Hand size and growth in untreated and IGF-I treated patients with Laron syndrome.

UNLABELLED: We have previously reported on the linear growth, growth of the head circumference and foot length in untreated and IGF-I treated patients with Laron syndrome (LS) (primary GH insensitivity). AIM: To assess the size and growth of the hands in patients with LS from early childhood to adult age. PATIENTS: Ten IGF-I treated children with LS (4 M, 6 F) and 24 untreated patients (10 M, 14 F) were studied. METHODS: Measurements of palm length were made on available standardized hand X-rays from infancy to adult age. The measurements were compared to normal references and SD values were calculated for each measurement. The growth of the hand was compared to the concomitant height of the body. RESULTS: Hand SDS in untreated patients with LS decreased with age, from a mean of -2.8 +/- 0.7 (age 1-3 years) to -7.3 +/- 0.8 (age 13-15 years) and to -9.0 +/- 3.9 (age 40-50 years). During 9 years of IGF-I treatment the hand size deficit SDS did not improve in contradistinction to the height SDS which decreased from -6.2 +/- 1.2 to -3.9 +/- 0.5. CONCLUSION: Congenital IGF-I deficiency, as in Laron syndrome, profoundly affects the size and growth of the hand as part of its growth retardation characteristics, resulting in acromicria.

Can exaggerated response to a GH provocative test identify patients with partial GH insensitivity syndrome?

OBJECTIVES: In the majority of children with short stature, the etiology is unknown. Mutations of the GH receptor (GHR) have been reported in a few children with apparent idiopathic short stature (ISS). These patients had low IGF-I, IGF-binding protein-3 (IGFBP-3) and GH-binding protein (GHBP), but a normal or exaggerated GH response to provocative stimuli, suggestive of partial GH insensitivity (GHI). We attempted to identify children with partial GHI syndrome, based on their response to GH provocative stimuli and other parameters of the GH-IGF-I axis. SUBJECTS AND METHODS: One hundred and sixty-four pre-pubertal children (97 boys, 67 girls) aged 7.2 (0.5-16.75) years were studied. All had short stature with height <3rd centile. The weight, bone age (BA) and body mass index (BMI) of the subjects, as well as the parents' heights and mid parental height (MPH) were assessed. Basal blood samples were taken for IGF-I, IGFBP-3 and GHBP. All subjects underwent a GH provocative test with either clonidine, arginine or insulin. The subjects were divided into three groups: (A) patients with peak GH concentration <18 mIU/l in two different provocative tests (GH deficiency - GHD, n=33); (B) patients with peak GH between 18.2 and 39.8 mIU/l (normal response, n=78); (C) patients with peak GH >40 mIU/l (exaggerated GH response, n=53). RESULTS: No significant differences were found in age, height (standard deviation score (SDS)), parental height (SDS) and the difference between chronological age and bone age (DeltaBA) between the groups. Patients with GHD were heavier (P=0.039) and had significantly higher BMI (SDS) (P=0.001) than the other groups. MPH (SDS) was lower in the group of exaggerated responders (P=0.04) compared with the other groups. No significant differences were found between the groups for the biochemical parameters when expressed nominally or in SDS, except for IGFBP-3 (SDS), which was lower in the GHD group (P=0.005). The GHBP levels were not lower in the group of exaggerated GH response to provocative stimuli. Height (SDS) correlated negatively with basal GH values in pooled data of all the subjects (r=-0.358, P<0.0001), in normal responders (r=-0.45, P<0.0001) and in the exaggerated responders (r=-0.341, P<0.0001), but not in the GHD group. CONCLUSION: Exaggerated GH response to provocative tests alone does not appear to be useful in identifying children with GHI.

A novel somatostatin analogue prevents early renal complications in the nonobese diabetic mouse.

BACKGROUND: PTR-3173 (S) is a novel somatostatin analogue that has been found to exert a prolonged inhibitory action on the growth hormone (GH)-insulin-like growth factor (IGF)-I axis, but not on insulin secretion. We investigated the potential effect of this agent on the development of markers of diabetic nephropathy in the nonobese diabetic (NOD) mouse model of insulin-dependent diabetes. METHODS: Female diabetic NOD mice treated with PTR-3173 (DS group) or saline (D) and their control groups of nonhyperglycemic age-matched littermates (C) and C mice treated with PTR-3173 (CS) were sacrificed three weeks after onset of diabetes. RESULTS: Serum GH was elevated in the D group, decreased in the DS group, and unchanged in the CS group. Serum IGF-I was significantly decreased in both the D and DS groups. Kidney weight, glomerular volume, albuminuria, and creatinine clearance were increased in the D animals and showed a trend toward normalization in the DS animals. Renal extractable IGF-I protein and IGFBP1 mRNA were increased in the D group and normalized in the DS group. CONCLUSIONS: GH antagonism by PTR-3173 has a blunting effect on renal/glomerular hypertrophy, albuminuria, and glomerular filtration rate (GFR) in diabetic NOD mice. This phenomenon is apparently associated with the prevention of renal IGF-I accumulation. Thus, modulation of GH effects may have beneficial therapeutic implications in diabetic nephropathy.

Testosterone stimulates growth of tibial epiphyseal growth plate and insulin-like growth factor-1 receptor abundance in hypophysectomized and castrated rats.

Puberty is associated with an increase in the plasma concentration of sex steroids, growth hormone (GH), and insulin-like growth factor-1 (IGF-1). Gonadal steroid hormones are important for the normal pubertal growth spurt and skeletal growth. The mechanism by which gonadal steroids induces skeletal growth is still not fully understood. To study the GH-independent effect of testosterone on growth, we investigated the effect of testosterone injections on the tibial epiphyseal growth plate (EGP) in an in vivo model of hypophysectomized and castrated male rats. Four groups (six animals each) of 28-d-old male rats were studied. Groups A, B, and C were hypophysectomized and castrated and received 500 microg/(kg x d) of hydrocortisone and 15 microg/(kg x d) of levothyroxine sodium. Groups A and B were also treated with daily sc injections of 10 microg of testosterone/100 g of body wt and 100 microg of testosterone/100 g of body wt, respectively, for 7 d. Group C was injected with vehicle alone. Group D were intact animals injected with saline (controls). Animals were sacrificed on 8 d. As expected, serum GH levels were found to be very low (1.13+/-0.1 ng/mL) in the hypophysectomized animals (group C, hypopit), and testosterone treatment did not change them significantly. Serum IGF-1 decreased from 502.9+/-13 ng/mL in group D to 167+/-41.4 ng/mL in group C (p < 0.001). Testosterone therapy had no stimulatory effect on serum IGF-1 levels in the hypopit + low-dose group (A) (220+/-94.8 ng/mL) and had an inhibitory effect in the hypopit + high-dose group (B) (39.3+/-17.5). Histomorphometric determinations demonstrated an EGP width of 472.3+/-39 microm in the intact animals but only 336.9+/-1.6 microm in the hypopit group (C) (p < 0.01). High-dose testosterone treatment (group B) significantly increased the EGP width (to 438.8+/-27.8), (p < 0.001), whereas low-dose testosterone (group A) did not. Immunohistochemistry studies revealed that the levels of IGF-1 in the EGP of the control animals were almost negligible and that testosterone did not change them. However, testosterone increased in a dose-dependent manner the abundance of IGF-1 receptor EGP. We conclude that testosterone has a direct, local, GH-independent effect on the EGP growth and IGF-1 receptor abundance.

Decreased insulin-like growth factor-I receptor sites on circulating mononuclear cells from children with acute leukemia.

Insulin-like growth factor-I (IGF-I) is a known mitogen for various cell types, including those of the hematopoietic cell system. To study the role of IGF-I in the neoplastic process of leukemia in children, the authors have determined the number of IGF-I binding sites on circulating mononuclear cells of children with acute leukemia as compared to normal children, using binding assays. The IGF-I binding sites per cell on peripheral mononuclear cells of children with leukemia decreased compared to those of the control group (411 +/- 73 and 1334 +/- 227, respectively, p < .001), while their affinity increased (Kd = 0.14 +/- 0.04 and 0.43 +/- 0.16, respectively, p = .05). Furthermore, in the patients, the number of the IGF-I binding sites was significantly lower in the subgroup of the peripheral mononuclear cells, which included lymphocytes and monocytes, as compared to their number in the peripheral blast cells (254 +/- 43.6 and 536 +/- 98.6, respectively, p = .02). A significant reduction was found in serum GHBP levels in the patients as compared to the controls (28.21 +/- 1.93 and 35.83 +/- 2.90, respectively, p = .02), while serum IGF-I and growth hormone levels were similar in patient and control groups. These results suggest a possible involvement of IGF-I in childhood acute leukemia, but further studies are needed to establish whether IGF-I plays a role in this disease.

Serum insulin-like growth factor-I (IGF-I) levels during long-term IGF-I treatment of children and adults with primary GH resistance (Laron syndrome).

Serum IGF-I levels were measured in 14 patients (9 children and 5 adults) with Laron syndrome (LS) during long-term treatment by IGF-I. Recombinant IGF-I (FK-780, Fujisawa Pharmaceutical Co. Ltd., Japan) was administered once daily subcutaneously before breakfast for 3-5 years to the children and for 9 months to the adults. The initial daily dose was 150 micrograms/kg for children and 120 micrograms/kg for adults. Before initiation of treatment the mean overnight fasting levels of serum IGF-I in the children was 3.2 +/- 0.8 nmol/l (mean +/- SEM), rising to 10 +/- 1.7 nmol/l during long-term treatment even on a dose of 120 micrograms/kg/day. The serum IGF-I levels 4 hours after injection rose from 31.2 +/- 3.5 to 48 +/- 2 nmol/l. In the adult patients, the initial basal IGF-I was 4.1 +/- 0.7 nmol/l, rising to 16.1 +/- 3.84 nmol/l after 8-9 months treatment. Serum IGF-I levels at 4 hours after injection rose in the adult patients from 24.1 +/- 5.8 up to 66.8 +/- 15.4 nmol/l. A progressively increasing half-life during long term exogenous administration of IGF-I to patients with Laron syndrome was demonstrated by following serum IGF-I dynamics after injection. Based on the fact that no antibodies to IGF-I were detected and on findings in previous studies, it is speculated that the increasing serum IGF-I levels during long-term IGF-I treatment are caused by an increase in serum IGFBP-3 induced by chronic IGF-I administration. It is concluded that treatment with IGF-I necessitates regular monitoring of serum IGF-I levels; in patients in whom the age adjusted maximal levels are exceeded, a reduction of the daily IGF-I dose is indicated to avoid undesirable effects.

Serum leptin in obese patients with Laron syndrome before and during IGF-I treatment.

Fifteen patients with primary GH resistance (Laron syndrome, LS) were studied before and during 6 months of daily replacement treatment with IGF-I. The main findings were that patients with LS and normal or high serum GH binding protein (GHBP) were less obese than those with a negative GHBP, and that serum leptin levels varied with body mass as in other types of obesity.

Development of hyperandrogenism during treatment with insulin-like growth factor-I (IGF-I) in female patients with Laron syndrome.

OBJECTIVE: Patients with Laron syndrome (LS) can now be treated with recombinant IGF-I. We describe the development of androgenization during IGF-I treatment of female LS patients. PATIENTS: Six female patients with LS--two clinically prepubertal (11.6 and 13.8 years of age) and four young adults (30 to 39 years old)--underwent long-term replacement treatment with recombinant IGF-I. The daily doses were 150 micrograms/kg/day by subcutaneous (s.c.) injection in the girls and 120 micrograms/kg/day in the adult women. METHODS: Testosterone, delta 4-androstenedione, LH, FSH, insulin and IGF-I were determined by radioimmunoassay. Blood samples were obtained after an overnight fast before the IGF-I injection. Serum IGF-I was also determined 4 hours after the s.c. injections. RESULTS: During IGF-I treatment, four out of the six patients (two girls and two adults) developed progressive clinical symptoms and signs of hyperandrogenism (oligo/amenorrhoea and acne). Laboratory determinations showed a significant elevation in serum testosterone, delta 4-androstenedione and LH/FSH ratio. The hyperandrogenism occurred concomitantly with an increase in IGF-I serum and a decrease in serum insulin concentrations. Reduction in IGF-I dose or interruption in IGF-I treatment restored androgen levels to normal values. At the same time, the acne and oligomenorrhoea resolved. CONCLUSIONS: Overdosage of IGF-I can lead to androgenization, a previously undescribed undesirable effect of IGF-I. Long-term IGF-I treatment necessitates progressive adjustment of the IGF-I dose to avoid overtreatment.

Increased number of IGF-I receptors on erythrocytes of women with polycystic ovarian syndrome.

OBJECTIVE: To test the hypothesis that insulin acts though ovarian IGF-I receptors to produce excessive amounts of androgens in polycystic ovarian syndrome (PCOS), by measuring the binding capacity of IGF-I receptors on erythrocytes and relating the findings to the degree of hyperandrogenism and hyperinsulinaemia. DESIGN: A case-control study of IGF-I receptors on erythrocytes of women with PCOS and age- and weight-matched controls. PATIENTS AND METHODS: IGF-I receptors on erythrocytes, serum levels of androgens, IGF-I, GH, basal insulin and insulin response during oral glucose tolerance test (oGTT) were measured after induced or spontaneous withdrawal bleeding in 10 women with PCOS and eight normo-ovulatory women. RESULTS: An increased number of IGF-I receptors was found on erythrocytes of patients with PCOS compared with the controls (P < 0.01), irrespective of their body mass index. Serum IGF-I levels were similar in both groups. The degree of hyperinsulinaemia, provoked by oGTT, correlated positively with basal insulin (r = 0.69; P = 0.003), but not with the number of IGF-I receptors. However, the number of IGF-I receptors correlated positively with androstenedione (r = 0.54, P = 0.0018). CONCLUSIONS: The findings in the present study that the number of IGF-I receptors and not the insulin levels correlate with serum androstenedione support the theory that the hyperandrogenism in PCOS is not a direct effect of the hyperinsulinaemia, but IGF-I mediated.

Lack of effect of methylphenidate on serum growth hormone (GH), GH-binding protein, and insulin-like growth factor I.

The aim of this study was to assess the growth hormone (GH) axis in methylphenidate (MPH)-treated and untreated boys with attention-deficit and hyperactivity disorder (ADHD), by evaluating serum GH, GH-binding protein (GHBP) activity, and insulin-like growth factor I (IGF-I) levels as compared to age-matched normal controls. Blood samples were taken from 42 boys (aged 6-16 years) diagnosed as having ADHD according to DSM-III-R criteria and confirmed by using the Schedule for Affective Disorder and Schizophrenia for school-age children (K[Kiddle]-SADS). A total of 21 patients were treated with MPH (5-20 mg/day; 0.15-0.77 mg/kg/day), on a drug holiday protocol, for 1-36 months, and 21 were drug naive. A total of 46 age-matched normal boys at height and weight within normal range served as controls. No significant differences were detected between the MPH-treated ADHD children, the untreated ADHD children, and the control children on fasting serum GH levels, GHBP activity, or IGF-I levels. Active treatment with MPH, in ADHD children on a drug holiday protocol, does not cause changes in GH axis as manifested by normal values of GH, GHBP, and IGF-I.

Intronic mutation in the growth hormone (GH) receptor gene from a girl with Laron syndrome and extremely high serum GH binding protein: extended phenotypic study in a very large pedigree.

Laron syndrome (LS) is a hereditary form of GH resistance due to molecular defects in the GH receptor (GHR). Most of the identified mutations are located in the extracellular domain of the receptor, resulting in a lack of serum GHBP in the majority of LS patients. We present an LS patient with supranormal levels of serum GHBP, in addition to 35 of her relatives. The proband is a 3.5 year-old Druse girl with severe short stature (height SDS -5.1), high GH (250 micrograms/l), low IGF-I (2.7 nmol/l) and IGFBP-3 (410 micrograms/l), both unresponsive to exogenous GH. The binding capacity of the serum GHBP was 22 nM (adult reference serum, 0.7 nM), with an affinity constant Ka = 1.9 x 10(9) M-1 comparable to that of normal sera (Ka = 1.7-2.1 x 10(9) M-1). The apparent MW of the GHBP was approximately 60-80 kDa, similar to that of control sera. In the proband's sister, parents, grandparents and uncles, extremely high GHBP values were observed (43.0 +/- 4.8 RSB, n = 10) compared with normal adults (0.81 +/- 0.06 RSB) (p << 0.001). The remaining subjects had normal or moderately elevated GHBP levels. Serum GH in adults with high GHBP was significantly elevated above control values (6.0 +/- 0.9 micrograms/l vs 0.76 +/- 0.13 microgram/l, p < 0.001). Serum IGF-I and IGFBP-3 levels were normal in all the subjects, with the exception of an aunt (IGF-I 3.9 nmol/l) and the proband's sister (IGFBP-3 460 micrograms/l). All the subjects' heights were within the normal range. Analysis of the GHR gene performed in the proband revealed an as yet undescribed homozygous intronic point mutation. It consists of a G-->T substitution at nucleotide 785-1 preceding exon 8, a sequence that encodes the transmembrane domain. This mutation, which destroys the invariant dinucleotide of the splice acceptor site, is expected to alter GHR mRNA splicing and to be responsible for skipping exon 8. The resulting truncated protein that retains GH binding activity is probably no longer anchored in the cell membrane, affecting signal transmission in the homozygous patient and causing high GHBP levels in the heterozygous relatives.

Serum and renal IGF-I levels after uninephrectomy in the rat.

The hypertrophy of the remaining kidney following uninephrectomy (UNx) has been related to an increase in renal insulin growth factor-I (IGF-I) content. However, while the increase in renal IGF-I lasts for only days after UNx, renal hypertrophy continues for months. In the present study we investigated whether IGF-I also plays a role in the late post uninephrectomy growth of the remaining kidney. Renal IGF-I in the remnant kidney was greater than that of control kidneys (78.3 +/- 17.3 vs 56.0 +/- 14.0 pmol g-1; p < 0.05) 3 days after UNx, tended to remain higher 30 days after UNx (83.8 +/- 23.6 vs 57.3 +/- 14.5 pmol g-1; p = 0.07), but was similar to that of the control kidney when examined 60 days after UNx (66.6 +/- 15.6 vs. 70.4 +/- 6.7 pmol g-1). Serum IGF-I in uninephrectomized rats was similar to that of controls 3 days after UNx, started to increase above the control level at day 10 after UNx and remained higher 30 and 60 days after UNx (75.9 +/- 6.9 vs. 48.7 +/- 7.3 nmol l-1 at 30 days, and 81.2 +/- 13.7 vs 52.9 +/- 11.0 nmol l-1 at day 60, p < 0.05 for both). The kidney weight of uninephrectomized rats was higher by 21% than that of controls 3 days after UNx, by 45% 30 days after UNx and by 63% 60 days after UNx (p < 0.05 for all three observations). At the end of the study, the glomerular volume of uninephrectomized rats was higher by 36% than that of the controls (p < 0.05) We suggest that in the rat, while the initial post uninephrectomy hypertrophy of the remnant kidney is associated with and most probably mediated by an increase in renal IGF-I, the hypertrophy that persists in later post UNx periods is associated with and may be mediated by an increase in serum IGF-I.

Growth hormone increases and insulin-like growth factor-I decreases circulating lipoprotein(a)

BACKGROUND: Elevated serum lipoprotein(a) (Lp(a)) is a strong risk factor for coronary artery disease (CAD). Genetic factors appear to account for the major variance in Lp(a) levels but the contribution hormones make in modulating Lp(a) levels is not yet clear. In the present investigation we determined the effects of human growth hormone (hGH) and insulin-like growth factor-I (IGF-I) on circulating Lp(a). METHODS: Four groups of patients were studied. Group a: adults with GH deficiency (n = 7) treated with hGH (0.05 U/kg/day, s.c.); group b: girls with Turner syndrome (n = 7) treated with hGH (0.1 U/kg/day, s.c.); group c: prepubertal boys with idiopathic short stature (n = 6) treated with the GH secretagogue (GHRP) hexarelin (60 micrograms t.i.d. intranasally); group d: Laron syndrome patients (n = 10) treated with IGF-I (100-200 micrograms/kg/day, s.c.). Following overnight fasting, serum was sampled before the initiation of treatment and during 6-9 months treatment. RESULTS: Serum IGF-I rose significantly in all the subjects in all four groups. In the first three groups in which IGF-I was elevated by exogenous or endogenous GH stimulation, serum Lp(a) increased significantly (119 +/- 35%, P < 0.01; 126 +/- 44%, P < 0.05; 102 +/- 29%, P < 0.01 for groups a, b, and c respectively). By contrast, serum Lp(a) levels decreased in group d to whom exogenous IGF-I was administered (-66 +/- 5%, P < 0.001). The differential effect of endogenous vs exogenous IGF-I on serum Lp(a) paralleled the behaviour of serum insulin. Insulin was significantly increased in all the subjects receiving hGH or GHRP (65.2 +/- 31%, P = 0.109; 93.7 +/- 53%, P = 0.062; 353.8 +/- 52.7%, P < 0.01 for groups a, b, and c respectively) whereas insulin levels were reduced following exogenous administration of IGF-I (-34.1 +/- 9.1%, P < 0.01). CONCLUSIONS: We conclude that long-term GH treatment increases and IGF-I decreases circulating levels of Lp(a). These findings may have clinical relevance in view of the increasing use of hGH in children and adults and the role of Lp(a) as a CAD risk factor.

Effect of different serum concentrations of growth hormone-binding protein (GHBP) on the regulation of GH receptor/GHBP gene transcription in a human hepatoma cell line.

Although high-affinity growth hormone (GH)-binding protein (GHBP) seems to mirror tissue GH receptor (GH-R) status and effects GH kinetics, the physiological importance and ultimate biological role of GHBP remain largely unknown and obscure. Therefore, the aims of this study were, first, to test the hypothesis that different serum concentrations of GHBP may regulate GH-R/GHBP gene transcription and, second, to define a new nonradioactive polymerase chain reaction (PCR) method to quantify GH-R/GHBP mRNA levels which was to compare with the RNase protection assay. Sera from patients with Laron-type dwarfism (n = 10) and adult obese patients (n = 7) containing distinct GH and GHBP concentrations were added to human hepatoma cells (HuH 7) cultured in a hormonally-adapted medium. GH-R/GHBP gene expression was studied 3 h after the addition of the sera. The results of the regulated GH-R/GHBP mRNA levels imply a direct impact of GHBP on GH-R/GHBP gene transcription under these circumstances. In conclusion, we set up a nonradioactive quantitative PCR method which enables the measurement and quantification of GH-R/GHBP mRNA. The results were identical with the data obtained using RNase protection assay. In addition, these results provide evidence that GHBP may have some effect on the regulation of the GH-R/GHBP transcription and that it is more than simply a shed or secreted product with extracellular destinations and functions. Our personal view, therefore, is that GHBP is rather an active player than an erratic extracellular domain of a receptor.

Long-term effects of insulin-like growth factor (IGF)-I on serum IGF-I, IGF-binding protein-3 and acid labile subunit in Laron syndrome patients with normal growth hormone binding protein.

A minority of patients with Laron syndrome have normal serum GH binding protein (GHBP), indicating that the defect is elsewhere than in the extracellular domain of the GH receptor. We have evaluated the effect of long-term IGF-I treatment on serum IGF-binding protein (IGFBP)-3 and the acid-labile subunit (ALS) in three sibling with Laron syndrome caused by a GH post-receptor defect and with normal GHBP. The children (a boy aged 3 years, a girl aged 4 years and a boy aged 10 years) were treated by daily s.c. injection of IGF-I in a dose of 150 micrograms/kg. IGFBP-3 was measured by RIA and Western ligand blotting, ALS by RIA. Based values of IGFBP-3 and ALS were low. During IGF-I treatment, the IGFBP-3 concentrations in the girl gradually increased, whereas in the boys there was a 60% decrease during the first week, followed by gradual increase towards baseline. The ALS concentrations followed a similar pattern. We conclude that IGF-I treatment induces and initial suppression and then an increase in the IGFBP-3 and ALS concentrations, confirming data from animal experiments that IGFBP-3 synthesis is not solely under GH control. The differences in responsiveness between the female and male siblings may reflect genetic differences, or lower circulating concentrations of IGF-I in the boys compared with the girl.

Insulin-like growth factor-I decreases serum lipoprotein (a) during long-term treatment of patients with Laron syndrome.

An increased circulating level of lipoprotein(a) [Lp(a)] is a well-recognized risk factor for coronary artery disease. While much remains to be understood about its regulation and physiological functions, we explored the effect of recombinant insulin-like growth factor-I (IGF-I) administration on circulating Lp(a) levels in 10 Laron syndrome (LS) patients (five children and five adults) with inherited IGF-I deficiency. There was no relationship between pretreatment or posttreatment Lp(a) levels and age and sex of the patients. With IGF-I treatment for 6 to 12 months, there was a significant reduction in Lp(a) (65.7% +/- 15.5%, P < .0001) from the pretreatment level of 76 +/- 45 mg/L to the posttreatment level of 29 +/- 26 mg/L. This decrease was dosage-dependent on the IGF-I administered (r = .685, F = 0.708, P = .029) and correlated more strongly with the dosage ratio of the end to the beginning of treatment (r = .78, F = 12.23, P = .008). The higher the IGF-I dose and the higher the dose ratio, the greater the Lp(a) decrease and the lower the Lp(a) at the end of treatment. In conclusion, we observed a dose-dependent relationship between IGF-I administration and Lp(a) reduction in patients with LS. Further studies are needed to elucidate the mechanism of the effect, but our findings suggest a possible metabolic link between these two and shed more light on the regulation of apolipoprotein(a) [apo(a)] expression. It could also open an avenue for additional therapeutic usage of IGF-I.