Polycystic ovary syndrome (PCOS) affects 5-10% of women worldwide, yet its origins remain unknown. Androgens are implicated in the development of PCOS, but the decisive, invasive studies needed to confirm and elucidate their roles are not feasible in women. Hence, using our innovative mouse models of androgen resistant female mice, this study will determine the role of androgens in PCOS aiming to better understand, and identify new treatments for this common female reproductive disorder.
Testis To Ovary: Hormonal Control Of Differentiation
Funder
National Health and Medical Research Council
Funding Amount
$803,379.00
Summary
We know very little of the genes that control development of the ovary in female fetuses; most study has focused on the formation of the testis in males. We will use a novel experimental model, a marsupial, where by hormonal treatment of developing males we can switch off testis formation and activate the ovarian pathway. These studies will potentially shed new light on the causes of reproductive diseases including ovarian cancer, as well as clarifying the basic biological processes that guide f ....We know very little of the genes that control development of the ovary in female fetuses; most study has focused on the formation of the testis in males. We will use a novel experimental model, a marsupial, where by hormonal treatment of developing males we can switch off testis formation and activate the ovarian pathway. These studies will potentially shed new light on the causes of reproductive diseases including ovarian cancer, as well as clarifying the basic biological processes that guide formation of the ovary.Read moreRead less
Hypospadias is one of the most common developmental defects in humans, yet over two thirds of the cases cannot be explained. Our recent studies using marsupials show that this process is mediated by 5-alpha-androstanediol, a hormone with previously undetermined physiological function. This study will provide novel data on the interactions of the genes and hormones that will inform our understanding of this common developmental defect of male development
Disorders of sexual development are among the most common form of birth defects in humans (1 in 4,000 births) because failure of the gonads to develop does not affect the viability of the individual. Such disorders can have profound psychological and medical consequences upon the individual, family, and society. Some intersexual conditions are the result of inappropriate exposure to hormones during fetal life, and others are due to spontaneous or inherited gene mutation. About 5-10% of ovarian c ....Disorders of sexual development are among the most common form of birth defects in humans (1 in 4,000 births) because failure of the gonads to develop does not affect the viability of the individual. Such disorders can have profound psychological and medical consequences upon the individual, family, and society. Some intersexual conditions are the result of inappropriate exposure to hormones during fetal life, and others are due to spontaneous or inherited gene mutation. About 5-10% of ovarian cancer cases, that affect 1 in 8000 Australian women, are due to the inheritance of a faulty gene. An understanding of the way gene expression and hence tissue differentiation is altered after sex reversal will inform us about the causes and consequences of normal and abnormal sexual development, gonadal malignancies and infertility. The gonad is unusual in that two completely different organs can arise from an essentially identical primordium, so that errors in development lead to intersexual phenotypes. We will use our new experimental animal model to clarify these processes.Read moreRead less
Much of our current knowledge on development of external genitalia (ExG), the penis and clitoris, comes from 20 &70 year-old studies (1); but with significant developments in contemporary imaging and new mouse models, we have new data. The overall goal of this project is to prove the hypothesis that penile and clitoral development is estrogen- (and androgen-) dependent and, to show that the administration of exogenous endocrine disrupting chemicals that alter the balance between estrogen and and ....Much of our current knowledge on development of external genitalia (ExG), the penis and clitoris, comes from 20 &70 year-old studies (1); but with significant developments in contemporary imaging and new mouse models, we have new data. The overall goal of this project is to prove the hypothesis that penile and clitoral development is estrogen- (and androgen-) dependent and, to show that the administration of exogenous endocrine disrupting chemicals that alter the balance between estrogen and androgen will disrupt ExG development.Read moreRead less
Biomarkers For The Diagnosis And Prognostic Analysis Of Male Infertility
Funder
National Health and Medical Research Council
Funding Amount
$631,370.00
Summary
Male infertility is a common condition, affecting 1 in 15 men. Although a standard semen analysis is often performed to test whether a man is infertile, it is far from definitive. We have developed a new approach, by looking at proteins that are commonly missing from infertile sperm cells. From this analysis, we can definitively diagnose male infertility and are beginning to understand why men are becoming infertile.
The Role Of Dynamin In Spermatogenesis, Sperm Maturation And Sperm-oocyte Interactions
Funder
National Health and Medical Research Council
Funding Amount
$551,950.00
Summary
Male infertility is an extremely common condition affecting 1 in 20 Australian men. One of the major reasons for this pathology is that the spermatozoa have lost their ability to interact with the egg and penetrate its outer vestments. In this project we shall investigate the role of dynamin in the regulation of these events. This research will provide new and powerful insights into the causes of male infertility, with practical implications for diagnosis and treatment of this condition.
Investigation Of The Mechanisms Underpinning HSPA2 Dysfunction In The Spermatozoa Of Infertile Patients
Funder
National Health and Medical Research Council
Funding Amount
$481,563.00
Summary
Male infertility is an extremely common condition, that is frequently associated with the production of sperm that have lost their ability to recognize the egg. We have shown that this defect is frequently associated with a deficiency in a specific protein (HSPA2). By determining the mechanisms underpinning the loss of HSPA2, this project will provide powerful insights into the causes of male infertility, with practical implications for prevention, diagnosis and treatment of this condition.
Impairment of virilisation is one of the most common developmental defects in humans, yet over half the cases cannot be explained by our current knowledge. Studies of these processes is hindered because in most mammals virilisation occurs in the early fetus. Our recent studies using marsupials, where virilisation occurs after birth show that this process is mediated by 5-alpha-androstanediol, a hormone with previously undetermined physiological function. We will conduct experiments using tammar ....Impairment of virilisation is one of the most common developmental defects in humans, yet over half the cases cannot be explained by our current knowledge. Studies of these processes is hindered because in most mammals virilisation occurs in the early fetus. Our recent studies using marsupials, where virilisation occurs after birth show that this process is mediated by 5-alpha-androstanediol, a hormone with previously undetermined physiological function. We will conduct experiments using tammar wallabies and rabbits, to test 3 hypotheses about 5-alpha-androstanediol and specific enzymes in the developing reproductive tissues that either convert this hormone to active and inactive forms. The results of these experiments will direct testing for corresponding gene mutations in our collection of over 200 specimens from patients with defects of virilisation (pseudohemaphroditism) whose causes are still unknown. It is our expectation that the findings in these studies will provide insight not only into the pathways by which testicular hormones masculinize the developing male, but will also explain instances of male pseudohemaphroditism of unknown aetiology in humans.Read moreRead less
New Models For The Onset Of Virilisation In The Developing Male
Funder
National Health and Medical Research Council
Funding Amount
$405,750.00
Summary
Impairment of virilisation is one of the most common developmental defects in humans, yet over half the cases cannot be explained by our current knowledge. Studies of these processes are hindered because in most mammals virilisation occurs in utero, in the early fetus. Our recent studies using marsupials, where virilisation occurs after birth show that this process is mediated by 5-alpha-androstanediol, a hormone with previously undetermined physiological function. We will conduct experiments us ....Impairment of virilisation is one of the most common developmental defects in humans, yet over half the cases cannot be explained by our current knowledge. Studies of these processes are hindered because in most mammals virilisation occurs in utero, in the early fetus. Our recent studies using marsupials, where virilisation occurs after birth show that this process is mediated by 5-alpha-androstanediol, a hormone with previously undetermined physiological function. We will conduct experiments using tammar wallabies, to test hypotheses that explain why different male tissues - such as the reproductive ducts, prostate and penis - start to differentiate at widely different times. We will investigate pathways of androgen formation and the activation and inactivation of hormones in the target organs, and the role of hormone binding proteins. We will also investigate the role of growth factors that may mediate growth of the penis during early development. The results of these experiments will direct funding in subsequent years to test for corresponding gene mutations in our collection of over 200 specimens from patients with defects of virilization (pseudohermaphroditism) whose causes are still unknown. It is our expectation that the findings in these studies will provide insight not only into the pathways by which testicular hormones masculinize the developing male, but will also explain instances of male pseudohermaphroditism of unknown aetiology in humans.Read moreRead less