Effects of low dose versus high dose human growth hormone on body composition and lipids in adults with GH deficiency: a meta-analysis of placebo-controlled randomized trials.

PURPOSE: Doses of growth hormone in adults with growth hormone deficiency are now lower than previously. However, it is not clear they are as effective as higher doses. The objective of this meta-analysis was to assess efficacy of low to moderate dose (LD) GH replacement on standard endpoints of GH compared to higher doses. METHODS: A meta-analysis was carried out using PubMed, Cochrane and Embase databases from 1960 to 9/23/12. Three reviewers identified randomized double-blind, placebo-controlled trials of 6 months duration. Of 173 publications, 28 representing 22 trials (591 GH-treated patients and 562 placebo) were included. Data were independently extracted by three reviewers. Endpoints were analyzed if ≥4 studies per dose group reported baseline and 6 month data. RESULTS: Mean lean body mass (LBM) increased by 2.61 kg in GH-treated subjects versus 0.04 in the placebo group (P < 0.0001). Fat mass (FM) was reduced by -2.19 kg versus 0.31 (GH vs. placebo) (P = 0.0002). Changes in LBM and FM were dose-related (P = 0.02 and 0.007, respectively), high dose (HD) being more effective than low dose (LBM P = 0.03 and FM P = 0.04). In contrast, treatment with GH reduced total cholesterol -0.38 mmol/L versus. 0.01 (placebo) (P < 0.0001), and low density lipoprotein cholesterol (LDL-C) -0.42 mmol/L versus -0.1 (P = 0.0009), but there were no differences between LD and HD GH. CONCLUSIONS: LDs of hGH improve total- and LDL-C, and body composition. Higher doses are more effective on body composition, but not lipids.

Insulin-like growth factor-I inhibition with pasireotide decreases cell proliferation and increases apoptosis in pre-malignant lesions of the breast: a phase 1 proof of principle trial.

INTRODUCTION: Estrogen inhibition is effective in preventing breast cancer in only up to 50% of women with precancerous lesions and many experience side effects that are poorly tolerated. As insulin-like growth factor I (IGF-I) underlies both estrogen and progesterone actions and has other direct effects on mammary development and carcinogenesis, we hypothesized that IGF-I inhibition might provide a novel approach for breast cancer chemoprevention. METHODS: In total, 13 women with core breast biopsies diagnostic of atypical hyperplasia (AH) were treated for 10 days with pasireotide, a somatostatin analog which uniquely inhibits IGF-I action in the mammary gland. They then had excision biopsies. 12 patients also had proliferative lesions and one a ductal carcinoma in situ (DCIS). Primary outcomes were changes in cell proliferation and apoptosis after treatment. Expression of estrogen receptor (ER), progesterone receptor (PR), and phosphorylated Insulin-like growth factor I receptor (IGF-1R), protein kinase B (AKT) and extracellular signal-regulated kinases 1/2 (ERK1/2) were also assessed. Core and excision biopsies from 14 untreated patients served as non-blinded controls. Hyperglycemia and other side effects were carefully monitored. RESULTS: Pasireotide decreased proliferation and increased apoptosis in all AH (from 3.6 ± 2.6% to 1.3 ± 1.2% and from 0.3 ± 0.2% to 1.5 ± 1.6%, respectively) and proliferative lesions (from 3.8 ± 2.5% to 1.8 ± 1.8% and from 0.3 ± 0.2% to 1.3 ± 0.6%, respectively). The DCIS responded similarly. ER and PR were not affected by pasireotide, while IGF-1R, ERK1/2 and AKT phosphorylation decreased significantly. In contrast, tissue from untreated controls showed no change in cell proliferation or phosphorylation of IGF-1R, AKT or ERK 1/2. Mild to moderate hyperglycemia associated with reduced insulin levels was found. Glucose fell into the normal range after discontinuing treatment. Pasireotide was well tolerated and did not cause symptoms of estrogen deprivation. CONCLUSIONS: IGF-I inhibition by pasireotide, acting through the IGF-1R, was associated with decreased proliferation and increased apoptosis in pre-malignant breast lesions and one DCIS. Assuming hyperglycemia can be controlled, these data suggest that inhibiting the IGF-I pathway may prove an effective alternative for breast cancer chemoprevention. TRIAL REGISTRATION: NCT01372644 Trial date: July 1, 2007.

Pasireotide, an IGF-I action inhibitor, prevents growth hormone and estradiol-induced mammary hyperplasia.

Mammary hyperplasia increases breast cancer risk. Tamoxifen prevents breast cancer in women with atypical hyperplasia, but has serious side effects. As estradiol action requires IGF-I, direct inhibition of IGF-I action theoretically might be an efficacious alternative to tamoxifen. After hypophysectomy and oophorectomy, 21-day-old female rats were treated with GH and E2. After 7 days all terminal end buds (TEBs) and 75% of ducts became hyperplastic. Co-treatment with pasireotide, a somatostatin analog that blocks GH secretion and IGF-I action in the mammary gland, prevented hormone-induced hyperplasia. The number and size of TEBs and moderately or floridly hyperplastic ducts was reduced by pasireotide (P < 0.01). In contrast, the same concentration of octreotide, which has a more selective somatostatin receptor subtype binding profile, was less effective than pasireotide. Tamoxifen inhibited hyperplasia when used alone with GH + E2, but did not add to the inhibitory effect of pasireotide when the two treatments were combined. Both pasireotide and tamoxifen acted via the IGF-I receptor signaling pathway and both were found to inhibit mammary cell proliferation and stimulate apoptosis. The number of epithelial cells expressing phosphorylated insulin receptor substrate (IRS)-1 in response to GH and E2 was reduced by pasireotide, as was staining intensity. These results support the concept that IGF-I inhibition, in this case by pasireotide, inhibits E2 and GH-induced mammary hyperplasia. As tamoxifen did not further increase the inhibitory effect of pasireotide, the peptide appears to be at least as effective as tamoxifen in preventing GH + E2-induced mammary hyperplasia.

IGF-I, GH, and sex steroid effects in normal mammary gland development.

Although the pubertal surge of estrogen is the immediate stimulus to mammary development, the action of estrogen depends upon the presence of pituitary growth hormone and the ability of GH to stimulate production of IGF-I in the mammary gland. Growth hormone binds to its receptor in the mammary fat pad, after which production of IGF-I mRNA and IGF-I protein occurs. It is likely that IGF-I then works through paracrine means to stimulate formation of TEBs, which then form ducts by bifurcating or trifurcating and extending through the mammary fat pad. By the time pubertal development is complete a tree-like structure of branching ducts fills the rodent mammary fat pad. In addition to requiring IGF-I in order to act, estradiol also directly synergizes with IGF-I to enhance formation of TEBs and ductal morphogenesis. Together they increase IRS-1 phosphorylation and cell proliferation, and inhibit apoptosis. In fact, the entire process of ductal morphogenesis, in oophorectomized IGF-I(-/-) knockout female mice, can occur as a result of the combined actions of estradiol and IGF-I. IGF-I also permits progesterone action in the mammary gland. Together they have been shown to stimulate a form of ductal morphogenesis, which is anatomically different from the kind induced by IGF-I and estradiol. Although both progesterone and estradiol synergize with IGF-I by increasing IGF-I action parameters, there must be other, as yet unknown mechanisms that account for the anatomical differences in the different forms of ductal morphogenesis observed (hyperplasia in response to IGF-I plus estradiol and single layered ducts in response to IGF-I plus progesterone).

Pregnancy outcomes following cabergoline treatment: extended results from a 12-year observational study.

OBJECTIVE: Cabergoline is a dopamine agonist used to treat hyperprolactinaemia. Because hyperprolactinaemia is a significant cause of infertility in women, cabergoline and other dopamine agonists are frequently prescribed to reduce prolactin levels and restore normal menses. They are usually discontinued shortly after the patient becomes pregnant. Although cabergoline has been used to treat hyperprolactinaemia since the mid-1990s, safety data related to maternal and foetal exposure to this agent are still limited. DESIGN: The current prospective, observational study reports on a total of 380 pregnancies. This extends by 154 pregnancies the results of a previously published interim report on the outcomes of 226 pregnancies in women treated with cabergoline up to 1994. MAIN OUTCOME MEASURES: Outcomes examined include the incidence of abortions and premature delivery and the number and types of foetal malformations or abnormalities. RESULTS: Follow-up data were available for 329 pregnancies, including 258 (78%) deliveries and 71 (22%) abortions. Of the 71 reported abortions, 31 (44%) were voluntary, 30 (42%) were spontaneous miscarriages, and nine (13%) were therapeutic. Of the 258 deliveries, 250 (97%) were live deliveries, four (2%) were stillbirths, and the status of delivery was unknown for the remaining four (2%). Of the 250 live deliveries, 193 (77%) were term deliveries (gestational period > 37 weeks), 45 (18%) were preterm deliveries (gestational period < or = 37 weeks), and 62% of the infants had normal birthweights (i.e. 3-4 kg). Neonatal abnormalities were recorded for 23 (9%) of the infants with no apparent pattern in type or severity. CONCLUSION: The results of this study suggest that foetal exposure to cabergoline through early pregnancy does not induce any increase in the risk of miscarriage or foetal malformation.

Insulin-like growth factor (IGF)-I controls prostate fibromuscular development: IGF-I inhibition prevents both fibromuscular and glandular development in eugonadal mice.

Although antiandrogen therapy has been shown effective in treating prostatic tumors, it is relatively ineffective in treating benign prostatic hyperplasia (BPH). In an attempt to understand better the role of androgens in the development of the normal prostate and BPH, we studied the relative effects of testosterone and IGF-I on the development of the two compartments of the prostate in castrated IGF-I((-/-)) male mice. Here we report that IGF-I stimulated the development of the fibromuscular compartment, but testosterone inhibited it (stromal epithelial ratio 2.17 vs. 0.83, respectively; P < 0.001). Testosterone also impaired IGF-I induced insulin receptor substrate-1 phosphorylation and cell division, and increased apoptosis in fibromuscular tissue. In sharp contrast IGF-I and testosterone both stimulated the development of the glandular compartment individually and together. The combined effects were either additive or synergistic on compartment size, cell division, insulin receptor substrate-1 phosphorylation, and probasin production. Together they also had a greater inhibitory effect on apoptosis in gland tissue. To determine whether IGF-I inhibition would inhibit both fibromuscular and glandular compartments, we tested the effect of IGF binding protein-1 on prostate development in two different models: castrated Ames dwarf mice and eugonadal normal male mice. IGF binding protein-1 blocked bovine GH-induced fibromuscular and glandular development in both. It also inhibited epithelial cell division and increased apoptosis in both prostate compartments in the eugonadal mice. The observed discordance between IGF-I and testosterone control of prostate compartment development might explain the relative failure of 5alpha-reductase inhibition in BPH and why testosterone inhibition might theoretically reduce gland volume but increase fibromuscular tissue. The work also provides a rationale for considering IGF-I inhibition as therapy for BPH to reduce the size of both prostate compartments.

SOM230 inhibits insulin-like growth factor-I action in mammary gland development by pituitary independent mechanism: mediated through somatostatin subtype receptor 3?

Somatostatin analogs (SAs) treat acromegaly by lowering pituitary GH secretion, which, in turn, lowers systemic IGF-I. The profound systemic effect is often greater than expected in the face of only partial GH suppression. Here we report that the SA SOM230 can also act by a nonpituitary-mediated inhibition of IGF-I action. SOM230 inhibited mammary development in intact and hypophysectomized female rats, a process requiring IGF-I. IGF-I overcame this inhibition. SOM230 also inhibited other actions of IGF-I (inhibition of apoptosis, phosphorylation of insulin receptor substrate-1, and cell division). SOM230 did not reduce IGF-I mRNA abundance in mammary gland but did stimulate IGF binding protein 5 (IGFBP5). IGFBP5 was 3.75 times higher in mammary epithelium of SOM230 than in placebo animals (P < 0.001). Administration of IGFBP-5 also inhibited GH-induced mammary development (P < 0.001). Measurement of sstr(1-5) (somatostatin subtype receptor) by real-time RT-PCR revealed that the mammary glands had an abundance of sstr(3) and lower amounts of sstr(4) and sstr(5) but no sstr(1) or sstr(2.) That mammary development was also inhibited to a lesser degree than SOM230 by octreotide, whose main action is through sstr(2), strongly suggests that sstr(3) is at least in part mediating the effects of the SAs. We conclude that 1) SAs inhibit IGF-I action in the mammary gland through a novel nonpituitary mechanism; 2) IGFBP-5, here shown to inhibit pubertal mammary development, might mediate the effect; and 3) Measurement of available sstr receptors in the mammary gland suggests that sstr(3) mediates the SA activity, but sstr(5) is also a possible mediator.

Progesterone stimulates mammary gland ductal morphogenesis by synergizing with and enhancing insulin-like growth factor-I action.

Progestins have been implicated in breast cancer development, yet a role for progesterone (Pg) in ductal morphogenesis (DM) has not been established. To determine whether Pg could cause DM, we compared relative effects of Pg, estradiol (E2) and IGF-I on anatomical and molecular biological parameters of IGF-I-related DM in oophorectomized female IGF-I(-/-) mice. Pg had little independent effect on mammary development, but together with IGF-I, in the absence of E2, Pg stimulated an extensive network of branching ducts, occupying 92% of the gland vs. 28.3% with IGF-I alone, resembling pubertal development (P < 0.002). Its major effect was on enhancing duct length and branching (P < 0.002). Additionally, Pg enhanced phosphorylation of IRS-1, increased cell division, and increased the antiapoptotic effect of IGF-I. Pg action was inhibited by RU486 (P < 0.01). E2 also stimulated DM by enhancing IGF-I action but had a greater effect on terminal end bud formation and side branching (P < 0.002). In contrast to previous findings, long-term exposure to E2 alone, without IGF-I, caused formation of ducts and side branches, a novel finding. Both IGF-I and E2 were found necessary for Pg-induced alveolar development. In conclusion, Pg, through Pg receptor can enhance IGF-I action in DM, and E2 acts through a similar mechanism; E2 alone caused formation of ducts and side branches; there were differences in the actions of Pg and E2, the former largely affecting duct formation and extension, and the latter side branching; and both IGF-I and E2 were necessary for Pg to form mature alveoli.

Variability and reliability of single serum IGF-I measurements: impact on determining predictability of risk ratios in disease development.

In recent years, a number of investigators have studied the relationship between IGF-I and risk of developing cancer, diabetes or cardiovascular disease. Upper tertile, quartile, and quintile IGF-Is were associated with higher risk of developing cancer, and lowest quartile with cardiac disease and diabetes. As part of a study to correlate serum IGF-Is and growth hormone dynamics in aging, we measured fasting serum IGF-I at baseline and two weeks later in a group of 84 normal volunteers between the ages of 50 and 90 years. Although the correlation between the two IGF-Is was high (r=0.922; p<0.0001) there were substantial differences between the two IGF-I values ranging from -36.25 to +38.24% between individual IGF-I values at the two blood draws and a significant difference between the mean IGF-Is at visits I and 2 (mean 120.28+/-53.5 vs. 114.95+/-50.03; p=0.03). When considered in quartiles, IGF-I changed from one quartile to another in 34/84 (40.5%) of the volunteers. When the group was divided in halves, tertiles,quartiles, or quintiles there was an increasing number of subjects who changed from one subdivision to another as the number of gradations increased. These results suggest that the predictive outcomes of earlier studies that used single IGF-I samples for analysis of risk ratios according to tertiles, quartiles, or quintiles could have been different if a second IGF-I was used to establish the risk ratio. The results also suggest that variability in IGF-I should be taken into account when designing such studies.

Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency.

Although the use of the insulin tolerance test (ITT) for the diagnosis of adult GH deficiency is well established, diagnostic peak GH cut-points for other commonly used GH stimulation tests are less clearly established. Despite that fact, the majority of patients in the United States who are evaluated for GH deficiency do not undergo insulin tolerance testing. The aim of this study was to evaluate the relative utility of six different methods of testing for adult GH deficiency currently used in practice in the United States and to develop diagnostic cut-points for each of these tests. Thirty-nine patients (26 male, 13 female) with adult-onset hypothalamic-pituitary disease and multiple pituitary hormone deficiencies were studied in comparison with age-, sex-, estrogen status-, and body mass index-matched control subjects (n = 34; 20 male, 14 female). A third group of patients (n = 21) with adult-onset hypothalamic-pituitary disease and no more than one additional pituitary hormone deficiency was also studied. The primary end-point was peak serum GH response to five GH stimulation tests administered in random order at five separate visits: ITT, arginine (ARG), levodopa (L-DOPA), ARG plus L-DOPA, and ARG plus GHRH. Serum IGF-I concentrations were also measured on two occasions. For purposes of analysis, patients with multiple pituitary hormone deficiencies were assumed to be GH deficient. Three diagnostic cut-points were calculated for each test to provide optimal separation of multiple pituitary hormone deficient and control subjects according to three criteria: 1) to minimize misclassification of control subjects and deficient patients (balance between high sensitivity and high specificity); 2) to provide 95% sensitivity for GH deficiency; and 3) to provide 95% specificity for GH deficiency. The greatest diagnostic accuracy occurred with the ITT and the ARG plus GHRH test, although patients preferred the latter (P = 0.001). Using peak serum GH cut-points of 5.1 microg/liter for the ITT and 4.1 microg/liter for the ARG plus GHRH test, high sensitivity (96 and 95%, respectively) and specificity (92 and 91%, respectively) for GH deficiency were achieved. To obtain 95% specificity, the peak serum GH cut-points were lower at 3.3 microg/liter and 1.5 microg/liter for the ITT and ARG plus GHRH test, respectively. There was substantial overlap between patients and control subjects for the ARG plus L-DOPA, ARG, and L-DOPA tests, but test-specific cut-points could be defined for all three tests to provide 95% sensitivity for GH deficiency (peak GH cut-points: 1.5, 1.4 and 0.64 microg/liter, respectively). However, 95% specificity could be achieved with the ARG plus L-DOPA and ARG tests only with very low peak GH cut-points (0.25 and 0.21 microg/liter, respectively) and not at all with the L-DOPA test. Although serum IGF-I levels provided less diagnostic discrimination than all five GH stimulation tests, a value below 77.2 microg/liter was 95% specific for GH deficiency. In conclusion, the diagnosis of adult GH deficiency can be made without performing an ITT, provided that test-specific cut-points are used. The ARG plus GHRH test represents an excellent alternative to the ITT for the diagnosis of GH deficiency in adults.

Prospective safety surveillance of GH-deficient adults: comparison of GH-treated vs untreated patients.

CONTEXT: In clinical practice, the safety profile of GH replacement therapy for GH-deficient adults compared with no replacement therapy is unknown. OBJECTIVE: The objective of this study was to compare adverse events (AEs) in GH-deficient adults who were GH-treated with those in GH-deficient adults who did not receive GH replacement. DESIGN AND SETTING: This was a prospective observational study in the setting of US clinical practices. PATIENTS AND OUTCOME MEASURES: AEs were compared between GH-treated (n = 1988) and untreated (n = 442) GH-deficient adults after adjusting for baseline group differences and controlling the false discovery rate. The standardized mortality ratio was calculated using US mortality rates. RESULTS: After a mean follow-up of 2.3 years, there was no significant difference in rates of death, cancer, intracranial tumor growth or recurrence, diabetes, or cardiovascular events in GH-treated compared with untreated patients. The standardized mortality ratio was not increased in either group. Unexpected AEs (GH-treated vs untreated, P ≤ .05) included insomnia (6.4% vs 2.7%), dyspnea (4.2% vs 2.0%), anxiety (3.4% vs 0.9%), sleep apnea (3.3% vs 0.9%), and decreased libido (2.1% vs 0.2%). Some of these AEs were related to baseline risk factors (including obesity and cardiopulmonary disease), higher GH dose, or concomitant GH side effects. CONCLUSIONS: In GH-deficient adults, there was no evidence for a GH treatment effect on death, cancer, intracranial tumor recurrence, diabetes, or cardiovascular events, although the follow-up period was of insufficient duration to be conclusive for these long-term events. The identification of unexpected GH-related AEs reinforces the fact that patient selection and GH dose titration are important to ensure safety of adult GH replacement.

The pivotal role of insulin-like growth factor I in normal mammary development.

Mammary development begins in puberty in response to an estrogen (E(2)) surge. E(2) does not act alone. It relies on pituitary growth hormone (GH) to induce insulin-like growth factor I (IGF-I) production in the mammary stromal compartment. In turn, IGF-I permits E(2) (and progesterone) action. During puberty, E(2) and IGF-I synergize for ductal morphogenesis. During pregnancy, progesterone joins IGF-I and E(2) to stimulate secretory differentiation necessary to produce milk. Prolactin stimulates milk production, while transforming growth factor-ß inhibits proliferation. The orchestrated action of hormones, growth factors, and receptors necessary for mammary development and function are also critical in breast cancer.

Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline.

OBJECTIVE: The aim was to formulate practice guidelines for the diagnosis and treatment of hyperprolactinemia. PARTICIPANTS: The Task Force consisted of Endocrine Society-appointed experts, a methodologist, and a medical writer. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society, The European Society of Endocrinology, and The Pituitary Society reviewed and commented on preliminary drafts of these guidelines. CONCLUSIONS: Practice guidelines are presented for diagnosis and treatment of patients with elevated prolactin levels. These include evidence-based approaches to assessing the cause of hyperprolactinemia, treating drug-induced hyperprolactinemia, and managing prolactinomas in nonpregnant and pregnant subjects. Indications and side effects of therapeutic agents for treating prolactinomas are also presented.

Moderate doses of hGH (0.64 mg/d) improve lipids but not cardiovascular function in GH-deficient adults with normal baseline cardiac function.

CONTEXT: Data regarding effects of lower-dose GH on cardiopulmonary function in GH-deficient (GHD) adults are limited. OBJECTIVES: The objective was to assess effects of lower-dose GH on exercise capacity and echocardiographic parameters in GHD adults. DESIGN: The study was a 6-month double-blind, placebo-controlled randomized trial. SETTING: The study was conducted at the General Clinical Research Center. PARTICIPANTS: Thirty hypopituitary adults with GHD were studied. INTERVENTION: Subjects were randomized to recombinant human GH or placebo for 6 months, followed by open-label recombinant human GH for 12 months. MAIN OUTCOME MEASURES: Primary endpoints were exercise duration, maximal oxygen consumption, and left ventricular ejection fraction. Secondary endpoints were echocardiographic indices of systolic and diastolic function, left ventricular mass, lipids, and body composition. RESULTS: In the 6-month double-blind phase, mean GH dose was 0.64 mg/d. Mean IGF-I sd score increased from -4.5 to -1.0. Exercise duration, maximal oxygen consumption, left ventricular ejection fraction, and other echocardiographic parameters were normal at baseline and did not change. GH decreased total and low-density lipoprotein cholesterol by 7.5% (P = 0.016) and 14.7% (P = 0.002) (P = 0.04 vs. placebo). Mean lean body mass increased by 2.2 kg (P = 0.004), fat mass decreased by 1.7 kg (P = 0.21), and percent body fat decreased by 2.5% (P = 0.018), although between-group changes were not significant. CONCLUSIONS: Human GH did not improve exercise performance or echocardiographic parameters or decrease fat mass but significantly decreased total and low-density lipoprotein cholesterol, increased IGF-I, and increased lean body mass. These results indicate that responses to human GH are variable and should be assessed at baseline and during treatment.

Growth hormone and insulin-like growth factor-I in the transition from normal mammary development to preneoplastic mammary lesions.

Adult female mammary development starts at puberty and is controlled by tightly regulated cross-talk between a group of hormones and growth factors. Although estrogen is the initial driving force and is joined by luteal phase progesterone, both of these hormones require GH-induced IGF-I in the mammary gland in order to act. The same group of hormones, when experimentally perturbed, can lead to development of hyperplastic lesions and increase the chances, or be precursors, of mammary carcinoma. For example, systemic administration of GH or IGF-I causes mammary hyperplasia, and overproduction of IGF-I in transgenic animals can cause the development of usual or atypical hyperplasias and sometimes carcinoma. Although studies have clearly demonstrated the transforming potential of both GH and IGF-I receptor in cell culture and in animals, debate remains as to whether their main role is actually instructive or permissive in progression to cancer in vivo. Genetic imprinting has been shown to occur in precursor lesions as early as atypical hyperplasia in women. Thus, the concept of progression from normal development to cancer through precursor lesions sensitive to hormones and growth factors discussed above is gaining support in humans as well as in animal models. Indeed, elevation of estrogen receptor, GH, IGF-I, and IGF-I receptor during progression suggests a role for these pathways in this process. New agents targeting the GH/IGF-I axis may provide a novel means to block formation and progression of precursor lesions to overt carcinoma. A novel somatostatin analog has recently been shown to prevent mammary development in rats via targeted IGF-I action inhibition at the mammary gland. Similarly, pegvisomant, a GH antagonist, and other IGF-I antagonists such as IGF binding proteins 1 and 5 also block mammary gland development. It is, therefore, possible that inhibition of IGF-I action, or perhaps GH, in the mammary gland may eventually play a role in breast cancer chemoprevention by preventing actions of both estrogen and progesterone, especially in women at extremely high risk for developing breast cancer such as BRCA gene 1 or 2 mutations.

GH peak response to GHRH-arginine: relationship to insulin resistance and other cardiovascular risk factors in a population of adults aged 50-90.

OBJECTIVE: To assess the GH response to GHRH-arginine in apparently healthy adults in relation to cardiovascular risk factors. DESIGN: Cross-sectional. PATIENTS: Eighty-six male and female volunteers aged 50-90. MEASUREMENTS: GH peak response to GHRH-arginine and cardiovascular risk factors, including obesity, insulin resistance, low levels of high density lipoprotein (HDL) cholesterol, elevated triglycerides, and hypertension. The primary outcome measurement was GH response to GHRH-arginine. The relationship between GH peak responses and cardiovascular risk factors was determined after data collection. RESULTS: GH peaks were highly variable, ranging from 2.3 to 185 microg/l (14% with GH peaks < 9 microg/l). An increasing number of cardiovascular risk factors were associated with a lower mean GH peak (P < 0.0001). By univariate analysis, fasting glucose, insulin, body mass index (BMI), HDL cholesterol and triglycerides were significantly associated with GH peak (all P < 0.0001). Multiple regression analysis revealed that fasting glucose, fasting insulin, BMI, triglycerides and sex accounted for 54% of GH peak variability. The role of abdominal fat as it relates to GH peak was explored in a subset of 45 subjects. Trunk fat and abdominal subregion fat measured by dual energy X-ray absorptiometry (DXA) were inversely related to GH peak (P < 0.008 and 0.001, respectively). Analysis of this subgroup by multiple regression revealed that subregion abdominal fat became the significant obesity-related determinant of GH peak, but still lagged behind fasting insulin and glucose. CONCLUSIONS: GH response to secretagogues was highly variable in apparently healthy adults aged 50-90 years. Peak GH was significantly related to fasting glucose, insulin, BMI, HDL cholesterol, triglycerides, trunk fat and abdominal subregion fat, with fasting glucose ranking first by multiple regression analysis. There was a strong relationship between cardiovascular risk factors and low GH, with individual risk factors being additive. Although these data do not differentiate between low GH being a cause or an effect of these cardiovascular risk factors, they indicate that the relationship between low GH and increased cardiovascular risk may be physiologically important in the absence of pituitary disease.