Medical Treatment with Somatostatin Analogues in Acromegaly: Position Statement

The Korean Endocrine Society (KES) published clinical practice guidelines for the treatment of acromegaly in 2011. Since then, the number of acromegaly cases, publications on studies addressing medical treatment of acromegaly, and demands for improvements in insurance coverage have been dramatically increasing. In 2017, the KES Committee of Health Insurance decided to publish a position statement regarding the use of somatostatin analogues in acromegaly. Accordingly, consensus opinions for the position statement were collected after intensive review of the relevant literature and discussions among experts affiliated with the KES, and the Korean Neuroendocrine Study Group. This position statement includes the characteristics, indications, dose, interval (including extended dose interval in case of lanreotide autogel), switching and preoperative use of somatostatin analogues in medical treatment of acromegaly. The recommended approach is based on the expert opinions in case of insufficient clinical evidence, and where discrepancies among the expert opinions were found, the experts voted to determine the recommended approach.

Medical Treatment with Somatostatin Analogues in Acromegaly: Position Statement / 대한내과학회지

Acromegaly is a chronic disorder caused by excessive growth hormone (GH) secretion. In most cases, the excess GH originates from GH-producing pituitary adenomas. Surgery is the preferred first-line treatment for patients with acromegaly, but medical management is considered when the disease persists after surgery or in cases where patients refuse surgery or are poor candidates for surgery. Somatostatin analogues are commonly used to treat acromegaly. The Korean Endocrine Society and the Korean Neuroendocrine Study Group have developed a position statement for the use of somatostatin analogues in the medical treatment of acromegaly. This position statement is based on evidence from the current literature and expert opinions. In the case of discrepancies among expert opinions, the experts voted to determine the recommended approach.

Medical Treatment with Somatostatin Analogues in Acromegaly: Position Statement / 대한내과학회지

Acromegaly is a chronic disorder caused by excessive growth hormone (GH) secretion. In most cases, the excess GH originates from GH-producing pituitary adenomas. Surgery is the preferred first-line treatment for patients with acromegaly, but medical management is considered when the disease persists after surgery or in cases where patients refuse surgery or are poor candidates for surgery. Somatostatin analogues are commonly used to treat acromegaly. The Korean Endocrine Society and the Korean Neuroendocrine Study Group have developed a position statement for the use of somatostatin analogues in the medical treatment of acromegaly. This position statement is based on evidence from the current literature and expert opinions. In the case of discrepancies among expert opinions, the experts voted to determine the recommended approach.

Gestational Diabetes Mellitus, Fetal Growth and Vitamin D

Vitamin D is an important secosteroid hormone in skeletal and non-skeletal systems. Vitamin D has relevance to muscle and immune function, hypertension, diabetes mellitus, cancer, and pregnancy because vitamin D receptors (VDR) are present in many non-skeletal tissues. Vitamin D acts on target tissues via the binding of its active form to VDR. As vitamin D affects not only bone metabolism but also glucose metabolism, vitamin D deficiency may affect the development of gestational diabetes mellitus and fetal growth. Although vitamin D deficiency is prevalent during pregnancy, there are conflicting reports on the effect of vitamin D deficiency on pregnancy complications, such as fetal growth restriction and gestational diabetes. This article reviews published papers on the effects of vitamin D on gestational diabetes and fetal growth.

The Efficacy of Bisphosphonates for Prevention of Osteoporotic Fracture: An Update Meta-analysis

BACKGROUND: The efficacy of bisphosphonates for osteoporotic fracture has been consistently reported in recent randomized controlled trials (RCTs) enrolling hundreds of patients. The objective of this study was to update knowledge on the efficacy of available bisphosphonates in the prevention of vertebral and non-vertebral fractures. METHODS: An approach “using systematic reviews” on PubMed and Cochrane Library was taken. Twenty-four RCTs investigating the effects of bisphosphonates for the prevention of osteoporotic fracture were included in final analysis. A pairwise meta-analysis was conducted with a random effects model. Subgroup analysis was performed according to the type of bisphosphonate. RESULTS: The use of bisphosphonate decrease the risk of overall osteoporotic fracture (odds ratio [OR] 0.62; P<0.001), vertebral fracture (OR 0.55; P<0.001) and non-vertebral fracture (OR 0.73; P<0.001). Subgroup analysis indicated that zoledronic acid showed the lowest risk reduction (OR 0.61; P<0.001) for overall osteoporotic fractures but no significance was observed for etidronate (OR 0.34; P=0.127). CONCLUSIONS: This update meta-analysis re-confirmed that bisphosphonate use can effectively reduce the risk of osteoporotic fracture. However, there is a lack of evidence regarding etidronate for the prevention of osteoporotic fracture.

Characteristics of Patients Diagnosed with Osteoporosis in South Korea: Results from the National Claim Registry

BACKGROUND: Although osteoporosis is increasing medical issue in the elderly population, attempts to analyze the characteristics of patients diagnosed with osteoporosis are rare in South Korea. We investigated the characteristics of patients diagnosed with osteoporosis using Korea's National Health Insurance claims data, which includes almost Korean population. METHODS: We evaluated the patients who were diagnosed and treated with osteoporosis in medical institute in South Korea, using the national database by the Health Insurance Review & Assessment Service (HIRA). We evaluated the characteristic of patients and state of medical service utilization in 2010. RESULTS: The number of patients who were diagnosed with osteoporosis were 1,733,685, and almost of them (91.1%) were females. Fourteen point three percent of the patients had experienced osteoporosis-related fracture. The most commonly used type of institute and department was hospital and orthopedic surgery. CONCLUSIONS: Considering increasing age population, basic information including characteristic of patients and current state of medical service utilization could be useful to perform appropriate management and treatment for osteoporosis patients in South Korea, using the National Health Insurance claims data.

Maternal Thyroid Function during the First Trimester of Pregnancy in Korean Women

BACKGROUND AND OBJECTIVES: Thyroid dysfunction during pregnancy can result in many complications for both mother and infant. Due to the physiologic changes in thyroid stimulating hormone (TSH) level during early pregnancy, it is recommend to use trimester-specific reference ranges for every population. We obtained the reference range of TSH during the first trimester in Korean women according to gestational week. MATERIALS AND METHODS: The study population consisted of pregnant women who had undergone a TSH screening during the first trimester of pregnancy (n=8365) and nonpregnant women (n=1835). RESULTS: Median concentration of serum TSH decreased significantly from the 5th to 8th week of gestation (median TSH concentration: 2.00 mIU/L for 5 weeks; 1.70 mIU/L for 6 weeks; 1.40 mIU/L for 7 weeks; 1.05 mIU/L for 8 weeks). However, there was no significant difference in median concentration of serum TSH from the 8th to 12th weeks of gestation. Using the fixed cut-off value of TSH >3.66 mIU/L, the diagnosis rate of subclinical hypothyroidism was 15.0% for 5 weeks, 10.0% for 6 weeks, 5.9% for 7 weeks, and 3.6% for 8-12 weeks. CONCLUSION: When interpreting the TSH test for pregnancy (maternal thyroid function), we should consider that the TSH level decreases significantly during the early first trimester.

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.

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 or =5 years started DH in 2006. Lumbar (L1-4), left femoral neck, total BMD, serum parameter (beta-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/cm2, P=0.115, respectively). Serum CTx and total alkaline phosphatase were increased significantly (0.205+/-0.120-->0.791+/-0.44 ng/mL, P60.42+/-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.

A Case of Hypothyroidism in Remission during Pregnancy

Hypothyroidism should be treated in pregnancy, because it has been associated with an increased risk of adverse pregnancy complications, as well as detrimental effects upon fetal neurocognitive development. The goal of L-thyroxine (LT4) treatment is to normalize maternal serum TSH values within the trimester-specific pregnancy reference range. 50% to 85% of hypothyroid women being treated with exogenous LT4 need to increase the dose during pregnancy. In this study, we report a case of a 29-year-old woman with hypothyroidism who had been in remission and discontinued LT4 treatment during her pregnancy. Three months after delivery she had a relapse of hypothyroidism and was retreated with LT4. Many factors can influence the gestational requirement for LT4, therefore maternal serum TSH should be monitored and the LT4 dose should be adjusted in pregnant patients with treated hypothyroidism.

Incidence and Mortality Following Hip Fracture in Korea

The authors evaluated the incidence of hip fracture and subsequent mortality in Korea using nationwide data obtained from the Health Insurance Review and Assessment Service. This study was performed on patient population, aged 50-yr or older who underwent surgical procedures because of hip fracture (ICD10; S720, S721). All patients were followed using patient identification code to identify deaths. Crude hip fracture rates increased from 191.9/100,000 in 2005 to 207.0/100,000 in 2008 in women and from 94.8/100,000 in 2005 to 97.8/100,000 in 2008, in men respectively. Crude mortality within 12 months after hip fracture showed a similar trend (18.8% in 2005 and 17.8% in 2007). The mean of standardized mortality ratio of hip fracture was 6.1 at 3 months, 3.5 at 1 yr, and 2.3 at 2 yr post-fracture. The increasing incidence and the high mortality after hip fracture are likely to become serious public health problems and a public health program should begin to prevent hip fractures in Korea.

Medical Service Utilization with Osteoporosis

BACKGROUND: Although osteoporosis is increasing in the elderly population, attempts to analyze the patterns of medical service utilization for osteoporosis are currently not sufficient. The medical services and treatment patterns were investigated using Korea's National Health Insurance claims data, which includes all of the Korean population. METHODS: Through the patient identification algorithm developed by using the administrative claims data in 2007, the adult patients (between 50-100 years) with osteoporosis were identified. The age and gender of the patients who used medical service for osteoporosis were described, in relation with six dichotomous variables. The medical service use patterns such as the type of medical institution and conducting bone mineral density measurement were investigated. RESULTS: The number of patients who used medical service were 1,230,580 (females 89.9%). Sixty one point six percent of the patients were prescribed osteoporosis medicine (indicated for osteoporosis only), and 12.9% of the patients had experienced osteoporotic fracture. The primary medical institutions for treatment were clinics (54.3%), while hospitals were mainly used among the patients with a history of fracture and disease or drug use that may induce secondary osteoporosis. The number of visited medical institutions was 6.4 (as an outpatient) and 0.2 (as admissions) during 6 months. The proportion of patients who conducted bone mineral density measurements within one year before and after the diagnosis of osteoporosis was 66.7% and DXA was the most frequently used densitometry (46.3%). The average number of days for the prescriptions for osteoporosis medicine was 70 days. CONCLUSION: In order to prevent further osteoporotic fractures, appropriate management and treatment should be implemented for osteoporosis patients. To do this, we need to understand the current state of medical service utilization and the treatment of osteoporosis using the National Health Insurance claims data.

Identification and Validation of Osteoporotic Hip Fracture Using the National Health Insurance Database

PURPOSE: The aim of this study was to develop and validate identification criteria for the cases of osteoporotic hip fracture using the National Health Insurance Database, and we calculated the incidence rate of osteoporotic hip fracture in the Korean population using these criteria. MATERIALS AND METHODS: The criteria to identify osteoporotic hip fracture using a diagnosis code, a procedure code, the type and number of medical service usages and the patients' ages were developed via discussions among experts. These criteria were validated by using a hip fracture cohort in which all the genuine osteoporotic hip fracture patients in the Jeju area were identified by reviewing the registered medical records and radiographs. By applying the identification criteria to the National Health Insurance Database that was accumulated until June 2009, we calculated the incidence rate of osteoporotic hip fracture in patients between 50 and 100 years of age in 2008. RESULTS: The identification criteria had a sensitivity of 93.1% and a positive predictive value of 77.4%. A total of 20,432 osteoporotic hip fracture cases were identified in 2008, and the incidence rate was 15.7 cases per 10,000 persons. The osteoporotic hip fracture incidence rate for females was 20.7 (per 10,000persons), and this was 2.1 times higher than that for the males (9.8case per 10,000persons), and the rates were increased with age. CONCLUSION: The incidence of osteoporotic hip fracture that occurred on a nationwide scale can be more precisely estimated by using the National Health Insurance Database with its comprehensive information on the overall details of treatment as well as the diagnosis codes, and so the incidence of osteoporotic hip fracture can be reliably calculated for each year. The results from this research could be used as evidence in a hip fracture management plan for establishing Korean Health policy.

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.

Gestational diabetes insipidus in the third trimester of pregnancy / 대한내과학회지

Gestational diabetes insipidus, which occurs rarely during late pregnancy, may injure the mother and fetus neurologically. It takes place in about 4 of every 100,000 pregnancies. Increased placental-derived vasopressinase in late pregnancy markedly degrades vasopressin. The decreased vasopressin activity causes hypotonic polyuria, polydipsia, and dehydration. We report a woman with gestational diabetes insipidus who had no abnormal laboratory tests before developing symptoms. The diabetes insipidus was controlled well by administering nasal desmopressin (1.desamino.8.D.arginine vasopressin, DDAVP) followed by resolution of the signs and symptoms after delivery. Although gestational diabetes insipidus is rare, a prompt diagnosis and appropriate treatment to reduce the risks of maternal and fetal injury are important.

Mutation Screening of HNF-1alpha Gene in Korean Women with Gestational Diabetes Mellitus / 당뇨병

BACKGROUNDS: Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or first detection during pregnancy and mostly caused by insulin resistance and beta-cell dysfunction like type 2 diabetes. However, autoimmune or monogenic diabetes can contribute to GDM. Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes characterized by an early age of onset and an autosomal dominant pattern of inheritance. Most MODY cases are attributable to mutations in HNF-1alpha gene, also known as MODY3. We investigated whether mutations in HNF-1alpha gene are present in Korean women with GDM. METHODS: A total of 96 Korean women with GDM who have a family history of DM were screened for mutations in the HNF-1alpha gene. We evaluated the clinical characteristics of GDM women with HNF-1alpha gene mutations. RESULTS: Five of 96 patients (5.2%) were found to have a mutation in HNF-1alpha gene. Four of those (-23C > G, 833G > A (Arg278Gln), 923C > T, IVS5 + 106A > G) were novel and one (-124G > C) in promoter region was reported in previous study. The mean age of GDM women with mutations of HNF-1alpha gene was 34 years. Four women with MODY3 gene mutations required insulin therapy during pregnancy. GDM women with MODY3 gene mutations appeared to be decreased insulin secretion (HOMA-%B) than those without mutations. CONCLUSIONS: We have found the existence of MODY3 as well as novel HNF-1alpha gene mutations in Korean women with GDM.

The Effects of C161-->T Polymorphisms in Exon 6 of Peroxisome Proliferator-Activated Receptor- Gene on Bone Mineral Metabolism and Serum Osteoprotegerin Levels in Healthy Korean Middle-aged Men / 대한내분비학회지

BACKGROUND: The peroxisome proliferator-activated receptor (PPAR) is a member of the nuclear receptor family known to be involved in adipocyte differentiation. Recent studies have revealed the inhibitory role of PPAR in osteoblastogenesis, which suggests its possibility as a candidate gene for osteoporosis. The frequency of C161-->T substitution in exon 6 of PPAR was observed in Korean men and the association of different genotypes with bone turnover markers, bone mineral density (BMD) and serum osteoprotegerin (OPG), which play inhibitory roles in osteoclastogenesis, examined. METHODS: In 72 healthy Korean men (mean age 54.5 6.4 yrs; range 42~69 yrs), anthropometric measurements, and lumbar spine and femoral neck BMD, and bone turnover markers, such as alkaline phosphatase (ALP), serum calcium, phosphorus, osteocalcin and cross-linked C-telopeptides of type I collagen (ICTP) measurements were performed. The levels of serum testosterone, estradiol and insulin-like growth factor (IGF-I), and those of serum OPG levels, were measured with a sandwich enzyme-linked immunosorbent assay (ELISA) method. The DNAs were extracted from the samples, and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the sequencing of the products were performed to confirm the substitution. RESULTS: The allele frequencies were 0.799 and 0.201 for the C and T allele, respectively, which were in Hardy-Weinberg equilibrium (p=0.80). Subjects with the CT genotype were older and those with the T allele showed higher blood pressure levels and lower body mass indices (p0.05). The levels of serum testosterone, estradiol, IGF-I and OPG were not different among the different genotype groups (p>0.05). The lumbar, femoral neck BMD (g/cm2) and T scores were significantly lower in subjects with T alleles, and those with CT genotypes showed the lowest BMD values (pT substitution in exon 6 of the PPAR gene in Korean men were similar to those observed in other races, and those with the T alleles showed significantly lower BMD values. These data imply the PPAR gene might be a candidate gene for the pathogenesis of osteoporosis