Growth hormone deficiency: an update.

Growth hormone (GH) deficiency (GHD) in humans manifests differently according to the individual developmental stage (early after birth, during childhood, at puberty or in adulthood), the cause or mechanism (genetic, acquired or idiopathic), deficiency intensity and whether it is the only pituitary-affected hormone or is combined with that of other pituitary hormones or forms part of a complex syndrome. Growing knowledge of the genetic basis of GH deficiency continues to provide us with useful information to further characterise mutation types and mechanisms for previously described and new candidate genes. Despite these advances, a high proportion of GH deficiencies with no recognisable acquired basis continue to be labelled as idiopathic, although less frequently when they are congenital and/or familial. The clinical and biochemical diagnoses continue to be a conundrum despite efforts to harmonise biochemical assays for GH and IGF-1 analysis, probably because the diagnosis based on the so-called GH secretion stimulation tests will prove to be of limited usefulness for predicting therapy indications.

Ten novel mutations in the NR5A1 gene cause disordered sex development in 46,XY and ovarian insufficiency in 46,XX individuals.

CONTEXT: Steroidogenic factor-1 (SF-1/NR5A1) is a nuclear receptor that regulates adrenal and reproductive development and function. NR5A1 mutations have been detected in 46,XY individuals with disorders of sexual development (DSD) but apparently normal adrenal function and in 46,XX women with normal sexual development yet primary ovarian insufficiency (POI). OBJECTIVE: A group of 100 46,XY DSD and two POI was studied for NR5A1 mutations and their impact. DESIGN: Clinical, biochemical, histological, genetic, and functional characteristics of the patients with NR5A1 mutations are reported. SETTING: Patients were referred from different centers in Spain, Switzerland, and Turkey. Histological and genetic studies were performed in Barcelona, Spain. In vitro studies were performed in Bern, Switzerland. PATIENTS: A total of 65 Spanish and 35 Turkish patients with 46,XY DSD and two Swiss 46,XX patients with POI were investigated. MAIN OUTCOME: Ten novel heterozygote NR5A1 mutations were detected and characterized (five missense, one nonsense, three frameshift mutations, and one duplication). RESULTS: The novel NR5A1 mutations were tested in vitro by promoter transactivation assays showing grossly reduced activity for mutations in the DNA binding domain and variably reduced activity for other mutations. Dominant negative effect of the mutations was excluded. We found high variability and thus no apparent genotype-structure-function-phenotype correlation. Histological studies of testes revealed vacuolization of Leydig cells due to fat accumulation. CONCLUSIONS: SF-1/NR5A1 mutations are frequently found in 46,XY DSD individuals (9%) and manifest with a broad phenotype. Testes histology is characteristic for fat accumulation and degeneration over time, similar to findings observed in patients with lipoid congenital adrenal hyperplasia (due to StAR mutations). Genotype-structure-function-phenotype correlation remains elusive.

The GnRH analogue triptorelin confers ovarian radio-protection to adult female rats.

There is a controversy regarding the effects of the analogues of the gonadotrophin-releasing hormone (GnRH) in radiotherapy. This has led us to study the possible radio-protection of the ovarian function of a GnRH agonist analogue (GnRHa), triptorelin, in adult, female rats (Rattus norvegicus sp.). The effects of the X-irradiation on the oocytes of ovarian primordial follicles, with and without GnRHa treatment, were compared, directly in the female rats (F(0)) with reproductive parameters, and in the somatic cells of the resulting foetuses (F(1)) with cytogenetical parameters. In order to do this, the ovaries and uteri from 82 females were extracted for the reproductive analysis and 236 foetuses were obtained for cytogenetical analysis. The cytogenetical study was based on the data from 22,151 metaphases analysed. The cytogenetical parameters analysed to assess the existence of chromosomal instability were the number of aberrant metaphases (2234) and the number (2854) and type of structural chromosomal aberrations, including gaps and breaks. Concerning the reproductive analysis of the ovaries and the uteri, the parameters analysed were the number of corpora lutea, implantations, implantation losses and foetuses. Triptorelin confers radio-protection of the ovaries in front of chromosomal instability, which is different, with respect to the single and fractioned dose. The cytogenetical analysis shows a general decrease in most of the parameters of the triptorelin-treated groups, with respect to their controls, and some of these differences were considered to be statistically significant. The reproductive analysis indicates that there is also radio-protection by the agonist, although minor to the cytogenetical one. Only some of the analysed parameters show a statistically significant decrease in the triptorelin-treated groups.