Risks of suboptimal and excessive thyroid hormone replacement across ages.

BACKGROUND: Hypothyroidism is prevalent at all ages and represents a non-communicable disease with preventable consequences. METHOD: Narrative review. REVIEW: In children and adolescents, the most devastating consequences of undertreatment with levothyroxine (LT4) are poor growth and development. Delayed treatment in congenital hypothyroidism can lead to permanent brain damage. In young to middle-aged adults, symptoms are often overlooked, and treatment delayed by many years. The resulting consequences are also at this age group compromised brain and physical function but less severe and partly reversible with treatment. The under-treated condition often results in a higher risk of, e.g., increased cardiovascular disease burden, obesity, hypertension, poor physical capacity, and poor quality of life. Excessive replacement is at all adult age groups associated with increased risk of cardiac death, osteoporosis, loss of muscle function, psychological instability and poor quality of life. In young fertile women, the consequences of undertreatment with LT4 are subnormal fertility, recurrent pregnancy loss, compromised fetal growth, and neurocognitive development. On the other hand, excessive LT4 treatment has been related to gestational hypertension, preeclampsia and preterm birth. In the elderly, care must be given to avoid confusing a slightly high age-related serum TSH with requirement for LT4 treatment in a truly hypothyroid patient. Excessive LT4 treatment in patients of high age is associated with an increased mortality. CONCLUSION: Suboptimal and excessive LT4 replacement of the preventable non-communicable disease hypothyroidism requires more focus from the healthcare system and from the global political systems to prevent the personally devastating and socioeconomically challenging consequences.

Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.

BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With Preterm Birth: A Systematic Review and Meta-analysis.

Importance: Maternal hypothyroidism and hyperthyroidism are risk factors for preterm birth. Milder thyroid function test abnormalities and thyroid autoimmunity are more prevalent, but it remains controversial if these are associated with preterm birth. Objective: To study if maternal thyroid function test abnormalities and thyroid autoimmunity are risk factors for preterm birth. Data Sources and Study Selection: Studies were identified through a search of the Ovid MEDLINE, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar databases from inception to March 18, 2018, and by publishing open invitations in relevant journals. Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4] concentrations) or thyroid peroxidase (TPO) antibody measurements and gestational age at birth were screened for eligibility by 2 independent reviewers. Studies in which participants received treatment based on abnormal thyroid function tests were excluded. Data Extraction and Synthesis: The primary authors provided individual participant data that were analyzed using mixed-effects models. Main Outcomes and Measures: The primary outcome was preterm birth (<37 weeks' gestational age). Results: From 2526 published reports, 35 cohorts were invited to participate. After the addition of 5 unpublished data sets, a total of 19 cohorts were included. The study population included 47 045 pregnant women (mean age, 29 years; median gestational age at blood sampling, 12.9 weeks), of whom 1234 (3.1%) had subclinical hypothyroidism (increased thyrotropin concentration with normal FT4 concentration), 904 (2.2%) had isolated hypothyroxinemia (decreased FT4 concentration with normal thyrotropin concentration), and 3043 (7.5%) were TPO antibody positive; 2357 (5.0%) had a preterm birth. The risk of preterm birth was higher for women with subclinical hypothyroidism than euthyroid women (6.1% vs 5.0%, respectively; absolute risk difference, 1.4% [95% CI, 0%-3.2%]; odds ratio [OR], 1.29 [95% CI, 1.01-1.64]). Among women with isolated hypothyroxinemia, the risk of preterm birth was 7.1% vs 5.0% in euthyroid women (absolute risk difference, 2.3% [95% CI, 0.6%-4.5%]; OR, 1.46 [95% CI, 1.12-1.90]). In continuous analyses, each 1-SD higher maternal thyrotropin concentration was associated with a higher risk of preterm birth (absolute risk difference, 0.2% [95% CI, 0%-0.4%] per 1 SD; OR, 1.04 [95% CI, 1.00-1.09] per 1 SD). Thyroid peroxidase antibody-positive women had a higher risk of preterm birth vs TPO antibody-negative women (6.6% vs 4.9%, respectively; absolute risk difference, 1.6% [95% CI, 0.7%-2.8%]; OR, 1.33 [95% CI, 1.15-1.56]). Conclusions and Relevance: Among pregnant women without overt thyroid disease, subclinical hypothyroidism, isolated hypothyroxinemia, and TPO antibody positivity were significantly associated with higher risk of preterm birth. These results provide insights toward optimizing clinical decision-making strategies that should consider the potential harms and benefits of screening programs and levothyroxine treatment during pregnancy.

THE ROMANIAN VERSION OF THE THYROID-RELATED PATIENT-REPORTED OUTCOMES THYPRO AND THYPRO-39. TRANSLATION AND ASSESSMENT OF RELIABILITY AND CROSS-CULTURAL VALIDITY.

BACKGROUND: ThyPRO is a recently developed thyroid-specific quality of life (QoL) questionnaire applicable to patients with benign thyroid disorders(BTD). The aim of the present study was to translate ThyPRO and ThyPRO-39 into Romanian, and to evaluate reliability and cross-cultural validity. METHODS: Standard methodology for translation and linguistic validation of patient-reported outcomes (PRO) was applied. The questionnaire was completed by 130 patients with benign thyroid diseases seen at Department of Endocrinology in the Emergency County Hospital, Tîrgu Mures, Romania, between October 2015 and March 2016. Internal reliability of the Romanian version of the ThyPRO (ThyPROro) scales was assessed for multi-item scales using Cronbach's alpha coefficient. An efficient method for testing cross-cultural validity is analysis of differential item functioning (DIF). Uniform DIF between the Romanian and the original Danish sample was investigated using ordinal logistic regression. The translation process proceeded without difficulties, and any disagreements were revised by one of the developers and the language coordinator. RESULTS: Internal reliability for ThyPRO was satisfactory. Cronbach`s alpha coefficients for the 13 scales ranged from 0.78 to 0.93 for the ThyPROro and 0.78 to 0.87 for the ThyPROro-39. In the 85-item ThyPRO, nine instances of DIF were found. Most were minor, explaining <3% of the variation in scale score, but DIF in positively worded items were larger, with explained variance (R2's) around 10-15%. CONCLUSION: The ThyPROro questionnaire is ready for assessment of health-related quality of life in Romanian patients with benign thyroid diseases.

Fabry disease in children: agalsidase-beta enzyme replacement therapy.

Fabry disease is a rare, multiorgan disease. The most serious complications involve the kidney, brain and heart. This study aims to assess the effect of enzyme replacement therapy (ERT) using agalsidase-beta in children with Fabry disease. We carried out a nationwide, descriptive and observational retrospective cohort study of 10 children (9-16 years at baseline), who underwent regular systematic investigations for 1-8 years after initiation of ERT with agalsidase-beta (Fabryzyme®, Genzyme). Ophthalmological, echocardiographic abnormalities and hypohidrosis were found at baseline and during the follow-up period. Serious kidney, heart or brain involvement had not developed at the last follow-up examination. For the majority of the patients improvements were found concerning headache, acroparaesthesias and gastrointestinal pain during the follow-up period. The level of energy and physical activity also increased. Treatment with agalsidase-beta was associated with a reduction of neuropathic and abdominal pain and headache. Although all aspects of the Fabry pain phenotype cannot be treated with ERT, the observed effects were clinically significant in the lives of the majority of Fabry children and together with the absence of serious Fabry manifestations at last follow-up, we argue that early initiation of ERT may be considered.

Acute presentation of craniopharyngioma in children and adults in a Danish national cohort.

We aimed to study the occurrence of acute-onset symptoms at initial presentation in a national Danish cohort of patients with childhood- or adult-onset craniopharyngioma, and to investigate potential risk factors for acute presentation. Medical records of 189 consecutive patients (39 children, 150 adults) presenting with craniopharyngioma during the period 1985-2004 were reviewed, and data regarding initial symptoms, neuroimaging results, vision and pituitary function were systematically collected. Acute symptoms preceding hospital admission were noted. Subgroup analyses were based on age, gender and calendar year period. Potential risk factors for acute presentation were analysed through uni- and multivariate analyses. Acute symptoms were reported in 24 (13%) patients. Acute visual symptoms, headache, nausea or vomiting were most frequently reported, and acute symptoms were more frequent among children (28%) than among adults (9%) (P < 0.01). There were no differences according to sex or calendar year period. Hydrocephalus was present in half of childhood cases and one-fifth of adult patients (P < 0.001). Intra-tumour haemorrhage was seen in two cases. Acute symptoms were more frequent among patients with tumours occupying the third ventricle (P < 0.01), radiologic signs of calcification (P < 0.05) or hydrocephalus (P < 0.01). In multivariate analysis, however, only childhood onset (P < 0.05) and calcification (P < 0.05) were independent risk factors for acute presentation. Craniopharyngioma presented with acute symptoms in 13% of patients. Childhood onset and radiologic signs of calcification were independent risk factors for acute presentation. Intra-tumour haemorrhage was rare.

Thyroid cancer in Denmark 1943-2008, before and after iodine supplementation.

Thyroid cancer incidence has increased worldwide during the previous decades. In this nationwide study, we aimed to identify the overall incidence of thyroid cancer in Denmark during 66 years (1943-2008) and incidences of the four main histological types of thyroid cancer from 1978 to 2008. Data were obtained from the nationwide Danish Cancer Registry, and we focused especially on the period after implementation of compulsory iodine supplementation, which was established on a national level in 2000. We calculated age-standardized incidence rates per 100,000 person-years, and age-period-cohort models were fitted to describe trends in incidence. To quantify trends in incidence over time, log-linear Poisson models were used to estimate annual percentage change. From 1943 to 2008, 1,947 men (29%) and 4,682 women (71%) were diagnosed with thyroid cancer. The age-standardized incidence increased in both sexes; in men from 0.41 to 1.57 per 100,000 and from 0.90 to 4.11 per 100,000 in women, corresponding to a significant average annual percentage change of 1.7 and 1.8%, respectively. The incidence increased with younger birth cohorts. The rise was almost exclusively caused by papillary carcinomas, and it was particularly present during the last decades of the study period. It cannot be ruled out that iodine supplementation may play a role for the risk of thyroid cancer, but as the strongest increase in incidence began in the years before the implementation, it is likely that improvement in diagnostic modalities increased diagnostic activity, and/or new unknown risk factors are also important contributors to the increase.

Incidence of craniopharyngioma in Denmark (n = 189) and estimated world incidence of craniopharyngioma in children and adults.

We studied the incidence of craniopharyngioma in Denmark during the period 1985-2004 and estimated worldwide incidence rates (IR) of craniopharyngioma based on a literature review. Craniopharyngioma patients diagnosed during the period 1985-2004 were identified from the Danish National Patient Registry, the Danish Cancer Registry and regional registries. Medical records were reviewed. Danish population data were obtained from Statistics Denmark. European and World population data were obtained from EU and WHO homepages. Prior studies providing data on craniopharyngioma IRs were identified via PubMed and, if appropriate, were included in a weighted analysis estimating overall and children's IRs of craniopharyngioma. IRs are given as new cases per million per year. We identified 189 patients with new verified (162) or probable craniopharyngioma. The overall WHO World-standardised incidence rate was 1.86 (1.60-2.14) for all ages and 2.14 (1.53-2.92) for children (age <15 years). Peak incidence rates were observed in age groups 5-9 and 40-44 years. Fifteen prior studies (including 1,232 craniopharyngioma cases) were identified. Seven and 11 studies, respectively, were eligible for weighted all-ages and childhood population IR analyses, yielding summary IRs of 1.34 (1.24-1.46) (all ages) and 1.44 (1.33-1.56) (children). We have provided a detailed survey of the incidence of craniopharyngioma in Denmark during a recent 20-year period. Overall IR of craniopharyngioma in Denmark was 1.86 (1.60-2.14) as compared to 2.14 (1.53-2.92) among children. Weighted estimates of craniopharyngioma world IRs were 1.34 (1.24-1.46) in all ages and 1.44 (1.33-1.56) among children.

Hair removal in hirsute women with normal testosterone levels: a randomized controlled trial of long-pulsed diode laser vs. intense pulsed light.

BACKGROUND: Hirsutism is a common disorder in women of reproductive age, and androgen disturbances may aggravate the condition. Limited evidence exists regarding efficacy of hair removal in this specific population and no data are available for patients with verified normal testosterone levels. OBJECTIVES: To compare efficacy and safety of intense pulsed light (IPL) vs. long-pulsed diode laser (LPDL) in a well-defined group of hirsute women with normal testosterone levels. METHODS: Thirty-one hirsute women received six allocated split-face treatments with IPL (525-1200 nm; Palomar Starlux IPL system) and LPDL (810 nm; Asclepion MeDioStar XT diode laser). Testosterone levels were measured three times during the study period. Patients with intrinsically normal or medically normalized testosterone levels throughout the study were included in efficacy assessments (n = 23). Endpoints were reduction in hair counts assessed by blinded photoevaluations at baseline and 1, 3 and 6 months after final treatment, patient-evaluated reduction in hairiness, patient satisfaction, treatment-related pain and adverse effects. RESULTS: IPL and LPDL reduced hair counts significantly, with median reductions from baseline of 77%, 53% and 40% for IPL and 68%, 60% and 34% for LDPL at 1, 3 and 6 months, respectively. At 6 months follow-up, there was no significant difference between treatments in terms of hair reduction (P = 0·427), patient assessment of hairiness (P = 0·250) and patient satisfaction (P = 0·125). Pain scores were consistently higher for IPL [median 6, interquartile range (IQR) 4-7] than LPDL (median 3, IQR 2-5) (P < 0·001). CONCLUSION: Hirsute women with normal or medically normalized testosterone levels responded equally well to IPL and LPDL treatments of facial hairiness, but the efficacy declined over 6 months.

Hypothyroidism is associated with signs of endothelial dysfunction despite 1-year replacement therapy with levothyroxine.

OBJECTIVE: Hypothyroidism is associated with elevated cardiovascular risk, not fully explained by classical risk factors. Instead, endothelial dysfunction may link hypothyroidism to atherosclerosis. The effect of levothyroxine substitution on endothelial function has been sparsely studied and the results are unclear. This study tested endothelial function as estimated by concomitant measurements of endothelial dependent vascular dilatory capacity and plasma concentration of von Willebrand factor antigen in patients with hypothyroidism and further examined the impact of subsequent levothyroxine substitution. DESIGN AND PATIENTS: Sixteen consecutive patients (13 women, 3 men, aged 46 +/- 11 years) with hypothyroidism were included and compared to 16 matched healthy controls (13 women, 3 men, aged 49 +/- 11 years). Patients with hypothyroidism were reexamined after 3, 6 and 12 months of levothyroxine substitution. MEASUREMENTS: Dilatory responses of the brachial artery to post-ischaemic increased blood flow (endothelium-dependent flow-associated dilatation) and to nitroglycerin (endothelium-independent nitroglycerin induced dilatation) were measured by ultrasound. Plasma concentrations of von Willebrand factor antigen were measured by ELISA. RESULTS: Flow-associated dilatation was impaired in patients with hypothyroidism as compared to controls (102.7 +/- 3.6 vs. 105.6 +/- 3.8%, P = 0.04) whereas no differences in plasma concentration of von Willebrand factor antigen were found. One year levothyroxine substitution did not improve flow-associated dilatation and was associated with an increase of the plasma von Willebrand factor antigen concentration. CONCLUSIONS: Hypothyroid patients are characterized by endothelial dysfunction sustained despite long-term levothyroxine substitution and potentially increasing the risk of atherosclerosis. Different estimates of endothelial dysfunction seem unequally influenced by hypothyroidism.

Reduced parietooccipital white matter glutamine measured by proton magnetic resonance spectroscopy in treated graves' disease patients.

CONTEXT: Graves' disease is an autoimmune disease of the thyroid gland. Patients often have affective and cognitive complaints, whether these disappear after treatment remains disputed. OBJECTIVE: Our objective was to evaluate cerebral biochemistry in acute and treated Graves' disease. DESIGN: We conducted a prospective study, investigating volunteers once and patients before and 1 yr after treatment. SETTING: The study was performed at a radiology department, a memory disorder clinic, and two endocrinology clinics. PATIENTS AND OTHER PARTICIPANTS: Of 53 consecutively referred, newly diagnosed, and untreated patients with Graves' thyrotoxicosis, 27 patients (34 +/- 8 yr) and 33 matched volunteers were included. INTERVENTIONS: Patients were treated with thionamide. MAIN OUTCOME MEASURES: We assessed brain metabolite concentrations. METHODS: Proton magnetic resonance spectroscopy of the brain and a battery of biochemical, affective, and cognitive tests were used. RESULTS: Previously reported findings of reduced choline and myo-inositol in acute Graves' disease were confirmed and reversibility was demonstrated. Parieto-occipital white matter glutamine was and remained significantly reduced (P < 0.01). Acute phase parieto-occipital white matter total choline correlated significantly (r = -0.57; P < 0.01) with impaired thyroid function. Pretreatment total T(3) predicted posttreatment occipital gray matter glutamine (r = -0.52; P < 0.01). Occipital gray matter total choline (r = -0.53; P < 0.01) and parietooccipital white matter glutamate (r = -0.54; P < 0.01) correlated with initial values of selected attention and concentration cognitive scores and predicted them at follow-up. CONCLUSIONS: The persistent reduction of glutamine in white matter, the decreasing glutamate in occipital gray matter, and the correlation with severity of the initial disease as well as with attention and concentration cognitive scores indicated that there was a persistent and possibly progressive disturbance of the glutamate glutamine cycling in Graves' disease.

Immunohistochemical staining for thyroid peroxidase (TPO) of needle core biopsies in the diagnosis of scintigraphically cold thyroid nodules.

BACKGROUND: Cold thyroid nodules are common, in particular in iodine-deficient areas, but only a minority of them are malignant requiring surgery. Thyroid peroxidase (TPO) immunostaining of fine-needle aspiration cytology (FNAC) material has proven helpful in diagnosing cells from malignant lesions, but the procedure has its limitations in a routine setting. PURPOSE: To improve diagnosis and reduce surgery rate, the FNAC procedure was replaced by needle core biopsy (NCB), which was routinely stained for TPO by the monoclonal antibody mAb 47. MATERIALS AND METHODS: During a 5-year period 427 consecutive patients with a cold thyroid nodule were evaluated by ultrasound-guided NCB, which had been routinely stained for TPO in an automated immunostainer. Sensitivity and specificity and predictive values of the TPO immunostaining were estimated, based on the final diagnosis obtained from surgical resection. RESULTS: The majority of nodules with benign NCB diagnosis were not surgically removed, and thus a subgroup of 140 operated nodules formed the basis for the calculations. Sensitivity and specificity for benign and malignant lesions were 100% if the oxyphilic variant of adenomas and minimally invasive follicular carcinomas were excluded. By inclusion of these, the values fell to 89% and 97%, respectively. The predictive value of a positive test was 96% and the predictive value of a negative test was 97%. CONCLUSION: TPO immunostaining was found to be a valuable adjunct to morphology in the diagnosis of cold thyroid nodules of the nonoxyphilic type.

Decrease in scale invariance of activity fluctuations with aging and in patients with suprasellar tumors.

Motor activity in healthy young humans displays intrinsic fluctuations that are scale-invariant over a wide range of time scales (from minutes to hours). Human postmortem and animal lesion studies showed that the intact function of the suprachiasmatic nucleus (SCN) is required to maintain such scale-invariant patterns. We therefore hypothesized that scale invariance is degraded in patients treated for suprasellar tumors that compress the SCN. To test the hypothesis, we investigated 68 patients with nonfunctioning pituitary macroadenoma and 22 patients with craniopharyngioma, as well as 72 age-matched healthy controls (age range 21.0-70.6 years). Spontaneous wrist locomotor activity was measured for 7 days with actigraphy, and detrended fluctuation analysis was applied to assess correlations over a range of time scales from minutes to 24 h. For all the subjects, complex scale-invariant correlations were only present for time scales smaller than 1.5 h, and became more random at time scales 1.5-10 h. Patients with suprasellar tumors showed a larger decrease in correlations at 1.5-10 h as compared to healthy controls. Within healthy subject, gender and age >33 year were associated with attenuated scale invariance. Conversely, activity patterns at time scales between 10 and 24 h were significantly more regular than all other time scales, and this was mostly associated with age. In conclusion, scale invariance is degraded in healthy subjects at the ages of >33 year as characterized by attenuation of correlations at time scales 1.5-10 h. In addition, scale invariance was more degraded in patients with suprasellar tumors as compared to healthy subjects.

Maternal exposure to UV filters: associations with maternal thyroid hormones, IGF-I/IGFBP3 and birth outcomes.

BACKGROUND: Several chemical UV filters/absorbers ('UV filters' hereafter) have endocrine-disrupting properties in vitro and in vivo. Exposure to these chemicals, especially during prenatal development, is of concern. OBJECTIVES: To examine maternal exposure to UV filters, associations with maternal thyroid hormone, with growth factor concentrations as well as to birth outcomes. METHODS: Prospective study of 183 pregnant women with 2nd trimester serum and urine samples available. Maternal concentrations of the chemical UV filters benzophenone-1 (BP-1) and benzophenone-3 (BP-3) in urine and 4-hydroxy-benzophenone (4-HBP) in serum were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The relationships between 2nd trimester maternal concentrations of the three chemical UV filters and maternal serum concentrations of thyroid hormones and growth factors, as well as birth outcomes (weight, height, and head and abdominal circumferences) were examined. RESULTS: Positive associations between maternal serum concentrations of 4-HBP and triiodothyronine (T3), thyroxine (T4), insulin-like growth factor I (IGF-I) and its binding protein IGFBP3 were observed in mothers carrying male fetuses. Male infants of mothers in the middle 4-HBP exposure group had statistically significantly lower weight and shorter head and abdominal circumferences at birth compared to the low exposure group. CONCLUSIONS: Widespread exposure of pregnant women to chemical UV filters and the possible impact on maternal thyroid hormones and growth factors, and on fetal growth, calls for further studies on possible long-term consequences of the exposure to UV filters on fetal development and children's health.

Posttraumatic hypopituitarism is associated with an unfavorable body composition and lipid profile, and decreased quality of life 12 months after injury.

OBJECTIVE: Our objective was to describe body composition, lipid profile, and health-related quality of life (HRQL) in patients with traumatic brain injury (TBI) in relation to the development of posttraumatic hypopituitarism. DESIGN: This is a cross-sectional evaluation with a nested prospective substudy. PATIENTS: The cross-sectional cohort included 104 hospitalized patients with TBI [26 females/78 males; median age 41 yr (range 18-64); body mass index (BMI) 25 kg/m(2) (range 17-39); and severity, mild (Glasgow Coma Scale score (GCS) 13-15) n = 44, moderate (GCS 9-12) n = 20, and severe (GCS <9) n = 40)]. A nested cohort of 46 patients was followed prospectively. MEASUREMENTS: BMI, waist circumference, lipid profile, total- and regional-fat mass were assessed 3 and 12 months (prospective) or only 12 months (cross-sectional) posttraumatically. HRQL questionnaires (Nottingham Health Profile, EuroQoL-5D, and the GH deficiency (GHD) specific instrument, Quality of Life Assessment of GHD in Adults) were completed "pre-traumatically," 3 and 12 months (prospective), or only 12 months (cross-sectional) posttraumatically. RESULTS: Patients with posttraumatic hypopituitarism had higher age-, gender-, and BMI-adjusted 12-month low-density lipoprotein-cholesterol, waist circumference, and total fat mass (P < 0.05 in all cases), and a higher increase in total cholesterol (P = 0.01) during follow-up compared with sufficient patients. These findings were unrelated to 12-month IGF-I and IGF-I sd scores. Hypopituitary patients also had worse age, BMI, and TBI severity adjusted overall EuroQoL-5D visual analog scale (P = 0.03) and Quality of Life Assessment of GHD in Adults (P = 0.01) scores, and worse Nottingham Health Profile dimension scores of sleep (P = 0.03), energy (P = 0.02), and social isolation (P = 0.04), compared with patients with an intact pituitary function. CONCLUSION: Posttraumatic hypopituitarism was an independent predictor of the classical phenotypical features of hypopituitarism, including an unfavorable lipid and body composition profile, as well as worsened HRQL.

Estrogen replacement in women of fertile years with hypopituitarism.

BACKGROUND: What form of estrogen to prescribe a young hypopituitary woman with gonadal failure remains an open question despite evidence that oral estrogen therapy induces GH resistance and an increase in fat mass. METHODS: Using an international surveillance study of hypopituitary patients, we examined two questions: 1) What estrogen is prescribed to young women of fertile years with hypopituitarism? 2) Is there a difference in body composition or IGF-I levels dependent on the type of estrogen prescribed? RESULTS: Six hundred twenty-eight GH-deficient women, aged 18-50 yr, were identified. Three hundred thirteen had normal gonadal function, and 315 were receiving estrogen therapy; of these 14% were using transdermal estradiol, and 86% were taking an oral estrogen preparation (38% oral estradiol, 18% conjugated estrogens, and 30% ethinyl estradiol in the oral contraceptive). There was no difference in weight, waist/hip ratio, or body composition between the women taking different estrogen therapies. However, if the oral estrogen groups were combined, they showed less change in waist and hip measurement and had a greater waist/hip ratio after 1 yr of GH treatment compared with patients with normal gonadal function (0.85 vs. 0.83; P = 0.022). Patients taking ethinyl estradiol had lower age-adjusted IGF-I sd scores and required almost twice the GH dose to achieve an IGF-I sd score that remained lower than patients with normal gonadal function and patients receiving transdermal estradiol. CONCLUSIONS: 1) The majority of women of fertile years with hypo-pituitarism take oral estrogen replacement therapy. 2) Waist/hip ratio was greater in women taking oral estrogens, and there is indirect evidence that oral estrogens reduce the action of GH on fat mass. 3) Patients using the oral contraceptive had lower IGF-I levels and required twice the GH dose compared with patients receiving transdermal estradiol.

Pregnancy outcome in type 1 diabetic women with microalbuminuria.

OBJECTIVE: To determine the influence of microalbuminuria on pregnancy outcome in women with type 1 diabetes. RESEARCH DESIGN AND METHODS: This prospective cohort study took place at the Obstetric Clinic at National University Hospital, Copenhagen, from January 1996 to February 2000. All Caucasian women with type 1 diabetes, unselected from the eastern part of Denmark, with a living fetus before 17 weeks of gestation on admission were asked to participate. For women with more than one delivery in the study period, only the first pregnancy was included. Of the remaining 246 women, 240 (98%) entered the study. They were categorized according to their urinary albumin excretion (normal urinary albumin excretion, <30 mg/24 h; microalbuminuria, 30-300 mg/24 h; or diabetic nephropathy, >300 mg/24 h) before pregnancy or in the first trimester. RESULTS: A total of 203 women (85%) had normal urinary albumin excretion, 26 (11%) had microalbuminuria, and 11 (5%) had diabetic nephropathy. Mean HbA(1c) at 2-6 weeks was 7.5% (SD 1.1), 8.1 (0.9), and 8.8 (1.3) (P < 0.001), respectively. Of all deliveries in women with normal urinary albumin excretion, microalbuminuria, and diabetic nephropathy, 35, 62, and 91% (P < 0.001), respectively, were preterm, and 2, 4, and 45% (P < 0.001), respectively, were small-for-gestational-age infants. Preeclampsia developed in 6, 42, and 64% of the women (P < 0.001), respectively. Category of urinary albumin excretion (P < 0.01) and HbA(1c) at 2-6 weeks (P < 0.05) were independently associated with preterm delivery. CONCLUSIONS: The prevalence of preterm delivery is considerably increased in women with microalbuminuria, mainly caused by preeclampsia. Classification according to urinary albumin excretion and metabolic control around the time of conception are superior to the White classification in predicting preterm delivery in women with type 1 diabetes.

The influence of growth hormone deficiency, growth hormone replacement therapy, and other aspects of hypopituitarism on fracture rate and bone mineral density. .

To assess the influence of factors affecting fracture risk and bone density in adult hypopituitary patients with growth hormone deficiency (GHD), data from a large-scale pharmacoepidemiological survey (the Pharmacia & Upjohn International Metabolic Database [KIMS]) were analyzed and compared with data from a control population (the European Vertebral Osteoporosis Study [EVOS]). The KIMS group consisted of 2084 patients (1112 men and 972 women) with various types of pituitary disease and EVOS consisted of 1176 individuals (581 men and 595 women). Fracture and bone mineral density (BMD) data were available from 2024 patients from the KIMS group and 392 patients from EVOS. The prevalence of fractures in patients with hypopituitarism was 2.66 times that in the non-GH-deficient EVOS population. Adult-onset hypopituitarism with GHD was associated with a higher fracture risk than childhood-onset disease, and patients with isolated GHD had a similar prevalence of fractures to those with multiple pituitary hormone deficiencies. Hormonal replacement therapy with L-thyroxine, glucocorticoids, and sex steroids did not affect the risk of fracture in KIMS patients. In addition, fracture rates in KIMS were independent of body mass index (BMI) and the country of origin. However, smoking was associated with a higher fracture rate in this group. In summary, this is the first large-scale analysis to support the hypothesis of an increased fracture risk in adult patients with hypopituitarism and GHD. This increased risk appears to be attributable to GHD alone, rather than to other pituitary hormone deficiencies or to their replacement therapy.

The effects of interleukin-1beta (IL-1beta) on human thyrocyte functions are counteracted by the IL-1 receptor antagonist.

The cytokine interleukin-1beta (IL-1beta) is an important regulator of thyroid cell function. IL-1 receptors are present on normal thyrocytes, but the signaling pathway is not fully clarified. As the adenylate cyclase is presumably not activated, we have in the present study investigated whether the cGMP pathway was involved in the actions of IL-1beta, whether the effects of IL-1beta on cultured human thyrocytes were reversible, and whether the effects were counteracted by IL-1 receptor antagonist (IL-1ra), a naturally occurring, specific blocker of IL-1 receptors on many cells. TSH-stimulated cultured human thyroid cells exposed for 72 h to IL-1beta (0.0002-20 microg/liter = 1-105 IU/liter) exhibited a dose-dependent and reversible inhibition of thyroglobulin and cAMP release and a dose-dependent stimulation of cGMP and IL-6 release. These effects were counteracted by coincubation with 250 or 125 microg/liter, but not with 25 and 2.5 microg/liter, IL-1ra. IL-1ra by itself inhibited the release of cAMP, but did not modulate the release of thyroglobulin, cGMP, or IL-6 from the thyrocytes, and IL-1ra was not produced in the extracellular compartment. The nitric oxide generator, sodium nitroprusside, dose dependently generated a TSH-independent release of nitric oxide and cGMP from the thyrocytes. These results indicate that all of the studied effects of IL-1beta on cultured human thyrocytes were exerted through activation of the IL-1 receptor with a signaling pathway involving activation of cGMP and inhibition of cAMP.

Influence of thyroglobulin on basal and stimulated human thyroid adenylate cyclase activity.

The interaction of thyroglobulin (Tg), thyroid-stimulating immunoglobulins (TSI), and TSH on human thyroid plasma membranes from nontoxic goiter was studied in vitro by an adenylate cyclase assay system using human thyroid homogenate. Purified Tg [3 X 10(-10) M (0.2 micrograms/ml) to 3 X 10(-8) M (20 micrograms/ml)] exerted a dose- and time-dependent inhibitory influence on basal adenylate cyclase activity. The inhibition was prevented by preincubation with Tg antibody in excess. Tg (3 X 10(-8) M) caused a significant reduction in the TSH- and TSI-stimulated adenylate cyclase activities, but did not influence stimulation with NaF (8 mM). Fractions of thyroid homogenates were obtained by differential centrifugation, and the maximal inhibitory influence of Tg was located in the 5000 X g fraction. Thus, Tg is an efficient inhibitor of basal and TSH- or TSI- stimulated adenylate cyclase activities, and might be involved in a short loop counterregulation of thyroid adenylate cyclase sensitivity in vivo.