| 1. |
- Cook, Michael J., et al.
(author)
-
Frailty and bone health in European men
- 2017
-
In: Age and Ageing. - : Oxford University Press (OUP). - 0002-0729 .- 1468-2834. ; 46:4, s. 635-641
-
Journal article (peer-reviewed)abstract
- Background: frailty is associated with an increased risk of fragility fractures. Less is known, however, about the association between frailty and bone health.Methods: men aged 40-79 years were recruited from population registers in eight European centres for participation in the European Male Aging Study. Subjects completed a comprehensive assessment which included quantitative ultrasound (QUS) scan of the heel (Hologic-SAHARA) and in two centres, dual-energy bone densitometry (dual-energy x-ray absorptiometry, DXA). Frailty was defined based on an adaptation of Fried's phenotype criteria and a frailty index (FI) was constructed. The association between frailty and the QUS and DXA parameters was determined using linear regression, with adjustments for age, body mass index and centre.Results: in total, 3,231 subjects contributed data to the analysis. Using the Fried categorisation of frailty, pre-frail and frail men had significantly lower speed of sound (SOS), broadband ultrasound attenuation (BUA) and quantitative ultrasound index (QUI) compared to robust men (P< 0.05). Similar results were seen using the FI after categorisation into 'high', 'medium' and 'low' levels of frailty. Using the Fried categorisation, frail men had lower femoral neck bone mineral density (BMD) compared to robust men (P < 0.05), but not lower lumbar spine BMD. Using the FI categorisation, a 'high' level of frailty (FI > 0.35) was associated with lower lumbar spine BMD (P < 0.05) when compared to those with low (FI < 0.2), but not lower femoral neck BMD. When analysed as a continuous variable, higher FI was linked with lower SOS, BUA and QUI (P < 0.05).Conclusions: optimisation of bone health as well as prevention of falls should be considered as strategies to reduce fractures in frail older people.
|
|
| 2. |
- Adhikari, Deepak, et al.
(author)
-
Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles
- 2010
-
In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:3, s. 397-410
-
Journal article (peer-reviewed)abstract
- To maintain the female reproductive lifespan, the majority of ovarian primordial follicles are preserved in a quiescent state in order to provide ova for later reproductive life. However, the molecular mechanism that maintains the long quiescence of primordial follicles is poorly understood. Here we provide genetic evidence to show that the tumor suppressor tuberous sclerosis complex 1 (Tsc1), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the quiescence of primordial follicles. In mutant mice lacking the Tsc1 gene in oocytes, the entire pool of primordial follicles is activated prematurely due to elevated mTORC1 activity in the oocyte, ending up with follicular depletion in early adulthood and causing premature ovarian failure (POF). We further show that maintenance of the quiescence of primordial follicles requires synergistic, collaborative functioning of both Tsc and PTEN (phosphatase and tensin homolog deleted on chromosome 10) and that these two molecules suppress follicular activation through distinct ways. Our results suggest that Tsc/mTORC1 signaling and PTEN/PI3K (phosphatidylinositol 3 kinase) signaling synergistically regulate the dormancy and activation of primordial follicles, and together ensure the proper length of female reproductive life. Deregulation of these signaling pathways in oocytes results in pathological conditions of the ovary, including POF and infertility.
|
|
| 3. |
- Ahern, Tomás, et al.
(author)
-
Natural history, risk factors and clinical features of primary hypogonadism in ageing men : Longitudinal Data from the European Male Ageing Study
- 2016
-
In: Clinical Endocrinology. - : Wiley. - 0300-0664. ; 85:6, s. 891-901
-
Journal article (peer-reviewed)abstract
- Objective: In ageing men, the incidence and clinical significance of testosterone (T) decline accompanied by elevated luteinizing hormone (LH) are unclear. We describe the natural history, risk factors and clinical features associated with the development of biochemical primary hypogonadism (PHG, T < 10·5 nmol/l and LH>9·4U/l) in ageing men. Design, Patients and Measurements: A prospective observational cohort survey of 3,369 community-dwelling men aged 40-79 years, followed up for 4·3 years. Men were classified as incident (i) PHG (eugonadal [EUG, T ≥ 10·5 nmol/l] at baseline, PHG at follow-up), persistent (p) PHG (PHG at baseline and follow-up), pEUG (EUG at baseline and follow-up) and reversed (r) PHG (PHG at baseline, EUG at follow-up). Predictors and changes in clinical features associated with the development of PHG were analysed by regression models. Results: Of 1,991 men comprising the analytical sample, 97·5% had pEUG, 1·1% iPHG, 1·1% pPHG and 0·3% rPHG. The incidence of PHG was 0·2%/year. Higher age (>70 years) [OR 12·48 (1·27-122·13), P = 0·030] and chronic illnesses [OR 4·24 (1·08-16·56); P = 0·038] predicted iPHG. Upon transition from EUG to PHG, erectile function, physical vigour and haemoglobin worsened significantly. Men with pPHG had decreased morning erections, sexual thoughts and haemoglobin with increased insulin resistance. Conclusions: Primary testicular failure in men is uncommon and predicted by old age and chronic illness. Some clinical features attributable to androgen deficiency, but not others, accompanied the T decline in men who developed biochemical PHG. Whether androgen replacement can improve sexual and/or physical function in elderly men with PHG merits further study.
|
|
| 4. |
- Anand-Ivell, Ravinder, et al.
(author)
-
Association of age, hormonal, and lifestyle factors with the Leydig cell biomarker INSL3 in aging men from the European Male Aging Study cohort
- 2022
-
In: Andrology. - : Wiley. - 2047-2919 .- 2047-2927. ; 10:7, s. 1328-1338
-
Journal article (peer-reviewed)abstract
- Background: Aging in men is accompanied by a broad range of symptoms, including sexual dysfunction, cognitive and musculoskeletal decline, obesity, type 2 diabetes, cardiovascular disease and hypertension, organ degeneration/failure, and increasing neoplasia, some of which are associated with declining levels of Leydig cell-produced testosterone. High natural biological variance, together with multiple factors that can modulate circulating testosterone concentration, may influence its interpretation and clinical implications. Insulin-like peptide 3 is a biomarker of Leydig cell function that might provide complementary information on testicular health and its downstream outcomes. Objectives: To characterize insulin-like peptide 3 as a biomarker to assess gonadal status in aging men. Methods and materials: A large European multicenter (European Male Aging Study) cohort of community-dwelling men was analyzed to determine how insulin-like peptide 3 relates to a range of hormonal, anthropometric, and lifestyle parameters. Results and discussion: Insulin-like peptide 3 declines cross-sectionally and longitudinally within individuals at approximately 15% per decade from age 40 years, unlike testosterone (1.9% per decade), which is partly compensated by increasing pituitary luteinizing hormone production. Importantly, lower insulin-like peptide 3 in younger men appears to persist with aging. Multiple regression analysis shows that, unlike testosterone, insulin-like peptide 3 is negatively dependent on luteinizing hormone and sex hormone-binding globulin and positively dependent on follicle-stimulating hormone, suggesting a different mechanism of gonadotropic regulation. Circulating insulin-like peptide 3 is negatively associated with increased body mass index or waist circumference and with smoking, and unlike testosterone, it is not affected by weight loss in obese individuals. Geographic variation in mean insulin-like peptide 3 within Europe appears to be largely explained by differences in these parameters. The results allowed the establishment of a European-wide reference range for insulin-like peptide 3 (95% confidence interval) adjusted for increasing age. Conclusion: Insulin-like peptide 3 is a constitutive biomarker of Leydig cell functional capacity and is a robust, reliably measurable peptide not subject to gonadotropin-dependent short-term regulation and within-individual variation in testosterone.
|
|
| 5. |
- Antonio, Leen, et al.
(author)
-
Associations Between Sex Steroids and the Development of Metabolic Syndrome: A Longitudinal Study in European Men
- 2015
-
In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 100:4, s. 1396-1404
-
Journal article (peer-reviewed)abstract
- Context: Low testosterone (T) has been associated with incident metabolic syndrome (MetS), but it remains unclear if this association is independent of sex hormone binding globulin (SHBG). Estradiol (E2) may also be associated with MetS, but few studies have investigated this. Objective: To study the association between baseline sex steroids and the development of incident MetS and to investigate the influence of SHBG, body mass index (BMI) and insulin resistance on this risk. Methods: Three thousand three hundred sixty nine community-dwelling men aged 40-79 years were recruited for participation in EMAS. MetS was defined by the updated NCEP ATP III criteria. Testosterone and E2 levels were measured by liquid and gas chromatography/mass spectrometry, respectively. Logistic regression was used to assess the association between sex steroids and incident MetS. Results: One thousand six hundred fifty one men without MetS at baseline were identified. During follow-up, 289 men developed incident MetS, while 1362 men did not develop MetS. Men with lower baseline total T levels were at higher risk for developing MetS [odds ratio (OR) = 1.72, P < .001), even after adjustment for SHBG (OR = 1.43, P < .001), BMI (OR = 1.44, P < .001) or homeostasis model assessment of insulin resistance (HOMA-IR) (OR = 1.64, P < .001). E2 was not associated with development of MetS (OR = 1.04; P = .56). However, a lower E2/T ratio was associated with a lower risk of incident MetS (OR = 0.38; P < .001), even after adjustment for SHBG (OR = 0.48; P < .001), BMI (OR = 0.60; P = .001) or HOMA-IR (OR = 0.41; P < .001). Conclusions: Inmen, lower Tlevels, but not E2, are linked with an increased risk of developing MetS, independent of SHBG, BMI or insulin resistance. A lower E2/T ratio may be protective against developing MetS.
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- Bentmar Holgersson, Magdalena, et al.
(author)
-
Androgen receptor polymorphism dependent variation in prostate specific antigen concentrations of European men.
- 2014
-
In: Cancer Epidemiology Biomarkers & Prevention. - 1538-7755. ; 23:10, s. 2048-2056
-
Journal article (peer-reviewed)abstract
- Background Androgens acting via the androgen receptor (AR) stimulate production of prostate specific antigen (PSA), which is a clinical marker of prostate cancer (PCa). Since genetic variants in the AR may have a significant impact on the risk of being diagnosed with PCa, the aim was to investigate if AR-variants were associated with the risk of having PSA above clinically used cut-off thresholds of 3 or 4 ng/mL in men without PCa. Methods Men without PCa history (n=1744) were selected from the European Male Ageing Study (EMAS) cohort of 40-80 year old men from 8 different European centers. Using linear and logistic regression models, with age and center as covariates, we investigated whether AR-variants (CAG repeat-length and/or SNP genotype) were associated with having serum PSA concentrations above 3 or 4 ng/mL, which often are set as cut-off concentrations for further investigation of PCa. Results Carriers of the SNP rs1204038 A-allele (16% of the men) were more likely to have PSA>3 and 4 ng/mL (OR; 95%CI 1.65; 1.13-2.40 and 1.87; 1.18-2.96, respectively) than G-allele carriers. They also had shorter CAG-repeats (median 20 vs. 23, p<0.0005), but CAG repeat length per se did not affect the PSA concentrations. Conclusion The A-allele of the SNP rs1204038 gives a 65% higher risk of having PSA above 3 ng/mL than the G-allele in men without PCa, and thereby an increased risk of being referred for further examination on suspicion of PCa. Impact Serum PSA as a clinical marker could be improved by adjustment for AR-genotype.
|
|
| 9. |
- Björkgren, Ida, et al.
(author)
-
Imbalanced lipid homeostasis in the conditional Dicer1 knockout mouse epididymis causes instability of the sperm membrane.
- 2015
-
In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860. ; 29:2, s. 433-442
-
Journal article (peer-reviewed)abstract
- During epididymal sperm maturation, the lipid content of the sperm membrane is modified, which facilitates sperm motility and fertility. However, little is known about the mechanisms regulating the maturation process. By generating a conditional knockout (cKO) of Dicer1 in the proximal part of the mouse epididymis, we studied the role of RNA interference in epididymal functions. The Dicer1 cKO epididymis displayed an altered lipid homeostasis associated with a 0.6-fold reduction in the expression of the gene elongation of very long chain fatty acids-like 2, an enzyme needed for production of long-chain polyunsaturated fatty acids (PUFAs). Furthermore, the expression of several factors involved in cholesterol synthesis was up-regulated. Accordingly, the Dicer1 cKO sperm membrane showed a 0.7-fold decrease in long-chain PUFAs, whereas the amount of cholesterol in acrosome-reacted sperm displayed a 1.7-fold increase. The increased cholesterol:PUFA ratio of the sperm membrane caused breakage of the neck and acrosome region and immotility of sperm. Dicer1 cKO mice sperm also displayed reduced ability to bind to and fertilize the oocyte in vitro. This study thus shows that Dicer1 is critical for lipid synthesis in the epididymis, which directly affects sperm membrane integrity and male fertility.-Björkgren, I., Gylling, H., Turunen, H., Huhtaniemi, I., Strauss, L., Poutanen, M., Sipilä, P. Imbalanced lipid homeostasis in the conditional Dicer1 knockout mouse epididymis causes instability of the sperm membrane.
|
|
| 10. |
- Boonen, Steven, et al.
(author)
-
Influence of bone remodelling rate on quantitative ultrasound parameters at the calcaneus and DXA BMDa of the hip and spine in middle-aged and elderly European men: the European Male Ageing Study (EMAS)
- 2011
-
In: European Journal of Endocrinology. - 1479-683X. ; 165:6, s. 977-986
-
Journal article (peer-reviewed)abstract
- Objective: To assess the influence of sex hormones on markers of bone turnover and to explore the association between these markers and bone health in middle-aged and elderly European men. Design: A cross-sectional population-based survey. Methods: Men aged 40-79 years were recruited from population registers in eight European centres. Subjects completed a postal questionnaire which included questions concerning lifestyle and were invited to undergo quantitative ultrasound (QUS) of the calcaneus and to provide a fasting blood sample from which the bone markers serum N-terminal propeptide of type 1 procollagen (P1NP) and crosslinks (beta C-terminal cross-linked telopeptide (beta-cTX)), total testosterone, total oestradiol (E-2), sex hormone-binding globulin (SHBG) and insulin-like growth factor 1 (IGF1) were measured. Dualenergy X-ray absorptiometry (DXA) of the hip and lumbar spine was performed in two centres. Results: A total of 3120, mean age 59.9 years (S.D. = 11.0) were included. After adjustment for centre, age, height, weight, lifestyle factors, season and other hormones, total and free E-2 were negatively associated with beta-cTX but not P1NP while SHBG, IGF1 and parathyroid hormone (PTH) were positively associated with both beta-cTX and P1NP. Total or free testosterone was not independently associated with either bone marker. After the same adjustments, higher levels of both bone markers were significantly associated with lower QUS parameters and lower DXA-assessed bone density at the total hip and lumbar spine. Conclusions: E-2, SHBG, IGF1 and PTH contribute significantly to the regulation/rate of bone turnover in middle-aged and older European men. Higher rates of bone remodelling are negatively associated with male bone health.
|
|
| 11. |
- Corona, Giovanni, et al.
(author)
-
Age-Related Changes in General and Sexual Health in Middle-Aged and Older Men: Results from the European Male Ageing Study (EMAS)
- 2010
-
In: Journal of Sexual Medicine. - : Oxford University Press (OUP). - 1743-6109 .- 1743-6095. ; 7:4, s. 1362-1380
-
Journal article (peer-reviewed)abstract
- Introduction. Limited information is available concerning the general and sexual health status of European men. Aim. To investigate the age-related changes in general and sexual health in middle-aged and older men from different countries of the European Union. Methods. This is a cross-sectional multicenter survey performed on a sample of 3,369 community-dwelling men aged 40-79 years old (mean 60 +/- 11 years). Subjects were randomly selected from eight European centers including centers from nontransitional (Florence [Italy], Leuven [Belgium], Malmo [Sweden], Manchester [United Kingdom], Santiago de Compostela [Spain]) and transitional countries (Lodz [Poland], Szeged [Hungary], Tartu [Estonia]). Main Outcome Measures. Different parameters were evaluated including the Beck's Depression Inventory for the quantification of depressive symptoms, the Short Form-36 Health Survey for the assessment of the quality of life (QoL), the International Prostate Symptom Score for the evaluation of lower urinary tract symptoms, and the European Male Ageing Study sexual function questionnaire for the study of sexual function. Results. More than 50% of subjects reported the presence of one or more common morbidities. Overall, hypertension (29%), obesity (24%), and heart diseases (16%) were the most prevalent conditions. Around 30% of men reported erectile dysfunction (ED) and 6% reported severe orgasmic impairment, both of which were closely associated with age and concomitant morbidities. Only 38% of men reporting ED were concerned about it. Furthermore, concern about ED increased with age, peaking in the 50-59 years age band, but decreased thereafter. Men in transitional countries reported a higher prevalence of morbidities and impairment of sexual function as well as a lower QoL. Conclusion. Sexual health declined while concomitant morbidities increased in European men as a function of age. The burden of general and sexual health is higher in transitional countries, emphasizing the need to develop more effective strategies to promote healthy aging for men in these countries. Corona G, Lee DM, Forti G, O'Connor DB, Maggi M, O'Neill TW, Pendleton N, Bartfai G, Boonen S, Casanueva FF, Finn JD, Giwercman A, Han TS, Huhtaniemi IT, Kula K, Lean MEJ, Punab M, Silman AJ, Vanderschueren D, Wu FCW, and EMAS Study Group. Age-related changes in general and sexual health in middle-aged and older men: Results from the European Male Ageing Study (EMAS). J Sex Med 2010;7:1362-1380.
|
|
| 12. |
- Corona, Giovanni, et al.
(author)
-
Self-Reported Shorter Than Desired Ejaculation Latency and Related Distress—Prevalence and Clinical Correlates : Results From the European Male Ageing Study
- 2021
-
In: Journal of Sexual Medicine. - : Oxford University Press (OUP). - 1743-6095. ; 18:5, s. 908-919
-
Journal article (peer-reviewed)abstract
- Background: Few data have looked at the occurrence and clinical correlates of self-reported shorter than desired ejaculation latency (rapid ejaculation, RE) and its related distress in the general population. Aim: To determine the prevalence and clinical correlates of self-reported RE and RE- related distress in middle age and older European men. Methods: Subjects were recruited from population samples of men aged 40-79 years across 8 European centers. Outcomes: Self-reported RE and its related distress were derived from the European male Aging Study (EMAS) sexual function questionnaire (EMAS-SFQ). Beck's depression Inventory (BDI) was used for the quantification of depressive symptoms, the Short Form 36 health survey (SF-36) for the assessment of the quality of life, the International Prostate Symptom Score (IPSS) for the evaluation of lower urinary tract symptoms. Results: About 2,888 community dwelling men aged 40-79 years old (mean 58.9 ± 10.8 years) were included in the analysis. Among the subjects included, 889 (30.8%) self-reported RE. Among them, 211 (7.3%) claimed to be distressed (5.9% and 1.4% reported mild or moderate-severe distress, respectively). Increasing levels of RE-related distress were associated with a progressive worse sexual functioning, higher risk of ED and with couple impairment, along with a higher prevalence of depressive symptoms (all P < 0.05). Furthermore, a worse quality of life and higher IPSS score were associated with RE-related distress (all P < 0.05). The aforementioned results were confirmed even when patients using drugs possibly interfering with ejaculation or those without a stable relationship were excluded from the analysis. Clinical Implications: RE is a frequent condition in men from the general population; however, its related distress is relatively modest. Nonetheless, men with any degree of self-reported RE show increasing levels of depression, worse quality of life and worse couple satisfaction. Strengths & Limitations: This is the first study estimating the prevalence of self-reported RE and its related distress, along with their biological and psychological correlates, in a population sample of European middle age and older men. However, is should be recognized that the diagnosis of RE was derived from patient reports and not supported by Intra-ejaculatory-Latency-Time (IELT) measurements. Conclusion: Self-reported RE is relatively common in European men aged more than 40 years. The reported limited RE-related distress may explain the relatively low number of medical consultations for RE. RE-related distress is associated with worse sexual function, couple impairment, and more LUTS resulting in a worse quality of life and mood disturbances. Corona G, Rastrelli G, Bartfai G, et al. Self-Reported Shorter Than Desired Ejaculation Latency and Related Distress—Prevalence and Clinical Correlates: Results From the European Male Ageing Study. J Sex Med Rev 2021;18:908–919.
|
|
| 13. |
- Deiktakis, Eleftherios E., et al.
(author)
-
Impact of add-back FSH on human and mouse prostate following gonadotropin ablation by GnRH antagonist treatment
- 2022
-
In: Endocrine Connections. - 2049-3614. ; 11:6
-
Journal article (peer-reviewed)abstract
- Objective: During androgen ablation in prostate cancer by the standard gonadotropin-releasing hormone (GnRH) agonist treatment, only luteinizing hormone (LH) is permanently suppressed while circulating follicle-stimulating hormone (FSH) rebounds. We explored direct prostatic effects of add-back FSH, after androgen ablation with GnRH antagonist, permanently suppressing both gonadotropins. Methods: The effects of recombinant human (rFSH) were examined in mice treated with vehicle (controls), GnRH antagonist degarelix (dgx), dgx + rFSH, dgx + flutamide, or dgx + rFSH + flutamide for 4 weeks. Prostates and testes size and expression of prostate-specific and/or androgen-responsive genes were measured. Additionally, 33 young men underwent dgx-treatment. Seventeen were supplemented with rFSH (weeks 1–5), and all with testosterone (weeks 4–5). Testosterone, gondotropins, prostate-specific antigen (PSA), and inhibin B were measured. Results: In dgx and dgx + flutamide treated mice, prostate weight/body weight was 91% lower than in controls, but 41 and 11%, respectively, was regained by rFSH treatment (P = 0.02). The levels of seminal vesicle secretion 6, Pbsn, Nkx3.1, beta-microseminoprotein, and inhibin b were elevated in dgx + rFSH-treated animals compared with only dgx treated (all P < 0.05). In men, serum inhibin B rose after dgx treatment but was subsequently suppressed by testosterone. rFSH add-back had no effect on PSA levels. Conclusions: These data provide novel evidence for the direct effects of FSH on prostate sizand gene expression in chemically castrated mice. However, in chemically castrated men, FSH had no effect on PSA production. Whether FSH effects on the prostate in humans also require suppression of the residual adrenal-derived androgens and/or a longer period of rFSH stimulation, remains to be explored.
|
|
| 14. |
- Dizeyi, Nishtman, et al.
(author)
-
Cell-based evidence regarding the role of FSH in prostate cancer
- 2019
-
In: Urologic Oncology: Seminars and Original Investigations. - : Elsevier BV. - 1078-1439. ; 37:4, s. 1-290
-
Journal article (peer-reviewed)abstract
- Introduction: Conversion of androgen-responsive prostate cancer (CaP) to castration-resistant CaP) is associated with an acceleration of the disease that often requires treatment modalities other than androgen deprivation therapy only. Recently, follicle-stimulating hormone (FSH) has been shown to play a role in CaP growth, and clinical data showed that high serum concentration of FSH in chemically castrated CaP patients was associated with a shorter time of progression to castration-resistant CaP. In this study, we sought to investigate if FSH could have direct effects on CaP cells, possibly through the androgen receptor and androgen receptor regulated genes, such as prostate-specific antigen (PSA). Materials and methods: The human CaP cell lines PC-3, LNCaP and C4-2, and nonmalignant PNT1A cells, were utilized to investigate the effects of FSH. qPCR, Western blotting analysis, and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymetoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium assays were performed in order to analyze the FSH effects. Results: The FSH receptor was present in all cell lines except PNT1A. FSH significantly increased PSA mRNA (P < 0.01) and protein (P < 0.03) levels in C4-2 cells in a dose-dependent manner. In LNCaP cells, FSH also increased PSA protein level, although to a lesser extent than in C4-2 cells, and the expression was reduced by the antiandrogen enzalutamide. In PC-3 cells, FSH was shown to increase their proliferation (P < 0.03) and β-catenin expression. Conclusion: These findings demonstrate that FSH may have a direct effect in CaP in an androgen-depleted environment. However, further research is needed to understand the significance of direct FSH action in the maintenance of CaP growth at the different phases of transition from androgen dependence to androgen independence.
|
|
| 15. |
- Doroszko, Milena, et al.
(author)
-
GnRH antagonist treatment of malignant adrenocortical tumors
- 2019
-
In: Endocrine-Related Cancer. - : BIOSCIENTIFICA LTD. - 1351-0088 .- 1479-6821. ; 26:1, s. 103-117
-
Journal article (peer-reviewed)abstract
- Aberrantly expressed G protein-coupled receptors in tumors are considered as potential therapeutic targets. We analyzed the expressions of receptors of gonadotropin-releasing hormone (GNRHR), luteinizing hormone/chorionic gonadotropin (LHCGR) and follicle-stimulating hormone (FSHR) in human adrenocortical carcinomas and assessed their response to GnRH antagonist therapy. We further studied the effects of the GnRH antagonist cetrorelix acetate (CTX) on cultured adrenocortical tumor (ACT) cells (mouse C alpha 1 and Y-1, and human H295R), and in vivo in transgenic mice (SV40 T-antigen expression under inhibin a promoter) bearing Lhcgr and Gnrhr in ACT. Both models were treated with control (CT), CTX, human chorionic gonadotropin (hCG) or CTX+hCG, and their growth and transcriptional changes were analyzed. In situ hybridization and qPCR analysis of human adrenocortical carcinomas (n = 11-13) showed expression of GNRHR in 54/73%, LHCGR in 77/100% and FSHR in 0%, respectively. CTX treatment in vitro decreased cell viability and proliferation, and increased caspase 3/7 activity in all treated cells. In vivo, CTX and CTX+hCG (but not hCG alone) decreased ACT weights and serum LH and progesterone concentrations. CTX treatment downregulated the tumor markers Lhcgr and Gata4. Upregulated genes included Grb10, Rerg, Nfatc and Gnas, all recently found to be abundantly expressed in healthy adrenal vs ACT. Our data suggest that CTX treatment may improve the therapy of human adrenocortical carcinomas by direct action on GNRHR-positive cancer cells inducing apoptosis and/or reducing gonadotropin release, directing tumor cells towards a healthy adrenal gene expression profile.
|
|
| 16. |
- Dubbaka Venu, Pradeep Reddy, 1982-, et al.
(author)
-
Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool
- 2008
-
In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 319:5863, s. 611-613
-
Journal article (peer-reviewed)abstract
- In the mammalian ovary, progressive activation of primordial follicles from the dormant pool serves as the source of fertilizable ova. Menopause, or the end of female reproductive life, occurs when the primordial follicle pool is exhausted. However, the molecular mechanisms underlying follicle activation are poorly understood. We provide genetic evidence that in mice lacking PTEN (phosphatase and tensin homolog deleted on chromosome 10) in oocytes, a major negative regulator of phosphatidylinositol 3-kinase (PI3K), the entire primordial follicle pool becomes activated. Subsequently, all primordial follicles become depleted in early adulthood, causing premature ovarian failure (POF). Our results show that the mammalian oocyte serves as the headquarters of programming of follicle activation and that the oocyte PTEN-PI3K pathway governs follicle activation through control of initiation of oocyte growth.
|
|
| 17. |
- Dubbaka Venu, Pradeep Reddy, 1982-, et al.
(author)
-
PDK1 signaling in oocytes controls reproductive aging and lifespan by manipulating the survival of primordial follicles
- 2009
-
In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 18:15, s. 2813-2824
-
Journal article (peer-reviewed)abstract
- The molecular mechanisms that control reproductive aging and menopausal age in females are poorly understood. Here, we provide genetic evidence that 3-phosphoinositide-dependent protein kinase-1 (PDK1) signaling in oocytes preserves reproductive lifespan by maintaining the survival of ovarian primordial follicles. In mice lacking the PDK1-encoding gene Pdk1 in oocytes, the majority of primordial follicles are depleted around the onset of sexual maturity, causing premature ovarian failure (POF) during early adulthood. We further showed that suppressed PDK1-Akt-p70 S6 kinase 1 (S6K1)-ribosomal protein S6 (rpS6) signaling in oocytes appears to be responsible for the loss of primordial follicles, and mice lacking the Rps6 gene in oocytes show POF similar to that in Pdk1-deficient mice. In combination with our earlier finding that phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in oocytes suppresses follicular activation, we have now pinpointed the molecular network involving phosphatidylinositol 3 kinase (PI3K)/PTEN-PDK1 signaling in oocytes that controls the survival, loss and activation of primordial follicles, which together determine reproductive aging and the length of reproductive life in females. Underactivation or overactivation of this signaling pathway in oocytes is shown to cause pathological conditions in the ovary, including POF and infertility.
|
|
| 18. |
- Dupont, Jolan, et al.
(author)
-
Inflammatory markers are associated with quality of life, physical activity, and gait speed but not sarcopenia in aged men (40–79 years)
- 2021
-
In: Journal of Cachexia, Sarcopenia and Muscle. - : Wiley. - 2190-5991 .- 2190-6009. ; 12:6, s. 1818-1831
-
Journal article (peer-reviewed)abstract
- Background: Age-related chronic low-grade inflammation (inflammaging) is one of the proposed mechanisms behind sarcopenia. However, findings regarding inflammatory markers in sarcopenic older adults are conflicting. This study aimed to determine the association between inflammatory markers, prevalent as well as incident sarcopenia, sarcopenia-defining parameters, quality of life (QoL), and physical activity in middle-aged and older men. Methods: Men aged 40–79 years (mean 59.66 ± 11.00y) were recruited from population registers in eight European centres for participation in the European Male Aging study (EMAS). Subjects were assessed at baseline (2003–2005) and again after a median follow-up of 4.29 years. In 2577 participants, associations between baseline inflammatory markers [high-sensitive C-reactive protein (hs-CRP), white blood cell count (WBC), albumin] and baseline physical activity (PASE) and QoL (SF-36) were analysed. In the Leuven and Manchester cohort (n = 447), data were available on muscle mass (whole-body dual X-ray absorptiometry) and strength. In this subgroup, cross-sectional associations between baseline inflammatory markers and sarcopenia-defining parameters (handgrip strength, chair stand test, appendicular lean mass, and gait speed) and prevalent sarcopenia were examined. In a further subgroup (n = 277), associations with knee extensor strength were explored. Longitudinally, predictive value of baseline inflammation on functional decline, physical activity, QoL, and incident sarcopenia was examined. Subgroup analyses were performed in subgroups with chronic inflammation and stratified by age. Linear and logistic regressions were used, adjusted for age, body mass index, centre, and smoking. Results: At baseline, hs-CRP and WBC were negatively associated with PASE score (hs-CRP: β = −7.920, P < 0.001; and WBC: β = −4.552, P < 0.001) and the physical component score of SF-36 (hs-CRP: β = −1.025, P < 0.001; and WBC: β = −0.364, P < 0.001). Baseline WBC levels were negatively associated with gait speed (β = −0.013; P = 0.025), quadriceps isometric 90° (β = −5.983; P = 0.035) and isokinetic 60°/s peak torque/body weight (β = −5.532; P = 0.027). The prevalence of sarcopenia at baseline was 18.1% (n = 81). Of those without sarcopenia at baseline, 64 (18.6%) satisfied criteria for sarcopenia at follow-up. There were no significant associations between baseline inflammatory markers and either prevalent or incident sarcopenia, or change in level of sarcopenia-defining parameters between baseline and follow-up. Conclusions: In middle-aged and older men, hs-CRP and WBC were negatively associated with QoL and PASE scores, while WBC was negatively associated with gait speed and knee strength. Associations with hs-CRP remained significant in all ages, whereas WBC levels were only associated with PASE, gait speed and knee strength in older adults (60–79 years). Baseline inflammatory markers (hs-CRP, WBC and albumin) did not predict functional decline, decline in physical activity, decreased QoL or incident sarcopenia.
|
|
| 19. |
- Eendebak, Robert J.A.H., et al.
(author)
-
Elevated luteinizing hormone despite normal testosterone levels in older men-natural history, risk factors and clinical features
- 2018
-
In: Clinical Endocrinology. - : Wiley. - 0300-0664. ; 88:3, s. 479-490
-
Journal article (peer-reviewed)abstract
- Objective: Elevated luteinizing hormone (LH) with normal testosterone (T) suggests compensated dysregulation of the gonadal axis. We describe the natural history, risk factors and clinical parameters associated with the development of high LH (HLH, LH >9.4 U/L) in ageing men with normal T (T ≥ 10.5 nmol/L). Design, Patients and Measurements: We conducted a 4.3-year prospective observational study of 3369 community-dwelling European men aged 40-79 years. Participants were classified as follows: incident (i) HLH (n = 101, 5.2%); persistent (p) HLH (n = 128, 6.6%); reverted (r) HLH (n = 46, 2.4%); or persistent normal LH (pNLH, n = 1667, 85.8%). Potential predictors and changes in clinical features associated with iHLH and rHLH were analysed using regression models. Results: Age >70 years (OR = 4.12 [2.07-8.20]), diabetes (OR = 2.86 [1.42-5.77]), chronic pain (OR = 2.53 [1.34-4.77]), predegree education (OR = 1.79 [1.01-3.20]) and low physical activity (PASE ≤ 78, OR = 2.37 [1.24-4.50]) predicted development of HLH. Younger age (40-49 years, OR = 8.14 [1.35-49.13]) and nonsmoking (OR = 5.39 [1.48-19.65]) predicted recovery from HLH. Men with iHLH developed erectile dysfunction, poor health, cardiovascular disease (CVD) and cancer more frequently than pNLH men. In pHLH men, comorbidities, including CVD, developed more frequently, and cognitive and physical function deteriorated more, than in pNLH men. Men with HLH developed primary hypogonadism more frequently (OR = 15.97 [5.85-43.60]) than NLH men. Men with rHLH experienced a small rise in BMI. Conclusions: Elevation of LH with normal T is predicted by multiple factors, reverts frequently and is not associated with unequivocal evidence of androgen deficiency. High LH is a biomarker for deteriorating health in aged men who tend to develop primary hypogonadism.
|
|
| 20. |
- Eendebak, Robert J A H, et al.
(author)
-
The androgen receptor gene CAG repeat in relation to 4-year changes in androgen-sensitive endpoints in community-dwelling older European men
- 2016
-
In: European Journal of Endocrinology. - 0804-4643. ; 175:6, s. 583-593
-
Journal article (peer-reviewed)abstract
- Context: The androgen receptor (AR) gene exon 1 CAG repeat length has been proposed to be a determinant of between-individual variations in androgen action in target tissues, which might regulate phenotypic differences of human ageing. However, findings on its phenotypic effects are inconclusive. Objective: To assess whether the AR CAG repeat length is associated with longitudinal changes in endpoints that are influenced by testosterone (T) levels in middle-Aged and elderly European men. Design: Multinational European observational prospective cohort study. Participants: A total of 1887 men (mean ± s.d. age: 63 ± 11 years; median follow up: 4.3 years) from centres of eight European countries comprised the analysis sample after exclusion of those with diagnosed diseases of the hypothalamic-pituitary-testicular (HPT) axis. Main outcome measures: Longitudinal associations between the AR CAG repeat and changes in androgen-sensitive endpoints (ASEs) and medical conditions were assessed using regression analysis adjusting for age and centre. The AR CAG repeat length was treated as both a continuous and a categorical (6-20; 21-23; 24-39 repeats) predictor. Additional analysis investigated whether results were independent of baseline T or oestradiol (E2) levels. Results: The AR CAG repeat, when used as a continuous or a categorical predictor, was not associated with longitudinal changes in ASEs or medical conditions after adjustments. These results were independent of T and E2 levels.
|
|
| 21. |
- Elenkov, Angel, et al.
(author)
-
Non-reproductive effects of follicle-stimulating hormone in young men
- 2023
-
In: Andrology. - : Wiley. - 2047-2919 .- 2047-2927. ; 11:3, s. 471-477
-
Journal article (peer-reviewed)abstract
- Objective: Follicle-stimulating hormone (FSH) receptor expression has been reported in many extra-gonadal tissues, raising the question of non-reproductive effects of FSH. Because of increasing usage of FSH in treatment of male infertility, deeper knowledge of possible harmful off-target effects of FSH is warranted. Methods: In total, 33 healthy young men (mean age 30 years) were included in the study. All received an s.c. injection of gonadotropin-releasing hormone (GnRH) antagonist and n = 16 were randomized to 300 IU recombinant FSH (300 IE 3 times/week) for 5 weeks at first visit (V1) whereas n = 17 served as controls. Blood samples were taken at (V1), after 3 weeks (V2), and after 5 weeks (V3), when the study ended. At V2, all subjects received 1000 mg testosterone undecanoate i.m. A standard set of bio- and inflammatory markers were compared between the groups using the Mann–Whitney test adjusted for multiple testing. Results: As compared to controls, the FSH treated men had higher SHBG and albumin concentrations at V2 (p = 0.024 and 0.027, respectively), and lower levels of alanine aminotransferase (p = 0.026) and magnesium (p = 0.028) at V3. However, none of the results remained statistically significant after Bonferroni correction (p > 0.0011). Conclusions: FSH had no significant effects on non-reproductive organs when given in standard therapeutic doses to young men for 5 weeks. Therefore, the FSH treatment can be considered safe in otherwise healthy young men, constituting candidates for the infertility treatment with FSH.
|
|
| 22. |
- Eriksson, Anna-Lena, 1971, et al.
(author)
-
Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men.
- 2018
-
In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 103:3, s. 991-1004
-
Journal article (peer-reviewed)abstract
- Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability.To investigate the genetic regulation of serum E2 and E1 in men.Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts.Genetic determinants of serum E2 and E1 levels.Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance.Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.
|
|
| 23. |
- Feng, Yi, et al.
(author)
-
Spatiotemporal expression of androgen receptors in the female rat brain during the oestrous cycle and the impact of exogenous androgen administration: a comparison with gonadally intact males.
- 2010
-
In: Molecular and cellular endocrinology. - : Elsevier BV. - 1872-8057 .- 0303-7207. ; 321:2, s. 161-74
-
Journal article (peer-reviewed)abstract
- Little is known about the regulation and cellular distribution of androgen receptors (ARs) in female rodent brains at various stages of the oestrous cycle. This information is critical for further studies of androgen signalling in the regulation of brain function under physiological and pathophysiological conditions. In this report, we show that the distribution of AR immunoreactivity in the female rat brain is consistent with reported AR mRNA hybridisation signals in the male brain, except for the dentate gyrus of the hippocampus. Immunohistochemical and Western blot analyses performed herein revealed that the onset of region-specific changes in AR proteins was strongly correlated with circulating and ovarian levels of estradiol and testosterone across the oestrous cycle. During the metestrus and diestrus stages, however, the highest levels of AR expression were abolished by chronic dihydrotestosterone (DHT) treatment. This demonstrates that fluctuations in endogenous androgens are required for the regulation of AR expression in the female rat brain. Colocalisation studies revealed that: (1) anatomical variations in AR protein localisation existed between female and male brains, (2) AR immunoreactivity was both neuronal and non-neuronal, and (3) AR protein expression was lower in female rat brains at all stages of the oestrous cycle compared to age-matched males. Our results indicate the presence of regional sex differences in AR expression and changes in the proportion of AR between different subcellular compartments. Furthermore, DHT was found to down-regulate the level of AR in the subcellular compartment in females in a region-specific manner. As a whole, the present study provides the first step toward understanding the dynamics of AR expression and regulation in the brain during normal physiological conditions and for differences in neuronal androgen effects based on sex.
|
|
| 24. |
- Gonzalez, Betina, et al.
(author)
-
Endogenously elevated androgens alter the developmental programming of the hypothalamic-pituitary axis in male mice.
- 2011
-
In: Molecular and cellular endocrinology. - : Elsevier BV. - 1872-8057 .- 0303-7207. ; 332:1-2, s. 78-87
-
Journal article (peer-reviewed)abstract
- Transgenic male mice that express human chorionic gonadotropin (hCG) α and β subunits constitutively hypersecrete hCG and produce elevated levels of androgens. The aim of this study was to characterize the hypothalamic-pituitary function of these transgenic (hCGαβ+) males by focusing on FSH regulation. Serum FSH levels and pituitary mRNA expression of Fshb, Lhb, Cga, Gnrhr and Esr1 were reduced, whereas Fst expression was increased in prepubertal hCGαβ+ males as compared with wild-type. In the hypothalamus, Cyp19a1 expression, GnRH concentration and ex-vivo GnRH pulsatility were elevated in prepubertal hCGαβ+ mice, whereas Kiss1 expression was decreased prepubertally and Gad67 expression was elevated neonatally. The effect of androgens on the developmental programming of the hypothalamic-pituitary axis of hCGαβ+ males was evaluated by perinatal and prepubertal antiandrogen (flutamide) administration. Our studies identified a critical window between gestational day 18 and postnatal day 14, during which chronically elevated androgens and/or their locally produced metabolites activate the hypothalamus and concomitantly shut-down the gonadotropin axis.
|
|
| 25. |
- Han, Thang S, et al.
(author)
-
Associations of obesity with socioeconomic and lifestyle factors in middle-aged and elderly men: European Male Aging Study (EMAS).
- 2015
-
In: European Journal of Endocrinology. - 1479-683X. ; 172:1
-
Journal article (peer-reviewed)abstract
- Background: Social and lifestyle influences on age-related changes in body morphology are complex because lifestyle and physiological response to social stress can affect body fat differently. Objective: We examined the associations of socioeconomic status (SES) and lifestyle factors with body mass index (BMI) and waist circumference (WC) in middle-aged and elderly European men. Design and setting: Cross-sectional study of 3,319 men aged 40-79 recruited from eight European centres. Outcomes: We estimated relative risk ratios (RRRs) of overweight/obesity associated with unfavourable SES and lifestyles. Results: The prevalence of BMI 30kg/m2 or WC 102cm rose linearly with age, except in the 8th decade when high BMI, but not high WC, declined. Among men aged 40-59y, compared to non-smokers or most active men, centre and BMI adjusted RRRs for having a WC between 94-101.9cm increased by 1.6-fold in current smokers, and 2.7-fold in least active men, maximal at 2.8-fold in least active men who smoked. Similar patterns but greater RRRs were observed for men with WC≥102cm, notably 8.4-fold greater in least active men who smoked. Compared to men in employment, those who were not in employment had increased risk of having a high WC by 1.4-fold in the 40-65y group and by 1.3-fold in the 40-75y group. These relationships were weaker among elderly men. Conclusion: Unfavourable SES and lifestyles associate with increased risk of obesity, especially in middle-aged men. The combination of inactivity and smoking was the strongest predictor of high WC, providing a focus for health promotion and prevention at an early age.
|
|
