Renata S. Auriemma

Hypertension in acromegaly and in the normal population: prevalence and determinants

Background  The GH/IGF‐I axis has a relevant role to play in the cardiovascular system but its implication in the pathogenesis of hypertension in the normal population and in acromegaly is not yet clear.

Effects of Initial Therapy for Five Years with Somatostatin Analogs for Acromegaly on Growth Hormone and Insulin-Like Growth Factor-I Levels, Tumor Shrinkage, and Cardiovascular Disease: A Prospective Study

OBJECTIVE The objective of the study was to evaluate the efficacy of 5 yr of depot somatostatin analogs (SSAs) as first-line therapy in acromegaly. OUTCOME MEASURES Primary measures were fasting GH 2.5 microg/liter or less and IGF-I normalized for age and tumor shrinkage. Secondary measures were control of hypertension, arrhythmias, left ventricular hypertrophy, diastolic and systolic dysfunction, and change in lipid and glucose profile. PATIENTS Patients included 45 de novo patients (18 women and 27 men, aged 20-82 yr); 28 were treated with octreotide-long-acting release and 17 with lanreotide. RESULTS GH was controlled in 100% and IGF-I levels in 97.8%, tumor shrinkage was 74.9 +/- 22.1 and 78.2+/-14.5%, in the octreotide-long-acting release and lanreotide groups, respectively. There was a significant improvement in the prevalence of hypertension (from 46.7 to 22.2%, P = 0.027), arrhythmias (from 17.8% to zero, P = 0.01), left ventricular hypertrophy (from 82.2 to 42.2%, P < 0.0001), diastolic dysfunction (from 60.0 to 15.6%, P < 0.0001), systolic dysfunction (from 40.0 to 4.4%, P < 0.0001), and hypertriglyceridemia (from 40.0 to 4.4%, P < 0.0001). The prevalence of impaired glucose tolerance (IGT; from 28.9 to 20.0%. P = 0.46) and diabetes mellitus (from 22.4 to 31.1%, P = 0.64) did not change. CONCLUSIONS In patients with severe comorbidities and those who refuse surgery, 5 yr of exclusive SSA therapy induce successful control of GH and IGF-I; tumor shrinkage (by median 80%), and improvement of hypertension, cardiac performance; and dyslipidemia. No patient was withdrawn from treatment because of side effects, and glucose tolerance was stable. We suggest that first-line SSA treatment may be safely continued in patients with acromegaly, according to an individual patients indications and preferences.

Beneficial effect of dose escalation of Octreotide-LAR as first-line therapy in patients with acromegaly

OBJECTIVE To evaluate the efficacy of dose escalation of Octreotide-long-acting repeatable (LAR) up to 40 mg/month we studied 56 newly diagnosed patients with acromegaly (24 women, 32 men; age 20-82 years). DESIGN Analytical, observational, open and prospective. METHODS Three months after LAR treatment beginning with a dose of 20 mg /q28d (every 28 days), 24 patients maintained the same dose (Group A), while 32 required a dose of 30 mg/q28d (Group B). The dose was further increased to 40 mg/q28d in 17 out of the 32 patients of Group B for another 12 months (Group C). RESULTS After 24 months, serum GH and IGF-I levels decreased by 93.1 +/- 8.6% (95% confidence limit (CL) 90.8-95.4%) and 62.7 +/- 13.4% (95% CL 59.1-66.3%) respectively. Control of GH and IGF-I levels was achieved in 45 patients (80.3%). Tumor shrinkage after 12 months was 49.8 +/- 23%; the relative tumor shrinkage during the second 12 months of treatment was 35.3 +/- 13.1% and overall tumor volume was 68.1 +/- 16.5% (95% CL 63.7-72.5%). Glucose tolerance impaired in eight patients (14.3%): four in Group A and four in Group C (16.7% vs 36.4%, P=0.39). The final dose was predicted by the patients age at diagnosis (t=-2.2; P=0.032) and baseline tumor volume (t=2.1; P=0.043). CONCLUSION An increase of the LAR dose up to 40 mg/q28d in patients resistant to 30 mg/q28d is followed by greater suppression of GH and IGF-I levels and tumor shrinkage without further significant impairment of glucose tolerance when compared with lower doses. These results suggest that a new dosage schedule of 40 mg every 28 days is applied in patients with acromegaly mostly of young age and with bigger tumors who are likely to be poorly responsive to standard doses of Octreotide-LAR.

Acromegaly and the Cardiovascular System

Acromegaly is characterized by an increased cardiovascular morbidity and mortality. In fact, growth hormone and insulin-like growth factor-I excess induces a specific cardiomyopathy. The heart is involved from the very early stages of the disease in which the hyperkinetic syndrome (high heart rate and increased systolic output) takes place. Frequently, if the disease is untreated for many years or unsuccessfully treated, concentric biventricular hypertrophy and diastolic dysfunction can develop and, at least, lead to diastolic congestive heart failure. Rhythm disturbances and valve dysfunction are also frequently described in acromegaly. The coexistence of other complications, such as diabetes and arterial hypertension, can induce the worsening of acromegalic cardiomyopathy. Control of acromegaly by surgery or pharmacotherapy could improve cardiovascular morbidity thanks to decreasing left ventricular mass and reducing cardiac dysfunction. In conclusion, an early diagnosis and a careful evaluation of cardiac function, morphology and activity seem to be mandatory in acromegaly.

Circulating insulin-like growth factor-I levels are correlated with the atherosclerotic profile in healthy subjects independently of age

To investigate the relationships between the GH-IGF-I axis and the atherosclerotic profile, we designed this open, observational, prospective study. Peak GH after GHRH+arginine (ARG) test, serum IGF-I and IGF binding protein-3 (IGFBP-3), lipid profile, homeostasis model assessment (HOMA) index and intima-media thickness (IMT) at common carotid arteries were measured in 174 healthy individuals (92 women, 82 men, aged 18–80 yr). Exclusion criteria for this study were: 1) body mass index (BMI) ≥30 kg/m2; 2) personal history of cardiovascular diseases; 3) previous or current treatments of diabetes or hypertension; 4) previous corticosteroids treatment for longer than 2 weeks or estrogens for longer than 3 months; 5) smoking of more than 15 cigarettes/day and alcohol abuse. Subjects were divided according to age in decade groups from <20 to >70 yr. BMI increased with age, as did systolic and diastolic blood pressures, although they remained in the normal range. The GH peak after GHRH+ARG test was significantly higher in the subjects aged <20 yr than in all the other groups (p<0.01), but was similar in the remaining groups. An inverse correlation was found between the IGF-I z-score and total/HDL-cholesterol ratio (p=0.02) and mean IMT (p=0.0009); IGFBP-3 z-score and mean IMT (p=0.043); IGF: IGFBP-3 molar ratio and total/HDL-cholesterol ratio (p<0.0001) and mean IMT (p<0.0001). Atherosclerotic plaques were found in 7 out of 12 subjects (53.8%) with a z-IGF-I score from ≤−2 to −1, in 4 out of 63 (6.3%) with a z-IGF-I score from −0.99 to 0.1 out of 66 (1.5%) with a z-IGF-I score from 0.1 to 1 and none of the 33 subjects with an IGF-I z-score >1 (p=0.006). At multi-step regression analysis, age was the best predictor of HDL-cholesterol levels and mean IMT, IGF-I level was the best predictor of total cholesterol and total/HDL-cholesterol ratio, the IGF-I/IGFBP-3 molar ratio was the best predictor of triglycerides levels. The z-scores of IGF-I and IGFBP-3 were the second best predictors of mean IMT after age. In conclusion, IGF-I and IGFBP-3 were negatively correlated with common cardiovascular risk factors, studied as total/HDL-cholesterol ratio, and/or early atherosclerosis, studied as IMT at common carotid arteries. The prevalence of atherosclerotic plaques, though not hemodinamically significant, was higher in the subjects having a z-score of IGF-I of ≤−2 to −1. Our results support a role of the IGF/IGFBP-3 axis in the pathogenesis of atherosclerosis.

Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients

Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity for age or final height >2 s.d. above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were ≥10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (r=0.23, P=0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 - X-linked acrogigantism (X-LAG) - occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in >50% of cases.

Significant tumour shrinkage after 12 months of lanreotide Autogel-120 mg treatment given first-line in acromegaly

Objective  To evaluate GH and IGF‐I control and tumour shrinkage in newly diagnosed patients with acromegaly treated first‐line with lanreotide‐Autogel (ATG) 120 mg.

Cardiovascular Disease in Cushing’s Syndrome: Heart versus Vasculature

Cushing’s syndrome (CS) causes metabolic abnormalities that determine an increased cardiovascular risk not only during the active phase of the disease but also for a long time after cure. Cardiovascular complications, such as premature atherosclerosis, coronary artery disease, heart failure, and stroke, in patients with CS cause a mortality rate higher than that observed in a normal population. The increased cardiovascular risk is mainly due to metabolic complications, such as metabolic syndrome, but also to vascular and cardiac alterations such as atherosclerosis and cardiac structural and functional changes. In the clinical management of patients with CS the focus should be on identifying the global cardiovascular risk and the aim should be to control not only hypertension but also other correlated risk factors, such as obesity, glucose intolerance, insulin resistance, dyslipidemia, endothelial dysfunction and the prothrombotic state. Considering that remission from hypercortisolism is often difficult to achieve and that the cardiovascular risk can persist even during disease remission, care and control of all cardiovascular risk factors should be one of the primary goals during the follow-up of these patients.

Impact of Treating Acromegaly First with Surgery or Somatostatin Analogs on Cardiomyopathy

OBJECTIVE The objective of the study was to investigate whether first-line surgery or somatostatin analogs (SSA) have a different outcome on cardiomyopathy after 12 months. DESIGN This was a retrospective, comparative, nonrandomized study. PATIENTS Fifty-six patients treated with SSA and 33 operated on by transsphenoidal approach participated in the study. For the purposes of this study, only controlled patients were included. MEASUREMENTS Primary outcome measures were changes in left ventricular mass index, diastolic (early to atrial mitral flow velocity), and systolic performance (left ventricular ejection fraction). Secondary outcome measures were reduction of total to high-density lipoprotein-cholesterol ratio as a cardiovascular risk parameter, and improvement of glucose profile and pituitary function as indirect causes of cardiovascular improvement. RESULTS SSA and surgery groups were similar for gender, age, estimated disease duration, GH and IGF-I levels, and severity of cardiomyopathy lipid and glucose profile. Twelve months after treatment in both groups, left ventricular mass index, early to atrial mitral flow velocity, diastolic blood pressure, and heart rate decreased significantly, whereas only in SSA-treated patients, left ventricular ejection fraction increased significantly. The total to high-density lipoprotein-cholesterol ratio significantly reduced only in SSA-treated patients, whereas fasting glucose levels significantly decreased only in surgery-treated patients. A normal pituitary function was found in 46.4% of SSA- and 36.4% of surgery-treated patients, with results unchanged in the former and slightly reduced in the latter. CONCLUSIONS Twelve months after first-line treatment with SSA or surgery, we found a similar improvement in left ventricular hypertrophy and diastolic filling. In contrast, systolic function improved more evidently in SSA-treated patients. Both a direct effect of SSA and a more preserved pituitary function might explain these results.

Results of a Single-Center Observational 10-Year Survey Study on Recurrence of Hyperprolactinemia after Pregnancy and Lactation

CONTEXT The current survey study investigated the recurrence rate of hyperprolactinemia after cabergoline (CAB)-induced pregnancy and after lactation as well as safety of CAB exposure during early gestation. PATIENTS AND METHODS From 1997-2008, 143 pregnancies were recorded in 91 patients with hyperprolactinemia (age 30.4 ± 4.7 yr, 76 microadenomas, 10 macroadenomas, and five nontumoral hyperprolactinemia). CAB therapy was discontinued within wk 6 of gestation in all. Pregnancies were monitored until delivery or termination, during and after lactation, twice yearly up to 60 months. The incidence of abortions, premature delivery, and fetal malformations was also analyzed. RESULTS Pregnancies resulted in 13 (9.1%) spontaneous abortions and 126 (88.1%) live births. No neonatal malformations and/or abnormalities were recorded. In 29 of 91 patients (three with macroadenomas), treatment with CAB had to be restarted within 6 months after lactation because of hyperprolactinemia recurrence, whereas in 68% of cases, no additional therapy was required up to 60 months. No tumor mass enlargement was observed. All patients but three were breastfeeding, 35 (38.5%) for less than 2 months and 56 (61.5%) for 2-6 months. Three months after cessation of lactation and 60 months after pregnancy, no difference in prolactin levels was found between patients nursing for less than 2 months and 2-6 months. CONCLUSIONS Fetal exposure to CAB at conception does not induce any increased risk of miscarriage or malformations. Pregnancy is associated with normalization of prolactin levels in 68% of patients. Breastfeeding does not increase the recurrence rate of hyperprolactinemia.