Massimo Giusti

Characterization of the intracellular mechanisms mediating somatostatin and lanreotide inhibition of DNA synthesis and growth hormone release from dispersed human GH‐secreting pituitary adenoma cells in vitro

objective Somatostatin is an endogenous inhibitor of hormone secretion and cell proliferation. Treatment with somatostatin analogues in humans causes a reduction in size and secretory activity of endocrine tumours, including GH‐secreting pituitary adenomas. This study was aimed to characterize the intracellular mechanisms mediating the in vitro antiproliferative and antisecretory effects of somatostatin and its analogue lanreotide, on primary cultures of GH‐secreting pituitary adenoma cells.

Absence of histological malignancy in a patient cohort with follicular lesions on fine-needle aspiration

Follicular lesions account for 4–6% of all thyroid fine-needle aspiration (FNA) cytologies. To date, no cytological criteria exist to distinguish follicular adenoma from carcinoma. For this purpose, histological evaluation after surgical exeresis is required. From 1993 to 2000 we performed 1238 US-assisted FNA biopsies in patients admitted to our unit for uni-or multi-nodular goiters. In the latter goiters, FNA was performed in the dominant nodule. Cytological examination revealed a follicular lesion in 71 patients (5.7%). All patients came from regions of Northern Italy with moderate iodine deficiency. In 48%, the lesion presented as a solitary nodule, while in the other 52% it occurred in the context of a multinodular goiter. Surgical exeresis of the neoplasm was recommended in all cases. Sixty-three patients (89%) underwent surgery (Group 1) while the other 8 patients (11%) opted for follow-up (Group 2). In Group 2, the mean nodule volume (3.2±0.5 ml) at baseline was slightly smaller (p=0.08) than that found in Group 1 (5.4±0.7 ml). In Group 1, histological examination after surgery showed a follicular adenoma in 52 patients (83%) and a colloid goiter in the others (17%). No malignancy was detected. Group 2 underwent a median follow-up of 46 months (range 24–96 months) on L-thyroxine suppressive regimen (dose range 75–125 μg/day), with TSH levels ranging from 0.1 to 0.3 mIU/l. Throughout the follow-up, no patient developed clinical or ultrasonographic features that could be considered worrisome for malignancy; thus, no further biopsy was performed. However, an overall slight increase (median +5.2%) in nodular volume in respect to baseline was observed. Although institutional and cytological bias cannot be ruled out, our data do not confirm the reported incidence of malignancy in histological specimens of follicular lesions diagnosed on FNA cytology, and prompt us to suggest a less aggressive first-step approach (i.e. careful clinical and instrumental evaluation, and suppressive LT4 therapy) for these lesions, unless anamnestic reports or clinical and ultrasonographic features of the nodules suggest malignancy.

Assessment of disease activity in acromegaly by means of a single blood sample: comparison of the 120th minute postglucose value with spontaneous GH secretion and with the IGF system

objective  It has been suggested that the threshold of 1 µg/l of GH nadir after glucose load for definition of controlled acromegalic disease proposed in the 2000 consensus statement should be lowered to 0·30. We evaluated these two cut‐off values in comparison with IGF‐I, ALS and IGFBP‐3 in a group of acromegalic patients. With the aim of simplifying the follow‐up protocol in these patients we also tested if one single sample taken after glucose load could replace the nadir value.

Cost-of-illness study in acromegalic patients in Italy

Introduction: acromegalic therapeutic goals are directed at removing the tumor, preventing tumor re-growth and reducing long-term morbidity and mortality. In this scenario, the acromegalic patient needs a variety of health resources (diagnostic tests, surgery, radiotherapy, specialist visits and drugs) for his/her cure, in order to decrease/stop the progression of the disease and to cure the co-morbid diseases. Lack of epidemiological data has suggested performing an Italian retrospective study aiming to assess the health resource consumption that is caused by acromegalic cure and the relative co-morbidities, in order to estimate the amount of the direct costs of acromegalic patients. Method: a retrospective study was performed on a total of 134 patients (142 patients selected, 76 in Genoa and 66 in Turin) for a period of about 7 yr preceding the enrolment date. Only direct costs were evaluated by performing an analysis on the perspective of Italian Healthcare Service (SSN). Results: the mean total direct costs for acromegaly cure ranged from 7.968,41 to 12.533,02 €/yr (p<0,01; Mann Whitney Test), respectively, for Responders and Non-Responders. The cost driver was drug (SS analogs) for acromegalic cure. The co-morbidity conditions associated to acromegalic Non-Responder patients are clearly higher than those with well-controlled disease. Conclusion: the study supports the hypothesis that controlled patients drove a saving for SSN in comparison to poor control patients that use more health resources.

The Hypothalamic‐Pituitary‐Adrenal and Gonadal Axes in Rheumatoid Arthritis

Abstract: The hypothalamic‐pituitary‐adrenal (HPA) and the hypothalamic‐pituitary‐gonadal (HPG) axes involvement or response to immune activation seems crucial for the control of excessive inflammatory and immune conditions such as autoimmune rheumatic diseases, including rheumatoid arthritis (RA). However, female patients seem to depend more on the HPA axis, whereas male patients seem to depend more on the HPG axis. In particular, hypoandrogenism may play a pathogenetic role in male RA patients because adrenal and gonadal androgens, both products of the HPA and HPG axes, are considered natural immunosuppressors. A significantly altered steroidogenesis of adrenal androgens (i.e., dehydroepiandrosterone sulfate, DHEAS and DHEA) in nonglucocorticoid‐treated premenopausal RA patients has been described. The menopausal peak of RA suggests that estrogens and/or progesterone deficiency also play a role in the disease, and many data indicate that estrogens suppress cellular immunity, but stimulate humoral immunity (i.e., deficiency promotes cellular Th1‐type immunity). A range of physical and psychosocial stressors are also implicated in the activation of the HPA axis and related HPG changes. Chronic and acute stressors appear to have different actions on immune mechanisms with experimental and human studies indicating that acute severe stressors may be even immunosuppressive, while chronic stress may enhance immune responses. The interactions between the immunological and neuroendocrine circuits is the subject of active and extensive ongoing research and might in the near future offer highly promising strategies for hormone‐replacement therapies in RA.

Balance between somatostatin and D2 receptor expression drives TSH-secreting adenoma response to somatostatin analogues and dopastatins

Context  First‐line therapy for thyrotropin‐secreting pituitary adenomas (TSHomas) is neurosurgery, while medical treatment rests mainly on somatostatin analogues. Clinically available sst2‐preferring analogues, octreotide and lanreotide, induce normalization of hormone levels in approximately 90% of patients and tumour shrinkage in 45%.

A case-controlled study on the quality of life in a cohort of patients with history of differentiated thyroid carcinoma

Although quality of life (QoL) has become an important aspect of cancer rehabilitation, psychometric studies on thyroid cancer patients are rare. We performed a case-controlled study on QoL in patients with differentiated thyroid carcinoma (DTC). QoL was evaluated in 61 patients with a history of DTC diagnosed from <1 to 23 yr earlier. An undetectable thyroglobulin (Tg) level after recombinant human TSH (rhTSH) testing was considered the best predictor of cure. QoL was evaluated by means of a general psychiatric interview, the self-rating Kellner Symptoms Questionnaire (KSQ) and the Hamilton Depression Scale (HDS). QoL was also evaluated in a control group of subjects on L-T4 therapy with a non-toxic multinodular goiter diagnosed from <1 to 25 yr earlier. DTC and control subjects were similar in age, male-female distribution and concomitant psychiatric therapies. Per-week dosage of L-T4 was higher in DTC patients than in controls (p<0.01). In neither group of subjects was there any correlation between current TSH levels or interval from diagnosis and KSQ or HDS scores. Only in DTC patients was there a positive correlation between age and KSQ (p<0.05) or HDS (p<0.01 ) scores. There was a significant difference in overall KSQ scores between DTC (33.4±2.1) and control (24.5±1.9; p<0.01 ) subjects. The subscales of KSQ showed a significant inter-group difference. HDS scores were higher in DTC subjects (35.8±1.0) than in controls (30.0±1.1; p<0.01). HDS score was significantly (p=0.02) higher in female than in male DTC patients. In patients with papillary carcinoma there was a positive correlation between the MACIS (metastases, age, completeness, invasiveness, size) score and KSQ (p=0.01) or HDS (p<0.01) scores. After rhTSH testing, detectable Tg levels were found in 13% of DTC patients. In Tg-positive patients, KSQ and HDS scores were not different from those of Tgnegative patients. After an 8–14 month period, a significant decrease in the KSQ scale somatization p=0.02) was found in a sub-set of 31 DTC patients. In conclusion, even in the age of rhTSH testing, DTC patients suffer an impairment of their QoL, as noted when short-term L-T4 withdrawal was the gold standard. Longitudinal evaluation seems to indicate a slight improvement in QoL when safe rhTSH testing is extensively used in the management of the disease.

In vitro effect of human recombinant leptin and expression of leptin receptors on growth hormone-secreting human pituitary adenomas

objective and study design Leptin is a circulating hormone secreted by adipose tissue and a few other tissues. It has recently been demonstrated that leptin and leptin receptors are expressed in normal and adenomatous pituitary cells. The aim of this study was to investigate the effect of recombinant human leptin on GH release from adenomatous GH‐secreting cells in culture. Specimens were obtained from 10 patients with acromegaly who had undergone selective transsphenoidal adenomectomy. Cells (2 × 105/well) preincubated for 24 h with leptin (10−10−10−8 m) or control medium were exposed to GHRH for 2 h. The GH released into the medium was measured before and after GHRH incubation. The expression of leptin receptor isoforms was evaluated by reverse‐transcriptase polymerase chain reaction (RT‐PCR) in cells obtained from five adenomas.

Three-hour spontaneous GH secretion profile is as reliable as oral glucose tolerance test for the diagnosis of acromegaly

The diagnosis of acromegaly, in an appropriate clinical context, usually relies on lack of GH suppression below 1 μg/l during OGTT coupled with elevated IGF-I levels. On the other hand, in normal subjects glucose-induced inhibition of GH secretory bursts without any further decrease of interpulse GH levels had already been shown. Based on the foregoing, we aimed to compare the diagnostic reliability of OGTT-induced GH nadir with that recorded during 3-h spontaneous GH secretion. In 59 acromegalic patients (17 male and 42 female, age, mean±SE 51.5±1.9, range 21–76 yr) and in 82 normal subjects (43 male and 39 female, age, mean±SE 35.7±1.5, range 15–72 yr) GH secretion was evaluated every 30 min from 0 to 180 min during slow saline infusion or OGTT (75 g at 0 min). A nadir GH concentration below 1 μg/l was recorded in all normal subjects either during OGTT or saline infusion if GH secretion was evaluated over 180 min. In contrast in acromegalic patients a nadir GH concentration below 1 μg/l never occurred in both conditions. This study shows that a 3-h spontaneous GH profile is as reliable as OGTT in the diagnosis of active acromegaly.

Endogenous opioid blockade and gonadotropin secretion: role of pulsatile luteinizing hormone-releasing hormone administration in anorexia nervosa and weight loss amenorrhea

In anorexia nervosa alterations in the hypothalamic-pituitary-gonadal unit were previously thought to have been connected to an increase of endogenous opiate tone. The authors tried to prove that the replacement of normal endogenous steroid levels could restore the functional coupling between opiatergic and luteinizing hormone-releasing hormone (LH-RH) neurons in patients with anorexia nervosa. Pulsatile LH-RH therapy has been used to achieve normal ovarian activity. The authors studied gonadotropin levels before and during intravenously (IV) pulsatile LH-RH therapy (50 to 100 ng/kg body weight/90 to 120 minutes) in three anorexia nervosa and two weight loss amenorrhea patients, during both placebo and naloxone administration (2 mg IV bolus plus 4 mg infusion lasting 120 minutes). Before therapy, naloxone administration did not significantly change gonadotropin levels in three out of five patients, while a decrease in gonadotropin levels was observed in the other two subjects. During LH-RH therapy, normal pituitary-gonadal activity was demonstrated and ovulatory cycles were found in all patients. Naloxone administration did not change gonadotropin release during LH-RH therapy. Data could support the hypothesis of either a primitive impairment of LH-RH neurons, or an alteration in central regulation of LH-RH pulsar in anorexia nervosa.