Update on the Management of Thyroid Disease during Pregnancy.

Thyroid dysfunction during pregnancy can result in serious complications for both the mother and infant; however, these complications can be prevented by optimal treatment of maternal overt thyroid dysfunction. Although several studies have demonstrated that maternal subclinical hypothyroidism is associated with obstetric complications and neurocognitive impairments in offspring, there is limited evidence that levothyroxine treatment can improve these complications. Therefore, most professional societies do not recommend universal screening for thyroid dysfunction during pregnancy, and instead recommend a case-finding approach in which only high-risk women are tested. However, recent studies have estimated that targeted thyroid function testing misses approximately 30% to 55% of hypothyroidism cases in pregnant women, and some associations and researchers have recommended universal screening of pregnant women to facilitate the early detection and treatment of overt hypothyroidism. This review summarizes recent data on thyroid function test changes, thyroid functional disorder management, and thyroid screening during pregnancy.

The Role of Nuclear Factor-E2-Related Factor 1 in the Oxidative Stress Response in MC3T3-E1 Osteoblastic Cells.

BACKGROUND: Reactive oxygen species (ROS) and antioxidants are associated with maintenance of cellular function and metabolism. Nuclear factor-E2-related factor 1 (NFE2L1, Nrf1) is known to regulate the expression of a number of genes involved in oxidative stress and inflammation. The purpose of this study was to examine the effects of NFE2L1 on the response to oxidative stress in osteoblastic MC3T3-E1 cells. METHODS: The murine calvaria-derived MC3T3-E1 cell line was exposed to lipopolysaccharide (LPS) for oxidative stress induction. NFE2L1 effects were evaluated using small interfering RNA (siRNA) for NFE2L1 mRNA. ROS generation and the levels of known antioxidant enzyme genes were assayed. RESULTS: NFE2L1 expression was significantly increased 2.4-fold compared to the control group at 10 µg/mL LPS in MC3T3-E1 cells (P<0.05). LPS increased formation of intracellular ROS in MC3T3-E1 cells. NFE2L1 knockdown led to an additional increase of ROS (20%) in the group transfected with NFE2L1 siRNA compared with the control group under LPS stimulation (P<0.05). RNA interference of NFE2L1 suppressed the expression of antioxidant genes including metallothionein 2, glutamatecysteine ligase catalytic subunit, and glutathione peroxidase 1 in LPS-treated MC3T3-E1 cells. CONCLUSION: Our results suggest that NFE2L1 may have a distinct role in the regulation of antioxidant enzymes under inflammation-induced oxidative stress in MC3T3-E1 osteoblastic cells.

Effects of Serum 25-hydroxy-vitamin D and Fetal Bone Growth during Pregnancy.

BACKGROUND: This study was conducted to observe the prevalence of vitamin D deficiency during pregnancy and the effects of maternal 25-hydroxy-vitamin D (25-[OH]D) levels on fetal bone growth. METHODS: Five hundred twenty-three Korean pregnant women were randomly recruited and serum 25-(OH)D level was measured. During pregnancy, fetal ultrasonography and serum 25-(OH)D measurements were carried out 3 times in 275 of 523 pregnant women. Fetal biparietal and occipitofrontal diameter, head and abdominal circumference, and femur and humerus length were measured through fetal ultrasonography. RESULTS: The prevalence of vitamin D deficiency (25-[OH]D<20 ng/mL) based on the 1st serum measurement of 25-(OH)D was 88.9%. There was no association between maternal serum 25-(OH)D level and fetal bone growth. In 275 pregnant women who completed study design, the mean value of 25-(OH)D was 12.97±5.93, 19.12±9.82, and 19.60±9.98 ng/mL at 12 to 14, 20 to 22, and 32 to 34 weeks of pregnancy, respectively and there was an association between the difference of serum 25-(OH)D level between 12 to 14 and 20 to 22 weeks and growth velocity of fetal biparietal diameter between 20 to 22 and 32 to 34 weeks of pregnancy. CONCLUSIONS: This study shows a high prevalence of vitamin D deficiency in Korean pregnant women and the change of serum 25-(OH)D levels is related with the growth of fetal biparietal diameter, however other parameters are not associated with serum 25-(OH)D levels.

Maternal vitamin D deficiency in early pregnancy is not associated with gestational diabetes mellitus development or pregnancy outcomes in Korean pregnant women in a prospective study.

The association between vitamin D deficiency in the first trimester and GDM development remains controversial in various ethnicities. We prospectively assessed whether pregnant women with vitamin D deficiency during early pregnancy had an increased likelihood of GDM development or poor fetal growth or pregnancy outcomes compared to those with sufficient vitamin D levels. Serum 25-OH-D measurements and fetal ultrasonograms were carried out at 12-14, 20-22, and 32-34 wk in 523 pregnant women. Each woman was screened for GDM at 24-28 wk. There were no differences in serum 25-OH-D levels at 12-14 wk or 22-24 wk of pregnancy between GDM and non-GDM women after adjusting for maternal age, BMI at prepregnancy, BMI at first visit, BMI at GDM screening, gestational age at sampling, previous history of GDM, vitamin D intake, and seasonal variation in sampling. The risk of GDM, insulin resistance, and impaired ß-cell function had no association with serum 25-OH-D levels in crude or adjusted logistic regression analysis. GDM was not associated with maternal serum 25-OH-D deficiency during the first trimester or fetal growth during the first and second trimesters. Pregnancy outcomes such as miscarriage, Apgar 1, Apgar 5 and birth weight were independent of maternal serum 25-OH-D levels during the first, second and third trimester of pregnancy. In conclusion, neither GDM prevalence nor fetal growth during pregnancy is associated with vitamin D deficiency at the first trimester in Korean women. Pregnancy outcomes are also independent of maternal vitamin D status.

Serum magnesium level is associated with type 2 diabetes in women with a history of gestational diabetes mellitus: the Korea National Diabetes Program study.

Gestational diabetes mellitus (GDM) is a strong predictor of postpartum prediabetes and transition to overt type 2 diabetes (T2DM). Although many reports indicate that low magnesium is correlated with deteriorated glucose tolerance, the association between postpartum serum magnesium level and the risk for T2DM in women with a history of GDM has not been evaluated. We analyzed postpartum serum magnesium levels and development of prediabetes and T2DM in women with prior GDM according to American Diabetes Association (ADA) criteria using the Korean National Diabetes Program (KNDP) GDM cohort. During a mean follow-up of 15.6 ± 2.0 months after screening, 116 women were divided into three groups according to glucose tolerance status. Ultimately, eight patients (6.9%) were diagnosed with T2DM, 59 patients (50.9%) with prediabetes, and 49 patients (42.2%) with normal glucose tolerance (NGT) after follow-up. The T2DM group had the lowest serum magnesium level (0.65 [0.63-0.68] mM/L) in the postpartum period, but there was no significant difference between the prediabetes group (0.70 [0.65-0.70] mM/L) and the NGT group (0.70 [0.65-0.70] mM/L) (P=0.073) Multiple logistic regression analysis showed that postpartum HOMA-IR was a significant predictor of both prediabetes and T2DM. Moreover, we found that postpartum serum magnesium level was also a possible predictor for T2DM development. Serum magnesium level in the postpartum period may be a possible predictor for T2DM development in women with a history of GDM.

Effects of a 'drug holiday' on bone mineral density and bone turnover marker during bisphosphonate therapy.

BACKGROUND: Recently long-term safety of bisphosphonate raises issues about the duration of therapy. We examined the effects of a drug holiday (DH) on bone mineral density (BMD) and bone turnover markers. METHODS: In Korean, 125 women of 50 years of age or older with T-score≤-3.0 of their lumbar or left femoral BMD initiated bisphosphonate from 1999 based on retrospective chart review. 125 patients who had used bisphosphonate≥5 years started DH in 2006. Lumbar (L1-4), left femoral neck, total BMD, serum parameter (ß-crossLaps [CTx], phosphorus, total calcium, total alkaline phosphatase), and urinary parameter (calcium/creatinine ratio) were measured before, the time of starting, and after DH. RESULTS: After DH, lumbar, femoral neck and total BMD did not change significantly (0.757±0.093→0.747±0.102, P=0.135, 0.567±0.079→0.560±0.082, P=0.351, 0.698±0.008→0.691±0.090 g/cm(2), P=0.115, respectively). Serum CTx and total alkaline phosphatase were increased significantly (0.205±0.120→0.791±0.44 ng/mL, P<0.001, 54.52±13.40→60.42±15.543 IU/L, P=0.001, respectively). Urinary calcium/creatinine ratio increased significantly (0.132±0.076→0.156±0.093, P=0.012). CONCLUSIONS: A DH could be cautiously considered in patients with long-term use of bisphosphonate if there is a concern about severe suppression of bone turnover with respect to long-term use because insignificant changes of BMD and significant increase of bone turnover markers are shown during the period.

Thyroid dysfunction associated with administration of the long-acting gonadotropin-releasing hormone agonist.

Gonadotropin-releasing hormone (GnRH) agonist has been used in the treatment of a wide variety of sex-hormone-related diseases, as the administration of GnRH agonist can alter the secretion of gonadotropin and sex hormones. Recently, we found that the long-acting GnRH agonist aggravated hyperthyroidism and induced painless thyroiditis. This is the first report to demonstrate the association of thyroid dysfunction with GnRH agonist injection in Korea. Here, we report three cases and emphasize the clinical importance of this aggravating factor in autoimmune thyroid disease.

Nutritional risk factors of early development of postpartum prediabetes and diabetes in women with gestational diabetes mellitus.

OBJECTIVE: Early detection of prediabetes and diabetes after delivery helps prevent and delay the development of overt type 2 diabetes in women with gestational diabetes mellitus (GDM). We sought to identify modifiable risk factors for the early development of postpartum type 2 diabetes in women with GDM that may help establish interventions for preventing or delaying the subsequent onset of type 2 diabetes. METHODS: Three hundred eighty-one women who developed GDM during pregnancy were tested for 1) antepartum anthropometric and biochemical measurements, 2) pregnancy outcome, 3) oral glucose tolerance test at 6 to 12 wk after delivery, and 4) postpartum anthropometric, biochemical, and nutritional measurements. The subjects were divided into three groups on the basis of the postpartum oral glucose tolerance test results: normal glucose tolerance group (n=193), prediabetes (n=161), and diabetes (n=27). RESULTS: The incidences of postpartum prediabetes and diabetes at 6 to 12 wk follow-up in Korean women with GDM were 44.8% and 5.2%, respectively. Antepartum modifiable risk factors for developing type 2 diabetes at early postpartum included higher body mass index, lower ß-cell function, insulin dosage during late pregnancy, and the non-modifiable risk factor of family history of diabetes (R2=0.14). Postpartum risk factors included higher body mass index, serum triacylglycerols, hemoglobin A1c, and energy intake and lower insulin secretion capacity (R2=0.43). Animal fat intake was higher in the prediabetes and diabetes groups than in the normal glucose tolerance group, whereas breast-feeding did not alter the risk for the development of postpartum diabetes. CONCLUSION: This study strongly suggests that the development of postpartum type 2 diabetes in women with GDM can be prevented and/or delayed by lifestyle and nutritional intervention during antepartum and postpartum.

Marked individual variation in isoflavone metabolism after a soy challenge can modulate the skeletal effect of isoflavones in premenopausal women.

Soy-isoflavones may act as estrogenic agonists or antagonists depending on the endogenous hormone status. These clinical effects can be exerted variably in individuals by the metabolic ability to produce a more potent metabolite than precursors. The objective of this randomized, double-blind, placebo-controlled study was to investigate the skeletal effect of isoflavones according to their metabolic variability in premenopausal women. Volunteers were randomly assigned to receive either soy-extract isoflavones (n=32) or lactose (n=21) once a day for three menstrual cycles. After intervention, the urinary excretions of isoflavones and their metabolites were significantly higher in the soy group than in the placebo group and showed a large inter-individual variation. Women in the soy group were divided into subgroups according to their ability to excrete more potent metabolites. Serum osteocalcin and urine deoxypyridinoline showed a tendency to increase after a challenge in equol high-excretors. Serum osteocalcin concentration in the genistein high-excretors increased significantly after a challenge (P=0.04) but did not increase in either the placebo or genistein low-excretors. An estrogenic antagonistic effect of isoflavones on bone turnover was observed in premenopausal women who are able to produce more potent metabolites.

The prevalence of GAD antibodies in Korean women with gestational diabetes mellitus and their clinical characteristics during and after pregnancy.

BACKGROUND: We conducted this research in order to evaluate the prevalence of glutamic acid decarboxylase antibodies (GADA) in Korean women with gestational diabetes mellitus (GDM), to identify the clinical characteristics of these women, and to gauge the prevalence of diabetes among them after childbirth. METHODS: We studied 887 Korean women with GDM who were screened for GADA, and assessed their antepartum clinical characteristics and the outcomes of their pregnancies. At 6 weeks' postpartum, 75 g oral glucose tolerance tests were performed to determine the diabetic status of GDM women with GADA. RESULTS: The prevalence of GADA in Korean women with GDM was 1.7%. Plasma glucose levels at 0- and 3-h during oral glucose tolerance tests were significantly different between GADA-positive and GADA-negative women with GDM. There were no significant differences between them in terms of age, body mass index, family history of diabetes, fasting insulin, and lipid profiles. However, GADA-positive women with GDM required insulin treatment during pregnancy more frequently than GADA-negative patients. The development of diabetes at early postpartum was significantly higher in GADA-positive women with GDM than those who were GADA negative. CONCLUSIONS: The prevalence of GADA in Korean women with GDM was low. However, GADA-positive women with GDM are more susceptible to subsequently developing type 1 diabetes, even in the early postpartum period. Long-term follow up studies and intervention to prevent type 1 diabetes among GADA-positive GDM women are needed.

Association of estrogen receptor alpha gene microsatellite polymorphism with annual changes in bone mineral density in Korean women with hormone replacement therapy.

Variation in drug response to hormone replacement therapy (HRT) may reflect genetic heterogeneity in the estrogen-related genes, possibly including estrogen receptor alpha (ERalpha) gene. However, only a few association studies of the drug response to HRT have been reported, focusing mainly on the intronic polymorphisms of the ERalpha gene. We therefore examined 284 postmenopausal women (mean age, 52.2 +/- 5.0 years) for the microsatellite thymine-adenine (TA) repeat polymorphism in the promoter of the ERalpha gene and its relationship to drug response by measuring changes in bone mineral density (BMD) after 1 year of HRT. In our study population, the most common number of TA repeats was 14, with a range of values between 11 and 27. At baseline, the number of TA repeats was neither associated with measured lumbar spine or femoral neck BMD nor with bone markers. When we categorized the subjects by the TA repeat numbers into an L group (n = 142), with a low mean number of repeats (TA < 16), and an H group (n = 142), with a high mean number of repeats (TA > or = 16), no significant genotypic differences were noted in spinal or femoral neck BMD or in bone markers. However, the drug response on lumbar spine BMD after 1 year of HRT correlated with the mean number of TA repeats (r = -0.131, P = 0.035) after adjustment for confounding factors such as body mass index and years since menopause. This correlation was also seen with the number of TA repeats on the shorter allele (r = -0.159, P = 0.012), which was defined as the allele with the lower number of TA repeats. However, this genotypic association was not found in the femoral neck BMD (r = 0.053, P = 0.396). When we defined the nonresponder group as women who had lost BMD even with HRT, 15.9% of the subjects were included, and this group was significantly younger and had higher initial BMD than the responder group. After further adjustment for age and initial BMD, the number of TA repeats on the shorter allele remained significantly associated with drug responsiveness (P = 0.005). These data indicate significant effects of the ERalpha TA repeat polymorphism on the estrogen responsiveness of lumbar spine BMD after 1 year of HRT in Korean women.

The changes in circulating osteoprotegerin after hormone therapy in postmenopausal women and their relationship with oestrogen responsiveness on bone.

OBJECTIVE: Oestrogen replacement reduces the increased rate of bone remodelling after the menopause. Osteoprotegerin (OPG) is a negative regulator of osteoclast-mediated bone resorption. In vitro studies have shown that oestrogen stimulates OPG production. However, the role of OPG in physiological bone remodelling and its regulation by oestrogen in vivo remain controversial. In this study, we analysed the association between changes in serum OPG levels and bone turnover status before and after hormone therapy (HT) in healthy postmenopausal women. PATIENTS AND MEASUREMENTS: Ninety-nine healthy postmenopausal women of Korean ethnicity, aged 42-64 years (52.3 +/- 4.9 years, mean +/- SD) were enrolled in our study. Serum OPG levels were assessed by a highly sensitive sandwich-type enzyme immunoassay. Serum concentrations of osteocalcin (OC) and carboxyterminal telopeptides (CTx) were determined by electrochemiluminescence immunoassays. Bone mineral density (BMD) at the lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry (DEXA). RESULTS: Baseline levels of OPG correlated neither a the bone formation marker, serum OC, nor with a bone resorption marker, serum CTx. No significant association of baseline OPG was found with baseline BMD measured at the lumbar spine and femoral neck. Serum OPG levels measured after 3 months and 1 year of HT decreased significantly compared to baseline (P < 0.001 in both). The changes in circulating OPG at 3 months of HT correlated with the changes in both serum OC (r = 0.226, P = 0.029) and serum CTx (r = 0.214, P = 0.038) at 3 months after HT. However, there was no significant association between the changes in circulating OPG after 3 months of HT and BMD values of the lumbar spine or femoral neck after 1 year of HT. CONCLUSIONS: Our results suggest that baseline OPG levels do not reflect bone turnover status and that serial measurements of serum OPG after HT are not a useful predictor of the long-term effects of oestrogen on bone density. The decrease in serum concentrations of OPG after HT may occur to compensate for the action of oestrogen in suppressing bone resorption.

Gestational diabetes mellitus in Korea: prevalence and prediction of glucose intolerance at early postpartum.

To determine the prevalence of glucose intolerance in Korean women with gestational diabetes mellitus (GDM) between 6 and 8 weeks postpartum and identify which antepartum variables were predictive of postpartum diabetes and impaired glucose tolerance (IGT), we prospectively performed 75 g oral glucose tolerance test (OGTT) between 6 and 8 weeks postpartum in women with GDM. WHO criteria were used for classification of glucose tolerance postpartum. Of 392 women with GDM were detected during the study period, 311 women participated in this study. Of the 311 participants, 119 (38.3%) women were found to have persistent glucose intolerance; 47 (15.1%) had diabetes and 72 (23.2%) had IGT. The prevalence of postpartum IGT and diabetes increased in parallel with the metabolic severity during pregnancy. Multiple logistic regression analysis revealed that pre-pregnancy weight, gestational age at diagnosis of GDM, 2-h glucose and 3-h insulin concentrations of diagnostic OGTT were independently associated with postpartum diabetes. Pre-pregnancy weight, 2-h glucose and 1-h insulin concentrations were independently associated with postpartum IGT. Our results support the importance of postpartum testing in Korean women with GDM, and demonstrated that impaired beta-cell function and pre-pregnancy obesity were associated with glucose intolerance at early postpartum.

A common mutation in cholesteryl ester transfer protein gene and plasma HDL cholesterol level before and after hormone replacement therapy in Korean postmenopausal women.

BACKGROUND: Plasma cholesteryl ester transfer protein (CETP) functions to transfer cholesteryl ester from HDL to triglyceride-rich lipoproteins and regulates plasma HDL cholesterol level. A common mutation, the exon 15 A to G substitution at codon 442 (D442G) results in reduced plasma CETP activity and increased plasma HDL cholesterol level. Meanwhile, hormone replacement therapy (HRT) in postmenopausal women increases plasma HDL cholesterol level. METHODS: We investigated the frequency of D442G mutation and its effect on plasma HDL cholesterol level in Korean women. We also examined if the mutation has any effect on an increase in plasma HDL cholesterol level during HRT. RESULTS: Two hundred and twenty eight women aged over 40 years were recruited in this study. Of 228 women, 22 (9.6%) were identified as having the D442G mutation; 21 heterozygotes and 1 homozygote. The subjects with the mutation had higher plasma HDL cholesterol levels than those without the mutation (61.6 +/- 17.3 vs. 55.1 +/- 14.0 mg/dL, p < 0.05). After 12 month HRT, HDL cholesterol increased by 6.4% (3.6 +/- 13.2 mg/dL, p < 0.05) and D442G mutation did not have any significant effect on the change of plasma HDL cholesterol level. CONCLUSION: D442G mutation is common in Korean postmenopausal women and it is associated with increased plasma HDL cholesterol level. HRT for postmenopausal women increased plasma HDL cholesterol level in similar amounts regardless of the presence or absence of D442G mutation.