The University of Newcastle, Australia

The Importance of Classical Versus Backdoor Androgen Production Pathways in Masculinisation, Fertility, and Lifelong Male Health

Closing Date: 31 July 2020


PhD Scholarship

Male development, fertility, and lifelong health are all androgen-dependent. Perturbed androgen action at any stage of life significantly impacts quality of life ([1]), and low androgens are an independent risk factor contributing to early death ([2]). The aim of the project is to understand the regulation of androgen production and identify factors that work to support this regulation. The final goal is to refine androgen-based therapies that support wellbeing through the course of life.

Male Bike

Androgens are synthesized by Leydig cells within the interstitial compartment. Testosterone can act (i) directly within the testis and local environment, and or (ii) indirectly, once secreted in the bloodstream, via the conversion into dihydrotestosterone (DHT). This route, the classical pathway, initiates masculinization and later promotes male fertility and health. Recently, an alternative metabolic route to DHT conversion, the backdoor pathway, was identified to bypass the testosterone step [3-8]. In humans, loss of function through mutation in HSD17B3 [11], SRD5A2 [12] all result in perturbed sexual differentiation. One of the more curious observations, arising from individuals with HSD17B3 and SRD5A2 mutations, is that they undergo late-onset virilisation during puberty. This suggests that the classical pathway does not encapsulate the entirety of the androgen story. Together these observations demonstrate the importance of both the classical and backdoor pathways in supporting male development and later male function, across the mammalian kingdom.

However, how these pathways intersect both inside and outside of the testis, and the relative importance of each pathway for specific androgen-responsive endpoints during sexual development and throughout later life has, thus far, been impossible to dissect, as animal models have simply not been available.

To support the objectives of this project we have generated in silico, in vivo and in vitro models to establish the fundamental roles classical and backdoor androgen production play in masculinisation, puberty, male reproductive function, and lifelong male health.

Completion of this project will transform our fundamental understanding of male endocrinology, with implications for future clinical, veterinary and agricultural practices. And will provide significant new insight into the control of androgen production in the male, which will underpin future efforts to support lifelong health and wellbeing in both humans and animals.

Our research team assembles multidisciplinary experts with a strong track record and history of successful collaboration; the team is uniquely placed both nationally and internationally to identify factors that could be applied to the development of therapies to support endogenous androgen production. Moreover the groups field of research aligns with the three highest ranking Excellence in Research for Australia (ERA) topics at the UON.

Project Summary overview:

To understand the regulation of androgen production and identify factors that work to support this, we will use a combination of in vivo, ex vivo, in vitro studies and in silico modelling, such as transgenic mouse models, “gene therapy”, applied biotechnologies as well as usual bio-molecular techniques. This project will define the fundamental control of androgen signalling through the classical and backdoor pathways.

Overall approaches:

  • Generate a dynamic in silico model of androgen production under different conditions.
  • Determine the roles of classical and backdoor androgen pathways during testis development and masculinisation.
  • Define the roles for classical and backdoor androgen pathways in postnatal maturation and adult function.
  • Identify factors regulating the androgen pathways.
  • Enhance classical pathway activity as a novel therapeutic tool.
  • Determine the impact of the loss of HSD17B3 in Females.

References cited:

  1. Spitzer, M., et al., Risks and benefits of testosterone therapy in older men. Nat Rev Endocrinol, 2013. 9(7): p. 414-24.
  2. Shores, M.M., The implications of low testosterone on mortality in men. Curr Sex Health Rep, 2014. 6(4): p. 235-243.
  3. Shaw, G., et al., Role of the alternate pathway of dihydrotestosterone formation in virilization of the Wolffian ducts of the tammar wallaby, Macropus eugenii. Endocrinology, 2006. 147(5): p. 2368-73.
  4. Leihy, M.W., et al., Administration of 5alpha-androstane-3alpha,17beta-diol to female tammar wallaby pouch young causes development of a mature prostate and male urethra. Endocrinology, 2002. 143(7): p. 2643-51.
  5. Leihy, M.W., et al., Virilization of the urogenital sinus of the tammar wallaby is not unique to 5alpha-androstane-3alpha,17beta-diol. Mol Cell Endocrinol, 2001. 181(1-2): p. 111-5.
  6. Wilson, J.D., et al., Virilization of the male pouch young of the tammar wallaby does not appear to be mediated by plasma testosterone or dihydrotestosterone. Biol Reprod, 1999. 61(2): p. 471-5.
  7. Mahendroo, M., et al., Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways. Mol Cell Endocrinol, 2004. 222(1-2): p. 113-20.
  8. Dhayat, N.A., et al., Androgen biosynthesis during minipuberty favors the backdoor pathway over the classic pathway: Insights into enzyme activities and steroid fluxes in healthy infants during the first year of life from the urinary steroid metabolome. J Steroid Biochem Mol Biol, 2016.
  9. Auchus, R.J., The backdoor pathway to dihydrotestosterone. Trends Endocrinol Metab, 2004. 15(9): p. 432-8.
  10. Biason-Lauber, A., et al., Of marsupials and men: "Backdoor" dihydrotestosterone synthesis in male sexual differentiation. Mol Cell Endocrinol, 2013. 371(1-2): p. 124-32.
  11. Mendonca, B.B., et al., 46,XY disorder of sex development (DSD) due to 17beta-hydroxysteroid dehydrogenase type 3 deficiency. J Steroid Biochem Mol Biol, 2016.
  12. Okeigwe, I. and W. Kuohung, 5-Alpha reductase deficiency: a 40-year retrospective review. Curr Opin Endocrinol Diabetes Obes, 2014. 21(6): p. 483-7.

PhD Scholarship details

Funding: $28,092 per annum (2020 rate) indexed annually. The living allowance scholarship is for 3.5 years and the tuition fee scholarship is for four years

Supervisor: Dr Diane Rebourcet

Available to: Domestic students

PhD

Eligibility Criteria

The candidate will join a growing multi-disciplinary team, consisting of experts in the field. Applicants should have a strong work ethic, self-motivation, developed communication, and teamwork skills. We are seeking applications from individuals who have completed first-class or second-class upper honors degree in a Biomedical Science or equivalent degree with laboratory experience.

Supervisors:

Primary Supervisor: Dr Rebourcet Diane, Faculty of Science UON

Secondary Supervisor: Dr Lee Smith, Faculty of Science UON

Application Procedure

Interested applicants should send an email expressing their interest along with scanned copies of their academic transcripts, CV, a brief statement of their research interests and a proposal that specifically links them to the research project.

Please send the email expressing interest to L.B.Smith@newcastle.edu.au by 5pm on 31 July 2020.

Applications Close 31 July 2020


Contact Professor Lee Smith
Phone (02) 4921 5906
Email L.B.Smith@newcastle.edu.au

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