Gender-affirming hormone therapy effect on cortisol levels in trans males and trans females.

PURPOSE: Previous studies have shown differences in baseline and stimulated cortisol levels between men and women. Whether this difference is secondary to sex hormones or to other factors, such as genetic or epigenetic changes, is unknown. We investigated the effect of gender-affirming hormone treatment (GAHT) on the hypothalamo-pituitary-adrenal axis of transgender subjects in an effort to throw light on this question. METHODS: Ten transgender males (TM) and eight transgender females (TF) underwent a low-dose (1 µg) adrenocorticotropic hormone (ACTH) stimulation test before and 6 months after GAHT initiation. Serum total, free and salivary cortisol (SC) levels were measured at baseline and at 20, 30 and 40 min. RESULTS: For the TM, all three levels were significantly lower at several time points after ACTH injection compared to pretreatment levels following 6 months of treatment (p < .05). Likewise, the overall SC response as calculated by the area under the curve was significantly lower (p = .0053). For the TF, the basal total cortisol (TC) level increased after 6 months of treatment (p < .01) while ACTH-stimulated SC levels decreased significantly. The basal ACTH levels were significantly lower following hormonal therapy (p < .001). CONCLUSION: Stimulated salivary cortisol levels decreased significantly after 6 months of GAHT in both male and female transgender subjects, possibly reflecting a decreased state of anxiety associated with treatment initiation. Additionally, basal and stimulated serum TC levels increased after hormonal treatment in the TF, probably secondary to the effect of oestrogen on cortisol-binding globulin.

Lower incidence of hip fractures among elderly Ethiopian immigrants to Israel: first assessment from the Israel National Trauma Registry (INTR) 2011-2020.

The incidence hip fractures (HF) among Ethiopian immigrants is unknown. In Israel, the incidence of HF among Ethiopian immigrants aged ≥ 50 years between 2011 and 2020 was lower than in the general Israeli population, but possibly on the rise. These data should be confirmed in other countries where the Ethiopian diaspora has settled. PURPOSE: The incidence of osteoporotic fractures in the aging Ethiopian population that immigrated to Western countries has not been reported. This study sought to provide a first assessment of the incidence of hip fractures in Ethiopian immigrants in Israel, as a proxy for osteoporosis in this population. METHODS: This is an epidemiologic study of the incidence of hip fractures (HF) in people aged ≥ 50 years in Israel, between 2011 and 2020. Data were extracted from the Israel National Trauma Registry (INTR). Annual age-adjusted HF incidence rates (IR), and standardized incidence ratios (SIR) among Ethiopian-born (EB) relative to non-EB subjects (others) were computed. RESULTS: During the study period, among subjects age ≥ 50 in the INTR, only 20.1% of the EB suffered a HF, in contrast to 32.3% of subjects from other origins (P < 0.0001). Although EB subjects were generally younger than their non-EB counterparts, the age at which they sustained a HF was similar: 80.45 ± 11.7 years for EB vs. 79.44 ± 10.32 years, P = 0.19. EB men were more likely to sustain a HF, as they represented 41.8% of all HF in their respective group, in comparison with 33.6% for others (P = 0.02). Annual IR of HF were lower for EB subjects throughout the study. Despite an initial rise in the SIR, these were also lower for most of the period. CONCLUSIONS: In Israel, EB subjects ≥ 50 years still enjoy protection from HF. Our data require confirmation from other Western countries where the Ethiopian diaspora is aging. If a secular upward trend is observed, contributing risk factors should be identified to enable preventative measures.

Refractory nonfunctioning pituitary adenomas.

Non-functioning pituitary adenomas (NFPAs) comprise silent tumors of different pituitary lineages that tend to escape early detection and present as invasive macroadenomas with symptoms of mass effect. Incomplete surgical resection is common and may be followed by significant rates of subsequent remnant progression. Pituitary tumors are defined as refractory when resistance to optimal standard therapies including surgery, radiotherapy, and medical treatment is documented. In the absence of approved medications for the treatment of NFPAs, the last criterion to classify these tumors as refractory is ill defined. Silent corticotroph and null cell adenomas have been reported, albeit not in all studies, to be larger and recur more often compared with silent gonadotroph tumors. Nevertheless, it is currently unknown if certain NFPA subtypes are more often refractory using well defined criteria. The response rate to temozolomide is lower in NFPA compared to that seen in functioning tumors. Refractory NFPAs present a significant diagnostic and therapeutic challenge and are associated with increased morbidity and mortality rates.

Routine statins use is associated with less adverse outcome in patients above 70 years of age admitted to hospital with COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to multiorgan insufficiency and death, particularly among the older adults. Statins have been suggested as potentially protective drugs due to their pleotropic effects, but the actual benefit of statin use among the older population in this setting is not clear. This study aimed to evaluate the association between preadmission statin use and the presentation and clinical outcomes of hospitalized COVID-19 patients older than 70 years of age. METHODS: A historical cohort study of all patients above 70 years of age who were hospitalized with COVID-19 infection in a large academic hospital between March and August 2020 was performed. The association between preadmission statin use and patients' presentation and adverse outcome was studied. Adverse outcome was defined as any of the following: shock, invasive or non-invasive ventilation, organ insufficiency, myocardial infarction, cerebrovascular accident, in-hospital or 30-day post-admission mortality, hospital stay longer than the median length of stay of all COVID-19 patients, referral to nursing home or rehabilitation center. RESULTS: Seventy-two (44%) of the 163 studied patients (median age 82 years, 45% males) had been preadmission treated with statins. The statin-treated patients (STP) had a higher prevalence of diabetes (40% vs 24%, p = 0.028) and cardiovascular disease (58% vs. 34%, p = 0.002). Seventy two percent of the STP had adverse outcome, compared to 86% of the non-STP (p = 0.033). After adjustment for potential confounders, prior statin use was associated with decreased risk for an adverse outcome (odds ratio = 0.4, 95% confidence interval 0.18-0.92, p = 0.03). CONCLUSIONS: The preadmission use of statins was associated with a lower risk of adverse outcome in older adults hospitalized with COVID-19. Continuation of statin treatment might be implemented for risk reduction of adverse outcomes in the older population in the era of new SARS-CoV-2 variants and less effective vaccines.

Endocrinology specialty service for inpatients: an unmet growing need.

BACKGROUND: There is recent concern regarding the documented mismatch between demand and supply, vis-à-vis the growing need for trained endocrinologists unmet by parallel rise in the world workforce of endocrinologist. Due to the increasing complexity of disease in inpatients, in recent years we have experienced a growing demand for inpatient endocrine consults. Surprisingly, the need for the endocrinology subspecialty in the overall care of inpatients in the current setting of general hospitals has received little attention. METHODS: A retrospective analysis of endocrine consult service based on solicited consults carried out during 3 consecutive months. RESULTS: During 3 months, there were 767 consults, comprised of 156 diabetes referrals and 611 endocrine/metabolic consult requests. The 611 "non-glucocentric" consult requests were related to 295 inpatients (2.1 ± 2.7 consults/patient). Mean patient age was 58.9 ± .18 years (range 21-92), with some F/M preponderance (58/42%). Requests for endocrine consults were evenly distributed (49.8%, 50.2%) between internal medicine and surgery wards. Case distribution was as follows: thyroid 45.4%, calcium & bone 11.5%, pituitary 12%, adrenal 10% and all others 8.1-0.7%. The mean response time was 4.4 ± 2.7 h. The consults had a discernible effect on the patients' disease management in 60% of the patients. Of these, the consults modified the hospital treatment in 74%, the discharge treatment recommendations in 19% and the diagnosis in 7%. CONCLUSION: At a large medical center, endocrine consults were requested for ~ 3.3% of all admitted inpatients. The endocrine consults modified pre-consult diagnosis or treatment in ~ 60% of the cases. Contrary to its common image as an exclusively outpatient-based subspecialty, endocrinology practiced by specialists and endocrine trainees has a notable role in the daily care of inpatients admitted to a referral general hospital.

Impaired aldosterone response to ACTH without hypoaldosteronism: An unrecognized secretory pattern in search of clinical implications.

CONTEXT: Aldosterone has been recently characterized as a 'stress hormone'. Stress per se elicits a sizable rise in aldosterone secretion, which could be replicated by the administration of a low dose (0.03-1 µg, IV) of adrenocorticotropic hormone (ACTH). Whether or not the aldosterone response to ACTH could be selectively impaired, that is, in association with intact cortisol response, is presently unknown. OBJECTIVE: To determine whether or not the aldosterone response to low dose of ACTH is impaired in subjects referred to assess the hypothalamic-pituitary-adrenal axis (HPA). DESIGN: Retrospective analysis. SETTING: Outpatient referral endocrine day care centre. PATIENTS: One hundred and ninety-five consecutive subjects who underwent the low dose (1 µg) ACTH test, in whom decreased cortisol reserve was suspected due to former/present glucocorticoid excess, pituitary disease or/and unexplained weakness. MAIN OUTCOME MEASURES: The outcome was the detection of lack of aldosterone response, defined as a rise <111 pmol/l. RESULTS: In all, 46/195 subjects had subnormal aldosterone response as compared with 52/195 subjects showing diminished cortisol response. Nine subjects had combined deficient aldosterone and cortisol response. In the 37 subjects with isolated subnormal aldosterone response common associations were the use of exogenous glucocorticoids, mostly prednisone (n = 16); former Cushing disease (n = 2); nonfunctioning pituitary adenoma (n = 8); hypothyroidism (n = 11); the use of statins (n = 11), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (n = 6), sex steroids in transgenders and orthostatic hypotension (n = 3). Twenty-seven percent (25/93) of the subjects with recent exposure to glucocorticoids had impaired aldosterone response to ACTH. CONCLUSION: Blunted aldosterone response to ACTH in the absence of hypoaldosteronism was seen in ~27% of subjects referred for HPA assessment using the low dose 1 µg ACTH test. Exposure to glucocorticoid excess was often linked to this impairment, independent of the cortisol response to ACTH.

Why fertility preservation rates of transgender men are much lower than those of transgender women.

RESEARCH QUESTION: What are the fertility preservation rates of transgender women and transgender men, and what are the factors that affect their decision-making? DESIGN: This prospective study included 97 transgender women and 91 transgender men referred to the Gender Clinic of the study medical centre's Endocrinology Institute and to the Gan Meir Community Health Care Centre. The responders completed a 28-item questionnaire during 2018. RESULTS: Most of the transgender women and transgender men wished to parent a child (67.4% and 61.9%, respectively, P = 0.447), but only 40.4% of the transgender women and 5.8% of the transgender men used fertility preservation (P < 0.001). The main reasons for not pursuing fertility preservation were unwillingness to postpone gender-affirming treatment (58.8% and 74.0%, respectively, P = 0.076), preference to adopt a child (58.8% and 60.9%, respectively, P = 0.818) and cost (44.9% and 60.9%, respectively, P = 0.086). Factors related to the fertility preservation process itself were specifically chosen by transgender men compared with transgender women as the reason for not pursuing this treatment, including distress caused by the fertility preservation technique (60.3% versus 29.3%, respectively, P = 0.006), fear of gender dysphoria caused by hormonal treatment (63.5% versus 28.3%, P = 0.002) and concern over the attitude of medical staff (44% versus 19%, P = 0.027). CONCLUSIONS: Fertility preservation rates were considerably lower among transgender men than transgender women, strongly related to the fertility preservation process itself. Finding ways to overcome the obstacles confronted by transgender individuals, especially transgender men, will enhance their future biological parenting.

Low-Dose Cyproterone Acetate Treatment for Transgender Women.

BACKGROUND: Transgender women with intact gonads receive lifelong hormonal treatment to suppress physiologic androgen production, the optimal efficacious and safe cyproterone acetate (CPA) dose has not been established. AIM: To assess the effectiveness and safety of low-dose (10-20 mg/day) compared with high-dose (50-100 mg/day) CPA treatment. METHODS: We conducted a historical cohort study of transgender women treated at a tertiary center for transgender health. OUTCOME MEASURES: Serum levels of testosterone, estradiol, prolactin, gonadotrophins, liver enzymes, and lipids. RESULTS: There were 38 transgender women in the low-dose group and 26 in the high-dose group. Age (median 24.9 years, interquartile range [IQR] 21-30 vs 25 years, IQR 19-35) and follow-up time (median 12 months, IQR 6-23 vs 15 months, IQR 12-36) were similar in the low- and high-dose groups, respectively. Serum gonadotropins and testosterone were suppressed to a similar level at all time points in both groups. Prolactin levels increased significantly in both groups, however, with a more substantial increase in the high- vs the low-dose group (804 ± 121 vs 398 ± 69 mIU/ml at 12 months, respectively, P = .004). Total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels were not significantly affected by the dose. CLINICAL IMPLICATIONS: We suggest an adjustment of current clinical practice guidelines to recommend lower doses of CPA for the treatment of transgender women. STRENGTHS & LIMITATIONS: This is the first demonstration that low-dose CPA treatment of transgender women is effective. Limitations include a relatively small sample and retrospective study design. CONCLUSION: Low-dose CPA treatment of transgender women is as effective as high-dose treatment and possibly safer. Zohar NE, Sofer Y, Yaish I, et al. Low-Dose Cyproterone Acetate Treatment for Transgender Women. J Sex Med 2021;18:1292-1298.

Pain and transition: evaluating fibromyalgia in transgender individuals.

OBJECTIVES: As members of a gender minority, transgender individuals face many challenges. Many experience distress, depression, anxiety and suicidal ideation related to gender non-conformity and transphobia. Stress and trauma may contribute to the development of fibromyalgia (FM) syndrome, characterised by widespread pain and fatigue. The prevalence of FM among transgenders is not known. METHODS: Transgender participants were recruited at a specialised clinic. Questionnaires included the Widespread Pain Index (WPI), the Symptom Severity Score (SSS) and the SF-36. Data concerning hormonal treatment protocols was retrieved from charts. The current prevalence of FM was determined, as well as the prevalence before and after testosterone treatment among TM. Pearson correlations were calculated between all measures. RESULTS: 115 participants were recruited, 62.6% transgender men (TM), 37.4% transgender women (TW). 17 individuals (14.8%) fulfilled the 2011 modified ACR FM criteria, for a rate of 19.4% among TM and 6.98% among TW. Among TM, FM was associated with younger age, smoking and SF-36 sub-scales related to physical functioning, role limitation due to physical pain, fatigue, pain and general health. Among TW, FM was associated with social status, employment, depression, existing medical treatment and substance abuse, as well as SF-36 subscales related to role limitations affected due to pain. CONCLUSIONS: Fibromyalgia symptoms are highly prevalent among Israeli transgender individuals and may be related to psychological distress and gender dysphoria. Healthcare professionals treating transgenders should remain vigilant for the occurrence of chronic pain, fatigue and other FM-related symptoms and be prepared to treat and/or refer such patients accordingly.

Revisiting Cushing Syndrome, Milder Forms Are Now a Common Occurrence: A Single-Center Cohort of 76 Subjects.

OBJECTIVE: Guidelines recommend initiating testing for Cushing syndrome (CS) based on strong clinical suspicion. Our recent experience suggests the absence of classical stigmata in the majority of patients with CS. We aimed to confirm this premise by revisiting the clinical features of this syndrome in a modern series of patients from a single center. METHODS: Computerized records of subjects with CS diagnosed at Tel Aviv Sourasky Medical Center between 2000 and 2018 were reviewed. A Cushing inventory score, including all clinical components of the syndrome, was computed for each subject. Data were compared between the subtypes and evaluated in light of those in the literature. RESULTS: Of the 76 subjects with CS (60 women/16 men), 49 (64.5%) had Cushing disease; 16 (21.1%), adrenal adenoma; 7 (9.2%), adrenocortical carcinoma; and 4 (5.3%), ectopic adrenocorticotropic hormone secretion. In only 15 of 74 cases (20.3%), clinical suspicion of CS led to testing. Catabolic signs of CS were present in less than 30% of cases. The most common symptom was weight gain (52/67, 77.6%), and the most common comorbidity was hypertension (47/76, 61.8%). There were no differences in the Cushing inventory score between the subtypes. Signs, symptoms, and comorbidities were all significantly less common than in the classical syndrome. CONCLUSIONS: Modern-day CS presents with subtler features than in the past. Initiating a testing cascade solely based on a strong clinical suspicion may lead to underdiagnosis of milder cases. A concerted effort to devise cost-efficient testing for CS in the current era is needed.

Fertility preservation rates among transgender women compared with transgender men receiving comprehensive fertility counselling.

RESEARCH QUESTION: What is the fertility preservation rate among transgender women who have received professional fertility counselling compared with transgender men? DESIGN: This retrospective cohort study included 56 transgender women and 56 transgender men referred for comprehensive fertility counselling at the Gender Clinic of the Tel Aviv Sourasky Medical Center's Fertility Institute between January 2017 and April 2019. Statistical analyses were performed to compare transgender men with transgender women who preserved fertility and transgender people who preserved fertility and those that did not. RESULTS: The fertility preservation rate of transgender women was significantly higher than that of transgender men (85.7% versus 35.7%, respectively, P < 0.001). The fertility preservation rate among transgender women was associated with being older and not having undergone gender-affirming hormone (GAH) treatment. The fertility preservation rate was higher among adolescent transgender boys compared with adolescent transgender girls (35% versus 6.25%, respectively, P = 0.005). The duration of GAH treatment among the transgender men who preserved fertility was 70 months compared with 18.6 months for transgender women (P = 0.05). All transgender boys opted for oocyte cryopreservation, while half of the transgender men who had not started GAH opted for oocyte cryopreservation, and half of those who had already started on GAH opted for embryo cryopreservation. CONCLUSIONS: High fertility preservation rates among transgender individuals were found after comprehensive fertility counselling. Fertility preservation rates among adults were higher among transgender women compared with transgender men, while the opposite was found in transgender adolescents.

Prolactinomas and menopause: any changes in management?

PURPOSE: Treatment goals in prolactinomas are to correct hypogonadism, restore fertility and control tumor mass in case of macroadenomas. According to current guidelines, medical treatment of asymptomatic postmenopausal women is not indicated. The purpose of this study was to review the current literature pertaining to biological behavior of prolactinomas during menopause, likelihood of successful dopamine agonist withdrawal during this period and possible prolactin-mediated increased morbidity that could modify current management. METHODS: A comprehensive literature search including papers published until July 2019 was conducted using PubMed and Medline databases. RESULTS: Women with prolactinomas entering menopause have a higher chance of prolactin normalization of treatment compared with women in their reproductive years. Although most prolactin secreting adenomas diagnosed during menopause are large, they respond well to dopamine agonist treatment. Data directly linking hyperprolactinemia with an increased risk of cancer and cardiovascular and metabolic morbidity are inconsistent. There is no data indicating that correction of hyperprolactinemia improves clinical outcomes in asymptomatic patients bearing microadenomas. CONCLUSION: There is no evidence that justifies changing current recommendations to withhold medical treatment of microprolactinomas in asymptomatic post-menopausal women. Macroprolactinoma patients should be treated according to standard clinical practice.

Differential Endocrine and Metabolic Effects of Testosterone Suppressive Agents in Transgender Women.

OBJECTIVE: Suppression of testosterone secretion and/or action in transgender women using cyproterone acetate (CPA), spironolactone, or gonadotropin-releasing hormone analogues (GA) is achieved through various mechanisms. Our objective was to characterize possible differential effects of these compounds on metabolic and endocrine variables. METHODS: We conducted a historic cohort study of transgender patients treated in a tertiary referral center. A longitudinal analysis of treatment naïve patients and a cross-sectional analysis of the whole cohort at the last visit was carried out. RESULTS: Among 126 transgender women (75 treatment-naïve), CPA was the predominant androgen suppressive therapy (70%), followed by spironolactone (17.6%), and GA (10.2%). Among those who were treatment-naïve, the increase in serum prolactin levels over baseline was greater at 3 months following CPA initiation (mean change 397 ± 335 mIU/L) than following spironolactone (20.1 ± 87 mIU/L) or GA initiation (64.6 ± 268 mIU/L; P = .0002). Prolactin levels remained higher in the CPA-treated group throughout follow-up, irrespective of estradiol levels, which were similar between the groups. A worse metabolic profile was associated with treatment with CPA than with spironolactone or GA. In the CPA compared to the spironolactone and GA groups, high-density lipoprotein-cholesterol levels were lower (47.1 ± 10.4, 54.4 ± 12.2, and 60.3 ± 13, respectively; P = .0076), while body mass index levels (24.3 ± 5, 21.7 ± 2.3, and 20.7±3.1 kg/m2; P = .03), and systolic (117 ± 12.1, 109 ± 12.2, and 105 ± 13.3mm Hg; P = .01) and diastolic (74 ± 9, 65.6 ± 5.5, and 65.4 ± 11 mm Hg; P = .0008) blood pressure levels were higher at the last visit. CONCLUSION: Treatment of transgender women with CPA was associated with hyperprolactinemia and a worse cardiovascular risk profile than treatment with spironolactone or GA. ABBREVIATIONS: BMI = body mass index; CPA = cyproterone acetate; E2 = estradiol; FSH = follicle-stimulating hormone; GA = gonadotropin-releasing hormone analogues; LH = luteinizing hormone.

Management of NFAs: medical treatment.

INTRODUCTION: Non-functioning pituitary adenomas (NFPAs) are in general large tumors that present with symptoms secondary to local pressure on adjacent structures. Transsphenoidal surgery is the first line of treatment but residual tumor mass is often detected post-operatively. Medical therapy, in any stage of tumor management, is not well established. METHODS: A literature search was performed to review the available data on medical treatment of NFPAs. RESULTS: Medications investigated for the treatment of NFPAs include dopamine receptor agonists (DA) and somatostatin receptor ligands. Randomized controlled trials are lacking, but available data suggest that DA have a positive effect on tumor remnant stabilization after surgery and could be considered in this setting. Temozolomide is reserved for aggressive tumors, although future studies are required. CONCLUSIONS: NFPA are often not amenable to complete surgical resection. Conservative follow-up after surgery is associated with a high prevalence of tumor remnant progression. DA therapy may prevent residual tumor enlargement in over 85% of these patients, with a substantial consequent reduction in the need for repeat surgery or radiation therapy. It is our view that DA treatment should be routinely considered for the management of NFPA patients with incompletely resected tumors.

IGF-1 levels may increase paradoxically with dopamine agonist treatment for prolactinomas.

OBJECTIVE: Hyperprolactinemia is common in acromegaly and in these patients, insulin-like growth factor (IGF)-1 level may decrease with dopamine agonist. We report a series of patients with prolactinoma and a paradoxical increase of IGF-1 levels during cabergoline treatment. METHODS: Clinical characteristics and response to treatment of patients with prolactinomas, in whom normal or slightly elevated baseline IGF-1 levels increased with cabergoline. RESULTS: The cohort consisted of ten prolactinoma patients (nine males, mean age 48 ± 14 years). Mean adenoma size was 23.8 ± 16.2 mm, with cavernous sinus invasion in eight. In five patients baseline IGF-1 levels were normal and in four levels were 1.2-1.5-fold the upper limit of the normal (ULN). One patient had IGF-1 measured shortly after initiating cabergoline and it was 1.4 × ULN. During cabergoline treatment (dose range 0.5-2 mg/week) PRL normalization was achieved in all and tumor shrinkage occurred in seven patients. The mean IGF-1 increase on cabergoline was 1.7 ± 0.4 × ULN. Cabergoline dose reduction or interruption was attempted in five patients and resulted in decreased IGF-1 levels in all, including normalization in two patients. Three patients were eventually diagnosed with acromegaly, one was referred for pituitary surgery followed by complete remission, another patient was switched to somatostatin analogue, and the third was treated by combination of somatostatin analogues with pegvisomant, with reduction of IGF-1 in all these patients. CONCLUSION: IGF-1 levels may increase to clinically significant levels during cabergoline treatment for PRL-adenoma. We suggest IGF-1 monitoring in all patients treated with dopamine agonists and not only in those presenting symptoms of acromegaly.

Paradoxical and atypical responses to pasireotide in aggressive ACTH-secreting pituitary tumors.

PURPOSE: Pasireotide is the only pituitary targeted medication registered for the treatment of Cushing's disease. Drug efficacy data are largely based on a major prospective study in which the vast majority of patients had microadenomas. The purpose of this study was to summarize results of pasireotide treatment of ACTH secreting macroadenomas from our center. METHODS: Retrospective review of data extracted from clinical files. RESULTS: Three patients presented with large and invasive macroadenomas that required several surgical interventions and radiotherapy treatments. Patient 1 is a 57 year-old male who developed an extreme (27-fold) paradoxical response of urinary free cortisol (UFC) levels as measured 2 weeks after pasireotide institution, which increased further (71-fold) in response to dose increment but decreased to baseline levels after treatment interruption. Patient 2 is a 44 year old woman with a long standing (26 years) ACTH-secreting carcinoma metastatic to bone and after bilateral adrenalectomy. After an initial excellent response to pasireotide treatment, ACTH levels escaped suppression and a further rebound was noted 6 weeks after treatment interruption. Patient 3 is a 53 year old man that after escape from temozolomide therapy was started on pasireotide and rapidly responded by almost normalizing UFC excretion after 4 weeks, but returned to baseline UFC levels after four additional weeks of treatment. CONCLUSIONS: We describe as yet unreported atypical responses to pasireotide treatment in patients with aggressive ACTH-secreting tumors. Increased vigilance is recommended during pasireotide treatment of such patients.

Arterial properties in acromegaly: relation to disease activity and associated cardiovascular risk factors.

PURPOSE: Acromegaly is associated with increased cardiovascular morbidity and mortality when inadequately treated, which may be secondary to associated comorbidities or to direct IGF-1 effects on the cardiovascular system. By using a control group carefully matched for traditional cardiovascular risk factors, we aimed to assess the direct contribution of disease activity and IGF-1 levels to arterial damage as assessed by measurements of arterial stiffness and endothelial function. METHODS: Twenty-nine subjects with acromegaly (11 males, 52 ± 14 year; 15 active acromegaly) and 24 matched controls underwent evaluation of large and small artery compliance using applanation tonometry, pulse wave velocity (PWV), augmentation index (Alx), carotid ultrasonography intima-media thickness, (IMT) and flow-mediated dilatation (FMD). RESULTS: IGF-1 expressed as times the upper limit of the normal range (x ULN) was 2.2 ± 1.1 in patients with active disease versus 0.7 ± 0.2 in patients in remission. Irrespective of disease activity, FMD was lower in patients with acromegaly than in control subjects, (3.4 ± 2.7 % in active acromegaly, 4.4 ± 3.3 % in controlled acromegaly and 7.5 ± 3.8 % in controls; p = 0.004). There were no significant differences in PWV, Alx, and IMT between groups. A positive correlation was found between IGF-1× ULN and IMT (r = 0.4; P = 0.02). Asymmetric dimethylarginine (ADMA), a novel cardiovascular risk factor, was positively correlated to arterial stiffness (r = 0.46; p = 0.017) and negatively with small vessel compliance (r = -0.44, p = 0.02). CONCLUSIONS: Patients with acromegaly have significantly impaired endothelial function as assessed by FMD, but other tested vascular parameters were similar to a control group that was adequately matched for cardiovascular risk factors.

Giant prolactinomas larger than 60 mm in size: a cohort of massive and aggressive prolactin-secreting pituitary adenomas.

OBJECTIVES: Prolactin (PRL)-secreting macroadenomas usually measure between 10 and 40 mm. Giant (adenoma size ≥40 mm) PRL-tumors are not common, and larger prolactinomas (maximal diameter ≥60 mm) are rare, and their management outcomes have not been well characterized. METHODS: We have identified 18 subjects (16 men, 2 females) with giant PRL-adenomas (size ≥60 mm; PRL > 1000 ng/ml) and summarized their characteristics and response to treatment. RESULTS: Mean age was 36.3 ± 13.5 years (range 12-59 years). Mean adenoma size was 71.8 ± 10.2 mm (60-92 mm). Complaints at presentation included headaches in 11 patients, visual deterioration in 9, sexual dysfunction in 9 males, and behavioral changes in two. Fourteen (78 %) had visual field defects. Mean PRL at presentation was 28,465 ng/ml (range 1300-270,000). All patients were treated with cabergoline (3.9 ± 2.0 mg/week), except for one who received bromocriptine. Treatment achieved PRL normalization in 11/18 patients within a median interval of 20 months. Visual improvement occurred in 12/14 patients with pre-treatment visual abnormalities. Nine patients underwent surgery (transsphenoidal, 7; transcranial, 2). None of the seven patients with elevated PRL before surgery achieved remission post-operatively. After a follow-up of 7.8 ± 5.1 years, 15/18 patients had significant adenoma shrinkage. Eleven patients are normoprolactinemic, 3 are partially controlled (PRL < 3 × ULN), and 4 remain with significantly elevated PRL. Most patients reported disappearance or improvement of their complaints. CONCLUSIONS: These enormous PRL-adenomas are invasive but respond fairly well to medical treatment. Long-term therapy with high dose cabergoline together with a pituitary surgery in some patients was the key for their successful management, achieving biochemical and clinical remission in most patients.

PANCREATIC INCIDENTALOMA: DIFFERENTIATING NONFUNCTIONING PANCREATIC NEUROENDOCRINE TUMORS FROM INTRAPANCREATIC ACCESSORY SPLEEN.

OBJECTIVE: To improve the preoperative assessment of pancreatic incidentalomas (PIs) by analysis of 1 index case and characterization of the published features of intrapancreatic accessory spleen (IPAS) compared to pancreatic neuroendocrine tumor (PNET). METHODS: A search of the literature using the online database MEDLINE. RESULTS: In all, 46 cases of IPAS have been described to date: 17 were "presumed" as IPAS based on technetium-99m (Tc-99m) scanning, fine-needle aspiration (FNA) stain for CD8, or contrast-enhanced sonography; 29 were misdiagnosed as PNET and underwent surgery. The pancreatic lesions were 1) mostly solitary; 2) solid on imaging; 3) well defined; 4) located predominantly at the pancreatic tail; 5) not exceeding 3 cm in the largest diameter; 5) all detected in adults (22-81 years); 6) not related to sex. In subjects referred for surgery, standard imaging studies/imaging protocols did not differentiate between IPAS and PNET. FNA was performed in 5/46 cases, all of which were false-positive for PNET. Immunohistochemical staining for T-cells on FNA material and specific imaging features (characteristic arciform splenic enhancement pattern on dynamic computed tomography [CT]; nuclear scintigraphies with radioisotope specifically trapped by splenic tissue [Tc-99m]) or contrast-enhanced sonography offered valuable clues. Still, distal pancreatectomy and splenectomy was carried out in 72%, and the rest had distal pancreatectomies. CONCLUSION: IPAS should be considered before surgery in patients with PIs. A new practical algorithm is presented for better preoperative evaluation of such lesions; it combines the recognition of early indicators and sequential consideration of cytologic and imaging features to decrease the hazards of unnecessary major surgery. ABBREVIATIONS: CT = computed tomography EUS = endoscopic ultrasound FNA = fine-needle aspiration HDRBC = heat-damaged red blood cells IPAS = intrapancreatic accessory spleen MRI = magnetic resonance tomography NF-PNET = nonfunctioning pancreatic neuroendocrine tumor PET = positron emission tomography PNET = pancreatic neuroendocrine tumor PI = pancreatic incidentalomas SPIO = superparamagnetic iron oxide Tc-99m = technetium-99m.

GENDER DETERMINES SERUM FREE CORTISOL: HIGHER LEVELS IN MEN.

OBJECTIVE: Because only the free fraction of serum cortisol can readily access glucocorticoid receptors, we investigated whether or not a gender-related difference in serum free cortisol (FC) exists in the basal and adrenocorticotropic hormone (ACTH)-stimulated state. METHODS: Serum total cortisol (TC) and FC were measured in 323 subjects (175 men; 148 women). Additionally, the low-dose 1-µg ACTH test was performed in 56 subjects (30 women, 26 men). Subjects were healthy volunteers, recruited in a preventive medicine screening program and an outpatient clinic. RESULTS: Overall, basal serum TC and FC level were ~18 and ~33%, respectively, higher in men than in women (TC, 14.5 ± 0.33 µg/dL vs. 12.3 ± 0.33 µg/dL; P<.0001; FC, 0.68 ± 0.02 µg/dL vs. 0.51 ± 0.02 µg/dL; P<.0001). The higher FC in men relative to women was apparent across a wide age range (17 to 86 years) and persisted after adjustment for age and body mass index. The FC fraction (%FC, out of TC) was concordantly higher in men (5.4 ± 0.09% vs. 4.8 ± 0.3%; P = .046). FC was not related to the estimated menopausal status (women age below and above 47, 50, or 53 years). ACTH-stimulated FC levels were significantly higher in men compared to women, as reflected by the area under the response curve (49.4 ± 3.4 µg × min vs. 39.6 ± 2.2 µg × min; P = .0014). CONCLUSION: Gender is an unrecognized determinant of serum FC in humans. The possibility of lifelong exposure to the higher bioactive fraction of cortisol under basal conditions or daily stress involving ACTH stimulation should be further investigated in the context of gender-related phenotypic features such as "android" (visceral) fat deposition and longevity. ABBREVIATIONS: ACTH = adrenocorticotropic hormone BMI = body mass index CBG = cortisol-binding globulin FC = free cortisol HPA = hypothalamic-pituitary-adrenal TC = total cortisol.