (AVP) in 22 healthy infants and 26 infants with cardiac diseases. Urine was collected for 8 hours from 10 p.m. to 6 a.m. In children with cardiac diseases we found significantly higher plasma levels of ANP ( = 225 ± 65 pg/ml) and cGMP ( = 8,5 ± 4,5 pmol/ml) and urinary levels of cGMP ( = 30 ± 5 nmol/8h/kg), Aldo ( = 800 ± 20 pg/8h/kg)and AVP (1100 ± 250 pg/8h/kg) than in control infants (p < 0.001). There was no correlation between ANP or cGMP levels and water- and sodiumexcretion.

E1, E2, LH and FSH were measured radioimmunologically in 81 plasma specimens of 28 sexually precocious girls 1 to 10 years of age. Prior to treatment in these girls the mean E1 value (15 pg/ml) was within the infantile normal range, but the mean values of E2. (26 pg/ml), LH (1, 2 ng/ml) and FSH (1, 6 ng/ml) were significantly elevated. However, out of 63 plasmas only 31 showed elevated E2, 24 LH and 34 FSH values above the normal range for age. Grouping the values according to breast development revealed considerably lower estrogens and gonadotropins in patients than in normally maturating girls of the same developmental stage. During treatment with CY (mean daily dose: 50 mg/m2) the mean estrogen and gonadotropin levels of 8 patients decreased significantly (E1 : p

Effect of opioid(pentazocine) and opioid-antagonist (naloxone) administration on plasma β-LH,FSH and Prolactin(PRL) levels in the perinatal period

The apparent inability of elevated atrial-natriuretic peptide (ANP) levels to cause natriuresis and diuresis in children with heart failure may be related to a reduced response of target organs to ANP. The cellular effects of ANP seem to be mediated by cGMP as the second messenger of ANP. Simultaneous measurement of ANP and cGMP has been shown to be a useful tool to study the cellular response to ANP. Therefore, plasma ANP and cGMP levels were measured by radioimmonoassay in 168 healthy children and in 47 children with congenital cardiac diseases. In healthy children ANP and cGMP plasma levels were measured in the range of 5-109 pg/ml (mean 45.5) and 0.2-2.8 pmol/ml (mean 1.3) respectively. In children with cardiac diseases significantly higher ANP (range 30-980, mean 280 pg/ml) and cGMP levels (range 0.2-6.0, mean 2.8 pmol/ml) were determined. There was a highly significant correlation between the two in children with cardiac diseases (p

The adrenal cortex seems to play an important role in the newborn's adaptation to extrauterine life. Since systematic studies on multiple CS in the same human newborn have not yet been reported, progesterone (P), deoxycorticosterone (DOC), 17α-hydroxyprogesterone (17α), corticosterone (B), aldosterone (A), cortisone (E) and cortisol (F) were followed in a single 250 μl peripheral plasma sample in 12 vaginally delivered full-term infants of either sex. Mean concentrations (after automated LH-20 multi-column chromatography and specific radioimmunoassays) were in ng/ml: Besides marked materno-fetal CS differences, P, 17α and DOC (predominantly of placental origin) disappear rapidly with varying half lives. A, B, E and F, however, remain elevated in comparison with later infancy, reflecting high adrenal biosynthetic activity. *(Approved by parents and Hospital's Ethical Committee)