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Funder J.W.,Prince Henrys Institute of Medical Research
Hypertension Research | Year: 2010

Two clinical trials will be reviewed, RALES 1 and ILLUMINATE.2 In RALES, low-dose spironolactone in addition to standard of care, produced a 30% improvement in survival in progressive heart failure, commonly assumed to reflect deleterious effects of aldosterone, with spironolactone competing with aldosterone for cardiac mineralocorticoid receptors. Recent evidence, however, points to cortisol rather than aldosterone as the hormone activating cardiac mineralocorticoid receptors, under conditions of tissue damage, and spironolactone as acting by mechanisms other than receptor blockade. ILLUMINATE compared the effects of torcetrapib, a cholesterol ester transport protein inhibitor, in combination with atorvastatin vs. atorvastatin alone, and was terminated after excess mortality was found in the torcetrapib arm. Subjects receiving torcetrapib showed effects consistent with increased aldosterone secretion, subsequently confirmed on patient samples and in vitro. In animal experiments, the pressor effect of torcetrapib was abolished by adrenalectomy but not by administration of trilostane, an inhibitor of aldosterone secretion. Although aldosterone (and probably cortisol) excess is involved in the off-target effects of torcetrapib, they may also involve secretion of endogenous oubain from the adrenal glomerulosa. This possibility may explain the enigma of aldosterone being homeostatic in chronic sodium deficiency, but deleterious in the presence of inappropriate sodium levels. © 2010 The Japanese Society of Hypertension All rights reserved. Source

McLachlan R.I.,Monash University | McLachlan R.I.,Prince Henrys Institute of Medical Research
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Male infertility affects 1 in 20 men and is the sole or contributory factor in half of assisted reproductive treatments (ARTs). A reduced sperm density (oligozoospermia) is often accompanied by poor motilityandmorphology reflecting qualitative and quantitative defects in spermatogenesis. Many reproductive and nonreproductive disorders and treatments may be responsible, but most cases remain unexplained (idiopathic). A thorough evaluation may identify treatable causes and allow natural fertility. Comorbidities more prevalent in infertile men, especially androgen deficiency and testicular cancer, should be sought. Idiopathic spermatogenic disorders are common, but evidence-based treatment is not available; full evaluation informs management and the decision to pursue ART using the low numbers of functional sperm available. Chromosomal anomalies may impact the chance of a normal healthy pregnancy, and new genetic causes of oligozoospermia are being discovered. ART, particularly intracytoplasmic sperm injection, bypasses instead of treats the sperm defect but has dramatically improved the fertility prospects. The clinical approach to the oligozoospermic man involves understanding reproductive endocrinology, aspects of urology and clinical genetics, modern ART options, and the realistic discussion of their outcomes, alternatives such as adoption or donor gametes, and appreciation of the psychosocial concerns of the couple. Copyright © 2013 by The Endocrine Society. Source

Robertson D.M.,Prince Henrys Institute of Medical Research
Molecular and Cellular Endocrinology | Year: 2012

Inhibins A and B are gonadal factors which are important in fertility. Their use as predictors of female reproductive health has centred on their application to ovarian cancer, Anorexia Nervosa, Down Syndrome and preeclampsia. Inhibin B also provides an index of the endocrine feedback relationship between the ovary and pituitary particularly when the ovarian follicle reserve is low. These applications are relevant in monitoring the onset of the menopause transition, ovarian recovery following chemotherapy and disturbances in pubertal development. Currently, these applications have only found widespread use in Down Syndrome and ovarian cancer. Activins, on the other hand, appear to have a limited application. © 2011 Elsevier Ireland Ltd. Source

Sonderegger S.,Prince Henrys Institute of Medical Research
Human reproduction (Oxford, England) | Year: 2011

Human trophoblast invasion and differentiation are essential for a successful pregnancy outcome. Dysregulation of these processes can lead to placental pathologies such as pre-eclampsia. The molecular mechanisms; however, are poorly understood. Interleukin (IL)11--a cytokine that regulates endometrial epithelial cell adhesion, trophoblast motility and invasion during implantation--may be involved in some of these processes. The effect of IL11 on protein expression was investigated in trophoblastic HTR8/SVneo cells and primary extravillous trophoblasts (EVTs) purified from first- trimester placentas. Two-dimension (2D)-differential in-gel electrophoresis analyses revealed that 731 spots were significantly differentially regulated by IL11 in HTR8/SVneo cells: seven spots were analyzed by liquid chromatography-tandem mass spectrometry and 14 unique proteins identified. Protein disulfide isomerase family A, member 3 (PDIA3; endoplasmic reticulum p57) and glucose-regulated protein 78 (GRP78) were further validated to be regulated by IL11 in HTR8/SVneo and primary EVT. One dimension western blot analysis confirmed that PDIA3 was down-regulated in EVT. 2D western blot analysis revealed that GRP78 was post-translationally modified following IL11 treatment. Moreover, IL11 stimulated the secretion of GRP78 in EVT. Data suggest that IL11, possibly via signal transducers and activators of transcription 3 signaling pathway, regulates PDIA3 protein expression and modification/secretion of GRP78. This is the first study to identify PDIA3 and GRP78 as IL11 targets in invasive trophoblasts and identifies a possible mechanism by which IL11 regulates trophoblast function. Source

Drummond A.E.,Prince Henrys Institute of Medical Research | Fuller P.J.,Prince Henrys Institute of Medical Research
Seminars in Reproductive Medicine | Year: 2012

Estrogen is essential for folliculogenesis with independent roles attributed to each of the two estrogen receptors (ERs). ER, expressed predominantly by the ovarian granulosa cells, is required for antrum formation, preovulatory follicle maturation, expression of genes involved in ovarian differentiation (luteinizing hormone, aromatase, etc.), and follicle rupture during ovulation. Ovulatory dysfunction is associated with polymorphisms of the ER gene, and endocrine disruptors that selectively activate ER cause reproductive dysfunction and impairment fertility. ER may also exhibit antitumorigenic properties, with a decline in ER levels in epithelial ovarian cancers associated with more severe disease and poor prognosis. In this review, we examine the models that have been used to elucidate the roles ER plays in the ovary and consider the clinical consequences of altered ER expression or inappropriate activation of ER signaling. Copyright © 2012 by Thieme Medical Publishers, Inc. Source

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