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Marie-Laure Goubillon, Jean-Marc Kaufman and Jean-Christophe Thalabard

Goubillon M-L, Kaufman J-M, Thalabard J-C. Hypothalamic multiunit activity and pulsatile luteinizing hormone release in the castrated male rat. Eur J Endocrinol 1995:133:585–90. ISSN 0804–4643

Using chronically implanted microelectrodes, multiunit electrical activity (MUA) was recorded from the arcuate nucleus of freely moving gonadectomized male rats. Intermittent increases in MUA activity (MUA volleys) closely associated with luteinizing hormone pulses measured in the peripheral circulation were observed, which confirms that this experimental approach can be used for monitoring the activity of the gonadotropin-releasing hormone-associated hypothalamic pulse generator in the male rat. The mean MUA volley frequency was 22.2 min (range 13–38 min), whereas the mean MUA volley duration was 2.7 ± 0.8 min (standard deviation). In addition to a large inter-individual variability, MUA volley intervals also showed an important intra-individual variability. This observation suggests that, beside the mean frequency of pulse generator activation, the degree of variability in gonadotropin-releasing hormone-associated pulse generator activity might be an additional relevant parameter in the characterization of the reproductive function in the male rat.

M-L Goubillon, Laboratoire d'Histologie et d'Embryologie, Faculté de Médecine, CNRS URA 1454, 69600 Oullins, France

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Greet Roef, Bruno Lapauw, Stefan Goemaere, Hans Zmierczak, Tom Fiers, Jean-Marc Kaufman and Youri Taes

Context

The hormonal factors involved in the regulation of peak bone mass (PBM) in men have not been fully investigated. Apart from gonadal steroids and somatotropic hormones, thyroid hormones are known to affect bone maturation and homeostasis and are additional candidate determinants of adult bone mass.

Objective

We aimed to investigate between-subject physiological variation in free and total thyroid hormone concentrations, TSH, and thyroid binding globulin (TBG) in relation to parameters of bone mass, geometry, and mineral density in healthy men at the age of PBM.

Design and setting

We recruited 677 healthy male siblings aged 25–45 years in a cross-sectional, population-based study. Areal and volumetric bone parameters were determined using dual-energy x-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT). Total and free thyroid hormones, TBG, and TSH were determined using immunoassays.

Results

Free and total thyroid hormone concentrations were inversely associated with bone mineral density (BMD) and bone mineral content (BMC) at the hip and total body (free triiodothyronine (FT3), total T3 (TT3), and total T4 (TT4)) and at the spine (FT3). TBG was negatively associated with BMC and areal BMD at all sites. At the radius, cortical bone area was inversely associated with TT3, TT4, and TBG, and trabecular bone density was inversely associated with free thyroxine, TT4, and TBG. We observed inverse associations between cortical bone area at the mid-tibia and FT3, TT3, TT4, and TBG. No associations between TSH and DXA or pQCT measurements were found.

Conclusion

In healthy men at the age of PBM, between-subject variation in thyroid hormone concentrations affects bone density, with higher levels of FT3, TT3, TT4, and TBG being associated with less favorable bone density and content.

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Greet Roef, Youri Taes, Kaatje Toye, Stefan Goemaere, Tom Fiers, Alain Verstraete and Jean-Marc Kaufman

Objective

Variation in thyroid hormone (TH) concentrations between subjects is greater than in a single subject over a prolonged period of time, suggesting an individual set point for thyroid function. We have previously shown that TH levels within normal range are associated with clinical indices such as bone mass, BMI, and heart rate. The aim of this study on young men was therefore to gain insight into the determinants of variation in TH levels among healthy subjects.

Methods

Healthy male siblings (n=941, 25–45 years) were recruited in a cross-sectional, population-based study; a history or treatment of thyroid disease and thyroid auto-immunity were exclusion criteria. A complete assessment of TH status was performed (TSH, free thyroxine (FT4), free triiodothyronine (FT3), thyroperoxidase, and thyroglobulin antibodies, reverse T3 (rT3), thyroid-binding globulin (TBG), and urinary iodine levels). Genotyping was performed by TaqMan and KASP (KBiosciences) genotyping assays.

Results

(F)T4, rT3, and TBG had heritability estimates between 80 and 90%. Estimates were lower for (F)T3 (60%) and lowest for TSH (49%).

Significant associations were observed between different single-nucleotide polymorphisms (SNPs) in the thyroid pathway and TSH, FT4, ratio FT3:FT4, and rT3. Nevertheless, these SNPs only explain a limited part of the heredity. As to age and lifestyle-related factors, (F)T3 was negatively related to age and education level, positively to smoking and BMI (all P<0.0001) but not substantially to urinary iodine concentrations. Smoking was also negatively related to TSH and positively to FT4.

Conclusion

Both genetic and lifestyle-related factors play a role in determining between-subject variation in TH levels in euthyroid young men, although genetic factors seem most important.

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Greet Roef, Bruno Lapauw, Stefan Goemaere, Hans-Georg Zmierczak, Kaatje Toye, Jean-Marc Kaufman and Youri Taes

Objective

Thyroid disorders affect metabolism and body composition. Existing literature has been conflicting on whether this is also the case for thyroid hormone levels within the euthyroid range. Therefore, we have investigated the relationship between thyroid hormone concentrations and body composition together with metabolic parameters in a population of healthy euthyroid men.

Methods

Healthy male siblings (n=941, 25–45 years, median BMI 24.6) were recruited in a cross-sectional, population-based study; a history or treatment of thyroid disease and thyroid autoimmunity were exclusion criteria. Body composition and muscle cross-sectional area were assessed by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Total (triiodothyronine (T3; TT3) thyroxine and (T4; TT4)) and free thyroid hormones (FT3 and FT4), TSH, and reverse T3 (rT3) and thyroid-binding globulin (TBG) were determined using immunoassays.

Results

BMI was positively associated with (F)T3 (P<0.0001). Whole body fat mass displayed positive associations with TT3 and with (F)T4 and TBG (P≤0.0006). Positive associations were further observed between leptin and (F)T3, TT4, and TBG (P≤0.0002). Inverse associations between lean mass and muscle cross-sectional area and (F)T3, (F)T4, and TBG were observed (P≤0.0003). Higher levels of (F)T3 and TBG were associated with lower insulin sensitivity, assessed by homeostatic model assessment of insulin resistance (IR; P≤0.0001). No associations between TSH and body composition or metabolic parameters were seen.

Conclusion

We show that a less favorable body composition (with higher fat and lower muscle mass and accompanying higher leptin concentrations) and IR are associated with higher thyroid hormone levels in healthy young men with well characterized euthyroidism.

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Hans Vermeersch, Guy T'Sjoen, Jean Marc Kaufman, John Vincke and Mieke Van Houtte

Objectives

Androgen activity has been implicated in a range of traits and behaviours that have well-documented sex differences. However, the results of the studies on the relationship between testosterone and these traits and behaviours are inconsistent. This study has analyzed i) whether CAG repeat length, a presumed modulator of androgen receptor sensitivity, is associated with sex-dimorphic traits and behaviours (aggressive and non-aggressive risk-taking (ART and NART), dominance, depressive symptoms and self-esteem), and ii) whether CAG repeat length interacts with free testosterone (FT) with respect to these traits and behaviours.

Design and methods

Data obtained from a group of adolescent boys (n=301; mean age: 14.4 years) were analyzed using multivariate general linear modelling (SPSS, Chicago, IL, USA 15.0).

Results

We found no direct correlation between CAG repeat length and dependent variables. We found significant interactions between CAG repeat length and testosterone, indicating that FT was more positively related to ART and NART with a shorter repeat length, and that an inverse association of FT with depressive symptoms and a positive association with self-esteem were stronger in boys with a longer CAG repeat length.

Conclusion

Our findings indicate the importance of studying FT and CAG repeat length simultaneously with respect to sex-dimorphic traits, taking into account the possible interactions between the two.

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Patricia Crabbe, Stefan Goemaere, Hans Zmierczak, Inge Van Pottelbergh, Dirk De Bacquer and Jean-Marc Kaufman

Objective: Across studies it has been suggested that leptin intervenes as a regulator of bone metabolism. This study assesses the contribution in elderly men of leptin and the Gln223Arg leptin receptor gene (LEPR) polymorphism to the variation in bone homeostasis, in relation to body composition and free estradiol as major confounders.

Design: We performed cross-sectional (n = 270) and longitudinal (mean follow-up 3.4 years, n = 214) evaluations in elderly men.

Methods: Serum leptin, LEPR genotype, baseline bone mineral density (BMD), longitudinal BMD changes at the hip and forearm, and biochemical markers of bone turnover were determined.

Results: In cross-sectional analyses absolute fat mass was the index of body composition most strongly associated with leptin (r = 0.74; P < 0.001). LEPR genotypes and serum leptin were not associated. Serum bone-specific alkaline phosphatase (S-BAP) was associated with LEPR genotypes (P = 0.05) and urinary C-terminal telopeptides of type I collagen (U-CTX) were associated with leptin levels (P = 0.03), independently from age, fat mass and free estradiol. Baseline BMD at the hip and forearm was neither associated with leptin nor with LEPR genotypes. Prospectively assessed BMD loss was not associated with serum leptin at the hip, whereas BMD loss was positively associated with leptin at the forearm (P = 0.01), independently from age, fat mass and free estradiol. Longitudinal changes in hip or forearm BMD were not associated with LEPR genotypes.

Conclusion: The findings suggest a possible role for leptin as determinant of bone homeostasis in elderly men, but with only modest impact independently from body composition and free estradiol.

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Veerle Bogaert, Griet Vanbillemont, Youri Taes, Dirk De Bacquer, Ellen Deschepper, Kristel Van Steen and Jean-Marc Kaufman

Objective

The human androgen receptor (AR) contains a polyglutamine and a polyglycine stretch which are highly polymorphic and are coded respectively by a CAG and GGN repeat in exon 1 of the AR gene. Although the in vitro studies indicated a possible effect of the GGN repeat polymorphism on the AR gene transcription and clinical observations suggest that it might modulate the androgen action, its functional significance remains unclear. We wanted to assess whether the GGN repeat affects the serum testosterone levels in healthy men, which is the expected outcome through feedback regulation if it influences androgen action as has been shown to be the case for the CAG repeat.

Design and patients

A population based cross-sectional cohort study including 1476 healthy young, middle-aged, and elderly men.

Measurement

Testosterone and LH levels were determined by immunoassay; free testosterone (FT) levels were calculated. Genotyping of the GGN repeat was performed using the sequencing technique.

Results

The GGN repeat number was significantly associated with circulating testosterone and FT levels (P=0.017 and P=0.013 respectively). However, taking into account that age, body mass index, and CAG are already in the regression model, the GGN repeat could explain only a small part of the variation of both testosterone and FT.

Conclusion

To our knowledge, this study is the first to demonstrate a significant positive association between the GGN repeat and androgen levels in a large cohort of healthy men. Although the present study thus adds credence to the view that the polyglycine tract in the AR can modulate AR action, this effect appears to be only small so that its clinical relevance remains questionable.

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Els Elaut, Griet De Cuypere, Petra De Sutter, Luk Gijs, Michael Van Trotsenburg, Gunter Heylens, Jean-Marc Kaufman, Robert Rubens and Guy T'Sjoen

Objective

An unknown proportion of transsexual women (defined as post-operative male-to-female transsexuals on oestrogen replacement) experience hypoactive sexual desire disorder (HSDD). It has been suggested that the absence of ovarian androgen production together with oestrogen treatment-related increase in sex hormone-binding globulin (SHBG) levels could be leading to HSDD, due to low levels of biologically available testosterone. This study wishes to document the HSDD prevalence among transsexual women and the possible association to androgen levels.

Design

Cross-sectional study.

Methods

Transsexual women (n=62) and a control group of ovulating women (n=30) participated in this study. Questionnaires measuring sexual desire (sexual desire inventory) and relationship and sexual satisfaction (Maudsley Marital Questionnaire) were completed. Serum levels of total testosterone, LH and SHBG were measured in blood samples obtained at random in transsexual women and in the early follicular phase in ovulating women.

Results

The transsexual group had lower levels of total and calculated free testosterone (both P<0.001) than the ovulating women. HSDD was reported in 34% of the transsexual and 23% of the ovulating women (P=0.30). Both groups reported similar levels of sexual desire (P=0.97). For transsexual women, no significant correlation was found between sexual desire and total (P=0.64) or free testosterone (P=0.82). In ovulating women, these correlations were significant (P=0.006, resp. P=0.003).

Conclusions

HSDD is reported in one-third of transsexual women. This prevalence is not substantially different from controls, despite markedly lower (free) testosterone levels, which argues against a major role of testosterone in this specific group.

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Flavia Tosi, Daniela Di Sarra, Cecilia Bonin, Francesca Zambotti, Marlene Dall'Alda, Tom Fiers, Jean-Marc Kaufman, Matilde Donati, Massimo Franchi, Maria Elisabetta Zanolin, Enzo Bonora and Paolo Moghetti

Objective

Pentraxin-3 (PTX3), like C-reactive protein (CRP), is an acute-phase protein that belongs to the pentraxin superfamily. Moreover, it is expressed in the cumulus oophorus and appears to be involved in female fertility. The aim of the present study was to assess whether PTX3 levels are altered in polycystic ovary syndrome (PCOS) women and whether they show any relationship with the main features of these subjects.

Design

A cross-sectional study was conducted at the outpatient clinic of an academic centre.

Methods

A total of 66 women affected with PCOS and 51 healthy controls were studied. Plasma PTX3 and serum CRP were measured by ELISA. Androgens were measured by liquid chromatography–mass spectrometry and free testosterone was measured by equilibrium dialysis. In PCOS women, insulin sensitivity was assessed by the glucose clamp technique.

Results

Adjusting for age and BMI, plasma PTX3 was reduced in PCOS women (P=0.036), in contrast with serum CRP, which was increased (P=0.004). In multiple regression analysis, serum androgens and other endocrine and ovarian features of PCOS were predictors of PTX3 levels, whereas body fat was the main independent predictor of CRP concentrations.

Conclusions

Plasma PTX3 levels were reduced in PCOS women and independently associated with hyperandrogenism and other endocrine and ovarian features of PCOS.