Androgens and male fertility

Lead Research Organisation: MRC Human Reproductive Sciences Unit

Abstract

Infertility affects 1 in 5 couples in the UK, of these about a third are due to problems in the male partner. Male fertility depends on the daily production of millions of sperm within the testis via a process known as spermatogenesis. This is a complex, lengthy process during which round diploid germ cells divide and are remodeled. During their development the germ cells are supported by specialised somatic (nurse) cells called Sertoli cells. The steroid hormone testosterone, made in the testes, acts on cells by binding to androgen receptors (AR) which are found in Sertoli cells but not in germ cells, Our studies are using cell cultures, transgenic mouse models and human tissue samples to examine why testosterone is essential for normal production of sperm. In collaboration with Belgian scientists we have discovered that male mice are infertile if they have no androgen receptors in their Sertoli cells. Future studies will investigate fertility in mice with deletions of AR in the other somatic cells of the testis, and in females with deletions of AR in ovarian and uterine (womb) cells. We believe that these new approaches will provide long sought-for insights into androgenic regulation of gametogenesis, which may have important implications for male infertility and the development of new contraceptive strategies.

Technical Summary

The adult testis performs two essential functions; the synthesis and secretion of steroid hormones notably testosterone, and the production of mature sperm from immature spermatogonial stem cells (a process known as spermatogenesis). Spermatogenesis takes place within a specialised compartment called the seminiferous epithelium and depends upon interactions between the somatic Sertoli cells and the germ cells. Testosterone plays an essential role in regulating the process of spermatogenesis and thus male fertility. The pathways through which androgens exert these effects remain unknown, but are likely to involve effects on the somatic components of the testis (Sertoli, Leydig and peritubular cells) as these are the only cells that contain nuclear androgen receptors (AR). Our studies are using cell cultures, animal models and human tissue samples. We are collaborating with groups in Belgium who have developed mice with modifications in the AR gene. In one transgenic mouse model we have demonstrated that selective ablation of AR in Sertoli cells (SCARKO) results in development of a phenotypically normal male mouse which is infertile because maturation of germ cells into sperm is blocked during meiosis. Microarray analysis has been used to identify candidate genes/gene pathways that may be androgen-regulated in controls but not in SCARKO Sertoli cells. Further evaluation of these candidates using immunohistochemistry, in situ hybridisation, Westerns, and RT-PCR/quantitative PCR, using testes/isolated seminiferous tubules from control/SCARKO males, rats in which androgen action (but not germ cell number) has been acutely modulated and human testicular tissue is underway. We will test if oestrogen treatment is able to rescue spermatogenesis in SCARKO males. These studies will be extended to investigate fertility in mice with targeted deletion of AR in the other somatic cells of the testis (Leydig, peritubular), in the male urogenital system and also females with deletion of AR in ovarian and uterine cells. We believe that these new approaches will provide long sought-for insights into androgenic regulation of gametogenesis, which may have important implications for male infertility and the development of new contraceptive strategies.

Publications

10 25 50

 
Description British Heart Foundation Project Grant
Amount £98,018 (GBP)
Funding ID PG/07/105 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2008 
End 03/2010
 
Description MRC Programme Grant
Amount £2,087,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2011 
End 10/2016
 
Description Tenovus Scotland
Amount £10,000 (GBP)
Organisation Tenovus 
Department Tenovus Scotland
Sector Charity/Non Profit
Country United Kingdom
Start 04/2008 
End 04/2009
 
Title Katnal-1 antibody 
Description We developed an antibody to Katnal-1. No commercial antibodies are availabe for this protein. 
Type Of Material Antibody 
Year Produced 2009 
Provided To Others? Yes  
Impact ongoing collaborative studies into the role of katnal1 in the brain and fertility 
 
Description Genetic analysis of a novel aortic dissection mouse model 
Organisation University of Edinburgh
Department Centre for Cardiovascular Science
Country United Kingdom 
Sector Academic/University 
PI Contribution I wrote the Home Offfice project licence to permit breeding of the mice. I wrote the grant applicaiton which was funded by the BHF, and supervised the Postdoctoral scientist on the project.
Collaborator Contribution Provided cardiovascular physiology expertise to complement the genetic analysis i undertook
Impact Production of a novel animal model that is being taken forward for potential licencing by MRC-T.
Start Year 2008
 
Description Somatic cell androgen receptor knock outs 
Organisation Catholic University of Louvain
Country Belgium 
Sector Academic/University 
PI Contribution We have imported mice from Belgium and produced a series of AR knockout models in collaboration with Professor Verhoeven's group
Collaborator Contribution Professor Verhoeven's group have collaborated with us in producing and analysing several testis somatic cell androgen receptor knockouts.
Impact 19392831, 19587329, 16166195.
 
Description Vascular Androgen receptor knockouts 
Organisation University of Edinburgh
Department Centre for Cardiovascular Science
Country United Kingdom 
Sector Academic/University 
PI Contribution I wrote the grant application and designed the experiments.
Collaborator Contribution Obtained an external grant from Tenovus Scotland to generate and conduct preliminary characterisation of vascular AR knockout mouse lines.
Impact Strengthening of intra-institute collaborations, generation of novel models for future exploitation into the role of androgens in cardiovascular disease risk
Start Year 2007
 
Title COl3a1-deletion mouse line 
Description Hemizygous deletion of 185kb including exons 1-39 of the Col3a1 gene. The mouse line develops spontaneous aortic dissection with variable penetrance, and faithfully models the vascular aspects of Vascular Ehlers Danlos syndrome. BHF funding obtained and initial characterisation paper published. 
Type Support Tool - For Fundamental Research
Current Stage Of Development Initial development
Year Development Stage Completed 2010
Development Status Actively seeking support
Impact Can be used to examine the basic biology of vascular disease. To identify genetic co-factors that prevent complete penetrance (e.g. modifier genes that could be exploited therapeutically for cardio-protection in humans). For testing of pharmaceutical compounds with revelance to aortic dissection/aneurysm/cardiovascular disease. Phenotypic penetrance represents a measurable outcome from trials. 
 
Description Public lecture - University of Edinburgh 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 200 members of the public attended a lecture I gave on development of novel non-hormonal male contraceptives. This led to a 30 minute question and answer session.

Uptake in an ongoing clinical study was increased
Year(s) Of Engagement Activity 2010
 
Description Talk: Androgen receptor function and male fertility 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact Talk at annual conference of UK Society for Study of Fertility - excellent feedback

Discussions with colleagues
Year(s) Of Engagement Activity 2007
 
Description Talk: Androgen regulation of spermatogenesis 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact Talk at European Congress of Endocrinology held in Budapest. International audience.

Collaborations, requests for expert reviewing
Year(s) Of Engagement Activity 2007
 
Description Talk: Androgens and Male Fertility 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Talk given to animal facility staff as part of their continuing education/training

Improved dialogue with support staff regarding needs of the project. Reduction/refinement of animal usage.
Year(s) Of Engagement Activity 2007
 
Description Talk: Cell selective ablation of androgen receptors 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact Talk at Institute Inter Centres meeting - audience included wide range of scientists many of whom were not working on reproduction

Collaborations with colleagues interested in the impact of androgens on the cardiovascular system
Year(s) Of Engagement Activity 2007
 
Description Talk: Genetic and Phenotypic Characterisation of a Novel Recessive Mouse ENU Mutant Exhibiting Male-Specific Infertility" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact Talk at European Testis Workshop, excellent discussion

Collaborations and publication
Year(s) Of Engagement Activity 2008
 
Description Talk: Impact of scrotal heat stress on testis function and fertility 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact Talk to British Andrology Society held at GlaxoSK - audience included industry employees and academic scientists

Lively discussion and interest from potential collaborators
Year(s) Of Engagement Activity 2007