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Effectiveness of the combined recombinant human growth hormone and gonadotropin-releasing hormone analog therapy in pubertal patients with short stature due to SHOX deficiency.

ABSTRACT: CONTEXT: Isolated heterozygous SHOX defects are the most frequent monogenic cause of short stature, and combined therapy with recombinant human GH (rhGH) and GnRH analog (GnRHa) in pubertal patients has been suggested, but there are no data on final height. OBJECTIVE: The aim of the study was to analyze adult height after rhGH and GnRHa therapy in patients with SHOX haploinsufficiency. PATIENTS: Ten peripubertal patients with isolated SHOX defects participated in the study. INTERVENTION: Five patients were followed without treatment, and five were treated with rhGH (50 mug/kg/d) and depot leuprolide acetate (3.75 mg/month). MAIN OUTCOME MEASURES: Adult height sd score (SDS) was measured. RESULTS: All patients followed without treatment had marked downward growth shift during puberty (height SDS, -1.2 +/- 0.7 at 11.4 +/- 1.4 yr; adult height SDS, -2.5 +/- 0.5). Conversely, four of five patients treated with rhGH for 2 to 4.9 yr associated to GnRHa for 1.4 to 5.8 yr improved their height SDS from -2.3 +/- 1.3 at 11.8 +/- 2.1 yr to a final height SDS of -1.7 +/- 1.6. The difference between the mean height SDS at the first evaluation and final height SDS was statistically significant in nontreated vs. treated patients (mean height SDS change, -1.2 +/- 0.4 vs. 0.6 +/- 0.4, respectively; P <0.001). CONCLUSION: A gain in adult height of patients with isolated SHOX defects treated with combined rhGH and GnRHa therapy was demonstrated for the first time, supporting this treatment for children with SHOX defects who have just started puberty to avoid the loss of growth potential observed in these patients during puberty.

SUBMITTER: Scalco RC

PROVIDER: S-EPMC2805492 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Effectiveness of the combined recombinant human growth hormone and gonadotropin-releasing hormone analog therapy in pubertal patients with short stature due to SHOX deficiency.

Scalco Renata C RC Melo Suzana S J SS Pugliese-Pires Patricia N PN Funari Mariana F A MF Nishi Mirian Y MY Arnhold Ivo J P IJ Mendonca Berenice B BB Jorge Alexander A L AA

The Journal of clinical endocrinology and metabolism 20091119 1

<h4>Context</h4>Isolated heterozygous SHOX defects are the most frequent monogenic cause of short stature, and combined therapy with recombinant human GH (rhGH) and GnRH analog (GnRHa) in pubertal patients has been suggested, but there are no data on final height.<h4>Objective</h4>The aim of the study was to analyze adult height after rhGH and GnRHa therapy in patients with SHOX haploinsufficiency.<h4>Patients</h4>Ten peripubertal patients with isolated SHOX defects participated in the study.<h4 ...[more]

PMID: 19926713

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Project description:Background: The exact nature of the interrelationship between pubertal brain development and hormones involvement has always attracted wide interest. Brain structural changes that occur during the pubertal developmental process mainly appear in the regions most closely linked with emotion, motivation and cognitive functions. Using a sheep model, we have previously shown that peri-pubertal pharmacological blockade of gonadotropin-releasing hormone (GnRH) receptors results in increased sex-differences in cognitive executive function and emotional control, as well as in a sex- and side-specific gene expression pattern of hippocampal genes associated with synaptic plasticity and endocrine signaling. In this study, we explore the effects of this treatment regime on the amygdalar gene expression profile. Methods: The study was conducted with 30 same-sex twin lambs (14 female and 16 male), half of which were treated with the GnRH agonist (GnRHa) goserelin acetate every 4th week, beginning before puberty, until 50 weeks of age. The gene expression profiles of left and right amygdala samples from all 30 animals were measured by using ovine 8 X 15 K Agilent microarrays. Furthermore, differential expression of a selected number of genes was confirmed by qRT-PCR (Quantitative real time PCR). Networking analyses and Gene Ontology (GO) Term analyses were performed with the Ingenuity Pathway Analysis (IPA), version 7.5 DAVID (Database for Annotation, Visualization and integrated Discovery) software packages respectively. Results: GnRHa treatment was associated with significant sex- and hemisphere-specific differential expression of genes. Interestingly, genome-wide transcription showed a set of 438 (p value <0.05) genes in female treated left and 46 (p value <0.0.5) genes in females treated right amygdala were differentially expressed but not in any treatment group of male animals. Conclusion: Our results indicate that GnRH directly and/or indirectly is involved in the regulation of sex- and side-specific differential expression of genes in amygdala. Hence, this finding should be considered when long-term peri-pubertal GnRHa treatment is used in children.

Project description:BackgroundThe main objective of the present work was to compare the effects of the gonadotropin-releasing hormone agonist (GnRH-a) and GnRH antagonist (GnRH-ant) on the gene expression profiles of oocytes obtained from Iranian infertile couples undergoing in vitro fertilization (IVF).MethodsFifty infertile couples who underwent IVF between June 2012 and November 2013 at the Infertility Center of Tehran Women General Hospital, Tehran University of Medical Sciences, were included in this study. We included women that had undergone IVF treatment because of male factor, tubal factor, or unexplained infertility. The women randomly underwent controlled ovarian stimulation (COS) with either the GnRH-a (n = 26) or the GnRH-ant (n = 24). We obtained 50 germinal vesicle (GV) oocytes donated by women in each group. After the sampling, pool of 50 GV oocytes for each group was separately analyzed by quantitative polymerase chain reaction (qPCR).ResultThe expression levels of Adenosine triphosphatase 6 (ATPase 6), Bone morphogenetic protein 15 (BMP15), and Neuronal apoptosis inhibitory protein (NAIP) genes were significantly upregulated in the GnRH-ant group compared to the GnRH-a group, with the fold change of 3.990 (SD ± 1.325), 6.274 (SD ± 1.542), and 2.156 (SD ± 1.443), respectively, (P < 0.001). Growth differentiation factor 9 (GDF9) mRNA did not have any expression in the GnRH-a group; however, GDF9 mRNA was expressed in the GnRH-ant group. Finally, it was found that the genes involved in the DNA repairing and cell cycle checkpoint did not have any expression in either group.ConclusionThe present study showed, for the first time, the expression levels of genes involved in the cytoplasmic maturity (BMP15, GDF9), adenosine triphosphate production (ATPase 6), and antiapoptotic process (NAIP), in human GV oocytes were significantly higher in the GnRH-anta group than in the GnRH-a group in COS. Higher expression level of these genes when GnRH-ant protocol is applied, this protocol seems to be a more appropriate choice for women with poly cystic ovarian syndrome, because it can probably improve the expression of the aforementioned genes.Trial registrationCurrent Controlled Trials: IRCT 2014031112307 N3.

Dataset Information

Effectiveness of the combined recombinant human growth hormone and gonadotropin-releasing hormone analog therapy in pubertal patients with short stature due to SHOX deficiency.

Publications

Effectiveness of the combined recombinant human growth hormone and gonadotropin-releasing hormone analog therapy in pubertal patients with short stature due to SHOX deficiency.

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