R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism

Normosmic congenital hypogonadotropic hypogonadism (nCHH) is a rare reproductive disease leading to lack of puberty and infertility. Loss-of-function mutations of GNRH1 gene are a very rare cause of autosomal recessive nCHH. R31C GNRH1 is the only missense mutation that affects the conserved GnRH decapeptide sequence. This mutation was identified in a CpG islet in nine nCHH subjects from four unrelated families, giving evidence for a putative “hot spot”. Interestingly, all the nCHH patients carry this mutation in heterozygosis that strikingly contrasts with the recessive inheritance associated with frame shift and non-sense mutations. Therefore, after exclusion of a second genetic event, a comprehensive functional characterization of the mutant R31C GnRH was undertaken. Using different cellular models, we clearly demonstrate a dramatic reduction of the mutant decapeptide capacity to bind GnRH-receptor, to activate MAPK pathway and to trigger inositol phosphate accumulation and intracellular calcium mobilization. In addition it is less able than wild type to induce lh-beta transcription and LH secretion in gonadotrope cells. Finally, the absence of a negative dominance in vitro offers a unique opportunity to discuss the complex in vivo patho-physiology of this form of nCHH

Daily life, needs and expectations of patients with acromegaly in France: An on-line survey

Acromegaly can impair quality of life, but impact on patients' daily life, needs and expectations have been poorly explored. Objectives. - To better understand the impact of acromegaly on patients' daily life, and evaluate their needs and expectations. Patients and methods. - An on-line questionnaire survey of acromegaly patient and relative community members was conducted on the Carenity website. Results. - Twenty-five patients and 3 relatives, with a mean age of 48.9 years, responded. Diagnosis of acromegaly was recent (60% within 10 years). Signs at diagnosis were mainly clinical (fatigue, headache) and physical changes (acral enlargement). Reported complications comprised morphological changes (93%), bone and joint symptoms (75%) and metabolic disorders (75%). Pain and fatigue impacted the daily life of 61% and 54% patients, respectively. Acromegaly had strong impact on mood (79%), leisure (75%) and social life (71%). Patients mostly got information from specialized websites (71%), their endocrinologist (61%) and patient associations (54%). The information sought was patient testimony (82%), practical advice (64%), and information on clinical trials (61%) and treatments (50%). Patients wished to have patient-physician discussion groups (25%), and better knowledge of acromegaly on the part of those they were in contact with (25%). Conclusion. - Acromegaly has a major impact on patients' daily life and mood. Patients wished their disease to be better known, and advocated setting up discussion groups. This study should encourage acromegaly education programs to adapt the services and information that are needed by acromegalic patients. (C) 2018 Elsevier Masson SAS. All rights reserved

Preoperative Medical Treatment for Patients With Acromegaly: Yes or No

Transsphenoidal surgery is the first-line treatment for acromegaly. However, several factors can modify surgical remission rates, such as the initial hormone levels, the size and invasiveness of the tumor, and the degree of experience of the surgeon. Physicians treating patients with acromegaly should thus consider how to improve surgical remission rates. As stated in recent guidelines, the major point is to consider that any patient with acromegaly should be referred to an expert neurosurgeon to maximize the chances of surgical sure. The benefits of presurgical medical treatment, mainly using somatostatin receptor ligands (SRLs), given 3 to 6 months before surgery, remain controversial. By normalizing growth hormone and insulin-like growth factor 1 levels, SRLs may improve the overall condition of the patient, thus decreasing anesthetic and surgical complications. By decreasing the tumor size and modifying the consistency of the tumor, SRLs might also make surgical excision easier. This is however theoretical as published data are contradictory on both points, and only limited data support the use of a systematical presurgical medical treatment. The aim of this review is to analyze the potential benefits and pitfalls of using presurgical medical treatment in acromegaly in view of the contradictory literature data. We also attempt to determine the profile of patients who might most benefit from this presurgical medical treatment approach as an individualized therapeutic management of acromegaly

Acromegaly in remission: a view from the partner

International audienceObjective A relative can be an asset in dealing with chronic illnesses, such as acromegaly, where quality of life (QoL) is altered even after remission. However, it has been shown that quality of life of caregivers can also be impacted. Our main objective was to compare the perception of acromegaly in remission in the patient–relative dyad. Methods In this observational study, 27 patients in remission and relatives were first asked to complete QoL, anxiety/depression and coping strategy questionnaires. Then, the patient’s body image and self-esteem were evaluated from both the patient’s and the relative’s point of view using the same questionnaires with modified instructions. Results Relatives had overall an accurate estimation of patient body image using the Figure Rating Scale by Stunkard. However, there were wide variations between the patient’s and the relative’s responses regarding self-esteem and body perception. The QoL of relatives was not altered and was significantly higher in the social domain than for the patient. Conclusions Our results show that relatives require education concerning all the steps involved in the management of acromegaly, as they likely do not fully understand the sequelae of acromegaly

Binding of WT and R31C GnRH to the GnRH receptor (GnRH-R).

<p>(<b>A</b>) COS-7 cells were transiently transfected with a human GnRH-R DNA construct and incubated with a ¹²⁵I-labeled GnRH agonist in the presence of indicated concentrations of WT GnRH or R31C GnRH. IC-50 values are WT GnRH, 2.8×10⁻⁹ M and R31C GnRH, 8.50×10⁻⁷ M. Data are given as means and SD of two experiments performed in duplicate. (<b>B</b>) Transfected COS-7 cells were pre-incubated with buffer alone, WT GnRH (10⁻⁸ M) or R31C GnRH (10⁻⁵ M) and then washed to allow dissociation of ligand not covalently attached to the GnRH-R. Pre-incubated cells were then incubated with ¹²⁵I-labeled GnRH agonist in the absence or presence of saturating concentration of unlabeled WT GnRH (NSB). Data are the means of two experiments performed in triplicate.</p

Effects of treatments on <i>lhb</i> transcription and LH secretion.

<p>(<b>A</b>) LbetaT2 cells were starved overnight in serum-free DMEM and treated either by 10 nM WT, R31C, 10 nM WT +10 nM R31C peptides or vehicle. After five hours treatment cells were lysed for RNA extraction (Trizol®). Mouse <i>lhb</i> levels were analyzed by quantitative real time RT-qPCR. Values are expressed as individual ratios on 18S and represented as fold induction on vehicle as means ± SEM, **p<0.01. This experience was conducted n = 7 times in duplicates. (<b>B</b>) LH concentrations from LbetaT2 cells culture <i>media</i>. Cells were starved overnight in serum-free DMEM and incubated with 10 nM WT, 10 nM R31C, 10 nM WT +10 nM R31C, or vehicle for 5 hours. LH levels were measured by a combined rat/mouse RIA. Values are expressed as individual values and as means ± SEM, *p<0.05, ***p<0.001. The experiment was conducted four times and each sample was assayed in duplicates.</p

Clinical, biological and genetic characterization of patients.

<p>NA: not available.</p>*<p>Reference ranges for hormone levels and method characteristics. Total testosterone: 3.5–8.5 ng/mL for adult men (RIA, Orion Diagnostica device, Spectria®, Espoo, Finland; detection limit: 0.01 ng/mL; intra- and interassay coefficients of variation (CVs): 3.2% and 4.6%); estradiol: 15–35 pg/mL for men, <16 for post-menopausal women (RIA, Orion Diagnostica, Spectria®; detection limit: 2 pg/mL; intra- and the interassay CVs: 2.8% and 5.8%); LH: 1.4–8 mU/mL for men, >30 mU/mL for post-menopausal women; FSH: 1.4–10 mU/mL for men, >30 mU/mL for post-menopausal women (for LH and FSH: Immunotech device, Beckman Coulter, Praha, Czech Republic; detection limits: 0.1 IU/L for both FSH and LH; intra- and interassay CVs: <6.3% for FSH, <6.7% for LH); AMH: 22–38 pmol/L for men, 14–48 for women (enzyme immunometric assay, Immunotech reagents, Beckman Coulter Company, Marseille, France; detection limit: 0.4 pmol/L; intra and interassay CVs: <12.3% and <14.2%,); Inhibin B: 80–327 pg/mL for men, <20 pg/mL for post-menopausal women (enzyme immunometric assay, Oxford Bio-Innovation reagents, Serotec, Oxford, UK; detection limit: 15 pg/mL; intra- and interassay CVs: 4.2% and 10.2%,).</p>**<p>Subjective olfactometry was performed by a computed-assisted validated test <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0069616#pone.0069616-Eloit1" target="_blank">[35]</a>.</p

IP accumulation.

<p>(<b>A</b>) COS-7 cells were transiently transfected with human GnRH-R expression vector and washed before the addition of myo-[2-³H]Inositol. After 16 hours cells were washed and incubated for 1 hour with graded concentrations of WT, R31C and equimolar WT+R31C GnRH. This experience was conducted three times each in triplicate. (<b>B</b>) Representation of individual values of EC-50 (calculated with Arcsin “P” root transformation) from n = 3 dose-response experiments. WT GnRH EC-50 was calculated at 0.52±0.22 nM, R31C EC-50 at 198.8±75.9 nM, WT+R31C EC-50 at 0.63±0.42 nM.</p