Lars Mørkrid

The endocrine transition around menopause--a five years prospective study with profiles of gonadotropines, estrogens, androgens and SHBG among healthy women.

OBJECTIVE The purpose of this study was to investigate the hormonal changes during the menopausal transition in a non-clinical population. METHODS Fifty-nine healthy Norwegian women participated in a five year prospective longitudinal study during the transition from pre- to post-menopause, starting one to four years before menopause, and ending one to four years postmenopausal. None of these women were given hormone replacement therapy (HRT). Blood samples were collected every 12 months and luteinizing hormone (LH), follicle stimulating hormone (FSH), steroid hormone binding globuline (SHBG), prolactin (PRL), estradiol (E2), estrone (E1), testosterone, androstendione, dehydroepiandrostendione-sulphate (DHEA-S), and thyroid stimulating hormone (TSH) were analyzed. RESULTS The serum levels of FSH and LH, E2 and E1 profile essentially confirmed previous data obtained in cross-sectional studies. A continuous increase in serum FSH and LH and a concomitant fall in E2 and E1 were observed in all women before menopause and in the two postmenopausal years. Both androstendione and testosterone showed a decline three years before menopause. After the menopause, however, there were fluctuations in the testosterone levels. Androstendione correlated positively with both E2 and E1 and testosterone postmenopausally. Body mass index (BMI) did correlate with testosterone, but not with androstendione. BMI correlated negatively with SHBG. No correlation was found between BMI and E2, E1, FSH and LH. CONCLUSION This longitudinal prospective study of hormonal changes during the transition from pre- to postmenopause indicates that not only estrogen hormonal changes, but androgen hormonal changes as well, precedes the menopause by several years.

Frequency of hyperprolactinaemia due to large molecular weight prolactin (150-170 kD PRL)

Of 605 hyperprolactinaemic sera (prolactin > 1000 mU l-1 determined with PRL DELFIA, Wallac) in the routine diagnostic (PRL was measured in 10,737 sera) 26% had an increased amount of PRL with molecular weight (MW) = 150-170 kD (150-170 kD PRL or bigbig PRL). In a series of serum samples from 660 healthy subjects, only one female with hyperprolactinaemia due to increased 150-170 kD PRL was found. The 150-170 kD PRL constituted less than 1% of the total PRL found in 11 patients with prolactinoma (macroprolactinoma, PRL 8800-500,000 mU l-1). When determined with five different commercially available immunometric assays, the PRL values in the sera with large amounts of 150-170 kD were increased in all sera in four of five assays, although they varied widely. The clinical implications of hyperprolactinaemia due to increased 150-170 kD PRL are still uncertain.

Kinetic Modeling of Storage Effects on Biomarkers Related to B Vitamin Status and One-Carbon Metabolism

BACKGROUND Biomarkers and metabolites related to B vitamin function and one-carbon metabolism have been studied as predictors of chronic diseases in studies based on samples stored in biobanks. For most biomarkers, stability data are lacking or fragmentary. METHODS Degradation and accumulation kinetics of 32 biomarkers were determined at 23 °C in serum and plasma (EDTA, heparin, and citrate) collected from 16 individuals and stored for up to 8 days. In frozen serum (-25 °C), stability was studied cross-sectionally in 650 archival samples stored for up to 29 years. Concentration vs time curves were fitted to monoexponential, biexponential, linear, and nonlinear models. RESULTS For many biomarkers, stability was highest in EDTA plasma. Storage effects were similar at room temperature and at -25 °C; notable exceptions were methionine, which could be recovered as methionine sulfoxide, and cystathionine, which decreased in frozen samples. Cobalamin, betaine, dimethylglycine, sarcosine, total homocysteine, total cysteine, tryptophan, asymetric and symmetric dimethyl argenine, creatinine, and methylmalonic acid were essentially stable under all conditions. Most B vitamins (folate and vitamins B2 and B6) were unstable; choline increased markedly, and some amino acids also increased, particularly in serum. The kynurenines showed variable stability. For many biomarkers, degradation (folate and flavin mononucleotide) or accumulation (pyridoxal, riboflavin, choline, amino acids) kinetics at room temperature were non-first order. CONCLUSIONS Data on stability and deterioration kinetics for individual biomarkers are required to optimize procedures for handling serum and plasma, and for addressing preanalytical bias in epidemiological and clinical studies.

Antiepileptic drugs alter reproductive endocrine hormones in men with epilepsy

Disturbances of reproductive endocrine hormones are more often found in men with epilepsy than in the general population. There is an ongoing debate whether this can be attributed to chronic use of antiepileptic drugs or to the epilepsy itself. The aim of the present study was to evaluate the degree of endocrine disturbances in men with epilepsy compared with healthy controls, and to investigate whether there was a drug‐specific effect of valproate (VPA) or carbamazepine (CBZ). Men with epilepsy, 20–40 years old, having used either VPA (n = 16) or CBZ (n = 19) as monotherapy for >2 years were included and compared with age‐matched controls. Men with epilepsy (VPA + CBZ) had significantly lower FSH values and higher C‐peptide values compared with controls. Regarding possible drug‐specific effects, the VPA treated patients had significantly higher dehydroepiandrosterone (DHEAS) levels and lower FSH and LH concentrations compared with the controls, whereas there were no differences in testosterone, testosterone/sexhormone‐binding globulin (SHBG) ratio or androstenedione levels. Men on VPA also had significantly lower free carnitine/total carnitine, which may have implications for sperm motility, and also higher insulin and C‐peptide concentrations. The CBZ treated patients had significantly lower testosterone/SHBG ratio than the controls. Compared with the CBZ treated patients, men on VPA had significantly higher DHEAS concentrations and lower levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) as well as a lower free carnitine/total carnitine ratio. A marked age dependency was found in all three groups regarding several of the endocrine hormones. In conclusion, drug‐specific endocrine effects of VPA and CBZ were found in men with epilepsy. Long‐term VPA treatment leads to significant changes in DHEAS, FSH, LH, insulin, C‐peptide and carnitine ratio. Long‐term CBZ treatment leads to significant lower testosterone/SHBG ratio. A strict age matching were found to be of importance in the evaluation of endocrine function in men.

The importance of anal endosonography in the evaluation of idiopathic fecal incontinence

PURPOSE: The aim of the study was to evaluate the use of anal endosonography in idiopathic incontinence. METHODS: In 29 patients and 26 normal controls, the relationship between sonography images and physiologic parameters was studied. RESULTS: External anal sphincter function, measured as fiber density by single-fiber electromyography (P=0.0001) and pudendal nerve terminal motor latency (P=0.04), was significantly impaired in patients with idiopathic incontinence compared with controls. Both the external and internal anal sphincter could be identified by anal endosonography, and the thickness directly measured. The thickness of the external anal sphincter was significantly negatively correlated to muscle fiber density (r=−0.65,P=0.0002) and to pudendal nerve distal conduction velocity (r=−0.74,P=0.008). The thickness of the internal anal sphincter was significantly correlated to resting pressure (r=−0.67,P=0.0001). CONCLUSION: The ratio between the thickness of the external and internal sphincter muscles measured on the sonography screen was significantly reduced in patients with neurogenic incontinence compared with controls (P<0.01).

Reversible Effects of Antiepileptic Drugs on Reproductive Endocrine Function in Men and Women with Epilepsy—A Prospective Randomized Double-blind Withdrawal Study

Summary:  Purpose: Epilepsy, antiepileptic drugs (AEDs), and reproductive endocrine function have complex interactions. In this study, we wanted to investigate the effects of AEDs on reproductive endocrine function after withdrawal of AEDs and look for reversible endocrine effects.

Stability of selected serum proteins after long-term storage in the Janus Serum Bank

Abstract Background: Human serum from biobanks is frequently used in prospective epidemiological studies. Long-term storage may modify its composition. A better understanding of the stability of the serum components may improve the interpretation of future studies. Methods: The concentrations of selected proteins; immunoglobulins, carrier proteins and enzymes in samples stored at –25°C for 25 years and 2 years were compared with 1-month-old samples. For each length of storage time, 130 specimens were randomly selected from apparently healthy male blood donors aged 40–49 years. We examined the distribution of values, compared dispersion and localization of central tendency, and established reference intervals for each component. Results: The study demonstrated non-significant or numerically small group differences in the concentrations of albumin, aspartate amino transferase, cystatin C, immunoglobulin E, immunoglobulin G, and sex hormone binding globulin. Mean values between fresh and 25-year-old samples suggested larger differences during storage for alanine amino transferase (–73.4%), creatinine kinase (–96.1%), insulin C-peptide (–98.7%), ferritin (–18.5%) and transferrin (+8.2%). Conclusions: The findings showed that long-term storage can introduce a considerable bias for vulnerable components. Clin Chem Lab Med 2009;47:596–603.

The development of a software program for analyzing spontaneous and externally elicited skin conductance changes in infants and adults

OBJECTIVES Changes in palmar and plantar skin conductance (SC) are due to outgoing bursts in the postganglionic efferent sympathetic cholinergic fibres, which responds to changes in central arousal state. The purpose of this study was designed to develop a software program for analyzing spontaneous and external elicited SC changes for infants and adults. METHODS The program was designed to calculate the number and mean amplitude of the waves as well as the mean basal level in a given period. Different pre-set values for the minimum amplitude, maximum slope and minimum width of the spontaneous waves were used in the analysis program, and the results were compared with manually counted waves. The program was also used to perform coherent averaging of repeated elicited SC changes. For the mean elicited skin conductance responses, the latency time, response amplitude and recovery time were calculated. The habituation pattern could be calculated semi-automatically by analyzing each response. RESULTS For SC waves, the minimum amplitude and the maximum slope should be, respectively, 0.02 microsiemens (microS) and 2 microS/s for infants and adults, and the width of the waves should be at least 1 s for adults, and unlimited for infants. The coherent average method was found to be a satisfactory method for revealing whether a subject responded to stimuli, and is recommended, especially for infants. CONCLUSIONS Spontaneous and stimulated skin conductance are easily analyzed by this software program.

Abnormal Thermoregulatory Responses in Adolescents With Chronic Fatigue Syndrome: Relation to Clinical Symptoms

OBJECTIVES. Chronic fatigue syndrome is a common and disabling disease of unknown etiology. Accumulating evidence indicates dysfunction of the autonomic nervous system. To further explore the pathophysiology of chronic fatigue syndrome, we investigated thermoregulatory responses dependent on catecholaminergic effector systems in adolescent patients with chronic fatigue syndrome. PATIENTS AND METHODS. A consecutive sample of 15 patients with chronic fatigue syndrome aged 12 to 18 years and a volunteer sample of 57 healthy control subjects of equal gender and age distribution were included. Plasma catecholamines and metanephrines were measured before and after strong cooling of 1 hand. Acral skin blood flow, tympanic temperature, heart rate, and mean blood pressure were measured during moderate cooling of 1 hand. In addition, clinical symptoms indicative of thermoregulatory disturbances were recorded. RESULTS. Patients with chronic fatigue syndrome reported significantly more shivering, sweating, sudden change of skin color, and feeling unusually warm. At baseline, patients with chronic fatigue syndrome had higher levels of norepinephrine, heart rate, epinephrine, and tympanic temperature than control subjects. During cooling of 1 hand, acral skin blood flow was less reduced, vasoconstrictor events occurred at lower temperatures, and tympanic temperature decreased more in patients with chronic fatigue syndrome compared with control subjects. Catecholamines increased and metanephrines decreased similarly in the 2 groups. CONCLUSIONS. Adolescent patients with chronic fatigue syndrome have abnormal catecholaminergic-dependent thermoregulatory responses both at rest and during local skin cooling, supporting a hypothesis of sympathetic dysfunction and possibly explaining important clinical symptoms.

Increased levels of C-reactive protein and interleukin-6 in hyperhomocysteinemic subjects.

Objective. Elevated plasma homocysteine concentration is considered to be an independent risk factor for cardiovascular disease. However, the mechanisms by which hyperhomocysteinemia are related to vascular disease are unclear. High‐sensitivity C‐reactive protein (CRP), a marker of inflammation, has been reported to be an independent predictor of future myocardial infarction among clinically healthy individuals. Interleukin (IL)‐6 is a regulator of CRP and has a key role in initiation of inflammation. The aim of this study was to investigate whether individuals with increased plasma homocysteine concentrations have altered levels of serum CRP and IL‐6. Material and methods. Serum concentrations of CRP and IL‐6 were measured in 39 individuals with hyperhomocysteinemia and in 39 control subjects matched for gender, age and body mass index (BMI). In addition, the inflammatory effect of IL‐6 on peripheral blood mononuclear cells was measured. Results. Compared to controls, hyperhomocysteinemic subjects have elevated serum levels of CRP and IL‐6 (p⩽0.001 and p<0.005, respectively). Importantly, this raised level of IL‐6 was also seen in hyperhomocysteinemic individuals without accompanying hypercholesterolemia or cardiovascular disease. IL‐6 increased the release of monocyte chemoattractant protein‐1 from peripheral blood mononuclear cells, with particularly enhancing effects in cells from patients with hyperhomocysteinemia. Conclusions. These data suggest that enhanced inflammation may be associated with homocysteine‐related cardiovascular disease, possibly involving IL‐6‐related mechanisms.