Giant prolactinomas are rare tumours, representing only 2-3% of all prolactin (PRL)-secreting tumours and raising special diagnostic and therapeutic challenges. Based on several considerations developed in this review, their definition should be restricted to pituitary adenomas with a diameter of 40  mm or more, significant extrasellar extension, very high PRL concentrations (usually above 1000  μg/l) and no concomitant GH or ACTH secretion. Giant prolactinomas are much more frequent in young to middle-aged men than in women, with a male to female ratio of about 9:1. Endocrine symptoms are often present but overlooked for a long period of time, and diagnosis is eventually made when neurologic complications arise from massive extension into the surrounding structures, leading to cranial nerve palsies, hydrocephalus, temporal epilepsy or exophthalmos. PRL concentrations are usually in the range of 1000-100,000  μg/l, but may be underestimated by the so-called 'high-dose hook effect'. As in every prolactinoma, dopamine agonists are the first-line treatment allowing rapid alleviation of neurologic symptoms in the majority of the cases, a significant reduction in tumour size in three-fourths of the patients and PRL normalization in 60-70%. These extensive tumours are usually not completely resectable and neurosurgery has significant morbidity and mortality. It should therefore be restricted to acute complications such as apoplexy or leakage of cerebrospinal fluid (often induced by medical treatment) or to patients with insufficient tumoural response or progression. Irradiation and temozolomide are useful adjuvant therapies in a subset of patients with aggressive/invasive tumours, which are not controlled despite combined medical and surgical treatments. Because of these various challenges, we advocate a multidisciplinary management of these giant tumours in expert centres.

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THERAPY OF ENDOCRINE DISEASE: The challenges in managing giant prolactinomas

Lateral flow assays (LFAs) have been the pillar of rapid point-of-care (POC) diagnostics due to their simplicity, rapid process, and low cost. Recent advances in sensitivity, selectivity, and chemical stability enhancement have ensured the foothold of LFAs in commercial POC diagnostics. This paper reviews recent developments in labeling strategies and detection methods of LFAs. Moreover, vertical flow assays (VFAs) have emerged as an alternate paper-based assay due to faster detection time and unique multiplexing capabilities. Smartphones as LFA readers have been transformed into a universal integrated platform for imaging, data processing, and storage, providing quantitative results in low-resource settings. Commercial LFAs and VFAs products are evaluated with regards to their performance, market trends, and regulatory issues. The future outlook of the flow-based assays for POC diagnostics is also discussed.

Lateral and Vertical Flow Assays for Point-of-Care Diagnostics.

The quantification of analyte concentrations using lateral flow assays is a low-cost and user-friendly alternative to traditional lab-based assays. However, sandwich-type immunoassays are often limited by the high-dose hook effect, which causes falsely low results when analytes are present at very high concentrations. In this paper, we present a reaction kinetics-based technique that solves this problem, significantly increasing the dynamic range of these devices. With the use of a traditional sandwich lateral flow immunoassay, a portable imaging device, and a mobile interface, we demonstrate the technique by quantifying C-reactive protein concentrations in human serum over a large portion of the physiological range. The technique could be applied to any hook effect-limited sandwich lateral flow assay and has a high level of accuracy even in the hook effect range.

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Mitigating the Hook Effect in Lateral Flow Sandwich Immunoassays Using Real-Time Reaction Kinetics.

Update on prolactinomas. Part 1: Clinical manifestations and diagnostic challenges

Clinically nonfunctioning adenomas range from being completely asymptomatic, and therefore detected either at autopsy or as incidental findings on head MRI or CT scans performed for other reasons, to causing significant hypothalamic/pituitary dysfunction and visual field compromise due to their large size. Patients with incidental adenomas should be screened for hypersecretion (prolactin, insulin-like growth factor 1, midnight salivary cortisol) and for hypopituitarism (macroadenomas). In the absence of hypersecretion, hypopituitarism, or visual field defects, patients may be followed by periodic screening by MRI for enlargement, at which point surgery may be necessary. Symptomatic patients with clinically nonfunctioning adenomas are generally treated by transsphenoidal surgery. Postoperative MRIs are done at 3-4 months after surgery to assess for completeness of resection and then repeated yearly for 3-5 years and subsequently less frequently to assess for regrowth. For those with no visible tumor on MRI, the tumor regrowth rate is about 13% and such patients may be followed with periodic MRIs. For those with visible tumor, the tumor regrowth rate is about 40%. This regrowth rate may be substantially reduced with the use of dopamine agonists and radiotherapy.

Nonfunctioning pituitary tumors

High-dose effect is a common phenomenon documented in various immunological and serological assays, which results in false-negative results. Due to limited amounts of reagent antibodies in the coated wells and extremely high concentrations of analyte in the sample leads to decrease in the formation of antigen-antibody complex and ultimately resulting in false low values of the analyte. High-dose hook effect has important medical implications, and simple methods of sample dilution helps in preventing false low concentrations.

High-dose hook effect

Pituitary hyperplasia with hyperprolactinemia has been described as a rare presentation of primary hypothyroidism. A 12-y-old child presented with intermittent headache, easy fatigability, coarseness of facial features, and hoarseness of voice for 6 mo duration. Brain imaging findings showed pituitary hyperplasia; hormonal assessment revealed primary hypothyroidism and hyperprolactinemia. Pituitary hyperplasia regressed with thyroid hormone replacement therapy. This report describes an unusual case of pituitary hyperplasia with hyperprolactinemia secondary to primary hypothyroidism.

Autoimmune Hypothyroidism Presenting as Pituitary Hyperplasia

Introduction: Alteration in the hypothalamo-pituitary-axis results in elevated thyroid stimulating hormone (TSH) in obesity. Aim: The aim of our study is to compare serum TSH level among obese and overweight children with normal weight and also to assess the relation between body mass index (BMI) and TSH in these children. Materials and Methods: A total of 124 patients aged between 6 and 17 years attending our obesity clinic were recruited. The patients were subdivided into three groups; Group 1: Normal weight (n = 24), Group 2: Overweight (n = 30), and Group 3: Obese (n = 70). All subjects underwent thyroid profile along with other routine tests. Fisher's exact test and Mann-Whitney U test were done to compare between study groups. Pearson's correlation analysis was done to assess the relationship between BMI and TSH. P < 0.05 was considered significant. Results: Out of 124 obese children and adolescents, 72 were females and 52 were and males. The overall mean age of the children was 11.99 ± 2.7 years (range 6.2-17 years). Subclinical hypothyroidism (5.5-10 mIU/L) was present 0/24 in Group 1, 13.33% (4/30) in Group 2, and 15.71% (11/70) in Group 3. The mean TSH values in Groups 1, 2, and 3 are 2.33, 3.03, and 3.35 mIU/L, respectively. Overall, serum TSH did not show correlation with BMI (r = 0.078; P = 0.681). Discussion: In this study, higher BMI resulted in elevated TSH levels, but there was no significant relation between severity of obesity and TSH. Large scale data from population based studies are required to confirm our findings.

Association of obesity and thyrotropinemia in children and adolescents

To assess the burden of type 2 diabetes (T2D) and its genetic profile in endogamous populations of India given the paucity of data, we aimed to determine the prevalence of T2D and estimate its heritability using family-based cohorts from three distinct Endogamous Ethnic Groups (EEGs) representing Northern (Rajasthan [Agarwals: AG]) and Southern (Tamil Nadu [Chettiars: CH] and Andhra Pradesh [Reddys: RE]) states of India. For comparison, family-based data collected previously from another North Indian Punjabi Sikh (SI) EEG was used. In addition, we examined various T2D-related cardiometabolic traits and determined their heritabilities. These studies were conducted as part of the Indian Diabetes Genetic Studies in collaboration with US (INDIGENIUS) Consortium. The pedigree, demographic, phenotypic, covariate data and samples were collected from the CH, AG, and RE EEGs. The status of T2D was defined by ADA guidelines (fasting glucose ≥ 126 mg/dl or HbA1c ≥ 6.5% and/or use of diabetes medication/history). The prevalence of T2D in CH (N = 517, families = 21, mean age = 47y, mean BMI = 27), AG (N = 530, Families = 25, mean age = 43y, mean BMI = 27), and RE (N = 500, Families = 22, mean age = 46y, mean BMI = 27) was found to be 33%, 37%, and 36%, respectively, Also, the study participants from these EEGs were found to be at increased cardiometabolic risk (e.g., obesity and prediabetes). Similar characteristics for the SI EEG (N = 1,260, Families = 324, Age = 51y, BMI = 27, T2D = 75%) were obtained previously. We used the variance components approach to carry out genetic analyses after adjusting for covariate effects. The heritability (h2) estimates of T2D in the CH, RE, SI, and AG were found to be 30%, 46%, 54%, and 82% respectively, and statistically significant (P ≤ 0.05). Other T2D related traits (e.g., BMI, lipids, blood pressure) in AG, CH, and RE EEGs exhibited strong additive genetic influences (h2 range: 17% [triglycerides/AG and hs-CRP/RE] - 86% [glucose/non-T2D/AG]). Our findings highlight the high burden of T2D in Indian EEGs with significant and differential additive genetic influences on T2D and related traits.

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Burden of Type 2 Diabetes and Associated Cardiometabolic Traits and Their Heritability Estimates in Endogamous Ethnic Groups of India: Findings From the INDIGENIUS Consortium

Amaresh Reddy Ponnala

Papers

High-dose hook effect

Autoimmune Hypothyroidism Presenting as Pituitary Hyperplasia

Association of obesity and thyrotropinemia in children and adolescents

Burden of Type 2 Diabetes and Associated Cardiometabolic Traits and Their Heritability Estimates in Endogamous Ethnic Groups of India: Findings From the INDIGENIUS Consortium