Osteoporosis: Economic Burden of Disease in Italy.

BACKGROUND AND OBJECTIVE: Today, osteoporosis is the most common bone disease and an important public health problem in all developed countries. The objective of this study was to estimate the costs associated with the management and treatment of osteoporosis in order to assess the economic burden in Italy for 2017, in terms of direct medical costs and social security costs. METHODS: A cost of illness model was developed to estimate the average cost per year sustained by the NHS (National Health Service) and Social Security System in Italy. A systematic literature review was performed to obtain epidemiological, direct and indirect costs parameters where available. Hospitalisation costs were calculated considering the administrative database of the hospital discharge records for the period 2008-2016. Patients were enrolled in the analysis if they report the subsequent inclusion criteria: age ≥ 45 years and presence of osteoporosis in primary or secondary diagnosis (ICD9-CM 733.0) and/or presence of a major fracture in primary or secondary diagnosis (excluding road accidents) in the following locations: spine (codes ICD9-CM: 805;806), femur (codes ICD9-CM: 820; 821), radius and ulna (codes ICD9-CM: 813.4; 813.5), humerus (codes ICD9-CM: 812.0-812.5), pelvis (code ICD9-CM: 808), tibia and fibula (codes ICD9-CM: 823), ankle (code ICD9: 824) and ribs (codes ICD9-CM: 807.0; 807.1). Costs were estimated considering the diagnosis-related group (DRG) national tariff associated with each hospitalisation. Finally, the administrative databases of the Italian National Social Security Institute (INPS) (2009-2015) were analysed for the estimate the pension and disability costs from the social perspective. RESULTS: The model estimated an average annual economic burden of osteoporosis in Italy of €2.2 billion. Of this cost, approximately 80% (€1.8 billion) was associated with hospitalisations, 16% (€351 million) for pharmacological treatments, 3% (€71 million) for ambulatory visits, and 0.6% (€13 million) for social security costs. The average yearly cost per patient was equal to €8691 (€8591 for hospitalisations). Analysing severe patients, hospitalisation costs increase to €12,336 (+ 44% if compared to non-severe osteoporosis patients). CONCLUSIONS: The analysis showed that osteoporosis represents one of the main health problems in Italy and the ability to maintain patients in a non-severe health state could decrease the economic burden from both NHS and social perspective.

Redundant modulatory effects of proinflammatory cytokines in human osteoblastic cells in vitro.

OBJECTIVES: The aim of our study was to investigate possible interaction of IL-17, TRAIL, and TNF-α in the modulation of osteoblast homeostasis in vitro, using human differentiated osteoblastic Saos-2 cells as in vitro model. METHODS: The effects of these cytokines on osteoblastic cell viability were assessed, by MTT assay, alone or in combination, at different times and concentrations. The effects of IL-17 and TNF-α on the regulatory system of osteoclast activity RANK/RANKL/ OPG were evaluated by Western blot and ELISA techniques in cell culture media. Quantitative expression of RANKL, OPG and pro-inflammatory factors were analysed at the mRNA level by quantitative real time RT-PCR. RESULTS: Effects of IL-17, TNF-α and TRAIL on osteoblastic cell viability indicated that IL-17 alone, or in combination with TNF-α did not alter Saos-2 cell viability. On the other hand, TRAIL, as expected, exhibited time- and concentration-dependent cytotoxicity. The expression both RANKL and OPG were increased at the mRNA level and protein release by IL-17 and TNF-α, either alone or in combination. The analysis of IL-17 and TNF-α on pro-inflammatory molecules mRNA expression, such as CXC family chemokines CXCL-1 and CXCL-5, COX-2 and IL-6 demonstrated an increase in these pro-inflammatory cytokines with cooperative effects of the combination. CONCLUSIONS: Overall, these results suggest that IL-17, TRAIL and TNF-α sustain bone tissue inflammation associated with decrease of calcified component. To do so, they act redundantly each other, to amplify the inflammatory response in the bone. In conclusion, unravelling novel molecular targets within the bone-cytokine network represents a platform for innovative treatment of bone diseases due to immunological diseases such as psoriatic arthritis.

Protein C and protein S changes in GH-deficient adults on r-HGH replacement therapy: correlations with PAI-1 and t-PA plasma levels.

BACKGROUND: In the rat liver, growth hormone (GH) affects the synthesis of vitamin-K-dependent factors, including Protein C (prot.C) and protein S (prot.S), two natural anticoagulants that prevent hypercoagulable states. Adults with GH deficiency (GHD) are at risk of thrombotic events. High circulating levels of PAI-1 and t-PA, that reflect hypercoagulable states, may contribute to such risk. In GHD adults on replacement therapy with recombinant human GH (r-HGH), %Δ PAI-1 and %Δ t-PA are related to %Δ insulin changes. OBJECTIVES: To evaluate changes in vitamin-K-dependent factors in GHD on r-HGH replacement. METHODS: In 60 GHD adults, to relate plasma levels of vitamin-K-dependent factors with those of PAI-1, t-PA and insulin before and after 6-month (6-mo) replacement therapy with r-HGH. RESULTS: After 6-mo r-HGH replacement, %Δ insulin enhancements occurred in 36/60 subjects. PAI-1, t-PA, Prot.C, Prot.S and FVIIact did not change in them. In the 24/40 subjects that experienced %Δ insulin reductions, Prot.C (p=0.025), Prot.S (p=0.031) and FVIIact (p=0.049) decreased significantly. PAI-1 (p=0.019) and t-PA antigen (p=0.009) behaved similarly. In a multivariate analysis, %∆ PAI-1 (ß=0.436, p<0.01) was the strongest predictor of %∆ prot.S, wheras %∆ t-PA (ß=0.385, p<0.008) and %∆ insulin (ß=0.429, p<0.004) were the strongest predictors of %∆ prot.C. In all cases, regardless of %Δ insulin changes, FII, FVII Ag and FIX levels did not change from baseline. CONCLUSIONS: In GHD adults on r-HGH replacement, changes in vitamin-K-dependent factors reflect a subtle adaptation of the natural anticoagulant system to PAI-1 and t-PA changes, via the response of insulin to r-HGH.

Predictors of pituitary dysfunction in patients surviving ischemic stroke.

BACKGROUND: Stroke is a leading cause of death in industrialized countries, representing the main cause of long-term disability. Recent studies indicate that hypopituitarism may be observed after an acute stroke. OBJECTIVE: The aim was to prospectively investigate incidence and pattern of pituitary dysfunction in patients suffering ischemic stroke and to assess the predictive value of different clinical and radiological parameters for hypopituitarism. PATIENTS AND METHODS: We assessed endocrine, clinical, radiological, and functional parameters in 56 patients (34 males; mean age, 64.8 ± 1.3 yr; mean body mass index, 25.8 ± 0.45 kg/m(2)) at 1-3 months (visit 1) and 12-15 months (visit 2) after an ischemic stroke. RESULTS: At visit 1, hypopituitarism was detected in 20 (35.7%) of 56 stroke patients, with multiple deficits in three and isolated deficits in 17. At visit 2, hypopituitarism was detected in 18 (37.5%) of 48 stroke patients, with multiple deficits in two. Four patients with previously diagnosed isolated GH or LH/FSH deficit exhibited normal pituitary function, whereas GH deficiency was newly diagnosed in three cases. Hypopituitarism was associated with worse outcome. We identified both clinical (preexisting diabetes mellitus, medical complications during hospitalization) and radiological (Alberta Stroke Programme Early CT Score ≤ 7) parameters as major risk factors for developing hypopituitarism after ischemic stroke. CONCLUSIONS: Hypopituitarism may associate with ischemic stroke in one third of cases and persist in a long-term period, aggravating the functional outcome. We identified specific risk factors for hypopituitarism after stroke, which may help to select patients needing an accurate endocrine evaluation to improve stroke outcome.

The effect of treatment with growth hormone on fertility outcome in eugonadal women with growth hormone deficiency: report of four cases and review of the literature.

OBJECTIVE: To highlight the clinical role of standard GH replacement treatment on fertility and pregnancy outcomes in four infertile eugonadal women with GH deficiency (GHD). DESIGN: Case report. SETTING: Department of endocrinology and infertility clinic, tertiary-care university hospital. PATIENT(S): Four normogonadotrophic, normoprolactinemic patients with long-standing infertility, affected by GHD. In two patients (aged 30 and 34 years) GHD was diagnosed after a brain injury. The third patient (age 30 years) had a primary empty sella, documented by magnetic resonance imaging of the pituitary. The last patient (age 28 years) underwent transsphenoidal surgery for Ratke's cyst. The LH and FSH responses to GnRH were normal in all four patients. Two of the four patients also had secondary hypoadrenalism and hypothyroidism. INTERVENTION(S): Patients received recombinant human GH replacement therapy (0.9-1.8 mg/week) for 6-12 months until pregnancy was first indicated by biochemical markers (beta-hCG) and later confirmed by transvaginal sonography. The GH therapy was discontinued after confirmation of pregnancy. MAIN OUTCOME MEASURE(S): Pregnancy. RESULT(S): All patients remained off treatment throughout pregnancy; they had uneventful pregnancies and term deliveries. The babies were healthy and normal in terms of length and weight. CONCLUSION(S): Our case studies confirm the important clinical role of the GH-insulin-like growth factor I system in oocyte fertilization and the beginning of pregnancy in a selected population of eugonadotrophic infertile women.

Cut-off limits of the GH response to GHRH plus arginine test and IGF-I levels for the diagnosis of GH deficiency in late adolescents and young adults.

OBJECTIVE: To define the appropriate diagnostic cut-off limits for the GH response to GHRH+arginine (ARG) test and IGF-I levels, using receiver operating characteristics (ROC) curve analysis, in late adolescents and young adults. DESIGN AND METHODS: We studied 152 patients with childhood-onset organic hypothalamic-pituitary disease (85 males, age (mean+/-s.e.m.): 19.2+/-0.2 years) and 201 normal adolescents as controls (96 males, age: 20.7+/-0.2 years). Patients were divided into three subgroups on the basis of the number of the other pituitary hormone deficits, excluding GH deficiency (GHD): subgroup A consisted of 35 panhypopituitary patients (17 males, age: 21.2+/-0.4 years), subgroup B consisted of 18 patients with only one or with no more than two pituitary hormone deficits (7 males, age: 20.2+/-0.9 years); and subgroup C consisted of 99 patients without any known hormonal pituitary deficits (60 males, age: 18.2+/-0.2 years). Both patients and controls were lean (body mass index, BMI<25 kg/m(2)). Patients in subgroup A were assumed to be GHD, whereas in patients belonging to subgroups B and C the presence of GHD had to be verified. RESULTS: For the GHRH+ARG test, the best pair of highest sensitivity (Se; 100%) and specificity (Sp; 97%) was found choosing a peak GH of 19.0 microg/l. For IGF-I levels, the best pair of highest Se (96.6%) and Sp (74.6%) was found using a cut-off point of 160 microg/l (SDS: -1.3). Assuming 19.0 microg/l to be the cut-off point established for GHRH+ARG test, 72.2% of patients in subgroup B and 39.4% in subgroup C were defined as GHD. In patients belonging to group B and C and with a peak GH response <19 microg/l to the test, IGF-I levels were lower than 160 microg/l (or less than 1.3 SDS) in 68.7 and 41.6% of patients respectively predicting severe GHD in 85.7% of panhypopituitary patients (subgroup A). CONCLUSIONS: In late adolescent and early adulthood patients, a GH cut-off limit using the GHRH+ARG test lower than 19.0 microg/l is able to discriminate patients with a suspicion of GHD and does not vary from infancy to early adulthood.

Anterior pituitary function may predict functional and cognitive outcome in patients with traumatic brain injury undergoing rehabilitation.

Traumatic brain injury (TBI) is the leading cause of death and disability in young adults. Growth hormone-insulin-like growth factor I (GH-IGF-I) system has an important role in the recovery of the central nervous system. The aim of the study was to evaluate the relationship between pituitary function (in particular, the GH-IGF-I axis) and outcome from TBI. We studied 72 patients (56 males; mean age 37.2 +/- 1.8 years) receiving rehabilitation after TBI. According to the Glasgow Coma Scale (GCS), 10 patients had moderate and 52 severe TBI. Ten patients had growth hormone GH deficiency (GHD), 10 LH-FSH, three TSH, and three ACTH deficiency. Overall pituitary dysfunction occurred in 22 (30.5%) patients, with anterior hypopituitarism in 19 (26.4%), isolated diabetes insipidus in one, and isolated hyperprolactinemia in two. GH response to GHRH + ARG (arginine) positively correlated with Functional Independence Measure (FIM D; r = 0.267, p < 0.02) and Level of Cognitive Functioning Scale (LCFS D; r = 0.287, p < 0.01) at discharge, and negatively with Disability Rating Score at discharge (DRS D; r = -0.324, p < 0.005). Unfavorable outcome measures (FIM D, LCFS D, and DRS D) occurred in patients with hypopituitarism as compared with normal pituitary function (p < 0.05). Multiple regression analysis identified both GCS (p < 0.005) and GH peak (p < 0.05) as strong independent predictors of outcome. In conclusion, recovery after TBI may be negatively influenced by concomitant pituitary dysfunction. The GH peak value is an independent predictor of outcome, indicating that recovery during an intensive rehabilitation program after TBI may be positively influenced by normal GH secretion.

Evaluation of an alternative dosing regimen with tadalafil, three times per week, for men with erectile dysfunction: SURE study in Italy.

AIM: To examine the preference for two dosing regimens of 20 mg of tadalafil, on demand or three times per week, in men affected with erectile dysfunction (ED) in Italy. METHODS: Scheduled Use versus on demand Regimen Evaluation (SURE) is a multicenter, crossover and open-label study, involving 94 urology centers in Italy. Patients aged 18 years or older affected with ED for at least 3 months were enrolled and randomized to 20 mg of tadalafil treatment on demand or three times per week for 5-6 weeks. After a 1-week washout, patients were crossed over to the alternate regimen for 5-6 weeks. A treatment preference question was used to determine the preferred treatment regimen. International Index of Erectile Function (IIEF) and Sexual Encounter Profile (SEP) questionnaire were used as efficacy measures. RESULTS: A total of 1 058 men (mean age 54.8 years), were randomized to treatment. Overall, 59.1% of patients preferred the on-demand regimen and 41.9% preferred the three times per week dosing. Both regimens were efficacious and well tolerated. Although a statistically higher improvement of the IIEF erectile function (IIEF-EF) domain score and the SEP questionnaire was reported for the three times per week compared to the on-demand treatment regimen, this difference was numerically minimal and lacking in clinical significance. CONCLUSION: Tadalafil is effective and well tolerated whether used on demand or three times per week. Patients should be given the option to choose the best treatment regimen according to personal needs and preferences.

An identikit of patients seeking treatment for erectile dysfunction in Italy: results from the EDOS Italian database.

OBJECTIVES: Erectile Dysfunction Observational Study (EDOS) is a 6 months observational, prospective, multicentre trial, which enrolled more than 8,000 patients referring to physicians to seek treatment for ED or to modify their current therapy; it was conducted in 9 European countries. Objective of this trial was to outline general characteristics of these populations and related treatment patterns, to assess their efficacy, motivation for treatment extension or discontinuation and patients' overall satisfaction in clinical practice. Baseline characteristics of Italian enrolled population provide the Italian patient profile seeking ED treatment. MATERIALS AND METHODS: The Italian centres involved in this study enrolled, from April 2003 to April 2004, 1,419 men, aged over 18. All of them had already requested to their general practitioner or specialist to start a treatment for ED or to modify a previously initiated therapy. Baseline assessment together with all demographic data, included collecting information about: education, socioeconomic position, clinical history, co-morbidities, ED current therapies, concomitant pharmacological therapies (antidepressants, antihypertensive and other cardiovascular drugs, hypolipidemic drugs, antipsychotics, and anti-cancer agents). All patients filled in IIEF-EF e SF-PAIRS questionnaires, and responded to single item question I (SIQ1: During last 6 months, did not your erection last long enough for you to start and have a successful sexual intercourse?). RESULTS: Of the 1,419 men enrolled, 1,357 were eligible for the study. Mean age was 55 years and BMI=26.8 kg/mn. 83% of patients' education was above primary school; 52% had a full time job, while 37% was retired. 88.5% reported a steady relationship, and 71.5% reported that this relationship had been longer than 10 years. 70.4% of patients were smokers or ex-smokers, while potus history was infrequent. ED was mild or moderate in 61.6% cases and had a psychogenic, organic or mixed origin respectively in 24%, 33% and 43%; 59% of patients had a story of ED more than one year. 43% was assuming other drugs for concurrent diseases, mainly antihypertensive drugs (71%). CONCLUSIONS: Italian outcomes from EDOS study allow us to outline the "average patient" profile, who in Italian clinical practice seeks treatment for ED.

Predictive value of circulating insulin-like growth factor I levels in ischemic stroke outcome.

CONTEXT: Cerebrovascular disease is highly prevalent in the general population, frequently leading to permanent invalidity and reduced quality of life. IGF-I is recognized as an important neuroprotective factor against cerebral hypoxic insult. OBJECTIVE: The objective of the study was to evaluate pituitary function, in particular GH-IGF-I axis, in adult patients receiving rehabilitation after an ischemic stroke. SUBJECTS AND METHODS: We studied 42 patients (12 females; age range, 50-88 yr) during rehabilitation after stroke, evaluating the relationship between the GH-IGF-I axis and the severity (National Institutes of Health stroke scale) and outcome [Rancho Los Amigos Scale of Cognitive Functioning (LCFS); Functional Independence Measure (FIM); modified Ranking Scale] from stroke. RESULTS: GH deficiency was demonstrated in five patients (11.9%). Peak GH after GHRH + arginine test and IGF-I levels did not correlate with severity of stroke. IGF-I was positively correlated with LCFS (r = 0.305, P < 0.05) and the difference between FIM on admission and at discharge from rehabilitation (DeltaFIM; r = 0.361, P < 0.02). Outcome indexes (LCFS, FIM at discharge, DeltaFIM) and occurrence of favorable outcome (modified Ranking Scale 0-1) were significantly (P < 0.05) higher in patients with IGF-I levels 161.8 mug/dl or greater (50th percentile of the patient distribution). LH-FSH deficiency (three cases), ACTH deficiency (one case), and hyperprolactinemia (two cases) were detected. One patient had primary hypogonadism, and six males had low testosterone with normal LH and FSH levels. By multivariate analysis, IGF-I level was the main significant predictor of DeltaFIM and LCFS. CONCLUSIONS: Ischemic stroke may be associated with pituitary dysfunction, particularly GH and gonadotropin deficiencies. The higher IGF-I levels observed in patients with better outcome suggest a possible neuroprotective role of IGF-I. Circulating IGF-I may predict functional performance during rehabilitation and ischemic stroke outcome.

Chronic glucocorticoid treatment alters spontaneous pulsatile parathyroid hormone secretory dynamics in human subjects.

OBJECTIVE: Spontaneous parathyroid hormone (PTH) secretory dynamics include tonic and pulsatile components. It is not known how glucocorticoids might alter these secretory dynamics. DESIGN: The aim of our study was to evaluate spontaneous fluctuations in serum PTH levels in six adult male patients (aged 31-64 years) receiving chronic (>6 months) therapy with glucocorticoids (daily dosage >7.5 mg of prednisone or dose equivalent of other corticosteroid) as compared with a control group of 10 age- and sex-matched normal subjects. METHODS: Peripheral venous blood sampling was performed every 3 min for 6 h from 0900 to 1500 h. Plasma PTH release profiles were subjected to deconvolution analysis, a method that resolves measured hormone concentrations into secretion and clearance components, and to an approximate entropy (ApEn) estimate, that in turn provides an integrated measure of the serial regularity or orderliness of the release process. RESULTS: In the glucocorticoid-treated group, the PTH tonic secretory rate was reduced (4.3+/-0.74 vs 8.8+/-1.4 pg/ml per min in controls, P = 0.017). There was, however, an increase in the fractional pulsatile PTH secretion (42+/-8.2 vs 18.3+/-3.9 pg/ml per min, P = 0.006) in glucocorticoid-treated vs normal subjects. Mean overall PTH concentration, as well as mean integrated area, was similar among normal and glucocorticoid-treated subjects. CONCLUSIONS: These results demonstrate, for the first time, that chronic glucocorticoid treatment induces a redistribution of spontaneous PTH secretory dynamics by reducing the amount released in tonic fashion and increasing the amount released as pulses.

Occurrence of pituitary dysfunction following traumatic brain injury.

Traumatic brain injury (TBI) may be associated with impairment of pituitary hormone secretion, which may contribute to long-term physical, cognitive, and psychological disability. We studied the occurrence and risk factors of pituitary dysfunction, including growth hormone deficiency (GHD) in 50 patients (mean age 37.6 +/- 2.4 years; 40 males, age 20-60 years; 10 females, age 23-87 years) with TBI over 5 years. Cranial or facial fractures were documented in 12 patients, and neurosurgery was performed in 14. According to the Glasgow Coma Scale (GCS), 16 patients had suffered from mild, 7 moderate, and 27 severe TBI. Glasgow Outcome Scale (GOS) indicated severe disability in 5, moderate disability in 11, and good recovery in 34 cases. Basal pituitary hormone evaluation, performed once at times variable from 12 to 64 months after TBI, showed hypogonadotrophic hypogonadism in 7 (14%), central hypothyroidism in 5 (10%), low prolactin (PRL) levels in 4 (8%), and high PRL levels in 4 (8%) cases. All subjects had normal corticotrophic and posterior pituitary function. Seven patients showed low insulin-like growth factor-I (IGF-I) levels for age and sex. Results of GHRH plus arginine testing indicated partial GHD in 10 (20%) and severe GHD in 4 (8%) cases. Patients with GHD were older (p <0.05) than patients with normal GH secretion. Magnetic resonance imaging demonstrated pituitary abnormalities in 2 patients; altogether pituitary dysfunction was observed in 27 (54%) patients. Six patients (12%) showed a combination of multiple abnormalities. Occurrence of pituitary dysfunction was 37.5%, 57.1%, and 59.3% in the patients with mild, moderate, and severe TBI, respectively. GCS scores were significantly (p <0.02) lower in patients with pituitary dysfunction compared to those with normal pituitary function (8.3 +/- 0.5 vs. 10.2 +/- 0.6). No relationship was detected between pituitary dysfunction and years since TBI, type of injury, and outcome from TBI. In conclusion, subjects with a history of TBI frequently develop pituitary dysfunction, especially GHD. Therefore, evaluation of pituitary hormone secretion, including GH, should be included in the long-term follow-up of all TBI patients so that adequate hormone replacement therapy may be administered.

Leptin stimulates growth hormone secretion via a direct pituitary effect combined with a decreased somatostatin tone in a median eminence-pituitary perifusion study.

The aim of this study was to examine the effect of recombinant human leptin on growth hormone (GH) secretion in perifused anterior pituitary slices from adult pigs. Anterior pituitary slices from sows were perifused and treated with recombinant human leptin (10 nM) and GH-releasing hormone (GHRH; 1 nM). In some experiments, pituitary slices were coincubated with stalk median eminence (SME). In a subset of the coincubation experiments, immunoneutralization of endogenous GHRH and somatostatin (SRIH) release was performed with antisera to GHRH and SRIH. Leptin increased GH secretion in pituitary slices alone (up to 100% vs. control at 40 min) as well as in pituitary slices coincubated with SME (up to 122% vs. control at 40 min). A significant difference was observed in GH secretion from pituitary slices when the tissue was coincubated with leptin and GHRH at a low concentration (0.1 nM), but not when GHRH was used at 1 and 10 nM. Furthermore, anti-SRIH antiserum increased GH release from pituitary slices in coincubation experiments with SME. Finally, SRIH secretion was significantly reduced by leptin (down by 35% vs. control from 0 to 30 min of treatment) in cultured SME. These data show that leptin is effective in stimulating GH secretion by acting at two different levels: (1) it stimulates GH secretion directly from pituitary slices, and (2) it reduces SRIH tone from the median eminence and, indirectly, increases GH secretion from the pituitary. These results support the hypothesis that leptin may be an interesting hormonal mediator of growth and related metabolic effects by acting directly on the hypothalamic-pituitary axis.

Long-term improvement of quality of life during growth hormone (GH) replacement therapy in adults with GH deficiency, as measured by questions on life satisfaction-hypopituitarism (QLS-H).

Questions on Life Satisfaction-Hypopituitarism (QLS-H) is a new quality-of-life (QoL) questionnaire developed for adults with hypopituitarism. To determine the effects of long-term GH treatment on QoL, we evaluated QLS-H Z-scores in 576 adult patients with GH deficiency (GHD) enrolled in HypoCCS, an international observational study, using data from five countries in which comparative QLS-H data from the general population were available. Baseline QLS-H Z-scores were significantly lower in GH-deficient patients than in the general population of the same age, gender, and nationality. Z-scores were also significantly lower in female patients vs. males (P = 0.006) and in adult-onset vs. childhood-onset GHD (P = 0.002). Multivariate analysis associated female gender, multiple pituitary hormone deficiencies, low serum IGF-I values (<75 micro g/liter), and concomitant antidepressant medication with low baseline Z-scores. QLS-H Z-scores increased from -1.02 +/- 1.43 (SD) at baseline to -0.25 +/- 1.34 (SD) after 1 yr of GH treatment (P < 0.001) and were no longer significantly different from the general population after 4 yr of treatment. There was no correlation between change in Z-score and GH dose or changes in IGF-I and IGF binding protein-3 during treatment. This study demonstrates that 1) improvements in QoL, as measured by the QLS-H, are maintained during long-term GH replacement therapy of adults with GHD, and 2) the QLS-H is a useful tool for evaluating QoL in hypopituitary patients treated in clinical practice. The authors suggest that evaluation of QoL should be a part of the routine clinical management of adult GH-deficient patients, complementing the measurement of surrogate biological markers or other clinical end points.

Decreased quality of life in adult patients with growth hormone deficiency compared with general populations using the new, validated, self-weighted questionnaire, questions on life satisfaction hypopituitarism module.

To develop reference ranges for the Questions on Life Satisfaction Hypopituitarism Module (QLS-H), a new quality of life questionnaire for patients with hypopituitarism, data from 8177 adults were collected in France, Germany, Italy, The Netherlands, Spain, the United Kingdom, and the United States QLS-H scores declined with age, were lower in females than males, and differed significantly among countries. From these reference ranges we derived equations for z-scores, which adjust for age, gender, and country. QLS-H results from 957 adults with GH deficiency (GHD) participating in clinical trials were analyzed. At baseline, QLS-H scores were lower in females and differed significantly among countries. QLS-H scores significantly increased after GH treatment (6-8 months), but differences by country persisted. Calculating z-scores for patients eliminated all gender and most country differences. Pooled z-scores (mean +/- SD) from all patients increased from -0.99 +/- 1.39 at baseline to -0.14 +/- 1.30 after GH treatment. Quality of life assessment in adults with GHD requires the use of z-scores to correct for age, gender, and country differences. This approach allows pooling of data from different cohorts and comparison with general populations. QLS-H scores in adults with GHD were significantly decreased at baseline and were almost normalized after 6-8 months of GH therapy.

Recombinant human GH replacement therapy and thyroid function in a large group of adult GH-deficient patients: when does L-T(4) therapy become mandatory?

The effect on thyroid function of GH administration to 66 adult patients with severe GH deficiency was studied. Seventeen patients were euthyroid, and 49 had central hypothyroidism and were adequately treated with L-T(4). Forty patients were assigned to a low recombinant human GH (rhGH) regimen (3 microg/kg body wt.d for 3 months followed by 6 microg/kg body wt.d for another 3 months) and 26 to a higher one (6 microg/kg body wt.d for 3 months followed by 12 microg/kg body wt.d for another 3 months). Serum IGF-I, TSH, free T(4) (FT(4)), free T(3) (FT(3)), reverse T(3), T(4)-binding globulin, and antithyroid autoantibody (TgAb and TPOAb) were measured in basal condition and after 3 and 6 months of therapy. Normalization of IGF-I levels was obtained after 6-month rhGH treatment in 67% of patients, independently from the dose, whereas a significant reduction in FT(4) and reverse T(3) levels was recorded (P < 0.01), without variations in all the other parameters studied, including serum TSH, FT(3), and T(4)-binding globulin circulating levels. Antithyroid autoantibodies were detected in 11 of 66 patients (16.6%). Eight of 17 (47%) euthyroid subjects and 9 of 49 (18.3%) central hypothyroid patients, despite adequate substitution at baseline, showed FT(4) levels under the normal range at the end of the study. Altogether, 17 of 66 patients (25.7%) worsened their thyroid function. This study shows that GH deficiency masks in a consistent number of adult patients a state of central hypothyroidism. Therefore, during rhGH treatment, a careful monitoring of thyroid function is mandatory to start or adjust L-T(4) substitutive therapy.

Human growth hormone replacement in adult hypopituitary patients: long-term effects on body composition and lipid status--3-year results from the HypoCCS Database.

The Hypopituitary Control and Complications Study is an international surveillance study evaluating efficacy and safety of GH therapy of adult GH-deficient patients in clinical practice. The present report examined baseline data from 1,123 adult onset (AO) and 362 childhood onset (CO) patients, as well as efficacy in 242 patients who had completed 3 yr of GH treatment. At study entry, mean height, body mass index, waist to hip ratio, and lean body mass were significantly (P < 0.001 for each) lower in CO compared with AO patients. After 3 yr on GH, lean body mass was significantly increased in AO males and females and CO males but not CO females, whereas fat mass was significantly decreased in AO males only. Serum total cholesterol was decreased in females (-0.32 +/- 1.00 mmol/liter; P = 0.045) and males (-0.36 +/- 0.96 mmol/liter; P = 0.004). High-density lipoprotein (HDL) cholesterol was increased for females (0.10 +/- 0.26 mmol/liter; P = 0.026) and males (0.10 +/- 0.34 mmol/liter; P = 0.022). The low-density lipoprotein/HDL ratio was decreased in AO males (-0.93 +/- 2.00; P = 0.003), AO females (-0.65 +/- 0.74; P < 0.001), and CO females (-0.69 +/- 0.76; P = 0.038), but the decrease in CO males was not significant (-0.84 +/- 2.85; P = 0.273). In AO patients, lean body mass increase from baseline was greatest in the those younger than 40 yr old, less but still significant in the middle group (40-60 yr) and unchanged in older (>60 yr) patients; conversely, decreases in the low-density lipoprotein/HDL ratio were small and not significant in the younger patients but greater and significant in the middle and older age groups. During the 3-yr treatment, 114 (7.7%) patients discontinued, including 9 (0.6%) for tumor recurrences, 9 (0.6%) for neoplasia, and 9 (0.6%) for side effects. Therefore, these observational data showed significant long-term efficacy of adult GH replacement therapy on body composition and lipid profiles and indicate that age is an important predictor of response.