Table 1.
GHRH-GH-IGF1 axis mini meta-analysis—main findings of included studies.
| Lead Author (Year)(Ref) | Participants with DS | Normal Controls | Age | Tests | Main findings |
|---|---|---|---|---|---|
| Milunsky A (1968) (8) | 7 | 7 | 2–6 (y) | Insulin test | Pathological 0% |
| Pozsonyi J (1971) (9) | 12 | – | 0.6–20 (m) | A–Fasting GH level B–Insulin test-(12) C–Arginine test-(4) |
A–Noticeably low levels (before the arginine test—0.1 compared to the other participants—developmental delay for another reason) B–Peak average 12.78 Ng/ml, one pathological C–Peak average 7.88 Ng/ml, one pathological |
| Ruvalcaba RH (1972) (10) | 7 | 8–11 (y) | Arginine test | 14% pathological | |
| Visci R Sara (1983) (11) | 21 | 0–11 (y) | IGF1 and IGF2 levels | IGF1 level is above normal in the first 2 years of life but fail to increase with advancing age, therefore over the years becomes pathological low. IGF2 level is elevated throughout life. |
|
| Annerén G (1986) (12) | 5 | 3–6(y) | A–Insulin-arginine test B–2 h Sleep test C– IGF1 generation test |
A–20% pathological B–60% pathological C–All were below the norm at baseline, and everyone entered the norm after 10 days |
|
| Annerén G (1990) (13) | 5 | - | 3.6–6 (y) | A–RIA IGF1 levels B–RIA IGF2 levels C–RRA IGF total levels |
A–2 years old—lower than normal and no later recovery B–Normal throughout life C–identifies both IGF1 and IGF2 and fetal form, beginning with post-natal period—high throughout life |
| Torrado C (1991) (14) | 13 | 1–5(y) | A–Clonidine test B–L Dopa test |
A–61.5% pathological B–61.5% pathological |
|
| Castells S (1992) (15) | 20 | 7 | 1–13(y) | A–Clonidine test B–L Dopa test C–Targeted concentration 12/24 h. |
A–65% pathological B–60% pathological C–100% pathological |
| Pueschel SM (1993) (16) | 8 | 1–6 (y) | A–Clonidine test B–L Dopa test C–GHRH test |
A–50% pathological B–37.5% pathological C–12.5% pathological |
|
| Barreca A (1994) (17) | 18 | 8 | 1–11 (y) | A–IGF1, IGF2 level-basal (39 patients) B–Arginine test C1–IGF1 levels 12,24 and 48 h. after arginine injection C2–IGF1 levels 12,24 and 48 h. after GH injection. D–GH RRA/ IRMA ratio E–Bind GHBP/total GHBP ratio (DS patients vs. non-DS control) |
A–Normal IGF2 level. Pathological low IGF1 level at 36% (GR1-low basal IGF1 concentration). In remaining patients (GR2-IGF1 in the low-normal range) B–GR1-peak average 29.6 Ng/ml. GR2-peak average 15.1 Ng/ml C1–GR1-no significant increase GR2-significant increase in IgF1 level C2–GR1—a lower peak compared to GR2, but a larger delta D–Ratio is lower in GR1—an expression of GH bioactivity. The difference in relation was on the significance boundary with p = 0.057. Especially in 2 patients, a very low level. Statistically significant correlation between the ratio and IGF1 level, and IGF1 peak after the arginine test. E–Similar ratio between groups |
| Castells S (1996) (18) | 14 | 7 | 1–5 (y) | A–Clonidine test B–L Dopa test C–GHRH test |
A–Pathological 50% B–Pathological 43% C–Pathological 0% |
| Castells S (1996) (19) | 40 | prepubertal | A-IGF1 B-L-DOPA test C- CLONIDINE test D-GH overnight test (2 children only) |
A- an average of 65 ng/ml per square, which is slightly above the lower border of the norm. B-at least 35% pathological, maximum 95% vs. 0% pathological in the control group C-at least 38% pathological to 100% maximum vs. 0% pathological in the control group D-one patient was tested after 2 normal tests, a pathological result. |
|
| Ragusa L (1996) (20) | 40 | 1–19 (y) | A-clonidine test B-Insulin test C -if discordant results—24-hr integrated concentration test) D- GHRH plus pyridostigmin test E-IgF1 levels in those with at least 1 pathological test (clonidine or insulin) |
A-pathological 62.5% B-pathological 40% C-integrative concentration test 24 h – 83.3% Pathological D-GHRH plus pyridostigmin 30% received pathological E- 43% pathological, And another 38% below average (25% below quarter, 15% below quarter, 10% below decile) |
|
| Proto C (1997) (21) | 31 | 1–20 (y) | A-IgF1 LEVEL B- IGFBP3 level | A-out of 18 DS children without growth hormone deficiency, in 5 IGF1 level was below the norm. Out of 13 with growth hormone deficiency, 6 had a low IGF1. B-only 3 had low IGFBP3 levels. | |
| Ragusa L(1996) (22) | 16 | 1.5–16.2 (y) | A-clonidine test B-insulin test C-GHRH test D-GHRH plus PD E-hexarelin |
A-average 13.3 Ng/ml B-average 23.1 Ng/ml C-average 27.2 Ng/ml D-average 47.8 Ng/ml E- average 58.4 Ng/ml |
|
| Ferri R (1996) (23) | 9 | 1 | 12.8 (y avg) | A–Compare average GH level between the various sleep stages B–Percentage of time spent in each sleep phase C–Number of GH secretion episode peaks D–Average peak amplitude E–Average peak duration F–Area under the curve of peaks alone G–Integrated concentration |
A–A significant low level of average GH level on S3 + 4 sleep stages compared to control. B–A significant low percentage on S3 + 4 sleep stages compared to control. In A + B No gross difference during wakefulness or the different sleep stages in DS patients C–The average number of peaks is 2.6 D–Significantly low in DS compared to control E–Significantly low in DS compared to control F–Significantly low in DS compared to control G–Significantly low in DS compared to control |
| Arvat E (1996) (24) | 15 | 15 | 13.5 &11.9 (Y, mean) | A–IGF1 level B–GHRH test C–GHRH plus PD test |
A–Similar IGF1 level between DS children compared to normal child control B–Similar GH results between DS children compared to normal children- controls C–Similar GH results between DS children compared to normal children- controls |
| Ragusa L (1998) (25) | 113 | 162 | 12–13 (y) | A– Average IGF1 Level in DS compared to control. B–percentage of children with IGF1 level below the norm for age and maturity level |
A–Significant slightly lower (258 mcg/L vs. 311 mcg/L) B–15% below the norm. |
| Yasuhara A (2001) (26) | 1 | 5(y) | A–IGF1 level B–Arginine test C–Glucagon test D–GHRH test E-2.5 h’ Sleep test |
A–Very low B- Pick 22.8 Ng/ml C-pick 23 Ng/ml D- Pick 17 Ng/ml E- Pick 5 Ng/ml, average 3.3 Ng/ml |
|
| El Gebali H (2014) (27) | 40 | 40 | 3–11 (y) | IgF1 level | A–No difference found between children with DS and healthy control |