Hyperinsulinemia Tends to Induce Growth Without Growth Hormone in Children with Brain Tumors After Neurosurgery

Reference

No. of patients with BT

No. of GWGH patients

No. of obese GWGH

Serum insulin at baseline

Insulin secretion after loading

Serum IGF-I

Serum IGFBP-3

Serum leptin

Serum prolactin

High

Normal

Low

High

Normal

Low

High

Normal

Low

High

Normal

Low

High

Normal

Low

High

Normal

Low

Holmes et al. (1968)

–

Kenny et al. (1968)

–

Finkelstein et al. (1972)

–

Saenger et al. (1974)

–

Costin et al. (1976)

–

Gluckman and Holdaway (1976)

–

Thomsett et al. (1980)

–

Carmel et al. (1982)

Lyen and Grant (1982)

Bucher et al. (1983)

–

Stahnke et al. (1984)

–

Blethen and Weldon (1986)

–

Sorva (1988)

–

Schoenle et al. (1995)

–

DeVile et al. (1996)

Tiulpakov et al. (1998)

Araki et al. (2000)

–

Pinto et al. (2000)

Pavlou et al. (2001)

–

Srinivasan et al. (2004)

–

Di Battista et al. (2006)

–

Nagasaki et al. (2010)

–

Simoneau-Roy et al. (2010)

–

Iwayama et al. (2011)

–

Total

460

180

69/98

(%)

(39)

(70)

(34)

(64)

(2)

(60)

(38)

(2)

(6)

(48)

(46)

(0)

(9)

(91)

(50)

(0)

(29)

(65)

(6)

BT brain tumors, GWGH growth without growth hormone, IGF insulin-like growth factor, IGFBP IGF binding protein, NA not available, ND not done

The location of brain tumors and the mode of surgery may affect the incidence of GWGH. GWGH has been more frequently found in the patients with suprasellar tumors (Bucher et al. 1983; Blethen and Weldon 1986; Tiulpakov et al. 1998). On the other hand, it was reported that 5 (42 %) of the 12 children with GWGH underwent a total resection of the tumors (Carmel et al. 1982). Thomsett et al. (1980) have shown that 4 (57 %) and 3 (43 %) of the 7 children with GWGH received total and partial resection of the tumors. Similarly, other investigators have suggested that the severity of HP dysfunction in the patients with GWGH was not related to the total or subtotal resection of the brain tumors (Di Battista et al. 2006). However, because of a limited data, it remains inconclusive whether the mode of surgery affects the incidence of GWGH among children with brain tumors after neurosurgery.

In patients with GWGH, the “catch-up” growth spurt is usually seen within the first 2 years after neurosurgery, which is often paralleled with weight gain (Holmes et al. 1968; Thomsett et al. 1980; Bucher et al. 1983; Sorva 1988; Tiulpakov et al. 1998). However, an unusual case of GWGH with teratoma has been reported (Araki et al. 2000), in which the linear growth was poor until 4 years without GH replacement therapy, but accelerated 5 years after neurosurgery despite before puberty. The “catch-up” growth spurt may be self-limited. It was reported that the linear growth was decelerated in older children with GWGH and that the final adult height for 3 (30 %) of the 10 patients with GWGH was more than −2.5 SD below the mean adult height for gender 1.5–6 years after neurosurgery (Blethen and Weldon 1986). In this study, all surviving patients with GWGH, who grew excessively, continued to grow at a relatively high or normal growth rate until the adult height was reached. Similar trend has been reported by other study (Bucher et al. 1983). Sorva (1988) has reported that of the 5 patients with CPs and GWGH, the growth rate declined in 1 with tumor recurrence, 1 subsequently needed the GH replacement therapy, and the remaining 3 (60 %) patients reached the final height with height SDS, ranging from +0.2 to −2.4 during 1.7–8.2 years after neurosurgery. In other series (Thomsett et al. 1980; Bucher et al. 1983; Schoenle et al. 1995; Tiulpakov et al. 1998), 57–100 % of the patients with GWGH achieved a relatively high or normal linear growth rate during 2–14 years after neurosurgery. These data suggest that some patients with GWGH do decelerate the linear growth 2 or more years after neurosurgery. Because of a lack of the long-term follow-up data, it remains unknown what is the frequency of the patients with GWGH who maintain normal or excessive linear growth till a final normal height is reached in adulthood.

GWGH and Puberty

Sex steroids, secreted by the control of gonadotropins (luteinizing hormone, LH, and follicle stimulation hormone, FSH), induce growth spurt during puberty. Approximately 71–95 % of the patients with CPs have gonadotropin deficiency after neurosurgery (Thomsett et al. 1980; Lyen and Grant 1982; Stahnke et al. 1984; Schoenle et al. 1995; DeVile et al. 1996; Gonc et al. 2004; Srinivasan et al. 2004; Di Battista et al. 2006; Iwayama et al. 2011). Only 1 (5 %) boy of the 20 patients with CPs and gonadotropin deficiency, older than 12 years of age, has been shown to develop precocious puberty 6 years after neurosurgery (Di Battista et al. 2006). In other study, of the 48 patients with CPs, only 3 (6 %) boys had precocious puberty and 1 (2 %) girl showed full adult sexual maturation 6.7 years after neurosurgery (DeVile et al. 1996).

Because of hypogonadotropic-hypogonadism, the patients with GWGH also lack sex steroids, resulting in failure or delay of growth spurt during puberty. It was shown that 14 of the 15 patients, including the patients with GWGH, had abnormal serum levels of LH and FSH, which did not differ between the patients with GWGH and those without (Bucher et al. 1983). Holmes et al. (1968) have found that all 4 patients with GWGH, more than 15 years of age, remained sexually immature with no detectable gonadotropin excretion. It was reported that of the 14 patients with GWGH, only 1 boy (7 %) and 2 girls (14 %) had precocious puberty and pubertal development, respectively, 1–6 years after neurosurgery (Lyen and Grant 1982). Schoenle et al. (1995) have found that 4 of the 6 patients with GWGH had no puberty and that only 2 (33 %) patients, including one of each boy and girl, developed puberty. The replacement therapy with sex steroids or gonadotropin was necessary to induce the onset of puberty in the majority of the patients with CPs after neurosurgery, including the patients with GWGH (DeVile et al. 1996). These data suggest that hypogonadotropic-hypogonadism, resulting in delayed puberty, is associated with the majority of the patients with GWGH and that hormone replacement therapy is necessary to induce pubertal growth spurt in these patients.

Recently, serum levels of insulin and insulin-like growth factor (IGF)-I have been shown to be higher in girls with precocious puberty than healthy controls (Sorensen et al. 2012). Thus, increased serum levels of insulin and/or IGF-I may play a role for the development of “catch-up” growth spurt, especially in girls with GWGH. However, because of a lack of data, it remains elusive whether puberty may develop more frequently in patients with GWGH than those without, and whether insulin- and IGF-I-induced signaling pathways play a role for promoting “catch-up” growth spurt in patients with GWGH.

GWGH and Hyperinsulinemia

Hyperinsulinemia is highly associated with the patients with GWGH compared to those without (Bucher et al. 1983; Iwayama et al. 2011). The incidence of hyperinsulinemia in the patients with GWGH ranges from 11 % to 100 % in some series (Kenny et al. 1968; Costin et al. 1976; Gluckman and Holdaway 1976; Bucher et al. 1983; Stahnke et al. 1984; Blethen and Weldon 1986; Sorva 1988; Tiulpakov et al. 1998; Srinivasan et al. 2004; Di Battista et al. 2006; Simoneau-Roy et al. 2010; Iwayama et al. 2011). Of the 55 patients with GWGH reported, in whom the data for serum insulin levels are available, serum levels of insulin are increased in 19 (34 %), within normal range in 35 (64 %), and decreased in only 1 (2 %) (Table 7.1). Of the 50 patients with GWGH, in whom the data for insulin secretion after loading are available, the insulin secretion is increased in 30 (60 %), normal in 19 (38 %), and decreased in only 1 (2 %). These data, although limited, suggest that approximately one thirds of the patients with GWGH have hyperinsulinemia and that the ability of insulin secretion is well preserved in almost all of these patients. It is noteworthy that only 2 patients with GWGH who had low serum insulin levels and/or insulin secretion have been reported (Holmes et al. 1968; Gluckman and Holdaway 1976).

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