Research Annual Report 2009

Transcription

1 Research Annual Report 2009 Molecular Medicine (MM) Clinical and experimental neuroendocrinology Regulation of calcium and bone metabolism Regulation of the bioactivity of thyroid hormone Signalling in reproduction and ageing Localisation, detection and radionuclide therapy of various diseases Regulation of follicle development, oocyte and endometrial embryo quality Pathophysiology of pediatric endocrine, metabolic and renal diseases Malignant transformation of hematopoietic stem cells: pathophysiology and development of therapy Hematopoiesis: regulation of the proliferation and differentiation of hematopoietic progenitor cells Molecular determinants of therapy response and outcome in childhood cancer Lymphoid differentiation and immunodeficiencies Immune regulation and autoimmunity Diagnosis, classification and treatment evaluation of leukemias and malignant lymphomas Solid tumors between bench and bed Improving accuracy and therapeutic ratio in radiation oncology 10599, B&T Ontwerp en advies (

2 Research Annual Report 2009 Molecular Medicine (MM) Hyperthermia: a treatment for cancer Photodynamic therapy Neuro-oncology and pain Pathophysiological aspects and treatment of gastro-intestinal diseases Innovative tumor model development/tumor vasculature/tumor targeting/locoregional control Clinical and experimental aspects of urological tumors Gynaecological oncology; basics, epidemiology and clinical aspects Developmental biology; pathophysiology of the newborn Experimental therapeutical approaches in inflammatory dermatoses and cutaneous oncology Translational genomics and proteomics of cancer Translational pharmacology Translational tumor immunology Neoplastic lesions and chronic inflammatation of the gastrointestinal tract Liverspecific immunopathology; mechanism and therapeutic modulation Human virus infections: immunity, therapy and epidemiology 10599, B&T Ontwerp en advies (

3 Research Annual Report 2009 Molecular Medicine (MM) Infections due to bacteria, fungi and parasites: diagnosis, molecular mechanisms, epidemiology, therapy and prevention Clinical research in infectious diseases in adults Renal insufficiency and organ transplantation Cell biological and pathophysiological investigations on pulmonary diseases Neuromuscular and Neuroinflammatory Disorders Organ transplantation Genitourinary tract disorders in children Disorders of the gastrointestinal tract in childhood Clinical, epidemiological and basic research of infectious diseases and immunological diseases in children 10599, B&T Ontwerp en advies (

4 EMC MM Clinical and experimental neuroendocrinology Programme design in brief A. Studies on the regulation of hormone secretion by the normal pituitary gland as well as by human pituitary tumours in vivo and in vitro. B. An integrative approach to the endocrinology of ageing. Hormonal factors related to the ageing process are investigated in population studies. Intervention studies with hormones (growth hormone, dehydroepiandrosterone) are carried out. C. An integrative approach to factors determining glucocorticoid sensitivity in man. Molecular studies of mutations in the glucocorticoid receptor and in the translational regulation of glucocorticoid action are carried out in cells obtained from patients with glucocorticoid resistance and from patients with transient changes in glucocorticoid sensitivity. D. Studies on the expression of growth factor and peptide receptors in cancer and in immune cells. E. The regulation of the growth and activity of immune and of tumour cells in vitro by manipulation of the expression of peptide receptors is studied in relation with the potential endocrine manipulation of immune diseases and cancer growth in vivo. F. An integrative approach of clinical and surgical endocrinology is used in studies aimed at improving patient care. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot internal medicine 1,8 0,82 1,15 2,25 6,02 reproduction and development 0, ,1 surgery 0, ,1 Total 2 0,82 1,15 2,25 6, Thesis Bruin, C. de (2009, juli 01). Somatostatin and dopamine receptors as molecular targets for the medical treatment of Cushing's disease. EUR (170 pag.). Prom./coprom.: Prof.Dr. S.W.J. Lamberts & Dr. L.J. Hofland. Rietveld, I. (2009, december 16). The role of a CA repeat polymorphism in the promoter region of the insulin-like growth factor gene in psyciology and the pathophysiology of diabetes mellitus. EUR (126 pag.). Prom./coprom.: Prof.Dr. S.W.J. Lamberts, Prof.Dr.Ir. C.M. van Duijn & Dr. J.A.M.J.L. Janssen. Article/Letter to the editor Akerstrom, G, Falconi, M, Kianmanesh, R., Ruszniewski, P. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Pre- and Perioperative Therapy in Patients with Neuroendocrine Tumors. Neuroendocrinology, 90(2), Akker, E.L.T. van den, Koper, J.W., Joosten, K.F.M., Jong, F.H. de, Hazelzet, J.A., Lamberts, S.W.J. & Hokken-Koelega, A.C.S. (2009). Glucocorticoid receptor mrna levels are selectively decreased in neutrophils of children with sepsis. Intensive Care Medicine, 35, Arnold, R., Chen, YJ, Costa, F, Falconi, M, Gross, D, Grossman, A.B., Hyrdel, R., Kos-Kudla, B, Salazar, R. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Follow-Up and Documentation. Neuroendocrinology, 90(2), Brugts, M.P., Luermans, JGLM, Lentjes, EGWM, Vrouwerff, NJ van Trooyen-van, Horst, FAL van der, Slee, PHTJ, Lamberts, S.W.J. & Janssen, JAML (2009). Heterophilic antibodies may be a cause of falsely low total IGF1 levels. European Journal of Endocrinology, 161(4), Bruin, C. de, Pereira, AM, Feelders, R.A., Romijn, J.A., Roelfsema, F, Sprij-Mooij, D.M., Aken, M.O. van, Lelij, A.J. van der, Herder, W.W. de, Lamberts, S.W.J. & Hofland, L.J. (2009). Coexpression of Dopamine and Somatostatin Receptor Subtypes in Corticotroph Adenomas. Journal of Clinical Endocrinology and Metabolism, 94(4), Bruin, C. de, Meij, BP, Kooistra, HS, Hanson, JM, Lamberts, S.W.J. & Hofland, L.J. (2009). Cushing's Disease in Dogs and Humans. Hormone Research, 71, Bruin, C. de, Feelders, R.A., Waaijers, A.M., Koetsveld, P.M. van, Sprij-Mooij, D.M., Lamberts, S.W.J. & Hofland, L.J. (2009). Differential regulation of human dopamine D-2 and somatostatin receptor subtype expression by glucocorticoids in vitro. Journal of Molecular Endocrinology, 42(1-2), Bruin, C. de, Feelders, R.A., Lamberts, S.W.J. & Hofland, L.J. (2009). Somatostatin and dopamine receptors as targets for medical treatment of Cushing's Syndrome. Reviews in Endocrine & Metabolic Disorders, 10(2), Caraglia, M, Marra, M, Tagliaferri, P, Lamberts, S.W.J., Zappavigna, S, Misso, G, Cavagnini, F., Facchini, G, Abbruzzese, A, Hofland, L.J. & Vitale, G. (2009). Emerging Strategies to Strengthen the Anti-Tumour Activity of Type I Interferons: Overcoming Survival Pathways. Current Cancer Drug Targets, 9(5), Casteren, N.J. van, Pieters, R., Dohle, G.R., Baalen, M. van, Neggers, S & Heuvel-Eibrink, M.M. van den (2009). Cranial irradiation does not result in pituitary-gonadal axis dysfunction in very long-term male survivors of childhood acute lymphoblastic leukemia. Leukemia, 23(12), Dekker, M.J.H.J., Akker, E.L.T. van den, Koper, F.J.W., Manenschijn, L., Geleijns, K, Ruts, L., Rijs, W. van, Tio-Gillen, A.P., Doorn, P.A. van, Lamberts, S.W.J. & Jacobs, B.C. (2009). Effect of glucocorticoid receptor gene polymorphisms in Guillain- Barre syndrome. Journal of the Peripheral Nervous System, 14(2),

5 Eriksson, B., Annibale, B, Bajetta, E, Mitry, E, Pavel, M, Platania, M, Salazar, R. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Chemotherapy in Patients with Neuroendocrine Tumors. Neuroendocrinology, 90(2), Feelders, R.A., Hofland, L.J., Aken, M.O. van, Neggers, SJ, Lamberts, S.W.J., Herder, W.W. de & Lely, A.J. van der (2009). Medical Therapy of Acromegaly Efficacy and Safety of Somatostatin Analogues. Drugs, 69(16), Ferone, D., Montella, L, Chiara, A De, Hofland, L.J., Lamberts, S.W.J. & Palmieri, G (2009). Somatostatin receptor expression in thymic tumors. Frontiers in Bioscience, 14, Forrer, F., Krenning, E.P., Kooij, P.P., Bernard, H.F., Konijnenberg, M.W., Bakker, W.H., Teunissen, J.J.M., Jong, M. de, Lom, K. van, Herder, W.W. de & Kwekkeboom, D.J. (2009). Bone marrow dosimetry in peptide receptor radionuclide therapy with [Lu- 177-DOTA(0),Tyr(3)]octreotate. European Journal of Nuclear Medicine and Molecular Imaging, 36(7), Froberg, A.C., Jong, M. de, Nock, B.A., Breeman, W.A.P., Erion, J.L., Maina, T, Verdijsseldonck, M.C.C., Herder, W.W. de, Lugt, A. van der, Kooij, P.P.M. & Krenning, E.P. (2009). Comparison of three radiolabelled peptide analogues for CCK-2 receptor scintigraphy in medullary thyroid carcinoma. European Journal of Nuclear Medicine and Molecular Imaging, 36(8), Hoek, J. van der, Hoorn, E.J., Jong, GMT de, Janssens, ENW & Herder, W.W. de (2009). Severe Hyponatremia with High Urine Sodium and Osmolality. Clinical Chemistry, 55(11), Hoek, M. van, Hofland, L.J., Rijke, Y.B. de, Nederveen, F.H. van, Krijger, R.R. de, Koetsveld, P.M. van, Lamberts, S.W.J., Lely, A.J. van der, Herder, W.W. de & Feelders, R.A. (2009). Effects of Somatostatin Analogs on a Growth Hormone-Releasing Hormone Secreting Bronchial Carcinoid, in Vivo and in Vitro Studies. Journal of Clinical Endocrinology and Metabolism, 94(2), Horst-Schrivers, ANA van der, Ieperen, E van, Wymenga, ANM, Boezen, H.M., Weijmar-Schultz, WCM, Kema, I.P., Meijer, W.G., Herder, W.W. de, Willemse, P.H.B., Links, T.P. & Vries, E.G.E. de (2009). Sexual Function in Patients with Metastatic Midgut Carcinoid Tumours. Neuroendocrinology, 89(2), Janssen, J.A.M.J.L. (2009). Advantages and disadvantages of GH/IGF-I combination treatment. Reviews in Endocrine & Metabolic Disorders, 10(2), Kiewiet, R.M., Aken, M.O. van, Weerd, K. van der, Uitterlinden, P., Themmen, A.P.N., Hofland, L.J., Rijke, Y.B. de, Delhanty, P.J.D., Ghigo, E., Abribat, T. & Lely, A.J. van der (2009). Effects of acute administration of acylated and unacylated ghrelin on glucose and insulin concentrations in morbidly obese subjects without overt diabetes. European Journal of Endocrinology, 161(4), Kloppel, G., Couvelard, A, Perren, A, Komminoth, P., McNicol, AM, Nilsson, O., Scarpa, A, Scoazec, JY, Wiedenmann, B., Papotti, M., Rindi, G. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Towards a Standardized Approach to the Diagnosis of Gastroenteropancreatic Neuroendocrine Tumors and Their Prognostic Stratification (vol 90, pg 162, 2009). Neuroendocrinology, 90(4), Kumsta, R., Moser, D, Streit, F, Koper, F.J.W., Meyer, J. & Wust, S (2009). Characterization of a Glucocorticoid Receptor Gene (GR, NR3C1) Promoter Polymorphism Reveals Functionality and Extends a Haplotype With Putative Clinical Relevance. American Journal of Medical Genetics Part B-Neuropsychiatric Genetics, 150B(4), Kwekkeboom, D.J., Krenning, E.P., Lebtahi, R, Komminoth, P., Kos-Kudla, B, Herder, W.W. de & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Peptide Receptor Radionuclide Therapy with Radiolabeled Somatostatin Analogs. Neuroendocrinology, 90(2), Kwekkeboom, D.J., Krenning, E.P., Scheidhauer, K, Lewington, V, Lebtahi, R, Grossman, A., Vitek, P, Sundin, A & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Somatostatin Receptor Imaging with In-111-Pentetreotide. Neuroendocrinology, 90(2), Lamberts, S.W.J. & Uitterlinden, A.G. (2009). Genetic Testing in Clinical Practice. Annual Review of Medicine, 60, Lely, A.J. van der (2009). Ghrelin and New Metabolic Frontiers. Hormone Research, 71, Manenschijn, L., Akker, E.L.T. van den, Lamberts, S.W.J. & Rossum, E.F.C. van (2009). Clinical Features Associated with Glucocorticoid Receptor Polymorphisms An Overview. Annals of the New York Academy of Sciences, Melmed, S., Colao, A., Barkan, A, Molitch, M, Grossman, A.B., Kleinberg, D, Clemmons, D, Chanson, P., Laws, E, Schlechte, J, Vance, M.L., Ho, K & Giustina, A (2009). Guidelines for Acromegaly Management: An Update. Journal of Clinical Endocrinology and Metabolism, 94(5), Messidoro, C., Elte, JWF, Cabezas, MC, Agteren, M. van, Lacroix, A. & Herder, W.W. de (2009). Food-dependent Cushing's syndrome. Netherlands Journal of Medicine, 67(5), Mulder, RL, Kremer, LCM, Santen, HM van, Ket, JL, Trotsenburg, A.S.P. van, Koning, CCE, Meeteren, AYN Schouten-van, Caron, H.N., Neggers, S.J.C.M.M. & Dalen, EC van (2009). Prevalence and risk factors of radiation-induced growth hormone deficiency in childhood cancer survivors: A systematic review. Cancer Treatment Reviews, 35(7), Muller, M., Beld, A.W. van den, Grobbee, D.E., Jong, F.H. de & Lamberts, S.W.J. (2009). Sex hormones and cognitive decline in elderly men. Psychoneuroendocrinology, 34(1),

6 Nederveen, F.H. van, Gaal, J., Favier, J, Korpershoek, E., Oldenburg, R.A., Bruyn, E.M.C.A. de, Sleddens, H.F.B.M., Derkx, P., Riviere, J, Dannenberg, H., Petri, B.J., Komminoth, P., Pacak, K., Hop, W.C.J., Pollard, PJ, Mannelli, M, Bayley, JP, Perren, A, Niemann, S, Verhofstadt, AA, Bruine, AP de, Maher, ER, Tissier, F, Meatchi, T, Badoual, C, Bertherat, J, Amar, L, Alataki, D, Marck, E. van, Ferrau, F., Francois, J, Herder, W.W. de, Peeters, MPFMV, Linge, A. van, Lenders, J.W.M., Gimenez-Roqueplo, AP, Krijgert, RR de & Dinjens, W.N.M. (2009). An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncology, 10(8), Neggers, S.J.C.M.M., Herder, W.W. de, Janssen, J.A.M.J.L., Feelders, R.A. & Lely, A.J. van der (2009). Combined treatment for acromegaly with long-acting somatostatin analogs and pegvisomant: long-term safety for up to 4.5 years (median 2.2 years) of follow-up in 86 patients. European Journal of Endocrinology, 160(4), Neggers, S.J.C.M.M. & Lely, A.J. van der (2009). Somatostatin analog and pegvisomant combination therapy for acromegaly. Nature Reviews Endocrinology, 5(10), Oberg, K, Ferone, D., Kaltsas, G., Knigge, UP, Taal, B & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Biotherapy. Neuroendocrinology, 90(2), O'Toole, D, Grossman, A., Gross, D, Fave, G. delle, Barkmanova, J, O'Connor, J, Pape, U.F. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Biochemical Markers. Neuroendocrinology, 90(2), Peeters, R.P., Hagendorf, A., Vanhorebeek, I, Visser, T.J., Klootwijk, W., Mesotten, D, Wouters, PJ, Koper, F.J.W., Jong, F.H. de, Feelders, R.A., Lamberts, S.W.J. & Berghe, G. van den (2009). Tissue mrna expression of the glucocorticoid receptor and its splice variants in fatal critical illness. Clinical Endocrinology, 71(1), Petri, B.J., Eijck, C.H.J. van, Herder, W.W. de, Wagner, A. & Krijger, R.R. de (2009). Phaeochromocytomas and sympathetic paragangliomas. British Journal of Surgery, 96(12), Pivonello, R., Martino, M.C. de, Cappabianca, P, Leo, M De, Faggiano, A, Lombardi, G., Hofland, L.J., Lamberts, S.W.J. & Colao, A. (2009). The Medical Treatment of Cushing's Disease: Effectiveness of Chronic Treatment with the Dopamine Agonist Cabergoline in Patients Unsuccessfully Treated by Surgery. Journal of Clinical Endocrinology and Metabolism, 94(1), Plockinger, U, Wiedenmann, B. & Herder, W.W. de (2009). ENETS Consensus Guidelines for the Standard of Care in Neuroendocrine Tumors. Neuroendocrinology, 90(2), Plockinger, U, Gustafsson, B, Ivan, D, Szpak, W & Davar, J (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Echocardiography. Neuroendocrinology, 90(2), Siiskonen, S.J., Visser, L.E., Tiemeier, H.W., Hofman, A., Lamberts, S.W.J., Uitterlinden, A.G. & Stricker, B.H.C. (2009). BclI glucocorticoid receptor polymorphism and smoking in the general population. Addiction Biology, 14(3), Spijker, AT, Rossum, E.F.C. van, Hoencamp, E, DeRijk, RH, Haffmans, J, Blom, M., Manenschijn, L., Koper, F.J.W., Lamberts, S.W.J. & Zitman, F.G. (2009). Functional polymorphism of the glucocorticoid receptor gene associates with mania and hypomania in bipolar disorder. Bipolar Disorders, 11(1), Spijker, AT & Rossum, E.F.C. van (2009). Glucocorticoid Receptor Polymorphisms in Major Depression Focus on Glucocorticoid Sensitivity and Neurocognitive Functioning. Annals of the New York Academy of Sciences, Stolk, L., Zhai, G., Meurs, J.B.J. van, Verbiest, M.M.P.J., Visser, J.A., Estrada, K, Rivadeneira, F., Williams, FM, Cherkas, L, Deloukas, P, Soranzo, N, Keyzer, J.J., Pop, VJM, Lips, P., Lebrun, C.E.I., Schouw, Y.T. van der, Grobbee, D.E., Witteman, J.C.M., Hofman, A., Pols, H.A.P., Laven, J.S.E., Spector, T.D. & Uitterlinden, A.G. (2009). Loci at chromosomes 13, 19 and 20 influence age at natural menopause. Nature Genetics, 41(6), Sundin, A, Vullierme, M.P., Kaltsas, G. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Radiological Examinations. Neuroendocrinology, 90(2), Teunissen, J.J.M., Krenning, E.P., Jong, F.H. de, Rijke, Y.B. de, Feelders, R.A., Aken, M.O. van, Herder, W.W. de & Kwekkeboom, D.J. (2009). Effects of therapy with [Lu-177-DOTA(0),Tyr(3)]octreotate on endocrine function. European Journal of Nuclear Medicine and Molecular Imaging, 36(11), Vila, G, Riedl, M, Resl, M, Lely, A.J. van der, Hofland, L.J., Clodi, M & Luger, A (2009). Systemic administration of oxytocin reduces basal and lipopolysaccharide-induced ghrelin levels in healthy men. Journal of Endocrinology, 203(1), Vitale, G., Koetsveld, P.M. van, Herder, W.W. de, Wansem, K. van der, Janssen, J.A.M.J.L., Colao, A., Lombardi, G., Lamberts, S.W.J. & Hofland, L.J. (2009). Effects of type I interferons on IGF-mediated autocrine/paracrine growth of human neuroendocrine tumor cells. American Journal of Physiology, Endocrinology and Metabolism, 296(3), E559-E566. Vitale, G., Caraglia, M, Koetsveld, P.M. van, Maroni, P, Marra, M, Colao, A., Lamberts, S.W.J., Cavagnini, F. & Hofland, L.J. (2009). Potential role of type I interferons in the treatment of pituitary adenomas. Reviews in Endocrine & Metabolic Disorders, 10(2), Voorhoeve, P.G., Akker, E.L.T. van den, Lamberts, S.W.J., Delemarre- van de Waal, H.A. & Hokken-Koelega, A.C.S. (2009). Glucocorticoid receptor gene polymorphism is less frequent in children born small for gestational age without catch-up growth. Hormone Research, 71,

7 Voorhoeve, P.G., Akker, E.L.T. van den, Rossum, E.F.C. van, Koper, F.J.W., Mechelen, W. van, Lamberts, S.W.J. & Waal, HA Delemarre-Van D (2009). Glucocorticoid receptor gene variant is associated with increased body fatness in youngsters. Clinical Endocrinology, 71(4), Winsen, LML van, Manenschijn, L., Rossum, E.F.C. van, Crusius, BA, Koper, F.J.W., Polman, C.H. & Uitdehaag, B.M.J. (2009). A Glucocorticoid Receptor Gene Haplotype (TthIII1/ER22/23EK/9 beta) Is Associated with a More Aggressive Disease Course in Multiple Sclerosis. Journal of Clinical Endocrinology and Metabolism, 94(6), Part of book - abstract Janssen, J.A.M.J.L. (2009). Combination of GH and IGF=I makes the difference! In DR Clemmons & AF Attanasio (Eds.), Hypothalamic-pituitary disease and obesity (pp ). Bristol: Bioscientifica. Neggers, S.J.C.M.M., Lamberts, S.W.J. & Lely, A.J. van der (2009). Long-term treatment. In JAH Wass (Ed.), Acromegaly. a handbook of history, current therapy and future prospects (pp ). Bristol: Bioscientifica.

8 EMC MM Regulation of calcium and bone metabolism Programme design in brief Research focus is skeletal and calcium homeostasis and development and progression of related disorders with particular emphasis on ageing. Increasing life span is accompanied by an increase in age-related diseases such as osteoporosis. Osteoporosis is an important common disease with a large impact on quality of life as well as health care budget. Development of pharmaceutical and life style interventions as prevention or as treatment is important and requires an optimal knowledge in aetiology and mechanisms of development of osteoporosis. Current therapies for osteoporosis are directed to inhibit bone loss and thereby its progression. There is, however, a major need for anabolic therapies, which stimulate bone formation because bone loss has already occurred when the consequences of osteoporosis have become overt. Directly coupled to this is improvement in early diagnostics. The overall aim of this research line is to develop better diagnostics and therapies for skeletal disorders and disturbances in calcium homeostasis by a combination of molecular, cellular, animal, epidemiological and eventually clinical studies. Four integrated lines of research can be identified. 1) Characterisation of molecular mechanisms of bone cell differentiation and of bone formation and degradation using human bone cell models by bioinformatic and systems biological analyses of gene, protein and enzyme activity profiles. 2) Identification of risk determinants for osteoporosis and osteoarthritis on basis of genetic epidemiological and serum proteomic studies within a.o. the Rotterdam Study. 3) Calcium homeostasis and skeletal metabolism in relation to ageing by analyses of experimental animal models, e.g. premature ageing mice, as well as human population research. 4) Development of medium/high throughput screenings procedures to quickly screen therapeutic targets and to evaluate novel therapeutic compounds. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot internal medicine 6,23 7,53 0 1,8 15,56 Total 6,23 7,53 0 1,8 15, Thesis Baars, G.J.A. (2009, oktober 30). Factors related to student achievement in medical school. EUR. Prom./coprom.: T.A.W. Splinter & Prof.Dr. T. Stijnen. Sniekers, Y.H. (2009, september 24). Estrogen effects on cartilage and bone changes in models for osteoarthritis. EUR (125 pag.). Prom./coprom.: Prof.Dr.Ir. H.H. Weinans, Prof.dr. J.P.T.M. van Leeuwen & Dr. G.J.V.M. van Osch. Stolk, L. (2009, december 01). Genetics of estrogen-related traits; from candidate genes to GWAS. EUR (187 pag.). Prom./coprom.: Prof.dr. A.G. Uitterlinden. Zillikens, M.C. (2009, oktober 07). The interplay of genes and diet in metabolic diseases and aging. EUR (216 pag.). Prom./coprom.: Prof.dr. A.G. Uitterlinden, Prof.Dr. B.A. Oostra & Prof.Dr.Ir. C.M. van Duijn. Article/Letter to the editor Alexander, RT, Woudenberg-Vrenken, TE, Buurman, J, Dijkman, H., Eerden, B.C.J. van der, Leeuwen, J.P.T.M. van, Bindels, RJ & Hoenderop, JG (2009). Klotho Prevents Renal Calcium Loss. Journal of the American Society of Nephrology, 20(11), Allikmets, R., Dean, M, Hageman, G.S., Baird, PN, Klaver, C.C., Bergen, AA & Weber, B.H. (2009). The SERPING1 gene and age-related macular degeneration. Lancet (UK), 374(9693), Aulchenko, Y.S., Ripatti, S, Lindqvist, I, Boomsma, D, Heid, IM, Pramstaller, P.P., Penninx, BWJH, Janssens, A.C.J.W., Wilson, JF, Spector, T., Martin, NG, Pedersen, NL, Kyvik, KO, Kaprio, J, Hofman, A., Freimer, N.B., Jarvelin, MR, Gyllensten, U, Campbell, H, Rudan, I, Johansson, A, Marroni, F, Hayward, C, Vitart, V, Jonasson, I, Pattaro, C, Wright, A, Hastie, N, Pichler, I, Hicks, AA, Falchi, M, Willemsen, G, Hottenga, J.J., Geus, E.J.C. de, Montgomery, GW, Whitfield, J, Magnusson, P, Saharinen, J, Perola, M, Silander, K, Isaacs, A.J., Sijbrands, E.J.G., Uitterlinden, A.G., Witteman, J.C.M., Oostra, B.A., Elliott, P, Ruokonen, A, Sabatti, C, Gieger, C, Meitinger, T, Kronenberg, F, Doring, A, Wichmann, HE, Smit, J.H., McCarthy, MI, Duijn, C.M. van & Peltonen, L. (2009). Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nature Genetics, 41(1), Becker, M.L., Visser, L.E., Newton-Cheh, C, Hofman, A., Uitterlinden, A.G., Witteman, J.C.M. & Stricker, B.H.C. (2009). A common NOS1AP genetic polymorphism is associated with increased cardiovascular mortality in users of dihydropyridine calcium channel blockers. British Journal of Clinical Pharmacology, 67(1), Benjamin, EJ, Rice, KM, Arking, DE, Pfeufer, A, Noord, C. van, Smith, AV, Schnabel, RB, Bis, JC, Boerwinkle, E., Sinner, MF, Dehghan, A., Lubitz, SA, D'Agostino, RB, Lumley, T, Ehret, GB, Heeringa, J., Aspelund, T, Newton-Cheh, C, Larson, MG, Marciante, KD, Soliman, EZ, Rivadeneira Ramirez, F., Wang, T.J., Eiriksdottir, G, Levy, D., Psaty, B.M., Li, M., Chamberlain, AM, Hofman, A., Vasan, RS, Harris, T.B., Rotter, JI, Kao, WHL, Agarwal, SK, Stricker, B.H.C., Wang, K, Launer, L.J., Smith, NL, Chakravarti, A, Uitterlinden, A.G., Wolf, PA, Sotoodehnia, N, Kottgen, A, Duijn, C.M. van, Meitinger, T, Mueller, M, Perz, S, Steinbeck, G, Wichmann, HE, Lunetta, KL, Heckbert, SR, Gudnason, V, Alonso, A., Kaab, S, Ellinor, PT & Witteman, J.C.M. (2009). Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nature Genetics, 41(8), Berends, A.L., Zillikens, M.C., Groot, C.J.M. de, Rivadeneira, F., Oostra, B.A., Duijn, C.M. van & Steegers, E.A.P. (2009). Body composition by dual-energy X-ray absorptiometry in women with previous pre-eclampsia or small-for-gestational-age offspring. Bjog-An International Journal of Obstetrics and Gynaecology, 116(3), Bergink, A.P., Uitterlinden, A.G., Leeuwen, J.P.T.M. van, Buurman, C.J., Hofman, A., Verhaar, J.A.N. & Pols, H.A.P. (2009). Vitamin D Status, Bone Mineral Density, and the Development of Radiographic Osteoarthritis of the Knee The Rotterdam Study. Jcr. Journal of Clinical Rheumatology, 15(5),

9 Botter, S.M., Glasson, SS, Hopkins, B, Clockaerts, S.B.F., Weinans, H., Leeuwen, J.P.T.M. van & Osch, G.J.V.M. van (2009). ADAMTS5-/- mice have less subchondral bone changes after induction of osteoarthritis through surgical instability: implications for a link between cartilage and subchondral bone changes. Osteoarthritis and Cartilage, 17(5), Despriet, D.D.G., Duijn, C.M. van, Oostra, B.A., Uitterlinden, A.G., Hofman, A., Wright, AF, Brink, J.B., Bakker, A., Jong, P.T.V.M. de, Vingerling, J.R., Bergen, A.A.B. & Klaver, C.C.W. (2009). Complement Component C3 and Risk of Age-Related Macular Degeneration. Ophthalmology, 116(3), Deure, W.M. van der, Peeters, R.P., Uitterlinden, A.G., Hofman, A., Breteler, M.M.B., Witteman, J.C.M. & Visser, T.J. (2009). Impact of thyroid function and polymorphisms in the type 2 deiodinase on blood pressure: the Rotterdam Study and the Rotterdam Scan Study. 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10 Mattace Raso, F.U.S., Smith, AV, Taylor, K., Scharpf, RB, Hwang, SJ, Sijbrands, E.J.G., Bis, JC, Harris, T.B., Ganesh, SK, O'Donnell, CJ, Hofman, A., Rotter, JI, Coresh, J, Benjamin, EJ, Uitterlinden, A.G., Heiss, G, Fox, CS, Witteman, J.C.M., Boerwinkle, E., Wang, T.J., Gudnason, V, Larson, MG, Chakravarti, A, Psaty, B.M. & Duijn, C.M. van (2009). Genome-wide association study of blood pressure and hypertension. Nature Genetics, 41(6), Lu, TT, Lao Grueso, O., Nothnagel, M, Junge, O, Freitag-Wolf, S, Caliebe, A, Balascakova, M, Bertranpetit, J, Bindoff, LA, Comas, D, Holmlund, G, Kouvatsi, A, Macek, M., Mollet, I, Nielsen, F, Parson, W, Palo, J, Ploski, R, Sajantila, A, Tagliabracci, A, Gether, U, Werge, T, Rivadeneira Ramirez, F., Hofman, A., Uitterlinden, A.G., Gieger, C, Wichmann, HE, Ruether, A, Schreiber, S., Becker, C., Nurnberg, P, Nelson, MR, Kayser, M. & Krawczak, M (2009). An evaluation of the genetic-matched pair study design using genome-wide SNP data from the European population. European Journal of Human Genetics, 17(7), Meurs, J.B.J. van, Uitterlinden, A.G., Stolk, L., Kerkhof, HJM, Hofman, A., Pols, H.A.P. & Bierma-Zeinstra, S.M.A. (2009). A functional polymorphism in the catechol-o-methyltransferase gene is associated with osteoarthritis-related pain. Arthritis & Rheumatism, 60(2), Newton-Cheh, C, Eijgelsheim, M., Rice, KM, Bakker, PIW de, Yin, XY, Estrada, K, Bis, JC, Marciante, K, Rivadeneira Ramirez, F., Noseworthy, PA, Sotoodehnia, N, Smith, NL, Rotter, JI, Kors, J.A., Witteman, J.C.M., Hofman, A., Heckbert, SR, O'Donnell, CJ, Uitterlinden, A.G., Psaty, B.M., Lumley, T, Larson, MG & Stricker, B.H.C. (2009). Common variants at ten loci influence QT interval duration in the QTGEN Study. Nature Genetics, 41(4), Omidvar, M., Stolk, L., Uitterlinden, A.G., Hofman, A., Duijn, C.M. van & Tiemeier, H. (2009). The effect of catechol-omethyltransferase Met/Val functional polymorphism on smoking cessation: retrospective and prospective analyses in a cohort study. Pharmacogenetics Genomics, 19(1), Oudshoorn, C., Cammen, T.J.M. van der, McMurdo, MET, Leeuwen, J.P.T.M. van & Colin, E.M. (2009). Ageing and vitamin D deficiency: effects on calcium homeostasis and considerations for vitamin D supplementation. 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11 H., Volzke, H & Blankenberg, S (2009). Genetic Variants Associated With Cardiac Structure and Function A Meta-analysis and Replication of Genome-wide Association Data. Jama - Journal of the American Medical Association, 302(2), Westerhoff, HV, Kolodkin, A, Conradie, R, Wilkinson, SJ, Bruggeman, FJ, Krab, K, Schuppen, JH van, Hardin, H, Bakker, BM, Mone, M.J., Rybakova, KN, Eijken, M, Leeuwen, HJP van & Snoep, JL (2009). Systems biology towards life in silico: mathematics of the control of living cells. Journal of Mathematical Biology, 58(1-2), Zillikens, M.C., Meurs, J.B.J. van, Sijbrands, E.J.G., Rivadeneira Ramirez, F., Dehghan, A., Leeuwen, J.P.T.M. van, Hofman, A., Duijn, C.M. van, Witteman, J.C.M., Uitterlinden, A.G. & Pols, H.A.P. (2009). SIRT1 genetic variation and mortality in type 2 diabetes: interaction with smoking and dietary niacin. Free Radical Biology and Medicine, 46(6), Part of book - abstract Uitterlinden, A.G., Meurs, J.B.J. van & Rivadeneira Ramirez, F. (2009). Building the evidence for using genetic information to improve health and prevent disease. In Khoury, Gwinn, Bradley, Little, Higgins & Ioannidis (Eds.), Human genome epidemiology. Oxford: Oxford University press. Patent Leeuwen, J.P.T.M. van & Eijken, H.J.M. (). Controlled bone mineralization. no EU-079= ; Ch.

12 EMC MM Regulation of the bioactivity of thyroid hormone Programme design in brief The prohormone T4 is converted by outer ring deiodination to the active hormone T3 and by inner ring deiodination to the inactive metabolite rt3. The three deiodinases (D1-3) involved are expressed in different tissues, where they play different roles in systemic and local control of T3 levels. The deiodinases are located in cell membranes with their active site exposed to the cytoplasm, while the T3 receptors (TRs) reside in the nucleus. Uptake of thyroid hormone across the plasma membrane is thus required for thyroid hormone action and metabolism, and is mediated by specific transporters. Recently, our group identified an important T3 transporter (MCT8) which was shown to be mutated in patients with severe psychomotor retardation and grossly elevated serum T3 levels. This project concerns the characterization of the deiodinases and transporters in human tissues as well as their importance in the regulation of the bioactivity of thyroid hormone in health and disease. In addition, the specific role of the alpha-type TR (TRa) in the tissue-specific action of thyroid hormone, particularly in the brain, is investigated. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot internal medicine 0,5 4, ,77 nuclear medicine 0, ,2 Total 0,7 4, , Thesis Deure, W.M. van der (2009, januari 14). Inter-individual differences in thyroid hormone bioactivity: the effect of genetic variation. EUR. Prom./coprom.: Prof.Dr.Ir. T.J. Visser. Article/Letter to the editor Cooper-Kazaz, R, Deure, W.M. van der, Medici, M., Visser, T.J., Alkelai, A, Glaser, B., Peeters, R.P. & Lerer, B (2009). Preliminary evidence that a functional polymorphism in type 1 deiodinase is associated with enhanced potentiation of the antidepressant effect of sertraline by triiodothyronine. Journal of Affective Disorders, 116(1-2), Deure, W.M. van der, Peeters, R.P., Uitterlinden, A.G., Hofman, A., Breteler, M.M.B., Witteman, J.C.M. & Visser, T.J. (2009). Impact of thyroid function and polymorphisms in the type 2 deiodinase on blood pressure: the Rotterdam Study and the Rotterdam Scan Study. Clinical Endocrinology, 71(1), Deure, W.M. van der, Hansen, PS, Peeters, R.P., Uitterlinden, A.G., Fenger, M, Kyvik, KO, Hegedus, L & Visser, T.J. (2009). The effect of genetic variation in the type 1 deiodinase gene on the interindividual variation in serum thyroid hormone levels: an investigation in healthy Danish twins. Clinical Endocrinology, 70(6), Heemstra, KA, Hoftijzer, HC, Deure, W.M. van der, Peeters, R.P., Fliers, E., Appelhof, BC, Wiersinga, W.M., Corssmit, EPM, Visser, T.J. & Smit, J.W.A. (2009). Thr92Ala polymorphism in the type 2 deiodinase is not associated with T4 dose in athyroid patients or patients with Hashimoto thyroiditis. Clinical Endocrinology, 71(2), Heemstra, KA, Soeters, MR, Fliers, E., Serlie, MJ, Burggraaf, J., Doorn, MB van, Klaauw, AA van der, Romijn, J.A., Smit, J.W., Corssmit, EP & Visser, T.J. (2009). Type 2 Iodothyronine Deiodinase in Skeletal Muscle: Effects of Hypothyroidism and Fasting. Journal of Clinical Endocrinology and Metabolism, 94(6), Hes, FJ, Madan, K., Rombout-Liem, IS, Szuhai, K, Sorensen, H, Amstel, H.K.P. van, Bakker, EM, Visser, T.J., Smit, J.W. & Hansson, K. (2009). Multiple Genomic Aberrations in a Patient With Mental Retardation and Hypogonadism: 45,X/46,X,psu dic(y) Karyotype, Thyroid Hormone Receptor Beta (THRB) Mutation and Heterozygosity for Wilson Disease. American Journal of Medical Genetics Part A, 149A(10), Heuer, H. & Visser, T.J. (2009). Minireview: Pathophysiological Importance of Thyroid Hormone Transporters. Endocrinology, 150(3), Kester, M.H.A., Toussaint, MJM, Punt, CA, Matondo, R, Aarnio, A.M., Darras, V.M., Everts, M.E., Bruin, A. & Visser, T.J. (2009). Large Induction of Type III Deiodinase Expression After Partial Hepatectomy in the Regenerating Mouse and Rat Liver. Endocrinology, 150(1), Mebis, L., Debaveye, Y, Ellger, B, Derde, S, Ververs, EJ, Langouche, L, Darras, V.M., Fliers, E., Visser, T.J. & Berghe, G. van den (2009). Changes in the central component of the hypothalamus-pituitary-thyroid axis in a rabbit model of prolonged critical illness. Critical Care, 13(5). Mebis, L., Paletta, D, Debaveye, Y, Ellger, B, Langouche, L, D'Hoore, A, Darras, V.M., Visser, T.J. & Berghe, G. van den (2009). Expression of thyroid hormone transporters during critical illness. European Journal of Endocrinology, 161(2), Peeters, R.P., Hagendorf, A., Vanhorebeek, I, Visser, T.J., Klootwijk, W., Mesotten, D, Wouters, PJ, Koper, F.J.W., Jong, F.H. de, Feelders, R.A., Lamberts, S.W.J. & Berghe, G. van den (2009). Tissue mrna expression of the glucocorticoid receptor and its splice variants in fatal critical illness. Clinical Endocrinology, 71(1), Ven, LTM van der, Kuil, T van de, Leonards, PEG, Slob, W, Lilienthal, H, Litens, S, Herlin, M, Hakansson, H, Canton, RF, Berg, M. van den, Visser, T.J., Loveren, H. van, Vos, J.G. & Piersma, AH (2009). Endocrine effects of hexabromocyclododecane (HBCD) in a one-generation reproduction study in Wistar rats. Toxicology Letters, 185(1), Visser, W.E., Philp, NJ, Dijk, T.B. van, Klootwijk, W., Friesema, E.C.H., Jansen, J., Beesley, PW, Ianculescu, AG & Visser, T.J. (2009). Evidence for a Homodimeric Structure of Human Monocarboxylate Transporter 8. Endocrinology, 150(11),

13 Visser, W.E., Jansen, J., Friesema, E.C.H., Kester, M.H.A., Mancilla, E, Lundgren, J, Knaap, M.S. van der, Lunsing, RJ, Brouwar, OF & Visser, T.J. (2009). Novel Pathogenic Mechanism Suggested by Ex Vivo Analysis of MCT8 (SLC16A2) Mutations. Human Mutation, 30(1), Visser, W.E., Heemstra, KA, Swagemakers, S.M.A., Ozgur, Z., Corssmit, EP, Burggraaf, J., Ijcken, W.F.J. van, Spek, P.J. van der, Smit, J.W.A. & Visser, T.J. (2009). Physiological Thyroid Hormone Levels Regulate Numerous Skeletal Muscle Transcripts. Journal of Clinical Endocrinology and Metabolism, 94(9), Visser, W.E., Friesema, E.C.H. & Visser, T.J. (2009). Transport of Thyroxine and 3,3 ',5-Triiodothyronine in Human Umbilical Vein Endothelial Cells. Endocrinology, 150(3), Vujovic, M, Nordstrom, K, Gauthier, K, Flamant, F, Visser, T.J., Vennstrom, B & Mittag, J. (2009). Interference of a Mutant Thyroid Hormone Receptor alpha 1 with Hepatic Glucose Metabolism. Endocrinology, 150(6),

14 EMC MM Signalling in reproduction and ageing Programme design in brief Glycoprotein hormones and members of the TGF /activin family of growth and differentiation factors play a central role in development and functioning of the organism throughout life. This program focuses on the effect of variations in signal transduction of hormones (including LH, hcg, FSH, ghrelin and unacylated ghrelin) and TGF- family members (including anti- Müllerian hormone, BMPs, inhibins and activins) during foetal and postnatal development and subsequent functioning and ageing of the organism. Furthermore, effects of mutations or single nucleotide polymorphisms in enzymes involved in biosynthesis or catabolism of steroid hormones are investigated. Variations in signaling through these pathways affect the early make-up of physiological response systems that can have effects during adult life and in the ageing process. Variations in signal transduction of ligand-receptor interaction, gene expression, proliferation and apoptosis are studied; not only at the molecular and cellular level, but also at the level of the whole body in animal models of ageing, in patients and in populations of ageing men and women. Specific areas are: 1.The role of TGF- family members in female ageing, oestrogen effects and age at menopause 2.The role of LH and LH receptor variations in female ageing 3.The influence of gene variants in female and male physiology 4.Development of animal models for the study of the role of genetic variations in the pathophysiology of ageing. 5.Causes and effects of changes in steroid biosynthetic pathways. 6.Evaluation of the (metabolic) role of natural and synthetic growth hormone secretatogues in peripheral tissues in vitro and in vivo Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot internal medicine 2, ,85 2,99 Total 2, ,85 2, Article/Letter to the editor Akker, E.L.T. van den, Koper, J.W., Joosten, K.F.M., Jong, F.H. de, Hazelzet, J.A., Lamberts, S.W.J. & Hokken-Koelega, A.C.S. (2009). Glucocorticoid receptor mrna levels are selectively decreased in neutrophils of children with sepsis. Intensive Care Medicine, 35, Alwani, R.A., Neggers, S.J.C.M.M., Klift, M. van der, Baggen, M.G.A., Leenders, G.J.L.H. van, Aken, M.O. van, Lely, A.J. van der, Herder, W.W. de & Feelders, R.A. (2009). Cushing's syndrome due to ectopic ACTH production by (neuroendocrine) prostate carcinoma. Pituitary, 12(3), Bannink, E.M.N., Sassen, C van, Buuren, S. van, Jong, F.H. de, Lequin, M.H., Mulder, P.G.H. & Muinck Keizer-Schrama, S.M.P.F. (2009). Puberty induction in Turner syndrome: results of oestrogen treatment on development of secondary sexual characteristics, uterine dimensions and serum hormone levels. Clinical Endocrinology, 70(2), Elfferich, P., Juniarto, A.Z., Dubbink, H.J., Royen, M.E. van, Molier, M., Hoogerbrugge, J.W., Houtsmuller, A.B., Trapman, J., Santosa, A, Jong, F.H. de, Drop, S.L.S., Faradz, SMH, Bruggenwirth, H & Brinkmann, A.O. (2009). Functional Analysis of Novel Androgen Receptor Mutations in a Unique Cohort of Indonesian Patients with a Disorder of Sex Development. Sexual Development, 3(5), Feelders, R.A., Hofland, L.J., Aken, M.O. van, Neggers, SJ, Lamberts, S.W.J., Herder, W.W. de & Lely, A.J. van der (2009). Medical Therapy of Acromegaly Efficacy and Safety of Somatostatin Analogues. Drugs, 69(16), Goossens, K., Juniarto, A.Z., Timmerman, M.A., Faradz, SMH, Wolffenbuttel, K.P., Drop, S.L.S. & Jong, F.H. de (2009). Lack of correlation between phenotype and genotype in untreated 21-hydroxylase-deficient Indonesian patients. Clinical Endocrinology, 71, Hoek, M. van, Hofland, L.J., Rijke, Y.B. de, Nederveen, F.H. van, Krijger, R.R. de, Koetsveld, P.M. van, Lamberts, S.W.J., Lely, A.J. van der, Herder, W.W. de & Feelders, R.A. (2009). Effects of Somatostatin Analogs on a Growth Hormone-Releasing Hormone Secreting Bronchial Carcinoid, in Vivo and in Vitro Studies. Journal of Clinical Endocrinology and Metabolism, 94(2), Kaay, D.C.M. van der, Jong, F.H. de, Rose, S.R., Odink, R.J.H., Bakker-van Waarde, W.M., Sulkers, E.J. & Hokken-Koelega, A.C.S. (2009). Overnight levels of luteinizing hormone, collicle-stimulating hormone and growth hormone before and during gonadotropin-releasing hormone analogue treatment in short boys born small for gestational age. Hormone Research, 71, Kaay, D.C.M. van der, Jong, F.H. de, Laven, J.S.E. & Hokken-Koelega, A.C.S. (2009). Overnight Luteinizing and Follicle Stimulating Hormone Profiles During GnRHa Treatment in Short Girls Born Small for Gestational Age. Journal of Pediatric Endocrinology & Metabolism, 22(2), Kerkhof, G.F., Leunissen, R.W.J., Willemsen, R.H., Jong, F.H. de, Stijnen, T. & Hokken-Koelega, A.C.S. (2009). Influence of preterm birth and birth size on gonadal function in young men. Journal of Clinical Endocrinology and Metabolism, 94(11), Kevenaar, M.E., Themmen, A.P.N., Kerkwijk, A.J. van, Valkenburg, O., Uitterlinden, A.G., Jong, F.H. de, Laven, J.S.E. & Visser, J.A. (2009). Variants in the ACVR1 gene are associated with AMH levels in women with polycystic ovary syndrome. Human Reproduction, 24(1),

15 Kiewiet, R.M., Aken, M.O. van, Weerd, K. van der, Uitterlinden, P., Themmen, A.P.N., Hofland, L.J., Rijke, Y.B. de, Delhanty, P.J.D., Ghigo, E., Abribat, T. & Lely, A.J. van der (2009). Effects of acute administration of acylated and unacylated ghrelin on glucose and insulin concentrations in morbidly obese subjects without overt diabetes. European Journal of Endocrinology, 161(4), Knauff, E.A.H., Eijkemans, M.J.C., Lambalk, C.B., Kate-Booij, M.J. ten, Hoek, A., Beerendonk, CCM, Laven, J.S.E., Goverde, A.J., Broekmans, F.J.M., Themmen, A.P.N., Jong, F.H. de & Fauser, B.C.J.M. (2009). Anti-Mullerian Hormone, Inhibin B, and Antral Follicle Count in Young Women with Ovarian Failure. Journal of Clinical Endocrinology and Metabolism, 94(3), Kuijper, T.M., Ritstier, K., Verhoef-Post, M., Piersma, D., Bruysters, M.W.P., Berns, P.M.J.J. & Themmen, A.P.N. (2009). LH receptor gene expression is essentially absent in breast tumor tissue: Implications for treatment. Molecular and Cellular Endocrinology, 302(1), Lely, A.J. van der (2009). Ghrelin and New Metabolic Frontiers. Hormone Research, 71, Lie Fong, S., Laven, J.S.E., Hakvoort-Cammel, F.G.A.J., Schipper, I., Visser, J.A., Themmen, A.P.N., Jong, F.H. de & Heuvel- Eibrink, M.M. van den (2009). Assessment of ovarian reserve in adult childhood cancer survivors using anti-mullerian hormone. Human Reproduction, 24(4), Lind van Wijngaarden, R.F.A. de, Joosten, K.F.M., Berg, S. van den, Otten, B.J., Jong, F.H. de, Sweep, C.G.J., Weerd, A.W. de & Hokken-Koelega, A.C.S. (2009). The relationship between central adrenal insufficiency and sleep-related breathing disorders in children with Prader-Willi Syndrome. Journal of Clinical Endocrinology and Metabolism, 94(7), Muller, M., Beld, A.W. van den, Grobbee, D.E., Jong, F.H. de & Lamberts, S.W.J. (2009). Sex hormones and cognitive decline in elderly men. Psychoneuroendocrinology, 34(1), Neggers, S.J.C.M.M., Herder, W.W. de, Janssen, J.A.M.J.L., Feelders, R.A. & Lely, A.J. van der (2009). Combined treatment for acromegaly with long-acting somatostatin analogs and pegvisomant: long-term safety for up to 4.5 years (median 2.2 years) of follow-up in 86 patients. European Journal of Endocrinology, 160(4), Neggers, S.J.C.M.M. & Lely, A.J. van der (2009). Somatostatin analog and pegvisomant combination therapy for acromegaly. Nature Reviews Endocrinology, 5(10), Peeters, R.P., Hagendorf, A., Vanhorebeek, I, Visser, T.J., Klootwijk, W., Mesotten, D, Wouters, PJ, Koper, F.J.W., Jong, F.H. de, Feelders, R.A., Lamberts, S.W.J. & Berghe, G. van den (2009). Tissue mrna expression of the glucocorticoid receptor and its splice variants in fatal critical illness. Clinical Endocrinology, 71(1), Perry, JRB, Stolk, L., Franceschini, N, Lunetta, KL, Zhai, GJ, McArdle, PF, Smith, AV, Aspelund, T, Bandinelli, S, Boerwinkle, E., Cherkas, L, Eiriksdottir, G, Estrada, K, Ferrucci, L, Folsom, A.R., Garcia, M, Gudnason, V, Hofman, A., karasik, D., Kiel, DP, Launer, L.J., Meurs, J.B.J. van, Nalls, MA, Rivadeneira Ramirez, F., Shuldiner, AR, Singleton, A., Soranzo, N, Tanaka, T, Visser, J.A., Weedon, MN, Wilson, S.G., Zhuang, V, Streeten, EA, Harris, T.B., Murray, A, Spector, T.D., Demerath, EW, Uitterlinden, A.G. & Murabito, JM (2009). Meta-analysis of genome-wide association data identifies two loci influencing age at menarche. Nature Genetics, 41(6), Pierik, F.H., Deddens, J.A., Muinck Keizer-Schrama, S.M.P.F., Jong, F.H. de, Weber, R.F.A. & Burdorf, A. (2009). Response: the hypothalamus-pituitary-testis axis in cryptorchid boys. International Journal of Andrology, 32, 90. Pierik, F.H., Deddens, J.A., Burdorf, A., Muinck Keizer-Schrama, S.M.P.F., Jong, F.H. de & Weber, R.F.A. (2009). The hypothalamus-pituitary-testis axis in boys during the first six months of life: a comparison of cryptorchidism and hypospadias cases with controls. International Journal of Andrology, 32(5), Ronde, W. de, Kulve, J ten, Woerdeman, J, Kaufman, J.M. & Jong, F.H. de (2009). Effects of oestradiol on gonadotrophin levels in normal and castrated men. Clinical Endocrinology, 71(6), Stolk, L., Zhai, G., Meurs, J.B.J. van, Verbiest, M.M.P.J., Visser, J.A., Estrada, K, Rivadeneira, F., Williams, FM, Cherkas, L, Deloukas, P, Soranzo, N, Keyzer, J.J., Pop, VJM, Lips, P., Lebrun, C.E.I., Schouw, Y.T. van der, Grobbee, D.E., Witteman, J.C.M., Hofman, A., Pols, H.A.P., Laven, J.S.E., Spector, T.D. & Uitterlinden, A.G. (2009). Loci at chromosomes 13, 19 and 20 influence age at natural menopause. Nature Genetics, 41(6), Teunissen, J.J.M., Krenning, E.P., Jong, F.H. de, Rijke, Y.B. de, Feelders, R.A., Aken, M.O. van, Herder, W.W. de & Kwekkeboom, D.J. (2009). Effects of therapy with [Lu-177-DOTA(0),Tyr(3)]octreotate on endocrine function. European Journal of Nuclear Medicine and Molecular Imaging, 36(11), Urlings-Strop, LC, Stijnen, T., Themmen, A.P.N. & Splinter, T.A.W. (2009). Selection of medical students: a controlled experiment. Medical Education, 43(2), Valkenburg, O., Uitterlinden, A.G., Piersma, D., Hofman, A., Themmen, A.P.N., Jong, F.H. de, Fauser, B.C.J.M. & Laven, J.S.E. (2009). Genetic polymorphisms of GnRH and gonadotrophic hormone receptors affect the phenotype of polycystic ovary syndrome. Human Reproduction, 24(8), Vila, G, Riedl, M, Resl, M, Lely, A.J. van der, Hofland, L.J., Clodi, M & Luger, A (2009). Systemic administration of oxytocin reduces basal and lipopolysaccharide-induced ghrelin levels in healthy men. Journal of Endocrinology, 203(1), Part of book - abstract Jong, F.H. de & Ronde, W. de (2009). Productie en afbraak van geslachtshormonen. In R Abs, MA Bex, RA Feelders, AJ van der lely, FRE Nobels & APN Themmen (Eds.), Erasmus Endocrinologie Cursus 2009 (pp ). Rotterdam: ErasmusMC.

16 Themmen, A.P.N. & Leeuwen, J.P.T.M. van (2009). Stamcellen komen klinisch steeds dichterbij. In R Abs, MA bex, RA Feelders, AJ van der Lely, F Nobels & APN Themmen (Eds.), Erasmus Endocrinologie Cursus. Rotterdam: ErasmusMC. Other output Jong, F.H. de (2009). De prognostische (on)mogelijkheden van SNP-gegevens. Tros Radar optreden: (2009, maart 02).

17 EMC MM Localisation, detection and radionuclide therapy of various diseases Programme design in brief Detection of disease: (Pre)clinical development and use of radiolabeled pharmaceuticals (e.g. peptides, anti-sense molecules, 18F-deoxy-glucose (FGD)) to localize and detect various diseases (e.g. tumour and heart imaging). Comparison of results with those of conventional imaging modalities (e.g. MRI, CT, US) and cost-benefit analyses. Investigation of predictive value of scintigraphy for success of various treatment modalities, e.g. unlabelled peptides versus cytostatic drugs. New radiolabelled peptide-analogues, such as of Bombesine, CCK, Substance P, neurotensin and adhesion molecules have been introduced for lesion visualization. As tumour cells have receptors on their surface for different peptides, many receptorpositive tumours may then be localized, possibly followed by therapy with unlabelled compound or by radionuclide therapy. Treatment of disease: As a new modality of cancer treatment, we introduced radionuclide therapy of somatostatin receptor-positive lesions by repeated administration of chelated somatostatin analogues (octreotide, [Tyr3]octreotide, [Tyr3]octreotate) radiolabelled with high doses of therapeutic radionuclides, like the auger electron emitter 111In, the high energy beta particle emitter 90Y and the low energy beta particle emitter 177Lu. Different phase1 studies have been started on radionuclide therapy of human tumours using these radiolabelled peptide analogues. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot nuclear medicine 2, ,35 4,1 surgery 0, ,1 Total 2, ,35 4, Article/Letter to the editor Akerstrom, G, Falconi, M, Kianmanesh, R., Ruszniewski, P. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Pre- and Perioperative Therapy in Patients with Neuroendocrine Tumors. Neuroendocrinology, 90(2), Arnold, R., Chen, YJ, Costa, F, Falconi, M, Gross, D, Grossman, A.B., Hyrdel, R., Kos-Kudla, B, Salazar, R. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Follow-Up and Documentation. Neuroendocrinology, 90(2), Beek, R.D. van, Heuvel-Eibrink, M.M. van den, Cammel, F.G.A.J., Bos, C. van den, Pal, HJH van der, Krenning, E.P., Rijke, Y.B. de, Pieters, R. & Muinck Keizer-Schrama, S.M.P.F. (2009). Bone mineral density, growth, and thyroid function in long-term survivors of pediatric Hodgkin's Lymphoma treated with chemotherapy only. Journal of Clinical Endocrinology and Metabolism, 94(6), Boot, A.M., Sluis, I.M. van der, Krenning, E.P. & Muinck Keizer-Schrama, S.M.P.F. (2009). Bone Mineral Density and Body Composition in Adolescents with Childhood-Onset Growth Hormone Deficiency. Hormone Research, 71(6), Eriksson, B., Annibale, B, Bajetta, E, Mitry, E, Pavel, M, Platania, M, Salazar, R. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Chemotherapy in Patients with Neuroendocrine Tumors. Neuroendocrinology, 90(2), Essen, M. van, Krenning, E.P., Kam, B.L.R., Jong, M. de, Valkema, R. & Kwekkeboom, D.J. (2009). Peptide-receptor radionuclide therapy for endocrine tumors. NATURE REVIEWS ENDOCRINOLOGY, 5(7), Forrer, F., Krenning, E.P., Kooij, P.P., Bernard, H.F., Konijnenberg, M.W., Bakker, W.H., Teunissen, J.J.M., Jong, M. de, Lom, K. van, Herder, W.W. de & Kwekkeboom, D.J. (2009). Bone marrow dosimetry in peptide receptor radionuclide therapy with [Lu- 177-DOTA(0),Tyr(3)]octreotate. European Journal of Nuclear Medicine and Molecular Imaging, 36(7), Froberg, A.C., Jong, M. de, Nock, B.A., Breeman, W.A.P., Erion, J.L., Maina, T, Verdijsseldonck, M.C.C., Herder, W.W. de, Lugt, A. van der, Kooij, P.P.M. & Krenning, E.P. (2009). Comparison of three radiolabelled peptide analogues for CCK-2 receptor scintigraphy in medullary thyroid carcinoma. European Journal of Nuclear Medicine and Molecular Imaging, 36(8), Jong, M. de, Breeman, W.A.P., Kwekkeboom, D.J., Valkema, R. & Krenning, E.P. (2009). Tumor Imaging and Therapy Using Radiolabeled Somatostatin Analogues. Accounts of Chemical Research, 42(7), Kloppel, G., Couvelard, A, Perren, A, Komminoth, P., McNicol, AM, Nilsson, O., Scarpa, A, Scoazec, JY, Wiedenmann, B., Papotti, M., Rindi, G. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Towards a Standardized Approach to the Diagnosis of Gastroenteropancreatic Neuroendocrine Tumors and Their Prognostic Stratification (vol 90, pg 162, 2009). Neuroendocrinology, 90(4), Kwekkeboom, D.J., Krenning, E.P., Lebtahi, R, Komminoth, P., Kos-Kudla, B, Herder, W.W. de & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Peptide Receptor Radionuclide Therapy with Radiolabeled Somatostatin Analogs. Neuroendocrinology, 90(2), Kwekkeboom, D.J., Krenning, E.P., Scheidhauer, K, Lewington, V, Lebtahi, R, Grossman, A., Vitek, P, Sundin, A & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Somatostatin Receptor Imaging with In-111-Pentetreotide. Neuroendocrinology, 90(2),

18 Lhommel, R., Goffette, P., Eynde, M. van den, Jamar, F., Pauwels, S., Bilbao, J.I. & Walrand, S.H.M. (2009). Yttrium-90 TOF PET scan demonstrates high-resolution biodistribution after liver SIRT. European Journal of Nuclear Medicine and Molecular Imaging, 36, Melis, M.L., Bijster, M., Visser, M., Konijnenberg, M.W., Swart, J. de, Rolleman, E.J., Boerman, O.C., Krenning, E.P. & Jong, M. de (2009). Dose-response effect of Gelofusine on renal uptake and retention of radiolabelled octreotate in rats with CA20948 tumours. European Journal of Nuclear Medicine and Molecular Imaging, 36(12), Muller, C.M., Mindt, TL, Jong, M. de & Schibli, R (2009). Evaluation of a novel radiofolate in tumour-bearing mice: promising prospects for folate-based radionuclide therapy. European Journal of Nuclear Medicine and Molecular Imaging, 36(6), Oberg, K, Ferone, D., Kaltsas, G., Knigge, UP, Taal, B & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Biotherapy. Neuroendocrinology, 90(2), O'Toole, D, Grossman, A., Gross, D, Fave, G. delle, Barkmanova, J, O'Connor, J, Pape, U.F. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Biochemical Markers. Neuroendocrinology, 90(2), Plockinger, U, Gustafsson, B, Ivan, D, Szpak, W & Davar, J (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Echocardiography. Neuroendocrinology, 90(2), Schroeder, R.P.J., Weerden, W.M. van, Bangma, C., Krenning, E.P. & Jong, M. de (2009). Peptide receptor imaging of prostate cancer with radiolabelled bombesin analogues. Methods-A Companion to Methods in Enzymology, 48(2), Sundin, A, Vullierme, M.P., Kaltsas, G. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Radiological Examinations. Neuroendocrinology, 90(2), Teunissen, J.J.M., Krenning, E.P., Jong, F.H. de, Rijke, Y.B. de, Feelders, R.A., Aken, M.O. van, Herder, W.W. de & Kwekkeboom, D.J. (2009). Effects of therapy with [Lu-177-DOTA(0),Tyr(3)]octreotate on endocrine function. European Journal of Nuclear Medicine and Molecular Imaging, 36(11), Yim, CB, Boerman, O.C., Visser, M., Jong, M. de, Dechesne, AC, Rijkers, DTS & Liskamp, RMJ (2009). Versatile Conjugation of Octreotide to Dendrimers by Cycloaddition ("Click") Chemistry to Yield High-Affinity Multivalent Cyclic Peptide Dendrimers. Bioconjugate Chemistry, 20(7),

19 EMC MM Regulation of follicle development, oocyte and endometrial embryo quality Programme design in brief General objectives: The ability of a primordial follicle to undergo folliculogenesis constitutes the very foundation of the expression of the menstrual cycle. During its growth important changes occur within the oöcyte, as well as in its granulose- and theca-cells. These changes include proliferation, differentiation and as well as growth and apoptosis. Hormones (steroid as well proteins) and growth factors control the early (gonadotropin-independent) and late (gonadotropin-dependent) follicle development. Regulation of follicle recruitment and dominant follicle selection as well as ovarian dysfunction is studied in the human model both in-vivo and in-vitro using morphometric, molecular and genetic techniques. Clinical studies involve a) Genetic (genotype - phenotype association) and environmental determinants of anovulatory infertility, especially polycystic ovary syndrome (PCOS) and premature ovarian failure (POF). b) Development of new ovulation induction strategies and optimization of fertility treatment and outcome in patients with ovarian dysfunction. c) Prevention of long-term health implications of reproductive, metabolic and cardiovascular components of ovarian dysfunction especially PCOS and POF. d) Gamete and embryo quality using genetic (preimplantation genetic aneuploidy screening) and molecular techniques in subfertile patients as well as in patients with anovulatory dysfunction Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot gynaecology/obstetrics 3, ,53 4,6 urology 1, ,8 Total 4, ,53 6, Thesis Gaast, M.H. van der (2009, mei 12). Ovarian stimulation and the endometrium. EUR. Prom./coprom.: Prof.Dr. B.C.J.M. Fauser & N.S. Macklon. Article/Letter to the editor Berg, I.M. van den, Laven, J.S.E., Stevens, M., Jonkers, I., Galjaard, R.J.H., Gribnau, J. & Doorninck, J.H. van (2009). X Chromosome Inactivation Is Initiated in Human Preimplantation Embryos. American Journal of Human Genetics, 84(6), Boxmeer, J.C., Macklon, N.S., Lindemans, J., Beckers, N.G.M., Eijkemans, M.J.C., Laven, J.S.E., Steegers, E.A.P. & Steegers- Theunissen, R.P.M. (2009). IVF outcomes are associated with biomarkers of the homocysteine pathway in monofollicular fluid. Human Reproduction, 24(5), Boxmeer, J.C., Smit, M., Utomo, E., Romijn, J.C., Eijkemans, M.J.C., Lindemans, J., Laven, J.S.E., Macklon, N.S., Steegers, E.A.P. & Steegers-Theunissen, R.P.M. (2009). Low folate in seminal plasma is associated with increased sperm DNA damage. Fertility & Sterility, 92(2), Casteren, N.J. van, Pieters, R., Dohle, G.R., Baalen, M. van, Neggers, S & Heuvel-Eibrink, M.M. van den (2009). Cranial irradiation does not result in pituitary-gonadal axis dysfunction in very long-term male survivors of childhood acute lymphoblastic leukemia. Leukemia, 23(12), Casteren, N.J. van, Linden, G.H.M. van der, Hakvoort-Cammel, F.G.A.J., Hahlen, K., Dohle, G.R. & Heuvel-Eibrink, M.M. van den (2009). Effect of childhood cancer treatment on fertility markers in adult male long-term survivors. Pediatric Blood & Cancer, 52, Casteren, N.J. van, Jong, J., Stoop, H., Steyerberg, E.W., Bekker- Grob, E.W. de, Dohle, G.R., Oosterhuis, J.W. & Looijenga, L.H.J. (2009). Evaluation of testicular biopsies for carcinoma in situ: immunohistochemistry is mandatory. International Journal of Andrology, 32(6), Casteren, N.J. van, Stoop, H., Dohle, G.R., Wit, R. de, Oosterhuis, J.W. & Looijenga, L.H.J. (2009). Noninvasive detection of testicular carcinoma in situ in semen using OCT3/4 reply tot Klau-Pieter Dieckmann's letter. European Urology, 55, Casteren, N.J. van, Looijenga, L.H.J. & Dohle, G.R. (2009). Testicular microlithiasis and carcinoma in situ overview and proposed clinical guideline. International Journal of Andrology, 32(4), Devroey, P., Fauser, B.C.J.M. & Diedrich, K. (2009). Approaches to improve the diagnosis and management of infertility. Human Reproduction Update, 15(4), Dijk, G. van & Laven, J.S.E. (2009). De willekeur voorbij. Medisch Contact, 64, Fleischer, K., Vliet, HA van, Rosendaal, F.R., Rosing, J., Tchaikovski, S & Helmerhorst, F.M. (2009). Effects of the contraceptive patch, the vaginal ring and an oral contraceptive on APC resistance and SHBG: A cross-over study. Thrombosis Research, 123(3), Gaast, M.H. van der, Macklon, N.S., Beier-Hellwig, K., Krusche, CA, Fauser, B.C.J.M., Beier, H.M. & Classen-Linke, I (2009). The feasibility of a less invasive method to assess endometrial maturation-comparison of simultaneously obtained uterine secretion and tissue biopsy. Bjog-An International Journal of Obstetrics and Gynaecology, 116(2), Heijden, G.W. van der, Berg, I.M. van den, Baart, E.B., Derijck, AAHA, Martini, E. & Boer, P. (2009). Parental Origin of Chromatin in Human Monopronuclear Zygotes Revealed by Asymmetric Histone Methylation Patterns, Differs Between IVF and ICSI. Molecular Reproduction and Development, 76(1),

20 Kaay, D.C.M. van der, Jong, F.H. de, Laven, J.S.E. & Hokken-Koelega, A.C.S. (2009). Overnight Luteinizing and Follicle Stimulating Hormone Profiles During GnRHa Treatment in Short Girls Born Small for Gestational Age. Journal of Pediatric Endocrinology & Metabolism, 22(2), Kevenaar, M.E., Themmen, A.P.N., Kerkwijk, A.J. van, Valkenburg, O., Uitterlinden, A.G., Jong, F.H. de, Laven, J.S.E. & Visser, J.A. (2009). Variants in the ACVR1 gene are associated with AMH levels in women with polycystic ovary syndrome. Human Reproduction, 24(1), Knauff, E.A.H., Eijkemans, M.J.C., Lambalk, C.B., Kate-Booij, M.J. ten, Hoek, A., Beerendonk, CCM, Laven, J.S.E., Goverde, A.J., Broekmans, F.J.M., Themmen, A.P.N., Jong, F.H. de & Fauser, B.C.J.M. (2009). Anti-Mullerian Hormone, Inhibin B, and Antral Follicle Count in Young Women with Ovarian Failure. Journal of Clinical Endocrinology and Metabolism, 94(3), Knauff, E.A.H., Franke, L, Es, MA van, Berg, L.H. van den, Schouw, Y.T. van der, Laven, J.S.E., Lambalk, C.B., Hoek, A., Goverde, A.J., Christin-Maitre, S., Hsueh, AJ, Wijmenga, C. & Fauser, B.C.J.M. (2009). Genome-wide association study in premature ovarian failure patients suggests ADAMTS19 as a possible candidate gene. Human Reproduction, 24(9), Korfage, I.J., Pluijm, S., Roobol-Bouts, M.J., Dohle, G.R., Schroder, F.H. & Essink-Bot, M.L. (2009). Erectile Dysfunction and Mental Health in a General Population of Older Men. Journal of Sexual Medicine, 6(2), Laven, J.S.E. (2009). Zwanger na kunst en vliegwerk. Kleine Maatjes, 31, 5-7. Lie Fong, S., Laven, J.S.E., Hakvoort-Cammel, F.G.A.J., Schipper, I., Visser, J.A., Themmen, A.P.N., Jong, F.H. de & Heuvel- Eibrink, M.M. van den (2009). Assessment of ovarian reserve in adult childhood cancer survivors using anti-mullerian hormone. Human Reproduction, 24(4), Olivennes, F., Howles, C, Borini, A, Germond, M, Trew, G, Wikland, M, Zegers-Hochschild, F, Saunders, H & Alam, V (2009). Individualizing FSH dose for assisted reproduction using a novel algorithm: the CONSORT study. Reproductive Biomedicine OnLine, 18(2), Pierik, F.H., Deddens, J.A., Burdorf, A., Muinck Keizer-Schrama, S.M.P.F., Jong, F.H. de & Weber, R.F.A. (2009). The hypothalamus-pituitary-testis axis in boys during the first six months of life: a comparison of cryptorchidism and hypospadias cases with controls. International Journal of Andrology, 32(5), Schoenmakers, S., Wassenaar, E., Hoogerbrugge, J.W., Laven, J.S.E., Grootegoed, J.A. & Baarends, W.M. (2009). Female Meiotic Sex Chromosome Inactivation in Chicken. PLoS Genetics, 5(5). Schouten, B.W.V., Bohnen, A.M., Dohle, G.R., Groeneveld, F.P.M.J., Willemsen, S.P., Thomas, S. & Bosch, J.L.H.R. (2009). Risk factors for deterioration of erectile function: the Krimpen study. International Journal of Andrology, 32(2), Stolk, L., Zhai, G., Meurs, J.B.J. van, Verbiest, M.M.P.J., Visser, J.A., Estrada, K, Rivadeneira, F., Williams, FM, Cherkas, L, Deloukas, P, Soranzo, N, Keyzer, J.J., Pop, VJM, Lips, P., Lebrun, C.E.I., Schouw, Y.T. van der, Grobbee, D.E., Witteman, J.C.M., Hofman, A., Pols, H.A.P., Laven, J.S.E., Spector, T.D. & Uitterlinden, A.G. (2009). Loci at chromosomes 13, 19 and 20 influence age at natural menopause. Nature Genetics, 41(6), Valkenburg, O., Uitterlinden, A.G., Piersma, D., Hofman, A., Themmen, A.P.N., Jong, F.H. de, Fauser, B.C.J.M. & Laven, J.S.E. (2009). Genetic polymorphisms of GnRH and gonadotrophic hormone receptors affect the phenotype of polycystic ovary syndrome. Human Reproduction, 24(8), Verberg, MFG, Eijkemans, M.J.C., Macklon, N.S., Heijnen, E.M.E.W., Baart, E.B., Hohmann, F.P., Fauser, B.C.J.M. & Broekmans, FJ (2009). The clinical significance of the retrieval of a low number of oocytes following mild ovarian stimulation for IVF: a meta-analysis. Human Reproduction Update, 15(1), Vujkovic, M., Vries, J.H. de, Dohle, G.R., Bonsel, G.J., Lindemans, J., Macklon, N.S., Spek, P.J. van der, Steegers, E.A.P. & Steegers-Theunissen, R.P.M. (2009). Associations between dietary patterns and semen quality in men undergoing IVF/ICSI treatment. Human Reproduction, 24(6), Book editorship Dohle, G.R., Jungwirth, A., Colpi, G., Giwercman, A., Diemer, T. & Hargreave, TB (Eds.). (2009). European association of urology guidelines on male infertility. --: --.