Association between biochemical control and comorbidities in patients with acromegaly: an Italian longitudinal retrospective chart review study.

PURPOSE: Achieving biochemical control (normalization of insulin-like growth factor-1 [IGF-1] and growth hormone [GH]) is a key goal in acromegaly management. However, IGF-1 and GH fluctuate over time. The true potential impact of time-varying biochemical control status on comorbidities is unclear and relies on multiple, longitudinal IGF-1 and GH measurements. This study assessed the association between time-varying biochemical control status and onset of selected comorbidities in patients with acromegaly. METHODS: Medical charts of adults with confirmed acromegaly and ≥ 6 months of follow-up at an Italian endocrinology center were reviewed. Patients were followed from the first diagnosis of acromegaly at the center until loss to follow-up, chart abstraction, or death. Biochemical control status was assessed annually and defined as IGF-1 ≤ the upper limit of normal, or GH ≤ 2.5 µg/L in the few cases where IGF-1 was unavailable. Time-varying Cox models were used to assess the association between biochemical control status and comorbidities. RESULTS: Among 150 patients, 47% were female, average age at diagnosis was 43.1, and mean length of follow-up was 10.4 years. Biochemical control was significantly associated with a lower hazard of diabetes (HR = 0.36, 95% CI 0.15; 0.83) and cardiovascular system disorders (HR = 0.54, 95% CI 0.31; 0.93), and a higher hazard of certain types of arthropathy (HR = 1.68, 95% CI 1.04; 2.71); associations for other comorbidities did not reach statistical significance. CONCLUSION: Results further support the importance of achieving biochemical control, as this may reduce the risk of high-burden conditions, including diabetes and cardiovascular system disorders. The association for arthropathy suggests irreversibility of this impairment. Due to limitations, caution is required when interpreting these results.

Circulating endothelial progenitor cells in acromegaly.

BACKGROUND: Endothelial progenitor cells (EPCs), involved in the repairing mechanisms of vascular damage, are positively correlated to insulin-like growth factor I (IGF-I) concentrations in healthy adults. However, the levels of EPCs and their role in acromegalic patients have never been investigated. AIM: We conducted a cross-sectional study in order to assess the levels of the different phenotypes of circulating EPC in acromegalic patients. SUBJECTS AND METHODS: The study was performed at the Endocrinology Unit of Federico II University and at the Unit of Metabolic Diseases and Endocrinology of the Second University of Naples. Fifty-five acromegalic patients and 65 healthy controls were studied. EPCs were assessed by flow cytometry and IGF-I by immunoradiometric assay. RESULTS: Compared with subjects of the control group, acromegalic patients showed significantly higher levels of EPCs phenotypes expressing KDR antigen [KDR+, cells per 106 events, median and interquartile range, 44 (28-67) vs 23 (13-40), p=0.006; CD34+KDR+ 25 (18-38) vs 12 (8-17), p<0.001; CD133+KDR+ 17 (13-30) vs 8 (6-12), p<0.001; CD34+KDR+CD133+ 16 (12-25) vs 8 (6-10), p<0.001]. There was a positive correlations between CD34+KDR+CD133+ cells count and IGF-I in acromegaly group (r=0.79, p<0.001). CONCLUSIONS: Acromegalic patients show higher circulating EPCs levels expressing KDR, positively correlated with IGF-I, suggesting a role for IGF-I in regulating the expression of this surface marker in the early phase of EPCs differentiation.

The cardiovascular system in growth hormone excess and growth hormone deficiency.

The clinical conditions associated with GH excess and GH deficiency (GHD) are known to be associated with an increased risk for the cardiovascular morbidity and mortality, suggesting that either an excess or a deficiency in GH and/or IGF-I is deleterious for cardiovascular system. In patients with acromegaly, chronic GH and IGF-I excess commonly causes a specific cardiomyopathy characterized by a concentric cardiac hypertrophy associated with diastolic dysfunction and, in later stages, with systolic dysfunction ending in heart failure if GH/IGF-I excess is not controlled. Abnormalities of cardiac rhythm and anomalies of cardiac valves can also occur. Moreover, the increased prevalence of cardiovascular risk factors, such as hypertension, diabetes mellitus, and insulin resistance, as well as dyslipidemia, confer an increased risk for vascular atherosclerosis. Successful control of the disease is accompanied by a decrease of the cardiac mass and improvement of cardiac function and an improvement in cardiovascular risk factors. In patients with hypopituitarism, GHD has been considered the under- lying factor of the increased mortality when appropriate standard replacement of the pituitary hormones deficiencies is given. Either childhood-onset or adulthood-onset GHD are characterized by a cluster of abnormalities associated with an increased cardiovascular risk, including altered body composition, unfavorable lipid profile, insulin resistance, endothelial dysfunction and vascular atherosclerosis, a decrease in cardiac mass together with an impairment of systolic function mainly after exercise. Treatment with recombinant GH in patients with GHD is followed by an improvement of the cardiovascular risk factors and an increase in cardiac mass together with an improvement in cardiac performance. In conclusion, acromegaly and GHD are associated with an increased risk for cardiovascular morbidity and mortality, but the control of GH/IGF-I secretion reverses cardiovascular abnormalities and restores the normal life expectancy.

Growth hormone, prolactin, and sexuality.

GH and PRL, although not considered as 'classical' sexual hormones, could play a role in the endocrine control of sexual function both in men and women. Physiologically, PRL seems to be involved in the central control of sexual behavior and activity, by modulating mainly the effects of dopaminergic and serotoninergic systems on sexual function. Indeed, circulating PRL levels increase after orgasm and may potentially play a role in the acute regulation of further sexual arousal following orgasm both in men and women. On the other hand, either short-term or long-term PRL increase can modulate central nervous system areas involved in the control of sexual function and, peripherally, can directly influence mechanisms of penile erection in men, and presently only as an hypothesis, mechanisms related to the sexual response of genitalia in women. Furthermore, chronic hyperprolactinemia is classically associated with hypogonadotropic hypogonadism and sexual dysfunction in both sexes. Successful treatment of chronic hyperprolactinemia generally restores normal sexual function both in men and women although this effect is not only related to relapse of gonadal function. Hypoprolactinemia is recently recognised as a possible risk factor of arteriogenic erectile dysfunction while a possible role on female sexual function is not known. The physiological role of GH on sexual function is not fully elucidated. GH is an important regulator of hypothalamuspituitary- gonadal axis and seems to participate in the regulation of the sexual response of genitalia in men, and potentially also in women. Sexual function in men and women with GH deficiency (GHD) and GH excess, particularly in acromegaly, is scantily studied and GH- or IGF-I-dependent effects are difficult to quantify. Nevertheless, a decrease of desire and arousability both in men and women, together with an impairment of erectile function in men, have been described both in patients with GHD and acromegaly, although it is not clear whether they are dependent directly on the hormone defect or excess or they are consequence of the hypogonadism or the different clinical complications or the physical disfigurement and psychological imbalance, which are associated with the diseases, and are potentially affecting sexual function. Data on beneficial effects of GH replacement therapy and specific surgical or pharmacological approach for acromegaly are far to be fully elucidated although restoring normal GH/IGF-I levels have been associated to improvement of sexual function.

Growth hormone, prolactin, and sexuality.

GH and PRL, although not considered as 'classi cal' sexual hormones, could play a role in the endocrine control of sexual function both in men and women. Physiologically, PRL seems to be involved in the central control of sexual behavior and activity, by modulating mainly the effects of dopaminergic and serotoninergic systems on sexual function. Indeed, circulating PRL levels increase after orgasm and may potentially play a role in the acute regulation of further sexual arousal following orgasm both in men and women. On the other hand, either short-term or long-term PRL in crease can modulate central nervous system areas involved in the control of sexual function and, peripherally, can directly influence mechanisms of penile erection in men, and presently only as an hypothesis, mechanisms related to the sexual response of genitalia in women. Furthermore, chronic hyperprolactinemia is classically associated with hypogonadotropic hypogonadism and sexual dysfunction in both sexes. Successful treatment of chronic hyperprolactinemia generally restores normal sexual function both in men and women although this effect is not only related to relapse of gonadal function. Hypoprolactinemia is recently recognised as a possible risk factor of arteriogenic erectile dysfunction while a possible role on female sexual function is not known. The physiological role of GH on sexual function is not fully elucidated. GH is an important regulator of hypothalamus-pituitary-gonadal axis and seems to participate in the regulation of the sexual response of genitalia in men, and potentially also in women. Sexual function in men and women with GH deficiency (GHD) and GH excess, particularly in acromegaly, is scantily studied and GH- or IGF-I-dependent effects are difficult to quantify. Nevertheless, a decrease of desire and arousability both in men and women, together with an impairment of erectile function in men, have been described both in patients with GHD and acromegaly, although it is not clear whether they are dependent directly on the hormone defect or excess or they are consequence of the hypogonadism or the different clinical complications or the physical disfigurement and psychological imbalance, which are associated with the diseases, and are potentially affecting sexual function. Data on beneficial effects of GH replacement therapy and specific surgical or pharmacological approach for acromegaly are far to be fully elucidated although restoring normal GH/IGF-I levels have been associated to improvement of sexual function.

Possible protective role of metformin therapy on colonic polyps in acromegaly: an exploratory cross-sectional study.

CONTEXT: Colonic polyps occur in 30-40% of acromegalic patients, increasing the risk of colon carcinoma. Although debated, there is emerging evidence that metformin may play a protective role in diabetic and non-diabetic patients with colonic polyps and its use in chemoprevention is currently explored. OBJECTIVE: Evaluate the prevalence of colonic polyps in acromegalic patients treated or not with metformin and explore its possible protective role. DESIGN: Exploratory cross-sectional study in two tertiary Italian referral centres. MET: hods: Out of 153 acromegalic patients, we selected 58 patients (36-82 years; f: 33) who had at least one colonoscopy performed within the first 2 years of diagnosis. Presence of colonic polyps/cancer and related risk factors, current metformin and acetylsalicylic acid intake, disease duration, therapies for acromegaly, hormonal and metabolic parameters were assessed. RESULTS: An overall prevalence of 36% polyps was found. Based on the presence of polyps, we identified two groups, comparable for age, BMI, disease duration, glucose, insulin, HOMA-IR, HbA1c, GH and IGF-I levels. Of the patients with polyps (including three adenocarcinomas) only 24% were treated with metformin vs 57% of patients without polyps. Multivariate analysis confirmed a significant negative association between colonic polyps and metformin intake (OR: 0.22, 95% CI: 0.06-0.77, P = 0.01), whereas no significant association was found between polyps and age (P = 0.10), overweight/obesity (P = 0.54), smoking (P = 0.15), acetylsalicylic acid intake (P = 0.99), disease duration (P = 0.96), somatostatin analogues treatment (P = 0.70). CONCLUSIONS: These findings, though deriving from an exploratory study, could suggest a protective role of metformin on the development of colonic polyps in acromegaly, and need to be confirmed in an extended study population.

Evaluation of the retinal nerve fibre layer and ganglion cell complex thickness in pituitary macroadenomas without optic chiasmal compression.

PURPOSE: The aim of this prospective study was to measure the thickness of the circumpapillary retinal nerve fibre layer (cpRNFL) and the ganglion cell complex (GCC) using spectral domain optical coherence tomography (SD-OCT) in a cohort of consecutive de novo patients with pituitary macroadenomas without chiasmal compression. PATIENTS AND METHODS: Twenty-two consecutive patients with pituitary macroadenoma without chiasmal compression (16 men, 6 women, aged 45.2±14.6 years, 43 eyes) entered the study between September 2011 and June 2013. Among them, 31.8% harboured a growth hormone-secreting pituitary adenoma, 27.3% a prolactin-secreting pituitary adenoma, 27.3% a corticotrophin-secreting pituitary adenoma, and 13.6% a non-secreting pituitary tumour. Eighteen subjects (nine females, nine males, mean age 36.47±6.37 years; 33 eyes) without pituitary adenoma, with normal ophthalmic examination, served as controls. In both patients and controls, cpRNFL and GCC thicknesses were measured by SD-OCT. RESULTS: Patients were significantly older (P=0.02) than controls. Best corrected visual acuity, intraocular pressure, colour fundus photography, and automatic perimetry test were within the normal range in patients and controls. Conversely, cpRNFL (P=0.009) and GCC (P<0.0001) were significantly thinner in patients than in controls. The average GCC (r=0.306, P=0.046) significantly correlated with the presence of arterial hypertension. OCT parameters did not differ significantly between patients with a tumour volume above the median and those with a tumour volume below the median. CONCLUSION: Pituitary macroadenomas, even in the absence of chiasmal compression, may induce GCC and retinal nerve fibre layer thinning. SD-OCT may have a role in the early diagnosis and management of patients with pituitary tumours.

The metabolic profile in active acromegaly is gender-specific.

CONTEXT: The sexual dimorphism of the somatotroph axis has been documented, but whether the acromegaly-related metabolic alterations are gender-dependent has never been investigated. OBJECTIVE: The aim of the study was to evaluate the impact of gender on the metabolic parameters in acromegaly. DESIGN: We conducted a retrospective, comparative, multicenter study. PATIENTS: The 307 newly diagnosed acromegalic patients included in the study were grouped by gender: 157 men (aged 48.01 ± 14.28 yr), and 150 women (aged 48.67 ± 14.95 yr; of which 77 were premenopausal and 73 postmenopausal). OUTCOME MEASUREMENTS: We measured each component of the metabolic syndrome (MS), hemoglobin A1c, the areas under the curve (AUCs) of glucose and insulin during 2-h oral glucose tolerance test, basal insulin resistance using the homeostasis model assessment of the insulin resistance index, stimulated insulin sensitivity using the insulin sensitivity index, early insulin-secretion rate using the insulinogenic index, ß-cell function relative to insulin sensitivity using the oral disposition index and the visceral adiposity index (VAI) as the surrogate of visceral fat function. RESULTS: Women showed a higher prevalence of MS (P < 0.001), higher fasting insulin levels (P < 0.001), AUC for insulin (P = 0.002), homeostasis model assessment of the insulin resistance index (P < 0.001), and VAI (P < 0.001) and a lower insulin sensitivity index (P = 0.002) than men, whereas no difference was found in fasting glucose, AUC for glucose, hemoglobin A1c, insulinogenic index, and oral disposition index. In women, fasting glucose and fasting insulin showed a significant trend toward increase (P < 0.001) and decrease (P = 0.004), respectively, from the first to the fourth quartiles of age, whereas VAI showed a trend toward increase in both groups (P < 0.001). A significantly higher prevalence of MS (P < 0.001), increased waist circumference (P < 0.001), low high-density lipoprotein cholesterol (P < 0.001), and overt diabetes mellitus (P < 0.001) was found in postmenopausal women compared with premenopausal women, as well as with men. CONCLUSIONS: The majority of metabolic features in acromegaly are gender-specific. Active acromegaly in women is strongly associated with higher visceral adiposity dysfunction, insulin resistance, and the features of MS. We suggest more accurate metabolic management in acromegalic women, especially in the postmenopausal years.