Adult GH Research Articles

American Association of Clinical Endocrinologists and American College of Endocrinology Disease State Clinical Review: Update on Growth Hormone Stimulation Testing and Proposed Revised Cut-Point for the Glucagon Stimulation Test in the Diagnosis Of Adult Growth Hormone Deficiency

The clinical features of adult GH deficiency (GHD) are nonspecific, and GH stimulation testing is often required to confirm the diagnosis. However, diagnosing adult GHD can be challenging due to the episodic and pulsatile GH secretion, concurrently modified by age, gender, and body mass index (BMI). PubMed searches were conducted to identify published data since 2009 on GH stimulation tests used to diagnose adult GHD. Relevant articles in English language were identified and considered for inclusion in the present document. Testing for confirmation of adult GHD should only be considered if there is a high pretest probability, and the intent to treat if the diagnosis is confirmed. The insulin tolerance test (ITT) and glucagon stimulation test (GST) are the two main tests used in the United States. While the ITT has been accepted as the gold-standard test, its safety concerns hamper wider use. Previously, the GH-releasing hormone-arginine test, and more recently the GST, are accepted alternatives to the ITT. However, several recent studies have questioned the diagnostic accuracy of the GST when the GH cut-point of 3 μg/L is used and have suggested that a lower GH cut-point of 1 μg/L improved the sensitivity and specificity of this test in overweight/obese patients and in those with glucose intolerance. Until a potent, safe, and reliable test becomes available, the GST should remain as the alternative to the ITT in the United States. In order to reduce over-diagnosing adult GHD in overweight/obese patients with the GST, we propose utilizing a lower GH cut-point of 1 μg/L in these subjects. However, this lower GH cut-point still needs further evaluation for diagnostic accuracy in larger patient populations with varying BMIs and degrees of glucose tolerance. AACE = American Association of Clinical Endocrinologists BMI = body mass index GH = growth hormone GHD = GH deficiency GHRH = GH-releasing hormone GHS = GH secretagogue GST = glucagon stimulation test IGF = insulin-like growth factor IGFBP-3 = IGF-binding protein 3 ITT = insulin tolerance test ROC = receiver operating characteristic WB-GST = weight-based GST.

Beneficial Effects of GH in Young Adults With Prader-Willi Syndrome: A 2-Year Crossover Trial.

Patients with Prader-Willi syndrome (PWS) are severely at risk to develop morbid obesity, diabetes mellitus type 2, and cardiovascular disease, leading to high mortality. They have an increased fat mass (FM) and decreased lean body mass (LBM). During childhood, GH treatment counteracts the natural course of increasing obesity. Discontinuation of GH treatment at attainment of adult height (AH) might deteriorate their improved clinical condition, whereas continuation might benefit them. To investigate the effects of GH versus placebo on body composition in young adults with PWS who were GH treated for many years during childhood and had attained AH. Two-year, randomized, double-blind, placebo-controlled crossover study with stratification for gender and body mass index in 27 young adults with PWS. PWS Reference Center in The Netherlands. Crossover intervention with GH (0.67 mg/m2 · d) and placebo, both during 1 year. Body composition, measured by dual-energy x-ray absorptiometry. During placebo, FM increased (relative change +21.5%; P < .001). Compared with placebo, GH treatment resulted in lower FM (-2.9 kg; P = .004) and higher LBM (+1.5 kg; P = .005), representing relative changes of -17.3% FM and +3.5% LBM. Both limb and trunk FM percentage were lower during GH versus placebo (relative change +17.3% and +15.6%; P < .001 and P = .007, respectively). No GH-related adverse events occurred. GH-treated young adults with PWS who have attained AH benefit from continuation of GH treatment. FM increases during placebo, whereas GH versus placebo results in lower FM and higher LBM. Thus, GH treatment maintains the improved body composition without safety concerns.

Cyp1b1 affects external control of mouse hepatocytes, fatty acid homeostasis and signaling involving HNF4α and PPARα

Cytochrome P450 1b1 (Cyp1b1) is expressed in endothelia, stellate cells and pre-adipocytes, but not hepatocytes. Deletion alters liver fatty acid metabolism and prevents obesity and hepatic steatosis. This suggests a novel extra-hepatocyte regulation directed from cells that express Cyp1b1. To characterize these mechanisms, microarray gene expression was analyzed in livers of normal and congenic Cyp1b1-ko C57BL/6 J mice fed either low or high fat diets. Cyp1b1-ko gene responses indicate suppression of endogenous PPARα activity, a switch from triglyceride storage to mitochondrial fatty acid oxidation and decreased oxidative stress. Many gene responses in Cyp1b1-ko are sexually dimorphic and correspond to increased activity of growth hormone mediated by HNF4α. Male responses stimulated by GH pulses are enhanced, whereas responses that decline exhibit further suppression, including Cyp regulation by PPARα, CAR and PXR. These effects of Cyp1b1 deletion overlap with effects caused by deletion of the small heterodimeric partner, a suppressor of these nuclear factors. Redirection of gene expression associated with liver fat homeostasis in Cyp1b1-ko mice that directs hypothalamic control of GH and leptin. Cyp1b1-ko suppresses neonatal Scd1 and delays adult maturation of dimorphic GH/HNF4α signaling. Alternatively, deletion may diminish hypothalamic metabolism of estradiol, which establishes adult GH regulation.

Revised GH and cortisol cut-points for the glucagon stimulation test in the evaluation of GH and hypothalamic-pituitary-adrenal axes in adults: results from a prospective randomized multicenter study.

Recent studies suggest using lower GH cut-points for the glucagon stimulation test (GST) in diagnosing adult GH deficiency (GHD), especially in obese patients. There are limited data on evaluating GH and hypothalamic-pituitary-adrenal (HPA) axes using weight-based dosing for the GST. To define GH and cortisol cut-points to diagnose adult GHD and secondary adrenal insufficiency (SAI) using the GST, and to compare fixed-dose (FD: 1 or 1.5mg in patients >90kg) with weight-based dosing (WB: 0.03mg/kg). Response to the insulin tolerance test (ITT) was considered the gold standard, using GH and cortisol cut-points of ≥3ng/ml and ≥18µg/dL, respectively. 28 Patients with hypothalamic-pituitary disease and 1-2 (n=14) or ≥3 (n=14) pituitary hormone deficiencies, and 14 control subjects matched for age, sex, estrogen status and body mass index (BMI) underwent the ITT, FD- and WB-GST in random order. Age, sex ratio and BMI were comparable between the three groups. The best GH cut-point for diagnosis of GHD was 1.0 (92% sensitivity, 100% specificity) and 2.0ng/mL (96% sensitivity and 100% specificity) for FD- and WB-GST, respectively. Age negatively correlated with peak GH during FD-GST (r=-0.32, P=0.04), but not WB-GST. The best cortisol cut-point for diagnosis of SAI was 8.8µg/dL (92% sensitivity, 100% specificity) and 11.2µg/dL (92% sensitivity and 100% specificity) for FD-GST and WB-GST, respectively. Nausea was the most common side effect, and one patient had a seizure during the FD-GST. The GST correctly classified GHD using GH cut-points of 1ng/ml for FD-GST and 2ng/ml for WB-GST, hence using 3ng/ml as the GH cut-point will misclassify some GH-sufficient adults. The GST may also be an acceptable alternative to the ITT for evaluating the HPA axis utilizing cortisol cut-points of 9µg/dL for FD-GST and 11µg/dL for WB-GST.

Pegvisomant-primed glucagon stimulation test in assessing GH reserve and GH/IGF kinetics in adults suspected of GH deficiency.

The accuracy of the glucagon stimulation test(GST) in diagnosing adult GH deficiency (GHD) has recently been questioned. Because pegvisomant (PegV)increases endogenous GH secretion, we hypothesized that priming PegV to the GST (PegV-GST) 72 h beforehand would improve the diagnostic accuracy of this test. This pilot study aimed to prospectively compare PegV-GST to two other diagnostic tests for adult GHD. Adults suspected of GHD underwent PegVGST,GST and insulin tolerance test (ITT) in random order.Growth hormone levels (measured by a PegV insensitive assay) during PegV-GST, GST and ITT were compared,and acute effects of PegV on GH/IGF kinetics were assessed. Ten subjects with hypothalamic-pituitary disease and 1–4 pituitary hormone deficiencies were studied. Basal and peak GH levels with the PegV-GST were comparable to those of the GST and ITT. The five subjects that failed the GST and ITT were the same subjects that failed the PegVGST,using the peak GH cut point of<3 ng/mL for this test. After PegV priming, basal GH and GH binding protein(GHBP) increased (both P<0.01) and total IGF-I and bioactive IGF decreased (both P<0.05), whereas IGF-II and IGFBPs -1, -2 and -3 were unchanged compared to pre-PegV priming. Serum PegV levels correlated positively with basal GH, peak GH, IGFBP-1 and IGFBP-2 levels, and negatively with D bioactive IGF and DGHBP (all P<0.05). Single dose PegV administration in adults suspected of GHD increased basal GH and GHBP, with concomitant rapid fall in IGF-I levels and bioactive IGF. PegV priming did not appear to improve the diagnostic accuracy of the GST. Further studies involving larger subject numbers are needed to verify the clinical utility of PegV-GST in evaluating adult GHD.

Audit of adult GH replacement therapy in Nottingham

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Proposal of a clinical response score and predictors of clinical response to 2 years of GH replacement therapy in adult GH deficiency.

There is no single clinical marker to reliably assess the clinical response to growth hormone replacement therapy (GHRT) in adults with growth hormone deficiency (GHD). The objective of this study was to propose a clinical response score to GHRT in adult GHD and to establish clinical factors that predict clinical response. This was a prospective observational cohort study from the international KIMS database (Pfizer International Metabolic Database). We included 3612 adult patients with GHD for proposing the response score and 844 patients for assessing predictors of response. We propose a clinical response score based on changes in total cholesterol, waist circumference and QoL-AGHDA quality of life measurements after 2 years of GHRT. A score point was added for each quintile of change in each variable, resulting in a sum score ranging from 3 to 15. For clinical response at 2 years, we analysed predictors at baseline and after 6 months using logistic regression analyses. In a baseline prediction model, IGF1, QoL-AGHDA, total cholesterol and waist circumference predicted response, with worse baseline parameters being associated with a favourable response (AUC 0.736). In a combined baseline and 6-month prediction model, baseline QoL-AGHDA, total cholesterol and waist circumference, and 6-month change in waist circumference were significant predictors of response (AUC 0.815). A simple clinical response score might be helpful in evaluating the success of GHRT. The baseline prediction model may aid in the decision to initiate GHRT and the combined prediction model may be helpful in the decision to continue GHRT.

Changes in circulating IGF1 receptor stimulating activity do not parallel changes in total IGF1 during GH treatment of GH-deficient adults.

Previously we demonstrated that IGF1 receptor stimulating activity (IGF1RSA) offers advantages in diagnostic evaluation of adult GH deficiency (GHD). It is unknown whether IGF1RSA can be used to monitor GH therapy. To investigate the value of circulating IGF1RSA for monitoring GH therapy. 106 patients (54 m; 52 f) diagnosed with GHD were included; 22 were GH-naïve, 84 were already on GH treatment and discontinued therapy 4 weeks before baseline values were established. IGF1RSA was determined by the IGF1R kinase receptor activating assay, total IGF1 by immunoassay (Immulite). GH doses were titrated to achieve total IGF1 levels within the normal range. After 12 months, total IGF1 and IGF1RSA increased significantly (total IGF1 from 8.1 (95% CI 7.3-8.9) to 14.9 (95% CI 13.5-16.4) nmol/l and IGF1RSA from 115 (95% CI 104-127) to 181 (95% CI 162-202) pmol/l). After 12 months, total IGF1 normalized in 81% of patients, IGF1RSA in 51% and remained below normal in more than 40% of patients in whom total IGF1 had normalized. During 12 months of GH treatment, changes in IGF1RSA did not parallel changes in total IGF1. Despite normalization of total IGF1, IGF1RSA remained subnormal in a considerable proportion of patients. At present our results have no short-term consequences for GH therapy of GHD patients. However, based on our findings we propose future studies to examine whether titrating GH dose against IGF1RSA results in a better clinical outcome than titrating against total IGF1.

Permanent uncoupling of male-specific CYP2C11 transcription/translation by perinatal glutamate

Perinatal exposure of rats and mice to the typically reported 4mg/g bd wt dose of monosodium glutamate (MSG) results in a complete block in GH secretion as well as obesity, growth retardation and a profound suppression of several cytochrome P450s, including CYP2C11, the predominant male-specific isoform — all irreversible effects. In contrast, we have found that a lower dose of the food additive, 2mg/g bd wt on alternate days for the first 9days of life results in a transient neonatal depletion of plasma GH, a subsequent permanent overexpression of CYP2C11 as well as subnormal (mini) GH pulse amplitudes in an otherwise normal adult masculine episodic GH profile. The overexpressed CYP2C11 was characterized by a 250% increase in mRNA, but only a 40 to 50% increase in CYP2C11 protein and its catalytic activity. Using freshly isolated hepatocytes as well as primary cultures exposed to the masculine-like episodic GH profile, we observed normal induction, activation, nuclear translocation and binding to the CYP2C11 promoter of the GH-dependent signal transducers required for CYP2C11 transcription. The disproportionately lower expression levels of CYP2C11 protein were associated with dramatically high expression levels of an aberrant, presumably nontranslated CYP2C11 mRNA, a 200% increase in CYP2C11 ubiquitination and a 70–80% decline in miRNAs associated, at normal levels, with a suppression of CYP2C expression. Whereas the GH-responsiveness of CYP2C7 and CYP2C6 as well as albumin was normal in the MSG-derived hepatocytes, the abnormal expression of CYP2C11 was permanent and irreversible.

Possible predictors for QOL improvement following GH replacement therapy in adult GHD

In addition to impaired physical activity, adult GH deficiency (GHD) can decrease quality of life (QOL). Hence, assessment of QOL is important to evaluate the efficacy of GH replacement therapy. This study aimed to identify factors that may be predictive of long-term improvement in QOL among clinical/laboratory variables during GH replacement therapy. The analysis included 83 Japanese adults with GHD who participated in the Hypopituitary Control and Complications Study (HypoCCS). Correlations between the change from baseline in clinical/laboratory variables at 6 months and the change from baseline in Quality of life (Short-Form 36 [SF-36] component scores) at 12 months were examined. Unexpectedly, all component scores were negatively correlated with the change in fasting plasma glucose concentration (FPG) (physical component summary [PCS], r = -0.456; mental component summary [MCS], r = -0.523; role/social component summary [RCS], r = -0.433). The change in MCS was positively correlated with the change in insulin-like growth factor-1 standard deviation score (IGF-1 SDS) (r = 0.417). The change in PCS was positively correlated with the change in body fat (r = 0.551). The change in RCS was positively correlated with the change in waist circumference (r = 0.528). Short-term changes in several clinical/laboratory variables, most notably FPG and IGF-1 SDS, were correlated with long-term changes in QOL. The clinical importance of these correlations for predicting GH replacement treatment efficacy warrants further investigation.

Overweight/Obese adults with pituitary disorders require lower peak growth hormone cutoff values on glucagon stimulation testing to avoid overdiagnosis of growth hormone deficiency.

Obesity is associated with diminished GH secretion, which may result in the overdiagnosis of adult GH deficiency (GHD) in overweight/obese pituitary patients. However, there are no body mass index (BMI)-specific peak GH cutoffs for the glucagon stimulation test (GST), the favored dynamic test for assessing adult GHD in the United States. The objective of the study was to determine a peak GH cutoff level for the diagnosis of adult GHD in overweight/obese individuals using the GST. This was a retrospective, cross-sectional study. The study was conducted at Massachusetts General Hospital and Oregon Health and Science University. A total of 108 subjects with a BMI ≥ 25 kg/m(2) were studied: healthy controls (n = 47), subjects with total pituitary deficiency (TPD) (n = 20, ≥ 3 non-GH pituitary hormone deficiencies), and subjects with partial pituitary deficiency (PPD) (n = 41, 1-2 non-GH pituitary hormone deficiencies). The intervention consisted of a standard 4-hour GST. The main outcome measure was peak GH level on GST. Using the standard peak GH cutoff of 3 ng/mL, 95% of TPD cases (19 of 20), 80% of PPD (33 of 41), and 45% of controls (21 of 47) were classified as GHD. In receiver-operator characteristic curve analysis (controls vs TPD), a peak GH value of 0.94 ng/mL provided the greatest sensitivity (90%) and specificity (94%). Using a peak GH cutoff of 1 ng/mL, 6% of controls (3 of 47), 59% of PPDs (24 of 41), and 90% of TPDs (18 of 20) were classified as GHD. BMI (R = -0.35, P = .02) and visceral adipose tissue (R = -0.32, P = .03) negatively correlated with peak GH levels in controls. A large proportion of healthy overweight/obese individuals (45%) failed the GST using the standard 3 ng/mL GH cutoff. Overweight/obese pituitary patients are at risk of being misclassified as GHD using this cutoff level. A 1-ng/mL GH cutoff may reduce the overdiagnosis of adult GHD in overweight/obese patients.

OR1-1: GH treatment modulates mortality in adult onset GH deficiency and a discordant socio-economic status is apparent

OR1-1: GH treatment modulates mortality in adult onset GH deficiency and a discordant socio-economic status is apparent

Impact of moderate interval exercise versus supine rest on the pharmacokinetics and pharmacodynamic profiles of subcutaneously administered growth hormone in adult growth hormone deficient patients

BackgroundDiurnal variation in serum growth hormone (s-GH) levels after exogenous GH delivery has previously been reported in patients with no endogenous GH secretion. Changes in postural position or physical activity, leading to changes in blood flow and/or lymphatic drainage may be underlying explanations. Primary objectivesThe primary aim of this study is to study a possible impact of exercise and supine rest on pharmacokinetics (PK) and day-to-day variation of subcutaneously (sc) administered GH in adult GH deficient (AGHD) patients. Secondary objectiveThe secondary aim of this study is to compare s-IGF-I, s-insulin, and plasma (p)-glucose profiles after a carbohydrate rich breakfast following sc GH injection vs. continuous infusion. Design and methodsDuring supine rest eight AGHD males (59.8±8years, BMI 29.7±4.9kg/m2) were treated with one daily sc GH injections of 3mg/24h for 48h (treatment sessions A, B) or a continuous sc GH infusion of 3mg/24h for 60h (treatment sessions C, D). Exercise comprised 1h bicycling with 50W load on two consecutive days during treatment sessions B and D. ResultsAdministration of GH as a bolus injection, but not as a continuous GH infusion, resulted in about 32% higher s-GH levels during exercise (60min) as well as 30min after (s-GH logAUC(B-A) difference was 0.28; 95% CI: 0.14–0.4; p<0.001). However, the total s-GHAUC 0–24h (p=0.75) and s-IGF-IAUC 0–48h levels (p=0.51) remained unchanged between the two occasions. P-glucose and insulin profiles were significantly higher after carbohydrate rich breakfast before first and second dosing both following sc GH injection and continuous infusion (p<0.05). ConclusionsModerate exercise intermittently increased s-GH levels. These changes seem to have no clinical short-term relevance, since total s-GH24h and s-IGF-I48h levels were unaffected.

Effects of up to 15 years of recombinant human GH replacement therapy on the skeleton in adult GH deficiency: the Leiden Cohort Study

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Assessing the Impact of Growth Hormone Deficiency and Treatment in Adults: Development of a New Disease-Specific Measure

Approximately 50 000 adults in the United States are diagnosed with GH deficiency, which has negative impacts on cognitive functioning, psychological well-being, and quality of life. This paper presents development and validation of a patient-reported outcome measure (PRO), the Treatment-Related Impact Measure-Adult Growth Hormone Deficiency (TRIM-AGHD). The TRIM-AGHD was developed to measure the impact of GH deficiency and its treatment. The development and validation of the TRIM-AGHD was conducted according to the Food and Drug Administration guidance on the development of PROs. Concept elicitation, conducted in three countries included interviews with patients, clinical experts, and literature review. Qualitative data were analyzed based on grounded theory principles, and draft items were cognitively debriefed. The measure underwent psychometric validation in a US clinic-based population. An a priori statistical analysis plan included assessment of the measurement model, reliability, and validity. Item functioning was reviewed using item response theory analyses. Forty-eight patients and six clinical experts participated in concept elicitation and 169 patients completed the validation study. TRIM-AGHD was measured. Factor analysis resulted in four domains: energy level, physical health, emotional health, and cognitive ability. The item response theory confirmed adequate item fit and placement within their domain. Internal consistency ranged from 0.82 to 0.95 and test-retest ranged from 0.80 to 0.92. All prespecified hypotheses for convergent validity and all but two for discriminant validity were met. The final 26-item TRIM-AGHD can be considered a reliable and valid PRO of the impact of disease and treatment for adult GH deficiency.

EXTENSIVE EXPERTISE IN ENDOCRINOLOGY: UK stance on adult GH replacement: the economist vs the endocrinologist

In the UK, through the use of a forced economic model, endocrinologists are in the curious position of offering GH replacement to some patients with severe GH deficiency (GHD) but withholding it from other patients with even more severe GHD. This approach is counter-intuitive to endocrine practice in treating endocrine deficiency states. For all other endocrine deficiencies, one would opt for treating those with the most severe biochemical evidence of deficiency first. If this endocrine approach was applied to adult GH replacement in an era of rationing, one would start with the GHD patients with a pathologically low IGF1 level. Given that the prevalence of subnormal IGF1 levels in a GHD population is age-dependent, this would result in GH replacement being offered to more young adult onset (AO) GHD and childhood onset GHD adults, and less often to middle-aged and elderly AO GHD adults. This in itself has the added advantage that the skeletal benefits appear more real in the former cohort of patients.

Comparison of two growth hormone stimulation tests and their cut-off limits in healthy adults at an outpatient clinic

ObjectiveA peak GH less than 3μg/L to insulin tolerance test (ITT) is commonly used as a threshold indicating severe adult GH deficiency (GHD). This cut-off is based on results obtained by polyclonal radioimmunoassays preferably under standard conditions at hospital. Our aim was to evaluate the validity of this cut-off limit using two currently used immunometric GH assays and to compare GH responses in the ITT and the GH releasing hormone+arginine (GHRH+ARG) test in healthy adults at our outpatient endocrine unit. DesignITT was performed on 73 subjects and the GHRH+ARG test on those 28 who showed insufficient response to the ITT. MethodsGH was measured by an immunofluorometric and immunochemiluminometric assay. ResultsGH peak above 3μg/L was observed in 56% of the healthy volunteers with adequate hypoglycemia in the ITT. Among the 28 subjects with a peak GH below 3μg/L, only two overweight men had a GH peak response below the commonly used cut-off limit of 9.1μg/L in the GHRH+ARG test. ConclusionsLean healthy adults could erroneously be classified as GH deficient by the ITT while their results in the GHRH+ARG test were normal. The GH results are highly dependent on the immunoassay used, but false positive results in the ITT are often obtained even if lower cutoff limits determined on the basis on the calibration of the GH assay are used. Confounding factors seemed to blunt the GH response to the ITT more than to the GHRH+ARG test at our outpatient clinic.

Idiopathic Growth Hormone Deficiency in Adults, Ben Johnson and the Somatopause

In his update on the syndrome of adult GH deficiency in this issue of the JCEM, Melmed (1) draws attention to the growing number of people being diagnosed with “idiopathic GH deficiency in adults.” He also states that “the propensity by some practitioners for inappropriate IAGHD (idiopathic adult-onset GH deficiency) diagnosis as a prelude to administering unsafe nonapproved GH supplementation for athletes or for the frail elderly underscores the need for a stringent diagnostic approach”— thus implying that the increase in idiopathic adult-onset GH deficiency diagnosis, typified by that seen in the HYPOCCS postmarketing surveillance database that he quotes (2), is because fellow practitioners are overdiagnosing the condition in order to legitimize undesirable practice. These are strong words. Although few doctors would prescribe GH (recombinant human GH [rhGH]) as a performance-enhancing drug for an athlete, few of us would not prescribe a trial of therapy in someone we believed to be suffering from GH deficiency and appearing to have ill health as a consequence. Let us not forget that in the early days of the use of rhGH in adults, there was considerable skepticism and some frank hostility to this from some established endocrinologists. It is difficult to distinguish the GH deficiency in older people from the GH deficiency secondary to pituitary or hypothalamic damage. There is a clear rationale for prescribing a trial of rhGH for prevention and/or treatment of frailty in suitable patients (3–5). Let us put this in context: athletes and their coaches were the first to discover the powerful anabolic actions of GH in adults (6, 7). GH was given a glowing write-up by the California “doping guru” Daniel Duchaine in “The Underground Steroid Handbook” (6); in 1982, he wrote: “We find that GH is the most expensive, most fashionable, and least understood of the new athletic drugs. It has firmly established itself in power-lifting and within a few years will be a commonly used drug in all strength athletics.” Thus, human GH was established as a drug of abuse in sport some 7 years before the results of the first 2 randomized controlled trials confirming its powerful anabolic actions in humans were published in the bona fide medical literature (8, 9). A year earlier, the sprinter Ben Johnson won a gold medal at the Olympic Games in Seoul, only to lose it 3 days later when his urine test confirmed that he had been taking the anabolic steroid stanozol; he subsequently admitted under oath that at the time he was also taking GH. These performance-enhancing effects of GH have now been confirmed using randomized controlled trials—first in abstinent, previously steroid-dependent athletes by Graham et al (10); and, together with sex steroids in young athletes, by Meinhardt et al (11), 29 years after Duchaine’s first publication. I use these anecdotes to illustrate that it is not always the scientists who make the discoveries; sometimes, like the athletes, it is the people who are most likely to benefit and who are always hungry for an effective new therapy. If they find such a substance, try it, and find that it works, then the word spreads and later we, as clinician scientists, come along and discover it “officially.” Athletic competition is so strong and the rewards are so great that new ways of improving performance are constantly being sought. The intelligent athletes and their coaches are constantly using the “trial of one” paradigm (12) to test new training regimes, diets, supplements, and substances. Athletes know their best performance for a given event to a

Idiopathic Adult Growth Hormone Deficiency

GH secretion is controlled by hypothalamic as well as intrapituitary and peripheral signals, all of which converge upon the somatotroph, resulting in integrated GH synthesis and secretion. Enabling an accurate diagnosis of idiopathic adult GH deficiency (IAGHD) is challenged by the pulsatility of GH secretion, provocative test result variability, and suboptimal GH assay standardization. The spectrum between attenuated GH secretion associated with the normal aging process and with obesity and truly well-defined IAGHD is not distinct and may mislead the diagnosis. Adult-onset GHD is mainly caused by an acquired pituitary deficiency, commonly including prior head/neck irradiation, or an expanding pituitary mass causing functional somatotroph compression. To what extent rare cryptic causes account for those patients seemingly classified as IAGHD is unclear. About 15% of patients with adult GHD and receiving GH replacement in open-label surveillance studies are reported as being due to an idiopathic cause. These patients may also reflect a pool of subjects with an as yet to be determined occult defect, or those with unclear or incomplete medical histories (including forgotten past sports head injury or motor vehicle accident). Therefore, submaximal diagnostic evaluation likely leads to an inadvertent diagnosis of IAGHD. In these latter cases, adherence to rigorous biochemical diagnostic criteria and etiology exclusion may result in reclassification of a subset of these patients to a distinct known acquired etiology, or as GH-replete. Accordingly, rigorously verified IAGHD likely comprises less than 10% of adult GHD patients, an already rare disorder. Regardless of etiology, patients with adult GHD, including those with IAGHD, exhibit a well-defined clinical phenotype including increased fat mass, loss of lean muscle mass, decreased bone mass, and enhanced cardiac morbidity. Definition of unique efficacy and dosing parameters for GH replacement and resultant therapeutic efficacy markers in true IAGHD requires prospective study.

THERAPY OF ENDOCRINE DISEASE: GH therapy in adult GH deficiency: A review of treatment schedules and the evidence for low starting doses

Recombinant human GH has been licensed for use in adult patients with GH deficiency (GHD) for over 15 years. Early weight- and surface area-based dosing regimens were effective but resulted in supraphysiological levels of IGF1 and increased incidence of side effects. Current practice has moved towards individualised regimens, starting with low GH doses and gradually titrating the dose according to the level of serum IGF1 to achieve an optimal dose. Here we present the evidence supporting the dosing recommendations of current guidelines and consider factors affecting dose responsiveness and parameters of treatment response. The published data discussed here lend support for the use of low GH dosing regimens in adult GHD. The range of doses defined as ‘low dose’ in the studies discussed here (∼1–4 mg/week) is in accordance with those recommended in current guidelines and encompasses the dose range recommended by product labels.