SE：Symposium-Endocrine (1-8

SE1-1 NEW DEVELOPMENTS IN REPRODUCTION AND GENETICS

MING CHEN, MD, PHD

Departments of Research, Genomic Medicine, and Ob/Gyn, Changhua Christian Hospital, Taiwan

In the past decade, the clinical practice as well as research in the field of reproductive genetics has evolved rapidly, from the classic cytogenetics and Sanger-sequencing based technologies that had prevailed since 1980 to recent advances; prenatal diagnostic techniques have become less invasive, and the adoption of preimplantation genetic testing (PGT) has also improved, largely due to the advances of newer instrumentation and technology such as multiplex fluorescence in situ hybridization (mFISH), digital PCR, microfluidics, chromosome microarray, next generation sequencing (NGS), and the optimization of bioinformatics. Reproductive genetics has become an important pillar in this NGS-dominant era. However, on many occasions such paradigm shifts in the practice of reproductive genetics have been pushed forward initially by the demand of patients, which is often before reliable randomized controlled trials are available. The ability to sequence the entire fetal genome noninvasively from the maternal blood in a timely, efficient, and affordable way has long been sought and is considered the “Holy Grail” of prenatal diagnosis.

Meanwhile, the attitudes of clinical practitioners are also evolving. It is now considered ethical by PGT-M (formerly known as preimplantation genetic diagnosis; “M” denotes monogenic diseases) to avoid the transmission of the monogenic inherited disorders from generation to generation; for PGT-A (formerly known as preimplantation genetic screening; “A” denotes aneuploidy) practitioners have divided opinions, wavering between full endorsement as a routine practice and total refusal. The rapid evolution of reproductive genetics also changed the practice and even training of subspecialties such as maternal fetal medicine (MFM) and in vitro fertilization (IVF) within the scope of obstetrics and gynecology. (Quoted from the Call for Papers of the Research Topic: “Emerging New Tests and Their Impact Upon the Practice of Reproductive Genetics”, published by Frontiers in Genetics, edited by Ming Chen, Kwok-Yin Leung, Antoni Borrell, Mark I Evans).

SE1-2 UPDATE ON PREMATURE OVARIAN INSUFFICIENCY

JENG-FU KUO

彰化基督教醫院內分泌新陳代謝科主治醫師

Premature ovarian insufficiency (POI), cessation of menstruation before the age of 40, is a condition of hypergonadotropic hypogonadism with early exhaustion of ovarian follicles. These patients undergo normal puberty and a variable period of cyclic menstruation followed by oligomenorrhea or amenorrhea with hot flashes and urogenital atrophy.

The cause of POI is largely unknown. POI usually manifests as an isolated autoimmune disease, but can be related to hypothyroidism, diabetes mellitus, hypoadrenalism, hypoparathyroidism, autoimmune polyendocrine syndrome, or systemic lupus erythematosus. Hypothyroidism, adrenal insufficiency and diabetes mellitus are the most common endocrine disorders associated with POI.

Two genetic syndromes associated with POI are gonadal dysgenesis with primarily mosaic X-chromosome defects and FMR1 (fragile X mental retardation 1) gene permutation. A chromosomal analysis is recommended for the POI patients younger than 30 years of age because of the increased risk of a gonadal tumor correlated with the presence of a Y chromosome. These malignant tumors originate from germ cells and include gonadoblastomas, dysgerminomas, yolk sac tumors, and choriocarcinoma.

Periodic endocrine testing for glucose intolerance, adrenal or parathyroid function, and autoimmune disease (e.g., SLE) should be considered according to clinical presentation. Treatment of POI should be targeted toward its specific cause. In most cases, a specific cause cannot be identified if karyotypic abnormalities are not present. Early menopause has been associated with increased cardiovascular mortality and stroke, bone fracture, colorectal cancer risk and lower overall quality of life. Hormone therapy, which uses combined estrogen and progestin or low-dose oral contraception, is central to managing these women.

SE1-3 THE NEW ERA IN REPRODUCTIVE MEDICINE

HUANG, SHANG-YU, M.D.

Attending Physician, Chang Gung Memorial Hospital, Linkou Branch Assistant Professor, Chang Gung University

The number of couples seeking IVF treatment has increased significantly. According to statistics from the National Health Administration in 2018, the number of IVF treatment cycles in Taiwan has reached 39,840 cycles per year, which has almost doubled compared to the 17,393 cycles in 2013. At the same time, more than one-third of the treatment cycle is for women over 40 years old. The difficulty that elderly women face in receiving IVF treatment is much higher than that of young people. With an average pregnancy rate of only 21%, how to help elderly women get pregnant smoothly through artificial reproductive technology is a topic that needs to be dealt urgently in contemporary times. In the process of IVF treatment, it is often necessary to inject a large number of gonadotropins for good ovulation stimulation. However, it can also cause medical complications such as ovarian hyperstimulation. A large number of injections will also increase the patient's physical burden. Therefore, the treatment of IVF has also tended to be customized in recent years. By predicting the patient's ovarian response, appropriate doses of injections are given to achieve the most appropriate treatment, which avoids over-stimulation and makes the overall treatment experience much friendly. In addition, we also began to explore the reasons for repeated implantation failures which including immune imbalance, endocrine system imbalance, shifting of implantation windows, and deficit in human microbiota. The advancement of germ cell freezing technology has also allowed cancer patients to preserve their fertility. The freezing technology also allows women who postpone her marriage or women with early ovarian aging tendency to preserve fertility. In this talk, we will introduce new developments and new concepts in the field of artificial reproductive medicine. We hope that more professionals in related fields can contribute their efforts in the field of artificial reproductive medicine and unlock more unknown answers.

SE2-1 CLINICAL IMPLICATION OF RADIOFREQUENCY ABLATION IN LOCALLY RECURRENT THYROID CANCER

WEI-CHE LIN, MD, PHD

Department of Radiology, Kaohsiung Chang Gung Memorial Hospital. Taiwan

PTC is the most common subtype of thyroid cancer. However, postoperative recurrence occurs in up to 20% and 59% of patients with low- and high-risk papillary thyroid cancer, respectively. Reoperation followed by radioactive iodine therapy and thyroid hormone therapy are the gold standard treatments for recurrence. However, reoperation can be difficult to perform because of distortion of the normal tissue planes and severe fibrosis caused by scar tissue formation in the surgical bed, which leads to a high risk of complications. RFA is recently reported on the possibility as nonsurgical therapeutic options for locoregional recurrent control even for tumors invading the airway in the longer-term period. In this talk, we will review the current evidence of RFA in cancer locoregional control, technique apply during the procedure and preliminary treatment result in KCGMH.

SE2-1 NOVEL TARGETED THERAPIES FOR THE TREATMENT OF ADAVNCED THYROID CANCERS

DHY SHEN, YF CHEN, Y LEE, CH KAO

Department of Nuclear Medicine & Multi-disciplinary team of thyroid cancer management, Tri-Service General Hospital, National Defense Medical Center, Taipei, R.O.C.

Advanced thyroid cancers such as radioiodine-refractory thyroid cancer (RR-DTC) and anaplastic thyroid cancer (ATC) usually lose the capacity of iodide uptake due to dysfunction of sodium iodide symporter (NIS). Genetic alterations driven mitogen-activated protein kinase (MAPK) pathway is recognized as the key event lead to oncogenesis as well as NIS dysfunction, thus leading to RAIrefractoriness of advanced thyroid cancers as well as aggressiveness of such tumors. Since a couple of years ago, two multi-tyrosine kinase inhibitors (i.e. sorafenib and lenvatinib), mainly through anti-VEGF activity, have been approved as systemic therapies of RR-DTC. Through recent studies, some more specific mutated gene-directed targeted therapies are recommended for advanced thyroid cancers. For example, inhibitors for neurotrophic receptor kinase (NTRK) fusion (e.g. larotrectinib and entrectinib) are suggested for advanced thyroid cancers harboring NTRK fusion. Similarly, RET and bRAF inhibition is suggested for advanced thyroid cancers with RET fusion-positive and mutated bRAF, respectively. For the later setting, bRAF inhibitors can be used in conjunction with MEK inhibitors in RR-DTC reverse RAI-refractoriness, i.e. serving as “re-differentiation” therapy, by which NIS function can be restored in order to render RAI treatment effective to achieve tumoricidal effects.

In very recently, the use of larotrectinib, a NTRK fusion inhibitor has also been reported to enhance RAI avidity of RR-DTC. Whether combination of these mutated gene-directed target therapies and RAI treatment can augment RAI effectiveness warrants for further clinical investigation.

SE2-3 NAVIGATION ASSISTED ENDOSCOPIC ORBITAL DECOMPRESSION FOR THYROID ORBITOPATHY

CHENG-HSIEN CHANG

Department of Ophthalmology, Kaohsiung Medical University, Kaohsiung, Taiwan

OBJECTIVE Surgical decompression of the orbit is a recognized management of thyroid orbitopathy (TO) for severe proptosis, optic neuropathy not responding to medical management, uncontrollable raised IOP, or aesthetic restoration. Endoscopic decompression of thyroid orbitopathy assisted with navigation image guide system is a relative safe when compared to traditional orbital decompression.

MATERIALS AND METHODS Patients with vision loss due to orbital compression by enlargement of extraocular muscles were initially treated with pulse therapy with methylprednisolone. Those patients who responded poorly to the medical treatment were immediately advised for orbital decompression. Our procedure is decompression of medial wall using transnasal endoscopic approach assisted with navigation system. Lamina papyracea was removed as close as possible to the orbital apex, aiming mainly on salvation of compromised optic nerve.

RESULTS Reduction of proptosis was from 2 to 3 mm. No complications were encountered in our procedures. Patients have no new onset postoperative diplopia. Stereotactic setup added less than 10min to preparation time. Patients with newly onset of visual loss had a better recovery than those with long-term visual loss. Postoperative recovery is quick and smooth with short period of admission. Patients are routinely discharged one day after the surgery.

CONCLUSIONS Navigation assisted endoscopic decompression of orbital medial orbital wall is an effective and safe procedure to save visual compromise.

SE3-1 STATISTICAL CHALLENGES OF PRECISION MEDICINE: INTEGRATIVE ANALYSIS OF LONGITUDINAL HEALTH RECORDS DATA

S-H CHANG

Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan, R.O.C.

OBJECTIVE The analysis of longitudinal cohort data is important to gain knowledge for understanding the evolution of disease and advancing the prevention and treatment of disease over time in precision medicine research. Electronic health records (EHR) data are a longitudinal collection of the digital records of patients’ health information and become a key data resource in precision medicine. Some potential statistical challenges are needed to be addressed in analysis of longitudinal data by extracting and linking EHR data with other types of data.

METHODS In precision medicine research, multiple repeated measurements and a single or multiple time-to-event outcomes are often encountered. For example, in the longitudinal studies of chronic diseases, patients are at risk for multiple events, such as recurrences and death. In EHR data, recurrent events, comorbid conditions, and biological markers are examined at intermittently clinical visits, which are dictated by physicians or patients. Therefore, visit times are likely to be related to patient’s health status. The traditional methods for analyzing a single or multiple time-to-event outcomes need to assume that the visiting process and multiple outcomes are mutually independent and the repeated measurements are missing completely at random. These assumptions for EHR data are unlikely to hold and may lead to biased inferences. The need of integrating EHR data with other types of data (for example, genomic data) is driven by precision medicine research. A variety of existing joint modelling methods have proposed to tackle these challenges and to address scientific questions.

CONCLUSIONS EHR data have become an important resource in precision medicine. Integrative analysis of longitudinal EHR and biomedical databases provides key insights into identifying dynamic risk factors and revealing new biomarkers in the long-term course of disease. Such data integration also presents a number of analytic challenges. Existing statistical methods and tools are available to analyze the need of such integrated data.

SE3-2 APPLICATION OF ANCILLARY DIAGNOSTIC TECHNIQUES IN THE DIAGNOSIS OF THYROID NODULE

陳瑜忻

國泰綜合醫院細胞學科主任暨內分泌新陳代謝科主治醫師

In general practice, ambiguous diagnostic impression would happen in routinely stained or a lesion would be identified with several diagnostic possibilities. Ancillary diagnostic techniques are utilized to confirm or support the ambiguous diagnoses or diagnostic possibilities. These tests range from simple histochemical stains to immunochemistry, electron microscopy, tissue cultures, flow cytometry, and image analysis.

Most of the thyroid lesions are relative easy to interpret. But, there are certain thyroid lesions continue to cause difficulties because the interpretation of the criteria for various lesions has turned out to be very subjective. These difficulties cause controversies in the diagnoses and patient management. The diagnostic difficulties involve not only in cytopathology but also in histopathology. In our practice, the diagnoses of thyroid lesion affect the management decisions and the extent of surgical procedures. The inability to make a precise diagnosis of a follicular lesion has led to ancillary diagnostic techniques. These new techniques would offer more information about the biologic behavior and prognosis of the disease and have change in patient management. The ancillary diagnostic techniques applicable to thyroid lesions include histochemical and immunocytohistochemical stains, flow cytometry, image analysis and more recently, molecular testing.

This is a brief description about the application of these ancillary tests in the diagnosis of thyroid disease.

SE3-3 MARKER TO PREDICT THE PROGNOSIS OF PATIENTS WITH THYROID CANCER

DH SU

Far Eastern Polyclinics

In clinical practice, the records of patients with chronic diseases is a form of the follow- data. At each patient’s visit, the physician will collect the signs or event information to understand the level of the patient's future risk of complications or death. According to the level of these risks, physicians need to take some appropriate actions to prevent or delay the occurrence of complications or death. So, how to quantify such risks is a clinically important issue.

Markers could predict the patients’ prognosis. The possible markers of thyroid carcinoma include the patients’ basic characteristics, lab data, imaging studies, events and pathological reports. The important events for patients with thyroid carcinoma are locoreginal recurrences and distant metastases. Their pathological characteristics are tumor size, surgical margin involved, lymph node metastases, extrathyroidal extension, capsular involved and so on.

To predict the prognosis of patients with thyroid carcinoma, the patients’ basic characteristics, such as age and sex, are important. In addition, lab data, imaging studies and pathological report are also important prognostic factors. During follow-up, the messages of thyroglobulin, sonographic finding, locoreginal recurrences and distant metastases are important predictor of their death.

Cox’s model is a very common regression model in the survival analysis and takes the advantage of long-term data with chronological features. Time-dependent Cox’s model was used to clearly construct the correlation between basic covariate, marker process and the termination event without the assumptions of the specific distributions of these variates.

The purpose of this lecture is to use the dynamic messages of marker and the patients’ basic characteristics to predict the patients’ survival.

SE3-4 THE UTILITY OF BIOMARKERS IN THE TREATMENT OF THYROID CANCERS

SHU-FU LIN

Division of Endocrinology and Metabolism, Department of Internal Medicine, New Taipei Municipal TuCheng Hospital (Built and Operated by Chang Gung Medical Foundation), New Taipei City 23652, Taiwan

Anaplastic thyroid cancer (ATC) is a rare disease with a dismal median survival of only 3 to 5 months using conventional treatment. Recently, the US Food and Drug Administration approved a BRAF inhibitor (dabrafenib) plus a MEK inhibitor (trametinib) for locally advanced, metastatic ATC with BRAFV600E mutation after a clinical trial showed a high response rate, durable responses and improved overall survival.

Papillary thyroid cancer (PTC) accounts for more than 85% of patients with thyroid carcinoma. Most patients with PTC survive for more than 10 years after diagnosis following standard treatment with surgery, radioactive iodine (RAI) and thyroid hormone therapy. However, a small proportion of patients who develop metastatic RAI-refractory PTC have the mean life expectancy of 3-5 years and the 10-year survival rate is only 10%. Chromosomal fusion events involving the carboxy-terminal kinase domain of NTRK and upstream amino-terminal partners have been demonstrated in various cancers and are implicated in up to 1% of all solid tumors. Larotrectinib, a potent and selective smallmolecule inhibitor of NTRK protein has demonstrated potent and durable antitumor activity in solid tumors with NTRK fusions, including PTC in a phase 1–2 trial.

Medullary thyroid cancer (MTC) originates from parafollicular C cells and accounts for 3-5% of all thyroid cancers. The clinical course of MTC can be indolent for years. However, aggressive MTC is associated with a high mortality rate. About 70% of MTC harbors mutant RET. Selpercatinib has demonstrated durable therapeutic efficacy in patients with RET-mutated MTC in a phase 1–2 trial.

In conclusion, these genetic alterations are pivotal biomarkers for thyroid cancer management.

SE4-1 UPDATE IN THE TREATMENT OF 2ND HYPERPARATHYROIDISM IN DIALYSIS PATIENTS

JIN-BOR CHEN

Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Taiwan, R.O.C.

Secondary hyperparathyroidism is a common event in chronic kidney disease(CKD) and dialysis patients. The pathogenesis is complex and consequently to deleterious outcomes in CKD population. Treatment measurements include medical option and surgical parathyroidectomy and ablation therapy. The outcomes of parathyroidectomy and ablation therapy relating to all-cause mortality and cardiovascular mortality remain to be validated by large-scale population study. Regarding medical therapy, several drug categories have been recommended by Clinical Practice Guidelines including Taiwan Guideline in 2015. These drugs include phosphate-binder, vitamin-D analogs and calcimimetics. In this presentation, the content will cover the relevant field including background of pathogenesis, clinical outcomes esp. experience in Kaohsiung Chang Gung Memorial Hospital in Taiwan, briefing clinical practice guidelines, potential monitoring biomarkers and therapeutic measures.

SE4-2 NEW TREATMENT FOR OSTEOPOROSIS IN TAIWAN

J-S H

Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taiwan, R.O.C.

Osteoporosis is a growing major public health problem in many countries, as well as in Taiwan. It’s the most common metabolic bone disorder, characterized by a decrease in bone mass and deterioration in skeletal microarchitecture, which lead to increased fragility and susceptibility to fractures, with an impact on quality and quantity of life that crosses medical, social, and economic lines.

The prevention and treatment of osteoporosis was changed significantly in recent years, osteoporosis can be stratified according to high-risk and very-high-risk features, which includes prior fractures. Stratification of the patient drives the choice of the initial agent as well as the duration of therapy. Several therapeutic options are available for the treatment or prevention of osteoporosis, and many drugs were proved to be as efficacious and safe in Asian population. These agents are alendronate, ibandronate, zoledronate, raloxifene, denosumab, and teriparatide. They increase BMD, improve bone strength, and reduce fracture risk.

Recently, the FDA approved romosozumab is a new class of osteoporosis treatment, a monoclonal antibody directed against sclerostin. Sclerostin binds with the Wnt receptor and inhibits the differentiation of precursor cells into mature bone-forming osteoblasts. Blocking sclerostin binding to osteoblasts allows osteoblast activity to increase. Bone turnover markers suggest an early anabolic effect, bone density increases are dramatic, and biopsies indicate an anabolic effect through both modeling and remodeling. In the two clinical trials, patients received either subcutaneous romosozumab 210 mg monthly or placebo for 12 months; then, received denosumab, and in the other trial, patients received monthly romosozumab or oral alendronate for 12 months; then, received alendronate. Both trials showed significant reductions in radio-graphic and clinical vertebral fractures at 12 months and 24 months.

SE4-3 LONG TERM DRUG TREATMENT FOR OSTEOPOROSIS IN TAIWAN – A PERSONAL PERSPECTIVE

K-S TSAI

Department of Internal Medicine, National Taiwan University Hospital, Taiwan, R.O.C.

There is a high prevalence rate of osteoporosis in the elderly Taiwanese. Physicians often need to see patients at around 65 year of age while they will live into their nighties. Since osteoporosis will progress with aging, we need to treat them long term. With the introduction of the anabolic drugs for osteoporosis, the patients would have more favorable effects. However, these drugs are allowed to be used for less than 2 years. Thus, anti-resorptives will be the main treatment in the 20 to 30 years of treatment periods. Embarrassingly, the 2 main side effects of long term anti-resorptive therapy, osteonecrosis of jaw bones, and atypical femoral fracture are common in Taiwan. As a results, high fracture risk patients are afraid and reluctant to use these drugs, and the physicians are having difficulties to draw a safe and effective long term treatment plan for the patients. We may wait for new drugs which do not have these problems, but globally there seems to be no new drug in the pipelines of the major pharmaceutical companies. Under the circumstances, it is reasonable to try to clarify the acceptable pathways to treat osteoporotic patient with different levels of fracture risks with the currently available drugs.

For patients with low or moderate fracture risk, raloxifene or half or one quarter dose of oral bisphosphonate may be the easy and cost benefit pathway. Patients should be followed with BMD measurement 2 to 3 years. If BMD could not hold, patients may use a larger dose of bisphosphonate or use denosumab. For patients with moderate to high fracture risks, regular dose of bisphosphonate for less than 4 to 5 years, or denosumab for up to 12 years may be used. More than 4 years of bisphosphonate use is associated with a 1% cumulated rate of osteonecrosis of jaw bones. Denosumab is the most potent antiresorptive currently. Its use are also associated with osteonecrosis of jaw bones. While effective, stopping using it without the coverage of other drugs is well known to cause a rapid rebound of bone loss and may cause multiple vertebral fractures. For patients with multiple fractures and very high fracture risks, the effects of using anabolics before long term antiresorptives are well documented. The duration of anabolic treatment may be somewhat shortened if cost is a concern, but any anabolic treatment should be followed by a certain period of antiresortive drug use, otherwise the BMD gained will be loss very fast.

Vitamin D and calcium supplement to replete the patients is mandatory, Non-drug management including fall prevention, exercise programs, and case management team are all very important. For a good compliance, discussion with the patients and family, and shared decision making are also required. These measures should be prepared for a successful, safe long term treatment program of the osteoporotic patients.

SE5-1 PRECISION THERAPY IN ACROMEGALY INDUCED BY PITUITARY ADENOMA

1N-C YEH

1Division of Endocrinology and Metabolism, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan

Acromegaly presents with a range of symptoms and comorbidities caused by chronic and progressive growth hormone and IGF-1 (insulin-like growth factor 1) elevations, such as hypersecretion, sleep apnea, diabetes mellitus or cardiovascular disease. Without complete biochemical control, there are a poorer outcome. Although pharmacological treatments got improvement compared with decades ago. A lot of patients still get stuck in unsuccessfully biochemical control. Assessment of current and novel predictors of responsiveness to distinct therapy can lead to precisely categorizing patients, allowing reduction of morbidity and mortality as¬sociated with acromegaly.

SE5-2 CONTEMPORARY SURGICAL MANAGEMENT OF ACROMEGALY

ABEL PO-HAO HUANG

National Taiwan University Hospital

Growth hormone (GH) hypersecretion from a pituitary adenoma results in acromegaly, an endocrinological disorder with multiple systemic manifestations that presents several unique challenges in terms of perioperative management and long term outcomes. Current guidelines provide stringent criteria for determining biochemical remission, necessitating an aggressive approach to management. Despite the development of several non-surgical therapies, transsphenoidal surgery, the endoscopic approach in particular, remains the primary line of treatment for rapid normalization of GH and Insulin-like growth factor with a low incidence of perioperative morbidity. Tumor size and invasiveness are important factors predicting surgical outcomes with better rates of postoperative remission seen in smaller and non-invasive tumors. Postoperative remission rates reported in literature with the 2020 consensus criteria vary from 30 to 85% probably reflecting varying prevalence rates of invasive tumors. Thus, a significant proportion of patients fail to achieve remission after surgery for whom treatment options for residual disease must be carefully considered. This review article discusses the surgical management of acromegaly and provides a summary of contemporary outcomes and current treatment controversies.

SE5-3 LOWER-DOSE GAMMA KNIFE RADIOSURGERY FOR ACROMEGALY

CHENG-CHIA LEE, MD, PHD

台北榮民總醫院神經醫學中心神經外科、國立陽明大學醫學系助理教授

Despite the extensive literature on the radiosurgical outcomes for acromegaly, conclusions drawn from analyses of these series have been limited by the heterogeneity in patient selection, radiosurgical techniques, follow-up lengths, and biochemical remission criteria. The reported biochemical remission rates vary widely, ranging from 17% to 65% at 3 to 4 years following stereotactic radiosurgery (SRS). The reported positive predictors of remission include high radiation dose, small tumor volume, and low initial serum growth hormone (GH) and insulin-like growth factor (IGF)-1 levels.

In this presentation, I will report our work in Taipei Veterans General Hospital. We have investigated the endocrine outcomes of patients with acromegaly who underwent Gamma Knife radiosurgery (GKRS). The goal of this presentation is to evaluate the efficacy and safety of GKRS and improve the co-work in treatment of acromegaly patients.

SE6-1 MANAGEMENT OF PROLACTINOMAS DURING PREGNANCY

1C-H LIN

1Division of Endocrinology and Metabolism, Department of Internal Medicine, Biomedical Park Hospital, HsinChu branch, National Taiwan University Hospital, Taiwan, R.O.C.

Hyperprolactinemia results in suppression of gonadotropin-releasing hormone (GNRH) followed by decrease of pulse amplitude and frequency of luteinizing hormone (LH). Therefore, patients with hyperprolactinemia often suffer from menstrual disorders and infertility. Prolactinomas are the most common cause of pathological hyperprolactinemia. In patients with macroprolactinoma, visual disturbance, headache and additional hypopituitarism could also be presented as a result of mass effects. The gold-standard treatment is dopamine agonist (DA), which can improve hypogonadism, infertility, hyperprolactinemia, and tumor shrinkage in most cases. However, DA exposure was reported to be associated with preterm birth and fetal malformations in the literature. In contrast, the elevated estrogen level during pregnancy stimulates lactotroph hyperplasia, increases prolactin level, and possibly causes enlargement of prolactinoma or compressive symptoms from tumor growth. The dilemma of DA use during pregnancy is sometimes troublesome for clinicians in making clinical decisions. Based on current evidence and guidelines, DA should be discontinued as soon as pregnancy is confirmed in patients with microprolactinomas and intrasellar macroprolactinomas. In invasive or extensive macroprolactinomas, maintenance of DA should be considered concerning the risks of tumor growth. Bromocriptine is the more favored DA because of its shorter half-life and larger experience of use during pregnancy as compared with cabergoline. Periodical follow-up and evaluation are mandatory to decide further strategy of management. If medical treatment fails, neurosurgery is indicated if compressive symptoms is present and tumor growth is confirmed by sellar MRI.

SE6-2 THYROID DISEASE AND IODINE INTAKE IN PREGNANCY

CHUN-JUI HUANG, MD, PHD

Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taiwan, R.O.C.

Pregnancy has a huge impact on the thyroid. Placental human chorionic gonadotropin stimulates thyroid hormone production and leads to suppressed maternal thyrotropin concentrations. The concentration of the thyroxine-binding globulin (TBG) is also increased in pregnancy causing total T4 and total T3 levels to be elevated. This makes normal thyroid function reference values different in the pregnant and non-pregnant population. Trimester specific thyroid function ranges are needed in each region and these values differ largely among ethnicities and iodine status. More iodine is lost from the urine as a result of increased glomerular filtration rate in pregnancy. The fetus is totally dependent on maternal supply of iodine during pregnancy. Therefore, the pregnant women have been considered the vulnerable groups for iodine deficiency and the world health organization (WHO) recommended that their daily iodine intake to be higher (250 μg) than the usual recommended amount (150 μg) for non-pregnant adults. Both hyper- or hypothyroidism results in unfavorable pregnancy outcome, including miscarriage, perinatal death, gestational hypertension, and low birth weight, etc. Subclinical hyperthyroidism with suppressed TSH levels is the result of physiological changes in pregnancy and is not associated with adverse pregnancy outcome On the contrary, subclinical hypothyroidism which is usually tolerable in non-pregnancy conditions has been shown to be associated with increased risk of miscarriage, pre-term labor, gestational hypertension, and low birth weight. Even thyroid peroxidase antibody positivity with or without subclinical hypothyroidism increases the risk of pregnancy complications. Correct diagnosis and prompt treatment of thyroid dysfunction in pregnancy is of crucial importance and could only be achieved using a reliable gestation specific reference standard.

SE6-3 PHEOCHROMOCYTOMA IN PREGNANCY

1YI-HSUAN LIN

Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan City, Taiwan, ROC

Pheochromocytoma in pregnancy is a rare condition. The reported incidence of 1 in every 54,000 pregnancies. It untreated, fetal and maternal mortality reaches approximately 40% to 50%. Owing to earlier recognition of the disease and the subsequent initiation of proper treatment, the overall maternal mortality associated with pheochromocytoma has progressively decreased from 48% before 1969 to 4% during the 1990s, and further drops to 2% when the diagnosis is made antepartum. However, fetal outcomes still remain poor, with a fetal mortality rate of 11% . It has been decreased from 55% in 1969 to current 7% if diagnosed antenatally.

The fetus is not exposed to maternal circulating levels of catecholamines due to the high placental expression of catechol O-methyltransferase and monoamine oxidase. The placental exposure to maternal hypertension and to high catecholamines levels, however, can cause constriction of the maternal uterine circulation, inducing uteroplacental insufficiency. Pregnant woman with pheochromocytoma sometimes can be asymptomatic. In a majority of cases, however, symptoms of pheochromocytoma in pregnant patients are similar to those detected in nonpregnant patients. Hypertension is the most common symptom, and other includes headache, palpitation, sweating, chest pain, dyspnea, vomiting, hyperglycemia, arrhythmia, Heart failure with pulmonary edema, postural hypotension, syncope, unexplained shock, intrauterine fetal death, fetal hypoxia, spontaneous abortion and fetal growth restriction.

Diagnosis usually is made in prenatal period in 73% of cases, during the second trimester in 32%, and during the third trimester in 42%. Therefore, in 27% of cases the diagnosis was missed and the tumor is diagnosed as a result of an acute complication. The clinical suspicion of PCC must be confirmed by increased catecholamines or their metabolites levels. The most sensitive test currently available is represented by plasmatic and urinary metanephrines. Catecholamine metabolism is unaltered during healthy pregnancy, and in patients with preeclampsia plasma catecholamine levels are only slightly increased.32 Possible interferences must be considered if patients are using a-methyldopa or labetalol, which can determinate false-positive results. Imaging based on ionizing radiation exposure is contraindicated in pregnancy for the possible negative effects on fetal outcome. In pregnant women, ultrasound and MRI are the imaging techniques more used to localize a tumor. Metaiodobenzylguanidine scinti scan is not considered safe for the fetus because of radioactive exposure. After diagnosis and during follow-up, genetic consultation should be considered, because diseaserelated mutations can be found in approximately 30% of cases of pheochromocytoma diagnosed during

pregnancy, an incidence similar to that detected in nonpregnant population.

Surgery represents the definitive treatment of pheochromocytoma in pregnancy. The time of surgery depends on gestational age, location of tumor, and maternal and fetal response to the medical treatment. It generally is recommended to remove the tumor in the second trimester (after the completion of the organogenesis). On the contrary, if the diagnosis is performed in the third trimester, it is recommended to plan the adrenalectomy after delivery. The adrenalectomy should be planned at least 10 days to 14 days after starting medical treatment. Preoperative medical treatment with α -adrenergic receptor blockade must be started for at least 10 days to 14 days before surgery. β -Adrenergic receptor blockers can be added to the treatment to contrast tachyarrhythmias and the possible a-adrenergic receptor blockade–associated reflex tachycardia. It’s should be Started after some days of appropriate α -adrenergic blockade. For pregnant women with pheochromocytoma in situ, there is no consensus about the preferred modality of delivery.

SE7-1 NEW PROGRESS IN THE DIAGNOSIS AND TREATMENT OF PRIMARY BILATERAL MACRONOCULAR HYPERPLASIA

1J-Y LU, 2T-S HUANG

1Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taiwan, R.O.C.; 2 Department of Internal Medicine, MacKay Memorial Hospital, Taiwan, R.O.C.

Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a rare cause of endogenous Cushing’s syndrome (CS) with diverse clinical presentations. Hypersecretion of cortisol caused by PBMAH is adrenocorticotropin (ACTH) independent; however, local secretion of ACTH in adrenal glands also affects the excessive production of cortisol through paracrine or autocrine mechanisms. The clinical presentations of PBMAH range from rare but severe overproduction of cortisol and adrenal enlargement to relatively asymptomatic or only mildly symptomatic cases, combined with less significant adrenal structural alteration. The signal transduction pathways include activation of cAMP/PKA, no matter through direct alteration of downstream signaling pathways, or the aberrant expression of G-protein-coupled receptor (GPCR), thus affecting the synthesis and secretion of cortisol and the proliferation of adrenocortical cells. The most common genetic defect is the germline mutation of Armadillo repeat containing 5 (ARMC5). The diagnosis of PBMAH includes imaging assessment, and the characteristics of hormonal secretion. Imaging assessment needs to evaluate and confirm the structure of every single adrenal lesions. Hormonal secretion should contain evaluation of primary aldosteronism, pheochromocytoma, and CS, including 1mg dexamethasone suppression of ACTH followed by morning cortisol testing, to ensure the endogenous over secretion of cortisol independent of ACTH, the midnight salivary cortisol and the 24-hour urinary free cortisol excretion. The concomitant examination of cortisol and ACTH can help confirm the hypercortisolism independent of ACTH secretion. Comparing with other forms of CS, such as adrenal adenoma or pituitary adenoma, PBMAH pertains the clinical feature of relatively inefficient steroidogenesis. The most suitable management of PBMAH remains controversial. In patients receiving bilateral adrenalectomy, life-long steroid supplement and the potential risk for adrenal crisis should be considered. Thus, bilateral adrenalectomy is only indicated in more severe form of CS. Otherwise, in selected patients, unilateral adrenalectomy is already enough to help control the clinical manifestations of PBMAH and prevent the complications related to hypercortisolism. Some patients with identifiable aberrant receptors can be treated with medications inhibiting the signal transduction of related pathways.

SE7-2 UPDATE IN ADRENAL INCIDENTALOMA – INVESTIGATION AND MANAGEMENT

T-W LEE

Division of Endocrinology and Metabolism, Wan Fang Hospital, Taipei Medical University, Taiwan, R.O.C.

An adrenal incidentaloma is a common endocrine diagnosis because of the widespread use of thoracic and abdominal imaging. A multidisciplinary approach is required to assess the hormonal status and malignant potential of an adrenal incidentaloma for effective management. The majority of adrenal incidentalomas are benign and nonfunctional. Measurement of precontrast Hounsfield units on computed tomography scan is an imaging study of choice to diagnose the etiology of an adrenal incidentaloma. All patients with adrenal incidentalomas should undergo careful evaluation to exclude cortisol and catecholamines excess. Aldosteronism should be excluded in patients with adrenal incidentaloma and concomitant hypertension or unexplained hypokalemia. Follow-up imaging studies and biological investigations are not necessary in patients who have a typical benign and hormonally inactive adrenal adenoma at initial evaluation unless new comorbidities appear. The application of novel adrenal imaging and urine steroid metabolomics will improve early detection and patient stratification in the future.

SE7-3 ADVANCES IN ADRENAL DISEASE:S STEROID PROFILING IN ADRENAL DISEASES

1MING-HSIEN WU

1Division of Endocrinology and Metabolism, Department of Internal Medicine, New Taipei Municipal TuCheng Hospital (built and operated by Chang Gung Medical Foundation), New Taipei City, Taiwan; 2Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan

OBJECTIVE Liquid chromatography–tandem mass spectrometry (LC–MS/MS) is an analytical chemistry technique used to analyze biochemical, organic, and inorganic compounds. Due to multiple hormones secretion in adrenal cortex, LC-MS can be used to reinforce the diagnosis of variable adrenocortical diseases by analyzing steroid profiling in urine or serum.

MATERIAL AND METHODS LC–MS/MS panels for the study of the adrenal secretion usually included pregnenolone, progesterone, 11-deoxycorticosterone, corticosterone, aldosterone, 18-oxocortisol, 18-hydroxycortisol, 17-hydroxyprogesterone, 21-deoxycortisol, 11-deoxycortisol, cortisol, cortisone, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androstenedione and testosterone. There existed different proportions of these hybrid steroids in adrenocortical diseases including primary aldosterone, hypercortisolism, adrenal insufficiency, adrenocortical carcinoma and disorders of sex development.

RESULTS In primary aldosterone, 18-oxocortisol was elevated in patients with aldosteroneproducing adenoma (APA) versus bilateral hyperplasia (BAH); correspondingly cortisol, corticosterone and Dehydroepiandrosterone level were lower in APA than BAH. In hypercortisolism, patients with adrenal cause had the lowest concentrations of androgens, whereas those with ectopic and pituitary cause showed the lowest concentrations of aldosterone. In adrenal insufficiency (AI), aldosterone level was significantly lower in primary PI than secondary AI.

In adrenocortical carcinoma (ACC), 11-deoxycortisol and 17-hydroxypregnenolone were confirmed invariably higher in plasma of ACC versus non-ACC patients. In disorders of sex development (DSD), different genes encoded different enzymes in adrenal steroidogenesis pathway. Thus, each mutation of these genes exited special steroid profiling.

CONCLUSIONS In the future, the measurement of a large panel of steroids by LC–MS/ MS may provide outstanding improvement in the diagnosis and subtypes discrimination of various adrenocortical diseases.

SE8-1 EVALUATION AND MANAGEMENT OF CHILDREN WITH SHORT STATURE

SHIH-YAO LIU

Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan

As the rapid improvement of worldwide economical and nutritional supply, human beings are indeed getting higher than before. On the other hand, the growth and development of each child have been more emphasized by the parents as well. A variety of height-promoting therapies are advocated in recent years; however, a number of those are not well-documented in evidence-based medicine and some children may enter certain unnecessary treatment courses before receiving appropriate evaluation.

Definitions and evaluations of short stature and growth retardation have been documented for decades. The diagnosis of growth hormone deficiency (GHD) remains a clinical one, where one synthesizes auxologic, anatomic, and laboratory data to arrive at a diagnosis. The measurement of serum insulin-like growth factor I (IGF-I) is an important component in the evaluation of a child with growth failure. With appropriate clinical settings for GH stimulation tests, the activity of GH-IGF-I axis can be assessed to confirm the diagnosis. Furthermore, the evolving understanding of growth plate physiology has led to an increasing focus on genetic testing and innovative therapies for extremely short children.

The use of recombinant human growth hormone in treating children with GHD has been proved to be a safe and effective management. Novel treatment approaches, including use of long-acting GH formulations as well as new GH secretagogues have prompted expert consideration. In this section, A brief overview of evaluation and management for short children will be addressed.

SE8-2 DIAGNOSIS AND MANAGEMENT OF PRECOCOUS PUBERTY

1,2W-H TING

1Department of Paediatric Endocrinology, MacKay Children’s Hospital, Taipei, Taiwan. 2Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.; 3MacKay Junior college of Medicine Nursing and Management, New Taipei City, Taiwan

Puberty is the transition stage between children and adult. Normal puberty onset vary greatly between individuals, and usually occur between 8-13 years in girls and 9-14 in boys. Therefore, precocious puberty is defined by the onset of secondary sexual characteristics before the age of 8 years in females and 9 years in males. Depending on the primary source of the hormonal production, precocious puberty may be classified as central (gonadotropin dependent) precocious puberty (CPP) or peripheral (gonadotropin independent) precocious puberty.

The impact of precocious puberty on children’s health include: 1. Pathological cause of precocious puberty. 2. Early and rapid progression of precocious puberty result in compromised adult height. 3. Psychological stress (including immature skills for self-management of menstruations).

Therefore, pediatricians should be familiar with the normal puberty onset mechanism, evaluation of precocious puberty, differentiation diagnosis, the possible CNS lesions in CPP patients (especially in boys), and the benefits and risk of Gonadotropin-releasing hormone analogs in treating CPP children. Besides, some normal pubertal variants, like premature thelarche, premature pubarche, and gynecomastia, are also frequent complaint in outpatient clinics, and should be differentiated from precocious puberty.

SE8-3 DELAYED PUBERTY

YI-CHING TUNG

Division of Pediatric Endocrinology, Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan, ROC

Delayed puberty is defined as the absence of breast development at 13 years in girls or lack of testicular development above 3mL at 14 years in boys. The commonest cause is constitutional delay of growth and puberty (CDGP), which is considered as benign variant and these patients usually have strong family history of delayed puberty. This represents the normal spectrum of late pubertal timing. Pubertal timing is determined by complex interactions between genetic and epigenetic factors. The environmental factors, such as nutrition and endocrine disrupting chemicals, may mediate the activation of hypothalamic-pituitary-gonadal (HPG) axis via epigenetic mechanism.

Permanent hypogonadism includes hypogonadotropic hypogonadism (HH) and hypergonadotropic hypogonadism, both can be congenital or acquired. Congenital HH, or isolated HH (IHH), is rare and caused by the failure of GnRH neuron migration or deficiency in the production, secretion and action of GnRH. Congenital HH is classified as Kallmann syndrome (KS) with anosmia or normosmic IHH (nIHH). Sixty of IHH patients could find the genetic etiology by whole exome sequencing (WES). CHD7, FGFR1, and ANOS1 were the common causative genes. Functional HH is usually seen in patients with chronic inflammatory disease, anorexia nervosa or in athletics with intensive training. Hypergonadotropic hypogonadism is due to primary gonadal failure, such as chromosomal abnormality or gonadal dysgenesis. Radiation or chemotherapy frequently causes acquired HH or hypergonadotropic hypogonadism, depending on the agents, dosages or site of radiation exposure.

Most children with CDCP may experience a period of retarded growth, compared with their peers. Psychological support is the choice of therapy. For those with extreme end of puberty delay and being bullied, low dose hormone induction therapy may be considered. Patients with permanent hypogonadism should start hormone replacement therapy (HRT) at appropriate time. HRT could be increased the dosage gradually to adult levels two to three years later, mimicking the normal process of puberty.