Adult growth hormone deficiency (GHD) is a well characterized yet nonspecific syndrome consisting of altered body composition with decreased muscle and bone mass, increased visceral fat, decreased aerobic exercise capacity, adverse cardiovascular disease (CVD) risk profile and decreased physical and mental well-being leading to impaired quality of life (QoL) [1], [2]. GHD is a heterogeneous disorder and may have differing predominant features and impact on health based on etiology, age at onset, age at treatment, gender, and comorbidity status [3] (Table 1).

In large part owing to the availability of recombinant human growth hormone replacement therapy (GHRT), our understanding of GHD and the effects of GH treatment has been informed by a large body of literature which has accumulated since the 1980s. Treatment with daily GH injections has been successful in ameliorating and reversing many of the symptoms and signs of GHD [4], *[5]. Review of data from clinical trials of GH replacement in adults has not only helped our understanding of the relative discrepancies in the syndrome of GHD between patients of different underlying causes of GHD, age of onset and age at treatment initiation, but also to inform our personalized practice by enhancing our knowledge of the differences in benefits of treatment and risks of side effects in these patient groups, thus resulting in the ability to better individualize patient care *[3], [4], *[6]. Younger patients, especially those having childhood-onset GHD (COGD) may have a more pronounced initial response of improvement in body composition with GHRT compared to older adults, whereas most studies suggest that gains in QoL are greater for older GHD patients and those with adult-onset disease (AOGHD) [7], [8]. A long-term prospective study comparing the effects of GHRT in COGHD patients to effects of treatment in AOGHD individuals found that improvements in body composition were similar among the groups at the end of the 5-year study period, while the COGHD group had a more marked initial response [9]. Other studies have suggested that age per se may not be the main determinate of treatment response as changes in body composition did not differ by age [10], [11].

As with any treatment, success of GHRT is in large part determined by adherence to the prescribed medication regimen. To date GHRT has been administered as a daily injection and has often been reported by patients to be inconvenient, painful, and distressing, leading to reduced treatment adherence and efficacy. While many studies have assessed the factors affecting adherence to GHRT in children, the corresponding literature in adults is less robust. To date such studies have used varying methods of assessment of medication compliance as well as heterogenous definitions of noncompliance with prescribed therapy. In a survey involving adults, adolescents and parents of children treated with daily GH replacement, Rosenfeld et al. reported noncompliance rates from 64% to 77% with the highest rates in teens [12]. Misperceptions about the effects of missed GH doses, pain from injections, perceived lack of treatment results, and insufficient contact with health-care providers were associated with noncompliance. A study conducted in Germany utilizing a more objective method for determining adherence by utilizing prescription data found an overall adherence rate of 74% and that younger patients, independent of age of GHD onset, had the lowest adherence [13]. That higher patient age positively correlates with greater treatment adherence was confirmed in a recent report in which the overall study cohort had a high rate of adherence to GHRT [14]. Furthermore, this study determined that insulin-like growth factor-1 (IGF-1) levels could not be used as a reliable indicator of treatment adherence. Lastly, in a more recent study based on patient questionnaires, COGHD patients had higher non-adherence scores than AOGHD patients, though this difference did not reach statistical significance [15]. This report also included 12 patients who had been treated with long-acting growth hormone (LAGH) of which 10 stated they preferred long-acting GH to standard GHRT. The authors of this study further evaluated underlying reasons for refusal of GHRT and found that disease knowledge and level of education were higher in treated patients compared to those who declined GHRT.

To overcome the obstacles posed by nonadherence to daily GH injections, LAGH has been proposed as a potential improvement to the current GHD treatment paradigm *[16], [17]. Several LAGH preparations have been developed of which many have been rigorously tested in clinical trials and a few have been approved by regulatory agencies [18]. The majority of LAGH preparations are delivered as once weekly injections and owe their longer-duration of action to either delayed absorption from the subcutaneous injection site or a slow release into target tissues from the circulation. Methods to develop LAGH have included reversible complexes stabilizing GH, production of sustained release formulations utilizing various matrices to hold GH, and structural modifications of the GH molecule *[16], [17], [18]. Large GH fusion proteins have the potential to exert different metabolic effects and side effects, especially if the size of the molecule prevents access of the modified GH differently in various target tissues [18].

The existing evidence regarding short-term LAGH treatment has been reassuring that LAGH is noninferior to daily GHRT based on effects on serum IGF-1, body composition and metabolic effects as well as adverse events profile, while long-term data on outcomes of interest such as QoL and safety are lacking [19]. Whether LAGH is cost effective and would improve treatment adherence in “real world” clinical practice is yet to be determined.