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.

[MERCAPTIZOL INDUCED HYPOGLYCEMIA - A CASE REPORT].

INTRODUCTION: This is a case study of a 25-year-old female, Ashkenazy Jewish, previously healthy, presented with a complaint of weakness. Her sugar level on the glucometer was 50 mg% and she felt better after ingestion of a small amount of sugar. Two weeks earlier, while traveling in Peru, she developed thyrotoxicosis and began taking Mercaptizol 30 mg a day and Atenolol 100 mg. She didn't drink iodine (iodinated preparations for water purification) while traveling and had no pain or fever. Her physical examination showed no goiter or exophthalmos. While I saw her she was already euthyroid and felt quite good except for fatigue. In the literature, we found a few case reports of Mercaptizol and PTU-induced insulin autoantibodies which cause symptomatic hypoglycemia. Most cases were described in the Asian population (especially Japanese people) and resolved a few weeks after stopping intake of the drug. In our patient, the hypoglycemia resolved after only one episode and discontinuation of Mercaptizol. Insulin antibodies were negative, and insulin levels (C-peptide) were relatively high. My conclusion is that physicians should be aware of Mercaptizol and PTU-induced hypoglycemia which can be life-threatening.

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.

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.