ADULT GROWTH HORMONE DEFICIENCY S M SHALET

Typical GHD Adult ADULT-ONSET and CHILDHOOD-ONSET UNDERLYING PATHOLOGIES ADDITIONAL PITUITARY HORMONE DEFICITS SEVERITY OF GHD

(Hoffman et al 1994)

Severe Adult GHD (ITT) P <0.0001 GHD0 GHD1 GHD2 GHD3 8 6 g/L) m 4 GH Peak ( 2 GHD0 GHD1 GHD2 GHD3 (Toogood et al. Clin. Endocrinol. 1994)

DIAGNOSING GHD IN ADULTS Clinical Picture GH Stimulation Tests ---1 vs 2 IGF-1 Level Major problem diagnostically in distinguishing Isolated GHD vs Obesity

CLINICAL PRESENTATION---ADULT GHD QoL Skeletal Health Mortality in Hypopituitary Populations (untreated GHD) Body Composition Adverse levels of surrogate markers of cardiovascular risk and skeletal health

GH REPLACEMENT Timelines Body Composition QoL Fractures Cardiovascular Risk

Long-term efficacy

126 hypopituitary adults (72 men) with adult-onset GH deficiency

QoL: long-term response to GH Kołtowska-Häggström M et al. Eur J Endocrinol 2006;155:109–19.

A 10-year prospective study of the metabolic effects of GH replacement in adult-onset GHD 87 patients with adult-onset GHD (52 men and 35 women) Mean age of 44 yr(range 22–74) ** *** *** *** Götherström G et al. J Clin Endocrinol Metab 2007;92:1442–5.

Visceral adipose tissue (cm2) Discontinuing long-term GH replacement therapy: a randomised, placebo-controlled crossover trial in adult GHD 60 GHD patients with mean duration of GH treatment of 10 years A randomised 4-month crossover discontinuation trial LDL-C (mM) hsCRP (mg/L) LDL-C (mmol/L) 3.0 2.0 1.0 4.0 Baseline GH Placebo p<0.01 p<0.05 2.8 2.7 2.3 3.6 Visceral fat mass (cm2) Visceral adipose tissue (cm2) 150 100 50 p<0.001 138.1 133.8 152.8 Filipsson Nyström H, et al. J Clin Endocrinol Metab 2012;97:3185–95. hsCRP, high sensitive CRP

GH and pituitary tumour regrowth

Action of GH and IGF-I in relation to tumour regrowth Increases cell growth and proliferation Inhibits cell apoptosis The risk of tumor re-growth has to be considered during long-term exposure to GH treatment

Tumour progression in non-functioning pituitary adenomas (NFPA) patients with and without GHRT Slide 7 These are the results for the growth hormone patients and the control patients. Here you can see that 74 % of the patients in the GH group managed without a tumor progression and the corresponding figure for the control group was 68 %. To visualize this further we did a Kaplan Meier regression of the progression free survival of the two groups. (Click the button). On the y-axe we have the rate of progression free survival and on the x-axe we can see the time span. The colors are showing the 95th percentile for each group. The GH group is indicated with a solid line and control group is seen with dotted line. As you all can se the groups follow each other very closely and there is no significant difference between them. An important aspect to look in to is the influence of radiotherapy. Therefore we have subdivided the two main groups in regard of if the patients have been initially treated with radiotherapy. Then the following figures emerge. If we first look at the patients without radiotherapy we can see that 69 % of the GH group did not get a tumor progression and the same number for the control group was 57 %. For the patients with initial radiotherapy we can see that 89 % of the GH patients did not get a tumor progression and all of the control patients with initial radiotherapy managed to stay without a tumor progression Important to say is that none of the differences between the subgroups were statistical significant. We have also visualized this in Kaplan Meier curve. Here again you have the progression free survival rate on the y-axe and on the x-axe we can see the time span. Patients initially treated with radiotherapy are indicated with thin lines and patients without initial radiotherapy treatment are seen with bold lines. The growth hormone groups have solid lines and the control group have dotted lines. As you all can se the two groups without radiotherapy follow each other very closely and there is no significant difference between them. In addition there is no significant difference between the two groups of patients who were treated with radiotherapy, even due we can see that there is a numeric difference between them. Important to say is that all patients with an enlargement or a recurrence regardless of how clinically insignificant the progression might been, they were classified in our study as a patients with a progression. No tumour progression GHRT patients Control patients All 74% (90/121) 68% (77/114) -without RT 69% (59/86) 57% (50/87) -with RT 89% (31/35) 100% (27/27) Tumour progression was defined as any tumour enlargement or recurrence regardless of clinical significance Olsson DS et al. Eur J Endocrinol 2009;161:663–9.

Tumour progression in craniopharyngioma patients with and without GHRT Slide 10 These are the result when the patients are divided depending on if they were treated with GH or not. The results are presented as 10 years progression free survival rates. The 10 years progression free survival rate for the GH treated group was 88% and the corresponding figure for the non GH treated group was 57%. To do a better evaluation of the GH:s impact at the progression free survival rate we did a cox regression were we used GH, initial radiotherapy, residual tumor after primary treatment and gender were selected as factors. Press the button Here you can se the adjusted 10 years progression free survival rate for the GH treated group and the non GH treated group. These figures have been adjusted for the uneven distribution of initial radiotherapy, residual tumor and gender. As you can see after the adjustment there is not a higher frequency of tumor progression in the GH treated group compared to the non GH treated group. To visualize this better we did a cox regression graph in which the two groups are adjusted for the uneven distributed frequencies of initial radiotherapy, residual tumor and gender. The progression free survival are shown on the y axis and the time span in years is shown on the x axis. The colors indicate the 95 percent confidence interval for each group. The GH group is indicated with a solid line and control group is seen with dotted line. As you can se the groups follow each other and there is no significant difference between them. 10-years progression-free survival Unadjusted Patients treated with GHRT (n=56) 88% Patients not treated with GHRT (n=70) 57% Adjusted* 85% 65% *for uneven distribution of RT, residual tumour and sex Olsson DS et al. Eur J Endocrinol 2009;161:663–9.

Conclusion: pituitary tumour The available data in adult GH recipients with benign pituitary tumours do not indicate an increased risk of recurrence during long-term GH replacement1,2 1. Fleseriu M et al. Hormone replacement in hypopituitarism in adults: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016; 2. Allen DB et al. GH safety workshop position paper: a critical appraisal of recombinant human GH therapy in children and adults. Eur J Endocrinol 2016; 147

GH replacement and risk of cardiovascular death

Cause-specific mortality in GH-deficient adults on GH replacement All-cause mortality SMR 1.13 (1.04–1.24) N=13,983 N=13,983; 69,056 patient-years Gaillard RC et al. Eur J Endocrinol 2012;166:1069–77. SMR, standardised mortality ratios

Summary of studies on GH replacement and vascular morbidity and mortality SMR all CVD 1.21 (0.81–1.74) 0.83 (0.63–1.08) 1.35 (0.95–1.94) SMR Stroke 1.82 (0.91–3.26) 1.88 (1.44–2.41) 2.54 (1.41–4.59) Stochholm K, Johannsson G. Growth hormone IGF Res. 2015;25:149–57. SMR, standardised mortality ratios

Life expectancy in patients with pituitary adenoma receiving GH replacement A case-controlled study in more than 426 patients Olsson DS et al. Eur J Endocrinol 2009;161(5):663–9.

Life expectancy in patients with pituitary adenoma receiving GH replacement A case-controlled study in more than 426 patients Expected no. Observed deaths SMR 95% CI Overall mortality All patients 124.6 122 0.98 0.81–1.17 - GHRT group 44.4 29 0.65 0.44–0.94 - Non-GHRT group 80.2 93 1.16 0.94–1.42 * * *Significant difference between the groups (p=0.009) Olsson DS et al. Eur J Endocrinol 2009;161(5):663–9.

Incidence of diabetes mellitus in GHD during GH replacement therapy Diabetes incidence per 100 patient-years (grey bar) Observed/expected cases when compared with a reference population in southern Sweden Luger A et al. Diabetes Care 2012;35:57–62.

Conclusions: glucose metabolism In patients with a propensity toward development of type II diabetes mellitus (T2DM), GH therapy can be associated with the development of glucose intolerance or T2DM in the first year of therapy1 GH treatment in patients with DM may require adjustments in anti-diabetic medications2 1. GH safety workshop position paper: a critical appraisal of recombinant human GH therapy in children and adults. Eur J Endocrinol 2016; 147 2. Hypopituitarism: An Endocrine Society Clinical Practice Guideline. ENDO 2016, BOSTON

GH replacement: conclusions Efficacy of long-term GH replacement has been demonstrated in open-label studies Discontinuation has adverse metabolic effects Glucose metabolism should be monitored Long-term GH replacement has no adverse effect on mortality Adult GHD is often part of a more extensive hypopituitarism, which may affect mortality Adrenal insufficiency and underlying disease