Acromegaly is a debilitating and disfiguring chronic disease, which occurs in both sexes at any age, associated with multiple comorbidities and increased mortality. It is typically caused by a GH-secreting pituitary adenoma that promotes exposure of body tissues to increased concentrations of GH and IGF-I. The diagnosis of acromegaly is still made very late in a substantial number of patients when the disease is already in advanced stages. An epidemiological study from Sweden has elegantly demonstrated that the longer the diagnostic delay in acromegaly, the higher the number of comorbidities. Moreover, about 25% of the Swedish patients had 10 years or more of diagnostic delay and in this group mortality rate was significantly increased. These results reinforce the importance of shortening the latency period between disease onset, diagnosis and treatment to improve patient outcomes. This commentary article discusses strategies to be embraced by the endocrine community to allow early identification of acromegaly among public and health professionals, as internists, primary care clinicians, different specialists and dentists are the first point of contact for most of the patients. We emphasize that acromegaly should be presented as a sporadic, rather than rare, insidious disease, meaning that there is a considerable chance for health professionals to see a patient with acromegaly throughout their careers. The motto ‘you must know it to think of it’ is advocated in awareness efforts to reduce time to diagnosis, which results in lower rates of morbidity and mortality and might positively impact healthcare costs.
Cesar Luiz Boguszewski
Adina F Turcu, Diala El-Maouche, Lili Zhao, Aya T Nanba, Alison Gaynor, Padma Veeraraghavan, Richard J Auchus, and Deborah P Merke
The clinical presentation of patients with nonclassic 21-hydroxylase deficiency (N21OHD) is similar with that for other disorders of androgen excess. The diagnosis of N21OHD typically requires cosyntropin stimulation. Additionally, the management of such patients is limited by the lack of reliable biomarkers of androgen excess. Herein, we aimed to: (1.) compare the relative contribution of traditional and 11-oxyandrogens in N21OHD patients and (2.) identify steroids that accurately diagnose N21OHD with a single baseline blood draw.
We prospectively enrolled patients who underwent a cosyntropin stimulation test for suspected N21OHD in two tertiary referral centers between January 2016 and August 2019.
Baseline sera were used to quantify 15 steroids by liquid chromatography-tandem mass spectrometry. Logistic regression modeling was implemented to select steroids that best discriminate N21OHD from controls.
Of 86 participants (72 females), median age 26, 32 patients (25 females) had N21OHD. Age, sex distribution, and BMI were similar between patients with N21OHD and controls. Both testosterone and androstenedione were similar in patients with N21OHD and controls, while four 11-oxyandrogens were significantly higher in patients with N21OHD (ratios between medians: 1.7 to 2.2, P < 0.01 for all). 17α-Hydroxyprogesterone (6.5-fold), 16α-hydroxyprogesterone (4.1-fold), and 21-deoxycortisol (undetectable in 80% of the controls) were higher, while corticosterone was 3.6-fold lower in patients with N21OHD than in controls (P < 0.001). Together, baseline 17α-hydroxyprogesterone, 21-deoxycortisol, and corticosterone showed perfect discrimination between N21OHD and controls.
Adrenal 11-oxyandrogens are disproportionately elevated compared to conventional androgens in N21OHD. Steroid panels can accurately diagnose N21OHD in unstimulated blood tests.
Rui Zhen Tan, Tze Ping Loh, and Samuel Vasikaran
France Devuyst, Paraskevi Kazakou, Danielle Balériaux, Orsalia Alexopoulou, Agnès Burniat, Sylvie Salenave, Philippe Chanson, Bernard Corvilain, and Dominique Maiter
Association of central diabetes insipidus (CDI) and pituitary stalk thickening (PST) may have several etiologies (including malignancies) and differential diagnosis remains often difficult.
The purpose of this study was to identify which clinical, biochemical or radiological features could help clinicians to make an etiological diagnosis, especially distinguishing neoplastic from non-neoplastic pituitary stalk lesions.
Design and methods
We retrospectively analyzed clinical, biochemical, radiological and histological data of 38 adult patients diagnosed with CDI and PST of proven etiology.
Of the 38 pituitary stalk lesions included, 11 (29%) were neoplastic. A histopathological diagnosis was obtained in 22/38 (58%) patients. The three most frequently observed etiologies of PST were neuroinfundibulitis (34%), germinoma (21%) and histiocytosis (18%). Pituitary stalk thickness was larger for neoplastic lesions, particularly germinomas. Male gender and a very young age were statistically associated with a risk of germinoma. At least one anterior pituitary deficit was observed in nearly 60% of patients. Patients with neoplastic PST were more affected by multiple anterior pituitary dysfunction than patients with benign PST. A high serum prolactin level was individually the best predictor of a neoplastic origin (90% sensitivity and 60% specificity for a serum prolactin level 1.27-fold above the normal upper limit (ULN)).
We confirm a relatively high risk of malignancy in adult patients presenting with the association of CDI and PST. Young age, male gender, a very large thickening of the stalk, multiple anterior pituitary deficits and prolactin above 1.3× ULN increase the likelihood of a neoplastic origin.
Jandee Lee, Chan Hee Kim, In Kyung Min, Seonhyang Jeong, Hyunji Kim, Moon Jung Choi, Hyeong Ju Kwon, Sang Geun Jung, and Young Suk Jo
The characteristics of metastatic lymph nodes (MLNs) have been investigated as important predictors of recurrence and progression in papillary thyroid cancer (PTC). However, clinically applicable risk stratification systems are limited to the assessment of size and number of MLNs. This study investigated the predictive value of detailed characteristics of MLNs in combination with currently used risk stratification systems.
Design and methods
We retrospectively characterized 2811 MLNs from 9014 harvested LNs of 286 patients with N1 PTC according to the maximum diameter of MLN (MDLN), maximum diameter of metastatic focus (MDMF), ratio of both diameters (MDMFR), lymph node ratio (LNR, number of MLNs/number of total harvested LNs), presence of extranodal extension (ENE), desmoplastic reaction (DR), cystic component, and psammoma body.
Factors related to the size and number of MLNs were associated with increased risk of recurrence and progression. Extensive presence of ENE (>40%) and DR (≥50%) increased the risk of recurrence/progression. The combination of MDLN, LNR, ENE, and DR had the highest predictive value among MLN characteristics. Combination of these parameters with ATA risk stratification or 1-year response to therapy improved the predictive power for recurrence/progression from a Harrell’s C-index of 0.781 to 0.936 and 0.867 to 0.960, respectively.
The combination of currently used risk stratification systems with detailed characterization of MLNs may improve the predictive accuracy for recurrence/progression in N1 PTC patients.
Kirstine Jespersen, Marie Lindhardt Ljubicic, Trine Holm Johannsen, Peter Christiansen, Niels E Skakkebaek, and Anders Juul
Non-palpable testes remain a diagnostic challenge, often involving exploratory laparoscopy. We evaluated the diagnostic value of a wide range of reproductive hormones in order to distinguish between bilateral cryptorchidism and bilateral anorchia.
In this retrospective study, we identified and included 36 boys with non-palpable testes (20 with cryptorchidism, 3 with congenital hypogonadotropic hypogonadism (CHH), and 13 with anorchia) at first examination during childhood.
Information on karyotype, phenotype, surgical results from laparoscopy, and biochemistry was retrieved from patient files. We compared serum concentrations of AMH, inhibin B, FSH, LH, testosterone, estradiol, and hCG stimulation testing in cryptorchid and anorchid boys to serum concentrations in a large, age-matched control group. Receiver-operating characteristic curves were used to determine the cut-off values of each reproductive hormone as a predictor of the presence of functional testicular tissue.
Concentrations of AMH in 0–1 year olds: ≥155 pmol/L and >1–15 year olds: ≥19 pmol/L, inhibin B (≥22 pg/mL and ≥4 pg/mL), FSH (≤28.9 IU/L and ≤20.3 IU/L) and hCG-induced testosterone (>1-15 year olds: ≥2 nmol/L) were significantly sensitive and specific markers in predicting the presence of functional testicular tissue in boys with non-palpable testes. In infancy, anorchid infants had significantly elevated gonadotropin levels, while CHH had low levels.
Our findings suggest that laparoscopy may not be necessary in all boys with non-palpable testes if reproductive hormones unequivocally confirm the presence of functional testicular tissue. However, proving the absence may still be a diagnostic challenge.
Melony C Fortuin-de Smidt, Amy E Mendham, Jon Hauksson, Olah Hakim, Darko Stefanovski, Louise Clamp, Lindokuhle Phiri, Jeroen Swart, Louise M Goff, Lisa K Micklesfield, Steven E Kahn, Tommy Olsson, and Julia H Goedecke
We investigated the effects of a 12-week exercise intervention on insulin sensitivity (SI) and hyperinsulinemia and associated changes in regional and ectopic fat.
Research design and methods
Healthy, black South African women with obesity (mean age 23 ± 3.5 years) and of isiXhosa ancestry were randomised into a 12-week aerobic and resistance exercise training group (n = 23) and a no exercise group (control, n = 22). Pre and post-intervention testing included assessment of SI, insulin response to glucose (AIRg), insulin secretion rate (ISR), hepatic insulin extraction (FEL) and disposition index (DI) (AIRg × SI) (frequently sampled i.v. glucose tolerance test); fat mass and regional adiposity (dual-energy X-ray absorptiometry); hepatic, pancreatic and skeletal muscle fat content and abdominal s.c. and visceral adipose tissue volumes (MRI).
Exercise training increased VO2peak (mean ± s.d.: 24.9 ± 2.42 to 27.6 ± 3.39 mL/kg/min, P < 0.001), SI (2.0 (1.2–2.8) to 2.2 (1.5–3.7) (mU/l)−1 min−1, P = 0.005) and DI (median (interquartile range): 6.1 (3.6–7.1) to 6.5 (5.6–9.2) × 103 arbitrary units, P = 0.028), and decreased gynoid fat mass (18.5 ± 1.7 to 18.2 ± 1.6%, P < 0.001) and body weight (84.1 ± 8.7 to 83.3 ± .9.7 kg, P = 0.038). None of these changes were observed in the control group, but body weight increased (P = 0.030). AIRg, ISR and FEL, VAT, SAT and ectopic fat were unaltered after exercise training. The increase in SI and DI were not associated with changes in regional or ectopic fat.
Exercise training increased SI independent from changes in hyperinsulinemia and ectopic fat, suggesting that ectopic fat might not be a principal determinant of insulin resistance in this cohort.
Wiebke Arlt, Olaf M Dekkers, Juliane Léger, and Robert K Semple
Wiebke Arlt, Stephanie E Baldeweg, Simon H S Pearce, and Helen L Simpson
We provide guidance on prevention of adrenal crisis during the global COVID-19 crisis, a time with frequently restricted access to the usual level of healthcare. Patients with adrenal insufficiency are at an increased risk of infection, which may be complicated by developing an adrenal crisis; however, there is currently no evidence that adrenal insufficiency patients are more likely to develop a severe course of disease. We highlight the need for education (sick day rules, stringent social distancing rules), equipment (sufficient glucocorticoid supplies, steroid emergency self-injection kit) and empowerment (steroid emergency card, COVID-19 guidelines) to prevent adrenal crises. In patients with adrenal insufficiency developing an acute COVID-19 infection, which frequently presents with continuous high fever, we suggest oral stress dose cover with 20 mg hydrocortisone every 6 h. We also comment on suggested dosing for patients who usually take modified release hydrocortisone or prednisolone. In patients with adrenal insufficiency showing clinical deterioration during an acute COVID-19 infection, we advise immediate (self-)injection of 100 mg hydrocortisone intramuscularly, followed by continuous i.v. infusion of 200 mg hydrocortisone per 24 h, or until this can be established, and administration of 50 mg hydrocortisone every 6 h. We also advise on doses for infants and children.
John Newell-Price, Lynnette K Nieman, Martin Reincke, and Antoine Tabarin
Clinical evaluation should guide those needing immediate investigation. Strict adherence to COVID-19 protection measures is necessary. Alternative ways of consultations (telephone, video) should be used. Early discussion with regional/national experts about investigation and management of potential and existing patients is strongly encouraged. Patients with moderate or severe clinical features need urgent investigation and management. Patients with active Cushing’s syndrome, especially when severe, are immunocompromised and vigorous adherence to the principles of social isolation is recommended. In patients with mild features or in whom a diagnosis is less likely, clinical re-evaluation should be repeated at 3 and 6 months or deferred until the prevalence of SARS-CoV-2 has significantly decreased; however, those individuals should be encouraged to maintain social distancing. Diagnostic pathways may need to be very different from usual recommendations in order to reduce possible exposure to SARS-CoV-2. When extensive differential diagnostic testing and/or surgery is not feasible, it should be deferred and medical treatment should be initiated. Transsphenoidal pituitary surgery should be delayed during high SARS-CoV-2 viral prevalence. Medical management rather than surgery will be the used for most patients, since the short- to mid-term prognosis depends in most cases on hypercortisolism rather than its cause; it should be initiated promptly to minimize the risk of infection in these immunosuppressed patients. The risk/benefit ratio of these recommendations will need re-evaluation every 2–3 months from April 2020 in each country (and possibly local areas) and will depend on the local health care structure and phase of pandemic.