Proyecto FOLTRA

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Growth Hormone deficiency (GHD) and cerebral palsy

Jesús Devesa^ª,*, MD, PhD; Nerea Casteleiro*, BSc; Cristina Rodicio*, BSc; Natalia López*, BSc; Pedro Reimunde ª^,*, PhD.

ª Department of Physiology, School of Medicine of Santiago de Compostela. Spain and * Medical Center Proyecto Foltra, 15886 Teo, Spain 

Abstract: Cerebral palsy (CP) is a catastrophic acquired disease, occurred in the development of fetal or infant brain, mainly affecting motor control centres of the developping brain, but also cognitive functions, and usually accompanied by a cohort of symptoms including lack of communication, epilepsy and alterations of the behaviour. Most of these children exhibit a short stature, progressively declining  from birth to puberty. We tested here whether this lack of normal growth might be due to an impaired or deficient GH secretion. The study was conducted in 46 CP children, 28 males and 18 females, aged 3 to 11 years old. Data obtained show that 70 % of these children lack a normal GH secretion. We conclude that GH replacement therapy should be commenced early in CP children, not only for achieving a normal height but because of the known neurotrophic effects of the hormone, perhaps able for correcting some of CP children disabilities. 

Key words: GH, IGF-I, cerebral palsy, short stature, GH and neural precursors proliferation.

Running header: GHD and cerebral palsy

Corresponding author: Prof. Jesús Devesa. Medical Center Proyecto Foltra, Cacheiras 64, 15886 Teo, Spain. Phone: +34981802928. Fax: +34 981802928.

Email adress: This e-mail address is being protected from spambots. You need JavaScript enabled to view it

Introduction

The cumulative incidence rate at the age of 5 to 7 years is 2.7 cases of cerebral palsy (CP) for 1000 live births.^1. Apart of motor disabilities, many of these CP children display a number of cognitive and sensorial affectations; among these, mental disadvantage is the most frequent one (IQ<50), followed by active seizures, mental disadvantage (IQ<50) and not walking, and blindness; up to 80% have at least some impairment of speech. Half of all children have gastrointestinal and feeding problems. ²

Major causes for CP include abnormal intrauterine developments, due to  fetal-maternal infections, asphyxia before birth, hypoxia during delivery and brain trauma during labor and delivery, and complications in the perinatal period. ³  Apart of these, prematurity is responsible for the 40-50% of the cases of CP. Periventricular leucomalacia (PVL) and parenchymal venous infarction complicating germinal matrix/intraventricular haemorrhage have long been recognised as the two significant white matter diseases responsible for the majority of cases of cerebral palsy in survivors of preterm birth. However, more recent studies using magnetic resonance imaging to assess the preterm brain have documented two new appearances, adding to the spectrum of white matter disease of prematurity: punctate white matter lesions, and diffuse excessive high signal intensity. These appear to be more common than PVL but less significant in terms of their impact on individual neurodevelopment. They may, however, be associated with later cognitive and behavioural disorders known to be common following preterm birth. ⁴  A recent and interesting hypothesis suggest that chronic fetal hypoxemia (CHX) may cause fetal brain injury by upregulating inflammatory cytokine cascades, culminating in apoptosis pathway activation. increasing the lactate/pyruvate and decreasing the glutathione (GSH)/oxidized glutathione (GSSH) ratios, confirming a shift to a prooxidant state. The end result was a >30% decrease in hippocampal neuron density. Based on a microarray spotted with 113 cytokines and receptors, 22 genes were upregulated by CHX in proportion to the degree of hypoxia; the findings were confirmed by quantitative polymerase chain reaction. Thus, CHX would trigger fetal brain inflammation inversely proportional to its severity characterized by increased apoptosis and neuronal loss. The authors suggest that CHX fetal brain injury is not directly caused by oxygen deprivation but rather would be an adaptive response that becomes maladaptive. ⁵

Independently of the causal factors responsible for the development of CP, the disease has a strong socio-economical impact. There is no cure for CP, and therapeutical approaches, such as physical therapy, occupational therapy, speech therapy, drugs to control seizures, surgery to correct anatomical abnormalities, etc, only report a small benefit for affected people. A study carried out in Denmark reveals that the lifetime cost of CP was about 860,000 euro for men and about 800,000 euro for women. The largest component was social care costs, particularly during childhood. ⁶

Most of CP children often have poor linear growth during childhood, resulting in a diminished final adult height. ⁷  However the number of studies reporting whether or not GH secretion is impaired in CP is quite limited. ^7-10 These studies reflect that GH provocative testing induced a GH deficient secretion. A recent study indicates that diminished circulating IGF-1 and GH concentrations may explain why children with CP are smaller than normally growing children.¹⁰ On the other hand, osteopenia is a common finding in children with CP,  and seems to be associated with decreased IGF-1 and IGFBP3 plasma levels, usual markers of deficient GH secretion¹¹. The large percentage of GH deficiency in CP children has been reported to be surprising.⁹ However, given the complexity of GH neurorregulation¹²  it seems to be logical that a strong brain damage may affect a number of neurotransmitters pathways involved in GH control, then affecting the normal secretion of the hormone. Other posibilities for decreased growth in CP include psychosocial deprivation and suboptimal nutritional status ⁹, but these are also involved in subnormal GH secretion ¹². 

Few studies report the benefits of GH-replacement therapy in children with CP, and most of these studies only reflect the increased growth observed during the treatment period with the hormone.  ^{7,8, 13}  A recent study indicates that 18 months of GH therapy in children with CP  is associated with significant improvements in bone mineral density, apart of increased linear growth. ¹³ 

The objective of this study was to assess wthether GH secretion is affected in children with CP, and to establish the percentage of this impaired GH secretion in a big sample of this CP population.

Patients and Methods

The study was conducted in 46 CP children, 28 males and 18 females, aged 3 to 11 years old, who attended the Medical Center Proyecto Foltra for physical and cognitive rehabilitation. Table 1 shows the presumably causes of CP, while Table 2 shows the disabilities found at admission according to the study carried out by Malkowicz et al. ^14.

Clinical exams include measurements of height and weight, and the exam of growth velocity in their pediatric card (if shown), and Tanner stage of sexual maturation. MRI or CT scans of the brain performed prior to their inicial evaluations documented the extension of white and gray matter damage. Blindness was confirmed by evoked visual potentials analysis.

A blood sample analyses was performed for routinary haemathological and biochemistry parameters. Anterior pituitary hormones baseline secretion and plasma levels of fT4 were measured by chemiluminiscents assays. In addition, fasting plasma IGF-1 and IGFBP3 were measured. by a solid-phase, enzyme-labeled chemiluminiscent immunometric assay (Inmulite 2000, Siemens).

To study whether or not GH secretion was deficient the insulin induced hypoglycemia test had been performed in 12 CP children.

Results.-

Ferropenic anemia was found in 55% of the children studied.

Most of the children showed a normal pituitary function, with the only exception of GH secretion,  which was shown to be impaired in 26 % of the patients according to the GH peak (< 9 ng.mL-¹ , 12 patients) in response to hypoglycemia and plasma IGF-I and IGFBP3 values. These correlated well (p < 0.01) with the diminished growth velocity (< 5 cm per year) and the low stature (under percentile 3, P3) for their chronological age.  However, 13 % of patients in whom GH secretion had not been studied, plasma IGF-I and IGFBP3 values were shown to be normal according to the laboratory range, although these values were very close to the lower limits of normality. These apparently normal values did not correlate with the short stature found in these children, all of them under P3 of height for his chronological age. In other 31 % of patients plasma IGF-1 and IGFBP3 were under the normal values for the age. Thus, in total, 70 % of the patients studied seemed to have a deficient GH secretion.

Subclinical hypothiroidism was found in 7 patients, and a premature adrenarche was found in 1 of the subjects studied. One of the children was shown to have an increased PRL secretion (35 ng.mL^-1). FSH and LH secretion was normal in all but one of the patients studied (that with premature adrenarche), ranging from undetectable to prepubertal values, and related with the chronological age and Tanner stage of sexual maturation.

Tanner stage of sexual maturation ranged between 1 and 3. 

Body mass index (BMI) was lower than normal in 52 % of CP children.

These results are shown in Table 3.

Discussion.-

Our results show that an impaired GH secretion is the most frequent anterior pituitary abnormality in CP children, independently of the causes leading to the disease.  We did not studied in detail the GH response to provocative tests or the nocturnal GH release, since the children joined us with studies carried out in their reference’s hospitals, but we measured in all the patients plasma IGF-I and IGFBP3 values, usually considered to be a clear indicative about how GH secretion occurs ¹¹.

Despite of the fact that our study followed a cross-sectional design and we could not test it, it seems to be a continuum in the decrease in growth velocity leading to a final short height. We know that this sort of trial design only allows to evaluate the prevalence but not the incidence of a certain affectation, such as decreased gowth velocity and GH-deficiency in this case. A longitudinal study would allow to reach more significant data. Despite of it, a decreased growth velocity in CP children may be explained by several reasons. Among these a common cause may be the shortening of flexor tendons, due to the lack of muscular cerebral control, but this situation has to be responsible for causing only a slight decrease in final height. Other causes include suboptimal psychosocial deprivation and nutritional status ⁹. Spasticity might also be responsible because of increased caloric expenditure due to the excessive and continuous muscle contraction in spastic CP children.

 IGF-I is responsible for most of the GH effects on longitudinal growth, but not for all of them. GH is early released from the pituitary after birth, however the hormone does not play a significant role on longitudinal growth during the first year of life. Nutritional status is the main factor for growing along this period of life by increasing hepatic IGF-I synthesis and release ¹².  In some situations a deficient GH secretion is not accompanied by low plasma IGF-I values; this can be observed in obese children. Childhood obesity is characterized by normal or even accelerated growth in spite of reduced growth hormone (GH) secretion, while plasma IGF-I levels are normal ^15,16.  A clear divergence between GH secretion and plasma IGF-I has been reported recently in amyotrophic lateral sclerosis patients, while a marked or severe GH deficiency exists, but IGF-I is significantly higher in these patients than in matched healthy controls ¹⁷.  Conversely, in Anorexia Nervosa patients, low circulating IGF-I levels are associated with enhanced GH production rate ^{18, 19}. Thus, a normal plasma IGF-I value can not exclude a deficient GH secretion.

There is a clear reluctance in the Spanish Committees, and perhaps in many other countries, responsible for prescribing GH treatment to children with CP when GH deficiency has been diagnosed. A clear reluctance exists too for studying whether or not GH secretion is deficient in CP children. The reasons given are based on the lack of benefits that growth brings to a child with serious neurological problems.

However, we know today that GH plays a very important role at the central level.

The growth hormone – insulin-like growth factor-1  system induces neurogenesis and increases brain plasticity ²⁰.  GH and IGF-1 are expressed in the brain ^21,23 and both hormones can cross the blood-brain barrier ²³. The GH receptor (GH-R) and the IGF-1 receptor (IGF-1-R) are widely expressed in several zones of rodent and human brain, including the hippocampus ^24-29.  Particularly, GH, GH-R and IGF-1-R are expressed in hippocampal neural progenitors, acting on the proliferation and differentiation of these neural stem cells ^{30, 31}. Thus, besides its major role in several metabolic processes, the GH – IGF-1 axis has multiple and important neurotrophic effects, related to cell proliferation and survival, both in the central and peripheral nervous system ^{20, 23}. According to this, GH-R expression is increased in the subventricular zone after focal ischemia ³² and GH has been demonstrated to increase cell proliferation in the hippocampus of adult hipophysectomized rats ³³. Similarly, IGF-1 increases cell proliferation in hippocampal cells ^30,34 and its expression is increased in the affected brain hemisphere after an ischemic injury ^35,36. Neuropsychological assessments have demonstrated that GHD is associated with reduced cognitive performance; specifically, most of the studies indicate that GHD can lead to clinically relevant changes in memory, processing speed, attention, vocabulary, perceptual speed, spatial learning and in reaction time tests as well ^37-43. Cognitive dysfunction appears to be specifically related to GH deficiency; this hypothesis is supported by the positive correlations between serum IGF-I concentration and IQ, whereas the lower emotional well-being and reduced perceptual-motor performance are attributed to other pituitary hormone deficiencies ³⁷. In this sense, previous studies show that hormone replacement therapy in GHD patients did not improve psychological well-being or perceptual-motor skill ^{37, 44}. Thus, although the number of reliable intervention studies is limited, it has been shown that cognitive disorders secondary to GHD may be reversed by GH replacement ^{39, 40}. Some authors have suggested the possibility of the involvement of the effects that GH has in the modification of the concentration of different neurotransmitters in the cerebrospinal fluid (CSF); GH substitutive treatment decreases the dopamine metabolite homovanillic acid, as the trycyclic antidepressants or the monoamine oxidase inhibitors do, and increases about 30% the levels of aspartate, a neurotransmitter with important effects in the hippocampal long-term potentiation and in attentional functions  ^{45, 46}.

Most of these studies have been carried out in adult GH-deficient patients and rodents, but given the high plasticity of the brain during childhood there are no reasons for thinking that they can not achieve similar results in children.

According to these and given the high incidence of GH-deficiency in CP children that we observed in this study, we propose that GH replacement therapy should be started as early as possible, together with specific rehabilitation, once CP is detected; most likely, the conjunction of GH therapy and rehabilitation would prevent or correct most of the disabilities seen in these children.

Acknowledgements

This study was supported by Foundation Foltra.

Disclosures

The authors report no conflicy of interest in this research.