Ilpo Huhtaniemi

Imperial College London, Londinium, England, United Kingdom

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Publications (349)1533.69 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The advent of technologies to genetically manipulate the mouse genome has revolutionised research approaches, providing a unique platform to study the causality of reproductive disorders in vivo. With the relative ease of generating genetically modified mouse models, the last two decades have yielded multiple loss-of-function and gain-of-function mutation mouse models to explore the role of gonadotrophins and their receptors in reproductive pathologies. This work has provided key insights into the molecular mechanisms underlying reproductive disorders with altered gonadotrophin action, revealing the fundamental roles of these pituitary hormones and their receptors in the hypothalamic-pituitary-gonadal axis. This review will describe genetically modified mouse models of gonadotrophins and their receptors with enhanced or diminished actions, specifically focussing on the male. We will discuss the mechanistic insights gained from these models into male reproductive disorders, and discuss the relationship and understanding provided into male human reproductive disorders originating from altered gonadotrophin action.
    Reproduction (Cambridge, England). 07/2014;
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    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.
  • Ilpo T Huhtaniemi
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    ABSTRACT: Andropause or late-onset hypogondism (LOH) is a situation where a middle-aged or older man has low serum testosterone (T) in conjunction with diffuse symptoms reminiscent of those of genuine male hypogonadism (e.g. reduced sexual function, loss of vigor, muscle weakness, depression). Opinions about the diagnostic criteria, prevalence and treatment options of andropause vary considerably amongst experts. We review here some salient findings on the prevalence, diagnostic criteria and impact on health of andropause, obtained from the European Male Ageing Study (EMAS), a multicenter study of ageing among community-dwelling middle-aged and older men.
    Annales d Endocrinologie 04/2014; · 1.02 Impact Factor
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    ABSTRACT: Reduced sex hormone-binding globulin (SHBG) concentration predicts insulin resistance and type 2 diabetes but its association with cardiovascular disease (CVD) risk is unclear. We examined the association between SHBG and cardiovascular risk factors, independently of total testosterone (TT), in young men. Observational, cross-sectional study SETTING: General community PARTICIPANTS: 2,716 31-year old men in the 1966 Northern Finland Birth Cohort with clinical examination data and fasting blood samples. Blood pressure (BP), lipids and C-reactive protein (CRP) as biological CVD risk markers. SHBG concentration was significantly and inversely related to systolic and diastolic BP, triglycerides and CRP but positively to high-density lipoprotein (HDL) cholesterol after adjusting for insulin, body mass index, waist circumference, smoking, education and physical activity (all P <0.05). These linearly graded associations persisted with additional adjustment for TT. SHBG was significantly associated with total cholesterol only with adjustment for covariates and TT (P <0.05). The direction and magnitude of associations between TT and risk factors were variable but further adjustment for insulin, adiposity and SHBG showed positive associations between TT and blood pressure, total and low-density lipoprotein cholesterol and triglycerides and an inverse association with CRP (all P<0.05), but its relation with HDL-cholesterol was no longer significant. In this cohort of young adult men, higher SHBG concentration was associated with a more favourable CVD risk profile, independently of TT. SHBG concentration modified the associations of TT with CVD risk factors.
    European Journal of Endocrinology 03/2014; · 3.14 Impact Factor
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    ABSTRACT: Testosterone (T), alone or in combination with progestin, provides a promising approach to hormonal male contraception. Its principle relies on enhanced negative feedback of exogenous T to suppress gonadotropins, thereby blocking the testicular T production needed for spermatogenesis, while simultaneously maintaining the extragonadal androgen actions, such as potency and libido, to avoid hypogonadism. A serious drawback of the treatment is that a significant proportion of men do not reach azoospermia or severe oligozoospermia, commensurate with contraceptive efficacy. We tested here, using hypogonadal luteinizing hormone/choriongonadotropin receptor (LHCGR) knockout (LHR(-/-)) mice, the basic principle of the T-based male contraceptive method, that a specific T dose could maintain extragonadal androgen actions without simultaneously activating spermatogenesis. LHR(-/-) mice were treated with increasing T doses, and the responses of their spermatogenesis and extragonadal androgen actions (including gonadotropin suppression and sexual behavior) were assessed. Conspicuously, all dose responses to T were practically superimposable, and no dose of T could be defined that would maintain sexual function and suppress gonadotropins without simultaneously activating spermatogenesis. This finding, never addressed in clinical contraceptive trials, is not unexpected in light of the same androgen receptor mediating androgen actions in all organs. When extrapolated to humans, our findings may jeopardize the current approach to hormonal male contraception and call for more effective means of inhibiting intratesticular T production or action, to achieve consistent spermatogenic suppression.-Oduwole, O. O., Vydra, N., Wood, N. E. M., Samanta, L., Owen, L., Keevil, B., Donaldson, M., Naresh, K., Huhtaniemi, I. T. Overlapping dose responses of spermatogenic and extragonadal testosterone actions jeopardize the principle of hormonal male contraception.
    The FASEB Journal 03/2014; · 5.70 Impact Factor
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    Laura D. Ratner, Susana B. Rulli, Ilpo T. Huhtaniemi
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    ABSTRACT: The development of genetically modified animals has been useful to understand the mechanisms involved in the regulation of the gonadotropin function. It is well known that alterations in the secretion of a single hormone is capable of producing profound reproductive abnormalities. Human chorionic gonadotropin (hCG) is a glycoprotein hormone normally secreted by the human placenta, and structurally and functionally it is related to pituitary LH. LH and hCG bind to the same LH/hCG receptor, and hCG is often used as an analog of LH to boost gonadotropin action. There are many physiological and pathological conditions where LH/hCG levels and actions are elevated. In order to understand how elevated LH/hCG levels may impact on the hypothalamic-pituitary-gonadal axis we have developed a transgenic mouse model with chronic hCG hypersecretion. Female mice develop many gonadal and extragonadal phenotypes including obesity, infertility, hyperprolactinemia, and pituitary and mammary gland tumors. This article summarizes recent findings on the mechanisms involved in pituitary gland tumorigenesis and hyperprolactinemia in the female mice hypersecreting hCG, in particular the relationship of progesterone with the hyperprolactinemic condition of the model. In addition, we describe the role of hyperprolactinemia as the main cause of infertility and the phenotypic abnormalities in these mice, and the use of dopamine agonists bromocriptine and cabergoline to normalize these conditions.
    Reproductive biology 03/2014; 14(1):9-15. · 1.22 Impact Factor
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    ABSTRACT: Transgenic female mice overexpressing the α- and β- subunits of human chorionic gonadotropin (hCGαβ+) exhibited precocious puberty, as evidenced by early vaginal opening. Chronically elevated hCG in 21-day-old hCGαβ+ females stimulated gonadal androgen production, which exerted negative feedback over the endogenous gonadotropin synthesis, and activated the hypothalamic GnRH pulsatility and gene expression. Transgenic females also exhibited elevated hypothalamic aromatization in the preoptic area (POA), which is the sexually-differentiated area that controls the LH surge in adulthood. Ovariectomy at 14 days of age was unable to rescue this phenotype. However, the blockade of androgen action by flutamide from postnatal day 6 onwards reduced the aromatase levels in the POA of hCGαβ+ females. Our results suggest that early exposure of females to androgen action during a critical period between postnatal days 6 to 14 induces sex-specific organizational changes of the brain, which affect the aromatase expression in the POA at the onset of precocious puberty.
    Molecular and Cellular Endocrinology 01/2014; · 4.04 Impact Factor
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    ABSTRACT: We previously reported that in male patients consulting for sexual dysfunction, low prolactin (PRL) levels were associated with metabolic syndrome (MetS), arteriogenic erectile dysfunction, and incident major cardiovascular events. The aim of this study is to assess the clinical associations of PRL levels in the European Male Ageing Study (EMAS). EMAS is a prospective, observational cohort of community-dwelling men aged 40-79 years old (mean age 60 ± 11 years old). PRL was available for 2,948 men. Different parameters were evaluated including the Short Form-36 questionnaire, Becks Depression Inventory, the Adverse Life Events Scale, the Physical Activity Scale for the Elderly, and the EMAS sexual function questionnaire (EMAS-SFQ). After the adjustment for confounders, PRL levels were inversely related with worsening of sexual function as compared with the previous year, as derived from change in sexual functioning domain of the EMAS-SFQ (adj. r = -0.043; P = 0.029). The strongest correlation (Wald = 6.840; P = 0.009) was observed between lower PRL levels and reduced enjoyment of orgasmic experiences. Furthermore, an inverse relationship between PRL levels and stressful life events or depressive symptoms was observed. Low PRL was also negatively associated with an unhealthy metabolic phenotype as well as with the MetS (Wald = 5.229; P = 0.022). In line with these data, low PRL was associated with a lower level of physical activity and feeling unhealthier. Low PRL is related to several metabolic, psychological, and sexual unhealthy characteristics in European men. Checking PRL might be useful to stratify men for cardiovascular risk and to encourage appropriate lifestyle changes.
    Journal of Sexual Medicine 01/2014; 11:240. · 3.51 Impact Factor
  • Ilpo T. Huhtaniemi
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    ABSTRACT: L’andropause ou hypogonadisme de survenue tardive est une situation dans laquelle un homme d’âge moyen ou plus âgé présente des taux de testostéronémie bas en conjunction avec une symptomatologie évocatrice d’un authentique hypogonadisme masculin (e.g. diminution de la fonction sexuelle, perte de vitalité, faiblesse musculaire, dépression). Les avis concernant les critères diagnostiques, la prévalence et les stratégies thérapeutiques de l’andropause varient considérablement parmi les experts. Nous revoyons ici les points les plus marquants de la prévalence, des critères diagnostiques et du retentissement sur la santé de l’andropause à partir des données de l’étude européenne des hommes vieillissants (EMAS), étude multi-centrique sur le vieillissement dans une population masculine européenne d’âge moyen ou plus âgée.
    Annales d'Endocrinologie. 01/2014;
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    ABSTRACT: G protein-coupled receptors (GPCRs) transduce signals from a wide variety of extracellular stimuli such as ions, photons, odors, tastants, hormones, and neurotransmitters and hence are central players in communication between the cells of multicellular organisms and their environment. Characterization of these receptors at the molecular level has shown that GPCRs form dimers or oligomers (for simplicity, herein called dimers), yet their function is just beginning to emerge. The activation of GPCRs as dimers presents the opportunity for trans-activation of receptors, where a ligand-bound GPCR can change the activity of a neighboring GPCR. Trans-activation of GPCRs can take place either via transmembrane domains (TMDs) of two or more receptors or through a ligand-bound extracellular domain (ECD) of one receptor to the TMD of another (referred to as intermolecular cooperation), for GPCRs with a distinct ligand-binding ECD such as the glycoprotein hormone receptors. Before explaining the phenomenon of intermolecular cooperation between domains of GPCR dimers, this chapter first discusses the molecular interactions between GPCR dimers, which leads to trans-activation, and then explains various experimental strategies employed to study the significance of intermolecular cooperation either in rescuing the signaling of mutant GPCRs by complementary receptors or in changing the allosteric properties of GPCR dimers. The physiological significance of intermolecular cooperation is also discussed in detail, as well as its clinical significance that lies in the use of agents that selectively activate or inhibit particular signaling pathways or affect GPCR dimer interactions.
    01/2014: pages 239-255; , ISBN: 9781627037785
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    ABSTRACT: Constitutively active mutants (CAMs) of gonadotropin receptors are, in general, rare conditions. Luteinizing hormone-choriogonadotropin receptor (LHCGR) CAMs provoke the dramatic phenotype of familial gonadotropin-independent isosexual male-limited precocious puberty, whereas in females, there is not yet any identified phenotype. Only one isolated follicle-stimulating hormone receptor (FSHR) CAM (Asp567Gly) has so far been detected in a single male patient, besides other FSHR weak CAMs linked to pregnancy-associated ovarian hyperstimulation syndrome or to impaired desensitization and internalization. Several animal models have been developed for studying enhanced gonadotropin action; in addition to unraveling valuable new information about the possible phenotypes of isolated FSHR and LHCGR CAMs in women, the information obtained from these mouse models has served multiple translational goals, including the development of new diagnostic and therapeutic targets as well as the prediction of phenotypes for mutations not yet identified in humans. Mutagenesis and computational studies have shed important information on the physiopathogenic mechanisms leading to constitutive activity of gonadotropin receptors; a common feature in these receptor CAMs is the release of stabilizing interhelical interactions between transmembrane domains (TMDs) 3 and 6 leading to an increase, with respect to the wild-type receptor, in the solvent accessibility at the cytosolic extension of TMDs 3, 5, and 6, which involves the highly conserved Glu/Asp-Arg-Tyr/Trp sequence. In this chapter, we summarize the structural features, functional consequences, and mechanisms that lead to constitutive activation of gonadotropin receptor CAMs and provide information on pharmacological approaches that might potentially modulate gonadotropin receptor CAM function.
    Advances in pharmacology (San Diego, Calif.) 01/2014; 70:37-80.
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    ABSTRACT: Background: vitamin D deficiency has been associated with an increased risk of mortality, but whether this relationship is causal or linked to co-existent comorbidity and adverse life factors remains uncertain. Our objective was to determine whether endogenous 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D) and parathyroid hormone (PTH) levels predicted all-cause, cardiovascular and cancer mortality independently of health and lifestyle factors.Setting: prospective cohort analysis within the European Male Ageing Study.Participants: 2,816 community-dwelling men aged 40-79 years at baseline.Methods: Cox regression was used to examine the association of all-cause mortality with 25(OH)D, 1,25(OH)2D and PTH; cardiovascular and cancer mortality were modelled using competing-risks regression. Results were expressed as hazard ratios (HR) and 95% confidence intervals (CIs) for Cox models; sub-hazard ratios (SHR) and 95% CIs for competing-risks models.Results: a total of 187 men died during a median of 4.3 years of follow-up. Serum levels of 25(OH)D (per 1 SD decrease: HR = 1.45; 95% CI = 1.16, 1.81) and 1,25(OH)2D (per 1 SD decrease: HR = 1.20; 95% CI = 1.00, 1.44) were associated with an increased risk of all-cause mortality after adjusting for age, centre, smoking, self-reported morbidities, physical activity and functional performance. Only levels of 25(OH)D <25 nmol/l predicted cancer mortality (SHR = 3.33; 95% CI = 1.38, 8.04).Conclusion: lower 25(OH)D and 1,25(OH)2D levels independently predicted all-cause mortality in middle-aged and older European men. Associations with cancer mortality were only observed among men with very low levels of 25(OH)D. These associations were only partially explained by the range of adverse health and lifestyle factors measured here.
    Age and Ageing 12/2013; · 3.82 Impact Factor
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    Ilpo Huhtaniemi
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    ABSTRACT: Although suppressed serum testosterone (T) is common in ageing men, only a small proportion of them develop the genuine syndrome of low T associated with diffuse sexual (e.g., erectile dysfunction), physical (e.g. loss of vigor and frailty) and psychological (e.g., depression) symptoms. This syndrome carries many names, including male menopause or climacterium, andropause and partial androgen deficiency of the ageing male (PADAM). Late-onset hypogonadism (LOH) describes it best and is therefore generally preferred. The decrease of T in LOH is often marginal, and hypogonadism can be either due to primary testicular failure (low T, high luteinizing hormone (LH)) or secondary to a hypothalamic-pituitary failure (low T, low or inappropriately normal LH). The latter form is more common and it is usually associated with overweight/obesity or chronic diseases (e.g., type 2 diabetes mellitus, the metabolic syndrome, cardiovascular and chronic obstructive pulmonary disease, and frailty). A problem with the diagnosis of LOH is that often the symptoms (in 20%-40% of unselected men) and low circulating T (in 20% of men >70 years of age) do not coincide in the same individual. The European Male Ageing Study (EMAS) has recently defined the strict diagnostic criteria for LOH to include the simultaneous presence of reproducibly low serum T (total T <11 nmol l-1 and free T <220 pmol l-1 ) and three sexual symptoms (erectile dysfunction, and reduced frequency of sexual thoughts and morning erections). By these criteria, only 2% of 40- to 80-year-old men have LOH. In particular obesity, but also impaired general health, are more common causes of low T than chronological age per se. Evidence-based information whether, and how, LOH should be treated is sparse. The most logical approach is lifestyle modification, weight reduction and good treatment of comorbid diseases. T replacement is widely used for the treatment, but evidence-based information about its real benefits and short- and long-term risks, is not yet available. In this review, we will summarize the current concepts and controversies in the pathogenesis, diagnosis and treatment of LOH.
    Asian Journal of Andrology 12/2013; · 2.14 Impact Factor
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    ABSTRACT: Context: Late-onset hypogonadism (LOH) has recently been defined as a syndrome in middle-aged and elderly men reporting sexual symptoms in the presence of low T. The natural history of LOH, especially its relationship to mortality, is currently unknown. Objective: The aim of this study was to clarify the associations between LOH, low T, and sexual symptoms with mortality in men. Design, Setting, and Participants: Prospective data from the European Male Aging Study (EMAS) on 2599 community-dwelling men aged 40'79 years in eight European countries was used for this study. Main Outcome Measure(s): All-cause, cardiovascular, and cancer-related mortality was measured. Results: One hundred forty-seven men died during a median follow-up of 4.3 years. Fifty-five men (2.1%) were identified as having LOH (31 moderate and 24 severe). After adjusting for age, center, body mass index (BMI), current smoking, and poor general health, compared with men without LOH, those with severe LOH had a 5-fold [hazard ratio (HR) 5.5; 95% confidence interval (CI) 2.7, 11.4] higher risk of all-cause mortality. Compared with eugonadal men, the multivariable-adjusted risk of mortality was 2-fold higher in those with T less than 8 nmol/L (irrespective of symptoms; HR 2.3; 95% CI 1.2, 4.2) and 3-fold higher in those with three sexual symptoms (irrespective of serum T; compared with asymptomatic men; HR 3.2; 95% CI 1.8, 5.8). Similar risks were observed for cardiovascular mortality. Conclusions: Severe LOH is associated with substantially higher risks of all-cause and cardiovascular mortality, to which both the level of T and the presence of sexual symptoms contribute independently. Detecting low T in men presenting with sexual symptoms offers an opportunity to identify a small subgroup of aging men at particularly high risk of dying.
    The Journal of clinical endocrinology and metabolism 12/2013; · 6.50 Impact Factor
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    ABSTRACT: Transgenic female mice overexpressing the hCGβ subunit (hCGß+) and producing elevated levels of LH/hCG bioactivity, present as young adults with enhanced ovarian steroidogenesis, precocious puberty and infertility. They subsequently develop pituitary prolactinomas, high circulating prolactin (PRL) levels and marked mammary gland lobuloalveolar development followed by adenocarcinomas. None of these phenotypes appear in gonadectomized mice, indicating that the hCG-induced aberrations of ovarian function are responsible for the extragonadal phenotypes. PRL receptor deficient (PRLR-/-) female mice are sterile, despite ovulating, due to a failure of embryo implantation, as a consequence of decreased ovarian LH receptor (Lhcgr) expression, and inadequate corpus luteum formation and progesterone production. To study further the presumed permissive role of PRL in the maintenance of gonadal responsiveness to LH/hCG stimulation, we crossed the hCGß+ and PRLR-/- mice. The double mutant hCGß+/PRLR-/- females remained sterile with an ovarian phenotype similar to PRLR-/- mice, indicating that LH action, Lhcgr expression and consequent luteinization are not possible without simultaneous PRL signalling. The high frequency of pituitary prolactinomas in PRL-/- mice was not affected by transgenic hCGβ expression. In contrast, none of the hCGß+/PRLR-/- females showed either mammary gland lobuloalveolar development or tumors, and the increased mammary gland Wnt-5b expression, possibly responsible for the tumorigenesis in hCGβ + mice, was absent in double mutant mice. Hence, high LH/hCG stimulation is unable to compensate for missing PRL signalling in the maintenance of luteal function. PRL thus appears to be a major permissive regulator of LH action in the ovary and of its secondary extragonadal effects.
    AJP Endocrinology and Metabolism 08/2013; · 4.51 Impact Factor
  • Article: Preface.
    Ilpo Huhtaniemi
    Best practice & research. Clinical endocrinology & metabolism. 08/2013; 27(4):465.
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    ABSTRACT: Few studies have directly compared the ability of the most commonly used models of frailty to predict mortality among community-dwelling individuals. Here, we used a frailty index (FI), frailty phenotype (FP), and FRAIL scale (FS) to predict mortality in the EMAS. Participants were aged 40-79 years (n=2929) at baseline and 6.6% (n=193) died over a median 4.3 years of follow-up. The FI was generated from 39 deficits, including self-reported health, morbidities, functional performance and psychological assessments. The FP and FS consisted of five phenotypic criteria and both categorized individuals as robust when they had 0 criteria, prefrail as 1-2 criteria and frail as 3+ criteria. The mean FI increased linearly with age (r(2)=0.21) and in Cox regression models adjusted for age, center, smoking and partner status the hazard ratio (HR) for death for each unit increase of the FI was 1.49. Men who were prefrail or frail by either the FP or FS definitions, had a significantly increased risk of death compared to their robust counterparts. Compared to robust men, those who were FP frail at baseline had a HR for death of 3.84, while those who were FS frail had a HR of 3.87. All three frailty models significantly predicted future mortality among community-dwelling, middle-aged and older European men after adjusting for potential confounders. Our data suggest that the choice of frailty model may not be of paramount importance when predicting future risk of death, enabling flexibility in the approach used.
    Archives of gerontology and geriatrics 07/2013; · 1.36 Impact Factor
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    ABSTRACT: Context:Immunoassay-based techniques, routinely used to measure serum estradiol (E2), are known to have reduced specificity, especially at lower concentrations, when compared with the gold standard technique of mass spectrometry (MS). Different measurement techniques may be responsible for the conflicting results of associations between serum E2 and clinical phenotypes in men.Objective:Our objective was to compare immunoassay and MS measurements of E2 levels in men and evaluate associations with clinical phenotypes.Design and Setting:Middle-aged and older male subjects participating in the population-based Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2599), MrOS US (n = 688), and the European Male Aging Study (n = 2908) were included.Main Outcome Measures:Immunoassay and MS measurements of serum E2 were compared and related to bone mineral density (BMD; measured by dual energy x-ray absorptiometry) and ankle-brachial index.Results:Within each cohort, serum E2 levels obtained by immunoassay and MS correlated moderately (Spearman rank correlation coefficient rS 0.53-0.76). Serum C-reactive protein (CRP) levels associated significantly (albeit to a low extent, rS = 0.29) with immunoassay E2 but not with MS E2 levels. Similar associations of immunoassay E2 and MS E2 were seen with lumbar spine and total hip BMD, independent of serum CRP. However, immunoassay E2, but not MS E2, associated inversely with ankle-brachial index, and this correlation was lost after adjustment for CRP.Conclusions:Our findings suggest interference in the immunoassay E2 analyses, possibly by CRP or a CRP-associated factor. Although associations with BMD remain unaffected, this might imply for a reevaluation of previous association studies between immunoassay E2 levels and inflammation-related outcomes.
    The Journal of clinical endocrinology and metabolism 04/2013; · 6.50 Impact Factor
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    ABSTRACT: The triazine herbicides, Atrazine (ATR), Simazine (SIM), Propazine (PRO) and Terbuthylazine (TBA) and their chlorinated metabolites have been implicated in the etiology of testicular dysgenesis by altering steroidogenesis. To further investigate their effects on testosterone biosynthesis, BLTK1 cells were used to evaluate steroid hormone levels and genome-wide gene expression. BLTK1 cells, a novel murine Leydig cell line, possess an intact steroidogenic pathway with constitutive low basal testosterone (T) levels that can be induced by recombinant human chorionic gonadotropin (rhCG). Triazines (ATR, SIM, PRO and TBA) and their chlorometabolites (DEA, DIA and DACT) induced concentration-dependent (1, 3, 10, 30, 100, 300 and 600 μM) increases in progesterone (P) and T levels relative to DMSO at 24 hrs. Temporal analysis (300 μM at 1, 2, 4, 8, 12, 24 or 48 hrs) elicited comparable P and T profiles to rhCG with compounds varying efficacies (ATR > TBA > PRO > DEA > DIA > DACT > SIM) that were similar to rhCG.ATR and TBA elicited time- and concentration-dependent induction of Star, Hsd3b6 and Hsd17b3 mRNA levels while Hsd3b1, Cyp17a1 and Srd5a1 mRNA expression was repressed. PRO elicited similar, albeit weaker effects while SIM had negligible effects consistent with their induction of P and T levels. Whole-genome microarrays identified 797 differentially regulated genes by 300 μM ATR, occurring primarily at later time points (> 12 hr) with over-represented functions associated with steroidogenesis and cholesterol metabolism. These results indicate that changes in P and T levels can be partially attributed to triazine-elicited alterations in steroidogenic gene expression.
    Toxicological Sciences 04/2013; · 4.33 Impact Factor
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    ABSTRACT: A link between elevated LH levels, GATA-4 and luteinizing hormone receptor (LHCGR) expression and gonadotropin-dependent adrenocortical tumorigenesis in humans and mice has been shown. To assess the mechanistic tumorigenic interrelationships between these factors, we transgenically expressed Gata4 under the 21-hydroxylase promoter (Cyp21a1, 21-OH) in C57Bl/6N mice. There was a gradual age-dependent increase of GATA-4 expression only in 21-OH-GATA-4 (TG) female adrenals, in association with slowly progressing neoplasia of non-steroidogenic spindle-shaped A cells in the subcapsular cortex. Gonadectomy (GDX), apparently through direct action of elevated serum LH, markedly enhanced the adrenocortical neoplasia, which now also appeared in GDX TG males. The neoplastic areas of the post-GDX TG adrenals contained, besides A cells, larger lipid-laden, steroidogenically active and LHCGR positive B cells. Prolonged (>10 months, mo) exposure to elevated post-GDX LH levels resulted in formation of adrenocortical adenomas in the TG mice. Intact and GDX TG mouse adrenals displayed elevated FOG-2 and decreased GATA-6 expression. Additionally, increased expression/activation of components of the Inhbb-Acvr2a-Acvr1c-Smad2/3 signaling system was observed in 12-mo-old GDX TG adrenals. Our findings showed the formation of two distinct GATA-4-dependent populations of neoplastic adrenocortical cells: non-steroidogenic, LH-independent A cells and steroidogenic, LH-dependent B cells.
    Journal of Cell Science 02/2013; · 5.88 Impact Factor

Publication Stats

7k Citations
1,533.69 Total Impact Points


  • 2003–2014
    • Imperial College London
      • • Department of Surgery and Cancer
      • • Institute of Reproductive and Developmental Biology
      Londinium, England, United Kingdom
  • 1988–2014
    • University of Turku
      • • Department of Physiology
      • • Institute of Biomedicine
      Turku, Province of Western Finland, Finland
  • 2002–2013
    • Texas Tech University Health Sciences Center
      • Department of Cell Biology and Biochemistry
      El Paso, Texas, United States
    • University of Aberdeen
      • Obstetrics and Gynaecology
      Aberdeen, SCT, United Kingdom
  • 2012
    • University of Oxford
      Oxford, England, United Kingdom
    • University of Tartu
      • Institute of Molecular and Cell Biology
      Tartu, Tartumaa, Estonia
  • 2008–2012
    • The University of Manchester
      Manchester, England, United Kingdom
    • Université René Descartes - Paris 5
      • Centre de Recherche Croissance et Signalisation (UMR_S 845)
      Paris, Ile-de-France, France
  • 2002–2012
    • University of Texas MD Anderson Cancer Center
      • Department of Experimental Radiation Oncology
      Houston, Texas, United States
  • 2011
    • Satakunta Hospital District
      Björneborg, Province of Western Finland, Finland
    • University of Indonesia
      • Department of Biology
      Depok, West Java, Indonesia
  • 2008–2011
    • University of Leeds
      • Institute of Psychological Sciences
      Leeds, ENG, United Kingdom
  • 2009
    • University of Florence
      • Dipartimento di Scienze Biomediche, Sperimentali e Cliniche
      Florence, Tuscany, Italy
  • 2007
    • Cranfield University
      • Cranfield Health
      Cranfield, ENG, United Kingdom
  • 2006
    • Alexandra Regional General Hospital
      Athínai, Attica, Greece
  • 2005
    • Institute of Animal Reproduction and Food Research of Polish Academy of Sciences
      • Institute of Animal Reproduction and Food Research
      Allenstein, Warmian-Masurian Voivodeship, Poland
  • 2001
    • New York University
      • Department of Obstetrics and Gynecology
      New York City, NY, United States
  • 2000
    • Erasmus Universiteit Rotterdam
      Rotterdam, South Holland, Netherlands
  • 1999
    • University of Oulu
      • Department of Obstetrics and Gynaecology
      Oulu, Oulu, Finland
  • 1997–1998
    • Oulu University Hospital
      • Department of Obstetrics and Gynecology
      Oulu, Oulu, Finland
  • 1983–1996
    • University of Helsinki
      • Department of Physiology
      Helsinki, Southern Finland Province, Finland
    • National Institute of Child Health and Human Development
      Maryland, United States
  • 1992
    • Universität Heidelberg
      • Center for Molecular Biology (ZMBH)
      Heidelberg, Baden-Wuerttemberg, Germany
  • 1986
    • Helsinki University Central Hospital
      Helsinki, Southern Finland Province, Finland
  • 1984
    • University of Colorado
      Denver, Colorado, United States
  • 1977
    • University of California, San Francisco
      • Department of Obstetrics, Gynecology and Reproductive Sciences
      San Francisco, CA, United States