Mikael Lehtihet

Association between treatment for erectile dysfunction and death or cardiovascular outcomes after myocardial infarction

Objective Erectile dysfunction (ED) is associated with an increased risk of cardiovascular disease in healthy men. However, the association between treatment for ED and death or cardiovascular outcomes after a first myocardial infarction (MI) is unknown. Methods In a Swedish nationwide cohort study all men <80 years of age without prior MI, or cardiac revascularisation, hospitalised for MI during 2007–2013 were included. Treatment for ED, defined as dispensed phosphodiesterase-5 inhibitors or alprostadil, was related to risk of death, MI, cardiac revascularisation or heart failure. Results Forty-three thousand one hundred and forty-five men with mean age 64 (±10) years were included, of whom 7.1% had ED medication dispensed during a mean 3.3 years (141 739 person-years) of follow-up. Men with, compared with those without treatment for ED, had a 33% lower mortality (adjusted HR 0.67 (95%CI 0.55 to 0.81)), and 40% lower risk of hospitalisation for heart failure (HR 0.60 (95% CI 0.44 to 0.82)). There was no association between treatment with alprostadil and mortality. The adjusted risk of death in men with 1, 2–5 and >5 dispensed prescriptions of phosphodiesterase-5 inhibitors was reduced by 34% (HR 0.66 (95% CI 0.38 to 1.15), 53% (HR 0.47 (95% CI 0.26 to 0.87) and 81% (HR 0.19 (95% CI 0.08 to 0.45), respectively, when compared with alprostadil treatment. Conclusions Treatment for ED after a first MI was associated with a reduced mortality and heart failure hospitalisation. Only men treated with phosphodiesterase-5 inhibitors had a reduced risk, which appeared to be dose-dependent.

S-testosterone decrease after a mixed meal in healthy men independent of SHBG and gonadotrophin levels.

Reproducible and accurate assessment of serum testosterone (S‐T), S‐LH and S‐SHBG is of crucial importance for assessment of testicular endocrine function and diagnosis of hypogonadism and investigating male health in a broader sense. Testosterone secretion has a circadian rhythm with the highest component in the morning and is influenced by a series of factors including physical activity, mental stress and nutrition. For diagnostic purposes, analysis of morning samples is recommended and reference values are generally based on samples drawn between 7 and 10 am. In the literature, there are also indications that food intake can influence serum levels but fasting has not been a standard procedure. To carefully address the influence of food intake, we analysed S‐testosterone, S‐LH and S‐SHBG after an overnight fasting compared to samples taken after a standard meal of 550 kcal. We found no change in S‐LH or S‐SHBG but a decline of S‐T of 30% from 60 to 120 min after food intake compared to samples taken in the fasting state. This decline may give false low S‐T values and overestimate the number of men with suspected hypogonadism. Until the mechanism behind this effect has been explored, we suggest that assessment of S‐T for diagnostic purposes should be collected in the morning after an overnight fasting.

Circulating Hepcidin-25 Is Reduced by Endogenous Estrogen in Humans.

Objective Hepcidin reduces iron absorption by binding to the intestinal iron transporter ferroportin, thereby causing its degradation. Although short-term administration of testosterone or growth hormone (GH) has been reported to decrease circulating hepcidin levels, little is known about how hepcidin is influenced in human endocrine conditions associated with anemia. Research design and methods We used a sensitive and specific dual–monoclonal antibody sandwich immunoassay to measure hepcidin-25 in patients (a) during initiation of in vitro fertilization when endogenous estrogens were elevated vs. suppressed, (b) with GH deficiency before and after 12 months substitution treatment, (c) with hyperthyroidism before and after normalization, and (d) with hyperprolactinemia before and after six months of treatment with a dopamine agonist. Results In response to a marked stimulation of endogenous estrogen production, median hepcidin levels decreased from 4.85 to 1.43 ng/mL (p < 0.01). Hyperthyroidism, hyperprolactinemia, or GH substitution to GH-deficient patients did not influence serum hepcidin-25 levels. Conclusions In humans, gonadotropin-stimulated endogenous estrogen markedly decreases circulating hepcidin-25 levels. No clear and stable correlation between iron biomarkers and hepcidin-25 was seen before or after treatment of hyperthyroidism, hyperprolactinemia or growth hormone deficiency.

Small mosaic deletion encompassing the snoRNAs and SNURF-SNRPN results in an atypical Prader–Willi syndrome phenotype

Genetic analyses were performed in a male patient with suspected Prader–Willi syndrome who presented with hypogonadism, excessive eating, central obesity, small hands and feet and cognition within the low normal range. However, he had no neonatal hypotonia or feeding problems during infancy. Chromosome analysis showed a normal male karyotype. Further analysis with array‐CGH identified a mosaic 847u2009kb deletion in 15q11‐q13, including SNURF‐SNRPN, the snoRNA gene clusters SNORD116 (HBII‐85), SNORD115, (HBII‐52), SNORD109 A and B (HBII‐438A and B), SNORD64 (HBII‐13), and NPAP1 (C15ORF2). MLPA confirmed the deletion and the results were compatible with a paternal origin. Metaphase‐FISH verified the mosaicism with the deletion present in 58% of leukocytes analyzed. Three smaller deletions in this region have previously been reported in patients with Prader–Willi syndrome phenotype. All three deletions included SNORD116, but only two encompassed parts of SNURF‐SNRPN, implicating SNORD116 as the major contributor to the Prader–Willi phenotype. Our case adds further information about genotype–phenotype correlation and supports the hypothesis that SNORD116 plays a major role in the pathogenesis of Prader‐Willi syndrome. Furthermore, it examplifies diagnostic difficulties in atypical cases and illustrates the need for additional testing methods when Prader‐Willi syndrome is suspected.

Rigiscan Evaluation of Men with Diabetes Mellitus and Erectile Dysfunction and Correlation with Diabetes Duration, Age, BMI, Lipids and HbA1c

Objective This study aimed to investigate differences between patients with type 1 and type 2 diabetes mellitus with erectile dysfunction (ED) evaluated with Rigiscan and if there were a correlation to age, duration of diabetes, BMI, sex hormones, lipids and HbA1c. Research design and methods: A retrospective study on patients with type 1 diabetes (n=15), type 2 diabetes (n=17) and a control group (n=31) that underwent Rigiscan examination for ED. Age, BMI, blood pressure, sex hormones, lipids and HbA1c were recorded and analyzed between groups. Results Diabetes duration and HbA1C did not correlate with Rigiscan outcome. Rigiscan measures did not differ between patients with type 1 diabetes and control subjects besides from fewer erectile episodes (p<0.01) and lower tumescence activity units in base (p<0.05). By contrast, patients with type 2 diabetes differed significantly with respect to RigiScan parameters both in comparison with the type 1 diabetic patients and the control group. BMI had a strong correlation to number of erectile episodes, duration of erection, duration of erection > 60 % and rigidity activated unit (RAU) in tip and base. Age and HDL-cholesterol had a significant correlation with number of erectile episodes during night (p <0.05). Conclusion Our results indicate that erectile dysfunction in men with diabetes differ between type 1 and type 2 diabetes patients. Neither diabetes duration nor HbA1C correlated to grade of erectile dysfunction among patients with diabetes. Increased BMI might be an explanation to the increased rate of erectile dysfunction seen in patients with type 2 diabetes.

Testosterone and gonadotropins but not SHBG vary with CKD stages in young and middle aged men

BackgroundThe aim of this study was to assess the effects chronic kidney disease (CKD) had on sex hormones and lipids in a subgroup of men between 18 and 50xa0years old with CKD 1–5 stage without diabetes and not treated with hemodialysis.MethodsData were collected from 101 men with different CKD stages.ResultsHigher CKD stage (lower function) had a significant negative linear trend on total testosterone level (pu2009<u20090.01) and free testosterone level (pu2009<u20090.01), with a significant increase of luteinizing hormone (LH) (pu2009<u20090.01), and prolactin (pu2009<u20090.01), while SHBG remained unchanged between the CKD stages. Triglycerides but not total cholesterol, HDL –cholesterol or LDL-cholesterol increased with higher CKD stage. A negative correlation was observed between BMI, SHBG and free testosterone (pu2009<u20090.01 for both) but not with other sex hormones. Age per se was related to a significant decrease of total and free testosterone level (pu2009<u20090.01 for both) even after correction for BMI.Decreased levels of total testosterone and estimated free testosterone levels had a significant correlation with an increased level of triglyceride levels (pu2009<0.01).ConclusionsOur results indicate that CKD stage per se is a factor affecting testosterone levels in combination with age in men between 18 and 50xa0years old with CKD 1–5 stage, not treated with hemodialysis.With increased CKD stage there was a significant increase in LH level and a pattern of hypergonadotropic hypogonadism. SHBG remained unchanged between the CKD stages.RésuméObjectifsLe but de cette étude était d’évaluer les effets d’une maladie rénale chronique (MRC) sur les hormones sexuelles et les lipides dans une sous-population d’hommes âgés de 18 à 50 ans porteurs d’une MRC de stade 1-5, non diabétiques et non traités par hémodialyse.MéthodesLes données ont été obtenues chez 101 hommes qui présentaient différents stades de MRC.RésultatsUn stade plus élevé de MRC (fonction plus réduite) a une tendance linéaire négative sur les taux de testostérone totale (p<0,01) et de testostérone libre (p<0,01), avec une augmentation significative de la LH (p<0,01) et de la prolactine (p<0,01), alors que les taux de SHBG ne diffèrent pas entre les stades. Les triglycérides augmentent avec les stades plus élevés de MRC, ce qui n’est pas le cas du cholestérol total, du cholestérol HDL, ou du cholestérol LDL. L’IMC est négativement corrélé à la SHBG (p<0,01) et à la testostérone libre (p<0,01), mais n’est pas corrélé aux autres hormones sexuelles. L’âge per se est lié à une diminution significative des taux de testostérone totale (p<0,01) et de testostérone libre (p<0,01), corrélation qui persiste après ajustement sur l’IMC. Des taux diminués de testostérone totale et de testostérone libre estimée sont significativement corrélés à un niveau augmenté des taux de triglycérides (p<0,01).ConclusionsNos résultats indiquent que le stade de la MRC per se est un facteur qui affecte les taux de testostérone en combinaison avec l’âge chez les hommes de 18 à 50 ans porteurs d’une MRC de stade 1-5 et non traités par hémodialyse.L’élévation du stade de MRC est associée à une augmentation significative du taux de LH et à un profil d’hypogonadisme hypergonadotrophique. La SHBG n’est pas modifiée par le stade de MRC.

Semen quality in men with chronic kidney disease and its correlation with chronic kidney disease stages

The aim of this study was to assess whether chronic kidney disease (CKD) has any impact on semen quality parameters in men with CKD stage 1–5. Results were collected from 66 men with different CKD stages (age 18–50 years). Age and BMI (body mass index) were recorded for each male. Higher CKD stage had a significant negative linear trend on semen volume (P < 0.05), progressive motility (P < 0.01), nonprogressive motility (P < 0.001), sperm concentration (P < 0.01), total sperm number (P < 0.01), cytoplasmic droplets (P < 0.01), teratozoospermia index (P < 0.05) and accessory gland markers, α‐glucosidase activity (P < 0.05), zinc (P < 0.01) and fructose (P < 0.01). BMI per se had no significant effect on semen volume, sperm number, sperm concentration, morphology, α‐glucosidase activity, fructose concentration or zinc level. A significant negative correlation between BMI and sexual‐hormone‐binding globulin (SHBG) (P < 0.01) was observed but not with other sex hormones. Age per se was related to a significant decrease of sperm concentration (P < 0.05), normal forms (P < 0.01) and testosterone level (P < 0.05). Our results indicate that CKD stage per se is a factor determining the number of spermatozoa available in the epididymis for ejaculation, in part independent of age‐related decrease of testosterone level and BMI.

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 24u2009h 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.

Atypical excretion profile and GC/C/IRMS findings may last for nine months after a single dose of nandrolone decanoate.

The use of the anabolic androgenic steroid nandrolone and its prohormones is prohibited in sport. A common route of nandrolone administration is intramuscular injections of a nandrolone ester. Here we have investigated the detection time of nandrolone and 19-norandrosterone and 19-noretiocholanolone metabolites in eleven healthy men after the administration of a 150 mg dose of nandrolone decanoate. The urinary concentrations of nandrolone and the metabolites were monitored by GC-MS/MS for nine months and in some samples the presence of 19-norandrosterone was confirmed by GC/C/IRMS analysis. The participants were genotyped for polymorphisms in PDE7B1 and UGT2B15 genes previously shown to influence the activation and inactivation of nandrolone decanoate. There were large inter-individual variations in the excretion rate of nandrolone and the metabolites, although not related to genetic variations in the UGT2B15 (rs1902023) and PDE7B1 (rs7774640) genes. After the administration, 19-norandrosterone was found at 2-8-fold higher concentrations than 19-noretiocholanolone. We showed that nandrolone doping can be identified 4 and 9 months after the injection of only one single dose in six and three individuals, respectively. We also noted that GC/C/IRMS confirms the presence of exogenous 19-norandrosterone in the urine samples, showing δ13 values around -32 ‰. This was true even in a sample that was not identified as an atypical finding after the GC-MS/MS analysis further showing the power of using GC/C/IRMS in routine anti-doping settings.