Patients on levothyroxine replacement in the community: association between hypothyroidism symptoms, co-morbidities and their quality of life.

INTRODUCTION: Patients may be symptomatic, resulting in lower quality of life (QOL), despite L-thyroxine (LT4) therapy for hypothyroidism or having normal thyroid function. We hypothesized that their clinical symptoms of hypothyroidism and co-morbidities were associated with QOL. OBJECTIVE: The study aimed to determine the association between the hypothyroid-related symptoms of Asian patients on LT4 treatment, their co-morbidities and their QOL. METHOD: A questionnaire survey was conducted from November 2015 to July 2016 on consecutive multi-ethnic Asian patients on LT4 treatment for their hypothyroidism in a public primary care clinic in Singapore. Data on their demography, clinical symptoms, morbidity status, QOL scores based on the EQ5D instrument and thyroid function tests were computed and analysed, including logistic regression analysis to identify factors associated with lower QOL. RESULTS: Complete data of 226 Asian patients (79.0% women; 74.2% Chinese, 10.0% Malay, 13.1% Indian and 2.6% other minority groups; median age 57 years; 27.5% had previous thyroid surgery) were analysed. Their QOL was not associated with their socio-demographic profiles, clinical parameters and latest thyroid-stimulating hormone and free thyroxine levels. Patients reporting weight gain, dry or coarse skin, leg swelling, feeling weak and carpal tunnel syndrome had significantly lower QOL; 53.6% of them with any single symptom had lower QOL. More patients had lower QOL if they had two or more symptoms and multiple medical conditions. CONCLUSION: In Asian patients with hypothyroidism, weight gain, feeling tired, feeling weak, having dry or coarse skin, leg swelling and increased number of co-morbidities and symptoms were significantly associated with poorer QOL.

Low-Dose Levothyroxine Reduces Intrahepatic Lipid Content in Patients With Type 2 Diabetes Mellitus and NAFLD.

Context: Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in patients with type 2 diabetes mellitus (T2DM) and associated with significant morbidity and mortality. Thyroid hormone (TH) increases ß-oxidation of fatty acids and decreases intrahepatic lipid content (IHLC) in rodents with NAFLD. Objective: We investigated the possibility of low intrahepatic TH concentration in NAFLD and studied the effect of TH treatment in humans. Design/Setting: This was a phase 2b single-arm study in six hospitals in Singapore. Intrahepatic thyroid hormone concentrations were measured in rats with induced NAFLD. Patients: Euthyroid patients with T2DM and steatosis measured by ultrasonography. Intervention: Levothyroxine was titrated to reach a thyroid-stimulating hormone level of 0.34 to 1.70 mIU/L before a 16-week maintenance phase. Main Outcome Measures: The primary outcome measure was change in IHLC measured by proton magnetic resonance spectroscopy after treatment. Results: Twenty male patients were included in the per-protocol analysis [mean ± SD: age, 47.8 ± 7.8 years; body mass index (BMI), 30.9 ± 4.4 kg/m2; baseline IHLC, 13% ± 4%]. After treatment, IHLC was decreased 12% (±SEM, 26%) relative to baseline (absolute change, -2%; 95% CI, -3 to 0; P = 0.046). Small decreases in BMI (P = 0.044), visceral adipose tissue volume (P = 0.047), and subcutaneous adipose tissue volume (P = 0.045) were observed. No significant changes in glucose regulation or lipid profile occurred. Conclusion: This study demonstrated the efficacy and safety of low-dose TH therapy for NAFLD in men. TH or TH analogs may be beneficial for this condition.

Androsterone glucuronide to dehydroepiandrosterone sulphate ratio is discriminatory for obese Caucasian women with polycystic ovary syndrome.

BACKGROUND: Androsterone glucuronide (ADTG) concentrations have been suggested as a marker of the effects of androgens at the target tissue level. As the mechanism for hyperandrogenemia in obese and nonobese polycystic ovary syndrome (PCOS) may differ, this study compared the different androgen parameters in non-obese compared to obese women with PCOS, and in normal subjects. METHODS: Eleven non-obese and 14 obese women with PCOS were recruited and compared to 11 control women without PCOS. Total testosterone, dehydroepiandrosterone sulphate (DHEAS), ADTG, and androstenedione were analysed using gold standard tandem mass spectrometry, and the free androgen index (FAI) was calculated. RESULTS: Total testosterone, ADTG and androstendione levels did not differ between non-obese (body mass index (BMI) ≤25 kg/m2) and obese PCOS (BMI >25 kg/m2) but all were significantly higher than for controls (p < 0.01). The ADTG to DHEAS ratio was significantly elevated 39 ± 6 (p < 0.01) in obese PCOS in comparison to non-obese PCOS and controls (28 ± 5 and 29 ± 4, respectively). The free androgen index (FAI) and insulin resistance (HOMA-IR) were significantly higher in obese PCOS compared to non-obese PCOS and controls (p < 0.01). DHEAS was significantly higher in the non-obese versus obese PCOS (p < 0.01). All androgen parameters were significantly lower and sex hormone binding globulin (SHBG) significantly higher in normal subjects compared to those with obese and non-obese PCOS. CONCLUSIONS: The ADTG:DHEAS ratio was significantly elevated in obese PCOS compared to non-obese PCOS and controls suggesting that this may be a novel biomarker discriminatory for obese PCOS subjects, perhaps being driven by higher hepatic 5α reductase activity increasing ADTG formation in these women.

Primary hypothyroidism in the community: Lower daily dosages of levothyroxine replacement therapy for Asian patients.

The goal of treatment in patients with primary hypothyroidism is to attain euthyroidism guided by the stipulated thyroid-stimulating hormone (TSH) levels range so as to minimize any potential long-term adverse effects. However, various factors may result in their Levothyroxine (T4) under and over-replacement.Our study aimed to evaluate the mean daily dose of L-T4 replacement for Asian patients with primary hypothyroidism. The secondary aims were to determine the proportion of those who were either over or under-replaced, and the factors associated with their thyroid function status and replacement adherence.Data collected using questionnaire survey from targeted patients managed in a typical public primary care center in Singapore: socio-demographic characteristics, clinical parameters, laboratory investigations, mean daily L-T4-replacement doses, and replacement regimens. The thyroid status of patients was classified based on thyroid function investigations.Complete data of 229 patients were analyzed. A total of 59.8% of patients had TSH within the normal range, 27.5% and 12.7% were under and over-replaced, respectively. About 60% of Asian patients with primary hypothyroidism achieved normal TSH status requiring average of 1.1 µg of daily L-T4/kgBW (kg body weight). Subjects who were over-replaced had a higher daily L-T4 dose/kgBW when compared to the euthyroid and the under replaced groups. Those with L-T4 over-replacement were largely due to excessive dosage. Patients who were younger, from lower socioeconomic strata, and higher BMI were more likely to be over or under-replaced.Majority of Asian patients with hypothyroidism required replacement of 1.1 µg of daily L-T4/kgBW. Their thyroid status was influenced by demographic and dosing factors.

Academy of Medicine-Ministry of Health Clinical Practice Guidelines: assessment and management of infertility at primary healthcare level.

The Academy of Medicine (AMS) and Ministry of Health (MOH) have developed the clinical practice guidelines on Assessment and Management of Infertility at Primary Healthcare Level to provide doctors and patients in Singapore with evidence-based treatment for infertility. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the AMS-MOH clinical practice guidelines on Assessment and Management of Infertility at Primary Healthcare Level, for the information of SMJ readers. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website: http://www.moh.gov.sg/content/moh_web/healthprofessionalsportal/doctors/guidelines/cpg_medical/2013/cpgmed_infertility.html. The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.

Sensitivity of A1C to diagnose diabetes is decreased in high-risk older Southeast Asians.

OBJECTIVE: To determine the effect of ageing on the performance of glycosylated haemoglobin A1C (A1C) for the diagnosis of diabetes mellitus (DM) in Southeast Asians. METHODS: A1C was measured in 511 subjects (mean age of 52.4 years; range 14-93) undergoing the 75-g oral glucose tolerance test (OGTT). Using receiver operating curve (ROC) analysis, the performance of A1C for the diagnosis of diabetes (using different standard criteria) was compared between 4 groups: <45 (n=156), 45-54 (n=132), 55-64 (n=122), ≥65 years (n=101). RESULTS: Subjects aged ≥65 years had the highest false-negative rates with fasting plasma glucose (60.8%) and A1C (35.1%), the smallest area under ROC curve (0.723, 95% CI 0.627-0.820), the lowest sensitivity (58.7%, 95% CI 50.4-65.7) and specificity (71.1%, 95% CI 57.3-82.6) of A1C 6.5%, compared to the younger age groups. CONCLUSION: OGTT is preferable for diagnosis of DM in older Southeast Asian adults.

HbA1c may not be a sensitive determinant of diabetic status in the elderly.

OBJECTIVE: American Diabetes Association (ADA) has recently recommended the use of glycated haemoglobin (HbA1c) to diagnose diabetes mellitus. We aim to determine if indeed this recommendation applies to the population in Singapore and whether it varies with age. METHOD: This is a cross sectional study of 90 patients without previous history of diabetes who underwent screening and had both oral glucose tolerance test (OGTT) and HbA1c done at the same time. These patients were stratified into 4 age groups. RESULT: We found that HbA1c of 6.2% is the best cut-off to diagnose diabetes using ROC curve analysis. At the specified HbA1c, the area under ROC curve (AUROC) reduces as age group increases suggesting that sensitivity and specificity of HbA1c as diagnostic marker reduces as age increases. CONCLUSION: HbA1c has a low sensitivity to diagnose diabetes in older Asian subjects and caution is required when using HbA1c in isolation. This raises the possibility that a different cut-off value for different age groups may be more appropriate.

The mean and the biological variation of insulin resistance does not differ between polycystic ovary syndrome and type 2 diabetes.

BACKGROUND: There is an assumption that the mean and biological variation of insulin resistance (IR) is less in polycystic ovary syndrome (PCOS), and intuitively higher in type 2 diabetes (T2DM). To test this hypothesis we compared the mean and biological variation in IR in PCOS to that of T2DM and to age- and weight-matched controls. METHODS: Twelve PCOS, 11 matched healthy women; 12 postmenopausal diet-controlled T2DM and 11 matched healthy postmenopausal women were recruited. Blood samples were collected at 4-d intervals on 10 consecutive occasions. The biological variability of IR was derived on duplicate samples. RESULTS: Mean and biological variability of HOMA-IR for PCOS did not differ from T2DM. Both measures were higher than the matched controls. There was no difference in insulin or IR measures between the body mass index matched pre- and postmenopausal women. Percentage beta cell function were 208.8%, 62.3%, 106.5% and 111.9%, respectively, in PCOS, postmenopausal women with T2DM, healthy premenopausal and healthy postmenopausal women. CONCLUSIONS: The progression from PCOS to the development of T2DM is unlikely to be due to a further increase in IR (or variability), but rather the progressive failure of pancreatic beta cells with a decrease in insulin production. The clinical trial registration number for this study is ISRCTN65353256.

Metformin maintains the weight loss and metabolic benefits following rimonabant treatment in obese women with polycystic ovary syndrome (PCOS).

OBJECTIVE: Rimonabant has been shown to reduce weight, free androgen index (FAI) and insulin resistance in obese patients with polycystic ovary syndrome (PCOS) compared to metformin. Studies have shown that significant weight regain occurs following the cessation of rimonabant therapy. This study was undertaken to determine if subsequent metformin treatment after rimonabant would maintain the improvement in weight, insulin resistance and hyperandrogenaemia in PCOS. DESIGN: An extension study for 3 months with the addition of metformin to the randomised open labelled parallel study of metformin and rimonabant in 20 patients with PCOS with a body mass index >or= 30 kg/m(2). Patients who were on 3 months of rimonabant were changed over to metformin for 3 months, whereas those on 3 months of metformin were continued on metformin for another 3 months. MEASUREMENTS: The primary end-point was a change in weight; secondary end-points were a change in FAI and insulin resistance. RESULTS: The mean weight loss of 6.2 kg associated with 3 months of rimonabant treatment was maintained by 3 months of metformin treatment (mean change +0.2 kg, P = 0.96). Therefore, the percentage reduction in weight remained significantly higher in the rimonabant/metformin group compared to metformin only subjects at 6 months compared to baseline (-6.0 +/- 0.1%vs. -2.8 +/- 0.1%, P = 0.04). The percentage change in testosterone and FAI from baseline to 6 months was also greater in the rimonabant/metformin group. [Testosterone (-45.0 +/- 5.0%vs. -16 +/- 2.0%, P = 0.02); FAI (-53.0 +/- 5.0%vs. -17.0 +/- 12.2%, P = 0.02)]. HOMA-IR continued to fall significantly in the rimonabant/metformin group between 0, 3 and 6 months (4.4 +/- 0.5 vs. 3.4 +/- 0.4 vs. 2.7 +/- 0.3, respectively, P < 0.01) but not at all in the metformin only group (3.4 +/- 0.7 vs. 3.4 +/- 0.8 vs. 3.7 +/- 0.8, respectively, P = 0.80). Total cholesterol and LDL reduced significantly in both groups, but improvements in triglycerides and HDL were limited to the rimonabant/metformin group. CONCLUSIONS: In these obese patients with PCOS, metformin maintained the weight loss and enhanced the metabolic and biochemical parameters achieved by treatment with rimonabant, compared to 6 months of metformin treatment alone.

A comparison between rimonabant and metformin in reducing biochemical hyperandrogenaemia and insulin resistance in patients with polycystic ovary syndrome (PCOS): a randomized open-label parallel study.

CONTEXT: Weight loss and metformin therapy are reported to be beneficial in improving the biochemical hyperandrogenaemia and insulin resistance of polycystic ovary syndrome (PCOS). Rimonabant has been found to reduce weight and improve the metabolic profile in patients with obesity, type 2 diabetes and metabolic syndrome. OBJECTIVE: To compare the effects of insulin sensitization with metformin to weight reduction by rimonabant on biochemical hyperandrogenaemia and insulin resistance in patients with PCOS. DESIGN: A randomized, open-label parallel study. SETTING: Endocrinology outpatient clinic in a referral centre. SUBJECTS: Twenty patients with PCOS and biochemical hyperandrogenaemia with a body mass index (BMI) >or= 30 kg/m(2) were recruited. INTERVENTION: Patients were randomized to 1.5 g daily of metformin or 20 mg daily of rimonabant. MAIN OUTCOME MEASURES: The primary end-point of the study was a change in total testosterone. RESULTS: After 12 weeks of rimonabant there was a significant reduction (mean +/- SEM) in weight (104.6 +/- 4.6 vs. 98.4 +/- 4.7 kg, P < 0.01), waist circumference (116.0 +/- 3.3 vs. 109.2 +/- 3.7 cm, P < 0.01), hip circumference (128.5 +/- 4.0 vs. 124.1 +/- 4.2 cm, P < 0.03), waist-hip ratio (0.90 +/- 0.02 vs. 0.88 +/- 0.01, P < 0.01) free androgen index (FAI) (26.6 +/- 6.1 vs. 16.6 +/- 4.1, P < 0.01), testosterone [4.6 +/- 0.4 vs. 3.1 +/- 0.3 nmol/l (132.7 +/- 11.5 vs. 89.4 +/- 8.65 ng/dl), P < 0.01] and insulin resistance as measured by the homeostasis model assessment (HOMA) method (4.4 +/- 0.5 vs. 3.4 +/- 0.4, P = 0.05). There was no change in any of these parameters in the metformin-treated group. CONCLUSION: This study suggests that the weight loss through rimonabant therapy may be of use in patients with PCOS and appears superior to insulin sensitization by metformin in reducing the FAI and insulin resistance in obese PCOS patients treated over a 12-week period.

Cardiometabolic aspects of polycystic ovarian syndrome.

It is estimated that 60%-7% of women of reproductive age have polycystic ovarian syndrome (PCOS). Women with this condition exhibit an adverse cardiovascular risk profile, characteristic of the cardiometabolic syndrome and given the high prevalence of PCOS in the female population, this condition may contribute towards the acceleration of cardiovascular disease among young women. This article summarizes the recent development and findings in the cardiometabolic abnormalities in patients with PCOS. Patients with PCOS have the clinical features of oligomenorrhoea, hirsutism and infertility; however, they also exhibit hyperinsulinemia, obesity, hypertension, dyslipidemia, and an increased pro-thrombotic state. They have an increased risk of type 2 diabetes and impaired glucose tolerance, and sleep apnea is also found more commonly in this population. However, despite the presence of cardiovascular risk factors and increased surrogate markers of cardiovascular disease it is unclear if they have accelerated atherosclerosis. End point studies are currently lacking and the available evidence are conflicting. Adipose tissue has emerged as an important endocrine organ over the last decade and gained recognition in having an important role in the cardiometabolic syndrome. Adiponectin that is secreted exclusively by adipocytes has recently been recognized as an important marker of cardiometabolic syndrome, obesity, type 2 diabetes, and coronary artery disease. Other adipocytokines like leptin and resistin have also recently been recognized. This article will address the current evidence for the adverse cardiovascular risk in PCOS and the other factors that may be implicated. Finally the therapeutic options for treatment will be discussed.

The LH/FSH ratio has little use in diagnosing polycystic ovarian syndrome.

BACKGROUND: The luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio is often requested to help diagnose polycystic ovarian syndrome (PCOS) despite a recent consensus recommending against its use. This study aimed to compare the variability of the LH/FSH ratio in PCOS with that of normal menstruating women over a full cycle in order to establish the diagnostic utility, or otherwise, of the test. METHODS: Twelve women with PCOS and 11 matched controls had blood collected at four-day intervals on 10 consecutive occasions over a complete menstrual cycle. RESULTS: The median LH/FSH ratio for individual subjects did not differ significantly between the PCOS and the non-affected group (1.6 versus 1.2, P = 0.14). Only 7.6% of samples from PCOS patients had an LH/FSH ratio above three, compared with 15.6% of samples from normal subjects. CONCLUSION: This study confirms that measurement of the LH/FSH ratio is of limited use in the diagnosis of PCOS.