Audit of long-term treatment outcomes of thyrotoxicosis in a single-centre virtual clinic: The utility of long-term antithyroid drugs.

OBJECTIVE: To investigate the long-term outcomes and prognosis of thyrotoxicosis in a large number of patients in a single UK county (Leicestershire). DESIGN: Retrospective cohort analysis of 56,741 thyroid function test (TFT) results, treatment modalities and outcomes in a well-established virtual thyrotoxicosis clinic database. PATIENTS: One thousand four hundred and eighty-nine patients were included with a median length of follow-up of 10.9 years. The aetiology of thyrotoxicosis was autoimmune (85.9%), nodular (9.1%) and mixed (5.0%). Treatment modalities included antithyroid drugs (ATDs), radioiodine (RAI; 555 MBq fixed dose) and thyroidectomy. METHODS: We analysed both individual TFTs and groups of sequential TFTs on or after the same thyroid treatment(s), which we describe as 'phase of thyroid care' (POTC). Patients studied entered the virtual clinic between 1 January 1995 and 1 January 2010; we exported data on every TFT sample up to April 2020. RESULTS: ATD had been used in 99.2% (median 2, maximum seven courses) with long-term ATD (>2 years) in 48%. RAI and thyroidectomy were used more commonly with nodular and mixed aetiology. Overall, T4 was more often controlled than thyroid-stimulating hormone (TSH), and at the latest follow-up, T4 was normal in >96%, TSH in >79% and both in >76% of different aetiologies. The mean percentage control of T4 was 85% and TSH 50%; in long-term ATD courses, this improved to 89% and 62%, respectively. In the latest POTC, control of T4 and TSH was best in cases off treatment (95%/87%) and on T4 without ablative therapy (94%/72%), but was broadly similar in patients on long-term ATD (90%/68%), after RAI (92%/60%) or after thyroidectomy (91%/58%). After the first course of ATD, remission or hypothyroidism was seen in 47.3% autoimmune, 20.9% nodular and 32.5% mixed, with 90% relapses seen within 4 years. Relapse was more common in patients with ophthalmopathy, but there was no difference between the sexes. CONCLUSIONS: Thyrotoxicosis can be well controlled with minimal specialist clinic attendance using a software-supported virtual shared-care scheme. Long-term ATD appears to be a valid patient choice achieving TFT control comparable to that seen after RAI or surgery. In patients with autoimmune disease, relapse is more common in patients with ophthalmopathy, and hypothyroidism is common after RAI. In nodular disease, we found that spontaneous remission may occur.

Long-term follow-up of a large prospective cohort of patients with nonfunctioning pituitary adenomas: The outcome of a conservative management policy.

OBJECTIVE: To assess the clinical outcome of a strategy of conservative monitoring of patients with nonfunctioning pituitary adenomas (NFPA) after pituitary surgery and in patients without surgery. DESIGN: Retrospective study of outcomes, using a clinical information system. PATIENTS: An unselected, clinical series of patients seen in a single centre between 1989 and 2015. MEASUREMENTS: Review of clinical information system data to obtain details and dates of surgery, radiotherapy, pituitary imaging and outcomes. RESULTS: We identified 190 cases of NFPA. Trans-sphenoidal surgery (TSS) had been performed as primary therapy in 132 cases (all macro-adenomas). At a mean 7.6-years follow-up after TSS without immediate pituitary radiotherapy, recurrence occurred in 10.7% of cases with no visible postoperative residual adenoma, 38.8% with intrasellar and 66.7% with extrasellar residuum. Recurrence was defined as growth of residual tumour requiring intervention. On survival analysis, at 10 years, recurrence-free survival was 75% in patients with no residual tumour and 40% with intrasellar residuum. Recurrence occurred in 12.5% of 24 patients who had received postop radiotherapy. Patients were monitored conservatively without initial surgery in 65 patients. After a mean of 5-year monitoring, only 20% required intervention during follow-up (18.5% TSS) and 30.8% died of nonpituitary causes during follow-up. CONCLUSION: This study suggests that a conservative approach may be safe and appropriate in patients with NFPA if followed up with appropriate imaging surveillance, whether postoperative or without primary surgery.

Clinical characteristics of polycystic ovary syndrome: investigating differences in White and South Asian women.

OBJECTIVE: To understand the phenotypic presentation of women with polycystic ovary syndrome (PCOS) of different ethnicities and at different ages. DESIGN: Cross-sectional, retrospective data analysis (1988 - 2009). SETTING: Specialist clinic in a University Hospital, Leicestershire, UK. PARTICIPANTS: Women with PCOS, n = 1310 (mean age 26·2 years), 70·9% White and 29·1% South Asian (SA) attending a speciality clinic in Leicester UK. MAIN OUTCOMES MEASURES: Clinical and demographic characteristics of women with PCOS including age at first clinic appointment, signs and symptoms, body mass index (BMI) and blood pressure (BP). RESULTS: Compared to White women, the SA were younger (24·3 vs 27·1 years, P < 0·001), less likely to smoke (3·7% vs 17·9% P < 0·001) and had a higher prevalence of acanthosis nigricans (AN) (16·8% vs 3·1% P < 0·001), type 2 diabetes (T2DM) (8·1% vs 5·6%, P < 0·01) and hirsutism (88·5% vs 77·4%, P < 0·001), with lower systolic (126·5 vs 133·0 mmHg, P < 0·001), diastolic BP (71·8 vs 75·1 mmHg P = 0·008) and BMI (29·3 vs 31·5 kg/m(2) P = 0·002). Differences in body weight remained when participants were classified as obese, overweight and normal according to ethnicity-specific cut-off points (P = 0·048). In both ethnicities, those aged ≥30 years old had higher rates of obesity, T2DM, hypertension and infertility, and less acne, and oligomenorrhoea. Obesity was associated with increased T2DM, AN, systolic/diastolic BP, hirsutism and infertility. CONCLUSION: The phenotypic and metabolic presentations of women with PCOS appear to be significantly different depending on ethnicity, obesity and age. This has implications for management strategies in these groups.

AIP mutation in pituitary adenomas in the 18th century and today.

Gigantism results when a growth hormone-secreting pituitary adenoma is present before epiphyseal fusion. In 1909, when Harvey Cushing examined the skeleton of an Irish patient who lived from 1761 to 1783, he noted an enlarged pituitary fossa. We extracted DNA from the patient's teeth and identified a germline mutation in the aryl hydrocarbon-interacting protein gene (AIP). Four contemporary Northern Irish families who presented with gigantism, acromegaly, or prolactinoma have the same mutation and haplotype associated with the mutated gene. Using coalescent theory, we infer that these persons share a common ancestor who lived about 57 to 66 generations earlier.

Control of growth hormone and IGF1 in patients with acromegaly in the UK: responses to medical treatment with somatostatin analogues and dopamine agonists.

OBJECTIVE: We investigated the control of GH and IGF1 in acromegaly in routine clinical practice in the UK on and off medical treatment. DESIGN: The UK Acromegaly Register collected routine biochemical and clinical data on patients with acromegaly from 31 UK centres with GH data covering >30y. PATIENTS: We identified 2572 patients. Somatostatin analogues (SMS) were used in 40·6% and dopamine agonists (DA) in 41·4%. MEASUREMENTS: We identified 29,181 GH records linked to data on IGF1, surgery, radiotherapy and medical treatment and derived data on 9900 distinct Periods of Care including 4206 courses of medical treatment. We considered GH controlled when ≤2 µg/l. RESULTS: Control of GH and IGF1 improved over time, particularly on medical treatment. Control on medical treatment was better after prior surgery and/or radiotherapy. On long-term SMS, GH was controlled in 75%, IGF1 in 69% and both in 55%; on long-term DA, GH control was similar but IGF1 worse (77%/55%/45%). Responses to long-term treatment with octreotide LAR and lanreotide autogel were broadly similar, but we noted a failure to escalate SMS to maximal effective dose. Increasing precourse GH levels were associated with a decreasing proportion who achieved control, despite greater suppression from baseline. CONCLUSIONS: Control of acromegaly in the UK is improving, but 'safe' GH levels are still only achieved in 75% on long-term medical treatment, with GH and IGF1 both normalized in no more than 55% on SMS and 36% on cabergoline. It remains unclear whether the control of GH, but not IGF1, observed in many patients is sufficient to restore long-term morbidity and mortality to normal.

Diabetes and cardiovascular events in women with polycystic ovary syndrome: a 20-year retrospective cohort study.

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) are potentially at increased risk of cardiovascular (CV) diseases due to well-established risk factors, including insulin resistance, obesity and type 2 diabetes mellitus (T2DM). However, data showing excess CV events in this population are still lacking. We investigated the incidence and prevalence of CV events in a cohort of women with PCOS. DESIGN: Retrospective cohort study (total follow-up >12,000 person-years). SETTING: Leicester, Leicestershire and Rutland (Total Female population of 434,859), UK. PARTICIPANTS: Two thousand three hundred and one women with PCOS (mean age = 29.6 years) attending a speciality clinic in Leicestershire, UK. MAIN OUTCOMES MEASURES: T2DM, myocardial infarction (MI), angina, heart failure (HF), stroke and CV-related death. RESULTS: Incidence of T2DM, MI, angina, HF, stroke and CV death was respectively 3.6, 0.8, 1.0, 0.3, 0.0 and 0.4 per 1000 person-years. At the end of follow-up, the prevalence of MI in the age groups 45-54, 55-64 and >65 years was 1.9%, 6.0% and 27.3% and of angina was 2.6%, 6.0% and 27.3%, respectively. Age-group-specific odds ratios for the prevalence of MI and angina compared to the local female population ranged between 2.6 (95% CI: 1.0-6.3) and 12.9 (CI: 3.4-48.6) with the highest ratio being for MI in the group >65 years old. Age, history of hypertension and smoking had significant correlations with CV outcomes in the PCOS patients. CONCLUSION: We have shown a high incidence and age-group-specific prevalence of T2DM, MI and angina in the women with PCOS, with over a quarter having had MI or angina in those >65 years. These findings should be considered in the treatment strategies and long-term planning for women with PCOS.

Diagnosis and treatment of hypothyroidism in TSH deficiency compared to primary thyroid disease: pituitary patients are at risk of under-replacement with levothyroxine.

OBJECTIVE: Achieving optimal thyroid hormone replacement is more difficult in TSH deficiency compared to primary hypothyroidism because of the inability to be guided by serum TSH levels. A combination of clinical symptoms and free thyroxine levels (fT4) are typically used to make a diagnosis and monitor replacement. We investigated the diagnosis of TSH deficiency in patients with pituitary disease and the adequacy of levothyroxine replacement compared with primary thyroid disease. DESIGN: Using our department's clinical information system, we identified all patients with a diagnosis of any type of pituitary tumour who had been seen in clinic over a 2-year period. We divided the patients into those at high risk and low risk of TSH deficiency based on the presence of macroadenoma and/or intervention by surgery or radiotherapy. We compared fT4 values in these patients with values in patients with primary thyroid disease in our thyrotoxicosis shared-care scheme (TSC) and hypothyroid register within the same timescale, assessing only those samples considered euthyroid in which TSH was in the normal range. RESULTS: A database query identified 525 patients with a pituitary tumour of whom 344 were considered at high risk of TSH deficiency. A free T4 (fT4) value was found for 514 patients (97·9%). TSC and thyroid register databases revealed fT4 values for comparison with simultaneous normal TSH in patients on no treatment (n = 3777 samples) or on levothyroxine alone (n = 11,805). fT4 levels overall were lower in pituitary patients than in equivalent controls. Of the high risk group not taking levothyroxine 17% had a free T4 ≤ 11 pmol/l compared to only 8·4% of untreated controls. Furthermore, 38·9% of patients on levothyroxine had a free T4 ≤ 13 pmol/l compared to 9·5% of controls on levothyroxine with previous thyrotoxicosis and 13·4% of controls with primary hypothyroidism. Median fT4 in controls on levothyroxine was 16 pmol/l and 20-80th centile range was 14-19 pmol/l. CONCLUSION: Levothyroxine doses were generally under-replaced in pituitary patients compared to primary thyroid disease and the data imply that some untreated patients were actually TSH deficient. The distribution of fT4 in patients with primary thyroid disease on levothyroxine may guide optimum replacement levels in pituitary disease.

How reliably can autoimmune hypophysitis be diagnosed without pituitary biopsy.

Autoimmune hypophysitis is a rare chronic inflammatory condition of the pituitary gland which typically presents with hypopituitarism and a pituitary mass. Cases involving anterior pituitary alone (65%) are six times more common in women, typically presenting during pregnancy or postpartum (57%). Anterior and posterior pituitary involvement (25%) are twice as common in women, and neurohypophysis alone (10%) occurs equally in both sexes. It has a prevalence of around 5 per million, an annual incidence of 1 in 7 to 9 million and in our experience represents the known or suspected cause of 0.5% of cases of hypopituitarism, <1% of pituitary masses and 2% of nonfunctioning macro lesions presenting to an endocrine clinic. However, 'missed' cases of autoimmune hypophysitis may be the aetiology of some other unexplained cases of hypopituitarism. Clinically, headache and visual disturbance are common. Anterior hypopituitarism shows a characteristic but atypical pattern of deficiency of ACTH followed by TSH, gonadotrophins and prolactin deficiency or hyperprolactinaemia. Eighteen percent of cases have evidence of another autoimmune condition. On magnetic resonance imaging (MRI), autoimmune hypophysitis is typically symmetrical and homogeneous with thickened but undisplaced stalk in contrast to typical findings with pituitary tumours. Ultimately, the histological diagnosis of autoimmune hypophysitis can only be confirmed by surgery but a presumptive diagnosis can often be made on the basis of a combination of context and clinical features, and pituitary biopsy is not always clinically necessary for effective clinical management of the patient.

Long-term outcome of hyperthyroidism diagnosed in childhood and adolescence: a single-centre experience.

Background The objective of the study was to evaluate the long-term outcome of paediatric-onset hyperthyroidism with follow-up into adulthood and to identify any early predictors of a need for definitive therapy (DT). Methods In a retrospective analysis of patients diagnosed with hyperthyroidism under the age of 18 years and at follow-up, a comparison was made by categorising them into those who underwent definitive therapy (DT group), i.e. thyroidectomy/radioactive iodine (RAI), those who remained on antithyroid drugs (ATD) (CBZ group) and those who had complete remission (RE group). Results Sixty-one (49 females, 12 males) patients with a median age of 15.1 years (range: 3.6-18) at diagnosis were studied. The duration of the first course of ATD varied from <1 year (7%), 1-2 years (26%), >2 years (46%) and ATD never discontinued (21%). Disease relapsed in 69% of patients with <1 year of ATD vs. 79% with >2 years of ATD. At follow-up, the median duration since diagnosis was 8.75 years (range 2.0-20.7 years) and the median age at follow-up was 23.2 years (8-36 years). Thirty-three percent (20/61) had undergone DT (DT group) - with 16.5% (n=10) on RAI and 16.5% (n=10) on surgery, 36% (22/61) were on ATD (CBZ group), whilst 32% (19/61) had undergone full remission (RE group). The comparison did not identify any statistically significant difference for predictor factors at diagnosis including age, T4 and free T4 levels, thyroid peroxidise antibody levels (TPO) and the duration of the first course of carbimazole (CBZ) treatment. Conclusion Long-term complete remission of paediatric-onset hyperthyroidism in our study was 31%. There were no predictors identified that could help predict the long-term outcome, especially into adulthood.

Structured education programme for women with polycystic ovary syndrome: a randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of a structured education programmes in women with polycystic ovary syndrome (PCOS). METHODS: Single-centre, randomised controlled trial, testing a single exposure to a group-based, face-to-face, structured education programme. Inclusion criteria were women with PCOS, aged 18-49 years inclusive and body mass index ≥23 kg/m2 for black and minority ethnicities or ≥25 kg/m2 for white Europeans. Primary outcome was step-count/day at 12 months. Secondary outcomes included indices of physical activity, cardiovascular risk factors, quality of life (QoL) and illness perception (IP). RESULTS: 161 women were included (78 control, 83 intervention); 69% white; mean age 33.4 (s.d. 7.6) years, of whom 100 (48 intervention; 52 control) attended their 12-month visit (38% attrition). 77% of the intervention arm attended the education programme. No significant change in step-count was observed at 12 months (mean difference: +351 steps/day (95% confidence interval -481, +1183); P = 0.40). No differences were found in biochemical or anthropometric outcomes. The education programme improved participants' IP in 2 dimensions: understanding their PCOS (P < 0.001) and sense of control (P < 0.01) and improved QoL in 3 dimensions: emotions (P < 0.05), fertility (P < 0.05), weight (P < 0.01) and general mental well-being (P < 0.01). DISCUSSION: A single exposure to structured education programme did not increase physical activity or improve biochemical markers in overweight and obese women with PCOS. However, providing a structured education in parallel to routine medical treatment can be beneficial for participants' understanding of their condition, reducing their anxiety and improving their QoL.

Risk Profile of the RET A883F Germline Mutation: An International Collaborative Study.

Context: The A883F germline mutation of the rearranged during transfection (RET) proto-oncogene causes multiple endocrine neoplasia 2B. In the revised American Thyroid Association (ATA) guidelines for the management of medullary thyroid carcinoma (MTC), the A883F mutation has been reclassified from the highest to the high-risk level, although no well-defined risk profile for this mutation exists. Objective: To create a risk profile for the A883F mutation for appropriate classification among the ATA risk levels. Design: Retrospective analysis. Setting: International collaboration. Patients: Included were 13 A883F carriers. Intervention: The intervention was thyroidectomy. Main Outcome Measures: Earliest age of MTC, regional lymph node metastases, distant metastases, age-related penetrance of MTC and pheochromocytoma (PHEO), overall and disease-specific survival, and biochemical cure rate. Results: One and three carriers were diagnosed at age 7 to 9 years (median, 7.5 years) with a normal thyroid and C-cell hyperplasia, respectively. Nine carriers were diagnosed with MTC at age 10 to 39 years (median, 19 years). The earliest age of MTC, regional lymph node metastasis, and distant metastasis was 10, 20, and 20 years, respectively. Fifty percent penetrance of MTC and PHEO was achieved by age 19 and 34 years, respectively. Five- and 10-year survival rates (both overall and disease specific) were 88% and 88%, respectively. Biochemical cure for MTC at latest follow-up was achieved in 63% (five of eight carriers) with pertinent data. Conclusions: MTC of A883F carriers seems to have a more indolent natural course compared with that of M918T carriers. Our results support the classification of the A883F mutation in the ATA high-risk level.