Androgens and the Testis
The Department of Andrology is interested in researching all available avenues to help those men seeking fertility but also the development of safe effective male contraception.
- Gonadotrophin Replacement Therapy in Treatment for Male Infertility
- Male Hormonal Contraception - for details link here
- Hormonal Control of Sertoli Cell Function and Spermatogenesis - for details link here
- Androgens and Post-testicular Control of Male Fertility - for details link here
• Gonadotrophin Replacement Therapy in Treatment for Male Infertility
A Idan, A Conway, DJ Handelsman
Most causes of male infertility are unknown and consequently there are very few treatment with proven effectiveness in treatment of men unable to produce pregnancy in their wives. Gonadotrophin deficiency is the most effectively treatable cause of male infertility. The Andrology Department has published the largest and most detailed analysis of gonadotrophin treatment for this condition. It also was a major participant in the clinical registration studies for the new recombinant (genetically engineered) FSH hormone which is one of two key hormones necessary for treatment of gonadotrophin deficient men.
The other key hormone required for treatment of gonadotrophin-deficient men is human chorionic gonadotrophin (hCG). For the last 5 decades this has traditionally been produced by purifying urine from pregnant women but in recent years it has become possible to produce recombinant hCG commercially via genetic engineering. As this recombinant hCG remains under patent to a single multinational company who market it solely for use in IVF, despite the clinical neeed it has not been tested in men. To rectify this deficit, the Andrology Department has conducted the only studies of recombinant hCG in men aiming to discover the most effective manner to use it in men. Currently we are conducting a study to compare the effects of the new recombinant hCG with the older standard form of hCG purified from pregnancy urine. If as expected this proves the rhCG as safe and effective in healthy males as the conventional form of purified hCG, this may open the way for this newer form of treatment for men with gonadotrophin deficient and infertility as well as in boys with pubertal failure.
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• Male Hormonal Contraception
L Turner, C Fennell, AJ Conway, PY Liu, M Jimenez, DJ Handelsman
A major practical application of knowledge about how hormones control sperm production is the development of a male hormonal contraceptive. Following a decade of preliminary feasibility and path-findings studies, in 2003 the Andrology Department published a proof of principle study establishing very high reliability of a depot combined hormonal male contraceptive. Through many preliminary studies using a depot form of testosterone, we defined the lowest effective dose of testosterone having sufficient suppression but avoiding undesirable side effects and tested it with a progestin to identify the best combination. The excellent result for our prototype hormonal combination was a major advance and made international headline news. These path-finding studies have led progress in optimising the approach to develop a practical hormonal male contraceptive regimen. Currently, based on our 2003 study, we are extending our clinical experience with the combined depot approach in providing first medical male hormonal contraceptive service offered anywhere in the world. Furthermore, a major CONRAD and WHO sponsored international multicentre trial is using a similar injectable depot androgen-progestin combination to extend and refine the findings on contraceptive effectiveness for this “leading candidate” approach for a marketable male hormonal contraceptive.
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• Hormonal Control of Sertoli Cell Function and Spermatogenesis
CM Allan, L Courcoran, J Spaliviero, M Jimenez, DJ Handelsman Collaboration: J Couse, K Korach (National Institute of Environmental Health Sciences, Research Triangle Park NC, USA) & M Griswold (Washington State University, Pullman USA); G Denyer (University of Sydney); P Stanton (Prince Henry’s Institute of Medical Research)
Reproductive hormones such as sex steroids and gonadotrophin proteins control testis development and sperm production (spermatogenesis). We have a major research focus (through external NHMRC-funding) on the functional development of Sertoli cells, vital cells that surround and nurture developing sperm cells. Our research has contributed to fundamental understanding of the specific roles of key hormones and their receptors found in Sertoli cells (SC), which coordinate the complex hormonal responses required for spermatogenesis and normal male fertility. New genetic models were created to study the androgen receptor (AR) and its role in SC function, in particular the direct binding of AR to DNA (ie. target genes). The specific loss of AR DNA-binding function in SC revealed that genomic AR interaction is vital for sperm development. In this model, the expression levels of two SC androgen-regulated genes, Rhox5 and Eppin known to be important for full male fertility, were reduced in the prepubertal testis. However, in the adult testis, Rhox5 remained low whereas Eppin expression became elevated, revealing differential developmental control for distinct AR-regulated genes. Expression of a known androgen-repressed gene (Ngfr) showed maintenance of a non-classical AR pathway independent of DNA binding, however the incomplete spermatogenesis in this model suggests such pathways are secondary, or play no major independent role in SC function. Other genetic models have been established to study the role of SC AR during development, and will allow the dissection of the AR-regulated pathways essential for initiating normal spermatogenesis and male fertility.
Another key research interest (supported by an external ARC Discovery grant) is to determine the role of sex steroids, such as androgens (eg. testosterone), estrogens (eg. estradiol) and progestins in testicular development and function. We use genetic models deficient in sex steroids (hypogonadal hpg model) or specific hormone receptors such as the AR and estrogen receptors (ERs) to dissect specific roles and actions of these major steroids. Recent analysis showed that estradiol, the classic female sex steroid, can stimulate spermatogenesis in the hpg model, and requires the presence of ERalpha but not ERbeta. This rather paradoxical estradiol-induced spermatogenic response also involves follicle-stimulating hormone (FSH) secretion, and requires the presence of a functional AR. In combination, these research projects are increasing our fundamental knowledge of the underlying biological pathways that control (or inhibit) spermatogenic development. Such research is predicted to provide valuable genetic targets for therapy (eg. male infertility) or for the treatment of testicular tumours, or to develop novel strategies for male contraception.
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• Androgens and Post-testicular Control of Male Fertility
U Simanainen, K McNamara, E Gao, DJ Handelsman
Action of male hormones, androgens, is essential not only for maintenance of spermatogenesis, but also in the posttesticular control of fertility. So far, it has not been possible to dissect in vivo the role of androgens in post-testicular fertility due to the close relationship and high androgen dependency of spermatogenesis in the testis. We have created a mouse model with tissue-selective androgen receptor (AR) inactivation in prostate, seminal vesicle, epididymis and vas deferens, while the testis is unaffected displaying normal spermatogenesis and testosterone production. This model will provide novel, in vivo information of androgen action in post-testicular male fertility, with specific data on molecular mechanisms underlying the reduced function of androgen deprived, post-testicular glands.
The dichotomy of reduced sex accessory gland structure and functions with normal testis development and function provide a so-far unique opportunity to develop novel insight into the molecular determinants of androgen-dependent, post-testicular sperm functional maturation. This model could identify hitherto unexplained causes of male infertility as well as creating novel targets for development of posttesticular, male fertility regulation mechanisms. This new knowledge could make new inroads into the detection, diagnosis and treatment of unexplained male infertility as well as in developing new male-based, hormonally targeted but non-hormonal contraceptives (neo-hormonal) for both human and animal application.
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