Disease control of acromegaly does not prevent excess mortality in the long term: results of a nationwide survey in Italy.

OBJECTIVE: This study aimed to assess the long-term outcome of patients with acromegaly. DESIGN: This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up. METHODS: Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population. RESULTS: A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4-2.0, p < 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1-1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population. CONCLUSIONS: Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.

Awareness and management of hyponatraemia: the Italian Hyponatraemia Survey.

BACKGROUND: Hyponatraemia is the most frequent electrolyte disorder in hospitalized patients and has been associated with increased morbidity, mortality and length of hospital stay. There is evidence that also mild chronic hyponatraemia may have clinical consequences, such as gait disturbances, attention deficits, falls, increased risk of fractures and reduced bone mineral density. Nevertheless, this condition appears to be rather often not taken into consideration, or inappropriately managed and treated, thus negatively affecting patients' outcome. AIM: The aim of this study was to investigate the awareness and management of hyponatraemia secondary to SIAD, a common cause of hyponatraemia, among Italian physicians (endocrinologists, nephrologists, internists) commonly involved as consultants. METHODS: A questionnaire, covering definition, diagnosis, management, treatment and prognosis of hyponatraemia secondary to SIAD, was developed with the support of the Italian Society of Endocrinology. RESULTS: Among the respondents (n=275), the majority was aware of the negative implications of hyponatraemia or of an inappropriate treatment. Nevertheless, the answers indicated that SIAD is still underdiagnosed and incorrectly managed in clinical practice. In particular, only 47% of respondents used the validated biochemical parameters to diagnose hyponatraemia secondary to SIAD. The survey also indicated a rather satisfactory knowledge of the therapeutic options, including the currently available vasopressin receptor antagonists. CONCLUSIONS: One of the main findings of the survey was that the diagnostic work-up of hyponatraemia still represents a critical issue. Therefore, there is urgent need of educational programs in order to improve the management of this condition and reduce morbidity, mortality and costs.

Validation of a clinicopathological score for the prediction of post-surgical evolution of pituitary adenoma: retrospective analysis on 566 patients from a tertiary care centre.

Objective and design A clinicopathological score has been proposed by Trouillas et al. to predict the evolution of pituitary adenomas. Aim of our study was to perform an independent external validation of this score and identify other potential predictor of post-surgical outcome. Methods The study sample included 566 patients with pituitary adenomas, specifically 253 FSH/LH-secreting, 147 GH-secreting, 85 PRL-secreting, 72 ACTH-secreting and 9 TSH-secreting tumours with at least 3-year post-surgical follow-up. Results In 437 cases, pituitary adenomas were non-invasive, with low (grade 1a: 378 cases) or high (grade 1b: 59 cases) proliferative activity. In 129 cases, tumours were invasive, with low (grade 2a: 87 cases) or high (grade 2b: 42 cases) proliferative activity. During the follow-up (mean: 5.8 years), 60 patients developed disease recurrence or progression, with a total of 130 patients with pituitary disease at last follow-up. Univariate analysis demonstrated a significantly higher risk of disease persistence and recurrence/progression in patients with PRL-, ACTH- and FSH/LH-secreting tumours as compared to those with somatotroph tumours, and in those with high proliferative activity (grade 1b and 2b) or >1 cm diameter. Multivariate analysis confirmed tumour type and grade to be independent predictors of disease-free-survival. Tumour invasion, Ki-67 and tumour type were the only independent prognostic factors of disease-free survival. Conclusions Our data confirmed the validity of Trouillas' score, being tumour type and grade independent predictors of disease evolution. Therefore, we recommend to always consider both features, together with tumour histological subtype, in the clinical setting to early identify patients at higher risk of recurrence.

Site and type of craniopharyngiomas impact differently on 24-hour circadian rhythms and surgical outcome. A neurophysiological evaluation.

This study aimed to quantify 24h body core temperature (BcT°) and sleep-wake cycle rhythm alterations in craniopharyngioma (CP) patients and to identify markers related to the postsurgical outcomes. Ten consecutive CP patients underwent neuroradiological, endocrinological and ophthalmological evaluations, 24h BcT° and sleep-wake cycle recordings before and after endoscopic endonasal surgery. The sample included four women and six men. Nocturnal sleep efficiency was pathologically reduced in eight patients before surgery. Seven out of ten patients presented one to three daytime naps. 24h BcT° rhythm was pathological in six out of ten cases. Post-surgery sleep efficiency normalized in four out of eight patients, whereas nine out of ten patients presented with two to six longer daytime naps. Diurnal naps were mainly present in patients showing pre-operative involvement of the third ventricle floor. 24h BcT° remained pathological in only one out of six cases, returned to normal in two and improved in three. 24h BcT° rhythm improved more in papillary CPs than in adamantomatous CPs. Our data confirmed that both CP and surgery frequently disrupt the sleep-wake cycle and BcT° rhythms. Tumour location and histotype may be related to a worse postsurgical outcome. Therefore, in-depth investigation including circadian monitoring is crucial for surgical outcome.

Estrogen replacement therapy in a man with congenital aromatase deficiency: effects of different doses of transdermal estradiol on bone mineral density and hormonal parameters.

The effects of different doses of transdermal estradiol (TE) on bone mineral density (BMD) in a man with aromatase deficiency were evaluated. The study protocol was divided in the following four phases: phase 1, before estradiol treatment; phase 2, 50 microg TE twice weekly for 6 months; phase 3, 25 microg TE twice weekly for 9 months; and phase 4, 12.5 microg TE twice weekly for 9 months. X-rays of hands, legs, and pelvis were performed, and BMD of the lumbar spine, hormonal parameters (LH, FSH, testosterone, and estradiol), and markers of bone turnover were determined during each phase. BMD in phase 1 was 0.933 g/cm2 and increased to 1.051 and 1.173 g/cm2 after 4 and 7 months of TE, respectively. In phase 3, BMD reached the maximum value (1.275 g/cm2). In phase 4, BMD decreased to 1.180 g/cm2 and was 1.029 g/cm2 at the end of the study protocol. A bilateral necrosis of femoral heads was also detected by x-ray films. In phase 1 serum testosterone was in the normal range, whereas serum estradiol was undetectable. During the 24-month period of treatment with TE (phases 2-4), estradiol was directly related to the amount of TE, whereas LH was inversely related to estradiol serum levels. Estradiol and gonadotropins reached optimal values only in phase 3, when FSH also was near normal; serum testosterone concentrations were normal in phases 3 and 4. This study confirms the role of estrogens in achieving and maintaining bone mineral content in the human male, providing further clinical tools useful in the management of bone loss in aromatase deficiency in the male. We suggest that the adequate substitutive dose of TE for maintaining both bone mass and normal estradiol serum levels in adult men with aromatase deficiency may be 25 microg twice weekly (0.47 microg/kg weekly).

Role of estrogen on bone in the human male: insights from the natural models of congenital estrogen deficiency.

The reports of congenital estrogen deficiency - notably, estrogen resistance and aromatase deficiency - have completely changed our knowledge on the role of estrogen on bone in males. Particularly, the bone changes at puberty, which were classically considered androgen-dependent, are now considered to be induced at least in part by estrogen action. Clinical cases of congenital estrogen deficiency have clearly demonstrated that the role of estrogens in epiphyseal closure, skeletal proportions and bone mineralization is crucial not only in women but also in men. In addition progress have been made in the treatment of such a rare disease even though further studies are needed to a definitive understanding of this issue.

Congenital estrogen deficiency: in search of the estrogen role in human male reproduction.

Recently, a remarkable progress has been made in our understanding about the role of sex steroids in male physiology. In this paper, we consider the clinical aspects of congenital estrogen deficiency - notably, estrogen resistance and aromatase deficiency - in men and we discuss both well-established and supposed estrogen roles in the human male reproductive function. These topics include the role of estrogens in the control of gonadotropin secretion, in male fertility determination and psychosexual behavior. Briefly, estrogens play a pivotal role in the control of serum gonadotropin concentrations in the human male. Furthermore, a possible role of estrogens on both human male fertility and sexuality has also been suggested by recent studies, even though the available data are far from being conclusive. Conversely, for what concern fertility and sexual behavior, a well-established effect of estrogens has been provided by recent studies on male rodents, which show impaired sexual behavior and fertility as a consequence of estrogen defect.

Hypopituitarism and growth hormone deficiency (GHD) after traumatic brain injury (TBI).

In adults, hypopituitarism and growth hormone deficiency (GHD) should be suspected and diagnosed within an appropriate clinical context. It has been demonstrated that all patients with primary hypothalamic-pituitary diseases before and after any medical intervention (defined as neurosurgery, radiotherapy and medical therapy) are at obvious risk - more than just at high risk - for hypopituitarism (greater than 80% had severe GHD). The same obvious risk applies to patients diagnosed as having congenital or acquired GHD in childhood (between 30% and 50% of patients with severe GHD after retesting). Taking into account the fragility of the infundibular-hypothalamic structure, patients with other common pathological conditions of the central nervous system (CNS), such as traumatic brain injury (TBI), subarachnoid haemorrhage (SAH) or primary brain tumours (BT) with related medical intervention could be at risk for developing hypopituitarism, including GHD. GHD is the first and most common sign of pituitary impairment. Despite the risk of pituitary dysfunction and the results of some studies that these risks are greater than previously believed, neuroendocrine evaluations are still not routinely included as part of the clinical management plan for patients with TBI and SAH. Preliminary results of a multicenter study performed under the auspices of the Italian Society of Endocrinology underscore the high risk of hypopituitarism and GHD under these clinical conditions. Thus, careful screening of pituitary function should always be performed in patients following TBI and SAH.

Predictors of morbidity and mortality in acromegaly: an Italian survey.

OBJECTIVE: To describe demographic and hormonal characteristics, comorbidities (diabetes mellitus and hypertension), therapeutic procedures and their effectiveness, as well as predictors of morbidity and mortality in a nationwide survey of Italian acromegalic patients. DESIGN: Retrospective multicenter epidemiological study endorsed by the Italian Society of Endocrinology and performed in 24 tertiary referral Italian centers. The mean follow-up time was 120 months. RESULTS: A total of 1512 patients, 41% male, mean age: 45±13 years, mean GH: 31±37 µg/l, IGF1: 744±318 ng/ml, were included. Diabetes mellitus was reported in 16% of cases and hypertension in 33%. Older age and higher IGF1 levels at diagnosis were significant predictors of diabetes and hypertension. At the last follow-up, 65% of patients had a controlled disease, of whom 55% were off medical therapy. Observed deaths were 61, with a standardized mortality ratio of 1.13 95% (confidence interval (CI): 0.87-1.46). Mortality was significantly higher in the patients with persistently active disease (1.93; 95% CI: 1.34-2.70). Main causes of death were vascular diseases and malignancies with similar prevalence. A multivariate analysis showed that older age, higher GH at the last follow-up, higher IGF1 levels at diagnosis, malignancy, and radiotherapy were independent predictors of mortality. CONCLUSIONS: Pretreatment IGF1 levels are important predictors of morbidity and mortality in acromegaly. The full hormonal control of the disease, nowadays reached in the majority of patients with modern management, reduces greatly the disease-related mortality.

Thyrotropin-secreting pituitary tumours: significance of "atypical adenomas" in a series of 10 patients and association with Hashimoto thyroiditis as a cause of delay in diagnosis.

BACKGROUND: Thyrotropin-secreting adenomas (TSH-As) are rare and, according to the World Health Organization criteria (WHO 2004), a significant proportion of them present features of atypical adenomas at the time of diagnosis. AIMS: To determine the frequency of "atypical adenomas" and the significance of this definition as regards follow-up. To investigate their possible association with Hashimoto thyroiditis, leading to a delay in diagnosis. METHODS: Case notes for patients who underwent trans-sphenoidal surgery between 1992 and 2006 were retrieved. Follow-up ranged from 6 to 180 months. RESULTS: Ten cases of TSH-As out of 908 pituitary adenomas were selected. Before surgery, eight patients had hyperthyroidism, one was euthyroid and another one showed hypothyroidism associated with Hashimoto thyroiditis. All cases were macroadenomas; six of them were invasive. Three cases met the criteria for classification as atypical. In none of the cases, including the three "atypical adenomas", were clinical or radiological signs of recurrence observed. CONCLUSIONS: The three cases with features of atypical adenoma did not recur or metastasise, suggesting that, at least in the present series, a strict relationship between the morphological criteria for diagnosing atypical adenomas and biological behaviour may be sometimes lacking. Furthermore, the casual association of TSH-As with Hashimoto thyroiditis may led to an adjunctive delay in diagnosis, because of low thyroid hormone levels.

Role of oestrogen in male sexual behaviour: insights from the natural model of aromatase deficiency.

OBJECTIVE: In order to evaluate the role of oestrogens on human male sexual behaviour, the gender-identity, psychosexual orientation and sexual activity of a man with a congenital lack of oestradiol resulting from an inactivating mutation of the aromatase P450 gene was investigated. The psychosexual and sexual behavioural evaluations were performed before and during testosterone treatment and before oestradiol treatment, during three phases of different dosages of oestradiol treatment. DESIGN: The study was performed before (phase A) and during (phase B) testosterone enanthate treatment (250 mg i.m. every 10 days, for 6 months), during testosterone withdrawal (phase C), and during each of the following transdermal oestradiol treatments: 50 microg twice a week for 6 months (phase D); 25 microg twice a week for 9 months (phase E), and 12.5 microg twice a week for 9 months (phase F). MEASUREMENTS: Sexual behaviour was investigated by a sexological interview and by a 2-month self-reported daily diary performed during each phase of the protocol study. Furthermore, during each oestradiol treatment (phase C, D, E and F), a study of depression, anxiety trait and sexual behaviour was performed by the Beck Depression Inventory (BDI), the Spielberger Trait Anxiety Inventory (STAI) and the Golombok-Rust Inventory of Sexual Satisfaction (GRISS), respectively. Sexual orientation and gender-identity were evaluated by the BEM Sex Role Inventory (BSRI). Serum testosterone and oestradiol were measured during each phase of the study. RESULTS: Before oestradiol treatment (phase C), serum oestradiol was undetectable, while it rose to 356.1, 88.1 and 55.1 pmol/l during phases D, E and F, respectively. Before any oestradiol treatment, during phase D, phase E and phase F serum testosterone was 18.13, 0.72, 14.3 and 18.51 nmol/l, respectively. The patient's gender-identity as assessed by BSRI and by the sexological interview was clearly male. The psychosexual orientation evaluated by BSRI, by the sexological interview and by the analysis of the self-filled diary was heterosexual. Relevant modification of the patient's sexual behaviour occurred only during oestrogen treatment. This was more evident during both phase E and phase F, and concerned the behavioural parameters with an increase of libido, frequency of sexual intercourse, masturbation and erotic fantasies. A reduction of BDI and STAI scores was detected during the oestrogen phases. CONCLUSIONS: The study of the sexual behaviour in this man with aromatase deficiency suggests that oestrogens in humans do not affect gender-identity and sexual orientation but could have a role in male sexual activity.

Circannual rhythm of plasma thyrotropin in middle-aged and old euthyroid subjects.

The circannual rhythm of plasma thyrotropin (TSH) was evaluated in 8,310 euthyroid, serially independent, young, middle-aged and old men and women. A statistically significant circannual rhythm of plasma TSH was validated, by the mean group-cosinor method, in the middle-aged and old men and women (p less than 0.05), with acrophase in December, whereas the young subjects did not show any rhythm. No significant correlation was found between TSH plasma levels and free thyroxine (fT4) or ambient temperature in any group. Moreover, plasma fT4 did not show seasonal variations.

Temporal changes in sulphated glycoprotein-2 (clusterin) and ornithine decarboxylase mRNA levels in the rat testis after ethane-dimethane sulphonate-induced degeneration of Leydig cells.

Short- (3-24 h) and long-term (4-50 days) changes in sulphated glycoprotein-2 (SGP-2) and ornithine decarboxylase (ODC) mRNA levels in the adult rat testis were studied following a single dose of ethane-dimethane sulphonate (EDS), to destroy the Leydig cells. Distribution patterns of SGP-2 and ODC labelling were consistent with prevailing expression of the two transcripts in Sertoli cells and germ cells, respectively. This pattern did not show appreciable changes following EDS administration. No labelling of SGP-2 mRNA was noted in the interstitium of control and EDS-treated rats. This finding indicates that Leydig cell death induced by EDS is not associated with increased SGP-2 mRNA levels, a phenomenon related to apoptotic cell death in many tissues. Semi-quantitative densitometric analysis of the preparations demonstrated differential changes in SGP-2 and ODC mRNA levels in the tubular compartment following EDS treatment. At 6, but not at 3 and 12, h following EDS administration, SGP-2 mRNA levels showed a significant increase, possibly secondary to a direct effect of the alkylating agent on Sertoli cells. A significant decrease in ODC mRNA levels was observed from day 7 to day 28, matching degenerative changes in the seminiferous epithelium. In contrast, a decrease in SGP-2 transcript levels was observed from days 21-35 after treatment. In conclusion, our findings demonstrate that SGP-2 mRNA, a putative marker of apoptosis, is not altered in the testicular interstitium during EDS-induced degeneration of Leydig cells.(ABSTRACT TRUNCATED AT 250 WORDS)