Italian Guidelines for the Management of Sporadic Primary Hyperparathyroidism.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of sporadic primary hyperparathyroidism (PHPT) in adults. PHPT management in pregnancy was not considered. METHODS: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology (AME) and Società Italiana dell'Osteoporosi, del Metabolismo Minerale e delle Malattie dello Scheletro (SIOMMMS) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for the clinical practice recommendations. RESULTS: The present GL provides recommendations about the roles of pharmacological and surgical treatment for the clinical management of sporadic PHPT. Parathyroidectomy is recommended in comparison to surveillance or pharmacologic treatment in any adult (outside of pregnancy) or elderly subject diagnosed with sporadic PHPT who is symptomatic or meets any of the following criteria: • Serum calcium levels >1 mg/dL above the upper limit of normal range. • Urinary calcium levels >4 mg/kg/day. • Osteoporosis disclosed by DXA examination and/or any fragility fracture. • Renal function impairment (eGFR <60 mL/min). • Clinic or silent nephrolithiasis. • Age ≤50 years. Monitoring and treatment of any comorbidity or complication of PHPT at bone, kidney, or cardiovascular level are suggested for patients who do not meet the criteria for surgery or are not operated on for any reason. Sixteen indications for good clinical practice are provided in addition to the recommendations. CONCLUSION: The present GL is directed to endocrinologists and surgeons - working in hospitals, territorial services or private practice - and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

Value of repeated US-guided fine-needle aspiration (US-FNAB) in the follow-up of benign thyroid nodules: a real-life study based on the MoCyThy (Modena's Cytology of the Thyroid) DATABASE with a revision of the literature.

PURPOSE: The utility of repeating ultrasound-guided fine-needle aspiration (US-FNAB) in the follow-up of benign (THY2) thyroid nodules is still debated. The aim of this study was to retrospectively investigate the diagnostic value of re-biopsy of thyroid nodules following an initially benign result. METHODS: We retrospectively analyzed US-FNABs performed at the Unit of Endocrinology of Modena from 2006 to 2009. The firstly benign cytological result was compared with the cytological results of subsequent US-FNABs (2nd and/or 3rd) executed on the same nodule. RESULTS: Among 10449 US-FNABs, 6270 (60%) received a THY2 cytological categorization. Of them, 278 (4.43%) underwent a subsequent US-FNAB: 86.7% maintained the same cytology, 32 (11.5%) changed to THY3 (indeterminate) and 5 (1.8%) to THY4 (suspicious of malignancy). Among the 24 nodules addressed to surgery, 9 (37%) were histologically malignant, with an overall miss rate of 3.2%. Male patients had higher risk of discordant results at subsequent US-FNAB (p = 0.005, OR:3.59, 95%CI:1.453-7.769) while dimensional increase above 5 mm was predictive of concordant benign cytology (p = 0.036, OR:0.249, 95%CI:0.068-0.915). Age, suspicious US characteristics, and distance between US-FNABs resulted not predictive. CONCLUSIONS: Re-biopsy of benign nodules confirmed the benign nature in most cases. In case of discordant cytology, relocation in indeterminate category was the most common. The histological diagnosis of cancer occurred in one quarter of nodules surgically removed, with a low overall clinically significant miss rate. Thus, a small percentage of false negatives exists; males and subjects with US suspicious nodules should be carefully followed-up, considering case by case re-biopsy possibility.

A Prospective Multicenter Study Examining the Relationship Between Thyroid Cancer Treatment Outcomes and the Presence of Autoimmune Thyroiditis.

Background: There is some controversy on the potential relationship between autoimmune processes and clinicopathologic features as well as prognosis of differentiated thyroid cancer (DTC), and the evidence is limited by its largely retrospective nature. We examined the relationship between the presence of autoimmune thyroiditis (AT) and 1-year thyroid cancer treatment outcomes in a large multicenter study using prospectively collected data. Methods: We included data from consecutive DTC patients enrolled in the Italian Thyroid Cancer Observatory (ITCO) database (NCT04031339). We divided the groups according to the presence (AT) or absence (no autoimmune thyroiditis [noAT]) of associated AT. We used propensity score matching to compare the clinical features and outcomes between the two groups at 1-year follow-up. Results: We included data from 4233 DTC patients, including 3172 (75%) females. The American Thyroid Association (ATA) risk levels were as follows: 51% (2160/4233) low risk, 41.3% (1750/4233) intermediate risk, and 7.6% (323/4233) high risk. There were 1552 patients (36.7%) who had AT. Before propensity score matching, AT patients were significantly younger and had a smaller and bilateral tumor (p < 0.0001). Patients with AT more frequently fell into the low- and intermediate-risk categories, while the ATA high risk was more frequent among noAT patients (p = 0.004). After propensity score matching, patients with AT more frequently showed evidence of disease (structural/biochemical incomplete response) versus excellent/indeterminate response, compared with patients without AT (7.3% vs. 4.5%, p = 0.001), with an odds ratio of 1.86 ([confidence interval: 1.3-2.6], p = 0.0001). However, when considering only structural persistence as the outcome, no statistically significant differences were observed between patients with or without AT (3.4% vs. 2.7%, p = 0.35). The elevated risk associated with the ATA intermediate and high risk at diagnosis remained consistently statistically significant. Conclusions: In this large prospective series, biochemical persistence was more frequent, at 1-year follow-up, in AT patients. However, there was no significant association between the presence of AT and structural persistence of disease. These findings may be explained by the presence of a residual thyroid tissue.

Bone Metastases and Health in Prostate Cancer: From Pathophysiology to Clinical Implications.

Clinically relevant bone metastases are a major cause of morbidity and mortality for prostate cancer patients. Distinct phenotypes are described: osteoblastic, the more common osteolytic and mixed. A molecular classification has been also proposed. Bone metastases start with the tropism of cancer cells to the bone through different multi-step tumor-host interactions, as described by the "metastatic cascade" model. Understanding these mechanisms, although far from being fully elucidated, could offer several potential targets for prevention and therapy. Moreover, the prognosis of patients is markedly influenced by skeletal-related events. They can be correlated not only with bone metastases, but also with "bad" bone health. There is a close correlation between osteoporosis-a skeletal disorder with decreased bone mass and qualitative alterations-and prostate cancer, in particular when treated with androgen deprivation therapy, a milestone in its treatment. Systemic treatments for prostate cancer, especially with the newest options, have improved the survival and quality of life of patients with respect to skeletal-related events; however, all patients should be evaluated for "bone health" and osteoporotic risk, both in the presence and in the absence of bone metastases. Treatment with bone-targeted therapies should be evaluated even in the absence of bone metastases, as described in special guidelines and according to a multidisciplinary evaluation.

Long-Term Use of Temozolomide as Safe and Effective Therapy for an Aggressive Corticotroph Adenoma in a Very Old Patient.

BACKGROUND: Temozolomide (TMZ) is safe and effective in the treatment of aggressive pituitary adenomas (PAs). However, the optimal duration of TMZ therapy is still unknown. Moreover, data about administration of TMZ in elderly (≥65 years) people to treat aggressive PAs are scarce. We report the case of the oldest female patient undergoing the longest TMZ protocol described so far to treat an aggressive, initially silent corticotroph PA. CASE REPORT: The patient initially underwent partial surgical removal of the PA. Subsequent treatment with cabergoline was applied, but it was unsuccessful in controlling the growth of the residual tumor. Pasireotide and external radiation also showed to be ineffective; therefore, treatment with TMZ was started at the standard dose of 200 mg/m2/day for 5 days every 4 weeks for a total of 47 cycles. At the time of treatment's beginning, the patient was 83 years old. Radiological follow-up documented a progressive, remarkable reduction of the adenoma and the last imaging, after 39 cycles of TMZ, showed an intrasellar lesion with large areas of cystic degeneration. The patient also developed adrenal deficiency managed with glucocorticoid replacement. No major side effects were observed throughout the treatment, with exception of nausea, well controlled with anti-emetic medication. TMZ therapy was discontinued after 47 cycles; hormonal and imaging follow-up investigations documented sustained functional and dimensional response. CONCLUSIONS: Our case supports the long-term use of TMZ, confirming its safety and efficacy also for elderly patients.

Robotic Versus Laparoscopic Adrenalectomy: Pluriannual Experience in a High-Volume Center Evaluating Indications and Results.

Background: Robotic adrenalectomy offers several clinical benefits if compared with laparoscopic adrenalectomy; however, its superiority is still under debate. The aim of this study was the investigation of differences between the two techniques, and a comparison when approaching right or left side adrenal lesions was further conducted. Materials and Methods: All patients undergoing laparoscopic and robotic unilateral adrenalectomy at our institution from January 2006 to December 2019 were collected and retrospectively analyzed. Statistical analysis was conducted; differences between the two cohorts were reported. Results: A total of 160 cases were included (84 patients in laparoscopic adrenalectomy-group [LA-g] 76 cases in robotic adrenalectomy-group [RA-g]). The groups were homogeneous for demographic data. No intraoperative complications were reported; mean amount of intraoperative blood loss was comparable. No cases of conversion to open surgery were required. RA-g presented a longer operative time than LA-g for right adrenalectomy (P = .05), no differences were noted for left side (P = .187). Overall morbidity was 21% for LA-g and 10.5% for RA-g (P = .087), with an inferior rate of surgical complications for RA-g (P = .024), and for robotic left adrenalectomy than robotic right procedure (P = .03). Length of hospital stay was shorter for RA-g (P = .005). Conclusions: Robotic adrenalectomy presents similar outcomes as laparoscopic approach with some benefits for selected cases. Left adrenal lesions seem to receive greater advantages from robotic technique. Large randomized controlled trials are required to determine the role of robotic adrenal surgery and if the indication can be standardized based on the laterality of adrenal procedure.

The Added Value of Operator's Judgement in Thyroid Nodule Ultrasound Classification Arising From Histologically Based Comparison of Different Risk Stratification Systems.

Objective: Several ultrasound classifications for thyroid nodules were proposed but their accuracy is still debated, since mainly estimated on cytology and not on histology. The aim of this study was to test the diagnostic accuracy and the inter-classification agreement of AACE/ACE-AME, American Thyroid Association (ATA), British Thyroid Association (BTA), and Modena Ultrasound Thyroid Classification (MUT) that stratifies malignancy risk considering also the clinician subjective impression. Methods: A prospective study collecting thyroid nodule features at ultrasound and histological diagnosis was conducted. Ultrasound features were collected following a preformed checklist in candidates for surgery because of indeterminate, suspicious, or malignant cytology. All the nodules, besides the cytologically suspicious one, were blinded analyzed. MUT score was applied prospectively, and the others retrospectively. Sensitivity, specificity, diagnostic cut-off value, and accuracy of each classification were calculated. The overall agreement between classifications was tested by Bland-Altman, and agreement between single nodule analysis by different classifications by Weighted Cohen's Kappa. Results: In classifying a total of 457 nodules, MUT has the highest accuracy (AUC 0.808) and specificity (89%), followed by ATA and BTA, and finally by AACE/ACE-AME. ATA, BTA, and MUT are highly interchangeable. Considering agreement between single nodule analyses, ATA and BTA had the best (κ = 0.723); AACE/ACE-AME showed slight agreement with BTA (κ = 0.177) and MUT (κ = 0.183), and fair agreement with ATA (κ = 0.282); MUT had fair agreement with both ATA (κ = 0.291) and BTA (κ = 0.271). Conclusion: Classifications have an acceptable overall diagnostic accuracy, improved using a less rigid system that takes into consideration operator subjective impression.

De novo Lesions Frequently Develop in Adult Normal Thyroid Over Almost Six Years.

Purpose: In order to understand how thyroid abnormalities emerge over time in adults, we evaluated incidence of thyroid diseases in healthy subjects, after almost 6 years from a previous negative ultrasound. Methods: Anamnestic and physical data were collected. Ultrasound neck evaluation was performed by an experienced endocrinologist, recording detailed thyroid and nodules characteristics. Nodules were classified according to American Thyroid Association classification for prediction of cancer risk. Serum samples were collected for subsequent evaluations (TSH, free thyroid hormones, calcitonin, anti-thyroid antibodies). Anamnestic, clinical, sonographic, and serological characteristics were analyzed with logistic regression analysis for subjects with nodules vs. those without. Results: One hundred and eleven subjects were enrolled (43M, 68F). Half of them developed nodules, mainly smaller than 1 cm and without suspicious characteristics. Ninety-seven percent were euthyroid. Only 4% had serological diagnosis of thyroiditis. Incidence of thyroid diseases was higher in women, especially nulliparous. Comparing clinical characteristics of subjects with and without nodules, the only statistically significant difference concerned thyroid volume adjusted for body weight or surface (p < 0.05), but not residual volume excluding nodules. Multivariate logistic regression analysis showed that female gender, higher BMI-adjusted thyroid volume and residual thyroid volume excluding nodules, nulliparity, age, and fT3 increase the risk of developing nodules. Conclusions: These results demonstrate that adult thyroid tissue undergoes changes that are already detectable by US after almost 6 years. Half of the enrolled subjects developed de novo nodules or colloid cysts of poor clinical relevance.

Expression and clinicopathological role of miR146a in thyroid follicular carcinoma.

PURPOSE: Dysregulation of microRNA expression has been involved in the development and progression of follicular thyroid carcinoma (FTC). The aim of this work was to study the expression of miRNA146a in FTC and the association with clinicopathological features of the disease. METHODS: Thirty-eight patients affected by FTC were included in the study. Twenty patients carrying follicular thyroid adenoma (FA) were also enroled as the benign counterpart of FTC. Total RNA including miRNA146a was extracted from formalin-fixed paraffin-embedded (FFPE) pairs of affected/unaffected tissue and its expression was assessed by real-time PCR. Two selected target genes, TRAF6 (tumour necrosis factor receptor-associated factor 6) and IRAK1 (Il-1 receptor-associated kinase 1/2), were also analysed. RESULTS: miR146a expression in FTC tissue was overall not downregulated in malignant versus unaffected tissue, but its expression was inversely correlated with clinicopathological features of FTCs at diagnosis. A decreased expression of miR146a became apparent in FTC thyroid tissue of widely compared to minimally invasive tumours. However, miR146a expression differences between contralateral unaffected tissue (extra-FTC) and FTC were not observed regardless of clinicopathological features. IRAK1, a known target for miR146a, was upregulated in FTC and the increase was mainly appreciable in Hurtle FTC variant. Unexpectedly, miR146a did not correlate with TRAF6 showing an inverse trend compared to IRAK1 although both genes regulate the activity of nuclear factor- kB (NF-kB). CONCLUSION: The results of this study indicate that downregulation of miR146a, inversely correlated with clinicopathological features of FTCs at diagnosis and suggest a possible involvement of miR146a in FTC development. IRAK1 over-expression in FTC may be related to tumour development/progression. In vitro experiments are needed to support this hypothesis.

Cured primary hyperparathyroidism after fine-needle aspiration biopsy-induced parathyroid disappearance.

Spontaneous or fine-needle aspiration (FNAB)-induced remission of primary hyperparathyroidism (PHPT) may occur, especially for cystic lesions. However, the disease generally relapses over a short time period. We present a case of PHPT due to an enlarged hyperfunctioning parathyroid that underwent long-term (almost 9 years) clinical and ultrasonographic remission after the disappearance of the lesion following ultrasound (US)-assisted FNAB. A 67-year-old woman with PHPT underwent biochemical and US examinations that confirmed the diagnosis and showed a lesion suggestive for parathyroid adenoma or hyperplasia. US-FNAB of the lesion confirmed its parathyroid nature by means of elevated levels of parathyroid hormone within the needle washing fluid. At the second visit, the patient referred slight neck swelling that resolved spontaneously in the days after the US-FNAB. At subsequent follow-up, the enlarged parathyroid was not found; it was visible neither with US nor with magnetic resonance imaging. Biochemical remission persists after 9 years. This is the first reported case of cure of PHPT after US-FNAB performed on a hyperfunctioning parathyroid resulting in its complete disappearance over a period of 9 years of negative biochemical and ultrasonographic follow-up. LEARNING POINTS: Spontaneous or fine-needle aspiration-induced remission of primary hyperparathyroidism can occur.Both circumstances may present disease relapse over a variable time period, but definite remission is also possible even though long-term periodic follow-up should be performed.Parathyroid damage should be ruled out in case of neck symptomatology after parathyroid fine-needle aspiration or spontaneous symptomatology in patients with history of primary hyperparathyroidism.

High-Resolution Melting Is a Sensitive, Cost-Effective, Time-Saving Technique for BRAF V600E Detection in Thyroid FNAB Washing Liquid: A Prospective Cohort Study.

OBJECTIVE: The diagnostic accuracy of thyroid fine needle aspiration biopsy (FNAB) can be improved by the combination of cytological and molecular analysis. In this study, washing liquids of FNAB (wFNAB) were tested for the BRAF V600E mutation, using the sensitive and cost-effective technique called high-resolution melting (HRM). The aim was to demonstrate the feasibility of BRAF analysis in wFNAB and its diagnostic utility, combined with cytology. DESIGN: Prospective cohort study. METHODS: 481 patients, corresponding to 648 FNAB samples, were subjected to both cytological (on cells smeared onto a glass slide) and molecular analysis (on fluids obtained washing the FNAB needle with 1 ml of saline) of the same aspiration. BRAF V600E analysis was performed by HRM after methodological validation for application to wFNAB (technique sensitivity: 5.4%). RESULTS: The cytological results of the FNAB were: 136 (21%) nondiagnostic (THY1); 415 (64%) benign (THY2); 80 (12.4%) indeterminate (THY3); 9 (1.4%) suspicious for malignancy (THY4); 8 (1.2%) diagnostic of malignancy (THY5). The BRAF V600E mutation was found in 5 THY2, 2 THY3, 6 THY4 and 6 THY5 samples. Papillary carcinoma diagnosis was histologically confirmed in all BRAF+ thyroidectomized patients. BRAF combined with cytology improved the diagnostic value compared to cytology alone in a subgroup of 74 operated patients. CONCLUSIONS: HRM was demonstrated to be a feasible method for BRAF analysis in wFNAB. Thanks to its sensitivity and cost-effectiveness, it might be routinely used on a large scale in clinical practice. In perspective, standby wFNAB samples could be analyzed a posteriori in case of indeterminate cytology and/or suspicious findings on ultrasound.

Are pre-miR-146a and PTTG1 associated with papillary thyroid cancer?

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy, with a steadily increasing incidence in the last few decades worldwide. The predisposition to developing this carcinoma by the heterozygous state of rs2910164 within the precursor of the miR-146a has been reported, but recently not confirmed. Interestingly, on the same chromosome, almost 50 kb separate the pre-miR-146a from the pituitary tumor-transforming gene 1 (PTTG1), a proto-oncogene involved in several tumors, including thyroid cancers. In this study, we analyzed, using a case-control design, the genetic association between PTC and the genomic region encompassing pre-miR-146a rs2910164 and PTTG1 rs1862391 and rs2910202. We enrolled 307 affected patients and 206 healthy controls. The possible presence of thyroid nodules in controls was excluded by ultrasonography. All the cases were submitted to single-nucleotide polymorphism (SNP) genotyping of pre-miR-146a and PTTG1, and risk association analyses were carried out. The genotypic and allelic frequencies of pre-miR-146a rs2910164 were not statistically different in the patients and controls, and this SNP was not in linkage disequilibrium with the investigated PTTG1 SNPs. Consistently, meta-analyses, the first including all the affected cases published to date, did not confirm the previously reported association of the heterozygous CG genotype with PTC. The PTTG1 SNPs exhibited the same allelic frequency in the patients and controls and were not associated with the disease. In conclusion, in a well-selected Italian population, neither pre-miR-146a rs2910164 nor PTTG1 rs1862391 and rs2910202 were found to be associated with the risk of developing PTC.

The diagnostic value of calcitonin measurement in wash-out fluid from fine-needle aspiration of thyroid nodules in the diagnosis of medullary thyroid cancer.

OBJECTIVES: The diagnostic value of calcitonin measurement in fine-needle aspiration biopsy (FNAB) wash-out fluid (Ct-FNAB) for medullary thyroid cancer (MTC) remains to be determined. This prospective study aimed to assess the diagnostic value of Ct-FNAB in thyroid nodules in comparison with basal serum calcitonin (Ct), pentagastrin-stimulated Ct (Pg-sCt), and cytology. METHODS: Among patients with goiter addressed with US-FNAB who had an initial clinical suggestion for thyroidectomy, 27 patients with thyroid nodule/s (n = 60) and normal, borderline, or increased Ct fulfilled the criteria for thyroidectomy. All 27 patients (enrolled according to exclusion/inclusion criteria) underwent ultrasonography (US), Ct, Pg-sCt, US-assisted FNAB of each patient's nodule for both cytology, and Ct-FNAB before thyroidectomy. RESULTS: Ct-FNAB always resulted in >1,000 pg/mL in MTC nodules at histology. For values between 36 and 1,000 pg/mL, MTCs and nodular or micronodular C-cell hyperplasia (CCH) results overlapped. Most of the nodules without MTC and/or CCH had Ct-FNAB ≤ 17 pg/mL. Ct-FNAB diagnostic power was superior to and similar to other diagnostic procedures (Ct, Pg-sCt, and cytology) in identifying both MTC and CCH, and MTC alone, respectively. CONCLUSION: The diagnostic power of Ct-FNAB is valuable compared with other routine procedures. Ct-FNAB is highly reliable for the early detection and accurate localization of MTC in thyroid nodules, but it does not differentiate between MTC and CCH. Ct-FNAB is an extremely valuable diagnostic tool, especially considering that other diagnostic procedures do not provide a definitive diagnosis, and it can be included in the clinical work-up of thyroid nodules when MTC is suspected.

Screening of Cushing's syndrome in outpatients with type 2 diabetes: results of a prospective multicentric study in Italy.

CONTEXT: Cushing's syndrome may remain unrecognized among patients referred for metabolic syndrome; thus, a proactive screening has been suggested in certain patient populations with features of the disorder. However, conflicting data have been reported on the prevalence of Cushing's syndrome in patients with type 2 diabetes. OBJECTIVE: Our aim was to evaluate the prevalence of unsuspected Cushing's syndrome among outpatients with type 2 diabetes. DESIGN AND SETTING: This was a cross-sectional prospective study in 24 diabetes clinics across Italy. PATIENTS: Between June 2006 and April 2008, 813 patients with known type 2 diabetes without clinically overt hypercortisolism were evaluated. Follow-up of the study was closed in September 2010. Patients were not selected for characteristics conferring a higher pretest probability of hypercortisolism. Patients underwent a first screening step with the 1-mg overnight dexamethasone suppression test. RESULTS: Forty patients failed to suppress serum cortisol less than 5.0 µg/dl (138 nmol/liter) and underwent a standard 2-d, 2-mg dexamethasone suppression test, after which six patients (0.6% of the overall series) failed to suppress cortisol less than 1.8 µg/dl (50 nmol/liter), receiving a definitive diagnosis of Cushing's syndrome that was adrenal dependent in five patients. Four patients were cured, being able to discontinue, or reduce, the glucose-lowering agents. CONCLUSIONS: The present data do not support widespread screening of patients with type 2 diabetes for Cushing's syndrome; however, the disorder is less rare than previously thought when considering epidemiology of type 2 diabetes. Our results support a case-finding approach in patients with uncontrolled diabetes and hypertension despite appropriate treatment.

Testosterone action on erythropoiesis does not require its aromatization to estrogen: Insights from the testosterone and estrogen treatment of two aromatase-deficient men.

Androgens act on erythropoiesis, but the relative role of testosterone (T) and estradiol (E(2)) on erythropoietic parameters in men is a poorly investigated issue. In order to evaluate separately the effects on erythropoiesis of high-dose T administration alone and of physiological dose of E(2) administration alone two adult men with aromatase deficiency were assessed before and during each treatment. Blood cell count, hemoglobin (Hb), hematocrit (Hct), erythrocyte mean cell volume (MCV), erythrocyte mean corpuscular hemoglobin (MCH), erythrocyte mean corpuscular hemoglobin concentration (MCHC), serum ferritin, iron and total iron-binding capacity (TIBC), serum erythropoietin, serum total testosterone and estradiol were evaluated. Hb, Hct and red cell count rose during testosterone treatment, consistently with the increase in circulating testosterone, but failed to increase during estradiol treatment. A decrease in Hb, Hct and red cell count was recorded in one of the two subjects during estradiol treatment, with a concomitant decrease in serum testosterone. Circulating T alone is capable of and sufficient to influence erythropoiesis, especially at supraphysiological dosage, while circulating E(2) have not the same effect on erythropoietic parameters, suggesting the hypothesis that the erythropoietic changes induced by androgens are not mediated via its aromatization to estrogens.

The osteoporotic male: overlooked and undermanaged?

Age-related bone loss in men is a poorly understood phenomenon, although increasing data on the pathophysiology of bone in men is becoming available. Most of what we know on bone pathophysiology derives from studies on women. The well-known association between menopause and osteoporosis is far from been disproven. However, male osteoporosis is a relatively new phenomenon. Its novelty is in part compensated for by the number of studies on female osteoporosis and bone pathophysiology. On the other hand, the deeper understanding of female osteoporosis could lead to an underestimation of this condition in the male counterpart. The longer life-span exposes a number of men to the risk of mild-to-severe hypogonadism which in turn we know to be one of the pathogenetic steps toward the loss of bone mineral content in men and in women. Hypogonadism might therefore be one among many corrigible risk factors such as cigarette smoking and alcohol abuse against which clinicians should act in order to prevent osteoporosis and its complications. Treatments with calcium plus vitamin D and bisphophonates are widely used in men, when osteoporosis is documented and hypogonadism has been excluded. The poor knowledge on male osteoporosis accounts for the lack of well shared protocols for the clinical management of the disease. This review focuses on the clinical approach and treatment strategy for osteoporosis in men with particular attention to its relationship with male hypogonadism.

Skeletal effects of long-term estrogen and testosterone replacement treatment in a man with congenital aromatase deficiency: evidences of a priming effect of estrogen for sex steroids action on bone.

The relative contribution of each sex steroid (i.e. estrogen and androgen) on bone in men and the relationships among sex steroids and changes in BMD and bone strength are still unknown. A defective BMD of bone tissue is constantly present in men with aromatase deficiency. This study evaluates the effects of different regimens of treatment with sex steroids over 7.3 years follow-up on BMD in an adult man affected by aromatase deficiency and by a concomitant mild hypogonadism, as previously described. The aim of the study is to provide additional data on the relative roles of androgens and estrogens in male bone metabolism. The effects of testosterone (T) treatment alone and estrogen (tE(2)) treatment alone as well as the effects of the combined treatment with testosterone and estradiol (T plus tE(2)) on areal BMD (aBMD) at dual-energy X-ray absorptiometry (DXA) and the effects of T plus tE(2) on volumetric BMD (vBMD), particular at cortical site, measured by peripheral quantitative computed tomography (pQCT), are investigated. Hormones and markers of bone turnover were monitored during all phases of the study. Treatment with tE(2) normalized serum estradiol, but only the combined treatment with T plus tE(2) normalized both serum estradiol and testosterone. Markers of bone turnover reached a pattern close to normality during T plus tE(2). The aBMD was little modified by T, but increased more during tE(2). T plus tE(2) resulted in a further increase in both aBMD at DXA and vBMD at pQCT. Cortical thickness increased during T plus tE(2) both in radius and tibia. Only the combined treatment led to optimal parameters of aBMD suggesting that testosterone needs estrogens as a permissive factor for a direct androgen anabolic action on bone in men.

Sildenafil improves sleep-related erections in hypogonadal men: evidence from a randomized, placebo-controlled, crossover study of a synergic role for both testosterone and sildenafil on penile erections.

To study the effects of sildenafil on human sleep-related erections according to the state of androgenization, we evaluated the effects of sildenafil on sleep-related erections in hypogonadal men before and during testosterone replacement treatment and in control subjects. We enrolled 24 hypogonadal men and 24 healthy men as a control group. All hypogonadal subjects had very low testosterone levels (<200 ng/dL [6.9 nmol/L]) [corrected] All subjects underwent nocturnal penile tumescence and rigidity monitoring (NPTRM) for 3 consecutive nights and were randomly assigned to consume either 50 mg of sildenafil or placebo 1 hour before bedtime on the second or third night of nocturnal penile monitoring. The hypogonadal subjects were tested twice, first without replacement treatment (H-T) and then after at least 6 months of testosterone replacement therapy (H+T). The subjects of the control group (C) were tested once. The following parameters of sleep-related erections were analyzed: total number of valid erections, total duration of both rigidity greater than or equal 70% and increase in penile circumference greater than or equal 30 mm, maximum rigidity, and maximum increase in penile circumference. NPTRM parameters were reduced in hypogonadal men before testosterone treatment (H-T+P) when compared with control subjects taking placebo (C+P). NPTRM parameters after testosterone (H+T+P) and sildenafil (H-T+S) administration were similar to that of control subjects taking placebo (C+P). When the statistical analysis was restricted to the hypogonadal men before testosterone treatment, sildenafil alone significantly increased NPTRM parameters when compared with placebo (H-T+S vs H-T+P). Testosterone restored normal erections when administered to hypogonadal subjects (H+T+P vs H-T+P); in hypogonadal men, however, the combined treatment (sildenafil plus testosterone) resulted in the maximum positive effect on NPTRM parameters. When the increase from baseline was analyzed, the effects of testosterone plus sildenafil were greater than the sum of the effects of each drug used alone. In conclusion, sildenafil administered at bedtime improves sleep-related erections in hypogonadal men, suggesting that the nitric oxide pathway may be pharmacologically enrolled and enhanced despite low serum testosterone. Furthermore, these data strongly support the idea of a synergic effect on sleep-related erections of sildenafil and testosterone.

Estrogens in males: what have we learned in the last 10 years?

This review focuses on the role of estrogen in men, mainly in male reproduction. The continuing increase in data obtained, and recent discoveries in this area will enable a better understanding of male physiology; these, in turn, will have important clinical implications.