Maternal thyroid function and offspring birth anthropometrics in women with polycystic ovary syndrome

ObjectivesPolycystic ovary syndrome (PCOS) and thyroid disorders have both been linked to adverse pregnancy and neonatal outcomes. Even small variations in thyroid function within the normal range may influence fetal growth. Our aim was to investigate whether maternal thyroid function is associated with newborn anthropometrics in PCOS and explore the potential modifying effect of metformin.MethodsPost-hoc analyses of two RCTs in which pregnant women with PCOS were randomized to metformin or placebo, from first trimester to delivery. Maternal serum levels of thyroid stimulating hormone (TSH) and free thyroxine (fT4) were measured at gestational weeks (gw) 5–12, 19, 32 and 36 in 309 singleton pregnancies. The mean z-scores of birthweight, birth length, and head circumference were estimated in the offspring. Associations of maternal thyroid parameters with offspring anthropometrics and the outcomes large for gestational age (LGA) and small for gestational age (SGA) were studied using linear and logistic regression models, with adjustment for body mass index (BMI) when relevant.ResultsMaternal fT4 at baseline was negatively associated with birth length (b= -0.09, p=0.048). Furthermore, ΔfT4 during pregnancy correlated positively to z-score of both birth weight and length (b=0.10, p=0.017 and b=0.10, p=0.047 respectively), independently of treatment group. TSH at baseline and gw19 was inversely associated with LGA (OR 0.47, p=0.012 and OR 0.58, p=0.042), while ΔTSH was positively associated with LGA (OR 1.99, p=0.023). There were inverse associations between TSH at baseline and SGA (OR 0.32, p=0.005) and between ΔfT4 and SGA (OR 0.59, p=0.005) in the metformin group only. There were no associations between maternal thyroid function and head circumference of the newborns.ConclusionIn women with PCOS, a higher maternal fT4 in early pregnancy and a greater decrease in fT4 during pregnancy was associated with a lower offspring birthweight and shorter birth length. Higher TSH by mid-gestation and smaller increase in TSH during pregnancy was associated with less risk of LGA. Subclinical variations in maternal thyroid function might play a role for birth anthropometrics of PCOS offspring

Alcohol and the effect on some appetite-regulating hormones in man

Beverage containing alcohol has been used for centuries to stimulate appetite. Ingestion of a moderate amount of alcohol increase energy intake. Regulation of food intake is complex. Several factors cooperate such as neural impulses from sensory organs; sight, smell, gut distension, social setting, memory, current energy status and hormones. How alcohol affects these factors is not well understood. This research project has focused on how alcohol influences the peripheral secretion of hormones, known to convey information from the periphery to hunger-regulating centers in the brain about the prevailing caloric homeostasis. Leptin produced by adipocytes - and gut-derived peptide YY (PYY) are two such hormones which inhibit food intake, whereas ghrelin produced by cells in the upper part of the gastro intestinal tract - stimulates appetite. These hormones have central effects on hypothalamic neuropeptide Y (NPY) and on pro-opiomelanocortin (POMC) which stimulates and down-regulates hunger, respectively. Other gut hormones, having central effects as well as influence on intestinal motility, are glucagon-like peptide (GLP-1) and obestatin. Liver derived insulin-like growth factor-1 (IGF-1) and its binding protein insulin-like growth factor binding protein-1 (IGFBP-1) are also of interest in this context, as they are affected by nutritional status and could be factors which influence appetite-regulating centers directly or indirectly via peripherally produced hormones. Aim: To study the effect of alcohol on the secretion of peripheral hormones known to be involved in the regulation of food intake. Material and Methods: 51 healthy subjects (26F/25M) were included in the study. All were young, healthy, normal weight and free of medication. In five separate experiments subjects were investigated in groups of 7 12 individuals. In exp 1, 2 and 3 the effect of alcohol on various hormone levels in serum, was compared with the effect of drinking water. In exp 2 the alcohol effect on urinary excretion of catecholamines was determined with or without oral beta-receptor blockade (propranolol). In exp 5 alcohol influence on gastro-intestinal hormones was investigated with or without sucralfate gastroprotection. Results and discussion: A moderate amount of alcohol induced a significant inhibition of both diurnal and nocturnal secretion of leptin. Factors known to affect the secretion of leptin such as insulin, glucose, cortisol, testosterone, and catecholamines were not influenced by the drug. IGFBP-1 increased significantly after alcohol, contrasting IGF-1, which remained unchanged. This resulted in a low IGF-1/IGFBP-1 ratio and, as a consequence, in a decreased IGF-1 bioavailability. Alcohol had both acute and prolonged inhibitory effect on serum levels of both total and octanoylated ghrelin, but was without significant influence on serum concentrations of NPY, PYY, GLP-1 and obestatin. Gastro-protection with sucralfate did not change the alcohol-induced inhibition of leptin and ghrelin secretion. Conclusion: Acute ingestion of alcohol inhibits the secretion of leptin and ghrelin, induces a marked decline in the IGF-1/IGFBP-1 ratio, but leaves NPY, PYY, GLP-1 and obestatin unchanged. Previous studies suggest that leptin may have long-term rather than acute inhibitory effects on hunger. Therefore, the present findings do not lend strong support to the hypothesis that alcohol has acute stimulatory effect on appetite by influencing peripherally produced hormones. If alcohol has appetite-stimulating properties in humans it is more likely that this is an effect caused by direct influence on appetite-regulating neurons in the brain

Initial clinical presentation and spectrum of pheochromocytoma: a study of 94 cases from a single center

Background: With the increasing access to imaging more pheochromocytomas are diagnosed in the workup of adrenal incidentalomas. This may have changed the occurrence of the classic presentation with hypertension and the classic triad (headaches, sweating and palpitation). Methods: We reviewed 94 consecutive cases of pheochromocytomas. Two cases of ectopic ACTH-syndrome were subsequently excluded. Results: Of the 92 cases included 64% had presented as an incidentaloma, 32% as a suspected pheochromocytoma and 4% had been screened because of previously diagnosed MEN2A. Those screened were youngest while those with incidentalomas were oldest. The females were more common in the incidentaloma and the screening groups, and males in the suspected pheochromocytoma group. Measurements of noradrenaline/ normetanephrine levels were highest in the suspected pheocromocytoma group and lowest in the screening group. Hypertension was present in 63% of the incidentalomas, 79% of suspected pheochromocytomas and in none of the screening group. Paroxysmal symptoms were present in almost all with suspected pheochromocytoma while only in half of the other groups. The suspected pheocromocytoma group had most symptoms and the screening group least. The classic triad was present in 14% of the incidentalomas, in 28% of the suspected and in none of the screening group, while no symptoms at all was present in 12%, 0% and 25%, respectively. Pheochromocytoma crisis occurred in 5%. There was a positive correlation between tumor size vs hormone levels, and catecholamine levels vs blood pressure. Conclusion: Clinicians need to be aware of the modern presentation of pheochromocytomas since early identification can be life-saving

Characteristics, Treatment, Outcomes, and Survival in Neuroendocrine G1 and G2 Pancreatic Tumors : Experiences From a Single Tertiary Referral Center

Purpose Neuroendocrine tumors of the pancreas (Pan-NETs) are usually hormonally inactive with a capacity to metastasize. Since Pan-NETs are rare, more knowledge is needed. Methods We reviewed all patients' medical files with Pan-NET treated at a tertiary center (2006-2019). Grade 1 (G1) and grade 2 (G2) tumors were compared. The latter group was subdivided arbitrarily based on proliferation index into G2a (3-9.9%) and G2b (10-19.9%). Results We found 137 patients (76 females, 61 males; G1 n=66, G2 n=42), the median age at diagnosis 61 years (interquartile range (IQR) 50-71), and tumor size 2 cm (1.3-5 cm). The initial surgery was performed in 101 patients. The remaining (n=36) were followed conservatively. Metastatic disease was evident in 22 patients (16%) at diagnosis while new lesions developed in 13 out of 22 patients (59%). In patients without previous metastatic disease, progressive disease was discovered in 29% of G1 vs. 55% of G2 patients (P=0.009), 47% of G2a vs. 75% of G2b patients (NS). Survival was poorer in patients with metastasis at diagnosis vs. those with local disease (P<0.001). During follow-up of 74 months, Pan-NET related death was found in 10 patients. Survival was not different between G1 vs. G2 or G2a vs. G2b, or if tumors were functional. Size <= 2 cm was associated with a better outcome (P=0.004). During the follow-up of small tumors (<= 2 cm, n=36) two were resected. Conclusion In small non-functional Pan-NETs, active surveillance is reasonable. Progressive disease was more common in G2, but survival was similar in G1, G2 and between G2 subgroups. Survival was poorer in patients with metastasis at diagnosis

Liothyronine Use in Hypothyroidism and its Effects on Cancer and Mortality

Background: The prescription of liothyronine (LT3) to treat hypothyroidism is increasing worldwide; however, the long-term safety of LT3 use has yet to be determined. Previous studies have suggested a possible association between LT3 use and breast cancer. The aim of this study was to examine the effects of LT3 use on cancer incidence and mortality. Methods: Our sample included the full adult population of individuals living in Sweden with at least three purchases of thyroid hormone therapy between July 2005 and December 2017. Individual-level data on drug purchases were linked to registry data on cancer incidence and mortality. There were 575,461 individuals with at least three purchases, of which 11,147 had made at least three purchases of LT3, including combinations of levothyroxine (LT4) and LT3. Individuals were followed for a median follow-up time of 8.1 years. We applied Cox regression with a time-varying exposure variable, comparing LT3 users (individuals with at least three cumulative purchases of LT3) with LT4-only users (the rest). Outcomes included breast cancer incidence, any cancer incidence, all-cause mortality, any cancer mortality, and breast cancer mortality. We adjusted for age, sex, previous thyroid cancer, previous other cancer, use of antithyroid preparations, use of sex hormones, and dose in multivariate analyses. Results: Multivariate analyses produced a hazard ratio of 0.93 (95% confidence interval [0.75-1.15]) for breast cancer incidence (only females), 0.97 (0.87-1.08) for any cancer incidence, 0.69 (0.61-0.77) for all-cause mortality, 0.78 (0.62-0.98) for any cancer mortality, and 0.91 (0.50-1.66) for breast cancer mortality (only females). Conclusions: In this large, Swedish, long-term registry-based study, the use of LT3 did not lead to increased breast cancer incidence, any cancer incidence, all-cause mortality, any cancer mortality, or breast cancer mortality compared with LT4 use. Somewhat surprisingly, there was evidence of lower mortality in LT3 users in models adjusting for dose, potentially an artifact of underlying associations between dose and health status/diagnosis

Assessing the impact of short-term Lugol’s solution on toxic nodular thyroid disease: a pre-post-intervention study

PurposePreoperative iodine therapy in toxic nodular goiter (TNG) is discouraged as iodine may cause aggravation of hyperthyroidism. We aimed to examine if a short course of iodine treatment is safe to administer in TNG.MethodsPatients with TNG (n=20) and subclinical to mild hyperthyroidism (free (f)T4 <30 pmol/L) without complicating illnesses were included in this pre-post-intervention study at Karolinska University Hospital. All participants received Lugol’s solution 5%, three oral drops thrice daily for 10 days. Heart rate, TSH, fT4, fT3 concentrations were collected before (day 0) and after treatment (day 10). Thyroid hormone concentrations were also measured at two time points during treatment to discover aggravations of hyperthyroidism. ThyPRO39se, a quality-of-life questionnaire, was filled out day 0 and day 10. Differences in heart rate, thyroid hormone concentrations, and quality-of-life before and after treatment were compared. Adverse reactions were reported.ResultsThe median age was 63.5 years. Female to male ratio 19:1. FT4 and fT3 concentrations decreased (both p<0.001), and TSH concentration increased (p<0.001) after 10 days of treatment. There was no difference in heart rate. No aggravations of thyrotoxicosis were noticed in any of the participants. ThyPRO39se scores improved on three scales, including hyperthyroid symptoms, while the remaining scale scores were unchanged. Mild and transient symptoms related to or possibly related to treatment were observed in six participants.ConclusionA short course of Lugol’s solution improved thyroid hormone concentrations, reduced patient-reported hyperthyroid symptoms and was safe in TNG. Lugol’s solution might be an option for preoperative treatment in TNG.Clinical trial registrationhttps://www.clinicaltrials.gov, identifier NCT04856488

A Prospective Investigation of Graves' Disease and Selenium: Thyroid Hormones, Auto-Antibodies and Self-Rated Symptoms

BACKGROUND: In Graves' thyrotoxicosis tachycardia, weight loss and mental symptoms are common. Recovery takes time and varies between patients. Treatment with methimazole reduces thyroid hormone levels. According to previous research, this reduction has been faster if selenium (Se) is added. OBJECTIVE: The objective was to investigate whether supplementing the pharmacologic treatment with Se could change the immune mechanisms, hormone levels and/or depression and anxiety. METHODS: We prospectively investigated 38 patients with initially untreated thyrotoxicosis by measuring the thyroid-stimulating hormone (TSH), free thyroxine (FT(4)), free triiodothyronine (FT(3)), thyroid receptor antibodies and thyroid peroxidase auto-antibodies before medication and at 6, 18 and 36 weeks after commencing treatment with methimazole and levo-thyroxine, with a randomized blinded oral administration of 200 µg Se/day or placebo. The selenoprotein P concentration was determined in plasma at inclusion and after 36 weeks. The patients were also assessed with questionnaires about depression, anxiety and self-rated symptoms before medication was started and after 36 weeks. RESULTS: FT(4) decreased more in the Se group at 18 weeks (14 vs. 17 pmol/l compared to the placebo group, p = 0.01) and also at 36 weeks (15 vs. 18 pmol/l, p = 0.01). The TSH increased more in the Se group at 18 weeks (0.05 vs. 0.02 mIU/l, p = 0.04). The depression and anxiety scores were similar in both groups. In the Se group, the depression rates correlated negatively with FT(3) and positively with TSH. This was not seen in the placebo group. CONCLUSIONS: Se supplementation can enhance biochemical restoration of hyperthyroidism, but whether this could shorten clinical symptoms of thyrotoxicosis and reduce mental symptoms must be investigated further

Pheochromocytomas and Abdominal Paragangliomas: A Practical Guidance

Pheochromocytomas and abdominal paragangliomas (PPGLs) are rare tumors arising from the adrenal medulla or the sympathetic nervous system. This review presents a practical guidance for clinicians dealing with PPGLs. The incidence of PPGLs has risen. Most cases are detected via imaging and less present with symptoms of catecholamine excess. Most PPGLs secrete catecholamines, with diffuse symptoms. Diagnosis is made by imaging and tests of catecholamines. Localized disease can be cured by surgery. PPGLs are the most heritable of all human tumors, and germline variants are found in approximately 30–50% of cases. Such variants can give information regarding the risk of developing recurrence or metastases as well as the risk of developing other tumors and may identify relatives at risk for disease. All PPGLs harbor malignant potential, and current histological and immunohistochemical algorithms can aid in the identification of indolent vs. aggressive tumors. While most patients with metastatic PPGL have slowly progressive disease, a proportion of patients present with an aggressive course, highlighting the need for more effective therapies in these cases. We conclude that PPGLs are rare but increasing in incidence and management should be guided by a multidisciplinary team

Highly proliferative anal neuroendocrine carcinoma : molecular and clinical features of a rare, recurrent case in complete remission

Background Poorly differentiated anal neuroendocrine carcinomas (ANECs) are rare lesions with poor prognosis, and the molecular etiology is only partially understood. Case presentation At our institution, we have treated and followed a patient with such a rare ANEC. He had primarily surgery followed by three rounds of repeated surgery for loco-regional recurrences. He also received three different combinations of chemotherapy and external beam radiation. At last follow-up 13 years since the primary diagnosis, the patient had been in complete remission for nine years. The patient's medical files were re-examined, including laboratory, radiology and clinical examinations. Histopathology was re-assessed, and expanded immunohistochemistry was performed from tissue specimens from the four surgical procedures. In addition, the molecular genetic status was evaluated through next-generation sequencing. The initial tumor was consistent with a 59 mm small cell neuroendocrine cancer with a Ki-67 index of 80%. Regional lymph node metastases were evident, and immunohistochemistry supported a neuroendocrine origin. A PCR screening detected human papilloma virus type 45 DNA (high-risk subtype), and focused next-generation sequencing found a missense mutation in thePhosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha(PIK3CA) gene. In tissues representing subsequent recurrences, the Chromogranin A expression was lost, and the Ki-67 index increased to 90%. Conclusions For the first time, we report the detection of HPV45 in a case of ANEC. To our belief,PIK3CAmutations have also not been previously demonstrated in this tumor entity. In highly malignant ANECs, cure can in rare cases be achieved. Although speculative, expression of HPV45 and/or thePIK3CAmutation may have contributed to the favorable outcome