Richardus Vonk

Publications of Richardus Vonk

• Estradiol release kinetics determine tissue response in ovariectomized rats.

  Authors: Christiane Otto, Ingrid Kantner, Reinhard Nubbemeyer, Jenny Schkoldow, Iris Fuchs, Elisabeth Krahl, Richardus Vonk, Christiane Schüler, Karl-Heinrich Fritzemeier, Reinhold G Erben

  Endocrinology. 02/2012; 153(4):1725-33.

  Estrogen replacement is an effective therapy of postmenopausal symptoms such as hot flushes, bone loss, and vaginal dryness. Undesired estrogen effects are the stimulation of uterine and mammaryEstrogen replacement is an effective therapy of postmenopausal symptoms such as hot flushes, bone loss, and vaginal dryness. Undesired estrogen effects are the stimulation of uterine and mammary gland epithelial cell proliferation as well as hepatic estrogenicity. In this study, we examined the influence of different estradiol release kinetics on tissue responsivity in ovariectomized (OVX) rats. Pulsed release kinetics was achieved by ip or sc administration of estradiol dissolved in physiological saline containing 10% ethanol (EtOH/NaCl) whereas continuous release kinetics was achieved by sc injection of estradiol dissolved in benzylbenzoate/ricinus oil (1+4, vol/vol). Initial 3-d experiments in OVX rats showed that pulsed ip estradiol administration had profoundly reduced stimulatory effects on the uterus and the liver compared with continuous release kinetics. On the other hand, both administration forms prevented severe vaginal atrophy. Based on these results, we compared the effects of pulsed (sc in EtOH/NaCl) vs. continuous (sc in benzylbenzoate/ricinus oil) estradiol release kinetics on bone, uterus, mammary gland, and liver in a 4-month study in OVX rats. Ovariectomy-induced bone loss was prevented by both administration regimes. However, pulsed estradiol resulted in lower uterine weight, reduced induction of hepatic gene expression, and reduced mammary epithelial hyperplasia relative to continuous estradiol exposure. We conclude that organ responsivity is influenced by different hormone release kinetics, a fact that might be exploited to reduce undesired estradiol effects in postmenopausal women.

• Impaired left-ventricular cardiac function in male GPR30-deficient mice.

  Authors: Martina Delbeck, Stefan Golz, Richardus Vonk, Wiebke Janssen, Tim Hucho, Jörg Isensee, Stefan Schäfer, Christiane Otto

  Molecular medicine reports. 01/2011; 4(1):37-40.

  G-protein-coupled receptor 30 (GPR30) has been reported to act as a membrane-bound estrogen receptor that is involved in the mediation of non-genomic estradiol signalling. In this study, weG-protein-coupled receptor 30 (GPR30) has been reported to act as a membrane-bound estrogen receptor that is involved in the mediation of non-genomic estradiol signalling. In this study, we demonstrated that male, but not female, GPR30-deficient mice suffer from impaired left‑ventricular cardiac function. Left ventricles from male mutant mice were enlarged. There were no malformations in the valves or outflow tract of the heart. Both the contractility and relaxation capacity of the left ventricle were reduced, leading to increased left‑ventricular end-diastolic pressure in GPR30-deficient mice. In conclusion, our data support a role for GPR30 in the gender-specific aspects of heart failure.

• Comparative analysis of the uterine and mammary gland effects of progesterone and medroxyprogesterone acetate.

  Authors: Christiane Otto, Iris Fuchs, Richardus Vonk, Karl-Heinrich Fritzemeier

  Maturitas. 04/2010; 65(4):386-91.

  In combined hormone replacement therapy (HRT) progestins are used to inhibit estradiol-activated uterine epithelial cell proliferation. In comparison to estradiol-only therapy, combined HRT leads toIn combined hormone replacement therapy (HRT) progestins are used to inhibit estradiol-activated uterine epithelial cell proliferation. In comparison to estradiol-only therapy, combined HRT leads to enhanced proliferation of mammary epithelial cells. In a quantitative mouse model, we assessed the balance between uterine and undesired mammary gland effects for two progestins that are widely used in HRT, progesterone and medroxyprogesterone acetate. Mice were ovariectomized and after 14 days they were treated subcutaneously with either vehicle, estradiol (100 ng) or estradiol plus increasing doses of progesterone or medroxyprogesterone acetate for three weeks. Measures for progestogenic mammary gland activity were stimulation of side-branching and stimulation of epithelial cell proliferation. Progestogenic activity in the uterus was assessed by measuring inhibition of estradiol-activated uterine epithelial cell proliferation. ED(50) and ID(50) values for the distinct readouts were obtained and dissociation factors for uterine versus mammary gland activity were calculated. MPA demonstrated uterine activity and mitogenic activity in the mammary gland at the same doses. In contrast, progesterone showed uterine activity at doses lower than those leading to significant stimulation of epithelial cell proliferation in the mammary gland. Progestins do not behave the same. Use of the natural hormone progesterone, but not MPA, in combined hormone therapy might offer a safety window between uterine effects and undesired proliferative activity in the mammary gland.

• GPR30 Does Not Mediate Estrogenic Responses in Reproductive Organs in Mice.

  Authors: Christiane Otto, Iris Fuchs, Gunther Kauselmann, Heidrun Kern, Branko Zevnik, Puk Andreasen, Gilda Schwarz, Helga Altmann, Mario Klewer, Michael Schoor, Richardus Vonk, Karl-Heinrich Fritzemeier

  Biology of reproduction. 10/2008;

  The G-protein-coupled receptor Gpr30 (Gper) was recently claimed to bind to estradiol and to activate cytoplasmic signal transduction pathways in response to estradiol. However, there are conflictingThe G-protein-coupled receptor Gpr30 (Gper) was recently claimed to bind to estradiol and to activate cytoplasmic signal transduction pathways in response to estradiol. However, there are conflicting data regarding the role of Gpr30 as an estrogen receptor: several laboratories were not able to demonstrate estradiol binding to GPR30 or estradiol-activated signal transduction in Gpr30 expressing cells. To clarify the potential role of Gpr30 as an estrogen receptor, we generated Gpr30-deficient mice. Although Gpr30 was expressed in all reproductive organs, histopathological analysis did not reveal any abnormalities in these organs in Gpr30-deficient mice. Mutant male and female mice were as fertile as their wildtype littermates indicating normal function of the hypothalamic-pituitary-gonadal axis. Moreover, we analyzed estrogenic responses in two major estradiol target organs, the uterus and the mammary gland. For that purpose, we examined different readout paradigms, such as morphological measures, cellular proliferation and target gene expression. Our data demonstrate that in vivo Gpr30 is dispensable for the mediation of estradiol effects in reproductive organs. These results are in clear contrast to the phenotype of mice lacking the classical estrogen receptor alpha (Esr1) or aromatase (Cyp19a1). We conclude that the perception of Gpr30 -- by homology related to peptide receptors -- as an estrogen receptor might be premature and has to be reconsidered.

• In vivo characterization of estrogen receptor modulators with reduced genomic versus nongenomic activity in vitro.

  Authors: Christiane Otto, Iris Fuchs, Helga Altmann, Mario Klewer, Gilda Schwarz, Rolf Bohlmann, Duy Nguyen, Ludwig Zorn, Richardus Vonk, Katja Prelle, Thua Osterman, Chira Malmström, Karl-Heinrich Fritzemeier

  The Journal of steroid biochemistry and molecular biology. 08/2008;

  Estrogen receptor (ER) ligands that are able to prevent postmenopausal bone loss, but have reduced activity in the uterus and the mammary gland might be of great value for hormone therapy. It is wellEstrogen receptor (ER) ligands that are able to prevent postmenopausal bone loss, but have reduced activity in the uterus and the mammary gland might be of great value for hormone therapy. It is well established that the classical ER can activate genomic as well as nongenomic signal transduction pathways. In this study, we analyse the in vivo behaviour of ER ligands that stimulate nongenomic ER effects to the same extent as estradiol, but show clearly reduced activation of genomic ER effects in vitro. Using different readout parameters such as morphological changes, cellular proliferation, and target gene induction, we are able to demonstrate that ER ligands with reduced genomic activity in vitro show a better dissociation of bone versus uterine and mammary gland effects than estradiol that stimulates genomic and nongenomic effects to the same extent. We conclude that pathway-selective ER ligands may represent an interesting option for hormone therapy.

• Comparative analysis of the uterine and mammary gland effects of drospirenone and medroxyprogesterone acetate.

  Authors: Christiane Otto, Iris Fuchs, Helga Altmann, Mario Klewer, Alexander Walter, Katja Prelle, Richardus Vonk, Karl-Heinrich Fritzemeier

  Endocrinology. 05/2008;

  The role of progestins in combined hormone therapy is the inhibition of uterine epithelial cell proliferation. The Women's Health Initiative (WHI) study provided evidence for an increased risk ofThe role of progestins in combined hormone therapy is the inhibition of uterine epithelial cell proliferation. The Women's Health Initiative (WHI) study provided evidence for an increased risk of breast cancer in women treated with conjugated equine estrogens (CEE) plus the synthetic progestin medroxyprogesterone acetate (MPA), compared to CEE-only treatment. These findings continue to be discussed and it remains to be clarified whether the results obtained for MPA in the WHI study are directly applicable to other progestins employed in hormone therapy. In this study we compared in a mouse model the effects of the synthetic progestins, MPA and drospirenone, in two major target organs: the uterus and the mammary gland. As quantitative measures of progestin activity, we analyzed maintenance of pregnancy, ductal sidebranching in the mammary gland, proliferation of mammary and uterine epithelial cells, as well as target gene induction in both organs. The outcome of this study is that not all synthetic progestins exhibit the same effects. MPA demonstrated uterine activity and mitogenic activity in the mammary gland at the same doses. In contrast, drospirenone behaved similarly to the natural hormone, progesterone, and exhibited uterine activity at doses lower than those leading to considerable proliferative effects in the mammary gland. We hypothesize that the safety of combined hormone therapy in postmenopausal women may be associated with a dissociation between the uterine and mammary gland activities of the progestin component.

• In vivo characterization of estrogen receptor modulators with reduced genomic versus nongenomic activity in vitro

  Authors: Christiane Otto, Iris Fuchs, Helga Altmann, Mario Klewer, Gilda Schwarz, Rolf Bohlmann, Duy Nguyen, Ludwig Zorn, Richardus Vonk, Katja Prelle, Thua Österman, Chira Malmström, Karl-Heinrich Fritzemeier

  The Journal of Steroid Biochemistry and Molecular Biology.

  Estrogen receptor (ER) ligands that are able to prevent postmenopausal bone loss, but have reduced activity in the uterus and the mammary gland might be of great value for hormone therapy. It is wellEstrogen receptor (ER) ligands that are able to prevent postmenopausal bone loss, but have reduced activity in the uterus and the mammary gland might be of great value for hormone therapy. It is well established that the classical ER can activate genomic as well as nongenomic signal transduction pathways. In this study, we analyse the in vivo behaviour of ER ligands that stimulate nongenomic ER effects to the same extent as estradiol, but show clearly reduced activation of genomic ER effects in vitro. Using different readout parameters such as morphological changes, cellular proliferation, and target gene induction, we are able to demonstrate that ER ligands with reduced genomic activity in vitro show a better dissociation of bone versus uterine and mammary gland effects than estradiol that stimulates genomic and nongenomic effects to the same extent. We conclude that pathway-selective ER ligands may represent an interesting option for hormone therapy.