Purpose
Growth hormone (GH) therapy has been studied as treatment for clinical manifestations of adult-onset growth hormone deficiency (AO-GHD), including cardiovascular risk, bone health, and ...quality of life. Patients with AO-GHD typically also have significant history of pituitary pathology and hypopituitarism, which raises the question of what proportion of their clinical presentation can be attributed to GHD alone. Currently, much of the existing data for GH therapy in AO-GHD come from uncontrolled retrospective studies and observational protocols. These considerations require careful reassessment of the role of GH as a therapeutic agent in adult patients with hypopituitarism.
Methods
We contrast results from placebo-controlled trials with those from uncontrolled and retrospective studies for GH replacement in patients with hypopituitarism. We also examine the evidence for the manifestations of AO-GHD being attributed to GHD alone, as well as the data on adults with congenital, life-long untreated isolated GHD.
Results
The evidence for increased morbidity and mortality in hypopituitary patients with GHD, and for the benefits of GH therapy, are conflicting. There remains the possibility that the described clinical manifestations of AO-GHD may not be due to GHD alone, but may also be related to underlying pituitary pathology, treatment history and suboptimal hormone replacement.
Conclusions
In the setting of inconsistent data on the benefits of GH therapy, treatment of AO-GHD remains an individualized decision. There is a need for more randomized, placebo-controlled studies to evaluate the long-term outcomes of GH therapy in adults with hypopituitarism.
BACKGROUND:Transsphenoidal surgery is the standard approach for treating Cushing disease. Evidence is needed to document effectiveness.
OBJECTIVE:To analyze results of transsphenoidal surgery in 276 ...consecutive patients, including 19 children.
METHODS:Medical records were reviewed for patients treated initially with surgery for Cushing disease from 1980 to 2012. Radiographic features, pathology, remissions, recurrences, and complications were recorded. Patients were categorized for statistical analysis based on tumor size (microadenomas, macroadenomas, and negative imaging) and remission type (type 1 = morning cortisol ≤3 μg/dL; type 2 = morning cortisol normal).
RESULTS:Females comprised 78% of patients and were older than men. Imaging showed 50% microadenomas, 13% macroadenomas, and 37% negative for tumor. Remission rates for microadenomas, macroadenomas, and negative imaging were 89%, 66%, and 71%, respectively. Patients with microadenomas were more likely to have type 1 remission. Pathology showed adrenocorticotropic hormone-secreting adenomas in 82% of microadenomas, in 100% of macroadenomas, and in 43% of negative imaging. The incidence of hyperplasia was 8%. The finding of hyperplasia or no tumor on pathology predicted treatment failure. The recurrence rate was 17%, with an average time to recurrence of 4.0 years. Patients with type 1 remission had a lower rate of recurrence (13% type 1 vs 50% type 2) and a longer time to recurrence. Children had similar imaging findings, remission rates, and pathology. There were no operative deaths.
CONCLUSION:Transsphenoidal surgery provides a safe and effective treatment for Cushing disease. For both adults and children, the best outcomes occurred in patients with microadenomas and/or those with type 1 remission.
ABBREVIATIONS:ACTH, adrenocorticotropic hormoneIPSS, inferior petrosal sinus sampling
To study the effect of chronic excess growth hormone on adipose tissue, we performed RNA sequencing in adipose tissue biopsies from patients with acromegaly (n = 7) or non-functioning pituitary ...adenomas (n = 11). The patients underwent clinical and metabolic profiling including assessment of HOMA-IR. Explants of adipose tissue were assayed ex vivo for lipolysis and ceramide levels. Patients with acromegaly had higher glucose, higher insulin levels and higher HOMA-IR score. We observed several previously reported transcriptional changes (IGF1, IGFBP3, CISH, SOCS2) that are known to be induced by GH/IGF-1 in liver but are also induced in adipose tissue. We also identified several novel transcriptional changes, some of which may be important for GH/IGF responses (PTPN3 and PTPN4) and the effects of acromegaly on growth and proliferation. Several differentially expressed transcripts may be important in GH/IGF-1-induced metabolic changes. Specifically, induction of LPL, ABHD5, and NRIP1 can contribute to enhanced lipolysis and may explain the elevated adipose tissue lipolysis in acromegalic patients. Higher expression of TCF7L2 and the fatty acid desaturases FADS1, FADS2 and SCD could contribute to insulin resistance. Ceramides were not different between the two groups. In summary, we have identified the acromegaly gene expression signature in human adipose tissue. The significance of altered expression of specific transcripts will enhance our understanding of the metabolic and proliferative changes associated with acromegaly.
Only a few days of overeating in humans reduces plasma GH concentration by about 80% prior to any gain in body weight.
Context:
The very low GH concentration in obesity is commonly attributed to high ...body fat mass; however, the influence of overeating on GH secretion is not clear.
Objective:
The aim of the study was to examine the effects of 2 wk of overeating on changes in GH secretion.
Setting:
Subjects were admitted to the hospital and stayed within the Michigan Clinical Research Unit throughout the entire 2-wk overeating period.
Participants:
We studied seven healthy, nonobese men (body mass index, 24 ± 1 kg/m2; age, 25 ± 1 yr).
Intervention:
Subjects ate standardized meals containing 70 kcal/kg fat free mass/d (∼4000 kcal/d) for 2 wk.
Main Outcome Measures:
Twenty-four-hour plasma concentrations of GH (every 20 min) and insulin (every 2 h) were measured before overeating (baseline), on d 3, and after 2 wk of overeating.
Results:
Compared with baseline, average 24-h plasma GH concentration declined nearly 80% by d 3 of overeating (1.30 ± 0.18 vs. 0.36 ± 0.09 ng/ml; P = 0.01). This marked suppression of GH secretion occurred in the absence of an increase in body weight (77.0 ± 2.2 vs. 76.4 ± 2.4 kg). At the same time, average 24-h insulin concentration doubled (16.6 ± 2.1 vs. 31.7 ± 5.8 μU/ml; P = 0.009). After 2 wk, body weight significantly increased (79.0 ± 2.1 kg; P < 0.001), and body fat increased by more than 10% (P = 0.002). However, this did not induce a further suppression in plasma GH concentration (0.33 ± 0.08 ng/ml).
Conclusion:
Only a few days of overeating markedly suppressed GH secretion before any measurable weight gain and was accompanied by chronic hyperinsulinemia. Increased body weight and body fat by 2 wk of overeating did not further suppress GH secretion.
The Role of Radiotherapy in Acromegaly Hannon, Mark J; Barkan, Ariel L; Drake, William M
Neuroendocrinology,
02/2016, Volume:
103, Issue:
1
Journal Article
Peer reviewed
Open access
Radiotherapy has, historically, played a central role in the management of acromegaly, and the last 30 years have seen substantial improvements in the technology used in the delivery of radiation ...therapy. More recently, the introduction of highly targeted radiotherapy, or 'radiosurgery', has further increased the therapeutic options available in the management of secretory pituitary tumors. Despite these developments, improvements in primary surgical outcomes, an increase in the range and effectiveness of medical therapy options, and long-term safety concerns have combined to dictate that, although still deployed in selected cases, the use of radiotherapy in the management of acromegaly has declined steadily over the past 2 decades. In this article, we review some of the main studies that have documented the efficacy of pituitary radiotherapy on growth hormone hypersecretion and summarize the data around its potential deleterious effects, including hypopituitarism, cranial nerve damage, and the development of radiation-related intracerebral tumors. We also give practical recommendations to guide its future use in patients with acromegaly, generally, as a third-line intervention after neurosurgical intervention in combination with various medical therapy options.
Background:
Anterior cruciate ligament (ACL) tears are common knee injuries. Despite undergoing extensive rehabilitation after ACL reconstruction (ACLR), many patients have persistent quadriceps ...muscle weakness that limits their successful return to play and are also at an increased risk of developing knee osteoarthritis (OA). Human growth hormone (HGH) has been shown to prevent muscle atrophy and weakness in various models of disuse and disease but has not been evaluated in patients undergoing ACLR.
Hypothesis:
Compared with placebo treatment, a 6-week perioperative treatment course of HGH would protect against muscle atrophy and weakness in patients undergoing ACLR.
Study Design:
Randomized controlled trial; Level of evidence, 2.
Methods:
A total of 19 male patients (aged 18-35 years) scheduled to undergo ACLR were randomly assigned to the placebo (n = 9) or HGH (n = 10) group. Patients began placebo or HGH treatment twice daily 1 week before surgery and continued through 5 weeks after surgery. Knee muscle strength and volume, patient-reported outcome scores, and circulating biomarkers were measured at several time points through 6 months after surgery. Mixed-effects models were used to evaluate differences between treatment groups and time points, and as this was a pilot study, significance was set at P < .10. The Cohen d was calculated to determine the effect size.
Results:
HGH was well-tolerated, and no differences in adverse events between the groups were observed. The HGH group had a 2.1-fold increase in circulating insulin-like growth factor 1 over the course of the treatment period (P < .05; d = 2.93). The primary outcome measure was knee extension strength, and HGH treatment increased normalized peak isokinetic knee extension torque by 29% compared with the placebo group (P = .05; d = 0.80). Matrix metalloproteinase–3 (MMP3), which was used as an indirect biomarker of cartilage degradation, was 36% lower in the HGH group (P = .05; d = –1.34). HGH did not appear to be associated with changes in muscle volume or patient-reported outcome scores.
Conclusion:
HGH improved quadriceps strength and reduced MMP3 levels in patients undergoing ACLR. On the basis of this pilot study, further trials to more comprehensively evaluate the ability of HGH to improve muscle function and potentially protect against OA in patients undergoing ACLR are warranted.
Registration:
NCT02420353 (ClinicalTrials.gov identifier)
Purpose
Approximately 25 % of cases of clinically active acromegaly cases treated in our academic center between 1996 and 2000, were diagnosed in patients who had elevated plasma IGF-1 levels, but ...apparently “normal” 24-h mean plasma GH levels. The current study served to update the data for patients with acromegaly referred to our facility, after increasing awareness of this “normal” GH subpopulation throughout the medical community.
Methods
A retrospective chart review was conducted on 157 patients with acromegaly who underwent resection of a confirmed somatotroph pituitary adenoma at the University of Michigan Health System between the dates of 1 Jan 2001 to 23 Sept 2015.
Results
Overall prevalence of acromegalic patients with “normal” GH levels, defined as GH <4.7 ng/mL, was 31 %. Over time, the percentage of patients with “normal” GH at diagnosis did not decline: 26 % from 2001 to 2005, 19 % from 2006 to 2010, and 47 % from 2011 to 2015. Mean pituitary tumor size was 1.8 ± 0.1 cm for the group with elevated GH, and 1.2 ± 0.1 cm for the group with “normal” GH (
p
< 0.001). Percent microadenomas was higher in a group with “normal” GH as compared to those with elevated GH (48 vs. 12 %,
p
< 0.001), and tumors >2 cm in the maximal diameter were encountered more frequently in the group with elevated GH (43 vs. 14 %,
p
< 0.001).
Conclusions
Our data show that a substantial percentage of patients with clinical acromegaly have “normal” GH, and therefore strengthens the growing body of evidence which supports the leading role of IGF-1 levels in diagnostic evaluation. At the present time, questions about the natural course of “micromegaly” and treatment benefits compared to the subpopulation with elevated GH levels remain unanswered, but research continues to build on our understanding of the heterogeneous population of individuals.
Glucocorticoids have major effects on adipose tissue metabolism. To study tissue mRNA expression changes induced by chronic elevated endogenous glucocorticoids, we performed RNA sequencing on the ...subcutaneous adipose tissue from patients with Cushing's disease (n=5) compared to patients with nonfunctioning pituitary adenomas (n=11). We found a higher expression of transcripts involved in several metabolic pathways, including lipogenesis, proteolysis and glucose oxidation as well as a decreased expression of transcripts involved in inflammation and protein synthesis. To further study this in a model system, we subjected mice to dexamethasone treatment for 12 weeks and analyzed their inguinal (subcutaneous) fat pads, which led to similar findings. Additionally, mice treated with dexamethasone showed drastic decreases in lean body mass as well as increased fat mass, further supporting the human transcriptomic data. These data provide insight to transcriptional changes that may be responsible for the comorbidities associated with chronic elevations of glucocorticoids.
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