Suresh Vaikkakara

The investigation and management of severe hyperandrogenism pre- and postmenopause: Non-tumor disease is strongly associated with metabolic syndrome and typically responds to insulin-sensitization with metformin

Background. An androgen-secreting tumor needs to be excluded in any woman with severe hyperandrogenism. We sought to characterize patients with biochemical hyperandrogenism in respect of tumor versus non-tumor etiologies, explore possible links between non-tumor hyperandrogenism and metabolic syndrome, and ascertain whether metformin therapy can elicit diagnostic reductions in serum testosterone (T). Patients and methods. Seven-year retrospective study of all women referred to a university hospital endocrinology service with baseline T >4.0 nmol/l. Dataset comprised age, menopausal status, body mass index (BMI), presence/absence of hypertension, diabetes, acanthosis or dyslipidemia, along with changes in BMI and serum T following intervention with metformin, oophorectomy or dexamethasone. Non-tumor hyperandrogenism was defined by normalization of serum T or >40% reduction from baseline. Results. Four out of 18 cases had adrenal carcinoma that was clinically obvious at initial presentation (one virilized, three Cushingoid). The remaining 14 were characterized by metabolic syndrome (BMI: 39.9 ± 8.1 kg/m2), serum T of 6.14 ± 1.6 nmol/l, and nadir serum T following intervention of 2.2 ± 1.04 nmol/l. Diagnostic reductions in serum T occurred in 11/12 patients treated with metformin. Conclusions. Non-tumor hyperandrogenism with markedly elevated serum T and associated metabolic syndrome is a defined clinical entity in postmenopause as well as in premenopausal women with polycystic ovary syndrome. This has hitherto been only sparsely documented in the published literature. A fall in serum T level in response to insulin-sensitizing therapy with metformin and lifestyle change may be a reassuring indicator that such women are highly unlikely to harbor an androgen-secreting tumor.

Phaeochromocytoma and ACTH‐dependent cushing's syndrome: tumour crf secretion can mimic pituitary cushing's disease

10% of corticotrophin (ACTH)‐dependent Cushings syndrome arises from secretion by extrapituitary tumours, with phaeochromocytoma implicated in a few cases. Ectopic secretion by phaeochromocytoma of corticotropin‐releasing hormone (CRF), with secondary corticotroph hyperplasia, is even rarer, with only five cases in the literature hitherto. However, such cases may be classified as ‘ectopic ACTH’ due to incomplete verification.

Impact of standardised reporting in adrenocortical carcinoma: a single centre clinicopathological review

Aims: Structured multicentre efforts are needed if the prognosis of adrenocortical carcinoma (ACC) is to be improved. Data collection may be enhanced through standardised histopathological reporting using criteria such as the recently published Royal College of Pathologists’ (UK) minimum dataset (MDS). This study aimed to perform a clinicopathological review of the adult patients treated at the Royal Victoria Infirmary, Newcastle upon Tyne, in the 10 years preceding the MDS. Methods: Case records were examined for all patients diagnosed with ACC between 1996 and 2006. Pathology was reviewed and compared with the Royal College of Pathologists’ MDS along with the original reports. A systematic evaluation of Ki-67 immunolabelling was also performed. Results: Eleven patients with ACC were diagnosed and treated. Histopathological reporting according to the MDS identified more features of malignancy than in the original reports (8.5±1.2 versus 5.1±0.8, p<0.02). The median number of microscopic criteria of malignancy was 7 (range 5–10), with ⩾5 features occurring in all cases. The most commonly observed features of malignancy were diffuse architecture, <25% clear cells, confluent necrosis, abnormal mitoses and mitotic count ⩾6 per 50 high-power fields. Capsular invasion and ⩾8 MDS criteria of malignancy were associated with a worse outcome (each p<0.01). Median Ki-67 index was 19.0% (range 3.7–44.1%) and was not apparently related to survival. Conclusions: Standardised criteria for histopathological reporting of ACC will improve the accuracy of data for cancer registration and may also assist in individual patient stratification. An elevated Ki-67 index is a feature of ACC, although it does not appear to predict individual patient survival.

Effects of thyroid hormone replacement on glycated hemoglobin levels in non diabetic subjects with overt hypothyroidism.

OBJECTIVE Glycated hemoglobin (HbA1c) may not accurately reflect the level of glycemia in conditions of altered erythrocyte turnover. Hypothyroidism is one condition associated with sluggish erythropoesis. To assess changes in HbA1c, independent of changes in plasma glucose after initiation of thyroxine replacement in patients with overt hypothyroidism. MATERIALS AND METHODS In this prospective longitudinal study carried out in a tertiary care centre, adult non-diabetic patients with overt hypothyroidism recruited between March 2012 to August 2013 were rendered euthyroid on thyroxine. They underwent testing for hemoglobin, HbA1c, reticulocyte count, thyroxine, thyrotropin and a standard oral glucose tolerance test, both before and at 3 months after restoration to the euthyroid state. Main outcome assessed was the change in HbA1c independent of the change in glucose parameters. RESULTS Thirty eight patients (35 female and 3 male) aged 37.8 ± 10.2 years with overt hypothyroidism (thyroxine 12.6 ± 13.4 ng/mL and thyrotropin -98.1 ± 63.7 µIU/mL respectively) were recruited. While HbA1c fell from 5.8 ± 0.7% to 5.6 ± 0.5% (p = 0.009) at 3 months following the correction of hypothyroidism, there were no changes in the fasting and the 2 hr post oral glucose tolerance test glucose (p = 0.67 and 0.56 respectively). The number of patients with dysglycemia diagnosed by HbA1c (i.e HbA1c ≥ 5.7%) fell from 25 (65.78%) to 17 (44.7%) after treatment (p = 0.008). There were 7 (18.4%) patients with HbA1c ≥ 6.5% at baseline, but this fell to just 4 (10.5%) (p < 0.001) after 3 months of euthyroidism. CONCLUSION HbA1c is not a reliable diagnostic test for diabetes in the presence of hypothyroidism.

Heterogenous origins of hyperandrogenism in the polycystic ovary syndrome in relation to body mass index and insulin resistance

Abstract Background: Insulin resistance and obesity are not universal features of polycystic ovary syndrome (PCOS). We planned to assess the differences between patients with nonobese /insulin-sensitive phenotype vs. obese/ insulin-resistant phenotype in terms of the potential mechanisms underlying their hyperandrogenism. Materials and methods: A total of 52 women satisfying Androgen Excess Society (AES) criteria were included. Hormonal and metabolic profile including prolactin, dehydroepiandrosterone sulfate (DHEAS), free testosterone, sex hormone binding globulin (SHBG), fasting plasma glucose and insulin were measured in follicular phase. Results: DHEAS was found to be higher in the nonobese patients as compared to the obese (p = 0.01). There was also a strong trend for a higher DHEAS among patients with lower insulin resistance by homeostatic model assessment (HOMA-IR< 2.3) (p = .06).While the total testosterone (p = .044) and SHBG (p = .007) were found to be lower in the more insulin-resistant group (HOMA-IR ≥ 2.3), the free testosterone levels were similar. However, the percentage of free testosterone was higher in the more insulin-resistant group (p = .005). Conclusions: The hyperandrogenic state in PCOS appears to have heterogenous origins. Nonobese patients with PCOS have adrenal hyperandrogenism as the underlying mechanism while their obese/ insulin-resistant counterparts have low SHBG and hence an increased fraction of free testosterone.

Atypical parathyroid adenoma with multiple brown tumors as initial presentation: A rare entity

Brown tumors seen in hyperparathyroidism are rare, non-neoplastic lesions because of abnormal bone metabolism, and they can mimic benign bone tumors or malignancy. Although biopsy is considered as the gold standard for diagnosis, it can be inconclusive. As the diagnosis of brown tumors is often challenging, a high index of suspicion is essential for diagnosis. We present a case of 21-year-old woman who presented with multiple painful bony lesions, which were initially misdiagnosed as fibrous dysplasia. Due to persistent bone pain and deterioration in her physical mobility, she was referred to tertiary care centre. After thorough clinical workup, she underwent Tc-99m methylene diphosphonate bone scintigraphy that raised strong clinical suspicion of hyperparathyroidism and brown tumors. Subsequently, Tc-99m-methoxy isobutyl isonitrile (MIBI) parathyroid scintigraphy revealed a solitary MIBI avid focal lesion, suggestive of left inferior parathyroid adenoma. Later parathyroidectomy was performed and histopathological examination confirmed it as atypical parathyroid adenoma.

Impact of severity of illness on the function of the hypothalamo-pituitary-gonadal axis in postmenopausal women with acute severe illness: Implications for predicting disease outcome

Background: While elevated levels of estradiol were predictive of mortality in critically ill surgical and trauma patients, their ability to predict outcome in nonsurgical patients has not been studied. We aimed to study the determinants of gonadotropin levels in acutely ill postmenopausal women with nonsurgical disease and the impact of changes in the gonadal axis on the outcome of these patients. Methods: Thirty-five postmenopausal women admitted to medical intensive care with acute severe illness and having a Simplified Acute Physiology Score (SAPS II score) ≥30 (in-hospital mortality rate ≥ 10%) were recruited. On the 5th day of hospitalization, fasting samples were collected at 8.00 am and tested for luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, free triiodothyronine, free thyroxine, thyrotropin, cortisol, prolactin, dehydroepiandrosterone, androstenedione, and sex hormone-binding globulin. Multiple linear regression analysis was performed to identify independent determinants if any of LH and FSH. Receiver operating characteristic (ROC) curves were drawn for different cutoffs of LH, FSH, and estradiol to diagnose mortality and prolonged hospitalization. Results: There was an independent negative association between the FSH and the SAPS II score (beta = −0.435; P = 0.014), but not with any of the other tested parameters (estradiol, prolactin, or cortisol). Among components of the SAPS II score, the total leukocyte count (TLC) was negatively associated with serum FSH (beta coefficient = −0.635, P = 0.013). None of these parameters were determinants of LH. On ROC analysis, neither estradiol nor gonadotropins were diagnostic for in-hospital mortality. However, among survivors, low estradiol was diagnostic for prolonged hospital stay (area under the curve = 0.785; P = 0.015). Conclusion: FSH, but not LH, is negatively associated with the severity of illness, particularly to its inflammatory component (TLC). Low estradiol in survivors was a predictor of prolonged hospital stay.

Contents Vol. 5, 2016

Maria Alevizaki – Athens University, Athens, Greece Ana Aranda – Universidad Autónoma de Madrid, Madrid, Spain Rebecca Bahn – Mayo Medical School, Rochester, Minn., USA Paul Banga – King’s College London School of Medicine, London, UK Luigi Bartalena – University of Insubria, Varese, Italy Bernadette Biondi – University of Naples Federico II, Naples, Italy Anita Boelen – Academic Medical Center, Amsterdam, Netherlands Georg Brabant – University of Lübeck, Lübeck, Germany Henning Dralle – Martin Luther University, Halle/Saale, Germany Creswell J. Eastman – The University of Sydney, Westmead, N.S.W., Australia Murat Erdogan – Ibni-i-Sina Hastanesi, Ankara, Turkey Valentin Fadeyev – Federal Endocrinological Scientific Centre, Moscow, Russia Ulla Feldt-Rasmussen – Copenhagen Univ. Hosp., Rigshospitalet, Copenhagen, Denmark Laszlo Hegedus – Odense University Hospital, Odense, Denmark George J. Kahaly – Gutenberg University Medical Center, Mainz, Germany Rui Maciel – Universidade Federal de São Paulo, São Paulo, Brazil Ana Luiza Maia – Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil Jens Mittag – University of Lübeck, Lübeck, Germany Ralf Paschke – Universität Leipzig, Leipzig, Germany Robin P. Peeters – Erasmus MC, Rotterdam, Netherlands

Correction of Hypothyroidism Leads to Change in Lean Body Mass without Altering Insulin Resistance

Background: Hypothyroidism is associated with insulin resistance, dyslipidemia, and abnormal body composition. This study assessed changes in body composition and insulin resistance after thyroxine (T4) replacement in overt hypothyroidism. Methods: In this prospective longitudinal study carried out in a tertiary care center, adult nondiabetic patients with overt hypothyroidism were rendered euthyroid on T4. Anthropometry including skinfold thickness (SFT) at the triceps and subscapularis was recorded. Patients underwent testing for fasting plasma glucose, creatinine, serum insulin, T4, thyrotropin (TSH) and body composition analysis by dual-energy X-ray absorptiometry (DEXA) both before and at 2 months after restoration to the euthyroid state. Results: Twenty-seven patients (20 female and 7 male) aged 35.3 ± 11.0 years (min-max: 17-59 years) with overt hypothyroidism were recruited. Serum T4 at the time of recruitment was 48.9 ± 24.6 nmol/l (normal range = 64.4-142 nmol/l). All patients had TSH ≥50 µIU/l. Following treatment, there was a mean body weight reduction of 1.7 kg (p = 0.01). Waist circumference as well as triceps and subscapularis SFT decreased significantly (p < 0.001). There was no change in fat mass (FM), percentage of fat (%FM) or bone mineral content in any of the specified regions or in the body as a whole. In contrast, mean lean body mass (LBM) decreased significantly by 0.8 kg (p < 0.01) in the trunk and 1.3 kg (p < 0.01) in the whole body. Insulin resistance and level of glycemia were not affected by treatment with T4. Conclusion: LBM decreases significantly without affecting FM after correction of hypothyroidism. Insulin resistance was not influenced by T4 treatment.

Multiple endocrine neoplasia-2A-revisited

Multiple endocrine neoplasia-2A (MEN-2A) is a rare syndrome. MEN-2 is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism. MTC is the most consistent feature in all subtypes of MEN-2. In MEN-2A, approximately 70–95% of individuals develop MTC, 50% develop pheochromocytoma, and 15–30% develop hyperparathyroidism. Identification of a germline REarranged in transfection mutation or the identification of the clinical features of MEN-2A in other first-degree relatives is required to make the diagnosis, in those patients with only one or two clinical features. We present the case of a family with MEN-2A syndrome. Here, the patient was first operated for MTC and following further investigation was detected to have pheochromocytoma. In her family history, she had a daughter who was earlier operated for MTC. After 5 years of follow-up, she is doing well. This is an additional case of MEN-2A.