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.

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.

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.

Long-term response to cabergoline and multi-modal treatment in men with macroprolactinoma: Does size really matter?

OBJECTIVE: To study the outcome of men with macroprolactinoma following cabergoline treatment based on tumour size. DESIGN: Retrospective cohort study. METHODS: The study included 94 men, divided into three groups according to adenoma diameter: 10-19 mm (Group A, n = 36); 20-39 mm (Group B, n = 41); or ≥40 mm (Group C, giant prolactinomas, n = 17). Patients were followed for a mean of 7.5 years with sellar magnetic resonance imaging, visual fields and hormone measurements. RESULTS: Mean baseline prolactin was 767, 2090 and 24,806 ng/ml in Groups A, B and C, respectively (p < .01). Prolactin suppression below three times the upper limit of normal (ULN) was achieved in 34 (94%; mean weekly cabergoline dose of 1.2 mg), 37 (90%; cabergoline dose, 2.1 mg) and 15 (88%; cabergoline dose, 2.8 mg) men (p = .31) in each group. After excluding patients who underwent surgery and radiotherapy, cabergoline suppressed prolactin below three times ULN in 32/35 (91%), 29/37 (78%) and 11/14 (79%) men in Groups A, B and C, respectively (p = .27). Visual deficits were observed in 5 (14%), 12 (29%) and 10 (59%) patients (p < .01); improvement was achieved in 5/5 (100%), 11/12 (92%) and 10/10 (100%) of men in Groups A, B and C. Low baseline testosterone was measured in 26 (72%), 39 (95%) and 17 (100%) patients in the three groups (p < .01). Following multi-modal treatment, hypogonadism persisted in 3 (8%), 5 (12%) and 2 (12%) men, respectively (p = .85). CONCLUSION: Macroprolactinomas in men were controlled with cabergoline in 84% of cases, independent of tumour size. Pituitary surgery and adjuvant radiotherapy further improved long-term response to 91%.

True hyperprolactinemia in men without visible pituitary adenoma.

PURPOSE: Men with mild to moderate hyperprolactinemia rarely present with normal pituitary on MRI with no visible adenoma, a condition entitled also "idiopathic hyperprolactinemia" or "non-tumoral hyperprolactinemia". We have characterized a cohort of hyperprolactinemic men with normal pituitary imaging. DESIGN: We have identified 13 men with true hyperprolactinemia and normal pituitary MRI. Baseline clinical and hormonal characteristics and response to medical treatment were retrospectively retrieved from medical records. RESULTS: Mean age at diagnosis was 51 ± 16 years (range, 20-77); mean serum prolactin level at presentation was 91 ng/ml (range, 28-264), eight men presented with low baseline testosterone. Initial complaints leading to diagnosis included sexual dysfunction in ten men and gynecomastia in five. All patients were treated with cabergoline, except for one who was given bromocriptine; none required pituitary surgery. All patients normalized prolactin and testosterone with subsequent clinical improvement reported by most men. Currently, after a mean follow-up of 72 months, ten patients continue treatment with caborgoline (median weekly dose, 0.25 mg), whereas three men discontinued treatment. CONCLUSIONS: Men with symptomatic hyperprolactinemia may rarely present with normal pituitary imaging. Medical treatment can lead to hormonal improvement with clinical benefit.

Hyperprolactinemia diagnosis in elderly men: a cohort of 28 patients over 65 years.

PURPOSE: To characterize a cohort of elderly men with prolactinomas and their response to treatment. METHODS: We have identified 28 elderly men diagnosed after the age of 65 with prolactinomas at seven different endocrine clinics in Israel. A retrospective electronic chart review identified a control group of 76 younger men with macroprolactinomas treated in one of the centers. RESULTS: Mean age at diagnosis was 71.3 ± 5.6 (range 65-86) years, and current age 76.6 ± 7.5 years. Initial complaints leading to diagnosis included sexual dysfunction in 17 males (61%), headaches in two patients (7%), and visual abnormalities in two (7%). Three men presented with osteoporosis. Ten patients (36%) were diagnosed incidentally following brain imaging for unrelated reasons. Seventeen patients (61%) had macroadenoma, while eleven (39%) presented with a microadenoma or no visible adenoma. Mean prolactin (PRL) at presentation was 1594 (median 382; range 50-18,329) ng/ml. Testosterone was low in 21 men. Patients were treated with cabergoline (max dose, 1.1 ± 0.5 mg/week), except for one given bromocriptine; none required pituitary surgery or radiotherapy. Treatment normalized PRL in 24 patients, and in three men PRL suppressed to <2 ULN. Fifteen men normalized testosterone, three improved without normalization, and in three the normal baseline level increased. After a mean follow-up of 5.3 years, 14/15 patients harboring a macroadenoma showed significant adenoma shrinkage. Most patients reported improvement of low libido/erectile dysfunction. In the control group 60 men (79%) achieved PRL normalization. CONCLUSIONS: Elderly men with prolactinomas are diagnosed incidentally in 36% of cases. Long-term medical therapy is successful, achieving biochemical remission, adenoma shrinkage, and clinical improvement in almost all patients.

Cushing's syndrome: comparison between Cushing's disease and adrenal Cushing's.

PURPOSE: The most common etiology of Cushing's syndrome (CS) is an ACTH-producing pituitary adenoma (pitCS), reported as 2-3 times more frequent than primary adrenal CS (adrCS). We aimed to analyze and compare features of patients with pitCS and adrCS. METHODS: A retrospective file review of 196 consecutive patients (age 46.8 ± 15.6 years, 76% female) diagnosed with CS in 2000-2017 and followed for 5.2 ± 4.2 years; 109 (55.6%) had pitCS and 76 (38.8%) adrCS. Epidemiologic, clinical and biochemical factors were compared between and within the pitCS and adrCS groups. RESULTS: The relative proportion of pitCS to adrCS (1.4) was lower than previously reported and gradually decreased during the study years to only 1.2 in 2012-2017. The most common reason for CS screening was weight-gain in the pitCS group (48.6%) and adrenal incidentaloma in the adrCS group (39.5%). The pitCS patients were diagnosed at younger age (42.5 ± 15.1 vs. 51.6 ± 15.1 years, p < 0.001) and had lower prevalence of hypertension (51.4 vs. 74%, p = 0.005). There was no between-group difference in severity of hypercortisoluria. Within the adrCS group, patients diagnosed after detection of an adrenal incidentaloma had milder hypercortisoluria than the remaining patients, presented with smaller adrenal lesions (35.9 ± 16.3 vs. 49.1 ± 33.7 cm, p = 0.04), and received post-adrenalectomy glucocorticoid treatment for shorter periods (13 ± 11.6 vs. 31 ± 40 months, p = 0.04). CONCLUSIONS: The relative proportion of adrCS to pitCS is rising, probably because of an increasing detection of cortisol-secreting adrenal incidentalomas associated with milder hypercortisolism. There is no difference between pitCS and adrCS in the severity of hypercortisoluria, although significant clinical differences were found.

Incidence of Cushing's syndrome in patients with significant hypercortisoluria.

OBJECTIVE: To investigate the incidence of Cushing's syndrome (CS) in patients with significant hypercortisoluria and the performance of urinary free cortisol (UFC) screening. DESIGN: Retrospective file review. METHODS: The computerized database of a publicly funded health maintenance organization (HMO) in Israel was searched for all patients who underwent 24-h UFC testing in 2005-2014 with a result of more than twice the upper limit of normal (ULN). The patients' medical files were reviewed for a subsequent diagnosis of CS by an expert endocrinologist. Findings were evaluated for patterns in CS diagnosis and UFC testing over time. RESULTS: Of 41 183 individuals tested, 510 (1.2%) had UFC >2× ULN (214 >3× ULN). Eighty-five (16.7%) individuals were diagnosed with CS (63 female and mean age 47.2 ± 15.1 years), mainly Cushing's disease (55.3%) or adrenal Cushing's syndrome (37.6%). The number of UFC tests increased steadily, from 1804 in 2005 to 6464 in 2014; yet, the resultant detection rate of CS remained generally stable. The calculated incidence of CS in the general HMO-insured population based only on the patients identified in the present cohort was 4.5 new cases/million/year (median 4.9/million/year, range 1.7-5.9/million/year), which was also relatively stable. The most common reason for referral for UFC screening was obesity. Of the 148 patients before bariatric surgery with UFC >2× ULN, 2 were diagnosed with CS. CONCLUSIONS: The incidence of CS is higher than previously suggested. The consistently increasing number of UFC tests being performed has not been accompanied by a similar increase in CS detection rate. The expected yield of routine UFC testing before bariatric surgery is low.

Beta1- or beta2-blockers to improve hemodynamics following endotracheal adrenaline administration.

BACKGROUND: The recommended dose for endotracheal adrenaline (0.02 mg/kg) causes a pronounced initial decrease in diastolic blood pressure which is detrimental at the initial phase of cardiopulmonary resuscitation. This effect was previously attributed to an early and preferential stimulation of the beta-adrenergic receptors causing vasodilatation unopposed by an alpha-adrenergic vasoconstriction. We hypothesized that inhibition of the beta2-adrenoreceptors is responsible for prevention of the deleterious initial decrease in blood pressure that takes place following endotracheal administration of adrenaline. METHODS: Adrenaline (0.02 mg/kg) diluted with normal saline (5 ml) was injected into the endobronchial tree of anesthetized dogs 3 min following pretreatment with the non-selective beta-blocker propranolol, selective beta1-blocker metoprolol (0.1 mg/kg, i.v.), or without pre-treatment. Heart rate, blood pressure and arterial blood gases were monitored. RESULTS: The selective beta-blocker metoprolol was almost as effective as the non-selective beta-blocker propranolol in attenuating the initial decrease in blood pressure following endotracheally administered adrenaline, a phenomenon that was previously attributed to inhibition of beta-adrenoreceptors. CONCLUSIONS: The outcome of this study might be explained by a dose-related loss of cardioselectivity of metoprolol. Further studies are warranted to refine the pharmacological means to abort the initial blood pressure-lowering effect of endotracheally administered adrenaline.

Tracheal epinephrine or norepinephrine preceded by beta blockade in a dog model. Can beta blockade bestow any benefits?

Tracheal epinephrine (adrenaline) has been associated with two major deletorious side effects: increased heart rate (HR) and an initial decrease of blood pressure (BP). This prospective randomized animal study compared the haemodynamic responses to tracheally administered epinephrine or norepinephrine (nor adrenaline) alone versus each after pretreatment with propranolol for ameliorating those two untoward effects associated with epinephrine administration. Five anaesthetized mongrel dogs underwent 25 experiments of tracheal epinephrine or norepinephrine (0.02 mg/kg diluted with normal saline to 5 ml total volume) with or without an I/V non-selective beta-blocker (propranolol 0.1 mg/kg) pretreatment, and served as their own controls. Tracheal epinephrine alone produced a rise in both diastolic and mean arterial BP and an increase of HR. Tracheal norepinephrine alone produced the largest increase of diastolic and mean BP but this change was associated with a significant tachycardia (from 37 to 72/m, P<0.001). While both epinephrine or norepinephrine after pretreatment with propranolol produced a significant increase in both diastolic (from 106 to 166 mmHg and from 118 to 169 mmHg, respectively) (P<0.01) and mean BP (from 122 to 183 mmHg and from 133 to 188 mmHg, respectively) (P<0.01), only propranolol-pretreated tracheal epinephrine yielded a significant decrease in HR (from 52 to 33/m, P=0.002). Pretreatment with a beta-blocker protected against the deleterious tachycardia associated with epinephrine or norepinephrine and, by doing so, may improve the myocardial oxygen supply-and-demand balance. At the same time, the pretreatment augmented the relatively mild diastolic BP increase associated with the beta-adrenergic effect of epinephrine.

Endobronchial adrenaline: should it be reconsidered? Dose response and haemodynamic effect in dogs.

BACKGROUND: Tracheal drug administration is a route for drug delivery during cardiopulmonary resuscitation when intravenous access is not immediately available. However, tracheal adrenaline (epinephrine) injection has been recently shown to be associated with detrimental decrease in blood pressure. This was attributed to exaggerated early beta2 mediated effects unopposed by alpha-adrenergic vasoconstriction. We hypothesized that endobronchial adrenaline administration is associated with better drug absorption, which may abolish the deleterious drop of blood pressure associated with tracheal drug administration. OBJECTIVE: To determine haemodynamic variables after endobronchial adrenaline administration in a non-arrest canine model. DESIGN: Prospective, randomized, laboratory study. METHODS: Adrenaline (0.02, 0.05, 0.1 mg/kg) diluted with normal saline was injected into the bronchial tree of five anaesthetized dogs. Injection of 10-ml saline served as control. Heart rate, blood pressure and arterial blood gases were monitored for 60 min after drug instillation. The protocol was repeated after 1 week. RESULTS: Adrenaline at a dose of 0.02 mg/kg produced only a minor initial decrease in diastolic (from 90 +/- 5 to 78 +/- 3 mmHg, P=0.05), and mean blood pressure (from 107 +/- 4 to 100 +/- 3 mmHg, P=0.05), in all dogs. This effect lasted less then 30 s following the drug administration. In contrast, higher adrenaline doses (0.05 and 0.1 mg/kg) produced an immediate increase in diastolic (from 90 +/- 5 to 120 +/- 7 mmHg; and from 90 +/- 5 to 170 +/- 6 mmHg, respectively), and mean blood pressure (from 107 +/- 4 to 155 +/- 10 mmHg; and from 107 +/- 4 to 219 +/- 6 mmHg, respectively). All adrenaline doses resulted in an immediate increase in systolic blood pressure and pulse. Endobronchial administration of saline (control) affected none of the haemodynamic variables. CONCLUSIONS: In a non-arrest model, endobronchial adrenaline administration, as opposed to the effect of tracheal adrenaline, produced only a minor decrease in diastolic and mean blood pressure. We suggest that endobronchial adrenaline administration should be investigated further in a CPR low-flow model when maintaining adequate diastolic pressure may be crucial for survival.

Should vasopressin replace adrenaline for endotracheal drug administration?

OBJECTIVE: Arginine vasopressin was established recently as a drug of choice in the treatment of cardiac arrest and in retractable ventricular fibrillation; however, the hemodynamic effect of vasopressin following endotracheal drug administration has not been fully elucidated. We compared the effects of endotracheally administered vasopressin vs. adrenaline on hemodynamic variables in a canine model, and we investigated whether vasopressin produces the same deleterious immediate blood pressure decrease as did endotracheal adrenaline in the canine model. DESIGN: Prospective controlled study. SETTING: Animal laboratory in Tel-Aviv University, Israel. SUBJECTS: Five adult mongrel dogs weighing 6.5-20 kg. INTERVENTIONS: Dogs were anesthetized; each dog was intubated orally, and both femoral arteries were cannulated for the measurement of arterial pressure and for sampling blood gases. Each dog was studied four times, 1 wk apart, by using the same protocol for injection and anesthesia: endotracheal placebo (10 mL NaCl 0.9%,), endotracheal vasopressin (1 units/kg), endobronchial adrenaline (0.1 mg/kg), and endotracheal adrenaline (0.1 mg/kg). Following placebo, vasopressin, and adrenaline instillation, five forced manual ventilations were delivered with an Ambu bag. Each dog was its own control. MEASUREMENTS AND MAIN RESULTS: Following placebo or drug administration, heart electrocardiography and arterial pressures were continuously monitored with a polygraph recorder for 1 hr. Endotracheal vasopressin produced an immediate increase of diastolic blood pressure (from 83 +/- 10 mm Hg [baseline] to 110 +/- 5 mm Hg at 1 min postinjection). This response lasted >1 hr. In contrast, both endotracheal and endobronchial administration of adrenaline produced an early and significant (p <.05) decrease in diastolic and mean blood pressures. The diastolic blood pressure increase from 85 +/- 10 mm Hg to 110 +/- 10 mm Hg took an ill-afforded 55 secs following endotracheal adrenaline. Diastolic blood pressure was significantly (p <.05) higher following vasopressin compared with adrenaline administration in both routes. CONCLUSIONS: Vasopressin accomplishes its hemodynamic effect, particularly on diastolic blood pressure, more rapidly, vigorously, and protractedly and to a significant degree compared with both endotracheal and endobronchial adrenaline. Evaluation of the effects of endotracheal vasopressin in a closed chest cardiopulmonary resuscitation model is recommended.

Endotracheal epinephrine: a call for larger doses.

UNLABELLED: Endotracheal administration of epinephrine 0.02 mg/kg (twice the IV dose) is recommended when IV access is unavailable during cardiopulmonary resuscitation. The standard IV dose has been considered too small for the endotracheal route by causing a detrimental decrease of arterial blood pressure (BP), presumably mediated by the beta-adrenergic receptor unopposed by alpha adrenergic vasoconstriction. We conducted a prospective, randomized, laboratory comparison of increasing doses of endotracheal epinephrine to ascertain the yet undetermined optimal dose of endotracheal epinephrine that would increase BP. After injecting normal saline (control), saline-diluted epinephrine (0.02, 0.035, 0.1, 0.2, and 0.3 mg/kg) was injected into the endotracheal tube of five anesthetized dogs at least 1 wk apart. Arterial blood samples for blood gases were collected before and at 14 time points up to 60 min after the drug administration. Heart rate and arterial BP were continuously monitored with a polygraph recorder. Only the 0.3 mg/kg dose successfully caused an increase in BP, observed 2 min after administration, and lasting for 10 min. An early decrease in BP was obviated only at a dose equivalent to 10-fold the currently recommended one. IMPLICATIONS: We conducted a prospective, randomized, laboratory comparison of increasing doses of endotracheal epinephrine to ascertain the yet undetermined optimal dose of endotracheal epinephrine that would increase arterial blood pressure (BP). A decrease in BP was obviated only at a dose equivalent to 10-fold the currently recommended one. Clinical studies using larger doses of endotracheal epinephrine and their use as first-line therapy in cardiac arrest are warranted.