Physiology and Pharmacology of Androgens
- Clinical Pharmacology of Testosterone
- Measuring Steroids in Serum and Biological Samples - for details link here
- Androgen Misuse and Abuse: Testosterone Overprescribing & Sports Doping - for details link here
- Healthy Male Ageing: The Health Man Study - for details link here
- Measuring Progress of Puberty in the Community - for details link here
• Clinical Pharmacology of Testosterone
A Conway, C Fennell, L Turner, DJ Handelsman
The Department of Andrology at Concord Hospital provides testosterone replacement therapy to testosterone deficient men. As an international leader in research into the physiology and pharmacology of androgens, we continue to research the best and most acceptable forms of delivery of testosterone treatment for men who are testosterone deficient. Our extensive research into the implantation of testosterone pellets has provided unique information in defining how best to minimise the problem of pellet extrusion, how long the treatment lasts, why and how it varies between men and at what threshold of blood testosterone levels people become aware of returning symptoms of insufficient blood testosterone levels. A newer 3 month injectable form of testosterone has been introduced into clinical practice and we have completed the first long-term, head-to-head comparison study between the implantable and injectable depot testosterone products. Our findings show that, although injectable and implanted testosterone differ in their hormonal profile, their overall effects are comparable and well accepted. Ongoing quality assurance initiatives including the regular review of biochemical parameters in the blood help us monitor the effects and side effects of testosterone therapy and provide evidence to inform our clinical practice. Further studies are planned to further customize and improve testosterone delivery.
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• Measuring Steroids in Serum and Biological Samples
A Conway, C Fennell, L Turner, DJ Handelsman
Accurate measurement of steroid hormones from clinical and biological samples is essential for the diagnosis and monitoring of reproductive disorders as well as being invaluable for a variety of applications within the research laboratory. Traditionally, either radioimmunoassay (RIA) or gas chromatography mass spectrometry (GC/ MS) has been used for this purpose. However, there are problems associated with using these techniques. These include large amounts of sample being required for GC/ MS and problems with cross-reactivity for RIA. Recently there has been growing interest in developing liquid chromatography mass spectrometry-based methods to measure steroid hormones from biological samples as affordable quantitative bench-top mass spectrometers which now match the sensitivity of immunoassays while maintaining reference level specificity.
Figure 1 LC-MS/MS total ion chromatogram from the analysis of a mixture containing targeted steroids (the identity of each peak is shown).
We have developed an ultra-sensitive LC-MS/MS method using a state-of- the-art API 5000 mass spectrometer (funded by an ARC LIEF grant). It is capable of quantifying androgens (testosterone, dihydrotestosterone and androstanediol isomers) and estrogens (estradiol and estrone) to low levels within a single run (Fig 1). In fact, we are now able to accurately measure serum levels of testosterone from women and estradiol from men, which have traditionally been difficult to measure using alternative methodologies. Sample preparation involves a simple liquid-liquid extraction procedure and with an analysis time of less than 10 minutes, six samples can be analyzed per hour. Also, there is potential for greater throughput by integration into a microtitre plate format and with simple adaptation, tissue and non-human samples can be analysed.
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• Androgen Misuse and Abuse: Testosterone Overprescribing & Sports Doping
A Idan, C Fennell, M Jimenez, DJ Handelsman in collaboration with A Death, L McRobb, K McGrath (Heart Research institute) and C Goebel, R Kazlausakas, G Trout, C Howe (National Measurement Institute)
Androgens play a major role in muscle strength, energy and quality of life in men. This can be dramatic in men with testosterone deficiency where testosterone replacement therapy often provides striking benefits.
Androgens, synthetic forms of testosterone, have major effects on muscle size and strength so that abuse of these well known effects has become entrenched in small pockets of the community among men and women seeking performance or image enhancement or as a panacea against ageing.
Androgens remain the most effective and popular drugs abused in sports doping. In recent years new designer androgens and indirect forms of androgen doping have been developed to evade detection of androgen doping. Maintaining effective bans on androgens requires continual vigilance in detection of illicit androgens and of indirect androgen doping. We are now undertaking World Anti- Doping Agency (WADA) and Australian Sports Anti-Doping Authority (ASDA) supported clinical and laboratory studies to develop new and more powerful detection tests for such novel androgens and other means to evade detection of androgen abuse.
Together with our collaborators at NMI, we continued to undertake studies to develop novel methods to detect abuse of other potential anabolic agents that act through increasing androgen output (such as hCG, and recombinant LH) or through other mechanisms (such as insulin). A recently completed pilot study revealed that short term use of an injectable GnRH analog produces a sustained increase in testosterone levels which may not only go undetected using the current method of sports doping urine tests but may also serve to “mask” the abuse of other androgens at the same time. Based on these important findings, a larger study has recently been funded by WADA to extend and detail these findings so as to develop more effective detection tests.
We developed a national, state-based surveillance of PBSfunded testosterone prescribing patterns. This has identified patterns of over-use that call for heightened surveillance and increased professional and public education to make clear the differences between valid evidence-based use of testosterone treatment and deterring misguided overuse lacking reliable evidence of safety and effectiveness. Fortunately, surveys of Australian high school students we have reviewed indicate that androgen abuse has remained at steady, relatively low levels during the last decade.
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• Healthy Male Ageing: The Health Man Study
G Sartorious, S Spasevska, AJ Conway, PY Liu, DJ Handelsman with Prof RI McLachlan and Dr C Allan (Prince Henry’s Institute of Medical Research, Melbourne)
Why do some men remain healthy well into old age and others do not? Our Healthy Man study aims to determine the role of circulating androgen levels in maintaining good health and to explore the reasons why testosterone concentrations vary in one man compared with another through the observation of up to 400 healthy men. This study will also define age-specific reference ranges for testosterone in an “elite” healthy male population. This project will extend our established reference panel methodology from our study of young men to middleaged and older men with the addition of multiple sampling and use of a reference testosterone assay using our new tandem-mass spectrometry method.
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• Measuring Progress of Puberty in the Community
T Sinvananthan, F Bathur, A Idan, A Conway, DJ Handelsman
Male sexual development and fertility develop relatively rapidly over a few years during adolescence, a period of time referred to as puberty. The triggers for puberty remain a mystery and the age at which it starts and its rate of progression vary widely between individuals for largely unknown reasons and have hardly ever been studied in the community. When boys pass the usual time for puberty without experiencing the expected body changes, the so-called secondary sexual characteristics (such as voice change and growth of muscle and body hair) that are the distinctive features of a man’s body, this is called delayed puberty. Delayed puberty can have deep and lasting effects on a developing man’s psyche because of the difficulties it creates in “fitting-in”, on how they are perceived as immature by others and themselves, creating difficulties in finding a social niche and forming life-long conjugal partnerships. Delayed puberty in boys is a common problem presenting to paediatricians and treatment is often further deferred while doctors and parents wait in hope that puberty may “catch-up” naturally. More pro-active and effective treatments for delayed male puberty are important area for further study.
The Andrology department is developing several study of male puberty. In one, the Department is coordinating a large multi-centre study of pubertal failure involving all major Australia and New Zealand pediatric endocrinology centres to test whether new recombinant gonadotrophin treatment is superior to the conventional form of testosterone treatment currently used world-wide. This study has the potential to change medical practice in the management of delayed puberty in adolescent boys. The Department is also supporting the ARCHER study, a rural community based adolescent cohort study of puberty, its variations and the impact of these on the development of health and wellbeing in young adults.
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