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Epigenetics connects genetic and environmental factors: it includes DNA methylation, histone post-translational modifications and the regulation of chromatin accessibility by non-coding RNAs, all of which control constitutive or inducible gene transcription. This plays a key role in harnessing the transcriptional programs of both innate and adaptive immune cells due to its plasticity and environmental-driven nature, piloting myeloid and lymphoid cell fate decision with no change in their genomic sequence. In particular, epigenetic marks at the site of lineage specific transcription factors and maintenance of cell type-specific epigenetic modifications, referred to as "epigenetic memory", dictate cell differentiation, cytokine production and functional capacity following repeated antigenic exposure in memory T cells. Moreover, metabolic and epigenetic reprogramming occurring during a primary innate immune response leads to enhanced responses to secondary challenges, a phenomenon known as "trained immunity". Here we discuss how stable and dynamic epigenetic states control immune cell identity and plasticity in physiological and pathological conditions. Dissecting the regulatory circuits of cell fate determination and maintenance is of paramount importance for understanding the delicate balance between immune cell activation and tolerance, in healthy conditions and in autoimmune diseases. This article is protected by copyright. All rights reserved.

In vitro culture models were used to characterize the effects of chemotherapeutic drugs and of LH on somatic cells from prepuberal mouse ovaries. All cell types (pre- and granulosa cells, pre-thecal and OSE cells) underwent apoptosis following Epirubicin (0.5μM) exposure for 24hrs (about 60%) and 48hrs (>80%). Cisplatin (10μM) and the Cyclophosphamide active metabolite, Phosphoramide Mustard (10μM), didn't cause apoptosis in 90% of pre-thecal and pre-granulosa cells up to 72hrs of exposure, although they suffered extensive DNA damage and cell cycle arrest, and acquired stress induced premature senescence (SIPS) features. Cultured granulosa cells didn't show evident DNA damage and remained viable without acquiring SIPS features; OSE cells were resistant to apoptosis and SIPS but not to DNA damage. These latter, like pre-thecal and pre-granulosa cells, were able of efficient DNA repair involving MLH1-dependent MMR pathways. SIPS features were also observed in ovary after in vivo treatment with Cisplatin. LH (200mIU/mL) didn't significantly influence apoptosis, SIPS and DNA damage but favoured DNA repair. These results show that somatic cells of prepuberal ovary response to drugs in different ways, either undergoing apoptosis or SIPS, either showing resistance to Cisplatin and Phosphoramide Mustard. Moreover, a new role of LH in promoting DNA repair was shown.

Breast cancer is a heterogeneous disease consisting of different biological subtypes, with differences in terms of incidence, response to diverse treatments, risk of disease progression, and sites of metastases. In the last years, several molecular targets have emerged and new drugs, targeting PI3K/Akt/mTOR and cyclinD/CDK/pRb pathways and tumor microenvironment have been integrated into clinical practice. However, it is clear now that breast cancer is able to develop resistance to these drugs and the identification of the underlying molecular mechanisms is paramount to drive further drug development. Autophagy is a highly conserved homeostatic process that can be activated in response to antineoplastic agents as a cytoprotective mechanism. Inhibition of autophagy could enhance tumor cell death by diverse anti-cancer therapies, representing an attractive approach to control mechanisms of drug resistance. In this manuscript, we present a review of autophagy focusing on its interplay with targeted drugs used for breast cancer treatment.

Purpose: Chemotherapy-induced nausea and vomiting (CINV) is a common adverse event with cancer chemotherapy, despite the availability of effective antiemetic agents. This is a prospective observational study of Italian breast cancer patients treated with anthracycline plus cyclophosphamide (AC), assessed CINV incidence, adherence to national antiemetic guidelines (AIOM 2012), and the relationship with CINV outcomes. Methods: Patients with breast cancer scheduled to receive their first cycle of an AC-based regimen were enrolled at 12 Italian centers and their clinical data prospectively recorded. CINV incidence was assessed from patient diaries after the first chemotherapy cycle. The relationship between guideline adherence and CINV outcomes was examined using multiple logistic regression. Results: The overall incidence rates of nausea and vomiting among 246 evaluable patients were 63.0 and 25.4%, respectively. Most patients received a 5-HT3-RA agent and dexamethasone for acute phase CINV prophylaxis, whereas a triple combination including aprepitant (NK1-RA), consistent with national guidelines, was used in only 45.5% of cases. In the delayed phase, the guideline adherence was 48.8%, while the overall adherence was 43.5%. After adjusting for confounding factors, adherence to antiemetic prophylaxis guidelines was associated with a significant reduction in the odds of three endpoints, namely any nausea, “significant nausea,” and vomiting (OR = 0.49, OR = 0.54, and OR = 0.48, respectively), and a 90% increase in the odds of overall complete protection (OR = 1.90). Conclusions: CINV is still a critical issue in AC-treated patients, despite antiemetic treatment. Non-adherence to antiemetic guidelines may lead to poorer outcomes and indicates the need for strategies to enhance the use of guidelines in clinical practice.

PURPOSE: The introduction of CDK4/6 inhibitors plus endocrine therapy (ET) represents the most relevant advance in the management of HR-positive/HER2-negative metastatic breast cancer. We carried out a meta-analysis of randomized controlled trials (RCTs) with the aims of better characterising the efficacy of CDK4/6 inhibitors in some relevant subgroups and of testing heterogeneity between different compounds with particular focus on their ability to improve OS. METHODS: We performed a systematic literature search to identify phase II/III RCTs of CDK4/6 inhibitors plus ET in AI-sensitive and AI-resistant patients. Pooled estimates of HRs were computed for PFS, OS and ORR analysis, by using both a fixed and random effect model. Predefined subgroup analyses were performed to better understand treatment effect concerning specific patients’ characteristics. Pooled survival curves were generated by pooling the data of all trials. RESULTS: 8 RCTs were included. Adding a CDK4/6 inhibitors to ET is beneficial in terms of PFS irrespective of the presence or not of visceral metastases, the number of metastatic sites, and the length of the TFI. The addition of CDK4/6 inhibitors significantly improves OS in AI-sensitive (HR 0.75, 95%CI [0.63-0.89]) and AI-resistant patients (HR 0.77, 95%CI [0.67-0.89]). Pooled data from each single drug show that Palbociclib remains the only class member not showing a statistically significant HR for OS (HR 0.83, 95% CI [0.68-1.02]). CONCLUSION: Our meta-analysis confirms the efficacy of CDK4/6 inhibitors overall and in major patients subgroups, supporting the use of CDK4/6 inhibitors plus ET as standard treatment for most HR+ MBC patients.

Premature ovarian failure and female infertility are frequent side effects of anticancer therapies, owing to the extreme sensitivity of the ovarian reserve oocytes to the damaging effects of irradiation and chemotherapy on DNA. We report here a robust protective effect of luteinizing hormone (LH) on the primordial follicle pool of prepubertal ovaries against the cisplatin (Cs)-induced apoptosis. In vitro LH treatment of prepubertal ovarian fragments generated anti-apoptotic signals by a subset of ovarian somatic cells expressing LH receptor (LHR) through cAMP/PKA and Akt pathways. Such signals, reducing the oocyte level of pro-apoptotic TAp63 protein and favoring the repair of the Cs-damaged DNA in the oocytes, prevented their apoptosis. Noteworthy, in vivo administration to prepubertal female mice of a single dose of LH together with Cs inhibited the depletion of the primordial follicle reserve caused by the drug and preserved their fertility in reproductive age, preventing significant alteration in the number of pregnancy and of delivered pups. In conclusion, these findings establish a novel ovoprotective role for LH and further support the very attracting prospective to use physiological 'fertoprotective' approaches for preventing premature infertility and risks linked to precocious menopause in young patients who survived cancer after chemotherapy.

The introduction of CDK4/6 inhibitors in combination with endocrine therapy (ET) represents the most relevant advance in the management of hormone receptor (HR) positive, HER2-negative metastatic breast cancer over the last few years. This meta-analysis of randomized controlled trials (RCTs) is aimed to better characterize the efficacy of CDK4/6 inhibitors in some relevant subgroups and to test heterogeneity between different compounds with a particular focus on their ability to improve overall survival (OS). Pooled estimates of hazard ratios (HRs) were computed for progression-free survival (PFS), OS, and objective response rate (ORR) analysis in predefined subgroups to better understand treatment effect concerning specific patients’ characteristics. To estimate the absolute benefit in terms of PFS, pooled survival curves were generated by pooling the data of all trials. A total of eight RCTs were included. Adding a CDK4/6 inhibitor to ET is beneficial in terms of PFS, irrespective of the presence or not of visceral metastases, the number of metastatic sites, and the length of the treatment-free interval (TFI). The addition of CDK4/6 inhibitors produces a significant OS improvement, both in aromatase inhibitor (AI)-sensitive (HR 0.75, 95% CI) and AI-resistant patients (HR 0.77, 95% CI [0.67–0.89]). Pooled data from each single drug show that palbociclib remains the only class member not showing a statistically significant HR for OS (HR 0.83, 95% CI [0.68–1.02]).

Aim The aim of the study is to analyse whether letrozole (L) and zoledronic acid plus L (ZL) are more effective than tamoxifen (T) as adjuvant endocrine treatment of premenopausal patients with breast cancer with hormone receptor–positive (HR+) tumours. Patients and methods In a phase 3 trial, 1065 premenopausal patients with HR + early breast cancer received triptorelin to suppress ovarian function and were randomly assigned (1:1:1) to adjuvant T, L or ZL for 5 years. Cancer recurrence, second breast or non-breast cancer and death were considered events for the intention-to-treat disease-free survival (DFS) analysis. Results With a 64-month median follow-up and 134 reported events, the disease-free rate at 5 years was 85.4%, 93.2% and 93.3% with T, L and ZL, respectively (overall P = 0.008). The hazard ratio for a DFS event was 0.52 (95% confidence interval [CI], 0.34 to 0.80; P = 0.003) with ZL vs T, 0.72 (95% CI, 0.48 to 1.07; P = 0.06) with L vs T and 0.70 (95% CI, 0.44 to 1.12; P = 0.22) with ZL vs L. With 36 deaths, there was no significant difference in overall survival (P = 0.14). Treatment was stopped for toxicity or refusal in 7.3%, 7.3% and 16.6% patients, and in the safety population, grade 3–4 side-effects were reported in 4.2%, 6.9% and 9.1% patients treated with T, L or ZL, respectively. Conclusion HOBOE study shows that in premenopausal patients with early breast cancer undergoing ovarian function suppression with triptorelin, ZL significantly improves DFS, while worsening compliance and toxicity, as compared with T. ( NCT00412022 )

Objective To study the role of recombinant human LH supplementation in women with hypo-response to ovarian stimulation. Methods We performed a systematic review and meta-analysis of prospective clinical trials in which recombinant FSH monotherapy protocols were compared with LH-supplemented protocols in hypo-responders. A search was conducted of the Scopus, MEDLINE databases without time or language restrictions. Primary outcome was clinical pregnancy rate. Results Significantly higher clinical pregnancy rates (odds ratio: 2.03, P = 0.003), implantation rates (odds ratio: 2.62, P = 0.004) and number of oocytes retrieved (weight mean differences: 1.98, P = 0.03) were observed in hypo-responders supplemented with recombinant LH versus hypo-responders who underwent FSH monotherapy. No differences in terms of mature oocytes or miscarriage rates were found between the two groups. Conclusion In conclusion, our analysis confirms that women with a hypo-response to exogenous gonadotropins might benefit from LH supplementation. However, more trials are required before a definitive conclusion can be drawn. Electronic supplementary material The online version of this article (10.1186/s12958-019-0460-4) contains supplementary material, which is available to authorized users.

Background: Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer. Methods: FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery, any pathological tumour size, and axillary nodal status. Key exclusion criteria were hormone replacement therapy, recurrent or metastatic disease, previous treatment with tamoxifen, and another malignancy in the previous 10 years. Patients were randomly assigned in an equal ratio to one of six treatment groups: oral anastrozole (1 mg per day), exemestane (25 mg per day), or letrozole (2·5 mg per day) tablets upfront for 5 years (upfront strategy) or oral tamoxifen (20 mg per day) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years (switch strategy). Randomisation was done by a computerised minimisation procedure stratified for oestrogen receptor, progesterone receptor, and HER2 status; previous chemotherapy; and pathological nodal status. Neither the patients nor the physicians were masked to treatment allocation. The primary endpoint was disease-free survival. The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2% difference in disease-free survival at 5 years. Primary efficacy analyses were done by intention to treat; safety analyses included all patients for whom at least one safety case report form had been completed. Follow-up is ongoing. This trial is registered with the European Clinical Trials Database, number 2006-004018-42, and ClinicalTrials.gov, number NCT00541086. Findings: Between March 9, 2007, and July 31, 2012, 3697 patients were enrolled into the study. After a median follow-up of 60 months (IQR 46–72), 401 disease-free survival events were reported, including 211 (11%) of 1850 patients allocated to the switch strategy and 190 (10%) of 1847 patients allocated to upfront treatment. 5-year disease-free survival was 88·5% (95% CI 86·7–90·0) with the switch strategy and 89·8% (88·2–91·2) with upfront treatment (hazard ratio 0·89, 95% CI 0·73–1·08; p=0·23). 5-year disease-free survival was 90·0% (95% CI 87·9–91·7) with anastrozole (124 events), 88·0% (85·8–89·9) with exemestane (148 events), and 89·4% (87·3 to 91·1) with letrozole (129 events; p=0·24). No unexpected serious adverse reactions or treatment-related deaths occurred. Musculoskeletal side-effects were the most frequent grade 3–4 events, reported in 130 (7%) of 1761 patients who received the switch strategy and 128 (7%) of 1766 patients who received upfront treatment. Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule (924 [52%] of 1766 patients vs 745 [42%] of 1761 patients). All other grade 3–4 adverse events occurred in less than 2% of patients in either group. Interpretation: 5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors. None of the three aromatase inhibitors was superior to the others in terms of efficacy. Therefore, patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting. Funding: Italian Drug Agency.

Premature ovarian failure and female infertility are frequent side effects of anticancer therapies, owing to the extreme sensitivity of the ovarian reserve oocytes to the damaging effects of irradiation and chemotherapy on DNA. We report here a robust protective effect of luteinizing hormone (LH) on the primordial follicle pool of prepubertal ovaries against the cisplatin (Cs)-induced apoptosis. In vitro LH treatment of prepubertal ovarian fragments generated anti-apoptotic signals by a subset of ovarian somatic cells expressing LH receptor (LHR) through cAMP/PKA and Akt pathways. Such signals, reducing the oocyte level of pro-apoptotic TAp63 protein and favoring the repair of the Cs-damaged DNA in the oocytes, prevented their apoptosis. Noteworthy, in vivo administration to prepubertal female mice of a single dose of LH together with Cs inhibited the depletion of the primordial follicle reserve caused by the drug and preserved their fertility in reproductive age, preventing significant alteration in the number of pregnancy and of delivered pups. In conclusion, these findings establish a novel ovoprotective role for LH and further support the very attracting prospective to use physiological 'fertoprotective' approaches for preventing premature infertility and risks linked to precocious menopause in young patients who survived cancer after chemotherapy.

e12654Background: Standard preoperative systemic therapy for HER2+ breast cancer (BC) patients (pts) includes chemotherapy (CT) and Trastuzumab (T). Two randomized phase II trials, NeoSphere and TR...

Purpose To compare the endocrine effects of 6 months of adjuvant treatment with letrozole + triptorelin or tamoxifen + triptorelin in premenopausal patients with early breast cancer within an ongoing phase 3 trial (Hormonal Adjuvant Treatment Bone Effects study). Patients and Methods Prospectively collected hormonal data were available for 81 premenopausal women, of whom 30 were assigned to receive tamoxifen + triptorelin and 51 were assigned letrozole + triptorelin ± zoledronate. Serum 17-β-estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), Δ4-androstenedione, testosterone, dehydroepiandrosterone-sulfate, progesterone, adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline and after 6 months of treatment. For each hormone, 6-month values were compared between treatment groups by the Wilcoxon-Mann-Whitney exact test. Results Median age was 44 years for both groups of patients. Letrozole + triptorelin (± zoledronate) induced a stronger suppression of median E2 serum levels (P = .0008), LH levels (P = .0005), and cortisol serum levels (P < .0001) compared with tamoxifen + triptorelin. Median FSH serum levels were suppressed in both groups, but such suppression was lower among patients receiving letrozole, who showed significantly higher median FSH serum levels (P < .0001). No significant differences were observed for testosterone, progesterone, ACTH, androstenedione, and dehydroepiandrosterone between the two groups of patients. Conclusion Letrozole in combination with triptorelin induces a more intense estrogen suppression than tamoxifen + triptorelin in premenopausal patients with early breast cancer.

The aim of this study was to evaluate the effect of acute human corticotropin (ACTH)-releasing hormone (CRH) administration (100 micrograms, as i.v. bolus) on tumor necrosis factor-alpha (TNF alpha) levels in the inferior petrosal sinuses and in the peripheral blood of 7 patients with Cushing's disease subjected to diagnostic inferior petrosal sinus sampling. Blood samples for ACTH, beta-endorphin (beta-EPH) and TNF alpha were collected from inferior petrosal sinuses and periphery simultaneously. In addition, TNF alpha concentrations were measured after CRH administration (10 nmol/l, 100 nmol/l and 1 mumol/l) in culture medium from primary cultures obtained in 3 of 7 patients. At baseline, plasma ACTH and beta-EPH levels were significantly higher in the inferior petrosal sinus ipsilateral to the ACTH-secreting adenoma than in the contralateral one and in the periphery (p < 0.001) whereas no significant difference was found as far as serum TNF alpha levels were concerned. CRH administration caused a significant increase of ACTH (p < 0.001), beta-EPH (p < 0.01) and TNF alpha (p < 0.01) levels greater in the ipsilateral inferior petrosal sinus than in the contralateral one and in the periphery. In addition, CRH increased ACTH, beta-EPH and TNF alpha levels in the culture medium of three ACTH-secreting tumors at the doses of 100 nmol/l and 1 mumol/l (greater than 300, 200 and 110% of baseline pretreatment incubation levels, respectively). These data suggest that CRH may increase TNF alpha concentrations in the inferior petrosal sinus ipsilateral to the ACTH-secreting adenoma and in the peripheral blood as well. In addition, it stimulated TNF alpha release both in vivo and in vitro. These findings suggest the possibility that an imbalanced intrapituitary TNF alpha production can be detected in ACTH-secreting adenomas.

Background To evaluate whether weekly schedules of docetaxel-based chemotherapy were superior to 3-weekly ones in terms of quality of life in locally advanced or metastatic breast cancer. Methods Patients with locally advanced or metastatic breast cancer, aged ≤ 70 years, performance status 0-2, chemotherapy-naive for metastatic disease, were eligible. They were randomized to weekly or 3-weekly combination of docetaxel and epirubicin, if they were not treated with adjuvant anthracyclines, or docetaxel and capecitabine, if treated with adjuvant anthracyclines. Primary end-point was global quality of life change at 6-weeks, measured by EORTC QLQ-C30. With two-sided alpha 0.05 and 80% power for 35% effect size, 130 patients per arm were needed. Results From February 2004 to March 2008, 139 patients were randomized, 70 to weekly and 69 to 3-weekly arm; 129 and 89 patients filled baseline and 6-week questionnaires, respectively. Global quality of life was better in the 3-weekly arm (p = 0.03); patients treated with weekly schedules presented a significantly worsening in role functioning and financial scores (p = 0.02 and p < 0.001). Neutropenia and stomatitis were worse in the 3-weekly arm, where two toxic deaths were observed. Overall response rate was 39.1% and 33.3% in 3-weekly and weekly arms; hazard ratio of progression was 1.29 (95% CI: 0.84-1.97) and hazard ratio of death was 1.38 (95% CI: 0.82-2.30) in the weekly arm. Conclusions In this trial, the weekly schedules of docetaxel-based chemotherapy appear to be inferior to the 3-weekly one in terms of quality of life in patients with locally advanced or metastatic breast cancer. Trial registration ClinicalTrials.gov NCT00540800.

Purpose We compared the endocrine effects of 6 and 12 months of adjuvant letrozole versus tamoxifen in postmenopausal patients with hormone-responsive early breast cancer within an ongoing phase III trial. Patients and Methods Patients were randomly assigned to receive tamoxifen, letrozole, or letrozole plus zoledronic acid. Serum values of estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, dehydroepiandrosterone-sulphate (DHEA-S), progesterone, and cortisol were measured at baseline and after 6 and 12 months of treatment. For each hormone, changes from baseline at 6 and 12 months were compared between treatment groups, and differences over time for each group were analyzed. Results Hormonal data were available for 139 postmenopausal patients with a median age of 62 years, with 43 patients assigned to tamoxifen and 96 patients assigned to letrozole alone or combined with zoledronic acid. Baseline values were similar between the two groups for all hormones. Many significant changes were observed between drugs and for each drug over time. Namely, three hormones seemed significantly affected by one drug only: estradiol that decreased and progesterone that increased with letrozole and cortisol that increased with tamoxifen. Both drugs affected FSH (decreasing with tamoxifen and slightly increasing with letrozole), LH (decreasing more with tamoxifen than with letrozole), testosterone (slightly increasing with letrozole but not enough to differ from tamoxifen), and DHEA-S (increasing with both drugs but not differently between them). Zoledronic acid did not have significant impact on hormonal levels. Conclusion Adjuvant letrozole and tamoxifen result in significantly distinct endocrine effects. Such differences can explain the higher efficacy of letrozole as compared with tamoxifen.

OBJECTIVE: To compare the molecular, histological, and functional characteristics of growth hormone (GH)- and pressure overload-induced cardiac hypertrophy, and their responses to ischemia-reperfusion and mechanical stretch. DESIGN: Four groups of male Wistar rats were studied: aortic banding (n=24, AB) or sham (n=24, controls) for 10 weeks, and GH treatment (n=24; 3.5mg/kg/day, GH) or placebo (n=24, controls) for 4 weeks. At 13 weeks, the rats were randomly subjected to: (i) assessment of basal left ventricular mRNA expression of sarcoplasmic reticulum calcium-ATPase (SERCA-2), phospholamban (PLB), and Na(+)-Ca(2+) exchanger (NCX) and collagen volume fraction (CVF) (Protocol A, 8 rats in each group); (ii) left ventricular no-flow ischemia with simultaneous evaluation of intracellular Ca(2+) handling and ATP, phosphocreatine (PCr) and inorganic phosphate (Pi) content (Protocol B, 12 rats in each group); or (iii) left ventricular mechanical stretch for 40 min with assessment of tumor necrosis-alpha (TNF-alpha) mRNA (Protocol C, 4 rats in each group). Protocol B and C were carried out in a Langendorff apparatus. RESULTS: In Protocol A, no difference was found as to myocardial mRNA content of Ca(2+) regulating proteins and CVF in GH animals vs controls. In contrast, in the AB group, myocardial mRNA expression of SERCA-2 and PLB was downregulated while that of NCX and CVF were increased vs. controls (p

Background —The reason why patients with growth hormone (GH) deficiency (GHD) are at increased risk for premature cardiovascular death is still unclear. Although a variety of vascular risk factors have been identified in GHD, little is known regarding vascular reactivity and its contribution to premature arteriosclerosis. Methods and Results —We assessed vascular function in 7 childhood-onset, GH-deficient nontreated patients (age 22±3 years, body mass index [BMI] 25±1 kg/m 2 ) and 10 healthy subjects (age 24±0.4 years, BMI 22±1 kg/m 2 ) by using strain gauge plethysmography to measure forearm blood flow in response to vasodilatory agents. The increase in forearm blood flow to intrabrachial infusion of the endothelium-dependent vasodilator acetylcholine was significantly lower in GH-deficient nontreated patients than in control subjects ( P P P P 2 ) who were receiving stable GH replacement therapy. In these patients, the response to both endothelium-dependent and -independent vasodilators, as well as forearm nitrite and cGMP, release was not different from that observed in normal subjects. Peak hyperemic response to 5-minute forearm ischemia was significantly reduced in GH-deficient nontreated patients (17.2±2.6 mL · dL −1 · min −1 , P −1 · min −1 ) compared with normal subjects (29.5±3.2 mL · dL −1 · min −1 ). Conclusions —The data support the concept that GH plays an important role in the maintenance of a normal vascular function in humans.

OBJECTIVE: The impairment of heart structure and function in adults with childhood onset GH deficiency has been recently described. However, previous echocardiographic studies have reported no differences in cardiac mass and function between adulthood onset GH deficient patients and healthy subjects. DESIGN: The aim of this study was to evaluate cardiac performance in adult patients with childhood and adulthood onset GH deficiency, using equilibrium radionuclide angiography, a method more accurate than echocardiography. PATIENTS: Eleven patients with childhood onset GH deficiency, 9 patients with adulthood onset GH deficiency and 12 age-, gender-, height- and weight-matched healthy subjects entered the study. MEASUREMENTS: All the study population underwent equilibrium radionuclide angiography at rest and during physical exercise. RESULTS: Both childhood and adulthood onset GH deficient patients had an impaired left ventricular systolic performance both at rest (ejection fraction was 55 +/- 6%, 55 +/- 10% and 66 +/- 6% in childhood and adulthood onset GH deficient patients and control group, respectively; P < 0.0001) and during physical exercise (ejection fraction was 54 +/- 9% in childhood onset GH deficient patients, 53 +/- 9% in adulthood onset GH deficient patients and 76 +/- 7% in normal subjects; P < 0.0001). Peak ejection rate was 3.2 +/- 0.8 end-diastolic volume/second, 3.0 +/- 0.6 end-diastolic volume/second and 3.9 +/- 0.8 end-diastolic volume/ second in childhood and adulthood onset GH deficient patients and control group, respectively (P < 0.01). Exercise-induced changes in end-systolic volume were increased in both groups of patients compared with healthy subjects. In contrast, exercise-induced end-diastolic volume changes were not different between GH deficient patients and controls. Resting peak filling rate was 2.6 +/- 0.7 end-diastolic volume/second, 2.5 +/- 0.7 end-diastolic volume/ second and 3.1 +/- 0.3 end-diastolic volume/second in the 2 groups of patients and healthy subjects, respectively (P < 0.05). Reduced exercise tolerance in all patients, as shown by the significantly lower values of peak workload (P < 0.0001), peak rate-pressure product (P < 0.01) and exercise duration (P < 0.0001) was observed. CONCLUSION: Patients affected by GH deficiency have left ventricular systolic dysfunction at rest and during physical exercise, suggesting that GH plays a physiological role in maintaining normal cardiac performance in humans. Furthermore, no difference between childhood and adulthood onset GH deficient patients was found indicating that both group of patients have an impairment of cardiac function.

An isovolumic normal rat heart Langendorff model was used to examine the effects of moderate (15 mmHg) and severe (35 mmHg) mechanical stretch on the time course (from 0 to 60 min) of myocardial expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and insulin-like growth factor (IGF)-1 and their cognate receptors. After 10 min of moderate stretch, TNF-alpha was de novo expressed, whereas constitutive IL-6 and IGF-1 levels were slightly upregulated; no further changes occurred up to 60 min. In comparison, severe stretch resulted in a higher and progressive increase in TNF-alpha, IL-6, and IGF-1 expression up to 20 min. After 20 min, whereas TNF-alpha expression further increased, IL-6 and IGF-1 levels progressively reduced to values lower than those observed under moderate stretch and in unstretched (5 mmHg) control myocardium (IL-6). Mechanical stretch did not significantly alter the expression of the cognate receptors. Indeed, the TNF-alpha receptor (p55) tended to be progressively upregulated under severe stretch over time. The current data provide the first demonstration that TNF-alpha, IL-6, and IGF-1 ligand-receptor systems are differentially expressed within the normal rat myocardium in response to graded mechanical stretch. Such findings may have potential implications with regard to compensatory hypertrophy and failure.