Ongoing Projects

AdmiR3 – Unravelling the mysteries of adrenarche.

PI: Prof. Dr. med. Christa E. Flück Pandey

Collaborators: Dr. med. Tanja Zingg, Dr. med. Marco Janner, and PD Dr. med. Claudia Böttcher

Supported by SNF 320030_207893

Adrenarche is a major event in human sexual maturation, occurring in both boys and girls around 6-8 years of age. Stereotypical signs are the appearance of pubic and axillary hair, of adult body odor, and acne. At a cellular level, adrenarche corresponds to the formation of a new tissue within the adrenal cortex, named zona Reticularis, which is responsible for the production of androgens. However, how the zona Reticularis forms and what controls androgen production remain unknown. To fill this gap of knowledge, we have just kickstarted a non-interventional study comparing children in which adrenarche occurs prematurely (premature adrenarche, i.e. PA) with individual featuring timely adrenarche. Developmental stage-matched clinical observations on 30 prospective cases and 60 paired controls will be accompanied by non-invasive examinations, routine labs, and blood and urine collection, for the investigation of candidate markers and the identification of novel biomarkers (e.g. within circulating micro RNAs). Systematic data collection will be carried out at adrenarche, thelarche, menarche, and adulthood, over a period of more than 10 years. Prospective outcomes will serve a better understanding of the physiology of adrenarche and the plausible connection between PA and hyperandrogenic syndromes.

Connected projects:

Cholesterol metabolism and adrenocortical function (PI: Emanuele Pignatti, PhD)

Tracing novel androgen pathways in human fetal biology (PI: Therina du Toit, PhD)

miRNA signature in adrenarche (PI: Dr. med. Jani Liimatta). Funded by: Sigrid Jusèlius Foundation and the Foundation for Pediatric Research

Cholesterol metabolism and adrenocortical function.

PI: Dr. Emanuele Pignatti (ORCID 0000-0002-5372-5692),

Funding: NCCR RNA&Disease Translational Fellowship Grant (E.P.), IFCAH grant (E.P.), Novartis Foundation for Medical-Biological Research (E.P., 22B088), and UniBE Initiator Grant (E.P.).

Adrenocortical steroids are essential regulators of blood pressure, immune response, glucose homeostasis, stress control, and sexual maturation, and they are all synthetized from cholesterol. However, how cholesterol metabolism impacts steroid biosynthesis has not been explored. We found that intracellular cholesterol negatively affects the production of dehydroepiandrosterone, an androgen precursor that marks the onset of adrenarche (Pignatti et al., Endocrinology. 2022, 163(7), bqac076). Using animal models and human tissues, we also associated ABCG1, a cholesterol exporter, with negative regulation of glucocorticoid biosynthesis, and speculate about the modulation of this transporter as a potential clinical target for adrenocortical insufficiency (in press).

Tracing novel androgen pathways in human fetal biology

PI: Dr. Therina du Toit (ORCID 0000-0002-3533-0590).

Funding: Marie Skłodowska-Curie Individual Fellowship (H2020-MSCA-IF-2020, #101023999) and an UniBE Initiator Grant

This project aims to identify novel androgen metabolites and characterize their metabolic pathway in human fetal biology, with the specific focus on adrenal-derived 11-oxy androgens (11OxyAs). Steroidogenic enzyme expression in the fetal adrenal and the placenta hints at the production and metabolism of 11OxyAs in the fetal-placental unit. Thus, 11OxyAs are present in placental tissue, fetal cord blood, fetal serum and amniotic fluid, and could have a particular role during fetal development. The metabolism of the 11OxyAs in the fetal unit, therefore, presents as a focal point of investigation (du Toit T & Swart AC, J Steroid Biochem Mol Biol. 2021, 212, 105946). As adrenal androgens are primarily metabolized by the fetal liver cytochrome P450 3A7 (CYP3A7) producing metabolites that circulate to the placenta (Pignatti E, et al., Rev Endocr Metab Disord. 2023, 24, 5-21), the role of CYP3A7 in this biological route from the adrenal to the liver to the placenta is of interest, as it would regulate the biological activity of the 11OxyAs ―especially in clinical conditions characterized by adrenal androgen excess. Notably, CYP3A7 expression decreases after birth, with a concomitant increase in the expression of its isoform, CYP3A4 and, to date, the catalytic activities of these CYP3A isoforms towards the 11OxyAs have not been studied. The significance of this project is that the characterization of 11OxyAs and their downstream metabolites could prove integral to our understanding of the transition from the fetal to the neonatal stage and endocrine-related disorders that present at these stages. State-of-the-art high resolution mass spectrometry platforms, including LC-MS and GC-MS, are utilized to study steroid conversions and to identify steroid products (Andrieu T, et al., Anal Bioanal Chem. 2022, 414(25), 7461-7472).

Swiss DSD Cohort Registry and Studies

PI: Prof. Dr. med. Christa E. Flück Pandey Supported by SGPED, SGED, Boveri Foundation Zürich, SNF 320030_207893, and I-DSD Glasgow

Differences of Sex Development (DSD) are rare diseases, but comprise a broad range of very different variations of genetic disorders. In medicine, they have been grouped according to the chromosomal sex since the Chicago consensus meeting in 2006. Meanwhile an international registry to collect patient data has been established at University of Glasgow (https://home.i-dsd.org/), where currently close to 7000 cases from around the world (43 countries) have been entered. Clinical collaborators enter patient data, while DSD researchers submit their research ideas and requests. After reviewing the requests by an expert panel, the platform brings clinicians and researchers into contact to support the research projects.

In 2012 the Swiss National Ethics Commission recommended that the DSD cases in CH should be registered and research supported to improve patient care. We first ran a pilot study in Bern to set up the Swiss DSD Registry within the I-DSD, and then expanded this to most units of pediatric endocrinology in Switzerland. Currently, we are running an epidemiology study to assess the prevalence of DSD cases in Switzerland from 2000-2020.

The registry also serves for our SF1next project to connect internationally.

SF1next – Understanding the clinical and genetic complexity of human steroidogenic factor 1 variants in sex and steroid biology

PI: Prof. Dr. med. Christa E. Flück Pandey Supported by SNF 320030_197725  

Steroidogenic Factor 1/ Nuclear Receptor Subfamily 5 Group A Member 1 (SF-1/NR5A1) is an essential transcription factor for the development and function of human sex and steroid organs. Individuals carrying SF-1 variants display a broad range of phenotypes (clinical outcomes), which often do not match the expected impact of each variant on protein function. Therefore, we hypothesize that additional hits in genes within the SF-1 network may contribute to this wide phenotype spectrum. Our aim is to investigate the clinical and genetic complexity of SF-1 variants in sex and steroid biology and explore the role of other contributing genes. To achieve this, we collect comprehensive clinical and genetic data from individuals carrying discrete SF-1 variants through international collaborations. Additionally, we perform whole exome /genome sequencing of patients’ material using a rare disease-specific algorithm tailored for this project and search for phenotype-genotype correlations. In parallel, we conduct mechanistic studies using cell lines and patient-derived fibroblasts to understand the impact of individual SF-1 variants on steroidogenic differentiation and steroid activity, and identify additional gene variants that contribute to human sex development and steroidogenesis.

Overall, this project will provide a comprehensive dataset of the phenotype/genotype correlations in more than 150 individuals carrying SF-1 variants from multiple study centers around the world, together with next generation sequencing data and mechanistic studies to shed light on the SF-1 genetic network and its pathological implications. Ultimately, we expect that our studies will increase our understanding of sex development and steroidogenesis in physiological and pathological contexts.

BEGRADE – The Bern Growth and Developmental Registry Studies

PI: Prof. Dr. med. Christa E. Flück Pandey

Collaborators: Dr. med. Christoph Saner

Supported by Pharmaceutical Multi-Sponsoring

Short stature is a common finding that affects per definition about 3% of the population. The underlying cause remains often unknown as growth relies heavily on genetic and environmental factors. Severe short stature (<2.5SDS) may be caused by a medical condition amenable to treatment. Isolated, severe short stature  may be treated successfully with recombinant human growth hormone (rhGH). In Europe, rhGH is currently offered to short children with specific disorders or biochemically proven growth hormone deficiency (GHD). However, biochemical testing for GHD is artificial and therefore controversial. Adding genetic testing may improve the diagnostic workup.

In an ongoing study, we perform whole exome sequencing (WES) in children with isolated short stature with biochemically proven GHD or severe idiopathic short stature (ISS) with a normal growth hormone stimulation test to evaluate the added value of a molecular diagnosis, and assess the genotype-phenotype correlation.

So far, we identified disease-causing or candidate variants in almost half of the children with isolated, severe short stature in a broad range of genes. These variants were found in children with isolated GHD and ISS, thus correlation with biochemical testing seems poor. We found no genotype-phenotype correlation in the different subgroups. The high diagnostic yield of WES in the workup of very short children demonstrates the added value of a molecular diagnosis. Genetic testing, together with auxiological and biochemical methods may improve the current clinical routine care of patients with short stature and rhGH in the near future.

Mechanistic studies of selected variants of unknown significance (VUS) in our research laboratory enhance the basic knowledge of genetic factors affecting growth.