Growth hormone (GH) is produced primarily by anterior pituitary somatotroph cells. Numerous acute human (h) GH treatment and long-term follow-up studies and extensive use of animal models of GH action have shaped the body of GH research over the past 70 years. Work on the GH receptor (R)-knockout (GHRKO) mice and results of studies on GH-resistant Laron Syndrome (LS) patients have helped define many physiological actions of GH including those dealing with metabolism, obesity, cancer, diabetes, cognition and aging/longevity. In this review, we have discussed several issues dealing with these biological effects of GH and attempt to answer the question of whether decreased GH action may be beneficial.
Reetobrata Basu, Yanrong Qian, and John J Kopchick
Sebastian J Neggers, John J Kopchick, Jens O L Jørgensen, and Aart J van der Lely
Medical treatment of acromegaly with long-acting somatostatin analogs (LA-SMSA) and the GH receptor antagonist, pegvisomant (PEGV), has made it possible to achieve normal serum IGF1 concentrations in a majority of patients with acromegaly. These two compounds, however, impact the GH–IGF1 axis differently, which challenges the traditional biochemical assessment of the therapeutic response. We postulate that LA-SMSA in certain patients normalizes serum IGF1 levels in the presence of elevated GH actions in extra-hepatic tissues. This may result in persistent disease activity for which we propose the term extra-hepatic acromegaly. PEGV, on the other hand, blocks systemic GH actions, which are not necessarily reliably reflected by serum IGF1 levels, and this treatment causes a further elevation of serum GH levels. Medical treatment is therefore difficult to monitor with the traditional biomarkers. Moreover, the different modes of actions of LA-SMSA and PEGV make it attractive to use the two drugs in combination. We believe that it is time to challenge the existing concepts of treatment and monitoring of patients with acromegaly.
Arne Hinrichs, Simone Renner, Martin Bidlingmaier, John J Kopchick, and Eckhard Wolf
Aim of the study is to find possible explanations for vanishing juvenile hypoglycemia in growth hormone receptor deficiency (GHRD) in human patients and animal models. We reviewed parameters of glucose metabolism in distinct age groups in two human cohorts (Israeli and Ecuadorian) of Laron syndrome (LS) patients, a mouse model (Ghr-KO mouse) and provide additional data for a porcine model (GHR-KO pig). Juvenile hypoglycemia is a common symptom of GHRD and vanishes in adulthood. In the Israeli cohort, developing metabolic syndrome is associated with decreasing insulin sensitivity, insulinopenia and glucose intolerance, increasing glucose levels with age. In Ecuadorian patients and both animal models, insulin sensitivity is preserved or even enhanced. Alterations in food intake and energy consumption do not explain the differences in glucose levels, neither is the accumulation of body fat associated with negative effects in the Ecuadorian cohort or the animal models. A reduced beta cell mass and resulting insulin secretory capacity is common and leads to glucose intolerance in Ghr-KO mice, while glucose tolerance is preserved in Ecuadorian patients and the GHR-KO pig. In human patients and the GHR-KO pig, a simultaneous occurrence of normoglycemia with the onset of puberty is reported. Reduced gluconeogenesis in GHRD is discussed to cause the juvenile hypoglycemia and a counter regulatory stimulation of gluconeogenesis can be hypothesized. A coherent study assessing endogenous glucose production and beta-cell capacity in the hypoglycemic and normoglycemic age group is needed. This can be performed in GHR-KO pigs, including castrated animals.
Diana Cruz-Topete, Britt Christensen, Lucila Sackmann-Sala, Shigeru Okada, Jens Otto L Jorgensen, and John J Kopchick
Transsphenoidal adenomectomy is the primary treatment for acromegaly. However, assessment of the therapeutical outcome remains problematic since the existing biomarkers of disease activity frequently show discordant results.
To discover novel serum biomarkers of disease activity in acromegalic patients before and after surgery.
Serum samples of eight newly diagnosed acromegaly patients before and after transsphenoidal surgery were analyzed for proteomic changes by two-dimensional gel electrophoresis. Protein spots displaying statistically significant changes, pre- versus post-surgery, were identified by mass spectrometry (MS), tandem MS (MS/MS), and western blot analysis.
Six protein spots displaying decreased intensities after surgery were identified as transthyretin (two isoforms), haptoglobin α2, β-hemoglobin, and apolipoprotein A-1 (two isoforms). One protein spot, identified as complement C4B precursor, was increased after the surgery.
Seven serum protein spots were differentially expressed following surgery in acromegalic patients. The identified proteins represent potential novel biomarkers to assess the effectiveness of surgical treatment in acromegalic individuals. Future studies will validate the use of the identified proteins as biomarkers of disease activity after medical treatment of acromegaly.
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.