F Bolfi, A F Neves, C L Boguszewski and V S Nunes-Nogueira
F Bolfi, A F Neves, C L Boguszewski and V S Nunes-Nogueira
To compare the acromegaly mortality rates with those expected for the general population from studies published before and after 2008.
We performed a systematic review and included observational studies in which the number of deaths observed in acromegaly was compared with the expected mortality for the general population mortality observed/expected (O/E). The following electronic databases were used as our data sources: EMBASE, MEDLINE and LILACS. From the observed and expected deaths, we recalculated all standardized mortality ratios (SMR) and their respective confidence intervals (95% CI), which were plotted in a meta-analysis using the software RevMan 5.3.
We identified 2303 references, and 26 studies fulfilled our eligibility criteria. From the 17 studies published before 2008, the mortality in acromegaly was increased, while from the nine studies published after 2008, the mortality was not different from the general population (SMR: 1.35, CI: 0.99–1.85). In six studies where somatostatin analogs (SAs) were used as adjuvant treatment, acromegaly mortality was not increased (SMR: 0.98, CI: 0.83–1.15), whereas in series including only patients treated with surgery and/or radiotherapy, mortality was significantly higher (SMR: 2.11; CI: 1.54–2.91). In studies published before and after 2008, the mortality was not increased in patients who achieved biochemical control, while it was higher in those with active disease. Cancer has become a leader cause of deaths in acromegaly patients in the last decade, period in which life expectancy improved.
Mortality in acromegaly is normalized with biochemical control and decreased in the last decade with the more frequent use of SAs as adjuvant therapy. Increased life expectancy has been associated with more deaths due to cancer.
Cesar L Boguszewski, Ludimyla H F Meister, Daniele C T Zaninelli and Rosana B Radominski
Objective: We have studied the effects on body composition and metabolism of a fixed low dose of growth hormone (GH), 0.6 IU (0.2 mg)/day, administered for 12 months to GH-deficient (GHD) adults.
Design and methods: Prospective open-label study, using 18 GHD patients (11 women, 7 men; aged 21–58 years). All investigations were performed at baseline and after 12 months. Body composition was determined by dual energy X-ray absorptiometry.
Results: Total body fat decreased (−1.74±2.87%) and lean body mass (LBM) increased (1.27±2.08 kg) after therapy (P < 0.05). Changes in truncal fat did not reach statistical significance, but a decrease varying from 0.72 to 2.78 kg (1 to 8.7%) was observed in 13 (72%) patients. Bone mineral density (BMD) increased at lumbar spine, total femur and femoral neck (P < 0.05). Levels of total and low-density lipoprotein (LDL)-cholesterol were lower after therapy (P < 0.05), and their changes were directly associated with values at baseline. Insulin levels increased and the insulin resistance index worsened at 12 months (P < 0.05). Median IGF-I s.d. score was −4.30 (range, −11.03 to −0.11) at baseline and −1.73 (range, −9.80 to 2.26) at 12 months. Normal age-adjusted IGF-I levels were obtained with therapy in 5 of 11 patients who had low IGF-I levels at baseline. Changes in IGF-I levels were not correlated with any biological end point, except changes in LBM (r = 0.53, P = 0.02). Side effects were mild and disappeared spontaneously.
Conclusions: One-year of a fixed low-dose GH regimen in GHD adults resulted in a significant reduction in body fat, total cholesterol and LDL-cholesterol, and a significant increase in LBM and BMD at lumbar spine and femur, regardless of normalization of IGF-I levels. This regimen led to an elevation of insulin levels and a worsening of the insulin resistance index.
D B Allen, P Backeljauw, M Bidlingmaier, B M K Biller, M Boguszewski, P Burman, G Butler, K Chihara, J Christiansen, S Cianfarani, P Clayton, D Clemmons, P Cohen, F Darendeliler, C Deal, D Dunger, E M Erfurth, J S Fuqua, A Grimberg, M Haymond, C Higham, K Ho, A R Hoffman, A Hokken-Koelega, G Johannsson, A Juul, J Kopchick, P Lee, M Pollak, S Radovick, L Robison, R Rosenfeld, R J Ross, L Savendahl, P Saenger, H Toft Sorensen, K Stochholm, C Strasburger, A Swerdlow and M Thorner
Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that ‘for approved indications, GH is safe’; however, the statement highlighted a number of areas for on-going surveillance of long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement.
Jens Sandahl Christiansen, Philippe F Backeljauw, Martin Bidlingmaier, Beverly M K Biller, Margaret C S Boguszewski, Felipe F Casanueva, Philippe Chanson, Pierre Chatelain, Catherine S Choong, David R Clemmons, Laurie E Cohen, Pinchas Cohen, Jan Frystyk, Adda Grimberg, Yukihiro Hasegawa, Morey W Haymond, Ken Ho, Andrew R Hoffman, Jeff M P Holly, Reiko Horikawa, Charlotte Höybye, Jens Otto L Jorgensen, Gudmundur Johannsson, Anders Juul, Laurence Katznelson, John J Kopchick, K O Lee, Kuk-Wha Lee, Xiaoping Luo, Shlomo Melmed, Bradley S Miller, Madhusmita Misra, Vera Popovic, Ron G Rosenfeld, Judith Ross, Richard J Ross, Paul Saenger, Christian J Strasburger, Michael O Thorner, Haim Werner and Kevin Yuen
The Growth Hormone (GH) Research Society (GRS) convened a workshop to address important issues regarding trial design, efficacy, and safety of long-acting growth hormone preparations (LAGH).
A closed meeting of 55 international scientists with expertise in GH, including pediatric and adult endocrinologists, basic scientists, regulatory scientists, and participants from the pharmaceutical industry.
Current literature was reviewed for gaps in knowledge. Expert opinion was used to suggest studies required to address potential safety and efficacy issues.
Following plenary presentations summarizing the literature, breakout groups discussed questions framed by the planning committee. Attendees reconvened after each breakout session to share group reports. A writing team compiled the breakout session reports into a draft document that was discussed and revised in an open forum on the concluding day. This was edited further and then circulated to attendees from academic institutions for review after the meeting. Participants from pharmaceutical companies did not participate in the planning, writing, or in the discussions and text revision on the final day of the workshop. Scientists from industry and regulatory agencies reviewed the manuscript to identify any factual errors.
LAGH compounds may represent an advance over daily GH injections because of increased convenience and differing phamacodynamic properties, providing the potential for improved adherence and outcomes. Better methods to assess adherence must be developed and validated. Long-term surveillance registries that include assessment of efficacy, cost-benefit, disease burden, quality of life, and safety are essential for understanding the impact of sustained exposure to LAGH preparations.