Importance of Dehydroepiandrosterone Sulfate Assessment with Special Attention for Adrenal Tumours and Arterial Hypertension.

OBJECTIVE: To investigate the significance of DHEAS assessment in males of different ages. METHODS: Retrospective cohort study of patients investigated in two large academic centres. RESULTS: The data of DHEAS assessment of 3533 patients (3013 females and 520 males) was analysed. DHEAS was 1.6 - 13.5 times more frequently investigated in women than in men. A peak of DHEAS evaluation test for women was at 25 years old and distribution was uniform in males over decades, excepting being lower in 0-9 and 75+ages. In the age group 10-24 years, DHEAS levels were higher in females. After 45 years, DHEAS was higher in men than in women. Analysis of 510 case records showed low DHEAS levels in boys (0-9 years) and in men aged 65 - 84+. Higher DHEAS levels were detected as a peak at 30 years old, but never after 55 years. In individuals with low DHEAS levels prevailed congenital adrenal hyperplasia (32%), adrenal tumours (30%) and primary or secondary adrenal insufficiency (19%). High DHEAS levels prevailed in patients with arterial hypertension (26%), overweight-obesity -(19%), non-toxic goiter (17%) and alopecia (9%). In the normal DHEAS miscellaneous diagnoses were met most frequently - 40%. Disorders exceeding 5% were non-toxic goiter (19%), adrenal tumours - 17%, overweight/obesity - 16% and arterial hypertension- 8%. In 71 women and 124 men adrenal neoplasms were detected. Higher frequency of these was observed in women in their 30s. A peak of adrenal neoplasms in men was at their 70s. This gender difference was not conditioned by earlier attempts to seek medical care by women. A significant correlation of DHEAS, weight, body mass index and systolic blood pressure with diastolic blood pressure was found. CONCLUSION: Our study permits to determine which DHEAS secretion and clinical pattern might be associated in males of different ages.

THE RARE CASE OF MIXED GONADAL DYSGENESIS, MOSAIC KARYOTYPE, PETROCLIVAL MENINGIOMA AND IDIOPATHIC HYPERDEHYDROEPIANDROSTERONISM.

BACKGROUND: Mosaic karyotype 45,X/46,XY related mixed gonadal dysgenesis. AIM: To report a case of mosaic karyotype and petroclival meningioma. METHODS: Presentation of a clinical case with comments. RESULTS: The case of a 37-year-old woman mosaic karyotype - 45,X/46,XY, infertility, virilisation, Turner syndrome-like phenotype, primary amenorrhea, the absence of labia majora and petroclival meningioma. Concentrations of dehydroepiandrosterone sulphate (DHEAS), testosterone, luteinizing hormone (LH) and follicular stimulating hormone (FSH) were increased indicating hypergonadotropic hypogonadism. Low and high dose dexamethasone suppression tests demonstrated incomplete suppression of DHEAS concentration without connection between pulses of LH/FSH and DHEAS. Response to adrenocorticotropic hormone (ACTH) was normal. The morning/evening concentration ratio of DHEAS was very low in comparison with cortisol, ACTH and testosterone. Head magnetic resonance imaging (MRI) demonstrated petroclival meningioma without any adrenal or ovary abnormality. Menstruation started after treatment with 2 mg of estradiol. At control visit 1.5 years later she had no complaints. MRI did not demonstrate any signs of tumour progression. CONCLUSIONS: The main lesson learned from this case is that in searching the DHEAS secreting tumours one can find unusual cases with sustained high DHEAS and lack of confirmations of polycystic ovary syndrome, adrenal or ovary tumours using available ultrasound, CT and MRI.

The number of CAG and GGN triplet repeats in the Androgen Receptor gene exert combinatorial effect on hormonal and sperm parameters in young men.

Androgen receptor (AR) is a transcription factor that is activated upon binding to testosterone (T) and is implicated in regulating the expression of reproduction-related genes. The human AR gene (Xq11-12) spans 186,588 bp and eight exons. N-terminal transactivation domain of the encoded AR protein harbours two polymorphic stretches of identical amino acids, a polyglutamine tract (encoded by 8-37 CAG-repeats) and a polyglycine tract (encoded by 10-30 GGN-repeats). We set forward to analyse independent and combinatory effects of the length of these repetitive tracts on male reproductive hormones, testicular and sperm parameters in a population-based cohort of Baltic young men (n = 974; aged 20.1 ± 2.1 years). We designed an assay to amplify and detect simultaneously the variants of both polymorphic repeats. The study revealed that elongated AR CAG tract was associated with lower FSH (linear regression: p = 0.0002, effect per repeat -0.056 IU/L). As a novel finding, the carriers of GGN-stretch with ≥24 repeats showed a trend for decreased sperm concentration (p = 0.027). Although neither of the variants exhibited an isolated effect on circulating T, their allelic combinations modulated serum T levels, as well as sperm concentration. The lowest T was measured for men carrying the AR gene with long CAG (n ≥ 25) and short GGN (n ≤ 21) repeat tracts (mean 18.8 vs. 25.5-28.6 nmol/L for the other AR variants, p = 0.017). The lowest sperm concentration was detected among individuals with both elongated repetitive stretches (CAG, n ≥ 25 and GGN, n ≥ 24; mean 49.0 vs. 68.4-72.1 mill/mL for the other variants; p = 0.00059). The innovative study design enabled to clearly demonstrate a combinatory impact of CAG and GGN repeat lengths at male reproductive parameters. As AR regulates transcription of over 900 genes in many tissues and organs, the combinatory effects of these common repeat-length variants on male physiology in the wider context and across lifetime are still to be assessed.

Compensated reduction in Leydig cell function is associated with lower semen quality variables: a study of 8182 European young men.

STUDY QUESTION: Is the Leydig cell function of young European men associated with semen quality? SUMMARY ANSWER: Compensated reduction in Leydig cell function, defined as increased LH concentration combined with adequate testosterone production is associated with lower semen quality. WHAT IS ALREADY KNOWN: Semen quality of young European men shows a heterogeneous pattern. Many have sperm counts below and in the lower WHO reference where there nevertheless is a significant risk of subfecundity. Little is known about differences in Leydig cell function between men with semen quality below and within the WHO reference range. STUDY DESIGN, SIZE AND DURATION: A coordinated, cross-sectional population-based study of 8182 men undertaken in 1996-2010. PARTICIPANTS, SETTING AND METHOD: Young men (median age 19.1 years) were investigated in centres in Denmark, Estonia, Finland, Germany Latvia, Lithuania, and Spain. The men originated from the general populations, all were young, almost all were unaware of their fecundity and each provided a semen and blood sample. Associations between semen parameters and serum levels of testosterone and luteinising hormone (LH), calculated free testosterone, and ratios between serum testosterone and LH were determined. MAIN RESULT AND ROLE OF CHANCE: Serum testosterone levels were not associated with sperm concentrations, total sperm counts, or percentage of motile or morphologically normal spermatozoa. There was an inverse association between the semen parameters and serum LH levels, and accordingly a positive association to testosterone/LH ratio and calculated-free-testosterone/LH ratio. LIMITATIONS, REASON FOR CAUTION: The size of the study mitigates the intra-individual variability concern. The distinction between different sub-categories of sperm motility and sperm morphology is subjective despite training. However, inter-observer variation would tend towards non-differential misclassification and would decrease the likelihood of detecting associations between reproductive hormone levels and semen variables, suggesting that the presented associations might in reality be even stronger than shown. Although we adjusted for confounders, we cannot of course exclude that our results can be skewed by selection bias or residual confounding. WIDER IMPLICATIONS OF THE FINDINGS: Compensated reduction in Leydig cell function, defined as increased LH concentration combined with adequate testosterone production is associated with lower semen quality. This is apparent even within the WHO reference range of semen quality. It is unknown whether impaired Leydig cell function in young men may confer an increased risk of acquired testosterone deficiency later in life. STUDY FUNDING/COMPETING INTERESTS: Support from The Research Fund of Rigshospitalet (grant no. R42-A1326) to N.J. made this study possible. The background studies of young men have been supported economically by several grants. ITALIC! Denmark: The European Union (contract numbers BMH4-CT96-0314, QLK4-CT-1999-01422, QLK4-CT-2002-00603 and most recently FP7/2007-2013, DEER Grant agreement no. 212844), The Danish Research Council (grants nos. 9700833 2107-05-0006), The Danish Agency for Science, Technology and Innovation (Grant no. 271070678), Rigshospitalet (Grant no. 961506336), The University of Copenhagen (Grant no. 211-0357/07-3012), The Danish Ministry of Health and the Danish Environmental Protection Agency, A.P. Møller and wife Chastine McKinney Møllers foundation, and Svend Andersens Foundation. ITALIC! Finland: European Union (contract numbers BMH4-CT96-0314, QLK4-CT-1999-01422, QLK4-CT- 2002-00603 and most recently FP7/2008-2012, DEER Grant agreement no. 212844), The Academy of Finland, Turku University Hospital Funds, Sigrid Juselius Foundation. ITALIC! Estonia, Latvia and Lithuania: European Union (QLRT-2001-02911), the Estonian Science Foundation, grant number 2991, Lithuanian Foundation for Research, Organon Agencies B.V. and the Danish Research Council, grant no. 9700833. ITALIC! Germany: European Union (contract numbers QLK4-CT-2002-00603). ITALIC! Spain: European Commission QLK4-1999-01422. M.F. received support from the Spanish Ministry of Science and Innovation (Program Ramon y Cajal). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. None of the authors have any competing interests to declare.

APPROACHES TO THE 26-36-YEAR-OLD LITHUANIAN MEN'S SEXUAL FUNCTION.

CONTEXT: In the year 2003-2004 a circumstantial investigation of young men reproductive health parameters was performed in Nordic and Baltic countries, but sexuality remained undetermined. OBJECTIVE: To determine the suitability of the European Male Ageing Study - Sexual Function Questionnaire (EMAS - SFQ) for investigation of sexuality of 26-36 year aged general population and to investigate sexuality of Kaunas participants in the project "The reproductive function of Estonian, Latvian and Lithuanian Young men (2003-2004)" (KELLY), using EMAS - SFQ. DESIGN: Sixty one 26-36 year aged KELLY men were recaptured from the list of participants in a 2003-2004 study and completed EMAS - SFQ. Their anthropometric characteristics, scores of sexuality (22 parameters from EMAS - SFQ, 3 calculated parameters and 2 parameters consisting from answers to the only question - masturbation and erectile function-for each participant) were analysed, in conjunction with anthropometric, sperm quality and hormone levels of 2003-2004 18-25 year old general population. RESULTS: Overall sexual functioning and masturbation were higher as compared to all the published data for different age men and different testosterone concentration groups of EMAS study. CONCLUSIONS: KELLY sexuality results, obtained using EMAS - SFQ, would be considered as referral values for young men in countries with generally good reproductive health.

'Carriers of variant luteinizing hormone (V-LH) among 1593 Baltic men have significantly higher serum LH'.

Luteinizing hormone (LH) is a pituitary heterodimeric glycoprotein essential in male and female reproduction. Its functional polymorphic variant (V-LH) is determined by two missense mutations (rs1800447, A/G, Trp8Arg; rs34349826, A/G, Ile15Thr) in the LH ß-subunit encoding gene (LHB; 19q13.3; 1111 bp; 3 exons). Among women, V-LH has been associated with higher circulating LH and reduced fertility, but the knowledge of its effect on male reproductive parameters has been inconclusive. The objective of this study was to assess the effect of V-LH on hormonal, seminal and testicular parameters in the Baltic young men cohort (n = 986; age: 20.1 ± 2.1 years) and Estonian idiopathic infertility patients (n = 607; 35.1 ± 5.9 years). V-LH was detected by genotyping of the underlying DNA polymorphisms using PCR-RFLP combined with resequencing of a random subset of subjects. Genetic associations were tested using linear regression under additive model and results were combined in meta-analysis. No significant difference was detected between young men and infertility patients for the V-LH allele frequency (11.0 vs. 9.3%, respectively). V-LH was associated with higher serum LH in both, the young men cohort (p = 0.022, allelic effect = 0.26 IU/L) and the idiopathic infertility group (p = 0.008, effect = 0.59 IU/L). In meta-analysis, the statistical significance was enhanced (p = 0.0007, resistant to Bonferroni correction for multiple testing; effect = 0.33 IU/L). The detected significant association of V-LH with increased serum LH remained unchanged after additional adjustment for the SNPs previously demonstrated to affect LH levels (FSHB -211G/T, FSHR Asn680Ser, FSHR -29A/G). Additionally, a suggestive trend for association with reduced testicular volume was observed among young men, and with lower serum FSH among infertility patients. The V-LH carrier status did not affect sperm parameters and other circulating reproductive hormones. For the first time, we show a conclusive contribution of V-LH to the natural variance in male serum LH levels. Its downstream clinical consequences are still to be learned.

Study in 1790 Baltic men: FSHR Asn680Ser polymorphism affects total testes volume.

Follicle-stimulating hormone receptor (FSHR) contains two common linked polymorphisms, Thr307Ala (rs6165) and Asn680Ser (rs6166), shown to modulate ovarian function in women. The effect on male fertility and reproductive parameters has been inconclusive. We studied FSHR Asn680Ser polymorphism in a large study group (n = 1790) from the Baltic countries. The population-based Baltic male cohort (Estonians, Latvians, Lithuanians; n = 1052) and Estonian oligo-/azoospermic (sperm concentration <20 × 10(6) /mL) idiopathic infertile patients (n = 738) were genotyped for the FSHR Asn680Ser using PCR-RFLP. Genetic associations were tested using linear regression under additive model and results were combined in meta-analysis. No statistical difference was detected in allelic distribution of the FSHR Asn680Ser between the Baltic cohort and Estonian male infertility group. A consistent significant association was detected between the FSHR Ser680 allele and lower total testes volume in both, the Baltic cohort (p = 0.010, effect = -1.16 mL) and Estonian idiopathic infertility group (p = 0.007, effect = -1.77 mL). In meta-analysis, the statistical significance was enhanced (p = 0.000066, effect = -1.40 mL). Meta-analysis supported further associations with moderate effect between the FSHR Ser680 variant and higher serum FSH (p = 0.072), lower Inhibin B (p = 0.037) and total testosterone (p = 0.034). No statistically significant associations were identified with serum LH and estradiol, and sperm parameters. In conclusion, the study in 1790 Baltic men shows statistically highly significant association of the FSHR Asn680Ser with total testes volume and supportive association with serum reproductive hormone levels indicative to the functional effect of the alternative FSHR variants on male reproductive physiology.

Higher than expected prevalence of congenital cryptorchidism in Lithuania: a study of 1204 boys at birth and 1 year follow-up.

BACKGROUND: Cryptorchidism at birth is one of the symptoms of testicular dysgenesis syndrome (TDS). The aim of the study was to detect prevalence of cryptorchidism in Lithuanian newborn boys. METHODS: A total of 1204 consecutively born boys were examined within the first days after birth in one regional hospital. Boys cryptorchid at birth were reexamined 1 year later. RESULTS: The prevalence of cryptorchidism at birth was 5.7% (69 cases). Cryptorchidism was associated with low birth weight (P < 0.0001), preterm delivery (P < 0.0001), small gestational weight (P = 0.03) and other congenital abnormalities of genitalia (P = 0.0001). No correlation between cryptorchidism at birth and maternal age, birth order or mode of delivery was demonstrated in this study, but paternal body mass index <20 kg/m2 was found to be a significant risk factor (P = 0.001). The prevalence of congenital cryptorchidism at 1 year of age was 1.4%. CONCLUSIONS: We detected lower frequency of cryptorchidism at birth in Lithuanian boys than in Danes (9.0%), but higher than in Finns (2.4%). We had expected the frequencies in Lithuania and Finland to be relatively similar because the other symptoms of TDS (incidence of testicular cancer and semen quality) are close in these countries.

Short-lasting behavioural effects of thyrotropin-releasing hormone in depressed women: results of placebo-controlled study.

The rapid and short-lasting behavioral effects of thyrotropin-releasing hormone (TRH) were investigated in female patients with DSM-III-R major depression syndrome (MDS). Twenty-six depressed patients free of any medication received 0.2 mg of Protirelin (synthetic TRH) intravenously and 16 received placebo. All patients completed the Zung Self-Rating Depression Scale and the Spielberger State and Trait Anxiety Inventory (SSAI and STAI) twice: before and 2 hr after protirelin or placebo administration. The significant improvement in patients' emotional state after TRH injection was observed on STAI (p < .001) and SSAI (p < .01). Protireline was superior to placebo on STAI (p < .005). There was no significant correlation between behavioral effects of Protirelin and changes in thyroid hormones and TSH secretion. The improvement in patients' emotional state was more evident in depressed patients without associated panic attacks than in MDS with panic. These findings suggest that TRH has rapid positive effects on depression and that they depend more on patients' emotional state than on the function of the hypothalamus-pituitary-thyroid axis.

Insulin-degrading activity and insulinase-inhibiting activity in acute leukemia.

Insulin-degrading and insulinase-inhibiting activity of whole blood and erythrocytes of 146 children affected with acute leucosis of different stages were investigated. No statistically reliable difference between the data of insulin-degrading activity in acute leucosis and healthy children was found. Insulinase-inhibiting activity of both the hemolysate of blood and erythrocytes was increased in children in the active stage of the disease.

Immunoreactive insulin in haemolyzed erythrocytes of normal humans.

Immunoreactive insulin level (IRI) in haemolyzed (HE) of normal fasting subjects was 49.2 +/- 3.5 microU/ml. It was approximately 5 times higher compared within the plasma levels of the same subjects. Recovery and dilution tests for insulin in HE were positive. After an intravenous glucose load IRI in HE decreased to 14.3 +/- 3.6 microU/ml with 5 minutes and was low during 1 hour after glucose administration. Authors results suggest the presence of insulin in human erythrocytes and it release from erythrocytes during the first phase after glucose loading.

The action of chlorpromazine upon the serum and hypophyseal levels of prolactin and TSH in the pinealectomized male rat.

The action of chlorpromazine (CPZ) administered intraperitoneally (i.p.) in a single dose of 1.0 mg (0.2 ml) upon the serum and hypophyseal levels of prolactin and TSH was investigated in sham-operated (Sh-O) and pinealectomized (Px) male rats. Fourteen days after surgery the animals received 0.2 ml of CPZ or 0.2 ml of isotonic natrium chloride solution and were killed one hour after. The following data were obtained: a) CPZ released pituitary prolactin in both Sh-O and Px groups; b) The TSH circulating levels were increased in the Px group receiving CPZ (p less than 0.01); however, the same sense of variation was observed also in the Sh-O group. The results are suggesting the lack of intervention of the pineal in the mechanism of action of CPZ on the pituitary hormones with or without target gland.