Lessons learned in Andrology: Keep your options open and do not hesitate to follow leads and change directions!

Topics such as this lead to a reflection on one's career and to the analysis of why particular pathways were followed. My first piece of advice to young people is to choose a career that you enjoy, as it then ceases to be work. I think of so many people who go to work because they have to earn a living. I am indeed privileged to have enjoyed my work and friends ask why a 74-year-old is still working. I respond ‘Its not work, its my hobby!’ My second piece of advice is, ‘Do not be afraid to change directions’. I knew in my last years at secondary school that I was very interested in biology and it seemed logical to follow through by studying Medicine. I was fortunate that I enjoyed studying and also the contact with patients. It led to good grades and hence, choices of where to undertake internships and residencies. I graduated with the qualification of Bachelor of Surgery and Bachelor of Medicine, a six-year course which enabled one to practise as a primary care physician in that era after a one-year internship. At this time, I made my wisest decisions that led to my marriage to Jan, now my wife of 51 years. She has been and still is a great supporter of my academic career, putting up with a husband who is always busy and who is reluctant to engage with reasonable frequency of other enjoyable activities. Having completed my internship, I decided that I wished to be a surgeon. In that era in Australia, it was customary that a year spent working in a department of anatomy was worthwhile and enhanced one's chances of passing the examination that constituted the first part of the Fellowship of the Royal Australasian College of Surgeons. Having passed that hurdle, I was persuaded to undertake a couple of years of research that would lead to a thesis to be submitted for a Doctorate of Medicine, a research degree in Australia. As an inducement, Graeme Schofield, the Professor of Anatomy, agreed to provide me with a salary as a lecturer, a ploy which he used to attract medical graduates to take several years away from their career path in their medical speciality and to undertake a postgraduate research degree and to teach students. Again fate played a path as a wonderful clinical endocrinologist, Prof Pincus Taft asked me to join a research project to treat infertile men with human pituitary FSH, LH and hCG (de Kretser et al., 1968). These hormones had only just been purified in reasonable quantities for therapeutic use, having been extracted from cadaveric human pituitary glands through a programme supported by the Federal Government of Australia. These included FSH, LH and growth hormone. This project expanded by knowledge of human male and female infertility and endocrinology. Apart from reading the relevant literature, my education involved sitting beside Pincus Taft to observe and learn about the management of anovulatory women and infertile men. He taught me more than that. By listening to him talk with lay people, I learned how to communicate complex medical concepts in ways that could be understood. These skills have been of great value to me. Clearly now, my surgical career was rapidly receding. I was consumed with my research that now expanded to look at the changes in testicular biopsies before and after gonadotrophic stimulation. This meant coming to terms with quantitative cytological techniques as well as becoming an expert in the analysis of testicular biopsies through a clear understanding of normal testicular histology. My thesis was also to look at the changes in the testis by electron microscopy, a technique that was novel at that time. Little did I realize that not a great detail was known about human spermatogenesis, and even less about the complex transformation of a round spermatid to a mature spermatozoa, termed spermiogenesis. These descriptions were published and the data contributed to the completion of my thesis and the award of my research MD (de Kretser, 1969). Expanding my knowledge about FSH and LH led to the use of iodinated tracers to look at their metabolism and clearance rates with my endocrinology mentors Bryan Hudson and Henry Burger. Collaborations with these two mentors led to many papers over subsequent years. The availability of iodinated FSH and LH by tissue autoradiography led to histological localization of sites of clearance and the first demonstration of LH binding to Leydig cells and the concept of receptors (de Kretser et al., 1968). Here again the friendship between Bryan Hudson, who had undertaken his postdoctoral work with Eik Nes at Salt Lake City, and Al Paulsen, an endocrinologist at the University of Washington in Seattle, led to my undertaking a postdoc in Seattle under Paulsen's tutelage. Not only did I have the opportunity of working in the laboratory, but also I expanded my clinical training as an endocrine fellow at the UHPHS Hospital in Beacon Hill in Seattle, now the site of Amazon. Paulsen also introduced me to the World Health Organisation's Special Program in Human Reproduction. This unique opportunity took me to many parts of the world for workshops and to form friendships across the globe. I remain extraordinarily grateful to the Government of the USA for their support as a Fogarty Fellow. In Seattle, I worked with Richard Santen and the late John Leonard who were also endocrine fellows. Radioimmunoassay for FSH and LH was a novel technique that I learned and put to good use by measuring serum levels in males with testicular disorders and demonstrating that FSH was not fully controlled by testosterone and that there was a basis for the existence on inhibin, the putative non-steroid substance called ‘inhibin’ by McCullagh (1932). Returning to Melbourne, I convinced my colleagues Henry Burger and Bryan Hudson that we should try to isolate inhibin. So laboriously, with many visits to the abattoirs by my PhD student, Victor Lee, we prepared water-soluble extracts of bovine testes, the starting material used by McCullagh, who first used the term ‘inhibin’ in his 1932 paper. These extracts were infused into castrate sheep in which we measured FSH and showed that it suppressed but LH did not. These data were the first substantial proof that inhibin existed. So, the laborious purification began to isolate this protein. We switched to bovine follicular fluid as a richer source of inhibin and developed a rat pituitary cells assay system to identify the fractions that contained inhibin. Of course, if the extracts were toxic to the cells, FSH levels would fall, so there were controls that need to be developed to identify false-positive assays. The team grew involving many who contributed their protein separation and sequencing techniques such as David Robertson, Frank Morgan, Dick Wettenhall and Milton Hearn. Finally, inhibin, the protein now called inhibin A, was isolated and shown to be a dimer of α and βA subunits (Robertson et al., 1985). The paper was submitted to Science but the review was extraordinarily prolonged leading Henry Burger to withdraw the paper. It was resubmitted to Biophysical Biochemical Research Communications and published rapidly. This was fortunate as very shortly thereafter, several papers appeared describing inhibin A and a second form, inhibin B which shares the same α subunit but a different βB subunit (Ling et al., 1985). We could not have achieved the goal without the collaborative effort of scientists with differing skills. The subsequent development of assays for the inhibins and also for the activin A (βAβA) and activin B (βBβB), the latter agents that stimulate FSH, have resulted in many applications in reproductive medicine. Their physiology was rapidly expanded by our collaborations with colleagues around the world who had clinical samples and with whom we worked. Clearly, these are great examples of how good collaborations work. This is a great necessity today as the pace of scientific discovery is rapid. Further an FSH suppressing protein, now called follistatin was isolated by us and suppresses FSH by binding activin (Robertson et al., 1987). Because inhibin disappeared from the circulation in a castrated animal, we repeated the experiment when follistatin was isolated. To our surprise, follistatin increased in castrated sheep but also in sham-operated animals as part of the acute phase response. This led us to demonstrate that activin A responded identically (Jones et al., 2000). These surprising responses have taken us on a journey that established activin A as a major pro-inflammatory pro-fibrotic cytokine and that follistatin has is anti-inflammatory and anti-fibrotic (Jones et al., 2007). Follistatin thus has many applications and has led us to commence the long road to its commercial development. Yet another quest commenced to acquire new skills. So, it has been quite a journey from surgery, to endocrinology and now to inflammation and tissue repair. Never a dull moment, especially if you follow leads that take you into unchartered territories. It has been a lifetime of discovery and learning and certainly fulfilling. Professor David de Kretser is a reproductive endocrinologist who is currently engaged in research as a Sir John Monash Distinguished Professor at Monash University in Melbourne. He has served as Professor of Anatomy, the Founding Director of the Monash Institute of Medical Research and Associate Dean for Biotechnology Development. He was the Governor of Victoria from 2006 to 2011, a non-executive role in Australia. He is a Companion of the Order of Australia and continues his research at Monash University. He is a Fellow of the Royal Australasian College of Physicians, the Australian Academy of Science and the Australian Academy of Technological Sciences and Engineering. He has served as the President of the International Society of Andrology. His research interests include defining the causes of male infertility, the hormonal regulation of reproduction and novel mechanisms influencing inflammatory and fibrotic responses. In 2000, he initiated a programme of community and professional education in male reproductive health called Andrology Australia that continues.