Bartolomeo Merola

Reproductive endocrine disorders in women with primary generalized epilepsy.

Summary: It is known that women suffering from temporal lobe epilepsy may frequently present reproductive endocrine disorders (REDs). We hypothesized that a high occurrence of REDs could be found also in primary generalized epilepsy (PGE), and therefore investigated the hormonal and ovarian echographic profiles in 20 PGE female patients of reproductive age. Fourteen reported normal menstrual cycles, while 6 complained of longstanding menstrual irregularities. All but three patients were receiving antiepileptic drug (AED) therapy. In all subjects, the basal levels of gonadotropins, prolactin, and gonadal steroids were assayed. The response of luteinizing hormone (LH) to gonadotropin‐releasing hormone was also investigated and ovarian ultrasonographic findings were evaluated. In five of six patients with menstrual problems (25% of the group), a well‐defined RED was diagnosed (polycystic ovarian disease in three cases and hypothalamic ovarian failure in two). The 14 patients with normal menstrual cycles showed an elevation of mean basal follicle‐stimulating hormone and prolactin, and a blunting of mean LH response. Our results suggest that a high occurrence of REDs may be found also in PGE. We hypothesize that a neurotransmitter dysfunction might be the common pathogenetic mechanism resulting in both REDs and PGE. The hormonal alterations observed in the patients with normal menstrual cycles seem to support our hypothesis. Previous data seem to rule out a possible AED effect accounting for the hormonal findings observed in our series. However, further studies are needed to confirm our preliminary results.

Left ventricular function in young adults with childhood and adulthood onset growth hormone deficiency

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.

Increased prevalence of colonic polyps and altered lymphocyte subset pattern in the colonic lamina propria in acromegaly

The balance of evidence suggests that acromegaly is a risk factor for colonic neoplasia. We have evaluated the prevalence of colonic polyps in acromegalics from Southern Italy and characterized the lymphocyte subsets in the colonic lamina propria in order to analyze differences in the colonic immunological environment.

Improved left ventricular function after growth hormone replacement in patients with hypopituitarism: assessment with radionuclide angiography.

Prolonged growth hormone deficiency (GHD) leads to marked cardiac dysfunction; however, whether reversal of this abnormality may be achieved after specific replacement therapy has not yet been completely clarified. Fourteen patients with childhood-onset GHD (nine men and five women, mean age 27±4 years) and 12 normal control subjects underwent equilibrium radionuclide angiography under control conditions at rest. Patients with GHD were also studied 6 months after recombinant human (rh) GH treatment (0.05 IU/kg per day). Normal control subjects and patients with GHD did not differ with respect to age, gender and heart rate. In contrast, left ventricular ejection fraction (53%±9% vs 66%±6%,P <0.001), stroke volume index (41±11 vs 51±8 ml/m2,P <0.01) and cardiac index (2.8±0.6 vs 3.±0.51/min/m2,P <0.001) were significantly lower in GHD patients than in normal control subjects. None of the GHD patients showed adverse or side-effects during rhGH therapy; thus none required a reduction in GH dose during the treatment period. Heart rate and arterial blood pressure were not significantly modified by rhGH treatment. After 6 months of rhGH therapy a significant improvement in left ventricular ejection fraction (from 53%±9% to 59%±9%,P <0.01), stroke volume index (from 41±11 to 47±13 ml/m2,P <0.05) and cardiac index (from 2.8±0.6 to 3.3±0.8 1/min/m2,P <0.01) was observed in GHD patients. In conclusion, prolonged lack of GH leads to impaired left ventricular function at rest. Reversal of this abnormality may be observed after 6 months of specific replacement therapy in patients with childhood-onset GHD.

Effectiveness of chronic treatment with alendronate in the osteoporosis of Cushing's disease

Osteoporosis is common in patients with Cushings disease and is likely due to an imbalance between bone formation and resorption. Alendronate is an aminobisphosphonate that is able to increase bone mass mainly by inhibiting bone resorption.

Abnormal Vascular Reactivity in Growth Hormone Deficiency

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/m2) and 10 healthy subjects (age 24±0.4 years, BMI 22±1 kg/m2) 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 <0.05). Likewise, forearm release of nitrite and cGMP during acetylcholine stimulation was reduced in GH-deficient nontreated patients (P <0.05 and P <0.002 versus controls). The response to the endothelium-independent vasodilator sodium nitroprusside was also markedly blunted in GH-deficient patients compared with control subjects (P <0.005). To confirm that abnormal vascular reactivity was due to GHD, we also studied 8 patients with childhood-onset GHD (age 31±2 years, BMI 24±1 kg/m2) 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 <0.01) but not in GH-treated patients (24.8±3.3 mL · dL−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.

Effect of surgery and radiotherapy on visual and endocrine function in nonfunctioning pituitary adenomas

The effect of surgery alone or followed by radiotherapy in recovering visual abnormalities, debulking tumor mass and restoring hormone impairments was evaluated in 84 patients with clinically nonfunctioning pituitary adenomas (NFPA) subjected to 1–10 yr follow-up. All patients underwent surgery via transsphenoidal (in 69) or transcranic-pterional approach (in 15). Radiotherapy was performed after surgery in 59 of 72 patients with incomplete tumor removal. The assessment of pituitary function was performed in all patients before and every 1–2 yr after surgery and/or radiotherapy. Radiological and ophthalmologic assessment was performed before and 3, 6 and 12 months after surgery, then yearly. At diagnosis, headache and visual disturbances occurred in 63 and 58 patients, respectively, while deficiency of GH, TSH, ACTH, FSH, LH and ADH was documented in 55, 7, 19, 47 and 6 patients, respectively. After surgery, gonadal function recovered in 12 women, visual disturbances improved in 43 patients (15 regained normal vision), pituitary function improved in 8 of 62 patients, worsened in 34 patients. At MRI, complete tumor removal was documented in 12 of 84 patients. After surgery alone, tumor regrowth was observed in 7 patients between 3–7 yr. After radiotherapy, vision improved in 9, remained unchanged in 49 and worsened in 1 of 59 patients. After radiotherapy, tumor regrowth was documented in 9 patients between 2–12 yr and the prevalence of hypopituitarism raised from 28.8% to 92% after 1 and 10 yr. In conclusion, surgery alone is effective only in a minority of patients (14.3%) and radiotherapy causes hypopituitarism in rather the totality of patients after 10 yr. The prevalence of tumor regrowth was similar in irradiated ones (15%) and non irradiated patients (28%; χ2, p=0.4). Therefore, a careful radiological follow-up is suggested after surgery so that radiotherapy can be performed promptly on the basis of clinical data, tumor regrowth and/or invasiveness documented at histology.

New Medical Approaches in Pituitary Adenomas

Recently, the medical approach to patients with secreting and clinically non-functioning pituitary adenomas has received great impulse thanks to the availability of new, selective and long-lasting compounds with dopaminergic activity, such as cabergoline, and of somatostatin analogues provided in slow-release formulations, such as lanreotide and octreotide long acting release (LAR). In particular, the use of cabergoline has induced control of hyperprolactinaemia and tumour shrinkage in the great majority of patients with micro- and macroprolactinomas. Cabergoline treatment restores fertility both in women and men, and partially improves osteoporosis, one of the major complications of hyperprolactinaemia. In acromegaly, disease control (growth hormone [GH] <2.5–1.0 μg/l as a fasting or glucose-suppressed value, respectively, together with age-normalised insulin-like growth factor [IGF]-I) is achievable in more than half of patients receiving treatment with lanreotide or octreotide-LAR. Improvement in cardiomyopathy, sleep apnoea and arthropathy has been reported during GH/IGF-I suppression after pharmacotherapy. A synthetic GH analogue, B2036-PEG, that antagonises endogenous GH binding to its receptor-binding sites and a GH-releasing hormone antagonist that blocks the effect of this releasing factor on the hypothalamus and pituitary are presently under investigation in acromegaly. Preliminary studies have clearly demonstrated the effectiveness of the GH receptor antagonist in suppressing IGF-I levels in acromegalic patients previously unresponsive to somatostatin analogues. Beneficial effects of subcutaneous octreotide and lanreotide have also been reported in adenomas secreting thyroid-stimulating hormone, while the results of treatment with dopamine agonists or somatostatin analogues remain disappointing in patients with clinically non-functioning adenomas. In these patients the possibility of visualising in vivo the expression of D2 receptors using specific radiotracers such as 123I-methoxybenzamide has allowed selection of patients likely to respond to cabergoline. Scant effects of pharmacotherapy have also been reported in patients with adenomas secreting adrenocorticotropic hormone. However, some preliminary data suggest a potential use of cabergoline in combination with ketoconazole, or alone, in selected cases of Cushing’s disease or Nelson’s syndrome.

Cardiovascular aspects in acromegaly: Effects of treatment

Patients with acromegaly have significant morbidity and mortality, associated with cardiovascular disease. Acromegaly is often complicated by other diseases such as diabetes mellitus, hypertension, and coronary artery disease, so the existence of acromegalic cardiomyopathy remains uncertain. Cardiac performance was investigated in patients with uncomplicated acromegaly. A subgroup of hypertensive acromegalics was also studied. In addition, the effects of chronic octreotide therapy or surgery on cardiac structure and function in acromegaly were studied. Twenty-six patients and 15 healthy controls underwent gated blood-pool cardiac scintigraphy and echocardiography at rest and during exercise. Echocardiography was repeated after 6 months of octreotide therapy (n = 11). Cardiac scintigraphy was repeated after 12 and 24 months of octreotide therapy (n = 10) or 12 to 24 months after surgery (n = 8). ECG, blood pressure, and heart rate were monitored during cardiac scintigraphy. Left ventricular mass (LVM) was calculated from the findings of the echocardiography. Serum growth hormone (GH) levels and plasma insulin-like growth factor-1 (IGF-1) levels were monitored. LVM index was significantly higher (P < .003) in acromegalics than controls and in hypertensive acromegalics than normotensives, but all other indices of cardiac function were similar. Chronic octreotide decreased GH and IGF-1 levels and improved the structural abnormalities as measured by echocardiography. Chronic octreotide or surgery did not alter cardiac function parameters. Thus, important changes in cardiac structure and function occur in uncomplicated acromegaly, and improvements can be demonstrated after chronic octreotide therapy. Heart disease in acromegaly appears to be secondary to high circulating GH levels.

Growth Hormone Deficiency in Patients with Chronic Heart Failure and Beneficial Effects of Its Correction

CONTEXT A reduced activity of the GH/IGF-I axis in chronic heart failure (CHF) has been described by several independent groups and is associated with poor clinical status and outcome. OBJECTIVE The aim of the current study was to investigate the prevalence of GH deficiency in a patient population with CHF and evaluate the cardiovascular effects of GH replacement therapy. DESIGN AND SETTING The randomized, single-blind, controlled trial was conducted at the Federico II University. PARTICIPANTS One hundred fifty-eight patients with CHF, New York Heart Association class II-IV, underwent a GH stimulation test. Sixty-three patients satisfied the criteria for GH deficiency, and 56 of them were enrolled in the trial. INTERVENTION The treated group (n = 28) received GH at a replacement dose of 0.012 mg/kg every second day (approximately 2.5 IU). MAIN OUTCOMES MEASURES Changes in physical performance and various cardiovascular indexes were measured. RESULTS GH replacement therapy improved quality of life score (from 46 +/- 5 to 38 +/- 4; P < 0.01), increased peak oxygen uptake and exercise duration (from 12.9 +/- .9 to 14.5 +/- 1 ml/kg x min and from 520 +/- 36 to 586 +/- 43 sec, respectively; P < 0.01), and flow-mediated vasodilation (from 8.8 +/- 1.3 to 12.7 +/- 1.2%; P < 0.01). GH increased left ventricular ejection fraction (from 34 +/- 2 to 36 +/- 2%; P < 0.01) and reduced circulating N-terminal pro-brain natriuretic peptide levels (from 3201 +/- 900 to 2177 +/- 720 pg/ml; P = 0.006). No significant changes from baseline were observed in controls. CONCLUSIONS As many as 40% of patients with CHF are GH deficient. GH replacement therapy in these patients improves exercise capacity, vascular reactivity, left ventricular function, and indices of quality of life.