Evidence that potassium deficiency induces growth retardation through reduced circulating levels of growth hormone and insulin-like growth factor I.

Growth retardation and impaired protein synthesis are major characteristics of potassium (K)-deficiency in animals and man. We have evaluated the effect of K-deficiency on growth, serum growth hormone (s-GH), insulin-like growth factor I (s-IGF-I), and insulin (s-insulin) in young rats. After 10 days on K-deficient fodder, 4 1/2-week-old rats showed a 54% reduction in serum potassium (s-K) and a weight gain that was reduced by 97%, compared with pair-fed controls. In addition, tail length, tibia length, and muscle weight of soleus in K-depleted animals were all significantly reduced compared with pair-fed controls. The growth retardation was accompanied by a 46% reduction in s-IGF-I, while s-insulin showed no decrease. K-repletion in animals depleted for 7 days showed complete normalization of s-K within 24 hours, in addition to a significant increase in both s-IGF-I and weight. In 4-week-old rats maintained on K-deficient fodder with variable K-content (1 to 260 mmol/kg) for 1 week, a strong correlation between the K-content of fodder and s-IGF-I could be established (r = .88, P less than .001), as well as between s-IGF-I and weight gain (r = .90, P less than .001). Furthermore, a stepwise reduction in basal s-GH was seen with the graded reduction of dietary K-content.(ABSTRACT TRUNCATED AT 250 WORDS)     

The bone mineral density in acquired growth hormone deficiency correlates with circulating levels of insulin-like growth factor I.

Insulin-like growth factor I (IGF-I) is an important anabolic factor for osteoblasts in vitro. Low plasma levels of IGF-I have been observed in young men with osteoporosis. In the present study, we have studied bone mineral density (BMD) and the circulating levels of IGF-I and growth hormone (GH) in adults with acquired GH deficiency. BMD was determined by dual-energy x-ray absorptiometry in 17 men and 12 women (age 27-54 years). Spinal BMD was positively correlated with the plasma levels of IGF-I (r = 0.43, P = 0.019), with the median of GH values obtained by repeated sampling at night (r = 0.43, P = 0.0019), and with the peak of GH values during GHRH provocation test (r = 0.49, P = 0.039). The total BMD was positively related to plasma IGF-I and median of GH values, but not to peak GH by GHRH provocation. In a multiple regression analysis model, IGF-I, peak GH by GHRH provocation test and duration of GH deficiency explained 49% of the variation in spinal BMD. As compared to healthy controls, total, but not spinal, bone mass was lower in men with GH deficiency, but no clinical symptoms of osteoporosis were observed. The positive relationships between BMD and circulating IGF-I and other indices of GH secretion suggest that IGF-I has an endocrine effect on bone mass.     

High parathyroid hormone,but not low vitamin D concentrations,expose elderly inpatients to hypertension

Aim: Serum parathyroid hormone (PTH) and 25‐hydroxyvitamin D (25OHD) concentrations might contribute to blood pressure (BP) levels. Mixed results in previous literature could be due to the failure to consider both these hormones concurrently, despite their long‐known relationship. Our objective was to examine the association of serum intact PTH and 25OHD concentrations with BP levels amongst older inpatients, while accounting for each other. Methods: The participants were 284 Caucasian older inpatients with no suspicion of primary hyperparathyroidism (mean age 85.87 ± 5.90 years; 65.8% female) admitted to the geriatric acute care unit of Angers University Hospital, France. They were divided into two groups according to the existence of hypertension (i.e. systolic blood pressure [SBP] >140 mmHg, or diastolic blood pressure [DBP] >90 mmHg). Age, sex, numbers of chronic diseases and of drugs taken daily, use of antihypertensive or corticosteroid drugs and of calcium supplements/vitamin D, thyroid‐stimulating hormone and albumin concentrations, creatinine clearance, and season tested were used as covariables. Results: Hypertensive participants (n = 106) had higher intact PTH concentrations than normotensive patients (P = 0.044). There was a positive linear association of BP with intact PTH concentrations (adjusted β = 0.08, P = 0.015 for SBP; adjusted β = 0.05, P = 0.044 for DBP), but not with vitamin D. Serum intact PTH concentration, unlike 25OHD, was associated with hypertension (adjusted OR 1.01, P = 0.038). Conclusions: Irrespective of 25OHD, PTH was associated with hypertension by increasing both SBP and DBP. Geriatr Gerontol 2013; 13: 783–791 .     

先天性心脏病手术后生长激素-胰岛素样生长因子轴的变化

目的 探讨先天性心脏病患儿手术后生长激素(growth hormone)和胰岛素样生长因子(insulin-like growth factor,IGF)轴的变化及意义.方法 先天性心脏病25例,采用放射免疫测定法测定治疗前、手术治疗后3个月、6个月和1年空腹血IGF-1及胰岛素样生长因子结合蛋白-3(insulinlike growth factor binding protein-3,IGFBP-3);对照组为正常儿童20名.结果 先天性心脏病患儿手术前血IGF-1和IGFBP-3浓度较正常儿童减低(P＜0.01);先天性心脏病手术治疗后患儿的IGF-1和IGFBP-3浓度随着术后时间增加而逐渐提高,至1年时与同龄儿童持平,差异无统计学意义(P＞0.05).结论 先天性心脏病患儿存在生长发育迟缓及生长激素-胰岛素样生长因子轴功能的紊乱能通过手术治疗纠正,从而改善先天性心脏病患儿生长发育.     

Low circulating insulin-like growth factor I in coeliac disease and its relation to bone mineral density.

BACKGROUND: Patients with coeliac disease have low bone mineral density (BMD), but the underlying mechanisms are unclear. Our aim was to study circulating insulin-like growth factor I (IGF-I) and its possible relationship to BMD in adults with untreated coeliac disease and after 1 year on a gluten-free diet. METHODS: In 29 consecutive adult coeliac patients fasting IGF-I and BMD (n = 28) were examined before and 1 year after starting a gluten-free diet. Intact parathyroid hormone (PTH) was measured (n = 20) before the gluten-free diet was started. RESULTS: Untreated coeliac patients had lower IGF-I values than controls matched for age and sex, and their BMD was low. A relationship was observed between BMD and IGF-I but not independent of age and body mass index. During the 1st year on a gluten-free diet BMD increased (P < 0.001), as did the circulating IGF-I levels in 21 of the 29 patients (P = 0.078). In the subgroup of 14 patients with normal initial PTH the increase in IGF-I correlated positively with the increase in BMD (femoral trochanter, r = 0.62, P < 0.05, and lumbar spine, r = 0.70, P < 0.02). CONCLUSIONS: BMD and circulating IGF-I levels are low in adults with untreated coeliac disease. In patients with normal initial PTH level there is an association between the change in BMD and circulating IGF-I, although this parallel increase may not be causally connected.     

The somatotrophic axis in young steers: influence of nutritional status on pulsatile release of growth hormone and circulating concentrations of insulin-like growth factor 1

The relationship between plasma GH profiles and circulating concentrations of insulin-like growth factor 1 (IGF-1) at three different planes of nutrition, chosen to represent a high, medium and low level of nutrition (3%, 1.8% and 1% dry matter of liveweight per day) was studied in 15 young Angus steers. All steers were maintained on 3% dry matter for 5 weeks, then on one of the three nutritional planes for 4 weeks and then all were returned to 3% dry matter for 3 weeks. Blood was sampled through jugular catheters at 15-min intervals for 25 h at the end of each phase of the study and additional samples were taken on 2 days each week. Pulsatile release of GH occurred episodically with a diurnal increase during night and morning hours only in steers on high nutritional intakes. Reduced feeding at both the medium and the low plane abolished the diurnal rhythm and significantly increased mean plasma GH concentrations, the amplitude of GH pulses and the area under the GH profiles. Baseline concentrations of GH and pulse frequency did not change through nutritional manipulation. Upon realimentation, plasma GH concentrations decreased in both previously undernourished groups, with those fed 1% dry matter still having increased levels 10 days after refeeding. Plasma IGF-1 concentrations showed no periodicity. With nutritional deprivation, a decrease in IGF-1 concentration was observed only at negative energy balance (1% group). In this group plasma IGF-1 concentrations were progressively restored within 1 week of realimentation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity

CONTEXT: Children with severe IGF-I deficiency due to congenital or acquired defects in GH action have short stature that cannot be remedied by GH treatment. OBJECTIVES: The objective of the study was to examine the long-term efficacy and safety of recombinant human IGF-I (rhIGF-I) therapy for short children with severe IGF-I deficiency. DESIGN: Seventy-six children with IGF-I deficiency due to GH insensitivity were treated with rhIGF-I for up to 12 yr under a predominantly open-label design. SETTING: The study was conducted at general clinical research centers and with collaborating endocrinologists. SUBJECTS: Entry criteria included: age older than 2 yr, sd scores for height and circulating IGF-I concentration less than -2 for age and sex, and evidence of resistance to GH. INTERVENTION: rhIGF-I was administered sc in doses between 60 and 120 microg/kg twice daily. MAIN OUTCOME MEASURES: Height velocity, skeletal maturation, and adverse events were measured. RESULTS: Height velocity increased from 2.8 cm/yr on average at baseline to 8.0 cm/yr during the first year of treatment (P < 0.0001) and was dependent on the dose administered. Height velocities were lower during subsequent years but remained above baseline for up to 8 yr. The most common adverse event was hypoglycemia, which was observed both before and during therapy. It was reported by 49% of treated subjects. The next most common adverse events were injection site lipohypertrophy (32%) and tonsillar/adenoidal hypertrophy (22%). CONCLUSIONS: Treatment with rhIGF-I stimulates linear growth in children with severe IGF-I deficiency due to GH insensitivity. Adverse events are common but are rarely of sufficient severity to interrupt or modify treatment.     

Growth hormone treatment in short children: relationship between growth and serum insulin-like growth factor I and II levels

Thirty-one children who were short but not GH deficient, whose serum GH responses to provocative tests were normal, and whose spontaneous GH secretion was low received daily sc injections of human GH (Crescormon; 0.1 IU/kg BW) for 1 yr. Their initial serum insulin-like growth factor I (IGF-I) and IGF-II responses to GH were compared with their 1-yr growth response to therapy. In the prepubertal group (n = 18) the growth rate of all but two children increased 3.4 +/- 0.2 (+/- SEM) cm (from 4.1 +/- 0.2 to 7.5 +/- 0.3 cm/yr). The mean increment in the growth rate of the pubertal group was 5.2 +/- 0.5 cm. In both groups the growth increase was strongly correlated with both the percent increase in serum IGF-I and the percent increase in serum IGF-II during the first 10 days of treatment. No correlation was found between the basal growth rate and basal serum IGF-I or IGF-II levels. In the prepubertal group of children, both the percent increase in serum IGF-I levels in response to GH and the age at start of treatment were predictors of long term growth. We conclude that this subgroup of normal short children with low spontaneous GH secretion and high percent increase in serum IGF values benefits from GH treatment with an increased growth rate.     

Serum homocysteine concentrations in children with growth hormone (GH) deficiency before and after 12 months GH replacement

OBJECTIVE: This open, prospective study was designed to evaluate the effect of growth hormone deficiency (GHD) and GH replacement therapy on serum homocysteine (Hcy) concentration in children with GHD. SUBJECTS: Seventeen prepubertal children with GHD (11 boys and six girls) aged 8.6 +/- 1.9 years were studied before and after 12 months of GH replacement therapy at a dose of GH of 30 microg/kg/day. Seventeen healthy children acted as controls and were matched for age, sex and body mass index (BMI). METHODS: At study entry, height, weight, blood pressure, serum Hcy, serum IGF-I, total-low density lipoprotein (LDL)- and high density lipoprotein (HDL) cholesterol, triglycerides, free T4, free T3, vitamin B12, folate, glucose and creatinine were measured in all subjects. The atherogenic index (AI) was also calculated as the ratio of total cholesterol/HDL cholesterol (T/HDL). In GHD children these parameters were also revaluated after 12 months of GH therapy. RESULTS: At study entry height and serum IGF-I were significantly lower, as expected, in GHD patients than in controls (P < 0.0001 and P < 0.007, respectively). Serum Hcy levels were significantly higher in GHD patients than in healthy children (8.4 +/- 2.9 vs. 6.0 +/- 2.9 micromol/l; P < 0.03), although the absolute values were within the normal values for age and sex. There were no significant differences at baseline with respect to blood pressure, serum vitamin B12, folate, fT3, fT4, lipid profile, creatinine and glucose levels. After 12 months of GH replacement therapy height and serum IGF-I increased significantly compared to pretreatment values (P < 0.0001); serum Hcy levels decreased significantly (6.0 +/- 3.3 micromol/l; P < 0.002) compared to baseline values, becoming similar to control values. Total cholesterol (3.5 +/- 0.6 mmol/l) and the AI (2.5 +/- 0.8) decreased significantly with respect to both pretreatment (4.2 +/- 1.0 mmol/l; P < 0.0002 and 3.4 +/- 0.8; < 0.002, respectively) and control values (4.2 +/- 0.4 mmol/l; P < 0.0005 and 3.3 +/- 1.1; P = 0.02, respectively). CONCLUSIONS: GHD in children is associated with higher serum levels of Hcy compared to controls, without significantly affecting the lipid profile. GH replacement for 12 months significantly decreased the Hcy levels and improved the lipid profile with a decrease of total cholesterol and the total/HDL cholesterol ratio, compared to pretreatment values. Given the small number of patients, further larger studies are needed to clarify whether these results may have significant effects in the prevention of cardiovascular disease in adulthood.     

Adult-onset growth hormone and insulin-like growth factor I deficiency reduces neoplastic disease, modifies age-related pathology, and increases life span

Disruption of the insulin/IGF-I pathway increases life span in invertebrates. However, effects of decreased IGF-I signaling in mammalian models remain controversial. Using a rodent model with a specific and limited deficiency of GH and IGF-I, we report that GH and IGF-I deficiency throughout life [GH deficiency (GHD)] has no effect on life span compared with normal, heterozygous animals. However, treatment of GHD animals with GH from 4-14 wk of age [adult-onset (AO) GHD] increased median and maximal life span by 14% and 12%, respectively. Analysis of end-of-life pathology indicated that deficiency of these hormones decreased tumor incidence in GHD and AO-GHD animals (18 and 30%, respectively) compared with heterozygous animals and decreased the severity of, and eliminated deaths from, chronic nephropathy. Total disease burden was reduced by 24% in GHD and 16% in AO-GHD animals. Interestingly, the incidence of intracranial hemorrhage increased by 154 and 198% in GHD and AO-GHD animals, respectively, compared with heterozygous animals. Deaths from intracranial hemorrhage in AO-GHD animals were delayed by 14 wk accounting for the increased life span compared with GHD animals. The presence of GH and IGF-I was necessary to maximize reproductive fitness and growth of offspring early in life and to maintain cognitive function and prevent cartilage degeneration later in life. The diverse effects of GH and IGF-I are consistent with a model of antagonistic pleiotropy and suggest that, in response to a deficiency of these hormones, increased life span is derived at the risk of functional impairments and tissue degeneration.     

In-vitro response of erythroid progenitors from children with thalassaemia major to human growth hormone and insulin-like growth factor I

OBJECTIVE Most short-statured children with β-thalassaemia major have markedly reduced levels of circulating insulin-like growth factor I (IGF-I). Both human growth hormone (hGH) and IGF-I enhance the in-vitro growth of erythroid progenitors, with hGH exerting its effects via paracrine production of IGF-I. The aim of this study was to characterize further the hGH-IGF-l axis abnormalities in thalassaemia major by evaluating the erythroid potentiating effects of both peptides in cultures of thalassaemic and control erythroid progenitors. DESIGN Ten short-statured thalassaemic children and nine age-matched healthy donors were evaluated for the in-vitro response of their peripheral blood erythroid progenitors to stimulation with hGH and IGF-I. MEASUREMENTS The frequency of erythroid progenitors in serum-free cultures of thalassaemic and control peripheral blood mononuclear cells was enumerated following 14 days of incubation in the presence of hGH or IGF-I. RESULTS Biosynthetic hGH induced a similar dose-dependent magnitude of colony enhancement in cultures of erythroid progenitors from thalassaemic children, as compared to controls. Significant enhancement of colony growth was detected at 42 μ/I hGH, with a maximal effect detected at 83 μ/I of this hormone (173 ± 8 vs 153 ± 9% of baseline erythroid progenitors in patients versus controls, respectively). Enhancement of both thalassaemic and control erythroid precursors by hGH was completely abrogated by monoclonal antibodies (αIR-3) directed against the IGF-I membrane receptor, thereby confirming the normal capacity of thalassaemic accessory cells to produce IGF-I in response to hGH. Biosynthetic IGF-I also enhanced the growth of thalassaemic and control erythroid precursors to 172±17 and 159±10% of baseline at 100 and 10 U/I, respectively. CONCLUSIONS Our detection of a normal capacity of thalassaemic peripheral blood target cells to response to hGH and IGF-I suggests that these patients do not suffer from a specific defect in receptor and/or post-receptor mechanism(s) involving the response of these cells to both peptides. The normal responsiveness of thalassaemic target cells to hGH and IGF-I suggests that both peptides may be useful in the treatment of growth retardation in thalassaemia.     

Changes in mRNA expression of grouper (Epinephelus coioides) growth hormone and insulin-like growth factor I in response to nutritional status

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are key links to nutritional condition and growth regulation in teleost. To understand the endocrine mechanism of growth regulation in grouper, we cloned the cDNAs for grouper GH and IGF-I and examined their mRNA expression during different nutritional status. Grouper GH cDNA is 936 base pairs (bp) long excluding the poly-A tail. It contained untranslated regions of 85 and 231bp in the 5'- and 3'-ends, respectively. It has an open reading frame of 612bp coding for a signal peptide of 17 amino acids (aa) and a mature hormone of 187aa residues. Based on the aa sequence of the mature hormone, grouper GH shows higher sequence identity (>76%) to GHs of perciforms than to GHs of cyprinids and salmonids (53-69%). Grouper preproIGF-I cDNA consisted of 558bp, which codes for 186aa. This is composed of 44aa for the signal peptide, 68aa for the mature peptide comprising B, C, A, and D domains, and 74aa for the E domain. Mature grouper IGF-I shows very high sequence identity to IGF-I of teleost fishes (84-97%) compared to advanced groups of vertebrates such as chicken, pig, and human (80%). Using DNA primers specific for grouper GH and IGF-I, the changes in mRNA levels of pituitary GH and hepatic IGF-I in response to starvation and refeeding were examined by a semi-quantitative RT-PCR. Significant elevation of GH mRNA level was observed after 2 weeks of food deprivation, and increased further after 3 and 4 weeks of starvation. GH mRNA level in fed-controls did not change significantly during the same period. Hepatic IGF-I mRNA level decreased significantly starting after 1 week of starvation until the 4th week. There was no significant change in IGF-I mRNA levels in fed-controls. One week of refeeding can restore the GH and IGF-I mRNA back to its normal levels. Deprivation of food for 1-4 weeks also resulted in cessation of growth and decrease in condition factor.     

Effect of growth hormone (GH) and insulin-like growth factor I on prostate diseases: an ultrasonographic and endocrine study in acromegaly, GH deficiency, and healthy subjects.

The role of insulin-like growth factor I (IGF-I) in prostate development is currently under thorough investigation because it has been claimed that IGF-I is a positive predictor of prostate cancer. To assess the effect of GH and IGF-I levels on prostate pathophysiology, 46 acromegalic (30 in active disease, 10 cured from acromegaly, and 6 affected from GH deficiency) and 30 age-matched male controls, free from previous or concomitant prostate disorders, underwent pituitary, androgen, and prostate hormonal assessments and transrectal ultrasonography. Compared to control values, GH (P < 0.0001), IGF-I (P < 0.0001), and IGFBP-3 (P < 0.001) levels were increased, whereas testosterone (P < 0.0001) and dihydrotestosterone levels (P < 0.0001) were reduced in active acromegalic patients. Hypogonadism was present in 28 of the 46 acromegalic patients (60.8%). The anteroposterior (P < 0.05), and transverse (P < 0.0001) prostate diameters and the transitional zone volume (P < 0.05) were increased in acromegalic patients compared to those in controls. Prostate volume (PV) was significantly higher in untreated acromegalic patients than in controls (41.7 +/- 3.2 vs. 21.9 +/- 1.4 mL; P < 0.0001), cured patients (23.6 +/- 1.6 mL; P < 0.0001), and GH-deficient patients (17.5 +/- 1.1 mL; P < 0.0001). In the patients, PV was correlated with disease duration (r = 0.606; P < 0.0001) and age (r = 0.496; P < 0.0001), whereas in controls it was correlated with age (r = 0.476; P < 0.01) and IGF-I levels (r = -0.448; P < 0.05). Benign prostate hyperplasia (PV > or = 30 mL) was found in 58% of the acromegalics and 26.6% of the controls. When grouped by age (<40, 40-60, and >60 yr), PV was increased in elderly patients compared to younger patients (P < 0.05) and to controls (P < 0.01). The prevalence of structural abnormalities, including calcifications, nodules, cysts, and vesicle inflammation, was significantly increased in patients compared to controls (78.2% vs. 23.3%; chi2 = 5.856; P < 0.05). No clinical, transrectal ultrasonography, or cytological evidence of prostate cancer was detected in acromegalic or control subjects. In conclusion, chronic excess of GH and IGF-I cause prostate overgrowth and further phenomena of rearrangement, but not prostate cancer.     

Plasma insulin-like growth factor I levels in the elderly: relation to plasma dehydroepiandrosterone sulfate levels, nutritional status, health and mortality.

BACKGROUND: Insulin-like growth factor I (IGF-I) has beneficial metabolic effects. Because plasma IGF-I levels have been reported to be enhanced by dehydroepiandrosterone (DHEA) administration, it has been suggested that the IGF-I may be implicated in some of the reported associations between low DHEA sulfate (DHEAS) levels and impaired health measures in elderly subjects. The nutritional status, which also regulates plasma IGF-I levels, is also an important determinant of health outcome. OBJECTIVE: We sought to investigate the associations between plasma IGF-I levels and plasma DHEAS levels, nutritional status, health, and mortality in the elderly. METHODS: In 256 community-dwelling subjects aged 65-101 years, enrolled in the Paquid study, a health questionnaire was used to acertain their functional disabilities, any history of medical disorders, self-perceived health, depressive symptoms, and their cognitive function. Biological measurements included levels of plasma IGF-I, albumin, transthyretin, and DHEAS. Mortality data were available for 6 years following blood sampling. RESULTS: In this elderly population with no impairment in nutritional status, the plasma IGF-I levels decreased significantly with age (p = 0.02). The plasma IGF-I levels correlated positively with those of transthyretin (p = 0.0001). IGF-I also correlated with DHEAS (p = 0.04), but the correlation did not remain significant after adjustment for age. As opposed to SDHEA, the plasma IGF-I levels did not correlate with the results from the health questionnaire. The baseline IGF-I values in the highest tertile were associated with a higher risk of short-term mortality than those in the lowest tertile (RR = 8.4 at 2 years, p = 0.007). CONCLUSIONS: Our results suggest that IGF-I is not connected with the association between low plasma DHEAS levels and the impaired results from the health questionnaire. The relationship between plasma IGF-I highest levels and mortality should be further explored.     

Changes in protein metabolism of ovine primary muscle cultures on treatment with growth hormone, insulin, insulin-like growth factor I or epidermal growth factor

Methods for the primary culture of muscle cells from fetal sheep were developed which gave high yields of cells. Myoblasts were grown in vitro, and allowed to fuse to form contractile multinucleate myotubes; these could be maintained in a good condition for at least 2 weeks. Protein turnover in these differentiated cultures was examined for sensitivity to each of four potentially anabolic peptide hormones and growth factors: insulin, insulin-like growth factor I (somatomedin C), epidermal growth factor and growth hormone. Insulin was found to have no effect except at high concentrations (1 mumol/l), compatible with its role as a somatomedin analogue. Insulin-like growth factor I was active at lower levels (1 nmol/l) but the cultures were not as responsive to it as were primary rat muscle cultures or differentiated L6 cells, which were tested in similar experiments. The maximum stimulation of protein synthesis observed with the ruminant system was only 16%. Epidermal growth factor was highly anabolic for primary cultures from sheep muscle, and the cells were very sensitive to it, half-maximal stimulation of protein synthesis being seen with concentrations as low as 20 pmol/l. No effects of bovine growth hormone were seen in the ovine system. However, an inhibition of protein breakdown was found with high concentrations (0.1 mumol/l) in the L6 rat myoblast cell line. It was found that the culture conditions used could affect the observed responses of protein synthesis and degradation, despite withdrawal of serum from the incubation media 22 h before testing.     

Gender difference in insulin-like growth factor I response to growth hormone (GH) treatment in GH-deficient adults: role of sex hormone replacement

GH production in healthy women is about thrice that in men. Yet insulin-like growth factor I (IGF-I) levels are similar, suggesting a lower responsivity to GH in women. In untreated GH-deficient adults, basal IGF-I levels are reportedly lower in females than in males, and the therapeutic recombinant human GH (rhGH) dose required to achieve optimal IGF-I levels is higher in the former, suggesting a pivotal role of estrogens on rhGH requirement in GH-deficient patients. We, therefore, analyzed our 2-yr data on the effect of rhGH on serum IGF-I in 77 GH-deficient patients (33 men, mean +/- SD age, 37.2 +/- 13.8 yr; 44 women, mean +/- SD age, 36.9 +/- 11.9 yr) with due attention to gender differences and to the effects of sex hormone replacement. Of the 44 women, 33 had estrogen substitution. Of the 33 men, 23 were on androgen replacement. Patients (11 premenopausal women and 10 men) not on hormonal replacement were eugonadal. Basal IGF-I levels in untreated GH-deficient women were significantly lower than in men (8.8 +/- 0.7 nmol/L vs. 12.2 +/- 0.9 nmol/L; P < 0.01), despite similar basal GH levels. The daily rhGH dose per kg body weight required to normalize IGF-I in women was higher than in men, the difference being statistically significant at all time points (P < 0.05-0.01). The IGF-I increase (delta) per IU GH/day x kg over the 24-month period was about twice higher in men than in women. Also calculated on a weight basis, rhGH responsivity (rhGH responsivity = (deltaIGF1(nmol/L)/dose (IU/day/kg)) was higher in men than in women at all time intervals (P < 0.05-0.01). Estrogen replacement in women significantly increased rhGH requirement. The rhGH dose per kg body weight required in estrogen-substituted women was significantly higher than in nonestrogen-substituted women (P < 0.01 at t = 18 and 24 months, respectively). In women on estrogen substitution, rhGH responsivity plateaued from 6 months on, whereas in eugonadal women without estrogen substitution the responsivity for rhGH increased over time. In men, the reverse was true; rhGH responsivity increased over time in men on androgen substitution, but plateaued in men without androgen substitution. The mechanisms underlying this gender difference are not known. Differential influences of estrogens and androgens on the expression of the GH receptor gene and IGF-I messenger RNA may be operative. The present study confirms short-term data published in the literature on a sex difference in rhGH dose requirement in GH-deficient patients. It furthers extends the data by demonstrating that this sex difference in GH responsivity persists and changes during the 24 months of the study. Moreover, it shows that estrogen replacement blunts the IGF-I response to rhGH in women, whereas in men with androgen substitution the responsivity increases over time, thus bearing a risk of undertreatment in women and overtreatment in men.