Cabergoline treatment for surgery-naïve non-functioning pituitary macroadenomas.

PURPOSE: The treatment strategy of non-functioning pituitary adenomas (NFPAs) includes surgery, radiotherapy, medical therapy, or observation without intervention. Cabergoline, a dopaminergic agonist, was suggested for the treatment of NFPA remnants after trans-sphenoidal surgery. This study investigates the efficacy of cabergoline in surgery-naive patients with NFPA. METHODS: Retrospective cohort study including surgery-naive patients with NFPA ≥ 10 mm, treated with cabergoline at a dose of ≥ 1 mg/week for at least 24 months. Patients with chiasmal damage were excluded. Data collected included symptoms, in particular visual disturbances, hormonal levels, tumor characteristics and size evaluated by MRI. Tumor growth was defined as an increase in maximal diameter of ≥ 2 mm, and shrinkage as reduction of ≥ 2 mm. RESULTS: Our cohort included 25 patients treated with cabergoline as primary therapy. Mean age was 63.3 ± 17.3 years, 56% (14/25) were males. Mean tumor size at diagnosis was 18.6 ± 6.3 mm (median 17 mm, range 10-36), and the average follow-up period with cabergoline was 4.6 ± 3.4 years. Out of the 25 tumors, five tumors (20%) decreased in size (mean decrease of 5.0 ± 3.0 mm), 12 tumors (48%) remained stable, and eight (32%) increased in size (mean growth of 5.0 ± 3.3 mm) with cabergoline treatment. During the first two years of cabergoline treatment, the median tumor size exhibited a reduction of 0.5 mm. Patients with an increase in tumor size had larger adenomas at diagnosis and a longer follow-up. Two patients (8%) underwent surgery due to tumor enlargement. CONCLUSION: Primary treatment with cabergoline is a reasonable approach for selected patients with NFPAs without visual threat.

Natural history of nonfunctioning pituitary macroadenomas followed without intervention: A retrospective cohort study.

OBJECTIVE: The treatment strategy for nonfunctioning pituitary adenomas (NFPA) includes surgery, radiotherapy, medical treatment, or follow-up. Prior series of patients with NFPAs followed without intervention include small numbers of patients with macroadenomas. This study investigated the natural history of patients with macroadenomas followed without treatment. DESIGN AND PATIENTS: Retrospective cohort study included patients>18 years, with a diagnosis of NFPA ≥ 10 mm who were naïve to surgery or medical treatment and followed more than 12 months after diagnosis. Patients with chiasmal threat were excluded. Follow-up terminated if the patient underwent surgery, received cabergoline or was lost to follow-up. MEASUREMENTS: Data collected included evaluation of tumour characteristics and size by MRI, symptoms including visual disturbances, and hormonal levels. Tumour growth was defined as maximal diameter increase of ≥2 mm. RESULTS: The cohort included 49 patients (30 males, mean age 68.0 ± 12.0 years). At diagnosis, the average tumour size was 17.8 ± 5.9 mm. Mean follow-up time was 4.9 ± 4.9 years. Increase in tumour size occurred in 16 patients (33%), with an average growth of 5.1 ± 4.4 mm. Reduction in tumour size occurred in 10 patients (20%), with a mean decrease of 3.5 ± 1.3 mm. Twenty-three patients remained with stable tumours. Overall, 33 patients (67%) were observed without any intervention; 3 patients were operated and 13 were treated with cabergoline. None of the parameters including age, gender, baseline tumour size, invasiveness, visual disturbances, or hypopituitarism at diagnosis, predicted tumour growth. CONCLUSION: Observation of NFPAs without surgery or medical therapy is a reasonable approach in selected patients. In our study, no parameter predicted tumour growth.

Cushing's syndrome in women: age-related differences in etiology and clinical picture.

OBJECTIVE: To evaluate the clinical presentation, biochemical profile, and etiology of Cushing's syndrome (CS) in women stratified by age. METHODS: Retrospective study of patients with CS, treated at Rabin Medical Center from 2000 to 2020, or Maccabi Healthcare Services in Israel from 2005 to 2017. Disease etiology, presentation and biochemical profile were compared according to age at diagnosis: ≤ 45, 46-64, or ≥ 65 years. Study was approved by the Ethics Review Boards of both facilities with waiver of consent. RESULTS: The cohort included 142 women (mean age, 46.0 ± 15.1 years):81 (57.0%) with Cushing's disease (CD), and 61 (43.0%) with adrenal CS. Pituitary etiology was more common among women < 45 (70.6%), compared with patients ≥ 65 years (31.6%) (P < 0.05). Among CS patients, hypercortisolism was diagnosed in the context of screening after an adrenal incidentaloma detection in 15.0% of patients < 45 and 53.8% of ≥ 65 years (P < 0.001). Weight gain was evident in 57.4% of women < 45 (56.3% CD, 60.0% CS), and 15.8% of women ≥ 65 years (50% CD, 0% CS) (P = 0.011). Mean UFC levels were highest for women < 45 (3.8 × ULN) and lowest for ≥ 65 years (2.3 × ULN) (P < 0.001). CONCLUSION: We have shown for the first time that women with CS ≥ 65 years of age more commonly have adrenal etiology. The initial presentation of CS also differs between age groups, where women < 45 years are likely to present with weight gain, while those ≥ 65 years are frequently diagnosed incidentally, when screening for hypercortisolism in the presence of an adrenal incidentaloma.

LONG-TERM OUTCOMES AND PROGNOSTIC FACTORS IN PATIENTS WITH DIFFERENTIATED THYROID CARCINOMA AND BONE METASTASES.

Objective: This institutional study sought to retrospectively evaluate disease progression and survival of patients with differentiated thyroid cancer (DTC) and bone metastases (BM) and to investigate variables predictive of better long-term outcomes. Methods: The Rabin Medical Center Thyroid Cancer Registry was searched for patients with bone-metastatic DTC. Variables including a patient's gender and age, pathology of the thyroid tumor, and characteristics of BM were retrieved and analyzed in association with disease progression and mortality. Results: The cohort included 64 patients (48.4% female). Mean age at diagnosis was 62.1 ± 14.3 years; mean primary tumor size was 41 ± 30 mm. Overall, 60.4% had stage T3/T4 disease; 46.3% had extrathyroidal extension; 40% had lymph-node metastases. Histopathology yielded papillary and follicular DTC in 40.6% and 32.8% of patients, respectively, and poorly/intermediately differentiated carcinoma in 26.6%. BM were synchronous in 50%. Mean follow-up was 11 ± 9.6 years from DTC detection. The common first sites of BM detection were spine (46.9% of patients), pelvis (37.5%) and ribs (21.9%). Nineteen patients (29.7%) presented with multiple-site BM, of whom 15 (78.9%) had spinal metastases. After initial treatment, 62/64 patients had structural persistence, and at last follow-up, 57.8% had progressive disease. Overall, 54.7% of patients died, 71.4% of DTC. Improved long-term outcomes were associated with younger age, lower tumor stage, no extrathyroidal extension, bone-only metastases, and non-spinal BM. Younger age and non-spinal BM were the only independent predictors for improved survival. Conclusions: Selected patients with bone-metastatic DTC may achieve fair long-term outcomes. Spinal metastases are associated with disseminated skeletal spread and increased mortality. Abbreviations: BM = bone metastases; COX = multivariate analyses; DM = distant metastases; DSM = disease-specific mortality; DSS = disease-specific survival; DTC = differentiated thyroid carcinoma; ETE = extrathyroidal extension; LNM = lymph node metastases; OM = overall mortality; OS = overall survival; PTCFV = papillary thyroid carcinoma; RAI = radioactive iodine; SM = spinal metastases; SRE = skeletal-related event; txWBS = whole-body scan after RAI therapy.

DISEASE PRESENTATION AND REMISSION RATE IN GRAVES DISEASE TREATED WITH ANTITHYROID DRUGS: IS GENDER REALLY A FACTOR?

OBJECTIVE: Male gender is considered an adverse prognostic factor for remission of Graves disease treatment with antithyroid drugs (ATDs), although published data are conflicting. This often results in early consideration of radioiodine treatment and surgery for men. Our objective was to compare disease presentation and outcome in men versus women treated with ATDs. METHODS: Retrospective study of 235 patients (64 men, 171 women) with Graves disease who were evaluated for features at presentation and outcome at the end of follow-up between 2010 and 2015. RESULTS: Disease presentation was similar in men and women for age at diagnosis (41.4 ± 14 years vs. 40 ± 15 years), duration of follow-up (6.6 ± 7 years vs. 7.7 ± 6 years), rates of comorbid autoimmune diseases, and rate of Graves ophthalmopathy. Smoking was more prevalent in males (31% vs. 15%; P = .009). Free thyroxine and triiodothyronine levels were comparable. ATDs were first-line treatment in all males and in 168 of 171 females, for a median duration of 24 and 20 months, respectively ( P = .55). Remission rates were 47% in men and 58% in women ( P = .14). Males had fewer adverse events (9% vs. 18%) and treatment discontinuation (5% vs. 16%). Disease recurrence was comparable (14% vs. 20%; P = .32), as was requirement for second-line treatment, either radioiodine therapy or thyroidectomy. CONCLUSION: Graves disease presentation is similar in men and women. Men treated with ATDs have high remission rates and similar recurrence rates compared to women, with fewer adverse events and less discontinuation of treatment. ATDs are an attractive first-line treatment for both genders. ABBREVIATIONS: ATA = American Thyroid Association; ATD = antithyroid drug; GO = Graves ophthalmopathy; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone.

CENTRAL DIABETES INSIPIDUS: CLINICAL CHARACTERISTICS AND LONG-TERM COURSE IN A LARGE COHORT OF ADULTS.

OBJECTIVE: Central diabetes insipidus (CDI) is a rare heterogeneous condition with various underlying causes. This study sought to increase the still-limited data on the clinical characteristics and long-term course in adults diagnosed with CDI. METHODS: Data on demographics, presentation, imaging findings, affected pituitary axes, treatment, and complications were collected retrospectively from the files of 70 adult patients with CDI followed at a referral endocrine clinic. RESULTS: Forty women and 30 men were included. Mean age was 46.8 ± 15 years at the time of this study and 29.3 ± 20 years at CDI diagnosis. Twenty-eight patients were diagnosed in childhood. Forty patients (57%) acquired CDI following surgery. Main sellar pathologies were: craniopharyngioma, 17 patients (11 diagnosed in childhood); Langerhans histiocytosis, 10 patients (5 diagnosed in childhood); 7 patients (all diagnosed as adults) had a growth hormone-secreting adenoma; 12 patients (17%; 6 diagnosed in childhood) had idiopathic CDI. At least one anterior pituitary axis was affected in 73% of the cohort: 59% had growth hormone deficiency, 56% hypogonadism, 55% central hypothyroidism, 44% adrenocorticotropic hormone-cortisol deficiency. Patients with postoperative/trauma CDI (n = 44) tended to have multiple anterior pituitary axes deficits compared to the nonsurgical group of patients. All patients were treated with vasopressin preparations, mostly nasal spray. Hyponatremia developed in 32 patients, more in women, and was severe (<125 mEq/L) in 10 patients. Hypernatremia (>150 mEq/L) was noticed in 5 patients. Overall, the calculated complication rate was 22 in 1,250 treatment-years. CONCLUSION: Most adult patients with CDI have anterior pituitary dysfunction. Stability is usually achieved with long-term treatment. Women were more susceptible to desmopressin complications, albeit with an overall relatively low complication rate. ABBREVIATIONS: ACTH = adrenocorticotropic hormone CDI = central diabetes insipidus GH = growth hormone MRI = magnetic resonance imaging.

LONG-TERM OUTCOMES AND PROGNOSTIC FACTORS IN PATIENTS WITH DIFFERENTIATED THYROID CANCER AND DISTANT METASTASES.

OBJECTIVE: Distant metastatic spread is the most frequent cause of thyroid cancer-related death. The objective of this study was to evaluate overall and disease-related survival of patients with differentiated thyroid cancer (DTC) and distant metastases (DM) attending a single medical center and to investigate variables predictive of better long-term outcomes. METHODS: The Rabin Medical Center Thyroid Cancer Registry was searched for patients with DM from DTC. RESULTS: The cohort included 138 patients (58.7% female) diagnosed at age 54.7 ± 19.5 years. Mean primary tumor size was 33.9 ± 26 mm. Most patients (57.7%) were stage T3/T4; 48.7% had extrathyroidal extension; 53.5% had lymph node metastases. Histopathology yielded papillary and follicular thyroid carcinoma in 66.7% and 13.8%, respectively, and intermediate/poorly differentiated carcinoma in 19.6%. All but 2 patients underwent total thyroidectomy, and 133/138 (96.4%) received radioactive iodine (RAI) therapy. DM were synchronous in 55.1%. The mean follow-up was 8.2 years from detection of metastases. The common sites of metastases were the lungs (85.6% of patients), bones (39.9%), brain (5.8%) and liver (3.6%). At last follow-up, resolution was documented in 24.6% of patients, improvement/stable disease in 31.6%, and structurally progressive disease in 43.4%. By the end of the study, 40.6% of patients died, 23.2% of DTC. Improved overall survival and disease progression were associated with younger age, lung-only DM, and metastatic RAI avidity. CONCLUSION: Patients with DTC and DM treated by standard-of-care approaches frequently achieve favorable long-term outcomes. Novel therapies might be necessary in only a minority of these patients, and the reported prognostic factors can aid in their identification. ABBREVIATIONS: CR = complete response; DM = distant metastases; DTC = differentiated thyroid cancer; ETE = extra-thyroidal extension; M0 = detected during follow-up; M1 = detected at diagnosis; MSKCC = Memorial Sloan Kettering Cancer Center; NED = no evidence of disease; OS = overall survival; PFS = progression free survival; PTC = papillary thyroid cancer; RAI = radioactive iodine; Tg = thyroglobulin.

[CLINICAL CHARACTERISTICS OF MALE PATIENTS WITH OSTEOPOROSIS REFERRED TO THE ENDOCRINE CLINIC OF A TERTIARY HOSPITAL].

INTRODUCTION: Osteoporosis in men is underdiagnosed and undertreated. The prevalence of male osteoporosis increases with age and it becomes a significant public health burden. Currently, there are a few clinical studies on male osteoporosis with limited knowledge of effective therapeutic options. AIMS: Our study aimed to characterize men with osteoporosis in a referral metabolic clinic in Rabin Medical Center at the Beilinson Campus. METHODS: In this study we retrospectively analyzed the medical records of 270 consecutive male patients with osteoporosis diagnosed and treated in our clinic during 2013. RESULTS: A total of 270 of 1940 (14%) patients with osteoporosis in our clinic were males. The mean age of men with osteoporosis was 67.9 ± 13.6; 113 (40%) men suffered from osteoporotic fractures, 57 of them (51%) had vertebral fractures, 28 (25%) had more than one fracture. Osteoporotic fracture was the first presentation of osteoporosis in 82% of men with fractures (age of presentation 62.2 ± 14.5). Furthermore, 141 patients (52%) had vitamin D insufficiency (25OHD levels < 60 nmol/l, normal 75-250 nmol/l), and the mean level was 39.9±12.6 nmol/l. Secondary osteoporosis was identified in 166 (61%) men. The most common etiologies were chronic glucocorticoid treatment (45%), hypogonadism (36%), hypercalciuria (23.4%) and hyperparathyroidism (19%). Most men (223) received bisphosphonates as primary therapy and alendronate was the mostly commonly prescribed agent. CONCLUSIONS: Osteoporosis in men usually remains an underdiagnosed disorder until an osteoporotic fracture occurs. Secondary causes for osteoporosis are commonly encountered, of which glucocorticoid treatment and hypogonadism are the most prevalent etiologies. Increasing awareness of osteoporosis in men may prevent the deleterious consequences of this disabling, yet treatable disease.

VARIATIONS IN CLINICAL AND IMAGING FINDINGS BY TIME OF DIAGNOSIS IN FEMALES WITH HYPOPITUITARISM ATTRIBUTED TO LYMPHOCYTIC HYPOPHYSITIS.

OBJECTIVE: To describe the various patterns of presentation, including assisting analyses, associated with the timing of diagnosis of females with hypopituitarism and suspected clinical diagnosis of lymphocytic hypophysitis. METHODS: A retrospective study of 9 consecutive females with pituitary dysfunction developed during or after pregnancy. All subjects were treated in our clinics between 2008 and 2014. Data were collected on clinical characteristics, pituitary hormone levels, and imaging findings. RESULTS: The study group included 9 patients with a mean age 33.7 ± 7.8 years at delivery. The probable cause of disease was lymphocytic hypophysitis. Headache or specific symptoms/signs of hypopituitarism appeared within 1 year of delivery. Five patients had headache, and 8 had difficulty breastfeeding or amenorrhea. Laboratory findings included central hypocortisolism (8/9 patients), hypogonadotropic hypogonadism (8/9), and central hypothyroidism (6/7). Insulin-like growth factor-1 (IGF-1) levels were low in 8/8 patients. Prolactin levels were low in 3/9 patients, and 1 patient had diabetes insipidus. Seven patients were diagnosed less than 1 year from symptom onset; 4 (57%) complained of headaches, and 5 (71%) had panhypopituitarism. Two patients were diagnosed later. Both had difficulty breastfeeding and amenorrhea, and one also had headaches. Both had panhypopituitarism and reduced pituitary volume. None of the patients fully recovered pituitary function. Normalization of the thyrotroph axis occurred in 3 patients, gonadotroph function in 3, the corticotroph axis in 2, and IGF-1 normalized in 1 subject. CONCLUSION: Hypopituitarism attributed to lymphocytic hypophysitis may present during pregnancy or early postpartum period with a clear clinical picture, or later, with indolent and nonspecific symptoms and signs.

Pituitary imaging findings in male patients with hypogonadotrophic hypogonadism.

CONTEXT: Data on pituitary imaging in adult male patients presenting with hypogonadotrophic hypogonadism (HH) and no known pituitary disease are scarce. OBJECTIVE: To assess the usefulness of pituitary imaging in the evaluation of men presenting with HH after excluding known pituitary disorders and hyperprolactinemia. DESIGN: A historical prospective cohort of males with HH. PATIENTS: Men who presented for endocrine evaluation from 2011 to 2014 with testosterone levels <10.4 nmol/L (300 ng/mL), normal LH and FSH levels and no known pituitary disease. RESULTS: Seventy-five men were included in the analysis. Their mean age and BMI were 53.4 ± 14.8 years and 30.7 ± 5.2 kg/m2, respectively. Mean total testosterone, LH, and FSH were 6.2 ± 1.7 nmol/L, 3.4 ± 2 and 4.7 ± 3.1 mIU/L, respectively. Prolactin level within the normal range was obtained in all men (mean 161 ± 61, range 41-347 mIU/L). Sixty-two men had pituitary MRI and 13 performed CT. In 61 (81.3%) men pituitary imaging was normal. Microadenoma was found in 8 (10.7%), empty sella and thickened pituitary stalk in one patient (1.3%) each. In other four patients (5.3%) a small or mildly asymmetric pituitary gland was noted. No correlation was found between testosterone level and the presence of pituitary anomalies. CONCLUSIONS: This study suggests that the use of routine hypothalamic-pituitary imaging in the evaluation of IHH, in the absence of clinical characteristics of other hormonal loss or sellar compression symptoms, will not increase the diagnostic yield of sellar structural abnormalities over that reported in the general population.

Long-term effectiveness of zoledronic acid in patients with Paget's disease of bone - a retrospective cohort study.

PURPOSE: The aims of the current study were to describe clinical and biochemical features of patients with Paget disease of bone (PDB) followed at our medical center, and to examine the long-term effectiveness of zoledronate. METHODS: Retrospective cohort study included consecutive patients≥18 years with a diagnosis of PDB, followed in the Rabin Medical Center (RMC) Institute of Endocrinology from 1973 to 2023. The cohort comprised two groups: patients treated/not treated with zoledronic acid (ZOL/NZOL). The primary outcome was the percentage of patients who achieved a biochemical therapeutic response. RESULTS: Overall, 101 patients with PDB were included, 68 in the ZOL group and 33 in the NZOL group. The mean age was 65.2 ± 10.0 years, and 47% were female. Notably, 77% exhibited monostotic involvement, and only 3% had experienced fractures attributed to PDB. Mean ALP level at diagnosis was 160 ± 70.6 U/L. The median follow-up duration was 17 years since PDB diagnosis, comparable between the groups. Primary outcome was more prevalent in the ZOL compared to the NZOL group [42 patients (88%) VS 11 patients (52%) respectively, P = 0.004]. At the end of follow-up, mean ALP levels in the NZOL group were significantly higher than the levels in the ZOL group irrespective of the number of infusions received. CONCLUSION: The majority of patients with PDB experience a mild disease course, marked by monostotic involvement and a low prevalence of fractures. Zoledronic acid effectively manages PDB, providing sustained biochemical response. The necessity for multiple zoledronic acid injections remains questionable, often implemented due to osteoporosis.

Oral daily PTH(1-34) tablets (EB613) in postmenopausal women with low BMD or osteoporosis: a randomized, placebo-controlled, six-month, phase 2 study.

Anabolic treatment is indicated for high and very-high risk patients with osteoporosis, but acceptance is limited because current anabolic medications require subcutaneous injections. The purpose of this study was to assess the effects of a novel orally administered parathyroid hormone (PTH) tablet on serum markers of bone formation [N-terminal propeptide of Type I procollagen (PINP) and osteocalcin (OC)] and bone resorption [crosslinked C-telopeptide (CTX)], bone mineral density (BMD) and safety in postmenopausal women with low BMD or osteoporosis. In this 6-month, double-blind, placebo-controlled study, 161 patients were randomized to oral PTH tablets containing 0.5, 1.0, 1.5, or 2.5 mg or placebo daily. Biochemical markers were assessed at 1, 2, 3 and 6 months and BMD of lumbar spine, total hip and femoral neck was measured at 6 months. Biochemical marker changes were dose dependent with minimal or no effect at the two lowest doses. At the highest dose (2.5 mg once daily), serum PINP and OC levels increased 30% within 1 month after oral PTH initiation (p < 0.0001), remained elevated through 3 months and were back to baseline at 6 months. In contrast, serum CTX levels declined 16% and 21% below baseline at 3 and 6 months respectively (both p ≤ 0.02). At 6 months, 2.5 mg tablets increased mean BMD vs placebo of the lumbar spine by 2.7%, total hip by 1.8%, and femoral neck by 2.8% (all p ≤ 0.01). There were no drug-related serious adverse events. The most common adverse events were headache, nausea, and dizziness. In contrast to subcutaneous PTH, the oral PTH tablet appears to increase BMD rapidly by the dual mechanism of stimulating formation and inhibiting bone resorption. This might be the first effective oral anabolic alternative to subcutaneous administration for the treatment of low BMD or osteoporosis.

Despite the superior benefits of bone building (anabolic) agents and guidelines supporting their use, these medications are used in a minority of patients for whom they are appropriate, in part because they require daily or monthly injections, which limit patient acceptance. An oral anabolic tablet has potential to address this substantial treatment gap. In this double-blind, placebo controlled, dose-finding randomized study, 161 postmenopausal women with low bone mineral density or osteoporosis were treated with varying doses of the active part of parathyroid hormone [PTH(1-34)] or placebo given in daily oral tablets for 6 months. The highest oral PTH tablet dose (2.5 mg), produced an increase in markers of bone formation while simultaneously decreasing the markers of bone breakdown. Significant gains in bone mineral density of the spine and hip were observed at the end of the 6-month study and there were no significant safety concerns. The 2.5 mg oral PTH tablet dose was well tolerated when patients were instructed to titrate up to the full dose. We conclude that this PTH tablet might be the first effective orally administered bone building medication and should be studied further in treatment of women with osteoporosis.

Hemoglobin decline as a signal for hyperprolactinemia onset prior to prolactinoma diagnosis in hypogonadal men.

BACKGROUND: Men harboring prolactinomas frequently suffer from central hypogonadism with secondary anemia. They present insidious and nonspecific symptoms of hypogonadism, making it difficult to diagnose the disease and determine its duration. The result is a delay in diagnosis, which may have harmful hormonal and metabolic consequences. We hypothesized that a decrease in hemoglobin (HB) levels prior to prolactinoma diagnosis, may signal hyperprolactinemia onset and estimate disease duration. METHODS: We retrospectively evaluated the prediagnosis temporal trends in HB levels of 70 males with prolactinoma, diagnosed from January 2010 to July 2022. Men without hypogonadism, patients that received testosterone, and those with unrelated anemia were excluded. RESULTS: Sixty-one of seventy men (87%) with prolactinoma presented with hypogonadism, and forty men (57%) had HB levels ≤13.5 g/dL at diagnosis. We identified 25 patients with "informative" HB curves (mean age, 46.1±14.9 years; median prolactin, 952 ng/mL; median follow-up, 14.0 years), demonstrating an obvious prediagnosis HB decrease (greater than 1.0 g/dL), from a prediagnosis baseline HB of 14.4 ± 0.3 to 12.9 ± 0.5 g/dL at diagnosis. The median "low-HB duration" (from the first low HB measurement to hyperprolactinemia diagnosis) was 6.1 years (IQR, 3.3-8.8 years). In symptomatic patients, we identified a correlation between "low-HB duration" and patient-reported sexual dysfunction duration (n = 17, R = 0.502, p = 0.04). The "low-HB duration" was significantly longer than the reported sexual dysfunction duration (7.0 ± 4.5 vs. 2.9 ± 2.5 years, p = 0.01). CONCLUSIONS: In our cohort of men with prolactinomas and hypogonadism, we found a marked decrease in HB levels that preceded prolactinoma diagnosis by a median of 6.1 years, with a mean delay of 4.1 years between HB decrease and hypogonadal symptoms appearance. These results suggest that HB decline prior to prolactinoma diagnosis may serve as a marker for hyperprolactinemia onset in a subset of hypogonadal men and allow a more accurate assessment of disease duration.

Resistant prolactinomas: a case series of 26 patients.

PURPOSE: Prolactin (PRL)-secreting tumors are the most common functional pituitary adenomas. They usually respond to dopamine agonist (DA) treatment, with PRL normalization and adenoma shrinkage. Our aim was to characterize patients with prolactinoma resistant to DA treatment. METHODS: This retrospective case series included patients diagnosed with DA-resistant prolactinomas between 1993-2017 in three medical centers. Resistance was defined as PRL levels above three times the upper limit of normal (ULN) despite a weekly dose of ≥2 mg cabergoline (CAB). Clinical and biochemical information, and response to treatment, were retrieved from medical records. RESULTS: Twenty-six patients were identified; 20 males. Of 25 macroadenomas, three were giant tumors (>40 mm) and 15 (57.7%) were invasive. The mean age at diagnosis was 31.8 ± 14.9 years (range: 13-62). The median maximal CAB dose was 3.5 mg/week (IQR, 2.5-5). Half the patients received only CAB in escalating doses, nine received CAB and underwent transsphenoidal surgery, and four underwent surgery and radiotherapy in addition to CAB treatment. PRL levels at baseline between patients treated only with CAB and those operated were (91.6 [51.1-296.7] vs. 73.1 [22.6-170.9] XULN p = 0.355), and under maximal CAB dose PRL levels between patients treated only with CAB and those operated were similar (5.77 [1.27-11.27] vs 5.27 (2.9-26) XULN p = 0.317). At the last visit patients who received combined therapy achieved lower PRL levels than those treated with DA only (5.22 [1.7-21.6] vs 1.1 [0.44-3.99] XULN p = 0.017) PRL normalization was attained in seven patients and levels below 3 × ULN in fourteen patients; the overall response was 56%. CONCLUSIONS: Resistant prolactinomas usually require a multi-modal treatment strategy. We were able to control 14/25 (56%) of resistant tumors.

Clinical Study and Systematic Review of Pituitary Microadenomas vs. Macroadenomas in Cushing's Disease: Does Size Matter?

Background: Reports on clinical and biochemical differences between adrenocorticotropic hormone (ACTH)-secreting pituitary microadenomas and macroadenomas are limited and inconsistent. Objective: Compare clinical and biochemical characteristics of patients with corticotroph microadenomas and macroadenomas and assess predictive factors for biochemical response to dynamic testing for Cushing's disease (CD) in a clinical trial and a systematic review. A second aim was to evaluate differences between macroadenomas with and without cavernous and sphenoid sinus invasion. Methods: Retrospective charts review of patients with CD, treated at Rabin Medical Center between 2000 and 2020 or at Maccabi Healthcare Services in Israel between 2005 and 2017. Clinical and biochemical factors were compared between patients with corticotroph microadenomas and macroadenomas. We have also performed a systematic review of all studies (PRISMA guidelines) comparing corticotroph microadenomas with macroadenomas up to 31 November 2021. Results: The cohort included 105 patients (82 women, 78%; mean age, 41.5 ± 14.5 years), including 80 microadenomas (mean size, 5.2 ± 2.2 mm) and 25 macroadenomas (mean size, 18.0 ± 7.7 mm). Other baseline characteristics were similar between groups. Most common presentation suggestive for hypercortisolemia among patients with both micro- and macroadenomas were weight gain (46.3% vs. 48.0%, p = NS) and Cushingoid features (27.5% vs. 20.0%, p = NS). Mean 24 h urinary free cortisol (5.2 ± 5.4 × ULN vs. 7.8 ± 8.7 × ULN) and serum cortisol following low-dose dexamethasone (372.0 ± 324.5 vs. 487.6 ± 329.8 nmol/L), though higher for macroadenomas, were not significant. Levels of ACTH were greater for macroadenomas (1.9 ± 1.2 × ULN vs. 1.3 ± 0.8 × ULN, respectively, p = 0.01). Rates of recurrent/persistent disease were similar, as were rates of post-operative adrenal insufficiency and duration of post-operative glucocorticoid replacement. Macroadenomas with sphenoid or cavernous sinus invasion were associated with higher ACTH, 24 h free urinary cortisol, and serum cortisol following low-dose dexamethasone, compared with suprasellar or intrasellar macroadenomas. Conclusions: While ACTH-secreting macroadenomas exhibit higher plasma ACTH than microadenomas, there was no association between tumor size with cortisol hypersecretion or clinical features of hypercortisolemia. Though overall rare, increased awareness is needed for patients with CD with tumor extension in the cavernous or sphenoid sinus, which displays increased biochemical burden, highlighting that extent/location of the adenoma may be more important than size per se. Our systematic review, the first on this topic, highlights differences and similarities with our study.

Gender differences in the presentation, course and outcomes of primary hyperparathyroidism.

OBJECTIVE: To investigate gender-associated differences in the presentation, course, and outcomes of primary hyperparathyroidism (PHPT). STUDY DESIGN: A retrospective institutional cohort. METHODS: The database of a tertiary endocrine institute was retrospectively screened for patients treated for PHPT in 2010-2018. Clinical, biochemical, and imaging data were collected. Presentation, management, and outcome variables were compared by gender and by age at diagnosis (<50/≥50 years). RESULTS: The cohort included 182 women and 161 men diagnosed with PHPT at age 57.6 ± 12.8 and followed for 6.3 ± 5.5 years. There were no gender differences in age at detection of hypercalcemia and basal levels of serum and urinary calcium, serum PTH, and serum 25-hydroxyvitamin D. Men had a higher prevalence of nephrolithiasis (33 % vs 21 %, p = 0.01). Women had a higher frequency of osteoporosis (65 % vs 45 %, p < 0.001), and a lower mean lumbar spine T-score at PHPT diagnosis. At last follow-up, women had worse bone mineral density (BMD) results in all measured sites (lumbar spine, femoral neck, distal radius) and more fractures (34 % vs 20 %, p = 0.004), despite more frequent and longer pharmacological treatment of osteoporosis. On analysis by age, all these gender-associated differences were statistically significant only in patients diagnosed at age ≥50 years. Parathyroidectomy was performed in 52 % of women and 42 % of men (p = 0.06). CONCLUSION: The main differences between male and female patients with PHPT are the higher prevalence, more intensive pharmacological treatment, and worse outcomes of osteoporosis in women. Tailoring the optimal medical and/or surgical treatment for fracture prevention in patients with PHPT remains a major challenge, especially in older women.

Denosumab-associated hypocalcemia: Does gender play a role?

OBJECTIVE: It is well recognized that the presentation, treatment, and outcomes of various diseases may differ between men and women. We recently reported a 7.4% rate of denosumab-associated hypocalcemia in community-dwelling osteoporotic patients. This study sought to investigate the role of gender in this complication. STUDY DESIGN: Retrospective community-dwelling cohort. METHOD: The databases of a large health maintenance organization were searched for adult patients treated with denosumab for osteoporosis in 2010-2018. Rates and predictors of denosumab-associated hypocalcemia (serum calcium ≤8.5 mg/mL) were analyzed by gender. RESULTS: The cohort included 1871 women and 134 men. Compared with the women, the men were characterized by older median age (81 vs. 77 years, p = 0.005), higher likelihood to receive denosumab as a first-line treatment (22% vs. 6%, p < 0.001), less treatment with calcium supplements (42% vs. 53%, p = 0.012), and lower median eGFR level (66.1 vs. 79.8 mL/min/1.73m2, p < 0.001). Denosumab-associated hypocalcemia developed in 133 women (7.1%) and 16 men (11.9%) (p = 0.04); the drug was discontinued in 75% and 61%, respectively. The strongest predictors of hypocalcemia in women were levels of pretreatment albumin-adjusted serum calcium (OR 0.08, 95% CI (0.04, 0.14)) and creatinine (OR 2.43, 95% CI (1.45, 4.05)). There were no predictors in men. On propensity matching of 126 men and 126 women, gender was not a predictor of hypocalcemia. CONCLUSION: Denosumab-treated men were significantly older than treated women and had a lower eGFR and more advanced osteoporosis. These findings suggest that selection bias rather than male genderper se underlies the higher rate of denosumab-associated hypocalcemia in men.

Risk for Infections During Treatment With Denosumab for Osteoporosis: A Systematic Review and Meta-analysis.

CONTEXT: Denosumab inhibits the receptor activator of nuclear factor κ-Β ligand, an immune system modulator. Safety endpoints including risk for infections were assessed as secondary outcomes in randomized controlled trials (RCTs) of the drug. OBJECTIVE: To assess the risk of serious adverse events of infections (SAEI) in denosumab-treated patients. DATA SOURCES: PubMed and Cochrane Central Register of Controlled Trials were searched up to May 27, 2019. STUDY SELECTION: All RCTs of denosumab (60 mg every 6 months) versus any comparator were included. We excluded trials in cancer patients for prevention of skeletal-related events. DATA EXTRACTION: Two reviewers independently applied selection criteria and extracted the data. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using a fixed effect model. Sensitivity analysis was based on risk of bias. DATA SYNTHESIS: Thirty-three studies (22 253 patients) were included. There was a higher incidence of SAEI during denosumab treatment versus any comparator (RR, 1.21; 95% CI, 1.04-1.40; I2 = 0%), mainly of ear, nose, and throat (RR, 2.66; 95% CI, 1.20-5.91) and gastrointestinal origin (RR, 1.43; 95% CI, 1.02-2.01). RR was similar in a sensitivity analysis based on adequate allocation concealment. The RR of any infection (RR, 1.03; 95% CI, 0.99-1.06) and infection-related mortality (RR, 0.50; 95% CI, 0.20-1.23) was comparable between groups. CONCLUSIONS: A higher incidence of SAEI is demonstrated during treatment with denosumab in an osteoporosis dose. Nevertheless, the overall risk for any infection or related mortality is similar to comparator groups. These findings merit consideration before therapy initiation.

Hyperparathyroidism in patients over 75: Clinical characteristics and outcome. Is conservative treatment a safe alternative?

OBJECTIVE: With the current aging of the world's population, primary hyperparathyroidism (PHPT) is increasingly detected in the elderly. Yet data on the presentation and outcome of PHPT in this group are scarce. The objective was to describe a cohort of patients aged 75 years or more with PHPT observed in our endocrine clinic. STUDY DESIGN: A retrospective analysis of medical records in an endocrine clinic at a tertiary hospital. We evaluated 182 patients with PHPT, aged 75 years or more at their last follow-up, all diagnosed at age 65 or more. Laboratory data were compared at diagnosis and last follow-up. RESULTS: Mean age at diagnosis was 73 ± 4 years, last follow-up was at 83 ± 4 years, and mean follow-up was 11.3 ± 5.5 years. Osteoporosis, fractures, and nephrolithiasis were diagnosed in 114(63 %), 84(46 %), and 43(24 %) patients, respectively. Overall, 150 patients had an indication for surgery; of them, the 29 who underwent parathyroidectomy were younger than the non-operated patients and had higher rates of hypercalciuria. During the follow-up of the 141 patients who did not undergo operation, serum and urinary calcium levels significantly had decreased, and vitamin D level had increased at last visit (10.4 ± 0.5 mg/dl, 161 ± 70 mg/24 h, 69 ± 17 nmol/l, p < 0.01 respectively) compared with levels at diagnosis (10.6 ± 0.2 mg/dl, 223 ± 95 mg/24 h, 53 ± 15 nmol/l, respectively, p = 0.001). Overall, 38 of the 182 patients (20 %) died during follow-up; these patients were significantly older at diagnosis (76 ± 5 vs. 72 ± 4 years) but there were no differences in laboratory variables. CONCLUSIONS: While most patients had a formal indication for surgery, few underwent parathyroidectomy. Serum and urinary calcium significantly decreased during follow-up in patients who did not undergo surgery. Our data are reassuring and support at least the consideration of conservative treatment for these patients.

Efficacy of long-term lanreotide treatment in patients with acromegaly.

We investigated the effectiveness of lanreotide for the treatment of active acromegaly in a retrospectively multicenter case series including 53 patients (24 male, 29 female; mean age at diagnosis, 49.5 +/- 13.9 years) with acromegaly treated with lanreotide in nine different centers. Mean tumor diameter was 20 +/- 13 mm; mean basal levels of growth hormone (GH) and insulin-like growth factor I (IGF-I) were 21.3 +/- 26.3 and 579 +/- 177 mug/l, respectively. The primary mode of treatment was surgery in 70% of patients. Twenty-nine patients received only lanreotide (Prolonged Release, Autogel), whereas 24 subjects were also treated with octreotide at another treatment stage. Primary therapy with lanreotide was administered in five patients. Maximal monthly dose of lanreotide Autogel (n = 44) was 60 mg in 45%, 90 mg in 26%, 120 mg in 21% and 180 mg in 8%. During 36 months of lanreotide treatment, mean IGF-I levels decreased from 443 +/- 238 to 276 +/- 147 mug/l (P < 0.001), and mean GH levels, from 5.2 +/- 6.4 to 3.2 +/- 3.0 mug/l (P < 0.001). IGF-I levels normalized in 51% of patients and decreased by >50% towards normal in 32%; the normalization rate was higher in women (65%) than men (33%, P = 0.04). Safe random GH levels (