Nina Gårevik

The normal equilibrium between CSF and plasma amyloid beta levels is disrupted in Alzheimer's disease

Amyloid-beta (Abeta) with 40 (Abeta40) and 42 (Abeta42) amino acids, the main components of amyloid plaques in the Alzheimers disease (AD) brain, can be measured in human cerebrospinal fluid (CSF) and plasma. Whereas CSF Abeta42 is decreased in AD, some studies have reported changed plasma Abeta levels in AD and in subjects with mild cognitive impairment (MCI). To this date it is unclear if and how CSF and plasma levels of Abeta correlate with each other in healthy individuals, albeit earlier studies on AD patients found no correlation between CSF and plasma Abeta. We have measured Abeta40 and Abeta42 in paired CSF and plasma samples from patients with AD (n=39), MCI (n=29) and healthy control subjects (n=18). We observed a clear correlation between CSF and plasma levels for both Abeta40 and Abeta42 in healthy individuals, whereas no such correlation could be seen for AD or MCI cases. Similarly to other studies we also found low levels of Abeta42 in AD CSF, whereas there were no significant differences in plasma Abeta levels between the diagnostic groups. Our findings suggest that the normal equilibrium between CSF and plasma Abeta may be disrupted with the initiation of amyloid deposition in the brain.

Long term perturbation of endocrine parameters and cholesterol metabolism after discontinued abuse of anabolic androgenic steroids.

AIMS To study the long-term impact of anabolic androgenic steroid (AAS) abuse on the cholesterol profile, and the potential to suppress endocrine activity in men working out at gym facilities. To study the relation between urinary biomarkers for testosterone and nandrolone abuse and the UGT2B17 genotype and time profile. EXPERIMENTAL DESIGN Subjects (N = 56) were recruited through Anti-Doping Hot-Line. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), plasma levels of low density lipoprotein (LDL), high density lipoprotein (HDL) and urinary steroid profile were regularly measured for a period of up to one year after cessation of intramuscular AAS abuse. RESULTS AND DISCUSSION A sustained suppression of LH, and FSH was observed for several months. The nandrolone urinary biomarker 19-NA was detectable several months after the last nandrolone intake and was correlated to the levels of LH and FSH. Testosterone abuse on the other hand was detectable only for a few weeks, and some of the testosterone abusers did not test positive due to a genetic deletion polymorphism of the UGT2B17. Significantly increased levels of HDL and decreased levels of LDL were observed for 6-months after cessation of AAS abuse. CONCLUSION Some individuals had a sustained suppression of LH and FSH for a period of 1 year whereas the cholesterol profile was normalized within 6 month. The long term consequences of these findings remain to be established.

Dual use of anabolic-androgenic steroids and narcotics in Sweden

BACKGROUND Anabolic-androgenic steroids (AAS) have long been used by body-builders seeking to increase muscle size, strength and beauty. AAS are sometimes used together with narcotic agents and are thought to serve as a gateway to narcotic substance use, but this theory has not yet been substantiated clinically or sociologically. METHODS Mandatory interviews were carried out with individuals (n=56) suspected of infringement of the narcotic laws in Sweden with confiscated and/or confirmed use of AAS. Data were collected over 12 months. RESULTS Seventy-three percent of subjects with confirmed use of AAS were also using narcotic substances. The use of AAS was preceded by the use of narcotic agents in 55% of subjects. Only one-fifth of the subjects in the study had used AAS before using narcotic agents. CONCLUSION Co-use of AAS and narcotics agents is frequent among young people taken into custody for criminal activity and investigated by the police in Sweden. The study does not lend support to the hypothesis that AAS are commonly a gateway drug to narcotic use.

Single dose testosterone increases total cholesterol levels and induces the expression of HMG CoA Reductase

BackgroundCholesterol is mainly synthesised in liver and the rate-limiting step is the reduction of 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) to mevalonate, a reaction catalysed by HMG-CoA reductase (HMGCR). There is a comprehensive body of evidence documenting that anabolic-androgenic steroids are associated with deleterious alterations of lipid profile. In this study we investigated whether a single dose of testosterone enanthate affects the cholesterol biosynthesis and the expression of HMGCR.Methods39 healthy male volunteers were given 500 mg testosterone enanthate as single intramuscular dose of Testoviron®--Depot. The total cholesterol levels prior to and two days after testosterone administration were analysed. Protein expression of HMGCR in whole blood was investigated by Western blotting. In order to study whether testosterone regulates the mRNA expression of HMGCR, in vitro studies were performed in a human liver cell-line (HepG2).ResultsThe total cholesterol level was significantly increased 15% two days after the testosterone injection (p = 0.007). This is the first time a perturbation in the lipoprotein profile is observed after only a single dose of testosterone. Moreover, the HMGCR mRNA and protein expression was induced by testosterone in vitro and in vivo, respectively.ConclusionHere we provide a molecular explanation how anabolic androgenic steroids may impact on the cholesterol homeostasis, i.e. via an increase of the HMGCR expression. Increasing knowledge and understanding of AAS induced side-effects is important in order to find measures for treatment and care of these abusers.

Non-Steroidal Anti-Inflammatory Drugs Do Not Influence the Urinary Testosterone/Epitestosterone Glucuronide Ratio

The UDP Glucuronosyl Transferase (UGT) enzymes are important in the pharmacokinetics, and conjugation, of a variety of drugs including non-steroidal anti-inflammatory drugs (NSAIDs) as well as anabolic androgenic steroids (AAS). Testosterone glucuronidation capacity is strongly associated with a deletion polymorphism in the UGT2B17 gene. As the use of high doses of NSAIDs has been observed in athletes there is a risk for a drug–drug interaction that may influence the doping tests for AAS. In vitro studies show inhibitory potential on UGT2B7, 2B15, and 2B17 enzymes by NSAIDs. The aim of this study was to investigate if concomitant use of NSAIDs and a single dose of testosterone enanthate would affect the excretion rate of testosterone and epitestosterone glucuronide (TG and EG) as well as the T/E ratio, thereby affecting the outcome of the testosterone doping test. The study was designed as an open, randomized, cross-over study with subjects being their own control. The 23 male healthy volunteers, with either two, one or no allele (ins/ins, ins/del, or del/del) of the UGT2B17 gene, received the maximum recommended dose of NSAID (Ibuprofen or Diclofenac) for 6 days. On day three, 500 mg of testosterone enanthate was administered. Spot urine samples were collected for 17 days. After a wash-out period of 4 months the volunteers received 500 mg testosterone enanthate only, with subsequent spot urine collection for 14 days. The glucuronides of testosterone and epitestosterone were quantified. NSAIDs did not affect the excretion of TG or EG before the administration of testosterone. The concomitant use of NSAIDs and testosterone slightly increased the TG excretion while the EG excretion was less suppressed compared to testosterone use only. The effects of the NSAIDs on the TG and EG excretion did not differ between the UGT2B17 genotype groups. In conclusion, the outcome of testosterone doping tests does not seem to be affected by the use of NSAIDs.

Urinary steroid profile in females –the impact of menstrual cycle and emergency contraceptives

Todays doping tests involving longitudinal monitoring of steroid profiles are difficult in women. Women have more complex hormonal fluctuations than men and commonly take drugs such as hormonal contraceptives that are shown to affect biomarkers used in these doping tests. In this study, we followed six womens urinary steroid profile during one menstrual cycle, including both glucuronides and sulfate conjugated fractions. Additionally, we studied what happens to the steroidal module of the Athlete Biological Passport (ABP) after administration of an emergency contraceptive (levonorgestrel, NorLevo®). The study shows that there are large individual variations in all metabolites included in the ABP and that the administration of emergency contraceptives may lead to suspicious steroid profile findings in the ABP. Urinary epitestosterone concentration increased during the menstrual cycle, leading to a decrease in the testosterone/epitestosterone ratio. The ratios followed in the ABP varied widely throughout the menstrual cycle, the coefficient of variation (CV) ranging from 4 to 99%. There was a 3-fold decrease in epitestosterone 24 h post administration of the emergency contraceptive pill and androsterone, etiocholanolone, and 5β- androstan-3α,17β-diol concentrations decreased about 2-fold. When analyzed with the ABP software, one of the six women had an atypical profile after taking the emergency contraceptive. Furthermore, we could not find any alterations in excretion routes (i.e., if the metabolites are excreted as glucuronide or sulfate conjugates) during the menstrual cycle or after administration of emergency contraceptive, indicating no direct effect on phase II enzymes. Copyright

Impact of single-dose nandrolone decanoate on gonadotropins, blood lipids and HMG CoA reductase in healthy men.

The aim was to study the effect and time profile of a single dose of nandrolone decanoate (ND) on gonadotropins, blood lipids and HMG CoA reductase [3‐hydroxy‐3‐methyl‐glutaryl‐CoA reductase (HMGCR)] in healthy men. Eleven healthy male participants aged 29–46 years were given a single dose of 150 mg ND as an intramuscular dose of Deca Durabol®, Organon. Blood samples for sex hormones, lipids and HMGCR mRNA analysis were collected prior to ND administration day 0, 4 and 14. A significant suppression of luteinising hormone (LH) and follicle‐stimulating hormone (FSH) was seen after 4 days. Total testosterone and bioavailable testosterone level decreased significantly throughout the observed study period. A small but significant decrease in sexual hormone‐binding globulin (SHBG) was seen after 4 days but not after 14 days. Total serum (S)‐cholesterol and plasma (P)‐apolipoprotein B (ApoB) increased significantly after 14 days. In 80% of the individuals, the HMGCR mRNA level was increased 4 days after the ND administration. Our results show that a single dose of 150 mg ND increases (1) HMGCR mRNA expression, (2) total S‐cholesterol and (3) P‐ApoB level. The long‐term consequences on cardiovascular risk that may appear in users remain to be elucidated.

Perturbation of the Hematopoietic Profile by Anabolic Androgenic Steroids

Objective. The aim of this study was to investigate the hematopoietic profile in AAS abusers, during or short after their last abuse and approximately six months later. Moreover, we studied if supraphysiological doses of testosterone influence the concentration of hemoglobin and erythropoietin in healthy volunteers. Design and Methods. Subjects ( ) were recruited through an antidoping hotline. The hematological profile was measured when the subjects entered the study and approximately 6 months later. Testosterone enanthate (500 mg) was administered to healthy volunteers ( ). Gene expression was studied in human hek293 cells exposed to 1 μM testosterone. Results. Decreased levels of hemoglobin, erythrocyte volume fraction, and erythrocyte counts were observed after 6 months without the use of AAS. Results in volunteers show that hemoglobin increased 3% four and 15 days after testosterone administration, whereas EPO was significantly increased by 38% four days after dose. Agreeingly, in vitro study shows that testosterone induces the mRNA level of EPO with 65% after 24-hour exposure. Conclusion. These results indicate that supraphysiological doses of testosterone may cause a perturbation in the hematopoietic profile. This is of interest in relation to the adverse cardiovascular effects observed in AAS abusers.