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.

Kinetics of SARS-CoV-2 anti-S IgG after BNT162b2 vaccination.

Deployment of the BNT162b2 mRNA Covid-19 Vaccine in Israel began in December 2020. This is a retrospective analysis of serological data, showing SARS-CoV-2 anti-S IgG kinetics in 116 Israeli health care workers receiving BNT162b2. Sero-conversion occurred in 14 days in all study participants, with IgG levels peaking approximately 30 days after initiation of the vaccination series. A statistically significant difference was observed in IgG levels between subjects younger than 50 years and older participants, although in all cases, IgG levels were well above the level considered reactive by the test's manufacturer. The importance of this difference needs to be studied further, but a potential difference in vaccine efficacy and vaccine effect length could possibly be present between these two groups.

Initial report of decreased SARS-CoV-2 viral load after inoculation with the BNT162b2 vaccine.

Beyond their substantial protection of individual vaccinees, coronavirus disease 2019 (COVID-19) vaccines might reduce viral load in breakthrough infection and thereby further suppress onward transmission. In this analysis of a real-world dataset of positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test results after inoculation with the BNT162b2 messenger RNA vaccine, we found that the viral load was substantially reduced for infections occurring 12-37 d after the first dose of vaccine. These reduced viral loads hint at a potentially lower infectiousness, further contributing to vaccine effect on virus spread.

Pheochromocytoma: Positive predictive values of mildly elevated urinary fractionated metanephrines in a large cohort of community-dwelling patients.

The diagnostic utility of different thresholds of elevated urinary fractionated metanephrine (UFM) for pheochromocytoma-paraganglioma (PPGL) was evaluated in 10 164 community-dwelling subjects (2012-2017). Levels were ≥1.5× the upper normal limit (UNL) in 276 subjects (2.7%) and ≥2×UNL in 138 (1.4%). PPGL was subsequently diagnosed in 59 (mean age 51.9 ± 14.3, 64% female); 58 (98.3%) with UFM ≥ 2×UNL. Positive predictive values (PPV) were 42% for UFM ≥ 2×UNL, 55% for UFM ≥ 2.5×UNL, and 69% for UFM ≥ 3×UNL. The main reason for PPGL screening (52.5%) was adrenal incidentaloma. Mean (median) metanephrine/normetanephrine levels were 6.7 ± 9×UNL (3 × UNL) and 6.1 ± 8.9×UNL (2.5 × UNL). Six patients (10.2%) had an extra-adrenal tumor (one malignant paraganglioma); one had bilateral pheochromocytoma. Only one patient presented with the "classic triad" (headache, palpitations, sweating). In conclusion, after excluding obvious reasons for false-positive results, thorough diagnostic assessment for PPGL is justified in all subjects with UFM ≥ ×2UNL. The PPV of milder UFM elevations is very low.

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.

First Israeli National Iodine Survey Demonstrates Iodine Deficiency Among School-Aged Children and Pregnant Women.

BACKGROUND: National data on iodine status in Israel are lacking. Reliance on iodine-depleted desalinated water, the absence of a salt iodization program, and reports of increased use of thyroid medication in Israel suggest that the population's iodine intake is likely inadequate. The aims of this study were therefore to determine the iodine status of Israeli school-age children (SAC) and pregnant women (PW) in a nationally representative sample obtained by a novel approach of using pre-discard urinalysis samples collected from a centralized national laboratory. METHODS: Spot urine samples from 1023 SAC and 1074 PW, representing all regions and major sectors in Israel, were collected during 2016 at the Maccabi Healthcare Services central laboratory. Urinary iodine concentration (UIC) was measured, and the results were analyzed by trimester, sex, region, and sector. RESULTS: SAC were iodine deficient, with a median (interquartile range [IQR]) UIC of 83 µg/L (52-127 µg/L); 62% of SAC UICs were below the World Health Organization adequacy range for SAC (100-199 µg/L). PW were also iodine deficient, with a median (IQR) UIC of 61 µg/L (36-97 µg/L); 85% of PW UICs were below the adequacy range for PW (150-249 µg/L). For both SAC and PW, the median UIC was below the World Health Organization's adequacy range across all sectors, sexes, and districts. Among SAC, the median (IQR) UIC was lower among females (75 µg/L; 48-119 µg/L) than males (92 µg/L; 59-133 µg/L; p < 0.05). Median UIC values of PW correlated significantly with the median UIC for SAC by sub-district (R2 = 0.3, p < 0.05). CONCLUSIONS: Urine sampling via a centralized national laboratory was efficient and cost-saving. Iodine deficiency in Israeli SAC and PW is a serious public-health concern. A national program of salt iodization and iodine supplementation of PW should be urgently considered.

Pregnancy outcomes in women with primary hyperparathyroidism.

OBJECTIVE: Primary hyperparathyroidism (PHPT) during pregnancy may pose considerable risks to mother and fetus. This study examined pregnancy outcomes in women with gestational PHPT in relation to clinical and laboratory parameters. DESIGN: This study was designed as a retrospective case series. METHODS: The study group included 74 women aged 20-40 years who were diagnosed with PHPT after a finding of serum calcium ≥ 10.5 mg/dL on routine screening at a health maintenance organization (2005-2013) and who became pregnant during the time of hypercalcemia (124 pregnancies). Clinical and laboratory data were collected from the files. Pregnancy outcomes were compared with 175 normocalcemic pregnant women (431 pregnancies) tested during the same period. RESULTS: The cohort represented 0.03% of all women of reproductive age tested for serum calcium during the study period. Abortion occurred in 12 of 124 pregnancies (9.7%), and other complications occurred in 19 (15.3%) with no statistically significant differences from controls. Hypercalcemia was first detected during pregnancy in 14 of 74 women (18.9%) and before pregnancy (mean, 33.4 ± 29 mo) in 60. Serum calcium was measured antenatally in 57 of 124 pregnancies (46%); the mean level was 10.7 ± 0.6 mg/dL (median, 10.6 mg/dL). Measurement of the serum PTH level (with consequent diagnosis of PHPT) was performed during the first studied pregnancy in 17 of 74 women (23%), before pregnancy (mean, 37.8 ± 25.5 mo; median, 34 mo) in 23 (31.1%), and after delivery (mean, 54.7 ± 45.7 mo; median, 35 mo) in 34 (45.9%). Forty-three women (58.1%) underwent parathyroidectomy, six during pregnancy, without maternal or fetal complications. No difference was found in abortion or any pregnancy-related complication between patients who subsequently underwent parathyroidectomy and those who did not. No significant correlation was found between calcium level during pregnancy and pregnancy outcomes. CONCLUSIONS: Serum calcium levels are usually only mildly elevated during pregnancy in women with PHPT. A significant proportion of cases go undiagnosed. Mild hypercalcemia in gestational PHPT is generally not associated with an increased risk of obstetrical complications.

Pregnancy outcomes in women with severe hypothyroidism.

OBJECTIVE: Hypothyroidism during pregnancy has been associated with adverse obstetrical outcomes. Most studies have focused on subjects with a mild or subclinical disorder. The aims of the present study were to determine the relative rate of severe thyroid dysfunction among pregnant women with hypothyroidism, identify related factors and analyse the impact on pregnancy outcomes. DESIGN: A retrospective case series design was employed. METHODS: The study group included 101 pregnant women (103 pregnancies) with an antenatal serum TSH level >20.0 mIU/l identified from the 2009-2010 computerised database of a health maintenance organisation. Data were collected from the medical records. Pregnancy outcomes were compared with those of a control group of 205 euthyroid pregnant women during the same period. RESULTS: The study group accounted for 1.04% of all insured pregnant women with recorded hypothyroidism during the study period. Most cases had an autoimmune aetiology. All women were treated with levothyroxine (L-T4) during pregnancy. Maximum serum TSH level measured was 20.11-150 mIU/l (median 32.95 mIU/l) and median serum TSH level 0.36-75.17 mIU/l (median 7.44 mIU/l). The mean duration of hypothyroidism during pregnancy was 21.2 ± 13.2 weeks (median 18.5 weeks); in 36 cases (34.9%), all TSH levels during pregnancy were elevated. Adverse pregnancy outcomes included abortions in 7.8% of the cases, premature deliveries in 2.9% and other complications in 14.6%, with no statistically significant differences from the control group. Median serum TSH level during pregnancy was positively correlated with the rate of abortions+premature deliveries and rate of all pregnancy-related complications (P<0.05). CONCLUSIONS: Abortions and premature deliveries occur infrequently in women with severe hypothyroidism. Intense follow-up and L-T4 treatment may improve pregnancy outcomes even when target TSH levels are not reached.