Willem de Ronde

Kennemer Gasthuis, Haarlem, North Holland, Netherlands

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Publications (34)125.62 Total impact

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    ABSTRACT: Androgen deprivation therapy by bilateral orchiectomy (surgical castration) or luteinizing hormone-releasing hormone agonist therapy (medical castration) is recommended for advanced or metastatic prostate cancer. Both methods aim at reducing serum testosterone concentrations to a castrate level which is currently defined as less than 50 ng/dl. The results of previous studies are based on testosterone immunoassays that have insufficient accuracy in the low range. In this study we reevaluated serum testosterone concentrations in men on androgen deprivation therapy using isotope dilution-liquid chromatography-tandem mass spectrometry, an accurate method of measuring testosterone in the castrate range. Subjects underwent surgical castration (34) or received a luteinizing hormone-releasing hormone agonist (32). Serum samples were obtained more than 3 months after surgery or initiation of luteinizing hormone-releasing hormone agonist therapy. Testosterone levels were determined using isotope dilution-liquid chromatography-tandem mass spectrometry. Dihydroepiandrosterone sulfate, androstenedione, sex hormone-binding globulin and inhibin B levels were determined. All subjects had serum testosterone values less than 50 ng/dl and 97% had testosterone concentrations less than 20 ng/dl. Medically castrated men had significantly lower testosterone levels (median 4.0 ng/dl, range less than 2.9 to 20.2) than those surgically castrated (median 9.2 ng/dl, range less than 2.9 to 28.8, p <0.001). No difference was found in dehydroepiandrosterone sulfate, androstenedione and sex hormone-binding globulin levels between the groups, whereas inhibin B levels were significantly higher in the luteinizing hormone-releasing hormone agonist treated group. Using an accurate technique for testosterone measurement, subjects on luteinizing hormone-releasing hormone agonist therapy had significantly lower testosterone concentrations than men who underwent surgical castration. The clinical relevance of these findings remains to be determined.
    The Journal of urology 03/2012; 187(5):1601-6. DOI:10.1016/j.juro.2011.12.063 · 3.75 Impact Factor
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    ABSTRACT: Kallmann syndrome (KS) and CHARGE syndrome are rare heritable disorders in which anosmia and hypogonadotropic hypogonadism co-occur. KS is genetically heterogeneous, and there are at least eight genes involved in its pathogenesis, whereas CHARGE syndrome is caused by autosomal dominant mutations in only one gene, the CHD7 gene. Two independent studies showed that CHD7 mutations can also be found in a minority of KS patients. We aimed to investigate whether CHD7 mutations can give rise to isolated KS or whether additional features of CHARGE syndrome always occur. We performed CHD7 analysis in a cohort of 36 clinically well-characterized Dutch patients with KS but without mutations in KAL1 and with known status for the KS genes with incomplete penetrance, FGFR1, PROK2, PROKR2, and FGF8. We identified three heterozygous CHD7 mutations. The CHD7-positive patients were carefully reexamined and were all found to have additional features of CHARGE syndrome. The yield of CHD7 analysis in patients with isolated KS seems very low but increases when additional CHARGE features are present. Therefore, we recommend performing CHD7 analysis in KS patients who have at least two additional CHARGE features or semicircular canal anomalies. Identifying a CHD7 mutation has important clinical implications for the surveillance and genetic counseling of patients.
    The Journal of Clinical Endocrinology and Metabolism 03/2012; 97(5):E858-62. DOI:10.1210/jc.2011-2652 · 6.31 Impact Factor
  • Marieke S Velema, Bibi H B Kwa, Willem de Ronde
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a widespread disease with high morbidity rates. Advanced stages can be complicated by unintentional weight loss and muscle wasting, which may contribute to increased morbidity and mortality. Reversal of weight loss increases muscle strength and exercise capacity and improves survival. This can partly be achieved by nutritional support, preferably combined with increase in exercise. Androgenic anabolic steroids (AASs), of which testosterone is the parent hormone, increase muscle size and strength. Due to these anabolic effects, AASs may emerge as a treatment option in COPD patients suffering from muscle wasting. Seven trials investigated the effects of AAS in patients with COPD. Some studies also included nutritional therapy and/or a pulmonary rehabilitation program. Compared with placebo, AASs increase lean body mass (LBM) and muscle size. However, no consistent effects on muscle strength, exercise capacity, or pulmonary function are seen. AASs increase LBM in patients with advanced stages of COPD. No consistent beneficial effect on other endpoints was demonstrated in the reviewed trials. However, probably higher doses of AASs are needed to exert a clinically meaningful effect on muscle strength or exercise capacity. Currently, no evidence is available to recommend AASs to all patients with COPD. In individual cases, treatment with AASs can be considered, particularly in men with advanced COPD, moderate-to-severe functional impairment, muscle wasting and on chronic corticosteroid therapy. Treatment with AASs should preferably be combined with a rehabilitation program and nutritional support. AASs should not be used in women or in men with symptomatic heart disease. When treatment with AASs is considered, intramuscular nandrolone-decanoate is preferred in a dose of 50-200 mg per week for a period of 12 weeks. However, the efficacy of AAS treatment in COPD patients needs further clarification in well designed, adequately powered clinical studies.
    Current opinion in pulmonary medicine 12/2011; 18(2):118-24. DOI:10.1097/MCP.0b013e32834e9001 · 2.96 Impact Factor
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    ABSTRACT: In aging men, circulating testosterone (T) declines which is associated with an increase in the levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) , albeit insufficient to maintain T at its original level. It has been speculated that a higher sensitivity of the hypothalamus and/or pituitary for the feedback effect of circulating sex hormones in older men is responsible. To compare the effect of experimentally varied plasma levels of estradiol on the LH and FSH secretion in young and old castrated male-to-female transsexuals, in almost absence of T. DESIGN, SUBJECTS, AND INTERVENTIONS: In 10 healthy, young (mean age 37.6 ± 6.2 years) and 11 healthy, old (mean age 68.1 ± 7.0) male-to-female transsexuals after gonadectomy plasma estradiol levels were experimentally varied with estradiol patches (the first week 100 μg/day patches, the second week 50 μg/day, the third week 25 μg/day and the fourth week no patch was applied) and plasma levels of LH and FSH were monitored after every week. Mean plasma bioavailable estradiol (E2) levels in the two groups ranged between 13.6 and 104 pmol/l. LH and FSH were inversely related to peripheral estradiol levels, were lower in the old group at all time points reaching statistical significance in the last week of the study when no patch was applied and estradiol levels were extremely low. The results of this study do not support the hypothesis of an age related increasing sensitivity of the hypothalamo-pituitary compartment for the negative feedback of E2, but suggest a deficient feed-forward drive in older male-to-female transsexuals.
    The Aging Male 09/2011; 14(3):155-61. DOI:10.3109/13685538.2010.511328 · 1.85 Impact Factor
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    Willem de Ronde, Frank H de Jong
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    ABSTRACT: Aromatase inhibitors effectively delay epiphysial maturation in boys and improve testosterone levels in adult men Therefore, aromatase inhibitors may be used to increase adult height in boys with gonadotropin-independent precocious puberty, idiopathic short stature and constitutional delay of puberty. Long-term efficacy and safety of the use of aromatase inhibitors has not yet been established in males, however, and their routine use is therefore not yet recommended.
    Reproductive Biology and Endocrinology 06/2011; 9:93. DOI:10.1186/1477-7827-9-93 · 2.41 Impact Factor
  • The Journal of Urology 04/2011; 185(4). DOI:10.1016/j.juro.2011.02.1687 · 3.75 Impact Factor
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    ABSTRACT: To investigate whether showering, to prevent the involuntary transfer of testosterone to others through skin contact, either 15 or 30 minutes after application of testosterone gel would significantly affect plasma testosterone levels. Prospective 3-way crossover trial. University hospital in the Netherlands. Ten agonadal female-to-male transsexuals who had sex-reassignment surgery at least 3 months earlier. Subjects were randomized to one of three application regimens for testosterone gel 50 mg/day, each lasting 7 days: testosterone application after showering (standard regimen), shower was taken 30 minutes after testosterone application, or shower was taken 15 minutes after testosterone application. Subjects then crossed over to each of the other two application regimens for a total of 21 days of study participation. On day 7 of each application regimen, mean plasma testosterone levels were determined before testosterone application and at 1, 4, 7, and 10 hours after application. With the standard regimen, mean plasma testosterone levels at all time points after application were in the normal range: mean ± SD average concentration 994 ± 1026 ng/dl. When a shower was taken 30 or 15 minutes after application, plasma testosterone levels at 1, 4, 7, and 10 hours were significantly lower: mean ± SD average concentration 401 ± 231 ng/dl for 30 minutes after application (p<0.01) and 320 ± 248 ng/dl for 15 minutes after application (p<0.01). Showering within 30 minutes after application of testosterone gel 50 mg/day reduces absorption of testosterone and results in unacceptably low plasma testosterone levels in most users. Therefore, this strategy cannot be recommended to prevent involuntary transfer of testosterone.
    Pharmacotherapy 03/2011; 31(3):248-52. DOI:10.1592/phco.31.3.248 · 2.20 Impact Factor
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    M S Velema, W de Ronde
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    ABSTRACT: Creatine is a nutritional supplement widely used in sport, physical fitness training and bodybuilding. It is claimed to enhance performance. We describe a case in which serum creatinine is elevated due to the use of creatine ethyl esther. One week after withdrawal, the plasma creatinine had normalised. There are two types of creatine products available: creatine ethyl esther (CEE) and creatine monohydrate (CM). Plasma creatinine is not elevated in all creatine-using subjects. CEE , but not CM, is converted into creatinine in the gastrointestinal tract. As a result the use of CEE may be associated with elevated plasma creatinine levels. Since plasma creatinine is a widely used marker for renal function, the use of CEE may lead to a false assumption of renal failure.
    The Netherlands Journal of Medicine 02/2011; 69(2):79-81. · 2.21 Impact Factor
  • Jorn Woerdeman, Willem de Ronde
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    ABSTRACT: INTRODUCTION: A variety of clinical conditions are complicated by loss of weight and skeletal muscle which may contribute to morbidity and mortality. Anabolic androgenic steroids have been demonstrated to increase fat-free mass, muscle mass and strength in healthy men and women without major adverse events and therefore could be beneficial in these conditions. AREAS COVERED: This review provides an overview of clinical trials with anabolic androgenic steroids in the treatment of chronic diseases including HIV-wasting, chronic renal failure, chronic obstructive lung disease, muscular disease, alcoholic liver disease, burn injuries and post operative recovery. Relevant studies were identified in PubMed (years 1950 - 2010), bibliographies of the identified studies and the Cochrane database. EXPERT OPINION: Although the beneficial effects of AAS in chronic disorders are promising, clinically relevant endpoints such as quality of life, improved physical functioning and survival were mainly missing or not significant, except for burn injuries. Therefore, more studies are needed to confirm their long term safety and efficacy.
    Expert Opinion on Investigational Drugs 01/2011; 20(1):87-97. DOI:10.1517/13543784.2011.544651 · 5.43 Impact Factor
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    ABSTRACT: Differentiation between subtle changes in low serum testosterone concentrations, common in women and children, is not possible with current commercially available assays. The objectives of the study were to develop a method based on stable isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) with adequate sensitivity and specificity and to investigate the applicability of this assay in serum samples from pre- and postmenopausal women. For 16 women, testosterone levels were measured in blood samples drawn two years before and after physiological menopause, and for eight women in samples drawn before and after bilateral oophorectomy. Testosterone was extracted from serum, derivatized and analysed on an LC-MS/MS. The developed ID-LC-MS/MS method allowed for specific and reproducible measurement of testosterone. Comparison with stable isotope dilution-gas chromatography coupled to mass spectrometry detection by Deming regression analysis gave a slope of 1.025 and an intercept of 0.055 nmol/L (r = 0.9998). A significant decrease was found in testosterone concentrations before and after bilateral oophorectomy (P = 0.02), whereas no significant difference was found before and after natural menopause (P = 0.4). The ID-LC-MS/MS assay measures serum testosterone with acceptable accuracy and is useful in female samples, supporting the conclusion that the postmenopausal ovary contributes to circulating testosterone. To our knowledge, our analytical method compares favourably to similar published methods in terms of sensitivity. The sensitivity and specificity of this method comply with the reference method for measurement of testosterone in serum samples of women, children and men suffering from hypogonadism and can also be used for men with testosterone in the reference range.
    Annals of Clinical Biochemistry 05/2010; 47(Pt 3):248-52. DOI:10.1258/acb.2010.009171 · 2.08 Impact Factor
  • Jorn Woerdeman, Jean-Marc Kaufman, Willem de Ronde
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    ABSTRACT: The classical interpretation of the feedback regulation of the male hypothalamo-pituitary-gonadal axis predicts that a partial inhibition of testosterone (T) synthesis will result in a compensatory rise in LH secretion. The question arises as to whether such a compensation is complete or that decreased T synthesis may result in a lower plasma T concentration. To investigate whether a moderate inhibition of T synthesis capacity will be fully compensated by increased LH secretion. DESIGN, SUBJECTS AND INTERVENTIONS: In nine young healthy men, we partially inhibited T synthesis capacity using ketoconazole (KTZ) 100 mg four times daily. On day -6 (1 week prior to KTZ intake), days 1 and 8 of KTZ administration blood was drawn [07:00 h (t(1)), 10:00 h (t(2)), 13:00 h (t(3))] for evaluation of T, LH, oestradiol (E2), 17-OH-progesterone (17OHP), progesterone (PR) and sex hormone binding globulin (SHBG). On day 8, 5000 IU of hCG were administered to evaluate the maximal T secretion under KTZ. Administration of KTZ resulted in an acute, moderate but significant decrease of plasma T concentration. On day 8, plasma LH, 17OHP and PR were elevated relative to day -6 and day 1, but mean T was still lower compared to day -6. Mean E2 and SHBG were only slightly affected by KTZ. After stimulation by hCG, plasma T was restored to its baseline level. These results argue against the assumption that a moderate decline in T synthesis capacity will be compensated completely by increased LH secretion.
    Clinical Endocrinology 06/2009; 72(1):76-80. DOI:10.1111/j.1365-2265.2009.03624.x · 3.35 Impact Factor
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    ABSTRACT: The prevalence of both low testosterone levels and depression increases with age. Currently, there is no consensus regarding the existence of an association. Our study analyses the cross-sectional association of testosterone levels with depressive symptoms and its prospective association with the development of incident depressive symptoms. Longitudinal population-based study; based on the data of the Longitudinal Aging Study Amsterdam (LASA) including 608 men aged >or=65 years (median age 75.6 years). Linear and logistic regression between total and free testosterone levels and depressive symptoms as measured by the Center of Epidemiologic Studies Depression (CES-D) scale, taking into account medical and lifestyle factors. Cox Proportional Hazards model was used to assess incident depressive symptoms. Unadjusted linear regression between square-root transformed CES-D scores and free testosterone levels showed a significant inverse association as a continuous variable (beta = -0.10, P < 0.05), lowest quartile compared to highest (beta = 0.12, P < 0.05) and with a threshold value of 170 pmol/l (beta = 0.13, P < 0.05). The results remained significant for the group below threshold after adjustment for all confounders (beta = 0.09, P < 0.05). Cox Proportional Hazards Model showed a decreased risk for incident depressive symptoms for men with higher free testosterone levels [HR = 0.997 CI (0.995-1.000)]. Men with the threshold value below 220 pmol/l were at increased risk of incident depressive symptoms [HR = 1.989 CI (1.173-3.374)]. Free testosterone levels below 170 pmol/l are associated with depressive symptoms, while free testosterone levels below 220 pmol/l (lowest quintile of our population) predict the onset of depressive symptoms.
    Clinical Endocrinology 05/2009; 72(2):232-40. DOI:10.1111/j.1365-2265.2009.03641.x · 3.35 Impact Factor
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    ABSTRACT: Testosterone inhibits gonadotrophin release in men either directly or after aromatization to oestradiol. We hypothesized that in males the androgen receptor-mediated effect of testosterone on LH release is negligible relative to that of oestradiol. To compare the effect of experimentally induced variations of plasma oestradiol levels on LH levels in normal (physiological testosterone levels) and castrated men (very low testosterone levels). Prospective, open label, intervention. We suppressed endogenous oestradiol in 10 young men with letrozole 2.5 mg once daily. In these men and in 10 young healthy castrated men, we restored plasma oestradiol levels with oestradiol patches (first week 100 mug/day, second week 50 mug/day, third week 25 mug/day and fourth week no oestradiol patch). The effect of the intervention on plasma levels of LH were monitored and compared between the groups. With the intervention, the mean plasma oestradiol level in the two groups varied from supraphysiological to below the lower reference range. Levels of LH mirrored plasma oestradiol levels in both the groups, as did testosterone in the intact group. Despite similar oestradiol levels, mean levels of LH were significantly higher in the castrated group compared to the intact group for all doses of oestradiol, and supraphysiological levels of oestradiol were unable to suppress LH into the physiological range in the castrated group. Physiological plasma oestradiol levels have a substantial suppressive effect on LH in men. However, low-normal testosterone levels are a prerequisite for suppression of LH into the normal range.
    Clinical Endocrinology 04/2009; 71(6):874-9. DOI:10.1111/j.1365-2265.2009.03573.x · 3.35 Impact Factor
  • Willem de Ronde
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    ABSTRACT: Testosterone supplementation is a standard treatment for young men with hypogonadism and has also been advocated as a treatment for symptomatic older men with low testosterone levels. Several modes of testosterone replacement are available including capsules, patches, injections, buccal tablets and gels. To review the literature concerning therapeutic efficacy and potential limitations of testosterone gels. The FDA medical reviews and the computerised database PubMed were searched for clinical trials studying currently approved testosterone gels. Testosterone gel has proved to be a valuable contribution to the existing modes of testosterone treatment, combining therapeutic efficacy, convenience and safety.
    Expert opinion on biological therapy 03/2009; 9(2):249-53. DOI:10.1517/14712590802653593 · 3.65 Impact Factor
  • Willem de Ronde, Anne de Haan, Madeleine L Drent
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    ABSTRACT: Klinefelter syndrome (KS) is a genetic disorder, characterized by an XXY karyotype, hypergonadotrophic hypogonadism and infertility, which affects approximately 1 in 700 men. KS has also been associated with neuropsychological alterations. To investigate whether quality of life (QoL) is reduced in patients with KS on androgen treatment. Observational study. Questionnaires (RAND-36) were sent to 46 KS patients on androgen treatment who regularly visit the outpatient clinic of an academic medical centre. QoL scores were compared with a Dutch male reference group. Forty (87%) questionnaires were returned which were suitable for evaluation. KS patients had significantly lower (worse) scores on eight of the nine domains of the RAND questionnaire compared with the male reference group. In KS patients, higher education was associated with significantly better QoL scores. QoL is reduced in patients with KS on androgen treatment.
    European Journal of Endocrinology 02/2009; 160(3):465-8. DOI:10.1530/EJE-08-0689 · 3.69 Impact Factor
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    Willem de Ronde
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    ABSTRACT: Topically applied testosterone gels are a widely used mode of testosterone replacement therapy. A concern associated with the use of testosterone gel is unintentional transfer to children or women by skin contact with the application site. We present a case of female hyperandrogenism most likely caused by transfer of testosterone gel used by her partner. Additionally, we searched the computerized database PUBMED and the FDA medical reviews for case reports and clinical trials concerning transfer risk. Several case reports and the results of clinical trials indicate that transfer of testosterone from gel-treated males to women and children is possible and clinically relevant. Thus, the potential of testosterone transfer in gel users should be recognized as a possible side effect of this form of testosterone replacement therapy.
    Human Reproduction 11/2008; 24(2):425-8. DOI:10.1093/humrep/den372 · 4.59 Impact Factor
  • W de Ronde
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    ABSTRACT: Androgenic anabolic steroids are compounds with a chemical structure and clinical effect very similar to those of the male hormone testosterone. Since their introduction these substances have been misused in an effort to improve athletic performance. Detection of misuse has long been inadequate. For this reason a state doping programme was developed by the government of the former German Democratic Republic (GDR). Systematic doping abuse ended with the collapse of the GDR and the introduction of out-of-competition surprise drug testing. The performance-enhancing effects of doping and the introduction of intensive doping surveillance are reflected in the decline in performance in several women's track and field events.
    Nederlands tijdschrift voor geneeskunde 09/2008; 152(33):1820-4.
  • W de Ronde, E J H Meuleman
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    ABSTRACT: Over the past few decades, female hormonal contraception has been seen to be very successful. However, this has still not resulted in a hormonal contraceptive for men. Certain injectable combinations ofandrogens and progestagens have been found to suppress spermatogenesis. All combinations that have been tested so far suffer from a relative lack of efficacy, a long lag time to achieve azoospermia, requiring the user to undergo one or more semen analyses, a moderate user friendliness, and concerns about the long-term safety and reversibility. It is not to be expected that male hormonal contraception will become a serious alternative to the already existing female equivalent during the coming 5 years.
    Nederlands tijdschrift voor geneeskunde 12/2007; 151(46):2558-61.
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    ABSTRACT: Hypercortisolism is associated with muscle weakness. This study examines the relationship between cortisol and physical performance in older persons. The study was conducted within the Longitudinal Aging Study Amsterdam (LASA), an ongoing cohort study in a population-based sample of healthy older persons in the Netherlands. Data from the second (1995/1996) and fourth (2001/2002) cycle were used pertaining to 1172 (65-88 years) and 884 (65-94 years) men and women, respectively. Physical performance was measured by adding up scores on the chair stands, tandem stand and walk test (range 0-12). In the second cycle serum total and calculated free cortisol were assessed; in the fourth cycle evening salivary cortisol was assessed. Regression analysis (stratified for sex, adjusted for age, body mass index, alcohol use, physical activity and region) was performed to examine the cross-sectional relationship between cortisol and physical performance. Women with higher calculated free cortisol scored less well on physical performance (b = -0.28 per SD higher cortisol, P = 0.016), which was mainly explained by poorer performance on the tandem stand (OR = 1.32 for a lower score per SD higher cortisol, P = 0.003). Men with higher salivary cortisol scored less well on physical performance (b = -0.90 in the highest vs. the lowest quartile, P = 0.008), which was mainly explained by poorer performance on the chair stands and walk test (OR = 1.88, P = 0.020 and OR = 1.81, P = 0.027, respectively, in the highest vs. the lowest quartile). Physical performance is negatively associated with high cortisol levels in older persons.
    Clinical Endocrinology 10/2007; 67(3):398-406. DOI:10.1111/j.1365-2265.2007.02900.x · 3.35 Impact Factor
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    ABSTRACT: Sex steroids play an important role in the maintenance of bone health. Association studies on sex steroids and fractures are not consistent. Our objective was to examine whether serum oestradiol (E2) and testosterone (T) are associated with quantitative ultrasound (QUS), bone mineral density (BMD), bone turnover markers and fracture incidence. The Longitudinal Ageing Study Amsterdam (LASA), an ongoing cohort study including 623 men and 634 women, aged 65-88 years. Serum levels of E2, T, SHBG, albumin, bone turnover markers serum osteocalcin (OC) and urinary deoxypyridinoline (DPD/Cr) were measured. QUS of the heel and BMD of the hip were assessed, and a 6-year fracture follow-up was performed. Men in the lowest quartile (Q1) of bioavailable E2 (bioE2) had higher levels of bone turnover and lower BMD (B = -0.09, P < 0.01) and QUS than men in the highest quartile (Q4). This also applied to Q1 of bioT. Women in Q1 of bioE2 had higher levels of bone turnover and lower BMD (B = -0.07, P < 0.01) and QUS than women in Q4. In men and women, levels of bioE2 below the median were associated with an increased risk of osteoporotic fractures after all adjustments [hazard ratio (HR) 1.53, 95% confidence interval (CI) 1.02-2.29]. In men, univariate analysis revealed that low bioT was associated with an increased fracture risk (HR 1.91, 95% CI 1.03-3.56), but after adjustment for age, this association was no longer significant. Low levels of bioE2 and bioT were found to be associated with high bone turnover, low QUS and BMD and high risk of osteoporotic fractures in both men and women.
    Clinical Endocrinology 08/2007; 67(2):295-303. DOI:10.1111/j.1365-2265.2007.02882.x · 3.35 Impact Factor

Publication Stats

593 Citations
125.62 Total Impact Points

Institutions

  • 2012
    • Kennemer Gasthuis
      Haarlem, North Holland, Netherlands
  • 2006–2012
    • VU University Medical Center
      • Department of Endocrinology
      Amsterdamo, North Holland, Netherlands
  • 2005–2011
    • VU University Amsterdam
      • Department of Social Gerontology
      Amsterdamo, North Holland, Netherlands
    • Erasmus MC
      • Department of Internal Medicine
      Rotterdam, South Holland, Netherlands