Little is known about temporal trends in the incidence of male hypogonadism and its correlation with socioeconomic status, which we examined in the present study.Data were extracted from the Maccabi Health Services computerized database between 2001-2017. The study population included 4,261 men aged 21 to 80 years with biochemically proven hypogonadism defined and classified according to the European Male Aging Study criteria. Patients on testosterone or testosterone-modifying drugs were excluded. The socioeconomic status was assessed based on verified financial data pertinent to the area of residence.The incidence of male hypogonadism increased with age in all the socioeconomic strata. Among the hypogonadal men, 75% had hypogonadotropic hypogonadism. The overall incidence of hypogonadism increased 1.4-fold between the 2001-2009 and 2010-2017 periods [from 41.7 (39.7-43.8) to 58.5 (56.4-60.8) per 100,000 person-years) (95% CI)], mainly due to an increase in hypogonadotropic hypogonadism. The temporal increase in hypogonadotropic hypogonadism occurred in all age groups and all socioeconomic strata but was notably more prominent in >51-year age groups of the more affluent socioeconomic strata. The mean body mass index remained unchanged throughout the study period.A temporal increase was observed in male hypogonadism, mainly hypogonadotropic hypogonadism, corresponding with previously observed temporal decreases in testosterone levels in men. This trend could be possibly partly attributed to an underappreciated increase in mental distress due to decreasing global happiness indices, increasing stress, and occupational burnout in specific occupations associated with more affluent populations (i.e., high-tech, finance, medical). This preliminary proposition deserves further investigation.

Little data exists on temporal changes in the incidence of definite hypogonadism and its correlation with socioeconomic status. We extracted data from the Maccabi Health Services computerized database between 2001-2017, which includes all electronic health records and laboratory data. The study included 4261 men with biochemically verified hypogonadism defined according to the European Male Study criteria. Male hypogonadism increased persistently with age in all the socioeconomic strata. 75% of the hypogonadal men had hypogonadotropic hypogonadism (HH). The overall incidence of hypogonadism increased 1.4-fold between the 2001-2009 and 2010-2017 periods, mainly due to an increase in HH. The temporal increase in hypogonadism occurred in all age groups of all socioeconomic strata but was notably more prominent in the >51 age group of the more affluent socioeconomic strata. BMI remained unchanged throughout the study period. The temporal increase in HH corresponds with previous observations of a temporal decrease in testosterone levels in men of a yet undetermined cause. Hypothetically, both could be linked to an underappreciated association between mental distress due to workplace demands and occupational burnout in specific occupations (i.e., high-tech, finance, medical) associated with more affluent populations, and reflected by decreased global happiness indices. This preliminary proposition deserves further investigation.

Ultraviolet (UV) light affects endocrinological and behavioral aspects of sexuality via an unknown mechanism. Here we discover that ultraviolet B (UVB) exposure enhances the levels of sex-steroid hormones and sexual behavior, which are mediated by the skin. In female mice, UVB exposure increases hypothalamus-pituitary-gonadal axis hormone levels, resulting in larger ovaries; extends estrus days; and increases anti-Mullerian hormone (AMH) expression. UVB exposure also enhances the sexual responsiveness and attractiveness of females and male-female interactions. Conditional knockout of p53 specifically in skin keratinocytes abolishes the effects of UVB. Thus, UVB triggers a skin-brain-gonadal axis through skin p53 activation. In humans, solar exposure enhances romantic passion in both genders and aggressiveness in men, as seen in analysis of individual questionaries, and positively correlates with testosterone level. Our findings suggest opportunities for treatment of sex-steroid-related dysfunctions.

AbstractDenosumab discontinuation is associated with rapid reversal of bone turnover suppression and with a considerable increase in fracture risk, including a risk for multiple vertebral fractures (MVF). Long-term follow-up of patients who sustained MVF after denosumab discontinuation has not been reported. This case-series was aimed to provide a long-term follow-up on the management and outcome of denosumab discontinuers who initially presented with multiple vertebral fractures. Denosumab discontinuers were identified from a computerized database of a large healthcare provider. Baseline and follow-up clinical, laboratory, and imaging data were obtained from the computerized database and electronic medical records. The post-denosumab discontinuers MVF patients consisted of 12 women aged 71±12. Osteoporotic fractures were prevalent before denosumab discontinuation in 6 of the patients. The majority received bisphosphonates before denosumab. MVF occurred 134±76 days after denosumab discontinuation. The patients were followed for a median of 36.5 (IQR 28.2, 42.5) months after MVF. Two patients passed-away. Two patients suffered recurrent vertebral fractures. Following MVF, patients were treated inconsistently with denosumab, teriparatide, oral, and intravenous bisphosphonates, in various sequences. Two patients underwent vertebroplasty/kyphoplasty. This long-term follow-up of real-world patients with MVF following denosumab discontinuation reveals that management is inconsistent, and recurrent fractures are not uncommon. It calls for clear management guidelines for patients with MVF after denosumab discontinuation and for special attention to this high-risk group.

Purpose We aimed to assess the incidence, clinical and biochemical course of immunotherapy-induced thyroiditis and its implication on patients' survival, based on an extensive clinical experience from a tertiary cancer center. Methods Analyses were based on data from the electronic medical records of cancer patients treated with CPIs. Data included demographic characteristics, cancer type, Thyroid function tests (TFT), and survival. Results Thyroid function tests were available for 934 patients. After excluding patients with impaired baseline TFT or levothyroxine treatment, 754 euthyroid patients were included in the core analyses. Of those, 301 (39.9%) patients developed thyroid dysfunction ('thyroiditis'). Thyroiditis was more prevalent in patients with renal cell carcinoma than other types of cancer. Survival rates were comparable in patients who developed thyroiditis and in those who did not. during the 5 years follow-up period, there was a non-significant trend toward improved survival in patients who developed TD in four predefined groups: melanoma, lung cancer, renal cell carcinoma, and transitional cell carcinoma. Nevertheless, we observed a highly significant survival benefit for patients with renal cell carcinoma who developed TD (HR = 0.19, 95% CI 0.06-0.60; p = 0.005). Conclusions Thyroiditis is common, often asymptomatic, and is more prevalent in patients treated with combinations of nivolumab and PD-L1 inhibitors, and in patients with renal cell carcinoma. Thyroiditis was associated with a trend for a survival benefit, particularly in patients with renal cell carcinoma.

Capillary-leak syndrome is strongly associated with cytokine activity states. It is an ill-recognized adverse effect of checkpoint inhibitors treatment, which are typically associated with cellular immune response. We describe two patients with capillary leak syndrome following immune checkpoint inhibitors treatment. We present linking mechanisms between checkpoint inhibitors, cellular immunity, cytokine action and endothelial damage. We suggest that capillary-leak syndrome is a unique adverse effect of immunotherapy, resulting from complex interactions between cellular and cytokine activation and that its expression is probably depending on inherent host immune variabilities.

Ultraviolet (UV) light affects endocrinological and behavioral aspects of human sexuality via an unknown mechanism. Using a unique male-female comparative approach, we discovered that the sexual behavioral and hormonal features enhanced by UVB are mediated by the skin. In mice, UV exposure increases hypothalamus-pituitary-gonadal axis hormone levels, resulting in enhanced ovary size, extended estrus days, and anti-Mullerian hormone (AMH) expression. It likewise enhances sexual responsiveness and attractiveness of females and heterosexual interactions of both males and females. Conditional knockout of p53 specifically in skin keratinocytes abolished UV’s effects. In humans, UV exposure enhanced romantic passion in both genders, increased testosterone levels in men and correlated with heightened plasma AMH levels in women. Our data, revealing that UVB triggers a skin-brain-gonadal axis through skin p53 activation, offers therapeutic opportunities for sex-steroid-related dysfunctions. We speculate that during human furless skin evolution, the skin became the front-line regulator of the response to UVB.

Objective: Serum calcium levels often decrease during acute illness in patients with an intact calcium-regulating system. However, the dynamics of serum calcium levels in hospitalized patients with primary hyperparathyroidism (PHPT) have not yet been described. Methods: Clinical and laboratory data were retrospectively retrieved from the electronic medical records of patients with PHPT before, during, and after hospitalization for various reasons (excluding parathyroid surgery). Results: There were 99 nonselected patients with asymptomatic, hypercalcemic PHPT, hospitalized for various reasons; 42% were admitted for apparent infectious or septic conditions, and 58% were admitted for noninfectious conditions. Total serum calcium increased >0.5 mg/dL in 7.4% of the patients: 10.9% and 2.5% of the patients with noninfectious and infectious conditions, respectively. In 65.7% of the patients, the mean total serum calcium (TsCa), but not albumin-corrected calcium (corrCa), decreased significantly during hospitalization, down to below the upper limit of the reference range. Although prehospitalization TsCa and corrCa were similar in patients with infectious and noninfectious conditions, during hospitalization, TsCa was lower in patients with infectious conditions (P = .02). Both TsCa and albumin returned to prehospitalization levels after recovery. Conclusion: TsCa increases in a minority of hospitalized PHPT patients. In the majority of hospitalized patients with PHPT, TsCa, but not corrCa, decreases to within the normal reference range, more so in patients with infectious conditions, obscuring the major characteristic of PHPT. Therefore, it is prudent to follow calcium and corrCa during hospitalization in patients with PHPT. Abbreviations: corrCa = albumin-corrected serum calcium; IQR = interquartile range; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone; TsCa = total serum calcium.

We thank Dr. Fu Sang et al. for their comments on our article on the control of Paget’s disease of bone with low dose weekly oral bisphosphonates [1]. Regarding the use of total alkaline phosphatase (ALP) as disease activity marker, we acknowledge that P1NP may be somewhat better correlated with disease activity, however, P1NP was not available in our system during the time of the study, and even according to the meta-analysis cited by Fu et al. notwithstanding its limitations, the difference between P1NP and ALP is small and probably not clinically significant in most patients, except those with concurrent hepato-biliary disease [2]. As our end-point was definite normalization of ALP, we believe that having used a different bone turnover marker and assessing PTH and 25(OH) D at the time of initiation of each treatment course (rather than checking them periodically, as we did) would not have changed our conclusions on the efficacy of low-dose oral bisphosphonates in the treatment of Paget’s disease of bone. Since bone density has not been checked regularly, we are not able to answer the question regarding the effect of bisphosphonates for Paget’s disease on bone mass. Compliance with ethical standards

BACKGROUND:There is ample evidence associating vitamin D deficiency in primary hyperparathyroidism (PHP) patients with more severe disease manifestations and increased risk of postoperative hypocalcemia. Yet, there is limited data regarding the safety of vitamin D repletion in these patients.AIM:To assess the safety of vitamin D repletion in PHP patients in a real-world setting.DESIGN:We included patients with asymptomatic PHP and few symptomatic patients who declined surgery, followed in our clinic, and treated on a routine basis with 2000 IU/day of vitamin D3.METHODS:Serum calcium (sCa), PTH, 25-hydroxyvitamin D, and 24 h urinary calcium (uCa) and creatinine collections were compared between the lowest and the highest vitamin D time points.RESULTS:There were 40 patients of a mean age was 63 ± 10 years. 25(OH)D at lowest and highest vitamin D time points was 15.5 ± 6.2 ng/ml and 33.2 ± 8, respectively (P < 0.001). Serum calcium was not affected by the changes in vitamin D levels. In none of the patients did sCa exceed 11.5 mg/dL. uCa was 220 ± 110 mg/24 h at the lowest vitamin D time point and 260 ± 140 at the highest vitamin D time point (P = 0.14). uCa exceeded 400 mg/24 h in two vs. five patients (P = 0.23) at the lowest and highest vitamin D time points, respectively. PTH was not significantly different between the different vitamin D time points.DISCUSSION/CONCLUSION:Vitamin D repletion in PHP seems safe. Considering the documented adverse influence of vitamin D deficiency in PHP, particularly on skeletal manifestations and on the postoperative course, vitamin D repletion is warranted.

Bisphosphonates are the mainstay of the treatment of Paget’s disease of bone (PDB). Clinical practice guidelines recommend treatment with intravenous zoledronic acid or high-dose oral nitrogen bisphosphonates (N-BPs). We present our long-term experience treating PDB patients with lower than recommended oral doses of N-BPs, equivalent to once-weekly doses used for treating osteoporosis.

To the Editor: I read with much interest the article by Drieling and colleagues1 reporting fracture results in Women's Health Initiative participants suggesting that long-term (10–13 years) oral bisphosphonate therapy may increase the risk of any clinical fracture more than short-term (2 years) oral bisphosphonate use and refer to several additional studies indicating that long-term oral bisphosphonate use may have no advantage over short-term use. The observed greater fracture risk during long-term oral bisphosphonate treatment was attributed to oversuppression of the bone remodeling process, which may damage bone quality and lead to greater bone fragility. I would like to suggest an alternative view. We recently showed,2 in a cohort of women with osteoporosis deemed to be compliant with treatment with oral bisphosphonates (mainly alendronate) for a mean period of 7.2 ± 3.1 years (range 2–15 years) in a real-world setup that the frequency distribution of results of a bone-resorption marker (urinary deoxypyridinoline) was clearly skewed to the right (higher values). Thus, although 62% of the women were in the normal range for premenopausal women, 31% were above the normal range for premenopausal women (exceeding 20% above the normal range in 17% and 30% above in 13%), and only 7.5% had suppressed bone resorption rates. We interpreted these results as indicating that oversuppression is uncommon during prolonged oral bisphosphonate treatment and that high bone turnover (reflecting treatment failure) is much more prevalent. We suggested that compliance or oral bisphosphonate bioavailability deteriorates with time, leading to greater bone turnover, potentially resulting in greater fracture risk, as Drieling and colleagues demonstrated.1 Although the current paradigm, as well as Drieling and colleagues,1 suggests putting people on prolonged bisphosphonate treatment on a drug holiday to reduce oversuppression of bone turnover,3 our results, as well as other observations indicating a greater incidence of fractures early after initiation of a drug holiday,4-6 suggest that a drug holiday could be risky for many people and that re-evaluation of individuals on a prolonged course of oral bisphosphonates should probably include, in addition to clinical and densitometric evaluation, an assessment of bone turnover, to exclude what could be classified as subclinical treatment failure. Individuals with high bone turnover could thus be considered for a parenteral antiresorptive drug. Conflict of Interest: No conflicts of interest. Author Contributions: The author is solely responsible for this manuscript's content. Sponsor's Role: This study involved no external funding.

OBJECTIVE:Late-onset hypogonadotropic hypogonadism (LOH) is a complex, heterogeneous entity. Whenever treatment is indicated, the endocrine literature has recommend testosterone replacement. We present our experience with clomiphene citrate treatment in patients with LOH and a review of the literature.METHODS:This retrospective case series included 18 male patients with hypogonadotropic hypogonadism, roughly according to the European Male Aging Study criteria for LOH, attended at an academic hospital outpatient clinic. Data were retrieved from the patients' electronic medical records.RESULTS:The patients' mean age (±SD) was 44.3 ± 6.3 years (range 21-67 years) referred for evaluation of low testosterone together with decreased libido, erectile dysfunction, fatigue or tiredness, anxiety, and osteoporosis. Clomiphene was initially prescribed at doses between 25 mg 3 times a week and 50 mg/day. At 6 to 8 weeks following initiation of treatment, mean basal total-testosterone increased from 7.6 ± 2.6 to 19.3 ± 5.2 nmol/L (P<.0001). Mean basal luteinizing hormone (LH) increased from 2.7 ± 2.1 to 8.3 ± 3.5 nmol/L (P<.0001). Mean basal follicle-stimulating hormone (FSH) increased from 4.2 ± 3.6 to 8.6 ± 6.2 nmol/L (P = .007). Testosterone and LH responses were invariably observed, including 2 patients with history of nonpituitary cranial pathologies, 2 with somewhat elevated FSH, and 1 with an eating disorder. Twelve (67%) patients reported improvement in symptoms. Side effects included transient nipple tenderness in 1 patient.CONCLUSION:Available data suggest that clomiphene is an efficient and convenient alternative to testosterone replacement therapy in a substantial subset of patients with LOH. Additional long-term controlled studies should further establish the role of clomiphene in LOH.ABBREVIATIONS:FSH = follicle-stimulating hormone LH = luteinizing hormone LOH = late-onset hypogonadotropic hypogonadism.

Objective: Little data exist to support concerns over bone turnover suppression during prolonged oral bisphosphonate treatment and on consequences of the recommended "drug holiday." This study was performed to assess bone resorption rates in postmenopausal osteoporotic women on prolonged oral bisphosphonate treatment and in response to switching to "drug holiday" intravenous bisphosphonate, or continuation of oral bisphosphonates.Methods: The frequency distribution of the bone resorption marker urinary deoxypyridinoline crosslinks (uDPD), was obtained retrospectively from 211 osteoporotic women attended at an academic hospital endocrine clinic, treated for >2 years with oral bisphosphonates. In some patients, uDPD was re-assessed following modification or continuation of treatment.Results: The mean duration of oral bisphosphonates treatment was 7.2 +/- 3.1 years. uDPD was within reference range for premenopausal women in 61.6% of the patients, below in 7.6% of the patients, and above upper limit in 30.8%. uDPD decreased significantly following intravenous zoledronic acid, increased significantly during "drug holiday," and slightly decreased in those continued on oral bisphosphonate treatment.Conclusion: In this real-world study, the majority of women on prolonged oral bisphosphonates maintained bone resorption rates within the normal reference range for premenopausal women. The likelihood for inadequate suppression was considerably greater than that of over-suppression. Implementing a " drug holiday" resulted in a marked increase in bone resorption rates. Additional studies should explore the potential role of bone turnover markers in the evaluation of patients on prolonged oral bisphosphonates and during " drug holiday" in different settings and using additional markers.

9 Background: Osteoporosis and breast cancer (BC) are each mediated by circulating estrogens. Insulin and insulin growth factors 1-2 have been linked to increased bone mineral density (BMD) and BC cell growth. The relationship between BMD and BC incidence has been analyzed in a number of retrospective studies with conflicting results. We have previously reported on a study of BC risk in 15,268 women who underwent BMD testing. Women in the highest Z-score tertile at the femoral neck had a higher risk of developing BC compared to those in the lowest tertile (OR 2.15, p = 0.004). The current study was undertaken in order to determine whether there is a direct correlation between BMD and BC when evaluated prospectively. Methods: This case-control study is planned to include 400 consecutive patients (pts) with newly diagnosed BC and 800 matched controls without BC. Pts and controls undergo BMD examination using dual photon technology. Serum is obtained for vitamin D, calcium, and a panel of bone turnover markers and cytokines. Pts and controls are interviewed and a questionnaire about BC and osteoporosis risk factors is completed. Results: We present clinical and BMD data from the first 200 BC patients recruited to the study. Median age 60, interquartile range 49.5-66. Body Mass Index: 28.4 ± 5.4 (mean ± SD). Postmenopausal: 148 patients, 74%. T-scores (mean ± SD): femoral neck: -0.68 ±-1.10, total hip: -0.28 ± 1.17, L1-L4: -0.52 ± 1.39. T-score of less than minus 2.5 (cut-off for osteoporosis) at any of the 3 sites, 24 (11.9 %) pts. Estrogen receptor pos: 162 (81%).BC stage: T0-T2, 175 (87.5 %). N0: 108 (54.5%), N1-2-3: 86 (43.4%). % pts node pos (N1-2-3) in each T score range: ≤ -2.5, 20%; -2.5 < T score ≤ -1,36%; -1 < T-score ≤+ 1,50%; +1 < T-score, 60%. % pts low grade in each T score range: ≤ -2.5, 25%;-2.5 < T-score ≤ -1,35%;-1 < T-score ≤ +1,37 % ;+1 < T-score, 20%. Conclusions: Only 11.9% of the first 200 BC patients studied had osteoporosis by BMD at diagnosis.Pts with higher BMD showed a trend for more nodal involvement. Pts with T-score > +1 had fewer cases of low grade histology compared to pts with lower T-scores. These preliminary results hint that higher BMD may be associated with more aggressive BC.

We have previously developed an architecture and a set of tools called the Digital electronic Guideline Library (DeGeL), which includes a web-based tool for structuring (marking-up) free-text clinical guidelines (GLs), namely, the URUZ Mark-up tool. In this study, we developed and evaluated a methodology and a tool for a mark-up-based specification and assessment of the quality of that specification, of procedural and declarative knowledge in clinical GLs. The methodology includes all necessary activities before, during and after the mark-up process, and supports specification and conversion of the GL's free-text representation through semi-structured and semi-formal representations into a machine comprehensible representation. For the evaluation of this methodology, three GLs from different medical disciplines were selected. For each GL, as an indispensable step, an ontology-specific consensus was created, determined by a group of expert physicians and knowledge engineers, based on GL source. For each GL, two mark-ups in a chosen GL ontology (Asbru) were created by a distinct clinical editor; each of the clinical editors created a semi-formal mark-up of the GL using the URUZ tool. To evaluate each mark-up, a gold standard mark-up was created by collaboration of physician and knowledge engineer, and a specialized mark-up-evaluation tool was developed, which enables assessment of completeness, as well as of syntactic and semantic correctness of the mark-up. Subjective and objective measures were defined for qualitative and quantitative evaluation of the correctness (soundness) and completeness of the marked-up knowledge, with encouraging results.

We introduce a three-phase, nine-step methodology for specification of clinical guidelines (GLs) by expert physicians, clinical editors, and knowledge engineers and for quantitative evaluation of the specification's quality. We applied this methodology to a particular framework for incremental GL structuring (mark-up) and to GLs in three clinical domains. A gold-standard mark-up was created, including 196 plans and subplans, and 326 instances of ontological knowledge roles (KRs). A completeness measure of the acquired knowledge revealed that 97% of the plans and 91% of the KR instances of the GLs were recreated by the clinical editors. A correctness measure often revealed high variability within clinical editor pairs structuring each GL, but for all GLs and clinical editors the specification quality was significantly higher than random (p<0.01). Procedural KRs were more difficult to mark-up than declarative KRs. We conclude that given an ontology-specific consensus, clinical editors with mark-up training can structure GL knowledge with high completeness, whereas the main demand for correct structuring is training in the ontology's semantics.

Well differentiated epithelial cell thyroid cancer is not classified amongst the most aggressive diseases. Notwithstanding, it can potentially both impair quality of life and affect life expectancy. Appropriate treatment has been shown to be crucial in obtaining optimal outcomes on the course of the disease. Successful treatment rests upon strict adherence to confirmed principles of diagnosis, treatment and follow-up. The aim of the position paper is to present the Israeli medical community with a set of commonly accepted principles for the diagnosis, treatment and follow-up of patients with well differentiated epithelial thyroid cancer and in addition to highlight areas of legitimate differences in approach where those differences occur. We have attempted to provide a link between the various medical disciplines involved in care of these patients: family physicians, surgeons, nuclear medicine specialists, oncologists, pathologists, radiologists and endocrinologists; and have attempted to decrease to a minimum areas of uncertainty and to offer a common approach for the best possible care of thyroid cancer patients in Israel. In addition, we find it our duty to point out those areas and resources which, in our opinion, need to be upgraded in Israel and even included in the Israeli official "health basket".