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Highlights of the Endocrine Society’s 88th Annual Meeting, Boston MA, June 24-28, 2006

« Back to Volume 22, Issue 4, December 2006 - Table of Contents

The Endocrine Society’s Annual Meeting provided exciting presentations in plenary sessions and symposia, endocrine updates, endocrine debates, and special sessions, including multiple reviews of pediatric interest. However, I could not do justice to encapsulate those presentations in a succinct manner. Thus, only the highlights of the poster and oral presentations of the scientific papers that attracted my attention are summarized, particularly the research focusing on growth.

Adrenals

A novel mutation of melanocortin 2 receptor accessory protein (MRAP) gene was identified in 2 brothers with familial glucocorticoid deficiency by Li Chan et al. The first codon exon TAC-TAA lead to a severely truncated protein at position 11 of the MRAP gene, which rendered the adrenal gland unresponsive to ACTH.

Bone

How much of a work-up is needed when healthy children present with frequent fractures? That was the question addressed by Robert Olney et al. Sixty-nine patients with low-energy fractures were evaluated and compared to 56 controls. Those with fractures did not present low whole body bone mineral density (BMD) and did not ingest lower calcium or vitamin D. The researchers concluded that occult metabolic bone disease was not a common cause of repeated fractures in children.

Low-dose pamidronate treatment of osteoporosis in non-ambulatory children was shown to be effective by Horacio Plotkin et al. They administered pamidronate 4.12 mg/kg/yr intravenously (administered over 2 days every 4 months). There was a significant increase in BMD with treatment without significant side effects.

Recombinant human growth hormone (rhGH) induced a marked and sustained elevation in circulating levels of osteocalcin and c-terminal telopeptide of type I collagen. The increased levels exceeded the impact of bone fracture alone. This was reported by Jens Christiansen et al. The increased levels persisted for up to 12 weeks after cessation of rhGH treatment, suggesting that osteocalcin and type I collagen could be markers of illicit administration of rhGH.

Diabetes

Data on 5928 children with diabetes from 7 pediatric endocrinology centers in the United States were reviewed by Vanessa Davis et al. Approximately 10% had type 2 diabetes mellitus (T2DM). Most of those with T2DM were initially treated with oral medications, but after 5 years with the disease, insulin became the most commonly used therapy. During the 5 year study, only 25% had an improved HbA1C, 46% worsened, 34% developed co-morbidities and complications, and 29% were unchanged. These data pointed out a worrisome trend of poor treatment adherence and an aggressive natural course of T2DM in children.

Growth

Humans with mutations in PROP1 present with hypopituitarism. Luciano Carvalho et al determined the molecular basis of the disease; they compared mice with a mutation of the PROP1 gene with Pit1 mutant mice. The mice with PROP1 mutation showed delayed vascular development, reduced cell proliferation, and elevated rate of apoptosis. These alterations may explain why the pituitary is very small in x-rays and MRI scans in patients with PROP1 hypopituitarism.

Did the small-bodied Hominis from Flores in Indonesia suffer from a molecular defect in the GH receptor (GHR) gene (Laron syndrome)? That provocative question was posed by Zvi Laron. Proposing a diagnosis due to a molecular defect in the GHR for the pathological findings of skeletons unearthed in Indonesia and whose age is 18 000 years is a challenge that may be resolved by DNA analysis; the possibility is interesting.

The response to rhGH therapy in 20 GH-deficient (GHD) patients receiving stimulant medication was assessed by Parm Gill et al. After one year of therapy, the growth rate of children treated with stimulant medication and rhGH was significantly lower than that of control patients with GHD, though the BMI of the 2 groups was similar.

The protein polymorphism of the GHR characterized by deletion of exon 3 has been linked to the magnitude of the response to rhGH treatment. Laura Audi et al demonstrated that the frequency of GHR polymorphism was higher among small for gestational age (SGA) patients than that of a control population with normal height. However, in 2 separate studies, Antonio Carrascosa et al and Veronica Mericq et al showed that in short SGA patients the response to rhGH treatment was not different among those with or without this genomic deletion. On the other hand, Gerhard Binder et al showed that Turner syndrome patients with a deletion of exon 3 presented a significantly reduced increment in height velocity during the first year of therapy with rhGH, as compared with Turner syndrome patients who did not have this genomic mutation. The differences in height gain persisted until adult height was attained.

As MRI techniques have become more sophisticated, there are incidental findings detected in children undergoing assessment for short stature. Elena Sutu described 44 incidental findings in 38 children. Patients received further evaluations and none required treatment for the incidentalomas.

The prevalence of recurrences of craniopharyngioma in rhGH treated children was reported by Edward Laws et al. There were 51 recurrences among 773 patients with a prior history of craniopharyngioma. The risk ratio over a 7-year period was approximately 7%.

The diagnosis of GH deficiency (GHD) is often based on the response to pharmacological agents that stimulate GH release. Susan Rose and Melissa May demonstrated that children who ingested a dietary electrolyte drink (Diet Sprite™ >15 mL/kg) had improved tolerance to clonidine stimulation testing. These patients had less hypotension, higher blood pressure, and did not require any intravenous fluids during or after the test; patients were discharged earlier than those who did not ingest the hydration solution prior to the test.

The cause-specific mortality of all GHD children and adults in Denmark was reported by Kirstine Stochholm et al. During the years 1980 to 1999, there were 1823 patients with childhood and adult onset GHD; 581 of them died. The mortality rates were higher among all groups of GHD patients, as compared with appropriately matched controls. Furthermore, mortality due to cancer was increased; this was evident even in patients who had no evidence of cancer prior to rhGH treatment. Cardiovascular mortality was also increased.

The reproducibility of the insulin-like growth factor (IGF)-I generation test was assessed in 15 adults by Helena Gleeson and Stephen Shalet. Subjects were given rhGH 7 mg on 2 occasions separated by 4 weeks. The incremental response of IGF-I levels had a reasonable reproducibility and the test was considered to be a valid tool to measure GH responsiveness.

The targeting of IGF-I levels as a means to adjusting rhGH dosages in pediatric patients with short stature was studied by John Germak et al. The investigators assessed the effectiveness of an IGF-I-based dosing algorithm in rhGH therapy in a large group of short children. They concluded that the dosing algorithm was effective and allowed the titration of rhGH to the IGF-I levels. This permitted the treatment with rhGH based on the sensitivity of the individual patient. Patients with GHD demonstrated a greater increase in height and higher IGF-I levels as compared with idiopathic short stature patients.

There were several interesting papers regarding the newly available IGF preparations approved for the treatment of primary IGF-I deficiency. Susan Park et al characterized the structure and heterogeneity of mecasermin (rDNA) as a monomeric polypeptide containing 70 amino acid residues and intramolecular disulfite bridges. Enona Gopinath showed that rhIGF-I injections supplied as a refrigerator-stable aqueous formulation had a long shelf-life (12 months) stored at 2°C–8°C.

In other studies, William Barr et al showed that the administration of a single dose of 0.5 mg/kg of rhIGF-I/rhIGFBP-3 to healthy adults was well-tolerated with no significant adverse events and produced a sustained elevation of serum IGF-I levels. These data supported the effectiveness of once-a-day dosing of this preparation. Additionally, Kenneth Attie et al demonstrated that the free levels of circulating IGF-I were sustained at a physiologic range following the administration of 0.5 mg/kg of rhIGF-I/rhIGFBP-3 given to adult volunteers. These data were in contrast to the substantial increase in free IGF-I levels induced by the administration of isolated rhIGF-I.

In a multicenter clinical trial, Cecilia Camacho-Hubner et al assessed the treatment with once daily-rhIGF-I/rhIGFBP-3 dosages on patients with severe primary IGF-I deficiency. There were 47 children from 13 countries given up to 1 mg/kg/day (low-dose group) or up to 2 mg/kg/day (high-dose group) titrated in accordance with the IGF-I levels. The height velocity in the low-dose group increased from 3.4 cm/yr to 6.4 cm/yr. The high-dose group increased the height velocity from a mean of 2.0 cm/yr to 8.3 cm/yr. The bone age advanced proportionately in both groups. Most patients developed antibodies to rhIGF-I/rhIGFBP-3, but this was not associated with adverse effects or growth attenuation. There were other adverse events that were considered mild, including hypoglycemia, headaches, erythema, and lipohypertrophy. Once-daily treatment with up to 2 mg/kg/day was effective and had an acceptable safety profile.

Patients with severe insulin resistance syndrome were treated with rhIGF-I/rhIGFBP-3 by Fiona Regan et al. The author reported improved glycemic control as well as growth in children with Leprechaunism and concluded that rhIGF-I/rhIGFBP-3 was an effective therapeutic agent.

Polycystic Ovary Syndrome (PCOS) and Metabolic Syndrome

In a large scale population study, Mark Goodarzi et al genotyped 3 variants in the FEM1A gene located in chromosome 19 in a cohort consisting of 287 women with PCOS and 187 healthy controls; all subjects were white. The researchers showed that carriers of the allele of rs8111833 had an increased risk of PCOS (odds ratio 2:1), and suggested that the FEM1A gene modulates the development of PCOS.

Susanne Tan et al showed that PCOS patients had an increased risk of metabolic syndrome and Jennifer Wolfang et al showed that lean, non-obese African-American women had double the prevalence rate of insulin resistance and cardiovascular risk factors compared with Hispanic and non-Hispanic white female counterparts. Race played an important role independent of BMI.

Vitamin D deficiency was linked to metabolic syndrome by Jose Botella-Carretero et al. They demonstrated that 60% of such patients had low serum 25-hydroxyvitamin D concentrations which may contribute to insulin resistance.

Pubertal Gynecomastia

Two ingredients common in many hair and skin products were linked to abnormal development of breasts in males with pubertal gynecomastia. Derek Henley et al showed that lavender and tea tree oil contained in personal care products turned on estrogen-regulated genes and inhibited an androgen-regulated gene in human breast cancer line MCF-7. Patients’ breast size decreased after they stopped using these products.

Thyroid

Mario Salvi et al showed the immunosuppressive drug rituximab was shown to exert a significant positive effect in the treatment of Graves’ ophthalmopathy. The monoclonal antibody rituximab blocked the production of B lymphocytes, particularly from the orbital area, thereby modifying the immune response and improving the ophthalmopathy.

Fima Lifshitz , MD

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Last Updated: 2/2/2011