LC-MS/MS based determination of basal- and ACTH-stimulated plasma concentrations of 11 steroid hormones: implications for detecting heterozygote CYP21A2 mutation carriers.

OBJECTIVE: Heterozygosity in 21-hydroxylase deficiency (21OHD) has been associated with hyperandrogenemic symptoms in children and adults. Moreover, the carrier status is mandatory for genetic counseling. We aimed at defining a hormonal parameter for carrier detection by mass spectrometry. DESIGN: Eleven basal and ACTH-stimulated steroid hormones of heterozygous carriers of CYP21A2 mutations and control individuals were compared. METHOD: Hormones were determined in plasma samples by liquid chromatography tandem mass spectrometry (LC-MS/MS) in 58 carriers (35 males, 23 females, age range 6-78 years) and 44 random controls (25 males, 19 females, age range 8-58 years). RESULTS: Heterozygotes could be identified best applying the 17-hydroxyprogesterone+21-deoxycortisol/cortisol×1000 ((17OHP+21S)/F×1000) equation 30  min after ACTH injection. An optimal cut-off value of 8.4 provided 89% sensitivity and specificity. Considering this data and a published frequency of heterozygotes of 1/50 to 1/61, the positive predictive value (PPV) of this cut-off is 12%. Of note, the negative predictive value (NPV) excluding heterozygosity in a given patient is 99.8%. CONCLUSION: Considering only marginal biochemical effects anticipated from heterozygosity, the stimulated ((17OHP+21S)/F×1000) identifies and excludes heterozygotes remarkably well. Nevertheless, LC-MS/MS cannot replace genetic testing, since sensitivity and specificity did not reach 100%. However, due to the considerably high NPV of the optimal cut-off and to a specificity of even 100% applying a cut-off higher than 14.7, hormonal assessment of heterozygosity can be of significant aid in conditions with limited access to genetic testing, as in some health care systems. The ((17OHP+21S)/F×1000) equation can guide diagnostic considerations in the differential diagnosis of hyperandrogenism.

Initially elevated TSH and congenital central hypothyroidism due to a homozygous mutation of the TSH beta subunit gene: case report and review of the literature.

Congenital central hypothyroidism (CCH) is a rare disease which can be caused by mutations in the gene for the thyrotropin (TSH) beta subunit ( TSHB). The diagnosis is usually delayed because the TSH serum levels in these patients are not elevated leading to a negative result in the neonatal TSH screening. Herein, we report a 2-year-old girl with CCH due to a mutation in the TSHB gene, in whom the unusual finding of an initially elevated TSH level complicated the diagnostic workup. The proposita, who had a supposedly normal TSH screening result, is a German girl of non-consanguineous parents. At 5 weeks of age, her thyroid function tests showed peripheral hypothyroidism with a moderately increased TSH (23.8 microIU/ml) so that thyroid hormone substitution was initiated. At the age of 2 years, the administration of TRH failed to increase the TSH serum concentrations, which prompted TSH measurements with two different assay systems. Variable TSH levels ranging from not detectable low to elevated were found so that central hypothyroidism due to a mutation in the TSHB gene was suspected. This was confirmed by molecular analysis of the TSHB gene, which identified a homozygous deletion (delta 313 T) in the coding sequence. This mutation has been found in the German population before and may be a founder mutation. We conclude that depending on the assay system variable TSH serum levels in individuals with mutations in the TSHB gene may complicate the diagnostic workup.

[Calcinosis cutis in Albright hereditary osteodystrophy: pseudohypoparathyroidism type Ia]. / Calcinosis cutis bei hereditärer Albright-osteodystrophie: pseudohypoparathyreoidismus typ Ia.

Albright hereditary osteodystrophy (AHO) is characterized by a symptom complex including short stature, brachymetacarpia, obesity, round facies, cutaneous osteomas, and mental retardation. AHO is caused by mutations in the GNAS-gene localized on chromosome 20 encoding for Gsalpha protein, a signal transducer of endocrine pathways. Therefore, AHO is often associated with endocrinopathy such as pseudohypoparathyroidism or hypothyroidism. A nine-month-old boy presented with typical features of this syndrome. The diagnosis was confirmed by biochemical and molecular analyses. An unusual feature was calcinosis cutis at such an early age, which led to extensive differential diagnostic procedures.

Complete virilization in congenital adrenal hyperplasia: clinical course, medical management and disease-related complications.

OBJECTIVE: In girls with congenital adrenal hyperplasia (CAH), genital ambiguity usually leads to a rapid neonatal diagnosis. Rarely, CAH causes complete virilization and male sex assignment with a delayed diagnosis. After being confronted with very specific problems in two of such patients, we collected data of patients with CAH and complete virilization in a nationwide study to delineate specific problems of these rare patients in order to improve their management. DESIGN AND PATIENTS: Through the German Working Group of Paediatric Endocrinology (Arbeitsgemeinschaft Pädiatrische Endokrinologie, APE), questionnaires were sent to all members caring for patients with CAH and complete virilization in their endocrine clinics. Data from 16 patients from 10 paediatric endocrine centres were assessed by questionnaire. RESULTS: The following problems have been encountered. (1) Sex assignment/gender identity: initially all patients had a male sex assignment. Six patients were diagnosed during the first month of life. Five were reassigned to female sex immediately, one at the age of 19 months. Except in one girl demonstrating some tomboyish behaviour, gender role behaviour in these patients did not differ from unaffected girls. Ten patients were diagnosed late at 3.4--7 years of age. In seven patients with a late diagnosis, male sex assignment was maintained; one of them expressed some concerns about living as a male. In three patients late sex reversal was performed, gender identity is very poor in one and new sex assignment is currently under consideration. (2) SURGERY: irrespective of the sex assigned, all patients had between one and three surgical procedures, including clitoris reduction and (repeated) vaginoplasties in patients with female sex assignment. Hysterectomy and ovarectomy were performed in patients with male sex assignment. (3) Short stature: patients with a late diagnosis of CAH had extremely advanced bone ages of +6.3 to +9.5 years, leading to severely reduced final height of 137 to 150 cm in adult patients. Patients tended to follow height percentiles of genetic females. One pubertal patient was suicidal due to short stature. (4) Central precocious puberty (CPP): prolonged exposition to adrenal androgens led to CPP in one patient. He was treated with GnRH analogues until gonadectomy. CONCLUSIONS: Patients with CAH and complete virilization have a high risk of being diagnosed late. There are major problems and uncertainties of the patients' families and the treating physicians concerning gender assignment. Gender identity is disturbed in some patients. In addition, multiple surgical procedures are necessary and short stature as well as central precocious puberty might be important to avoid late sequelae. While some surgical interventions are probably unavoidable, most of these issues could be resolved with an early diagnosis. Thus, especially for these patients, a neonatal screening programme for CAH would be of paramount importance.

Effect of glucocorticoid excess on the cortisol/cortisone ratio.

OBJECTIVE: The conversion of cortisol, which binds avidly to the mineralocorticoid receptor, to cortisone, which no longer has mineralocorticoid function, is predominantly catalyzed by the 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD 2). It was the objective of the present study to examine the impact of different forms of glucocorticoid excess on the cortisol/cortisone ratio and to differentiate their role in the genesis of hypertension. DESIGN AND METHODS: Plasma cortisol and cortisone levels were determined in 12 adults with Cushing's disease, 12 adults with hypercortisolism due to an adrenal tumor, and 20 healthy volunteers before and after an intravenous ACTH test, using specific radioimmunoassays after automated Sephadex LH 20 chromatography. RESULTS: The cortisol/cortisone ratios were significantly higher in patients with Cushing's disease (13.9 +/- 1.1), adrenal tumors (11.5 +/- 2.3), and in healthy volunteers after ACTH stimulation (14.1 +/- 2.0) than in untreated controls (6.0 +/- 0.5) (P < 0.001, P < 0.05, and P < 0.001, respectively). Similar differences were seen for cortisol plasma concentrations, whereas cortisone concentrations did not differ among the groups. CONCLUSIONS: Our data suggest that the excessive mineralocorticoid effects in patients with hypercortisolism are inflicted by elevated cortisol/cortisone ratios possibly due to an insufficient conversion of cortisol to cortisone by 11beta-HSD 2. This may provide a possible explanation for the occurrence of hypertension. This effect seems to be independent of the role of ACTH in the mechanism of hypercortisolism.

Longitudinal imaging reveals pituitary enlargement preceding hypoplasia in two brothers with combined pituitary hormone deficiency attributable to PROP1 mutation.

Mutations of the PROP-1 gene cause combined pituitary hormone deficiency. Progressive ACTH/cortisol insufficiency is found in a few patients. Congenital hypoplasia of the anterior pituitary gland is the most common magnetic resonance imaging finding in patients with PROP-1 mutations. We present two brothers with compound heterozygosity for the two mutations 150delA and 301-302delAG of the PROP-1 gene. Both showed combined pituitary hormone deficiency of GH, TSH, PRL, and gonadotropins, as is typical for PROP-1 deficiency. We observed a developing insufficiency of ACTH and cortisol secretory capacity in both patients. Computed tomography revealed an enlarged pituitary in the older brother at 3.5 yr of age. Repeated magnetic resonance imaging after 12 yr showed a constant hypoplasia of the anterior pituitary lobe. Similarly, magnetic resonance imaging of the younger brother showed a constant enlargement of the anterior pituitary gland until 10 yr. At the age of 11 yr, the anterior pituitary was hypoplastic. The reason for pituitary enlargement in early childhood with subsequent decrease in pituitary size is not known. We speculate that altered expression of early transcription factors could be involved. Because both patients have the same PROP-1 mutations and an identical pattern of combined pituitary hormone deficiency, we suggest that early pituitary enlargement may be the typical course in such patients in whom pituitary surgery is not indicated.

Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens.

Precocious puberty is generally defined as the appearance of secondary sex characteristics before age 8 years in girls (or menarche before age 9 years) and before 9 years in boys. The overall incidence of sexual precocity is estimated to be 1:5,000 to 1:10,000 children. The female-to-male ratio is approximately 10:1. In addition to the psychosocial disturbances associated with precocious puberty, the premature pubertal growth spurt (with less time for prepubertal growth) and the accelerated bone maturation result in reduced adult height. Precocious puberty may be gonadotrophin-dependent [i.e. of central origin with premature activation of the gonadotrophin-releasing hormone (GnRH) pulse generator] or gonadotrophin-independent (i.e. peripheral where the GnRH pulse generator is suppressed). This can be determined by GnRH testing. The pathophysiology is the basis for different diagnostic and therapeutic strategies, i.e. in the first case a stimulated LH/FSH ratio >1 and suppressive treatment with GnRH agonists (e.g. in hypothalamic hamartoma), and in the second decreased gonadotrophins and removal or suppression of the endogenous or exogenous sex steroid source (e.g. congenital adrenal hyperplasia). While several cases of gonadotrophin-independent precocious puberty due to oestrogen exposure via the transdermal, oral, or inhalative route have been reported, no case is known with the development of subsequent secondary central precocious puberty. Food contamination with oestrogens is theoretically possible, but would most probably be sporadic and, thus, would not lead to precocious puberty. As steroid hormones in meat production are banned in the European Union, no data on the impact of environmental oestrogenic substances on human maturation are currently available. In conclusion, the risk for children to develop precocious puberty through exposure to oestrogens (or androgens) in the environment or in food is very low. Nevertheless, studies of the effects of defined environmental oestrogenic substances on the human reproductive system and on pubertal development are warranted.

Treatment of central precocious puberty: lessons from a 15 years prospective trial. German Decapeptyl Study Group.

There is still controversy about the auxological outcome of GnRH agonist treatment in patients with CPP and about the favorable age and auxological characteristics at start of treatment for achieving a normal final height (FH) or for preserving height potential. We analyzed the FH data of 52 young women from a prospective multicentric trial which was started in 1985. The aim of this analysis was to determine factors that may predict a favorable FH or a good height gain. Chronological age (CA) was 5.2 +/- 2.1 yr (+/- SD) at start of puberty, 6.2 +/- 2.0 yr at start of triptorelin depot treatment, 11.1 +/- 1.1 yr at end of treatment, and 16.7 +/- 2.6 yr at FH evaluation. After 4.8 +/- 2.2 yr (1.1-9.9 yr) of treatment duration, FH was 160.6 +/- 8.0 cm (vs 154.9 +/- 9.6 cm of initial height prediction [PAH], p<0.05). A FH within TH range or in excess of mean TH was achieved by 78% or 41% of patients. FH was above the 3rd percentile of the normal German population in 29% of patients (63% had an initial PAH < 156 cm). The group of patients with start of puberty at age < or = 6 yr (Group 1) showed a significantly higher height gain (FH - initial PAH) and lower height deficit compared to TH than older patients (Group 2). Furthermore, the percentage of patients from Group 1 reaching TH range or mean TH showed a significant increase with GnRH agonist treatment whereas this was not the case in Group 2. Stepwise regression analysis showed that height SDS at end of treatment, age at menarche, bone age (BA) at start of treatment, and BA advancement at end of treatment were determinants of FH (r2=0.923). Initial BA advancement and treatment duration were the factors that explained 68% of the variability of height gain. Although BA advancement at initiation of treatment was negatively associated with FH it was a positive predictor of height gain. In addition, height gain correlated significantly with CA and BA at start of treatment (r= -0.430, p=0.004 and r=0.359, p=0.018). Growth after interruption of treatment had no significant predictive effect on FH. It is concluded that a higher percentage of patients below 6 yr of age at start of puberty do profit from GnRH agonist treatment with respect to achieving a normal FH. BA, BA advancement, and height SDS at treatment start are important factors for determining outcome.

Serum leptin levels in patients with progressive central precocious puberty.

Leptin is a metabolic signal that may be involved in signaling adequacy of energy metabolism for the onset of reproductive function. The aim of this study was to investigate the relationship between leptin serum levels and pubertal development in girls with progressive central precocious puberty (CPP). We investigated longitudinally 14 girls with CPP before and during treatment with depot leuprorelin acetate. Mean (+/-SEM) chronological age and bone age at start of therapy were 6.0+/-0.6 y and 9.5+/-0.7 y, respectively. Leptin was determined by RIA. Girls with CPP showed no significant difference in leptin levels at pretreatment and after 1 and 2 y of treatment compared with healthy girls of the same body mass index (BMI). Mean leptin SD score adjusted for BMI was 0.31+/-0.4, 0.24+/-0.2, and 0.49+/-0.3, respectively (not significant). In a stepwise regression analysis model with BMI, bone age, chronological age, basal and stimulated LH, estradiol, dehydroepiandrosterone, androstenedione, and clinical pubertal signs, BMI was the only parameter that showed a significant correlation with leptin (p = 0.006). In conclusion, these data suggest that serum leptin levels are not significantly elevated at the onset of CPP compared with normal girls. Treatment with depot gonadotropin releasing hormone agonist seems to have no influence on leptin concentrations. As in normal girls, serum leptin levels in girls with CPP are mainly determined by BMI. Thus, we have no evidence that alterations of leptin are related to premature onset of puberty.

Gonadal histology with testicular carcinoma in situ in a 15-year-old 46,XY female patient with a premature termination in the steroidogenic acute regulatory protein causing congenital lipoid adrenal hyperplasia.

Mutations in the steroidogenic acute regulatory protein (StAR) gene cause congenital lipoid adrenal hyperplasia, characterized by diminished or absence of adrenal and gonadal steroids, resulting in severe adrenal insufficiency and ambiguous or complete female external genitalia in genetic males. We report on a 15-yr-old 46,XY phenotypic female, referred because of lack of pubertal development. ACTH and gonadotropin concentrations were elevated; and aldosterone, cortisol and its precursors, and sex steroids before and after stimulation were below the lower limit of detection. In the StAR gene, a homozygous nonsense mutation (TGG --> TAG) in exon 7 (W250X) was identified. Histologic examination after gonadectomy showed seminiferous tubules containing immature Sertoli cells and a few single germ cells with positive placental-like alkaline phosphatase immunoreactivity, indicating carcinoma in situ. This is the first report on testicular morphology, at a pubertal age, in a female patient with 46,XY karyotype and a mutation in the StAR gene, in whom gonadal neoplasia had developed.

A mutation in the first transmembrane domain of the lutropin receptor causes male precocious puberty.

We describe a patient with onset of puberty at the age of 5 yr. characterized by accelerated growth, enlargement of genitalia, pubarche, and serum hormone levels compatible with noncentral precocious puberty. Exon 11 of the LH receptor gene was amplified from genomic DNA by PCR and directly sequenced. We identified a heterozygous C to T base change at nucleotide position 1126, exchanging codon 373 from Ala to Val in the first transmembrane domain. The LH receptor sequence of the parents was normal. The mutated receptor displayed an up to 7.5-fold increase in basal cAMP production compared to that of the wild-type receptor in transiently transfected COS-7 cells. Treatment of the patient with ketoconazole resulted in inconsistent suppression of serum testosterone levels. At the age of 9.1 yr, central activation of the hypothalamic-pituitary-gonadal axis occurred. Additional treatment with a GnRH agonist led to complete suppression of testosterone secretion. This is the first description of constitutive activation of the LH receptor in the first transmembrane segment. It suggests the involvement of the first transmembrane helix in signal transduction and provides further insight into the structural organization of the seven transmembrane domains of the glycoprotein hormone receptor proteins.

Relevance of major histocompatibility complex class II expression as a hallmark for the cellular differentiation in the human adrenal cortex.

Major histocompatibility complex (MHC) class II antigens are expressed on adrenocortical cells of the zona reticularis and have been shown to be a marker of dignity. This suggests a correlation to the zellular differentiation of the adrenal cortex. Therefore, we immunohistochemically investigated the MHC class II expression in the context of the ontogenesis of the zonal and cellular differentiation in fetal, postnatal, childhood, and adult adrenals. Cell types and cell turnover were studied using specific immune markers (including expression of CD95/ Fas), in situ end labeling of apoptosis, and electron microscopy. We show that prenatal (fetal and definitive) steroid cells, as well as postnatal adrenals, reveal no expression of MHC class II. In childhood, these antigens first appear by the fourth year, in parallel with the differentiation of reticularis cells. The expression index in childhood was 7.43% +/- 2.78 (mean +/- SEM), in adult adrenals 18.63% +/- 3.14 (third decade), and 15.15% +/- 1.26 (fourth through sixth decade). In conclusion, MHC class II expression and the development of the functional maturation of the adult adrenal cortex occur simultaneously. The expression of MHC class II on steroid cells may thus be involved in potential immune-adrenal interactions.

A higher rate of hyperandrogenic disorders in female-to-male transsexuals.

In an effort to elucidate the aetiology of female-to-male transsexualism (FM-TS) 12 out of an annual sample of 16 untreated female-to-male transsexuals (FMT), aged 19 years 7 months (19;7) to 44 years 8 months (44;8) [median age (M) 27;5] were assessed by means of sexual-medical questionnaires, physical and endocrinological examination. The control group consisted of 15 healthy women (CF), aged 19 years 2 months (19;2) to 36 years 1 month (36;1) (M 22;7) without gender identity disorder, who were not under hormonal medication (including contraceptives). Baseline levels of testosterone (T; ng/dl), androstenedione (A4; ng/dl), dehydroepiandrosterone sulfate (DHEAS; ng/ml), luteinizing hormone (LH; IU/l), follicle stimulating hormone (FSH; IU/l), and sex-hormone binding globuline (SHBG; microgram/dl) were measured. A standard single-dose ACTH stimulation test (250 micrograms ACTH IV; Synacthen) was performed with all subjects. Aldosterone (ALDO), corticosterone (B), deoxycorticosterone (DOC), progesterone (PROG), 17-hydroxyprogesterone (17OHP), 11-deoxycortisol (S), cortisol (F), cortisone (E), pregnenolone (PREG) and 17-hydroxypregnenolone (OHPREG) were assessed before and 60 min after ACTH stimulation. Transvaginal ultrasound was performed in nine out of 12 FMT (20;11 to 44;8, M 27;5; m 29.1 +/- 7.5) but not in CF. Results showed that 10 FMT (83.3%) and five CF (33.3%) were above normal values for at least one of the measured androgens. Baseline levels of T and A4 were significantly higher in FMT than in CF (T: 54.0 +/- 13.8 vs. 41.1 +/- 12.8; A4: 244.8 +/- 73.0 vs. 190.5 +/- 49.3; p < .05), whereas DHEAS, SHBG, LH and FSH did not differ between the groups. Unbound T (T/SHBG ratio) was higher in FMT (72.0 +/- 67.6) than in CF (26.4 +/- 15.1). Baseline levels of 17OHP, OHPREG and DOC were higher in FMT than in CF (p < .05). After ACTH stimulation 17OHP and OHPREG remained higher in FMT than in CF (p < .05). Single case analysis of ACTH stimulation test together with physical examination revealed symptoms for non-classical congenital adrenal hyperplasia (NC-CAH) in six FMT (50%) and two CF (13.3%). Eight out of nine FMT who were assessed by means of transvaginal ultrasound (i.e. 88.9%; 50.0% of 16) had polycystic ovaries (PCO). Oligomenorrhoea or menstrual dysregularities (81.7% of 16 FMT vs. 0% of CF), hirsutism (56.2% of 16 FMT vs. 13.3% of 15 CF) and adiposity (25.0% vs. 0%) were frequent in FMT, but not in CF. Hyperandrogenism with polycystic ovarian syndrome (PCOS) and adrenocortical hyperresponsiveness to ACTH seems to be a common finding in FMT. This offers support for a hormonal factor in the genesis of FM-TS. Because the prevalence of PCOS and NC-CAH in the female population is higher than FM-TS, the true nature of this factor and its interaction with environmental influences remains unknown.

Impairment of 11 beta-hydroxylase but not 21-hydroxylase in adrenal 'incidentalomas'.

Recent reports have shown an exaggerated response of 17-hydroxyprogesterone in up to 70% of patients with incidentally detected adrenal adenomas ('incidentalomas'). This has been explained by pre-existing 21-hydroxylase deficiency which may be a pathogenetic factor in the development of adrenal tumours. However, other defects in steroidogenesis, such as mild 11 beta-hydroxylase deficiency, could also result in increased 17-hydroxyprogesterone secretion. We therefore studied the glucocorticoid and mineralocorticoid pathways in patients with adrenal 'incidentalomas' by measuring multiple adrenal steroids before and after 1-24 ACTH stimulation. Twenty patients with adrenal 'incidentalomas' (14 females, 6 males) and 27 healthy controls (14 females, 13 males) were studied. All subjects underwent a 1-24 ACTH stimulation test (250 micrograms i.v.) with determination of progesterone, 11-deoxycorticosterone, corticosterone, 17-hydroxyprogesterone, 11-deoxycortisol and cortisol at 0 and 60 min. All steroids were measured by RIA after extraction and HPLC. Patients with 'incidentalomas' had higher stimulated concentrations of 17-hydroxyprogesterone (21.6 +/- 8.4 vs 4.2 +/- 0.3 nmol/I; P < or = 0.001), 11-deoxycortisol (8.1 +/- 1.2 vs 3.6 +/- 0.3 nmol/I; P < or = 0.001), progesterone (8.28 +/- 2.82, vs 1.08 +/- 0.15 nmol/I; P < or = 0.001), and 11-deoxycorticosterone (2.1 +/- 0.39 vs 0.78 +/- 0.12 nmol/I; P = 0.002) compared with controls. In contrast, cortisol and corticosterone concentrations were not different. There was evidence for impairment of 11 beta-hydroxylase activity by an increased 11-deoxycortisol/ cortisol ratio (0.012 +/- 0.003 vs 0.005 +/- 0.001 in controls; P = 0.002) and 11-deoxycorticosterone/ corticosterone ratio (0.04 +/- 0.003 vs 0.015 +/- 0.003; P = 0.003). The conclusions reached were that patients with adrenal 'incidentalomas' have increased responses of precursors of the mineralocorticoid and glucocorticoid pathway including 17-hydroxyprogesterone after stimulation with ACTH. This seems to be caused by impairment of 11 beta-hydroxylase activity rather than by impaired 21-hydroxylase activity in these tumours.

Diagnosis and treatment of central precocious puberty--can final height be improved? German/Dutch Central Precocious Puberty Study Group.

Central precocious puberty is characterized by premature activation of the hypothalamic gonadotrophin-releasing hormone (GnRH) pulse generator, resulting in accelerated growth and bone maturation with clinical signs of gonadarche before the age of 8 years in girls and 9 years in boys. In rapidly progressing central precocious puberty, the plasma luteinizing hormone (LH) response to exogenous GnRH exceeds the reference range for sex and stage of puberty, and the ratio of LH:follicle-stimulating hormone after GnRH is usually above 1. Short adult stature, with unfavourable body proportions, i.e. an increased upper:lower segment ratio, is probably the only handicap of idiopathic central precocious puberty that persists into adulthood. This cannot be avoided by treatment with either medroxyprogesterone or cyproterone acetate. Following the first report of pituitary-gonadal suppression in a 2-year-old girl with central precocious puberty using daily injections of the gonadotrophin-releasing hormone (GnRH) agonist deslorelin, various short-acting GnRH agonists have been studied in children with central precocious puberty. Some of the older patients treated for shorter periods have now reached adult or near-final height. By 1985, slow-release (depot) GnRH agonists, such as triptorelin and later leuprorelin, were available. These are injected only once every 4 weeks instead of daily or given by nasal spray six times daily, making long-term treatment much more acceptable to patients and their parents. Moreover, suppression of gonadarche is more complete with long-acting (e.g. triptorelin) compared with short-acting (e.g. buserelin) agonists, resulting in significantly slower bone age progression and, thus, greater improvement in predicted, and probably also in achieved, final height.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnosis and treatment of 17-hydroxylase deficiency.

Leading symptoms of 17-hydroxylase/17,20-lyase deficiency in childhood are hypertension and hypokalemia. We found this enzyme defect in 3 phenotypically female siblings aged 12, 15 and 16 years. Two of the sibs have a 46,XY chromosome pattern, the third is genetically female. Pubertal development did not occur. Both of the 46,XY sibs have male internal and female external genitalia. The 46,XX sister has normal female internal genitalia. At the time of diagnosis, two of the three siblings had hypertension (RR between 190/135 and 160/110 mmHg). Two of the three siblings had low serum potassium and metabolic alkalosis. All three patients had excessively high plasma levels of 11-deoxycorticosterone (DOC) and corticosterone. Aldosterone was also elevated whereas plasma renin activity was suppressed. Plasma cortisol and its 17-hydroxylated precursors were low, as were plasma testosterone, dihydroepiandrosterone sulphate and estradiol, while the gonadotropins LH and FSH were elevated in all three patients. We studied the steroid profiles of these three patients during long term glucocorticoid treatment with dexamethasone, which is now followed for 13 years. Blood pressure and serum potassium became normal. Plasma aldosterone, corticosterone and DOC were clearly lower but not fully normalized. The two genetically male sisters obtained estrogens for induction of female secondary sex characteristics. The third 46,XX sister has normal menstruations during substitution with cyclic estrogen/gestagen therapy. All three patients lack pubic and axillary hair, and reached normal adult heights both for phenotypic sex and for target height. The psychosocial orientation is female in all of them. Apart from rare reports of development of malignant hypertension, prognosis is better than in other enzyme deficiencies causing congenital adrenal hyperplasia since no Addisonian crises occur due to DOC and corticosterone overproduction resulting in apparently normal endogenous glucocorticoid activity.

Comparison of complete and incomplete suppression of pituitary-gonadal activity in girls with central precocious puberty: influence on growth and predicted final height. The German-Dutch Precocious Puberty Study Group.

The question as to whether treatment with short-acting or with slow-release gonadotropin-releasing hormone (GnRH) agonists has different effects on growth and bone maturation when treating girls with central precocious puberty has not yet been studied. In a meta-analysis, we compared 21 naive girls with central precocious puberty who were treated with buserelin with 22 naive girls with central precocious puberty who received Decapeptyl in depot form. Treatment lasted for at least 18 months. At the start of therapy, chronological age, bone age, growth velocity and pubertal stage in the two groups were very similar. During the first 6 months of treatment, significantly more phases of incomplete suppression of pituitary-gonadal activity occurred in the buserelin group. As a result, growth velocity and bone maturation (delta bone age/delta chronological age) remained significantly higher than in the Decapeptyl Depot group (p < 0.0001 and p < 0.01, respectively). In contrast to the Decapeptyl Depot group, the height standard deviation score (SDS) for bone age in the buserelin group did not change significantly in the first 6 months of treatment, and the predicted adult height decreased. Between the 6th and 18th months of therapy, the development of growth rate, delta bone age/delta chronological age, height SDS for bone age and predicted adult height in both groups became almost identical. However, the rate of growth and bone maturation in the buserelin group remained faster than in the Decapeptyl group, though not significantly so. The mean predicted adult height had risen significantly after 18 months in the Decapeptyl Depot group but not in the group treated with buserelin.(ABSTRACT TRUNCATED AT 250 WORDS)

[Prenatal diagnosis and therapy of adrenogenital syndrome with 21-hydroxylase deficiency]. / Pränatale Diagnostik und Therapie des Adrenogenitalen Syndroms (AGS) mit 21-Hydroxylase-Defekt.

Genetic counselling of the parents is prerequisite before prenatal diagnosis and prenatal therapy of CAH. Today, chorionic villous biopsy with DNA probe is the method of choice to identify homozygous CAH-fetuses. The aim of prenatal therapy is to prevent intrauterine virilization of the external genitalia in affected female fetuses. Therefore, dexamethasone (3 x 0.5 mg/d p.o.) is given to the mother immediately when pregnancy is confirmed, before prenatal diagnosis and karyotyping is possible. After the result of prenatal diagnosis, treatment is continued until term only when the fetus is affected and female. Prenatal diagnosis and effective treatment of female CAH fetuses greatly reduces the need for corrective surgery and thus helps to alleviate anxieties of prospective parents and therefore encourages further pregnancies. However, prenatal treatment of CAH to date still is an experimental therapy [corrected].