Accepted treatment of acute ischemic stroke until now are reperfusion therapy with tissue plasminogen activator or intra-arterial thrombolysis or mechanical thrombectomy. But due to limited time window, still majority of patient cannot benefit from these treatments and even after all the successful standard therapy, neurological deficit still remains. Therefore, strategies for protecting neurons must continue from the beginning to the end of the treatment. From this point of view, pleiotropic functioning material can be expected to be more effective [1]. Insulin-like growth factor-1 (IGF-1) is appropriate candidate because it has pleiotropic effects such as neurogenesis [2], increasing muscle mass [3] and involved in ocular growth by influencing the synthesis of the extracellular matrix of the sclera [4]. The recombinant human growth hormone (rhGH) can increase serum IGF-1 level and can enhance injured brain plasticity, cell regeneration and may lead to functional recovery. Song et al. [5] reported administration of rhGH resulted in the improvement of motor function recovery in completed stroke patients. The purpose of this study was to evaluate effectiveness of rhGH on functional recovery of acute stroke patients.

The objective of this study was to investigate whether the use of rhGH would be helpful for functional recovery in acute stroke patients in proportional to treatment duration. The reason why this study excluded other cerebral artery infarction other than MCA is because K-MBI and mRS scale mostly reflects motor functional deficit. We aimed to concentrate primarily on rhGH and motor dysfunction recovery other than sensory, balance, cognition, or mood problems.

To compare rhGH effect among 3 groups, all the populations in this study had received nearly same management such as dual (sometimes triple) antiplatelet, warfarin or non-vitamin K antagonist oral anticoagulation, statin, antidiabetic and antihypertensive medication therapy along with citicoline until reaching 1 year after the stroke. This could be achieved easily because most of drugs are used to control stroke risk factors that could not be quitted halfway.

Citicoline is well known neuroprotective adjuvant treatment in ischemic stroke and Korean health insurance review and assessment service admit and permit citicoline use of 2,000 mg/day/6-week if initial NIHSS scale is 8 or over starting within 24 hours of stroke onset [67]. Citicoline has therapeutic effects at several stages of the ischemic cascade in acute ischemic stroke and has demonstrated efficiency in a multiplicity of animal models of acute stroke. Long-term treatment with citicoline is safe and effective, improving post-stroke cognitive decline and enhancing patients' functional recovery [8].

All the study populations involved in our study scored more than 8 points. So basically, all the 3 groups (citicoline plus rhGH 6 months, citicoline plus rhGH 3 months, citicoline alone) used citicoline. In this study, GH6 group showed improvement in the K-MBI and mRS score compared to control group after the treatment. GH3 group, however, showed no statistically significant improvement from control. The result from this study highlight prolonged and continuous treatment with rhGH have additive therapeutic potency in functional recovery of stroke patients.

The rhGH increases IGF-I and IGF-1 is a pleiotropic pivotal peptide that exerts prosurvival signals on neurons, oligodendrocytes, and other glial cells. IGF-1 also inhibits glutamate, nitric oxide, and hydrogen peroxide-induced apoptosis and able to modulate brain plasticity by influencing neurite outgrowth, synaptogenesis, neuronal excitability, and neurotransmitter release [91011]. The rhGH, in addition, promote improvement of body components such as muscle fiber, bone mineralization to improve muscle strength and exercise performance, ocular tissues such as extracellular matrix of the sclera for emmetropization. Previous animal model studies proposed that rhGH increased serum IGF-1 level and it is essential for recovery of the nervous system. Other studies reported cognitive function such as mini mental status evaluation score did not changed even though motor function increased compared to control. These findings seem to suggest that rhGH not only increases neuronal regeneration but also related to gain of muscle function [12]. These could be one of the reason for explanation of prolonged rhGH efficacy on motor function recovery even after insulted nerve stabilized.

Acute stroke patients have lower IGF-1 level and furthermore, rhGH-induced elevation of level of IGF-1 does not sustain after quitting exogenous rhGH probably due to growth hormone — IGF-1 axis negative feedback adaptation [5]. Therefore, it appears that early start and repeated supply of rhGH could be beneficial. Present study compared 3-month and 6-month rhGH treatment outcome. As a consequence, functional outcome from longer treatment of rhGH was better. So, we should expect more effective results by continuous rhGH even after 6 months and dose elevation.

This study had several limitations. First, the number of initial enrolled subject was small and it was open-labeled study. Second, we could not collect data on serial serum IGF-1 level and rehabilitation treatment methods because patients transferred to other rehabilitation centers immediately after the acute stroke manage. Therefore, whether the rhGH therapy can exactly increase serum level of IGF-1, which could not be determined in our study. The correlation of IGF-1 in the rhGH treatment and functional outcome should be enlightened through further studies. Third, many patients dropped out during the study due to prolonged use of rhGH. Since the number of each group decreased, statistical confidence could be declined. The reasons of high drop-out rates during the study were due to cost and distance. The drop out patients or their family could not afford the cost of rhGH for that long period (54,750 Korean won or 49 US dollar/week). Next, after finishing acute treatment for one week, the patients were transferred to rehabilitation hospital or nursing home. Even though patients and their family accepted initial rhGH treatment, they soon retracted their will due to inconvenience. Fourth, we excluded mild and severe stroke patients (NIHSS < 8 or > 15) which could have affected the outcome of the study. However, we presumed that patients with very mild stroke symptoms (NIHSS < 8) could expect good recovery with pre-existing standard treatment and because of the ceiling effect, we thought it would be hard to compare between treatment groups. On the other hand, patients with severe symptoms (NIHSS > 15) were unable to properly determine the function recovery due to frequent infections or other complications. Fifth, because the patients transferred to different rehabilitation centers after acute stroke manage, we could not control various factors affecting post stroke functional outcome, such as rehabilitation program, depression control and previous cognitive function. Socioeconomic status could affect functional outcome as well. In addition, functional recovery measures other than K-MBI and mRS such as manual muscle strength test, Fugl-Meyer assessment, fatigue scale, and Korean version of the mini-mental status examination could not be performed. Finally, we could not conduct brain MRI follow up after the study. In general, it is not recommended to repeat brain MRI within 2 years after stroke if there is no indicative symptom change. Therefore, to explore whether rhGH treatment facilitated functional outcome and IGF-1 level increased in proportion to rhGH dose, studies with double blind, large sample size, long-term IGF-1 level collection, controlling many factors affecting functional outcome, many functional recovery measurement scale and less drop out study plan are needed. Also, serial brain MRI follow up study and higher doses of rhGH treatment trial should be needed to find out whether it has further beneficial effect on functional and imaging outcome.

However, in spite of above-mentioned many limitations such as no direct data on method, duration, intensity of physical/psychiatric rehabilitation program which could give a big impact on functional recovery, we could collect from families or caregivers of patients about rehabilitation time, frequency, how well the patient performs and cognition, mood changes. Of the patients enrolled in this study, no special drug adjustment was made until the end of the study. In addition, it is estimated that patients obtained similar rehabilitation therapy in average because, due to insurance related issues in Korea, patients need to move hospital to hospital in every 3 months and treatment protocol, equipment and services of every rehabilitation hospital are basically similar. And finally, although there were small numbers in each group, mRS and K-MBI score showed statistically significant improvement in intra-group analysis and based on these findings, inter-group analysis showed GH6 group improved more than GH3 and control group. For the above reasons, we could conclude that the effects of rhGH are significant.

In conclusion, prolonged administration of rhGH treatment at least 6 months could give effect on functional outcome in acute stroke patients.