Gender-affirming hormone treatment: friend or foe? Long-term follow-up of 755 transgender people.

PURPOSE: Gender-affirming hormone treatment (GAHT) is one of the main demands of transgender and gender diverse (TGD) people, who are usually categorised as transgender assigned-male-at birth (AMAB) and assigned-female-at birth (AFAB). The aim of the study is to investigate the long-term therapeutic management of GAHT, considering hormonal targets, treatment adjustments and GAHT safety. METHODS: A retrospective, longitudinal, observational, multicentre clinical study was carried out. Transgender people, both AMAB and AFAB, were recruited from two Endocrinology Units in Italy (Turin and Modena) between 2005 and 2022. Each subject was managed with specific and personalized follow-up depending on the clinical practice of the Centre. All clinical data routinely collected were extracted, including anthropometric and biochemical parameters, lifestyle habits, GAHT regime, and cardiovascular events. RESULTS: Three-hundred and two transgender AFAB and 453 transgender AMAB were included. Similar follow-up duration (p = 0.974) and visits' number (p = 0.384) were detected between groups. The transgender AFAB group reached therapeutic goals in less time (p = 0.002), fewer visits (p = 0.006) and fewer adjustments of GAHT scheme (p = 0.024). Accordingly, transgender AFAB showed a higher adherence to medical prescriptions compared to transgender AMAB people (p < 0.001). No significantly increased rate of cardiovascular events was detected in both groups. CONCLUSION: Our real-world clinical study shows that transgender AFAB achieve hormone target earlier and more frequently in comparison to transgender AMAB individuals. Therefore, transgender AMAB people may require more frequent check-ups in order to tailor feminizing GAHT and increase therapeutic adherence.

POR polymorphisms are associated with 21 hydroxylase deficiency.

PURPOSE: Genotype-phenotype correlation in congenital 21 hydroxylase deficiency is strong but by no means absolute. Indeed, clinical and hormonal features may vary among patients carrying similar CYP21A2 mutations, suggesting that modifier genes may contribute to the phenotype. Aim of the present study was to evaluate whether polymorphisms in the p450  oxidoreductase (POR) gene may affect clinical features in patients with 21 hydroxylase deficiency METHODS: Sequencing of the POR gene was performed in 96 patients with 21 hydroxylase deficiency (49 classic, 47 non-classic) and 43 control subjects. RESULTS: Prevalence of POR polymorphisms in patients with 21 hydroxylase was comparable to controls and known databases. The rs2228104 polymorphism was more frequently associated with non-classic vs classic 21 hydroxylase deficiency (allelic risk 7.09; 95% C.I. 1.4-29.5, p < 0.05). Classic 21 hydroxylase-deficient carriers of the minor allele in the rs2286822/rs2286823 haplotype presented more frequently the salt-wasting form (allelic risk 1.375; 95% C.I. 1.138-1.137), more severe Prader stage at birth (allelic risk 3.85; 95% C.I. 3.78-3.92), higher ACTH levels, and younger age at diagnosis. CONCLUSIONS: Polymorphisms in the POR gene are associated with clinical features of 21 hydroxylase deficiency both as regards predisposition to classic vs non-classic forms and severity of classic adrenal hyperplasia.

Quality of life and hormones after sex reassignment surgery.

BACKGROUND: Transpeople often look for sex reassignment surgery (SRS) to improve their quality of life (QoL). The hormonal therapy has many positive effects before and after SRS. There are no studies about correlation between hormonal status and QoL after SRS. AIM: To gather information on QoL, quality of sexual life and body image in transpeople at least 2 years after SRS,to compare these results with a control group and to evaluate the relations between the chosen items and hormonal status. SUBJECTS AND METHODS: Data from 60 transsexuals and from 60 healthy matched controls were collected. Testosterone,estradiol, LH and World Health Organization Quality of Life (WHOQOL-100) self-reported questionnaire were evaluated. Student's t test was applied to compare transsexuals and controls. Multiple regression model was applied to evaluate WHOQOL's chosen items and LH. RESULTS: The QoL and the quality of body image scores intranspeople were not statistically different from the matched control groups' ones. In the sexual life subscale,transwomen's scores were similar to biological women's ones, whereas transmen's scores were statistically lower than biological men's ones (P = 0.003). The quality of sexual life scored statistically lower in transmen than intranswomen (P = 0.048). A significant inverse relationship between LH and body image and between LH and quality of sexual life was found. CONCLUSIONS: This study highlights general satisfaction after SRS. In particular, transpeople's QoL turns out to be similar to Italian matched controls. LH resulted inversely correlated to body image and sexual life scores.

Medical treatment in gender dysphoric adolescents endorsed by SIAMS-SIE-SIEDP-ONIG.

PURPOSE: Despite international guidelines being available, not all gender clinics are able to face gender dysphoric (GD) youth population needs specifically. This is particularly true in Italy. Centers offering specialized support are relatively few and a commonly accepted Italian approach to GD youth has still not been defined. The aim of the present Position Statement is to develop and adhere to Italian guidelines for treatment of GD adolescents, in line with the "Dutch Approach", the Endocrine Society (ES), and the World Professional Association for Transgender Health (WPATH) guidelines. METHODS: An in-depth brainstorming on the application of International guidelines in the Italian context was performed by several dedicated professionals. RESULTS: A staged approach, combining psychological support as well as medical intervention is suggested. In the first phase, individuals requesting medical help will undergo a psycho-diagnostic procedure to assess GD; for eligible adolescents, pubertal suppression should be made available (extended diagnostic phase). Finally, from the age of 16 years, cross-sex hormonal therapy can be added, and from the age of 18 years, surgical sex reassignment can eventually be performed. CONCLUSIONS: The current inadequacy of Italian services offering specialized support for GD youth may lead to negative consequences. Omitting or delaying treatment is not a neutral option. In fact, some GD adolescents may develop psychiatric problems, suicidality, and social marginalization. With access to specialized GD services, emotional problems, as well as self-harming behavior, may decrease and general functioning may significantly improve. In particular, puberty suppression seems to be beneficial for GD adolescents by relieving their acute suffering and distress and thus improving their quality of life.

Childhood maltreatment in subjects with male-to-female gender identity disorder.

Childhood maltreatment (CM) is quite common and constitutes a nonspecific risk factor for a range of different psychiatric symptoms during lifespan. It has been demonstrated that sexual minorities are at higher risk of maltreatment and abuse, and a high proportion of transsexual subjects report CM. The aim of this study is to evaluate the prevalence of reported CM in a clinical sample of patients with male-to-female Gender Identity Disorder (MtF GID), and to explore the relationship between these early life events, body image and different psychopathological and clinical variables. A consecutive series of 162 patients with male genotype was evaluated from July 2008 to May 2010. A total of 109 subjects (mean age 36 ± 10 years) meeting the criteria for MtF GID and giving their informed consent were considered. The occurrence of CM experiences was evaluated through a face-to-face clinical interview. Patients were asked to complete the Body Uneasiness Test and Symptom Checklist-90 Revised. More than one-fourth of patients reported CM. Maltreated subjects reported a higher body dissatisfaction and display a worse lifetime mental health. The presence of reported CM in these patients has relevant psychopathological implications, and therefore should be carefully investigated.

Genotype, phenotype and hormonal levels correlation in non-classical congenital adrenal hyperplasia.

Non-classical congenital adrenal hyperplasia (NCAH) is a morbid condition sustained by the reduced function of one of the enzymes involved in the adrenal steroid biosynthesis pathway, mainly the 21-hydroxylase. Different degrees of enzyme activity impairment determine different clinical pictures, with childhood or post-pubertal onset. The aim of this study was to evaluate the relationship between genotype, phenotype, and adrenal hormonal levels in a group of 66 patients affected by NCAH attending outpatient pediatric or endocrinological Clinics. Our findings show that age at pubarche/menarche was significantly younger, height SD score) and Δ bone age-chronological age were significantly higher in patients with a more severe enzyme activity impairment, while cutaneous androgenization and menstrual irregularities in post-pubertal girls were not related to the grading of genotype.

Correlation between genotype and hormonal levels in heterozygous mutation carriers and non-carriers of 21-hydroxylase deficiency.

Congenital adrenal hyperplasia, both in its classic (CCAH) and non-classic form (NCAH), is a morbid condition sustained by the absent or reduced function of one of the enzymes involved in cortisol biosynthesis - mainly 21 hydroxylase - associated with different levels of clinical androgenization. In a wide group of relatives of patients affected by CCAH and NCAH (no.=222) and healthy volunteers (no.=30), a clinical, hormonal and genetic evaluation was performed in order to differentiate between the condition of heterozygous mutation carrier and non-carrier of any among 21-hydroxylase gene (CYP21) mutations. This study shows that clinical presentation and basal 17α-hydroxyprogesterone (17α-OHP) are not able to differentiate between heterozygous carriers and non-carriers, whereas 17α-OHP value after ACTH bolus is significantly different between heterozygous carriers and non-carriers: p<0.001 with a cut-off value of 3 ng/ml (90% sensitivity and 74,3% specificity). Moreover, our data indicate that 17α-OHP response to ACTH may be a useful tool to select subjects for genetic analysis.

Male sexual disturbances in liver diseases: what do we know?

The alterations of sexual function known as the erectile dysfunction are quite frequent among patients affected by liver diseases and they tend to increase in advanced liver failure. This process is directly linked to cirrhosis or its treatments, such as liver transplantation, or to certain drugs (e.g. beta-blockers). Independent of cirrhosis, other factors may cause sexual problems in these patients. Alcohol itself seems to worsen sexual function in the absence of cirrhosis. Viral hepatitis has an uncertain influence on male gonadic function and even antiviral therapy itself can worsen some seminal and hormonal parameters, although it is reversible. Quality of life may be greatly decreased in cases of cirrhosis where these alterations are present, so it is important to value and care for them, if possible. This review investigates the major male sexual disturbances in liver diseases of various origins.

Exogenous platelet-activating factor improves the motility of human spermatozoa evaluated with C.A.S.A.: optimal concentration and incubation time.

The objective of this study is to determine the optimal conditions for human semen incubation treated with exogenous platelet activating factor (ePAF) for intra-uterine insemination (IUI). This prospective study was carried out on 32 infertile men and each semen sample was processed with the ISolate Sperm Separation Medium, washed with sperm washing medium (SWM) and resuspended either in SWM alone (control samples), or with ePAF 0.1, 0.5, and 1.0 µM. Each concentration was subsequently incubated and evaluated at 5, 15, 30, and 60 min. The motility parameters were evaluated by the computer-aided sperm analysis (C.A.S.A.) system. Curvilinear velocity, straight line velocity, average path velocity, rapid and progressive motility significantly increased compared to control samples at an ePAF concentration of 0.1 µM (with at least 15 min of incubation). The best results were obtained with ePAF concentrations of: 0.1 µM (60 min of incubation) and 0.5 µM (30-60 min of incubation). In conclusion, results are enhanced when ePAF is added to standard semen preparation for IUI. An ePAF concentration of 0.1 µM, with an incubation time of 15 min, can be used for semen samples with normal motility. Whilst, for semen samples with poor motility, the ePAF concentration is best increased to 0.5 µM and/or the incubation time prolonged to 60 min.

Endocrine treatment of transsexual persons: an Endocrine Society Clinical Practice Guideline: commentary from a European perspective.

The treatment of transsexual subjects is a challenging task for the endocrinologist who, in collaboration with the mental health professional and the surgeon, is called upon to confirm the diagnosis and adjust hormonal treatment aimed at suppressing endogenous sex hormones and to develop hormone characteristics of the desired gender. These guidelines are structured to provide evidence-based suggestions or, where evidence is lacking, expert recommendations on diagnostic procedures and hormonal treatment in adolescent and adult transsexuals, including long-term care and eligibility for surgery. The multidisciplinary approach to treatment, the additional diagnostic role of hormone administration and the need to maintain hormone levels within the physiological range are key suggestions stressed in the guidelines which are particularly important for an endocrinologist unfamiliar with this field. The need for psychological assessment before surgery is not common in many countries and should be stressed further in the guidelines. Some important issues such as time and method of hormone withdrawal before surgery together with when and which hormones should be administered after sex reassignment surgery has been completed also remain unclear. These guidelines represent a pivotal document for endocrinologists setting a standard for the care of transsexuals and providing directions for future research.

Prolonged treatment with N-acetylcysteine and L-arginine restores gonadal function in patients with polycystic ovary syndrome.

Nitric oxide (NO) plays a wide spectrum of biological actions including a positive role in oocyte maturation and ovulation. Free radicals levels have been shown elevated in polycystic ovary syndrome (PCOS) and therefore would be responsible for quenching NO that, in turn, would play a role in determining oligo- or amenorrhea connoting PCOS. Eight patients with PCOS displaying oligo-amenorrhea from at least 1 yr underwent a combined treatment with N-acetylcysteine (NAC) (1200 mg/die) plus L-arginine (ARG) (1600 mg/die) for 6 months. Menstrual function, glucose and insulin levels, and, in turn, homeostasis model assessment (HOMA) index were monitored. Menstrual function was at some extent restored as indicated by the number of uterine bleedings under treatment (3.00, 0.18-5.83 vs 0.00, 0.00-0.83; p<0.02). Also, a well-defined biphasic pattern in the basal body temperature suggested ovulatory cycles. The HOMA index decreased under treatment (2.12, 1.46-4.42 vs 3.48, 1.62-5.95; p<0.05). In conclusion, this preliminary, open study suggests that prolonged treatment with NAC+ARG might restore gonadal function in PCOS. This effect seems associated to an improvement in insulin sensitivity.

Radiological treatment of male varicocele: technical, clinical, seminal and dosimetric aspects.

PURPOSE: The purpose of this study was to present our experience with percutaneous treatment of male varicocele considering technical, clinical, seminal and dosimetric aspects. MATERIALS AND METHODS: At baseline and at 6 months' follow-up, 290 male patients aged between 18 and 37 (average age 27.3 years) with left (266 cases) or bilateral (24 cases) varicocele underwent clinical assessment, Doppler ultrasonography (US), laboratory testing of free and total serum testosterone, leutenising hormone (LH) and follicle stimulating hormone (FSH) gonadotropins, inhibin B and spermiogram. In 223 cases, selective catheterisation of the spermatic vein was performed with a right transfemoral approach. Two hundred and six out of 223 underwent radiological treatment of varicocele; in 194, hydroxy-poliethoxydocanol (Aetoxysclerol) was used only whereas in 12 cases (5.8%), 5 ml of absolute alcohol and a Gianturco coil (0.038-in. Cook coil, 10 mmx50 mm) were also used. In 17/223 patients (7.6%), sclerotherapy was contraindicated or not technically feasible. Sixty-seven patients refused radiological treatment and were used as a control group. In 20 patients, the following parameters were measured: dose area product, entrance surface dose, effective dose and gonad dose. RESULTS: Technical success was achieved in 206/223 cases; two phlebographic examinations (immediately following administration of the sclerosing agent and after 15-20 min) showed prethrombotic endoluminal alterations of the internal spermatic vein. At 6 months' follow-up, 172/206 patients (83.49%) showed complete resolution of the varicocele whereas 34/206 (16.5%) had only partial disengorgement of the pampiniform plexus. In these 206 patients, the spermogram showed a significant increase in sperm concentration (52.1+/-4.1 vs. 44.2+/-3.6 million/ml, p=0.002) and motility (40.5+/-2.2 vs. 33.3+/-2.0%, p=0.0001), with negligible morphological changes. In the control group and in the other 17 untreated patients, no variations in seminal parameters were observed. The following minor procedural complications were recorded: two cases of acute abdominal pain, three of vagal crisis during administration of sclerosing agent that resolved spontaneously and two of spermatic cord inflammation that resolved within days after medical therapy. We recorded no statistically significant differences with regard to testicular volume or serum hormone levels between the treated and untreated groups. Maximum effective dose and maximum gonad dose equivalent were 6.9 mSv and 0.69 mSv, respectively. DISCUSSION AND CONCLUSIONS: Percutaneous radiological treatment of varicocele is a minimally invasive technique, which is well tolerated by patients and able to significantly improve seminal parameters. The principal technical limitation to percutaneous treatment is related to difficult selective catheterisation of the spermatic vein due to anatomic alterations, spasms and intimal dissection of the vein. Moreover, when the cremasteric vein is incontinent, inguinal surgical ligation provides better results. In the majority of cases, administration of at least 3 ml sclerosing agent at 3% ensures occlusion of the gonadic vein above the abdominal collaterals, which are responsible for long-term recurrence if not treated. In the remaining cases, absolute alcohol and metallic coils can be used to complete the treatment. The positive results in seminal parameters do not, however, allow for reliable assessment of patients' fertility. Finally, we believe that radiological procedures are not indicated or justified when prolonged catheterisation with elevated gonadic irradiation is needed.

Glutathione levels in patients with erectile dysfunction, with or without diabetes mellitus.

The reduced form of glutathione (GSH) is the most important cell antioxidant and is also an essential cofactor for nitric oxide (NO) synthase that synthesizes NO from l-arginine. Reduced levels of GSH, due both to a hyperglycaemia-induced increase of free radical production and to a decrease of NADPH levels [like in diabetes mellitus (DM)], can hamper the endothelial cell functions. This condition may play an important role in the aetiology of some clinical signs, like erectile dysfunction (ED). The aim of this study was to test the hypothesis that GSH concentration is reduced in patients with ED and type 2 diabetes mellitus. We studied 111 male patients with ED: 64 with diabetes (ED/DM) and 47 without diabetes (ED/wDM); 20 patients with diabetes but without ED (DM) and 26 male normal subjects as a control group (C). The GSH red blood cell concentration was significantly lower in ED than in C (X +/- SD; 1782.12 +/- 518.02 vs. 2269.20 +/- 231.56 mumol/L, p < 0.001). In particular, GSH was significantly reduced in ED/DM vs. ED/wDM (1670.74 +/- 437.68 vs. 1930.63 +/- 581.01 micromol/L, p < 0.01). In DM, GSH was significantly lower than in C and significantly higher than in ED/DM (2084.20 +/- 118.14 vs. 2269.20 +/- 231.56 and vs. 1670.74 +/- 437.68 micromol/L, p < 0.002 and p < 0.001 respectively). GSH showed a negative correlation with fasting glucose concentrations (r = -0.34, p < 0.01) and with the duration of DM (r = -0.25, p < 0.05). A GSH depletion can lead to a reduction of NO synthesis, thus impairing vasodilation in the corpora cavernosa.

Acute goserelin administration inhibits gonadotropin and androgen secretion in post-menopausal women with ovarian hyperandrogenism.

The aim of this study was to verify the effect of goserelin, a GnRH agonist, in women with post-menopausal virilization. Six patients with post-menopausal virilization and increase in 17-hydroxyprogesterone (17-OHP), total (TT) and free testosterone (FT) levels underwent single subcutaneous administration of goserelin, 3.6 mg. Serum 17-OHP, TT, FT, LH, FSH, E2, delta4 and 3alpha-andro-stanediol glucuronide levels were measured before and 4, 8 and 18 days after goserelin administration. Goserelin administration was followed by progressive inhibition of FSH and LH, which fell to premenopausal levels on day 18, and progressive normalization of androgen parameters. The low E2 levels recorded at baseline were further reduced by goserelin administration. Four patients then underwent ovariectomy while in two patients, rejecting surgical treatment, goserelin treatment was protracted up to 6 and 12 months, respectively, with remission of hyperandrogenism. This study shows that in post-menopausal patients with virilization GnRH agonist allows to confirm the diagnosis of gonadotropin-dependent ovarian hyperandrogenism: its administration induces inhibition of gonadotropin levels, normalization of androgen parameters, and remission of virilization when the treatment is protracted in patients waiting for surgery.

Follow-up of varicocele treated with percutaneous retrograde sclerotherapy: technical, clinical and seminal aspects.

Varicocele is a common cause of male infertility; it can be treated by percutaneous retrograde embolization of the internal spermatic vein in order to improve sperm parameters and male fertility. The aim of this study was to verify the improvement of semen parameters after varicocele retrograde sclerotherapy. We evaluated 223 patients with left (206) or bilateral (17) varicocele (mean age +/- SD, 27.3 +/- 4.7 yr, range 18-37) by clinical, Doppler and seminal examinations; all the patients underwent phlebography, using 5F Cobra catheter from the right femoral vein access to the internal spermatic vein and varicocele sclerosing with Hydroxy-polyaethoxydodecanol. Doppler and seminal examinations 6 months after sclerotherapy were requested for the follow-up. Sixty-seven patients with left or bilateral varicocele who did not undergo sclerotherapy were studied as controls. Six months after sclerotherapy, a complete resolution of left varicocele was present in 172 patients (77.1%), while a partial improvement was obtained in 34 patients (15.3%). In these 206 patients seminal examination showed a significant improvement of sperm concentration (mean +/- SEM, 52.1 +/- 4.1 vs 44.2 +/- 3.6 million/ml, p = 0.002) and progressive motility (40.5 +/- 2.2 vs 33.3 +/- 2.0%, p = 0.0001), but not of normal sperm morphology (38.9 +/- 2.3 vs 37.4 +/- 2.1%, ns). In the control group no significant variations of seminal parameters were observed 6 months after the basal examination. In conclusion, varicocele retrograde sclerotherapy is a well-tolerated technique with a low cost-benefit ratio, able to improve semen parameters.

Gonadotroph cell pituitary adenomas in males.

BACKGROUND: Considered exceptional in the past, gonadotroph cell pituitary adenomas account for 3.5-6.4% of total surgically excised pituitary adenomas when examined with immunospecific staining. The aim of this study was to describe the clinical, hormonal, radiological and immunohistochemical features, the management and the follow-up of our patients with gonadotroph adenoma. METHODS: In this retrospective study we describe 14 male subjects aged 19-70 yrs affected by gonadotroph cell pituitary adenomas; the patients were studied by hormonal, radiological and immunohistochemical investigations and followed up for 3-13 yrs by ambulatory and/or hospitalized care. RESULTS: Visual impairment and/or decreased libido and erectile dysfunction were the symptoms at presentation. Increased serum gonadotropin concentrations were shown in 3 patients. Reduced levels of testosterone were present in 9 patients, and normal in the remainder. At diagnosis all patients had pituitary macroadenomas, with wide extrasellar extension in 12. All patients underwent trans-sphenoidal surgery and immunohistochemical staining of surgically excised specimens showed the presence of gonadotroph and alpha-subunit cells in all pituitary adenomas. After surgery 3 patients had clear radiological evidence of normal pituitary; in the others a doubtful MRI picture or a residual adenomatous tissue were present. In the patients who did not undergo radiotherapy immediately after surgery, a regrowth of tumoral tissue was shown in 1-10 yrs. CONCLUSIONS: We stress the importance of a close follow-up of patients with gonadotroph adenomas after surgery, and we raise the question of whether radiotherapy may be useful for avoiding any further adenomatous regrowth.

[International prostate symptom score: comparison of doctor and patient]. / International prostate symptom score: medico e paziente a confronto.

The AUA 7 score was originally designed and validated to be self administrated to patients with LUTS, its subsequent endorsement by the WHO - BPH committee made it the most widely used. Translation into different was provided and sometime validated. Aim of the study was to investigate the possibility to self administer the IPSS questionnaire to patients referred to our Institution for lower urinary tract symptoms. Two hundred and thirty-tree consecutive patients were given the IPSS questionnaire as a part of the routine diagnostic schedule; a senior resident was available to answer any possible question from the patient. After the form was returned, a second IPSS questionnaire was filled in by investigator following patient interview. Data were entered into an Excel database and the following parameters were investigate: number of forms completely filled in by patient, number of question answered in incomplete forms, degree of concordance between patient and investigator. One hundred and fifteen patients were able to fill the AUA 7 form completely; the quality of life question was answered by ninety-six patients only. Comparison of individual scores provided by the patient or assigned by the investigator showed a trend for the physician to underscore the patient problem for question 1-4 and to overestimate it in questions 5 to 7. At the lower range of the IPS score (0-7) no significant different between physician and patient was found. In the intermediate range (8-19) the physician tended to overestimate the patient symptoms. The reverse situations was found in the high score range (20-35). Globally, there was a trend for the patient score to be higher than the one assigned by the investigator, Doctor IPSS and quality of life scores appeared to be significantly related. No relation was found between doctor IPSS and the degree of bladder outlet obstruction as measured by parameter of pressure-flow study and diagnostic nomograms. The IPSS form appeared to be a difficult questionnaire for our patients and less than half of them were able to fill it in properly. Overall, the investigators tended to underestimate the patient voiding disturbances. Careful linguistic review of the Italian version of the IPSS questionnaire is required to make self evaluation of patient symptom possible. Symptom grading by a trained investigator did not seem to introduce any significant bias which might be of importance for the sake of clinical trials.

[The Studer orthotopic ileal neobladder: patient compliance]. / Neovesciche ileali ortotopiche sec. Studer: "compliance" del paziente.

Radical cystectomy represents the gold standard for locally advanced bladder cancer. Orthotopic neobladder is considered the surgical option which may offer the least modification of body image and the best life condition to the unfortunate patient requiring radical cystectomy. Objective of this study was to investigate long term clinical outcome of orthotopic ileal bladder substitute with special reference to late complications and patient compliance. Twenty male patients 48 to 71 years old (mean age 59.8 + 7.4 years) underwent radical cystectomy and Studer orthotopic ileal neobladder for invasive carcinoma of the bladder. Before surgery all patients filled in a phycometric test for evaluating their knowledge capacity; after surgery they underwent a course of biofeedback and instructed to avoid overfilling of the neobladder with timed micturitions and a regular regimen of fluid intake. Pressure flow study was included in the routine follow-up carried out at six months and then yearly. Seventeen patients (85%), with a good knowledge capacity, reported a good compliance to the modified life style imposed by the bladder substitute, they all were dry during the day with 3 to 5.5 hour interval between micturitions; fourteen of these patients were continent at night with timed micturitions every 3-4 hours (mean: 3.2); an average cystometric capacity of 450 ml was found in these patients with no residual urine; three patients (18%) had incontinence episodes once or twice a week during the night; no decompensation of the neobladder, significant ureteral reflux or dilatation were reported; elongation of the afferent loop was found in one patient following small bowel resection for ileal volvulus. Three patients (15%), with a reduced knowledge capacity, who did not follow the suggested life style: fluid intake was irregular, micturitions were not timed during both day and night time, had residual urine larger than 400 ml. and incontinence episodes requiring pads; nevertheless no dilation of the upper urinary tract was found. Our experience suggests that careful compliance of patients to the new life style imposed by the orthotopic neobladder is of importance to avoid its decompensation. The possible causative role of gastrointestinal hormones such as enteroglucagon (EG) and peptide tyrosine-tyrosine (PYY) in the elongation of the afferent limb of the Studer neobladder is proposed. In conclusion, we believe that orthotopic ileal neobladder is an ideal surgical option on in the young, educated and cooperative patients.