Karolinska Institutet
Medicine Huddinge
Testicular germ cell cancer (TGCC) is the most common malignancy in young men. Genetic variants known to be associated with risk of TGCC only partially account for the observed familial risks. We aimed to identify additional polymorphisms... more
Testicular germ cell cancer (TGCC) is the most common malignancy in young men. Genetic variants known to be associated with risk of TGCC only partially account for the observed familial risks. We aimed to identify additional polymorphisms associated with risk as well as histological and clinical features of TGCC in 367 patients and 214 controls. Polymorphisms in ESR2 (rs1256063; OR = 0.53, 95% CI: 0.35–0.79) and LHCGR (rs4597581; OR = 0.68, 95% CI: 0.51–0.89, and rs4953617; OR = 1.88, 95% CI: 1.21–2.94) associated with risk of TGCC. Polymorphisms in ESR1 (rs9397080; OR = 1.85, 95% CI: 1.18–2.91) and LHCGR (rs7371084; OR = 2.37, 95% CI: 1.26–4.49) associated with risk of seminoma and metastasis, respectively. SNPs in ESR1 (rs9397080) and LHCGR (rs7371084) were predictors of higher LH levels and higher androgen sensitivity index in healthy subjects. The results suggest that polymorphisms in ESR1, ESR2 and LHCGR contribute to the risk of developing TGCC, histological subtype, and risk to metastasis.► Testicular germ cell cancer (TGCC) has a significant, multi-genetic component. ► We aim to identify additional risk alleles associated with TGCC. ► SNPs in ESR1, ESR2, and LHCGR associate with features of TGCC. ► SNPs in ESR1 and LHCGR are predictors of hormone levels in healthy subjects. ► Genetic polymorphisms in ESR1, ESR2 and LHCGR contribute to the aetiology of TGCC.
- by Leon Brokken and +3
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- Genetics, Polymorphism, Histology, Adolescent
In the Western world, testicular germ cell cancer (TGCC) is the most common malignancy of young men. The malignant transformation of germ cells is thought to be caused by developmental and hormonal disturbances, probably related to... more
In the Western world, testicular germ cell cancer (TGCC) is the most common malignancy of young men. The malignant transformation of germ cells is thought to be caused by developmental and hormonal disturbances, probably related to environmental and lifestyle factors because of rapidly increasing incidence of TGCC in some countries. Additionally, there is a strong genetic component that affects susceptibility. However, genetic polymorphisms that have been identified so far only partially explain the risk of TGCC. Many of the persistent environmental pollutants act through the aryl hydrocarbon receptor (AHR). AHR signaling pathway is known to interfere with reproductive hormone signaling, which is supposed to play a role in the pathogenesis and invasive progression of TGCC. The aim of the present study was to identify whether AHR-related polymorphisms were associated with risk as well as histological and clinical features of TGCC in 367 patients and 537 controls. Haplotype-tagging single-nucleotide polymorphisms (SNPs) were genotyped in genes encoding AHR and AHR repressor (AHRR). Binary logistic regression was used to calculate the risk of TGCC, non-seminoma versus seminoma, and metastasis versus localized disease. Four SNPs in AHRR demonstrated a significant allele association with risk to develop metastases (rs2466287: OR = 0.43, 95% CI 0.21-0.90; rs2672725: OR = 0.49, 95% CI: 0.25-0.94; rs6879758: OR = 0.27, 95% CI: 0.08-0.92; rs6896163: OR = 0.34, 95% CI: 0.12-0.98). This finding supports the hypothesis that compounds acting through AHR may play a role in the invasive progression of TGCC, either directly or through modification of reproductive hormone action.
- by Leon Brokken and +2
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- Genetics, Polymorphism, Histology, Aryl Hydrocarbon Receptor
Relevant information for clinical decision-making in a wide spectrum of diseases includes the extent to which sexual function is intact, how important it is to preserve sexual capacity and whether waning sexual function causes distress.... more
Relevant information for clinical decision-making in a wide spectrum of diseases includes the extent to which sexual function is intact, how important it is to preserve sexual capacity and whether waning sexual function causes distress. Little information is available on elderly men. We aimed to obtain this basic information.
- by Stefan Arver and +1
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- Psychology, Aging, Sweden, Age
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.... more
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.
Objective To assess the validity and reliability of a potency/impotence' between the tests. The sensitivity and specificity of the questionnaire assessment com-questionnaire assessing 'physiological potency'. Patients and methods The... more
Objective To assess the validity and reliability of a potency/impotence' between the tests. The sensitivity and specificity of the questionnaire assessment com-questionnaire assessing 'physiological potency'. Patients and methods The study comprised 89 patients pared with the RigiScan method were 40% and 100%, respectively, when the question assessing sexually with prostate cancer and 43 men without; the latter were attending a consultation clinic because of prob-stimulated erectile rigidity was used alone. Using 'physiological potency', the sensitivity increased to lems with erection. All men answered three questions assessing erectile rigidity during sexual activity, morn-about 60% without jeopardizing the specificity, and when men reporting depression were excluded from ing and spontaneous erections. In the questionnaire, 'potency' was defined as erectile rigidity 'suBcient for the analysis, the sensitivity increased to about 80%. Conclusions The test-retest reliability of the question-intercourse most of the time' or better. 'Potency' in one or more of the three aspects of erection was naire was satisfactory. Using questions in a selfadministered questionnaire, 'physiological impotence' defined as 'physiological potency'. The patients with prostate cancer answered the questionnaire twice with can be diagnosed with complete and 'physiological potency' with 60-80% sensitivity. The sensitivity of a 3-week interval. The men attending the consultation clinic underwent two nights of erectile monitoring the self-assessment for 'potency' depended on the number of questions asked and the proportion of men (using the RigiScan device) and the minimum criterion for RigiScan potency was defined as 55% rigidity at reporting depression. Keywords Potency, erection, RigiScan, questionnaire, both tip and base. Results The test-retest assessment showed 93% conform-sensitivity, specificity, validity, reliability ity in the questionnaire diagnosis of 'physiological rigidity that can be used eBciently in large populations,
A case of a renin-producing paraganglioma of adrenal origin with metastases to the retroperitoneal area, paravaginal area, and the ovary is reported with immunohistochemical findings indicating expression of multiple neuropeptide... more
A case of a renin-producing paraganglioma of adrenal origin with metastases to the retroperitoneal area, paravaginal area, and the ovary is reported with immunohistochemical findings indicating expression of multiple neuropeptide immunoreactivities. The patient was 23 years old at the time of diagnosis, and died from metastatic spread of the tumor 7 years later.
- by Stefan Arver and +1
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- Cancer
Gender dysphoria is suggested to be a consequence of sex atypical cerebral differentiation. We tested this hypothesis in a magnetic resonance study of voxel-based morphometry and structural volumetry in 48 heterosexual men (HeM) and women... more
Gender dysphoria is suggested to be a consequence of sex atypical cerebral differentiation. We tested this hypothesis in a magnetic resonance study of voxel-based morphometry and structural volumetry in 48 heterosexual men (HeM) and women (HeW) and 24 gynephillic male to female transsexuals (MtF-TR). Specific interest was paid to gray matter (GM) and white matter (WM) fraction, hemispheric asymmetry, and volumes of the hippocampus, thalamus, caudate, and putamen. Like HeM, MtF-TR displayed larger GM volumes than HeW in the cerebellum and lingual gyrus and smaller GM and WM volumes in the precentral gyrus. Both male groups had smaller hippocampal volumes than HeW. As in HeM, but not HeW, the right cerebral hemisphere and thalamus volume was in MtF-TR lager than the left. None of these measures differed between HeM and MtF-TR. MtF-TR displayed also singular features and differed from both control groups by having reduced thalamus and putamen volumes and elevated GM volumes in the right insular and inferior frontal cortex and an area covering the right angular gyrus.The present data do not support the notion that brains of MtF-TR are feminized. The observed changes in MtF-TR bring attention to the networks inferred in processing of body perception.
OBJECTIVE An important aim in treating male hypogonadism is restoration of physiological concentrations of testosterone and its metabolites. We have assessed hormone levels, pharmacokinetics and clinical response, including safety, of a... more
OBJECTIVE An important aim in treating male hypogonadism is restoration of physiological concentrations of testosterone and its metabolites. We have assessed hormone levels, pharmacokinetics and clinical response, including safety, of a permeationenhanced testosterone transdermal system (TTD) in the treatment of hypogonadal men for a 12-month period. DESIGN Open-label, multicentre study with four consecutive periods: Period I (3 weeks)-evaluation of patients' current androgen therapy, which consisted primarily of testosterone enanthate injections (mean dose 229 mg; mean interval 26d); Period II (8 weeks)androgen washout; Period III (3-4 weeks)-singledose pharmacokinetic studies of TTD systems; Period IV (12 months)-efficacy, safety, and steadystate pharmacokinetic evaluation of TTD systems (5 mg/day nominal delivery rate of testosterone). Results from Periods I, II, and IV were compared. PATIENTS Thirty-seven hypogonadal men 21-65 years old enrolled; 34 entered Periods III and IV; 29 (9 primary, 20 secondary hypogonadism) completed the study. Four patients withdrew because of adverse events (Period II, one; Period IV, three). MEASUREMENTS Morning serum levels of total testosterone (T), bioavailable testosterone (BT), dihydrotestosterone (DHT), and oestradiol (E 2 ) levels. Circadian pattern of T profiles and 24-hour time-average T level. LH levels in patients with primary hypogonadism. Reduction of hypogonadal symptoms. Safety assessments including skin tolerability, prostate parameters, lipid profile, and systemic parameters. RESULTS Twelve months of TTD therapy normalized morning serum T levels in 93% of patients, and produced greater than 80% normalization of BT, DHT and E 2 levels. The TTD system mimicked the circadian variation in T levels seen in healthy young men and normalized 24-hour time-average T levels in 86% of patients. Luteinizing hormone was suppressed in 8 of 9 men with primary hypogonadism, and normalized in 5 of these. Subjective symptoms of hypogonadism, including decreased libido and fatigue, showed improvement after 2-4 weeks of TTD treatment in most patients. The majority of adverse events were local skin reactions, and 3 patients (9%) discontinued the study for this reason. Prostate assessments showed a lower prostate-specific antigen level during TTD therapy compared to IM injections (0 . 66 vs 1 . 00 mg/l P < 0 . 001), while prostate size did not differ significantly between the two treatment regimens. CONCLUSIONS The permeation-enhanced testosterone transdermal system produces physiological levels and circadian patterns of testosterone, and its metabolites, in hypogonadal men. Although transient erythema and itching is commonly reported, the TTD is generally well tolerated by most patients. This system offers a new treatment option for testosterone replacement therapy that results in physiological serum levels of sex hormones in hypogonadal men.
- by Stefan Arver and +1
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- Testosterone, Clinical, Prostate, Clinical Sciences
Risk Metastasis A B S T R A C T Increasing incidence of testicular germ cell cancer (TGCC) is most probably related to environment and lifestyle. However, an underlying genetic predisposition may play a role and since sex steroids are... more
Risk Metastasis A B S T R A C T Increasing incidence of testicular germ cell cancer (TGCC) is most probably related to environment and lifestyle. However, an underlying genetic predisposition may play a role and since sex steroids are assumed to be important for the rise and progression of TGCC, a study of androgen receptor (AR) gene polymorphisms in relation to the risk, histological type and progression of TGCC was undertaken.
- by Jakob Eberhard and +3
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- Polymorphism, Sex Hormones, Sweden, Denmark
The serotonin system and the hypothalamic-pituitary-adrenal (HPA) axis are involved in the biological vulnerability to suicidal behaviour. Altered levels of dehydroepiandrosterone (DHEA) and its sulphate ester DHEAS have been reported in... more
The serotonin system and the hypothalamic-pituitary-adrenal (HPA) axis are involved in the biological vulnerability to suicidal behaviour. Altered levels of dehydroepiandrosterone (DHEA) and its sulphate ester DHEAS have been reported in neuropsychiatric conditions. The aim of this study was to investigate CSF levels of 5-Hydroxyindoleacetic acid (5-HIAA) and CSF and plasma levels of cortisol and DHEAS in 28 medication free suicide attempters and 19 healthy volunteers. Another aim was to investigate the relationship between neuroendocrine measures and childhood trauma in suicide attempters. As the study design includes a longitudinal part, we investigated whether CSF cortisol, 5-HIAA or DHEAS would predict subsequent suicide. We hypothesized higher cortisol levels in suicide attempters and lower CSF 5-HIAA levels and higher cortisol levels in suicide victims. Suicide attempters had higher CSF and plasma cortisol levels compared to healthy volunteers. Male suicide attempters had higher CSF DHEAS levels and female suicide attempters had lower CSF 5-HIAA levels compared to male and female healthy volunteers respectively. Exposure to interpersonal violence as a child showed a negative correlation with CSF cortisol/DHEAS ratio adjusted for age, gender and depression severity in a regression analysis. Suicide victims tended to have low CSF 5-HIAA and high CSF cortisol. Abused suicide victims had higher CSF cortisol compared to suicide victims with low exposure to interpersonal violence as a child. The results underlie the important role of the serotonergic system and HPA axis in suicidal behaviour and suggest that CSF DHEAS may be elevated in male suicide attempters.
- by Stefan Arver and +1
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- Violence, Depression, Suicide, Sweden
The synaptonemal complex (SC) is involved in the pairing of chromosomes during meiosis. We found that antibodies raised against a protein component (PI) of the mouse synaptonemal complex, mouse SCP1, also identified the SC in human... more
The synaptonemal complex (SC) is involved in the pairing of chromosomes during meiosis. We found that antibodies raised against a protein component (PI) of the mouse synaptonemal complex, mouse SCP1, also identified the SC in human primary spermatocytes. Biopsies from 18 men presented with infertility were evaluated by light-field microscopy and grouped into five categories: normal spermatogenesis, Sertoli cell-only syndrome, meiotic disturbances, spermiogenic (i.e. differentiation) disturbances, and other combined disturbances. In all the normal subjects the SCP1 antibody distinctly stained the synaptonemal complexes of primary spermatocytes, whereas Sertoli cells, spermatogonia or spermatids were never stained. In three of the groups, which had germ cells but showed spermatogenic disturbances, the staining was similar to that seen in normal subjects. In sharp contrast to this, in sections from men with Sertoli cell-only syndrome no specific staining was seen. This study demonstrates that a SCPl-related protein is also conserved in the synaptonemal complex in meiotic cells from man. Further studies will reveal to what extent the absence or the non-functionality of SCP1 contributes to male infertility.
Recent studies have strongly indicated that at least three regions [azoospermia factor (AZF) a±c] on the long arm of the Y-chromosome code for factors involved in spermatogenesis. In order to reveal the prevalence of microdeletions in... more
Recent studies have strongly indicated that at least three regions [azoospermia factor (AZF) a±c] on the long arm of the Y-chromosome code for factors involved in spermatogenesis. In order to reveal the prevalence of microdeletions in these regions in a Swedish population, 192 men consecutively referred to our andrology unit due to infertility and showing oligozoospermia (n 53) or azoospermia (n 139) but no obstruction or hormonal disturbances, were investigated. For this study we used a multiplex polymerase chain reaction (PCR) method including 13 pairs of primers divided into ®ve different primer mixes. It was found that four men, all with azoospermia, had deletions including part of the AZFb region and probably the entire AZFc region. Testis biopsies showed different morphology ranging from absence of germ cells to hypospermatogenisis. Of special interest was one patient that was ®rst investigated 10 years ago due to primary infertility and oligozoospermia. Today he has developed azoospermia. It is concluded that the number of patients with microdeletions on the Y chromosome is rather low (less than 3% in highly selected azoospermic men) in our study compared to a number of other studies in which a 1±55% incidence have been reported. It is possible that ethnic differences, selection criteria and methodological aspects can contribute to the difference between the present and previous studies.
Recent studies have indicated that at least three regions (AZF a±c) on the long arm of the Y-chromosome code for factors are involved in spermatogenesis. One of the candidate genes in the AZFb region is RBM1a, coding for a protein with an... more
Recent studies have indicated that at least three regions (AZF a±c) on the long arm of the Y-chromosome code for factors are involved in spermatogenesis. One of the candidate genes in the AZFb region is RBM1a, coding for a protein with an RNA binding motif. In this study, poly clonal antibodies raised against a 15 amino acid peptide, corresponding to residues 263±304 of the deduced amino acid sequence of RBM1a, has been used to localize the RBM1a protein in the human testis. Immunohistochemistry on normal human testis using this RBM1a antibody, localized the antigen to the nuclei of spermatogonia, primary spermatocytes, and round spermatids but not to the nuclei of elongated spermatids. The antibody also speci®cally identi®ed the nuclei of Sertoli cells, although the¯uorescence was not as strong as in the germ cell nuclei it identi®ed. No speci®c¯uorescence was seen in the nuclei of either peritubular, endothelial or Leydig cells. Western blot of normal human testicular tissue using the anti-RBM1a antibody gave rise to a single speci®c band of approximately 55 kDa, corresponding to the expected size of RBM1a. In view of its expression in germ cells, and because RBM1a has an RNA binding domain, RBM1a may be involved in RNA processing, such as RNA splicing or RNA export which are events necessary for normal spermatogenesis.
Topic: Urology/Testosterone and Hypogonadism
be viewed as phytoandrogens (having a similar effect) (Pechersky A.V., et al., 2000). At the same time, phytopreparations cannot replace the missing testosterone completely. When there is an obvious need to conduct androgen-replacement... more
be viewed as phytoandrogens (having a similar effect) (Pechersky A.V., et al., 2000). At the same time, phytopreparations cannot replace the missing testosterone completely. When there is an obvious need to conduct androgen-replacement therapy, the dose of the preparation should not exceed the quantity of the hormone that decreases with age. The danger of prescribing surplus doses of testosterone preparations was shown in research done in the last century on the mechanisms of development of prostate cancer. As a hypothesis, one can suppose that prescribing small doses of testosterone (suiting the age-related decrease in hormone production) between courses of conducting an androgen blockade will help improve the results of treatment of patients with prostate cancer. It is possible that this therapy will be effective for active surveillance of the above-mentioned patients.
- by Stefan Arver
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voiding subscores at month 48 was significantly greater (p≤0.01) with combination therapy than with both monotherapies in men with prostate volume (PV) 30-≤58 cc, and significantly greater (p < 0.001) than with tamsulosin in men with PV... more
voiding subscores at month 48 was significantly greater (p≤0.01) with combination therapy than with both monotherapies in men with prostate volume (PV) 30-≤58 cc, and significantly greater (p < 0.001) than with tamsulosin in men with PV ≥58 cc. For each individual storage or voiding question (except combination vs dutasteride for question 6), mean improvement in score at month 48 was significantly greater (p < 0.01) with combination therapy than with either monotherapy. Conclusions: Combination therapy provides significantly superior and sustained improvements in storage and voiding symptoms compared with tamsulosin irrespective of PV (≥30 cc), and compared with dutasteride in men with PV 30-≤58 cc.
Purpose: We identified factors that affect sexual function in men 50 to 80 years old and, therefore, may confound the comparison among groups of elderly men. In particular, we identified factors that may influence a comparison between... more
Purpose: We identified factors that affect sexual function in men 50 to 80 years old and, therefore, may confound the comparison among groups of elderly men. In particular, we identified factors that may influence a comparison between prostate cancer patients and the general population, or confound the relationship when comparing subgroups of patients in nonrandomized studies.
- by Stefan Arver and +1
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- Urology, Sexuality, Prostate Cancer, Erectile dysfunction
Klinefelter syndrome (47, XXY) is a sex chromosome aneuploidy associated with mild deficits in cognitive and language functions. Dysfunctions have also been reported in performance of tasks which examine executive functions. However, it... more
Klinefelter syndrome (47, XXY) is a sex chromosome aneuploidy associated with mild deficits in cognitive and language functions. Dysfunctions have also been reported in performance of tasks which examine executive functions. However, it is unclear whether the impaired performance is caused or accentuated by problems with semantic processing and information processing speed. In the present study we used an experimental task which is relatively insensitive to these confounding factors. We examined inhibitory executive functions in a group of XXY males compared with male (XY) and female (XX) controls, using a dichotic listening speech sound task with instructions to focus attention on either the right or the left ear stimulus. With this task, inhibitory executive functions can be assessed separately from language, processing speed, and attention orientation abilities. We found that XXY males showed a selective deficit in inhibitory executive functions compared to both control groups, whereas attentional orientation was not impaired. The present findings suggest that executive dysfunctions associated to Klinefelter syndrome can be selectively identified, and are particularly accentuated in the inhibitory sub-component. Such improved understanding of the nature of executive dysfunctions in XXY males may aid the development of specific neuropsychological rehabilitation strategies.
Mean \ m=+-\s.e.m. concentrations (nmol/108 cells) of zinc and magnesium in bull spermatozoa were 30\m=.\6\ m=+-\ 6\m=.\6 and 119 \m=+-\28\m=.\8,respectively. Corresponding values for boar spermatozoa were 16\m=.\9\ m=+-\1\m=.\98 and... more
Mean \ m=+-\s.e.m. concentrations (nmol/108 cells) of zinc and magnesium in bull spermatozoa were 30\m=.\6\ m=+-\ 6\m=.\6 and 119 \m=+-\28\m=.\8,respectively. Corresponding values for boar spermatozoa were 16\m=.\9\ m=+-\1\m=.\98 and 57\m=.\1\ m=+-\4\m=.\3.Bull spermatozoa washed twice in a standard buffered salt solution, pH 7\m=.\75, lost 72\m=.\6%of their zinc and 46\m=.\5%of their magnesium. Boar spermatozoa lost 40% of Zn and 18% of Mg, respectively. Addition of albumin (4% final concentration) to the washing solution did not increase the loss of ions from bull spermatozoa but increased the loss of zinc and magnesium from boar spermatozoa to 52% and 41%, respectively. the sperm content of these ions after different treatments.